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CROSS-REFERENCE TO RELATED APPLICATIONS
This is a continuation-in-part of U.S. patent application Ser. No. 08/918,067, filed Aug. 25, 1997, entitled "Boundary Layer water Pickup Device", now U.S. Pat. No. 5,890,939 which is hereby incorporated herein by reference.
STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT
Not applicable
BACKGROUND OF THE INVENTION 1. Field of the Invention
This invention relates to water pickup devices for watercraft and more particularly, to a unique boundary layer water pickup device which includes a curved, grooved or slotted flange with a low profile fitted against the hull of a watercraft to take advantage of the relatively constant total head of the fluid boundary layer phenomenon. The through-hull device thus facilitates a flow of water through the device into the watercraft with an amply low and fairly constant total head or pressure and with low drag at various speeds of the watercraft.
2. General Background
Water pickup devices for channeling water into a watercraft for various purposes, including cooling the engine, providing water for line bait wells, boat wash down, marine toilets, desalinators, an auxiliary generator and other marine purposes, have long been known in the art. In the common "through hull" design, the water pickup device includes a curved flange or lip which is fitted to the hull below the waterline and a threaded nipple extends from the lip through the hull, where it receives a nut for securing the device in the hull. Water pickup using this device is adequate to a speed of about 40 mph, beyond which the device fails to provide water to the watercraft interior.
One of the problems which is inherent in the operation of other water pickup devices with "scoops" in watercraft, is that of wide pressure variation in the water pickup system. This pressure varies from zero when the watercraft is at rest, to sometimes undesirably high pressures as the watercraft gains speed. Since the pressure varies widely, adequate water supply in the watercraft at a suitable working pressure is unpredictable. These devices typically extend well below the profile of the watercraft hull to deflect water into the hull and the pressure of the water being deflected by the scoop varies with the speed of the watercraft over the water.
An early such water pickup device entitled "Valve" is detailed in U.S. Pat. No. 835,854, dated Nov. 13, 1906, to G. E. Franquist. The water pickup extends well below the plane of the bottom of the watercraft for scooping the water into a vertical chamber provided with a valve for controlling the flow of water into the watercraft.
U.S. Pat. No. 1,641,670, dated Sep. 6, 1927, to G. M. French, details an "Intake" which is mounted against the bottom of the watercraft and is fitted with parallel slots and an optional, downwardly-extending flute for scooping water and channeling the water into a conduit extending into the watercraft.
A "Cooling Water Intake Apparatus For Marine Vessels" is detailed in U.S. Pat. No. 3,874,317, dated Apr. 1, 1975, to Hikita. The device includes a tubular block which is adapted to be fitted into a through-hole provided in a watercraft hull, an intake pipe removably inserted in the tubular block and a strainer provided in the intake pipe for straining the water moving through the intake pipe. A valve is also provided on the tubular block to control the rate of flow of water through the apparatus.
U.S. Pat. No. 3,878,807, dated Apr. 22, 1975, to Reskusic et al, details a "Water Intake Strainer For Use On Boats" provided on a watercraft. The strainer includes an upward-tapering housing oriented in the normal direction of travel to expose a surface of desired profile for water pickup.
U.S. Pat. No. 4,061,571, dated Dec. 6, 1977, to Philip M. Banner, details a "Marine Water Inlet Device" provided with adapters that attach to the inlet pipe and a signal apparatus that indicates when a clogging condition exists in the water circulation system of the watercraft.
U.S. Pat. No. 4,809,632, dated Mar. 7, 1989, to J. P. Hamel, details a "Bottom Scoop For Engine Cooling Water". The device includes an outer body portion secured to the outside surface of the hull of a watercraft and an inner body portion is removably disposed in the outer body portion. The inner body portion has openings in one end that admit water into a cavity in the inner body, from which cavity the water flows to the cooling system of a marine power plant.
BRIEF SUMMARY OF THE INVENTION
It is an object of this invention to provide a unique, low profile water pickup device that utilizes fluid boundary layer phenomenon to channel water through the device at an amply low and fairly or suitably constant total head or pressure at varying speeds of the watercraft.
Another object of this invention is to provide a boundary layer water pickup device which has a low profile, grooved flange secured in the hull of the watercraft, to take advantage of the characteristics of the boundary layer and thus provide a flow of water with an adequately low and fairly constant total head or pressure through the device with low drag and at varying speeds of the watercraft.
Still another object of this invention is to provide a boundary layer water pickup device which is characterized by a unique "through-hull" fitting mounted in the hull of a watercraft below the waterline. The fitting has a continuous, curved flange or lip provided with an opening and at least one water pickup groove located in the direction of motion of the watercraft, to channel water from the boundary layer of the watercraft, through the groove or grooves and opening elements of the pickup device with an amply or adequately low and fairly constant total head or pressure and with low drag at various speeds of the watercraft through the water.
Those and other objects of the invention are provided in a unique boundary layer water pickup device having a continuous, flange or lip fitted with at least one, and preferably three, water pickup grooves having curved saddles and groove walls of dissimilar thickness, and a hollow, threaded nipple projecting from the flat base of the lip for extending through the flange and the hull of a watercraft.
The lip is positioned against the hull in the boundary layer of water flowing past the watercraft hull and the groove or grooves face the direction of motion of the watercraft, to provide a flow of water with a suitably low and fairly constant total head or pressure through the device at varying speeds of the watercraft.
An installation tool aligns the device with the watercraft longitudinal center line during tightening of the assembly nut to the external flanged fitting. The installation tool has projections that fit grooves on the flange.
BRIEF DESCRIPTION OF THE SEVERAL VIEWS OF THE DRAWINGS
The invention will be better understood by reference to the accompanying drawing, wherein:
FIG. 1 is a perspective view of a preferred embodiment of the boundary layer water pickup device of this invention;
FIG. 2 is a bottom view of the boundary layer water pickup device illustrated in FIG. 1;
FIG. 3 is a top view of the boundary layer water pickup device illustrated in FIG. 1;
FIG. 4 is a sectional view of the boundary layer water pickup device illustrated in FIGS. 1 and 2, mounted in functional configuration in the hull of a watercraft, with the water pickup grooves oriented in the direction of travel of the watercraft;
FIG. 5 is a sectional view of the boundary layer water pickup device mounted in the hull as illustrated in FIG. 3, with the grooves facing the viewer; and
FIG. 6 is a sectional view of the boundary layer water pickup device illustrated in FIGS. 1 and 5 mounted in the hull of a watercraft, with the grooves disposed 180 degrees with respect to the groove orientation illustrated in FIG. 5;
FIG. 7 is a fragmentary, sectional elevational view of the preferred embodiment of the apparatus of the present invention illustrating the lower end portion thereof;
FIG. 8 is a fragmentary, sectional, elevational view of an alternate embodiment of the apparatus of the present invention illustrating the lower end portion thereof;
FIG. 9 is a perspective view of the preferred embodiment of the apparatus of the present invention shown in operative position through the bottom of a boat hull and during installation using the installation tool portion of the apparatus of the present invention;
FIG. 10 is a front, elevational view of the installation tool portion of the preferred embodiment of the apparatus of the present invention;
FIG. 11 is a top view of the installation tool of FIG. 10;
FIG. 12 is a partial, side elevational view of the installation tool of FIGS. 10 and 11;
FIG. 13 is a bottom view of the installation tool of FIGS. 10, 11, 12; and
FIG. 14 is a side elevational view of the preferred embodiment of the apparatus of the present invention illustrating installation in a through hull opening and using the installation tool of the apparatus of the present invention.
DESCRIPTION OF THE PREFERRED EMBODIMENTS
Referring initially to FIGS. 1-6 of the drawing, in a preferred embodiment the boundary layer water pickup device of this invention is generally illustrated by reference numeral 1. In this embodiment the flange 2 is round and includes a top-curved flange lip 3, having a flange outer surface at bottom 3a, and an inside surface 3b that can be shaped to define a concave flange cup. The outer surface 3a can be flat with a peripheral chamfer (see FIG. 7) or rounded in transverse cross section (see FIG. 8).
The flange lip 3 is fitted at outer surface 3a with three water pickup grooves 4, each preferably having a groove saddle 5. A thin groove wall 6 separates one of the two outer grooves 4 from the middle groove 4 and a thick groove wall 7 separates the opposite outer groove 4 from the middle groove 4, as illustrated. In a preferred embodiment the center groove 4 is oriented slightly off of a diameter of the flange 2, while the remaining outside grooves 4 are each positioned at a chord of the flange 2, as further illustrated in FIG. 2.
A nipple 9 extends from the flat side of the flange 2, opposite the flange lip 3. The nipple 9 is provided with nipple threads 10 for receiving a nut 12, in order to mount the boundary layer water pickup device 1, as hereinafter described. The nipple 9 is also fitted with an open ended nipple bore 11, which extends through the flange 2 and communicates with the grooves 4, as further illustrated in FIGS. 1 and 2.
Referring now to FIGS. 1-3 of the drawing and particularly to FIG. 3, the boundary layer water pickup device 1 is mounted in the nipple opening 16 of the hull 15 below the waterline of a watercraft 14 by applying sealant to the flange inside surface 3b and to hull external surface 25 and then tightening the nut 12, as illustrated. Accordingly, when the boundary layer water pickup device 1 is mounted in this manner in the hull 15, the nipple bore 11 communicates with the interior hull surface 35 of the watercraft 14 and may be connected to an auxiliary water conduit for supplying water at a suitable pressure or head and with adequate quantities for marine engines, marine generators, marine air conditioning, marine toilets, desalinators, and salt water wash down, and like purchase well known to those skilled in the art. Furthermore, referring again to FIG. 3 of the drawings, the grooves 4 are positioned facing in the same direction as the direction of motion arrow 18, while water pressure is exerted on the respective grooves 4 in the direction of the water pressure arrow 19.
Referring now to FIGS. 5 and 6 of the drawings, in FIG. 5, the grooves 4 are illustrated facing the viewer, while in FIG. 6 the grooves 4 face away from the viewer, to more particularly illustrate the facility for orienting the grooves 4 in any direction in a 360 degree circle in the hull 15 of the watercraft 14, to precisely and effectively position the grooves 4 in the direction of the direction of motion arrow 18, as illustrated in FIG. 4.
In operation, referring to the drawing (see FIGS. 7 and 8), it will be appreciated that when the watercraft 14 is at rest, a static head or pressure condition exists in the boundary layer water pickup device 1, allowing water to flow through the nipple bore 11 of the nipple 9 into the interior of the watercraft 14, as with a common through-hull design. However, as the watercraft 14 gains speed in the direction indicated by the direction of motion arrow 18 in FIG. 4, water pressure builds on the flange 2 in the direction indicated by the water pressure arrow 19.
As the water flows over the curved groove saddles 5 in the respective grooves 4, it is caused to impinge upon that portion 36 of the interior of the nipple 9 and flange 2 located opposite the grooves 4 (see FIGS. 7 and 8. The disparity in thickness between the thin groove wall 6 and the thick groove wall 7, as well as the position of the middle groove 4 off-center with respect to a diameter of the nipple bore 11, and the location of the outside grooves 4 along a chord of the round flange 2, effect a spiraling action of the water through the nipple bore 11, into the interior of the watercraft 14. An increase in speed of the watercraft 14 effects a continuous flow of water through the grooves 4 and the nipple bore 11 without significantly changing the velocity head or pressure of the water flowing through the nipple bore 11. Accordingly, since the flange bottom 3a of the flange 2 is located snugly against the hull 15 of the watercraft 14 and the flange 2 is positioned in the boundary layer of water against the hull 15, it has been found that water continues to flow across the flange lip 3, through the grooves 4 in a continuous flow through the nipple bore 11 into the watercraft 14 at a head or pressure which is ample and adequate to service the auxiliary watercraft systems at a wide range of speed of the watercraft 14. In addition to this suitably constant head or pressure phenomenon in the water-hull boundary layer, the flange 2 offers a low profile to the flow of water and thus creates minimum drag on the hull 15 of the watercraft 14.
It will be appreciated by those skilled in the art that one or more grooves 4 of various size and/or shape may be provided in the flange lip 3 according to the teachings of this invention.
However, it has been found that three such grooves 4, using a thin groove wall 6 and a thick groove wall 7, and preferably having the curved groove saddles 5, are adequate and sufficient to take advantage of the relatively constant total head or pressure in the boundary layer of water against the hull 15 of the watercraft 14.
FIGS. 7 and 8 show the flow of water from a position in front of and below hull 15 into bore 11 of pickup device 1. In FIG. 7, the flange 3 has a curved outer surface 3a presented to the water surrounding the bottom 25 of hull 15. In FIGS. 7-8, the pickup fitting is designated as 1A and is configured at its lower end portion with a flat surface 3a rather than the curved surface 3a shown in FIGS. 4-6 and 7. In FIG. 8, the water pickup device 1A provides a lower most flange 2 attached to nipple 9. The flange 2 has a lower most flat surface 21 that communicates with cylindrically shaped bore 23 extending through both flange 20 and nipple 9 as well as communicating with a beveled annular surface or chamfer 22 that defines the periphery of flange 20.
In FIG. 9, an installation tool 8 is shown for use in combination with either water pickup device 1 or 1A. The installation tool 8 includes handle 13 that can provide an outer knurled or textured gripping surface. Above handle 13 is annular flange 26 having flat upper surface 27. A probe 17 portion extends upwardly from flange 26, the probe communicating with flat surface 27 and being surrounded by the flat surface 27 as shown in FIG. 9. The probe 17 is preferably cylindrically shaped, having a cylindrical outer surface 31 and a flat top surface 32. A pair of projections 28, 29 are generally parallel to one another and mounted upon flat annular surface 27.
The projections 28, 29 are placed in a position that enables them to interlock with and fit the two outer most grooves 4 of flange 2 or flange 20 as shown in FIG. 14. A space 30 is provided in between the projections 28, 29 for enabling the thin wall 6 and thick wall 7 to be fitted in between projections 28, 29 during installation as shown in FIG. 14.
Arrow 34 in FIG. 14 illustrates the rotation that can be applied to nut 12 in order to torque the nut 12 during installation through an opening 16 in hull 15. The user simply grips handle 13 and places the probe 17 into bore 11 or 23 of pickup device 1 or 1A at nipple 9. The cylindrically shaped probe 17 is preferably the same size and shape as the bore 11 or 23. The projections 28, 29 are placed into the two outermost grooves 4, as shown in FIG. 14. A socket wrench is then used to torque the nut 12 in the direction of arrow 34 so that the fitting 1 or 1A can be tightened with respect to the hull 15. The installation tool 8 enables the user to line up the grooves 4 with the longitudinal center line of the boats hull and its direction of travel so that the grooves 4 will be aligned with the boat's longitudinal center line and the direction of travel during use. An alignment mark or indicia (such as arrow 37) can be placed on flange 26 to indicate the proper location for projections 8, 29 and grooves 4 relative to the longitudinal center line of hull 15.
It will be further appreciated that the boundary layer water pickup device 1 can be utilized by all types of watercraft capable of higher speeds, including performance boats, yachts, pleasure boats, fishing boats, and jet skis, in non-exclusive particular.
While the preferred embodiments of the invention have been described above, it will be recognized and understood that various modifications may be made in the invention and the appended claims are intended to cover all such modifications which may fall within the scope and spirit of the invention.
______________________________________PARTS LIST______________________________________ 1 water pickup device 1A water pickup device 2 flange 3 curved flange lip 3A flange bottom 3B flange cup 4 groove 5 saddle 6 thin wall 7 thick wall 8 installation tool 9 nipple10 threads11 bore12 nut13 handle14 watercraft15 hull16 opening17 probe18 arrow19 arrow20 flange21 flat surface22 beveled annular surface23 bore25 bottom of hull26 annular flange27 flat surface28 projection29 projection30 space31 cylindrical outer surface32 flat top33 flange curved surface34 arrow35 interior hull surface36 inside37 arrow______________________________________
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A through-hull water pickup device for mounting in a watercraft below the water line where the layer of water next to the hull is known as the boundary layer. The device includes a flange having grooves that channel water into the watercraft via an open ended bore, at an amply low and fairly constant pressure or head and with low drag at varying speeds of the watercraft.
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BACKGROUND OF THE INVENTION
[0001] 1. Field of the Invention
[0002] The instant disclosure relates to a cathode catalyst; in particular, to a cathode catalyst which is applied with an ozone generating device for catalyzing hydrogen ions generated from an anode to react and generate water and preventing production of hydrogen gas.
[0003] 2. Description of Related Art
[0004] Ozone is known as a fairly powerful natural oxidizing agent, whose oxidizing power is 3000 times stronger than chloride, and unlike chloride which will remains in the environment for a long period of time, resulting in the rapid and extended use of ozone in various industries.
[0005] Presently, common ozone manufacturing methods include ultraviolet light, Corona discharge method and electrolytic ozone generation, etc. Of the three methods, ultraviolent light and Corona discharge method are commonly applied in the industry and household sector with deficiencies such as relatively high energy consumption, complex system composition, high production cost, and requiring ozone gas to dissolve in liquid water, therefore, the rise of water electrolytic ozone generating technology.
[0006] In general, water electrolysis ozone generating devices includes a solid polymer electrolyte membrane (cation exchange membrane) and the sealed anode and cathode arranged on two sides thereof. Successively, water electrolysis reactions take place between the three phases (three phase interface), the cation exchange membrane, the electrode catalyst (such as the anode electrode catalyst of iridium, a cathode electrode catalyst using platinum-carbon catalyst), and liquid phase for generating ozone from the anode and hydrogen gas from the cathode.
[0007] However, during electrolysis, the hydrogen gas generated from the three phase interface among cathode catalyst, cation exchange membrane and water will permeate through the cation exchange membrane, reach the cathode, mix with oxygen, and outwardly discharge via the pressure inside bubbles as a driving force.
[0008] According to the Young-Laplace equation (P g −P L =2γ/r, where P g : bubble internal pressure; P L : liquid pressure; y: the surface tension of the liquid; r: radius of the bubble), when liquid pressure is fixed, the smaller the radius of the bubble, the larger the internal pressure therein, which correspondingly leads to a decline in the ozone purity or the current efficiency of the gas generated (i.e. degradation in the performance of a water ozone generating device).
[0009] Moreover, during the generation of ozone, oxygen, and hydrogen in the ozone generating device, since hydrogen gas move towards the cathode (4.65% volume of an ozone, oxygen, and hydrogen gas mixture is hydrogen gas), the lower explosion limit of hydrogen might be exceeded. Particularly, when electrodes produce high concentration of gas at a relatively high current density, device safety is likely to become a concern. Moreover, the resulting hydrogen ion generated can easily lead to electrode corrosion which reduces the usable life of the electrodes.
[0010] To address the above issues, the inventor strives via associated experience and research to present the instant disclosure, which can effectively improve the limitation described above.
SUMMARY OF THE INVENTION
[0011] The object of the instant disclosure is to provide a manufacturing method for a cathode catalyst suitable for an ozone generating device which can generate ozone for an extended period. The cathode catalyst can prevent the generation of hydrogen gas which is a safety concern, thus, increase the stability of the ozone generating device.
[0012] According to a first embodiment of the instant disclosure, the manufacturing method of the cathode catalyst comprises an iron-based starting material and a nitrogen-based starting material mixed into an organic medium, thus, forming a mixture. Then, a carbon material is added into the mixture and heat-treated to form a solid precursor. Thereafter, the solid precursor undergoes milling to form a precursor powder, and successively, the precursor powder is calcinated in the presence of ammonia to form the cathode catalyst.
[0013] According to the aforementioned cathode catalyst, the instant disclosure further provides an ozone generating device comprises a cation exchange membrane, an anode reservoir, and a cathode reservoir. The anode reservoir is arranged on a side of the cation exchange membrane and has an anode in contact with a face of the cation exchange membrane, in which the anode comprises an anode substrate and an anode catalyst layer formed on the anode substrate. The cathode reservoir is arranged on the other side of the cation exchange membrane, in which the cathode comprises a cathode substrate and a cathode catalyst layer formed on the cathode substrate. The cathode catalyst layer comprises the cathode catalyst made from the aforementioned manufacturing method.
[0014] In summary, the cathode catalyst in accordance with the embodiments of the instant disclosure comprises at least three elements: iron, nitrogen, and carbon. When the anode of the ozone generating device transforms water into ozone, the by-products, hydrogen ions, will permeate through the cation exchange membrane to the cathode. The hydrogen ions react with the cathode catalyst of the instant disclosure via an oxidation reaction to produce water, which can effectively prevent hydrogen gas generation, a safety concern, lower the possibility of hydrogen ion corrosion to electrodes, and increase safety and stability of the ozone generating device.
[0015] In order to further understand the instant disclosure, the following embodiments and illustrations are provided. However, the detailed description and drawings are merely illustrative of the disclosure, rather than limiting the scope being defined by the appended claims and equivalents thereof.
BRIEF DESCRIPTION OF THE DRAWINGS
[0016] FIG. 1 is a cross-sectional view illustrating the ozone generating device of the instant disclosure;
[0017] FIG. 2 is a flow diagram illustrating the cathode catalyst manufacturing method of the instant disclosure;
[0018] FIG. 3 is an X-ray diffraction pattern graph of cathode catalysts made at different calcination temperature of the instant disclosure;
[0019] FIG. 4 is a graph of the instant disclosure illustrating the oxygen reduction reactivity with respect to cathode catalysts made at different calcination temperature;
[0020] FIG. 5 is a graph of the instant disclosure illustrating the relationships of the hydrogen peroxide generation rate and the number of electrons transferred with respect to the electric potential of cathode catalysts made at different calcination temperature; and
[0021] FIG. 6 is a graph of the instant disclosure illustrating the electric potential of three different iron-based starting materials.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
[0022] The aforementioned illustrations and detailed descriptions are exemplarities for the purpose of further explaining the scope of the instant disclosure. Other objectives and advantages related to the instant disclosure will be illustrated in the subsequent descriptions and appended drawings.
[0023] The following is a more detailed description of the manufacturing method of an ozone generating device and a cathode catalyst according to the instant disclosure, in which the ozone generating device can consistently generate ozone for an extensive amount of time.
[0024] Please refer to FIG. 1 as a top view of the instant disclosure. An ozone generating device 100 comprises a cation exchange membrane 1 , an anode reservoir 2 , and a cathode reservoir 3 . The anode reservoir 2 is arranged proximate to a side of the cation exchange membrane 1 and have an anode 21 formed on a face of the cation exchange membrane 1 . Furthermore, an anode chamber 22 is defined between the anode 21 and the anode reservoir 2 . The anode 21 includes an anode substrate 211 upon which an anode catalyst layer 212 is supported. The anode substrate is a conductive porous structure. Specifically, the anode catalyst layer 212 is applied on a face of the anode substrate 211 while the other face contacts the cation exchange membrane 1 for generating ozone.
[0025] The cathode reservoir 3 is arranged proximate to another side of the cation exchange membrane 1 and has a cathode 31 formed on the other face of the cation exchange membrane 1 . Furthermore, a cathode chamber 32 is defined between the cathode 31 and the cathode reservoir 3 . The cathode 31 includes a cathode substrate 311 upon which a cathode catalyst layer 312 is supported. Specifically, the cathode catalyst layer 312 is applied on a face of the cathode substrate 311 while the other face contacts the cation exchange membrane 1 for generating hydroxide.
[0026] In the instant embodiment, the membrane 1 is preferably a perfluorosulfonic acid cation exchange membrane which has high cation selective permeability, high chemical and thermal stability, high mechanical strength, low-electrolyte diffusion rate, and a low resistance, etc.
[0027] Proximate to an anodic portion of the cation exchange membrane 1 , the anode substrate 211 is generally a structure having conductivity and corrosion resistance to antioxidants such that the gas produced can be fully released and the electrolyte can circulate adequately. For example, sheet or rolled form of carbon fiber body (carbon paper or carbon cloth) or metals such as titanium, tantalum, niobium, and zirconium as the substrate material having the form of a porous body, mesh body, fibrous body, foamed body, but not limited thereto. Furthermore, the porous body can be formed by mixing fluororesin with metal particles, in which the fluororesin is preferably polytetrafluoroethylene (PTFE). Alternatively, the porous body can be porous metal plate or a metal fiber sintered body.
[0028] The anode catalyst layer 212 may be formed on the surface of the anode substrate 211 with materials having relatively high oxygen overvoltage through a process such as electroplating, thermal decomposition, coating, hot pressing, etc. The anode catalyst layer 212 may be lead dioxide or conductive diamond.
[0029] Proximate to a cathodic portion of the cation exchange membrane 1 , the cathode substrate 311 can be sheet or rolled form of carbon fiber body (carbon paper or carbon cloth) or metals such as nickel, stainless steel, and zirconium as the substrate material having the form of a porous body, mesh body, fibrous body, foamed body, but not limited thereto. More importantly, the cathode catalyst layer 312 of the instant disclosure comprises a cathode catalyst made from the following manufacturing method.
[0030] Please refer to FIG. 2 as the process flow diagram of the manufacturing method for a first embodiment of the instant disclosure. Initially, an iron-based starting material and a nitrogen-based starting material are mixed into an organic medium to form a mixture. In the instant embodiment, the iron-based starting material is ferrous acetate (Fe (C 2 H 3 O 2 ) 2 ) while the nitrogen-based starting material is phosphorus phenanthroline and the organic medium is ethanol. Then, ferrous acetate and phosphorus phenanthroline are mixed into ethanol at a molarity ratio of 1.7:11.1 and further homogeneously mixed for about 12 hours to form the mixture. During the mixing process, a chelate is formed by iron ions of the ferrous acetate and phosphorus phenanthroline and the mixture is then dissolved in ethanol.
[0031] Thereafter, a carbon material is added into the mixture and undergoes a heat-treating process to form a solid precursor. Specifically, the carbon material can be carbon black, graphite whiskers, amorphous carbon, activated carbon, mesoporous carbon, porous carbon fiber, carbon nanofiber, carbon nanotubes or carbon fibers. Particle size of the carbon material is less than 10 microns. Subsequently, the mixture having the carbon material is placed into an oven for the heat-treating process at a temperature between 60° C. to 80° C., and then maintained temperature for about 8 to 16 hours for removing the solvent to form the solid precursor.
[0032] Next, the solid precursor is milled into a powder precursor. During milling, the solid precursor is placed in a milling tank and undergoes milling via zirconium ball for about 2 to 4 hours to form the powder precursor.
[0033] Successively, the powder precursor is calcined in the presence of ammonia to form the cathode catalyst. During calcination, the power precursor is placed in a high-temperature furnace in the presence of ammonia, and calcining at a temperature between 500° C. to 1000° C. for about 1 to 3 hours to form the powder form of cathode catalyst which includes at least three elements: iron, nitrogen, and carbon. Furthermore, the powder form cathode catalyst is first mixed with a resin to form a paste like mixture, then coated on a surface of the cathode substrate 311 , and thereafter dried to form the cathode catalyst layer 312 .
[0034] As shown in FIG. 3 is an X-ray diffraction pattern graph of cathode catalysts made at different calcination temperature specifically illustrating the crystalline phase during each process from mixing the material to milling the solid precursor into the powder precursor. As illustrated, between 500° C. to 600° C., calcinated catalysts shows no significance of Fe 2 N phase growth whereas between 700° C. to 900° C., calcinated catalysts shows relatively higher significance of Fe 2 N phase growth, and at around 1000° C., Fe 2 N in calcinated catalysts completely transformed into FeN 0.056 .
[0035] As shown in FIG. 4 is a graph of the oxygen reduction reactivity with respect to cathode catalysts made at different calcination temperature, in which the Y axis respectively shows from top to bottom the density of the ring current and the disc current. Specifically, catalysts made at different calcination temperature are formed on the disc electrode of the rotating ring-disc electrode (RRDE), and using linear voltammetry to measure the redox reaction (oxygen reduction reaction, ORP) activity in an 0.5M aqueous solution of oxygen-rich sulfuric acid.
[0036] As illustrated in figures, the half-wave potential of the cathode catalyst in the instant disclosure shifts towards the high potential as the calcination temperature rises which means that the redox reaction activity increases as the calcination temperature rises. However, when the calcination temperature exceeds 800° C., the half-wave potential will shifts towards the low potential as the calcination temperature continues to rise. In addition, catalytic activity results derived from theoretical calculations in literatures point out that the onset potential of the catalyst will determine the adsorption energy of the oxygen adsorbed on the surface of the catalyst. In other words, the lower the onset potential the higher the starting potential.
[0037] Therefore, cathode catalysts calcined at a calcination temperature between 700° C. to 800° C. not only has the highest half-wave potential, but can also effectively reduce the adsorption energy of oxygen. As a result, a temperature between 700° C. to 800° C. is the most preferably calcining temperature.
[0038] As illustrated in FIG. 5 is the graph illustrating the relationships of the hydrogen peroxide generation rate and the number of electrons transferred with respect to the electric potential of cathode catalysts made at different calcination temperature. As shown, cathode catalysts at a calcination temperature between 500° C. to 800° C. will catalyze a redox reaction path involving four electrons (as shown in chemical reaction 1 below) while the calcinated catalysts at a calcination temperature between 900° C. to 1000° C. will catalyze a redox reaction involving two electrons (as shown in chemical reaction 2 below) and resulting in higher concentrations of hydrogen peroxide.
[0000] O2+4H++4e−→2H2O (Reaction 1)
[0000] O2+2H++2e−→H2O2 (Reaction 2)
[0039] As mentioned above, the cathode catalysts of the instant disclosure includes Fe 2 N, and the Fe 2 N is formed on the carbon carriers which can catalyze hydrogen and oxygen ions to form water through a four-electron transfer reaction. In other words, by applying the ozone generating device 100 with the aforementioned cathode catalysts, hydrogen ions generated from the anode 21 can transform into water to prevent hydrogen gas from generating, as a result increasing the safety and stability of the ozone generating device 100 . Moreover, the ozone generating device 100 may also prevent electrodes from corrosion subjected to hydrogen ions, thereby extending the usable life of electrodes.
Second Embodiment
[0040] Please refer to FIG. 6 as the graph illustrating electric potentials of the three different iron-based starting materials. The iron ion activity of ferrous acetate (Fe (C 2 H 3 O 2 ) 2 ), ferrous sulfate (FeSO 4 ), and ferrous oxalate (FeC 2 O 4 ) can be derived from the respective slope of the current density, in which the greater the slope is more preferable.
[0041] As illustrated, the three starting materials show no significant difference therebetween, therefore, the iron-based starting material can be ferrous sulfate or ferrous oxalate. Furthermore, ferrous sulfate and phosphorus phenanthroline are mixed into ethanol at a molarity ratio of 2.8: 11.1, respectively.
[0042] Moreover, ferrous oxalate and phosphorus phenanthroline are mixed into ethanol at a molarity ratio of 1.5: 11.1, respectively, to form a mixture. In addition, the organic medium can be one selected from methanol, ethanol, butanol, isopropanol, and propanol. Thereafter, continue with the remaining steps to make the cathode catalyst of the instant disclosure.
[0043] In summary, the instant embodiments of the cathode catalyst and ozone generating device have the following objectives. The aforementioned manufacturing method is simple, rapid, and lower cost than platinum and other catalysts of precious metals, therefore, of great value. Furthermore, cathode catalyst made by the aforementioned manufacturing method has 4-electron transport efficiency which can catalyze hydrogen and oxygen ions via a 4-electron transport reaction to produce water, prevent hydrogen from corroding the electrodes, and reduce the probability of the secondary reaction of a 2-electron transport to produce hydrogen peroxide. In addition, when the anode of the ozone generating device 100 transforms water into ozone gas, the by-products, hydrogen ions, will permeate through the cation exchange membrane 1 to the cathode 31 and react with the aforementioned cathode catalyst via an oxygen reaction to produce water which effectively prevent the safety concern of hydrogen gas generation, lower the possibility of hydrogen corrosion on electrodes, and increase safety and stability of the ozone generating device 100 .
[0044] The figures and descriptions supra set forth illustrated the preferred embodiments of the instant disclosure; however, the characteristics of the instant disclosure are by no means restricted thereto. All changes, alternations, combinations or modifications conveniently considered by those skilled in the art are deemed to be encompassed within the scope of the instant disclosure delineated by the following claims.
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The instant disclosure relates to a manufacturing method of cathode catalyst, comprising the following steps. Initially, mix an organic medium with an iron-based starting material and a nitrogen-based starting material to form a mixture. Followed by adding a carbon material to the mixture and subsequently executing a heating process to form a solid-state precursor. Then mill the solid-state precursor to form a precursory powder. Successively, calcinate the precursory powder in the presence of NH 3 to form a cathode catalyst. The cathode catalyst can reduce the activation energy of hydrogen ion reacting with oxygen to make water. The instant disclosure further provides an ozone-generating device.
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BACKGROUND OF THE INVENTION
[0001] a) Field of the Invention
[0002] The present invention relates to methods and composition of matter for improving cell implantation and cardiac function.
[0003] b) Description of the Prior Art
[0004] Chronic ischemic heart disease is a worldwide health problem of major proportions. According to the American Heart Association, 61 800 000 Americans have at least one type of cardiovascular disease (1) . In particular, coronary heart disease (CHD) cause myocardial infarction (MI) for 7 500 000 American patients and congestive heart failure (CHF) for 4 800 000 American patients. Almost 450 000 deaths in the United States alone were deemed to derive from CHD (1) .
[0005] Current CHD treatments include medication, percutaneous transluminal coronary angioplasty and coronary artery bypass surgery. These procedures are quite successful to increase blood flow in the myocardium thus reducing ischemia and ameliorating the condition of the patient. However, due to the progressive nature of CHD, the beneficial effects of these procedures are not permanent and new obstructions can occur. Patients that live longer through effective cardiovascular interventions eventually run out of treatment options. Also an important patient population is still refractory to these treatments due to diffuse athereosclerotic diseases and/or small caliber arteries.
[0006] Severe and chronic ischemia can cause MI which is an irreversible scarring of the myocardium. This scarring reduces heart contractility and elasticity and consequently the pumping function, which can then lead to CHF. Treatments available to CHF patients target kidney function and peripheral vasculature to reduce the symptoms but none are treating the scar or increasing pump function of the heart.
[0007] An emerging treatment for CHF patients is cellular cardiomyoplasty (CCM), a treatment aiming at reducing the scar and improving heart function. It consists in the injection of cells in the scar, replacing the fibrotic scar by healthy tissue and increasing elasticity. When the injected cells are of muscular origin, they can also contribute to contractility. The net result of this cell therapy is an improvement in heart function. Coupling CCM with therapeutic angiogenesis can improve engraftment of injected cells by increasing the blood supply to the injected cells. Furthermore, the adjacent tissue will benefit from the relief of ischemia. An important limitation of CCM is the high cell death rate at the early stages after implantation. It would be highly desirable to improve cell survival in order to increase efficacy of the treatment.
[0008] Regulators of hypoxia include the transcription factors of the Hypoxia Inducible Factors family (HIF). These include HIF-1α (also known as MOP1 2 ; and are discussed in U.S. Pat. Nos. 5,882,314; 6,020,462 and 6,124,131, Endothelial PAS 1 (EPAS1), (also known as HIF-2α, MOP2, HIF-related factor (HRF) and HLF (HIF-like factor) 3 , and are also discussed in U.S. Pat. No. 5,695,963, and the newly discovered HIF-3α 4 .
[0009] These factors are highly labile in normal conditions, but are stabilized in response to low oxygen tension. This stabilization allows them to bind to cis DNA elements of target genes, and stimulate transcription of hypoxia induced genes that help cell survival in low oxygen conditions. These target genes are implicated in processes such as anaerobic metabolism (glucose transporters and glycolytic enzymes), vasodilatation (inducible nitric oxide synthase (iNOS) and heme oxygenase-1 (HO-1)), increased breathing (tyrosine hydroxylase), erythropoiesis (erythropoietin) and angiogenesis (VEGF).
[0010] However, prior to the present invention, it has never been demonstrated or suggested that EPAS1, HIF-1α and HIF-3α could induce the expression of cell induced cell survival genes, nor that EPAS1, HIF-1α and HIF-3α modified cell transplanted increased cell survival in vivo as indicated by increased metabolic activity in the cells they are introduced in. Among the cell survival genes some improve cell survival, for instance, by inhibiting apoptosis and others have a cardioprotective activity, preventing scarring of the heart tissue and reducing heart failure.
SUMMARY OF THE INVENTION
[0011] An object of the present invention is to provide a method and compositions of matter for improving cell therapy treatment by increasing cell survival.
[0012] Another object of the invention is to provide a method and compositions of matter for improving cardioprotection, which prevents myocardial scarring and reduces heart failure.
[0013] More particularly, the present invention is concerned with the use of nucleotide sequences encoding EPAS1, HIF-1α and HIF-3α transcription factors and functional analogs for treating coronary and cardiac diseases in mammals. The use of such transcription factors and its analogs may also be useful in the treatment of disorders that may be treated by cell therapy such as peripheral vascular disease (PVD), neurodegenerative disease including Parkinson's syndrome, muscular dystrophies, stroke, diabetes, hemophilia, wound and others.
[0014] An advantage of the present invention is that it provides more effective means for inducing the expression of a plurality of cell survival genes and thereby stimulating cell survival.
[0015] The invention is thus very useful for the treatment of coronary and cardiac diseases in mammals and more particularly for the relief of myocardial ischemia, the regeneration of cardiac tissue subsequent to a myocardial infarction and for the reduction of CHD and also in peripheral vascular disease (PVD).
[0016] Tissue engineering constructs, such as skin equivalent to treat skin ulcers, would benefit from an EPAS1, HIF-1α and HIF-3α treatment.
[0017] Other objects and advantages of the present invention will be apparent upon reading the following non-restrictive description of several preferred embodiments, made with reference to the accompanying drawings.
BRIEF DESCRIPTION OF THE DRAWINGS
[0018] FIG. 1 is a bar graph indicating the change in metabolic activity in a scarred area of rat hearts following treatment with autologous myoblasts modified or not with EPAS1 gene. High metabolic activity indicate a high cell survival and prevention of scarring.
DETAILED DESCRIPTION OF THE INVENTION
[0000] A) General Overview of the Invention
[0019] An object of the invention is to provide methods and cells for improving cell therapy treatment such as CCM by increasing cell survival. The methods of the present invention are particularly useful for treating coronary and cardiac diseases in mammals. The invention also provides genetically modified cells expressing a plurality of cell survival genes.
[0020] The invention is based on the use of a nucleotide sequence encoding a functional EPAS1, HIF-1α or HIF-3α transcription factor or a functional analog thereof for improving cellular survival in engraftment procedures, cell therapy and/or coronary and cardiac treatments and for improving the metabolic activity of a muscular cell.
[0021] As it will be shown in the exemplification section, the present inventors have demonstrated that the induction of expression of EPAS1, HIF-1α and HIF-3α transcription factors stimulate the expression of cell survival genes such as leukemia inhibitory factor (LIF), leukemia inhibitory factor receptors (LIF-R), cardiotrophin 1 (CT 1) and adrenomedullin in myoblasts which in turn increases cell survival. The inventors showed, in a rat model of CHF, that EPAS1 modified cells transplanted in the scar tissue survived better and improved metabolic activity. It is expected that these genes are also stimulated by EPAS1, HIF-1α and HIF-3α in other cell types.
[0022] In the context of the present invention, the expression “cardioprotective gene” refers to a gene that can prevent the formation of myocardial scar and heart failure following a myocardial infarction.
[0023] The expression “cell survival gene” refers to a gene that can prevent cell death in stress condition, such as high hypoxia or implantation in a new host milieu.
[0000] B) Methods of Treatment
[0024] According to a first aspect, the invention is directed to a method for improving cell therapy by increasing cell survival and cardioprotection by inducing in a cell such as a muscular mammalian cell, the expression of at least one cell survival gene. The method comprises the step of introducing and expressing in the cell a nucleic acid sequence encoding a functional EPAS1, HIF-1α and HIF-3α transcription factor or a functional analog thereof.
[0025] In a further aspect, the invention is directed to a method for improving cardiac tissue functions of a mammal, comprising the step of providing to the cardiac tissue of the mammal a plurality of genetically modified cells expressing a nucleic acid sequence encoding a functional EPAS1, HIF-1α and HIF-3α transcription factor or a functional analog thereof.
[0026] The inventors have found that EPAS1 gene transfer induces the expression of a plurality of cell survival genes such as LIF, LIF-R, adrenomedullin and cardiotrophin 1.
[0027] HIF-1α is described in Wang et al. Proc. Natl. Aca. Sci . (1995) 92:5510-5514 and in U.S. Pat. Nos. 5,882,314; 6,020,462 and 6,124,131. EPAS1 is described in Tian et al. Genes & Dev . (1996) 11:72-82 and U.S. Pat. No. 5,692,963. HIF-3α is described in Gu et al. Gene Expression (1998) 7:205-213 and U.S. provisional application 60/292,630 filed on May 22, 2001. All these documents are incorporated herein by reference.
[0028] According to a preferred embodiment, the nucleic acid sequence encoding the transcription factor used in the present invention is a cDNA. The nucleotide sequence may be introduced in the cell or tissue using well known methods. Indeed, the sequence(s) may be introduced directly in the cells of a given tissue, injected in the tissue, or introduced via the transplantation of previously genetically modified compatible cells. For instance, this may be achieved with adenoviral vectors, plasmid DNA transfer (naked DNA or complexed with liposomes) or electroporation. Methods for introducing a nucleotide sequence into eukaryote cells such as mammalian muscular cells or for genetically modifying such cells are well known in the art. Isner Nature (2002) 415:234-239 discusses myocardial gene therapy methods and US patent application US20010041679A1 or U.S. Pat. No. 5,792,453 provides methods of gene transfer-mediated angiogenesis therapy.
[0029] In a preferred embodiment, a plurality of genetically modified cells are transplanted into the heart of a compatible recipient. In this embodiment, the transplantation is autologous. The transplantation improves the survival of implanted cells. Transplantation methods are well known in the art. For detailed examples of muscular cell transplantation, one may refer to U.S. Pat. Nos. 5,602,301 and 6,099,832.
[0030] In another preferred embodiment, the muscle cell or the muscular tissue is an ischemic muscular tissue. Accordingly, the expression of at least one cell survival gene and/or the transplantation of previously genetically modified compatible cells in these ischemic cells or tissue increases tissue function. Also, the efficacy of cell survival and engraftment being a limiting step, the expression of at least one cell survival gene is desirable.
[0031] It should be noted that in both of these preferred embodiments, the level of expression of the transcription factor(s) is such that the cell survival genes are expressed at a level that is sufficient to improve cell survival and sustain cardioprotection. For a better control on the expression and selectivity of these cell survival genes, the transcription factor may be inducible.
[0032] In a further aspect, the invention is directed to a genetically modified cell expressing a functional EPAS1, HIF-1α and HIF-3α transcription factor or a functional analog thereof. Preferably also, the cell comprises a cDNA encoding the transcription factor. Preferably, the cell is a myoblast, a skeletal muscular cell or a cardiac cell. The genetically modified cells could also be components of bone marrow, fibroblasts or stem cells. The nature of the cell used in the methods of the present invention will vary depending on the disorder to be treated. In conditions such as dystrophies, cells such as myoblasts are useful. In stroke and Parkinson's disease, neurons or bone marrow cells may be useful and in diabetes, pancreatic islets cells may be useful. For the treatment of wounds, fibroblasts or keratinocytes are useful.
[0033] As mentioned previously, such cells may be particularly useful when transplanted in a compatible recipient for increasing the metabolic activity of a mammalian muscular tissue, and/or increasing muscular function in CHF, locally or in surrounding transplanted tissue.
[0034] Of course, the genetically modified cells of the present invention could also be used for the formation of artificial organs or for tissue constructions. Also, other cell types, such as bone marrow cells and their sub-populations, fibroblasts, smooth muscle cells, endothelial cells, endothelial progenitor cells and embryonic stem cells, have other desirable properties for the implantation in other tissue or other type of muscle. Genetic modification of these cells with EPAS1, HIF-1α and HIF-3α to improve perfusion and engraftment is also an aspect of the invention.
[0035] As it will now be demonstrated by way of an example hereinafter, the present invention is useful for increasing cell survival and tissue function in CHD and in PVD.
EXAMPLES
[0036] The following example is illustrative of the wide range of applicability of the present invention and is not intended to limit its scope. Modifications and variations can be made therein without departing from the spirit and scope of the invention. Although any method and material similar or equivalent to those described herein can be used in the practice for testing of the present invention, the preferred methods and materials are described.
Example 1
Use of EPAS1 to Induce Angiogenesis
[0000] 1) Materiel and Methods
[0000] Adenovirus Production
[0037] EPAS1/pcDNA3 plasmid was kindly provided by S. L. McKnight (3) and was used to produce adenoviral vectors with the Ad.Easy™ technology using manufacturer methodology (Q-Biogene).
[0000] Infection
[0038] Early passage human (Clonetics) or rat myoblasts were plated in 100 mm dishes and grown until they reached ˜70% confluence. Cells were rinsed with PBS and covered with 4 ml DMEM with 10% fetal calf serum (FCS) and adenoviruses at a MOI of 500. Cells were incubated at 37° C. with constant but gentle agitation for 6 hours. 6 ml of DMEM with 10% FCS was added and cells were incubated overnight at 37° C.
[0000] Gene Chip Hybridization
[0039] Total RNA was isolated from human myoblasts (Clonetics) infected with either Ad.Null™ (Q-Biogene) or Ad.EPAS1 as described (7) . Probes were prepared and hybridized to Atlas Human 1.2 Array (Clontech) and to 8K Human Atlas Array (Clontech) according to the manufacturer's instructions. The arrays were exposed to phosphorimager screen and analyzed with the Atlas 2.01 software (Clontech).
[0000] Cell Survival in Infarct Heart
[0040] Normal or EPAS1 modified rat autologous myoblasts were implanted in infarcted rat hearts 10 days after permanent left anterior descending coronary artery ligation (Myoinfarct™ rats, Charles River Laboratories) by direct myocardial injection of 2 millions cells via a mini-thoracotomy (N=12). Metabolic activity was measured 5 days post ligature and 8 weeks post treatment by injection of 18 FDG acquisition using a small animal PET-Scan (Sherbrooke University). FDG uptake in the infarct was quantified and a % change (post vs pre treatment) was calculated.
[0000] 2) Results
[0000] Activation of Cell Survival Genes by EPAS1 In Vitro
[0041] To evaluate EPAS1 potential as a cell survival modulator, gene expression was compared in human Myoblast infected either with Ad.EPAS1 or Ad.Null™ using gene chip technology. cDNA probes derived from either cell population was hybridized on a Atlas human 1.2 Array™ or 8K Human Atlas Array (Clontech) assessing expression of almost 1200 genes or 8000 genes. Cell survival and cardioprotective genes were also found to be upregulated by EPAS1: LIF is known to enhance survival of Myoblast, which would be useful in cell therapy. Its receptor, LIF-R, was also stimulated. In the same gene family, cardiotrophin 1 (CT-1) enhances muscle cells survival and protects from heart injury. CT-1 is a survival factor for cardiomyocytes. Adrenomedullin is a potent cardioprotective gene, it has a beneficial effect on left ventricular remodeling after MI and helps prevent heart failure.
TABLE 1 Genes activated by EPAS1. Gene Fold induction Category LIF up Growth factor LIF-R up Receptor Adrenomedullin 4.87 Growth factor CT-1 up Growth factor Inductions labeled “up” are representing the activation from a previously undetected gene.
[0042] To support the idea that cell survival could be increased by EPAS1, a myoblast implantation in infarcted heart study was conducted. It was found that an improved metabolic activity was seen in infarct implanted with EPAS1 modified myoblasts, whereas a deterioration of metabolic activity was seen when unmodified myoblasts were implanted ( FIG. 1 ). This result indicates that cell survival was improved, resulting in an increased metabolic activity.
[0043] It was shown that adrenomedullin, a cardioprotective gene, was induced by EPAS1 (z) , but never was it shown for cardiotrophin 1, which also have cardioprotective activity. Z: T. Tanaka et al. J Mol Cell Cardiol 2002 Endothelial PAS Domain Protein 1 (EPAS1) induces adrenomedullin gene expression in cardiac myocytes: Role of EPAS1 in an inflammatory response in cardiac myocytes. 34: 739-48.
[0000] 3) Discussion
[0044] The analysis of genes activated by EPAS1 revealed the induction of several cell survival genes (Table I). These genes play a role in various aspects of cell survival and cardioprotection and the resulting improved activity is thus expected to be strong and well organized. This is a major advantage compared to the use of a single protective factor.
[0045] While several embodiments of the invention have been described, it will be understood that the present invention is capable of further modifications, and this application is intended to cover any variations, uses or adaptations of the invention, following in general the principles of the invention and including such departures from the present disclosure as to come within knowledge or customary practice in the art to which the invention pertains, and as may be applied to the essential features hereinbefore set forth and falling within the scope of the invention.
REFERENCES
[0046] Throughout this paper, reference is made to a number of articles of scientific literature that are listed below and incorporated herein by reference:
1. 2002 Heart and stroke statistical update, American Heart Association. 2. Wang, G. L., Jiang, B.-H., Rue, E. A., and Semenza, G. L. Hypoxia-inducible factor 1 is a basic-helix-loop-helix-PAS heterodimer regulated by cellular O 2 tension. Proc. Natl. Aca. Sci. USA (1995) 92: 5510-5514. 3. Tian, H., McKnight, S. L. and Russel, D. W. Endothelial PAS domain protein 1 (EPAS1), a transcription factor selectively expressed in endothelial cells. Genes & Dev . (1996) 11: 72-82. 4. Gu, Y. Z., Moran, S. M., Hogenesch, J. B., Wartman, L. and Bradfield C A. Molecular characterization and chromosomal localization of a third alpha-class hypoxia inducible factor subunit, HIF3alpha. Gene Expression (1998). 7:205-213. 5. Jiang, B.-H., Zheng, J. Z., Leung, S. W., Roe, R. and Semenza, G. L. Transactivation and inhibitory domains of Hypoxia-inducible factor 1α. J. Biol. Chem . (1995) 272: 19253-19260. 6. Vincent, K. A., Shyu, K.-G., Luo, Y., Magner, M., Tio, R. A., Jiang, C., Goldberg, M. A., Akita, G. Y., Gregory, R. J. and Isner, J. M. Angiogenesis is induced in a rabbit model of hindlimb ischemia by naked DNA encoding an HIF-1α/VP16 hybrid transcription factor. Circulation (2000) 102: 2255-2261. 7. Staffa, A., Acheson, N. H. and Cochrane, A. Novel exonic elements that modulate splicing of the human fibronectin EDA exon. J. Biol. Chem . (1997) 272: 33394-401. 8. Tsurumi, Y., Takeshita, S., Chen, D., Kearney, M., Rossow, S. T., Passeri, J., Horowitz, J. R., Symes, J. F. and Isner J. M. Direct intramuscular gene transfer of naked DNA encoding vascular endothelial growth factor augments collateral development and tissue perfusion. Circulation . (1996) 94: 3281-3290. 9. Houle, B., Rochette-Egly, C. and Bradley, W. E. Tumor-suppressive effect of the retinoic acid receptor beta in human epidermoid lung cancer cells. Proc. Natl. Aca. Sci. USA (1993) 90: 985-989. 10. Xia et al., Cancer (2001), 91:1429-1436. 11. Isner J., Nature (2002), 415:234-239.
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The present invention concerns the use of nucleotide sequences encoding EPAS1, HIF-1α and HIF-3α transcription factors and functional analogs for treating coronary and cardiac diseases in mammals. The use of such transcription factors and its analogs is useful in the treatment of disorders that may be treated by cell therapy such as peripheral vascular disease (PVD), neurodegenerative disease including Parkinson's syndrome, muscular dystrophies, stroke, diabetes, hemophilia, wound and others.
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FIELD OF INVENTION
[0001] The present invention relates to a hand truck and, more specifically, to a hand truck with new integrated safety and improved use features.
BACKGROUND
[0002] Many devices have been developed over the years to aid people in the movement and transportation of items that otherwise would be too heavy or unwieldy to move. There exists a multitude of powered devices such as cranes, forklifts, hydraulic ramps, etc. that simplify moving. A similar variety of non-powered devices also exist for people to choose from. Non-powered devices, such as pulleys, ropes, clamps, levers and hand trucks, are commonly available to consumers. The ease of use of contemporary hand trucks makes the hand truck an ideal tool for transporting heavy objects and has led to the common use of hand trucks by tremendous numbers of people.
[0003] The wide utilization of hand trucks has caused many manufacturers to research improvements in the design of the modem hand truck. Today, industrial quality hand trucks are produced that have frames made of sturdier, tougher materials to simplify transporting appliances and other items that are too large for smaller sized hand trucks. These industrial quality hand trucks are useful for transporting exceedingly larger items, and are often even capable of handling appliances or equipment that are much greater in size than the user who is navigating the hand truck.
[0004] One drawback of current hand trucks is the lack of features and capabilities to help users manage large, heavy loads and provide adequate safety precautions. Basic features, such as straps, are commonly used to hold the load in place on the hand truck and prevent it from moving or falling off the truck. However, exceptionally heavy loads often require additional safety features to prevent injury to the user. For example, the common procedure for using hand trucks is to tip the truck to a given angle, such as 45 degrees, to balance the primary weight of the load on the wheels. However, when tipping the truck, exceptionally heavy loads may be hard to manage and may pull the truck away from the user, risking both injury to the user and damage to the load.
[0005] Additionally, some trucks include safety features that can be deployed by the user to assist in handling and navigating the truck when handling large loads. However, often times, users are required to take at least one hand off of the primary handling location of the hand truck in order to activate or deploy such safety or load assist features. Removing one or both hands from the hand truck may be dangerous and maybe defeat the purpose of the safety feature altogether if the load or truck becomes unstable.
[0006] Accordingly, an improved hand truck is needed in the art.
SUMMARY
[0007] A hand truck is generally presented. The hand truck includes a frame, a toe plate connected to the frame, a pair of wheels rotatably secured to the frame, and a handle connected to the frame. A fourth-wheel attachment is pivotally connected to the frame at a first point and removable connected to the frame at a second point. A lever is positioned adjacent to the handle. Activation of the lever causes the removable connection between the fourth-wheel attachment and the frame to be released, allowing the fourth-wheel assembly to pivot away from the frame.
[0008] In an embodiment, the fourth wheel assembly includes a latch connected to the frame. The latch is configured to interconnect with a latch bar positioned on the fourth-wheel attachment. The handle is connected to a first end of a cable or connecting device. The cable or connecting device is connected at a second end to the latch. Activating the lever may pull the cable or connecting device upward and apply a force on the spring to release the latch.
[0009] The cable or connecting device may be connected at a third end to the fourth-wheel attachment. Activating the lever may pull the cable or connecting device upward and apply a force to the fourth-wheel attachment to move the fourth-wheel attachment from a deployed position toward an upright position.
[0010] In an embodiment, a hand truck includes a frame, a toe plate connected to the frame, a pair of wheels rotatably connected to the frame, and a break back bar pivotably connected to the frame. The break back bar may be biased toward the upright position.
[0011] The break back bar may be pivoted to a down position to contact the ground. A weight applied to the break back bar when in a down position may prevent the hand truck from rolling.
[0012] The break back bar may be biased by a spring. The spring may be positioned on an axis positioned between portions of the frame. The axis may also be connected to the wheels to allow them to rotate with respect to the frame.
[0013] In an embodiment, a hand truck includes a frame, a toe plate connected to the frame, a pair of wheels rotatably connected to the frame, a handle connected to the frame, and a break back bar pivotably connected to the frame. The hand truck further includes a fourth-wheel attachment pivotally connected to the frame at a first point and removable connected to the frame at a second point and an activation lever adjacent to the handle. Activation of the lever causes the removable connection between the fourth-wheel attachment and the frame to be released, allowing the fourth-wheel assembly to pivot away from the frame.
BRIEF DESCRIPTION OF THE DRAWINGS
[0014] The operation of the invention may be better understood by reference to the detailed description taken in connection with the following illustrations, wherein:
[0015] FIG. 1 illustrates a perspective view of a hand truck in upright position;
[0016] FIG. 2 illustrates a side view of the hand truck in upright position;
[0017] FIG. 3 illustrates a front perspective view of a hand truck in reclined position;
[0018] FIG. 4 illustrates a side view of a hand truck in reclined position;
[0019] FIG. 5 illustrates a rear perspective view of a hand truck in reclined position;
[0020] FIG. 6 illustrates a perspective view of a fourth-wheel attachment;
[0021] FIG. 7 illustrates a detailed side view of a fourth-wheel attachment connected to a hand truck in upright position;
[0022] FIG. 8 illustrates a perspective view of a fourth-wheel attachment connected to a hand truck in upright position;
[0023] FIG. 9 illustrates a detailed view of a roller axle assembly for a fourth-wheel attachment;
[0024] FIG. 10 a illustrates a side view of a latch assembly;
[0025] FIG. 10 b illustrates a perspective assembly view of a latch assembly;
[0026] FIG. 11 illustrates a detailed side view of a handle assembly;
[0027] FIG. 12 illustrates a detailed perspective view of a handle assembly;
[0028] FIG. 13 illustrates a front perspective view of a latch assembly connected to a cable;
[0029] FIG. 14 illustrates a perspective view of a break back bar;
[0030] FIG. 15 illustrates a break back bar in upright position;
[0031] FIG. 16 illustrates a break back bar in activated position;
[0032] FIG. 17 illustrates a rear perspective view of a hand truck having pivot sockets on the fourth-wheel assembly;
[0033] FIG. 18 illustrates a fourth-wheel assembly with pivot sockets in reclined position;
[0034] FIG. 19 illustrates a fourth-wheel assembly with pivot sockets; and
[0035] FIG. 20 illustrates a fourth-wheel assembly with pivot sockets in upright position.
DETAILED DESCRIPTION
[0036] Reference will now be made in detail to exemplary embodiments of the present invention, examples of which are illustrated in the accompanying drawings. It is to be understood that other embodiments may be utilized and structural and functional changes may be made without departing from the respective scope of the invention. Moreover, features of the various embodiments may be combined or altered without departing from the scope of the invention. As such, the following description is presented by way of illustration only and should not limit in any way the various alternatives and modifications that may be made to the illustrated embodiments and still be within the spirit and scope of the invention.
[0037] A hand truck 10 is generally presented, as illustrated in FIGS. 1-16 . The hand truck 10 may be configured to receive and move a load, such as an appliance or other large objects. The hand truck 10 may include various new features as described below, including features that assist a user in managing excessively large loads and prevent the hand truck from tipping or slipping away from the user while in use.
[0038] The hand truck 10 may include a frame 12 . The frame may comprise a pair of vertical supports 14 and a plurality of horizontal cross supports 16 . The vertical supports may extend from the base of the hand truck 10 to the near top of the hand truck and may be connected at the top by a connecting bar 18 , such as the u-shaped connected bar 18 illustrated in FIG. 1 . The horizontal cross supports 16 may connect to and span the vertical supports 14 . The cross supports 16 may be evenly spaced along the height of the frame 12 . The hand truck 10 may include any appropriate number of cross supports 16 .
[0039] The frame 12 may be made of any appropriate material, such as a high strength, lightweight material, such as aluminum or extruded aluminum. However, it will be appreciated that the frame 12 may be made of any appropriate material, such as steel, stainless steel, or high-density plastic, or the like.
[0040] The hand truck 10 may include a toe plate 20 . The toe plate may be located at the base of the frame 12 and may be connected thereto. The toe plate 20 may be any appropriate shape, such as having a 90 degree bend to form two portions, as shown in FIGS. 1-5 . The first portion 22 may extend vertically from the base of the frame 12 and connect to the frame. The second portion 24 may extend horizontally away from the fame 12 and close to the ground when the hand truck 10 is in use. The toe plate 20 may be configured to receive a load thereon and hold the load in place during transportation and balancing of the hand truck 10 . The toe plate 20 may be made of any appropriate material, such as steel, aluminum, or the like.
[0041] The hand truck 10 may include wheels 26 . The wheels 26 may be any appropriate size and may be positioned near and connected to the base of the frame 12 . The wheels 26 may be connected to an axle 27 to allow them to rotate with respect to the frame 12 . The axle 27 may be spaced a distance away from the frame 12 by a bracket or other connecting feature, to provide space for the wheels to rotate. The wheels 26 may allow a load on the toe plate 20 to be pivoted and transported.
[0042] The hand truck 10 may include one or more handles 28 . The handles 28 may be connected to a portion of the frame 12 , such as an upper portion of the frame 12 . The handles 28 may protrude from the frame 12 in an opposite direction as the toe plate 20 . The handles 28 may comprise a curved portion, such as illustrated in FIGS. 1-5 . The handles may be covered with padding or other grip friendly material to assist with handling.
[0043] The hand truck 10 may include various features to assist in maintaining the load positioning on the hand truck 10 . For example, the hand truck 10 may include one or more wing plates 30 . The wing plates 30 may be connected to the vertical supports 14 and may extend beyond the perimeter of the frame 12 to provide support for wide loads. The wing plates 30 may be any appropriate shape, such as generally rectangular, and may be made of any appropriate material, such as steel, aluminum, or the like.
[0044] The hand truck 10 may further include on or more strap assemblies 32 . The strap assemblies may be mounted to the rear side of the frame 12 , opposite the toe plate 20 , as illustrated in FIGS. 1-5 . The strap assemblies 32 may include a base and a strap for securing a load to the frame 12 . The strap may wind around the base for storage and may be unwound and connected to itself or another strap or to the frame to fix the load in place. As shown, the straps may comprise retractable straps, such as retractable straps contained within enclosures. Alternatively, the straps may include loose or manually adjustable straps, such as e-track straps, that may be manually positioned and adjusted by a user to the desired length and position.
[0045] In an embodiment, the hand truck 10 may include a fourth-wheel attachment 34 . The fourth-wheel attachment, as illustrated in FIG. 6 , may comprise a pair of side supports 36 connected by a support bar 38 . A wheel 40 , such as a caster wheel as illustrated in FIG. 6 , may be connected to a bottom end of each side support.
[0046] The fourth-wheel attachment 34 may be connected to the frame 12 and capable of pivoting with respect to the frame 12 . For example, as illustrated in FIG. 4 , a bracket 42 may be connected to each of the vertical supports 14 . The side supports 36 may be pivotally connected to the brackets 42 to allow the fourth-wheel attachment 34 to pivot with respect to the frame 12 .
[0047] The fourth-wheel attachment 34 may include a sliding axle 44 . The sliding axle 44 may be connected to the side supports 36 and configured to move or slide with respect to the supports 36 . For example, the side supports 36 may each include an inner channel or opening 46 , as shown in the detailed view in FIG. 9 . A bearing 48 may be positioned within each channel 46 and capable of sliding within the channel 46 . The bearing 48 may be a plastic self-lubricating bearing 48 , or any appropriate bearing 48 . The upper and lower boundaries of the channels 46 may be closed to prevent the bearings 48 from escaping out of the channel. The sliding axle 44 may connect to the bearings 48 at each end of the axle 44 to allow the sliding axle 44 to slide with respect to the fourth-wheel attachment 34 .
[0048] As best seen in FIGS. 4 and 7 , a brace 50 may interconnect the sliding axle 44 and the frame 12 . The brace 50 may comprise a bar, such as a portion of aluminum extrude. The brace 50 may connect at a first end to the sliding axle 44 . For example, the first end of the brace 50 may be connected to a first collar 52 . The first collar 52 may connect to the sliding axle 44 and be rotatable with respect to the sliding axle 44 . The second end of the brace 50 may be connected to a second collar 53 . The second collar 53 may be connected to a pivot axis 54 . The pivot axis 54 may be connected between the vertical supports 14 near the base of the frame 12 . The second collar 53 may be rotatable with respect to the pivot axis 54 .
[0049] In an embodiment, illustrated in FIGS. 17-20 , the engagement between the brace 50 and fourth-wheel attachment 34 may include a pair of pivot sockets 56 . The pivot sockets 56 may comprise a hollow body with open ends. The pivot sockets 56 may be positioned around the side supports 36 and slide with respect thereto. An axle 58 may extend between the two pivot sockets 56 . Instead of the bearing 48 positioned within the channel 46 , as shown in FIGS. 1-16 , the pivot sockets 56 may slide up and down the length of the side supports. The first collar 52 may connect to the axle 58 and pivot or rotate with respect to the axle 58 .
[0050] A latch 60 , positioned on the frame 12 , may be configured to receive and hold the fourth-wheel attachment 34 in a first position, as further described below. The latch 60 may be connected to any appropriate portion of the frame 12 , such as a cross support 16 . The latch may include a mounting bracket 59 to mount and connect the latch 60 to the frame 12 . The latch may further include a spring 64 , locking cam 66 , and pivot cam 68 . The spring 64 may be interconnect and apply a biasing force to the locking cam 66 and pivot cam 68 . The locking cam 66 and pivot cam 68 may be biased to an open position, as shown in FIG. 10 a, when nothing is held within the latch 60 . In open position, the latch 60 may be capable of receiving a bar therein, expanding the spring 64 , and locking the bar between the locking cam 66 and pivot cam 68 . The bar may be removed from the latch 60 by expanding the spring 64 to relieve the locking force and removing the bar from the latch 60 .
[0051] The brace 50 may include a latch bar 62 to lock the brace 50 and fourth-wheel attachment 34 to the latch 60 . The latch bar 62 may be spaced a distance away from the brace 50 to provide room for the bar to latch within the latch mechanism described above.
[0052] The hand truck 10 may be movable between upright and reclined positions. In upright position, as shown in FIGS. 1 and 2 , the latch bar 62 may be held within the latch 60 to lock the fourth-wheel attachment 34 into general alignment with the frame 12 . In reclined position, as shown in FIGS. 3-5 , the fourth-wheel attachment 34 may be removed from the latch 60 and the sliding axle 44 may slide to the distal end of the channel 46 . The side supports 36 may be positioned approximately perpendicular to the ground and the frame 12 may pivot to an angle of approximately 45 degrees with respect to the ground in reclined position.
[0053] The hand truck 10 may include a fourth-wheel attachment release mechanism to provide ease of use for activating and stowing the fourth-wheel attachment 34 . One or more activation handles 70 may be positioned near the handles 28 of the hand truck 10 . As shown in FIGS. 11 and 12 , the hand truck 10 may include two activation handles 70 , one on each side near the upper portion of the frame 12 . The one or more activation handles 70 may be positioned in near proximity to the hand truck handles 28 , such as 2 inches, 4 inches, or 6 inches from the handles 28 . It will be appreciated that the proximity of the activation handle or handles 70 to the hand truck handles 28 may be important in allowing a user to activate the fourth-wheel attachment 34 without removing their hands from the hand truck handles 28 . Accordingly, the one or more activation handles 70 may be positioned within finger's reach from the truck handles 28 , such as between the handles 28 , to allow a user to both hold the handles 28 and grasp the activation handle 70 simultaneously.
[0054] The one or more activation handles 70 may be connected to a rod 72 . The rod may extend from the base of the activation handles 70 and span laterally between the vertical supports 14 . In an embodiment having two or more handles 70 , the rod 72 may interconnect the handles 70 such that pulling on any of the handles 70 will rotate the rod 72 . A bracket 74 may extend from a portion of the rod 72 , such as a central portion of the rod 72 . The bracket 74 may be tied to a cable 76 that extends down from the bracket 74 . It will be appreciated that the hand truck 10 is not limited to using a cable 76 , and may instead use any similar or workable device, such as a chain, connecting rod, or the like. Pulling up on the activation handles 70 will apply an upward force on the cable 76 , and releasing the activation handle will allow the cable 76 to return to its original position.
[0055] The cable or connecting device 76 may extend down and connect to the latch 60 , as shown in FIG. 13 . A twist link 61 may be connected to the end of the cable 76 and connected to the spring 64 . The twist link 61 may comprise a bracket having a quarter or 90 degree turn. The 90 degree turn or twist may allow the twist link 61 to connect to a side of the cable 76 and be properly oriented to connect to the spring 64 . When the activation handle 70 is pulled up and activated, it will pull the cable upward and apply a force on the spring 64 . The force may decompress the spring 64 and pivot the locking cam 66 and pivot cam 68 to release the latch 60 and allow the latch bar 62 to exit the latch 60 .
[0056] A lower end of the cable 76 may extend past the latch 60 and continue further down and connect to the brace 50 . When the fourth-wheel attachment 34 is stowed in upright position, the lower end of the cable 76 may have slack. When the fourth-wheel attachment 34 is employed in the reclined position, the slack in the lower end of the cable 76 may be drawn tight. In the reclined position, when the activation handle 70 is activated the lower cable 76 will apply any upward force on the brace 50 , pulling on the fourth-wheel attachment 34 to make it pivot back up into stowed, upright position.
[0057] In use, the hand truck 10 may be configured in stowed, upright position with the fourth-wheel attachment 34 connected to the latch 60 by the latch bar 62 . To adjust the hand truck 10 into reclined position and deploy the fourth-wheel attachment 34 , one or more activation handles 70 may be activated. Pulling the activation handle 70 will apply an upward force on the cable 76 , which in turn will expand the spring 64 and open the latch 60 . When the hand truck 10 is pivoted about its wheels 26 while the activation handle 70 is activated, the gravitational force may pull the latch bar 62 out of the latch 60 and the fourth-wheel attachment 34 may deploy. The bearings 48 may slide within the channels 46 to a distal end of the channels 46 and the brace 50 may pivot out away from the frame, extending the fourth-wheel attachment 34 . Alternatively, in the embodiment illustrated in FIGS. 17-20 , the pivot sockets 58 may slide along the side supports 36 toward the wheels 40 , extending the fourth-wheel attachment 34 . The hand truck 10 may then be rested on the fourth-wheel attachment wheels 40 and the hand truck wheels 26 to fully support and transport the load in reclined position.
[0058] To stow the hand truck 10 back into upright position, the truck 10 may be partially pivoted on the wheels 26 back towards upright position. The activation handle 70 may then be actuated, which will apply an upward force on the brace 50 , pivoting the brace 50 and fourth-wheel attachment 34 back toward the frame 12 . The latch bar 62 may engage the latch 60 and lock therein, and the hand truck 10 may be moved back to upright position with the fourth-wheel attachment 34 stowed.
[0059] In an embodiment, the hand truck 10 may include a break back bar 80 , as illustrated in FIGS. 14-16 . The break back bar 80 may be useful in helping to stabilize the hand truck 10 when pivoting back towards the reclined position to prevent the load from running away from the user.
[0060] The break back bar 80 may be any appropriate shape and size, such as generally thin and rectangular shaped. The break back bar 80 may have an angled end 82 positioned at a slight angle to the remainder of the break back bar 80 . The angled end 82 may include a small opening or handle hole 84 .
[0061] The break back bar 80 may be connected to the wheel axle 27 , as illustrated in FIGS. 15 and 16 . A collar 86 may be positioned about the axle 27 and rotatable with respect to the axle 27 . The break back bar 80 may be connected to the collar 86 and capable of pivoting with respect to the axle 27 and frame 12 between an up position generally adjacent to the frame 12 and shown in FIG. 15 , and a down position generally parallel to the ground and shown in FIG. 16 .
[0062] The break back bar 80 may be biased toward the upright position. For example, the axle 27 may include one or more springs 88 configured to bias the collar 86 to pivot upward toward the frame 12 . The spring 88 may be positioned on and wound about the axle 27 and connected to the collar 86 at one end, as illustrated in FIG. 15 . It will be appreciated, however, that any type of spring or biasing device may be used to bias the break back bar 80 toward the upright position.
[0063] In use, the break back bar 80 may be biased toward the upright position while the hand truck 10 is also in upright position. A user may pivot the break back bar down toward the ground by applying a force with their hand or foot, and may then step onto the break back bar 80 to apply their entire weight, or a portion thereof, to the bar 80 . The hand truck 10 may then be pivoted to a reclined position without risk of rolling away from the user. Once the hand truck 10 is in a secure, balanced position, the user may remove their foot from the bar 80 and it will return to its upright position. The break back bar 80 may again be used to assist in returning a reclined load to upright position. The user may once again pivot and deploy the break back bar 80 using their hand or foot and step on the bar, pinning the bar to the ground. The load may then be pivoted back to upright position without risk of losing control. Using the break back bar 80 may reduce the strain and potential injury to a user by allowing them to maintain an upright posture while pivoting the load, instead of any awkward bending.
[0064] It will be appreciated that the hand truck 10 , as described herein, may include a break back bar 80 but not a fourth-wheel attachment 34 , or alternatively, may include a fourth-wheel attachment 34 but not a break back bar 80 . Each feature may operate separately from the other and provide the benefits as described herein.
[0065] In an embodiment, as illustrated in the FIGS. 1-16 , the hand truck 10 may include both a fourth-wheel attachment 34 and a break back bar 80 . The two features may work in concert to assist a user in stabilizing and controlling the hand truck 10 . In use, the hand truck 10 may be stowed in the upright position with the fourth-wheel-attachment 34 positioned adjacent to the frame 12 , and the break back bar 80 biased toward the frame 12 behind the fourth-wheel attachment 34 , as shown in FIG. 15 . To deploy the fourth-wheel attachment 34 , a user may first pivot and step on the break back bar 80 , as described above. The activation handles 70 may then be actuated to release the fourth-wheel attachment 34 and move the truck 10 into reclined position, as shown in FIG. 16 . To revert back to upright position, the truck may be tilted towards upright position and the activation handle 70 may again be actuated to pull the fourth-wheel attachment 34 up and latch it into stowed position. The break back bar 80 , which is biased as described above, will then pivot back up into upright position.
[0066] Although the embodiments of the present invention have been illustrated in the accompanying drawings and described in the foregoing detailed description, it is to be understood that the present invention is not to be limited to just the embodiments disclosed, but that the invention described herein is capable of numerous rearrangements, modifications and substitutions without departing from the scope of the claims hereafter. The claims as follows are intended to include all modifications and alterations insofar as they come within the scope of the claims or the equivalent thereof.
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A hand truck includes a frame, a toe plate connected to the frame, a pair of wheels rotatably secured to the frame, and a handle connected to the frame. A fourth-wheel attachment is pivotally connected to the frame at a first point and removable connected to the frame at a second point. A lever positioned adjacent to the handle causes the removable connection between the fourth-wheel attachment and the frame to be released, allowing the fourth-wheel assembly to pivot away from the frame. An embodiment of a hand truck includes a break back bar. The break back bar is pivotable with respect to the frame. The break back bar may be deployed and stood on by a user to prevent movement of the hand truck while pivoting a load.
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CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application is related to and claims priority from earlier filed U.S. Provisional Patent Application No. 60/889,075 filed Feb. 9, 2007.
BACKGROUND OF THE INVENTION
[0002] This invention relates generally to product packages that include integrated dispensing devices. More specifically, the present invention relates to product packages containing fluid media that include metering dispensing devices that can controllably dispense the fluid media from the product package containing the fluid media.
[0003] Various types of fluid material and media are employed for different purposes throughout commerce and industry. For example, there are various products in the areas of personal care, home care, air care, transportation care and food industries that require a fluid material to be dispensed in some manner from a source of such material.
[0004] Further, when this material is sold in commerce, it must be contained and stored in some type of container while awaiting use. Ultimately, when that product is used, it must be dispensed from its storage container to the desired location for use.
[0005] In the prior art, there are many different types of dispensers that are employed for the delivery of a stored fluid material to their desired location for use. For example, a storage container having a flexible body with a nozzle tip extending therefrom is commonly provided for such a purpose. An example of such use can be seen in the context of a ketchup dispenser, where a user squeezes the container body to urge the fluid material (ketchup) out from container body and through the nozzle tip to accurately deposit the fluid material at the desired location. In such an application, the amount of fluid that is ultimately delivered is determined by the how much the user actually squeezes the container body. While this method has provided marginally acceptable results, this method also typically yields an erratic fluid volume since more or less fluid material may be delivered on each successive squeeze of the container body. Also, the container must be held upright to avoid leakage because no valves are employed in the fluid nozzle tip.
[0006] In another example of a prior art dispensing device, a flexible container is provided that holds a volume of fluid material to be delivered. In an attempt to overcome the leakage issue noted above, a single one-way check valve is provided at the exit port of the flexible container. When the flexible body is squeezed, the material is urged out under pressure through the valve. The difficulty here is that the valve over time becomes partially clogged thereby requiring that the user apply additional pressure to cause the valve to open. As a result, once the valve opens, the additional pressure causes more fluid material to be deposited than the user typically would have desired.
[0007] In addition to the above noted need for simply dispensing a volume of fluid material, there is also a desire for the ability to immediately apply the dispensed fluid material, such as to a surface. In the prior art, the solution was to provide squeezable container bodies that are equipped with some type of applicator head for this purpose. For example, in the personal care industry, body wash devices commonly include some type of squeezable container body and an abrasive applicator material, such as fabric or foam, applied to the output port thereof. Thus, when the fluid material is dispensed to the exterior of the container body, it is dispensed onto the applicator and the applicator assists in spreading the material on the body of the user providing a better and more even distribution thereof. Applicators are particularly useful for even distribution in personal care industry, such as for applying shoe polish, to ensure a quality even and smooth coat.
[0008] In addition to the provision of applicator disposed at the outlet of the container, there have been attempts in the prior art to provide a dispenser that can easily deliver fluid material to an applicator that is positioned about the entire exterior surface of a container body. These prior art devices employ, for example, spring-loaded buttons that open an exit port in the main container body to permit flow of the fluid contained therein to an outer applicator material layer. This is in contrast to requiring the user to squeeze the entire body of the container. However, these devices are incapable of delivering a substantially equal dose of fluid with each dispensing operation because they simply open up the container body and permit the fluid to flow into the surrounding applicator material by gravity. Further, this construction requires that the fluid material exit through an opening at a lower side of the container. Therefore, it is not possible to dispense fluid on more than one side of the container or in a direction opposite to that of gravity. To dispense fluid material without concern for gravity, squeezable container bodies must be employed in connection with all of the disadvantages, as described above.
[0009] In view of the foregoing, the fluid dispensing and devices of the prior art suffer from various disadvantages that make them difficult and awkward to use. Further, these prior art dispensers often provide a user with unexpected results. Therefore, there is a need for a fluid dispenser that is easy to operate. There is a further need for a fluid dispenser that is capable of delivering a metered dose of fluid with each dispensing operation in order to produce predictable flow and a better application of the fluid material. There is also a need for such a dispenser that can operate independent of gravity. There is an additional need for the fluid to be capable of being delivered in a manner that allows the fluid to exit at any point on the surface of container. There is still a further need for a dispenser to include an applicator that facilitates even distribution and even application of the fluid material, as desired. Many of these needs are met by commonly owned, co-pending U.S. patent application Ser. No. 11/074,817, filed on Mar. 8, 2005 and U.S. patent application Ser. No. 11/951,351, filed on Dec. 6, 2007, which are incorporated herein by reference. This application sets forth a device for dispensing liquids in a metered fashion and provides for an exit port that can be located at any position on the fluid container. However there is still a further need to controllably deliver fluid from the exit port, namely, in an atomized or spray form.
BRIEF SUMMARY OF THE INVENTION
[0010] In this regard, the present invention preserves the advantages of prior art dispensing devices. In addition, the present invention provides new advantages not found in currently available devices and overcomes many disadvantages of such currently available devices. The present invention is generally directed to a novel and unique atomizer dispenser for delivering, via a spray nozzle, a substantially equal metered dose of fluid material for each dispensing operation.
[0011] The main flexible pouch and metering mechanism employed within the present invention is substantially similar to that found in the above noted U.S. patent application Ser. Nos. 11/074,817 and 11/951,351. The fluid dispensing device includes a container with an interior fluid storage region therein. A metering housing, having a preferably flexible construction, is disposed in fluid communication with the fluid storage region and a first one-way valve is disposed between the container and the flexible metering housing. When the flexible metering housing is depressed and released a vacuum action generates a one-way flow from the interior fluid storage region of the container that serves to fill the predetermined volume of the chamber within the metering housing. A second valve, in fluid communication with the metering housing output port, permits one-way fluid flow from the metering chamber to the exterior outer region of the container when the metering housing is depressed again. Each time the metering housing is depressed a substantially equal volume of fluid is dispensed from the container, while upon release, the metering housing is refilled by drawing fluid from the fluid storage region.
[0012] Further, in the context of the present invention, a spray nozzle or atomizer is attached to the exit port of the dispensing device after the second valve so that the liquid is delivered in metered fashion in spray form. It is also possible that the neck of the atomizer may be flexible to facilitate dispensing of the fluid.
[0013] It is therefore an object of the present invention to provide a fluid dispensing device that can deliver a substantially equal volume of fluid material in spray form from each dispensing operation. It is also an object of the present invention to provide a fluid dispensing device with a spray nozzle that is insensitive to gravity. It is a further object of the present invention to provide a metered fluid dispensing device that includes a spray applicator to ensure desired delivery of the fluid material. It is still a further object of the present invention is to provide a fluid dispensing device that can deliver spray flow at any point from the device. Finally, it is an object of the present invention to provide a fluid dispensing device that can deliver spray flow at multiple locations from the device.
[0014] These together with other objects of the invention, along with various features of novelty that characterize the invention, are pointed out with particularity in the claims annexed hereto and forming a part of this disclosure. For a better understanding of the invention, its operating advantages and the specific objects attained by its uses, reference should be had to the accompanying drawings and descriptive matter in which there is illustrated a preferred embodiment of the invention.
BRIEF DESCRIPTION OF THE DRAWINGS
[0015] In the drawings which illustrate the best mode presently contemplated for carrying out the present invention:
[0016] FIG. 1 is a top perspective view of the dispensing device of the present invention;
[0017] FIG. 2 is a bottom perspective view of the dispensing device of the present invention;
[0018] FIG. 3 is a cross-sectional view through the line 3 - 3 of FIG. 1 ;
[0019] FIG. 4 is a close-up perspective view of the metering housing with stand-off legs;
[0020] FIG. 5 is a close-up perspective view of the metering housing with coil spring;
[0021] FIG. 6 is a top plan view of an alternative embodiment of the present invention;
[0022] FIG. 7 is a front perspective view of another embodiment of the invention; and
[0023] FIG. 8 is a cross-sectional view through the line 8 - 8 of FIG. 7 .
DETAILED DESCRIPTION OF THE INVENTION
[0024] Now referring to the drawings, the dispensing device of the present invention is shown and generally illustrated at 10 in the figures. As can be seen at FIGS. 1 and 2 , the dispensing device 10 of the present invention is shown to include an outer covering, generally referred to as 12 , which serves as an applicator material. This applicator material 12 can be formed of any type of material to suit the application at hand. For example, as seen in FIGS. 1 and 2 , the outer covering 12 is preferably formed from of two different types of material 12 a , 12 a allowing it to serve two purposes when in use. Preferably, the top section 12 a is of a foam material while the bottom section 12 b is of a mesh or “pouf” material. The top section 12 a can be secured to the bottom section 12 b by, for example, welding. A snap-fit cover 14 seals a re-fill port 16 , as will be described in more detail in connection with FIG. 3 . A hang strap or cord 18 can also be provided. The configuration of the outer cover 12 applicator material is just one of many different types of applications of the present invention which will be discussed in more detail below.
[0025] Turning now to FIG. 3 , a cross-sectional view through the line 3 - 3 of FIG. 1 is shown to illustrate the internal construction of the dispensing device 10 of the present invention. A container body 20 is provided which includes a fluid storage region 22 that contains a volume of fluid material 24 therein. The container 20 is preferably made of a flexible material, such as plastic or nylon. Thus, as fluid material 24 is evacuated from within the container body 20 , it will collapses gradually for a compact structure.
[0026] A metering housing 26 is provided at a first opening 28 of the container body 20 . The metering housing 26 includes an intake one-way valve 30 , such as a check valve, to pull fluid 24 from the fluid storage region 22 of the container body 20 into a metering chamber 32 of a predetermined size. Any type of valve can be used to suit the given application. The intake valve 30 is positioned in a base plate 34 of the metering housing 26 . Thus, fluid 24 can only flow in one way from the fluid storage region 22 into the metering chamber 32 . The metering chamber 32 is defined by a flexible membrane 36 in the form of a button or bulb that is accessible and manipulateable through a gap 38 in the applicator material 12 . The button 36 is preferably clear to provide an indicator to the consumer when the metered dosage of fluid material 24 is ready for delivery.
[0027] An output valve 40 is provided in fluid communication with the metering chamber 32 of the metering housing 26 . Thus, the fluid residing in the metering chamber can only exit through the output valve 40 . Also, a fluid conduit 42 is provided to direct the exit of fluid 24 at any location through the container body. Preferably, as seen in FIG. 3 , the fluid conduit 42 connects the output valve 40 of the metering housing 26 to an exit port 44 located on the bottom of the container body. This permits the metering housing 26 to be on an opposite side as the side through which the fluid 24 exits. The fluid conduit 42 can be directed and located to exit at any point through the container body 20 depending on the application at hand. Also, the output valve 40 may be located at the exit port 44 , as an alternative depending on the requirements of the application.
[0028] In accordance with the metering dispensing flexible pouch with spray nozzle of the present invention, a spray nozzle member 60 is attached to the exit port 44 . The spray nozzle 60 may be installed directly into the exit port 44 or may be installed at the end of a leader tube 62 to allow the user additional directional control of the fluid 24 dispensed by the nozzle 60 . It can also be appreciated by one skilled in the art that the exit port 44 can be located anywhere on the dispensing device 10 , as is shown below in FIGS. 7 and 8 . Also, the spray nozzle 60 can be of any configuration that can deliver the liquid in a spray or atomized form. The spray nozzle 60 can be modified to provide different type of spray shapes and densities, according to the application desired and type of liquid being dispensed. Further, the spray nozzle 60 can be provided with an adjustment feature to allow the end user to adjust the spray pattern 64 with each use if desired and the leader tube 62 may be rigid or flexible.
[0029] In accordance with the present invention, each press of the flexible membrane 36 causes a metered amount of liquid 24 to be forced through the spray nozzle 60 to provide the desired atomized delivery application. This button/membrane 36 can be placed anywhere on the device, as needed. Further, the main pouch can be of any configuration, such as a flat pouch or stand up pouch (SUP), for example. In addition, further layers can be provided, such as laminations of foam, fabric, paper, plastic, and the like, to enhance the touch and appearance of the overall device.
[0030] Still referring to FIG. 3 , the operation of the dispensing device 10 is further explained which is applicable to the present invention which includes a spray nozzle 60 attached to a leader tube 62 that extends from the exit port 44 . The button 36 of the metering housing 26 is depressed to initiate a vacuum operation. More specifically, when the button 36 is further released, fluid 24 is pulled from the fluid storage region 22 of the container body 20 into the metering chamber 32 which is configured to be of a certain known volume. The act of releasing the button 36 fills the metering chamber 32 to substantial capacity. Thus, a metered amount of fluid material 24 is contained within the metering chamber 32 in preparation for delivery. The size of the metering chamber 32 can be selected according to the type of fluid material 24 to be dispensed, the application therefor and the desired dosage volume.
[0031] A further depression of the button 36 urges the measured volume of fluid 24 within the metering chamber 32 to exit out through the output valve 40 of the metering housing 26 . This known amount of fluid material 24 is then either directly routed to the applicator 12 for use or through a fluid conduit 42 , as seen in FIG. 3 , for more targeted introduction into the applicator 12 . In this case, it is preferred that the metered volume of fluid material 24 be routed to the spray nozzle 60 . The fluid exiting the spray nozzle 60 can then be directed onto a desired surface or back into the applicator 12 as indicated by the intended use.
[0032] Referring back to FIG. 1 , an efficient method of manufacturing a quality dispensing device 10 is to employ heat welding to construct the container 20 and the applicator material 12 thereon. For example, a top portion 20 a is typically heat welded to a bottom portion 20 b about their periphery 20 c to form a container 20 with an interior fluid storage region 22 therein. The applicator material 12 is similarly secured to the container 20 by heat welding or other similar process, such as gluing, either about its periphery or its entire contact surface with the container 20 .
[0033] Turning now to FIGS. 4 and 5 , further enhancements to the metering housing 26 construction are shown in detail. As seen in FIG. 4 , a number of stand-off legs 50 emanate downwardly from the base plate 34 of the metering housing 26 . These legs 50 prevent the base plate 34 from completely bottoming out against the container 20 wall thereby blocking flow of fluid material 24 into the intake valve 30 . The stand-off legs 50 are particularly useful when the volume of fluid material 24 left in the container 20 is running low and the container 20 is becoming relative flat in configuration. In this situation, there is a possibility that the aforesaid bottoming out may occur. However, the use of the stand-off legs 50 of FIG. 4 prevent this from occurring.
[0034] FIG. 5 illustrates a further modification of the metering housing 26 to ensure that maximum suction is achieved and that the entire metering chamber 32 is filled upon each depression and release of the button 36 . A spring-biasing structure 52 resides within the button or bulb structure 36 of the metering housing 26 . Thus, the button 36 recovers quickly while providing a strong suction or vacuum to fill the interior of the metering chamber 32 with the desired metered volume of fluid material 24 . A coil spring is preferred for the spring-biasing structure 52 but other spring-biasing structures, such as leaf springs and foam material may be employed for this purpose. Further, while various spring-biasing structures 52 are shown, it is also within the scope of the invention that the resiliency of the bulb structure 36 material is selected to exhibit sufficient memory to return to its original shape quickly without the need for spring-biasing structures 52 . In this manner, the present invention clearly provides for an overall construction that requires dramatically less parts for operation as compared to the prior art conventional spray dispensers.
[0035] FIG. 6 illustrates a further alternative embodiment 200 of the present invention where a container, such as container 220 or 120 , includes a series of tabs 202 that emanate outwardly from the container 220 . An outer frame or skeleton 204 is connected to the container 220 via the tabs 202 . Applicator material 206 , such as “poof” or fabric material, is then attached to the frame 304 with the container 220 residing therein. This embodiment 200 is particularly well-suited to permit free flowing of fluid material about the dispenser 200 .
[0036] Turning now to FIGS. 7 and 8 , details are shown of a another alternate device 300 that includes the improved valving of the present invention that prevents inadvertent or accidental dispensing of liquid 302 even when pressure is placed on the dome pump 326 or storage container 320 . FIG. 8 illustrates a perspective view of a metering dispenser 300 that employs the improved valving in accordance with the present invention. An outer storage container 320 is provided that may be formed of two sheets of material 304 , 306 secured together, such as by welding, or a tube of material. A metering pump, generally referred to as 326 , pulls liquid 302 from the storage container 320 , meters it, and then dispenses it via an exit port 308 into a leader tube 310 and ultimately out of a spray nozzle 312 .
[0037] In the dome pump 326 of the present invention, the base plate 410 , through which the flow through aperture 412 passes, is preferably slightly convex, although it may be flat, if desired. Resting above the aperture 412 and within the cavity 405 of the dome is a flapper valve 408 of preferably thin film construction. It is possible that this flapper valve 408 be configured of a normally open condition but also may be configured to lie flat when at rest. As long as the plate 410 with the aperture remains convex, the flapper valve 408 does not seal against the aperture 412 such that any inadvertent contact with the flexible dome pump housing 404 does not result in the dispensing of the product. Instead, since the flapper valve 408 is open, liquid product residing inside the cavity 405 of the flexible pump housing 404 will tend to simply flow back through the inlet aperture 412 to the reservoir within the storage container itself, as indicated by the arrow in FIG. 8 , rather than flow undesirably out through the exit valve to outside of the dispenser 300 . In use, if a person has the dispenser in their pocket or purse and pressure is accidentally or unintentionally placed on the flexible housing 404 of the dome pump 426 , liquid will not flow outside the dispenser thereby preventing a mess from being made due to unintentionally dispensed product.
[0038] FIG. 8 illustrates intentional dispensing of liquid 302 . When it is desired to actually dispense the liquid product 302 , the user's thumb 430 can depress the flexible dome 404 and the user's index finger 432 can invert the base plate 410 from convex to concave, by application of force against the stand-off legs 424 , such that flexible dome 404 , with the assistance of the stand-off legs 422 under the flexible dome, securely seals and provides a positive lock of the flapper valve 408 over and about the aperture 412 thereby closing the liquid flow passage back into the reservoir 434 of the storage container 320 . It is also possible that the base plate 410 is concave and then is inverted to a convex configuration. Other fingers of the user may be used to carry out this operation. Thus, the only path for the liquid 302 contained within the cavity 405 of dome 404 is to exit through the one-way outlet valve 436 for intended dispensing of the product, as indicated by the arrows in FIG. 8 .
[0039] It should be understood that the stand-off legs 422 on the bottom of the flexible dome housing 404 and the stand-off legs 424 on the bottom of the base plate 410 can be modified in size, length and configuration to adjust the amount of squeezing necessary by the user's fingers 430 , 432 to effectuate sealing of the flapper valve 408 . For example, preferably four stand-off legs 422 are provided on the bottom of the flexible dome housing 404 in a 2×2 array and can be 1/32 of an inch in length. It is also possible that these stand-off legs 422 can be a single downwardly depending wall, such as in the shape of a circle or square. Such an array is configured to downwardly press against the one-way flapper valve 408 outside of the diameter of the aperture 412 through the base plate 410 to provide a good seal of the flapper valve 408 to the base plate 410 .
[0040] The dispensing device 10 of the present invention has a wide array of applications of use to take advantage of the unique metered dosage capability of the present invention. Virtually any dispenser with any type of applicator material or combinations of applicator materials in different configurations can employ the present invention.
[0041] For example, the personal care industry has particular application in the controlled and metered dispensing of bath and shower gels. Also, medicines, cosmetics, hair care products, such a shampoos, skin care products, such as lotions, insect repellants and sunscreen products can employ the present invention. Also, various home products can be delivered in a device 10 according to the present invention. These include products for furniture cleaning and polishing, tub and shower cleaning, floor cleaning and polishing, window cleaning, odor elimination, oven cleaning, laundry cleaning and apparel treatment. Also, air treatment device can employ the present invention.
[0042] The device with a spray nozzle 60 of the present invention has particular application in dispensing liquid that is best suited for being sprayed or atomized for delivery. For example, the present invention is very well suited for dispensing air freshener, which is typical sprayed for delivery. As an advance over the prior art, the present invention provides controlled metering of the sprayed liquid, which is not found in the prior art.
[0043] Still further, cleaning products can be dispensed in a controlled fashion, such as those for cleaning cars, bikes, planes and trucks. The food industry has numerous potential applications, particularly for the dispensing of condiments, sauces and vitamins. These items can be sprayed as well.
[0044] To employ the dispensing device 10 of the present invention, the size and construction of the metering housing 26 as well as the positioning of where the fluid material 24 is delivered to the surface of the device can be easily modified to suit the given application. The materials used for the container 20 and the metering housing 26 , while preferably flexible plastic, can be any suitable material for the application at hand. Also, the container 20 can be made of a different material than the metering housing 26 .
[0045] The applicator material 12 can be foam, such as open cell foam, fabric, blended material, co-extruded material and combinations thereof. It should be understood that these materials are just examples of the types of materials that can be used in connection with the dispenser 10 of the present invention. The specific material is determined by the given application and the type of material to be dispensed. Non-woven materials or fibers may also be employed as the material for the applicator 12 on one or both sides of the device. For example, reticulated foam may also be employed. These materials would be well-suited as applicators 12 for more harsh chemicals, such as tire cleaner and paint remover where toughness is required. Also, more abrasive material can be provided on one side of the device for more aggressive cleaning, for example, while the opposing side has a polishing type surface. In general, the size, density and wicking action of the cells and overall size of the applicator 12 can be modified to suit the particular fluid to be applied.
[0046] Any type of spray nozzle 60 can be used to deliver the liquid in a spray form. The type shown on the attached invention disclosure is just one example of the type of spray nozzle 60 that can be used in the present invention.
[0047] In summary, a new and novel dispenser 10 is provided that can deliver consistent metered dosages such fluid material 24 in an atomized spray form. The dispenser 10 has a greatly improved construction where the fluid material 24 is even distributed throughout the applicator material 12 for a more efficient and more effective fluid dispensing. The dispenser includes a unique spray nozzle 60 to deliver the metered liquid in a spray form, which is new in the art.
[0048] It would be appreciated by those skilled in the art that various changes and modifications can be made to the illustrated embodiments without departing from the spirit of the present invention. All such modifications and changes are intended to be covered by the appended claims.
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An atomizing fluid dispenser for delivering, via a spray nozzle, a substantially equal metered dose of fluid material for each dispensing operation is disclosed. The fluid dispensing device includes a container with an interior fluid storage region therein. A metering housing, when depressed, generates a one-way flow from the interior fluid storage region of the container that serves to fill the predetermined volume of the chamber within the metering housing. When the metering housing is depressed a second time a substantially equal volume of fluid is dispensed from the container, while upon release, the metering housing is refilled by drawing fluid from the fluid storage region. A spray nozzle or atomizer is attached to the exit port of the dispensing device so that the liquid is delivered in metered fashion in spray form.
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FIELD OF THE INVENTION
This invention relates to a dynamic system for track tensioning on tracked vehicles and particularly to a hydraulically controlled track tensioner dynamically responsive to vehicle conditions.
BACKGROUND OF THE INVENTION
In a tracked vehicle, especially a tank or the like which is subject to rough terrain and severe operating conditions, the track and wheel dynamics cause widely fluctuating track tension. Typically an idler wheel is provided to adjust tension but prior arrangements are limited in ability to control the tension. An ideal system would maintain, for all mobility scenarios, a track tension which is relatively uniform and of the lowest possible magnitude which provides proper guiding of the track throughout its entire path. Such an ideal system would maximize track and running gear life; aid in minimizing rolling resistance, which would improve drive train efficiency; assure a high level of mobility during aggressive and/or high speed maneuvering situations; and, in general, enhance the combat readiness, reliability, and maintenance characteristics of the vehicle over its life cycle.
Prior to this invention the track tensioning systems could be grouped into two basic types: fixed idler systems and movable idler systems. The fixed idler systems have an idler wheel initially adjusted for a desired static tension. The idler is then rigidly anchored to the hull. The movable idler systems have a track tensioning idler wheel connected to the forward road arm through a link whose length can be adjusted for a desired static tension. The geometry of the linkage is arranged so that as the road arm approaches its jounce, or uppermost, position the tensioning idler is moved forward. This motion attempts to maintain a uniform total periphery about all track-contacting elements; i.e. the road wheels, final drive sprocket, return rollers, and tensioning idler.
The tracks, of course, may operate in either a driving or a braking mode. In driving mode, the track is driven by the drive sprocket and applies a tractive effort to the ground which maintains or increases the track velocity. In braking mode the opposite occurs to decrease the track velocity. The tension in a given section of track varies greatly as the track moves around the drive sprocket, the tension being greater on the side of the sprocket nearest the road wheels when in driving mode and less during braking mode. Reverse travel and turning changes the tension conditions on one or both tracks. The negotiation of an obstacle at high speed accentuates the difference in tensions. Thus the tensions can vary widely and rapidly, if not controlled, and the wheels are affected as well.
For example, when the vehicle is traveling forward with both tracks driving, the rear wheels tend to compress to a degree dependent on the tractive effort. This reduces the total periphery of the track supporting members allowing the track to loosen and partially disengage from the tensioning idler. This condition can produce a thrown track if the vehicle should suddenly encounter an obstacle or attempt an abrupt steer maneuver.
SUMMARY OF THE INVENTION
It is therefore an object of the invention to provide a track tension control system for improving the uniformity of tension. It is another object to provide such a system for maintaining the tension at the lowest value suitable for the vehicle operating conditions.
The invention is carried out by a dynamic track tension system for a tracked vehicle comprising; means for detecting vehicle conditions and producing condition signals, hydraulic control means responsive to the condition signals for developing variable hydraulic pressure for each track in accordance with the vehicle conditions, and a hydraulic track adjuster for each track coupled to and operated by the hydraulic pressure for applying controlled tension to each track according to the detected vehicle conditions.
More specifically the invention comprehends a movable track idler wheel positioned hydraulically under a selected hydraulic pressure and responsive to the detected vehicle conditions to selectively maintain a set position of the idler wheel or allow movement of the wheel under the hydraulic force.
BRIEF DESCRIPTION OF THE DRAWINGS
The above and other advantages of the invention will become more apparent from the following description taken in conjunction with the accompanying drawings wherein like references refer to like parts and wherein:
FIG. 1 is an elevation of a tracked vehicle having a dynamically adjustable track tension idler wheel according to the invention;
FIGS. 2 and 3 are schematic illustrations of two different mounting geometries for the idler wheel of FIG. 1;
FIGS. 2A and 3A are force diagrams for the geometries of FIGS. 2 and 3, respectively.
FIG. 4 is a schematic diagram of the control system and a cross section of the idler wheel actuator according to the invention;
FIG. 5 is a block diagram of a logic controller of the control system of FIG. 4; and
FIG. 6 is a cross sectional elevation of a control valve manifold for the system of FIG. 4.
DESCRIPTION OF THE PREFERRED EMBODIMENT
FIG. 1 shows a tracked vehicle such as a tank or the like having a hull 10 supporting a plurality of road wheels 12, a forward idler tension wheel 14, a drive sprocket 16, a few upper idler wheels 18, and a track 20 extending around and mounted on the elements 12 through 18. The road wheels 12 are mounted on conventional suspensions allowing arcuate movement in response to vertical forces from their normal static position to a fully compressed jounce position at one extreme to a fully extended or rebound position at the other extreme. Variations in track path length caused by such movement of the road wheels is accommodated by the idler wheel 14 which is adjustable on a moment by moment basis to maintain a more uniform tension than can be obtained by the previous systems. A hydraulic actuator 22 controls the position of the idler wheel 14.
To permit adjustment, as shown in FIG. 2, the idler wheel 14 is rotatably mounted at 24b on an idler arm 24 near the upper and lower ends of the arm. The upper arm end is pivoted to the hull 10 at 24a and the lower end of the arm 24 is pivotally coupled to one end of the actuator 22 at 24c. The other end of the actuator is mounted to a trunnion 26 on the hull 10. The idler arm 24 is the same as that sometimes used with a tensioning link instead of an actuator. The tensioning link is adjustable in length only as a maintenance procedure and has a fixed length during tank operation. Thus the hydraulic actuator 22 can be incorporated in vehicles of the illustrated design without change of the idler wheel mounting arrangement. When the actuator is thus used, along with the control to be described, improvements in track tension uniformity can be realized. In the case of the illustrated design, the force vector resulting from track tension is identified in FIG. 2A by reference numeral 23. In another embodiment, the idler arm is bent and the center of the idler wheel is moved forward a few inches, as shown in FIG. 3. Such arrangement improves tension uniformity on the track 20 with force variations from the static height to the extreme limits being on the order of five or six percent. The bent idler arm 24' then takes the form of a bell crank with a hull pivot 24'a, an idler wheel center 24'b and an actuator pivot 24'c.
In such case, the force vector 23' is very near perpendicular to the idler arm 24' throughout its stroke and the compensating tension moment is near equal and opposite to the force vector movement. Force diagrams of each embodiment are shown in FIGS. 2A and 3A respectively.
In FIG. 2A, the arc of the idle wheel center is shown at 24a,b and the arc of the actuator pivot is shown at 24c. The jounce, static and rebound positions are marked J, S and R.
In FIG. 3A the arc of the bent idler arm 24' includes an idler wheel center arc 24'b and an actuator pivot arc 24'c. Comparison of the arcs (and associated force vectors) confirms the more uniform tensioning produced by the FIG. 3 case.
The actuator 22, as best shown in FIG. 4, is a single acting linear hydraulic actuator having a piston 30 driving a piston rod 32 which connects to the idler arm 24. If desired the piston rod length can be adjustable using a known technique (not shown) of a secondary cylinder and piston preloaded with a pressurized grease to extend the length to a desired amount. A hydraulic fluid inlet 34 on the side of the piston opposite the piston rod 32 admits fluid under pressure so that the actuator 22 can only exert force on the idler in a direction to increase track tension. A pilot operated check valve 36 in the inlet 34 has a normal closed position to prevent flow from the actuator and an open position when pilot pressure is applied to permit bidirectional flow. In closed position, the valve 36 maintains the actuator position against the forces exerted by the track 20 on the idler wheel 14 and also protects the remainder of the hydraulic system from the large hydrostatic pressures which may be generated within the actuator.
The pressure is supplied to the actuator 22 from a suitable hydraulic supply 38 through a manifold 40 which regulates the applied pressure as well as the pilot pressure. The actuator 22 and hydraulic manifold 40 serve the left side of the vehicle while an identical actuator 22' and manifold 40', shown as blocks, serve the right side of the vehicle. Electrical controls for setting both the right and left manifold pressures include a drivers manual control 42 and an electronic logic controller 44. Several sensors monitor vehicle operating conditions (or vehicle condition parameters which are processed to produce vehicle control parameters) or commands to provide information to the logic controller 44.
The sensors provide information about three mutually exclusive pairs of vehicle conditions: right and left steer, forward and reverse travel, and acceleration and deceleration. The blocks forward 46 and reverse 48 represent the source of information on that pair of conditions. Where the vehicle transmission is electrically shifted the shift command can be tapped to yield that information. The blocks left steer 50 and right steer 52 represent the source of that information and is implemented by a cam actuated dual switch assembly added to the driver's steering tiller bar to detect displacement from center which represents a steering command. The block representing speed 54 is an existing device providing the vehicle speedometer input. In one proposal, the speed sensor is a digital magnetic speed pickup measuring the transmission output. Its output is fed to the vehicle speedometer and is used as the speed signal. However, other speed sensors are equally suitable for practicing the invention. The speed signal is utilized by the electronic logic controller 44 to determine acceleration and deceleration.
The logic controller 44, as shown in FIG. 5, includes two major sections. The first section receives the digital speed signal and includes a frequency to voltage converter 56 to output an analog speed voltage, and a differentiator 58 for determining acceleration or deceleration and yielding corresponding logic signals for those two conditions. The second section comprises a ROM 60 having a lookup table programmed to output suitable control signals on lines 62 and 64 which couple to the right and left manifolds 40' and 40, respectively. The inputs to the ROM 60 are the acceleration and deceleration signals as well as the forward, reverse, left steer and right steer signals. The following table exemplifies the ROM logic. For each operating condition a decision is made for the right and left actuators whether the pilot operated check valve should be open (0) or closed (C) and the logic level of the signal on lines 62 and 64 convey that information to the manifolds 40 and 40'.
__________________________________________________________________________VehicleOperational Mode 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27__________________________________________________________________________Sensor IndicationVehicle X X X X X X X X XAcceleratingVehicle X X X X X X X X XDeceleratingTransmission in X X X X X X X X XForwardTransmission in X X X X X X X X XReverseLeft X X X X X X X X XSteer EngagedRight X X X X X X X X XSteer Engaged*Condition ofActuator PilotCheck ValvesLeft Track O O O C O C O O O C C C C O C O O O O O C C C O C O ORight Track O O O C O C O C C C O O C O O O O C O C O C C C O O O__________________________________________________________________________ *With valve open (O), actuator operates as zero rate spring. With valve closed (C), actuator is hydrostatically locked in position.
The driver's manual control also sends a logic level signal to the manifolds 40 and 40' on line 66. The control 42 is simply a switch controlled by the driver to signal the manifolds to decrease the pressure to the actuators whenever the driver judges that the expected operating conditions will require no abrupt maneuvers. In those conditions the resulting lower track tension improves track life and vehicle operating efficiency.
The manifold 40 depicted in FIGS. 4 and 6 has a supply input port 70 connected to the supply 38, a return port 72 connected to the system sump, an actuator port 74 coupled to the actuator 22 and a pilot pressure port 76 coupled to the check valve 36 of the corresponding actuator. The control line 64 is coupled to a solenoid valve 78 and the control line 66 is connected to a solenoid valve 80.
A pressure regulating valve 82 comprises a main bore in the manifold having a long ported sleeve 83 at one end containing a spool 86 with end lands 88 and 90 and a central land 92. The center land 92 separates the supply port 70 from the return port 72 and regulates the output to the actuator port 74. A restricted passage 94 in the spool couples the supply pressure to the top end of the spool 86. The output pressure at port 74 is coupled to the bottom end of the spool through an internal passage 96 and a port 98 in the sleeve 83 to normally maintain the output pressure at the supply pressure. The control for a second, reduced pressure comprises a second sleeve 100 in the main bore at the bottom end of the sleeve 83 and having a smaller internal diameter. A piston 102 in the second sleeve 100 bears against the bottom end of the spool 86 so that if supply pressure is applied to the bottom end of the piston the force on the top end of the spool will be partially offset to reduce the regulated pressure at the output port 74. The pressure is selectively applied to the piston 102 by the solenoid valve 80 through the passage 104 and aperture 106. The solenoid valve 80 positions a spool 108 in sleeve 109 to apply return or zero pressure to passage 104 via internal porting 110 when the solenoid is deenergized. When voltage is applied to the solenoid the spool is displaced to couple the supply pressure to the passage 104 and to the bottom of the piston 102. The solenoid valve 78 is identical to valve 80 and is connected to internal passages to normally couple the pilot pressure port 76 to the return or zero pressure. When energized, the spool 112 of that valve 78 is displaced to couple the supply pressure to the pilot port 76.
As shown, a step 102a is provided in piston 102 and passage 103 connects the system return to the reduced area at the top end of piston 102.
It will thus be seen that the control system enables the operator to select full pressure or reduced pressure, as required for optimum track tension. It is also feasible to modify the system to allow for another pressure level also selectable by the operator.
It is also evident that the tension control by the hydraulic actuator provides for a hydrostatic lock preventing idler retraction when such retraction would make the track loose and vulnerable to being thrown off. When that danger is absent the actuators act as zero rate springs to apply uniform force to the tracks. The decision of which mode is appropriate for each track is encoded into the ROM in accordance with the above table. According to the table when the vehicle is moving straight forward and accelerating, the check valve would be open for both tracks and the idler wheels would experience a constant spring force from the actuators. If, however, the brakes are applied and deceleration is sensed, both check valves are closed and the idler wheels will be prevented from retracting. In the case of steering it frequently occurs that one valve will be open and the other will be closed.
It should be apparent that the dynamic track tension system according to the invention is effective to improve tension uniformity and reduce the tension to a minimum value under appropriate operating conditions.
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The tracks of a tracked vehicle are subject to a tension control system which includes a movable idler wheel for applying force to each track, a hydraulic actuator for dynamically applying force to each track at a zero spring rate, a pilot controlled check valve for selectively locking the actuator against tension relieving return movement, and a control sensitive to vehicle steering, direction of movement, acceleration and deceleration for deciding according to a preset program whether each actuator should be locked or free to move. An operator controlled switch modifies system hydraulic pressure to permit an optional low pressure operation.
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BACKGROUND OF THE INVENTION
[0001] 1. Field of the Invention
[0002] The present invention relates to a production process for an oxide magnetic material capable of being used in a stacked composite device and an inductor and to the oxide magnetic material.
[0003] 2. Related Art
[0004] In recent years, a demand for downsizing has been increasingly built up in a small-sized electronic device such as a portable telephone. In such a situation, plural electronic circuits constituting an electronic device have been integrated into a stacked composite device on a single chip for mounting on a main substrate.
[0005] [0005]FIG. 7 is a perspective view showing an example of stacked composite device and FIG. 8 is an exploded perspective view thereof. A stacked composite device, as shown in FIGS. 7 and 8, is constructed by stacking plural ceramic layers 3 and 4 . Plural circuit element patterns 11 each including an inductor or a capacitor are formed on surfaces of the ceramic layers 3 and 4 . The circuit element patterns 11 are connected to each other by via holes 12 passing through the ceramic layers 3 and 4 or by conductor patterns formed on the ceramic layers 3 and 4 , thereby to construct an electronic circuit such as a filter.
[0006] It is proposed that in a case where the ceramic layers 3 are magnetic ceramic layers and the ceramic layers 4 are dielectric ceramic layers, a pattern (L pattern) constituting an inductor is formed on each of the magnetic ceramic layers 3 and a pattern (C pattern) constituting a capacitor is formed on each of the dielectric ceramic layers 4 (Japanese Patent Laid Open No. S60-106114, Japanese Patent Laid Open No. H6-333743 and others).
[0007] As magnetic materials used in such a stacked composite device and an inductor, there has been generally heretofore used: a NiCuZn base spinel type ferrite. FIG. 9 is a graph showing frequency characteristics of magnetic permeability of a NiCuZn base spinel type ferrite. In FIG. 9, there are shown normalized values of a real part μ′ and an imaginary part μ″ of a complex magnetic permeability with the μ′ at 10 MHz as 1. As shown in FIG. 9, the real part μ′ of a complex magnetic permeability takes a comparatively high value in a region up to as high as a value in the vicinity of 100 MHz.
[0008] As magnetic materials capable of adapting to higher frequencies, there can be named a hexagonal ferrite. The hexagonal ferrite includes crystal structures of phases which are analogous to each other, such as a Z type, a Y type, a W type and an M type. The phase of the Z type, among them, shows a comparatively high magnetic permeability and reduction in magnetic permeability is minimized in a region up to as high as the GHz band.
[0009] A prior art spinel ferrite such as that of NiCuZn base, as shown in FIG. 9, can be used in a region up to as high as 100 MHz, whereas a natural resonance occurs in a region of higher frequencies to decrease a real part μ′ of magnetic permeability but to contrary to this, increase an imaginary part μ″ thereof (which is a Snoek limit). Furthermore, in a prior art hexagonal ferrite having the Z type structure, reduction in magnetic permeability is minimized and excellent in a high-frequency characteristic in a region up to as high as the GHz band, whereas a crystallization temperature is as high as 1300° C. Since Ag and Cu as materials of a conductor pattern are molten. at such a high temperature, a problem arises that the conductor pattern cannot be heated simultaneously with sintering of a magnetic material.
SUMMARY OF THE INVENTION
[0010] It is an object of the present invention to provide a production process for an oxide magnetic material, with the composition of a hexagonal ferrite and being small in loss in a high-frequency band; and an oxide magnetic material obtained by the production process.
[0011] A production process of the present invention includes: a step of blending raw material powder so as to take the composition of a hexagonal ferrite including: at least one kind of an element A selected from the group consisting of Ba, Sr and Ca; Co and Cu; Fe; and O (Oxygen); and a step of sintering the blended powder at a temperature lower than 1000° C.
[0012] The present inventors have found that by sintering the raw material powder blended so as to take the composition of a hexagonal ferrite at a temperature lower than 1000° C., which is lower than 1300° C. of a crystallization temperature of the hexagonal ferrite, an oxide magnetic material can be obtained that has magnetic permeability almost as high as the oxide magnetic material sintered at 1300° C. which is a crystallization temperature thereof, leading to the present invention. In the present invention, a sintering temperature is more preferably in the range of from 850 to 950° C., further more preferably in the range of from 880 to 920° C.
[0013] According to the present invention, since sintering can be performed at a temperature lower than 1000° C., magnetic material powder can be sintered in the co-existence of a conductor such as Ag or Cu, thereby enabling a stacked composite device, an inductor and others to be produced in simpler and easier process.
[0014] In a more preferable embodiment according to the present invention, after blending the above raw material powder, the blended powder is preliminarily sintered, followed by pulverizing of obtained preliminarily sintered power and the substantive sintering is performed after the pulverization. A temperature of preliminary sintering is preferably higher than a temperature of the substantive sintering by 300° C. or more.
[0015] In the present invention, a molar ratio of elements of a hexagonal ferrite, which is a compositional ratio of the raw material powder obtained by blending, is preferably A: Co+Cu:Fe:O=1 to 6:1 to 6:30 to 38:57 to 60.
[0016] A limited aspect of the production process of the present invention includes: a step of blending raw material powder so as to take the composition of a hexagonal ferrite including: at least one kind of an element A selected from the group consisting of Ba, Sr and Ca; Co and Cu; Fe; and O, wherein a molar ratio of elements of the hexagonal ferrite composition is A:Co+Cu:Fe:O=1 to 6:1 to 6:30 to 38:57 to 60; a step of preliminarily sintering the raw material powder after blending, and pulverizing obtained preliminarily sintered powder; and a step of sintering the pulverized powder at a temperature lower than 1000° C., wherein a temperature of the preliminarily sintering is higher than a temperature of the sintering by 300° C. or more.
[0017] A magnetic material of the present invention is an oxide magnetic material produced by the production process of the present invention described above.
[0018] A magnetic material of the present invention has a feature that a real part μ′ of a complex magnetic permeability is larger than an imaginary part μ″ thereof at 1 GHz. Therefore, in an oxide magnetic material of the present invention, a loss can be suppressed in a region up to a high-frequency band beyond the Snoek limit.
[0019] Furthermore, a magnetic material of the present invention has a feature that in the magnetic material, there are included particles each of 10 μm or more in diameter and particles each of 1 μm or less in diameter in a mixed condition. The particles each of 1 μm or less in diameter are preferably present in the amount of 10 vol. % or more. Further, a mean diameter of the particles each of more than 1 μm in diameter is preferably 10 μm or more. In the present invention, a diameter of the magnetic material can be measured under observation by an electron microscope.
[0020] In the present invention, Cu is included as an element substituting Co. A degree of substitution of Co with Cu is preferably in the range of from 20 to 80 atomic %.
[0021] A limited aspect of a magnetic material of the present invention has a feature that the magnetic material includes particles each of 10 μm or more in diameter and particles each of 1 μm or less in diameter in a mixed condition.
BRIEF DESCRIPTION OF THE DRAWINGS
[0022] [0022]FIG. 1 is a photograph taken with a scanning electron microscope (with a magnification of×1000) showing a sectional view of a molded body obtained in an example of the present invention;
[0023] [0023]FIG. 2 is a photograph taken with a scanning electron microscope (with a magnification of×1000) showing a sectional view of a molded body obtained in a comparative example;
[0024] [0024]FIG. 3 is a photograph taken with a scanning electron microscope (with a magnification of×1000) showing a sectional view of a molded body obtained in another comparative example;
[0025] [0025]FIG. 4 is a schematic view showing an oxide magnetic material of the present invention;
[0026] [0026]FIG. 5 is a graph showing frequency characteristics of an oxide magnetic material obtained in the example of the present invention;
[0027] [0027]FIG. 6 is a graph showing a relationship between a sintering temperature and magnetic permeability;
[0028] [0028]FIG. 7 is a perspective view showing an example of stacked composite device;
[0029] [0029]FIG. 8 is an exploded, perspective view showing the example of stacked composite device;
[0030] [0030]FIG. 9 is a graph showing frequency characteristics of magnetic permeability of a prior art magnetic material (a NiCuZn base ferrite).
[0031] [0031]FIG. 10 is a graph showing magnetic permeability of each oxide magnetic material obtained when a sintering temperature is 900° C. and a preliminarily sintering temperature is varied in the range of 900° C. to 1300° C.
DESCRIPTION OF THE PREFERRED EMBODIMENTS
[0032] Hereinafter, the present invention is described in more detail by reference to the Examples, which are not intended to limit the scope of the present invention.
[0033] (Experiment 1)
[0034] Raw material powders of BaO, CoO, CuO and Fe 2 O 3 all with high purity were weighed so as to be 18, 6, 6 and 70 mol %, in terms of BaO, CoO, CuO and Fe 2 O 3 , respectively and then blended and pulverized with a ball mill using a pot and balls made of zirconia for 24 hours. Thereafter, the blended powder was preliminarily sintered at 1300° C. for 2 hours and the obtained preliminary sintered powder was further pulverized with a ball mill using a pot and balls made of zirconia for 24 hours.
[0035] A half of the powder of the oxide magnetic material obtained in a way described above was put into the ball mill together with a PVA base binder and an organic solvent and blended for 24 hours in a wet condition. Added amounts of the PVA-base binder and the organic solvent were 4 parts by weight and 50 parts by weight, respectively, relative to 100 parts by weight of the magnetic material powder. Thereafter, the wet blended powder was dried and screened to be molded into a ring-shaped body of 8 mm in outer diameter, 4 mm in inner diameter and 2 mm in height. The molded body was sintered at 900° C. for 2 hours. The obtained ring-shaped sample was subjected to measurement on magnetic permeability with an impedance analyzer.
[0036] [0036]FIG. 5 is a graph showing measurment results of magnetic permeability. In FIG. 5, values of magnetic permeability are normalized with an initial magnetic permeability of NiCuZn base spinel ferrite (a real part μ′ of magnetic permeability at 10 MHz) as 1. In an oxide magnetic material obtained according to the present invention, as shown in FIG. 5, a real part μ′ of magnetic permeability takes a high values in a region up to as high as 1 GHz (1000 MHz). Furthermore, it is understood that an imaginary part μ″ of magnetic permeability shows almost no increase in a region up to as high as a value in the vicinity of 1 GHZ (1000 MHz). Therefore, it is understood the oxide magnetic material in this example can be used in the GHz band.
[0037] The magnetic material in the obtained molded body was confirmed to be hexagonal ferrites of the Y type structure (Ba 2 CoCuFe 12 O 22 ) and the Z type structure (Ba 3 CoCuFe 24 O 41 ) as the result of the X-ray diffraction analysis.
[0038] Furthermore, a section of the obtained molded body was observed with a scanning electron microscope (SEM). In FIG. 1, there is shown a photograph taken with the scanning electron microscope (with a magnification of×1000) at this time. As can be seen from the photograph of FIG. 1, fine particles each of 1 μm or less in diameter are present in a mixed condition among planar particles each of about 30 μm in diameter. The particles each of 1 μm or less in diameter are present in the amount of about 15 vol. %.
[0039] For comparison, sintering of ring-shaped bodies were performed at 1000° C., 1100° C., 1200° C. and 1300° C. as a sintering temperature to obtain molded bodies. In each sintering, the temperature was held for 2 hours. Magnetic permeability of the obtained molded bodies was measured using the impedance analyzer in a similar way to the case described above.
[0040] [0040]FIG. 6 is a graph showing a real part μ′ of magnetic permeability at 1 GHz (1000 MHz) of each of the molded bodies. Note that the values of μ′ are normalized values in a similar way to those in FIG. 5.
[0041] As is clear from FIG. 6, it is understood that the molded body sintered at 900° C. according to the present invention shows magnetic permeability value at almost the same level as the molded body sintered at 1300° C.
[0042] Observation with SEM was performed on molded bodies sintered at temperatures of 1100° C. and 1300° C. in a similar way to the cases described above.
[0043] [0043]FIG. 2 shows a sectional view of the molded body sintered at 1100° C. and FIG. 3 shows a sectional view of the molded body sintered at 1300° C. Magnifications of photographs are both at×1000. As are clear from FIGS. 2 and 3, no presence of fine particles each of 1 μm or less in diameter are recognized in any of the molded bodies sintered at 1100° C. and 1300° C. From this fact, it is considered that in an oxide magnetic material of the present invention, a good high-frequency characteristic is achieved by the presence in a mixed condition of fine particles each of 1 μm or less in diameter.
[0044] [0044]FIG. 4 is a schematic view showing a state shown in the SEM photograph of FIG. 1. In an oxide magnetic material of the present invention, as shown in FIG. 4, it is considered that magnetic loss in high frequency is reduced by the presence of fine particles 2 each of 1 μm or less in diameter together with particles 1 larger in diameter.
[0045] The remaining half of the above obtained oxide magnetic material powder was added with a PVA base binder together with an organic solvent so that a content of the PVA base binder is 5 wt. %, followed by blending in a ball mill to prepare a slurry. With the slurry, green sheets each of a desired thickness were formed by means of a doctor blade. An Ag paste was printed on each of the green sheets by a printing method to form a desired passive circuit. The plural green sheets were stacked with each other and pressed by a hydraulic press, followed by a main sintering at 900° C. to prepare a stacked inductor. The obtained stacked inductor was confirmed to have a good high-frequency characteristic.
[0046] (Experiment 2)
[0047] Powder of oxide magnetic material was prepared similarly to the procedure in Experiment 1 except that the blended powder was preliminarily sintered at 900° C., 1000° C., 1100° C., 1200° C., or 1300° C. Each obtained powder was molded into a ring-shaped body, which was then sintered at 900° C. for 2 hours to obtain a ring-shaped sample, similarly to the procedure in Experiment 1. The preliminarily sintering was kept for 2 hours similarly to Experiment 1.
[0048] The obtained ring-shaped sample was subjected to measurement on magnetic permeability with an impedance analyzer.
[0049] [0049]FIG. 10 is a graph showing measurment results of magnetic permeability. In FIG. 10, values of magnetic permeability are normalized with an initial magnetic permeability of NiCuZn base spinel ferrite as 1.
[0050] As seen from FIG. 10, preliminarily sintering at a temperature of 1200° C. or more provides the improvement in a real part of magnetic permeability. Accordingly, it is understood that a temperature of preliminarily sintering is preferably higher than a temperature of the subsequent sintering by 300° C. or more.
[0051] A section of each molded body was observed with a scanning electron microscope to measure a mean diameter of the particles each of more than 1 μm in diameter. The measurement results are shown in Table 1.
TABLE 1 Preliminarily Sintering Mean Diameter of Particles of Temperature (° C.) more than 1 μm in Diameter (μm) 900 6 1000 6 1100 8 1200 12 1300 30
[0052] As seen from Table 1, when sintered at 1200° C. or 1300° C., a mean diameter of the particles each of more than 1 μm in diameter is 10 μm or more. Accordingly, it is understood that a mean diameter of the particles each of more than 1 μm in diameter is preferably 10 μm or more.
[0053] Further, the volume ratio of the particles each of 1 μm or less in diameter relative to the whole particles was measured in each molded body. The measurement results are shown in Table 2.
TABLE 2 Preliminarily Sintering Volume Ratio of Particles of 1 μm Temperature (° C.) or less in Diameter (vol. %) 900 18 1000 14 1100 12 1200 11 1300 15
[0054] As seen from the results shown in Table 1, in any cases, the particles each of 1 μm or less in diameter are present in the amount of 10 vol. % or more.
[0055] In the above examples, while an oxide magnetic material of the present invention is blended with a binder, followed by molding, magnetic material powder may be mixed with resin or the like, followed by molding to obtain a magnetic body.
[0056] Furthermore, a glass component such as borosilicate glass or a low melting point oxide such as Bi 2 O 3 may also be added into an oxide magnetic material of the present invention.
[0057] According to a production process of the present invention, there can be produced an oxide magnetic material, which is a hexgonal ferrite, small in loss in a high-frequency band at a low sintering temperature. Accordingly, there can be provided an oxide magnetic material, small in loss in the GHz band, capable of being sintered in the co-existence of a conductor of Ag, Cu or the like. Therefore, an oxide magnetic material of the present invention is suitable for application to a stacked composite device, a stacked inductor, an LC filter, an RF module and others.
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A production process for an oxide magnetic material comprising the steps of blending raw material powder so as to take the composition of a hexagonal ferrite including: at least one kind of an element A selected from the group consisting of Ba, Sr and Ca; Co and Cu; Fe; and O; and sintering said blended powder at a temperature lower than 1000° C.
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[0001] The invention pertains to machines for brewing and dispensing espresso drinks. In particular, the invention is an apparatus and associated method for controlling, automating, and duplicating the brewing conditions for multiple doses of espresso.
[0002] Machines for preparing espresso drinks in a commercial retail environment are well known. In general, these espresso machines include a heating source for generating steam and hot water in a reservoir, a basket for holding ground espresso, and a dispensing spout. There are several increasingly sophisticated means of controlling the flow of the hot water through the espresso, out the spout, and into the cup. Perhaps the simplest means is a manually-controlled valve which is opened to permit a pressurized flow of hot water through the grounds and out the spout into a cup below. More modern machines, such as the Hydra™ espresso machine manufactured by Synesso Incorporated of Seattle Wash., incorporate computer control of the valve. The operator of such machines either presses a button or operates a toggle switch, sensed by the computer to control the valve. Some espresso machines fully automate the brewing sequence, such that a single operation of the button provides a precise dose of water through the grounds, with attendant precise control of the water temperature and driving pressure. Commercial machines may include several dispensing heads.
[0003] A commercial establishment for preparing and selling espresso drinks faces several inter-related problems, each of which is influenced by the particular espresso machine that the establishment has chosen to adopt. The first problem is one of reliability and robustness of the espresso machine. Because it is often a primary source of business revenue, the espresso machine must enjoy high operational uptime, despite a large number of operations involving high temperature water, pressure, and steam. Electro-mechanical parts, such as switches, potentiometers, and rheostats, are particularly susceptible to failure simply because the user is operating them constantly.
[0004] The second problem is serviceability of the espresso machine. Because existing machines have become relatively complex, the electromechanical parts such as those described above are difficult to service. Such operating parts must be protected from physical and environmental damage. Thus, the parts are usually sealed within the machine and are difficult to access.
[0005] In addition, electromechanical parts used in existing machines, such as roller switches, reed switches, etc. involve springs and other parts which degrade or change characteristics over time. Such parts, even if they don't fail, often require physical calibration for the machine to operate properly. One such prior art part is a roller or reed switch connected to a user handle, or wand, for initiating an espresso “shot”. After a large number of operations, the roller or reed switch can unexpectedly break or otherwise lose its spring action and become inoperable. Such a breakdown is intolerable in a busy commercial environment, and so the switch must be routinely inspected, serviced, and calibrated. Another problem pertaining to reed switches in espresso machines is the difficulty of ensuring accuracy and consistency of operation across each of the manufactured machines. Most existing reed switches require calibration at the factory prior to shipping due to the variation in the reed switch manufacturing tolerances. Calibration of reed switches is especially critical for machines which use systems of reed switches that operate together to perform certain linear or proportional functions.
[0006] Another problem with existing espresso machines is that the operating mechanism that is available to the user is largely limited to an on/off switch or button. The competing problem to simplifying the operation for employees also serves to limit the ability of them to vary the espresso making process to account for changes in the coffee. The taste of the final espresso product can vary significantly with the type of coffee, the grind, and the age of the coffee, for example. Current machines have very limited capability for the experienced user to adjust the brew on the fly to account for these changes.
[0007] The inventors have recognized these problems in the prior art, and have arrived at a novel and ingenious solution. An improved manually operated control mechanism for an espresso machine is described here which incorporates a non-contact sensor for detecting the operating input from the user. This control mechanism is referred to as a group control head because in general the mechanism will be co-located with its respective espresso dispensing head. The sensor also has a capability for analog sensing of the input, so that an experienced user can vary the brewing process on the fly, and without the need for time-consuming programming or process set-up. The inventive group head control mechanism requires no calibration, is more reliable, and requires less servicing than prior art mechanisms. Thus, the invention simultaneously provides for a better coffee brew and increased product throughput.
[0008] In accordance with the principles of the present invention, an improved espresso brewing apparatus is described which incorporates a non-contact operating mechanism within its user control interface. The apparatus includes a novel and inventive group control head. The group head has a control handle or paddle which is connected to a magnet. When the control handle and magnet is rotated to a first position, a non-contact sensor such as a linear/proportional Hall Effect sensor senses the rotation. The sensor then provides a corresponding control input to the espresso machine dosing mechanism which may include a controller. A centering post in the mechanism provides an opposing biasing force on the magnet that returns the control handle to an idle position when the handle is released.
[0009] Also in accordance with the principles of the present invention, a group control head for dispensing a controlled dose of espresso from an espresso machine is described which comprises a base having a center axis, a top plate rigidly fixed to the base, the top plate comprising a pivot pin disposed on the center axis. The group head also includes a centering post disposed at a radial idle position offset orthogonally from the center axis, and at least one proximity sensor, such as a linear/proportional Hall Effect sensor disposed at a fixed angle from the radial idle position. An actuator is rotationally disposed on the pivot pin, the actuator including a magnet which is disposed near the radial idle position and adjacent to the centering post. A handle is affixed to the actuator. The handle is disposed to manually rotate the actuator away from the radial idle position in which the magnet is adjacent to the centering, wherein the centering post and magnet provide a biasing force that biases the actuator position to automatically return the actuator to the radial idle position. A second proximity sensor at a second fixed angle can be included to provide further operative utility.
[0010] Also in accordance with the principles of the present invention, an espresso machine which incorporates the above described group control head is described. The espresso machine also comprises an espresso dosing unit which includes a pressurized hot water brew tank, a filter for holding coffee grounds, a control valve disposed between the brew tank and the filter, and an outlet spout. A pump is disposed at an inlet of the brew tank. The machine also includes a controller that is in electrical communication with an input signal from the group control head and in controlling communication with the control valve and the pump. An actuation of the group control head handle actuates at least one of the controller, the pump and the control valve to provide a controlled dose of hot water from the source to the spout. Also in accordance with the principles of the present invention, a method is described for using the espresso machine as previously described. The method includes the steps of momentarily actuating the group head handle to an angular brew position and automatically controlling both of the pump and the valve to provide a controlled dose of hot water through the machine. A second actuation can control or stop the ongoing programmed sequence.
[0011] As used herein for purposes of the present disclosure, the term “processor” or “controller” is used generally to describe various apparatus relating to the operation of the inventive apparatus, system, or method. A processor can be implemented in numerous ways (e.g. such as with dedicated hardware) to perform various functions discussed herein. A processor is also one example of a controller which employs one or more microprocessors that may be programmed using software (e.g. microcode) to perform various functions discussed herein. A controller may be implemented with or without employing a processor, and may also be implemented as a combination of dedicated hardware to perform some functions and a processor (e.g., one or more programmed microprocessors and associated circuitry) to perform other functions. Examples of controller components that may be employed in various embodiments of the present disclosure include, but are not limited to, conventional microprocessors, application specific integrated circuits (ASICs), and field-programmable gate arrays (FPGAs).
[0012] It is understood that the term “memory” refers to computer storage memory of types generally known in the art. Memory may be volatile or non-volatile computer memory such as RAM, PROM, EPROM, and EEPROM, floppy disks, compact disks, optical disks, magnetic tape, etc. In some implementations the computer memory media may be encoded with one or more programs that, when executed on the one or more processors and controllers, perform at least some of the functions discussed herein. Various storage media may be fixed within a processor or controller or may be transportable, such that the one or more programs stored thereon can be loaded into a processor or controller so as to implement various aspects of the present invention. The terms “program” or “computer program” are used herein in a generic sense to refer to any type of computer code (e.g. software or microcode) that can be employed to program one or more processors or controllers.
[0013] In various implementations, there terms “outputs”, “inputs”, “signals”, and the like may be understood to be electrical or optical energy impulses which represent a particular detection or processing result.
IN THE DRAWINGS
[0014] FIG. 1 illustrates an embodiment of an espresso machine according to the present invention.
[0015] FIG. 2 illustrates the plumbing system of the FIG. 1 espresso machine.
[0016] FIG. 3 illustrates an exploded diagram of one embodiment of the inventive group control head.
[0017] FIGS. 4( a ), 4( b ) and 4( c ) illustrate the operation of the FIG. 3 group control head.
[0018] FIG. 5 is a system block diagram of one embodiment of the electrical sensing and control circuit.
[0019] FIG. 6( a ) and FIG. 6( b ) illustrate two embodiments of a visual display for the espresso machine of the present invention.
[0020] FIG. 7 illustrates a brewing sequence for the espresso machine.
[0021] FIG. 8 illustrates an embodiment of an inventive method for operating the espresso machine of the present invention.
[0022] FIG. 9 illustrates a flow chart method for saving and retrieving a set of brew parameters in the espresso machine.
[0023] FIG. 10 is a state machine diagram for a simplified method of saving a set of brew parameters to the espresso machine.
[0024] FIGS. 11( a ), 11( b ), 11( c ), and 11( d ) illustrate a set of state machine diagrams for a various operating modes of the espresso machine.
[0025] FIG. 12 illustrates a visual display for saving a set of brew parameters from one dosing unit to other dosing units in the espresso machine.
[0026] FIG. 13 illustrates a more detailed view of an external programming controller for the espresso machine.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
Espresso Machine Including Improved Non-contact Group Control Head
[0027] Now turning to the illustrations, FIG. 1 shows an espresso machine of the present invention. Espresso machine 100 includes an espresso dosing unit 102 having at least one group control head 110 which controls the operation of the machine to provide an espresso dose. Espresso machine 100 includes an internal source of water and steam pressure. Each dose of espresso is dispensed from a brew tank 150 at the outlet of the water source. Brew tank 150 is sized to contain hot water under pressure with enough volume, for example about 1.9 liters, for one or more doses of espresso. Typically, brew tank 150 includes a heating element to maintain the water temperature at an optimal temperature for brewing.
[0028] At the outlet of brew tank 150 is a filter 160 for holding ground coffee. Filter 160 is sized to hold enough tamped-in grounds for one dose of espresso. Filter 160 is of course removable so that coffee grounds can be replaced after each use. At the outlet of filter 160 is an outlet spout 170 for guiding the dispensed dose of espresso into a cup, not shown, held or placed below the spout. For the purposes of this description, an espresso dosing unit 102 is generally understood to include at minimum the brew tank 150 , filter 160 and outlet spout 170 .
[0029] Many commercial espresso machines include a visual display 180 disposed on the group control head 110 , or on the machine 100 adjacent the dosing unit or group control head. Visual display 180 can display basic shot parameters such as time to completion, dose size, and the like. Because of the need for quick and efficient dosing of espresso shots in commercial settings, it is important that the information provided on visual display 180 is kept as simple, clear and as uncluttered with unneeded data as possible.
[0030] It may be noted that the type of grounds placed in the filter 160 may vary. The harvested source and variety of coffee, the texture of the grind, and the age of the coffee grounds affect the taste of the final product in several ways. The coffee variation may affect the tamp of the grounds in the filter 160 and the resulting pressure differential between the brew tank and the spout. The coffee variation also affects the interaction between the grounds and the hot water flowing through them. Each of these factors changes the taste of the dosed espresso. An experienced user desiring to optimize taste needs the ability to vary properties of the brew to account for these variations.
[0031] The espresso machine of FIG. 1 also illustrates additional dosing units which include additional group control heads such as second group control head 110 ′ and third group control head 110 ″. The additional dosing units allow for increased throughput of espresso drinks. Each of the additional dosing units may also include dedicated visual displays such as shown in FIG. 1 at second visual display 180 ′ and third visual display 180 ″. The number of dosing units is not important to the invention.
[0032] Any of the optional dosing units may be pre-programmed using an optional external programming controller 190 . Default brew parameters such dispensing temperature, dose size, and applied pressure profile may be entered via programming controller 190 . With reference to FIG. 13 , programming controller 190 includes a programmer display 192 , which may display text related to a current state of the selected dosing unit or may display text related to a programmed brewing sequence parameter. User selection of the text to be viewed on the controller 190 may be selected via one or more programmer selection buttons 194 disposed next to the corresponding text line, or may be selected via a set of up-and-down programmer scrolling arrows 196 . Adjustment of parameters may be entered via the scrolling arrows 196 . Other user interfaces such as keyboards, touch pad screens, and the like may be used as well for these functions.
[0033] It should be noted that efficient use of controller 190 may entail a more advanced operating skill, and may distract from the ongoing dosing unit operation. Thus, use of programming controller 190 may be generally more desirable during business idle time or downtime.
[0034] Now referring to FIG. 2 , a plumbing arrangement 200 that may be incorporated within the FIG. 1 espresso machine is shown. A single steam tank 202 is generally located within the main housing of the espresso machine, heated to provide a constant temperature and pressure steam source that is commonly used for foaming milk and the like. An external water source 210 , such as from building plumbing, and associated valve arrangement provides fill water for the steam tank 202 . The water source 210 is also used by a pump 204 as a source of water to brew tank 250 and optional brew tanks 250 ′ and 250 ″. Pump 204 may also operate under computer control to control or vary the pressure in brew tank 250 and consequently the pressure profile across the coffee grounds in the filter 260 as the shot is flowing. An optional bypass control valve 208 and associated plumbing from the pump 204 discharge, i.e. between brew tank 250 and pump, back to the pump 204 suction is also shown. Computer control may operate the optional bypass control valve 208 during the pump operation to establish a time-pressure profile across the filter by diverting the high pressure pump water away from the operating brew group.
[0035] As can be seen in FIG. 2 , flow of pressurized water from pump 204 to brew tank 250 may pass through the steam tank 202 . This feature permits feed water to be pre-heated before entering the brew tank 250 , which makes temperature control at the brew group more precise.
[0036] Brew tank 250 holds pressurized hot water that is ready for dispensing through the filter 260 . Brew tank 250 typically includes a heating element for continued precise temperature control, as well as a temperature sensor and an optional pressure sensor. Brew tank 250 or the dedicated plumbing leading to it may also include a flowmeter.
[0037] Control valve 206 starts and stops the pressurized hot water flow from brew tank 250 through filter 260 through the outlet spout 170 . In a preferred embodiment, control valve 206 is operated under control of an automated controller, which in turn operates responsive to an actuation signal input from the group control head. Control valve 206 under such control thus provides a controlled volume output of the shot.
[0038] If control valve 206 is opened without the pump 204 operating, a reduced flow through the brew tank still occurs. This state is useful at the beginning of a brew to pre-infuse dry coffee grounds with hot water before pumped flow begins. This state may also be useful at the end of the brew to avoid excessive “blonding” of the flow as the grounds are expended. The time between the stopping of the pump and final closing of the control valve establishes a low pressure finish. The value of the low pressure finish may be a percentage of the pumped flow volume to the total flow volume of the brew shot.
[0039] FIG. 3 illustrates an exploded diagram of a preferred embodiment of a group control head 300 assembly according to the present invention. The assembly is mounted to the espresso machine 100 via a base 302 . Base 302 may be generally cylindrically shaped with a center axis disposed in the vertical plane. Base 302 may optionally be part of brew tank 250 , and may include a shroud surrounding the lower vertical portion.
[0040] A top plate 324 is disposed on base 302 . Top plate 324 comprises a pivot pin 325 centered on the center axis. Pivot pin 325 is arranged to provide a rotational axis for an actuator 340 . In addition, a centering post 350 is disposed at a radial idle position on the top plate 324 , the post arranged orthogonally from the vertical center axis. Preferably, centering post 350 is disposed near an edge of top plate 324 . Centering post 350 is preferably constructed of a ferrous material that is magnetically attractive to a magnet.
[0041] Actuator 340 is disposed on top plate 325 at pivot pin 325 . Actuator 340 includes a mounting arm, at the end of which a magnet 342 is disposed. The arrangement of actuator 340 on top plate 325 is such that magnet 342 rests adjacent to but not touching center post 350 . Actuator 340 is also free to rotate about pivot pin 325 but is held in an idle position 400 , FIG. 4 , by the magnetic force between magnet and post. This biasing force opposes any rotational force which rotates the actuator 340 , and causes the actuator to return to the radial idle position when the rotational force is removed. This holding feature thus serves as an automatic centering feature.
[0042] Affixed to top plate 324 is at least one proximity sensor 375 which is operable to sense a position of the magnet 342 with respect to the sensor. Proximity sensor 375 is disposed at a fixed angle away from the radial idle position. When an actuating force rotates the actuator magnet 342 away from the idle position, magnet 342 is positioned near sensor 375 . An optional second proximity sensor 376 may be disposed at a second fixed angle from the radial idle position. The second fixed angle may be the opposite angle from the radial idle position. Similarly, when an actuating force rotates the actuator magnet 342 in the opposite direction away from the idle position, magnet 342 is positioned near and is detected by sensor 376 .
[0043] Proximity sensors 375 , 376 are preferably arranged on a proximity sensor board 374 which is held in fixed position above top plate 324 and actuator magnet 342 . Magnet 342 is thus free to rotate under the proximity sensor board. In addition, a preferred arrangement is of a single magnet 342 which serves as both an automatic centering magnet and a positioning source to be detected. The arrangement is simpler and requires fewer parts. Of course, the particular arrangement of magnet to sensor(s) may be modified within the scope of the invention.
[0044] A preferred type of proximity sensor 375 , 376 is a linear type Hall Effect sensor. Such a sensor is commonly understood to provide an analogue output which corresponds to the relative position of a magnet. One advantage of a Hall Effect sensor is that it is non-contact and so has no parts to wear out. The Hall Effect sensor requires minimal periodic adjustment or calibration, and optionally could be used with a comparator to provide a more precise positioning over a large number of cycles.
[0045] Importantly, the Hall Effect sensor provides an analogue output that contains more than a simple binary actuation signal or pattern of binary signals. The sensor can provide a signal input to a device controller which is representative of the magnitude of the magnet movement, the velocity of relative movement, and the duration of a held magnet rotation. Thus, the Hall Effect sensor provides the user with a more precise and useful control of the group head.
[0046] The user interface portion of the FIG. 3 group control head is a rotational handle 314 , which is fixed by screws or other means to actuator 340 . The handle 314 may comprise a protective shell which fits over the top plate 324 , actuator 340 and the arrangement of sensors 375 , 376 . A paddle 316 is preferably disposed on handle 314 extending away from the protective shell and in such a manner as to provide easy rotational actuation of the group control head.
[0047] In operation, the user experiences a resistive force not unlike a spring force when she rotates the paddle. When the paddle is released, the entire group head control assembly returns to the idle position due to the attraction of magnet and post.
[0048] FIGS. 4( a ), 4( b ) and 4( c ) illustrate the operation of the FIG. 3 group control head 300 , wherein magnet 342 may be positioned over an arc in proximity to, but not in contact with, at least one proximity sensor. At rest, the group control head is automatically centered and held in the idle position 400 as shown in FIG. 4( a ) . The magnetic attraction between magnet 342 and post 350 provides the holding force. The output of proximity sensor 375 and/or optional sensor 376 indicates that the magnet 342 is in the idle position 400 .
[0049] FIG. 4( b ) shows the group control head 300 in a brew position 410 . Here, the user has rotated paddle 316 in the clockwise, or left, direction such that proximity sensor 375 senses the proximity of magnet 342 . The user also experiences a counterclockwise resistive force not unlike a spring force when she rotates the paddle 316 , due to the ongoing attraction between displaced magnet 342 and post 350 . The attraction repositions the actuator 342 to the idle position 400 when the paddle 316 is released. The effect of the paddle rotation of FIG. 4( b ) is to send an input signal corresponding to the sensed magnet position to a controller. The controller in turn may begin a programmed sequence of outputs to the espresso machine to dispense a shot of coffee.
[0050] FIG. 4( c ) illustrates an optional control position 420 of the group control head 300 corresponding to a counterclockwise, or right, rotation of paddle 316 . Second proximity sensor 376 senses the proximity of magnet 342 . The user also experiences a clockwise counter-force not unlike a spring force when she rotates the paddle 316 , due to the ongoing attraction between displaced magnet 342 and post 350 . The attraction repositions the actuator 342 to the idle position 400 when the paddle 316 is released. The effect of the paddle rotation of FIG. 4( c ) is to send a second input signal corresponding to the sensed magnet position to a controller. The controller in turn may perform an auxiliary action, such as ending an ongoing shot.
[0051] The user of course experiences the above described group control head 300 as having one actuator which has a clockwise, or left, paddle position and a counter-clockwise, or right, paddle position. As will be further described, actuations of short duration and longer duration may provide different responses in the machine control. A short duration actuation may be referred to as a “bump”, while longer duration actuations may be referred to as a “hold” or a “long hold.” A bump may be, for example, a paddle rotation and release lasting less than 250 milliseconds. An example hold may be from greater than 250 milliseconds up to greater than about 2.5 seconds.
[0052] FIG. 5 illustrates a system block diagram of one embodiment of the electrical sensing and control circuit for an espresso machine electrical system 500 . The electrical system 500 can be arranged on a single central printed circuit board or may be distributed among several sub-units. For example, FIG. 5 shows one hardware controller 510 , but system 500 could equivalently include a separate controller 510 disposed on each group control head in the apparatus. Either the single visual display 520 as shown or a display 520 dedicated to each separate group control head may be used to convey status information. A power supply 540 provides electrical power to the system 500 .
[0053] The heart of system 500 is controller 510 , which can be any of a known CPU or other computer processing unit such as an application specific integrated circuit (ASIC), field programmable gate array (FPGA), or reduced instruction set computing (RISC) type. Controller 510 operates to control the espresso brewing process in response to various inputs. Controller 510 may also operate in accordance with a computer program stored in a computer memory 530 . Controller 510 and the computer program then provide a repeatable and coordinated sequence of outputs that generate a controlled dose of espresso. Controller 510 may also be arranged in a programming mode to accept programming instructions from external programming controller 190 and to store those instructions in memory 530 for later use. Similarly, controller 510 may provide a program control data set point or parameter from a user interface to memory 530 . Controller 510 may also provide output to a visual display 520 that is located near the respective group control head such that important operating status information can be seen at a glance.
[0054] Also shown in FIG. 5 is that memory 530 is preferably apportioned into several parts. A first part is the computer temporary brew memory 532 , which as will be described saves parameters related to the current brewing process. The temporary brew memory essentially contains a set of brewing parameters established at the last brew. For example, if the user shortens a pre-infusion period by actuating the group control head handle, that new pre-infusion duration is captured in the temporary brew memory. Each dosing unit has its own temporary brew memory.
[0055] Another part of memory 530 comprises a computer storage memory 534 for storing previously saved complete sets of brewing parameters. The portions may be arranged in pages, with a left portion and a right portion for each page. In one embodiment, each dosing unit is provided with from one to three pages. More preferably, computer storage memory 534 comprises at least two storage locations, without any paging arrangement. Shown in FIG. 5 is an exemplary embodiment of storage memory 534 having six storage locations 541 through 546 . Each portion or storage location is sized to contain one set of brewing parameters. Each dosing unit has its own computer storage memory 534 .
[0056] Outputs from each group head are provided as inputs to controller 510 . Examples of inputs are a group head water flow meter 502 and a brew tank temperature sensor 504 . Controller 510 may use these inputs to start or stop the brew program or to otherwise control various heating and pumping components. Controller 510 preferably operates under the further control of an internal clock or timer to shift between various phases of the brew process.
[0057] Controller 510 also accepts signal inputs from each respective group control head 300 via proximity sensor outputs 375 , 376 . The accepted signal inputs control the program sequence that provides the espresso dose. An example is a received input from non-contact proximity sensor 375 that corresponds to a single actuation of the group control head handle. Controller 510 then issues a coordinated program sequence of output instructions to provide the dose. The outputs can be one or more of a pump control output 522 , a control valve control output 524 , and a bypass valve output 526 .
[0058] A second input control example is a received signal input from the second non-contact proximity sensor 376 that corresponds to a different single actuation of the group control head handle. Controller 510 responsively issues an output to one or more of a pump control output 522 , a control valve control output 524 , and a bypass valve output 526 to, for example, immediately end the controlled dose.
[0059] FIG. 6( a ) and FIG. 6( b ) illustrate two embodiments of the information provided on the optional visual display 180 for the espresso machine of the present invention. The displayed information provides the user with the current status of the machine and group control head guidance instructions with simple indications.
[0060] FIG. 6( a ) shows an operational display 600 provided during normal operation or during a programmed brewing sequence. The most prominent feature of this display is a shot timer 602 . Shot timer 602 will typically display the total duration of the shot, e.g. 32 seconds, during idle times between brews. During the brew sequence, shot timer 602 preferably displays the elapsed time from the start of the shot, although similar indications of shot progression such as count-down time or time from the start of a particular sequence phase are included within the scope of this invention.
[0061] Mode icon 604 shows the espresso machine mode of operation, which may include a manual mode, a manual program or a volumetric program mode. Here shown on icon 604 is the volumetric program mode icon VP. An espresso machine operating in volumetric program mode is typically controlled on a flow basis as sensed by the flow meter. An espresso machine operating in manual program mode MP is typically controlled by the sequence timer with some control by the user. Manual mode M is typically a mode of operation under full control by the user.
[0062] Phase icon 606 indicates a relative duration of each phase of the brewing sequence. The phases will be described in more detail with reference to FIG. 7 . The embodiment shown uses simple bar graphs to display the relative length of each of three phases.
[0063] Memory storage location icon 608 shows the memory portion of computer storage memory 534 that is currently selected for use. Here, icon 608 is a dot which points to a first memory storage location. Additional storage location icons, if available, may be arrayed below icon 608 or along the right border of display 600 . If the storage memory location is ready to receive data, a save icon 610 is shown.
[0064] FIG. 6( b ) shows a save mode display 620 that is shown during the transfer of brew parameters between the temporary memory and/or storage memory locations. When in save mode, and when the storage memory location is ready to receive data, one display embodiment incorporates a save left icon 622 and a storage memory cycling icon 624 guides the user to save the current data via a left bump and to select the storage memory for saving by cycling through the locations with one or more right bumps of the group control head respectively. In this case, the “M” mode icon 604 indicates that the saving is being performed from a manual mode of operation.
[0065] FIG. 7 illustrates a brewing sequence 700 for the espresso machine. From an idle state, the sequence is started at start step 702 by the user operating the group control head paddle or by pushing a button. The controller 510 initiates the programmed sequence at step 716 using the currently-selected set of brew parameters and also begins to save brewing data into the temporary memory 532 .
[0066] The brewing phases then begin at a pre-infusion brew phase 717 . During this phase, controller 510 opens the dosing unit control valve 524 , 206 to pre-infuse the dry coffee grounds with unpressurized water from the brew tank 250 . This phase typically begins in response to the same first input signal received from the user at the start step 702 .
[0067] At the end of the pre-infusion phase, an optional pressure ramp up phase 720 begins. The transition from pre-infusion to pressure ramp up may be in response to a programmed sequence time or to a user input from the group control head paddle. Pressure ramp up phase 720 starts the pump 204 and optionally opens the bypass control valve 208 to gradually pressurize the brew tank 250 to drive water through the grounds.
[0068] In response to a programmed sequence time or to a user input from the group control head paddle, a full pressure brew phase 720 begins. During this phase, the bypass control valve is closed and the pump is running to provide maximum shot flow through the grounds.
[0069] Depending on the particular grounds in use, an undesirable “blonding” of the flow may occur as the grounds are used up during the full pressure brew phase 720 . To avoid the effects of blonding, the sequence may then transition to an optional pressure ramp down phase 724 . Like ramp up phase 720 , the pump is running and the bypass control valve is opened to gradually reduce pressure on the grounds. The beginning of this phase may occur in response to a programmed sequence time or to a user input from the group control head paddle.
[0070] A stop shot phase 726 ends the brewing sequence. This phase typically functions to ensure that the precise shot volume is dispensed. Here, the pump is not running but the control valve is still open. The transition into the stop shot phase 726 may be in response to a programmed sequence time or to a user input from the group control head paddle. Similarly, the stop shot phase is ended by closing control valve 524 , 206 when the full dose has been dispensed as sensed by elapsed time, flow meter volume, or by user input. The machine then re-enters an idle mode at end step 727 .
[0071] Shown next to each phase of the sequence is an exemplary operational display 600 on visual display 180 . Shown is the total time of the sequence at the beginning and end as well as the elapsed time during the sequence. Also shown is the Manual Programming MP operating mode and the stored parameter set that is in use. Optionally, display 180 may show a volume dispensed instead of an elapsed time during the brewing phases.
[0072] The above described sequence is driven by a set of parameters or settings which control each phase. For example, the set of parameters may include a pre-infusion time, a low pressure ramp up time, a full pump dispense time, a ramp down time, and a total dose water volume dispensed. Generally, a set can be defined with four parameters. End step 726 , for example, can be defined with the low pressure finish percent, which may be a percent of overall shot time or overall shot volume.
[0073] Method and Apparatus for Optimizing a Set of Brew Parameters
[0074] FIG. 8 illustrates a flow chart for an inventive method of operating the espresso machine of the present invention, and in particular a method 800 for optimizing and storing the conditions for a controlled dose of hot water dispensed from the machine. The method then saves the optimized set of brew parameters for a subsequent use of the espresso machine. Method 800 begins at start step 802 . The method then proceeds to a step 804 of providing the espresso machine apparatus as previously described, including the dosing unit, the group control head 110 , 300 , the pump 204 , the temporary brew memory, and the controller. Providing step 804 may also include the steps of activating the apparatus, initiating the program stored in memory, preheating and pre-pressurizing the system, and/or preparing and installing the grounds filter. After completion of providing step 804 , the espresso machine is ready to dispense espresso, and begins to monitor at the group control head proximity sensor 375 , 376 inputs.
[0075] Step 806 is for monitoring and sensing a momentary actuation or bump of the group control head handle to a particular angular brew position. Step 806 pauses at monitoring sub-step 807 until controller 510 senses an actuation. When an actuation is sensed, another sub-step, mode decision step 808 determines the type of actuation and continues the method accordingly. For example, a sensed bump actuation may send the method into the brew mode 812 , and a long duration actuation may send the method into a programming or saving mode of operation 912 . The saving mode of operation, and its return to the monitoring step 806 will be described in more detail.
[0076] An actuation direction decision step 810 immediately follows step 808 . The direction of actuation, clockwise/left (CW) or counter-clockwise/right (CCW), may cause the method 800 to respond differently depending on whether a shot is brewing at the time of actuation or not, i.e. in an idle state. If no shot is brewing at actuation, as sensed by the controller at shot brewing decision steps 814 and 820 , the direction may determine which of two sets of parameters is used for the subsequent shot, i.e. the set stored in the current computer temporary brew memory or a different set stored in the computer storage memory respective to the CW left or CCW right bump. In a preferred embodiment, a sensed CCW right bump with no shot brewing causes the controller to retrieve the set of brew parameters stored at the next sequential memory storage location 541 - 546 for that group head at cycling step 821 . That set is placed into the temporary brew memory at step 824 . If the CCW right bump is repeated, the brew parameters at the next sequential memory storage location 541 - 546 is retrieved into temporary memory at 821 , and so on. Thus, the operator experiences a cycling of stored recipes on that group head.
[0077] If a CW left bump is sensed while in the idle state, method 800 proceeds to begin the programmed sequence at step 816 according to the selected set of parameters stored from step 824 in the temporary computer brew memory. The programmed brew sequence then begins as described in FIG. 7 with the pre-infusion step 717 of opening the control valve to begin the controlled dose of hot water. Step 816 also initiates a saving into the computer temporary memory of subsequent actuation steps. Then the method 800 returns to the sensing/monitoring step 806 to await the next sensed actuation of the group control head paddle.
[0078] If no further actuations occur, the programmed sequence of FIG. 7 automatically completes itself and delivers a controlled dose in accordance with the selected set of parameters. The set of parameters saved to the temporary brew memory would in this case be identical to the selected set.
[0079] If the selected set of parameters is set to a null manual MAN setting or the mode of operation is in the Manual mode, the method 800 may continue in a completely manual sequence. The sequence still follows the FIG. 7 sequence, but the transition between each phase occurs at an actuation sensing and never at an elapsed time. In an example manual mode operation, the first momentary action of the group control head handle begins the pre-infusion step whereby the control valve is opened and the parameter saving is initiated. The controller would respond to subsequent CW momentary actuations of the handle by repeatedly proceeding along the cycle of step 808 , step 810 , step 814 , a proceed to next shot phase 818 , and a return to step 806 . Thus, the full pressure phase, and/or the optional pressure ramp up or ramp down phase is controlled by the repeated sensed CW actuations at next shot phase 818 . These phases involve starting and running the pump to provide the controlled dose of hot water through the dosing unit. At each phase transition, a parameter related to the duration of each phase is saved into the computer temporary memory at saving step 824 .
[0080] In one embodiment of the completely manual mode, the third actuation of the proceed to next shot phase 818 stops the pump to end the controlled dose of hot water. Optionally, a fourth actuation of the next shot phase 818 closes the control valve at the proper shot dose volume corresponding to end sequence step 726 . The duration of each of these phases is saved into the temporary memory at saving step 824 . The overall saving of these steps thus creates a complete set of brew parameters in memory. The saved set of brew parameters may be used in subsequent programmed brew sequences.
[0081] As can be seen in FIG. 8 , a CCW bump of the group control head handle sensed at step 810 while the shot is brewing as sensed at step 820 always causes the method to immediately proceed to stop shot step 822 . This step 822 stops the pump and closes the control valve to end any further flow through the dosing unit. A user may also perform this actuation if, for example, when the desired brew volume has already been reached but the flow is continuing under the ongoing programmed sequence.
[0082] FIG. 8 also illustrates how the method 800 may be used to dynamically adjust, while operating in the automatic programmed brew sequence mode, a set of parameters that have already been saved in memory. In this situation, the espresso machine is prepared to dispense the next dose using a previously saved set of parameters. When the momentary actuation is repeated and sensed at step 806 , the control valve is re-opened and the controller newly initiates the saving of parameters into the temporary memory. The new programmed brew sequence begins again. If no further actuations are sensed during the brew, then the programmed brew sequence automatically controls the control valve and pump to replicate the previous controlled dose of hot water.
[0083] But if the user desires to adjust, i.e. shorten, one or more of the sequence phases, then she merely again bumps the paddle CW to truncate that phase and immediately start the next phase at step 818 . This action may, for example be a repeat of the third momentary actuation step, which stops the pump and therefore stops the replication. The phase duration as defined by the actuation is saved into the temporary memory as part of a new, i.e. second, set of brew parameters. In one embodiment the saving at step 824 further comprises the step of overwriting the previous set of brew parameters with the second set of parameters in the temporary memory. This second set can then be used for subsequent brews. In a preferred embodiment, adjustment of every brew phase is enabled for Manual mode of operation, and a limited adjustment of only the low pressure finish phase, step 724 of FIG. 7 , is enabled during Manual Program mode of operation.
[0084] A summary of the FIG. 8 operation is illustrated in state table 801 . There shown is the response in the espresso machine corresponding to each particular operation of the group head control handle during the normal, or brew mode of operation.
[0085] The espresso machine apparatus that is previously described may be modified to use the method 800 for storing and adjusting the dosing conditions. In addition, the machine may optionally comprise visual display 180 , which displays the phase of the sequence as the sequence proceeds. After the sequence is complete, the visual display 180 may display an indication that the phases have been saved as a new set of parameters.
Example
[0086] The barista prepares the espresso dosing unit and refreshes the grounds in the filter. She decides to manually brew a shot. The barista bumps the group control head paddle to the left to begin pre-infusion and watches for the first drips to pass the filter basket. Once the basket is saturated, she bumps the paddle left again to add pump pressure. The shot speed begins to increase and the color of the flow begins to lighten toward the end of the shot. She bumps the paddle left again to return to line pressure, then bumps it right to end the shot.
[0087] Example parameters saved into temporary memory for this manual shot are 6.2 seconds pre-infusion and 60 milliliters water volume with a 97% low pressure finish. This set of parameters is now available to save for future replication.
[0088] Of course, if the sequence is not progressing satisfactorily, a bump of the paddle to the right while the shot is in progress immediately ends the shot.
[0089] Method and Apparatus for Saving an Optimized Set of Brew Parameters
[0090] FIG. 9 continues the FIG. 8 method flow, further describing a method 900 for storing brewing parameters in an espresso machine. The method starts when the first sensed actuation of the group control head handle at step 806 enters the machine into a program and save mode of operation 912 . This path is shown by the indicator AP. An example first actuation is a long hold, e.g. greater than 250 milliseconds, to enter this mode.
[0091] Responsive to entering the program and save mode of operation 912 , the current set of brew or shot parameters is obtained from the computer temporary brew memory at step 902 . The visual display 180 corresponding to the dosing unit may begin to flash the save icon 610 at this time to indicate the saving/programming mode of operation. One object of this invention is that this current set of shot parameters can then be assigned to as many computer storage memory locations on as many different group control heads in the system as desired. In addition, the visual display 180 may also begin to indicate the current set of brew parameters. Of course, if the operator desires to store a set of brew parameters that is not currently in the computer temporary brew memory, she may transfer the desired set of parameters from a computer storage location to the temporary brew memory prior to the obtaining step above. Preferably, this is done by selecting the computer storage location with the desired parameters with one or more right bumps from idle, step 821 , and then running that shot with a left bump, step 816 shown in FIG. 8 .
[0092] Also responsive to entering the program and save mode of operation 912 at the first sensed actuation, the controller selects a default or initial computer storage memory location at initial storage memory step 903 . This default computer storage location may be pre-selected to appear each time the save mode is entered, or may simply be the last storage memory location used. If the espresso machine has multiple dosing units, the controller may select a default memory location at each group control head. Preferably, the visual di splay(s) 180 displays the active computer storage memory location at this step. The group control head of the first sensed actuation may optionally display brew parameters from the set in the temporary brew memory or the computer storage memory at the obtaining step.
[0093] Method for Storing Brewing Parameters, Single Dosing Unit
[0094] After entering the save mode of operation 912 , the method proceeds to the step of saving the set of parameters from the last shot brewed, i.e. the parameters in the computer temporary brew memory, into a computer storage memory location. In one simple embodiment, the operator merely bumps the group control head handle to the left, sensed as a second actuation by the controller. The method flow shows the bump sensed as a left actuation at direction step 906 and as a bump at duration step 910 . The left bump causes the controller to save the set of brew parameters into the default or initial storage memory from step 903 .
[0095] The operator may wish to save the set of brew parameters into a different computer storage memory location than the default location. The operator selects a different location by scrolling through the available locations with one or more right bumps of the group control head handle. The controller senses the input at direction step 906 and duration step 911 to scroll to the next available storage memory at step 914 . Step 914 preferably includes the display of the computer storage memory location on visual display 180 , as exemplified in FIG. 6( b ) . A subsequent left bump, steps 906 , 910 saves the set of parameters to the selected location at step 908 . It is preferable that the bumps for scrolling and saving are in opposite directions of the handle, but the particular directions described above may be swapped within the scope of the invention.
[0096] The operator exits the save mode of operation at step 940 and returns to the brew mode of operation. The controller may exit the save mode in several ways, e.g. by a time-out or immediately upon the saving step. Preferably, an affirmative actuation triggers the exit, such as a group head control handle “right hold” actuation, as shown by the path of direction step 906 and as a hold at duration step 911 .
[0097] An additional function may be provided while in the save mode of operation. The controller may cycle to another of a group mode at cycle mode step 909 , e.g. Manual Mode or Manual Program Mode or Volumetric Program Mode, responsive to a sensed left hold from the group control head handle via direction step 906 and duration step 910 . When a set of parameters is subsequently saved, the set will correspond to that particular group mode.
[0098] A summary of the FIG. 9 operation is illustrated in state table 901 . There shown is the response in the espresso machine corresponding to each particular operation of the group head control handle during the program and save mode of operation.
[0099] Transferring a Set of Brew Parameters Between Espresso Dosing Units
[0100] If the espresso machine is a multi-head device having a plurality of previously described espresso dosing units, the machine may be arranged to transfer a desired set of brewing parameters from one of the dosing units to another. In this embodiment, a controller 510 is in communication with all of the group control heads, temporary memories, and storage memories. A visual display is optionally associated with each dosing unit.
[0101] The system is arranged such that when a program and save mode of operation is entered at any of the dosing units, for example by the method flow chart of FIG. 9 , controller 510 activates all of the dosing units for saving.
[0102] FIG. 12 illustrates one embodiment of the group display 1200 . After entering the save mode 900 and obtaining the desired set of brew parameters with one of the group control heads, all of the visual displays 180 , 180 ′, 180 ″ will display a save screen 620 , 620 ′, 620 ″ and a flashing save icon 610 . Any of the other group control heads can be scrolled as described above to select that dosing unit's desired storage location for saving. Then each group control head can separately save the desired set of brew parameters to the selected memory and exit the save mode as described above. Exiting from the save mode alternatively may be accomplished all at once by exiting the save mode, step 940 , at the source group control head.
[0103] After either of the above described transferring steps, a programmed brew sequence may be initiated at any of the dosing units according to the transferred set of brew parameters. When a subsequent group control handle bump for another of the dosing units is sensed at its step 806 , then a new programmed brew sequence is initiated according to the transferred set of parameters. The espresso machine then automatically conducts the programmed sequence at step 812 to dispense the new dose of espresso. Thus the conditions for the desired dose are replicated across the dosing units.
[0104] FIG. 10 illustrates example visual display graphics and state machine diagram 1000 that accompany the program and save mode of operation. Prior to entering the save mode, the espresso machine is in the brew mode of operation 1001 , and typically runs a shot to automatically save the last shot into the computer temporary brew memory at step 1002 . The operator then performs a right hold, e.g. for 2.5 seconds, at enter save mode step 1004 , whereupon the visual display 180 begins to flash the save icon. The operator then optionally bumps right one or more times at step 1006 to change the desired computer storage memory location for saving. When the desired location is selected, the operator bumps left at save step 1008 to save the shot parameters to the location. The operator then exits the save mode at step 1010 with a right hold, e.g. for 2.5 seconds.
[0105] After the save mode of operation ends at exit step 940 , the espresso machine is then ready to enter the brew mode again with the newly saved and selected set of brew parameters. If a different set of brew parameters is desired, the operator simply bumps right one or more times to cycle through the recipes, and stops when the desired recipe is reached. When a subsequent group control handle bump is sensed at step 806 , then the new programmed brew sequence is initiated according to this new second set of parameters. The espresso machine then automatically conducts the programmed sequence at step 812 to dispense the new dose of espresso.
[0106] FIGS. 11( a ) through 11( d ) illustrate an additional series of state machine diagrams for the operation of the espresso machine. FIG. 11( a ) illustrates program mode adjustment state machine 1102 . When the controller senses a left hold, e.g. 2.5 seconds, on a group control head handle, the controller enters the cycle program mode. Subsequent left holds cause the controller to cycle its program mode through the available programs, here shown the modes Manual 1104 , Manual Program 1106 , Volumetric Program 1108 , and cycle back to Manual 1110 . Further detail about operating in these modes is shown in FIG. 11( b )-( d ) .
[0107] FIG. 11( b ) illustrates one exemplary operation of the Manual Mode 1120 , a mode that allows the operator complete control of the shot parameters. Starting from an idle state at steps 802 , 804 , the operator bumps left to start the shot by pre-infusion at start step 1122 . The controller begins the pre-infusion operation, and awaits subsequent bumps left before advancing the shot to the next phases of pressure ramp-up step 1124 , full pressure brew step 1126 , and pressure ramp-down step 1128 respectively. The shot is stopped at step 1129 at a sensed bump right. The brew parameters are retained within the computer temporary brew memory. Visual display 180 may display the current phase and parameters during the shot.
[0108] FIG. 11( c ) illustrates one exemplary operation of the Manual Program Mode 1130 , a mode that allows the operator limited control of the shot parameters. Starting from an idle state at steps 802 , 804 , the operator bumps left to start the shot by pre-infusion at start step 1132 . The controller automatically advances the shot to the next phases of pressure ramp-up step 1134 , full pressure brew step 1136 , and pressure ramp-down step 1138 . The shot is stopped at step 1139 at a sensed bump right. The operator may adjust the “blonding” of the shot at step 1136 with a left bump to truncate the shot pressure, and then may end the shot at the desired volume (if necessary) with a right bump at stop step 1139 . Visual display 180 may display the current phase and parameters during the shot.
[0109] FIG. 11( d ) illustrates one exemplary operation of the Volumetric Program Mode 1140 , a mode that allows the operator control of the start of the shot only. Starting from an idle state at steps 802 , 804 , the operator bumps left to start the shot by pre-infusion at start step 1142 . The controller then automatically advances the shot to each next phase at pressure ramp-up step 1144 , full pressure brew step 1146 , and pressure ramp-down step 1148 according to the program brew parameters in use. The shot is automatically stopped at step 1149 upon reaching the pre-programmed volume as sensed by the flowmeter. In this program mode, the operator may truncate the shot at any time with a bump right. The visual display 180 may display the current phase and parameters during the shot.
[0110] The functionality of the various program modes corresponds to the method flow steps as shown in FIG. 8 . For example, a sensed CCW actuation at step 810 with a shot brewing at step 820 which immediately ends the shot at step 822 . This corresponds to the right bumps at FIG. 11 steps 1129 and 1139 .
[0111] When the paddle is released, the save mode of operation then exits at exit step 940 . The espresso machine is then ready to enter the brew mode again with the newly saved and selected set of brew parameters. When a subsequent group control handle bump is sensed at step 806 , then a new programmed brew sequence is initiated according to this new second set of parameters. The espresso machine then automatically conducts the programmed sequence starting at step 812 to dispense the new dose of espresso.
[0112] Retrieving a Stored Set of Parameters for Use
[0113] FIG. 8 at state machine table 801 also illustrates a method for obtaining from storage memory a set of parameters for use, where the set of parameters has been previously stored in one of the page portions instead of the temporary brew memory. This functionality is enabled simply by cycling through the memory storage locations by means of scrolling with the group control head handle. In the FIG. 9 embodiment, the group control head handle is bumped right one or more times to cycle through the storage locations, up to six. When cycled, visual display 180 preferably highlights the particular location. A subsequent bump to the opposite left side then starts the shot using that selected recipe. The shot parameters are also transferred to the temporary brew memory during the shot, for subsequent saving and use.
Example
[0114] Some example settings for a page in computer storage memory appear in Table 1 below:
[0000]
Brew Group 2 (Volumetric Mode)
Program 1
Pre-infuse
4.0
Ramp Up
1.8
% of Shot Brewed
91%
Total Water Volume
350
[0115] A note from the morning barista says that they made a great shot earlier in the day and saved it in Brew Group 2 Program 1. We are currently using Program 2 on the second group, so the first step is to cycle to the Program 1 by bumping the group head control handle five times until Program 1 is highlighted on visual display 180 ′. Then we prepare a filter puck and bump left. The programmed sequence will run through 4 seconds of pre-infusion, ramp up for 1.8 seconds, and then run the pump until 91% of the total flow meter count of 350, corresponding to about 60 ml of water, has been dispensed. The pump will then shut off and the shot will finish at line pressure.
[0116] An espresso machine apparatus as described in FIGS. 1 through 6 comprises each of the elements that are necessary to perform the methods described above. An optional external programming controller 190 , described in FIG. 13 may be used in concert with the group control heads, controller, memories, and programmed sequences for additional flexibility in programming.
[0117] FIG. 13 shows an embodiment of the optional external programming controller 190 that may be used with the inventive espresso machine. Controller 190 is preferably handheld and communicatively connected to the controller 510 by wired or wireless means. Controller 190 includes three main features. Programmer display 192 displays information related to the stored programs. Programmer selection buttons 194 are arranged next to the display to enable the user to select particular items in display 192 . Programmer scrolling arrows 196 enable the user to adjust values of the displayed items.
[0118] If no useful set of brewing parameters yet exists in computer storage memory, or if it is desired to enter the values without brewing, one or more of the parameter set values may be more easily entered via the controller 190 . For example, the user wishes to adjust the volume of the shot on number 2 brew group, i.e. dosing unit. She scrolls with the scrolling arrows 196 until Brew Group 2 is displayed. The desired set of brew parameters resides in the memory storage location 1, so she presses the button 194 that is adjacent that label. Then she presses the scrolling arrows to adjust the volume to the desired amount. Another press of the button 194 deselects the line and updates the set of brew parameters at that memory location. As previously described, this new set of brew parameters can be saved to any of the other memory locations in any of the other brew groups, and can be used with the group control head controls during the next brew. The entry of data using programmer 190 may also be conducted in concert with selection and saving of that data via the group control head operations as described above.
[0119] Modifications to the device, method, and displays as described above are encompassed within the scope of the invention. For example, various configurations of the plumbing and electrical systems which fulfill the objectives of the described invention fall within the scope of the claims. Also, the particular appearance and arrangement of the apparatus may differ.
[0000]
Table of Elements
Number
Name
100
Espresso machine
102
Espresso dosing unit
110
Group control head
110′
Second group control head
110″
Third group control head
150
Brew tank
160
Filter
170
Outlet spout
180
Visual display
180′
Second visual display
180″
Third visual display
190
External programming controller
192
Programmer display
194
Programmer selection buttons
196
Programmer scrolling arrows
200
Espresso machine
202
Steam tank
204
Pump
206
Control valve
208
Bypass control valve
210
Water source
250
Brew tank
250′
Second brew tank
250″
Third brew tank
260
Filter
300
Group control head
302
Base
314
Handle
316
paddle
324
Top plate
325
Pivot pin
340
Actuator
342
Magnet
350
Centering post
374
Proximity sensor board
375
First proximity sensor
376
Second proximity sensor
400
Idle position
410
Brew position
420
Control position
500
Espresso machine electrical system
502
Group head flow meter
504
Brew tank temperature sensor
510
Controller
520
Visual display
522
Pump control output
524
Control valve control output
526
Bypass valve output
530
Computer memory
532
Computer temporary brew memory
534
Computer storage memory
Computer storage memory page
Page left portion
Page right portion
540
Power supply
541-546
Computer storage memory storage locations
600
Operational display of programmed sequence
602
Shot timer display
604
Mode icon
606
Brew sequence phase display
608
Memory storage location icon
610
Save icon
620
Save mode display of brew parameter set transfer
620′
Second save mode display (not used)
620″
Third save mode display (not used)
622
Save left icon
624
Storage memory cycling icon
700
Espresso machine brewing sequence
702
Brewing start step
716
Brewing initiation step
717
Pre-infusion brew phase
720
Pressure ramp up phase
722
Full pressure brew phase
724
Pressure ramp down phase
726
Stop shot phase
727
End step
800
Method for providing hot water dose
802
Method start step
804
Providing an espresso machine step
806
sensing step
807
Monitoring step
808
mode decision step
810
actuation direction decision step
812
brew mode
814
shot brewing decision step
816
begin programmed sequence step
818
Proceed to next phase in sequence step
820
shot brewing decision step
821
Cycle recipe step
822
stop shot step
824
save into temporary memory step
900
Method for storing brewing parameters in an espresso machine
901
Saving method state table
902
Obtain brew parameters step
903
initial computer storage memory location step
906
Sense actuator direction step
908
Save to selected storage memory step
909
Group mode cycling step
910
Duration step
911
Duration step
912
Enter program and save mode of operation
914
scroll to the next available storage memory at step
940
Exit from program and save mode of operation
1000
Visual display state machine diagram, save mode
1001
Initial brew mode of operation
1002
Save last shot into computer temporary brew memory step
1004
enter save mode step
1006
change computer storage memory location step
1008
save to active computer storage memory step
1010
Exit save mode step
1102
Program mode adjustment state machine
1104
Manual mode
1106
Manual program mode
1108
Volumetric program mode
1110
Manual mode cycle
1120
Manual (M) mode of operation
1122
M start and pre-infusion step
1124
M pressure ramp-up step
1126
M full pressure brew step
1128
M pressure ramp-down step
1129
M stop step
1130
Manual Program (MP) mode of operation
1132
MP start and pre-infusion step
1134
MP pressure ramp-up step
1136
MP full pressure brew step
1138
MP pressure ramp-down step
1139
MP stop step
1140
Volumetric Program (VP) mode of operation
1142
VP start and pre-infusion step
1144
VP pressure ramp-up step
1146
VP full pressure brew step
1148
VP pressure ramp-down step
1149
VP stop step
1200
Groups display
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An espresso machine that includes a group control head for controlling the brewing and dispensing of espresso drinks. In particular, the group control head includes a novel arrangement of proximity switches, magnets, and centering post that allows for a more efficient workflow in the controlling, automating, and duplicating the brewing of multiple doses of espresso. An associated method for using the group control head is also described.
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This application is a continuation of U.S. Ser. No. 08/524,240 filed Sep. 6, 1995 and now U.S. Pat. No. 5,819,663.
FIELD OF THE INVENTION
The present invention relates generally to the field of printing, such as the printing and production of magazines formed by multiple signatures. More specifically, the invention relates to methods and apparatus for printing and gathering signatures.
BACKGROUND OF THE INVENTION
The printing industry has recognized the need for flexibility in producing different versions of the same publication to be mailed to users in the same geographical location, and the value of printing personalized messages (e.g. directed to a specific consumer or group of consumers) on each publication. Ink jet printing is commonly used for producing such personalized messages in these publications.
One method of conveying printed products uses a gripper conveyor. A gripper conveyor includes a plurality of gripper elements that accommodate a plurality of single printed products in shingled (i.e. overlapping) relation. These gripper conveyors are particularly useful because they are capable of conveying printed products at a high rate. However, when printed products are conveyed by such gripper conveyors, ink jet printing is limited to the exposed, non-overlapped portion of the product, as is generally described in U.S. Pat. No. 4,538,161.
U.S. Pat. No. 5,100,116 discloses an apparatus that can print on the full page of signatures. The disclosed printing apparatus removes signatures from a stack and separates the signatures for printing. The signatures are subsequently fed to a collating conveyor where the signatures are gathered to form a book block.
SUMMARY OF THE INVENTION
The present invention provides the flexibility of ink jet printing on an entire printed product while maintaining the high output rate of gripper conveyors. To do this, the present invention provides an accelerating and printing apparatus that accommodates ink jet printing on the full page of each product conveyed. At the same time, the invention further provides a gripper conveyor that conveys printed products at a much higher rate and, combined with the accelerating and printing apparatus, accommodates printing on the full page of the printed product.
The present invention includes an apparatus for providing printed products to a gatherer. The apparatus includes a product supplier for feeding printed products, a product accelerator positioned to receive printed products from the product supplier and to separate the printed products into a separated stream, a printer positioned adjacent to the separated stream and positioned to print on the separated printed products, and a gripper conveyor positioned to receive the separated printed products from the printer and to form a shingled stream. The gripper conveyor is positioned to provide the shingled products to the gatherer.
In one embodiment, the printed products are supplied to the product accelerator at a first speed, and the product accelerator includes an accelerator belt moving at a second speed greater than the first speed. The product accelerator can further include an additional accelerator belt moving at a speed greater than the second speed. In another embodiment, the printer is an ink jet printer, preferably one positioned on either side of the separated stream to allow for printing on both sides of the printed products. A lower guide can be positioned to support the printed products as the printed products are fed from the printer to the gripper conveyor. In addition, or alternatively, a leading edge guide can be positioned to guide a leading edge of the printed products into the gripper conveyor. Preferably, the leading edge guide is spaced from the lower guide. In another embodiment, the apparatus further includes means for deflecting a trailing edge of the printed products. Preferably, the means for deflecting includes an air guide operatively positioned between the printer and the gripper conveyor.
The present invention also provides a method of providing printed products to a gatherer. The method includes the steps of accelerating the printed products into a separated stream, printing on the printed products while the printed products are separated in the separated stream, receiving the printed products into a gripper conveyor, decelerating the printed products into a shingled stream, and providing the printed products to a gatherer.
In one embodiment, the step of accelerating the printed products includes the steps of feeding the printed products in a shingled stream, and separating the printed products to form a separated stream. In addition, or alternatively, the step of accelerating the printed products can include the step of positioning the printed products between an accelerator belt and a pinch belt. The step of receiving the printed products preferably includes the step of feeding the printed products over a lower guide, and further preferably includes the step of feeding the printed products over a leading edge guide. In another embodiment, the step of receiving the printed products includes the step of deflecting a trailing edge of the printed products.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 is a side elevation view of a prior art feeder and gripper conveyor.
FIG. 2 is a side elevation view of a gripper conveyor device embodying the present invention.
FIG. 3 is an enlarged side elevation view of the feeder and the accelerating and printing apparatus of the device illustrated in FIG. 2.
FIG. 4 is a top plan view of the accelerating and printing apparatus illustrated in FIG. 3.
FIG. 5 is an enlarged side elevation view of the gripper entry device.
DETAILED DESCRIPTION
The prior device shown in FIG. 1 includes a high speed feeder 10 that receives a stream of shingled, folded signatures at an infeed area 14. The illustrated high speed feeder is a Ferag ZF Feeder available from Ferag AG of Hinwil, Switzerland. The stream can be provided, for example, by a conventional manual supplier (not shown) such as a Ferag HDA Supplier available from Ferag AG. The shingled stream is supplied to the high speed feeder 10 with the folded edges of the signatures oriented upstream (i.e., toward the direction of travel). The high speed feeder 10 transports the signatures to an outfeed area 16 to form a stack of signatures with the stream being fed into the bottom of the stack. The high speed feeder includes an engaging device that lifts the top signature off of the stack and feeds the signature 12 to an adjacent gripper conveyor 18.
The gripper conveyor 18 includes a plurality of gripper elements 20 that travel along a track 22. As each signature 12 enters the gripper conveyor 18, a gripper element 20 grips the signature 12. A following signature 12 is gripped by a following gripper element 20 that is positioned a short distance form the preceding gripper element so that the signatures 12 are maintained in shingled relation. The gripper conveyor 18 then conveys the shingled signatures 12 to a gatherer (not shown in FIG. 1) that gathers the signatures 12 into a book block. The illustrated gripper conveyor is a Ferag UTR Gripper Conveyor, available from Ferag AG.
FIG. 2 illustrates an apparatus embodying the present invention. The illustrated apparatus includes a high speed feeder 24 that is supplied with a shingled stream 26 of signatures 28 at an infeed area 30 and provides the signatures to an outfeed area 32. Instead of forming a stack at the outfeed area 32, the illustrated apparatus feeds the shingled signatures directly to an accelerating and printing device 34 positioned adjacent the outfeed area 32 of the high speed feeder 24. It should be appreciated that other types of feeders could be used for the present invention, such as folder style feeders, stack feeders, or high-speed multiform feeders.
The accelerating and printing device 34 separates the shingled stream 26 into a separated stream 36 so that the signatures 28 do not overlap. The accelerating and printing apparatus 34 prints onto each separated signature 28, and then feeds the separated stream 36 to an adjacent gripper conveyor 38. Such feeding to the gripper conveyor 38 causes deceleration of the signatures 28, thereby resulting in the signatures being formed back into a shingled stream 40. The signatures are subsequently fed to an appropriate gatherer 42, such as a Ferag SHT Gatherer available from Ferag AG.
Referring to FIGS. 3 and 4, the outfeed area 32 of the high speed feeder 24 includes side guides 44 extending from the outfeed area 32 to the accelerating and printing apparatus 34. The side guides 44 are generally in parallel relation to each other and to the path of the shingled stream 26. The side guides 44 are positioned a distance from each other approximately equal to the width of a signature 28 to thereby maintain lateral registration of the signatures during printing operations.
The accelerating and printing apparatus 34 includes an accelerator device 46, a registration device 48, a printer device 50, and a gripper entry device 52. The accelerator device 46 is positioned adjacent to the outfeed area 32 of the high speed feeder 24 and is designed to receive the signatures 28 directly from the high speed feeder 24. The accelerator device 46 includes a transport belt 54, a roller 56, a first accelerating belt 58, a first pinch belt 60, a second accelerating belt 62, and a second pinch belt 64. The transport belt 54 is positioned adjacent to the output area 32 so that the shingled stream 26 can be positioned onto the transport belt 54 and between the side guides 44. The roller 56 provides downward force to the signatures to maintain contact with the transport belt 54. The transport belt 54 rotates clockwise at approximately the same speed as the shingled stream 26 being fed thereto.
The first accelerating belt 58 and associated first pinch belt 60 are designed to receive signatures 28, one at a time, from the transport belt 54 and to accelerate each signature 28 to about three times its incoming speed. In this regard, the first accelerating belt 58 and associated first pinch belt 60 rotate to produce a surface speed that is about three time faster than the surface speed of the transport belt 54.
In a similar sense, the second accelerating belt 62 and associated second pinch belt 64 are designed to receive signatures, one at a time, from the first accelerating belt 58 and associated first pinch belt 60 and to accelerate each signature 28 to about three times its incoming speed. In this regard, the second accelerating belt 62 and associated second pinch belt 64 rotate to produce a surface speed that is about three time faster than the surface speed of the first accelerating belt 58 and associated first pinch belt 60, thereby resulting in a product speed that is about nine times faster than that provided by the high speed feeder 24.
The above-described accelerator belts are of conventional design and do not require further discussion.
The registration device 48 includes a lugged registration belt 68 and a speeder belt 70 positioned above the registration belt. The lugged registration belt 68 includes a plurality of registration lugs 72 that extend outward from the registration belt 68 and that are separated from each other by a distance greater than the length of a signature 28. The lugged registration belt 68 rotates at a speed that is about equal to the speed of the second accelerating belt 62. The speeder belt 70 is positioned adjacent to and above the lugged registration belt 68. The speeder belt 70 rotates clockwise at a higher speed than the lugged registration belt 68. The positioning and rotation of the lugged registration belt 68 and speeder belt 70 ensures that the leading edge of a separated signature 28 is engaged with the corresponding registration lug 72. Once the signature 28 is engaged to the registration lug 72, the signature 28 is in registration, thereby facilitating proper positioning of the subsequent ink jet printing. The use of registration belts and speeder belts is conventional and is generally set forth in U.S. Pat. No. 5,100,116.
The printer device 50 includes an upper belt 74, a lower belt 76, and an ink jet printer 78. The upper belt 74 rotates clockwise at a constant speed. The upper belt 74 is supported so that the printer apparatus 50 can accommodate signatures 28 of varying thicknesses. The lower belt 76 rotates counterclockwise, opposite the direction of the upper belt 74 and at a constant speed equal to that of the upper belt 74. The positioning and rotation of the upper belt 74 and lower belt 76 maintains the registration of each signature 28 in the separated stream 26, as achieved in the operation of the registration device 48. The lower belt 76 can include registration lugs 77 to maintain such registration.
The upper belt 74 and the lower belt 76 are shaped and positioned to expose all but the outermost edges of the separated signature 28 to the ink jet printer 78. The ink jet printer 78 includes numerous ink jet printer heads 80 that are positioned on both the upper side and lower side of the printer apparatus 50 and the separated stream 26. In the illustrated embodiment, the ink jet printer comprises a Videojet SR-50 available from Videojet Systems International, Inc.
Referring to FIG. 5, the gripper entry device 52 includes a lower guide 82, an air guide bar 84, a solenoid controlled valve 86, an L.P. air supply 88, a solenoid 90, and a leading edge guide 92. The lower guide 82 is movable and extends from the lower belt 76 toward the gripper conveyor 38. Positioned above the lower guide 82 and extending from the upper belt 74 is an air guide bar 84. The air guide bar 84 has a plurality of openings 94 in its bottom side. A supply of low pressure air 88 with the solenoid controlled valve 86 communicates with the air guide bar 84. A solenoid 90 controls the valve 86 to release a flow of air into the air guide bar 84 to be expelled out of the openings 94. The leading edge guide 92 is positioned below the gripper conveyor 38. The leading edge guide 92 is shaped so that the leading edge of the signatures 28 will be fed into the gripper conveyor 38 and gripped by a corresponding gripper element 96 after exiting the printer apparatus 50. The lower guide 82 is positioned so that when the leading edge 98 of a signature 28 is engaged in the gripper element 96, the trailing edge 100 of the same signature has dropped off of the lower guide 82. With this configuration, a subsequent blast of air from the air guide bar 84 will force the trailing edge 100 of the signature 28 downward to allow the following signature 28 to overlap and be fed into the next gripper element 96.
For purposes of example, the following discussion of the operation of the present invention focuses on a single signature 28 as it is processed through the apparatus illustrated in FIGS. 2-4. Each following signature 28 is processed in the same manner as the exemplary signature 28.
Referring to FIG. 2, a shingled stream 26 of signatures 28 is received by the high speed feeder 24 at the infeed area 30, as is known in the art. The high speed feeder 24 transports the shingled stream 26 along a conveyor belt system to the outfeed area 32. Referring to FIG. 3, the shingled stream 26 then enters the accelerator device 46. The side guides 44 of the outfeed area 32 ensure that the signatures 28 are maintained in proper orientation. The transport belt 54 and associated roller 56 receive the shingled stream 26 from the outfeed area 32 and supply the shingled stream 26 to the first accelerating belt 58 and associated first pinch belt 60.
The first accelerator belt 58 and associated first pinch belt 60 engage the leading edge 98 of the signatures 28, one at a time, and accelerate the signatures 28 to about three times their incoming speed. Similarly, the second accelerator belt 62 and associated second pinch belt 64 further accelerate the signatures 28 to about three times their incoming speed. When the signatures 28 exit the accelerator device 46, the signatures 18 are in a separated stream 36 so that there is no overlap.
Each signature 28 is then drawn into the registration apparatus 48. The higher speed of the speeder belt 70 forces each signature 28 forward, ahead of the rotation of the lugged registration belt 68, until the leading edge 98 of the signature 28 engages the registration lug 72 supported by the lugged registration belt 68. The engagement of the signature 28 with the registration lug 72 places the signature 28 in registration so that proper positioning of the subsequent printing operation is facilitated.
The signature 28 then enters the printer device 50. The rotation and position of the upper and lower belts 74, 76 maintains the signature 28 in registration, as achieved in the operation of the registration device 48. The belts 74 and 76 are shaped and positioned so that all but the outermost edges of the signature 18 are exposed to the ink jet printer 78. As the separated stream 36 of signatures 28 passes between the printer heads 80, the desired printing is performed on the signature 18.
Referring to FIG. 5, the signature 28 is fed from the printer device 50 to the gripper conveyor 38 via the gripper entry device 52. The friction on the upper and lower belts 74, 76 moves the signature 28 leftward. As the leading edge 98 of a signature 28 exits the upper and lower belts 74, 76, it is supported by the lower guide 82. As the signature 28 continues to move leftward and passes the end of the lower guide 82, the leading edge 98 of the signature 28 is supported by the leading edge guide 92. The signature 28 continues to move leftward until it is gripped by a corresponding gripper element 96 on the gripper conveyor 38.
After the leading edge 98 of the signature 28 has been gripped by the corresponding gripper element 96, the trailing edge 100 of the signature 28 moves beyond the end of the lower guide 82. At this time, the solenoid 90 opens the valve 86 in the air supply 88, causing an amount of air to be released through the air guide bar 84 and out of the openings 94. The pressure of the air forces the trailing edge 100 of the signature 28 downward so that the leading edge 98 of a following signature 28 does not move below the leading signature 28 as it is decelerated by the gripper conveyor 38. The following signature 28 is then gripped by a following gripper element 96. The gripper conveyor 38 rotates at a gripper speed that is slower than the stream speed of the separated stream 36. The slower gripper speed causes the gripped signatures 28 to decelerate and form a shingled stream 40. The signatures 28 are thus arranged back into a shingled relation by the gripper conveyor 38.
Subsequent processing of the signatures can be conventional in nature. In the illustrated embodiment, the signatures are fed to a rotary gatherer.
The foregoing description of the present invention has been presented for purposes of illustration and description. Furthermore, the description is not intended to limit the invention to the form disclosed herein. Consequently, variations and modifications commensurate with the above teachings, and the skill or knowledge of the relevant art, are within the scope of the present invention. The embodiments described herein are further intended to explain best modes known for practicing the invention and to enable others skilled in the art to utilize the invention in such, or other, embodiments and with various modifications required by the particular applications or uses of the present invention. It is intended that the appended claims be construed to include alternative embodiments to the extent permitted by the prior art.
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An apparatus for providing printed products to a gatherer, including a product supplier for feeding printed products, a product separator positioned to receive printed products from the product supplier and to separate the printed products into a separated stream, a printer positioned adjacent to the separated stream and positioned to print on the separated printed products, and a gripper conveyor positioned to receive the separated printed products from the printer and to form a shingled stream.
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BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to beverage dispensing nozzles and more particularly, but not by way of limitation, to a beverage dispensing nozzle for use in dispensing medium to low flow applications. Further embodiments include dispensing flavor additives and dispensing multiple flavored drinks from a single nozzle without intermingling drink flavors.
2. Description of the Related Art
In the food and beverage service industry, counter space is at a premium. As such, it is desirable to minimize the space requirements of counter top dispensers through dispensing multiple flavors of drinks, including flavor additives, from a single nozzle. Problems associated with multiple flavor dispensing nozzles include syrup carryover, proper mixing, and excessive foaming problems. U.S. Pat. Nos. 6,098,842, 6,047,859 and 6,345,729 disclose multiple flavor nozzles that provide solutions to these problems. These multiple flavor nozzles are designed for use in high volume beverage dispensing accounts and thus produce higher than normal finished drink flowrates. While the designs of the referenced patents address the foregoing problems, they did not address problems associated with delivery of products at lower flowrates for medium to low volume beverage dispensing accounts. Furthermore, medium to low volume accounts may not require a multi-flavor beverage dispensing nozzle to satisfy the demand.
At lower flowrates, problems arise due to different system dynamics, wherein the product stream flows out of the nozzle in an irregular pattern and not the prescribed stream. Visually, the water segment of the product stream looks as if the water is exiting the nozzle on only one side. This training effect is present when the flow system energy does not overcome the surface tension properties of the mixing fluid in a lower flowrate system. This type of problem must be corrected to ensure proper mixing, as well as being aesthetically functional.
A second problem with the lower flowrate nozzles is the surface tension of the water as it leaves the underside of the nozzle. In a lower flowrate system, the water adhesion properties take over at the end of a dispense, wherein the mixing fluid then clings to the underside of the nozzle. Liquid clinging to the underside of the nozzle that contacts both the mixing fluid ports and the syrup ports can create avenues for intermingling of the different varieties of products, as well as discoloring and distaste of a dispensed drink. Accordingly, a beverage dispensing nozzle that operates at lower product flowrates would be beneficial for use in medium to low volume beverage dispensing accounts.
SUMMARY OF THE INVENTION
A method and apparatus for a beverage dispensing nozzle equipped with at least one flow director allow products to be dispensed at lower flowrates. In a first embodiment, a single flavor beverage dispensing nozzle equipped with the at least one flow director segment the flow to provide a reduced cross sectional area. As the nozzle cavity fills, the product is forced to move down a flow director channel. A method of using the beverage dispensing nozzle with the at least one flow director is also provided.
A second embodiment provides an improvement to an existing beverage dispensing nozzle, by adding at least one flow director in an annular channel of a multi-flavor beverage dispensing nozzle. The addition of the at least one flow director in the annular channel has provided the beverage dispensing nozzle with the ability to dispense product at lower flowrates by increasing the velocity component of the exiting product. The exiting product now has sufficient energy to separate from the beverage dispensing nozzle. A method of using the beverage dispensing nozzle with the at least one flow director is also presented.
It is therefore an object of this invention to provide a beverage dispensing nozzle suitable for use with lower flowrates.
It is further an object of this invention to provide an increased velocity component to the product exiting the beverage dispensing nozzle.
It is yet further an object of this invention to segment the flow of product within the beverage dispensing nozzle.
It is still yet further an object of this invention to provide a visually acceptable fluid stream exiting from the beverage dispensing nozzle.
Still other objects, features, and advantages of the present invention will become evident to those of ordinary skill in the art in light of the following. Also, it should be understood that the scope of this invention is intended to be broad, and any combination of any subset of the features, elements, or steps described herein is part of the intended scope of the invention.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 provides a section view of a single flavor beverage dispensing nozzle according to the preferred embodiment.
FIG. 2 provides a method flowchart for using flow directors in a single flavor nozzle according to the preferred embodiment.
FIG. 3 provides an exploded view of beverage dispensing nozzle as viewed from above according to the preferred embodiment.
FIG. 4 provides an exploded view of nozzle as viewed from below according to the preferred embodiment.
FIG. 5 is a cross section view of the nozzle as assembled according to the preferred embodiment.
FIG. 6 is a cross section view of the nozzle as assembled according to the preferred embodiment.
FIG. 7 is a cross section view of the nozzle as assembled according to the preferred embodiment.
FIG. 8 a is a top view of the outer housing after the addition of flow directors according to the preferred embodiment.
FIG. 8 b is a section view of the outer housing after addition of the flow directors according to the preferred embodiment.
FIG. 9 a provides a side view of the assembled beverage dispensing nozzle according to the preferred embodiment.
FIG. 9 b provides a section view of the beverage dispensing nozzle before the addition of flow directors according to the preferred embodiment.
FIG. 9 c provides a section view of the beverage dispensing nozzle after the addition of flow directors according to the preferred embodiment.
FIG. 10 provides a cross section of an embodiment of the beverage dispensing nozzle that inlcudes flavor additives according to the preferred embodiment.
FIG. 11 a provides a method flowchart for using flow directors in a beverage dispensing nozzle with a single beverage flavor according to the preferred embodiment.
FIG. 11 b provides a method flowchart for using flow directors in a beverage dispensing nozzle with two beverage flavors according to the preferred embodiment.
FIG. 11 c provides a method flowchart for using flow directors in a beverage dispensing nozzle with three beverage flavors according to the preferred embodiment.
FIG. 11 d provides a method flowchart for using flow directors in an embodiment that delivers flavor additives according to the preferred embodiment.
FIG. 12 a provides a method flowchart for using flow directors in a standard beverage dispensing nozzle dispensing a single beverage flavor according to the preferred embodiment.
FIG. 12 b provides a method flowchart for using flow directors in a standard beverage dispensing nozzle dispensing two beverage flavors according to the preferred embodiment.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
As required, detailed embodiments of the present invention are disclosed herein; however, it is to be understood that the disclosed embodiments are merely exemplary of the invention, which may be embodied in various forms. It is further to be understood that the figures are not necessarily to scale, and some features may be exaggerated to show details of particular components or steps.
U.S. Pat. Nos. 6,098,842, 6,047,859 and 6,345,729, the disclosures of which are herein incorporated by reference, disclose a nozzle designed to mix beverage concentrates with a mixing fluid at high flowrates, up to 5 oz./sec. An important feature of the previously disclosed beverage dispensing nozzle is the annular discharge of a beverage syrup, wherein the annularly discharged mixing fluid contacts the beverage syrup in mid-air below the dispensing nozzle. The annular discharge shape of the beverage syrup and the mixing fluid significantly increases the contact surface area between the two streams, resulting in more effective mixing. The embodiments of this invention improve over the previously disclosed nozzle by broadening the working range of the nozzle, therein making the beverage dispensing nozzle suitable for use in lower flowrate applications, as well as the higher flowrate applications. Further embodiments of this invention include a single flavor beverage dispensing nozzle and dispensing of product flavorings.
As shown in FIG. 1 , a first embodiment of a beverage dispensing nozzle 300 includes a body 301 having a single syrup flowpath 309 and a single mixing fluid flowpath 302 . The syrup flowpath 309 includes a syrup inlet port 303 , a syrup outlet port 304 and a beverage syrup channel 305 . The mixing fluid flowpath 302 includes a mixing fluid inlet port 306 , a mixing fluid outlet port 307 and a mixing fluid channel 308 disposed around the syrup flowpath 309 . The mixing fluid channel 308 further includes at least one flow director 310 to increase the velocity of the mixing fluid. Multiple flow directors 310 may be used for increased control of the mixing fluid flow dynamics. The flow director 310 segments a lower portion of the large mixing fluid channel 308 into at least one smaller channel known as a flow director channel 312 .
In operation, a beverage syrup is delivered to the beverage syrup inlet port 303 of the beverage dispensing nozzle 300 and a mixing fluid is delivered to the mixing fluid inlet port 306 . The beverage syrup is then delivered from the beverage syrup inlet port 303 to the beverage syrup outlet port 304 via a beverage syrup channel 305 disposed in the nozzle 300 . The beverage syrup is then discharged from the beverage syrup outlet port 304 . The mixing fluid is delivered from the mixing fluid inlet port 306 to the mixing fluid channel 308 surrounding the syrup flow path 309 . Once inside the mixing fluid channel 308 , the mixing fluid flows towards the mixing fluid outlet port 307 , therein passing the at least one flow director 310 . Upon reaching the at least one flow director 310 , the mixing fluid's downward velocity component is increased as the mixing fluid is forced through the reduced cross-sectional flow area and the hydraulic pressure of the incoming mixing fluid. The mixing fluid is then discharged from the mixing fluid outlet port 307 to contact exiting beverage syrup.
As shown in FIG. 2 , a method of using flow directors in a beverage dispensing nozzle 300 commences with step 80 , delivering a beverage syrup to a beverage syrup inlet port 303 of the beverage dispensing nozzle 300 . A mixing fluid is then delivered to a mixing fluid inlet port 306 of the beverage dispensing nozzle 300 , step 81 . In step 82 , the beverage syrup is delivered from the beverage syrup inlet port 303 to a beverage syrup discharge port 304 via a syrup flowpath 309 disposed inside of the beverage dispensing nozzle 300 . The method continues with step 83 , wherein the mixing fluid is delivered from the mixing fluid inlet port 306 to the mixing fluid channel 308 surrounding the beverage syrup flowpath 309 . Step 84 provides for the discharge of the beverage syrup from the beverage syrup discharge port 304 . The velocity of the mixing fluid is increased as it passes the flow director 310 in the flow director channel 312 as shown in step 85 . In step 86 , the mixing fluid is discharged from the beverage dispensing nozzle 300 to mix with exiting beverage syrup.
In a second embodiment, a beverage dispensing nozzle 10 characteristic of the nozzle disclosed in the referenced U.S. Patents is equipped with an at least one flow director 200 to permit the nozzle 10 to operate at lower flowrates. As shown in FIGS. 3–7 , the nozzle 10 includes a cap member 11 , an o-ring 12 , a plurality of gaskets 13 – 15 , an inner housing 16 , a first or outer annulus 17 , a second or intermediate annulus 18 , a third or inner annulus 19 and an outer housing 20 . The inner housing 16 defines a chamber 40 and includes an opening 44 into the chamber 40 . The inner housing 16 includes a plurality of cavities 41 – 43 that communicate with the chamber 40 through a plurality of conduits 45 – 47 , respectively. The conduits 45 – 47 are concentrically spaced apart; namely, conduit 47 is innermost, conduit 45 is intermediate, and conduit 46 is outermost (see FIGS. 3–7 ). The conduits 45 – 47 are concentrically spaced apart so that beverage syrup may enter the chamber 40 at three separate points. The interior wall of the inner housing 16 defining the chamber 40 includes a plurality of stair steps 48 – 51 .
The first or outer annulus 17 includes an upper member 52 and a discharge member 53 . The first or outer annulus 17 fits within the chamber 40 of the inner housing 16 such that a portion of the upper member 52 engages the stair-step 49 . That portion of the upper member 52 may press fit with the stair step 49 or an adhesive may be used to secure that portion of the upper member 52 with the stair step 49 . The first or outer annulus 17 and the interior wall of the inner housing 16 defining stair step 48 form a first beverage syrup channel 54 that connects with the conduit 46 of the inner housing 16 . The first beverage syrup channel 54 insures a large volume of beverage syrup flows uniformly about the first or outer annulus 17 during discharge. The discharge member 53 includes a plurality of discharge channels 55 to aid the first beverage syrup channel 54 in discharging the beverage syrup because the discharge member 53 is sized to substantially reside within the lower portion of the interior wall for the inner housing 16 . The discharge member 53 operates to discharge the beverage syrup in a restricted flow to insure uniform distribution of the beverage syrup as it exits from the beverage dispensing nozzle 10 , thereby providing a maximum surface area for contact with mixing fluid also exiting from the beverage dispensing nozzle 10 .
The second or intermediate annulus 18 includes an upper member 56 and a discharge member 57 . The second or intermediate annulus 18 fits within the first or outer annulus 17 such that a portion of the upper member 56 engages the stair step 50 . That portion of the upper member 56 may press fit with the stair step 50 or an adhesive may be used to secure that portion of the upper member 56 with the stair step 50 . The second or intermediate annulus 18 and the interior wall of the first or outer annulus 17 form a second beverage syrup channel 58 that connects with the conduit 45 of the inner housing 16 . The second beverage syrup channel 58 insures a large volume of beverage syrup flows uniformly about the second or intermediate annulus 18 during discharge. The discharge member 57 includes a plurality of discharge channels 59 to aid the second beverage syrup channel 58 in discharging the beverage syrup because the discharge member 57 is sized to substantially reside within the lower portion of the interior wall of the first or outer annulus 17 . The discharge member 57 operates to discharge the beverage syrup in a restricted flow to insure uniform distribution of the beverage syrup as it exits from the beverage dispensing nozzle 10 , thereby providing a maximum surface area for contact with mixing fluid also exiting from the beverage dispensing nozzle 10 .
The third or inner annulus 19 includes a securing member 60 , an intermediate member 61 and a discharge member 62 . The inner annulus 19 fits within the intermediate annulus 18 such that the securing member 60 protrudes through the opening 44 of the inner housing 16 and engages the interior wall of the inner housing 16 defining the opening 44 . The securing member 60 may be press fit with the interior wall of the inner housing 16 defining the opening 44 or an adhesive may be used to secure the securing member 60 with the interior wall of the inner housing 16 defining the opening 44 . The third or inner annulus 19 , the stair step 51 and the interior wall of the second or intermediate annulus 18 form a third beverage syrup channel 64 that connects with the conduit 47 of the inner housing 16 . The third beverage syrup channel 64 insures a large volume of beverage syrup flows uniformly about the third or interior annulus 19 during discharge. The discharge member 62 includes a plurality of discharge channels 63 to aid the third beverage syrup channel 64 in discharging the beverage syrup because the discharge member 62 is sized substantially reside within the lower portion of the interior wall for the second or intermediate annulus 18 . The discharge member 62 operates to discharge the beverage syrup in a restricted flow to insure uniform distribution of the beverage syrup as it exits from the beverage dispensing nozzle 10 , thereby providing a maximum surface area for contact with mixing fluid also exiting from the beverage dispensing nozzle 10 .
The cap member 11 includes a plurality of beverage syrup inlet ports 21 – 23 that communicate with a respective beverage syrup outlet port 24 – 26 via a respective connecting conduit 37 – 39 through the cap member 11 . The beverage syrup outlet ports 24 – 26 snap fit within a respective cavity 41 – 43 of the inner housing 16 to secure the inner housing 16 to the cap member 11 . The gaskets 13 – 15 fit around a respective beverage syrup outlet port 24 – 26 to provide a fluid seal and to assist in the securing of the inner housing 16 to the cap member 11 . With the inner housing 16 secured to the cap member 11 , a beverage syrup path involving the beverage syrup inlet port 21 ; the conduit 37 ; the beverage syrup outlet port 24 ; the cavity 41 ; the conduit 46 ; and the first beverage syrup channel 54 , which includes the discharge channels 59 is created. A beverage syrup path involving the beverage syrup inlet port 22 ; the conduit 38 ; the beverage syrup outlet port 25 ; the cavity 42 ; the conduit 45 ; the second beverage syrup channel 58 , which includes the discharge channels 55 , and one involving the beverage syrup inlet port 23 ; the conduit 39 ; the beverage syrup outlet port 26 ; the cavity 43 ; the conduit 47 ; the third beverage syrup channel 64 , which includes the discharge channels 63 are also created.
The cap member 11 includes a mixing fluid inlet port 27 that communicates with a plurality of mixing fluid outlet channels 66 – 71 via a connecting conduit 28 through the cap member 11 . The mixing fluid outlet channels 66 – 71 , in this preferred embodiment, are uniformly spaced within the cap member 11 and communicate with an annular cavity 36 defined by a portion of the cap member 11 to deliver mixing fluid along the entire circumference of the annular cavity 36 . Nevertheless, one of ordinary skill in the art will recognize that other mixing fluids, such as plain water may be used. Furthermore, although the preferred embodiment discloses the formation of a beverage from a beverage syrup and a mixing fluid, such as carbonated water or plain water, one of ordinary skill in the art will recognize that a mixing fluid, such as carbonated or plain water, may be dispensed individually from a beverage path as described above instead of a beverage syrup.
The outer housing 20 snap fits over the cap member 11 , including the o-ring 12 which provides a fluid seal and assists in the securing of the inner housing 16 to the cap member 11 . The outer housing 20 has an inwardly extending lip portion 73 at its exit end to direct exiting mixing fluid into the exiting beverage syrup. An inner surface 201 of the outer housing 20 in combination with the portion of the cap member 11 defining the annular cavity 36 and an exterior wall 202 of the inner housing 16 define a mixing fluid channel 72 . With the outer housing 20 secured to the cap member 11 , a mixing fluid path involving the mixing fluid inlet port 27 , the conduit 28 , the mixing fluid outlet channels 66 - 71 , the annular channel 36 and the mixing fluid channel 72 is created.
Similarly, upon mating the outer housing 20 and the cap member 11 , three different beverage flow paths are defined. Beverage syrup enters the beverage syrup inlet ports 21 , 22 , 23 , flows through the conduits 37 , 38 , 39 and the beverage system outlet ports 24 , 25 , 26 to the cavities 41 , 42 , 43 ; the beverage syrup then flows through the conduits 46 , 45 , 47 , the first, second and third beverage syrup channels 54 , 58 , 64 , the discharge channels 55 , 59 , 63 , and the discharge members 53 , 57 , 62 , respectively, prior to being discharged from the beverage dispensing nozzle 10 .
In operation, mixing fluid enters the beverage dispensing nozzle through the mixing fluid inlet port 27 and travels through the conduit 28 to the mixing fluid outlet channels 66 – 71 for delivery into the annular cavity 36 . Under high flow rates, the annular cavity 36 receives a large volume of mixing fluid to insure the mixing fluid channel 72 remains full for uniform flow as the mixing fluid moves downwardly through the mixing fluid channel 72 to the discharge end of the nozzle. The objective is to maintain a uniform distribution of mixing fluid exiting the entire circumference of the mixing fluid channel 72 . The inwardly extending lip portion 73 of the outer housing 20 directs the mixing fluid inwardly toward a beverage syrup stream exiting from one of the discharge members 53 , 57 , or 62 .
The beverage syrup inlet ports 21 – 23 each receive a different flavor of beverage syrup, which is delivered through a conduit by a beverage syrup source (not shown). Each beverage syrup travels through its particular flow path for discharge from the beverage dispensing nozzle 10 as previously described. Illustratively, a beverage syrup delivered to the beverage syrup inlet port 21 flows through the conduit 37 , the beverage syrup outlet port 24 , the cavity 41 , the conduit 46 , the first beverage syrup channel 54 , and the discharge channels 55 prior to discharge from the beverage dispensing nozzle 10 . The first, second ad third beverage syrup channels 54 , 58 , and 64 provide a large volume of beverage syrup around each of a respective first or outer, second or intermediate, and third or inner annulus 17 , 18 , and 19 for discharge through one of the discharge members 53 , 57 , and 62 . The discharge members 53 , 57 , and 62 restrict the flow of beverage syrup to insure uniform distribution of the beverage syrup as it exits from the beverage dispensing nozzle 10 , thus insuring a maximum surface area for contact with the mixing fluid exiting from the mixing fluid channel 72 . Although only one beverage syrup is typically dispensed at a time, it should be understood that more than one beverage syrup may be discharged from the beverage dispensing nozzle 10 at a time to provide a mix of flavors.
As a solution to the problems associated with dispensing at lower flowrates, the outer housing 20 of the nozzle 10 has been outfitted with a plurality of flow directors 200 , eight in this preferred embodiment, on an inner surface 201 of the outer housing 20 . The flow directors 200 extend upward from the inwardly extending lip portion 73 at its exit end to the edge of the inner surface 201 as shown in FIGS. 8 a and 8 b . The flow directors 200 do not run the full length of the mixing fluid channel 72 . Full-length flow directors 200 would prevent the filling of an upper section of the mixing fluid channel 72 around the beverage syrup flowpath. The addition of the flow directors 200 segments a lower section of the mixing fluid channel 72 into a plurality of smaller flow channels or flow director channels 210 . It should be noted that the quantity and length of flow director 200 features may vary depending on mixing requirements for different products and additives.
With the installation of flow directors 200 , assembly of the cap member 11 and the outer housing 20 now define a slightly different flow path for the mixing fluid. The inner surface 201 of the outer housing 20 in combination with the portion of the cap member 11 defining the annular cavity 36 and the exterior wall 202 of the inner housing 16 define the mixing fluid channel 72 which now encompasses flow director channels 210 . The flow director channels 210 are defined by the inner surface 201 of the outer housing 20 , the outer wall 202 of the inner housing 16 , and two adjacent flow directors 200 as shown in FIG. 9 c . FIGS. 9 b and 9 c provide section views of the beverage dispensing nozzle 10 before and after the addition of flow directors 200 . With the outer housing 20 secured to the cap member 11 , a mixing fluid path involving the mixing fluid inlet port 27 , the conduit 28 , the mixing fluid outlet channels 66 – 71 , the annular channel 36 , the mixing fluid channel 72 and the flow director channels 210 is created.
With the flow directors 200 in place, the upper section of the mixing fluid channel 72 fills with mixing fluid. Once filled, the hydraulic pressure of the incoming mixing fluid forces the mixing fluid in the upper section of the mixing fluid channel 72 into the series of flow director channels 210 defined by the flow directors 200 . The reduced cross sectional area of the flow director channels 210 provides an increased velocity component for the mixing fluid exiting the nozzle 10 since the velocity component of the mixing fluid is being directed downward through all of the flow director channels 210 . The increased velocity component provides the mixing fluid stream with enough energy to separate from the nozzle 10 at the end of the dispense. The increased velocity of the mixing fluid eliminates the problem of the mixing fluid clinging to the underside of the nozzle 10 , and crossing over into other discharge ports. The addition of flow directors 200 improves the distribution of mixing fluid by regaining the desired discharge velocity for a more effective mix.
In a dispense, the syrup and mixing fluid flow separately through the nozzle 10 to mix with beverage syrup discharged from the nozzle 10 . Illustratively, syrup enters the nozzle 10 through a syrup inlet port 21 , flows through the conduit 37 , moves into the beverage system outlet port 24 to the cavity 41 ; the syrup then flows through the conduit 46 , the beverage syrup channel 54 , the discharge channel 55 , and finally, the discharge member 53 . Concurrently, a mixing fluid enters the nozzle 10 through the mixing fluid inlet port 27 , moves through the conduit 28 , exits the mixing fluid outlet channels 66 – 71 , flows into the annular channel 36 , through the mixing fluid channel 72 , and flows through the flow director channels 210 to the end of the nozzle 10 . Once the mixing fluid exits the flow director channels 210 , it is redirected inward into the syrup stream exiting the nozzle 10 by the inwardly extending lip portion 73 . As both fluids are being dispensed in concentric annular rings, the opportunity for mixing is increased. While the preferred embodiment provides for annularly shaped discharging of the syrup and mixing fluid, it should be apparent to those of ordinary skill in the art, that the shape of the discharge streams is not limited to annular rings. Additionally, it should be further apparent to one skilled in the art that the beverage syrup and the mixing fluid flowpaths may be switched for products with fractional mixing ratios, wherein the mixing fluid could exit the center of the beverage dispensing nozzle.
As illustrated in FIG. 10 , an embodiment of the beverage dispensing nozzle 900 provides for delivery of flavor additives from the beverage dispensing nozzle 900 along with beverage syrup and mixing fluid. Examples of flavor additives in this embodiment include, but are not limited to, cherry or vanilla, which are utilized to form new drink combinations such as cherry cola. In this embodiment, the third or inner annulus 919 includes a securing member 960 , an intermediate member 961 , and a discharge member 962 . The third or inner annulus 919 mounts within the second or intermediate annulus 18 , protrudes through the opening of the inner housing 16 , and engages the interior wall of the inner housing 16 defining the opening identically as previously described with reference to the beverage dispensing nozzle 10 . The third or inner annulus 919 , however, includes a pair of passageways 907 and 908 therethrough, which are utilized to deliver flavor additives from the third or inner annulus 919 . The intermediate member 961 and the discharge member 962 are identical to the intermediate member 61 and the discharge member 62 of the third or inner annulus 19 , except the intermediate member 961 and the discharge member 962 define a portion of the passageways 907 and 908 . The securing member 960 is identical to the securing member 60 of the third annulus 919 , except the securing member 60 defines a cavity 909 as well as a portion of the passageways 907 and 908 .
The cap member 911 is configured and operates as the cap member 11 , except the cap member 911 further includes a plurality of flavor additive inlet ports 901 and 902 that communicate with a respective flavor additive outlet port 903 and 904 via a respective connecting passageway 905 and 906 through the cap member 911 . Identical to the cap member 11 , beverage syrup outlet ports of the cap member 911 snap fit within a respective cavity of the inner housing 16 to secure the inner housing 16 to the cap member 911 . Gaskets fit around a respective beverage syrup outlet port to provide a fluid seal and to assist in the securing of the inner housing 16 to the cap member 911 . In addition, the securing member 960 of the third or inner annulus 919 extending through the opening of the inner housing 16 snap fits around a protrusion 35 of the cap member 911 to aid in the securing of the inner housing 16 to the cap member 911 . With the inner housing 16 secured to the cap member 911 , a flavor additive conduit involving the flavor additive inlet port 901 ; the passageway 905 ; the flavor additive outlet port 903 ; and the passageway 907 is created. Similarly, a flavor additive conduit involving the flavor additive inlet port 902 ; the passageway 906 ; the flavor additive outlet port 904 ; and the passageway 908 is created.
The operation of the beverage dispensing nozzle 900 in delivering a mixing fluid for combination with a beverage syrup to produce a desired drink is identical to the operation of the beverage dispensing nozzle 10 . However, the beverage dispensing nozzle 900 provides a user the option of altering drink flavor through the addition of flavor additives, such as cherry or vanilla, delivered from flavor additive sources. When the user has selected a flavor additive, the flavor additive enters a respective passageway 907 or 908 via a respective passageway 905 or 906 and flavor additive outlet port 903 and 904 . The selected additive flavor traverses a respective passageway 907 or 908 and exits the third or inner annulus 919 , where the flavor additive combines with the flowing beverage syrup and mixing fluid to produce an alternatively flavored drink, such as cherry or vanilla cola.
A method flowchart for using flow directors 200 in a beverage dispensing nozzle 10 mixing a single beverage syrup and a mixing fluid is shown in FIG. 11 a . The process begins with step 98 , wherein a beverage syrup is delivered to a first beverage syrup inlet port 21 . In step 102 , a mixing fluid is delivered to a mixing fluid inlet port 27 . Step 103 provides for delivering the beverage syrup from the first beverage syrup inlet port 21 to the first beverage syrup channel 54 . Next, the mixing fluid is delivered from the mixing fluid inlet port 27 to the mixing fluid channel 72 , step 107 . The process continues with step 108 , wherein the beverage syrup is discharged from the first beverage syrup channel 54 . In step 112 , the velocity of the mixing fluid is increased as the mixing fluid passes the flow directors 200 . Step 113 provides for discharging the mixing fluid from the mixing fluid channel 72 to contact exiting beverage syrup to mix therewith outside of the beverage dispensing nozzle 10 .
In embodiments where a second beverage dispensing stream is also being dispensed from the nozzle 10 , the method of FIG. 11 a would further include steps 99 , 104 and 109 as shown in FIG. 11 b . Similarly, the process begins with step 98 , wherein a beverage syrup is delivered to a first beverage syrup inlet port 21 . A second beverage syrup is then delivered to a second beverage syrup inlet port 22 as shown in step 99 . Next, step 102 , a mixing fluid is delivered to a mixing fluid inlet port 27 . The process then moves to step 103 , wherein the first beverage syrup is delivered form the first beverage syrup inlet port 21 to a first beverage syrup channel 54 . In step 104 , the second beverage syrup is delivered to a second beverage syrup channel 58 . The mixing fluid is delivered from the mixing fluid inlet port 27 to a mixing fluid channel 72 in step 107 . Next, the first beverage syrup is discharged from the first beverage syrup channel 54 , step 108 . Likewise, the second beverage syrup is discharged from the second beverage syrup channel 58 , step 109 . In step 112 , the velocity of the mixing fluid is increased by passing it through the flow directors 200 . The mixing fluid is then discharged from the mixing fluid channel 72 to mix therewith outside of the beverage dispensing nozzle 10 with exiting beverage syrup.
In an embodiment wherein three syrups are desired, the method of FIG. 11 b further includes steps 100 , 105 and 110 , as shown in FIG. 11 c . Similarly, the process begins with step 98 , wherein a beverage syrup is delivered to a first beverage syrup inlet port 21 . A second beverage syrup is then delivered to a second beverage syrup inlet port 22 as shown in step 99 . In step 100 , a third beverage syrup is delivered to a third beverage syrup inlet port 23 . Next, step 102 , a mixing fluid is delivered to a mixing fluid inlet port 27 . The process then moves to step 103 , wherein the first beverage syrup is delivered form the first beverage syrup inlet port 21 to a first beverage syrup channel 54 . In step 104 , the second beverage syrup is delivered to a second beverage syrup channel 58 . The process then moves to step 105 , wherein the third beverage syrup is delivered to a third beverage syrup channel 63 . The mixing fluid is delivered from the mixing fluid inlet port 27 to a mixing fluid channel 72 in step 107 . Next, the first beverage syrup is discharged from the first beverage syrup channel 54 , step 108 . Likewise, the second beverage syrup is discharged from the second beverage syrup channel 58 , step 109 , and the third beverage syrup is discharged from the third beverage syrup channel 63 , step 110 . In step 112 , the velocity of the mixing fluid is increased by passing it through the flow directors 200 . The mixing fluid is then discharged from the mixing fluid channel 72 to mix therewith outside of the beverage dispensing nozzle 10 with exiting beverage syrup.
In an embodiment where a flavor additive is desired while using the beverage dispensing nozzle 900 , the method flowchart of FIG. 11 a further includes steps 101 , 106 and 111 as shown in FIG. 11 d . The process begins with step 98 , wherein a beverage syrup is delivered to a first beverage syrup inlet port 21 . The process then moves to step 101 , wherein a flavor additive is delivered to a flavor additive inlet port 901 . In step 102 , a mixing fluid is delivered to a mixing fluid inlet port 27 . Step 103 provides for delivering the beverage syrup from the first beverage syrup inlet port 21 to the first beverage syrup channel 54 . The process then moves to step 106 , wherein the flavor additive is then delivered from the flavor additive inlet port 901 to a flavor additive passageway 905 in the third annulus 919 . Next, the mixing fluid is delivered from the mixing fluid inlet port 27 to the mixing fluid channel 72 , step 107 . The process continues with step 108 , wherein the beverage syrup is discharged from the first beverage syrup channel 54 . The process moves to step 111 , wherein the flavor additive is discharged form the third annulus 919 . In step 112 , the velocity of the mixing fluid is increased as the mixing fluid passes the flow directors 200 . Step 113 provides for discharging the mixing fluid from the mixing fluid channel 72 to contact exiting beverage syrup to mix therewith outside of the beverage dispensing nozzle 900 .
In another embodiment, the beverage dispensing nozzle 10 may be a standard beverage dispensing nozzle, i.e. not an air-mix beverage dispensing nozzle, wherein the beverage syrup and the mixing fluid streams mix in a mixing chamber prior to exiting the nozzle. The method flowchart for this embodiment is shown in FIG. 12 a . The method process commences with step 115 , wherein a beverage syrup is delivered to a first beverage syrup inlet port 21 . In step 117 , a mixing fluid is delivered to a mixing fluid inlet port 27 . Step 118 provides for delivering the beverage syrup from the first beverage syrup inlet port 21 to the first beverage syrup channel 54 . Next, the mixing fluid is delivered from the mixing fluid inlet port 27 to the mixing fluid channel 72 , step 120 . The process continues with step 121 , wherein the beverage syrup is discharged from the first beverage syrup channel 54 . In step 123 , the velocity of the mixing fluid is increased as the mixing fluid passes the flow directors 200 . Step 124 provides for discharging the mixing fluid from the mixing fluid channel 72 to mix with exiting beverage syrup.
A method flowchart for one variation of using flow directors 200 in an application with two beverage syrups is shown in FIG. 12 b . Similar to the method shown in FIG. 12 a , the process commences with a delivery of a first beverage syrup to a first beverage syrup inlet port 21 , step 115 . A second beverage syrup is then delivered to a second beverage syrup inlet port 22 in step 116 . The process continues with the delivery of a mixing fluid to a mixing fluid inlet port 27 as shown in step 117 . Step 118 provides for delivering the first beverage syrup from the first beverage syrup inlet port 21 to a first beverage syrup channel 54 . Similarly, the second beverage syrup is delivered from the second beverage syrup inlet port 22 to a second beverage syrup channel 58 in step 119 . Delivery of the mixing fluid from the mixing fluid inlet port 27 to a mixing fluid channel 72 follows in step 120 . The first beverage syrup is then discharged from the first beverage syrup channel as shown in step 121 . Likewise, the second beverage syrup is discharged from the second beverage syrup channel 58 in step 122 . The velocity of the mixing fluid is increased in the mixing fluid channel 72 as it passes the flow directors 200 disposed therein in step 123 . In step 124 , the mixing fluid is discharged from the mixing fluid channel to mix with exiting beverage syrup.
Although the present invention has been described in terms of the foregoing preferred embodiment, such description has been for exemplary purposes only and, as will be apparent to those of ordinary skill in the art, many alternatives, equivalents, and variations of varying degrees will fall within the scope of the present invention. That scope, accordingly, is not to be limited in any respect by the foregoing detailed description; rather, it is defined only by the claims that follow.
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A method and apparatus for a beverage dispensing nozzle equipped with at least one flow director dispenses at lower flowrates. In a first embodiment, a single flavor beverage dispensing nozzle equipped with at least one flow director segments the flow and reduces the cross sectional area of the fluid stream, thereby forcing product to move downward. A second embodiment provides an improvement to an existing beverage dispensing nozzle, by adding at least one flow director in an annular channel of the beverage dispensing nozzle. The addition of the at least one flow director in the annular channel provides the beverage dispensing nozzle with the ability to dispense product at lower flowrates by increasing the velocity component of the exiting product. The exiting product now has sufficient energy to separate from the beverage dispensing nozzle. Methods for using the beverage dispensing nozzles with the at least one flow director are also presented.
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The present invention relates generally to protective garments for use with gloves, for example surgical gowns used with surgical gloves.
Protective garments, such as coveralls and gowns, designed to provide barrier protection to a wearer are well known in the art. Such protective garments are used in situations where isolation of a wearer from a particular environment is desirable, or it is desirable to inhibit or retard the passage of hazardous liquids and biological contaminates through the garment to the wearer.
In the medical and health-care industry, particularly with surgical procedures, a primary concern is isolation of the medical practitioner from patient fluids such as blood, saliva, perspiration, etc. Protective garments rely on the barrier properties of the fabrics used in the garments, and on the construction and design of the garment. Openings or seams in the garments may be unsatisfactory, especially if the seams or openings are located in positions where they may be subjected to stress and/or direct contact with the hazardous substances.
Gloves are commonly worn in conjunction with protective garments, particularly in the medical industry. Typically, the gloves are pulled up over the cuff and sleeve of a gown or garment. However, the interface between the glove and the protective garment can be an area of concern. For example, a common issue with surgical gloves is glove “roll-down” or slippage resulting from a low frictional interface between the interior side of the glove and the surgical gown sleeve. When the glove rolls down or slips on the sleeve, the wearer is at greater risk of exposure to patient fluids and/or other contaminants.
An additional problem associated with the use of surgical gloves is that as a result of the gloves being pulled up over the cuff and sleeve of the gown, a phenomenon known as “channeling” occurs. That is, the sleeve of the gown is bunched up under the glove as a result of pulling and rolling the glove up over the cuff and sleeve. Channels may develop along the wearer's wrist which may become accessible to patient fluids running down the outside of the sleeve of the gown. Such fluids may enter the channels and work down along the channels between the outer surface of the gown and inner surface of the surgical glove. The fluids may then contaminate the gown cuff, which lies directly against the wearer's wrist or forearm, particularly if the cuff is absorbent or fluid pervious.
Surgeons and other medical personnel have attempted to address concerns with the glove and gown interface in different ways. For example, it has been a common practice to use adhesive tape wrapped around the glove portion extending over the gown sleeve to prevent channels and roll down of the glove on the sleeve. This approach unfortunately has some drawbacks. Many of the common adhesives utilized in tapes are subject to attack by water and body fluids and the seal can be broken during a procedure. Another approach has been to stretch a rubber band around the glove and sleeve. This practice is, however, awkward to implement and difficult to adjust or to vary the pressure exerted by the rubber band other than by using rubber bands of different sizes and tensions, which of course necessitates having a variety of rubber bands available for use. Yet another approach has been to incorporate a band of elastomeric polymer on the gown around the sleeve just above the cuff to provide a surface for the glove to cling to. This approach has also proved less than completely satisfactory.
A need exists for an improved device and method for providing an effective sealing interface between a glove and sleeve of a protective garment, wherein the device is easily incorporated with the protective garment and economically cost effective to implement. A further need exists for a gown sleeve that provides a more effective barrier to fluid while retaining a glove.
SUMMARY
The present invention provides a protective garment incorporating an effective and economical means for improving the interface area between the sleeves of the garment and a glove pulled over the sleeves. The improvement inhibits the proximal end of the glove from rolling or sliding back down the garment sleeves once the wearer has pulled the gloves on. In this way, the garment according to the invention addresses at least certain of the disadvantages of conventional garments discussed above.
It should be appreciated that, although the present invention has particular usefulness as a surgical gown, the invention is not limited in scope to surgical gowns or the medical industry.
The protective garment according to the present invention has wide application and can be used in any instance wherein a protective coverall, gown, robe, etc., is used with gloves. All such uses and garments are contemplated within the scope of the invention.
In an embodiment of the invention, a protective garment is provided having a garment body. The garment may be, for example, a surgical gown, a protective coverall, etc. The garment body includes sleeves, and the sleeves may have a cuff disposed at the distal end thereof. The cuffs may be formed from or include elastic fibers, and may be liquid retentive or liquid impervious.
In one embodiment, the sleeve is formed with a layer of spunbond elastomeric fibers on the outside, where it may be contacted by a glove. The entire sleeve may advantageously be made of the elastomeric fiber or it may be a component of the outer layer along with non-elastomeric fibers. The elastomeric fibers are by their nature more tacky than non-elastomeric fibers and so provide a higher surface friction between the glove and garment to help keep the glove in place.
The elastomeric fibers prevent glove roll-down while not causing the sleeves to adhere to the gown body when the gown is folded.
Embodiments of the protective garment according to the invention are described below in greater detail with reference to the appended figures.
BRIEF DESCRIPTION OF THE FIGURES
FIG. 1 is a partial side view of an embodiment of a protective garment according to the present invention.
FIG. 2 is a partial side view of a garment sleeve according to an embodiment of the present invention.
FIG. 3 is an illustration of an exemplary flat sleeve piece before it is formed into a separate sleeve.
DETAILED DESCRIPTION
Reference will now be made in detail to one or more examples of the invention depicted in the figures. Each example is provided by way of explanation of the invention, and not meant as a limitation of the invention. For example, features illustrated or described as part of one embodiment may be used with another embodiment to yield still a different embodiment. Other modifications and variations to the described embodiments are also contemplated within the scope and spirit of the invention.
As used herein the term “spunbonded fibers” refers to small diameter fibers which are formed by extruding molten thermoplastic material as filaments from a plurality of fine, usually circular capillaries of a spinneret with the diameter of the extruded filaments then being rapidly reduced as by, for example, in U.S. Pat. No. 4,340,563 to Appel et al., and U.S. Pat. No. 3,692,618 to Dorschner et al., U.S. Pat. No. 3,802,817 to Matsuki et al., U.S. Pat. Nos. 3,338,992 and 3,341,394 to Kinney, U.S. Pat. No. 3,502,763 to Hartman, and U.S. Pat. No. 3,542,615 to Dobo et al. Spunbond fibers are generally not tacky when they are deposited onto a collecting surface. Spunbond fibers are generally continuous and have average diameters (from a sample of at least 10) larger than 7 microns, more particularly, between about 10 and 20 microns. The fibers may also have shapes such as those described in U.S. Pat. No. 5,277,976 to Hogle et al., U.S. Pat. No. 5,466,410 to Hills and U.S. Pat. No. 5,069,970 and U.S. Pat. No. 5,057,368 to Largman et al., which describe fibers with unconventional shapes.
As used herein the term “meltblown fibers” means fibers formed by extruding a molten thermoplastic material through a plurality of fine, usually circular, die capillaries as molten threads or filaments into converging high velocity, usually hot, gas (e.g. air) streams which attenuate the filaments of molten thermoplastic material to reduce their diameter, which may be to microfiber diameter. Thereafter, the meltblown fibers are carried by the high velocity gas stream and are deposited on a collecting surface to form a web of randomly dispersed meltblown fibers. Such a process is disclosed, for example, in U.S. Pat. No. 3,849,241 to Butin et al. Meltblown fibers are microfibers which may be continuous or discontinuous, are generally smaller than 10 microns in average diameter, and are generally tacky when deposited onto a collecting surface.
As used herein “multilayer nonwoven laminate” means a laminate wherein some of the layers are spunbond and some meltblown such as a spunbond/meltblown/spunbond (SMS) laminate and others as disclosed in U.S. Pat. No. 4,041,203 to Brock et al., U.S. Pat. No. 5,169,706 to Collier, et al, U.S. Pat. No. 5,145,727 to Potts et al., U.S. Pat. No. 5,178,931 to Perkins et al. and U.S. Pat. No. 5,188,885 to Timmons et al. Such a laminate may be made by sequentially depositing onto a moving forming belt first a spunbond fabric layer, then a meltblown fabric layer and last another spunbond layer and then bonding the laminate in a manner described below. Alternatively, the fabric layers may be made individually, collected in rolls, and combined in a separate bonding step. Such fabrics usually have a basis weight of from about 0.1 to 12 osy (6 to 400 gsm), or more particularly from about 0.75 to about 3 osy. Multilayer laminates may also have various numbers of meltblown layers or multiple spunbond layers in many different configurations and may include other materials like films (F) or coform materials, e.g. SMMS, SM, SFS, etc.
FIG. 1 illustrates a protective garment 10 according to the invention. The garment 10 includes a main body portion 12 , a neck portion 14 , and sleeves 16 (one sleeve shown). The sleeves 16 may be made separately and attached at to the main body portion 12 at a seam 18 or formed as an integral component with the main body portion 12 . Each sleeve 16 may include an upper or proximal end 20 , a lower of distal end 22 , and an exterior surface 24 .
The garment 10 is depicted as a surgical gown for illustrative purposes only. The garment 10 may be any type or style of protective covering that is generally worn about the body and includes sleeves.
The terms “lower” or “distal” are used herein to denote features that are closer to the hands of the wearer. The terms “upper” or “proximal” are used to denote features that are closer to the shoulder of the wearer.
It should be appreciated that the type of fabric or material used for garment 10 is not a limiting factor of the invention. The garment 10 may be made from a multitude of materials, including multilayer nonwoven laminates suitable for disposable use. For example, gown embodiments of the garment 10 may be made of a stretchable nonwoven material so that the gown is less likely to tear during donning or wearing of the gown.
A material particularly well suited for use with the present invention is a three-layer nonwoven polypropylene material known as SMS. “SMS” is an acronym for Spunbond, Meltblown, Spunbond, the process by which the three layers are constructed and then laminated together. One particular advantage is that the SMS material exhibits enhanced fluid barrier characteristics. It should be noted, however, that other multilayer nonwoven laminates as well as other materials including wovens, elastic fibers, foam/elastic fiber laminates, and combinations thereof may be used to construct the garment of the present invention, provided a layer containing elastomeric spunbond fibers is provided as the outermost surface. Examples include SMS laminates where one of the outer layers is spunbond elastic fiber.
The sleeves 16 may incorporate a cuff 26 attached to the distal end 22 thereof. The cuff 26 also has a distal end 28 and a proximal end 30 . The configuration and materials used in the cuff 26 may vary widely. For example, short, tight-fitting cuffs made from a knitted material may be provided. The cuff 26 may be formed with or without ribs. The cuff may be formed of a liquid repellant material or a liquid retentive material. Cuffs suitable for use with garments according to the present invention are described in U.S. Pat. Nos. 5,594,955 and 5,680,653, both of which are incorporated herein in their entirety for all purposes.
As shown for example in FIG. 2 , protective garments are frequently used with gloves, such as a surgical glove 32 that is pulled over the hand of the wearer and has a sufficient length so that a proximal portion of the glove 32 overlaps the cuff 26 and a portion of the sleeve 16 . An interface is thus established between the glove interior surface and the exterior surface 24 of the sleeve 16 and cuff 26 . This interface region preferably inhibits undesirable fluids or other contaminants from running down the sleeve 16 to the cuff 26 or hand 34 of the wearer. However, glove slippage or roll-down occurs if the frictional interface between the glove interior surface and the sleeve exterior surface is insufficient to maintain the glove in position above the cuff 26 . When glove roll-down occurs, the wearer is at greater risk of exposure to contaminants, particularly during a surgical procedure.
Many types of protective gloves, particularly elastic synthetic or natural rubber surgical gloves, have a thickened bead or region at the open proximal end 36 . This thickened portion or bead is intended to strengthen the glove 32 and provide an area of increased elastic tension to aid in holding the glove 32 up on the sleeve 16 .
According to one embodiment of the invention, the garment 10 includes an elastic fiber layer 40 formed on the outside of the sleeves 16 from the proximal end 30 of the cuff 26 ( FIGS. 1 and 2 ). The elastic fiber layer 40 thus acts as a high friction surface against which the thickened proximal end 36 of the glove 32 contacts if the glove tends to slip down the exterior surface 24 of the glove. The elastic fiber layer 40 inhibits further slippage or roll-down of the glove 32 . The terms “elastic” and “elastomeric” in reference to fibers means a fiber or fibrous web which, when stretched up to 100 percent of its unstretched length, will, once the stretching force is removed, recover to at most 150 percent of its unstretched length. If, for example, an elastic fibrous web is stretched from 10 centimeters in length to 20 centimeters in length and the stretching force released, it will recover to a length of at most 15 centimeters.
The elastic fiber layer 40 may extend up the sleeve 16 a distance greater than the proximal end 36 of the glove 32 extends when the glove is normally donned. The dimensions of the elastic fiber area may vary as the size of the gown may also vary. As shown in FIG. 3 , the elastic fiber area may extend away from the cuff 26 for a distance of about 20 inches (51 cm), more particularly about 10 inches (25 cm).
It should be appreciated that the elastic fiber layer 40 can take on many different configurations. FIG. 3 shows a flat sleeve piece before it is formed into a separate sleeve 16 . The sleeve 16 may be formed by bonding, for example ultrasonically, the two edges 50 , 52 to each other and thereafter bonding the sleeve 16 to the main body portion 12 at the sleeve's distal end 20 to form a seam 18 . The elastic fiber layer 40 may be continuous around the sleeve 16 . The particular geometric configuration of the elastic fiber layer 40 may vary widely so long as a generally circumferentially extending area or region is provided, with the elastic fiber being sufficient to inhibit glove slippage or roll-down.
The inventors have surprisingly found that a relatively uniform elastic fiber layer of a low-tack, high-friction polymer is quite effective and lends itself easily to modern manufacturing techniques. The elastic fiber layer 40 may be formed on the sleeve in various known ways and from a variety of materials. It is contemplated that the most cost-effective and rapid is the direct formation of the elastic layer onto the meltblown layer in, for example, as the spunbond layer of an SMS laminate.
The elastic fiber layer 40 may be formed of an inherently low-tack material with high frictional characteristics. This type of elastic fiber increases slip resistance between the glove and sleeve 16 and may be applied directly onto the exterior surface 24 of the sleeve to form the elastic fiber layer 40 . In general, the elastic fiber could be any polymer that is sufficiently soft and pliable so as to cling to the inside surface of the glove 32 but at the same time should not have too high a tack level so as to cause the garment sleeve 16 to stick to the garment body 12 when the garment 10 is folded, hence the term “low-tack”. The term “high frictional characteristics” means that the coefficient of friction of the fabric having the elastic fiber is higher than the same fabric without an elastic fiber.
Polymers such as metallocene based polyolefins are suitable examples of acceptable elastic fiber formers. Such polymers are available from ExxonMobil Chemical under the trade names ACHIEVE® and Vistamaxx™ for polypropylene based polymers and EXACT® and EXCEED® for polyethylene based polymers. Dow Chemical Company of Midland, Mich. has polymers commercially available under the names ENGAGE® and VERSIFY®. These materials are believed to be produced using non-stereo selective metallocene catalysts. ExxonMobil generally refers to their metallocene catalyst technology as “single site” catalysts while Dow refers to theirs as “constrained geometry” catalysts under the name INSIGHT® to distinguish them from traditional Ziegler-Natta catalysts which have multiple reaction sites.
Vistamaxx™ polymers are advertised as having a melt flow rate of 0.5 to 35 g/10 min., a glass transition temperature of from −20 to −30° C. and a melting temperature of from 40-160° C. Two new Vistamaxx™ grades, VM-2120 and 2125 have recently become available and these grades have a melt flow rate of about 80 with the VM-2125 grade having greater elasticity. Commercial ACHIEVE® grades include 6936G1 and 3854.
Dow's VERSIFY® polymers have a melt flow rate from 2 to 25 g/10 min., a glass transition temperature of from −15 to −35° C. and a melting temperature of from 50-135° C.
U.S. Pat. No. 5,204,429 to Kaminsky et al. describes a process which may produce elastic copolymers from cycloolefins and linear olefins using a catalyst which is a sterorigid chiral metallocene transition metal compound and an aluminoxane. The polymerization is carried out in an inert solvent such as an aliphatic or cycloaliphatic hydrocarbon such as toluene. The reaction may also occur in the gas phase using the monomers to be polymerized as the solvent. U.S. Pat. Nos. 5,278,272 and 5,272,236, both to Lai et al., assigned to Dow Chemical and entitled “Elastic Substantially Linear Olefin Polymers” describe polymers having particular elastic properties.
Other suitable elastic fibers include, for example, ethylene vinyl acetate copolymers, styrene-butadiene, cellulose acetate butyrate, ethyl cellulose, synthetic rubbers including, for example, Kraton® block copolymers, natural rubber, polyurethanes, polyethylenes, polyamides, flexible polyolefins, and amorphous polyalphaolefins (APAO).
In the practice of the instant invention, elastic polyolefins like polypropylene and polyethylene are desirable, most desirably elastic polypropylene. Elastic fiber may be from 100 percent of the layer to as little as 10 percent, more particularly between 50 and 100 percent. The basis weight of the fabric may be between 0.1 and 10 osy (0.34 and 34 gsm), desirably between 0.5 and 5 osy (0.6 and 15.8 gsm) more desirably between 0.5 and 1.5 osy (0.6 and 51 gsm).
Other materials may be added to the elastic fiber to provide particular characteristics. These optional materials may include, for example, dyes, pigment or other colorants to give the elastic fiber area a visually perceptible color such as yellow, green, red or blue (e.g. Sudan Blue 670 from BASF). These colors may be used to indicate the protection level accorded by the gown according to, for example, the standards of the Association for the Advancement of Medical Instrumentation (AAMI), e.g., ANSI/MMI PB70:2003. A user would thus be able to select a gown for a surgical procedure where the sleeve color corresponded to or indicated the fluid protection level of the gown.
Fabrics were produced by the spunbond process in order to test the invention. These fabrics were then tested for the coefficient of friction (COF) according to ASTM test method D1894. A control sleeve fabric made from ExxonMobil's PP3155 homopolymer polypropylene (36 g/10 min. melt flow) had a COF of 0.414 in the machine direction (MD) and of 0.538 in the cross machine direction (CD). An inventive fabric made from ExxonMobil's Vistamaxx™ polypropylene had a COF of 0.868 in the MD and of 0.1.332 in the CD. An inventive fabric made from Dow's VERSIFY® polypropylene had a COF of 0.858 in the MD and of 0.1.042 in the CD. The inventive sleeve fabric, therefore, had a COF in either the machine or cross-machine directions that was at least twice that of a traditional spunbonding polypropylene like ExxonMobil's PP3155. Fibers that produce fabrics with such high frictional characteristics will result in less glove slip-down and better protection for the wearer. In addition, these fabrics were not so tacky as to cause “blocking” or the inability to separate them, after they were folded over onto themselves.
It should be appreciated by those skilled in the art that various modifications and variations can be made to the embodiments of the present invention described and illustrated herein without departing from the scope and spirit of the invention. The invention includes such modifications and variations coming within the meaning and range of equivalency of the appended claims.
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A protective garment, such as a surgical gown, includes a garment body defining sleeves. A cuff may be secured at respective ends of the sleeves. An elastic fiber layer is disposed on the sleeves beginning at the sleeve or cuff. The elastic fiber layer has a high friction surface such that an end of a glove pulled over the elastic fiber layer is inhibited from rolling or sliding back over the elastic fiber and down the sleeve. The elastic fiber may be formed of a polyolefin or other polymers according to known processes and may include a dye or colorant that may be used to indicate the fluid protection level of, for example, a surgical gown.
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BACKGROUND OF THE INVENTION
There has recently been great interest on the part of consumers in alternative forms of cleansing products. One such form is called the body wash. This is a liquid or gelled product which can be used as an alternative to the more traditional soap bars.
One problem with the use of these alternative washing products is that the consumer lacks an implement with which physically to wash. Many consumers are used to using the soap bar for scrubbing. Also, there may at times be a perception that the lathering which is obtained with the alternative products is not as copious as that which is obtained with many soap bars. As a result of these concerns, various implements have been considered for use in connection with alternative cleansing agents. These have included diamond-mesh sponges (also known as poufs) and other types of sponges such as reticulated sponges.
The increased use of washing implements has presented the packaging engineer with the need to package appealingly combinations of the new cleansing agents with the washing implements. Since the sponges tend to be porous, non-dense materials, it can be awkward to package them together with the cleansing agents, which are formulations and can be packaged in more traditional packages such as bottles.
Inserts have long been used in packaging. However, where used it is desirable that inserts comprise a minimal amount of material. In the case of the new washing products, if inserts are to be used they must function to support the cleansing agent and washing implement while displaying them attractively to the consumer.
Fox, U.S. Pat. No. 1,930,235 discloses a carton made from a single blank which has partitions for receiving and compartmentalizing beverage bottles or the like.
Menten, U.S. Pat. No. 1,932,705 discloses a receptacle for transporting articles comprising article supports at each end having aligned openings adapted to receive an end of the article.
Vatter, U.S. Pat. No. 2,353,376 is directed to a container including an inner merchandise containing slide member disclosed in, e.g., FIGS. 2 and 7.
Sparks, U.S. Pat. No.2,827,219 discloses a container insert in, e.g., FIGS. 1 and 2.
Banks et al., U.S. Pat. No. 3,093,290 is directed to a carton having a product support at each end.
Roccaforte, U.S. Pat. No. 4,300,683 discloses a product display card having product securing orifices at each end.
Roccaforte, U.S. Pat. No. 4,109,786 discloses a carton having a product support at its top and its bottom.
Brintazzoli, U.S. Pat. No. 5,358,116 is directed to a package for products such as vials and the like having an element of support inserted into the box, which element has a U-shape and which element also includes a first wing having at least a first hole in which the body of the product is inserted and a second wing having at least a second hole coaxial with the first. The second hole has radial splits which form flexible segments which elastically hold the neck of the tubular product.
SUMMARY OF THE INVENTION
The present invention provides an insert, a blank for the insert and a combination of carton and insert, and a combination of insert plus cleansing agent bottle plus washing implement optionally with a carton. Preferably, the insert is designed to include a plurality of supports, especially five supports, which may include three bottom supports and two top supports, as part of the carton blank. The insert relies on the supports to stabilize the cleansing agent bottle and the washing implement to minimize movement and for a clean appearance in the carton. Some previous cartons with inserts have required false top and bottom for the carton. The need for this is eliminated with the insert of the present invention.
The insert is preferably made from a single unitary carton blank rather than multiple carton blanks. Again the carton with which the insert is used preferably does not include a false top and bottom; only closure flaps at the very top and the very bottom of the carton are required.
The insert of the invention includes a central panel and top and bottom panels. Both the top and bottom panels include flaps formed therein which are used to support the insert. Formation of the flaps also at least in part results in the formation of top and bottom product receiving apertures, which are suitable for holding the top and bottom of e.g. the cleansing agent bottle. Preferably, these apertures are disposed within the front two-thirds of the top and bottom panels so that a space is provided between the cleansing agent bottle and the central panel wherein the sponge or other washing implement may be disposed.
Another advantageous feature of the insert is that cuts are formed at the top and bottom ends of the central panel whereby top and bottom central panel extensions are formed to support the insert. These extensions respectively extend above and below the levels of the top and bottom panels so that the extensions together with the top and bottom panel supporting flaps provide parallel support for the top and bottom panels. In addition, the bottom panel includes an additional supporting flap which is distal to the central panel, at the front of the insert. Thus five supports, namely, the distal bottom panel flap, the top and bottom panel support flaps and the top and bottom central panel extensions are present.
When the cleansing agent container is received within the top and bottom apertures, the container assists in supporting the insert. The top and bottom panels in turn limit the movement of the cleansing agent container and also support the sponge. The sponge may be wedged between the cleansing agent bottle and the central panel whereby its position is stabilized between the top and bottom panels and the central panel and the cleansing agent bottle.
For a more complete understanding of the above and other features and advantages of the invention, reference should be made to the following detailed description of the preferred embodiments and to the accompanying drawings.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 is a perspective view of a carton housing the insert of the invention together with a wag implement and a cleansing agent bottle.
FIG. 2 is a top plan view of a blank for the insert of the invention.
FIG. 3 is a cross section above the lines 3--3 of FIG. 1.
FIG. 4 is a cross section along the lines 4--4 of FIG. 1.
FIG. 5 is cross section along the lines 5--5 of FIG. 1.
FIG. 6 is perspective view of an erected insert of the invention together with a carton, a cleansing agent bottle and a washing implement.
DETAILED DESCRIPTION OF THE INVENTION
Referring to FIGS. 2 and 6, insert 10 comprises central panel 12, top panel 14 and bottom panel 16. The blank from which insert 10 is erected is denoted as reference 10' in FIG. 3.
Top panel 14 is separated in part from central panel 12 by lateral foldlines 18 and 20 on either side of the blank. Top panel 14 is also separated from central panel 12 by full cut lines 22, 24 and 26. Flap 28 is formed from top panel 14 by interrupted cut line 30 and by cut lines 32, 34 and 36.
Aperture 38 is formed in top panel 14 partially as a result of folding upwardly flap 28 and partially from curve cut line 40.
Folding at lateral foldlines 18 and 20 and the cuts at lines 22, 24 and 26 results in formation of an extension 42 to the central panel 12. As can be seen in FIG. 6, flap 28 and central panel top extension 42 extend the same distance above top panel 14. This is done so that both flaps will support the insert by just touching the bottom of the top closure panels or flaps of the carton and eliminate the need for a false bottom of the carton. The bottom of the carton's top closure panels or flaps will be generally parallel to panel 14.
Bottom panel 16 is separated from central panel 12 by bottom lateral scorelines 50 and 52 and by full cut lines 54, 56 and 58. The presence of the foldlines 50 and 52 on the sides of the central panel and the cut lines 54, 56 and 58 result in the formation of a bottom extension 60 to central panel 12.
Formed within the front two-thirds of bottom panel 16 is flap 62, which is defined by interrupted cut line 64 and by cut lines 66, 68 and 70. When flap 62 is folded downwardly as shown in FIG. 6, aperture 72 is formed in bottom panel 16. Aperture 72 includes the opening formed by folding flap 62 downwardly as well as the opening 74 formed in the blank by cut line 68 and curved cut line 76.
At the distal or front end of bottom panel 16 is supporting flap 78 which is separated from panel 16 by interrupted cut line (fold line) 80.
As can be seen from FIG. 6, extension 60 and flaps 62 and 78 extend approximately the same distance below bottom flap 16. These flaps and extension support bottom flap 16 within the carton, just as flap 28 and extension 42 help stabilize the position of top flap 14 against the top closure flaps of the carton. The bottom closure panels and/or flaps will be generally parallel to flap 16.
As best seen in FIGS. 2 and 3, cleansing agent bottle 90 is received within bottom aperture 72 and top aperture 38. Preferably, the apertures are dimensioned so that the container is snugly received within the apertures. The bottle can therefore provide some support to the insert, particularly to top panel 14.
As indicated above, preferably, as illustrated in FIG. 6, apertures 38 and 72 are disposed within two-thirds of the top and bottom panels distal to the central panel 12. This leaves room for the washing implement, such as sponge 92 illustrated in FIGS. 1 and 3-6. Sponge 92 is snugly accommodated between bottle 90 and central panel 12. Thus, bottle 90 is retained within apertures 72 and 38 of the insert whereas sponge 92 is retained between bottle 90 and central panel 12 and also is confined by top panel 14 and bottom panel 16.
The blank 10' is used by folding bottom and top panels 14 and 16 in the same direction perpendicularly to central panel 12. Then, top flap 28 is folded perpendicularly and upwardly from top panel 14 and bottom flap 62 is folded downwardly and perpendicularly to bottom flap 16. Then, bottom support flap 78 is folded downwardly and perpendicularly to bottom panel 16. The washing agent container is then placed within apertures 72 and 38 and the sponge 92 is inserted behind bottle 90. The insert as thus assembled is then slid into carton 100 through either open top or bottom panels or flaps.
The insert holds the sponge 92 and bottle 90 stably in position within carton 100. Display window 102 of carton 100 permits consumers to view the bottle 90 and sponge 92. As mentioned earlier, flaps 78 and 62 and bottom extension 60 support the insert against the bottom closure flaps of carton 100. Flap 28 and extension 42 stabilize top flap 14 against the top closure panels of carton 100. Flaps 78, 62, 28 and extensions 60 and 42 avoid the need for false top and bottom panels, e.g., panels spaced from the top and bottom of the carton, in the carton 100. That is, only closure panels and/or flaps at the very top and very bottom of the carton are required.
The insert and the carton may be made of paperboard. The container for the cleansing agent may be a bottle or a carton or other suitable container. If a bottle, it will preferably be made of a plastic material. If a carton, the cleansing agent container may be either plastic or paperboard or some combination thereof.
The washing implement may be a sponge formed from polymeric diamond mesh material, also known as a pouf. The pouf may be made by gathering an endless diamond mesh tube, stretching the tube, binding the tube at the center and releasing the tube from the stretched condition to rebound into a rounded sponge shape. Alternatively, a pouf may be made in accordance with the procedure disclosed in Campagnoli, U.S. Pat. No. 5,144,744 which involves stretching a plurality of tubes, binding the tubes together near a common center of all the stretched tubes and releasing all the tubes from their stretched condition to form the rounded sponge shape.
The mesh material may be made of addition polymers of olefin monomers other than ethylene or of polyamides of polycarboxylic acids and polyamines. An alternative mesh material is nylon. The tubular netting mesh from which poufs are formed are preferably strong, flexible polymeric materials. Such mesh materials are described in e.g Sanford, U.S. Pat. No. 4,462,135, the disclosure which is incorporated herein by reference. The cord for the sponge, if present, may be made of a natural material such as rope or a synthetic material polymer such as nylon, polyethylene or polypropylene.
It has been suggested that the diamond-mesh poufs coact with washing formulations which include surfactant and a skin moisturizer. Whether or not a pouf is used, the washing agent may be a liquid personal wash cleaning formulation which includes a surfactant and a skin conditioning and moisturizing ingredient. Preferably the surfactant is a mild surfactant. Among the mild surfactants which may be used are cocamidopropyl betaine and sodium cocoylisethionate. Among other surfactants which may be used are soap and sodium laureth sulfate. Among the moisturizers which may be used are glycerine mono, di and tri-esters, mineral oil and silicone oil. A preferred moisturizer is the dimethicone emulsion sold as Dow Q2-1656, which is a 50% silicone emulsion. Thickeners such as ammonium sulfate and opacifiers such as mica/titanium dioxide may be used.
A preferred washing implement is a reticulated, i.e., open-celled sponge. The sponge may be made of any suitable polymeric material such as polyethylene. Advantageously the sponge is somewhat resilient.
In the case of the reticulated sponge, the sponge is preferably formed from a reticulated foam. Preferably the foam is made from a synthetic polymer. The foam is preferably within the pore size range of 10 to about 100 pores per linear inch, especially from 10 to 60 pores per linear inch. Foams are available from companies such as Scott Paper Company of Chester, Pa. Methods for reticulation of open celled plastic foams are described in U.S. Pat. Nos. 3,475,525 and 3,476,933, which are incorporated by reference herein.
It may be desirable to vary the pore size to influence the formation of foam. For an immediate transfer of foam, a large cell size of 40 to 90 cells per square inch, especially from 40 to 70, may be used. For intermediate foam transfer, 91 to 145, especially from 100 to 130 cells per square inch may be used. For long lasting foam retention, from 146 to 200, particularly from 170 to 200 cells per square inch may be employed.
It may also be desirable to include varied pore sizes on the sponge. For instance, the top surface of the sponge may have cells within one of the above ranges, e.g. designed for immediate transfer and the bottom surface may have cells within a different range, e.g. designed for long lasting foam retention. For instance, this may be achieved by laminating two or more layer of sponge together, each layer having a different pore size.
Foams which may be reticulated for the washing implement in accordance with the invention include polyurethane, polyester, polyethylene, polyether, polyester base urethane, and polyolefins such as polypropylene, silicate foams, ceramic foams, latex and natural rubber foams and cellulose sponges. Polyether base urethane reticulated foams are particularly preferred because of their enhanced resistance to moisture and solvents. Polyvinyl alcohol may be used.
Pore diameters may, for example, be in the range of 300-400 microns.
It should be understood of course that the specific forms of the invention herein illustrated and described are intended to be representative only as certain changes may be made therein without departing from the clear teachings of the disclosure. Accordingly reference should be made to the following appended claims in determining the full scope of the invention.
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The present invention provides an insert, a blank for the insert and a combination of carton and insert, plus the combination of insert and cleansing agent bottle and the combination of insert plus cleansing agent bottle plus washing implement. The insert is designed to include five supports, three bottom supports and two top supports as part of the carton blank. The insert relies on the bottle for support. The insert stabilizes the cleansing agent bottle and the washing implement to minimize movement.
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CROSS-REFERENCE TO RELATED APPLICATION(S)
[0001] This application is a continuation of U.S. patent application Ser. No. 10/915,625, filed Aug. 10, 2004, which claims priority from U.S. Provisional Patent Application No. 60/494,132, filed Aug. 1, 2003. The contents of these applications are incorporated herein by reference in their entirety.
FIELD OF INVENTION
[0002] The present invention relates to the field of drug delivery devices and more specifically implantable drug deliver/devices made of polyurethane based polymers.
BACKGROUND OF THE INVENTION
[0003] Due to its excellent biocompatibility, biostability and physical properties, polyurethane or polyurethane-containing polymers have been used to fabricate a large number of implantable devices, including pacemaker leads, artificial hearts, heart valves, stent coverings, artificial tendons, arteries and veins. See e.g., www.polymertech.com, www.cardiotech-inc.com, and www.thermedicsinc.com. Also see Hsu et al., Soc. Biomaterials Trans., April 1998.
[0004] Known in the art is U.S. Pat. No. 3,975,350 which discloses the use of polyurethanes to make implants containing pharmaceutically active agents. This patent discloses that the active agents are mixed with the polyurethane polymer prior to being cast (or shaped) into a number of forms, including tubes, rods, films, etc.
[0005] Also known is U.S. Pat. No. 3,993,073 which discloses a delivery device for the controlled and continuous administration of a drug to a body site. The device disclosed therein comprises a reservoir containing a dissolved drug surrounded by a shaped wall which is insoluble in body fluid.
[0006] U.S. Pat. No. 3,948,254 discloses a drug delivery device for the administration of a drug. The drug is contained within a reservoir and the device comprises pores filled with a liquid which is permeable to the passage of the drug.
[0007] The inventors are not aware of any prior art polyurethane based drug delivery devices which can contain a drug in a solid form and which does not require a liquid medium or carrier for the diffusion of the drug at a zero order rate.
SUMMARY OF THE INVENTION
[0008] It is an object of the present invention to provide polyurethane based long term drug delivery devices.
[0009] It is a further object of the present invention to provide biocompatible and biostable polyurethane based devices for the delivery of drugs or other compounds in a living organism.
[0010] This is accomplished through a drug delivery device for releasing one or more drugs at controlled rates for an extended period of time to produce local or systemic pharmacological effects, said drug delivery device having a reservoir comprising:
a) a polyurethane based polymer completely surrounding the reservoir; b) at least one active ingredient; and, optionally, c) at least one pharmaceutically acceptable carrier;
[0014] Preferably, the drug delivery device has a cylindrically shaped reservoir.
[0015] Preferably also, the polyurethane based polymer is selected from the group consisting of: thermoplastic polyurethane, and thermoset polyurethane. Even more preferably, the thermoplastic polyurethane is made of macrodials, diisocyanates, difunctional chain extenders or mixtures thereof.
[0016] Preferably, the thermoset polyurethane is made of multifunctional polyols, isocyanates, chain extenders or mixtures thereof.
[0017] Preferably also, the thermoset polyurethane comprises a polymer chain and cross-linking members, said thermoset polyurethane contains unsaturated bonds in the polymer chains and appropriate crosslinkers and/or initiators as cross-linking members.
[0018] Preferably, the drug delivery device is made of polyurethane which comprises functional groups selected from hydrophilic pendant groups and hydrophobic pendant groups. More preferably, the hydrophilic pendant groups are selected from ionic, carboxyl, ether, hydroxyl groups and mixtures thereof. Even more preferably, the hydrophobic pendant groups are selected from alkyl and siloxane groups and mixtures thereof.
[0019] Another object of the present invention is a process of manufacturing a drug delivery device, said process comprising:
a) precision extrusion or injection molding step to produce a hollow tube made of thermoplastic polyurethane with two open ends with desired physical dimensions; b) sealing one of the open ends of the hollow tube; c) loading a reservoir containing a desired formulation containing actives and, optionally, carriers or filling a reservoir with pro-fabricated pellets; d) sealing the second open end of the hollow tube; and e) conditioning and priming of the drug delivery devices to achieve the desired delivery rates for the actives.
[0025] Preferably, the sealing steps may be carried out by using pro-fabricated plugs which are inserted on the open ends of the hollow tube with heat or solvent or by applying heat or solvent while sealing or any other means to seal the ends, preferably permanently.
[0026] Yet another object of the present invention is a process of manufacturing drug delivery devices made with thermoset polyurethanes, said process comprising:
a) precision reaction injection molding or spin casting a hollow tube having two open ends; b) curing the hollow tube; c) scaling one end of the hollow tube; d) loading a reservoir containing a desired formulation containing actives and, optionally, carriers or filling a reservoir with pro-fabricated pellets; e) sealing the second end of the hollow tube; and f) conditioning and priming of the drug delivery devices to achieve the desired delivery rates for the actives.
[0033] Yet another object of the present invention is a process of manufacturing drug delivery devices made with thermoset polyurethanes, said process comprising.
a) precision reaction injection molding or spin casting a hollow tube having one open end; b) curing the hollow tube; c) loading a reservoir containing a desired formulation containing actives and, optionally, carriers or filling a reservoir with pre-fabricated pellets; d) sealing the open and of the hollow tube; and e) conditioning and priming of the drug delivery devices to achieve the desired delivery rates for the actives.
[0039] Another object of the present invention is a process of manufacturing drug delivery devices made with thermoset polyurethanes, wherein the production of the hollow tube and sealing of an open end, is done with an appropriate light-initiated and/or heat-initiated thermoset polyurethane formulation and initiating and curing the light-initiated and/or heat-initiated thermoset polyurethane formulation with light and/or heat or any other means to seal the ends, preferably permanently.
[0040] Also another object of the present invention involves a process of manufacturing drug delivery devices made with thermoset polyurethanes, wherein the sealing of an open end, is done by inserting a pre-fabricated end plug at the open end of the hollow tube by suitable means, for example, as described in U.S. Pat. No. 5,292,515. Such suitable means are preferably pharmaceutically acceptable adhesives.
[0041] Yet another object of the invention is a process of manufacturing drug delivery devices made with thermoset polyurethanes, wherein the sealing of an open end, is done by inserting a pre-fabricated end plug at the open end of the hollow tube and by applying an appropriate light-initiated and/or heat-initiated thermoset polyurethane formulation on interface between the pre-fabricated end plug and the open end and initiating and curing with light and/or heat or any other means to seal the ends, preferably permanently.
[0042] In one instance there is provided a drug delivery device for releasing one or more drugs at controlled rates for an extended period of time to produce local or systemic pharmacological effects, said drug delivery device having a reservoir comprising:
i. at least one active ingredient; and, optionally, ii. at least one pharmaceutically acceptable carrier, and iii. a polyurethane based polymer completely surrounding the reservoir.
[0046] Preferably the drug delivery device has a cylindrically shaped reservoir.
[0047] Preferably, the polyurethane based polymer is selected from the group comprising: thermoplastic polyurethane, and thermoset polyurethane. More preferably, the thermoplastic polyurethane is made of macrodials, diisocyanates, difunctional chain extenders or mixtures thereof. Also more preferably, the thermoset polyurethane is made of multifunctional polyols, isocyanates, chain extenders or mixtures thereof.
[0048] Even more preferably, the thermoset polyurethane comprises a polymer chain and cross-linking members, said thermoset polyurethane contains unsaturated bonds in the polymer chains and appropriate crosslinkers and/or initiators as cross-linking members.
[0049] Preferably, the polyurethane comprises functional groups selected from hydrophilic pendant groups and hydrophobic pendant groups. More preferably, the hydrophilic pendant groups are selected from ionic, carboxyl, ether, hydroxyl groups and mixtures thereof. Also preferably, the hydrophobic pendant groups are selected from alkyl, siloxane groups and mixtures thereof.
[0050] In one instance there is provided for a process of manufacturing drug delivery devices made with thermoplastic polyurethanes, said process comprising:
a) precision extrusion or injection molding step to produce a hollow tube made of thermoplastic polyurethane with two open ends with desired physical dimensions; b) sealing one of the open ends of the hollow tube; c) loading a reservoir containing a desired formulation containing actives and, optionally, carriers or filling a reservoir with pre-fabricated pellets; d) sealing the second open end of the hollow tube; e) conditioning and priming of the drug delivery devices to achieve the desired delivery rates for the actives.
[0056] Preferably, the sealing steps may be carried out by using pro-fabricated plugs which are inserted on the open ends of the hollow tube with heat or solvent or by applying heat or solvent while sealing or any other means to seal the ends, preferably permanently.
[0057] In one instance there is provided for a process of manufacturing drug delivery devices made with thermoset polyurethanes, said process comprising:
a) precision reaction injection molding or spin casting a hollow tube having two open ends; b) curing the hollow tube; c) scaling one end of the hollow tube; d) loading a reservoir containing a desired formulation containing actives and, optionally, carriers or filling a reservoir with pro-fabricated pellets; e) sealing the second end of the hollow tube; and f) conditioning and priming of the drug delivery devices to achieve the desired delivery rates for the actives.
[0064] In another instance there is provided for a process of manufacturing drug delivery devices made with thermoset polyurethanes, said process comprising:
a) precision reaction injection molding or spin casting a hollow tube having one open end; b) curing the hollow tube; c) loading a reservoir containing a desired formulation containing actives and, optionally, carriers or filling a reservoir with pro-fabricated pellets; d) sealing the open end of the hollow tube; and e) conditioning and priming of the drug delivery devices to achieve the desired delivery rates for the actives.
[0070] Preferably, the production of the hollow tube and the sealing of an open end are done with an appropriate light-initiated and/or heat-initiated thermoset polyurethane formulation and initiating and curing the light-initiated and/or heat-initiated thermoset polyurethane formulation with light and/or heat or any other means to seal the ends, preferably permanently.
[0071] More preferably, the sealing of an open end, is done by inserting a pre-fabricated end plug at the open end of the hollow tube by suitable means, for example, as described in U.S. Pat. No. 5,292,515. Such suitable means are preferably pharmaceutically acceptable adhesives. Even more preferably, the sealing of an open end, is done by inserting a pro-fabricated end plug at the open end of the hollow tube and by applying an appropriate light-initiated and/or heat-initiated thermoset polyurethane formulation on interface between the pro-fabricated end plug and the open end and initiating and curing with light and/or heat or any other means to seal the ends, preferably permanently.
DETAILED DESCRIPTION OF THE FIGURES
[0072] FIG. 1 is a side view of an implant with two open ends as used in the present invention.
[0073] FIG. 2 is a side view of the pre-fabricated end plugs used to plug the implants according to the present invention.
[0074] FIG. 3 is a side view of an implant with one open and as used in the present invention.
[0075] FIG. 4 is a graph of the elution rate of histrelin using an implant according to the present invention.
[0076] FIG. 5 is a graph of the elution rate of naltrexone using implants according to the present invention.
[0077] FIG. 6 is a graph of the elution rate of naltrexone from polyurethane implants according to the present invention.
[0078] FIG. 7 is a graph of the elution rate of LHRH agonist (histrelin) from a polyurethane implant according to the present invention.
[0079] FIG. 8 is a graph of the elution rate of clonidine from a polyurethane implant according to the present invention.
DETAILED DESCRIPTION OF THE INVENTION
[0080] To take the advantage of the excellent properties of polyurethane based polymers, this invention uses polyurethane based polymers as drug delivery devices for releasing drugs at controlled rates for an extended period of time to produce local or systemic pharmacological effects. The drug delivery device is preferably comprised of a cylindrically shaped reservoir surrounded by polyurethane based polymer through which controls the delivery rate of the drug inside the reservoir. The reservoir is comprised of active ingredients and, optionally, pharmaceutically acceptable carriers. The carriers are formulated to facilitate the diffusion of the active ingredients through the polymer and to ensure the stability of the drugs inside the reservoir.
[0081] The current invention provides a drug delivery device that can achieve the following objectives: a controlled release rate (zero order release rate) to maximize therapeutic effects and minimize unwanted side effects; an easy way to retrieve the device if it is necessary to end the treatment; an increase in bioavailability with less variation in absorption and no first pass metabolism.
[0082] The release rate of the drug is governed by the Fick's Law of Diffusion as applied to a cylindrically shaped reservoir device (cartridge). The following equation describes the relationship between different parameters:
[0000] dM =2π hpΔC
[0000] dt ln( r o /r i )
[0000] where:
dM/dt: drug release rate; h: length of filled portion of device;
[0085] ΔC: concentration gradient across the reservoir wall;
r o /r i : ratio of outside to inside radii of device; and p: permeability coefficient of the polymer used.
[0088] The permeability coefficient is primarily regulated by the hydrophilicity/hydrophobicity of the polymer, the structure of the polymer, and the interaction of drug and the polymer. Once the polymer and the active ingredient are selected, p will be a constant, h, r□, and r i are fixed and kept constant once the cylindrically shaped device is produced. ΔC is maintained constant by the carriers inside the reservoir.
[0089] To keep the geometry of the device as precise as possible, the preferably cylindrically shaped device can be manufactured through precision extrusion or precision molding process for thermoplastic polyurethane polymers, and reaction injection molding or spin casting process for thermosetting polyurethane polymers.
[0090] The cartridge can be made with either one end closed or both ends open. The open end can be plugged with pre-manufactured end plug to ensure a smooth end and a solid seal. The solid actives and carriers can be compressed into pellet form to maximize the loading of the actives.
[0091] To identify the location of the implant, radiopaque material can be incorporated into the delivery device by inserting it into the reservoir or by making it into end plug to be used to seal the cartridge.
[0092] Once the cartridges are sealed on both ends with filled reservoir, they are conditioned and primed for an appropriate period of time to ensure a constant delivery rate.
[0093] The conditioning of the drug delivery devices involves the loading of the actives (drug) into the polyurethane based polymer which surrounds the reservoir. The priming is done to stop the loading of the drug into the polyurethane based polymer and thus prevent loss of the active before the actual use of the implant. The conditions used for the conditioning and priming step depend on the active, the temperature and the medium in which they are carried out. The conditions for the conditioning and priming may be the same in some instances.
[0094] The conditioning and priming step in the process of the preparation of the drug delivery devices is done to obtain a determined rate of release of a specific drug. The conditioning and priming step of the implant containing a hydrophilic drug is preferably carried out in an aqueous medium, more preferably in a saline solution. The conditioning and priming step of a drug delivery device comprising a hydrophobic drug is usually carried out in a hydrophobic medium such as an oil based medium. The conditioning and priming steps are carried out by controlling three specific factors namely the temperature, the medium and the period of time.
[0095] A person skilled in the art would understand that the conditioning and priming step of the drug delivery device will be affected by the medium in which the device is placed. As mentioned previously, a hydrophilic drug would be preferably conditioned and primed in an aqueous solution and more preferably, in a saline solution. For example, Histrelin and Naltrexone implants have been conditioned and primed in saline solution, more specifically, conditioned in saline solution of 0.9% sodium content and primed in saline solution of 1.8% sodium chloride content.
[0096] The temperature used to condition and prime the drug delivery device may vary across a wide range of temperatures but, in some instances 37° C., has been preferably used.
[0097] The time period used for the conditioning and priming of the drug delivery devices may vary from a single day to several weeks depending on the release rate desired for the specific implant or drug.
[0098] A person skilled in the art will understand the steps of conditioning and priming the implants is to optimize the rate of release of the drug contained within the implant. As such, a shorter time period spent on the conditioning and the priming of a drug delivery device results in a lower rate of release of the drug compared to a similar drug delivery device which has undergone a longer conditioning and priming step.
[0099] The temperature in the conditioning and priming step will also affect the rate of release in that a lower temperature results in a lower rate of release of the drug contained in the drug delivery device when compared to a similar drug delivery device which has undergone a treatment at a higher temperature.
[0100] Similarly, in the case of aqueous solutions, which are in some cases preferably saline solutions, the sodium chloride content of the solution will also determine what type of rate of release will be obtained for the drug delivery device. More specifically, a lower content of sodium chloride would result in a higher rate of release of drug when compared to a drug delivery device which has undergone a conditioning and priming step where the sodium chloride content was higher.
[0101] The same conditions apply for hydrophobic drugs where the main difference in the conditioning and priming step would be that the conditioning and priming medium be hydrophobic medium, more specifically an oil based medium.
[0102] The drug (actives) that can be delivered include drugs that can act on the central nervous system, psychic energizers, tranquilizers, anti-convulsants, muscle relaxants, anti-parkinson, analgesic, anti-inflammatory, anesthetic, antispasmodic, muscle contractants, anti-microbials, anti-malarials, hormonal agents, sympathomimetic, cardiovascular, diuretics, anti-parasitic and the like.
[0103] The current invention focuses on the application of polyurethane based polymers, thermoplastics or thermosets, to the creation of implantable drug devices to deliver biologically active compounds at controlled rates for prolonged period of time. Polyurethane polymers are preferably made into cylindrical hollow tubes with one or two open ends through extrusion, (reaction) injection molding, compression molding, or spin-casting (see e.g. U.S. Pat. Nos. 5,266,325 and 5,292,515), depending on the type of polyurethane used.
[0104] Thermoplastic polyurethane can be processed through extrusion, injection molding, or compression molding. Thermoset polyurethane can be processed through reaction injection molding, compression molding, or spin-casting. The dimensions of the cylindrical hollow tube are very critical and need to be as precise as possible.
[0105] Polyurethane based polymers are synthesized from multi-functional polyols, isocyanates and chain extenders. The characteristics of each polyurethane can be attributed to its structure.
[0106] Thermoplastic polyurethanes are made of macrodials, diisocyanates, and difunctional chain extenders (e.g. U.S. Pat. Nos. 4,523,005 and 5,254,662). Macrodials make up the soft domains. Diisocyanates and chain extenders make up the hard domains. The hard domains serve as physical crosslinking sites for the polymers. Varying the ratio of these two domains can alter the physical characteristics of the polyurethanes.
[0107] Thermoset polyurethanes can be made of multifunctional (greater than difunctional) polyols and/or isocyanates and/or chain extenders (e.g. U.S. Pat. Nos. 4,386,039 and 4,131,604). Thermoset polyurethanes can also be made by introducing unsaturated bonds in the polymer chains and appropriate crosslinkers and/or initiators to do the chemical crosslinking (e.g. U.S. Pat. No. 4,751,133). By controlling the amounts of crosslinking sites and how they are distributed, the release rates of the actives can be controlled.
[0108] Different functional groups can be introduced into the polyurethane polymer chains through the modification of the backbones of polyols depending on the properties desired. When the device is used for the delivery of water soluble drugs, hydrophilic pendant groups such as ionic, carboxyl, ether, and hydroxy groups are incorporated into the polyols to increase the hydrophilicity of the polymer (e.g. U.S. Pat. Nos. 4,743,673 and 5,354,835). When the device is used for the delivery of hydrophobic drugs, hydrophobic pendant groups such as alkyl, siloxane groups are incorporated into the polyols to increase the hydrophobicity of the polymer (e.g. U.S. Pat. No. 6,313,254). The release rates of the actives can also be controlled by the hydrophilicity/hydrophobicity of the polyurethane polymers.
[0109] Once the appropriate polyurethane polymer is chosen, the next step is to determine the best method to fabricate the cylindrically shaped implants.
[0110] For thermoplastic polyurethanes, precision extrusion and injection molding are the preferred choices to produce two open-end hollow tubes (see FIG. 1 ) with consistent physical dimensions. The reservoir can be loaded freely with appropriate formulations containing actives and carriers or filled with pro-fabricated pellets to maximize the loading of the actives. One open end needs to be sealed first before the loading of the formulation into the hollow tube. To seal the two open ends, two pr-fabricated end plugs (see FIG. 2 ) are used. The sealing step can be accomplished through the application of heat or solvent or any other means to seal the ends, preferably permanently.
[0111] For thermoset polyurethanes, precision reaction injection molding or spin casting is the preferred choice depending on the curing mechanism. Reaction injection molding is used if the curing mechanism is carried out through heat and spin casting is used if the curing mechanism is carried out through light and/or heat. Preferably, hollow tubes with one open end (see FIG. 3 ) are made by spin casting. Preferably, hollow tubes with two open ends are made by reaction injection molding. The reservoir can be loaded in the same way as the thermoplastic polyurethanes.
[0112] Preferably, to seal an open end, an appropriate light-initiated and/or heat-initiated thermoset polyurethane formulation is used to fill the open end and this is cured with light and/or heat. More preferably, a pre-fabricated end plug can also be used to seal the open and by applying an appropriate light-initiated and/or heat-initiated thermoset polyurethane formulation on to the interface between the pre-fabricated end plug and the open end and cured it with the light and/or heat or any other means to seal the ends, preferably permanently.
[0113] The final process involves the conditioning and priming of the implants to achieve the delivery rates required for the actives. Depending upon the types of active ingredient, hydrophilic or hydrophobic, the appropriate conditioning and priming media will be chosen. Water based media are preferred for hydrophilic actives and oil based media are preferred for hydrophobic actives.
[0114] As a person skilled in the art would readily know many changes can be made to the preferred embodiments of the invention without departing from the scope thereof. It is intended that all matter contained herein be considered illustrative of the invention and not it a limiting sense.
Example 1
[0115] Tecophilic polyurethane polymer tubes are supplied by Thermedics Polymer Products and manufactured through a precision extrusion process. Tecophilic polyurethane is a family of aliphatic polyether-based thermoplastic polyurethane which can be formulated to different equilibrium water content contents of up to 150% of the weight of dry resin. Extrusion grade formulations are designed to provide maximum physical properties of thermoformed tubing or other components.
[0116] The physical data for the polymers is provided below as made available by Thermedics Polymer Product.
[0000]
Tecophilic Typical Physical Test Data
HP-60D-
HP-60D-
HP-60D-
HP-93A-
ASTM
20
35
60
100
Durometer
D2240
43D
42D
41D
83A
(Shore
Hardness)
Spec Gravity
D792
1.12
1.12
1.15
1.13
Flex Modulus
D790
4,300
4,000
4,000
2,900
(psi)
Ultimate
D412
8,900
7,800
8,300
2,200
Tensile
Dry (psi)
Ultimate
D412
5,100
4,900
3,100
1,400
Tensile
Wet (psi)
Elongation
D412
430
450
500
1,040
Dry (%)
Elongation
D412
390
390
300
620
Wet (%)
[0117] Hp-60D-20 is extruded to tubes with thickness of 0.30 mm with inside diameter of 1.75 mm. The tubes are then cut into 25 mm in length. One side of the tube is sealed with heat using a heat scaler. The sealing time is less than 1 minute. Four pellets of histrelin acetate are loaded into the tube. Each pellet weighs approximately 13.5 mg for a total of 54 mg. Each pellet is comprised of a mixture of 98% histrelin and 2% stearic acid. The second end open of the tube is sealed with heat in the same way as for the first end. The loaded implant is then conditioned and primed. The conditioning takes place at room temperature in a 0.9% saline solution for 1 day. Upon completion of the conditioning, the implant undergoes priming. The priming takes place at room temperatures in a 1.8% saline solution for 1 day. Each implant is tested in vitro in a medium selected to mimic the pH found in the human body. The temperature of the selected medium was kept at approximately 37° C. during the testing. The release rates are shown on FIG. 4 .
[0000]
Histrelin elution rates
WEEKS OF ELUTION
HP-60D-20 (μg/day)
1
451.733
2
582.666
3
395.9
4
310.29
5
264.92
6
247.17
7
215.93
8
201.78
9
183.22
10
174.99
11
167.72
12
158.37
13
153.95
14
146.46
15
139.83
16
129.6
17
124.46
18
118.12
19
120.35
Example 2
[0118] HP-60D-35 is extruded to tubes with thickness of 0.30 mm with inside diameter of 1.75 mm. The tubes are then cut into 32 mm in length. One side of the tube is sealed with heat using a heat sealer. The sealing time is less than 1 minute. Six pellets of naltrexone are loaded into the tubes and both open sides of the tubes are sealed with heat. Each pellet weighs approximately 15.0 mg for a total of 91 mg. The second end open of the tube is sealed with heat in the same way as for the first end. The loaded implant is then conditioned and primed. The conditioning takes place at room temperature in a 0.9% saline solution for 1 week. Upon completion of the conditioning, the implant undergoes priming. The priming takes place at room temperatures in a 1.8% saline solution for 1 week. Each implant is tested in vitro in a medium selected to mimic the pH found in the human body. The temperature of the selected medium was kept at approximately 37° C. during the testing. The release rates are shown on FIG. 5 .
[0000]
Naltrexone elution rates
WEEKS OF
RELEASE
HP-60D-35-1
HP-60D-35-2
HP-60D-35-3
0
(μg/day)
(μg/day)
(μg/day)
1
1529.26
767.38
1400.95
2
1511.77
1280.03
1498.86
3
1456.01
1635.97
1449.49
4
1378.27
1607.13
1500.42
5
1393.05
1614.52
1558.37
6
1321.71
1550.39
1436.03
7
1273.07
1424.24
1300.73
8
1172.82
1246.48
1221.57
Example 3
[0119] In FIG. 6 there is a comparison of the release rates of naltrexone in vitro using two grades of polymer at two different water contents. Three runs were carried out and analyzed where the polymer of the implant had a water content of 24% and three runs were carried out where the polymer of the implant had a water content of 30%. The release rates were plotted against time. The polymer used for the runs at 24% water content was Tecophilic HP-60-D35 from Thermedics. The polymer used for the runs at 30% water content was Tecophilic HP-60-D60 from Thermedics. The data obtained in this example demonstrates the good reproducibility of the implants as prepared according to the present invention.
Example 4
[0120] FIG. 7 shows a plot of the release rate of histrelin (LHRH Agonist) versus time. The polymer in this example had a water content of 15%. The polymer used was Tecophilic HP-60-D20 from Thermedics. The data points were taken weekly.
Example 5
[0121] FIG. 8 shows a plot of the release rate of clonidine versus time. The polymer in this example has a water content of 15%. The polymer used was Tecophilic BP-60-D20 from Thermedics. The data points were taken weekly.
|
This invention is related to the use of polyurethane based polymer as a drug delivery device to deliver biologically active compounds at a constant rate for an extended period of time and methods of manufactures thereof. The device is very biocompatible and biostable, and is useful as an implant in patients (humans and animals) for the delivery of appropriate bioactive substances to tissues or organs. The drug delivery device for releasing one or more drugs at controlled rates for an extended period of time to produce local or systemic pharmacological effects comprises:
1. a reservoir, said reservoir comprising; 2. at least one active ingredient; and, optionally, 3. at least one pharmaceutically acceptable carrier,
a polyurethane based polymer completely surrounding the reservoir.
| 0 |
CROSS REFERENCE TO RELATED APPLICATION
This application is a continuation in part of application Ser. No. 424,665, filed Dec. 14, 1973, now abandoned.
BACKGROUND OF THE INVENTION
FIELD OF THE INVENTION
This invention is directed to new organic compounds, and more particularly to 9H-dibenzoimidazo compounds, intermediates therefor and a process of production thereof.
The novel compounds, intermediates and processes of production thereof can be illustratively represented by the following schemes of formulae: ##SPC3##
Wherein R 3 ' and R 4 ' are hydrogen or alkyl of 1 to 3 carbon atoms, inclusive, and wherein R 2 and R 6 are hydrogen, halogen, or -CF 3 .
Compound III can be further modified as shown by Scheme B: ##SPC4##
wherein X" is bromine or chlorine, wherein R' 1 is alkyl of 1 to 3 carbon atoms, inclusive, ##SPC5##
In which W is H, chlorine, or fluorine, or R 1 is ##EQU5## IN WHICH N IS AN INTEGER OF 2 TO 4 AND R 0 ' and R 0 " are hydrogen and alkyl, defined as above, or together ##EQU6## PYRROLIDINO, PIPERIDINO, MORPHOLINO, OR N-methylpiperazino, and R 2 and R 6 are defined as in Scheme A, above.
Hydrolysis of those compounds of formula IIIA in which R 1 is: ##SPC6##
In which W is defined as above, provides compounds of formula IIIB: ##SPC7##
in which R 2 , R 3 ', R 4 ', R 6 , and W are defined as herein above.
Compounds of formula III wherein R 1 is methyl can also be obtained by the methods of Scheme C. ##SPC8##
wherein R 2 and R 6 are defined as herein above. If an alkyl group is in compound III, compounds such as III D and III E can be produced: ##SPC9## ##SPC10##
For Schemes D and E, R 2 and R 6 are defined as herein above, and Alkyl of 1 to 3 carbon atoms, inclusive.
A compound of formula III wherein R 3 ' is alkyl and R 4 ' is hydrogen can be converted with formaldehyde and a secondary amino compound ##EQU7## in which ##EQU8## is as described herein above, in monoglyme and in the presence of hydrochloric acid, into a compound of formula IIIF: ##SPC11##
wherein R 2 and R 6 and alkyl are defined as herein before and wherein ##EQU9## is pyrrolidino, piperidino, morpholino, N-methylpiperazino or dimethylamino.
In the same manner, compound IIIG: ##SPC12##
wherein R 2 , R 6 , Alkyl and ##EQU10## are defined as above, is prepared from compound III, wherein R 4 ' is alkyl and R' 3 is hydrogen.
The compounds of this invention can therefore be represented by the formula IIIH: ##SPC13##
wherein R 1 is selected from the group consisting of hydrogen, alkyl of 1 to 3 carbon atoms, inclusive, ##SPC14##
or R 1 is ##EQU11## in which n is an integer of 2 to 4, and R 0 ' and R 0 " are hydrogen or alkyl defined as above or, together ##EQU12## is pyrrolidino, piperidino, N-methylpiperazino, and morpholino; wherein R 3 and R 4 are hydrogen or alkyl as defined above, or, R 3 and R 4 can be ##EQU13## in which ##EQU14## is defined as above; and wherein R 2 and R 6 are selected from the group consisting of hydrogen, halogen, or CF 3 , and the pharmacologically acceptable acid addition salts thereof.
The more preferred compounds are those of formula III(I) ##SPC15##
wherein R" 1 is alkyl or ##EQU15## in which n is 2 to 4 and alkyl is in each of 1 to 3 carbon atoms, inclusive, and the pharmacologically acceptable acid addition salts thereof.
Other preferred compounds include those of the formula IIIJ. ##SPC16##
wherein R 1 '" is hydrogen or alkyl of 1 to 3 carbon atoms, inclusive, and wherein R" 3 and R" 4 are hydrogen or alkyl as defined above, or R" 3 or R" 4 can be ##EQU16## in which R 0 ' and R 0 " are hydrogen or alkyl as defined above, or together ##EQU17## is pyrrolidino, piperidino, N-methylpiperazino, or morpholino, and the pharmacologically acceptable acid addition salts thereof.
The method of scheme A comprises treating a compound of formula 1 with a compound of formula ##EQU18## wherein R 3 ' and R 4 ' are hydrogen or alkyl of 1 to 3 carbon atoms, inclusive, to give compound II; and treating II with sulfuric acid to obtain a compound of the formula III.
The method of Scheme B comprises: Treating a compound of structure III with a strong base, e.g. sodium hydride, and then with a chloride or bromide of the formula RX" wherein R is alkyl of 1 to 3 carbon atoms, inclusive, ##SPC17##
in which W is hydrogen, chlorine, or fluorine, or R is ##EQU19## in which n is an integer of 2 to 4, and R 0 ' and R 0 " are hydrogen, or alkyl defined as above, or together ##EQU20## is pyrrolidino, piperidino, morpholino, or N-methyl-piperazino, and wherein X" is chlorine or bromine, to give the compound IIIA.
Hydrolysis of those compounds of formula IIIA in which R 1 is ##SPC18##
defined as above gives the corresponding keto compound.
In the method of schemes C, D, and E a compound of formula III is treated with formaldehyde in formic acid to give a product IIIC or if already methylated in the 2- or 3-position to give a 2- or 3-hydroxymethyl derivative of the compound III, which may additionally be methylated in the 9-position (such as compouns IIIE).
The 2- or 3-hydroxymethyl compounds, IIID or IIIE, can be further treated with triethylamine and methanesulfonyl chloride followed by a secondary amine such as morpholine, pyrrolidine, piperidine, or N-methylpiperazine, to convert the alcoholic group to the corresponding amino group such as seen in compounds IIIF and IIIG.
Compounds IIIF and IIIG can also be directly obtained from a compound of formula III in which R 3 ' or R 4 ' is alkyl, by direct reaction of a compound of formula III with formaline, hydrochloric acid and a selected base such as pyrrolidine, piperidine, morpholine, N-methylpiperazine, or dimethylamine, in monoglyme at elevated temperatures.
DESCRIPTION OF THE PREFERRED EMBODIMENT
Lower alkyl groups of 1 to 3 carbon atoms, inclusive, are exemplified by methyl, ethyl, propyl, and isopropyl.
The group (CH 2 )n wherein n is 2 to 4 comprises -(CH 2 ) 2 -, -(CH 2 ) 3 -, or -(CH 2 ) 4 -.
Halogen is defined as fluorine, chlorine, or bromine.
The novel compounds IIIH of this invention are agents for tranquilization and as antidepressants. They can be used in mammals and birds, particularly for animals in transport, like for zoo animals, e.g. lions, tigers, elephants, parrots; farm animals, e.g. cattle, sheep, swing, or domestic pet animals e.g. cats and dogs.
The new compounds were tested for sedative and antidepressant activity in laboratory animals as follows:
SEDATION-TRANQUILIZATION
Chimney test -- [Med. Exp. 4, 145 (1961)]: The test determines the ability of mice to back up and out of a vertical glass cylinder within 30 seconds. At the effective dosage, ED 50 , 50% of the mice failed doing it.
Dish test -- Mice in Petri dishes (10 cm. diameter, 5 cm. high, partially embedded in wood shavings), climb out in a very short time, when not treated. Mice remaining in the dish for more than 3 minutes indicates tranquilization. ED 50 equals the dose of test compound at which 50% of the mice remain in the dish.
Pedestal test -- The untreated mouse leaves a standard pedestal in less than a minute to climb back to the floor of the standard mouse box. Tranquilized mice will stay on the pedestal for more than 1 minute.
Nicotine antagonism test -- Mice in a group of 6 are injected with the test compound. Thirty minutes later the mice including control (untreated) mice are injected with nicotine salicylate (2 mg./kg.). The control mice show over-stimulation, i.e., (1) running convulsions followed by (2) tonic extensor fits; followed by (3) death.
THE ANTIDEPRESSANT ACTION
The main function of an antidepressant is to return the depressed individual up to normal function. This should be carefully differentiated from psychic stimulants such as the amphetamines which produce overstimulation in the normal individual.
Many different methods have been and are used to evaluate antidepressant activity. In general these methods involve antagonism to a depressant such as reserpine or tetrabenazine or a synergistic increase of the toxicity of certain compounds (i.e., yohimbine or 3,4-dihydroxyphenylalanine) and comparison of the drug action of the new compound with other known antidepressants. No single test alone can determine whether or not a new compound is an antidepressant or not, but the profile evidenced by various tests will establish the anti-depressant action if present. A number of such tests are described below.
Hypothermic tests with oxotremorine: [1-[4-(pyrrolidinyl)-2-butynyl]-2-pyrrolidinone].
Oxotremorine (as well as apomorphine and tetrabenazine) produces hypothermic responses in mice. This response is blocked by anticholinergics and anti-depressants such as atropine and imipramine.
Oxotremorine produces a very pronounced hypothermia which reaches a peak 60 minutes after administration.
At 0.6 mg./kg. the body temperature of a mouse is decreased about 13° F. (when the mouse is kept at room temperature). This temperature decrease is antagonized by anti-depressants e.g. desipramine, imipramine, doxepine, and others.
The present compounds were tested as follows. Four male mice of 18-22 g. (Strain CF=Carworth Farms) were injected intraperitoneally with 1 mg. of oxotremorine. The lowering of the body temperature was measured rectally with an electronic thermometer, before and 30 minutes after drug administration. After the drug administration the mice were kept at 19° C. in cages. A raise of 4° Fahrenheit over the oxotremorine-produced lowered body temperature was taken as indicative of anti-depressant activity.
Potentiation of yohimbine aggregation toxicity: the LD 50 of yohimbine hydrochloride in mice is 45 mg./kg. i.p. Administration of 30 mg./kg. of yohimbine hydrochloride was non-lethal. If an antidepressant is administered prior to the yohimbine hydrochloride (30 mg.), the lethality of the yohimbine hydrochloride is increased.
Ten male CF mice, 18-22 g., were injected with yohimbine hydrochloride in saline solution. After two hours the LD 50 are determined. Groups of ten mice are injected with the antidepressant 30 minutes before the administration of yohimbine hydrochloride [YCl] (30 mg.). No mice or only one mouse is killed from 30 mg. of [YCl]. If [YCl] is administered in the presence of an anti-depressant an increase in the toxicity of [YCl] is found. ED 50 value of the test compound is the dosage which causes 50% of the mice to die.
Potentiation of apomorphine gnawing: a group of 4 mice (male, CF, 18-22 g.) are administered the test compound intraperitoneally 1 hour prior to the subcutaneous injection of apomorphine hydrochloride 1 mg./kg. The mice are then placed in a plastic box (6 inches × 11 inches × 5 inches) lined at the bottom with a cellophane-based, absorbent paper. The degree of damage to the paper at the end of 30 min. is scored from zero to 4. The scores 3 and 4 indicate that the compound is a potentiator of apomorphine in this test. Positive tests in this series show that the new compounds have anxiolytic antidepressant and tranquilizing sedative action.
The pharmaceutical forms of compounds of formula IIIH (including IIIB, IIIC, IIID, IIIE, IIIF, and IIIG, and the preferred compounds III(I) and IIIJ, and salts thereof) contemplated by this invention, include pharmaceutical compositions suited for oral, parenteral, and rectal use, e.g., tablets, powder packets, cachets, dragees, capsules, solutions, suspensions, sterile injectable forms, suppositories, bougies, and the like. Suitable diluents or carriers such as carbohydrates, lactose, proteins, lipids, calcium phosphate, cornstarch, stearic acid, methylcellulose and the like may be used as carriers or for coating purposes. Water or oils such as coconut oil, sesame oil, safflower oil, cottonseed oil, and peanut oil, may be used for preparing solutions or suspensions of the active drug. Sweetening, coloring, and flavoring agents may be added.
For mammals food premixes with starch, oatmeal, dried fishmeat, fishmeal, flour, and the like can be prepared.
As sedatives and antidepressants the compounds of formulae III (including IIIA through IIIH) and their pharmacologically acceptable acid addition salts can be used in dosages of 0.2-30 mg./kg.; preferably from 1.0 to 10 mg./kg. in oral in injectable preparations as described above to alleviate anxieties and depression occurring in stressful situations. Such situations are those for example, when animals are changing ownerships or are temporarily put into kennels while their owners are absent from home, or are traveling.
Acid addition salts of the compounds of formula III (and IIIB, C, D, E, F, G, H, I and J) can be made, such as the flosilicic acid addition salts which can be applied as mothproofing agents, and salts with trichloracetic acid, useful as herbicides against Johnson grass, Bermuda grass, yellow and red foxtail, and quack grass.
The starting materials of this invention are dihydrodibenzodiazepinethiones I which are either known or can be synthesized, for e.g. by treating the corresponding oxo compounds [Arzneim. Forschung 13, 324 (1963)] with phosphorus pentasulfide as further illustrated by the Preparations.
In carrying out the process of this invention according to scheme A, a selected thione I is heated for 1 to 12 hours with an aminoacetaldehyde dimethylacetal of the formula: ##EQU21## wherein R 3 ' or R 4 ' is hydrogen or alkyl of 1 to 3 carbon atoms, inclusive. The reaction is conveniently carried out in an inert organic solvent such as ethanol, 1-propanol, 2-propanol, 1- and 2-butanol, tetrahyrdofuran, dioxane or the like, the resulting product II is obtained by conventional procedures, such as removal of solvents by evaporation, preferably in vacuo, extraction, chromatograpahy, and crystallization.
Compound II is then cyclized preferably in concentrated sulfuric acid between 0° to 35° C. during 1/2 to 6 hours. The product III is produced by quenching the sulfuric acid reaction mixture cautiously in cold water and neutralizing the resulting precipitated slurry with sodium or potassium hydroxide or carbonate. From this mixture the product III is extracted with an organic solvent e.g. chloroform, methylene chloride, benzene or the like, and the pure product III is obtained by conventional procedures, such as removal of the solvents by evaporation, preferably in vacuo, extraction, chromatography, and crystallization.
Carrying out the method B, a chloro or bromo organic compound such as an alkyl chloride, a dialkylaminoalkyl chloride, or a pyrrolidino, piperidino, morpholino, or piperazino alkyl chloride or bromide or a halide compound of the formula ##SPC19##
wherein W is hydrogen, chlorine, or fluorine and X' is chlorine, or bromine, is treated with a compound of formula III in the presence of a strong base such as sodium or potassium hydride. Equimolar amounts of the strong base, compound III and the organic chloride or bromide are used in this reaction.
The reaction, first between Compound III and the base, is carried out at a temperatuare of 60°-120° C during a period of 10-60 minutes and is continued with the addition of the reactant organic chloride or bromide at the same temperature for 1-6 hours. After the reaction is terminated the product IIIA is obtained by conventional procedure such as extractions, chromatography, crystallization, and the like.
In methods C, D, E, a 2- or 3-alkyl compound III is reacted with formaldehyde in formalin (37% aqueous formaldehyde). The reaction is best carried out at the boiling temperature of the mixture i.e. near 100° C. for a period of 1-48 hours the products IIIC, IIID, or IIIE are recovered from the reaction mixture by conventional procedures such as extraction, chromatography, and crystallization.
Alternatively a compound of formula IIIF is prepared by treating a compound of formula III wherein R 3 ' is alkyl and R 4 ' is hydrogen, with formalin, a compound selected from pyrrolidine, piperidine, morpholine, dimethylamine or diethylamine, in the presence of hydrochloric acid, in monoglyme. In the preferred method of the invention, the mixture is heated for 12-48 hours on a steam bath at 100° C. However, temperatures between 60°-130° C. are suitable. The product is separated and purified by standard procedures such as extraction, concentration, recrystallization, and chromatography.
Preparation 1 -- 7-Chloro-5,10-dihydro-11H-dibenzo[b,e]-[1,4]diazepine-11-thione
A mixture of 7-chloro-5,10-dihydro-11H-dibenzo[b,e]-[1,4]diazepin-11-one (30.5 g., 0.125 mole), phosphorus pentasulfide (27.8 g., 0.131 mole) and one l. of pyridine is heated at reflux temperature for 4 hours and the pyridine is evaporated in vacuo. The residue is stirred for 1 hour with one l. each of saturated aqueous sodium bicarbonate and methylene chloride and filtered to remove some solid product. The organic layer of the filtrate is washed successively with sodium bicarbonate solution and with saturated salt solution, dried over anhydrous magnesium sulfate and evaporated. The residue is combined with the solid obtained above and triturated with hot chloroform and methanol. In this way, 12.2 g. of 7-chloro-5,10-dihydro-11H-dibenzo[b,e][1,4]diazepine-11-thione of melting point 274°-275° C is obtained. Concentration of the chloroform-methanol washings affords an additional 8.4 g. of product having the same melting point. Recrystallization from dimethylformamide-water gives an analytically pure sample in the form of pale yellow needles of melting point 276°-277° C.
Preparation 2 -- 5,10-Dihydro-5-methyl-11H-dibenzo[b,e]-[1,4]diazepine-11-thione
A mixture of 5,10-dihydro-5-methyl-11H-dibenzo[b,e]-[1,4]diazepin-11-one (6.1 g., 0.0272 mole), phosphorus pentasulfide (6.51 g., 0.0286 mole) and 175 ml. of pyridine is heated at reflux temperature for 3.75 hours and the pyridine is then evaporated in vacuo. The residue is shaken with chloroform and saturated aqueous sodium bicarbonate. The resulting suspension is filtered to give solid A. The chloroform layer of the filtrate is washed successively with saturated aqueous sodium bicarbonate and with saturated salt solution, dried over anhydrous magnesium sulfate and evaporated. The residue is crystallized from methylene chloride-methanol to give 3.5 g. of 5, 10-dihydro-5-methyl-11H-dibenzo[b,e][1,4]diazepin-11-thione of melting point 217°-218° C., which is unchanged after recrystallization. A second crop weighs 0.8 g. and melts at 214°-215° C.
Solid A is shaken with methylene chloride and 10% sodium hydroxide and processed as above to give an additional 1.5 g. of the thione, at melting point 216°-217° C.
Anal. calcd. for C 14 H 12 N 2 S: C, 69.96; H, 5.30; N, 11.66; S, 13.34; Found: C, 69.79; H, 5.20; N, 11.37; S, 13.29.
In the same manner shown by the above preparation, other starting compounds can be obtained, such as:
2-chloro-5,10-dihydro-11H-dibenzo[b,e][1,4]diazepine-11-thione;
3-chloro-5,10-dihydro-11H-dibenzo[b,e][1,4]diazepine-11-thione;
7-dichloro-5,10-dihydro-11H-dibenzo[b,e][1,4]diazepine-11-thione;
6-chloro-5,10-dihydro-11H-dibenzo[b,e][1,4]diazepine-11-thione;
2,8-bromo-5,10-dihydro-11H-dibenzo[b,e][1,4]diazepine-11-thione;
8-ethyl-5,10-dihydro-11H-dibenzo[b,e][1,4]diazepine-11-thione;
8-chloro-5,10-dihydro-11H-dibenzo[b,e][1,4]diazepine-11-thione;
5,10-dihydro-8-trifluoromethyl-11H-dibenzo[b,e][1,4]diazepine-11-thione;
5,10-dihydro-7-methoxy-11H-dibenzo[b,e][1,4]diazepine-11-thione;
5,10-dihydro-3-methoxy-11H-dibenzo[b,e][1,4]diazepine-11-thione;
3-methyl-5,10-dihydro-11H-dibenzo[b,e][1,4]diazepine-11-thione;
5,10-dihydro-8-propyl-11H-dibenzo[b,e][1,4]diazepine-11-thione;
8-fluoro-5,10-dihydro-11H-dibenzo[b,e][1,4]diazepine-11-one;
and the like.
EXAMPLE 1
[(5H-dibenzo[b,e][1,4]diazepine-11-yl)amino]-acetaldehyde dimethyl acetal
5,10-Dihydro-11H-dibenzo[b,e][1,4]diazepine-11-thione (33.75 g., 150 mmol.) is suspended in 450 ml. of n-butyl alcohol and treated with 47.25 g. (450 mmol.) of commerical aminoacetaldehyde dimethyl acetal. The reagents are heated for 5.5 hours during which time the solution turns brown. The solution is cooled to room temperature and the solvent is removed in vacuo. The residue is dissolved in 600 ml. of hot ethyl acetate, filtered, concentrated to 400 ml. and cooled to give 36.0 g. (81%) of [(5H-dibenzo[b,e][1,4]diazepin-11-yl)amio]acetaldehyde dimethyl acetal of melting point 181°-182.5° C. A second crop (2.55 g., 5.7%) of melting point 181.5°-184° C. is also collected.
Anal. calcd. for C 17 H 19 N 3 O 2 : C, 68.66; H, 6.44; N, 14.13 Found: C, 68.52; H, 6.55; N, 14.10.
EXAMPLE 2
9H-Dibenzo[b,f]imidazo[1,2-d][1,4]diazepine [(5H-dibenzo[b,e][1,4]diazepine-11-yl)amino]acetaldehyde dimethyl acetal (30.0 g., 101.0 mmol.) is dissolved in 100 ml. of concentrated sulfuric acid and stirred at room temperature for 3 hours. The product is isolated by pouring the acid solution cautiously, and in portions into ice-cold distilled water, and carefully adding the resulting slurry to 3.0 L. of cold 10% aqueous sodium hydroxide solution. The product is extracted with chloroform; the chloroform layer is back-extracted with 10% aqueous sodium hydroxide followed by washing with a brine soltuion and then the chloroform solution is dried over magnesium sulfate. After filtration and concentration in vacuo, a residue is obtained, which is dissolved in 800 ml. of hot ethyl acetate, filtered to remove insoluble material, and then concentrated to a volume of 500 ml. On colling, 16.34 g. (70.0%) of 9H-dibenzo[b,f]imidazo[1,2-d][1, 4]diazepine of melting point 215°-217° C. is obtained in the form of prisms. An additional 5.23 g. (22.4%) of product is obtained in two additional crops.
Anal. calc. for C 15 H 11 N 3 : C, 77.23; H, 4.75; N, 18.01. Found: C, 76.93; H, 4.92; N, 17.90.
EXAMPLE 3
2-Methyl-9H-dibenzo[b,f]imidazo[1,2-d][1,4]-diazepine
A. in a 250-ml., three-neck flask fitted with a condenser, is heated to reflux 6.25 g. of 5,10-dihydro-11H-dibenzo-[b,e][1,4]diazepine-11-thione (30.0 mmol.) and 10.8 g. of aminopropionaldehyde dimethyl acetal (90.0 mmol.) in 60 ml. of n-butanol, during 2 hours. An additional 60 ml. of n-butanol is added and the mixture is refluxed overnight (22 hours). At this point, 60 ml. of n-butanol is distilled from the reaction mixture and refluxing is maintained for an additional 18 hours. On cooling, 2.0 g. of crude starting material is obtained. This is added to the reaction mixture along with an additional 5.4 g. of aminopropionaldehyde acetal (40.0 mmol.) and heating is maintained over a weekend (65 hours). On cooling and removal of the solvent in vacuo, 10 g. of brown oil is obtained. The oil is dissolved in 80 ml. of concentrated sulfuric acid and stirred at room temperature under nitrogen for 10 hours. The reaction mixture is then poured into ice and carefully neutralized with 50% aqueous sodium hydroxide solution. The basic aqueous solution is extracted thoroughly with chloroform. The combined chloroform extracts are washed with brine, dried over anhydrous potassium carbonate and concentrated in vacuo. The resulting oil is taken up in ethyl acetate, treated with activated charcoal and filtered. On concentrating and cooling the filtered solution, 3.2 g. of 2-methyl-9H-dibenzo[b,f]imidazo[1,2-d][1,4]diazepine is obtained in 2 crops (yield 40%) of melting point 232°-236° C.
B. a suspension of 67 g. (0.3 mol.) of 5,10-dihydro-11H-dibenzo[b,e][1,4]diazepine-11-thione 72 g., (0.6 mol.) of aminopropionaldehyde dimethyl acetal and 300 ml. of diethylene glycol is heated to 190° in a 1 l-flask and kept under nitrogen for 24 hours, by which time, nearly all the starting material is consumed. The solution is cooled to room temperature and treated with 50 ml. of concentrated sulfuric acid for 2 hours. The reaction mixture is then permitted to stir overnight, and is then worked up by pouring onto ice and neutralizing with a 50% sodium hydroxide solution. The product is extracted with chloroform, washed with water and dried over anhydrous potassium carbonate. On evaporating the solvent in vacuo, a brown oil is obtained which is crystallized to give 15 g. of 2-methyl-9H-dibenzo-[b,f]imidazo[1,2-d][1,4]diazepine (20.2%) in the form of yellow prisms, of melting point 233°-235° C.
Anal. calcd. for C 16 H 13 N 3 : C, 77.71; H, 5.30; N, 16.99. Found: C, 77.49; H, 5.49; N, 17.44.
EXAMPLE 4
7-chloro[(5H-dibenzo[b,e][1,4]diazepin-11-yl)-amino]acetalde dimethyl acetal.
In the manner given in Example 1, 7-chloro-5,10-dihydro-11H-dibenzo[b,e][1,4]diazepine-11-thione is treated with aminoacetaldehyde dimethyl acetal in n-butanol to give 7-chloro-[(5H-dibenzo[b,e][1,4]diazepin-11-yl)amino]-acetaldehyde dimethyl acetal.
EXAMPLE 5
7-Chloro-9H-dibenzo[b,e]imidazo[1,2-d][1,4]-diazepine
In the manner given in Example 2, 7-chloro-[(5H-dibenzo[b,e][1,4]diazepin-11-yl)amino]acetaldehyde dimethyl acetal is treated with concentrated sulfuric acid to give 7-chloro-9H-dibenzo[b,f]imidazo[1,2-d][1,4]diazepine.
EXAMPLE 6
8-Trifluoromethyl-[(5H-dibenzo[b,e][1,4]diazepin-11-yl)amino]acetaldehyde dimethyll acetal
In the manner given in Example 1, 8-trifluoromethyl-5,10-dihydro-11H-dibenzo[b,e][1,4]diazepine-11-thione is treated with amino acetaldehyde dimethyl acetal in n-butanol to give 8-trifluoromethyl-[(5H-dibenzo[b,e][1,4]diazepin-11-yl)amino] acetaldehyde dimethyl acetal.
EXAMPLE 7
6-trifluoromethyl-9H-dibenzo[b,f]imidazo[1,2-d]-[1,4]diazepine
In the manner given in Example 5, 8-trifluoromethyl-[(5H-dibenzo[b,e][1,4]diazepin-11-yl)amino]acetaldehyde dimethyl acetal is treated with concentrated sulfuric acid to give 6-trifluoromethyl-9H-dibenzo[b,f]imidazo-[1,2-d][1,4]diazepine.
EXAMPLE 8
2-chloro-[(5H-dibenzo[b,e][1,4]diazepin-11-yl)-amino]acetaldehyde dimethyl acetal
In the manner given in Example 4, 2-chloro-5,10-dihydro-11H-dibenzo[b,e][1,4]diazepine-11-thione is treated with amino acetaldehyde dimethyl acetal in n-butanol to give 2-chloro-[(5H-dibenzo[b,e][1,4]diazepin-11-yl) amino]-acetaldehyde dimethyl acetal.
EXAMPLE 9
12-chloro-9H-dibenzo[b,f]imidazo[1,2-d][1,4]-diazepine
In the manner given in Example 5, 2-chloro-[(5H-dibenzo[b,e][1,4]diazepin-11-yl)amino]acetaldehyde dimethyl acetal is treated with concentrated sulfuric acid to give 12-chloro-9H-dibenzo[b,f]imidazo[1,2-d][1,4]diazepine.
EXAMPLE 10
8-methyl-[(5H-dibenzo[b,e][1,4]diazepin-11-yl)-amino]acetaldehyde dimethyl acetal
In the manner given in Example 4, 8-methyl-5,10-dihydro-11H-dibenzo[b,e][1,4]diazepine-11-thione is treated with amino acetaldehyde dimethyl acetal in n-butanol to give 8-methyl-[(5H-dibenzo[b,e][1,4]diazepin-11-yl)amino]-acetaldehyde dimethyl acetal.
EXAMPLE 11
6-methyl-9H-dibenzo[b,f]imidazo[1,2-d][1,4]-diazepine
In the manner given in Example 5, 8-methyl-[(5H-dibenzo[b,e][1,4]diazepin-11-yl)amino]acetaldehyde dimethyl acetal is treated with concentrated sulfuric acid to give 6-methyl-9H-dibenzo[b,f]imidazo[1,2-d][1,4]diazepine.
EXAMPLE 12
3-methoxy-[(5H-dibenzo[b,e][1,4]diazepin-11-yl)amino]acetaldehyde dimethyl acetal
In the manner given in Example 4, 3-methoxy-5,10-dihydro-11H-dibenzo[b,e][1,4]diazepine-11-thione is treated with amino acetaldehyde dimethyl acetal in n-butanol to give [(5H-dibenzo[b,e][1,4]diazepin-11-yl)amino]acetaldehyde dimethyl acetal.
EXAMPLE 13
11-methoxy-9H-dibenzo[b,f]imidazo[1,2-d][1,4]-diazepine
In the manner given in Example 5, 3-methoxy[(5H-dibenzo[b,e][1,4]diazepin-11-yl)amino]acetaldehyde dimethylacetal is treated with concentrated sulfuric acid to give 11-methoxy-9H-dibenzo[b,f]imidazo[1,2-d][1,4]diazepine.
EXAMPLE 14
3-methyl-9H-dibenzo[b,f]imidazo[1,2-d][1,4]diazepine In the manner given in example 3 B, a suspension of 5,10-dihydro-11H-dibenzo[b,e][1,4]diazepine-11-thione and aminoacetone ethylene ketal in diethylene glycol is heated to 190° C. for 24 hours, cooled to room temperature, and treated with concentrated sulfuric acid to give 3-methyl-9H-dibenzo[b,f]imidazo[1,2-d][1,4]diazepine.
EXAMPLE 15
9-Methyl-9H-dibenzo[b,f]imidazo[1,2-d][1,4]-diazepine
9H-Dibenzo[b,f]imidazo[1,2-d][1,4]diazepine (2.35 g., 10 mmol.) is dissolved in 13.0 g. of 88% formic acid (150 mmol.), treated with 6.75 ml. of 37% aqueous formalin solution (90.0 mmol.) and heated for 22 hours at 100° C. At the end of this period, the reaction is permitted to cool to room temperature, poured into 200 ml. of cold 5% aqueous sodium hydroxide, extracted with methylene chloride, dried over anhydrous magnesium sulfate, and concentrated in vacuo to give an oil which crystallized from ethyl acetate to give 1.76 g. (71.0%) of 9-methyl-9H-dibenzo[b,f]imidazo[1,2-d][1,4]diazepine of melting point 194.5°-197° C.
Anal. calcd. for C 16 H 13 N 3 : C, 77.71; H, 5.30; N, 16.99. Found: C, 77.45; H, 5.39; N, 16.92.
EXAMPLE 16
9-[2-(dimethylamino)ethyl]-9H dibenzo[b,f]-imidazo[1,2-d][1,4]diazepine dihydrobromide
9H-dibenzo[b,f]imidazo[1,2-d][1,4]diazepine (1.17 g., 5.0 mmol.) is dissolved in 50 ml. of dimethyl formamide, treated with 250 mg. of a 57% sodium hydride dispersion (in oil, 6.0 mmol. of reagent) and heated to 95° C. for 30 min. A deep red color of the anion formed. To this solution is added rapidly, on one portion, a solution of 2.7 g. of dimethylaminoethyl chloride (12.5 mmol.) in 50% wt/wt xylene. Within 5 minutes, a precipitate forms and the red color of the anion is replaced by a brown solution. Heating is maintained for 4-5 hours, at which time the heater is removed and the reaction is permitted to stand overnight. The solid is filtered and dried over anhydrous sodium sulfate and the solution is concentrated to dryness in vacuo. The resulting oil is taken up in 25 ml. of methylene chloride and 25 ml. of water. The layers are separated and the aqueous layer is extracted with four 20 ml. portions of methylene chloride. The combined organic layers are washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated in vacuo. The hydrobromide salt is formed in ethyl acetate/ethanol and 700 mg. of 9-[2-(dimethylamino)ethyl]-9H-dibenzo[b,f]imidazo]1,2-d][1,4]diazepine dihydrobromide of melting point 270°-272° is collected. A portion is recrystallized from 2-propanol to give 200 mg. of melting point 269°-270° C. containing 0.61% 2-propanol (melt solvate).
Anal. calcd. for C 19 H 22 Br 2 N 4 : C, 48.94; H, 4.75; N, 12.02; Br 34.28 Found: C, 48.70; H, 4.88; N, 12.03; Br, 33.75.
EXAMPLE 17
9-[3-(Dimethylamino)propyl]-9H-dibenzo-[b,f]imidazo[1,2-3][1,4]diazepine dihydrobromide
9H-dibenzo[b,f]imidazo[1,2-d][1,4]diazepine (1.17 g., 5.0 mmol.) is dissolved in 50 ml. of dimethyl formamide, treated with 250 mg. of a 57% sodium hydride dispersion (in oil) (6.0 mmol. of reagent), and heated to 95° C. for 30 minutes. To the red solution of the anion is added rapidly and in one portion a solution of 3.06 g. (12.5 mmol.) of dimethylaminopropyl chloride in 3.06 g. of xylene. A precipitate forms and the red color of the anion is replaced by a dark blue solution, the color of which gradually disappears on heating. After 6 hours the mixture is cooled to room temperature and the solid is filtered off and washed with chloroform. The dimethyl formamide is removed in vacuo and the residue is treated with 25 ml. of methylene chloride and 25 ml. of water. The aqueous layer is further extracted with methylene chloride and the combined organic extract is washed in a saturated aqueous sodium chloride solution, dried and concentrated in vacuo. The oil is converted to its dihydrobromide salt and crystallized from ethyl acetate/ethanol to give 500 mg. of yellow solid. This solid is recrystallized from isopropanol (200 mg. of solid in 10 ml. of solvent) to give 90 mg. of 9-[2-(dimethylamino)propyl]-9H-dibenzo[b,f]imidazo[1,2-d][1,4]diazepine dihydrobromide in crystalline form of melting point 268°-269° C. (decomposed). In the same way, 220 mg. of pure product is obtained from the remaining 300 mg. of crude product.
Anal. calcd. for C 20 H 24 N 4 Br 2 : C, 50,02; H, 5.04; N, 11.66; Br, 33.28. Found: C, 50.06; H, 5.08; N, 11.71; Br, 30.87.
EXAMPLE 18
9-[3-[2-(p-fluorophenyl)]-5,5-dimethyl-m-dioxan-2-yl]propyl]-9H-dibenz[b,f]imidazo[1,2-d][1,4]diazepine 9H-dibenzo[b,f]imidazo[1,2-d][1,4]diazepine (7.0 g., 30.0 mmol.) is dissolved in 250 ml. of dimethylformamide, treated with 1.5 g. of a 57% sodium hydride in oil dispersion (0.855 g., 37.6 mmol. of reagent) and heated to 95° C. for 0.5 hours. To the red solution of the anion is added 7.5 g. of ω-chloro-p-fluorobutyrophenone dimethyl ketal (30.0 mmol.) dissolved in 50 ml. of dimethylformamide and the solution is heated for 2 hours. Analysis of a aliquot indicated that some starting material is still present; therefore an additional 1.5 g. (6.5 mmol.) of ω-chloro-p-fluorobutyrophenone dimethyl ketal is added along with potassium iodide (2.4 g., 14.5 mmol.) and the mixture is heated at 95° C., for an additional two hours. During this heating period, the red color of the anion disappears. The reaction mixture is permitted to stir overnight at room temperature and is the poured into ice, made basic with an aqueous 5% sodium hydroxide solution and extracted with chloroform. The chloroform extract is washed with water, dried over anhydrous sodium sulfate and concentrated in vacuo to yield a pink oil. The product is chromatographed on 1 kg. of silica gel using a 50% ethyl acetate/cyclohexane solution as eluent. The product is collected in fractions 11 to 30 (200 ml. fractions are collected) and crystallized by trituration with a mixture of petroleum ether and ether to give 12 g. (86%) of 9-[3-[2-(p-fluorophenyl]-5,5-dimethyl-m-dioxan-2-yl]propyl]-9H-dibenz[b,f]imidazo-[1,2-d][1,4]diazepine as a white powder of melting point 138°-140° C.
Anal. calcd. for C 30 H 30 FN 3 O 2 : C, 74.51; H, 6.25; N, 8.69; F, 3.93 Found: C, 74.30; H, 6.22; N, 8.51; F, 3.99.
EXAMPLE 19
4'-Fluoro-4-[(9H-dibenzo[b,f]imidazo[1,2-d]-[1,4-diazepin-9-yl]butyrophenone
A solution of 2.0 g. (4.0 mmol.) of 9-[3-[2-(p-fluorophenyl)-5,5-dimethyl-m-dioxan-2-yl]propyl]-9H-dibenz-[b,f]imidazo[1,2-d][1,4]diazepin in 20 ml. of methanol is treated with 5.0 ml. of 2N hydrochloric acid and stirred at room temperature overnight. It is poured into an ice-water mixture, neutralized with a 5% aqueous sodium hydroxide solution and extracted with ether. The ether solution is dried over anhydrous sodium sulfate and concentrated in vacuo to yield a white solid which crystallized from ethyl acetate to afford 900 mg. of 4'-fluoro-4(9H-dibenzo-[b,f]imidazo[1,2-d][1,4]diazepin-9-yl)butyrophenone of melting point 163°-165°.
Anal. calcd. for C 25 H 20 FN 3 O: C, 75.55; H, 5.07; N, 10.58; F, 4.78. Found: C, 75.51; H, 5.00; N, 10.55; F, 4.70.
EXAMPLE 20
2,9-Dimethyl-3-hydroxymethyl-9H-dibenzo[b,f]-imidazo[1,2-d][1,4]diazepine
2-Methyl-9H-dibenzo[b,f]imidazo[1,2-d][1,4]diazepine (0.4925 g., 2.00 mmol.) is dissolved in 2.62 g. of 88% formic acid, treated with 1.35 ml. of a 37 % aqueous formalin solution and heated for 22.5 hours, then quenched in a cold 5% aqueous sodium hydroxide solution, extracted with chloroform, dried over anhydrous magnesium sulfate and concentrated in vacuo. Crystallization of the product from ethyl acetate/hexane afforded 270 mg. (41.3%) of 2,9-dimethyl-3-hydroxymethyl-9H-dibenzo [b,f]imidazo[1,2-d][1,4]diazepine of melting point 187°-190° C. in the form of white needles.
Anal. calcd. for C 18 H 17 N 3 O: C, 74.20; H, 5.88; N, 14,43. Found: C, 74.06; H, 6.01; N, 14.14.
EXAMPLE 21
2-Methyl-3-(1-pyrrolidinylmethyl)-9H-dibenzo-[b,f]imidazo[1,2-d][1,4]diazepine
A mixture of 1.2 ml. of a 37% aqueous formalin (14.8 mmol.) solution. 0.50 ml. (0.426 g., 6.0 mmol.) of pyrrolidine, 3.0 ml. of 2N hydrochloric acid, dissolved in 4.0 ml. of monoglyme is placed in a 20 ml. round bottom flask. To the magnetically stirred solution is added 0.4925 g. of 2-methyl-9H-dibenzo[b,f]imidazo[1,2-d][1,4]diazepine (2.00 mmol.) and the solution is heated on a steam bath overnight (22 hrs.). The entire reaction mixture is worked up by quenching in a cold 5% aqueous sodium hydroxide solution, extracting with chloroform, drying over anhydrous sodium sulfate and concentrating in vacuo to a yellow oil. The oil is taken up in ethyl acetate and filtered from a small amount of floculent white solid. The product crystallized from ethyl acetate/hexane to give 200 mg. (30.2%) of 2-methyl-3-(1-pyrrolidinylmethyl)-9H-dibenzo-[b,f]imidazo[1,2-d][1,4]diazepine of melting point 217°-220° C. (decomposed). A portion is recrystallized from ethyl acetate/hexane to give the desired product in the form of prisms of melting point 225°-228° C. decomp.
Anal. Calcd. for C 21 H 22 N 4 : C, 76.33; H, 6.71; N, 16.96. Found: C, 76.29; H, 6.97; N, 16.87.
EXAMPLE 22
2,9-dimethyl-3-(1-pyrrolidinylmethyl)-9H-dibenzo[b,f]imidazo[1,2-d][1,4]diazepine hydrobromide
In a 50-ml. round bottom flask, 1.32 g. of 2-methyl-3-[1-pyrrolidinylmethyl]-9H-dibenzo[b,f]imidazo [1,2-a] [1,4]diazepine (4.00 mmol.) is dissolved in 5.24 g. of an 88% formic acid (60.0 mmol.) solution. To it is added 5.4 ml. (36.0 mmol.) of a 37% aqueous formalin solution. The mixture is heated on a steam bath for 24 hours under a nitrogen atmosphere. The entire reaction mixture is quenched in a 5% aqueous sodium hydroxide solution and extracted with chloroform. The chloroform layer is washed twice with water and dried over anhydrous sodium sulfate. The solvent is removed in vacuo to yield 800 mg. of a yellow oily residue. The product is separated from minor amounts of impurities by column chromatography (silica gel, using 3% methanol-97% chloroform as eluent) to yield 300 mg. of oil. The oil is converted to its hydrobromide salt and crystallized from methanol-ethyl acetate to afford 150 mg. of 2,9-dimethyl-3-(1-pyrrolidinylmethyl)-9H-dibenzo-[b,f]imidaze[1,2-d][1,4]diazepine hydrobromide of melting point 198°-200° C.
Anal. calcd. for C 22 H 25 BrN 4 : C, 62.12; H, 5.93; N, 13.17. Found: C, 62.09; H, 5.96; N, 13.00.
EXAMPLE 23
2-Methyl-3-(1-morpholinylmethyl)-9H-dibenzo-[b,f]imidazo[1,2-d][1,4]diazepine
In a 100-ml. round bottom flask, 2.5 g. (10.0 mmol.) of 2-methyl-9H-dibenzo[b,f]imidazo[ 1,2-d][1,4]diazepine is dissolved in 20 ml. of monoglyme and treated with 6.0 ml. (2.25 g., 74.0 mmol.) of a 37% aqueous formalin solution, 2.60 g. (30.0 mmol.) of morpholine and 15 ml. of a 2N hydrochloric acid solution. The solution is stirred for 18 hours on a steam bath under a nitrogen atmosphere. The reaction is quenched in a cold aqueous 10% sodium hydroxide solution and the product is extracted with chloroform. The chloroform layer is washed twice with water and dried over anhydrous sodium sulfate. After drying, it is filtered and concentrated in vacuo to give 3.0 g. of a tan oil, which is chromatographed over 300 g. of silica gel using a 3% methanol-97% chloroform solution as eluent to afford 2.5 g. of a yellow oil. On trituration with ether, 1.0 g. of a tan powder is obtained of melting point 180°-185° C. The ether solution, on cooling, affords 700 mg. of 2-methyl-3-(1-morpholinylmethyl)-9H-dibenzo[b,f]-imidazo[1,2-d][ 1,4]diazepine of melting point 182°-184° C. This latter fraction is crystallized from ethanol to afford 550 mg. of prisms of melting point 218°-219° C.
Anal. calcd. for C 21 H 22 N 4 O: C, 70.38; H, 7.19; N, 14.28. Found: C, 70.08; H, 7.12; N, 14.12.
EXAMPLE 24 3.9-Dimethyl-2-hydroxymethyl-9H-dibenzo [b,f]-imidazo[1,2-d][1,4]diazepine
In the manner given in example 19
3-methyl-9H-dibenzo[b,f]imidazo[1,2-d][1,4]diazepine is dissolved in 88% formic acid, treated with 37% aqueous formalin solution and heated for 24 hours, to give 3,9-dimethyl-2-hydroxymethyl-9H-dibenzo [b,f]-imidazo[1,2-d][1,4]diazepine.
EXAMPLE 25
3,9-Dimethyl-2-(4-methyl-1-piperazinyl) methyl-9H-dibenzo[b,f]-imidazo[1,2-d][1,4]-diazepine
A sampmle of 3,9-dimethyl-2-hydroxymethyl-9H-dibenzo[b,f]-imidazo[1,2-d] [1,4]diazepine is suspended in a chloroform/tetrahydrofuran mixture and treated with triethylamine. After cooling to -20° C. methanesulfonyl chloride is added with stirring at -20° C. The mixture is treated with 4-methylpiperazine and warmed gradually to room temperature. Work-up from an aqueous base followed by the usal purification techniques affords the product 3,9-dimethyl-2-(4-methyl-1-piperazinyl)methyl-9H-dibenz[b,f]-imidazo[1,2-d][1,4]diazepine as a yellow oil.
Treatment of the compounds of the formula III (which includes IIIA, IIIB, IIIC, IIID, IIIE, IIIF, IIIG, IIIH, III(I), and IIIJ) with pharmacologically acceptable acids preferably in a solvent e.g. water, ethanol, ether, dioxane and the like, provides the pharmacologically acceptable acid addition salts of these 9H-dibenzoimidazodiazepine compounds. Examples of such addition salts are the hydrochlorides, fumarates, hydrobromides, hydriodides, sulfates, methanesulfonates, toluenesulfonates, citrates, tartrates, lactates, palmoates, laurates, acetates, succinates, and the like.
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9H-Dibenzoimidazodiazepine compounds of the formula: ##SPC1##
Wherein R 1 is hydrogen, alkyl, ##SPC2##
In which W is H, chlorine, or fluorine, or R 1 is ##EQU1## IN WHICH N IS AN INTEGER OF 2 TO 4, AND R o ' and R o ' are hydrogen or alkyl defined as above, or together ##EQU2## IS PYRROLIDINO, PIPERIDINO, N-methylpiperazino, or morpholino, wherein R 3 and R 4 are hydrogen or alkyl as defined above, or, R 3 or R 4 can be ##EQU3## IN WHICH ##EQU4## IS DEFINED AS ABOVE AND WHEREIN R 2 and R 6 are selected from the group consisting of hydrogen, halogen, or -CF 3 , are produced by multistep reactions.
The compounds of the formula above and the pharmacologically acceptable acid addition salts thereof are useful sedatives and anti-depressants. They can also be administered to mammals to alleviate anxieties and produce tranquilization and sedation.
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The present application is a continuation of PCT/EP04/000888, filed Jan. 30, 2004, which claims priority to U.S. Provisional Application 60/444,351, filed Jan. 30, 2003. The content of these applications is incorporated herein by reference.
BACKGROUND OF THE INVENTION
The present invention relates to shelf-life stable liquid formulations of palonosetron that are especially useful in the preparation of injectable and oral medicaments.
Emesis is a devastating consequence of cytotoxic therapy, radiotherapy, and post-operative environments that drastically affects the quality of life of people undergoing such treatments. In recent years a class of drugs referred to as 5-HT 3 (5-hydroxytryptamine) receptor antagonists has been developed that treat such emesis by antagonizing cerebral functions associated with the 5-HT 3 receptor. See Drugs Acting on 5- Hydroxytryptamine Receptors: The Lancet Sep. 23, 1989 and references cited therein. Drugs within this class include ondansetron, granisetron, alosetron, tropisetron, and dolasetron. These 5-HT 3 antagonists are often administered intravenously shortly before chemotherapy or radiotherapy is initiated, and can be administered more than once during a cycle of chemotherapy or radiotherapy. In addition, they are often supplied as tablets or oral elixirs to either supplement an intravenous administration, or to ease home usage of the drug if the patient is self-administering the chemotherapeutic regimen.
Because some chemotherapeutic agents can induce emesis over extended periods of several days even when they are administered only once, it would be desirable to administer an emesis-inhibiting drug such as a 5-HT 3 antagonist every day until the risk of emesis has substantially subsided. The present class of 5-HT 3 antagonists has not proven especially helpful meeting this need, however, because the 5-HT 3 receptor antagonists currently marketed have proven to be less effective in controlling delayed nausea and vomiting than they are at controlling acute emesis. Sabra, K, Choice of a 5 HT 3 Receptor Antagonist for the Hospital Formulary . EHP, October 1996;2 (suppl 1):S19-24.
Recently, clinical investigations have been made concerning palonosetron, a new 5-HT 3 receptor antagonist reported in U.S. Pat. No. 5,202,333. These investigations have shown that the drug is an order of magnitude more potent than most existing 5-HT 3 receptor antagonists, has a surprising half-life of about 40 hours, and is effective to reduce delayed-onset nausea induced by chemotherapeutic agents. However, formulating palonosetron in liquid formulations has not proven an easy task, typically due to shelf-stability issues. U.S. Pat. No. 5,202,333 discloses an intravenous formulation of palonosetron in example 13 that contains the following ingredients:
Ingredient
Mg
Palonosetron HCI
10-100
mg.
Dextrose Monohydrate
q.s. to make Isotonic
Citric Acid Monohydrate
1.05
mg.
Sodium Hydroxide
0.18
mg.
WFJ
To 1.0
ml.
The formulation has a pH of 3.7 and a shelf stability of less than the 1-2 year time period required by health authorities in various countries.
Ondansetron, its uses, and medicaments made with ondansetron are disclosed in U.S. Pat. Nos. 4,695,578, 4,753,789, 4,929,632, 5,240,954, 5,344,658, 5,578,628, 5,578,632, 5,922,749, 5,622,720, 5,955,488, and 6,063,802. Commercially it is distributed by GlaxoSmithKline as Zofran® and is indicated for prevention of postoperative nausea and vomiting (PONV), cancer chemotherapy-induced nausea and vomiting (CINV), and radiotherapy-induced nausea and vomiting (RINV) and it is available as an injection, tablets and solution, and as Zofran ODT® (ondansetron) Orally Disintegrating Tablets.
Granisetron, its uses, and medicaments made with granisetron are disclosed in U.S. Pat. Nos. 4,886,808, 4,937,247, 5,034,398 and 6,294,548. Commercially it is distributed by Roche Laboratories Inc. as Kytril®, indicated for the prevention of nausea and vomiting associated with chemotherapy or radiation therapy, and is offered in tablet form, oral solution, and as an injection.
Alosetron, its uses, and medicaments made with alosetron are disclosed in U.S. Pat. Nos. 5,360,800 and 6,284,770. Commercially it is distributed by GlaxoSmithKline as Lotronex®.
Tropisetron is commercially available as Navoban® (Novartis) CAS-89565-68-4 (tropisetron); CAS-105826-92-4 (tropisetron hydrochloride) and it is indicated for treatment of PONV and CINV.
Dolasetron, its uses, and medicaments made with ondansetron are disclosed in U.S. Pat. Nos. 5,011,846, and 4,906,755. Commercially it is distributed by Aventis Pharmaceuticals Inc. as Anzemet®, indicated for prevention of both PONV and CINV, and it is offered in the form of a tablet or an intravenous solution.
Therefore, there exists a need for a palonosetron formulation with increased stability and thereby increased shelf life. There also exists a need for an appropriate range of concentrations for both the 5-HT 3 receptor antagonist and its pharmaceutically acceptable carriers that would facilitate making a formulation with this increased stability.
It is an object of the present invention to provide a formulation of Palonosetron hydrochloride with increased pharmaceutical stability for preventing and/or reducing emesis.
It is another object of the invention to provide an acceptable range of concentrations which will stabilize a formulation containing Palonosetron hydrochloride.
It is a further object of the invention to provide a formulation of Palonosetron which would allow for prolonged storage.
It is also an object of the invention to provide a formulation of Palonosetron which would allow terminal sterilization.
SUMMARY OF THE INVENTION
The inventors have made a series of discoveries that support a surprisingly effective and versatile formulation for the treatment and prevention of emesis using palonosetron. These formulations are shelf stable for periods greater than 24 months at room temperature, and thus can be stored without refrigeration, and manufactured using non-aseptic, terminal sterilization processes.
In one aspect, the inventors have discovered that formulations which include the active ingredient palonosetron require in some instances only 1/10 th the amount of other previously known compounds for treating emesis, which surprisingly allows the use of concentrations of palonosetron far below those that would ordinarily be expected. Thus, in one embodiment the invention provides a pharmaceutically stable solution for preventing or reducing emesis comprising a) from about 0.01 mg/mL to about 5 mg/mL palonosetron or a pharmaceutically acceptable salt thereof; and b) a pharmaceutically acceptable carrier.
The inventors have further discovered that by adjusting the formulation's pH and/or excipient concentrations it is possible to increase the stability of palonosetron formulations. Therefore, in another embodiment, the invention provides a pharmaceutically stable solution for preventing or reducing emesis comprising a) palonosetron or a pharmaceutically acceptable salt thereof; and b) a pharmaceutically acceptable carrier, at a pH from about 4.0 to about 6.0. In another embodiment the invention provides a pharmaceutically stable solution for preventing or reducing emesis comprising from about 0.01 to about 5.0 mg/ml palonosetron or a pharmaceutically acceptable salt thereof; from about 10 to about 100 millimoles citrate buffer; and from about 0.005 to about 1.0 mg/ml EDTA.
The inventors have further discovered that the addition of mannitol and a chelating agent can increase the stability of palonosetron formulations. Therefore, in still another embodiment the invention provides a pharmaceutically stable solution for preventing or reducing emesis comprising a) palonosetron or a pharmaceutically acceptable salt thereof and b) a pharmaceutically acceptable carrier, wherein the pharmaceutically acceptable carrier comprises a chelating agent and mannitol.
DETAILED DESCRIPTION OF THE INVENTION
Definitions
“Vial” means a small glass container sealed with the most suitable stopper and seal, other suitable primary containers may be used, for instance, but not limited to, pre-filled syringes. Vial also means a sealed container of medication that is used one time only, and includes breakable and non-breakable glass vials, breakable plastic vials, miniature screw-top jars, and any other type of container of a size capable of holding only one unit dose of palonosetron (typically about 5 mls.).
Throughout this specification the word “comprise,” or variations such as “comprises” or “comprising,” will be understood to imply the inclusion of a stated element, integer or step, or group of elements, integers or steps, but not the exclusion of any other element, integer or step, or group of elements, integers or steps
“Palonosetron” means (3aS)-2,3,3a,4,5,6-Hexahydro-2-[(S)-1-Azabicyclo[2.2.2]oct-3-yl]2,3,3a,4,5,6-hexahydro-1-oxo-1Hbenz[de]isoquinoline, and is preferably present as the monohydrochloride. Palonosetron monohydrochloride can be represented by the following chemical structure:
Concentrations—When concentrations of palonosetron are given herein, the concentration is measured in terms of the weight of the free base. Concentrations of all other ingredients are given based on the weight of ingredient added to the solution.
“Pharmaceutically acceptable” means that which is useful in preparing a pharmaceutical composition that is generally safe, non-toxic and neither biologically nor otherwise undesirable and includes that which is acceptable for veterinary use as well as human pharmaceutical use.
“Pharmaceutically acceptable salts” means salts which are pharmaceutically acceptable, as defined above, and which possess the desired pharmacological activity. Such salts include acid addition salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or with organic acids such as acetic acid, propionic acid, hexanoic acid, heptanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, o-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2,-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid p-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, p-toluenesulfonic acid, camphorsulfonic acid, 4-methylbicyclo[2.2.2]oct-2-ene-1-carboxylic acid, glucoheptonic acid, 4,4′-methylenebis(3-hydroxy-2-ene-1-carboxylic acid), 3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid, and the like.
In addition, pharmaceutically acceptable salts may be formed when an acidic proton present is capable of reacting with inorganic or organic bases. Acceptable inorganic bases include sodium hydroxide, sodium carbonate, potassium hydroxide, aluminum hydroxide and calcium hydroxide. Acceptable organic bases include ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucamine and the like.
Discussion
The fact that palonosetron can be formulated in some instances at concentrations of only about 1/10 th the amount of other previously known compounds for treating emesis, surprisingly allows the use of concentrations of palonosetron far below those that would ordinarily be expected. Thus, in one embodiment the invention provides a pharmaceutically stable solution for preventing or reducing emesis comprising a) from about 0.01 mg/mL to about 5 mg/mL palonosetron or a pharmaceutically acceptable salt thereof; and b) a pharmaceutically acceptable carrier. Similarly, in another embodiment the invention provides a method of formulating a pharmaceutically stable solution of palonosetron comprising admixing from about 0.01 mg/mL to about 5 mg/mL palonosetron or a pharmaceutically acceptable salt thereof; with a pharmaceutically acceptable carrier. In alternative embodiments, the formulation includes palonosetron or a pharmaceutically acceptable salt thereof in a concentration from about 0.02 mg/mL to about 1.0 mg/mL, from about 0.03 mg/mL to about 0.2 mg/mL, and most optimally about 0.05 mg/ml.
A particular advantage associated with the lower dosages of intravenous palonosetron is the ability to administer the drug in a single intravenous bolus over a short, discrete time period. This time period generally extends from about 10 to about 60 seconds, or about 10 to about 40 seconds, and most preferably is about 10 to 30 seconds. In one particular embodiment the palonosetron is supplied in vials that comprise 5 ml. of solution, which equates to about 0.25 mg of palonosetron at a concentration of about 0.05 mg/ml.
The inventors have further discovered that by adjusting the formulation's pH and/or excipient concentrations it is possible to increase the stability of palonosetron formulations. Therefore, in another embodiment, the invention provides a pharmaceutically stable solution for preventing or reducing emesis comprising a) palonosetron or a pharmaceutically acceptable salt thereof; and b) a pharmaceutically acceptable carrier, at a pH from about 4.0 to about 6.0. Similarly, in another embodiment the invention provides a method of formulating a pharmaceutically stable solution of palonosetron comprising admixing a) palonosetron or a pharmaceutically acceptable salt thereof; and b) a pharmaceutically acceptable carrier, at a pH from about 4.0 to about 6.0. In alternative embodiments, the pH is from about 4.5 to about 5.5, and most optimally about 5.0. There are many examples to those of skill in the art of suitable solutions to adjust the pH of a formulation. Two exemplary solutions are sodium hydroxide and hydrochloric acid solution, either of which could be used to adjust the pH of the formulation.
In another embodiment the invention provides a pharmaceutically stable solution for preventing or reducing emesis comprising from about 0.01 to about 5.0 mg/ml palonosetron or a pharmaceutically acceptable salt thereof and (i) from about 10 to about 100 millimoles citrate buffer, and/or (ii) from about 0.005 to about 1.0 mg/ml EDTA. Similarly, in another embodiment the invention provides a method of formulating a pharmaceutically stable solution of palonosetron comprising admixing from about 0.01 to about 5.0 mg/ml palonosetron or a pharmaceutically acceptable salt thereof and (i) from about 10 to about 100 millimoles citrate buffer, and/or (ii) from about 0.005 to about 1.0 mg/ml EDTA. The citrate buffer can be in the form of citric acid and/or a salt of citric acid such as trisodium citrate. In various embodiments, the ranges of one or more of the foregoing ingredients can be modified as follows:
The formulation may comprise palonosetron or a pharmaceutically acceptable salt thereof in a concentration from about 0.02 mg/mL to about 1.0 mg/mL, from about 0.03 mg/mL to about 0.2 mg/mL palonosetron hydrochloride, and most optimally about 0.05 mg/ml. The formulation may comprise citrate buffer in a concentration of from about 10 to about 40 millimoles, or 15-30 millimoles. The formulation may comprise EDTA in a concentration of from about 0.005 mg/ml to about 1.0 mg/ml, or about 0.3 to about 0.7 mg/ml, and most optimally about 0.5 mg/ml.
The inventors have further discovered that the addition of mannitol and a chelating agent can increase the stability of palonosetron formulations. Therefore, in still another embodiment the invention provides a pharmaceutically stable solution for preventing or reducing emesis comprising a) palonosetron or a pharmaceutically acceptable salt thereof and b) a pharmaceutically acceptable carrier, wherein the pharmaceutically acceptable carrier comprises a chelating agent and mannitol. Similarly, in another embodiment the invention provides a method of formulating a pharmaceutically stable solution of palonosetron comprising admixing a) palonosetron or a pharmaceutically acceptable salt thereof and b) a pharmaceutically acceptable carrier, wherein the pharmaceutically acceptable carrier comprises a chelating agent and mannitol. The chelating agent is preferably EDTA, and, in various embodiments the chelating agent is present in a concentration of from about 0.005 to about 1.0 mg/mL or from about 0.05 mg/mL to about 1.0 mg/mL or from about 0.3 to about 0.7 mg/ml, or most optimally about 0.5 mg/ml. In various embodiments the mannitol is present in a concentration of from about 10.0 mg/ml to about 80.0 mg/ml, from about 20.0 mg/mL to about 60.0 mg/ml, or from about 40.0 to about 45.0 mg/ml.
Injectable formulations are typically formulated as aqueous solutions in which water is the primary excipient. Oral formulations will differ from injectable formulations generally by the additional presence of flavoring agents, coloring agents, or viscosity agents. Natural or synthetic sweeteners include, among others, mannitol, sorbitol, saccharose, saccharine, aspartame, acelsulphame K, or cyclamate. These agents are generally present in concentrations in excess of 100 mg/ml or 250 mg/ml when used as sweetening agents, in contrast to the 41.5 mg/ml concentration of mannitol described in some of the embodiments of the invention, in which mannitol is acting simply as a tonicifying agent.
The formulations of the present invention are particularly suited for use in injectable and oral liquid formulations, but it will be understood that the solutions may have alternative uses. For example, they may be used as intermediates in the preparation of other pharmaceutical dosage forms. Similarly, they may have other routes of administration including intranasal or inhalation. Injectable formulations may take any route including intramuscular, intravenous or subcutaneous.
Still further embodiments relate to improvements in the ease with which the palonosetron formulation can be stored or manufactured. In particular, the inventors have discovered that the formulations of the present invention allow storage of the product for extended periods at room temperature. Thus, in yet another embodiment the invention provides a method of storing one or more containers in which are contained a solution of palonosetron or a pharmaceutically acceptable salt thereof comprising: a) providing a room comprising said one or more containers; b) adjusting or maintaining the temperature of the room at greater than about ten, 15, or 20 degrees celcius; and c) storing said containers in said room for one month, 3 months, 6 months, one year, 18 months, 24 months or more (but preferably not exceeding 36 months), wherein (i) the palonosetron or pharmaceutical salt thereof is present in a concentration of from about 0.01 mg/mL to about 5.0 mg/mL, (ii) the pH of the solution is from about 4.0 to about 6.0, (iii) the solution comprises from about 0.01 to about 5.0 mg/ml palonosetron or a pharmaceutically acceptable salt thereof, from about 10 to about 100 millimoles citrate buffer and from about 0.005 to about 1.0 mg/ml EDTA, (iv) the solution comprises a chelating agent, or (v) the solution comprises from about 10 to about 100 milliMoles of a citrate buffer.
The stability of the foregoing formulations also lends itself well to terminal sterilization processes in the manufacturing process. Therefore, in still another embodiment the invention provides a method of filling a container in which is contained a solution of palonosetron or a pharmaceutically acceptable salt thereof comprising: a) providing one or more sterile open containers (preferably 5 ml. vials); b) filling said containers with a solution of palonosetron in a non-aseptic environment; c) sealing said filled containers; and d) sterilizing said sealed, filled containers, wherein (i) the palonosetron or pharmaceutical salt thereof is present in a concentration of from about 0.01 mg/mL to about 5 mg/mL, (ii) the pH of the solution is from about 4.0 to about 6.0, (iii) the solution comprises from about 0.01 to about 5.0 mg/ml palonosetron or a pharmaceutically acceptable salt thereof, from about 10 to about 100 millimoles citrate buffer and from about 0.005 to about 1.0 mg/ml EDTA, (iv) the solution comprises a chelating agent, or (v) the solution comprises from about 10 to about 100 milliMoles of a citrate buffer.
EXAMPLES
Example 1
Stabilizing pH
A study was conducted to determine the effect of pH on formulations containing palonosetron hydrochloride, measuring the stability at 80° C. at pH 2.0, 5.0, 7.4, and 10.0. The results indicated that palonosetron hydrochloride is most stable at pH 5.0.
Example 2
Stabilizing Concentration Ranges
A formulation optimization study was performed using an experimental design software. Twenty-four lots of drug product were analyzed to investigate the appropriate concentration ranges for palonosetron hydrochloride (0.05 mg/mL to 5.0 mg/mL), citrate buffer (0 to 80 mM) and EDTA (0 to 0.10%). The level of EDTA and citrate buffer were selected based on the optimal formulation, which was shown to be formulated with EDTA 0.05% and 20 mM citrate buffer at pH 5.0. The results of this study indicated that palonosetron concentration was also a critical factor in chemical stability, with greatest stability seen at the lowest palonosetron concentrations.
Example 3
Tonicifying Agent
Formulations of palonosetron hydrochloride in citrate buffer were prepared including either a) sodium chloride or b) mannitol. The palonosetron hydrochloride formulation including mannitol showed superior stability. The optimum level of mannitol required for an isotonic solution was found to be 4.15%.
Example 4
Formulation I
The following is a representative pharmaceutical formulation containing palonosetron that is useful for intravenous formulations, or other liquid formulations of the drug.
Ingredient
mg/mL
Palonosetron Hydrochloride
0.05*
Mannitol
41.5
EDTA
0.5
Trisodium citrate
3.7
Citric acid
1.56
WFJ
q.s. to 1 ml
Sodium hydroxide solution and/or
pH 5.0 ± 0.5
hydrochloric acid solution
*calculated as a free base
Example 5
Formulation II
The following is a representative pharmaceutical formulation containing palonosetron that is useful for oral formulations, or other liquid formulations of the drug.
Ingredient
mg/mL
Palonosetron Hydrochloride
0.05*
Mannitol
150
EDTA
0.5
Trisodium citrate
3.7
Citric acid
1.56
WFJ
q.s. to 1 ml
Sodium hydroxide solution and/or
pH 5.0 ± 0.5
hydrochloric acid solution
Flavoring
q.s.
*calculated as a free base
Example 6
Stability of Palonosetron without Dexamethasone
The physical and chemical stability of palonosetron HCl was studies in concentrations of 5 μg/mL and 30 μg/mL in 5% dextrose injection, 0.9% sodium chloride injection 5% dextrose in 0.45% sodium chloride injection, and dextrose 5% in lactated Ringer's injection. The admixtures were evaluated over 14 days at 4° C. in the dark and for 48 hours at 23° C. under fluorescent light.
Test samples of palonosetron HCl were prepared in polyvinyl chloride (PVC) bags of the infusion solutions at concentrations of 5 and 30 μg/mL. Evaluations for physical and chemical stability were performed on samples taken initially and after 1, 3, 5, 7, and 14 days of storage at 4° C. and after 1, 4, 24, and 48 hours at 23° C. Physical stability was assessed using visual observation in normal room light and using a high-intensity monodirectional light beam. In addition, turbidity and particle content were measured electronically. Chemical stability of the drug was evaluated by using a stability-indicating high performance liquid chromatographic (HPLC) analytical technique.
All samples were physically stable throughout the study. The solution remained clear, and little or no change in particulate burden and haze level were found. Additionally, little or no loss of palonosetron HCl occurred in any of the samples at either temperature throughout the entire study period.
Example 7
Stability of Palonosetron with Dexamethasone
The physical and chemical stability of palonosetron HCl 0.25 mg admixed with dexamethasone (as sodium phosphate) 10 mg or 20 mg in 5% dextrose injection or 0.9% sodium chloride injection in polyvinyl chloride (PVC) minibags, and also admixed with dexamethasone (as sodium phosphate) 3.3 mg in 5% dextrose injection or 0.9% sodium chloride injection in polypropylene syringes at 4° C. in the dark for 14 days and at 23° C. exposed to normal laboratory fluorescent light over 48 hours, was studied.
Test samples of palonosetron HCl 5 μg/mL with dexamethasone (as sodium phosphate) 0.2 mg/mL and also 0.4 mg/mL were prepared in polyvinyl chloride (PVC) minibags of each infusion solution. Additionally, palonosetron HCl 25 μg/mL with dexamethasone (as sodium phosphate) 0.33 mg/mL in each infusion solution were prepared as 10 mL of test solution in 20-mL polypropylene syringes. Evaluations for physical and chemical stability were performed on samples taken initially and after 1, 3, 7, and 14 days of storage at 4° C. and after 1, 4, 24, and 48 hours at 23° C. Physical stability was assessed using visual observation in normal room light and using a high-intensity monodirectional light beam. In addition, turbidity and particle content were measured electronically. Chemical stability of the drug was evaluated by using a stability-indicating high performance liquid chromatographic (HPLC) analytical technique.
All samples were physically compatible throughout the study. The solutions remained clear, and little or no change in particulate burden and haze level were found. Additionally, little or no loss of palonosetron HCl and dexamethasone occurred in any of the samples at either temperature throughout the entire study period.
This invention has been described with reference to its preferred embodiments. Variations and modifications of the invention will be obvious to those skilled in the art from the foregoing detailed description of the invention.
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The present invention relates to shelf-stable liquid formulations of palonosetron for reducing chemotherapy and radiotherapy induced emesis with palonosetron. The formulations are particularly useful in the preparation of intravenous and oral liquid medicaments.
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BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to waste water treatment by anaerobic fermentation and, more particularly, to a method of and apparatus for controlling waste water treatment by anaerobic fermentation.
2. Description of the Related Art
Heretofore, waste water treatment in which organic substances that are contained in industrial waste water, sewage sludge, etc. are decomposed by anaerobic bacteria has been employed to treat particularly waste water that has a relatively high concentration of organic substances.
A typical example of the waste water treatment by anaerobic fermentation is methane fermentation, in which organic substances such as carbohydrates, fats and proteins are first decomposed into volatile fatty acids such as acetic acid, propionic acid and butyric acid by the activities of acid-forming bacteria and the like, and then formed into methane gas (CH 4 ) by the activities of methane-forming bacteria. Methane gas may also be formed from methanol, formic acid, acetic acid or carbon dioxide and hydrogen by the activities of methane-forming bacteria.
Anaerobic fermentation treatment is preferably carried out with a maximal operating efficiency. It is, however, necessary in order to increase the operating efficiency to constantly control various fermentation conditions such as temperature, pH, ORP (Oxidation-Reduction Potential), sludge concentration, space loading and the concentration of fermentation inhibitor.
A lowering of the operating efficiency during a waste water treatment by anaerobic fermentation may be known by monitoring various kinds of indicator, for example, a lowering in gasification (CH 4 ), a change in the gas composition (i.e., a decrease in the content of CH 4 gas), a change in the pH and ORP in the waste water, total organic carbon (TOC), suspended solid (SS), etc. However, these indicators show only the final results in the anaerobic fermentation tank (reactor).
Accordingly, in an operation based on these indicators, by the time that a lowering in the operating efficiency is recognized, an unfavorable condition in the reactor will have progressed to a considerable extent and a great deal of labor and a large number of days will be needed to return the reactor to the normal, well-conditioned state.
In addition, the measurement of the conventional indicator such as gas composition and TOC needs special, expensive measuring devices, for example, a gas chromatograph and a TOC analyzer.
Incidentally, a method wherein acetic acid or propionic acid in the treated water is measured is known as a technique of relatively high sensitivity, that is, a technique of predicting a lowering in the operating efficiency. It is possible with this method to know a lowering in the operating efficiency in advance. However, this method also needs a special measuring device, for example, a high-pressure liquid chromatograph (HPLC) or gas chromatograph.
Generally speaking, these special devices are costly and necessitate operational training. In addition, since waste water of high concentration is used in the measurement, the maintenance of columns and other associated equipment becomes a serious problem. Further, a long time is needed for the measurement. In particular, high-pressure liquid chromatography (HPLC) and gas chromatography, although highly sensitive, involve the problem that these means are likely to catch a noise and obtain an erroneous value due to a deviation of the standard peak.
The prior art also suffers from the problem that the measuring operation requires much time and labor. For example, high-pressure liquid chromatography (HPLC) needs to inject a standard solution after the replacement of a buffer.
With regard to the temporal relationship between the lowering in the operating efficiency and the acid formation in the reactor in the waste water treatment by anaerobic fermentation, there is such a constant time lag that the operating efficiency begins to lower after a predetermined time has elapsed since the rate of acid formation began to increase. More specifically, in an ordinary plant-scale operation the operating efficiency begins to lower after about one week has elasped since the rate of acid formation began to increase. This means that a future lowering in the operating efficiency can be predicted about one week before the operating efficiency actually lowers by monitoring the acid formation condition.
However, the above-described time lag is not sufficiently long to control various fermentation conditions so as to prevent a lowering in the operating efficiency of the reactor.
More specifically, even if an operation of controlling various fermentation conditions is initiated after an increase in the rate of acid formation is found, it will be too late for completely preventing a lowering in the operating efficiency.
The necessity for "early discovery and early treatment", which is said as to the human health care, also applies to the field of waste water treatment by anaerobic fermentation.
Under these circumstances, it has been desired to develop a means which enables prediction of a lowering in the anaerobic fermentation operating efficiency in advance of the increase in the rate of acid formation.
It has also heretofore been difficult to judge whether or not a slight peak of acetic acid or methanol in the first stages of lowering in the operating efficiency is a noise.
Further, the construction of methane fermentation tanks is easier in a rural area than in an urban area from the viewpoint of land prices, environmental problems and so forth; however, the maintenance of precision machinery (i.e., the replacement of parts, trouble shooting and machine adjustment service) at such a rural area is not easy.
Accordingly, it has been strongly demanded to provide a means which enables prediction of a lowering in the operating efficiency in an anaerobic fermentation system earlier, readily, inexpensively, sensitively, stably and reliably.
SUMMARY OF THE INVENTION
In view of the present state of waste water treatment by anaerobic fermentation, the present inventors conducted exhaustive studies in order to solve the above-described problems.
In the process of our studies, we collected waste water samples from a thermophilic methanogenic digestion tank in a normal state where methanol was a main carbon source as in the case of kraftpulp manufacture industry sewage and from a thermophilic digestion tank in an abnormal state where acetic acid, propionic acid, etc. had already appeared, and measured 1 the activities of enzymes and the concentration of adenosine triphosphate (ATP) in "raw water" and 2 the enzyme activity of various kinds of enzyme in "the solid content (mainly microorganisms) in the raw water" after centrifugal separation, together with a change (rise or fall) in the adenosine triphosphate (ATP) concentration.
As a result, the present inventors have found that, among the various enzymes, "acid phosphatase", "alkaline phosphatase", "various kinds of transaminase", "amylase" and so forth can serve as highly sensitive indicators which are useful to judge whether a particular fermentation condition is good or bad and that ATP can also serve as a highly sensitive indicator useful for the judgement of a fermentation condition.
More specifically, the present inventors have discovered that the activity of the above-described enzymes and the ATP concentration are recognized to be increasing in a stage which is considerably ahead of the time of appearance of organic acids such as acetic acid, propionic acid, etc. in the process of anaerobic fermentation, as described later in specific Examples. As is generally known, ATP is a compound that participates in various kinds of energy metabolism as an energy carrier in organisms and hence plays an important part in the acquisition and utilization of energy.
The studies conducted by the present inventors have also revealed that these indicators are superior in sensitivity to any of those which have heretofore been used. More specifically, the above-described enzymes and ATP serve as indicators which enable prediction of a lowering in the operating efficiency in the reactor earlier than any of the conventional indicators, for example, the time at which the rate of generation of methane gas changes, or the time at which the rate of acid formation changes.
For example, in a plant-scale reactor for waste water treatment by anaerobic fermentation, the point of time when the rate of acid formation begins to increase is about one week before the operating efficiency begins to lower, whereas, the formation of the above-described enzymes and ATP occurs noticeably about three to four weeks before the operating efficiency begins to lower.
The present invention, which has been accomplised on the basis of the above-described finding, provides (1) a method of controlling waste water treatment by anaerobic fermentation, which comprises continuously measuring the enzyme activity or ATP concentration in the water treated by the anaerobic fermentation and controlling various fermentation conditions as occasion demands on the basis of the result of the measurement, and also provides (2) an apparatus for controlling waste water treatment by anaerobic fermentation, which comprises a device that continuously measures the enzyme activity or ATP concentration in the water treated in an anaerobic fermentation tank.
Unlike the conventional method of controlling waste water treatment by anaerobic fermentation, which is based on a physicochemical measurement, the present invention controls waste water treatment by anaerobic fermentation by biochemically measuring an active condition of microorganisms in the reactor in terms of the enzyme activity or the ATP concentration.
According to the present invention, the fact that the condition in the reactor is proceeding to an abnormal state can be predicted earlier than in the case of the prior art. It is therefore possible to carry out earlier the control of various fermentation conditions, so that even if an abnormality begins to occur in the fermentation conditions of the waste water treated in the fermentation tank, the fermentation conditions can be returned to normal with ease and within a short period of time.
The measurement itself is simple and less costly and needs neither special device (the measurement being capable of being effected with a simple spectrophotometer or visual observation, for example) nor special skill, so that accurate data can be obtained at once even by an unskilled person. By feeding back the result of the measurement to control various fermentation conditions, the waste water treatment in the anaerobic fermentation tank can be controlled to and maintained in optimal conditions speedily, easily and precisely. As a result, it is possible to maintain highly efficient fermentation treatment, which is carried out in the waste water treatment tank by anaerobic fermentation, for a long period of time.
It should be noted that the method of the present invention may be used together with the conventional method to obtain even more accurate data and execute an even more excellent waste water treating operation.
Technical matters which are relevant to the present invention will next be explained.
1 Mechanism of Lowering in Operating Efficiency of Methane Fermentation
This is equivalent to a lowering in the rate of generation of methane gas, which is directly attributable to a lowering in the activity of methane-forming bacteria (that is, a lowering in the activity of methane-forming bacteria, extinction thereof, a decrease in the number of methane-forming bacteria, etc.).
On the other hand, a lowering in the activity of methane-forming bacteria invites a rise in the activity (including an increase in the number of bacteria) of acid-forming bacteria (i.e., bacteria that participate in formation of volatile fatty acids such as acetic acid, propionic acid, etc.). Thus, there is also the following relativity: ##STR1##
It is therefore also possible to predict a change in the operating efficiency of methane fermentation by detecting a degree to which acid-forming bacteria have been activated.
2 Measurement of Various Indicators Concerned with Operating Efficiency of Methane Fermentation
As has been described above, the prior art measures as indicators a lowering in the rate of generation of gas (CH 4 ), a change in the gas composition (a reduction in the CH 4 gas content), changes in the pH and ORP of the waste water, an increase in the total organic carbon (TOC), suspended solid (SS), etc. These indicators are, however, the final results inside the fermentation tank (reactor).
Accordingly, the measurement of these indicators involves a considerable time lag from the initial change (i.e., for example, a change of a polymeric organic substance in the waste water into a monomeric substance). Therefore, in an operation based on these indicators, by the time that a lowering in the operating efficiency is recognized, an unfavorable condition in the reactor will have progressed to a considerable extent and a great deal of time and labor will be needed to return the reactor to the normal state of fermentation conditions.
Under these circumstances, the present inventors noted enzymes, such as polymer decomposing enzymes (e.g., amylase) and enzymes that are related to the formation of acids, together with ATP, which act in the first stages of the change of organic substances into volatile fatty acids during the waste water treatment by anaerobic fermentation.
Generally speaking, in the waste water treatment by methane fermentation, enzymes (polymer decomposing enzymes and enzymes related to the formation of acids) participate in the process: ##STR2##
Next, methane (gas)-forming enzymes participate in the process: ##STR3##
3 Difference in the Metabolic Pathway Between Methane-Forming Bacteria (Archaebacteria) and Bacteria (Mainly, Eubacteria) in the Reactor in an Abnormal State
In general, methane-forming bacteria form methane from relatively simple compounds (methanol, H 2 +CO 2 ), formic acid, acetic acid, methylamine, etc.) and therefore can live without depending upon complex organic compounds except for vitamins.
It is also considered that, unlike other general bacteria (eubacteria), methane-forming bacteria have no enzyme system that decomposes complex organic compounds into simple compounds. In addition, unlike other bacteria, methane bacteria have no peptidoglycan layer in the cell wall. That is, methane-forming bacteria contain no peptidoglycan forming enzyme.
Further, with regard to methane-forming bacteria, the activity of metabolic enzymes and the ATP concentration, which are common to all bacteria, are considered to be relatively low.
It is therefore expected that the activity of polymer decomposing enzymes (e.g., amylase) and matabolic enzymes (e.g., acid phosphatase, alkaline phosphatase, transaminase, etc.) and the ATP concentration, which are common to all bacteria, will be higher at the time when the methane fermentation is in an abnormal state (in addition, eubacteria may be considered to be predominant in the reactor) than at the time when the methane fermentation is in a normal state (methane-forming bacteria is predominant).
Accordingly, by monitoring a rise in the activity of these enzymes as being indicators, a lowering in the operating efficiency of the methane fermentation can be readily predicted.
For the reasons stated in 1 to 3 according to the present invention, the concentrations of polymer decomposing enzymes, acid-forming enzymes, methane-forming enzymes, metabolic enzyme and ATP are measured and various conditions, such as the pH, ORP, space loading and organic matter concentration, are controlled on the basis of the results of the measurement, thereby correcting an abnormal state which is expected to occur and avoiding the occurrence of any abnormality, and thus enabling a normal operation to continue over a long period of time.
With a view to measuring variations in the enzyme activity with high sensitivity, it is preferable to adopt a method that employs a specific substrate (colorimetric system), which is a simple and easy method that is commonly used in the field of clinical medicine. With this method, it is possible to amplify variations in the enzyme activity. Therefore, the detection of enzymes by using antibody against them is useful.
To measure variations in the ATP concentration with high sensitivity, it is preferable to adopt, for example, a method that employs a specific substrate (colorimetric system) of luciferin-luciferase system, which is a known simple and easy measuring method. This method enables amplification of variations in the ATP concentration.
Other measures may be taken to prevent lowering in the operating efficiency, in addition to the above-described measurement of an absolute value of the enzyme activity or other indicators. For example, the enzyme activity may be measured in the form of a differential value as a rate of change to effect feedback control. This method is preferable from the viewpoint of capability of speedily and accurately coping with a predicted lowering in the operating efficiency.
Although in the foregoing four kinds of enzyme (i.e., amylase, acid phosphatase, alkaline phosphatase and transaminase) and ATP are mentioned as preferable indicators, it is also possible to employ in the present invention various other enzymes, such as peptidoglycan synthetases, metabolic enzymes that produce energy from proteins, fats and polysaccharide, and various other common enzymes, for example, those which are present in archaebacteria and eubacteria.
Although in the experiments the present inventors studied a mesophilic methane fermentation (i.e., methane-forming bacteria belonging to genus Methanolobus) and a thermophilic methane fermentation (i.e., methane-forming bacteria belonging to genus Methanosarcina), in which methanol in kraftpulp manufacture industry sewage was a carbon source, the present invention may also be applied to other waste water fermentation treatment by known thermophilic, mesophilic and psychrophilic bacteria, such as those mentioned below, which participate in ordinary methane fermentation systems:
Genera Methanobacterium, Methanobrevibacter and Methanosphaera (Methanobacteriaceae family); Methanothermus (Methanothermaceae family); Methanococcus (Methanococcaceae family); Methanomicrobium, Methanogenium and Methanospirillum (Methanomicrobiaceae family); Methanoplanus (Methanoplanaceae family); Methanosarcina and Methanothrix (Methanosarcinaceae family); Methanolobus; Methanococcoides; Methanohalophilus; Methanocorpasculum; and Methanohalobium.
It should be noted that, in an industrial application of the present invention, it is preferable to use a biosensor or a biochip which can measure the enzyme activity in waste water, and to automate the control process by utilizing an automatic sampling system and an automatic measuring system, which are generally employed in the clinical field.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 is a block diagram showing one embodiment of the apparatus according to the present invention; and
FIG. 2 is a graph showing changes with time of the values of various components of the effluent flowing out of an anaerobic fermentation tank.
DETAILED DESCRIPTION OF THE INVENTION
One embodiment of the present invention will be described below in detail with reference to the accompanying drawings.
Referring first to FIG. 1, which is a block diagram showing one embodiment of the apparatus according to the present invention, reference numeral 1 denotes a raw waste water supply pipe, 2 a pH control tank, 3 an anaerobic fermentation tank (reactor), 3' a thermostatic chamber, 4 a level control tank, 5 and 5' heaters, 6 a desulfurizer, 7 a gas meter, 8 an alkaline solution tank, 9 an acid solution tank, 10 an enzyme or ATP measuring tank, P1 to P5 pumps, V1 to V6 solenoid valves, and S1 to S6 various sensors.
The operation of the waste water treating apparatus by anaerobic fermentation will next be explained.
First, raw waste water flowing through the supply pipe 1 enters the pH control tank 2 and is then introduced into the anaerobic fermentation tank 3.
On the way to the anaerobic fermentation tank 3, the raw waste water passes through the first pump P1, the first solenoid valve V1, the sixth solenoid valve V6 and the second pump P2.
In the anaerobic fermentation tank 3, bacteria such as anaerobic ferment bacteria (e.g., methane-forming bacteria) are growing, so that organic components (mainly, BOD components) in the raw waste water are consumed, thereby purifying the waste water.
Produced biogas (e.g., methane gas) is led out from the top of the anaerobic fermentation tank 3 to the desulfurizer 6 where hydrogen sulfide is removed from the biogas, and then passed through the gas meter 7 and accumulated in a gas holder (not shown).
The anaerobic fermentation tank 3 is surrounded by the thermostatic chamber 3' so that the fermented liquid inside the tank 3 is constantly controlled at an appropriate fermentation temperature. The temperature control is effected by opening and closing the solenoid valve V3 or turning on and off the heater 5 in response to a signal from the temperature sensor S1.
The level of the fermented liquid in the anaerobic fermentation tank 3 is controlled by discharging the treated water by the operation of the level control tank 4 that is provided with the second solenoid valve V2.
Circulation of the fermented liquid in the anaerobic fermentation tank 3 is conducted mainly by 1 a system that comprises the level control tank 4 → the fifth pump P5 → the anaerobic fermentation tank 3 and 2 a system that comprises the anaerobic fermentation tank 3 → the pH control tank 2 → the second pump P2 → the anaerobic fermentation tank 3 and also performed a little by 3 a system that comprises the enzyme or ATP measuring tank 10 → the third pumpe P3 → the anaerobic fermentation tank 3.
In the enzyme or ATP measuring tank 10, the concentrations of polymer decomposing enzymes (e.g., amylase), common enzymes (e.g., acid phosphatase, alkaline phosphatase and transaminase) and ATP are measured with a biosensor or by a colorimetry using a reagent, which is carried out after the liquid sampling process.
The result of the measurement is sent in the form of an electric signal to the solenoid valve V4 of the alkaline solution tank 8, the solenoid valve V5 of the acid solution tank 9, the solenoid V6 or a temperature setting device T to open or close the valve concerned or set a specific temperature, thereby executing control and management of optimal fermentation conditions in the anaerobic fermentation tank 3. In addition, the electric signal representative of the result of the measurement may be sent to the valve V1 for controlling the supply of raw waste water to control the degree of opening of the valve V1.
Although in this embodiment the sampling and measurement are carried out at the fermentation tank, it should be noted that the arrangement may be such that an automatic measuring device is installed in a receiver tank or a treated water pipe and the result of the measurement is fed back to control fermentation conditions.
In this embodiment, a 200 l methane fermentation tank (reactor) 3 was employed, and methane fermentation treatment was carried out at a high temperature of 55° C. with a medium containing methanol as a main carbon source.
In order to artificially cause a lowering in the operating efficiency during the fermentation process, waste water with a high methanol concentration was employed as a liquid to be treated, and essential nutrient sources (for example, N, P and K sources) were removed from the medium or a fermentation inhibitor (for example, a coenzyme analog) was added thereto.
Regarding the Measurement of the Enzyme Activity of the ATP Concentration
The measurement of the enzyme activity or the ATP concentration in a chromophoric system that employs a chromophoric substrate is widely adopted in the field of clinical chemistry and can be carried out extremely easily. In this embodiment, however, alkaline phosphatase and acid phosphatase were measured by Kind-King method, transaminase by Reitman-Frankel method, amylase by Marchall J. L. et al., and the ATP concentration by a method employing a specific substrate (chromophoric system) of luciferin-luciferase system.
After the color development, the activity of each enzyme was measured with a spectrophotometer at the maximum absorption wavelength thereof.
Regarding the Preparation of Samples
1 Preparation of a Sample of the Treated Water from the Reactor:
The sampled treated water was subjected to centrifugal separation or passed through a 0.45 um filter, and the resulting supernatant or the water that passed through the filter was used.
It should be noted that, since a turbidity in a sample in the measurement of the enzyme activity or ATP concentration in a chromophoric system appears to be pseudo-positive, centrifugal separation or filtration is needed.
2 Preparation of a Sample of the Precipitate in the Treated Water from the Reactor:
The sample treated water was centrifugally separated, and the resulting precipitate (mainly containing microorganisms) was collected.
5 ml of precipitate was subjected to ultrasonication for 3 minutes under the conditions of 20 kHz and 130 W to crush cells and then subjected to centrifugal separation. The resulting supernatant was employed as an enzyme measuring solution or an ATP concentration measuring solution.
EXPERIMENTAL EXAMPLE 1
Table 1 below shows the rate of gas generation and various properties of the treated water in a normal state and an abnormal state.
TABLE 1______________________________________ Normal Abnormal______________________________________TOC (mg/l) 250 840Acetic acid (mg/l) 0 1600Propionic acid (mg/l) 0 150Methanol (mg/l) 0 280Acid phosphatase.sup.1) 1 scores of timesAlkaline phosphatase.sup.1) 1 ten-odd timesAmylase.sup.1) 1 ten-odd timesTransaminase.sup.1) 1 ten-odd timesATP 1 scores of timesGasification (l/d) 400 300______________________________________ .sup.1) the specific activity in an abnormal state in the case where the activity in a normal state is determined to be "1".
The above results were obtained by carrying out high-temperature (thermophilic) digestive treatment on waste water containing methanol as a main carbon source at a TOC loading of about 230 g/day. The sample that was employed for the measurement was an enzyme or ATP measuring solution obtained by the method stated in the sample preparation 2.
It will be clear from the results shown in Table 1 that, when the methane fermentation treatment is in an abnormal state, there are increases not only in the leakage of methanol, acetic acid and propionic acid but also in the enzyme activity of the four different kinds of enzyme and the ATP concentration.
EXPERIMENTAL EXAMPLE 2
An enzyme measuring solution obtained by the sample preparation method 2 in the same way as in Experimental Example 1 was measured. FIG. 2 shows changes with time of the properties of the liquid being treated in the reactor on the basis of the results of the measurement.
It should be noted that in the figure the gasification, the enzyme activity and the ATP concentration are each shown on a scale where the value in a normal state is determined to be "1". In the figure, the day when the gas generation rate actually began to lower is shown to be "0".
It will be understood from FIG. 2 that the enzyme activity of acid phosphatase and amylase and the ATP concentration had already begun to rise at least 10 days before the appearance of acetic acid or other volatile fatty acids.
Accordingly, it will be understood that the change in the enzyme activity or the ATP concentration can serve as a considerably excellent indicator for prediction of the occurrence of an abnormality in the reactor.
Although in the above Experimental Examples 1 and 2 experiments were carried out on waste water containing methanol as a main carbon source, results similar to those shown in Table 1 and FIG. 2 were obtained in experiments carried out on general waste water containing organic substances, such as carbohydrates, fats and proteins, as main carbon sources.
As has been detailed above, it is possible according to the present invention to predict a lowering in the operating efficiency of the waste water treatment by anaerobic fermentation a considerably long time ahead of the time at which the lowering in the operating efficiency occurs. In addition, it is possible to effect the prediction with a simple and easy measuring means within a short time and with high sensitivity as well as stably and reliably. By feeding back the results of the measurement, various fermentation conditions can be precontrolled.
Accordingly, the present invention, in which various fermentation conditions are precontrolled on the basis of the measured enzyme activity or ATP data, enables efficient and excellent waste water treatment to continue over a long period of time while constantly and stably maintaining optimal anaerobic fermentation conditions.
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A method for monitoring and regulating waste water treatment by anaerobic fermentation by measuring enzymatic activity or adenosine triphosphate (ATP) concentration. The method provides for earlier detection of abnormal fermentation conditions and allows adjustment of controllable variables prior to the appearance of abnormal effluents.
Also described is an apparatus for controlling waste water treatment by a device which continuously measures the enzyme or ATP concentration in the treated water.
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CROSS-REFERENCE TO RELATED APPLICATIONS
The present application is a continuation-in-part of U.S. patent application Ser. No. 09/217,530, filed on Dec. 21, 1998, now abandoned which a continuation-in-part application of U.S. patent application Ser. No. 08/933,805, filed on Sep. 19, 1997, now U.S. Pat. No. 5,851,053.
FIELD OF THE INVENTION
The present invention relates to a hanging chair that is generally comprised of a chair member and a structure for suspending the chair from an overhead support.
BACKGROUND OF THE INVENTION
A hanging chair is comprised of a chair and a suspension structure that connects the chair to an overhead support. In one type of hanging chair, the chair is comprised of a flexible panel that is defined by an upper edge, left edge, right edge and lower edge. The distance between the upper and lower edges is generally adequate for supporting the head, torso and at least a portion of the lower extremities of the typical user. Similarly, the distance between the left and right edge is generally sufficient to support the width of the typical user. The suspension structure includes a laterally extending support member, i.e., a member that extends left to right across the body of a user when the user is in the chair, that is connected to the left and right sides of the flexible panel. Also part of the suspension structure is a rope for connecting the laterally extending support member to the overhead support. The ends of the rope are attached to the ends of the laterally extending support member. A loop at the midpoint of the rope is used to suspend the chair from a hook or similar structure that is anchored into the overhead support. In this particular embodiment, the laterally extending support member is generally of a length that is greater than the lateral or left-right dimension of the typical user. As a consequence, the laterally extending support member prevents the left and right sides of the flexible panel from folding in on the user when the user reclines in the chair.
In another embodiment that employs a flexible panel, the suspension system has been modified so that it also prevents the upper and lower edges of the panel from folding in on the user when the user reclines in the chair. This is accomplished by using two side support members that extend along the sides of the chair. One end of each of the side support members is connected to the upper end of a side and the other end is connected to the lower end of the side, thereby preventing the upper and lower edges of the panel from folding in on the user. The ends of the two side support members are connected to the ends of the laterally extending support member, which is connected to the overhead support as previously described.
A further type of hanging chair employs a chair that is comprised of a rigid peripheral structure, which is generally made of wood or some kind of tubing, and a web that spans the rigid peripheral structure. Typically, ropes or cables are used to attach the rigid peripheral structure to the overhead support.
Yet another type of hanging chair uses a chair in which at least one of the back and seat portions is made of wood, plastic or other relatively rigid material. The lateral sides of the chair member are typically attached to the overhead support member using ropes or chains. An example of this type of chair is the well known porch swing.
SUMMARY OF THE INVENTION
The present invention is directed to a hanging chair that provides the user with the ability to readily adjust the angle of the chair relative to the ground. One embodiment of the invention includes a chair with a back portion for supporting the user's torso and a seat portion for supporting at least a portion of the lower extremities of the user. The chair is also generally symmetrical about a longitudinal axis that divides the back and seat portions into a left lateral side and a right lateral side. When in use, the user's body generally reclines in a direction that is parallel to the longitudinal axis of the chair. A suspension structure is provided that serves both to hang the chair from an overhead support and to provide the user with the ability to readily adjust the angle of the chair relative to the ground. The suspension structure includes a longitudinally extending rod or pole, a first linkage for connecting the chair to the rod, and a second linkage for connecting the rod to the overhead structure. In adjusting the angle of the chair relative to the ground, the first linkage serves to maintain the position of the chair relative to the rod. As a consequence, the angle of the rod relative to the ground substantially determines the angle of the chair relative to the ground. The second linkage provides the ability to easily and quickly adjust the angle of the rod and the angle of the chair relative to the ground. In one embodiment, the second linkage includes a rope whose ends are attached to the ends of the rod and a slip knot that engages a hook or similar structure associated with the overhead support. By adjusting the location of the slip knot, the angle of the rod and chair relative to the ground can be readily adjusted. In another embodiment, the second linkage again uses a rope whose ends are attached to the ends of the rod. However, in this embodiment, a fixed knot is employed and the length of the rope extending between the ends of the rod is adjusted to change the angle of the chair. The length of rope is adjusted by changing the point on the rope at which the rope is attached to one end of the rod. In a third embodiment, the angle of the rod is altered by employing a second linkage that contacts the rod at a single location which can be adjusted. For example, if the second linkage joins the rod at a point that is closer to the back portion of the chair than the seat portion of the chair, the chair will be oriented in a relatively upright position. If the point at which the second linkage joins the rod is then moved more towards the seat portion of the chair, the chair is oriented in a more reclined position.
The present invention also provides for adjustment of the angle of the chair relative to the ground by permitting the distance between the seat portion and the ground to be adjusted. In this adjustment, the length of the linkage between the top of the back portion of the chair and the ground cannot be adjusted. However, the length of the linkage between points lower down on the back portion of the chair or on the seat portion of the chair and the ground can be adjusted. Adjustment of the length of this linkage, in effect, causes the chair to rotate about the top of the back portion of the chair, thereby changing the angle of the chair relative to the ground. Alternatively, a linkage associated with the seat portion of the chair could be of fixed length and the length of the linkage associated with points further up the chair could be adjustable to alter the angle of the chair relative to the ground.
Also provided by the present invention is a combination hanging chair and footrest that employs a less complex suspension structure than known hanging chairs. The chair portion of the invention is comprised of a flexible material. A suspension structure serves to hang the chair from an overhead support and to deploy the flexible material of the chair such that the chair does not collapse in upon the user. The suspension structure includes three rods and a linkage that connects the rods to the chair. The rods serve both to prevent (1) the left and right sides of the chair from collapsing in on the user and (2) the seat and back portions of the chair from collapsing in on the user. In other words, the rods serve to hold the flexible material of the chair open. At least one of the rods extends laterally, i.e. across the user's body when the user is in the chair. This rod is also employed to support the footrest. Know hanging chairs require at least four rods to accommodate a combination hanging chair and footrest.
The present invention also provides a hanging chair that is made of a flexible material and dimensioned to seat more than one person and a suspension structure that connects the chair member to an overhead support structure. Further, to prevent the individuals residing in the chair from being pushed towards one another, the chair includes a dividing member. In one embodiment, the dividing member includes a pair of straps that are located on a line that bisects the chair and that are attached to the suspension structure created an inverted V-shape in the flexible material to, in effect, separate a first chair from a second chair.
In another embodiment, the suspension structure is adapted to distribute the load that two or more individuals can create over a length of the overhead support. This serves, at least where the overhead support is supported at both of its ends, to reduce the possibility that the either the overhead support or suspension structure will fail under load. The load distribution aspect of the suspension structure is also applicable to hanging chairs that are dimensioned to seat a single individual. In one embodiment, the suspension structure is adapted to connect to at least two locations on the overhead beam. By establishing connections at two, spaced apart locations, the load of the chair and any occupants is divided such that a portion of the load is borne at one location and the remainder of the load is borne at the other location.
One embodiment of a hanging chair that can accommodate more than one individual employs a suspension structure that includes a longitudinal support member that, when the chair is suspended from an overhead support, lies substantially in a plane that bisects the chair member and is perpendicular to the ground. Also part of the suspension structure is a lateral support member that extends substantially perpendicular to the longitudinal support structure. The longitudinal and lateral support members serves, among other things, to hold a chair member that is made from flexible material open. In the case of a chair that accommodates more than one person, the lateral support member is longer than the longitudinal support member. For a two person chair, the lateral support member has a length greater than about four feet.
A further embodiment of the hanging chair includes a swivel that is located between the hanging chair and the overhead support. The swivel permits the chair to rotate about a vertical axis while prevent twisting or the binding of the remainder of the suspension structure. This prevents the chair from being rotated in, for example, a clockwise direction a number of times to establish a twist in the suspension structure and then later rotating in a counter-clockwise direction. Moreover, if a eye bolt is used to connect the chair member to the overhead support, the swivel prevents torque that could otherwise loosen the bolt.
A further embodiment of the hanging chair includes a chair member with a longitudinal line that bisects the chair member. When the chair member is suspended from an overhead support, the longitudinal line defines a plane that is substantially perpendicular to the ground. A suspension structure connects the chair member to the overhead support. The suspension structure includes a support member that has at least two points which lie in the plane defined by the longitudinal line; a first portion for connecting the chair member to the support member; and a second portion that connects the support member to the overhead support and lies substantially in the plane defined by the longitudinal line. Suitable support members include a rod that lies substantially entirely within the plane. Another suitable support member includes a hoop with two, diametrically opposite points located within the plane. Support members with many different shapes are possible, provided that the support member has at least two points that lie in the plane. In one embodiment, the second portion of the suspension structure also provides the ability to adjust the angle of the support member and, as a consequence, the angle of the chair member relative to the ground.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 is a perspective view of the hanging chair of the present invention;
FIG. 2 is a plan view of the chair portion of the hanging chair illustrated in FIG. 1;
FIGS. 3A and 3B are sides view of the hanging chair that illustrate the use of the longitudinally extending rod in adjusting the angle of the chair relative to the ground;
FIGS. 4A and 4B are side views of the hanging chair that illustrate the use of an adjustable linkage to alter the angle of the chair relative to the ground; and
FIGS. 5A and 5B illustrate an alternative structure for adjusting the angle of the chair relative to the ground;
FIGS. 6A and 6B illustrate another alternative structure for adjusting the angle of the chair relative to the ground;
FIG. 7 illustrates an alternative suspension structure that utilizes an I-shaped frame;
FIG. 8 illustrates a hanging chair that is capable of accommodating two, adult individuals; and
FIG. 9 illustrates a hoop shaped, support member.
FIG. 10 illustrates a hanging chair that is capable of accommodating two, adult individuals while also providing a structure for separating the two individuals from one another.
DETAILED DESCRIPTION
FIG. 1 illustrates an embodiment of a hanging chair 10 of the present invention. Generally, the hanging chair 10 includes a chair 12 , a suspension structure 14 for suspending the chair 12 from an overhead support 16 , and a footrest 18 .
With reference to FIG. 2, the chair 12 is comprised of a back portion 22 for supporting the user's back, a seat portion 24 for supporting the lower extremities of the user, and right and left side portions 26 A, 26 B that cooperate with the back portion 22 and seat portion 24 to form a “bucket” type seat. The chair 12 also includes right and left padded armrests 28 A, 28 B. A padded seat edge 29 is also provided for the user's comfort. The chair is further defined by four suspension points 30 A, 30 B, 30 C and 30 D that are the points of contact between the chair 12 and the suspension structure 14 . The four suspension points 30 A, 30 B, 30 C and 30 D also roughly define a quadrilateral shape and more specifically a trapezoidal shape. To elaborate, a line drawn between the first and second suspension points 30 A, 30 B is substantially parallel to, but shorter than a line drawn between the third and fourth suspension points 30 C, 30 D. Further, a line drawn between the first and third suspension points 30 A, 30 C is substantially the same length as, but not parallel to a line drawn between the second and fourth suspension points 30 B, 30 D. It should also be appreciated that the chair 12 is substantially symmetrical about a longitudinal axis 32 . In the illustrated embodiment the chair is made of a flexible material, such as canvas, upholstery fabric, tapestry fabric, woven mesh, leather, pack cloth and the like.
The suspension structure 14 includes aback lateral bar 36 that is connected to the first and second suspension points 30 A, 30 B by back suspension straps 38 A, 38 B that include webbing cups, which are used throughout the suspension structure 14 . Similarly, a seat lateral bar 40 is connected to the third and fourth suspension points 30 C, 30 D by seat suspension straps 42 A, 42 B whose lengths can be adjusted by seat buckles 43 A, 43 B, respectively. Also forming part of the suspension structure 14 is a longitudinal bar 44 that is oriented substantially parallel to and preferable in the same plane as the longitudinal axis 32 of the chair 12 . The longitudinal bar 36 is connected to the back lateral bar 36 by a back rope 46 and connected to the seat lateral bar 40 by a seat rope 48 . The back lateral bar 36 , seat lateral bar 40 and longitudinal bar 44 cooperate to hold the chair, which is made of a flexible material, open so that it does not fold in on the user when the user reclines in the chair 12 . To elaborate, the back lateral bar 36 and seat lateral bar 40 prevent the right and left sides of the chair 12 from folding in on the user. Similarly, the longitudinal bar 44 prevents the back portion 22 and seat portion 24 of the chair 12 from collapsing in on a user. The lengths of the back lateral bar 36 , seat lateral bar 40 and longitudinal bar 44 are respectively 2, 3 and 4 feet. The bars are made of a hardwood, such as ash. However, other materials can also be used, such as plastic or metal piping.
Also part of the suspension structure 14 is a top rope 50 with ends that are operatively attached to the ends of the longitudinal bar 44 . Located intermediate to the ends of the top rope 50 is a slip knot that facilitates altering the angle of the longitudinal bar 44 and the chair 12 relative to the ground. A height adjustment rope 54 and hook 56 complete the suspension structure 12 . The height adjustment rope 54 allows the distance between the chair 12 and the ground to be adjusted to suit the user. In some cases, the height adjustment rope 54 may be unnecessary.
With reference to FIGS. 3A and 3B, adjustment of the reclination angle or angle of the chair relative to the ground is discussed. FIG. 3A illustrates the chair 12 at a first angle relative to the ground and the longitudinal bar 44 substantially parallel to the ground. The angular orientation of the chair 12 and longitudinal bar 44 is determined by the location of the slip knot 52 . In this particular case, the slip knot 52 is located substantially midway between the ends of the top rope 50 . The components of the suspension structure located between the longitudinal bar 44 and the chair 12 have little effect on the angle of the longitudinal bar 44 and the chair 12 relative to the ground. As a consequence, these components substantially maintain the positional relationship of the chair 12 relative to the longitudinal bar 44 .
FIG. 3B illustrates the chair 12 in a more reclined position relative to the chair 12 in FIG. 3 A. Also apparent from comparison of FIGS. 3A and 3B is that the longitudinal bar 44 in FIG. 3B is no longer substantially parallel to the ground. The change in the angles of the chair 12 and the longitudinal bar 44 relative to the ground is attributable to a change in the location of the slip knot 52 , which is now located more towards the seat portion 24 of the chair 12 than the slip knot 52 of FIG. 3 A. From the foregoing, it can be appreciated that the angle of the chair 12 relative to the ground can be easily and quickly adjusted by adjusting the location of the slip knot 52 in the top rope 50 . In contrast, the suspension structures of other known hanging chairs requires that two ropes or linkages, one associated with each side of the chair, be adjusted to change the angle of the chair relative to the ground. If the two linkages are not adjusted equally these chairs become skewed. Consequently, time must be taken to adjust two separate structures and to assure that both structures are adjusted equally.
With reference to FIGS. 4A and 4B, a different manner of adjusting the reclination angle of the chair 12 is discussed. This manner of adjusting the angle of reclination involves changing the distance between the seat portion 24 of the chair 12 and the ground 60 . In the illustrated embodiment, this adjustment is achieved by changing the lengths of the seat suspension straps 42 A, 42 B using buckles 43 A, 43 B. In FIG. 4A, the seat suspension straps 42 A, 42 B are relatively long. As a consequence, the seat portion 24 of the chair 12 is relatively close to the ground and the chair 12 is in a relatively upright position. FIG. 4B, in contrast, illustrates the use of the buckles 43 A, 43 B to shorten the length of the seat suspension straps 42 A, 42 B and thereby place the chair 12 in a more reclined position with the chair 12 positioned further from the ground 60 relative to the chair in FIG. 4 A. To facilitate making the seat suspension straps 42 A, 42 B of equal length, the straps are made from a webbing material that has a colored thread which is exposed at a predetermined interval, such as once every inch.
The padded footrest 18 is connected to the seat lateral bar 40 by footrest suspension straps 64 A, 64 B. The position of the footrest 18 is adjusted by changing the length of the footrest suspension straps 64 A, 64 B using footrest buckles 66 A, 66 B. To assure that both of the footrest suspension straps 64 A, 64 B are of equal length, the straps are marked at a predetermined interval, as with the seat suspension straps 42 A, 42 B.
With reference to FIGS. 5A and 5B, a different linkage for adjusting the angle of the longitudinal rod 44 and the chair 12 is discussed. In this case, a length adjustable top rope 70 is provided with a fixed knot 72 located between the ends of the rope. As shown in FIG. 5A, the fixed knot 72 is located substantially midway between the points of the rope that are connected to the ends of the longitudinal bar 44 . As a consequence, the longitudinal bar 44 is oriented substantially parallel to the ground 50 . The chair 12 has an orientation relative to the ground that is dependent upon the linkage between the longitudinal rod 44 and the chair 12 . By changing the point at which one end of the rope 70 is attached to the end of the longitudinal rod, the length of the rope 72 between the ends of the longitudinal rod 44 is changed. Changing the length of the rope 70 causes the fixed knot 72 to be moved more towards the back portion 22 of the chair 12 . Moving the fixed knot 72 , in turn, changes the angle of the longitudinal bar 44 and the chair 12 relative to the ground 60 . It is also possible to change the point at which the other end of the rope 70 attaches to the other end of the longitudinal rod 44 to affect the angle of the longitudinal rod 44 and chair 12 relative to the ground 60 .
With reference to FIGS. 6A and 6B, a further structure for changing the angle of the longitudinal bar 44 and chair 12 is discussed. This particular linkage includes a fixture 76 that can be fixed in place at any point along the length of the longitudinal bar 44 . A linkage 78 that can swivel or rotate with respect to the fixture 76 provides at least part of the connection between the fixture 76 and the overhead support 16 . In FIG. 6, the fixture 76 is located substantially midway between the ends of the longitudinal bar 44 and the longitudinal bar 44 is positioned substantially parallel to the ground 60 . This, in turn, places the chair 12 in a particular orientation. As shown in FIG. 6B, the position of the fixture 76 has been changed relative to the position shown in FIG. 6 A. As a consequence, the angle of the longitudinal bar 44 relative to the ground 60 has been changed. This, in turn, has changed the angle of the chair 12 relative to the ground as previously discussed.
With reference to FIG. 7, a single piece bar 82 for use in the suspension structure 14 is illustrated. The unitized bar 82 combines the back lateral bar 36 , seat lateral bar 40 and longitudinal bar 44 associated with the suspension structure discussed with respect to FIG. 1 into a monolithic unit that avoids the need for the back rope 46 and seat rope 48 . The unitized bar 82 can be constructed in from conventional piping materials or by other methods known in the art.
The adjustment of the angle of the chair 12 via adjustment to the angle of the longitudinal bar 44 is applicable to other types of chairs from that disclosed with respect to FIG. 1 . For instance, the adjustment of the angle of the chair disclosed hereinabove can be applied to chairs that have a rigid peripheral framework that is spanned by a flexible web. The structure for adjusting the reclining angle of a chair can also be applied to chairs that use a panel of relatively rigid material, such as wood, to realize the back and/or seat portion of the chair. If a chair structure is utilized in which at least a portion of the periphery or outer edges of the back or seat portions is rigid, as with either of the two noted types of chairs, the suspension structure is susceptible to modifications that eliminate either or both of the lateral bars but retain the longitudinal bar 44 and associated structure for adjusting the angle of the longitudinal bar 44 . For example, if a chair is utilized in which the back and seat portions are made from panels of wood and connected to one another so that their positions with respect to one another are fixed, the lateral bars are no longer needed to hold the chair in an open position. As a consequence, linkages between the chair and the longitudinal bar 44 that do not incorporate the lateral bars are feasible. The structure for adjusting the reclining angle of a chair can also be applied to chairs of different shapes. For instance, the structure can be applied to oval, round, and rectangular chair shapes, as well as many other chair shapes.
With reference to FIG. 8, an embodiment of a hanging chair 100 that is capable of accommodating two individuals is illustrated. Elements of the hanging chair 100 that are common to the hanging chair 10 are given the same reference numbers as the comparable elements of the hanging chair 10 . However, to differentiate the elements of the hanging chair 100 that are common to the chair 10 , the reference numbers associated with the hanging chair 100 are given primed reference numbers. The chair 12 ′ has substantially the same length as the hanging chair 12 . As a consequence, the longitudinal bar 44 ′ of the hanging chair 100 is substantially the same length as the longitudinal bar 44 , i.e, approximately four feet in length. However, the chair 12 ′ is of a greater width that is capable of accommodating two adults. Due to this greater width, the back lateral bar 36 ′ and seat lateral bar 40 ′ are also of greater lengths. The back lateral bar 36 ′ is approximately 3 ½ feet in length. The seat lateral bar 40 ′ is approximately five feet in length. To address the greater load, the diameters of the back lateral bar 36 ′, seat lateral bar 40 ′ and longitudinal bar 44 ′ are appropriately increased. If a hanging chair capable of accommodating a greater number of individuals is required, the dimensions of the chair 12 ′, back lateral bar 36 ′ and seat lateral bar 40 ′ are scaled accordingly.
To address the greater load associated with more than one individual in the hanging chair 100 , the suspension structure for connecting the chair 12 ′ to the overhead support 16 includes a load distribution device 102 . The load distribution device include two, eye bolts 104 A, 104 B that engage the overhead support 16 . Also included in the load distribution device is a loop 106 that, in operation, extends through the eye bolts 104 A, 104 B. The loop 106 is, in turn, attached to the top rope 50 ′. This attachment scheme distributes the load of the chair 12 ′ and any occupants over a length of the overhead support 16 rather than concentrating the load at a single point on the overhead support 16 . Attachment devices other than the eye bolts 104 A, 104 B are also feasible. For instance, bolts that extend laterally through the overhead support can be used. Further, an alternative to the loop 106 is a length of rope with one end attached to the eye bolt 104 A , the other end attached to the eye bolt 104 B, and an intermediate point attached to the top rope 50 ′. In situations where the overhead support 16 is exposed in two places such that a rope can be tied around the support 16 , holes can be drilled through the overhead support 16 in two places, or the overhead support 16 is exposed in one location and a hole can be drilled in another location, the use of bolts can be avoided. In this case, one end of rope is attached to one locations, the other end of the rope is attached to the other location, and a point on the rope that is located intermediate to the two ends of the rope is attached to the top rope 50 ′. It should be appreciated that the a structure for distributing the load can also be used with chair 10 if needed.
Adjustment of the angle of the chair 12 ′ can be accomplished as shown in FIGS. 3A and 3B or as shown in FIGS. 5A and 5B. With appropriate modifications, adjustment of the angle of the chair 12 ′ can also be accomplished as shown in FIGS. 6A and 6B. In addition, adjustment of the angle of the chair 12 ′ can be accomplished using the buckles 43 A′, 43 B′.
The chair 100 also includes two, padded foot rests 108 A, 108 B, one for each the potential occupants of the chair 12 ′. The foot rest 108 A includes foot rest suspension straps 110 A, 110 B that extend from the seat lateral bar 40 ′ and buckles 112 A, 1121 B that permit adjustment of the lengths of the strap 110 A, 111 B. Likewise, foot rest 108 B includes foot rest suspension straps 114 A, 114 B and adjustment buckles 116 A, 1163 B.
To provide the ability to rotate the chair about a vertical axis, the chair 100 includes a swivel 118 that is disposed between the chair 12 ′ and the overhead support 16 . The swivel 118 also prevents twisting of the suspension structure that would create a torque that might loosen any bolts or other threaded elements that are used to engage the overhead support 16 .
With reference to FIG. 9, a unitary bar structure 120 that has at least two points that lie in the plane defined by the bisecting line of the chair 12 is illustrated. The unitary bar structure 120 is in the shape of a hoop that has two, diametrically opposite points that lie in the noted plane. As noted with respect to the single piece bar 82 of FIG. 7, the use of a unitary bar structure avoids the need for the back rope 46 and seat rope 48 . It should be noted that there are many unitary bar structure shapes that satisfy the criteria of having at least two points located in the noted plane. Characteristic of many, but not necessarily all of these structures is that they are symmetrical about the plane. When using the unitary bar structure 120 , adjustment of the angle of the chair 12 or the chair 12 ′ is accomplished as shown in FIGS. 3A and 3B or as shown in FIGS. 5A and 5B. In addition, adjustment of the angle of the chair 12 or chair 12 ′ can be accomplished using the buckles 43 A, 43 B.
With reference to FIG. 10, an embodiment of a hanging chair 130 that is capable of accommodating two individuals is illustrated. For ease of illustration, the footrests have been omitted. Elements of the hanging chair 130 that are common to the hanging chair 100 are given the same reference numbers as the comparable elements of the hanging chair 100 . The hanging chair 130 includes a dividing structure that divides the chair 12 ′ into a first chair 132 A and a second chair 132 B. The dividing structure includes a first strap system 134 and a second strap system 136 that cooperate to create a ridge 138 with an inverted V-shape cross section that runs along the longitudinal axis of the chair 12 ′ to divide the first chair 132 A from the second chair 132 B. The first strap system 134 includes a first D-ring 140 that is attached to the edge of the chair 12 ′ by a piece of reinforcing fabric 142 . Also part of the first strap system 134 is a first strap 144 with one end that includes a first snap hook 146 for engaging the first D-ring 140 . The other end of the first strap 144 is attached to an end of the longitudinal bar 44 ′. Located between the ends of the first strap 144 is a first buckle 148 that permits the length of the first strap 144 to be adjusted. The second strap system includes a second D-ring 150 that is attached to the edge of the chair 12 ′ by a piece of webbing 152 . Also part of the second strap system 136 is a second strap 154 with one end that includes a second snap hook 156 for engaging the second D-ring 150 . The other end of the second strap 154 is attached to an end of the longitudinal bar 44 ′. Located between the ends of the second strap 154 is a second buckle 158 that permits the length of the second strap 154 to be adjusted.
When the dividing system is in use, the shape of the ridge 138 is adjusted by adjusting the lengths of the first strap 144 and the second strap 154 using, respectively, the first buckle 148 and the second buckle 158 . Further, if desired, the first snap hook 146 and the second snap hook 156 can be respectively disengaged from the first D-ring 140 and the second D-ring 150 to eliminate the ridge 138 dividing the chair 12 ′ into the first chair 132 A and second chair 132 B.
The foregoing description of the invention has been presented for purposes of illustration and description. Further, the description is not intended to limit the invention to the form disclosed herein. Consequently, variations and modifications commensurate with the above teachings, and the skill or knowledge in the relevant art are within the scope of the present invention. The embodiment described hereinabove is further intended to explain the best mode known of practicing the invention and to enable others skilled in the art to utilize the invention in various embodiments and with the various modifications required by their particular applications or uses of the invention. It is intended that the appended claims be construed to include alternate embodiments to the extent permitted by the prior art.
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Disclosed is a hanging chair that is capable of accommodating more than one individual. Also provided is a hanging chair that includes a suspension structure that distributes the increased load that is associated with having more than one person in the chair over a length of the overhead support. By distributing the load, the possibility of the overhead support or the suspension structure failing is, inmost situations, reduced. The present invention further provides a hanging chair that is capable of rotating about a vertical axis without causing binding or twisting of the suspension structure.
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RELATED APPLICATIONS
[0001] This application is a divisional of U.S. patent application Ser. No. 10/759,906, filed Jan. 16, 2004, which claims the benefit of U.S. provisional application Ser. No. 60/440,997, filed Jan. 16, 2003, the contents of which are incorporated herein.
[0002] The present invention relates to a novel synthesis of irbesartan.
BACKGROUND OF THE INVENTION
[0003] Irbesartan is a known angiotensin II receptor antagonist (blocker). Angiotensin is an important participant in the renin-angiotensin-aldosterone system (RAAS) and has a strong influence on blood pressure. The structure of irbesartan is shown below (I).
[0004] The synthesis of irbesartan is discussed, inter alia, in U.S. Pat. Nos. 5,270,317 and 5,559,233; both of which are incorporated herein in their entirety by reference. In the synthesis therein disclosed, the prepenultimate reaction step (exclusive of work-up and purification) involves the reaction of a cyano group on the biphenyl ring with an azide, for example tributyltin azide. Reaction time as long as 210 hours can be required. See, e.g., '317 patent.
[0005] U.S. Pat. No. 5,629,331 also discloses a synthesis of irbesartan from a precursor 2-n-butyl-3-[(2′-cyanobiphenyl-4-yl)methyl]-1,3-diazaspiro [4.4]non-1-ene-4one with sodium azide using a dipolar aprotic solvent. As acknowledged in the '331 patent, there are safety risks involved in the use of azides (column 4, line 39). Also, dipolar aprotic solvents (e.g. methylpyrrolidone) are relatively high boiling and can be difficult to remove.
[0006] There is a need for an improved synthetic route to irbesartan.
SUMMARY OF THE INVENTION
[0007] In one aspect, the present invention relates to a method of making 2-butyl-3-[[2′-(1-trityl-1H-tetrazol-5-yl)biphen-4-yl]methyl]1,3-diazaspiro[4.4]non-1-ene-4-one (IRB-03) including the steps of reacting 2-butyl-3-(4′-bromophenyl)-1,3-diazaspiro[4.4]non-1-ene-4-one (IRB-05) with 2-(1-trityl-1H-tetrazol-5-yl)phenylboronic acid (IRB-07) in the presence of a first solvent, especially tetrahydrofuran (THF) or dimethoxyethane, a second solvent, especially water, particularly combined with a base, and a catalyst that includes especially a palladium complex, e.g., Pd(O(O)CCH 3 ) 2 and a phosphine, especially a triarylphosphine, e.g. triphenyl phosphine (PPh 3 ).
[0008] In another aspect, the present invention relates to a process for making a 3-(haloaryl)-1,3-diazaspiro[4.4]non-1-ene-4-one compound, especially 3-(4′-bromobenzyl)-1,3-diazaspiro[4.4]non-1-ene-4-one, including the step of reacting (combining), in the presence of a phase transfer catalyst (e.g. tetrabutylammonium sulfate), an acid addition salt, especially a hydrochloride, of 1,3-diazaspiro[4.4]non-1-ene-4-one with a haloaryl compound, especially a bromobenzyl halide compound (e.g. 4-bromobenzyl), in a solvent system including a first solvent, especially an aromatic hydrocarbon, and a second solvent, especially brine containing a base.
[0009] In another aspect, the present invention relates to the compound 2-butyl-3-(4′-bromobenzyl)-1,3-diazaspiro[4.4]non-1-ene-4-one, especially when prepared according to the forgoing process.
[0010] In still a further aspect, the present invention relates to a method of making a 5-phenyl-1-trityl-1H-tetrazole compound including the step of reacting 5-phenyl-1-H-tetrazole with chlorotriphenylmethane (trityl chloride) in a solvent, especially tetrahydrofuran, in the presence of a base, especially triethylamine.
[0011] In yet another aspect, the present invention relates to a method of making 2-(tetrazol-5-yl)phenylboronic acid including the step of reacting 5-phenyl-1-trityl-1H-tetrazole with a borate, especially a trialkyl borate (e.g. tri-isopropyl borate) in a solvent, especially tetrahydrofuran, and in the presence of a base, especially n-butyllithium.
[0012] In still yet another aspect, the present invention relates to a method of making irbesartan that includes the step of reacting 2-butyl-3-(4′bromobenzyl)-1,3-diazaspiro[4.4]non-1-ene-4-one with 2(1-trityl-1H-tetrazol-5-yl)phenylboronic acid in a two-phase solvent system having a first solvent, especially THF or dimethoxyethane or a mixture of these, and a second solvent, especially water, in the presence of a catalyst, especially a palladium complex or a nickel complex.
[0013] In a further aspect, the present invention relates to a process of making irbesartan that includes the step of reacting an acid addition salt, especially the hydrochloride, of 2-butyl-1,3-diazaspiro[4.4]non-1-ene-4-one with a haloaryl compound, especially 4-bromobenzyl bromide in the presence of a base, especially KOH or NaOH, in a two-phase solvent system having a first solvent, especially toluene, and a second solvent, especially water or brine.
DETAILED DESCRIPTION OF THE INVENTION
[0014] The present invention provides a novel synthesis of irbesartan and analogues thereof, including the step of reacting a 2-(5-tetrazoyl)phenylboronic acid with a 3-(haloaryl)-1,3-diazaspiro[4.4]non-1-ene-4-one. The step is carried out in the presence of a palladium or nickel catalyst. Such a synthetic step is known by one of skill in the art as a Suzuki coupling reaction. See, e.g., N. Miyaura et al., Tetrahedron Letters 1979, 3437. See also, N. Miyaura, A. Suzuki, Chem. Commun. 1979, 866. The step can be carried out in a two-phase reaction system having first and second liquid phases.
[0015] The first and second phases include first and second solvents, respectively, which are substantially immiscible in each other so that, when combined in a reaction vessel, a two-phase system is formed. Solvents are substantially immiscible in each other when equal volumes of them are mixed together, a two-phase system is formed in which the volume of the two phases is essentially equal. Preferably, substantially immiscible solvents are soluble in each other to the extent of about 1% (weight basis) or less.
[0016] The first solvents are organic solvents. Examples of preferred organic solvents include, but are not limited to: ether solvents such as 1,2-dimethoxyethane (DME), diethoxymethane, (glymes), and tetrahydrofuran (THF); formals such as diethyl formal; and hydrocarbon solvents such as, toluene, m-xylene, o-xylene, the tetralins; and mixtures of any of the foregoing. Other hydrocarbons useful as first solvents in the practice of the present invention will be apparent to the skilled artisan. Diethyl formal is the preferred formal. 1,2-dimethoxyethane (DME) is the preferred glyme and is particularly preferred as an ether first solvent, especially in combination with THF when the catalyst includes a palladium complex.
[0017] The second solvent can be water, or, preferably, an inorganic base combined with water. When an inorganic base is used, the preferred inorganic base is potassium carbonate. Potassium hydroxide and sodium hydroxide are other examples of inorganic bases.
[0018] The novel synthesis of irbesartan, and analogues thereof, of the present invention includes the step of reacting a protected (e.g. tritylated) 2-(5-tetrazoyl)phenylboronic acid with a 3-haloaryl-1,3diazaspiro[4.4]non-1-ene-4-one. A preferred 2-(5-tetrazoyl)phenylboronic acid is 2-(5-(1-trityl-1H-tetrazole))phenylboronic acid (IRB-07), Structure II. A preferred 3-haloaryl-1,3-diazaspiro[4.4]non-1-ene-3-4-one is 2-butyl-3-(4′-bromobenzyl)-1,3-diazaspiro[4.4]non-1-ene-3-one (IRB-05), Structure III.
[0019] The step is carried out in a two-phase reaction system having first and second liquid phases.
[0020] A catalyst is combined with the first liquid phase, preferably including an ether solvent. Any known catalyst for the Suzuki reaction can be used. Preferably, the catalyst is selected from palladium and nickel complexes. Most preferred catalysts include Pd(O(O)CCH 3 ) 2 , Pd Cl 2 and NiCl 2 . When a palladium complex such as Pd(O(O)CCH 3 ) 2 [e.g. PdOAc 2 ] is used, the catalyst also includes a triaryl phosphine, especially triphenyl phosphine. When the catalyst includes a palladium complex, the first solvent preferably includes an ether solvent, like DME, that can form a complex with Pd.
[0021] As described above, the first liquid phase is an organic solvent phase, most preferably and particularly when the catalyst includes a palladium complex, the first liquid phase is a mixture of 1,2-dimethoxyethane and THF. The ratio of 1,2-dimethoxyethane: THF can be from about 10:1 to about 1:5, the most preferred ratio of 1,2-dimethoxyethane: THF is from about 6:1 to about 2:1. The reaction is carried out in the presence of a catalyst.
[0022] Subsequently, IRB-07 is combined with the solvent mixture. Water, a base, and IRB-05 are added, preferentially sequentially, to the reaction mixture, and a two-phase reaction system having a first organic solvent phase and a second aqueous phase is formed. The reaction mixture is heated under reflux conditions for a reaction time of between 2 to 4 hours.
[0023] After the reaction time, the reaction mixture is allowed to cool, and the two phases are separated. If desired, the aqueous phase can be extracted one or more times with toluene and the extract(s) combined with the first (aromatic hydrocarbon) phase. The first phase is evaporated to obtain crude residue of product IRB-03.
[0024] In embodiments in which 2-(1-trityl-1H-tetrazol-5-yl)phenylboronic acid, (IRB-07), is the phenylboronic acid, the synthetic method of the present invention can and preferably does include a further step in which the trityl group is cleaved from the tetrazole ring to produce irbesartan (IRB-00), or an analogue thereof. Crude residue produced in the synthetic step described above is dissolved in a suitable water-miscible solvent. A solvent is water miscible if it is miscible with water at least in any proportion from 80:20 to 20:80 (weight basis). Acetone is a preferred water-miscible solvent. The resulting solution is acidified and agitated at a temperature between about 15° C. and about 30° C. The time of the cleavage reaction can be conveniently monitored using thin layer chromatography. The acid is neutralized with a molar excess of base, preferably aqueous KOH or NaOH, and the water-miscible solvent is evaporated, preferably at reduced pressure. The trityl alcohol formed is separated and the liquid phase is acidified (e.g. to a pH of about 4), preferably with mineral acid, most preferably with HCl or H 2 SO 4 . The resulting suspension is cooled and the product recovered by, for example, filtration. If desired, the isolated product can be washed with an organic solvent, preferably a lower aliphatic alcohol, most preferably iso-propanol or butanol, and dried, preferably at reduced pressure.
[0025] The 2-(5-tetrazoyl)phenylboronic acid and 1,3-diazaspiro[4.4]non-1-ene-3-(haloaryl)-4-one which are reacted in the method of the present invention to produce irbesartan or an analogue thereof, can be prepared by methods known in the art, or by the following synthetic procedures.
[0026] The 2-(tetrazol-5-yl)phenylboronic acid can be prepared by first reacting a 5-phenyl-1H-tetrazole with chlorotriphenylmethane in the presence of a base, especially an amine (e.g. triethylamine) in a suitable solvent system to provide a 5-phenyl-1-trityl-1H-tetrazole. A preferred 5-phenyl-1-trityl-1H-tetrazole is IRB-06 (structure shown in Examples). Suitable solvents for the solvent system include organic solvents. A particularly preferred solvent system is a mixture of THF and triethyl amine as the base. Following removal of by-products, the 5-phenyl-1-trityl-1H-tetrazole, such as IRB-06, can be isolated prior to use in the next step of the synthesis, or used in solution form. The protected tetrazole so formed is subsequently reacted with a suitable borate in the presence of a base, to form the desired boronic acid derivative, such as 2-(1-trityl-1H-tetrazol-5-yl)phenylboronic acid (IRB-07; structure shown in Examples). The reaction is carried out in solution, preferably in an organic solvent. The organic solvent is most preferably THF. Suitable bases will be apparent to the skilled artisan. A preferred base is butyllithium. The preparation can be at any suitable temperature, preferably at a temperature lower than about −20° C. The reaction is allowed to proceed for a time that the skilled artisan will know to adjust according to the reaction temperature.
[0027] The 3-haloaryl-1,3-diazaspiro[4.4]non-1-ene-4-one can be prepared by combining a 1,3-diazaspiro[4.4]non-1-ene-4-one acid addition salt, preferably a hydrochloride salt, with a haloaryl compound. A preferred 1,3-diazaspiro[4.4]non-1-ene-4-one acid addition salt is 2-butyl-1,3-diazaspiro[4.4]non-1-ene-4-one hydrochloride (IRB-01). A preferred haloaryl compound is 4-bromobenzyl bromide. Reaction of 2-butyl-1,3-diazaspiro [4.4]non-1-ene-4-one hydrochloride (IRB-01) with 4-bromobenzyl bromide leads to the production of 2-butyl-3-(4′-bromobenzyl)-1,3-diazaspiro[4.4]non-1-ene-4-one (IRB-05). 2-Butyl-1,3-diazaspiro[4.4]non-1-ene-4-one is known in the art and is disclosed, for example, in U.S. Pat. No. 5,559,233, which is incorporated herein by reference.
[0028] The reaction is carried out in a two-phase reaction system having first and second liquid phases.
[0029] A first liquid phase comprising the haloaryl compound and a phase transfer catalyst in a suitable solvent is prepared. The solvent may be an organic solvent. A most preferred solvent is toluene.
[0030] Phase transfer catalysts are well known to one skilled in the art of organic synthesis. Phase transfer catalysts are of particular utility when at least first and second compounds to be reacted with each other have such different solubility characteristics that there is no practical common solvent for them and, accordingly, combining a solvent for one of them with a solvent for the other of them results in a two-phase system.
[0031] Typically, when such compounds are to be reacted, the first reactant is dissolved in a first solvent and the second reactant is dissolved in a second solvent. Because the solvent for the first reactant is essentially insoluble in the solvent for the second reactant, a two-phase system is formed and reaction occurs at the interface between the two phases. The rate of such an interfacial reaction can be greatly increased by use of a phase transfer catalyst (PTC).
[0032] Several classes of compounds are known to be capable of acting as phase transfer catalysts, for example quaternary ammonium compounds and phosphonium compounds, to mention just two. Tetrabutylaminonium hydrogensulfate is a preferred PTC for use in the practice of present invention.
[0033] A second liquid phase comprising a 1,3-diazaspiro[4.4]non-1-ene-4-one acid addition salt, water and a base, preferably an inorganic base, most preferably, KOH. The base is present in an amount between about 1 and about 6 molar equivalents relative to the number of moles of 1,3-diazaspiro[4.4]non-1-ene-4-one acid salt.
[0034] The first and second solutions are combined to form a reaction system (mixture) that has first and second phases. The combining can be in any suitable vessel that is equipped with means for vigorous agitation of the reaction system to maximize the interfacial area between the two phases. The combining can be at any temperature from about 20° C. to about 95° C., preferably at about 90° C. The reaction is allowed to proceed in the two phase system for a time that the skilled artisan will known to adjust according to the reaction temperature. When the reaction temperature is about 90° C., a reaction time between about 1 and about 2 hours is usually sufficient.
[0035] After the reaction time, the reaction system is allowed to cool, the two phases are separated. If desired, the aqueous phase can be extracted one or more times with toluene and the extract(s) combined with the first (aromatic hydrocarbon) phase. The first phase is evaporated to obtain crude residue.
[0036] The present invention can be illustrated in one of its embodiments by the following non-limiting example.
Example 1A. Preparation of IRB-05 Weight; Mw volume Mmol Eq. IRB-01 230.73 57.7 g 250 1.25 4-Bromobenzyl bromide 249.49 50.0 g 200 1.0 Potassium hydroxide, 85% 56.11 49.6 g 750 3.75 Water 200 mL Bu 4 NHSO 4 339.54 8.5 g 0.125 Toluene 800 mL
[0037] To a preheated (90° C.) solution of 4-bromobenzyl bromide and phase transfer catalyst (Bu 4 NHS0 4 ) in toluene was added a prestirred (40 min at room temperature) solution of KOH and IRB-01 in water. The resulting two-phase mixture was heated for 1 hour at 90° C. with vigorous stirring. The mixture was cooled to room temperature, water (500 mL) was added and the mixture was stirred for additional 30 min. The phases were separated and the aqueous phase was extracted with an additional portion of toluene (100 mL). The combined organic portions were washed with water and brine, dried over Na 2 SO 4 and evaporated under reduced pressure. 74.0 g of IRB-05 was obtained as a colorless oil. The yield was 94%, with a purity of 94%.
Example 1B. Preparation of IRB-06 Weight; Mw volume Mmol Eq. 5-Phenyl-1H-tetrazol 146.15 56.0 g 383 1.0 Chlorotriphenylmethane 278.78 112.0 g 402 1.05 Et 3 N 101.2 61.0 ml, 440 1.15 THF 400 mL
[0038] To a solution of 5-phenyl-1H-tetrazol and triethylamine in dry THF was added, in one portion, chlorotriphenylmethane. The reaction was slightly exothermic, about 40° C. The resulting suspension was stirred under argon for 2 hours (TLC monitoring; Hex/EtOAc 4:1). The mixture was cooled to 0° C., stirred for 30 min and the precipitated triethylammonium chloride was filtered and washed with cold THF (100 mL). The filtrate was evaporated under reduced pressure and the yellow solid residue (approx. 180 g) was crystallized from acetonitrile (800 mL) to give 141.5 g. The yield was 94%, with a purity of 94%.
Example 1C. Preparation of 2-(5-(1-trityl-1H-tetrazol)phenylboronic acid (IRB-07) Weight, Mw volume mmol Eq. IRB-06 388.46 39.0 g 100 1.0 BuLi (1.6 M in hexane) 75.0 mL 120 1.2 Triisopropyl borate 188.08 30.0 mL 130 1.3 THF 250 mL
[0039] The solution of 5-phenyl-1-trityl-1H-tetrazole (IRB-06) in dry THF (Prepared in Example 1B) was cooled to −20° C. under Argon. Traces of water were quenched with n-butyllithium (approx. 5 mL). When the mixture remained red for 5 minutes the addition was stopped. The main charge of n-butyllithium was then added dropwise at temperature below −15° C. and the resulting red suspension was stirred for additional 30 minutes at −20° C. The mixture was cooled to −30° C., and triisopropyl borate was slowly added, with the reaction temperature maintained at below −20° C. At this point, the slurry was dissolved and the resulting red solution was stirred for 30 minutes at −25° C., and then warmed to room temperature over 40 minutes. The solvents were evaporated under reduced pressure and the yellow semisolid residue was extracted with isopropyl alcohol (IPA) (200 mL) and cooled to 0° C. Saturated aqueous NH 4 Cl (40 mL, approx. 180 mmol) was slowly added, keeping the temperature below 10° C., and the slurry of boronic acid was warmed to room temperature. Water (160 mL) was added over 20 minutes, and the resulting suspension was stirred for 2 hours at room temperature. The solid was filtered, washed with IPA/H 2 O/Et 3 N 50:50:2 (2×50 mL) and dried under reduced pressure at 40° C. until constant weight to give 47.0 g of IRB-07 as the 1:0.5 THF—H 2 O solvate (off-white solid) that was used without additional purifications. The yield was 92%, with a purity of 94.5%.
Example 1D. Preparation of 2-butyl-3-[2′-(triphenylmethyltetrazol-5- yl)-biphenyl-4-yl methyl]-1,3-diazaspiro[4.4]non-1-ene-4-one (IRB-03) Weight, Mw volume mmol Eq. 2-butyl 1,3-diazaspiro[4.4]non- 363.3 0.96 g 2.64 1.0 1-ene-3-(4-bromobenzyl)-4- one (IRB-05) IRB-07-THF-0.5 H 2 O 513.3 1.42 g 2.77 1.05 Pd(OAc) 2 224.49 5.7 mg 0.026 1.15 Triphenylphosphine 262.5 27.3 mg 0.104 1,2-Dimethoxyethane 8 mL THF 2 mL Potassium carbonate 138.21 0.912 g 6.60 2.5 Water 18.0 0.119 mL 6.60 2.5
[0040] A mixture of DME and THF was degassed by vacuum/nitrogen purges (3 times) and Ph 3 P was added in one portion. After the triphenylphosphine dissolved, Pd(OAc) 2 was added, and the yellow-green mixture was degassed again (2 times), and stirred for 30 min at room temperature. IRB-07 was suspended, and stirring was continued for 10 min at room temperature. The water was added, and the slurry was stirred for additional 30 min. Powdered K 2 CO 3 and IRB-05 were then added sequentially and the resulting mixture was degassed (3 times), and refluxed (approx. 80° C.) for 3 hours (TLC monitoring: Hex/EtOAc 2:1). The solvents were evaporated under reduced pressure, and toluene (20 mL) and water (20 mL) were added. After separation, the aqueous phase was extracted with toluene (10 mL) and the combined organic phases were washed with water and brine, dried over Na 2 SO 4 and evaporated under reduced pressure to give 2.1 g of the semisolid residue. The crude material was crystallized from IPA (15 mL) to give 1.6 g of IRB-03 as a white solid. The yield was 90%, with a purity of 98%.
Example 1E. Preparation of Irbesartan (IRB-00) Weight, Mw volume mmol Eq. IRB-03 670.84 1.0 g 1.49 1 HCl, 3N 1.5 mL 4.5 3 Acetone 3 mL KOH, 85% 56.11 0.42 g 5
[0041] IRB-03 (as produced in Example 1D) was dissolved in acetone and 3N HCl, and stirred for 2 hours at room temperature (TLC or HPLC monitoring). A solution of KOH in 3 mL of water was slowly added, and acetone was evaporated under reduced pressure. The precipitate (Trityl alcohol) was filtered and washed with water (2×5 mL). The combined aqueous filtrate washed with 5 mL of ethyl acetate, and slowly acidified to pH 4 with 3N aqueous HCl. The resulting suspension was cooled down to 0-4° C., stirred for additional 30 min and filtered. The cake was washed several times with water and dried under reduced pressure at 50-60° C. The yield was 0.58 g of IRB-00.
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Provided are a method of making irbesartan via a Suzuki coupling reaction and a novel intermediate, 2-butyl-3-(4′-bromobenzyl)-1,3-diazaspiro[4.4]non-1-ene-4-one, for such process. The novel process includes the step of reacting such intermediate with a protected imidazolephenylboronic acid.
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BACKGROUND OF THE INVENTION
The invention generally relates to vascular catheters suitable for maintaining the patency of a blood vessel after a vascular procedure therein, such as angioplasty. In particular, the present invention relates to angioplasty apparatus facilitating rapid exchanges and a method for making rapid exchanges of angioplasty devices.
In typical percutaneous transluminal coronary angioplasty (PTCA) procedures, a guiding catheter having a preformed distal tip is percutaneously introduced into the cardiovascular system of a patient through the brachial or femoral arteries and is advanced therein until the distal tip thereof is in the ostium of the desired coronary artery. A guide wire and a dilatation catheter having an inflatable balloon on the distal end thereof are introduced through the guiding catheter with the guide wire slidably disposed within an inner lumen of the dilatation catheter. The guide wire is first advanced out of the distal end of the guiding catheter and is then maneuvered into the patient's coronary vasculature containing the lesion to be dilated, and is then advanced beyond the lesion. Thereafter, the dilatation catheter is advanced over the guide wire until the dilatation balloon is located across the lesion. Once in position across the lesion, the balloon of the dilitation catheter is filled with radiopaque liquid at relatively high pressures (e.g., greater than about four atmospheres) and is inflated to a predetermined size (preferably the same as the inner diameter of the artery at that location) to radially compress the atherosclerotic plaque ofthe lesion against the inside of the artery wall to thereby dilate the lumen of the artery. The balloon is then deflated so that the dilatation catheter can be removed and blood flow resumed through the dilated artery.
A common problem that sometimes occurs after an angioplasty procedure is the development of restenosis at or near the site of the original stenosis in the body lumen which requires a second angioplasty procedure, a bypass surgery, or similar procedure to reduce or remove the restenosis. In recent years, various devices and methods (other than bypass surgery) for the prevention of restenosis after arterial intervention in a patient's body lumen have become known which typically use an expandable graft (commonly termed "stent") on the distal end of the catheter designed for implantation in the body lumen.
Stents generally are designed for permanent implantation within the body lumen. By way of example, several stent devices and methods can be found in commonly assigned and commonly owned U.S. Pat. No. 5,158,548 (Lau et al.); U.S. Pat. No. 5,242,399 (Lau et al.); U.S. Pat. No. 5,344,426 (Lau et al.); U.S. Pat. No. 5,514,154 (Lauetal.); U.S. Pat. No. 5,360,401 (Turnlandetal.); and U.S. Ser. No. 08/454,599 (Lam), which are incorporated in their entirety herein.
In recent years in practicing angioplasty, it is often desirable to exchange one dilatation catheter for another. In doing so, it is necessary to use extension wires or long exchange wires having a total length of approximately 200 to 300 centimeters, both of which typically require two operators. During the procedure, it is necessary that the operators communicate with each other to coordinate their efforts, which makes the procedure more involved and time consuming.
In addition, because the extension wires or exchange wires are long, they are awkward to handle. For that reason, they may come in contact with the floor or otherwise extend out of the sterile surgical field and become contaminated. If contaminated, the entire apparatus being utilized for the angioplasty procedure must be removed from the patient and replaced.
There have been improvements in the field of rapid exchange catheters to rectify some of the shortcomings. For example, U.S. Pat. No. 4,748,982 to Horzewski et al. discloses a method and apparatus relating to a rapid exchange balloon dilatation catheter with slitted exchange sleeve. The sleeve has a slit extending longitudinally from the proximal extremity of the sleeve to a region adjacent the balloon to permit the guide wire, which is used to assist guiding the catheter in to a vessel of a patient, to be removed therethrough. U.S. Pat. No. 5,040,548 to Yock discloses methods for performing angioplasty procedures within a patient's coronary artery to facilitate rapid exchanges of angioplasty devices. U.S. Pat. No. 5,180,368 to Garrison discloses a rapidly exchangeable and expandable cage catheter for repairing damaged blood vessels. Garrison discloses an intravascular catheter having an expandable cage mounted on the distal end of a tubular member that is radially expanded and contracted by means of a control wire. The device includes a flexible tubular element extending through the expandable cage interior to facilitate the rapid exchange of the catheter. U.S. Pat. No. 5,061,273 to Yock discloses another angioplasty apparatus facilitating rapid exchanges.
During rapid exchange catheter procedures known in the art, it is necessary for the surgeon to introduce the balloon dilitation catheter onto the guide wire already positioned within the body lumen by a backloading technique. Specifically, the guide wire remains stationary in the patient's vasculature while the distal extremity of the catheter is advanced over the guide wire proximal end. The guide wire proximal end exits through an opening on the outer surface of the catheter proximal to the balloon. However, threading the guide wire through this opening on the outer surface of the catheter is difficult and requires time and precision, especially when the catheter is covered by a protective sheath.
In addition, recent developments in stent delivery systems require use of a protective sheath to cover the stent during the delivery process, which sheath is retracted so the stent can be deployed. Use of such a sheath complicates the backloading of the guide wire during the rapid exchange catheter procedure because the guide wire must not only pass through the outer surface opening in the catheter, but it must also pass through a similar opening in the sheath. If the two openings are misaligned, backloading the guide wire becomes even more difficult.
Accordingly, there is a need for a rapid exchange catheter having a design that facilitates easy front loading and backloading of the catheter so that the guide wire passes through the catheter and sheath quickly and precisely without numerous attempts by the surgeon to align catheter and sheath openings to thread the guide wire therethrough.
SUMMARY OF THE INVENTION
The present invention is directed to a stent delivery system and method for delivery of an expandable stent within a body lumen. Preferably, a rapid exchange type catheter coupled with a sheath is used to deliver and implant the stent in a body lumen, such as a coronary artery. The stent delivery system preferably comprises an elongated sheath having proximal and distal portions and having a guide wire exit notch, and a catheter covered by the sheath and having proximal and distal portions with a guide wire lumen and an inflation lumen extending therethrough. The catheter includes a guide wire port in communication with the guide wire lumen, and an inflatable balloon disposed at the distal portion of the catheter. The balloon includes an interior in communication with the inflation lumen. The expandable stent is disposed on the balloon beneath the protective sheath.
A first telescoping sleeve is attached to the guide wire port where the interior of the first sleeve is in communication with the guide wire lumen. A second telescoping sleeve is slidably connected to the first telescoping sleeve, and the second sleeve is attached to the sheath such that an interior of the first sleeve is in communication with the guide wire lumen. The invention further includes a guide wire that passes through the guide wire lumen, the first and second telescoping sleeves, and exits from the sheath.
In a preferred embodiment, a manipulator handle is connected to the proximal portions of the catheter and sheath to impart relative axial movement thereto to expose the balloon and stent during delivery of the stent. The handle is flirter used to control inflation and deflation of the balloon and accordingly the proper expansion of the stent to implant it in the body lumen.
After deployment of the stent through conventional methods, the catheter is separated from the guide wire in a manner known in the art. Specifically, this special process for a rapid exchange catheter is discussed in, for example, U.S. Pat. No. 4,748,982 to Horzewski et al., which is incorporated herein by reference.
When it is desired to exchange a rapid exchange dilatation catheter (not shown) for the rapid exchange stent delivery catheter of the invention, the guide wire is retained in its position in the patient and the dilatation catheter is removed by withdrawing same until the guide wire exit notch appears outside of the guiding catheter. Thereafter, as the catheter is withdrawn, the guide wire can be pulled out through a slit formed in the side of the catheter until the catheter has been withdrawn to a point just proximal of the balloon. Thereafter, the catheter can be withdrawn on the guide wire until the balloon clears a rotating hemostasis valve which is attached to the proximal end of the guiding catheter. The dilatation catheter is then removed from the guide wire and the stent delivery catheter is threaded onto the proximal end of the guide wire and advanced through the rotating hemostasis valve and over the guide wire which is still in position inside the patient.
In order to insert the stent delivery catheter into the patient in this rapid exchange procedure, the guide wire is introduced into the stent delivery catheter by a back-loading technique, wherein the proximal end of the guide wire is inserted through the distal end of the catheter, and into the guide wire lumen. The guide wire is held stationary while the distal portion of the catheter is advanced over the guide wire until the guide wire is guided through the first and second telescoping sleeves, attached to the guide wire lumen, and out the guide wire exit notch in the sheath. The telescoping sleeves of the present invention thus guide the proximal end of guide wire out of the catheter and sheath with precision and without multiple attempts by the physician to try to align the exit ports on the catheter and the sheath.
An important aspect of the invention is that the telescoping feature of the sleeves permits the use of a sliding sheath that is initially used to protect the stent during delivery. The sleeves ensure that the proximally located guide wire port and the sheath opening are aligned so that the proximal extremity of the guide wire can be threaded therethrough, despite displacement of the sheath proximally relative to the catheter. Because one segment of the complementary telescoping sleeves is affixed to the sheath and the other complementary segment is affixed to the catheter, the movement of the sheath proximally relative to the catheter creates the telescoping action of the sleeves. So despite movement of the sheath relative to the catheter, the telescoping sleeves ensure that there is an uninterrupted passageway that is in communication with the guide wire lumen to permit passage of the guide wire through the sheath opening. In view of the foregoing, it is therefore an important aspect of the present invention to provide an assembly for easy backloading of a rapid exchange catheter onto a guide wire in position in the patent. It is also desired to provide a mechanism in a rapid exchange catheter employing a protective sheath that moves axially relative to the catheter during deployment of an expandable stent. It is yet another advantage of the present invention to employ telescoping sleeves that are in communication with a guide wire lumen inside the catheter to provide alignment between the sheath and catheter to permit passage of the proximal extremity of the guide wire therethrough during a backloading procedure. These and other advantages of the present invention will become apparent from the following detailed description thereof when taken in conjunction with the accompanying exemplary drawings.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 is a side elevational view, partially in cross-section, depicting an intravascular catheter having rapid exchange design employing features of the present invention.
FIG. 2 is a cross-sectional view taken along the line 2--2 of FIG. 1.
FIG. 3 is a cross-sectional view taken along the line 3--3 of FIG. 1.
FIG. 4(a) is a cross-sectional view taken along line 4--4 of FIG. 1.
FIG. 4(b) is a cross-sectional view of an alternative embodiment showing a coaxial-type catheter having a guide wire lumen that is coaxial with the inflation lumen.
FIG. 5 is a cross-sectional view taken along the line 5--5 of FIG. 1.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
The present invention is directed to a stent delivery system for delivery of an expandable stent within a body lumen. In particular, the present invention is directed to a rapid exchange balloon catheter wherein the balloon carries a stent which is covered by a retractable sheath, and wherein the catheter includes telescoping sleeves in communication with a guide wire lumen so that during a rapid exchange procedure of the catheter, the catheter can be backloaded onto the guide wire quickly since the sheath and catheter are aligned to permit the guide wire to exit easily.
While the invention is described in detail as applied to coronary arteries, those skilled in the art will appreciate that it can be used in other body lumens as well, such as in peripheral arteries and veins. Where different embodiments have like elements, like reference numbers have been used.
FIG. 1 is a side elevational view, partially in cross-section, of a preferred embodiment of the present invention. In particular, FIG. 1 illustrates an elongated catheter 10 suitable for rapid exchange procedures known in the art. Such rapid exchange catheters are taught in, for example, U.S. Pat. No. 4,748,982 to Horzewski et al., mentioned above. The catheter 10 has an elongated shape, generally about 135 cm, and is substantially covered by retractable sheath 12. The retractable sheath 12 covers stent 14 and balloon 16 and provides a means for protecting and safely delivering stent 14 through the vasculature. As is known, once the stent 14 is positioned at the desired location in the body lumen, the sheath 12 is retracted to uncover stent 14, and balloon 16 is then inflated to expand the stent 14 and implant it in the body lumen.
As seen in FIGS. 1-4(a), catheter 10 is a side-by-side lumen design wherein the inflation lumen 18 is adjacent and parallel to guide wire lumen 20.
The present invention preferably includes guide wire 22 that passes through distal guide wire port 24 at a distal portion of catheter 10. The guide wire lumen 20 of the present invention generally extends through about the distal most 10 to 50 cm of the 135 cm catheter 10. At about point 33 of the catheter 10, the present invention includes telescoping sleeves 26,28 through which the guide wire 22 passes. Telescoping sleeve 26 preferably protrudes into the catheter 10 a short distance via guide wire exit port 30 at guide wire notch 32 formed in the catheter 10. This can be seen in FIGS. 2-5, which provide cross-sectional views of the catheter 10 at various locations.
The sheath 12 also includes guide wire exit port 34 through which the sleeve 28 passes. Once it emerges outside of the catheter 10 and sheath 12, sleeve 28 is held against the outer wall of the sheath 12 by adhesively bonding it to the sheath 12 outer wall or by wrapping it with an optional external sleeve 36. FIG. 3 depicts a cross-sectional view of the external sleeve 36 and telescoping sleeve 28. As seen in FIG. 1, the guide wire 22 includes a proximal extremity 17 and a distal extremity 19 that are free and clear of the catheter 10.
A manipulator handle 21 is connected to the catheter 10 and sheath 12. The manipulator handle 21 is similar to that disclosed in, for example, U.S. Pat. Nos. 5,391,172 to Williams et al. and 5,458,615 to Klemm at al., the entire contents of which are incorporated by reference herein. Other manipulator handles known in the art may be used as well. As seen in FIG. 1, a reciprocating push-button slide switch 23 on the handle 21 is used to retract the sheath 12 proximally to expose the stent 14 at the deployment site as explained above. To prevent unexpected movement of the sheath 12, the push-button slide switch 23 can be mechanically locked in place so that it does not shift.
An inflation fluid is injected through a Luer lock (not shown) at the proximal end of the handle 21. The fluid flows through the Luer lock, the inflation lumen 18 of the catheter 10, and into the interior 27 of the balloon 16, thus expanding the balloon 16.
As seen in FIG. 4(b), in an alternative embodiment, catheter 11 has an inflation lumen 13 that is coaxial with guide wire lumen 15. In the FIG. 4(b) view, guide wire 22 extends through guide wire lumen 15 and sleeve 26. Guide wire lumen 15 is formed by inner member 40 which also has a rapid exchange slit 41 that the guide wire pulls through.
The preferred method of use of the present invention is described as follows. A guiding catheter, known in the art, is first introduced into the vasculature through conventional methods. An elongated catheter of the appropriate size is selected and, along with a guide wire, are introduced into the guiding catheter by preferably first advancing the guide wire past the stenosis and thereafter advancing the catheter so that a dilatation balloon is positioned within the stenosis. Thereafter, the balloon is inflated in a conventional PTCA manner.
In keeping with the preferred method, the dilatation catheter is withdrawn from the patient and stent delivery catheter 10 is inserted. Distal end 37 of catheter 10 is threaded over proximal end 17 of guide wire 22 which remains stationary in the patient. Catheter 10 is advanced distally over guide wire 22. Telescoping sleeves 26, 28 help guide the proximal extremity 17 of guide wire 22 through the guide wire lumen 20, guide wire notch 32, sheath opening 34, and finally emerging out of sheath 12. The preferred method allows the stent delivery catheter to be backloaded more easily because the telescoping sleeves prevent the proximal extremity 17 of guide wire 22 from hanging up at the sheath opening 34 by providing perfect alignment with the guide wire notch 32.
Catheter 10 is then advanced over the guide wire and once the stent 14 and underlying balloon 16 are in position within the body lumen, the sheath 12 is retracted, exposing the stent 14. Inflation fluid is inserted through inflation lumen 18, which inflation fluid flows through opening 25 and into the interior 27 of the inflation balloon 16. Internal pressure of the inflation balloon 16 inflates the balloon thereby expanding the stent 14.
In keeping with the preferred method, as the sheath 14 is withdrawn proximally, it translates telescoping sleeve 28 relative to telescoping sleeve 26. This occurs because sleeve 28 is attached to the sheath 12 by use of an optional external sleeve 36 wrapped thereon, by use of a bonding agent at one or more contact points between the sleeve 28 and the sheath 12, or both. Sleeve 26 translates relative to sleeve 28 since sleeve 26 is bonded to the guide wire lumen 20. As a result, retracting the sheath 12 causes a telescoping action between the sleeves 26,28 with the overall length of the telescoping sleeves 26, 28 increasing as the sheath 12 is retracted. The increasing length of the sleeves 26,28 is proportional to the amount of axial movement the sheath 12 undergoes to expose stent 14, generally about 20-40 mm proximally.
After the stent has been implanted in the body lumen, the catheter is removed from the patient. As seen in FIG. 1, the guide wire 22 emerges from the guide wire notch 32 outside of the sheath 12 through sheath opening 34. The catheter 10 can be removed from the guide wire 22 by pulling the guide wire 22 out through slit 38, which is formed in the catheter outer wall and extends longitudinally from the guide wire port 30 to a region 35 just proximal of the inflation balloon 16. Sheath 12 and external sleeve 36 also both have a slit 39, seen in FIGS. 3 and 4, which extends from sleeves 26, 28 to a point corresponding with slit 38 in catheter 10. Thus, guide wire 22 pulls through slit 39 and catheter slit 38 to effect the rapid exchange procedure. Of course, sleeves 26,28 also have slit 38 to permit the guide wire to be pulled therethrough during the catheter exchange.
By the described method it can be seen that it is possible to accomplish the rapid exchange of a catheter by merely making the exchange over a very short length, such as 10-50 centimeters of the distal portion of the catheter. Thus, with the catheter of the present invention, it is possible to utilize conventional guide wires without the necessity of long exchange wires as has been the practice in the past. In addition, it has been possible to accomplish such an exchange utilizing a stent carrying balloon catheter that incorporates a protective sheath.
In the preferred embodiment, the telescoping sleeves are made from a polyimide tubing. The external sleeve is preferably made from polyether ether ketone tubing. The bonding agent used to bond the telescoping sleeves to the sheath and catheter is preferably polymethylmethacrylate or its equivale. The balloon 16 is made from a material such as polyethylene.
The sheath 12 may preferably include one or more radiopaque markers 31 and the balloon 16 may have one or more radiopaque markers to assist in positioning those structures within the patient's vessels.
It is recognized that other modifications can be made to the present invention without departing from the scope thereof. The specific dimensions, inflation times, and materials of construction are provided as examples and substitutes are readily contemplated which do not depart from the invention.
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A rapid exchange catheter system provides a delivery vehicle to carry a stent through a patient's vasculature and deploy the stent after a protective sheath covering the stent has been withdrawn. In order to facilitate the rapid exchange of catheters and specifically the backloading of a catheter onto the proximal end of a guide wire, the catheter includes telescoping sleeves within the guide wire lumen that translate relative to each other as the sheath is retracted to expose the stent. The telescoping sleeves align the catheter and the sheath when the catheter is backloaded onto the distal extremity of the guide wire by aligning the guide wire notch of the catheter with an opening in the sheath thus providing a continuous guide wire passageway.
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RELATED CASES
Priority for this application is hereby claimed under 35 U.S.C. §119(e) to commonly owned and U.S. Provisional Patent Application No. 61/135,731 which was filed on Jul. 23, 2008 and which is incorporated by reference herein in its entirety.
FIELD OF THE INVENTION
The present invention relates in general to stabilizer pads for vehicles, and more particularly to stabilizer pads used with backhoe-type vehicles for supporting stabilizer arms of the vehicle.
BACKGROUND OF THE INVENTION
Construction equipment, such as earth-moving vehicles and the like, must be stabilized during construction or digging operations to limit movement of the equipment or vehicles. Typically, stabilization is provided by hydraulically actuated arms that extend from the vehicle and that have earth-engaging pads mounted on their distal ends. When the vehicle or equipment is moved into a working position, if extra stability is needed, the stabilizer arms are hydraulically operated to move from a retracted position, in which the arms generally extend upwardly and out of the way, to a user position in which the arms extend downwardly at an acute angle to the ground surface so that the pads contact the ground surface. When it is desired to move the vehicle, the arms are returned to the retracted position, and the vehicle is moved to a new operating location.
Reversible stabilizer pads for construction equipment, such as earth-moving vehicles and the like, are well-known in the prior art. Examples of such pads are found in U.S. Pat. Nos. 4,761,021; 4,889,362; 5,992,883 and 6,270,119. Such stabilizer pads generally have a first surface for engagement with a softer surface, such as gravel and soft earth, and a more resilient second surface on the opposite side of the first surface for engagement with harder surfaces, such as concrete or asphalt. Typically, the first surface includes flanges with grouser points that permit the pads to dig into the softer, unfinished surface formed by gravel or soft earth, to better anchor and stabilize the vehicle when encountering difficult digging conditions. The first surface is unsuitable for contact with a hard surface, since the grouser points could damage or mar the hard asphalt or concrete. The second surface of the pad typically is formed of a laminated, rubber pad for better stability on the more solid surface provided by concrete or asphalt. The stabilizer pad typically is pivotally mounted to the distal end of the hydraulically operated arm so that the pad may be rotated to contact the ground with either the first surface or the second surface.
U.S. Pat. No. 4,889,362 discloses a reversible stabilizer pad for earth moving vehicles having a generally flanged first surface for engagement with, for example, gravel and soft earth, and a resilient surface for engagement with, for example, concrete or asphalt. This patent describes the use of rubber pads on one side of the stabilizer pad for ground contact when the vehicle is on a finished surface, such as concrete or asphalt, and flanges with grouser points on the opposite side of the stabilizer pad for ground contact when the vehicle is on an unfinished but hard ground surface that requires that the pads dig into the surface in order to better anchor and stabilize the vehicle when encountering difficult digging conditions. The flange side of the pad is unsuitable for contact with a finished surface since it could damage and/or mar the finished surface. The stabilizer pad is pivotally mounted to the end of a hydraulically operated arm such that the pad may be rotated to contact the ground with either the rubber pad side or the flange side facing down to contact the ground surface. When the vehicle is moved into a working position, if extra stability is needed, the stabilizer arms, on which the pads are mounted, are hydraulically operated to move from a retracted position, in which the arms generally extend upwardly and out of the way, to a use position, in which the arms extend downward at an angle with the pads contacting the ground surface. When the vehicle is to be moved, the arms are lifted back to the retracted position, the vehicle is moved to a new operating location and the stabilizer arms are brought down into the use position again, if necessary.
Reference is also now made to co-pending application Ser. No. 11/726,226 filed on Mar. 21, 2007 and describing further improvements to a stabilizer pad, particularly relating to providing a more economical pad and one that is both lightweight and durable. In this pad structure the main metal plate member is formed using certain bending steps so as to minimize the welding of components.
It is an object of the present invention to provide still further improvements to stabilizer pads to enhance their durability, to enable them to be manufactured more economically and to enable effective stability thereof even with a lighter weight construction.
SUMMARY OF THE INVENTION
To accomplish the foregoing and other objects, features and advantages of the present invention there is provided a stabilizer pad structure comprising: a weldment formed of a metal plate material that includes at least one mounting plate that defines a pocket; a resilient pad mounted in the pocket of the mounting plate; and a pair of clamping bars disposed in the pocket, one on each side of the resilient pad; and wherein each clamping bar is constructed and arranged to interlock with the mounting plate.
Other aspects of the present invention include tabs disposed on the clamping bar that interlock with corresponding holes on the mounting plate; the tabs inhibit movement of the clamp bar in a direction along a longitudinal axis of the clamp bar; the tabs transfer force from the pad, through the clamp bar, to the mounting plate; the tabs define a shoulder which engages the underside of a base of the mounting plate; the weldment is adapted for connection with a stabilizer arm of earth moving equipment; and the clamping bars include a plurality of partially open holes along a bottom edge, corresponding to holes on the resilient pad, constructed and arranged to engage with support pins for supporting the resilient pad.
In accordance with another version of the invention there is provided a stabilizer pad structure for supporting earth moving equipment, comprising: a weldment formed of a metal plate material and adapted for connection with a stabilizer arm of the earth moving equipment; a pad constructed of a resilient material having one and another support sides and including opposed wear surfaces; at least one mounting plate secured to the weldment and defining a pocket for receiving the resilient pad; and a pair of clamping bars disposed in the pocket, one on each side of the resilient pad; and wherein the pair of clamping bars and the mounting plate include respective engagement elements that provide an interlock between the clamping bars and mounting plate.
In accordance with still other aspects of the present invention the engagement elements inhibit movement in a direction of the longitudinal axis of the clamping bar; the engagement elements transfer force from the pad, through the clamping bar to the mounting plate; the engagement elements comprise tabs disposed on the clamping bar that interlock with respective holes disposed on the mounting plate; the tabs define a shoulder which engages the underside of a base of the mounting plate; the mounting plate defines side flanges that include a pair of hexagonal-shaped holes for receiving securing members; and the securing members comprise a hexagonal-head shaped bolt and corresponding hexagonal-shaped nut for securing the resilient pad within the weldment.
DESCRIPTION OF THE DRAWINGS
It should be understood that the drawings are provided for the purpose of illustration only and are not intended to define the limits of the disclosure. The foregoing and other objects and advantages of the embodiments described herein will become apparent with reference to the following detailed description when taken in conjunction with the accompanying drawings in which:
FIG. 1 is a perspective view of a preferred embodiment of the improved stabilizer pad of the present invention;
FIG. 2 is a side elevation view of the stabilizer pad of FIG. 1 ;
FIG. 3 is a rear elevation view of the stabilizer pad of FIG. 1 ;
FIG. 4 is a cross-sectional view taken along line 4 - 4 of FIG. 2 ;
FIG. 5 is a cross-sectional view taken along line 5 - 5 of FIG. 2 ;
FIG. 6 is an exploded perspective view of the stabilizer pad illustrated in FIG. 1 ;
FIG. 7 is a perspective view of flat metal blanks that are usable in constructing the main metal base of the stabilizer pad;
FIG. 8 is an exploded perspective view illustrating a further step in forming the main base of the stabilizer pad with preformed components and before the welding of the assembly;
FIGS. 9A and 9B are fragmentary cross-sectional views illustrating one embodiment;
FIGS. 10A and 10B are fragmentary cross-sectional views illustrating a preferred embodiment in accordance with the present invention;
FIG. 11 is a schematic perspective view illustrating the replaceable pad with one side surface worn;
FIG. 12 is a schematic exploded perspective view showing the resilient pad as separated from the clamp bars; and
FIG. 13 is a schematic perspective view illustrating the resilient pad having been reversed to illustrate the opposed surface now as a ground contacting surface.
DETAILED DESCRIPTION
Reference is now made to the drawings for an illustration of a preferred embodiment of the stabilizer pad of the present invention. The pad that is depicted in the drawings is comprised of a metal weldment that primarily includes the base plate 12 and separately mounted mounting plates 14 . Refer, for example, to FIG. 1 . The stabilizer pad depicted in the drawings is considered as having a grouser side defined by the separately disposed flanges 20 and a resilient pad side that includes the pair of laminated pads 34 . Although laminated pads are illustrated in FIG. 1 of the drawings, and are preferred, it is also understood that the pad 34 may be a solid one piece pad such as a molded rubber pad. It is furthermore anticipated that the principles of the present invention can apply to a stabilizer pad construction in which there is no grouser side of the pad. This is typically referred to as a “street” pad.
In the stabilizer pad of the present invention the base plate 12 is considered of generally U-shape and is formed by a series of bending operations, as will be discussed in further detail hereinafter. Each of the two mounting plates 14 is generally of U-shape and is also formed by a bending operation that is also described in further detail hereinafter. One of the objectives of the present invention is to minimize the amount of welding steps for the pad construction and thus bending steps are used which can be performed more efficiently and with less cost in connection with the construction of the pad. Welds are basically used only between the base plate 12 and the mounting plates 14 . These are depicted as welds 22 in the drawings.
The stabilizer pad that is illustrated in the drawings is meant for support from a stabilizer arm 6 of earth moving equipment such as a backhoe. The stabilizer pad, particularly the weldment and the base plate 12 , is supported from the stabilizer arm 6 by means of a pin 10 , as illustrated in FIGS. 1-3 . For a similar support stabilizer arm refer, for example, to my earlier U.S. Pat. No. 6,270,119 which is hereby incorporated by reference in its entirety. In addition, the following U.S. Patents and Publications are hereby incorporated by reference in their entirety U.S. Pat. Nos. 4,761,021; 4,889,362; 5,992,883; 6,270,119; 6,422,603; 6,471,246; 6,634,672; 6,726,246; 6,986,530; 7,040,659; 7,073,821; 7,172,216; 7,267,368; 2006/0011800; 2008/0048427 and 2008/0122212.
The stabilizer pad is constructed using a main base plate 12 that is generally of U-shape. The base plate 12 supports separately disposed pad mounting plates 14 . The base plate 12 includes parallel disposed flanges 20 and an interconnecting bridge piece 16 . Each of the flanges 20 define multiple grouser points as illustrated at 25 in FIGS. 1 and 2 . To support the base plate 12 with the mounting plates 14 , there are also provided, associated with each flange 20 , a pair of gussets 20 A. A series of welds 22 are used to interconnect the flange 20 , as well as the gussets 20 A with the base 28 of each of the mounting plates 14 . The mounting plates 14 each include, in addition to the base 28 , orthogonally bent flanges 30 . The base 28 and the flanges 30 together define a pocket into which is disposed the resilient pad 34 . Each of the mounting plates 14 is also provided with spaced slots 60 disposed at the outer respective corners between the base 28 and the flange 30 . These slots 60 accommodate tabs 58 of the clamp bar 50 , as will be described in further detail hereinafter.
FIG. 1 also illustrates the pivot pin 10 which is attached to the flanges 20 by means of respective bushings 26 . Each of the bushings 26 may be welded to its corresponding grouser flange 20 . The pin 10 may be free to rotate in its corresponding bushing 26 , or alternatively, a securing bolt (not shown) may pass through the pin and bushing combination to prevent relative rotation therebetween.
As indicated previously, each of the flanges 20 is provided with spaced grouser points 25 . In this regard refer to the side elevation view of FIG. 2 which illustrates the grouser points 25 , one disposed on each side of the pin 10 . Although two grouser points are illustrated in the disclosed embodiment, a single grouser point may be used or more than two grouser points may be used. Also, as indicated previously, for a street pad that is meant to be used primarily only on the resilient pad side, grouser points do not need to be provided. In addition, for a street pad, sections of the flange 20 construction can be removed so that the pad is lighter in weight.
Reference is now made to further details of the stabilizer pad of the present invention as illustrated in FIGS. 4-6 . As indicated previously, the resilient pad 34 is illustrated as a laminated pad including a plurality of laminations 36 . Each of these laminations preferably has a wave shape 37 at both opposed surfaces such as illustrated at opposed surfaces 42 and 44 in FIG. 6 . Although this wave shape is preferred, the upper and lower surfaces may also be of other shapes or even planar. For the support of the resilient pad 34 , there are provided a series of support pins 38 . The resilient pad 34 is provided with a series of holes 39 for accommodating these support pins 38 . The resilient pad 34 is also provided with a further pair of holes 41 for accommodating the bolt 40 . There is actually a pair of holes 41 at opposite ends of the pad 34 , as depicted in, for example, FIG. 6 . This accommodates a bolt 40 at each end of the pad 34 . A like pair of bolts 40 secures the other pad in the other mounting plate 14 . A pair of holes 41 is used so that the different holes can be used by the bolt 40 depending on the positioning of, or reversal of, the pad 34 . In this regard refer to the cross-sectional view of FIG. 4 that depicts the bolt 40 passing through an upper hole 41 . When the pad is reversed then the bolt 40 will engage the other hole 41 .
Each of the mounting plates 14 is provided with an inwardly facing hole 31 for each of the bolts 40 to pass through and securing the resilient pad in place in the mounting plate pocket. There are two holes 31 disposed along the inner flange 30 , such as illustrated in FIG. 6 . The outer flange 30 is also provided with a pair of holes 33 which in the particular illustrated embodiment is each a hexagonal-shaped hole for receiving the hex nut 52 . The holes 33 are similarly spaced apart on the outer flange 30 as were the holes 31 on the inner flange 30 . The threaded end of bolt 40 is for engagement with the hex nut 52 . The inter-engagement between the hex nut 52 and its accommodating hex-shaped hole 33 prevents rotation of the nut 52 while permitting the bolt 40 to be tightened urging the hex nut 52 against the clamp bar 50 as is clearly illustrated in FIG. 4 .
The cross-sectional views of FIGS. 4 and 5 illustrate further details of the clamp bars 50 . Refer also to the exploded perspective view of FIG. 6 . In the disclosed embodiment both the clamps bars 50 are identical in configuration. Each of the clamp bars includes an upwardly directed set of tabs 58 for accommodation in the respective slots 60 . At the bottom edge of each of the clamp bars 50 there is provided partially open holes 56 for accommodating respective support pins 38 . In the embodiment illustrated in FIG. 6 there are six support pins 38 and thus also six corresponding holes 56 in each of the clamp bars 50 . Lastly, each of the clamp bars 50 is provided with a somewhat elongated slot 54 . The slots 54 are for receiving the bolts 40 . A pair of slots 54 is provided disposed at respective ends of the clamp bar 50 . The slots 54 allow a small amount of “play” in the event that some debris is deposited between the pad and mounting plate.
FIG. 4 is a cross-sectional view taken along line 4 - 4 of FIG. 2 . This cross-sectional view illustrates the hex nut 52 disposed within the hexagonal-shaped hole 33 of the flange 30 . FIG. 4 also illustrates by arrow 47 a tightening or rotation of the bolt 40 at its head which causes the nut 52 , which remains rotationally stationary, to be urged against the side of the left-most clamp bar 50 . This pressure is indicated in FIG. 4 by the arrows 48 . In FIG. 4 the bolt 40 at each side is illustrated as extending through the slot 54 . FIG. 4 also illustrates the top of each clamp bar 50 with the tab 58 extending through the slot 60 . In this position of bolt 40 , the resilient pad 34 is at an initial position with a first wear surface 42 in a position facing the ground support surface. In this position it is noted that the bolt 40 passes through the upper one of the through holes 41 .
FIG. 5 is a cross-sectional view taken along line 5 - 5 of FIG. 2 and taken through one of the support pins 38 . FIG. 5 also illustrates the wear surface 42 . The support pin 38 also has its ends extending through respective holes 56 in the clamp bars 50 . The side flanges 30 of the mounting plate 14 prevent the pin 38 from disengaging from the resilient pad. The pins 38 may be lose fitting within the resilient pad 34 or the pins 38 may be force fit with the resilient pad 34 . FIGS. 4 and 5 also illustrate an upper second wear surface at 44 . Thus, in accordance with the present invention it is preferred that the resilient pad be supported so that after a first wear surface 42 has worn down sufficiently, the resilient pad can be inverted so that the other wear surface, namely surface 44 then becomes the downwardly facing ground engaging wear surface.
In accordance with one aspect of the present invention the stabilizer pad structure is of a relatively more simplified design requiring fewer components and one in which the resilient pad is positively engaged with its retaining structure regardless of which side of the pad is being used as the ground engaging side. In the past bumper bars have been used on either side of the resilient pad structure itself, integral with the resilient pad laminations. In accordance with the present invention rather than providing integral bumper bars on either side of the resilient pad itself, the resilient pad is held primarily by the support pins 38 .
In accordance with the present invention, rather than using a pair of bumper bars in combination with the clamp bar, separate clamp bars are used as illustrated by the clamp bars 50 herein. Moreover, these clamp bars are now interlocked with the mounting plate structure via tabs 58 in slots 60 . By placing the resilient pack in the pocket defined by the mounting plate, the support pins are prevented from creeping out. Moreover, the clamp bars themselves now serve as support members. In this way, the structure of the present invention is quite simplified, is economical to produce and is characterized by damaged-proof components. In accordance with the present invention, an effective wear surface is provided essentially with less metal and in a smaller-sized resilient pad.
With further reference to FIG. 5 , it is noted that the slots 60 are disposed on opposite sides of the mounting plate 14 essentially at the corners between the base 28 and the side flanges 30 . Each of the slots 60 extend a sufficient distance, particularly along the base 28 so that as the bolts 40 are tightened the gap 32 is formed with the nut 52 pressing against the left most clamp bar 50 . The interlock between the clamp bars 50 and the mounting plate 14 , by means of the tabs 58 in slots 60 , keep the tabs from sliding in the direction of arrow 19 in FIG. 2 . This interlock stabilizes the position of the pad relative to the pad mounting plate 14 . Moreover, each of the tabs 58 defines a shoulder 59 which engages the underside of the base 28 . This engagement transfers force form the resilient pad, through the support pins 38 to the clamping bar and from there to the mounting plate 14 . Refer also to the cross-sectional view of FIG. 5 where the arrow 17 is indicative of the transfer of force from each of the support pins 38 to the mounting plate 14 via the clamping bars 50 . This transfer of force occurs in both sides of the resilient pad by virtue of the pair of clamping bars both of which interlock on opposite sides of the base 28 as illustrated in FIGS. 4 and 5 .
In the embodiment disclosed herein each of the clamping bars has two tabs. In other embodiments of the present invention fewer or greater numbers of tabs may be provided on each of the clamping bars. These tabs are for interlock with receiving pockets in the resilient pad pocket. As indicated previously, the purpose of these tabs is to limit the movement of the clamping bars, particularly when the first side of the rubber pack is worn down and the rubber pack is reversed. This interlock prevents any potential rollover of the resilient pad when it is reversed. Another function of the interlock between the clamp bar and the mounting plate is to limit the fore and aft movement of the resilient pad pack, particularly when the earth moving equipment is moving. This arrangement allows for the use of smaller, less expensive securing bolts 40 . Because most of the force is not transferred through the bolts 40 , the primary function of the bolts is now to simply clamp the laminated layers of the resilient pad together and prevent it from falling out of the pocket.
As indicated previously, one of the advantages of the pad structure of the present invention is the ability to form the basic metal part of the pad using bending steps and attempting to minimize the need for weld points. In this regard, reference is now made to FIG. 7 which shows basic blanks that can be used for forming both the base plate 12 as well as the two mounting plates 14 . In FIG. 7 each of the blanks is flat and is meant to be bent along bend lines 15 . Thus, the flat blank for the base plate 12 has bend lines 15 for forming the flanges 20 as well as bend lines 15 for forming the gussets 20 A. Reference may now be made to FIG. 8 for an illustration of the base plate 12 once the bends have been completed.
FIG. 7 also illustrates two additional blanks that are used for forming the mounting plates 14 . These blanks are also bent along lines 15 to form, from the base 28 , the side flanges 30 . Again, refer to FIG. 8 for the next step in which the bends have occurred and the pad mounting plates 14 are then in their final position forming a pocket for receiving the resilient pad, as well as the pair of clamping bars 50 .
The resilient pad 34 may be a single piece molded rubber pad, but is preferably a laminated pad that is comprised of a series of laminated layers 36 as illustrated in, for example, FIGS. 1 and 6 . These laminated layers 36 are preferably held together by a series of support pins 38 that pass through holes 39 in the laminated layers. FIGS. 5 and 6 illustrate the configuration of each pad layer. Each of these pad layers, as mentioned previously, preferably has a wave-like ground contact surface 37 . The laminated layers may be tied together by means of a force fit of the pins with the holes. Alternatively, the pins 38 may be relatively loosely fit within the holes in each laminated layer.
Reference is now made to FIGS. 9 and 10 . FIG. 9 is actually separated into FIGS. 9A and 9B and FIG. 10 is separated into FIGS. 10A and 10B . Each of these figures is a cross-section through the bolt and support pin. FIG. 9A shows an arrangement in which the bolt 40 passes through a hole in the clamp bar 50 . FIG. 9A also illustrates the support pin 38 which is of a relatively large diameter and larger than the diameter of the bolt 40 . In this arrangement the pin 38 may have a diameter of one inch. FIG. 9A also illustrates a wear surface depth W 1 which may be on the order of 1⅛ inch or 1.125 inch. This defines a wear surface 42 . Also shown in FIG. 9A is the upper wear surface 44 that is not yet in place. Reference to FIG. 9B illustrates the pad pack having been worn down at 43 and reversed so that the wear surface 44 can then be in a position for ground engagement. In FIG. 9B the wear area depth W 2 may be on the order of 1.125 inch. The second wear surface 44 is now shown in a position for ground engagement.
FIGS. 10A and 10B illustrate a preferred arrangement in which the bolt 40 rides in a slot 54 that is somewhat elongated. Moreover, the support pin 38 in the embodiment of FIG. 10 is of a smaller diameter and may be in a range of ½-¾ inch or preferably about ⅝ inch in diameter. This provides a wear surface depth W 1 that may be on the order of 1.25 inch. FIG. 10B illustrates the resilient pad having been reversed so that the worn surface 43 is now facing upwardly and the new second wear surface 44 is in a position for ground engagement. This provides a wear surface depth W 2 of 0.875 inch.
The arrangement illustrated in FIGS. 10A and 10B allows for a smaller diameter support pin 38 to be used as indicated previously. This may be on the order of 0.625 inch in diameter. This, in turn, allows for a reduction in the amount of rubber that need be used while still offering a double-sided rubber construction that provides for two useful wearing surfaces illustrated as surfaces 42 and 44 . The first wear surface depth W 1 in FIG. 10A is on the order of 1.25 inch and the opposite surface illustrated in FIG. 10B is on the order of 0.875 inch. This is possible as a result of not having to clamp as much rubber in the pin 38 area.
Reference is now made to FIGS. 11-13 for a schematic illustration of the manner in which the resilient pad of the present invention is readily reversible. FIG. 11 is a perspective view illustrating the resilient pad 34 with its associated clamping bars 50 . The support pins 38 extend through the resilient pad 34 as well as through the holes 56 in the clamping bars 50 . As indicated previously, the pins 38 may be loose fit in the resilient pad or may be force fit therein.
FIG. 12 is an exploded perspective view illustrating the reversal of the position of the resilient pad by means of arrow 62 . The two clamping bars 50 may be readily disengaged from the resilient pad as in the direction of arrows 63 . The resilient pad 34 may then be reversed in position. Lastly, FIG. 13 is a perspective view illustrating one side of the worn side 43 facing upwardly while the clamping bars 50 have been re-engaged with the support pins 38 so that the assembly shown in FIG. 13 is now ready for re-engagement with the pocket in the mounting plate 14 .
The foregoing has been a detailed description of illustrative embodiments of the invention. Various modifications and additions can be made without departing from the spirit and scope of this invention. Each of the various embodiments described above may be combined with other described embodiments in order to provide multiple features. Furthermore, while the foregoing describes a number of separate embodiments of the apparatus and method of the present invention, what has been described herein is merely illustrative of the application of the principles of the present invention. For example, bolts having hex-shaped heads and corresponding hex nuts are depicted for securing the resilient pad within the mounting plate. However, any appropriate securing member can be employed for securing the pad within the mounting plate. Furthermore, the sizing and exemplary numbers used herein are for illustrative and exemplary purposes only. The teachings are clearly applicable to all types of resilient pad structures retained within a pocket formed of a weldment. Accordingly, this description is meant to be taken only by way of example, and not to otherwise limit the scope of this invention.
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A stabilizer pad structure for supporting earth moving equipment is provided. A weldment is formed of metal plate material that is adapted for connection with a stabilizer arm of earth moving equipment. The weldment includes a mounting plate that defines a pocket, that can be integrally formed with the weldment or a separate material plate secured thereto, for receiving the resilient pad. The structure includes a pair of clamping bars disposed in the pocket, one on each side of the resilient pad. The clamping bars and mounting plate include respective engagement elements for interlocking the clamping bar and mounting plate together. This inhibits the clamp bars from movement in a longitudinal direction, and transfers force from the pad, through the clamp bar, to the mounting plate.
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FIELD OF THE INVENTION
The invention provides an absorbent article having a multi-tone signal of at least one color. The effect of the multi-tone signal creates a perception of depth by a user viewing the topsheet surface of the absorbent article.
BACKGROUND OF THE INVENTION
Printing on or below the top surface of an absorbent article is known in the art. Printing to create a signal that masks stains is also known. Overcoming the problem of unsightly stain during, for example, a woman's menstrual period has been disclosed. What has not been disclosed or taught is the use of multi-toned printing to create a signal that provides a perception of depth to an absorbent article when the article is viewed from its top or viewing surface. By creating a perception of depth within the absorbent article a user is reassured prior to use and during use that fluid will be drawn deep inside the product and away from a user's body.
Through the use of innovative topsheet materials, secondary topsheet materials, absorbent gelling materials and breathable backsheets, the technology in absorbent articles, and particularly sanitary napkins, has drastically advanced to provide women with more than adequate, if not excellent, products that absorb menses and other fluids away from a woman's body. However, much of this technology is often hidden and therefore not viewable. When seen, absorbent components often do not readily or visually communicate to a user the existence of this enhanced technology.
The ability to communicate to a consumer the existence of enhanced functioning of an absorbent article is a premium asset to any absorbent article. Hence, the use of the multi-toned signals has been created to begin to address the problem of such communication. This is especially so since mostly all of the products on the market today have as their main function the objective to mask menses rather than conveying the product's enhanced functioning power. The art is replete with examples of the use of a one-tone signal for such masking.
Communicating enhanced functioning characteristics by creating the perception of depth within an absorbent article is one unique and novel way to solve this problem, that prior to this reduction to practice has not been taught, suggested or disclosed by the prior art. Using multiple tones (i.e., at least two) of a color and/or multiple tones and multiple colors together to create a perception of depth can engender in a user the perceived belief of better protection and enhanced functioning by creating the perception of depth once a user has viewed the multi-tone configuration from the viewing surface of the absorbent article, such perception continuing through and after wear of the absorbent article.
SUMMARY OF THE INVENTION
Accordingly, the invention provides an absorbent article having an upper surface, a lower surface and a periphery comprising a topsheet having a bottom surface and a viewing surface positioned opposite to the bottom surface. The viewing surface faces upwardly towards the upper surface of the absorbent article. The absorbent article further comprises a backsheet having a garment facing surface and a user facing surface positioned oppositely to the garment facing surface, the backsheet being joined to the topsheet.
An absorbent core having a top surface and a bottom surface that is positioned opposite to the top surface. The absorbent core is positioned between the topsheet and the backsheet. The viewing surface of the absorbent article preferably, but not necessarily, has at least two portions, i.e., a colored portion and a non-colored portion. The colored portion and the non-colored portion are viewable from the viewing surface of the topsheet. The colored portion has at least two shades, a first shade and a second shade. The first shade is positioned substantially within the second shade. The second shade is different, either in lightness, darkness, and/or color, from the first shade. The multi-shades operate to create a perception of depth within the absorbent article by a user looking upon the viewing surface of the topsheet. In one embodiment herein, the first shade of the color is darker than the second shade of the color. Alternatively, the first shade is lighter than the second shade.
The color of the first shade and the second shade of the colored portion and the non-colored portion are measured by reflectance spectrophotometer ASTM standard test methodology. Tristimulus L*, a*, b* values are measured from the viewing surface of the topsheet inboard of the absorbent article's periphery. These L*, a*, b* values are reported in terms of the CIE 1976 color coordinate standard The color differences between the colored portion and the non-colored portion are measured at a first point, a second point, and a third point on the viewing surface of the topsheet inboard of the periphery of the absorbent article. Preferably, each one of the points noted (i.e., 1, 2 and 3) resides fully within the periphery of the absorbent core. For example, the first point is measured within the first shade, the second point is measured within the second shade, and the third point is measured within the non-colored portion of the absorbent article. The color differences are calculated according to method ASTM D2244-99 “Standard Test Method for Calculation of Color Differences from Instrumentally Measured Color Coordinates.”
The difference in color (i.e., ΔE*) between the first shade and the second shade should be at least 3.5. The ΔE* is calculated by the formula ΔE*=[(L* X. −L* Y ) 2 +(a* X. −a* Y ) 2 +(b* X −b* Y ) 2 ] 1/2 . X may represent points 1, 2 or 3. Y may represent points 1, 2 or 3. X and Y should never be the same two points of measurement at the same time. In other words, X≠Y. The difference in color between the first shade and the non-colored portion is at least 6. The difference in color between the second shade and the non-colored portion is at least 3.5. Preferably, the size of the colored portion ranges from about 5% to about 100% of the viewing surface of the topsheet. Also preferably, the first shade of the colored portion is positioned substantially centrally in relation to the second shade of the colored portion. However, so long as the shades are in proper spatial relationship to one-another such that the depth perception phenomena is created, any suitable positioning of the shades is suitable and foreseeable by one of skill in the art and are therefore acknowledged as suitable alternative embodiments of the invention.
In one embodiment herein, the colored portion may be an insert positioned between the topsheet and the absorbent core. In another embodiment, the colored portion forms a part of the topsheet. In yet another embodiment herein, the colored portion forms a part of the absorbent core whereby the colored portion is viewable from the viewing surface of the topsheet. Alternatively, the colored portion may be a multi-layered insert positioned beneath the topsheet.
Any topsheet material that allows the colored portion to be readily seen from the viewing surface of the topsheet is suitable. For example, formed film material, nonwovens, other topsheet materials known in the art or combinations thereof are suitable.
In an alternative embodiment herein, the absorbent article provides a colored portion and is substantially without a non-colored portion. The colored portion is viewable from the viewing surface of the topsheet and has at least two shades, a first shade and a second shade. The first shade is positioned substantially within the second shade, the second shade being different from the first shade. The at least two shades operate to create a perception of depth within the absorbent article by a user looking upon the viewing surface of the topsheet.
BRIEF DESCRIPTION OF THE DRAWINGS
While the specification concludes with claims particularly pointing out and distinctly claiming the subject matter which is regarded as forming the present invention, it is believed that the invention will be better understood from the following descriptions which are taken in conjunction with the accompanying drawings in which like designations are used to designate substantially identical elements, and in which:
FIG. 1 is a perspective drawing of the absorbent article;
FIG. 2 is a planar view of the absorbent article of FIG. 1 ;
FIG. 3 is a planar view of an alternative embodiment of FIG. 1 ; and
FIG. 4 is a planar view of the proper testing form of the absorbent article of FIG. 1 .
DETAILED DESCRIPTION OF THE INVENTION
“Absorbent articles” as referred to herein are primarily sanitary napkins, pantiliners, or incontinence pads that are worn in the crotch region of an undergarment. It is even conceivable that baby diapers, adult incontinence diapers, and human waste management devices benefit from the present invention even though they are conventionally not worn in conjunction with an undergarment.
The term ‘color’ as referred to herein include any primary color, i.e., white, black, red, blue, violet, orange, yellow, green, and indigo as well as any declination thereof or mixture thereof. The term ‘non-color’ or ‘non-colored’ refers to the color white which is further defined as those colors having an L* value of at least 90, an a* value equal to 0±2, and a b* value equal to 0±2.
The term ‘disposable’ is used herein to describe absorbent articles that are not intended to be launched or otherwise restored or reused as absorbent articles (i.e., they are intended to be discarded after a single use and, preferably to be recycled, composted or otherwise disposed of in an environmentally compatible manner).
Non-limiting examples of panty liners and sanitary napkins which may be provided with a multi-tone signal that operates to create depth perception include those manufactured by The Procter & Gamble Company of Cincinnati, Ohio as: ALWAYS® Pantiliners with DriWeave® manufactured according to U.S. Pat. Nos. 4,324,246; 4,463,045; and 6,004,893; ALWAYS® Ultrathin Slender Maxi with Wings manufactured according to U.S. Pat. Nos. 4,342,314, 4,463,045, 4,556,146, B1 4,589,876, 4,687,478, 4,950,264, 5,009,653, 5,267,992, and Re. 32,649; ALWAYS® Regular Maxi; ALWAYS® Ultra Maxi with Wings; ALWAYS® Maxi with Wings; ALWAYS® Ultra Long Maxi with Wings; ALWAYS® Long Super Maxi with Wings; and ALWAYS® Overnight Maxi with Wings, each aforesaid publication being incorporated by reference herein.
FIG. 1 provides a perspective view of the absorbent article 10 . FIG. 2 provides a planar view of the absorbent article of FIG. 1 . The absorbent article 10 herein has an upper surface 13 , a lower surface 14 (not seen) and a periphery 12 comprising a topsheet 25 having a bottom surface 27 (not shown) and a viewing surface 28 positioned opposite to the bottom surface 27 . The viewing surface 28 faces upwardly towards the upper surface 13 of the absorbent article 10 . The absorbent article 10 further comprises a backsheet 15 (not shown) having a garment facing surface 16 (not shown) and a user facing surface 17 (not shown) positioned oppositely to the garment facing surface 16 , the backsheet 15 being joined to the topsheet 25 .
The absorbent article 10 also comprises an absorbent core 20 having a top surface 21 and a bottom surface 22 (not shown) that is positioned opposite to the top surface 21 . The absorbent core 20 is positioned between the topsheet 25 and the backsheet 15 . In the embodiment shown in FIG. 1 the absorbent article 10 has at least two portions, i.e., a colored portion 40 and a non-colored portion 50 . The colored portion 40 and the non-colored portion 50 are viewable from the viewing surface 28 of the topsheet 25 . The colored portion 40 has at least two shades, a first shade 42 and a second shade 44 . Preferably, but not necessarily, and as is shown in FIG. 1 , the first shade 42 is positioned substantially within the second shade 44 . The second shade 44 is different, either in lightness, darkness, and/or color, from the first shade 42 . The multi-shades operate to create a perception of depth within the absorbent article by a user looking upon the viewing surface 28 of the topsheet 25 . In one embodiment herein, the first shade 42 of the color is darker than the second shade 44 of the color. Alternatively, the first shade 42 is lighter than the second shade 44 . The lightness and darkness of the shades, whether two or greater than two shades, are configured to create a perception of depth by a user looking upon the viewing surface 28 of the absorbent article 10 .
The color of the first shade 42 and the second shade 44 of the colored portion 40 and the non-colored portion 50 are measured by the reflectance spectrophotometer according to the colors' L*, a*, and b* values. The L*, a*, and b* values are measured from the viewing surface 28 of the topsheet 25 inboard of the absorbent article's periphery 12 . The color differences between the colored portion 40 and the non-colored portion 50 are measured at a first point 100 , a second point 110 , and a third point 120 on the viewing surface 28 of the topsheet 25 inboard of the periphery 12 of the absorbent article 10 . Preferably, each one of the points 100 , 110 , and 120 resides fully within the periphery 12 of the absorbent core 20 . For example, the first point 100 is measured within the first shade 42 , the second point 110 is measured within the second shade 44 , and the third point 120 is measured within the non-colored portion 50 of the absorbent article 10 .
The color differences are calculated using the L*, a*, and b* values by the formula ΔE=[(L* X. −L* Y ) 2 +(a* X .−a* Y ) 2 +(b* X −b* Y ) 2 ] 1/2 . Herein, the ‘X’ in the equation may represent points 1, 2 or 3. Y may represent points 1, 2 or 3. X and Y should never be the same two points of measurement at the same time. In other words, X≠Y. Where greater than two shades of a color(s) are used, the ‘X’ and ‘Y’ values alternately include points of measurement in them also. The key to the ΔE calculation herein is that the ‘X’ and ‘Y’ values should not stem from the same measured point on the viewing surface. In those instances where there is effectively no non-colored portion 50 within the confines of the measurement area, the ‘X’ values should flow from a point different in spatial relationship to the ‘Y’ values, but within the confines of the absorbent core periphery (see FIG. 4 ).
The difference in color (ΔE*) between the first shade 42 and the second shade 44 should be at least 3.5. The difference in color between the first shade 42 and the non-colored portion 50 is at least 6. The difference in color between the second shade 44 and the non-colored portion 50 is at least 3.5.
“Preferably, to size of the colored portion 40 ranges from about 5% to about 100% of the viewing surface 28 of the topsheep 25 . Also preferably, the first shade 42 of the colored portion 40 is positioned substantially centrally in relation to the second shade 44 of the colored portion 40 . However, so long as the shades are in proper spatial relationship to one-another such that to depth perception phenomena is created, any suitable positioning of the shades is foreseeable by one of skill in the art and are therefore acknowledged as suitable alternative embodiments of the invention.”
In one embodiment herein, the colored portion 40 may be an insert positioned between the topsheet 25 and the absorbent core 20 . In another embodiment, the colored portion 40 forms a part of the topsheet 25 . In yet another embodiment herein, the colored portion 40 forms a part of the absorbent core 20 whereby the colored portion 40 is viewable from the viewing surface 28 of the topsheet 25 . Alternatively, the colored portion 40 may be a multi-layered insert positioned beneath the topsheet 28 .
Any topsheet material that allows the colored portion to be readily seen from the viewing surface 28 of the topsheet 25 is suitable. For example, formed film material, nonwovens, or combinations thereof are suitable.
In an alternative embodiment herein, the absorbent article 10 provides a colored portion 40 wherein the viewing surface 28 of the topsheet 25 is substantially without a non-colored portion. By the term ‘substantially without a non-colored portion’ it is meant herein that color white is less than or equal to 5% of the total surface area of the viewing surface 28 . FIG. 3 provides an absorbent article wherein the first shade 42 is lighter and the second shade 44 is darker.
Also alternatively is an embodiment in which a color different from the color of the first shade 42 and the second shade 44 operates as a boundary between the two shades. In other words, this boundary 48 (not shown) rings the outer perimeter of the second shade 44 and separates the second shade 44 from the first shade 42 .
Analytical Methodology—Hunter Color
The color scale values, utilized herein to define the darkness/lightness of the materials of the absorbent articles according to the present invention, is the widely accepted CIE LAB scale. Measurements are made with a Hunter Color reflectance meter. A complete technical description of the system can be found in an article by R. S. Hunter, ‘photoelectric color difference Meter’, Journal of the Optical Society of America, Vol. 48, pp. 985-95, 1958. Devices specially designed for the measurement of color on the Hunter scales are described in U.S. Pat. No. 3,003,388 to Hunter et al., issued Oct. 10, 1961. In general, Hunter Color “L” scale values are units of light reflectance measurement, and the higher the value is, the lighter the color is since a lighter colored material reflects more light. In particular, in the Hunter Color system the “L” scale contains 100 equal units of division. Absolute black is at the bottom of the scale (L=0) and absolute white is at the top of the scale (L=100). Thus in measuring Hunter Color values of the materials used in the absorbent articles according to the present invention, the lower the “L” scale value, the darker the material. The absorbent articles herein, and hence the materials of which the absorbent articles are made of, might be of any color provided that the L Hunter value defined herein is met.
Colors can be measured according to an internationally recognized 3D solid diagram of colors where all colors that are perceived by the human eye are converted into a numerical code. The CIE LAB system is similar to Hunter L, a, b an is based on three dimensions, specifically L*, a*, and b*.
When a color is defined according to this system L* represents lightness (0=black, 100=white), a* and b * independently each represent a two color axis, a* representing the axis red/green (+a=red, −a=green), while b* represents the axis yellow/blue (+b=yellow, −b=blue). FIG. 4 shows the proper representation of the L, a, and b axes.
A color may be identified by a unique ΔE value (i.e., different in color from some standard or reference), which is mathematically expressed by the equation:
Δ E *=[( L* X .−L* Y ) 2 +( a* X .−a* Y ) 2 +( b* X −b* Y ) 2 ] 1/2
‘X’ represents the standard or reference sample which may either be a ‘white’ sample or a ‘colored’ sample, e.g., one colored shade may be compared to another colored shade.
It is to be understood that the tristimulus color values and ΔE* considered herein are those measured on the materials of interest (e.g., the colored and non-colored portions on the viewing surface of the topsheet disclosed herein).
The Hunter color meter quantitatively determines the amount (percent) of incident light reflected from a sample onto a detector. The instrument is also capable of analyzing the spectral content of the reflected light (e.g., how much green is in the samples). The Hunter color meter is configured to yield 3 values (L*, a*, b* and ΔE* which is total color). The L* value is simple the percent of the incident (source) light that is reflected off a target sample and onto the detector. A shiny white sample will yield an L* value near 100 while a dull black sample will yield an L* value of about 0. The a* and b* value contains spectral information for the sample. Positive a* value indicates the amount of green in the sample.
Testing is conducted using a Lab Scan XE 45/0 geometry instrument to measure the different shaded options for the visual signal zone. The Hunter Color in CIE lab scale 2° C. was measured on each pad in 3 portions. A 0.7 inch diameter port was used having a 0.50 inch area view, which was the largest size able to measure each zone discretely; i.e., this 0.5 inch area view is important for the purposes these measurements and should not be made smaller than the 0.5 inch area view prescribed. The instrument was calibrated using standard white and black tiles supplied by the instrument manufacturer.
Color Zone Measurement for Pad Topsheet Appearance
For measuring the L*, a*, and b* values for the invention herein, a standard, industry-recognized procedure is used. The topsheet color is measured using a reflectance spectrophotometer in accordance with method ASTM E 1164-94, “Standard Practice for Obtaining Spectrophotometric Data for Object-Color Evaluation”. This standard method is followed but specific instrument settings and sampling procedure are given here for clarity. Sample color is reported in terms of the CIE 1976 color coordinate standard as specified in ASTM E 1164-94 and ASTM D2264-93, section 6.2. This consists of three values; L* which measures sample “lightness”, a* which measures redness or greenness, and b* which measures yellowness or blueness.
Apparatus
Reflectance Spectrophotometer . . . 45°/0° Hunter Labscan XE, or equivalent HunterLab Headquarters, 11491 Sunset Hills Road, Reston Va. 20190-5280 Tel: 703-471-6870 Fax: 703-471-4237 http://www.hunterlab.com.
Standard plate . . . Sandard Hunter White Tile Source: Hunter Color.
Equipment Preparation
1. Assure that the Spectrophotometer is configured as follows:
Illumination . . . Type C Standard Observer . . . 2° Geometry . . . 45/0° Measurement angle Port Diameter . . . 0.70 inch Viewing area . . . 0.50 inch (and no smaller) UV Filter: Nominal
2. Calibrate the spectrophotometer using standard black and white tiles supplied with the instrument according to manufacturer's instructions before beginning any testing.
Sample Preparation
1. Unwrap, unfolded and lay the product or pad samples flat without touching or altering the color of the body facing surface. 2. Areas on the body-facing surface of the product should be selected for measurement and must include the following:
The non-colored portion of the topsheet. The colored portion of the topsheet; including the two or more shaded portions. Any other portions of the topsheet above the absorbent core having a visibly or measurably different color from the first shaded zone. Embossed channels and folds should not be included in zones of measurement as they may skew the proper results. Measurements should not be made overlapping the border of two shaded portions.
Test Procedure
1. Operate the Hunter Colorimeter according to the instrument manufacturer's instructions.
2. Pads should be measured laying flat over the 0.70 inch aperture on the instrument. A white tile should be placed behind the pad.
3. The pad should be placed with its long direction perpendicular to the instrument.
4. Measure the same zones selected above for at least 3 replicate samples.
Calculation Reporting
1. Ensure that the reported results are really CIE L*,a*,b*.
2. Record the L*,a*,b* values to the nearest 0.1 units.
3. Take the average L*, a*, b* for each zone measured.
4. Calculate ΔE* between different shaded portions and ΔE* between each shaded portion and the non-colored portion where the non-colored portion exists.
Human Sensitivity to Light
The human sensitivity threshold for the lightness of a dark green color is a ΔE* of about 1.0. For a dark green color, if only the a* and b* change, human sensitivity is a ΔE* of 2.4. In the context of an absorbent article herein (e.g., a sanitary napkin) it is highly likely that many people would not see a color difference if the ΔE* is less than 2. This sensitivity is described in the following reference: “The Measurement of Appearance”, by Hunter and Harold, 2nd edition, 1987, (ISBN 0-471-83006-2).
Chapter 4 of Hunter's book describes human color sensing and chapter 9 is about color scales. By making side-by side comparison, humans can differentiate up to 5 to 10 million different colors. In the 1940s, a researcher named MacAdam did human chromaticity discrimination experiments. He found the thresholds of sensitivity and showed these depend on the color. Later work by Brown and MacAdam came up with a logarithmic lightness dimension scale for human sensitivity to go with the earlier color scale. Based on the reduction to practice of the invention, experimentation and the foregoing work by Brown and MacAdam, it has been found herein that a ΔE≧3.5 is the preferred range to effect proper differentiation between the shades that provides the proper appearance of depth. However, where the ΔE is as small as about 1 and still operates to provide a perception of depth between the shades, this ΔE is also contemplated and included herein. An example where ΔE may be between at last two shades of one or more colors may be found in an alternative embodiment that provides a multi-color and/or shade gradient of a color across the viewing surface of the absorbent article.
CHART I
Sample
Topsheet
Colored
Number
Type
Options
ΔE* 23
ΔE* 12
ΔE* 13
1
Formed Film
Two-tone
6.10
10.83
16.86
inner/outer color
2
Formed Film
One-tone color
0.25
8.60
8.80
3
Non-woven
One-tone color
0.22
10.63
10.81
4
Non-woven
Two-tone
5.98
11.03
16.92
inner/outer color
5
Formed Film
Two-tone light
10.01
2.88
12.80
outer color/inner
dark color
6
Formed Film
Two-tone medium
7.51
6.37
13.61
outer color/inner
dark color
7
Formed Film
Two-tone darker
5.60
19.16
14.22
outer color liner
dark color
8
Formed Film
Two-tone
4.58
6.00
8.06
(secondary
topsheet colored
outer color)/(core
colored dark color)
9
Formed Film
One-tone outer
0.21
8.90
8.84
color
As has been noted previously, the difference in color between the first shade and the second shade should be at least 3.5. The difference in color between the first shade and the non-colored portion is at least 6. The difference in color between the second shade and the non-colored portion is at least 3.5. Through experimentation and reduction to practice of the invention, it has been determined that the preferred creation of depth perception happens at about and above these set parameters. For products substantially not having a non-colored portion within the measurement zone (i.e., a gradient or fully colored product), the above criteria for the shaded portions (i.e., ΔE*≧3.5) remains the preferred standard.
Chart I above clearly shows the ΔE*s obtained between multi-tone (e.g., two tone) and single tone signals. Formed films and nonwovens useful for the invention herein are those which will allow the sufficient penetration of light therethrough such that the shaded portions may be clearly discerned and such that such discernment produces the depth perception effect. The color may be any suitable color fitting within the parameters herein for ΔE* between colored portions and non-colored portion (where it exists). For example, the colors green, blue, red, yellow, orange, purple and any other color within the color spectrum are suitable for the purposes described herein.
Sample Nos. 1 and 2 are clearly distinct in their ΔE* 23 . Specifically, the ΔE* 23 (which is 6.10) is greater than 3.5. This ΔE 23 indicates that there is a perceptible difference in color or lightness/darkness between the two points of measurement; i.e., between the second shaded portion and the non-colored (or white) portion (see FIG. 4 ). As noted above for human perception, Sample No. 2's ΔE*23 of 0.25 would not be perceptible to the human eye. This indicates that the signal is only a one or single tone signal (i.e., color portion).
The disclosures of all patents, patent applications (and any patents which issue thereon, as well as any corresponding published foreign patent applications), and publications mentioned throughout this patent application are hereby incorporated by reference herein. It is expressly not admitted, however, that any of the documents incorporated by reference herein teach or disclose the present invention. It is also expressly not admitted that any of the commercially available materials or products described herein teach or disclose the present invention.
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The absorbent article provides a signal viewable from the top surface of the absorbent article that gives a perception of depth within the absorbent article. This creation of depth perception is accomplished by the use of at least two tones within a color and/or by the use of multiple tones and multiple colors operating together to create a perception of depth within the absorbent article.
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CROSS REFERENCE TO RELATED APPLICATIONS
This application is a divisional of U.S. patent application Ser. No. 12/706,057, filed Feb. 16, 2010, which application claims priority to U.S. provisional patent application Ser. No. 61/617,750, filed Apr. 8, 2009, each of which is incorporated herein in its entirety by this reference thereto.
BACKGROUND OF THE INVENTION
1. Technical Field
The invention generally pertains to ink jet printers, and particularly, to such printers using a binary imaging solution and multiple drop size ink jet print head technology.
2. Description of the Prior Art
A binary imaging solution uses colorants that each comprise a mixture of two ink components, where the two components are combined at the time the colorant is applied to a recording surface. Traditionally, to use a binary imaging solution in an ink jet printer, one channel of colorant per channel of reactant is used to ensure proper mixture of the two-part solution. This implementation, although feasible, has never really seen wide range adoption due to the cost associated with ink jet print head assemblies. In effect, this implementation would require double the number of print heads as compared to a uniary imaging solution.
As the demand for higher print quality and speeds has progressed in digital ink jet printing, print head technology has progressed in kind, starting from airbrush technology, having print resolutions of 4-9 dpi, to the newer drop-on-demand ink jets, having print resolutions up to 2400 dpi. At the older resolutions of sub-10 dpi it did not take many print heads to deliver acceptable printing speed considering that the size of the printed dot was 1/10 of an inch. Now consider that to generate images in the range of 1200 dpi the drop size would need to be 1/1200 of an inch. When working with drop sizes so small it takes many more drops to get an acceptable fill pattern when working with solid colors. This can only be accomplished in one of two ways: populate more ink jets into the product to increase coverage per pass of the print head array; or interlace many more print head passes of the print head array with the same number of print heads.
The first option would drive up printer cost to an unacceptable level, while the second option would drop productivity to unacceptable levels.
With the advancement in print head technology into grey scale functionality, the print head technology for grey scale functionality has provided an answer to this issue. These print heads generate multiple drop sizes from the same nozzle assembly. Therefore, one can generate a larger drop size when a good solid fill pattern is needed and a smaller drop size when higher detail is needed.
Prior to the introduction of grey scale print head technology the application of a binary imaging fluid was somewhat hampered also. For example, a traditional ink jet printer may have four color channels, including Cyan, Magenta, Yellow and blacK (CMYK). Other color channels employing colors such as White, Blue, Red, Orange and Green may also be used to increase functionality and color gamut. For these examples it is assumed that a printer uses seven color channels, one each for Cyan, Magenta, Yellow, blacK White, Blue, and Red, (CMYKWBR).
In traditional methods, for the application of binary solutions one of two options is selected. The first option is to use only one channel of reactant (CMYKWBRr), whereby one drop of reactant is applied to a location in an ‘OR’ methodology, where it would be applied to any drop location that is slated to receive, or already has received, a colorant drop. This method, although acceptable for a surface preparation type of implementation or an over coating application, is not effective for accurate metering of the binary mixture ratio. This is because each printed location could have anywhere from one to seven colorant drops placed in that location and only one drop of reactant. The ratio of reactant to colorant drops, assuming similar drop sizes, could be anywhere from 1:7 to 1:1. This is the method taught by Allen (U.S. Pat. No. 5,635,969), whereby the reactant channel is used as a pre coat for the colorant to control dot gain and other print artifacts.
A second option would be to have one channel of reactant per channel of colorant to provide for accurate mixing of the solution (CrMrYrKrWrBrRr). To provide the same speed and functionality as the previous example it would require 14 separate channels to provide accurate ratio metering at speed. This method is taught by Vollert (U.S. Pat. No. 4,599,627), whereby every drop of colorant is matched to a single drop of reactant to ensure a consistent ratio.
Although this solution is functional in providing an accurate mixture of the binary solutions in a controlled ratio, it is largely cost prohibitive due to the volume of additional print heads needed and ancillary equipment needed to support them as compared to uniary print systems.
Thus, a heretofore unaddressed need exists in the industry to address the aforementioned deficiencies and inadequacies in connection with binary imaging.
SUMMARY OF THE INVENTION
An embodiment of the invention comprises a method and apparatus for applying a binary imaging solution to a print media in such a way as to provide for accurate ratio metering of two parts of the imaging solution. By exploiting grey scale print head technology in the application of binary imaging solutions to a medium, it is possible to meter a more precise mixture ratio of the two parts with the addition of only one or possibly two jetting channels of reactant for multiple color channels.
In the preferred embodiment of the invention, the ink jet printer may have, for example, seven color channels including Cyan, Magenta, Yellow, blacK, White, Blue, and Red, and one or two channels for reactant (rCMYKWBRr') or (rCMYKWBR). Metering of the proper ratio of colorant to reactant is accomplished by calculating a summed total volume of colorant drops applied to a particular location and adjusting the drop sizes generated by the reactant channel, or both channels in the case of multiple channels, to apply the proper mixture ratio of the solutions. The use of multiple channels, for example, two channels also aids in the mixing of the solutions by adjusting the order in which the colorants and reactant are applied to the drop location.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 is a perspective view of a printing system in accordance with the invention;
FIG. 2 is a schematic view of a carriage of the printing system of FIG. 1 having a plurality of print heads and one reactant channel in accordance with the invention;
FIG. 3 is a schematic view of a carriage of the printing system of FIG. 1 having a plurality of print heads and multiple (n) reactant channels in accordance with the invention; and
FIG. 4 is a simplified functional block diagram illustrating an algorithm that inputs the printing of a volume of multiple colorants, sums it, multiplies it with a mixture ratio to reactant, and determines the volume to be deposited via each reactant channel in accordance with the invention.
DETAILED DESCRIPTION OF THE INVENTION
An embodiment of the invention comprises a method and apparatus for the precise metering of a binary imaging solution to each pixel location of an ink jet image on a substrate. The two parts of the binary imaging solution, when combined in the proper ratio, initiate a chemical curing reaction the causes the fluid to transform into a solid or near solid state in a predetermined amount of time. Additionally the chemical reaction of the two fluids causes the material to bond with the substrate and allow for consistent adhesion and imaging characteristics.
FIG. 1 shows a printing system, generally identified as 1 , provided with a carriage 4 . The bottom surface of the carriage holds a series of grey scale ink jet print heads configured for printing images on a variety of substrates. Typical substrates include both flexible and non-flexible substrates, such as textiles, polyvinyl chloride (PVC), reinforced vinyl, polystyrene, glass, wood, foam board, and metals.
In addition to the carriage 4 , the printing system 1 includes a base frame 2 , a substrate transport belt 3 that is used to transport a substrate 23 ( FIG. 2 ), which is held to the top of the transport belt 3 through the depth of print platen area 7 , and a rail system 5 that is attached to the base frame 2 . The carriage 4 is transported along the rail system 5 , thus providing a motion path oriented perpendicular to the substrate transport direction and parallel to the surface of the print platen area 7 . The carriage motion along the rail system 5 is facilitated by an appropriate motor drive system, thus allowing it to traverse the width of the print platen area 7 at a reasonably controlled rate of speed. Accordingly, the transport belt 3 intermittently moves the substrate 23 ( FIG. 2 ) through the depth of the print platen area 7 in such a way that the carriage 4 is allowed to traverse back and forth over the substrate 23 ( FIG. 2 ) and deposit imaging solution droplets onto the substrate 23 ( FIG. 2 ) via a series of multiple drop size, also referred to as grey scale, ink jet print heads 14 ( FIG. 2 ).
Grey scale print heads 14 typically have a native drop volume, which is the smallest drop volume that can be deposited by the head. These print heads facilitate the application of variable drop sizes to the substrate 23 in a particular pixel location by applying multiples of the native drop volume to a pixel location.
For example, if the native drop volume of a particular print head is 10 pico-liters (0.000000000010 liters) and has four grey levels, i.e. the native drop volume multiplied by 0, 1, 2, and 3, then the available drop sizes for that print head are 0 pl, 10 pl, 20 pl, and 30 pl, respectively.
After a carriage pass is completed and a portion of the image is applied to the substrate, the substrate is indexed, or stepped, again via the transport belt 3 and located accurately for the next pass of the carriage 4 and the next portion of the image to be printed. This process is repeated until the entire image is applied to the print substrate.
The series of print heads 14 ( FIG. 2 ) receives one or more colored imaging solutions (colorants) as well as one or more channels of reactant from a set of secondary fluid containers 12 ( FIG. 2 ) which are also mounted in the carriage 4 . In addition, a set of primary fluid containers 10 ( FIG. 2 ) supply the colorants and reactant to the secondary fluid containers. Unlike the secondary fluid containers 12 ( FIG. 2 ), the primary fluid containers 10 ( FIG. 2 ) are located remotely from the carriage 4 , for example, on a shelf 8 located on the frame structure 2 . The base frame 2 and rail system 5 is typically covered by a system of covers 6 for safety and aesthetic reasons.
FIG. 2 shows in more detail the fluid delivery path from primary fluid tanks 10 - 1 to 10 - 8 to a series of grey scale print heads 14 - 1 to 14 - 8 associated with each imaging fluid (both colorants and reactant) for a system with a single channel of reactant. The series of print heads 14 - 1 to 14 - 8 may contain a single print head or a plurality of print heads. Each series of print heads 14 - 1 to 14 - 8 is in fluid communication with its associated secondary fluid tank 12 - 1 to 12 - 8 via a manifold delivery system 13 - 1 to 13 - 8 . Likewise, the imaging fluids are delivered from primary fluid containers 10 - 1 to 10 - 8 to secondary fluid tanks 12 - 1 to 12 - 8 via a series of delivery tubing, filters, and pump systems illustrated in FIGS. 2 as 11 - 1 to 11 - 8 . Accordingly, by depositing various droplets of colorants and reactant onto the substrate 23 , which is held in place by the transport belt 7 , in the appropriate pixel locations, the desired image is formed. The fluids are combined on the substrate 23 through impingement mixing and allowed to cure chemically.
A fluid channel 22 is considered a single fluid path from start to finish including the primary fluid tank 10 , the delivery system 11 , the secondary fluid tank 12 , the manifold delivery system 13 , and an associated series of print heads 14 .
Note that the invention is not limited to the colors, number of color fluid channels, or color order and orientation illustrated in FIG. 2 . The colorant fluid channels and the reactant fluid channel orientation vary by application. Therefore, the orientation and order shown is for illustration purposes only. As shown in FIG. 3 , more than one reactant fluid channel can also be used, up to one less channel than the number of colorant fluid channels in use.
FIG. 4 shows a graphical representation of an algorithm to be executed in a computing device containing a processor and memory, both sized appropriately to accommodate the image size in question. This algorithm allows the computing device to determine the sum total volume of colorant that is to be applied to a pixel location by all the colorant channels and multiplies it by the mixture ratio to determine the proper volume of reactant to be applied to the same pixel location. If the volume of reactant is larger than the volume that can be applied by a single channel of reactant, or if a better granularity of the mixture ratio can be achieved by distributing the volume of reactant to different drop sizes across multiple channels, the algorithm distributes the volume of reactant accordingly.
The volume of each colorant 30 - 1 to 30 - 7 to be deposited to a particular pixel location is additively summed in function block 31 and represented by the variable sV for summed Volume. This summed volume (sV) is then multiplied in function block 32 by a proper mixture ratio (ra) to determine the total volume of reactant needed, represented by the variable rV. The proper mixture ratio (ra) is determined by the chemical properties of the binary printing solution and supplied by the manufacturer of said solution.
If the reactant channels in the printer are configured with print heads of the same drop volume, then the volume of reactant needed for the pixel location, represented by the variable rV, is then divided in function block 33 by the number of reactant fluid channels (rn) used in the printer system, resulting in the volume of reactant (Vr) to be deposited by each reactant channel 34 used in the printer.
The reactant channels in the printer may also be configured with print heads of different native drop volumes. If the printer is configured in this way then the volume of reactant to be deposited by each channel to a particular pixel location is adjusted according to the drop volumes of the print heads used in each channel. This configuration can be used to obtain the optimal granularity of mixture ratios possible with the given drop volumes delivered by various print heads.
Note that the invention is not limited to the colors, or number of colors in FIG. 4 , and more than one reactant fluid channel can also be used, up to one less channel than the number of colorant fluid channels used.
An important consideration in practicing the invention is the fact that the reactant is not a surface preparation material and may be deposited before, after, or in between colorant drops. As long as the droplets are given ample opportunity for impingement mixing, and the proper mixture ratio is achieved, the two components of the binary imaging solution may be applied in any order or, in some cases, depending on the characteristics of the imaging solution, portions of the colorant and reactant may be applied in a specific order to accelerate the impingement mixing.
Although the invention is described herein with reference to the preferred embodiment, one skilled in the art will readily appreciate that other applications may be substituted for those set forth herein without departing from the spirit and scope of the present invention. Accordingly, the invention should only be limited by the Claims included below.
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A multi-color ink jet printing system uses a two-part (Binary) imaging solution, where the precise mixture of the multiple fluid parts (Colorant(s) and Reactant) is controlled with the use of multiple drop size (Grey Scale) ink jet print heads. The precise mixture of colorant(s) and reactant initiates a chemical reaction, which cures the imaging solution into a solid or nearly solid compound that ensures proper drop location.
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FIELD OF INVENTION
[0001] This invention relates to a digester for human waste handling, treatment and disposal in mobile public carriers. In particular the invention provides an apparatus for efficient biodegradation of human waste and chemical treatment for safe environmental disposal.
BACKGROUND OF THE INVENTION
[0002] There are various types of organic pollutants that mostly comprise of human waste (night soil), animal waste, food and chemical industry wastes. These, if discharged to aquatic bodies are subjected to decomposition by natural microbial population which consumes the dissolved oxygen of the surroundings resulting in disturbance of aquatic flora and fauna. Among these wastes human waste is of high concern because of its aesthetic and environmental nuisance. Its deterioration starts even before it is discharged from the human body. Besides leading to organic pollution, it is a store house of pathogens and is responsible for various water borne diseases such as cholera, jaundice and typhoid.
[0003] Historically, humans used to defecate in open areas where it was left for drying/natural degradation. Subsequently, the human waste was physically transported to an isolated area earmarked for its natural degradation which was not only generating off odorous compounds but also polluting and contaminating the natural surroundings. With the development of civilization, researchers are continually searching for newer methods for safe disposal of human waste. At present there are various options being practiced in various parts of the world, which include physical transportation, chemical and biological treatment (U.S. Pat. No. 5,580,457). Transporting of wastes from high population density is a costly affair because of the high cost of land in the adjoining areas and operational cost associated if waste is removed to remote locations of low cost. This is particularly problematic if liquid waste is to be transported to the disposal site. Incineration of the waste is facing increasing public resistance due to the release of noxious gases and high costs. In general chemicals used to treat the waste do not completely degrade the human waste and as a result add to the environmental pollution.
[0004] Biodegradation is considered to be the most preferable way of treating the waste because of its self-sustainability, cost effectiveness and eco-friendliness. It is carried out in two different ways: aerobically and an aerobically. Aerobic process employs bacteria, which have ability to use oxygen in energy generation. Because of this ability the addition of oxygen or air to a bioreactor/digester can increase the aerobic population rapidly. This increase in population results in increased rate of biodegradation but unfortunately aerobic population becomes the sludge/pollutant. This sludge must be removed prior to discharge of treated material into the environment. Moreover, aerobic process is an energy intensive process requiring energy for aeration. On the other hand, anaerobic process employs bacteria, which grow strictly in the absence of air/oxygen. These bacteria are inhibited by oxygen rich environment. Anaerobic process does not essentially require the energy for its operation and the amount of sludge generated are comparatively very less because of lower biomass produced in absence of oxygen. The main products of anaerobic degradation include methane, carbon dioxide and hydrogen sulphide. Methane is primary component of natural gas and is readily combustible and thus can be burnt to produce energy without posing any significant environmental hazards. Moreover, anaerobic processes are known to inactivate the pathogens present in the human waste.
[0005] There are two kinds of human waste treatment systems. In the first kind all residences, businesses and the institutions in a municipality are connected through a network of sanitary sewers to a central sewage treatment plant. The second kind is the septic tank system mostly installed for single family where usually connection to a sewer is not available. However, there is no system/apparatus available, which can be used for human waste treatment in public carriers like train, bus, boat, aeroplane etc. for on-site treatment. The only option in these public transports is to collect the waste in a closed container and to transport it to the site of the treatment. To avoid the foul smell at the site of collection, chemicals are added to the collection which ultimately delay/retard the biodegradation process but create the problem at the site of biological treatment. In other words, this approach requires manpower, infrastructure and money for disposal of human waste generated in the public transport vehicles. Indian railway is the biggest public carrier in the world. Presently, there is no provision for storage collection and transportation of human waste generated during journey in the toilets is discharged on the rail tracks, thus creating aesthetic nuisance, foul smell, breeding place for insects and also the risks of various diseases because of the presence of pathogens. The situation is even more precarious at railway stations.
[0006] Therefore, there is a need of an apparatus (hereafter called as digester) which can be fitted onto a public transport vehicle and degrade the human waste for its safe disposal.
OBJECTS OF THE INVENTION
[0007] The primary object of the present invention is to provide a digester capable of biochemical degradation of the human waste.
[0008] Another object of the present invention is to provide a digester capable of anaerobic degradation of the human waste.
[0009] Yet another object of the invention is to perform the chlorination of the biologically treated waste to make it free from foul smelling compounds and pathogenic microorganisms.
[0010] Further, object of the present invention is to provide digester, which can be fitted onto a public transport vehicle without affecting the sitting capacity of the vehicle.
[0011] Still another object of the digester which is easy to use, maintain and cost effective.
[0012] Further object of the present invention is to provide digester, which is long lasting and resistant to the jerks and various environmental conditions.
[0013] Another object is that in the process is to design the self sustainable digester, i.e., the digester does not require any external energy for its operation.
[0014] Another object is that in the process of human waste treatment, repeated addition of bacteria is not required and one time addition of the inoculum is sufficient.
[0015] Yet another objective is to provide a digester, which can convert the human waste into odorless and inflammable biogas.
[0016] Another object of the present invention is to provide a matrix for immobilization of bacteria for maintaining them at high concentration for fast biodegradation.
[0017] Yet another object is to provide the biodegrading surface for bacterial attachment so that the digester can withstand washout of bacteria during excessive use of water by passengers.
SUMMARY OF THE INVENTION
[0018] In order to achieve the above mentioned objectives the present invention provides a digester for degradation of human waste comprising a main tank ( 1 ) having biochemical treatment compartment ( 2 ) and chemical treatment compartment ( 3 ) connected by connecting pipe ( 4 ) as a passage for biochemically treated waste to chemical treatment compartment; the biochemical treatment compartment having at least one loosely fitted partitioned wall ( 5 ) and at least one inlet ( 6 / 7 ) for receiving the wastes, at least one gas outlet pipe ( 9 / 10 ) and at least one waste drain pipe ( 11 / 12 ) to remove sludge; the chemical treatment compartment has discharge means ( 8 ) to discharge treated waste and excess of liquid, and float ball assembly ( 14 ) to release chemical for chemical treatment.
[0019] The loosely fitted partitioned walls ( 5 ) are open from above or below or combination thereof in the biochemical compartment.
[0020] The loosely fitted partitioned wall ( 5 ) are attached with PVC sheet on its at least one side. The inner side of ( 13 ) and the bottom of the biochemical compartment have also been attached with PVC sheets.
[0021] The connecting pipe ( 4 ) is inverted “L” shaped galvanized iron pipe.
[0022] The chemical treatment compartment ( 3 ) have float ball assembly ( 14 ) fitted onto lever to supply chemical for chemical treatment in the chemical treatment compartment. Further, the chemical used for chemical treatment is chlorine balls.
[0023] The discharge means ( 8 ) is a siphon.
[0024] The main tank ( 1 ) has groove ( 15 ) in the central top portion for supply lines connecting different railway compartments.
[0025] Further the main tank has at least four hooks and at least two inbuilt support. Moreover, at least two handles are provided at the top lid of the digester for maintenance.
DESCRIPTION OF THE DRAWINGS
[0026] The present invention will now be illustrated with the help of accompanying drawing, which illustrates an embodiment of the present invention. It is to be noted that the principles and features of the invention may be incorporated in different embodiments without departing from the scope of the present invention.
[0027] FIG. 1 : shows the isometric view of the digester.
[0028] FIG. 2 : shows the isometric inner view of the digester.
[0029] FIG. 3 : shows the isometric view of the digester.
DESCRIPTION OF THE INVENTION
[0030] The present invention will now be illustrated with the help of accompanying drawing, which illustrates embodiments of the present invention. It is to be noted that the principles and features of the invention may be incorporated in different embodiments without departing from the scope of the present invention.
[0031] In the first embodiment of the invention is provided a digester for continuous degradation of human waste by anaerobic bacteria. The digester has two chambers; one for biological degradation of human waste and second for chemical treatment. The digester is made up of stainless steel, rectangular in shape and is sufficient to treat the human waste of 35-40 persons. The tank is to be fitted on the bottom of the coach. It covers almost full width of the coach and has one central notch as passage for supply lines connecting different railway compartments. The waste, from toilets enters to one side of the digester through two inlet pipes where biological treatment is carried out. Polyvinyl chloride sheets attached on sides of the partition walls, bottom wall and on both sides of intermediary partitions serve as immobilization matrix for anaerobic microbial consortium to resist the washout of cultures and for better tolerance of microorganisms for adverse conditions like extremes of pH, VFA, and temperature. The fermented human waste enters the chlorination chamber via galvanized iron pipe. Chlorine balls are added to the waste through a float ball assembly connected through a pipe to a box containing chlorine balls. The effluent from chlorination tank is discharged out of the digester through a siphon arrangement. Biogas from the fermentation chamber is released continuously through gas pipes. Two drain outlets are provided on the bottom of the tank for maintenance of the digester.
[0032] Referring to FIG. 1 , the digester consists of one rectangular SS tank ( 1 ) having thickness of 3 mm with working volume of 650-750 L. The tank is divided into two chambers; one for biological treatment ( 2 ) and another for chemical treatment ( 3 ). The tank has dimensions of 2350-2500 mmL×650-750 mmW×575-625 mmD and has a groove of 475-525 mmL×650-750 mmW×175-225 mmD in the central top portion ( 15 ). The two submerged inlet pipes ( 6 , 7 ) of diameter 70-100 mm are meant for connecting the two opposing toilets of the coach to the tank. The fermentation chamber has four partition walls of 475-500 mm height across width of SS tank having a thickness of 2 mm ( 5 ). PVC sheets having a surface area 59 m 2 /g and thickness of 7-10 mm are provided on both sides of the partition walls ( 5 ) as well as on inner side walls ( 13 ) besides at the bottom of the biochemical treatment compartment. The chlorination tank ( 3 ) is made opposite to inlet side of the main tank by providing a SS wall. The dimensions of the chlorination tank are 190-210 mm×650-750 mm×575-625 mm. The partition between fermentation and chlorine tank contains an inverted ‘L’ shape galvanized iron pipe ( 4 ) of 35-40 mm diameter as passage for fermented waste to pass into the chlorination tank. Chlorination tank is fitted with a chlorine ball dispensing assembly ( 14 ) to dispense the chlorine balls one by one into the biologically treated waste. Chlorination assembly is meant for automatic addition of chlorine balls into the biologically treated waste. It is based on hydraulic movement of float ball fitted on to the lever connected to a wheel containing a notch for resting of one chlorine ball at a time. Chlorine balls are filled in a box outside the digester which is connected with the assembly through a tube. As the biologically treated waste water accumulates in the chlorination tank, the float ball of the chlorine assembly starts lifting up as a result the wheel of the assembly also starts rotating. After reaching a pre-set height the notch in the wheel gets away from the tube fills with chlorine balls, and thus the balls falls down. As the float ball lifts up further due to accumulation of the treated water, a stage comes when the outlet pipe ( 8 ) made of 12-17 mm diameter is filled completely with the treated water. This outlet pipe is designed to work like a siphon. At this stage siphon gets activated and results in complete discharge of the treated water from the chlorination chamber. After complete discharge of the treated water, the wheel and the float ball of the chlorination assembly come to their original position and get ready for another cycle of chlorine ball addition and discharge of the treated waste through activation of siphon. The digester has two gas outlet pipes ( 9 , 10 ) of 10-12 mm diameter, and waste drain pipes ( 11 , 12 ) of 35-40 mm diameter for maintenance purpose on either side.
[0033] In the second embodiment ( FIGS. 2 and 3 ) of the invention is provided a digester for continuous degradation of human waste by anaerobic bacteria. The digester is made of stainless steel (SS), rectangular in shape and is sufficient to treat the human waste of 15-20 persons. The tank is to be fitted on the bottom of the coach. The digester has two chambers; one for biological degradation of human waste ( 1 ), and second for chemical treatment ( 2 ). The waste from the toilet enters to one side of the digester through an inlet pipe ( 3 ) where biological treatment is carried out. Polyvinyl chloride (PVC) sheets attached on side walls, bottom wall and on both sides of intermediary partitions serve as immobilization matrix ( 4 , 5 ) for anaerobic microbial consortium to resist the washout of cultures and for better tolerance of microorganisms for adverse conditions like extremes of pH, VFA, and temperature. The fermented human waste enters the chlorination chamber ( 2 ) via galvanized iron (GI) pipe ( 6 ). Chlorine is added to the biologically treated waste through an inlet pipe ( 7 ) in the chlorination chamber ( 2 ). The effluent from chlorination tank is discharged out of the digester through an outlet pipe ( 8 ). Biogas from fermentation chamber is released continuously through a gas pipe ( 9 ). A window ( 10 ) is provided on the side of the fermentation chamber for maintenance, if required. Four hooks are provided with two inbuilt stainless steel support ( 11 ). Two handles ( 12 ) are provided on the top lid of the digester for maintenance.
[0034] The immobilization matrix in the form of PVC on partitions, bottom and sides for attachment of bacteria to prevent washout, having higher cell mass for enhanced fermentation, better tolerance of bacteria for adverse environmental conditions and to have better baffling. The submerged inlet pipes prevent the entry of foul smelling gases from the head space to the toilet. The maintenance Window on the side of fermentation chamber helps in removal of sludge and maintenance.
[0035] Referring to FIGS. 1 and 2 , the apparatus consists of one rectangular SS tank having thickness of 3 mm with working volume of 300-400 L. The tank is divided into two chambers; one for biological treatment ( 1 ) and another for chemical treatment ( 2 ). The tank has dimensions of 900-1000 mml×650-750 mmW×575-625 mmD. One submerged inlet pipe ( 3 ) of diameter 70-100 mm is meant for connecting the toilet of the coach to the tank. The fermentation chamber is divided into five sub-chambers, with the help of partition walls of 475-500 mm height having a thickness of 2 mm ( 4 , 5 ). PVC sheets having a surface area of 59 m 2 /g and thickness of 7-10 mm are provided on both sides of partition walls ( 4 ) as well as on inner side of side walls ( 5 ) besides at the bottom. The chlorination tank ( 2 ) is made alongside the inlet chamber by providing a SS wall. The dimensions of the chlorination tank are 190-210 mm×325-425 mm×575-625 mm. The partition between fermentation and chlorination tank contains an inverted ‘L’ shape GI pipe ( 6 ) of 50-60 mm diameter as passage for fermented waste to pass into the chlorination tank. Chlorination tank is fitted with an inlet pipe ( 7 ) connected with the chlorine dispensing assembly to dispense the chlorine into the biologically treated waste. The digester has one effluent discharge pipe ( 8 ) of 50-60 mm diameter. The digester has one gas outlet pipe ( 9 ) of 10-12 mm diameter, and a maintenance window ( 10 ) of 150×150 mm for maintenance purpose. The digester is also provided with two inbuilt stainless steel supports culminating into four hooks ( 11 ) that will be used for fixing the digester under the coach. Two handles ( 12 ) on the lid of the digester are provided to facilitate its opening for maintenance.
ADVANTAGES OF THE INVENTION
[0036] The present has the following advantages:
[0037] The digester is useful for the onboard treatment of human waste for railways, buses and other public transport systems for converting it into the effluent which is odorless, free from pathogens and does not create any aesthetic nuisance.
[0038] The digester provides onsite treatment of human waste avoiding the need for its transportation to the site of treatment.
[0039] The digester has an anaerobic chamber has long path and time for biological treatment.
[0040] The immobilization matrix in the form of PVC on partitions, bottom and sides for attachment of bacteria to prevent washout, having higher cell mass for enhanced fermentation, better tolerance of bacteria for adverse environmental conditions and to have better baffling.
[0041] The submerged inlet pipes prevent the entry of foul smelling gases from the head space to the toilet.
[0042] The maintenance window on the side of fermentation chamber helps in removal of sludge and maintenance.
[0043] The digester provides biochemical treatment of human waste with integrated chlorination chamber.
[0044] An apparatus with automated chlorination of fermented waste.
[0045] An apparatus for final and safe discharge of biochemically treated human waste in continuous mode.
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A digester for degradation of human waste comprising a main tank having biochemical treatment compartment and chemical treatment compartment connected by connecting pipe as a passage for bio-chemically treated waste to chemical treatment compartment; the biochemical treatment compartment has at least one loosely fitted partitioned wall and at least one inlet to receive waste, at least one gas outlet and at least one waste drain pipe to remove sludge; the chemical treatment compartment has discharge means to discharge treated waste and excess of liquid, and float ball assembly to release chemical for chemical treatment.
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RELATED APPLICATIONS
The present invention is a division of co-pending U.S. application Ser. No. 14/220,830 entitled, “Spinal Alignment Correction System And Methods Of Use” filed on Mar. 20, 2014.
TECHNICAL FIELD
The present invention is directed to a device for use in correcting various lumbar and thoracic spinal maladies including reduction of Spondylolisthesis and various other corrective procedures and surgical treatment including scoliosis, trauma and other malalignments of the spine.
BACKGROUND OF THE INVENTION
A recently published paper in The Journal of Bone and Joint Surgery Incorporated 2014; 96: 53-8 entitled “Evidence—Based Surgical Management of Spondylolisthesis Reduction Or Arthrodesis In Situ” reported “The role of reduction in the operative management of spondylolisthesis is controversial because of its potential complications, including neurologic deficits, prolonged operative time, and loss of reduction.” This study reported “The decision to correct high-grade slippage defects by reduction is still a controversial one. In an attempt to determine which patients should be treated with reduction, some authors have investigated the relationship between sagittal spinal parameters and pelvic morphology and orientation. Patients with high-grade spondylolisthesis could be classified on the basis of the orientation of the pelvis as having a “balanced” or unbalanced” pelvis. The balanced pelvis type of spondylolisthesis includes patients with low pelvic tilt and high sacral slope, whereas the unbalanced type includes patients with a retroverted pelvis having a high pelvic tilt and low sacral slope. On the basis of this classification, some authors suggest reduction of the deformity, restoring the spinopelvic balance, only in patients with an unbalanced pelvis, whereas arthrodesis in situ without correction would be preferred in patients with a balanced pelvis. Although reduction can potentially result in complications, complication rates in the present analysis did not differ between the reduction and arthrodesis in situ groups. On the other hand, reduction of a high-grade spondylolisthesis would improve overall spine biomechanics by correcting the local kyphotic deformity and reducing the vertebral slippage. We manage patients with high-grade spondylolisthesis by performing reduction under intraoperative neurophysiologic monitoring such as SSEPs combined with spontaneous electromyography. We usually perform a posterolateral or circumferential instrumented arthrodesis. In conclusion, we found no definite benefit of reduction over arthrodesis in situ except for a significantly lower rate of pseudarthrosis. Further adequately powered randomized trials with appropriate subjective and objective outcome measures are required to establish evidence-based surgical management of high-grade spondylolisthesis.”
The current surgical practice for low to medium grade spondylolisthesis reduction employs the use of pedicle screws with connective rods. Wherein the surgeon measures the amount of reduction required to realign the vertebrae and then uses the connecting rod to pull the upper vertebral body back causing a lever type action and placing the rod fastener into the tulip connection to fix the connections. As one can appreciate, this current best practice is at best an estimate of final reduction, due in part to a lack of control; the final results are typically a compromised approximation, but not a true alignment. Often this procedure of moving the adjacent vertebral bodies closer to alignment is a sufficient improvement to help the patient; however, this inability of the surgeon to precisely control the reduction is far from ideal. Furthermore, if the reduction achieved is less than satisfactory, the surgeon must start over loosening the rod and repositioning the pedicle screws, thus extending the surgical procedure.
The ideal reduction procedure would allow the surgeon to accomplish the reduction by controlling the movement in a consistent reliable and adjustable fashion so the exact optimal alignment is always achieved in the absence of predicting the preferred location, but rather controlling the movement to that exact location. Most importantly, this ability must occur in a timely fashion without unduly extending the surgical procedure.
The present invention as described herein accomplishes all these objectives and does so in typically less than 5 minutes added surgical time, most typically less than 4 minutes. Most advantageously, the system of the present invention is so accurate and reliable it virtually eliminates any need to redo the steps as there is no estimation made as to final placement, but rather a controlled movement to alignment which is fixed by the independent adjustment capability of the device in the hands of the surgeon aided by fluoroscopic vision.
These and other features of the system and its components afford new techniques in lumbar and thoracic spine surgery for use in a variety of indications as explained hereafter and shown in the attached drawings.
SUMMARY OF THE INVENTION
A method of treating and correcting a spinal misalignment is summarized in the steps: after exposing the spine and preparing it for instrumentation; Step 1—place MAC Pins bilaterally into the affected vertebral body, then one places standard top loading tulip pedicle screws into the vertebral body below. The listhesed segment such that two vertebral bodies are instrumented. Next a contoured rod is chosen based on the distance between the macpin and the pedicle screw discovered interoperatively. This rod is secured in an opening in the caudal edge of the coupler with a nut in the contoured position. The coupler is then slipped over the MAC Pin down into the surgical wound with the caudal edge of the rod falling into the top loading tulip of the pedicle screw below. At this point, the end cap is placed on the standard pedicle screw in the tulip and is tightened into position locking rods in the bilateral pedicle screws into a monoaxial and fixed relationship with regard to the instrumented vertebral bodies, the pedicle screws and the rods. The next step is to place the cannulated reduction tower over the macpin and through clockwise rotation of the reduction tower the listhesis is reduced in a slow, controlled and accurate method until the interoperative fluoroscope indicates a satisfactory reduction thus appropriate sagittal alignment. At this point, the second nut on the coupler is tightened with a wrench and this locks the entire construct into a rigid position therefore securing the spondylolisthesis reduction in place. The outer cannulated tower is then removed and the MAC Pins are sheared off flush with the coupler. It is at this point a laminectomy or decompression of the neural elements can be performed if so desired. Following the laminotomy, an interbody preparation fusion and graft placement can then take place. An alternative method would be to close the surgical wound and perform an anterior lumbar interbody fusion or a lateral transpsoas interbody fusion according to the pathology, indications and surgeon's surgical strategy.
A spinal alignment correction system has an elongated shaft and a rod coupler assembly. The elongated shaft has an inner pedicle screw portion with pedicle threads, an outer second thread portion with second threads and a transition or intermediate portion disposed between the pedicle screw portion and the second thread portion. The rod coupler has a pair of openings, a first opening for passing over the elongated shaft and being movable lengthwise within the transition or intermediate portion and a second opening for receiving a rod. The rod coupler is rotationally movable about said shaft. The spinal alignment correction system further has a cannulated tower. The cannulated tower has a longitudinally extending opening having internal threads complimentary to said second thread of said elongated shaft. The cannulated tower when mounted over said elongated shaft abuts said coupler along an outer cam surface and further tightening rotation of the cannulated tower causes outward movement of the elongated shaft. The spinal alignment correction system further has a handle removably attached to the cannulated tower to facilitate rotation of the cannulated tower. The spinal alignment correction system further has a rod fastener, said rod fastener when attached to said rod connector locks a rod securely fixed in the rod receiving opening. The spinal alignment correction system further has a washer and a locking nut for attachment onto the coupler and abuttingly locking said washer against said coupler.
The spinal alignment correction system further has a rod, a rod fastener and a pedicle screw with rod receiving connection. The pedicle screw when affixed to a lower vertebral body has the rod extend to the second rod receiving opening of the rod coupler positioned over the elongated shaft affixed to an upper vertebral body, when the rod is at one end is placed in said rod receiving connection of the pedicle screw and fixed by said fastener, the opposite rod is placed in the second rod opening of said coupler and fixed to said coupler after a desired vertebral alignment is achieved. The elongated shaft preferably is made of titanium.
BRIEF DESCRIPTION OF THE DRAWINGS
The invention will be described by way of example and with reference to the accompanying drawings in which:
FIG. 1 is a perspective view of the system or device of the present invention.
FIG. 1A is a view of the system of FIG. 1 installed in a spine segment.
FIG. 2 is an exploded view of the present invention of the system shown in FIG. 1 .
FIG. 3 is a perspective view of the posted pedicle screw or MAC Pin.
FIG. 3A a view of the MAC Pin with rod coupler assembly.
FIG. 4 is an exploded view of the rod coupler.
FIG. 4A is an exploded side view of the rod coupler.
FIG. 4B is an as assembled view of the coupler.
FIG. 4C shows an additional view of an alternative multiaxial or polyaxial coupler providing an ability to slightly tilt angle the MAC Pin in any direction to facilitate installation of the system.
FIG. 4D is the alternative coupler of FIG. 4C shown in a perspective view assembled.
FIG. 4E is a side view of the coupler of 4 D assembled.
FIG. 4F is an alternative embodiment of the present invention shown in an exploded perspective view illustration of the MAC Pin made as a multi-piece posted lumbar pedicle screw and illustrating a medial offset or lateral offset coupler design.
FIG. 4G is a side view of the alternative embodiment.
FIG. 4H is a perspective view.
FIG. 4I is an assembled view.
FIG. 5 is a side view of the cannulated tower.
FIG. 5A is a cross sectional view of the cannulated tower.
FIG. 6 is a view of the handle for use with the cannulated tower.
FIG. 6A is a cross section of the handle.
FIG. 7 is a view of the wrenches shown above MAC Pins and cannulated towers of the system for final nut tightening.
FIG. 7A shows the wrenches in place over the system to provide final nut tightening to fix the MAC Pin to the coupler.
FIGS. 8A-8J are various views of spines having the system of the present invention used showing the various steps employed.
FIG. 9A is a side view illustrating a malaligned spine and a use of the system showing the reduction direction as the handle is rotated.
FIG. 9B shows the corrected spine segment of FIG. 9A .
FIG. 10A shows a scoliosis treatment and how the system can be used to also provide a rotational correction of a vertebral body.
FIG. 10B is a view showing the correction result provided to the spine segment of FIG. 10A .
FIG. 11 is a view of a cannulated MAC Pin for use with a K-wire in a percutaneous procedure.
FIG. 12A is a perspective view of an insertion tool, inserting a stabilizer rod into a bone screw system with leg extensions for use in a percutaneous procedure.
FIG. 12B is a perspective view of the insertion tool of FIG. 12A , showing the insertion tool using the connector as a fulcrum to maneuver the stabilizer rod into position.
FIG. 12C is a perspective view of the insertion tool of FIG. 12A , showing the insertion too using the connector as a fulcrum to further maneuver the stabilizer rod into position.
DETAILED DESCRIPTION OF THE INVENTION
The following description is best understood by reference to the attached drawings depicting one embodiment of the present invention. With reference to FIGS. 1 , 1 A and 2 .
The device or spinal alignment system 1 is shown as described has a double threaded post lumbar pedicle screw 10 hereinafter also referred to as a Maximum Alignment Correction Pin (MAC Pin) that is placed in the vertebral body 201 and coupled with a special screw rod coupler or coupler assemblies 20 and that adjoins the posted screw 10 to a rod 100 connected into a lower vertebral body 202 of a particular segment of the spine 200 . The posted screw 10 is attached to the rod 100 and the other end of the rod 100 attached to a typical pedicle screw 110 placed in the vertebral body 202 below. The device or system 1 will include a double threaded post lumbar/thoracic pedicle screw thread end portion 12 on the screw 10 as well as a coupler 20 and there is also a technique for using this implanted device or system 1 .
As shown in FIGS. 3 and 3 a , this posted pedicle screw 10 has a one piece shaft 11 with a double threaded pedicle screw thread 12 of a typical pedicle screw. The thread 12 extends from a leading tip 11 A to a length at least 40 mm, preferably of about 50-55 mm in length up the shaft 11 , thereafter the posted screw 10 has a smooth shaft portion 16 between two threaded portions. The pedicle threads of the screw 10 are in the range of 5.0 to 8.0 mm in size, more typically between 5.5 and 7.5 mm and have a self-tapping feature as shown at end 11 A. A second thread 14 at the other end of the shaft 11 of the screw 10 of the screw is used for the actual reduction or translation technique. The outer end 11 B of the second screw portion 14 that will be sticking out of the spine 200 may have a squared off or flat feature that will be able to connect to a handle or wrench that will allow the posted pedicle screw 10 to be installed into the vertebral bone 202 , independent of the rod coupler 20 . This shafted post pedicle screw 10 is called the MAC Pin (Maximum Alignment Correction Pin). For the first time this pedicle screw 10 and coupler 20 enables the vertebral body 201 to be pulled back in the sagittal plane to be realigned with the other vertebral bodies 202 to establish perfect mechanical alignment, restore the mechanical alignment of the spine 200 , believed to be the best outcome for the patient. The coupler 20 enables the tip 11 B of the posted pedicle screw or the MAC Pin 10 , once the pedicle portion 12 of the MAC Pin 10 has been placed within the vertebral body 201 of the lumbar spine 200 , to be pulled back. That threaded portion 14 will be used to pull the vertebrae 201 back 35-50 or 65 mm. The coupler 20 is slipped over outer the tip 11 B of the MAC Pin 10 , the coupler 20 as an assembly, but untightened, falls into the spine interoperatively into the smooth shaft portion 16 of the MAC Pin 10 between the two threaded 12 and 14 areas of the MAC Pin 10 . The coupler 20 is attached to an end of a contoured rod 100 which when placed down over the MAC Pin 10 , the opposite end of that rod falls into the top of aa top loading tulip 120 of the tulip headed pedicle screw 110 in the vertebral body 202 below. When the coupler 20 fixed to the rod 100 is placed within the pedicle screw 110 this enables not only translation again also distraction or compression of the motion segment 202 between the two vertebral bodies 201 , 202 . Once this assembly is accomplished, the technique can begin.
With referenced to FIGS. 3A , 4 , 4 A and 4 B the rod coupler assembly 20 is shown, the coupler 20 has two holes 21 , 22 , one hole 21 is able to slip over the posted pedicle screw or MAC Pin 10 and then the other hole 22 will allow the contoured rod 100 to fit within it and then prior to placing the coupler 20 and rod 100 over the posted pedicle screw or MAC Pin 10 the surgeon will lock the rod 100 by choosing various lengths of rods according to what is discovered as needed interoperatively with the 5.5 diameter rod 100 , the rod 100 will slip into the caudal edge of the coupler 20 . Once the rod 100 is slipped into the caudal edge, there is a separate nut or set screw 102 and tightener that tightens this rod 100 in place into the threaded opening 103 of the coupler 20 .
As shown in FIGS. 4 , 4 A, 4 B and 4 C, the rod coupler assembly 20 has a coupler body 24 which has the openings 21 and 22 for receiving and holding the MAC Pin 10 and rod 100 respectively. At the bottom of FIG. 4 is a hollow shaft holding coupling 90 with a threaded end 98 with flats 95 and an opposite rounded or spherical end 99 with a plurality of slots 97 to allow the end 27 to grip the MAC Pin 10 when the coupler assembly nut 60 is tightened against the washer 62 and the teeth 25 serrated sidewalls 23 . The washer 62 having can have complimentary flats 63 with or without serrated teeth 65 that interlock as the nut 60 threads onto the threads 98 of the shaft holding coupling 90 as shown in FIGS. 4 , 4 A- 4 E. Initially, the entire coupling assembly 20 is connected, but loosely so the coupling can slide freely over the MAC Pin 10 and move angularly about the smooth shaft portion 16 . Only when the proper vertebral body alignment is achieved by the use of the cannulated tower 40 and the handle 50 is the nut 60 tightened locking the coupler 20 onto the MAC Pin 10 fixing its position. As noted, all the parts aligned with opening 21 have openings allowing the MAC Pin 10 to pass as shown. The shaft holding coupling mechanism 90 provides for limited angular motion of the MAC Pin 10 . Nevertheless, this ability to tilt the assembly is beneficial to the installation of the instrumentation. As further illustrated, the system 1 further has a cannulated reduction tower or shaft 40 mounted over the MAC Pin 10 and resting on a nut 60 of the coupler assembly 20 . Above and removably affixed to the tower 40 is a handle 50 which is used to rotate the cannulated reduction tower 40 as the system 1 is employed to align the vertebral body 202 in the spine 200 .
Once the rod 100 and coupler 20 are joined through this nut 102 , a fixed relationship is established between the rod 100 and coupler 20 . At that point, the other end, the cranial end, of the coupler 20 would then slip over the MAC Pin 10 until the coupler falls into the dorsal aspect of the bone of the vertebral body 201 which is the base of the lumbar pedicle and also at that point it will be positioned within the smooth shaft portion 16 of the MAC Pin 10 , the threaded pedicle portion 12 of the MAC Pin 10 would have been driven transpedicularly into the vertebral body 201 where whatever length has been chosen of the threaded pedicle portion 12 of the threads 12 A will be countersunk into the vertebral body and pedicle shaft. This can be anywhere from 35 mm up to 50-65 mm within the vertebral body 201 . At this point, sticking out of the posterior aspect of the pedicle and vertebral body 201 would be the MAC Pin 10 , the smooth shaft portion 16 and also the second thread portion 14 as well as the squared off tip 11 B. So when the coupler 20 slips over the post MAC Pin 10 , the coupler 20 is positioned within the smooth shaft portion 16 enabling it to more or less cam back and forth on the MAC Pin 10 so that a smooth frictionless relationship exists with the MAC Pin 10 and the rod. At this point again, simultaneously when the coupler 20 and the rod 100 are slipped over the MAC Pin 10 , the caudal of the 5.5 rod 100 would fall down into the opening of the tulip 120 the top loading tulip pedicle screw 110 and the vertebral body 201 . At that point, the end fastener cap 130 on the tulip 120 of the top loading pedicle screw 110 would be placed and the end cap 130 would be tightened after whatever distraction or compression is desired. Once the coupler 20 and the rod 100 slide down over the MAC Pin 10 and fall within the tulip 120 , the end cap 130 of the tulip 120 would then be placed. At this point, a distractor or a compressor can be utilized to distract between the MAC Pin 10 from the pedicle screw 110 once it achieves distraction of the this or the posterior neuroforamen, independently of the translation of the vertebral body 201 that follows this distraction. Once distraction or compression is accomplished, the end cap 130 and the posted pedicle screw 10 below would be tightened and then the rod 100 and the posted pedicle screw 10 relationship would become fixed. At that point the only motion that is still available between the MAC Pin 10 and the pedicle screw 110 below or at the rod 100 is the translation or the reduction of the spondylolisthesis.
To visually appreciate the procedure, after the MAC Pins 10 have been inserted bilaterally, the surgeon would place the coupling assembly 20 over the MAC Pin 10 as shown in FIGS. 8E-8G and lock the connector rod 100 to the pedicle screw as discussed. Thereafter, the cannulated towers 40 and handles 50 would be placed over the MAC Pins 10 as shown in FIGS. 8A-8D . At this point, the rod coupler assembly is assembled, but is loose sitting over the smooth shaft portion 16 free to allow the MAC Pin 10 to be retracted. As shown in FIG. 8D , once the towers engage the second threads 14 A by rotation of the handle 50 , the MAC Pins 10 are retracted. The tower 40 abuts on the nut 60 which acts as a cam. Importantly, as the tower 40 rotates, the MAC Pin 10 does not rotate, but rather moves longitudinally in the direction of the handle rotation. In this way, the pedicle portion 12 does not change neither tightening nor loosening. This allows the vertebral body 202 to retract toward alignment. Once the desired alignment is achieved, the handle 50 can be removed and a wrench 70 , shown in FIGS. 7 and 7A , can pass over the tower 40 to securely tighten the nut 60 fixing and locking the rod coupler 20 to the MAC Pin 10 . This occurs as the slots 97 at the end of the coupling mechanism 90 close about the shaft 11 at the smooth portion 16 of the MAC Pin 10 . Once locked in position, the wrench 70 is removed and the cannulated tower 40 is removed from its attachment to the exposed second threaded portion 14 of the MAC Pin 10 . Once removed, the surgeon cuts the MAC Pin 10 flush to the nut 60 of the rod coupler assembly 20 as shown in views 8 H- 8 J.
In FIGS. 9A and 9B an exemplary procedure of a spinal segment 200 is shown with the system 1 installed and being turned to retract the spondylolisthesis of vertebral body 202 as the rod 100 is fixed to the lower vertebral body 201 at the pedicle screw 111 . Once alignment is achieved, the tower 40 is removed after the nut 60 is tightened, see FIG. 9B . This is accomplished preferably using two MAC Pins 10 bilaterally as previously discussed in reference to FIGS. 8A-8J .
The next step would be slipping a cannulated tower 40 , shown in FIG. 5 and cross section in FIG. 5A , over the exposed outer tip 11 B of the MAC Pin 10 with a handle 50 on that cannulated tower 40 . The cannulated tower 40 has an inner threaded portion 42 that threads onto the second set of threads 14 A on the exposed MAC Pin 10 . At this point, the handle 50 on the cannulated tower 40 is rotated moving the tower 40 over that threaded portion 14 of the MAC Pin 10 and as you move the handle 50 , the cannulated tower 40 moves down the threads 14 until it abuts against the nut 2 of the coupler; the pedicle screw portion and rod relationship and begins to pull that vertebral body into a more aligned position such that the surgeon would be able to translate or reduce the spondylolisthesis anywhere between 1 mm up to 2-3 cm and this is a unique property of the system 10 in that no other system allows an independent translation and independent distraction and compression of the motion segment that is so accurate. Once you begin to translate the MAC Pin 10 on the coupler 20 , it allows complete independent and accuracy whether or not you need 1 mm of reduction or 3 cm of reduction. The surgeon is able to dial that in interoperatively and stop at whatever point he wants between that 0 to 3 cm. There is no guesswork, no estimation, the surgeon simply begins to dial in the amount of reduction he wants and by checking interoperative fluoroscope he can judge when the reduction is complete and therefore stop the process at that point.
As shown in FIG. 5 , the cannulated tower 40 has an end 40 A with flats 45 to receive the handle 50 . The tower 40 , as shown, further has a window opening 46 which allows the surgeon to see the MAC Pin 10 movement. A graduated scale 48 marked 10-60 increments of 10 mm is provided adjacent the window opening 46 . The handle 50 , shown in FIGS. 6 and 6A , when placed onto the tower 40 has an opening 54 that allows the MAC Pin 10 to pass. The opening 52 receives the end 40 A and has flats 55 to compliment the flats 45 to rotationally fix the tower to the removable handle 50 .
Another unique feature of this system is the fact that as the surgeon reduces the spondylolisthesis, let's say for example 2 cm, and for whatever reason perhaps the nerve begins to show signal of being pinched, he can then go back and translate the vertebral body 201 forward again back to say 1 or 1.5 cm. Essentially, this device 10 gives the surgeon complete control of an accurate reduction, distraction and rotation of the vertebral body 202 like no other product does. Once the translation or rotation has been performed through the MAC Pin 10 and the cannulated tower 40 and handle 50 , at that point a separate wrench 70 and nut 60 are placed over the cannulated tower 40 and the MAC Pin 10 being held in place. The surgeon, using the separate wrench 70 , tightens a nut 60 on the coupler 20 , this locks the relationship between the coupler 20 and MAC Pin 10 so that is now a fixed relationship and once that fixed relationship is achieved, then the reduction is complete and locked in. At that point, the wrench 70 comes off the cannulated tower 40 and then the cannulated tower 40 is removed from the MAC Pin 10 and then a MAC Pin cutter 80 fits over the exposed tip of the MAC Pin 10 and cuts the MAC Pin 10 flush with the coupler 20 . Now the procedure is completed with a fully distracted or compressed and reduced vertebral body 202 in the spondylolisthesis. At this point, every relationship between the MAC Pin 10 , the pedicle screw 110 and the rod 100 are locked down and fixed ensuring the spondylolisthesis has been exactly reduced. At this point, that would be the completion of the procedure.
Now the technique described above typically would be performed open, in an open procedure and also bilaterally with both pedicles and the right and the left side of the vertebral body that is in listhesis would be addressed. And then the procedure would alternate right versus left a little bit of reduction the right and then a little bit of reduction left, and then alternate the right to left so that the vertebral body is translated or reduced in a symmetrical fashion so that no undue rotation is performed during the reduction technique. And then after the reduction is complete, then again the MAC Pin 10 cut off flush to the coupler 20 . This procedure can be performed on a one level spondylolisthesis, a two level spondylolisthesis or in a situation where a spondylolisthesis is a top 1-2 or 3 segments that need to be instrumented according to the indications of the particular surgeon.
This procedure can also be done percutaneous by cannulating the MAC Pin 10 so that this procedure could be performed percutaneously. That way a percutaneous posterior instrumentation of the vertebral body could be performed in adjunct with an anterior lumber interbody fusion or in adjunct with a trans lateral interbody fusion. So that this procedure and this system 10 can be utilized with almost any spinal pathology, spondylolisthesis, isthmic spondylolisthesis, traumatic spondylolisthesis also scoliosis, whether it be idiopathic or a degenerative condition, and finally spinal trauma.
This system 10 also provides a different coupler 20 MO that is called a medial offset of lateral offset coupler. In this particular coupler 20 MO, the MAC Pin 10 would still be placed in the vertebral body 202 , but the coupler 20 MO would be placed not cranial and caudal but rather medial or lateral to the MAC Pin 10 and in that situation the holes 21 where the rod 100 adjoins to the coupler 20 MO would now be parallel with the rod 100 so that it could be medial or lateral to the MAC Pin 10 . And that would enable the surgeon to perform multiple spondylolisthesis reductions. For example, if you had a (L4 L5) as well as a (L5 S1) grade 1 or grade 2 spondylolisthesis, one could use the medial offset coupler 20 MO with a MAC Pin 10 at every vertebral body with a MAC Pin 10 placed at L4, L5 and S1 and then one could place a medial coupler 20 MO on each MAC Pin 10 and therefore one could perform independent distraction or compression between both motion segments and then also independent and accurate reduction of both the L4 body on L5 as well as the L5 body on S1 once again achieving complete and consistent accuracy. And that is the uniqueness this particular device 10 .
The system 10 is designed to reduce spondylolisthesis whether it be grade 1, grade 2 or grade 3 according to the surgeon's desire to reduce the spine.
In practicing these procedures, it is preferable that the surgeons are triangulating the MAC Pins 10 into the vertebral body 201 so that when the vertebral body 201 is pulled back or reduced that the force that is pulling the vertebral body 201 back to alignment is not only axial pullout strength, but also an actual purchase of the vertebral body through triangulating the MAC Pins 10 or converging the MAC Pins 10 from the right and left side in a triangular fashion in the vertebral body 201 so a separate force is pulling back against the mass of vertebral body 201 , not only axial pullout strength of the MAC Pin 10 .
In describing how the triangulation of the MAC Pins 10 within a vertebral body 201 would work, consider for example if the surgeon is fixing a L4,5 degenerative spondylolisthesis that means that the L4 body is translated or listhesed out of proper alignment forward or anteriorly may be 2 mm may be 2 cm. He has to pull that L4 body back where it belongs in a direct line within the sagittal plane. That direct line must be consistently and accurately reproduced from surgery to surgery or else it could create rotation within the motion segment that will put a mechanical malalignment and possibly other problems. Every time he pulls back on spondylolisthesis an upper bone on top of a lower bone it must be in a symmetrical fashion and also along a vector directly within the sagittal plane. In order to do that, what is going to be done is to put a standard pedicle screw in the vertebral body below. The rod 100 is fixed within that pedicle screw 110 so that the pedicle screw 100 , the rod 100 , the vertebral body 202 are all fixed with respect to each other. This will serve as an anchor to pull back the L4 vertebral body within that sagittal plane. In order to establish a strong foothold in the upper vertebral body L4, the surgeon must do one thing and that is to insure a very strong purchase or grasp of that L4 vertebral body 201 and pull it back using the rod 100 , pedicle screw 110 and vertebral body 202 below once again as an anchor. Once the coupler 20 is placed on the MAC Pin 10 and the surgeon begins to pull the vertebral body above 201 , back within that sagittal plane, he must have achieved a strong foot hold and grasp of that L4 vertebral body 201 . The preferred way he would do that is from the right side and left side. He would place the MAC Pins 10 in the upper vertebral body at angles. He would come in at as an obtuse or oblique angle with respect to the sagittal plane or the vector within the sagittal plane that the bone must pull back in. In the way he want the MAC Pins 10 not only with strong axial pullout strength, but also wants the two MAC Pins 10 coming in from both the right and left side at an angle, preferably anywhere between 15 and 25 degrees in a convergent way so that the tips of the MAC Pins 10 are coming together within the midline of the upper vertebral body 201 . For example L4, once the MAC Pins 10 are hooked into the anchor at the rod 100 again to translate both right and left MAC Pins 10 with respect to the anchor or rod 100 the vertebral body 201 , the vertebral body can be translated posteriorly into alignment symmetrically within the sagittal plane. The foothold that is achieved by doing this is twofold. One, the MAC Pin 10 itself has an axial pullout strength that is going to add to the foothold. Two, by angulating the two MAC Pins 10 in a convergent manner within the vertebral body 202 increases the foothold on the medial aspect of the each of the MAC Pins 10 purchasing the mass of the vertebral body 202 , the mass of the bone also serves as a foothold for a grasp of the vertebral body 202 as the surgeon pulls the vertebral body 202 along a straight vector within the sagittal plane. It is because the angles of the MAC Pins 10 that are oblique to the sagittal plane, the force begins to pull within the vector of the sagittal plane. The obliqueness of the MAC Pin 10 has added strength for pulling the vertebral body back within that sagittal plane. Once that alignment is achieved, then the MAC Pins 10 are locked down and the actual pullout strength as well as the convergence of the two MAC Pins within the vertebral body 202 continue to hold that vertebral body within an aligned or reduced position until the fusion takes place.
This system 1 allows the surgeon to pull from left and right sides if desired. The MAC Pin in the right or the left side allows not only for independent distraction or compression right versus left according to the need, but they also allow complete independent rotational control so that a surgeon if he wanted to could pull the right MAC Pin 10 back 1.5 cm, pull the left MAC Pin only 1 cm to create rotation within the vertebral motion segment so that the spondylolisthesis or scoliosis can be tuned to the situation the surgeon is seeing. The benefit of this device 10 is that if he had a rotation that could place the vertebral out of alignment, the surgeon would be able to distinctly and independently rotate, distract or reduce the vertebral right versus the left independent of each other the right or the left sides. It all depends on the technique the surgeon uses whether he reduces by the handle on the right side or the left side or both simultaneously or he can, if he chooses, utilize the MAC Pin 10 and the handle the right side versus the left side differently at different times completely independent of one another.
There is nothing on the market that allows this reproducible, consistent accuracy with regard to distraction, rotation, and in particular reduction. The market has been flooded by multiple spinal instrumentation companies with what's called “reduction screws”. Reduction screws are just standard pedicle screws that have a long extended tulip. They are based on the fact that you can try and lock the lower pedicle screw in the lower vertebral body and then estimate again estimate the amount of reduction, translation or rotation that one might need and then a reduction screw is placed in the vertebral body above. At this point the theory is the rod is again fixed to the vertebral body below and again in this system the vertebral body below and the pedicle screw and the rod are fixed together and are going to be used as an anchor while the tulip and the end cap is placed on the reduction screw above. So the theory is that as the screw end cap down into this elongated reduction tulip at the relationship between the upper vertebral body and the lower vertebral body are going to remain the same and that is just simply never true and never accurate and never reproducible.
As one begins to reduce the spondylolisthesis with a reduction screw, what happens is, the surgeon must rely on the anchor in the lower vertebral body 202 , the standard pedicle screw 110 and the rod 100 . And the theory is that he would like the rod 100 to be sitting the exact same distance in the tulip that he desires the spondylolisthesis to be reduced. So he is looking at an interoperative forum, so when the surgeon says he wants the reduce this spondylolisthesis let's say 5 mm, he is going to set the rod 5 mm above the bottom of the tulip on the reduction screw, then he is going to put the end cap in the reduction screw and tighten the end cap until the rod sits on the base of the tulip which will be 5 mm. The only problem with this system is that it requires that the pedicle screw and rod relationship in the vertebral body below does not change a bit. And that is where the problem with this system comes in is that it always changes. So what happens is the surgeon puts 5 mm between the rod and the tulip head and begins to tighten the end cap and what happens is that as the end cap tightens down the rod takes the vertebral body below into a different angulation and into a different position such that once you get to 5 mm of tightened down with the end cap, he may only have achieved 1-2 may be 3 mm of reduction, and once that end cap is set within the tulip that is all he's got. So that means he wanted to reduce 5 mm, but the vertebral changed in its angle relationship, then he only had 3 mm, then he has to reset that and there is no way to change that unless he takes out the rod and starts over. That adds time to the patient's surgery and a surgeon may find himself readjusting this 2, 3 to 4 times trying to get the estimation correctly based on something he has no control over. This relationship is based on the strength of the bone, meaning that if the pedicle screw in the vertebral body below moves, if it toggles within the vertebral body then that is going to take away 2-3 mm or if the polyaxial head of the screw anchor in the lumber vertebral body below starts to move at all will take away 2-4 mm of reduction. And finally, if the relationship within the sagittal plane of the upper vertebral body and the lower vertebral body begin to change with the respect to one another as the end cap is tightened down assuming the rod, the pedicle screw and the lower vertebral body are indeed fixed, then what has happened is the two vertebral bodies move inappropriately with relationship to each other and then again a loss of 3, 4, 5 mm of reduction occurs and so what it's going to result in is making the surgeon accept mediocrity. While reducing a grade 2 spondylolisthesis, to 0 in perfect alignment is usually found with that type of prior art instrumentation is a grade is not completely reduced, not completely restored within that mechanical alignment in the sagittal plane. In the present invention system 1 , the surgeon does not have to worry about those things. He won't have to even consider any of those things that cause problems with the reduction screw system, because the MAC Pin 10 allows adjustable, and reproducible amount of reduction or translation regardless of the relationship of the lower vertebral body 202 , it has no bearing on the procedure other than being an anchor point. You can take it to 1-2 cm, if you want to you can take anterior again, so you have complete control forward and backwards moving this vertebral body anywhere in space you want to and that is within the interoperative amount of time which is so important that with the system 1 which takes less than 5 minutes to reproduce consistently, the device 10 allows free independent reduction and rotation of vertebral body 201 with an additional time of less than 5 minutes. And no one can argue that the reduction pedicle screws allow for that amount of control with that few minutes of interoperative time addition.
With regard to application of the system 1 in scoliosis, the MAC Pin 10 would be used and probably in every level of the scoliosis. As shown in FIGS. 10A and 10B , in a scoliotic spine 200 where a curve had to be reduced in the sagittal plane but also rotationally reduced, the MAC Pin 10 would be placed bilaterally, most likely, sometimes unilaterally in multiple levels throughout the entire affected instrumented spine. Every level that is going to be addressed with instrumentation in scoliosis may have one or two MAC Pins 10 in them. With regard to the coupler 20 , in scoliosis, most likely the coupler 20 could be a medial offset coupler 20 MO or a lateral offset coupler 20 LO as opposed to the cranial coupler 20 that would be used in spondylolisthesis. In the coupler 20 MO or 20 LO, the rod connection opening is positioned on a side of the coupler body 24 as shown in FIGS. 4F-4I . In this alternative embodiment, the MAC Pin 10 is made as at least a two part assembly, the pedicle screw 12 and the smooth transition 16 and second threaded portion 14 are separate pieces. Otherwise the alternative embodiment is similar in construction as the system 1 previously discussed. As designed one can use a coupler 20 as previously described in FIGS. 4-4B having monoaxial adjustment or a polyaxial construct as shown in FIGS. 4C-4E , or use a fixed coupler 20 design as illustrated for the couplers 20 LO/ 20 MO which by design are the same in terms of the location of the rod opening 22 . This allows the use of multiple MAC Pins 10 within the spine 200 and then the rod 100 would be placed either medially or laterally through the MAC Pin 10 and then coupled to the MAC Pin 10 again from the medial side or the lateral side. The rod 100 would most likely be utilized bilaterally in both the right and the left side to add a foothold or strength to the purchase of the various vertebral bodies of the spine 200 for not only reduction in not only the sagittal and coronal plane again also rotational such that again the MAC Pin 10 on the right side of the vertebral body 201 versus the MAC Pin 10 on the left side of the vertebral body 201 . Either way has complete independence from each other so that a surgeon may be able to utilize the MAC Pin 10 for rotation on the right side by leaving the left side in place. So the medial coupler 20 MO purpose or lateral coupler 20 LO simply would allow the MAC Pin 10 to be utilized in the vertebral body at multiple different levels. The MAC Pin 10 with regard to scoliosis procedures likely would be exactly the same, however, the coupler 20 going from what is called the cranial coupler to a medial or a lateral offset coupler, required the coupler design to be slightly different in the fact that the coupler 20 is slipped over the MAC Pin 10 and if for example the medial offset is placed on the MAC Pin 10 , the rod 100 would be placed medial to the MAC Pin 10 so therefore the slot or the hole 21 within the coupler 20 would need to run parallel with the axis of the spine 200 , such that the only difference would be that the coupler 20 MO allows the rod to be medial to the MAC Pin 10 as opposed to being caudal to the MAC Pin 10 . So the wrenches 70 that would be used would be the same, the two nuts 60 would be very similar, the only difference would be the relationship to the right of the MAC Pin and this is all based on the fact that the surgeon would need to place multiple MAC Pins 10 throughout the spine 200 .
With regard to the physical structure of the MAC Pin 10 , this will be a one piece titanium pin with two sets of threads, there will be a pedicle screw portion 12 that will measure anywhere from 35 to 55 mm and will replicate at this point a pedicle screw thread. That typically is a double lead pedicle screw self-tapping thread with the single pole. Alternatively, in future generations the thread can be with the double threaded dual core system for the pedicle portion of the MAC Pin 10 . Beyond the inner tip 11 A of the pedicle screw portion 12 of the MAC Pin 10 there will be a smooth shaft portion 16 that will be from 1 to 2 cm or 1 to 3 cm in length and will be the same dimensions or radius as the inner core or shaft of the MAC Pin 10 most likely of the pedicle screw portion and that will be the space that is allowed for coupling of the coupler 20 to come down over the MAC Pin 10 . Furthermore beyond the smooth shaft portion 16 of the MAC Pin 10 there will be an outer portion 14 with a second set of threads. That second set of threads will be the threads that are actually used for the reduction or rotation of the vertebral body 201 by virtue of the fact that cannulated smooth shaft hitting a smooth surface of the coupler 20 over the MAC Pin 10 and this smooth cannulated tower has an inner set of threads that will operate and engage with the outer second set of threads on the outer portion 14 of the MAC Pin 10 . When the cannulated handle goes over the tip 11 B of the MAC Pin 10 and one rotates the outer cannulated tower 40 with respect to the MAC Pin 10 and because the coupler 20 is fixed to the rod 100 and vertebral body below, as you rotate the shaft 40 over the MAC Pin 10 that begins to pull the MAC Pin 10 in posteriorly within the sagittal plane and obviously the pedicle screw itself threaded within in the vertebral body 202 is going to pull the vertebral body back. So the final and last portion of the post or end of the MAC Pin 10 is simply again some type of squared off structure that will allow potentially a grasp of the MAC Pin so it can be rotated, if desired. The tip of the MAC Pin 10 may be smooth or squared off, it doesn't matter to the function of the MAC Pin because all of the function of the MAC Pin 10 takes place in the second set of threads within the cannulated tower 40 . The MAC Pin 10 is a screw that can be used with an open procedure, but the same pin can be cannulated for the purpose of percutaneous reductions and percutaneous use. The coupler 20 is loose on the non-threaded smooth shaft portion 16 . The coupler 20 that is on the MAC Pin 10 is loose on the smooth shaft portion of the MAC Pin and that relationship is not fixed. So although the tower between the outer diameter of the shaft pin and the inner diameter of the coupler is quite small it does allow the MAC Pin 10 to shift or cam within the coupler 20 so that as you are tightening down the cannulated tower 40 , the MAC Pin 10 is actually shifting or moving with respect to the coupler 20 so that the vertebral body portion of the MAC Pin 10 is remaining fixed. So the MAC Pin 10 within the vertebral body does not move, it only pulls the vertebral body 201 back through the cam action between the cannulated tower 40 and the coupler 20 and the MAC Pin 10 . That is why the MAC Pin 10 is made smooth on that one portion of the pin 10 . As you are pulling the vertebral body 201 back you are rotating the cannulated tower 40 moving outwardly the MAC Pin so the inner threads within the shaft 40 are operating in conjunction with the outer threads of the MAC Pin 10 so that the both sets of threads are slowly driving the vertebral body back within the sagittal plane. The MAC Pin 10 moves fore or aft relation to the rotational direction of the shaft 40 . Importantly, the MAC Pin 10 is not rotating as the cannulated tower 40 rotates and pushes against the coupler 20 . The rod 100 has already been placed in the coupler 20 , the rod 100 and the pedicle screw 110 below are the anchor. The MAC Pin 10 could spin within the coupler 20 at this point, but keep in mind the coupler 20 is fixed to the rod 100 which is fixed to the pedicle screw 110 below. The only motion that is remaining is the camming effect with respect to the MAC Pin 10 inside of the coupler 20 . Once the cannulated tower 40 has reduced the spondylolisthesis to the desired amount the cannulated tower 40 stays in place, one takes the handle or cogwheel 50 off the top and a cannulated wrench 70 is placed over both the cannulated tower 40 and the MAC Pin 10 and goes all the way to the coupler 20 where there is a nut 60 to tighten. As the nut 60 tightens, the relationship between the coupler 20 and MAC Pin 10 becomes fixed. There are two nuts on the coupler 20 , one nut 102 is in order to fix the coupler 20 to the rod 100 , the other nut 60 is placed on the threaded end of the coupler 20 over the MAC Pin 10 . So the nut compresses the coupler at the same hole that accommodates the MAC Pin 10 , so when the coupler is all the way down on the bone one tighten the nut and it fixes the relationship between the MAC Pin 10 and the coupler 20 . When one sends the cannulated tower 40 down the MAC Pin 10 the threads between those two entities are locked together that is what gave the reduction and so you leave that cannulated tower 40 on until one puts the wrench 70 over and tightens the nut 60 . That fixes everything, it fixes the relationship between the coupler 20 and the MAC Pin 10 , therefore locks in the reduction achieved with the vertebral body in place. The nut 60 is sitting there on the coupler 20 and doesn't get tightened until one tightens it with the cannulated wrench 70 . The nut 60 as designed will slide over the cannulated tower 40 and onto the coupler 20 so the nut 60 is going to slide over the shaft 40 and tighten on that slotted thread end area on the coupler 20 and when that area on the coupler 20 gets tightened down it will tighten down on the smooth shaft portion 16 of the MAC Pin 10 .
Interbody fusion is not necessary, but if desired after shearing off MAC Pin post. The only implant you would have would be an interbody implant.
After the instrumentation has been placed after the MAC Pin has been sheared off flush with the coupler, the reduction and the distraction or compression of the spondylolisthesis has been achieved and has been fixed with regard to the instrumentation. If a surgeon chooses at this point to decompress the neural elements or wishes to provide an interbody discectomy fusion or placement of an interbody posterior implant, now is the time that would be performed. At this point again after the instrumentation is complete with respect to the MAC Pin and the rod, a laminectomy or a laminotomy can be performed decompressing the neural elements. At this point a standard posterior lumber interbody fusion or a transforaminal lumbar interbody fusion can be performed. In which case the nerve root that has distracted from the midline and anulotomy is performed and the discwork including a total discectomy endplate preparation, insertion of bone graft material of choice and lastly insertion of a posterior interbody bone graft or cage dependent on surgeon's choice can be placed within the interbody space of the affected motion segment.
In that situation, the inventor has found that after distracting with the rod posteriorly that one can now place an interbody graft within the anterior column of the disc space and create a parallel distraction of the disc height and therefore restoring lordosis. At this point it is also available with this system once the interbody implant has been placed in the anterior column of the intervertebral disc space, it is now possible to leave the coupler and the MAC Pin fixed but if a surgeon wanted to compress on an interbody implant he would then simply go to the lower pedicle screw in the lower vertebral body, loosen the end cap and therefore enable them to compress on the rod thus, interbody implant and then retighten the end caps maintaining the listhesis but allowing once again independent distraction or compression.
With regard to placing the interbody implant, once the instrumentation is performed and the spondylolisthesis is reduced and locked in placed and fixed at that time a laminectomy or a laminotomy can be performed according to the surgeon's indication. At this point also would be a laminotomy and perhaps a posterior lumbar interbody fusion or a transforaminal interbody fusion. Also at that time the vertebral body may be retracted toward the midline and an anulotomy is made, and then finally a discectomy is performed in preparation and insertion of bone graft material according to the surgeon's choice. Once the bone graft has been placed in the interbody space, the surgeon then inserts the posterior interbody graft or cage according to his desire.
After the placement of the interbody structure the surgery would be complete. There is an option if the surgeon wants to create more lordosis, he has two different ways to do that. One would be to insert a large interbody graft anteriorly in the anterior column as one is opening up the anterior disc space creating parallel disc height distraction or even a lordotic alignment. The second method by which the surgeon could create lordosis with this system 1 is at this point once the interbody implant is placed in the anterior column. He can loosen the end caps in the lower vertebral body standard pedicle screw and then perform compression of the rod within the standard pedicle screws at which point he will therefore be compressing not only the interbody graft or cage but also creating a lordotic alignment within the motion segment that has been instrumented. Once that compression takes place, then the surgeon would simply tighten up the end caps in the pedicle screws below and then the entire concept would be rigid and fixed. All the while the spondylolisthesis by virtue of the MAC Pin 10 and the coupler 20 have been made fixed and therefore the spondylolisthesis does not change, this is a unique feature to the system 1 . If a reduction pedicle screw on the lower pedicle screw is locked in the monoaxial position, and forms the anchor by which the reduction screw is going to be utilized using the prior art technique, the surgeon can then not go back and loosen this tulip head or else the reduction would be lost if the reduction screw had changed. This unique system 1 allows that feature which is again another benefit to accuracy and reproducible consistency of the system. The system with regard to rotational control as well as reduction control within that part of the spine. At this point the surgery would be complete and the surgeon would then begin his standard closure.
One of the other features that is unique within the coupler 20 is that the MAC Pin 10 relationship within the coupler 20 not only has a cam relationship that can shift within the coupler 20 up and down, but it also will be able to change angulation with respect to the coupler 20 . That is the MAC Pin 10 will be able to change the angulation with regard to the coupler within the sagittal plane. There is a shaft holding coupling mechanism 90 within the coupler 20 , a separate shaft holding coupling mechanism 90 , within the titanium coupler 20 that moves with relationship to the coupler 20 itself, so as the MAC Pin 10 comes down through the coupler 20 it is also coming through this separate device 90 so that this coupling 90 allows movement within the sagittal plane with respect to the coupler and the importance of that is to allow MAC Pin 10 to enter into the pedicle at the vertebral body at different angles cranial or caudal within the sagittal plane. So that when the coupler 20 and the rod 100 are introduced simultaneously over the MAC Pin 10 , if there is an odd or unexpected angle in order for the caudal aspect of the rod 100 to fall into the top loading tulip of the pedicle screw 110 , this motion within the coupler 20 will accommodate that need. Such that when the coupler 20 is placed over the MAC Pin 10 , and the rod 100 needs to fall down into the space of the tulip head of the pedicle screw 110 below that shaft holding coupling mechanism 90 within the coupler 20 and that motion would then apply to the frame to allow that accommodation to occur. A side to side motion with respect to the device 90 inside the coupler 20 also can be provided to match the couple relationship. That purpose will be to allow surgeons a larger margin of error with regard to the angle at which he places his MAC Pin 10 into the vertebral body. So the system 1 allows for a margin of error respecting the fact that not all surgeons are going to optimally position the device 10 every time. The device 10 automatically can compensate for this fact. The placement of pedicle screws has long been known to be a skill that is developed and learned by each individual spine surgeon. So it was desirable to want to remove as much requirement for the perfect placement of this MAC Pin within the vertebral body as possible, therefore allowing the largest margin of error for surgeons to place the MAC Pin and then connect it through a rod, pedicle screw below. This device within the coupler currently has the ability to move within the sagittal plane both cranial and caudally allows for that and allows the coupler 20 to be attached to the rod 100 in the pedicle screws. Preferably, the coupler 20 is designed with 360 degree motion so as to allow the surgeon margin of error not only in the sagittal plane but also within the coronal plane such that regardless of the surgeons ability to place the MAC Pin 10 appropriately within the vertebral body, the attachment into the rod 100 and the pedicle screw 110 below would be made even easier for that surgeon.
In another embodiment, the device or system 1 provides a percutaneous MAC Pin 10 . The MAC Pin 10 design would be the same; however, it is cannulated inside the entire length pin such that this could be done with a minimally invasive procedure as opposed to an open procedure. That would decrease the patient's postoperative pain, decrease the blood loss, decrease the hospital stay length, as well as decrease the patient's long term postoperative pain. Another benefit of doing this procedure percutaneously is that one could then couple this procedure with an anterior lumbar interbody fusion or perhaps a translateral interbody fusion and use a separate approach while placing these pins and reduce the spondylolisthesis percutaneously or in a minimally invasive technique.
With regard to the coupler 20 , the coupler 20 probably would not change although modification improvements of the coupler 20 are certainly possible. The most important part of the procedures would remain the same the MAC Pin and the fact that under fluoroscopic assistance interoperatively a stab wound in the skin would be made as opposed to a complete opening of the skin and muscle tissue. So a small k wire (kirschner wire) could be inserted into the pedicle and finally into the vertebral body maintaining the above described technique and that would be followed by the placement of MAC Pins that would be cannulated and then attached to the coupler and the pedicle screw below. Similarly described in the open procedure. A jamsheedy needle would be used to place the guide wire into the vertebral body again percutaneously or minimally invasive and this is certainly a standard well known part of the procedure. However, once the guide wire 80 had been placed and confirmed to be in the appropriate placement, per the interoperative fluoroscope and that would be followed by measuring of the pedicle screw portion of the MAC Pin and then placement of the MAC Pin 10 with a cannulated opening 13 over the guide wire 80 and into the vertebral body to appropriate position based on the interoperative fluoroscope.
The next step would be placement of percutaneous pedicle screws, shown in FIGS. 12A-12C , in the previously described placement of percutaneous pedicle screws already established by the assignee of this system as described in co-pending US patent publication 2013/0172937 A1 entitled “Extended Tab bone Screw System” filed Dec. 19, 2012; which is incorporated by reference herein in its entirety; and finally the coupler 20 would be applied over the MAC Pins 10 as described in the open technique and placed within the tulip head below through a minimally invasive being separately described. In another aspect, the two leg extensions are connected via a connector 249 positioned at a point spaced therefrom the first end of the leg extension and spanning the first insertion tool pathway 270 . In one aspect, the connector is positioned substantially perpendicular to the longitudinal axis AL. Positioning the connector 249 a predetermined distance from the first end provides a fulcrum point from which a rod insertion tool can rotate. As seen in FIGS. 19 , 20 and 21 , the stabilizer rod is positioned between the leg extensions with the insertion tool. As the stabilizer rod is positioned lower and toward the second end of the leg extensions, the insertion tool is partially positioned between the leg extensions. At this point, the handle of the insertion tool can be lifted, using the connector as a fulcrum to push the stabilizer rod into position within the rod receiving channel. At that point once again, the end caps on the pedicle screws below would be tightened and fixed once again to serve as an anchor for the MAC Pin after which the surgeon would go back to the MAC Pin 10 and begin the translation and distraction procedure as described above such that after reduction was achieved through the action of the MAC Pin, the cannulated wrench would be slipped over and the nut would once again be tightened and a separate shearing device would be developed to shear the MAC Pin flush with the coupler. And once again the surgeon has achieved a fixed reduced spondylolisthesis that he can now go and perform either anterior lumbar interbody fusion, lateral and foraminal interbody fusion or a posterior lumbar interbody fusion and perhaps even “OLIF” at this point consistent with amendia's portfolio.
Variations in the present invention are possible in light of the description of it provided herein. While certain representative embodiments and details have been shown for the purpose of illustrating the subject invention, it will be apparent to those skilled in this art that various changes and modifications can be made therein without departing from the scope of the subject invention. It is, therefore, to be understood that changes can be made in the particular embodiments described, which will be within the full intended scope of the invention as defined by the following appended claims.
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A spinal alignment correction system ( 1 ) has a posted lumbar pedicle screw called a MAC Pin ( 10 ) which has an elongated shaft ( 11 ) and a rod coupler assembly ( 20 ) and a cannulated tower ( 40 ). The elongated shaft ( 11 ) has an inner pedicle screw portion ( 12 ) with pedicle threads ( 12 A), an outer second thread portion ( 14 ) with second threads ( 14 A) and a transition or intermediate portion ( 16 ) disposed between the pedicle screw portion ( 12 ) and the second thread portion ( 14 ). The cannulated tower ( 40 ) when mounted over said elongated shaft ( 11 ) abuts said coupler ( 20 ) along an outer cam surface and further tightening rotation of the cannulated tower ( 40 ) causes outward movement of the elongated shaft ( 11 ). The system ( 1 ) allows for a controlled alignment correction of malaligned vertebral bodies using a number of methods used to correct a variety of indications.
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FIELD
[0001] The embodiments disclosed herein relate generally to retractable aircraft stabilization struts for stabilizing an aircraft fuselage, e.g., at either the tail or the front of the fuselage, during ground-based loading/unloading operations.
BACKGROUND
[0002] Cargo aircraft typically have a center of gravity (CG) that is typically forward of the main landing gear. There may thus be a tendency during loading/unloading applications for those aircraft equipped with rear cargo ramps for the aircraft to shift about the main landing gear assembly which in turn raises the aircraft nose. In extreme situations, aircraft shifting during loading/unloading could cause a severe tail strike damaging the airframe and/or exposing personnel to injury hazard. For these reasons, it is advisable for cargo aircraft to include additional tail ground-stabilization aft of the main landing gear during loading/unloading operations.
[0003] A variety of aircraft tail stabilization assemblies are generally known. For example, tail stabilization assemblies are known which are positionally fixed and consist of a fixed support that is typically associated with ground-based equipment manually placed under the aircraft. As can be appreciated such fixed stabilization assemblies require the pre-positioning of the ground based equipment as well as a substantial time to install thereby prolonging the loading/unloading operation, each being an obvious disadvantage if the cargo aircraft is being loaded/unloaded in an active combat zone.
[0004] On-board stabilization systems which may be mechanically or manually operated are also known. For example telescopic strut stabilization systems are know that usually employ on-board hydraulic and/or electric actuators. Telescopic strut stabilization systems typically include a main strut and a retraction actuator as the same component.
[0005] An on-board tail jack assembly is also known from U.S. Pat. No. 4,593,871, the entire content of which is expressly incorporated hereinto by reference, which includes a manually activated hydraulic jack system and a strut that may be operatively fixed to the jack system. The operator may thus extend/retract the strut as may be needed to stabilize the tail. However, when not in use, the strut must be physically disconnected from the jack and stored remotely (e.g., as part of the tail stairwell).
[0006] Retractable strut stabilization systems are also know which employ hydraulic and/or electric actuators so as to be capable of deployment between a stowed condition within a strut bay of the aircraft fuselage and an extended condition whereby the strut stabilizes the aircraft tail. Such retractable stabilization systems will typically be equipped with a strut door which can be manually operated or actuated by a mechanism linked to the stabilizer or by a dedicated door actuator.
[0007] Retractable strut stabilization systems however are problematic to operate in the event that the strut is not aligned with the strut bay during retraction. That is, when a retractable strut stabilization system is deployed during an aircraft loading/unloading operation, side loads can be experienced which can cause the strut to become off-centered or misaligned with the strut bay. If the strut is then attempted to be retracted into the strut bay while off-centered or misaligned, it could become jammed thereby precluding operation of the aircraft.
[0008] What has been needed in the art, therefore, are retractable strut assemblies that have a self-aligning mechanism to address the problems associated with the strut being off-centered or misaligned as a result of the aircraft loading/unloading operations. As such, a self-alignable retractable strut assembly would provide a measure of safety and reliability for the cargo aircraft operations. It is towards fulfilling such needs that the embodiments of the invention herein are directed.
SUMMARY
[0009] The embodiments disclosed herein are generally directed toward self-aligning retractable strut stabilization assemblies that are ground engagement in use to stabilize a vehicle, e.g., a cargo aircraft during loading/unloading operations. In certain embodiments, the strut stabilization assembly will be on-board equipment associated with an aircraft that may be actuated (e.g., via on-board hydraulic and/or electric actuation systems) by the aircraft operator so as to stabilize the aircraft during certain ground operations, e.g., cargo and/or personnel loading/unloading operations.
[0010] According to some embodiments, therefore, an aircraft is provided with an on-board self-aligning strut stabilization assembly which is moveable between a retractable position wherein the strut stabilization assembly is housed within a strut bay of the aircraft, and an extended position wherein the strut stabilization assembly is in ground-engaging contact to stabilize an aft portion of the aircraft. The strut stabilization assembly will advantageously include a main strut pivotally connected to supporting structure of the aircraft for pivotal movements between the extended and retracted positions thereof, a strut extension member operatively associated with the main strut for movements between a retracted state and a ground-engaging extended state, an actuator operatively connected to the main strut for moving the main strut and the strut extension member operatively associated therewith between the extended and retracted positions, and a pair of laterally separated double-acting spring-biased centering mechanisms each having one end pivotally attached to the supporting structure of the aircraft and an opposite end attached to the main strut.
[0011] In preferred embodiments, the centering mechanisms will each define a zero-spring bias load state corresponding to an aligned condition of the main strut such that a displacement of the main strut out of the aligned condition responsively causes at least one centering mechanism to exert a spring-biased load in an opposite direction of the displacement causing the at least one centering mechanism to return to the zero-spring bias load state thereby returning the main strut to the aligned condition thereof. The centering mechanisms may comprise extendible extension posts having a terminal end pivotally attached to the supporting structure of the aircraft.
[0012] The strut extension member may be telescopically received within the main strut for reciprocal rectilinear movements between the retracted and ground-engaging states thereof. A ground-engageable foot pad may advantageously be connected to a terminal end of the strut extension member.
[0013] A main strut door may operatively be connected to the main strut for covering the strut assembly when stowed in the strut bay. A main strut door linkage may be provided to operatively link the main strut door to the main strut so as to cause the main strut door to move from between opened and closed states in response to the main strut being pivotally moved between the extended and retracted positions thereof. A secondary strut door may also be provided in which case a linkage yoke operatively mechanically links the secondary strut door the main strut door so that the main and second strut doors are slaved to one another for movements between opened and closed states thereof.
[0014] These and other aspects and advantages of the present invention will become more clear after careful consideration is given to the following detailed description of the preferred exemplary embodiments thereof.
BRIEF DESCRIPTION OF ACCOMPANYING DRAWINGS
[0015] The disclosed embodiments of the present invention will be better and more completely understood by referring to the following detailed description of exemplary non-limiting illustrative embodiments in conjunction with the drawings of which:
[0016] FIG. 1 is a partial side elevational view of a cargo aircraft which includes a retractable self-aligning stabilization strut assembly in accordance with an embodiment of the invention;
[0017] FIG. 2 is a detailed perspective view of the retractable self-aligning stabilization strut assembly in accordance with an embodiment of the invention shown in a retracted position;
[0018] FIG. 3 is detailed perspective view of the self-aligning stabilization strut assembly in accordance with an embodiment of the invention shown in an extended position;
[0019] FIGS. 4-7 show an operational sequence whereby the self-aligning stabilization strut assembly is retracted from its extended operational position ( FIG. 4 ) and into a retracted position whereby the strut assembly is housed within the strut bay ( FIG. 7 );
[0020] FIGS. 8-10 are aft-facing elevational views of the kinematic ranges of motion for the self-aligning strut assembly in accordance with an embodiment of the invention that may occur during lateral displacements of the aircraft;
[0021] FIGS. 11-13 are lateral-facing elevational views of the kinematic ranges of motion for the self-aligning strut assembly in accordance with an embodiment of the invention that may occur during longitudinal (forward and aft) displacements of the aircraft;
[0022] FIG. 14 is a detailed view of the freedoms of motion for the strut stabilization assembly and associated centering mechanism; and
[0023] FIGS. 15-18 are end views of the self-aligning strut assembly in accordance with an embodiment of the invention showing self-alignment when retracted.
DETAILED DESCRIPTION
[0024] Accompanying FIG. 1 depicts a cargo aircraft 10 in which an embodiment of a self-aligning stabilization strut assembly 20 according to the invention may operationally be employed. The exemplary cargo aircraft 10 includes a fuselage 10 - 1 having an aft main cargo ramp 10 - 2 which is shown in an opened condition to allow cargo to be physically loaded into the cargo space 10 - 1 a within the fuselage 10 - 1 .
[0025] The stabilization strut assembly 20 is pivotally moveable into and out of a strut bay 10 - 4 within the fuselage 10 - 1 of the aircraft 10 by way of suitable hydraulic and/or electric actuators (see, e.g., actuator 30 depicted, for example, in FIGS. 2 and 3 ). For example, as is depicted in solid line in FIG. 1 , the stabilization strut assembly 20 is shown as being in an extended and operational position aft of the aircraft main landing gear assembly 10 - 3 in engagement with the ground surface GS to thereby stabilize the aft portion of the aircraft fuselage 10 - 1 when cargo is loaded/unloaded via the ramp 10 - 2 when opened. When the cargo loading/unloading operation is complete, however, the cargo ramp 10 - 2 may be closed and the strut assembly 20 pivotally moved (arrow A 1 ) into a retracted position within the strut bay 10 - 4 of the fuselage 10 - 1 as shown in dashed line in FIG. 1 . Conversely, in preparation for a loading/unloading operation, the stabilization strut assembly 20 may be pivotally moved (arrow A 1 ) from its stowed position within the strut bay 10 - 4 and into an operative ground-engaging position as will be described in greater detail below.
[0026] Accompanying FIGS. 2 and 3 depict the self-aligning strut stabilization assembly 20 disembodied from the aircraft 10 in its retracted and extended positions, respectively. The strut stabilization assembly is generally comprised of main strut 22 which includes a strut extension member 24 which in the embodiment depicted is telescopically received within the main strut 22 and thereby reciprocally rectilinearly extendible (e.g., via suitable hydraulic and/or electrical actuation (not shown)) between a retracted state as shown in FIG. 2 and an extended ground-engaging state as shown in FIG. 3 . The terminal end of the strut extension member 24 includes a foot pad 26 that is adapted to engage the ground surface GS when the strut extension member 24 is in its extended condition as shown in FIG. 3 to provide load transmission from main strut 22 to the ground surface GS.
[0027] The upper end of the main strut 22 is pivotally connected to supporting structure 10 - 5 of the aircraft fuselage 10 - 1 by a pivot pin assembly 28 . A hydraulically or electrically activated actuator 30 is pivotally connected at one end to a support boss 10 - 5 a of the supporting structure 10 - 5 and includes an extensible actuator piston 30 - 1 connected pivotally at its terminal end to a connection lug 22 - 1 associated with the main strut 22 .
[0028] The strut assembly 22 is also provided with main and secondary strut doors 32 , 34 , respectively. The main strut door 32 includes a pair of laterally separated main door hinges 32 a, 32 b. The second strut door 34 is supported by a support bracket 34 b which is connected to the fuselage 10 - 1 of the aircraft 10 by pivot pints 34 a - 1 . A door linkage yoke 36 pivotally interconnects the main door hinges 32 a, 32 b to the secondary door support bracket 34 a. A strut door linkage arm 38 is pivotally connected at one end to the main strut 22 and at an opposite end thereof to the main door 32 so as to operatively link the main strut 22 to the main door 32 . Movement of the main strut 22 between its retracted and extended positions will therefore responsively cause the main strut door to be moved between its closed and opened conditions by virtue of the interconnection therebetween provided by the linkage arm 38 . The mechanical linkage between the main strut door 32 and the secondary strut door 34 provided by way of the door linkage yoke 36 will concurrently cause the secondary strut door 34 to be moved between its closed and opened positions.
[0029] The strut assembly 20 also includes a laterally separated pair of spring-biased centering mechanisms 40 , 42 each having an extension post 40 - 1 , 42 - 1 being journally connected at its terminal end 40 a, 42 a to a proximal end of the main door hinges 32 a, 32 b. The mechanisms 40 , 42 are also journally connected at an end opposite to the ends 40 a, 42 a to the lateral connection lobes 40 b, 42 b of the main strut 22 , respectively. (Only connection lobe 40 b is visible in FIG. 3 , but see for example FIGS. 8-11 .) Each of the centering mechanisms 40 , 42 houses a double-acting spring cartridge (not shown) having a nominal length corresponding to a centered position both laterally and longitudinally relative to the longitudinal axis of the aircraft fuselage 10 . When the strut assembly 20 is in a longitudinally and vertically aligned (centered) position, therefore, each of the centering mechanisms will define a nominal length whereby a zero-spring bias load is presented. Lateral and/or longitudinal movements of the main strut 22 (e.g., that may occur during loading/unloading operations of the aircraft 10 when the strut extension 24 is in engagement with the ground surface GS) will cause extension and/or retraction the extension posts 40 - 1 and/or 42 - 1 which in turn responsively changes the nominal length of at least one of the double acting spring cartridges associated with the centering mechanisms 40 and/or 42 , respectively. This change in the nominal spring length will thereby in turn cause a spring-bias load to be generated in an opposite direction that encourages the extension posts 40 - 1 and/or 42 - 1 to return to their nominal or centered zero-spring bias load state.
[0030] Accompanying FIGS. 4-7 depict an operational sequence to retract the strut assembly 20 into the strut bay 10 - 4 of the aircraft fuselage 10 - 1 . When in the extended position as shown in FIG. 4 , the strut extension member 24 will need to initially be retracted by operation of on-board hydraullically electrically activated actuation systems (not shown) operatively associated with the main strut 22 . The retracted state of the strut extension member 24 relative to the main strut 22 is depicted in FIG. 5 . Thereafter, actuation of the actuator 30 associated with the main strut 22 will therefore cause the actuator arm 30 - 1 to retract thereby responsively causing the main strut 22 to be pivotally moved about the pivot pin assembly 28 . Pivotal movement of the main strut 22 about the pivot pin assembly 28 also responsively cause the main and secondary strut doors 32 , 34 , respectively, to follow due to the mechanically slaved linkage thereby provided by the main strut door linkage yoke 36 and main strut door linkage arm 38 . An intermediate state of the strut retraction is depicted in FIG. 6 . Continued retraction of the main strut 22 will therefore cause it to be fully housed within the strut bay 10 - 4 whereby the main and secondary strut doors 32 , 34 , respectively are flush with the exterior skin of the fuselage 10 - 1 . Such a fully retracted state of the strut assembly 20 is depicted in FIG. 7 . As can be appreciated, when in the retracted position as shown in FIG. 7 , actuation of the actuator 30 will therefore cause the actuator arm 30 - 1 to extend thereby responsively causing the main strut 22 to be pivotally moved about the pivot pin assembly 28 into the extended position as shown in FIG. 4 , i.e., in an operational sequence opposite to that depicted sequentially by FIGS. 4-7 .
[0031] FIGS. 8-10 are aft-facing elevational views of the kinematic ranges of motion for the self-aligning strut assembly 20 that may occur during lateral displacements of the aircraft, it being appreciated that FIG. 9 shows the assembly 20 in a longitudinally aligned (centered) state. FIGS. 11-13 on the other hand are lateral-facing elevational views of the kinematic ranges of motion for the self-aligning strut assembly 20 that may occur during longitudinal (forward and aft) displacements of the aircraft, it being appreciated that FIG. 12 shows the assembly 20 in a vertically aligned (centered) state. It will be noted that the journal connections of the actuator 30 and centering mechanisms 40 , 42 have sufficient play so as to allow predetermined degrees of misalignment relative to the aircraft's longitudinal and vertical axes. Such angular misalignments that are permitted by any of the journal connections of the actuator 30 and centering mechanisms 40 , 42 are also depicted by the dashed lines of FIG. 14 , whereby the solid lines thereof depict the assembly 20 in a longitudinally and vertically aligned state.
[0032] Accompanying FIGS. 15-18 depict an end view of the strut assembly 20 showing how the centering mechanisms 40 , 42 serve to physically return the main strut 22 to its aligned (centered) state to allow full retraction thereof into the strut bay 10 - 4 of the fuselage 10 - 1 .
[0033] While the invention has been described in connection with what is presently considered to be the most practical and preferred embodiment, it is to be understood that the invention is not to be limited to the disclosed embodiment, but on the contrary, is intended to cover various modifications and equivalent arrangements included within the spirit and scope thereof.
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Self-aligning retractable strut stabilization assemblies that are ground engageable in use are provided to stabilize a vehicle, e.g., a cargo aircraft during loading/unloading operations. The strut stabilization assembly may be on-board equipment associated with an aircraft that may be actuated (e.g., via on-board hydraulic and/or electric actuation systems) by the aircraft operator so as to stabilize the aircraft during certain ground operations, e.g., cargo and/or personnel loading/unloading operations. A laterally separated pair of centering mechanisms are attached to the main strut and define a zero-spring bias load state corresponding to an aligned condition of the main strut. Displacement of the main strut out of the aligned condition responsively causes at least one centering mechanism to exert a spring-biased load in an opposite direction of the displacement causing the at least one centering mechanism to return to the zero-spring bias load state thereby returning the main strut to the aligned condition thereof.
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CROSS REFERENCE TO RELATED APPLICATIONS
[0001] This application is a continuation of and claims the benefit of priority under 35 U.S.C. §120 from U.S. application Ser. No. 13/601,134, filed Aug. 31, 2012, which is a continuation of U.S. application Ser. No. 11/957,876, filed Dec. 17, 2007, now U.S. Pat. No. 8,256,430, which is a divisional of U.S. application Ser. No. 10/701,834, filed Nov. 5, 2003, now U.S. Pat. No. 7,344,529, which is a continuation-in-part of U.S. application Ser. No. 10/014,846, filed Dec. 14, 2001, now U.S. Pat. No. 7,167,741, the entire contents of each of which is incorporated herein by reference, and which is a continuation-in-part of International Application No. PCT/CA01/00905, filed Jun. 15, 2001, which claims priority to U.S. application Ser. No. 09/593,699, filed Jun. 15, 2000, now U.S. Pat. No. 6,418,337.
BACKGROUND OF THE INVENTION
[0002] The treatment of tumors by hyperthermia is known. In one known process, tumors and other lesions to be treated can be heated above a predetermined temperature of the order of 55 C so as to coagulate the portion of tissue heated. The temperature range is preferably of the order of 55 to 65 C and does not reach temperatures that can cause carbonization or ablation of the tissue.
[0003] One technique for effecting the heating is to insert into the lesion concerned an optical fiber, which has at its inserted end an element that redirects laser light from an exterior source in a direction generally at right angles to the length of the fiber. The energy from the laser thus extends into the tissue surrounding the end or tip and effects heating. The energy is directed in a beam confined to a relatively shallow angle so that, as the fiber is rotated, the beam also rotates around the axis of the fiber to effect heating of different parts of the lesion at positions around the fiber. The fiber can thus be moved longitudinally and rotated to effect heating of the lesion over the full volume of the lesion with the intention of heating the lesion to the required temperature without significantly affecting tissue surrounding the lesion. We define the term “lesion” as used herein to mean any pathologic change in the tissue or organs of a mammalian subject including, but not limited to, tumors, aortic or other aneurysms, artery and vein malformations such as thrombosis, hemorrhages, and embolisms.
[0004] At this time the fiber is controlled and manipulated by a surgeon with little or no guidance apart from the knowledge of the surgeon of the anatomy of the patient and the location of the lesion. It is difficult therefore for the surgeon to effect a controlled heating which heats the entire lesion while minimizing damage to surrounding tissue.
[0005] It is of course well known that the location of tumors and other lesions to be excised can be determined by imaging using a magnetic resonance imaging system. The imaging system thus generates for the surgeon a location of the lesion to be excised but there is no system available which allows the surgeon to use the imaging system to control the heating effect. In most cases it is necessary to remove the patient from the imaging system before the treatment commences and that movement together with the partial excision or coagulation of some of the tissue can significantly change the location of the lesion to be excised thus eliminating any possibility for controlled accuracy.
[0006] It is also known that magnetic resonance imaging systems can be used by modification of the imaging sequences to determine the temperature of tissue within the image and to determine changes in that temperature over time.
[0007] U.S. Pat. No. 4,914,608 (LeBiahan) assigned to U.S. Department of Health and Human Services issued Apr. 3, 1990 discloses a method for determining temperature in tissue.
[0008] U.S. Pat. No. 5,284,144 (Delannoy) also assigned to U.S. Department of Health and Human Services and issued Feb. 8, 1994 discloses an apparatus for hyperthermia treatment of cancer in which an external non-invasive heating system is mounted within the coil of a magnetic resonance imaging system. The disclosure is speculative and relates to initial experimentation concerning the viability of MRI measurement of temperature in conjunction with an external heating system. The disclosure of the patent has not led to a commercially viable hyperthermic treatment system.
[0009] U.S. Pat. Nos. 5,368,031 and 5,291,890 assigned to General Electric relate to an MRI controlled heating system in which a point source of heat generates a predetermined heat distribution which is then monitored to ensure that the actual heat distribution follows the predicted heat distribution to obtain an overall heating of the area to be heated. Again this patented arrangement has not led to a commercially viable hyperthermia surgical system.
[0010] An earlier U.S. Pat. No. 4,671,254 (Fair) assigned to Memorial Hospital for Cancer and Allied Diseases and issued Jun. 9, 1987 discloses a method for a non surgical treatment of tumors in which the tumor is subjected to shock waves. This does not use a monitoring system to monitor and control the effect.
[0011] U.S. Pat. No. 5,823,941 (Shaunnessey) not assigned issued Oct. 20, 1998 discloses a specially modified endoscope which designed to support an optical fiber which emits light energy and is moved longitudinally and rotates angularly about its axis to direct the energy. The device is used for excising tumors and the energy is arranged to be sufficient to effect vaporization of the tissue to be excised with the gas thus formed being removed by suction through the endoscope. An image of the tumor is obtained by MRI and this is used to program a path of movement of the fiber to be taken during the operation. There is no feedback during the procedure to control the movement and the operation is wholly dependent upon the initial analysis. This arrangement has not achieved commercial or medical success.
[0012] U.S. Pat. No. 5,454,807 (Lennox) assigned to Boston Scientific Corporation issued Oct. 3, 1995 discloses a device for use in irradiating a tumor with light energy from an optical fiber in which in conjunction with a cooling fluid which is supplied through a conduit with the fiber to apply surface cooling and prevent surface damage while allowing increased levels of energy to be applied to deeper tissues. This arrangement however provides no feedback control of the heating effect.
[0013] U.S. Pat. No. 5,785,704 (Bille) assigned to MRC Systems GmbH issued Jul. 28, 1996 discloses a particular arrangement of laser beam and lens for use in irradiation of brain tumors but does not disclose methods of feedback control of the energy. This arrangement uses high speed pulsed laser energy for a photo-disruption effect.
[0014] Kahn, et al. in Journal of Computer Assisted Tomography 18 (4):519-532, July/August 1994; Kahn, et al. in Journal of Magnetic Resonance Imaging 8: 160-164, 1998; and Vogl, et al. in Radiology 209: 381-385, 1998 all disclose a method of application of heat energy from a laser through a fiber to a tumor where the temperature at the periphery of the tumor is monitored during the application of the energy by MRI. However none of these papers describes an arrangement in which the energy is controlled by feedback from the monitoring arrangement. The paper of Vogl also discloses a cooling system supplied commercially by Somatex of Berlin Germany for cooling the tissues at the probe end. The system is formed by an inner tube through which the fiber passes mounted within an outer tube arrangement in which cooling fluid is passed between the two tubes and inside the inner tube in a continuous stream.
BRIEF SUMMARY OF THE INVENTION
[0015] It is one object of the present invention, therefore, to provide an improved method and apparatus for effecting treatment of a patient by hyperthermia.
[0016] According to a first aspect of the invention there is provided a method for effecting treatment in a patient comprising:
Identifying a volume in the patient the whole of which volume is to be heated to a required temperature, the volume being defined by a peripheral surface of the volume; providing a heat source and applying heat to the volume within the patient by; providing the heat source on an invasive probe having a longitudinal axis and an end; inserting the end of the probe into the volume; arranging the probe to cause directing of heat from the end in a direction at an angle to the longitudinal axis such that a heating effect of the probe lies in a disk surrounding the axis; arranging the direction of the heat so as to define a heating zone which forms a limited angular orientation of heating within the disk such that, as the probe is rotated, the probe causes heating of different angular segments of the volume within the disk; with the probe at a fixed axial position, rotating the probe about the axis so that the heating zone lies in a selected segment; wherein the application of heat by the probe to the selected segment causes heat to be transferred from the segment into parts of the volume outside the segment surrounding the end of the probe; and applying cooling to the end of the probe so as to extract heat from the parts surrounding the probe by conduction of heat therefrom.
[0026] Cooling of the probe may be optional. For example, when utilizing focused ultrasound and e-beam energy, cooling may not be as relevant or may not be required. With ultrasound energy, fluid may be used as the conduction medium as more specifically describe below. When cooling is used, preferably the amount of cooling to the probe is arranged relative to the heating such that the parts of the volume surrounding the end of the probe are cooled sufficiently to cause a net heating effect by which substantially only the segment of the heating zone is heated to the required temperature and the parts outside the segment are not heated to the required temperature. This is preferably arranged so that the cooling maintains the parts outside the segment below a temperature sufficient to cause coagulation of the tissues therein. Thus when the probe is rotated to take up a new angle within a new segment, the tissue in the new segment is not in a condition by pre-heating that would interfere with the transmission and diffusion of the heat to that segment.
[0027] The arrangement of the present invention, that is the method defined above or the method or probe defined hereinafter, can be used on a rigid probe which is intended to be inserted in a straight line into a specific location in the body of the patient, or can be used on a flexible probe which can be guided in movement through a part of the body such as a vein or artery to a required location.
[0028] While the most likely and currently most suitable energy source is that of laser light, the arrangements described and defined herein can also be used with other energy sources of the type which can be directed at an angle from the axis of the probe through which they are supplied such as electron beams or ultrasound generators.
[0029] In one exemplary arrangement, the above method can be used with MRI real time control of the surgery by which a non-invasive detection system, such as MR1, is operated to generate a series of output signals over a period of time representative of temperature in the patient as the temperature of the patient changes during that time. The output signals are used to monitor at least one temperature of the volume as the temperature changes over the period of time. The application of heat to the probe is then controlled in response to the changes in temperature wherein the temperature at the peripheral surface of the volume is monitored and a measure of the temperature at a location on the peripheral surface of the volume is used as the determining factor as to when to halt heating by the probe to the location. However the cooling effect can be used without the MRI monitoring to provide an enhanced system in which the whole of the volume required can be heated to the required temperature.
[0030] In the method in which temperature is monitored, the determination as to when to halt heating by the probe to the location is made based upon the temperature at the peripheral surface of the volume, with the exception that temperatures within the volume may be monitored to ensure that no serious or dangerous over-temperature occurs within the volume due to unexpected or unusual conditions. Thus any such over-temperature may be detected and used to halt further treatment or to trigger an alarm to the doctor for analysis of the conditions to be undertaken.
[0031] When used as a rigid probe for treatment within a body part such as the brain or liver, the probe itself may be sufficiently rigid and strong to accommodate the forces involved and not require the use of a cannula or, alternatively, there may be provided a cannula through which the probe is inserted, the cannula having an end which is moved to a position immediately adjacent but outside the volume and the probe having a rigid end portion projecting from the end of the cannula into the volume. When used as a non-rigid probe for treatment within a body part such as the brain or liver, the probe itself may require the use of a cannula through which the probe is inserted as described herein.
[0032] In one embodiment of the present invention, the heat source comprises a laser, an optical fiber for communicating light from the laser and a light-directing element at an end of the fiber for directing the light from the laser to the predetermined direction relative to the fiber forming the limited angular orientation within the disk.
[0033] In accordance with one embodiment of the present invention which provides the necessary level of cooling in a readily controllable process, the end of the probe is cooled by liquid-to-liquid, liquid-to-gas and gas-to-gas cooling by:
providing on the probe a supply duct for a cooling fluid extending from a supply to the end of the probe; providing an expansion zone of reduced pressure at the end of the probe so as to cause the cooling fluid to expand as a gas thus generating a cooling effect; and providing on the probe a return duct for return of the expanded gas from the end of the probe.
[0037] In this arrangement, the return duct is preferably of larger cross-sectional area than the supply duct and the supply duct includes a restricting orifice at its end where the return duct is larger in cross-sectional area by a factor of the order of 200 times larger than the orifice of the supply duct.
[0038] Preferably where the probe comprises a tube the supply duct is arranged inside the tube and the return duct is defined by an inside surface of the tube.
[0039] In this arrangement, the supply duct is attached as tube to an inside surface of the tube and the fiber itself is attached also to the inside.
[0040] In this arrangement, the orifice is provided by a restricting valve or neck in the supply duct immediately upstream of the expansion chamber at the end of the probe.
[0041] Where the fiber has a chamfered end of the fiber it may include a reflecting coating thereon for directing the light energy to the side. The arrangement of the chamfered end can have the advantage or feature that the chamfered end is located in the gas rather than being wetted by cooling fluid which can, when there is no coating, interfere with the reflective properties of the coating and thus with the proper control and direction of the light.
[0042] In this arrangement, the chamfered end can be arranged directly at 45 degrees to provide a light direction lying wholly in a radial plane at right angles to the axis of the fiber. The chamfered end may carry a coating arranged to reflect light at two different wavelengths.
[0043] In order to accurately control the cooling effect to maintain the net heating required, there is preferably provided a temperature sensor at the end of the probe, which may be located inside the tube with the connection therefor passing through the probe to the control system outside the probe.
[0044] Preferably the temperature at the end of the probe is controlled by varying the pressure in the fluid as supplied through the supply duct. This system can allow the temperature to be maintained between about zero and minus 20 degrees Celsius, which provides the required level of cooling to the probe for the net heating effect.
[0045] According to a second aspect of the invention there is provided a method for effecting treatment in a patient comprising:
identifying a volume in the patient to be heated to a required temperature; providing a heat source for applying heat to the volume within the patient, providing a probe mounting the heat source allowing invasive insertion of an end of the probe into the patient, providing a position control system for moving the end of the probe to a required position within the patient; inserting the end of the probe into the volume; providing on the probe a supply duct for a cooling fluid extending from a supply to the end of the probe; providing an expansion zone of reduced pressure at the end of the probe so as to cause the cooling fluid to expand as a gas thus generating a cooling effect; and providing on the probe a return duct for return of the expanded gas from the end of the probe.
[0054] According to a third aspect of the invention there is provided a probe for use in effecting treatment in a patient comprising:
a heat source for applying heat to a volume within the patient, a probe body mounting the heat source thereon for allowing invasive insertion of an end of the probe into the patient, a supply duct on the probe body for a cooling fluid extending from a supply to the end of the probe; the probe body being arranged to provide an expansion zone of reduced pressure at the end of the probe body so as to cause the cooling fluid to expand as a gas thus generating a cooling effect; and a return duct on the probe body for return of the expanded gas from the end of the probe.
[0060] According to a fourth embodiment of the present invention there is provided a method of applying heat to tissue in vivo comprising:
identifying a quantity of tissue as a target; inserting an elongate transmitting medium percutaneously and feeding said elongate transmitting medium toward said target until a distal end of said elongate transmitting medium is operationally proximate said target; applying energy to said target by sending energy through said elongate transmitting medium, said energy exiting said distal end and heating said target; monitoring said energy application to ensure surrounding non-targeted tissue is not damaged by heat; determining whether the entire targeted area has been heated; if necessary, translating said elongate transmitting medium to an unheated area of said target; applying energy to said unheated area of said target.
[0068] The step of identifying a quantity of tissue as a target may be accomplished by analyzing magnetic resonance images and mapping out the extents of a tumor imaged thereby; or by conducting a body contouring analysis to determine areas of fatty tissue to be removed; or by analyzing magnetic resonance images to locate a lesion imaged thereby.
[0069] The step of inserting an elongate transmitting medium percutaneously and feeding said elongate transmitting medium toward said target until a distal end of said elongate transmitting medium is operationally proximate said target may be accomplished by:
determining a safest straight path between the skull and the target; forming a hole in the skull; inserting said elongate transmitting medium through said hole toward said target until said distal end of said elongate transmitting medium is operationally proximate said target
[0073] Alternatively, the step of inserting an elongate transmitting medium percutaneously may include the step of inserting a cannula into said hole until a distal end of said cannula is operably proximate said target;
securing the cannula relative the skull; and inserting said elongate transmitting medium through said cannula toward said target until said distal end of said elongate transmitting medium is operationally proximate said target; or by: inserting said elongate transmitting medium in an artery; feeding said elongate transmitting medium through the artery until a distal end of the elongate transmitting medium is operationally proximate a lesion or other target; or by percutaneously inserting the elongate transmitting medium proximate an area of fat targeted for heat treatment.
[0080] The step of applying energy to the target through the elongate transmitting medium may be accomplished by sending light, laser, collimated, or non-collimated, through an optical fiber. More specifically, this step may be accomplished by:
a) causing said energy to exit said distal end at an angle, greater than zero, to a longitudinal axis of the elongate transmitting medium; b) rotating said elongate transmitting medium around said longitudinal axis, thereby creating a shaped area of treated tissue; c) advancing said elongate transmitting medium; d) repeating steps a)-c) until the entire target has been heated.
[0085] Step a) may be accomplished by causing said energy to exit said distal end approximately perpendicularly to said longitudinal axis of the elongate transmitting medium such that performing step b) results in a shaped area of treated tissue that is disc-shaped; or by causing said energy to exit said distal end at an angle other than perpendicular to said longitudinal axis of the elongate transmitting medium such that performing step b) results in a shaped area of treated tissue that is cone-shaped.
[0086] Alternatively, the step of applying energy to said target by sending energy through said elongate transmitting medium, said energy exiting said distal end and heating said target, may be accomplished by allowing said energy to exit said distal end along a longitudinal axis of the elongate transmitting medium.
[0087] The step of monitoring said energy application to ensure surrounding non-targeted tissue is not damaged by heat may be accomplished by taking temperature readings on non-targeted tissue immediately adjacent said targeted tissue; or by cycling cooling fluid to and from the distal end of the elongate transmitting medium as necessary to prevent damaging said surrounding nontargeted tissue.
[0088] A fifth embodiment of the present invention provides a method of destroying unwanted fat cells comprising:
a) identifying fat cells to be destroyed thereby defining a target that is a volume of fat cells; b) percutaneously inserting a probe having a distal end capable emitting energy; c) positioning said probe such that said distal end is operationally proximate said target; d) emitting energy from the distal end of the probe sufficient to destroy fat cells; e) moving the distal end of the probe through the volume of fat cells and emitting energy from the distal end, either successively or simultaneously, until the targeted volume of fat cells has been destroyed.
[0094] This method may also include cooling the distal end of the probe to prevent overheating cells that are not included in the volume of fat cells.
[0095] A sixth embodiment of the present invention provides a method of coagulating blood in a vascular lesion that includes
a) identifying a vascular lesion; b) percutaneously inserting a probe having a distal end capable emitting energy; c) positioning said probe such that said distal end is operationally proximate said lesion; d) emitting energy from the distal end of the probe sufficient to coagulate said vascular lesion wherein said coagulation results in cessation or reduction of flow to said vascular lesion.
[0101] Step b) may include forming an entry hole in the skull of the patient, fastening a cannula to the entry hole that is constructed and arranged to create an insertion path for a rigid or nonrigid probe that is aimed directly at the lesion, and inserting the probe into the cannula.
[0102] A seventh embodiment of the present invention provides a method of repairing, reconstruction or removing tissue comprising:
a) identifying a target that comprises healthy tissue to be repaired, reconstructed or removed; b) percutaneously inserting a probe having a distal end capable emitting energy; c) positioning said probe such that said distal end is operationally proximate said target; d) emitting energy from the distal end of the probe sufficient to repair, reconstruct or remove said target; e) moving the distal end of the probe through the target tissue and emitting energy from the distal end, either successively or simultaneously, until the targeted volume has been repaired, reconstructed or removed.
[0108] This method may also include cooling the distal end of the probe to prevent overheating cells that are not included in the targeted tissue.
[0109] The method may also include targeting healthy tissue or targeting scar tissue.
BRIEF DESCRIPTION OF THE DRAWINGS
[0110] FIG. 1 is a schematic illustration of an apparatus for effecting MRI guided laser treatment according to the present invention.
[0111] FIG. 2 is a schematic illustration of the apparatus of FIG. 1 on an enlarged scale and showing the emission of laser energy into the brain of a patient.
[0112] FIG. 3 is a side elevation of the laser probe of the apparatus of FIG. 1 .
[0113] FIG. 4 is an end elevation of the laser probe of the apparatus of FIG. 1 .
[0114] FIG. 5 is a cross-sectional view of the laser probe and drive motor therefor of the apparatus of FIG. 1 .
[0115] FIG. 6 is an exploded view of the drive motor of the apparatus of FIG. 1 .
[0116] FIG. 7 is a schematic illustration of the shielding of the apparatus of FIG. 1 .
[0117] FIG. 8 is a schematic illustration of the effect of the apparatus on a tumor or other lesion to be coagulated.
[0118] FIG. 9 is a longitudinal cross-sectional view through an alternative form of a probe that provides a flow of cooling fluid to the end of the probe for cooling the surrounding tissue.
[0119] FIG. 10 is a cross-sectional view along the lines 10 - 10 of FIG. 9 .
[0120] FIG. 11 is a longitudinal cross-sectional view through a further alternative form of probe which provides a flow of cooling fluid to the end of the probe for cooling the surrounding tissue.
[0121] FIG. 12 is a cross-sectional view along the lines 12 - 12 of FIG. 11 .
[0122] FIG. 13 is a photograph of a cross-section of a tissue sample that has been heated in three separate segments showing the absence of heating outside the segments.
DETAILED DESCRIPTION OF THE INVENTION
[0123] In FIG. 1 is shown schematically an apparatus for carrying out MRI controlled laser treatment. The apparatus comprises a magnetic resonance imaging system including a magnet 10 provided within a shielded room 11 . The magnet 10 can be of any suitable construction and many different magnet arrangements are available from different manufacturers. The magnet includes field coils for generating variations in the magnetic field which are not shown since these are well known to one skilled in the art together with a radio frequency antenna coil which receives signals from the sample in this case indicated as a human patient 13 .
[0124] The patient 13 rests upon a patient support table 14 on which the patient is supported and constrained against movement for the operative procedure. The fields of the magnet are controlled on an input control line 15 and the output from the antenna coil is provided on an output line 16 both of which communicate through a surgeon interface 17 to the conventional MRI control console 18 . The MRI console and the magnet are shown only schematically since these are well known to one skilled in the art and available from a number of different manufacturers.
[0125] The apparatus further includes a laser treatment system including an optical fiber assembly 20 that transmits heat energy in the form of light from a laser 21 mounted outside the room 11 . The fiber assembly 20 extends from the laser 21 to a terminus 36 ( FIG. 2 ), from which the energy escapes into the relevant part of the patient 13 as discussed hereinafter. The position of the fiber assembly 20 within the patient 13 and the orientation of the fiber are controlled by a drive motor 22 supported in fixed adjustable position on a stereotaxic frame 23 . The motor communicates through a control line 24 to a device controller 25 . In general the device controller 25 receives information from the MRI console 18 and from position detectors of the motor 22 and uses this information to control the motor 22 and to operate a power output from the laser 21 , thereby controlling the position and amount of heat energy applied to the part within the body of the patient 13 .
[0126] In FIG. 2 is shown on a larger scale the patient table 14 . The stereotaxic frame 23 is attached to the table 14 and extends over the head 26 of the patient 13 . The frame 23 is shown schematically and suitable details will be well known to one skilled in the art, but carries the motor 22 in a position on the frame 23 through the use of a motor bracket 27 . The position of the motor 22 on the frame 23 remains fixed during the procedure but can be adjusted in the arcuate direction 28 around the arch of the frame 23 . The frame 23 can also be adjusted forwardly and rearwardly on the table 14 . The bracket 27 also allows rotation of the motor 22 about a point 30 within the frame 23 so that the direction of the fiber assembly 20 projecting forwardly from the motor 22 can be changed relative to the frame. 23 .
[0127] Referring now to FIG. 3 , the basic components of the fiber assembly 20 of the apparatus are shown. The fiber assembly 20 includes a rigid cannula 31 surrounding a glass fiber element 35 , and arranged to allow sliding and rotational movement of the fiber element 35 within the cannula 31 while holding the fiber element 35 in a direction axial of the cannula. 31 . The cannula 31 is formed of a suitable rigid MRI compatible material such as ceramic so that it is stiff and resistant to bending and has sufficient strength to allow the surgeon to insert the cannula 31 into the required location within the body part of the patient. 13 .
[0128] In the arrangement as shown, the apparatus is arranged for operating upon a tumor 32 ( FIG. 2 ) within the brain 33 of the patient. 13 . The surgeon therefore creates an opening 34 in the skull of the patient 13 and directs the cannula 31 , in the absence of the rest of the fiber assembly 20 , through the opening 34 to the front edge of the tumor 32 . The cannula 31 , once in place, will act as a guide for the remainder of the fiber assembly 20 .
[0129] The position of the tumor 32 is determined in an initial set of MRI experiments using conventional surgical and an analytical techniques to define the boundaries, that is a closed surface within the volume of the brain 33 which constitutes the extremities of the tumor 32 . The surgical analysis by which the surgeon determines exactly which portions of the material of the patient 13 should be removed is not a part of this invention except to say that conventional surgical techniques are available to one skilled in the art to enable an analysis to be carried out to define the closed surface.
[0130] The angle of insertion of the cannula 31 is selected to best avoid possible areas of the patient 13 that should not be penetrated, such as major blood vessels, and also so the cannula 31 is pointed toward a center of the tumor 32 .
[0131] The fiber assembly 20 further includes an actual glass fiber element 35 , which has an inlet end (not shown) at the laser 21 and a terminus 36 . At the terminus 36 is provided a reflector or prism, which directs the laser energy in a beam 37 to one side of the terminus 36 . Thus the beam 37 is directed substantially at right angles to the length of the fiber and over a small angle around the axis of the fiber. The beam 37 forms a cone having a cone angle of the order of 12 to 15 degrees. Such fibers are commercially available including the reflector or prism for directing the light at right angles to the length of the fiber.
[0132] The fiber element 35 is encased to allow the fiber element 35 to be manipulated in the motor 22 . Around the fiber element 35 is a sleeve 38 including a first end portion 39 and a longer second portion 40 . The end portion 39 encloses the terminus 36 , which is spaced from a tip 41 of the end portion 39 . The end portion 39 has a length on the order of 7 to 11 cm. The second portion 40 is on the order of 48 to 77 cm in length and extends from a forward end 141 through to a rear end 42 . The first end portion 39 is formed of a rigid material such as glass. The second portion 40 is formed of a stiff material which is less brittle than glass and yet maintains bending and torsional stiffness of the fiber element 35 so that forces can be applied to the second portion 40 to move the terminus 36 of the fiber element 35 to a required position within the tumor 32 . The second portion 40 is formed of a material such as fiber-reinforced plastics.
[0133] The two portions 39 and 40 are bonded together to form an integral structure of common or constant diameter selected as a sliding fit through the cannula 31 . The first end portion 39 and the cannula 31 are sized so that it the first end portion 39 can extend from the distal end of the cannula 31 and reach a distal end of the tumor 32 . An average tumor might have a diameter of the order of 0.5 to 5.0 cm so that the above length of the forward portion is sufficient to extend through the full diameter of the tumor 32 while leaving a portion of the order of 1.25 cm within the end of the cannula 31 . In this way, the substantially rigid first end portion 39 remains relatively coaxial with the cannula 31 .
[0134] The second portion 40 has attached to it a polygonal or non-circular section 44 and a stop section 45 , both of which act as attachment points for rotational and longitudinal sections, respectively. Thus the polygonal section 44 is arranged to co-operate with a drive member that acts to rotate the second portion 40 and therefore the fiber element 35 . The stop section 45 is arranged to co-operate with a longitudinally movable drive element that moves the second portion 40 , and therefore the fiber element 35 , longitudinally. In this way the terminus 36 can be moved from an initial position, just beyond the outer end of the cannula 31 , outwardly into the body of the tumor 32 until the tip reaches the far end of the tumor 32 . In addition the terminus 36 can be rotated around the axis of the fiber element 35 so that heat energy can be applied at selected angles around the axis. By selectively controlling the longitudinal movement and rotation of the terminus 36 , therefore, heat energy can be applied throughout a cylindrical volume extending from the end of the cannula 31 along the axis of the cannula 31 away from the end of the cannula. 31 . In addition by controlling the amount of heat energy applied at any longitudinal position and angular orientation, the heat energy can be caused to extend to required depths away from the axis of the cannula 31 so as to effect heating of the body part of the patient 13 over a selected volume with the intention of matching the volume of the tumor 32 out to the predetermined closed surface area defining the boundary of the tumor 32 .
[0135] As shown in FIG. 4 , the non-circular cross-section of section 44 is rectangular with a height greater than the width. However of course other non-circular shapes can be used provided that the cross-section is constant along the length of the non-circular section 44 and provided that the non-circular section 44 can co-operate with a surrounding drive member to receive rotational driving force therefrom. The stop section 45 is generally cylindrical with a top segment 45 A removed to assist the operator in insertion of the fiber into the drive motor.
[0136] Turning now to FIGS. 5 and 6 , the drive motor 22 is shown in more detail for effecting a driving action on the fiber through the sections 44 and 45 into the sleeve 38 for driving longitudinal and rotational movement of the terminus 36 .
[0137] The drive motor comprises a housing 50 formed by an upper half 51 and a lower half 52 both of semi-cylindrical shape with the two halves engaged together to surround the sections 44 and 45 with the sleeve 38 extending axially along a center of the housing. 50 . At the front 53 of the housing 50 is provided a boss defining a bore 54 within which the sleeve 38 forms a sliding fit. This acts to guide the movement of the sleeve at the forward end of the housing.
[0138] Within the housing is provided a first annular mount 55 and a second annular mount 56 spaced rearwardly from the first. Between the first annular mount 55 and the front boss is provided a first encoder 57 and behind the second annular mount 56 is provided a second encoder 58 . The first annular mount 55 mounts a first rotatable drive disk 59 on bearings 60 . The second annular mount carries a second drive disk 61 on bearings 62 . Each of the drive disks is of the same shape including a generally flat disk portion with a cylindrical portion 63 on the rear of the disk and lying on a common axis with the disk portion. The bearings are mounted between a cylindrical inner face of the annular portion 55 , 56 and an outside surface of the cylindrical portions 63 . Each of the disks is therefore mounted for rotation about the axis of the fiber along the axis of the housing.
[0139] The disk 59 includes a central plug portion 64 , which closes the center hole of the disk portion and projects into the cylindrical portion 63 . The plug portion has a chamfered or frustoconical lead in section 65 converging to a drive surface 66 surrounding the section 44 and having a common cross-sectional shape therewith. Thus the tip portion 41 of the sleeve 38 can slide along the axis of the housing and engage into the conical lead in section 65 so as to pass through the drive surface or bore 66 until the section 44 engages into the surface 66 . In the position, rotation of the disk 59 drives rotation of the sleeve 38 and therefore of the fiber. As the noncircular section 44 has a constant cross-section, it can slide through the drive surface 66 forwardly and rearwardly.
[0140] The disk 61 includes a plug member 67 , which engages into the central opening in the disk member 61 . The plug 67 has an inner surface 68 , which defines a female screw thread for co-operating with a lead screw 69 . The lead screw 69 has an inner bore 70 surrounding the sleeve 38 so that the sleeve 38 is free to rotate and move relative to the bore 70 . The lead screw 69 also passes through the cylindrical portion 63 of the disk 61 . Rotation of the disk 61 acts to drive the lead screw longitudinally along the axes of the housing and the sleeve 38 . A rear end 71 of the lead screw is attached to a clamping member 72 . The clamping member 72 includes a first fixed portion 73 attached to the rear end 71 of the lead screw and a second loose portion 74 which can be clamped into engaging the fixed portion so as to clamp the end stop members 45 in position within the clamping member. The loose portion 74 is clamped in place by screws 75 . The top segment 45 A of the end stop 45 engages into a receptacle 76 in the fixed portion 73 so as to orient the sleeve 38 relative to the lead screw.
[0141] The disks 59 and 61 are driven in a ratcheting action by drive motors 77 and 78 respectively. In an exemplary embodiment the drive motors are provided by piezoelectric drive elements in which a piezoelectric crystal is caused to oscillate thus actuating a reciprocating action that is used to drive by a ratchet process angular rotation of the respective disk.
[0142] The reciprocating action of the piezoelectric crystal 77 and 78 is provided by two such motors 77 co-operating with the disk 59 and two motors 78 co-operating with the disk 61 . Each motor is carried on a mounting bracket 77 A, 78 A that is suitably attached to the housing. The end clamp 72 is generally rectangular in cross-section and slides within a correspondingly rectangular cross-section duct 72 A within the housing. Thus the lead screw 69 is held against rotation and is driven axially by the rotation of the disk 61 while the fiber is free to rotate relative to the lead screw. The use of a piezoelectric crystal to drive disks is particularly suitable and provides particular compatibility with the MRI system but other drive systems can also be used as set forth previously.
[0143] In other alternative arrangements (not shown), the ratcheting action can be effected by a longitudinally moveable cable driven from the device controller 25 outside the room 11 . In a further alternative arrangement, the motor may comprise a hydraulic or pneumatic motor which again effects a ratcheting action by reciprocating movement of a pneumatically or hydraulically driven prime mover. Thus selected rotation of a respective one of the disks can be effected by supplying suitable motive power to the respective motor.
[0144] The respective encoder 57 , 58 detects the instantaneous position of the disk and particularly the sleeve portion 63 of the disk, which projects into the interior of the encoder. The sleeve portion therefore carries a suitable element, which allows the encoder to accurately detect the angular orientation of the respective disk. In this way the position of the disks can be controlled by the device controller 25 accurately moving the disk 59 to control the angular orientation of the fiber and accurately moving the disk 61 to control the longitudinal position of the fiber. The longitudinal position is obtained by moving the lead screw, which carries the end stop 45 . The movements are independent so that the fiber can be rotated while held longitudinally stationary.
[0145] As the motor driving movement of the fiber is used while the magnet and the MRI system is in operation, it is essential that the motor and the associated control elements that are located within the room 11 are compatible with the MRI system. For this purpose, the power supply or control cable 24 and the motor must both be free from ferromagnetic components that would be responsive to the magnetic field. In addition it is necessary that the motor 22 and the cable 24 are both properly shielded against interference with the small radio frequency signals that must be detected for the MRI analysis to be effective.
[0146] Referring now to FIG. 7 , the room 11 is shielded to prevent radio waves from penetrating the walls of the room 11 and interfering with the proper operation of the MRI machine 10 . Additionally, the cable 24 and the motor 22 are surrounded by a conductor 80 , which extends through an opening 81 in the wall of the room 11 . The conductor also passes through a cable port 82 within a wall 83 of the enclosure so that the whole of the motor and the cable are encased within the conductor 80 .
[0147] In the method of operation, the patient 13 is located on the patient table and restrained so that the head of the patient 13 remains motionless to prevent motion artifacts. The MRI system is then operated in conventional manner to generate images of the targeted tumor 32 . The images are used to determine the size and shape of the tumor 32 and to define the external perimeter 90 of the tumor 32 ( FIG. 8 ). The surgeon also determines an optimal location to place the cannula 31 so that the cannula 31 is aimed at the targeted tumor 32 without causing damage to surrounding tissue. Next, the opening 34 is formed in the skull of the patient 13 and the cannula 31 inserted.
[0148] With the cannula 31 in place, the motor 22 is mounted on the frame 23 and the frame 23 adjusted to locate the motor 22 so that the fiber assembly 20 can be inserted directly into the cannula. 31 . With the motor 22 properly aligned along the axis of the cannula, 31 , the fiber assembly 20 is inserted through the bore of the motor 22 and into the cannula 31 so as to extend through the cannula 31 until the terminus 36 emerges just out of the outer end of the cannula 31 . The distance of the motor from the cannula 31 can be adjusted so that the terminus 36 just reaches the end of the cannula 31 when the lead screw is fully retracted and the end stop is located in place in the clamp 72 .
[0149] With the motor and fiber thus assembled, the MRI system measures temperatures in the boundary zone 90 . The temperature is detected over the full surface area of the boundary rather than simply at a number of discrete locations. While the measurements are taken, the fiber is moved longitudinally to commence operation at a first position just inside the volume of the tumor 32 . At a selected angular orientation of the beam, pulses of radiation are emitted by the laser and transmitted into the tumor 32 through the beam 37 . The pulses are continued while the temperature in the boundary layer 90 is detected. As the pulses supply heat energy into the volume of the tumor 32 , the tumor 32 is heated locally basically in the segment shaped zone defined by the beam but also heat is conducted out of the volume of the beam into the remainder of the tumor 32 at a rate dependant upon the characteristics of the tumor 32 itself. Heating at a localized area defined by the beam is therefore continued until the heat at the boundary layer 90 is raised to the predetermined coagulation temperature on the order of 55 to 65 C. Once the boundary layer reaches this temperature, heating at that segment shaped zone within the disk is discontinued and the fiber is moved either longitudinally to another disk or angularly to another segment or both to move to the next segment shaped zone of the tumor 32 to be heated. It is not necessary to predict the required number of pulses in advance since the detection of temperature at the boundary is done in real time and sufficiently quickly to prevent overshoot. However, predictions can be made in some circumstances in order to carry out the application of the heat energy as quickly as possible by applying high power initially and reducing the power after a period of time.
[0150] It is desirable to effect heating as quickly as possible so as to minimize the operation duration. Heating rate may be varied by adjusting the number of pulses per second or the power of the heat source. Care is taken to vary these parameters to match the characteristics of the tumor 32 , as detected in the initial analysis. Thus the system may vary the energy pulse rate or power-time history of the heat source to modify the penetration depth of the heat induced lesion so that it can control the heating zone of an irregularly shaped lesion. The energy application rate should not be high enough to result in over heating the tissue outside of the perimeter of the tumor. The rate of heat application can also be varied in dependence upon the distance of the boundary from the axis of the fiber. Thus, the axis of the fiber is indicated at 91 in FIG. 8 and a first distance 92 of the beam to the boundary is relatively short at the entry point of the fiber into the tumor 32 and increases to a second larger distance 93 toward the center of the tumor 32 . In addition to pulses per second, it is also possible to adjust the power-time history of the laser energy to maximize penetration into the lesion. That is to use high power first for a short period of time and then ramp the power down throughout the duration of the treatment at that particular location.
[0151] In some cases it is desirable to maintain the fiber stationary at a first selected longitudinal position and at a first selected angular orientation until the temperature at the boundary reaches the required temperature. In this case the fiber is then rotated through an angle approximately equal to the beam angle to commence heating at a second angular orientation with the fiber being rotated to a next angular orientation only when heating at that second orientation is complete. In this way heating is effected at each position and then the fiber rotated to a next orientation position until all angular orientations are completed.
[0152] After a first disk shaped portion of the tumor 32 is thus heated, the fiber is moved longitudinally through a distance dependant upon the diameter of the tumor 32 at that location and dependant upon the beam angle so as to ensure the next heated area does not leave unheated tumor tissue between the two successive disk shaped areas. Thus the fiber is moved longitudinally in steps, which may vary in distance depending upon the diameter and structure of the tumor 32 as determined by the initial analysis. However the total heating of the tumor 32 is preferably determined by the temperature at the boundary without the necessity for analysis of the temperatures of the tumor 32 inside the boundary or any calculations of temperature gradients within the tumor 32 . When the complete boundary of the tumor 32 has been heated to the predetermined coagulation temperature, the treatment is complete and the apparatus IS disassembled for removal of the fiber assembly 20 and the cannula 31 from the patient 13 .
[0153] The system allows direct and accurate control of the heating by controlling the temperature at the surface area defined by the boundary of the tumor 32 so that the whole of the volume of the tumor 32 is properly heated to the required temperature without heating areas external to the tumor 32 beyond the coagulation temperature. In order to maximize the amount of heat energy which can be applied through the fiber and thereby to effect treatment of larger tumors, it is highly desirable to effect cooling of the tissue immediately surrounding the end of the fiber so as to avoid overheating that tissue. Overheating beyond the coagulation temperature is unacceptable, as it will cause carbonization, which will inhibit further transmission of the heat energy. Without cooling it is generally necessary to limit the amount of heat energy that is applied. As energy dissipates within the tissue, such a limitation in the rate of application of energy limits the size of the tumor to be treated since dissipation of energy prevents the outside portions of the tumor from being heated to the required coagulation temperature.
[0154] In FIGS. 9 and 10 is therefore shown a modified laser probe which can be used in replacement for the probe previously described, bearing in mind that it is of increased diameter and thus minor modifications to the dimensions of the structure are necessary to accommodate the modified probe.
[0155] The modified probe 100 comprises a fiber 101 which extends from a tip portion 102 including the light dispersion arrangement previously described to a suitable light source at an opposed end of the fiber as previously described. The probe further comprises a support tube 103 in the form of a multi-lumen extruded plastics catheter for the fiber which extends along the fiber from an end 104 of the tube just short of the tip 102 through to a position beyond the fiber drive system previously described. The tube 103 thus includes a cylindrical duct 104 extending through the tube and there are also provided two further ducts 105 and 106 parallel to the first duct and arranged within a cylindrical outer surface 107 of the tube.
[0156] The supporting tube 103 has at its end opposite the outer end 104 a coupling 108 which is molded onto the end 109 and connects individual supply tubes 110 , 111 and 112 each connected to a respective one of the ducts 104 , 105 and 106 . Multi-lumen catheters of this type are commercially available and can be extruded from suitable material to provide the required dimensions and physical characteristics. Thus the duct 104 is dimensioned to closely receive the outside diameter of the fiber so that the fiber can be fed through the duct tube 110 into the duct 104 and can slide through the support tube until the tip 102 is exposed at the end 104 .
[0157] While tubing may be available which provides the required dimensions and rigidity, in many cases, the tubing is however flexible so that it bends side to side and also will torsionally twist. The support tube is therefore mounted within an optional stiffening tube or sleeve 114 , which extends from an end 115 remote from the tip 102 to a second end 106 adjacent to the tip 102 . The end 116 is however spaced rearwardly from the end 104 of the tubing 103 , which in turn is spaced from the tip 102 . The distance from the end 106 to the tip 102 is arranged to be less than a length of the order of 1 inch. The stiffening tube 114 is formed of a suitable stiff material that is non-ferro-magnetic so that it is MRI compatible. The support tube 103 is bonded within the stiffening tube 114 so that it cannot rotate within the stiffening tube and cannot move side to side within the stiffening tube. The stiffening tube is preferably manufactured from titanium, ceramic or other material that can accommodate the magnetic fields of MRI. Titanium generates an artifact within the MRI image. For this reason the end 116 is spaced as far as possible from the tip 102 so that the artifact is removed from the tip to allow proper imagining of the tissues.
[0158] At the end 116 of the stiffening tube 114 is provided a capsule 120 in the form of a sleeve 121 and domed or pointed end 122 . The sleeve surrounds the end 116 of the stiffening tube and is bonded thereto so as to provide a sealed enclosure around the exposed part of the tube 103 . The capsule 120 is formed of quartz crystal so as to be transparent to allow the escape of the disbursed light energy from the tip 102 . The distance of the end of the stiffening tube from the tip is arranged such that the required length of the capsule does not exceed what can be reasonably manufactured in the transparent material required.
[0159] The tube 111 is connected to a supply 125 of a cooling fluid and the tube 112 is connected to a return collection 126 for the cooling fluid. Thus, the cooling fluid is pumped through the duct 105 and escapes from the end 104 of the tube 103 into the capsule and then is returned through the duct 106 . The cooling fluid can simply be liquid nitrogen allowed to expand to nitrogen gas at cryogenic temperatures and then pumped through the duct 105 and returned through the duct 106 where it can be simply released to atmosphere at the return 126 .
[0160] In an alternative arrangement the supply 125 and the return 126 form parts of a refrigeration cycle where a suitable coolant is compressed and condensed at the supply end and is evaporated at the cooling zone at the capsule 120 so as to transfer heat from the tissue surrounding the capsule 120 to the cooling section at the supply end.
[0161] The arrangement set forth above allows the effective supply of the cooling fluid in gaseous or liquid form through the ducts 105 and 106 and also effectively supports the fiber 101 so that it is held against side to side or rotational movement relative to the stiffening tube 114 . The location of the tip 102 of the fiber is therefore closely controlled relative to the stiffening tube and the stiffening tube is driven by couplings 130 and 131 shown schematically in FIG. 9 but of the type described above driven by reciprocating motor arrangements as set forth hereinbefore.
[0162] In FIGS. 11 and 12 is shown the tip section of an alternative probe in which cooling of the tip section is effected using expansion of a gas into an expansion zone. The tip only is shown as the remainder of the probe and its movements are substantially as previously described.
[0163] Thus the probe comprises a rigid extruded tube 200 of a suitable material, for example titanium, that is compatible with MRI (non-ferromagnetic) and suitable for invasive medical treatment. A further smaller cooling fluid supply tube 202 is also separately formed by extrusion and is attached by adhesive to the inside surface of the outer tube. An optical fiber 204 is also attached by adhesive to the inside surface the outer tube so that the fiber is preferably diametrically opposed to the tube 202 .
[0164] The tube 202 is swaged at its end as indicated at 205 , which projects beyond the end of the tube 201 , to form a neck section of reduced diameter at the immediate end of the tube 202 . Thus in manufacture the extruded tube 201 is cut to length so as to define a tip end 207 at which the outer tube terminates in a radial plane. At the tip end beyond the radial plane, the outer of the inner tube 202 is swaged by a suitable tool so as to form the neck section 205 having an internal diameter of the order of 0.003 to 0.005 inch.
[0165] The fiber 204 is attached to the tube 201 so that a tip portion 208 of the fiber 204 projects beyond the end 207 to a chamfered end face 209 of the fiber which is cut at 45 degrees to define a reflective end plane of the fiber.
[0166] The end 207 is covered and encased by a molded quartz end cap 210 that includes a sleeve portion 211 closely surrounding the last part of the tube 200 and extending beyond the end 207 to an end face 212 , which closes the capsule. The end face 212 is tapered to define a nose 213 , which allows the insertion of the probe to a required location as previously described. The end of the tube 201 may be reduced in diameter so that the capsule has an outer diameter matching that of the main portion of the tube. However in the arrangement shown the capsule is formed on the outer surface so that its outer diameter is larger than that of the tube and its inner diameter is equal to the outer diameter of the tube.
[0167] A thermocouple 214 is attached to the inside surface of the outer tube 200 at the end 207 and includes connecting wires 215 which extend from the thermocouple to the control unit schematically indicated at 226 . Thus the thermocouple provides a sensor to generate an indication of the temperature at the end 207 within the quartz capsule. The quartz capsule is welded to or bonded to the outer surface of the tube as indicated at 215 so as to form a closed expansion chamber within the quartz capsule beyond the end 207 . The inner surface 216 of the quartz capsule is of the same diameter as the outer surface of the tube 200 so that the expansion chamber beyond the end of the tube 200 has the same exterior dimension as the tube 200 .
[0168] The quartz capsule is transparent so as to allow the reflected beam of the laser light from the end face 209 of the fiber to escape through the transparent capsule in the limited angular direction substantially at right angles to the longitudinal axis of the fiber and within the axial plane defined by that longitudinal axis.
[0169] The tube 202 is connected at its end opposite to the tip to a fluid supply 219 , which forms a pressurized supply of a suitable cooling fluid such as carbon dioxide or nitrous oxide. The fluid supply 219 is controlled by the control unit 216 to generate a predetermined pressure within the fluid supply to the tube 202 which can be varied so as to vary the flow rate of the fluid through the neck 205 . The fluid is supplied at normal or room temperature without cooling. The fluid is normally a gas at this pressure and temperature but fluids that are liquid can also be used provided that they form a gas at the pressures within the expansion chamber and thus go through an adiabatic gas expansion through the restricted orifice into the expansion chamber to provide the cooling effect.
[0170] Thus the restricted orifice has a cross-sectional area very much less than that of the expansion chamber and the return duct provided by the inside of the tube 201 . The items that reduce the effective cross-sectional area of the return tube 201 are the optical fiber, the supply tube, two thermocouple wires, the shrink tube that fixes the thermocouple wires to the optical fiber and the adhesives used to bond the items into place (at the inlet of the discharge duct). Without the area of the adhesives included in the calculation, the exhaust duct area is about 300 times larger than a delivery orifice diameter of 0.004″ (the target size). When considering the area occupied by the adhesives, the exhaust duct inlet area would be approximately 200 to 250 times larger than the 0.004″ diameter orifice. Considering the manufacturing tolerance range of the supply tube orifice diameter alone, the exhaust duct area could be anywhere between 190 to 540 times larger than the orifice area (without considering the area occupied by adhesives). It is our estimation that a 200/1 gas expansion will be required to achieve appropriate cooling.
[0171] This allows the gas as it passes into the expansion chamber beyond the end 205 to expand as a gas thus cooling the quartz capsule and the interior thereof at the expansion chamber to a temperature in the range −20 C to 0 C. This range has been found to be suitable to provide the required level of cooling to the surface of the quartz capsule so as to extract heat from the surrounding tissue at a required rate. Variations in the temperature in the above range can be achieved by varying the pressure from the supply 219 so that in one example the pressure would be of the order of 700 to 850 psi at a flow rate of the order of 5 liters per min.
[0172] The tube 202 has an outside diameter of the order of 0.014 inch OD, while the tube 203 has a diameter of the order of 0.079 inch. Thus a discharge duct for the gas from the expansion chamber is defined by the inside surface of the tube 200 having a flow area which is defined by the area of the tube 200 minus the area taken up by the tube 202 and the fiber 207 . This allows discharge of the gas from the expansion chamber defined within the quartz capsule at a pressure of the order of 50 psi so that the gas can be simply discharged to atmosphere if inert or can be discharged to an extraction system or can be collected for cooling and returned to the fluid supply 219 if economically desirable. Tip cooling is necessary for optimum tissue penetration of the laser or heating energy, reduction of tissue charring and definition of the shape of the coagulated zone. The gas expansion used in the present invention provides an arrangement that is suitable for higher power densities required in this device to accommodate the energy supplied by the laser heating system.
[0173] The tip 208 of the fiber 204 is accurately located within the expansion zone since it is maintained in fixed position within the quartz capsule by its attachment to the inside surface of the outer tube. The fiber is located forwardly of the end 207 sufficiently that the MRI artifact generated by the end 207 is sufficiently removed from the plane of the fiber end to avoid difficulties in monitoring the temperature within the plane of the fiber end. The outlet orifice of the tube 202 is also located forwardly of the end 207 so as to be located with the cooling effect generated thereby at the plane of the fiber end.
[0174] The end face 209 is located within the expansion chamber 216 so that it is surrounded by the gas with no liquid within the expansion chamber. Thus, in practice there is no condensate on the end face 209 nor any other liquid materials within the expansion chamber that would otherwise interfere with the reflective characteristics of the end face 209 .
[0175] The end face 209 is coated with a reflective coating such as a dual dielectric film. This provides a reflection at the two required wavelengths of the laser light used as a visible guide beam and as the heat energy source such as He—Ne and Nd:YAG respectively. An alternative coating is gold, which can alone provide the reflections at the two wavelengths.
[0176] The arrangement of the present invention provides excellent MRI compatibility both for anatomic imaging as well as MR thermal profiling. Those skilled in the art will appreciate that the cooling system in accordance with the present invention may also be used with circumferential fibers having point-of-source energy.
[0177] In operation, the temperature within the expansion zone is monitored by the sensor 214 so as to maintain that temperature at a predetermined temperature level in relation to the amount of heat energy supplied through the fiber 204 . Thus the pressure within the fluid supply is varied to maintain the temperature at that predetermined set level during the hyperthermic process.
[0178] As described previously, the probe is moved to an axial location within the volume to be treated and the probe is rotated in steps so as to turn the heating zone generated by the beam B into each of a plurality of segments within the disk or radial plane surrounding the end face 209 . Within each segment of the radial plane, heat energy is supplied by the beam B that is transmitted through the quartz capsule into the tissue at that segment. The heat energy is dissipated from that segment both by reflection of the light energy into adjacent tissue and by conduction of heat from the heated tissue to surrounding tissue. As stated previously, those skilled in the art will appreciate that the probe used with the cooling system in accordance with the present invention may include circumferential fibers having point-of-source energy.
[0179] The surface of the capsule is cooled to a temperature so that it acts to extract heat from the surrounding tissue at a rate approximately equal to the dissipation or transfer of heat from the segment into the surrounding tissue. Thus the net result of the heating effect is that the segment alone is heated and surrounding tissue not in the segment required to be heated is maintained without any effective heating thereon, that is no heating to a temperature which causes coagulation or which could otherwise interfere with the transmission of heat when it comes time to heat that tissue in another of the segments. In this way when a first segment is heated to the required hyperthermic temperature throughout its extent from the probe to the peripheral surface of the volume, the remaining tissues in the areas surrounding the probe are effectively unheated so that no charring or coagulation has occurred which would otherwise prevent dissipation of heat and in extreme cases completely prevent penetration of the beam B.
[0180] Thus when each segment in turn has been heated, the probe can be rotated to the next segment or to another segment within the same radial plane and further heating can be effected of that segment only.
[0181] In practice in one example, the laser energy can be of the order of 12 to 15 watts penetrating into a segment having an angle of the order of 60 to 80 degrees to a depth of the order of 1.5 cm. In order to achieve this penetration without causing heating to the remaining portions of the tissue not in the segment, cooling of the outside of the capsule to a temperature of the order of minus 5 degrees C. is required.
[0182] In FIG. 13 is shown an actual example of a cross-section of tissue that has been heated in three separate segments marked as sectors 1, 2 and 3. The central dark area is where the probe was located before it was removed to allow the cross-sectional slice to be taken. The darker area that forms approximately 100 degrees opposite sector 2 indicates no heating has been applied to that area. The lighter color in the sectors 1, 2 and 3 indicates coagulation of the tissue. Similarly it will be noted that the tissue is of the darker color (not heated) in the smaller areas between sectors 2 and 3 and between sectors 1 and 2. Thus the cooling effect of the present invention achieves the effect required of limiting or prevention heating to the areas outside the selected segments.
[0183] The tube 200 is in the example shown above of a rigid structure for insertion in a straight line as previously described into a specific location. The use of a rigid material such as titanium for the outer tube avoids the necessity for the cannula 31 previously described and allows the alignment of the probe in its mounting and drive arrangement as previously described to the required location in the patient 13 without previously setting up a cannula 31 . However other arrangements can be provided in which the tube 200 is formed of a fully or partial flexible material allowing the tube 200 to bend so as to allow insertion along suitable passageways such as veins or arteries within the patient 13 by using guiding systems well known to one skilled in the art.
[0184] Another exemplary embodiment of the invention provides a method of using a directed energy beam in conjunction with an MRI machine to heat targeted tissue in a patient. In accordance with the aforementioned teachings, the method can be used, not only to destroy tumors, but any tissue, healthy or otherwise, that has been identified as undesirable. While the apparatus of the present invention has been described as useable for the identification and destruction of lesions, in particular tumors, the following applications are also considered within the scope of the present invention.
[0185] A first application pertains to treating patients having aneurysms and stokes. One object of the present invention is to treat aneurysms before the rupture that results in hemorrhagic stroke. Symptoms of aneurysms are found and diagnosis is made during the “pre-event” period prior to stroke. During this period, patients are typically treated with endovascular coils. Once the aneurysm “pops” and hemorrhagic stroke occurs, the current therapy involves clipping the ruptured vessel, usually within three days of the event. The goal is to prevent rebleeding. Both procedures are risky and treatment can be much more easily accomplished with the probe and cooling system in accordance with the present invention.
[0186] Strokes occur when an aneurysm in a blood vessel in the brain ruptures, causing brain damage. Aneurysms and ruptured blood vessels have long been treated using open brain surgery, an extremely risky procedure. Recently, a procedure known as coil embolization has gained popularity because it obviates the need to open the skull and expose the brain. Coil embolization involves feeding a catheter into an artery in the groin and guiding the catheter through the arteries to the affected site in the brain. Platinum coils are then sent up through the catheter to the aneurysm, where the coils fill the ballooned area. The coils are detached and left in the artery permanently, blocking the flow.
[0187] Coil embolization is not free of complications. For example, if the aneurysm opening is too wide, allowing the coils to slip out, a stent or flexible mesh tube must be inserted across the opening of the artery to hold them in place. Sometimes, surgery is still necessary if the aneurysm is not the appropriate shape for embolization. Even without complications, the procedure requires significant patience and skill to feed a catheter from the groin into a targeted area of the brain.
[0188] The method of the present invention can be used to treat vascular lesions, such as aneurysms, and strokes and avoid many of the complications of coil embolization. Targeting the lesion or rupture is accomplished in the same manner as locating a tumor. The size and location of the targeted lesion or rupture is determined and an optimal placement for the cannula is chosen. Targeted vessels should be on the order of 1 mm to 5 mm and are more preferably on the order of 2 mm to 3 mm in diameter. A hole is drilled or otherwise formed in the skull and the cannula is carefully inserted so that the cannula assumes the intended placement. A fiber assembly is inserted through the cannula in the aforementioned manner until the target is reached. Notably, the execution of heating the targeted area may be effected using a straight beam rather than an angled beam if the targeted area is sufficiently small. Additionally, the energy source may include non-collimated light or other form of radiant energy. It may be true that the necessary temperature to effect the cauterization of the lesion will be lower than that needed to terminate tumor tissue. Alternatively, cauterization of an lesion could be effected, according to the present invention, by threading a more flexible, yet otherwise structurally similar, catheter through an artery in the groin to the targeted site. Obviously, the catheter, or fiber assembly, would be much longer than that used with the aforementioned cannula.
[0189] A second alternative application of the present invention is useful in cosmetic surgery. The field of cosmetic surgery includes many procedures that remove excess healthy tissue such as skin, manipulate muscle tissue and remove fat cells, for example.
[0190] Fat cells are removed using liposuction, a procedure that involves sucking the cells through a small vacuum tube. Liposuction is a relatively violent way of removing cells and often causes damage to the cells immediately surrounding those removed. Predictably, a significant amount of fluid is also sucked through the vacuum probed during the procedure. Fluid loss is a major concern when performing liposuction.
[0191] The probe, cooling system and method of the present invention can be used to destroy targeted fat cells by heating the cells with radiant energy, such as collimated or non-collimated light. The fat cells are heated to a temperature just below the carbonization temperature and the remains are absorbed by the body. No fluid is removed from the body, thereby allowing a more extensive shaping procedure to be performed. Again, this procedure may be performed with a probe having an angled beam or an axial, point-of-source energy beam.
[0192] The probe, cooling system and method in accordance with the present invention may also be used in cosmetic surgical procedures such as rhytidectomy, which involves the removal and redraping of excess skin and resupporting and tightening underlying muscles and tissues; blepharoplasty, which involves the removal of lax or excess kin on the upper and lower eyelids to minimize sagging; laser resurfacing to remove superficial scars, age lines and sometimes, precancerous skin lesions; rhinoplasty, which involves the reconstruction and sculpting of the bone and cartilage to reshape the nose; and trauma reconstruction, which involves the repair of facial injuries or deformities from previous injuries. Other cosmetic surgical procedures involving the removal, repair or reconstruction of tissue are also within the scope of the present invention and these procedures may be performed with a probe having an angled beam or an axial, point-of-source energy beam.
[0193] Since various modifications can be made in my invention as herein above described, and many apparently widely different embodiments of same made within the spirit and scope of the claims without departing from such spirit and scope, it is intended that all matter contained in the accompanying specification shall be interpreted as illustrative only and not in a limiting sense.
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In vivo hyperthermia treatment of a target tissue can include imaging the target tissue with a magnetic resonance imaging (MRI) system, positioning a hyperthermia treatment probe in or proximate to the target tissue based on the imaging, and heating the target tissue by the probe. During the heating, changes in temperature of a volume of tissue that includes the target tissue can be monitored with the MRI system to determine an amount of the heating applied to the target tissue, and the heating can be terminated when the amount of the heating reaches a predetermined amount.
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CROSS REFERENCE TO RELATED APPLICATIONS
[0001] This application claims benefit of the filing date and right of priority under 119(e) to U.S. 60/980,449, the contents of which are incorporated herein in their entirety.
STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT
[0002] No federal government funds were used in researching or developing this invention.
[0003] Names of Parties to a Joint Research Agreement
[0004] The George Washington University
[0005] The Institute for Genomic Research
[0006] Reference to a Sequence Listing
[0007] A table or a computer list appendix on a compact disc
[0008] [ ] is
[0009] [ ] is not
[0010] included herein and the material on the disc, if any, is incorporated-by-reference herein.
BACKGROUND
[0011] Field of the Invention
[0012] This invention relates to compounds for improving plant growth and characteristics, improved modified plants, processes for obtaining the same, and improved methods of obtaining plant products.
[0013] Background of the Invention
[0014] The current state of knowledge is as follows. The transcription factor, MYB61, that has been shown to be is necessary and sufficient for the remobilization of carbon into lignin, and it is know that MYB61 mediated lignin biosynthesis is stimulated in det3 mutants in the dark grown seedlings via a AtGLR (Dubos et al. 2005. Plant J. 43:348-355), the control and regulation of the process was not know to be specifically modulated by AtGLR1.1. Here we show that silencing of AtGLR1.1 stimulates lignin biosynthetic genes. Prior to this work it was not known which of the twenty AtGLRs actually regulated MYB61 and lignin biosynthesis.
[0015] Likewise, it has been postulated that carbon is remobilization into starch via an AtGLR-mediated mechanism (Dubos et al. 2005. Plant J. 43:348-355). Here we show that silencing of AtGLR1.1 stimulates starch biosynthetic genes and starch biosynthesis. Prior to this work it was known which of the twenty AtGLRs actually regulated C remobilization into starch.
[0016] The MYB transcription factors PAP1, PAP2 and MYB123 have been shown to control anthocyanin biosynthesis. Here we show that silencing of AtGLR1.1 stimulates PAP 1, PAP2 expression and expression of the genes in the anthocyanin biosynthetic pathway as well as anthocyanin accumulation.
[0017] It is known that phosphoenolpyruvate carboxylase kinase (PPCK1) phosphorylates phosphoenolpyruvate carboxylase (PEPC) that catalyzes the synthesis of OAA from phosphoenolpyruvate (PEP) and bicarbonate. The constitutive over-expression of a positive dominant PEPCK construct in Arabidopsis redirected carbon from sugars into organic acids and amino acids. Here we show that AtGLR1.1 regulates this process because the down regulation of AtGLR1.1, results in the opposite affect: that is OAA is reallocated from amino acid biosynthesis into lipid.
BRIEF SUMMARY OF THE INVENTION
[0018] The novel component of this work identifies the AtGLR or plant glutamate receptor as carbon sensors and regulators of carbon mobilization, allocation and partitioning,
[0019] The invention described here demonstrates that the AtGLRs function to regulate carbon metabolism and carbon partitioning, reallocation, redistribution, sensing and they modulate growth and development and will affect nitrogen, sulfur and phosphate, sensing, up-take, distribution, assimilation, partitioning and allocation.
[0020] The present invention can be used to:
[0021] Develop plants with higher lignin, lignin biosynthesis, biomass, growth and yield;
[0022] Develop plants with higher modified in cell wall composition;
[0023] Develop plants with higher sucrose levels;
[0024] Develop plants with higher oil or lipid content; and
[0025] Develop plants with altered amino acid content
[0026] The present invention relates to polynucleotides and polypeptides that may be used to improve or modify plant carbon metabolism, allocation, distribution, reallocation, redistribution, partitioning and assimilation. More specifically, this invention is related to the role of Arabidopsis thaliana glutamate receptors (AtGLRs) in the regulation of the biosynthesis, metabolism, catabolism, transport and mobilization of carbon metabolites, carbohydrates and carbon-based polymers, and the utilization of the AtGLRs to alter carbon-based signaling molecules, growth regulators, structural compounds to control and improve plant growth, development, yield and crop quality.
[0027] This invention describes the use of plant glutamate receptors (GLRs) to reallocate carbon metabolites in higher plants or to alter the accumulation or distribution of carbon metabolites or compounds such as sugars, organic acids, carbohydrates, starch, oils, lipids, callose, cellulose, hemicellulose and secondary compounds such as anthocyanins, flavonoids and lignins in plants (Paul and Pellny 2003, J. Exper. Bot. 54:539-547). Increased levels of these compounds are useful for the development of food chemistry, biofuels, oils, fiber, wood, and plant protectants.
[0028] Accordingly, provided herein in a preferred embodiment is a method of delivering to a plant target cell a DNA that is expressed in the target cell comprising administering a vector to the target cell, wherein said vector transduces the target cell; and wherein said vector has been modified to comprise a DNA which comprises an expressible gene and said gene is expressed in said target cell either constitutively or under regulatable conditions, and wherein the expressible gene encodes a messenger RNA which is antisense with respect to a messenger RNA transcribed from a gene endogenous to said cell, and wherein the antisense RNA is antisense to the mRNA which is translatable into a glutamate receptor.
[0029] In another preferred embodiment is provided the method wherein the glutamate receptor is Arabidopsis thaliana glutamate receptor 1.1 (AtGLR1.1).
[0030] In another preferred embodiment is provided a method of regulating plant metabolism, comprising: delivering to a plant target cell a DNA that is expressed in the target cell comprising administering a vector to the target cell, wherein said vector transduces the target cell; and wherein said vector has been modified to comprise a DNA which comprises an expressible gene and said gene is expressed in said target cell either constitutively or under regulatable conditions, and wherein the expressible gene encodes a messenger RNA which is antisense with respect to a messenger RNA transcribed from a gene endogenous to said cell, and wherein the antisense RNA is antisense to the mRNA which is translatable into a glutamate receptor.
[0031] In another preferred embodiment is provided the method wherein the antisense RNA is antiGLR and is capable of altering carbon-based signaling molecules, growth regulators, structural compounds to control and improve plant growth, development, yield and crop quality.
[0032] In another preferred embodiment is provided the method wherein the antisense RNA is antiGLR and is capable of reallocating carbon metabolites in higher plants and altering the accumulation or distribution of carbon metabolites or compounds, wherein said metabolites or compounds comprise sugars, organic acids, carbohydrates, starch, oils, lipids, callose, cellulose, hemicellulose and secondary compounds including anthocyanins, flavonoids and lignins.
[0033] In another preferred embodiment is provided the method wherein the glutamate receptor is Arabidopsis thaliana glutamate receptor 1.1 (AtGLR1.1).
[0034] In another preferred embodiment is provided a DNA vector comprising an expressible gene that is expressed in a target plant cell, wherein the expressible gene encodes a messenger RNA which is antisense with respect to a messenger RNA transcribed from a gene endogenous to said cell, and wherein the antisense RNA is antisense to the mRNA which is translatable into a glutamate receptor.
[0035] In another preferred embodiment is provided, a plant comprising the DNA vector described herein.
BRIEF DESCRIPTION OF THE DRAWINGS
[0036] FIG. 1A and 1B are a series of protein gel electrophoresis results.
[0037] FIG. 2A , 2 B, 2 C, and 2 D are gene expression charts.
[0038] FIG. 3 is a series of bar graphs showing sugar, starch and anthocyanin results.
[0039] FIG. 4 is a bar graph of amino acids in antiAtGLR1.1 versus wild type.
[0040] FIG. 5 is a bar graph of the expression (log 2 ratio) of various mRNAs or transcripts.
DETAILED DESCRIPTION OF THE INVENTION
[0041] Definitions
[0042] The following definitions are provided as an aid to understanding the detailed description of the present invention.
[0043] The phrases “coding sequence,” “coding region,” “structural sequence,” and “structural nucleic acid sequence” refer to a physical structure comprising an orderly arrangement of nucleotides. The nucleotides are arranged in a series of triplets that each form a codon. Each codon encodes a specific amino acid. Thus, the coding sequence, coding region, structural sequence, and structural nucleic acid sequence encode a series of amino acids forming a protein, polypeptide, or peptide sequence. The coding sequence, coding region, structural sequence, and structural nucleic acid sequence may be contained within a larger nucleic acid molecule, vector, or the like. In addition, the orderly arrangement of nucleotides in these sequences may be depicted in the form of a sequence listing, figure, table, electronic medium, or the like.
[0044] The phrases “DNA sequence,” “nucleic acid sequence,” and “nucleic acid molecule” refer to a physical structure comprising an orderly arrangement of nucleotides. The DNA sequence or nucleotide sequence may be contained within a larger nucleotide molecule, vector, or the like. In addition, the orderly arrangement of nucleic acids in these sequences may be depicted in the form of a sequence listing, figure, table, electronic medium, or the like.
[0045] The term “expression” refers to the transcription of a gene to produce the corresponding mRNA and translation of this mRNA to produce the corresponding gene product (i.e., a peptide, polypeptide, or protein).
[0046] The phrase “expression of antisense RNA” refers to the transcription of a DNA to produce a first RNA molecule capable of hybridizing to a second RNA molecule, said second RNA molecule encodes a gene product that is desirably down-regulated.
[0047] The term “homology” refers to the level of similarity between two or more nucleic acid or amino acid sequences in terms of percent of positional identity (i.e., sequence similarity or identity). Homology also refers to the concept of similar functional properties among different nucleic acids or proteins.
[0048] The term “heterologous” refers to the relationship between two or more nucleic acid or protein sequences that are derived from different sources. For example, a promoter is heterologous with respect to a coding sequence if such a combination is not normally found in nature. In addition, a particular sequence may be heterologous with respect to a cell or organism into which it is inserted (i.e., does not naturally occur in that particular cell or organism).
[0049] The term “hybridization” refers to the ability of a first strand of nucleic acid to join with a second strand via hydrogen bond base pairing when the two nucleic acid strands have sufficient sequence complementarity. Hybridization occurs when the two nucleic acid molecules anneal to one another under appropriate conditions.
[0050] The terms “plants” and “plant”, in the context of the present invention, refer to higher plants.
[0051] The phrase “operably linked” refers to the functional spatial arrangement of two or more nucleic acid regions or nucleic acid sequences. For example, a promoter region may be positioned relative to a nucleic acid sequence such that transcription of the nucleic acid sequence is directed by the promoter region. Thus, a promoter region is operably linked to the nucleic acid sequence.
[0052] The terms “promoter” or “promoter region” refers to a nucleic acid sequence, usually found upstream (5′) to a coding sequence, which is capable of directing transcription of a nucleic acid sequence into mRNA. The promoter or promoter region typically provides a recognition site for RNA polymerase and the other factors necessary for proper initiation of transcription. As contemplated herein, a promoter or promoter region includes variations of promoters derived by inserting or deleting regulatory regions, subjecting the promoter to random or site-directed mutagenesis, and the like. The activity or strength of a promoter may be measured in terms of the amounts of RNA it produces, or the amount of protein accumulation in a cell or tissue, relative to a second promoter that is similarly measured.
[0053] The term “5′-UTR” refers to the untranslated region of DNA upstream, or 5′, of the coding region of a gene.
[0054] The term “3′-UTR” refers to the untranslated region of DNA downstream, or 3′, of the coding region of a gene.
[0055] The phrase “recombinant vector” refers to any agent by or in which a nucleic acid of interest is amplified, expressed, or stored, such as a plasmid, cosmid, virus, autonomously replicating sequence, phage, or linear single-stranded, circular single-stranded, linear double-stranded, or circular double-stranded DNA or RNA nucleotide sequence. The recombinant vector may be derived from any source and is capable of genomic integration or autonomous replication.
[0056] The phrase “regulatory sequence” refers to a nucleotide sequence located upstream (5′), within, or downstream (3′) with respect to a coding sequence. Transcription and expression of the coding sequence is typically impacted by the presence or absence of the regulatory sequence.
[0057] The phrase “substantially homologous” refers to two sequences that are at least about 90% identical in sequence, as measured by the CLUSTAL W method in the Omiga program, using default parameters (Version 2.0; Accelrys, San Diego, Calif.).
[0058] The term “transformation” refers to the introduction of nucleic acid into a recipient host. The term “host” refers to bacteria cells, fungi, animals or animal cells, plants or seeds, or any plant parts or tissues including plant cells, protoplasts, calli, roots, tubers, seeds, stems, leaves, seedlings, embryos, and pollen.
[0059] As used herein, the phrase “transgenic plant” refers to a plant having an introduced nucleic acid stably introduced into a genome of the plant, for example, the nuclear or plastid genomes.
[0060] As used herein, the phrase “substantially purified” refers to a molecule separated from substantially all other molecules normally associated with it in its native state. More preferably, a substantially purified molecule is the predominant species present in a preparation. A substantially purified molecule may be greater than about 60% free, preferably about 75% free, more preferably about 90% free, and most preferably about 95% free from the other molecules (exclusive of solvent) present in the natural mixture. The phrase “substantially purified” is not intended to encompass molecules present in their native state.
[0061] As used herein, “variants” have substantially similar or substantially homologous sequences when compared to reference or wild type sequence. For nucleotide sequences that encode proteins, “variants” also include those sequences that, because of the degeneracy of the genetic code, encode the identical amino acid sequence of the reference protein. Variant nucleic acids also include those that encode polypeptides that do not have amino acid sequences identical to that of the proteins identified herein, but which encode an active protein with conservative changes in the amino acid sequence.
[0062] Plant Metabolism
[0063] Carbon is critical for many aspects of plant metabolism. Carbon is a basic building block for sugars (mono-, di- and polysaccharides), organic acids, carbohydrates, starch, cellulose, hemi-cellulose, callose, pectin and lignins (Paul and Pellny 2003, J. Exper. Bot 54:539-547). Sugars can function as important signaling molecules in plants (Rolland et al. 2002. Plant Cell 14:S185-205) and are required for nucleotide, starch, callose, cellulose, pectin and hemi-cellulose biosyntheses. Carbon pathways such as the pentose phosphate shunt and the Calvin cycle provide reductant (energy) for many biological processes, such as nitrogen and sulfur up-take, assimilation, and metabolism. Carbon, in the form of organic acids, function as buffers, chelators, key components of energy cycles (Calvin and Kreb cycles) that are involved in photosynthesis and the generation of energy in mitochondria. Organic acids also provide backbones or skeletons for amino acid biosynthesis and are intimately linked with the assimilation of nitrogen into amino acids (Chen and Gadal 1990. Plant Physiol. Biochem. 28:141-145; Lancien et al. 2000. Plant Physiol. 123: 817-824; Hodges 2002. J. Exper. Bot. 53, 905-991) and may have signaling properties (Lancien et al. 2000. Plant Physiol. 123: 817-824; Hodges 2002. J. Exper. Bot. 53, 905-991). Carbon assimilation, transport, allocation, redistribution and sequestration are important to many aspects of agriculture, food industry, forestry, and horticulture and fiber production. Furthermore, as the levels of CO 2 are expected to continue to rise, this invention could provide alternatives for the sequestration of CO 2 and thus could be a viable solution to the Greenhouse Gas problem.
[0064] Hexokinase has been proposed to be a glucose sensor that controls several developmental and stress-related processes in plants (Jang et al. 1997. Plant Cell 9, 5-19; Sheen et al. 1999. Curr Opin. Plant Biol. 2: 410-408). Although hexokinase has been proposed to be the glucose sensor. Although hexokinase is the glucose sensor its role in carbon allocation, partitioning, or distribution, has not been established. Likewise the receptors or sensors for other carbon compounds carbohydrate or organic acids have not been identified (Smeekens. 2000. Ann. Rev. Plant Physiol. Plant Mol. Boil. 51:49-81; Polge & Thomas 2006. Trens Plant Sci. 12:20-28). The proteins and genes that control and regulate carbon partitioning, allocation and distribution have not been identified or established. Components of the carbon signaling and sensing system, or matrix, is hypothesized to be part of an integrated system that is connected with other assimilatory and metabolic pathways or networks (Coruzzi & Zhou 2001. Curr. Opin. Plant Biol. 4, 247, Coruzzi & Bush 2001. Plant Physiol. 125, 61). The mechanism(s) that control carbon metabolism are intimately linked with those that control the up-take, assimilation, transport, mobilization and metabolism of other elements required for plant growth and metabolism, i.e. nitrogen, sulfur (, and phosphate (Plaxton and Carswell 1999. In: HR Lerner, ed. Plant responses to environmental stresses: from phytohormones to genome reorganization. Pp. 349-372. Nielsen et al. 2001. Exp Bot 52: 329-339:Wu et al. 2003. Plant Physiol. 132, 1260-1271; Jain et al. 2007 Plant Physiol 16, on line asDOI:10.1104/pp. 106.092130). The sensing and subsequent reallocation or redistribution of carbon may have wide ramifications and extend to improvements in nitrogen-use-efficiency and utilization of nitrogen and sulfur, metabolism and accumulation of amino acids and secondary metabolites that are composed of these compounds, such as anthocyanins (Deikman and Hammer, 1995 Plant Physiol. 108: 47-57; Martin et al., 2002; Mita et al., 1997. Plant J. 11: 841-851; Tsukaya et al., 1991. Plant Physiol. 97: 1414-1421), flavonoids (Nikiforova et al., 2003. Plant J. 33: 633-650), and glucosinolates (Bones and Rossiter 1996. Physiol. Plant. 97: 194-208). These metabolic changes may result in physiological improvements and may positively affect water-use-efficiency (Martin et al. 1999. Crop Science 39:1775-1783), biomass (Martin et al. 1999. Crop Science 39:1775-1783), fiber quality (Pettigrew 2001 Crop Science 41:1108-1113) and wood production (Myneni 2001. PNAS 98, 14784-14789), and affect plant growth and development and crop productivity and quality (Mokhtari et al. 2006. J. Food Agricul. Environ. 4: 288-294).
[0065] In animals the ionotropic glutamate receptors (iGLRs) control signaling across a small gap between adjacent neurons called the synapse (Madden DR 2002. Nat. Rev. Neurosci.3:91-101). Plants, such as Arabidopsis (Lam et al. 1998. Nature 396:125-126) and rice and some bacteria, such as Synechosystis PCC 6803 (Chen et al. 1999. Nature 402:817-821) also contain putative iGLR homologs. It has been suggested that these receptors function in a primitive well-conserved sensing system that existed before animals, and components in the system may have evolved into neuronal signaling in higher animals.
[0066] There are twenty iGLRs homologs in the plant Arabidospsis , designated the Arabidopsis thaliana glutamate receptors (AtGLRs). The 20 AtGLRs separate into three distinct phylogenetic groups, or clades, called AtGLR1, AtGLR2 and AtGLR3. Specific AtGLRs are designated by the clade number followed by the “member” number, i.e. the first member of clade 3 is AtGLR3.1 (Lacombe et al. 2001. Science. 292: 1486-1487). AtGLRs are structurally similar to the animal N-methyl-D-aspartate (NMDA)-type iGLRs (Davenport 2002. Ann. Bot. 90: 549-557) that control neural signaling (Meldrum 2000. J. Nutr. 130; 1007S-1015S). The mammalian N-methyl-D-aspartate (NMDA)-type iGLRs have two potential binding domains (BDs). One in the amino terminal domain (ATD) that contains a region called the leucine-isoluecine-valine-binding-protein (LIVBP)-like domain (LIVBP-LD) that binds modulators (Zheng et al. 2001. Nat. Neurosci. 4;894-901; Huggins and Grant 2005. J. Mol. Graph. Model. 23; 381-388) and functions in dimerization and receptor assembly (Perez-Otano et al. 2001. J. Neurosci. 21;1228-1237. The other BD, the lysine-arginine-ornithine-binding-protein (LAOBP)-like domain (LAOBP-LD), binds the ligand, or agonist(s), to activate the receptor (Mayer and Armstrong 2004. Ann. Rev. Physiol. 66:161-181: Mayer 2006. Nature 440:456-462). Plus there are the three (1, 2 and 3) transmembrane (TM) and one pore forming (P), domains.
[0067] The expression of all twenty AtGLRs has been determined in Arabidopsis organs i.e. leaves, roots, flowers, or siliques (Chiu et al. 2002. Mol. Biol. Evol. 19:1066-1082) and their phylogenetic relationship to bacterial and animal GLRs has been well documented (Chiu et al. 1999. Mol. Biol. Evol. 16, 826-838; Chiu et al. 2002. Mol. Biol. Evol. 19:1066-1082; Turano et al. 2001. Mol. Biol. Evol. 18:1417-1420). Physiological analyses show that these receptors are involved in the regulation of carbon and nitrogen metabolism (Kang and Turano. 2003. PNAS. 100:6872-6877), carbon allocation (Dubos et al. 2005. Plant J. 43:348-355), calcium homeostasis (Kim et al. 2001. Plant Cell Physiol. 42:74-84), and stress responses (Meyerhoff et al. 2005. Planta. 222:418-27), starch and lignin biosyntheses (Dubos et al. 2005. Plant J. 43:348-355).
[0068] Antisense directed at AtGLR1.1 (antiAtGLR1.1) resulted in a decrease in the AtGLR1.1 peptide ( FIG. 1A ), this decrease in protein was shown previously (Kang and Turano. 2003. PNAS. 100:6872-6877) and semi-quantitative RT-PCR ( FIG. 1B ) showed that the endogenous AtGLR1.1 transcript (Sense) is significantly lower (˜65%) in antiAtGLR1.1 than in WT lines, due to the over-expression of the antisense AtGLR1.1 (Anti) transcript. The difference between the observed levels of the AtGLR1.1 transcript (˜35%) and AtGLR1.1 peptide (˜0%) in antiAtGLR1.1 versus WT lines is due to translational suppression of N-related peptides in antiAtGLR1 lines as previously reported (Kang and Turano. 2003. PNAS 100:6872-6877). RT-PCR analysis showed no detection of transcripts for AtGLR2.1, 2.2, 2.3, 2.6, 2.8 and 2.9 in WT or antiAtGLR1.1 plants. Eleven AtGLR transcripts were readily detected in leaves (1.1, 1.2, 1.3, 1.4, 2.5, 2.7, 3.2, 3.3, 3.5, 3.6 and 3.7), and three other AtGLRs (2.4, 3.1 and 3.4) had appreciable accumulation in both plants. These findings are similar to those observed by Chiu et al. (Chiu et al. 2002. Mol. Biol. Evol. 19:1066-1082). The data show that AtGLR1.1 has been “silenced” by using an antisense approach ( FIG. 1 ).
[0069] To elucidate the role of antiAtGLR1.1 in the regulation of metabolic networks, an Arabidopsis genome-wide microarray analysis was used to determine the difference in transcript accumulation between two independently transformed homozygous antiAtGLR1.1 and WT lines. 876 genes were shown to have different expression patterns by performing a t-test (P<0.05) and average log ratios greater than 0.6 or less than —0.6 were retained in the dataset. The false discovery rate of the 876 genes, determined by Significance Analysis of Microarrays (SAM) was 0.013. There was a significant increase in 533 transcripts, where as there was a significant decrease in 343 transcripts in antiAtGLR1.1 versus WT lines (Table 1), the data were categorized according to Usadel et al. into functional gene classes and large gene families ( FIG. 2 ) and in to metabolic and biosynthetic pathways using the Metabolic Map in AraCyc at TAIR (http://www.arabidopsis.org: 1555/ARA/new-image?type=OVERVIEW) and MAPMAN (Usadel et al. 2005. Plant Physiol. 138: 1195-1204). The accumulation of several carbon-related transcripts (Table 2) was significantly (P-value<0.05) altered in leaves of 30-d-old antiAtGLR1.1 versus WT plants.
Sucrose Metabolism and Redistribution
[0070] Transcripts of several sucrose (Suc)-metabolic genes significantly increase in antiAtGLR1.1 lines (Table 2). A Suc synthase (Sus) transcript (At5g20830), that encodes a key enzyme in Suc metabolism and catalyzes the reversible conversion of Suc and UDP to UDP-glucose and fructose, increased in antiAtGLR1.1 lines. A light-regulated basic domain/leucine zipper TF (ATB2/AtbZIP11 At1g75390), which is stimulated by exogenous Suc , increased in antiAtGLR1.1 lines. In addition, the sugar-porter family protein 1 (SFP1 At5g27350) and SFP-members (At3g05400, At3g05160) were significantly elevated in antiAtGLR1.1 plants.
[0071] To determine if carbon metabolism was actually altered in antiAtGLR1.1 lines endogenous levels of several sugars and starch were measured in leaves of plants grown ( FIG. 3 ). The Suc content in antiAtGLR1.1 plants significantly increased approximately 68% relative to that in WT. There was also a small (10 to 15%) but reproducible increase in starch in the antiAtGLR1.1 versus WT plants. The levels of glucose (Glc) and fructose (Fru) were unchanged in leaves of antiAtGLR1.1 versus WT plants.
Carbon Metabolism and Redistribution; Lignin and Cell Wall Biosyntheses
[0072] Genes whose products synthesize or modify cell wall components such as cellulose, lignin, pectin, and structural proteins were significantly elevated in antiAtGLR1.1 plants (Table 2), they include; cellulose synthase-like proteins (At4g16590, At4g23990, At5g17420), putative pectinesterases (At2g43050, At3g10720, At3g59010, At4g33220), putative arabinogalactan-proteins (At1g68725, At5g60490, At5g10430, At5g03170). Several genes associated with lignin biosynthesis were significantly up-regulated in the antiAtGLR1.1 lines, these include, cytochrome P450 coumarate to p-Coumaryl-CoA (At1g74540), a putative S-adenosyl-L-methionine: trans-caffeoyl-Coenzyme A 3-O methyltransferase (CCOMTL2, At1g67990), two cinnamyl alcohol dehydrogenases (CAD, At4g34230, At1g09500), prephenate dehydratase (PrD, At5g22630), kynurenine aminotransferase/glutamine transaminase (KAT/GT, At1g77670), several laccases (At2g38080, At2g29130, At2g40370, At3g09220, At5g05390, At5g60020), peroxidase (At5g42180 At5g05340) and putative dirigent genes (DIR11 At2g22900, DIR6 At4g23690).
[0073] There was an increase in a transcription factor, MYB61, that has been shown to be is necessary and sufficient for the remobilization of carbon into lignin biosynthesis. MYB20 (At1g66230), which was shown to have an expression profile that clustered with lignin biosynthetic genes (Ehlting et al. 2005. Plant J. 42: 618-640), is significantly less in the antiAtGLR1.1 plants than in WT. Although Dubos et al. (Dubos et al. 2005. Plant J. 43:348-355) proposed that AtGLRs, through activation of an agonist, may function to negatively modulate endogenous sugar signals that redistribute carbon metabolites into lignin synthesis via a MYB61-mediated pathway, that work was conducted in an vacuolar ATPase deficient mutant called det3 in dark grown seedlings. Furthermore, Dubos et al. (Dubos et al. 2005. Plant J. 43:348-355) showed the general involvement of AtGLRs and did not demonstrate utility of a specific AtGLR in plants grown in the light. This invention specifically demonstrates how to use AtGLR1.1 to control that signaling network to reallocate, redistribute or transport carbon into lignin biosynthesis, since antiAtGLR1.1 lines have high levels of Suc and a transcript profile consistent of an activated MYB61-mediated lignin biosynthetic pathway.
[0074] C Metabolism; Fatty Acid and Lipid Metabolism and Redistribution
[0075] In the antiAtGLR1.1 lines there is a shift of carbon from oxaloacetate (OAA) metabolism and amino acid biosynthesis into lipid metabolism. This is evidenced in two sets of data the (i) decrease in Asp and other Asp derived amino acids and (ii) increase in genes associated with lipid metabolism and mobilization. Free Asp titers in antiAtGLR1.1 lines decreased an average of 33%, relative to WT; this decrease coincides with the reduction in AAT2 transcript and peptide that we previously reported in the antiAtGLR1.1 lines. This finding is consistent with reports that show AAT2, a cytosolic isoform, is the major source of free Asp synthesized in leaves (Schultz et al. 1998. Genet. 149: 491-499). There were significant decreases in the Asp-derived amino acids, Ile and Lys with mean reductions of 43% and 35%, respectively ( FIG. 4 ). The levels of two other amino acids significantly decreased in antiAtGLR1.1 lines relative to WT are Leu, which dropped an average of 45%, and Val, which decreased by an average of 27%. The decrease in these amino acids could be attributed to the drop in Ile, since synthesis of Ile and Val share four common catalytic steps, and Leu is produced from an intermediate of Val synthesis. Consistent with this findings of the amino acid levels several Lys biosynthetic genes in the Asp-derived amino acids, a putative Lys-sensitive Asp kinase (AK At3g02020) and dihydrodipicolinate reductase (DHPR At5g52100), significantly decreased in antiAtGLR1.1 plants. Higher plants synthesize Lys from Asp. Asp is synthesized by the transfer of the amino group from Glu to Asp by asparate aminotransferase (AAT) or from Asn via asparaginase . Asp kinase, the first enzyme in the AFBCAA pathway, is a key enzyme that regulates Lys synthesis. Two 3-isopropylmalate dehydrogenases (IPMDH, At5g14200, At1g31180), Leu biosynthetic genes, were significantly decreased in antiAtGLR1.1 lines. In bacteria, IPMDH catalyzes the oxidative decarboxylation of 3-isopropylmalate to 2 ketoisocaproic acid. Evidence for the role of IPMDH in the control of Leu biosynthesis in higher plants has not been reported but this data strongly suggests that IPMDH plays a key role in Leu biosynthesis, as it does in yeast and E. coli . The expression profiling data was validated by qRT-PCR ( FIG. 5 ), on AK (At3g02020), DHPR (At5g52100) and IPMDH (At5g14200). In agreement with the expression profiling data), the transcripts significantly decreased in all of the antiAtGLR1.1 versus WT lines.
[0076] The relocation of OAA for amino acids into lipid metabolism can be explained by the significant decrease in phosphoenolpyruvate carboxylase kinase (PPCK1; At1g08650) and the increased accumulation of two pyruvate decarboxylase (PDC, At5g01320, At4g33070) transcripts. PPCK1 phosphorylates phosphoenolpyruvate carboxylase (PEPC) that catalyzes the synthesis of OAA from phosphoenolpyruvate (PEP) and bicarbonate. PEPC activity is deregulated by phosphorylation. The constitutive over-expression of a positive dominant PEPCK construct in Arabidopsis redirected carbon from sugars into organic acids and amino acids. Therefore the significant decrease in PPCK1 transcript is consistent with the observed decrease in specific the aspartate amino acids and the reallocation or redistribution of carbon into lipid metabolism. The significant increase in two PDCs, the committal steps to alcohol or lipid biosynthesis, transcripts lend further support to redistribution of carbon. Although there is evidence that some of the carbon in antiAtGLR1.1 plants may be diverted into ethanol production, based on the increased accumulation of one alcohol dehydrogenase (ADH, At3g42960) transcript. However, based on the significant increased accumulation of a large number of transcripts associated with lipid metabolism and transport, the carbon is being allocated, distributed or partition diverted from PEPC is channeled into lipid metabolism in antiAtGLR1.1 lines. There are significant changes in the accumulation of the following lipid associated transcripts two putative beta-ketoacyl-CoA synthase (At2g46720, At3g10280) and four genes for putative lipid transfer protein (LTP4; At5g59310, LTP6; At3g08770, At3g51590, At2g44300). Other genes that are associated with lipid metabolism, catabolism or transport that significantly increase in the antiAtGLR1.1 lines are a plastid-lipid associated protein PAP (At1g51110), GDSL-motif lipases/hydrolases (At2g31540, At1g29660, At3g04290, At1g74460, At1g28570, At2g42990, At2g23540), esterase/lipase/thioesterase proteins (At1g08310, At1g54570), and extracellular lipase 6 (EXL6; At1g75930).
[0077] The plant hormone jasmonic acid (JA) is derived from lipids. In the antiAtGLR1.1 lines, eight transcripts involved in JA biosynthesis significantly increased in antiAtGLR1.1 lines. These include a pathogen-responsive alpha-dioxygenase (At3g01420), AOS1 (At5g42650), four allene oxide cyclases (At3g25780, At3g25770, At3g25760, At1g13280), OPR1 (At1g76680) and OPR2 (At1g76690).
Carbon Mediated Anthocyanin Biosynthesis
[0078] Anthocyanins are pigmented flavonoids that are predominantly synthesized in the upper epidermis in response to various environmental stresses including light and nutrient deficiency. There was a significant increase in the transcripts for anthocyanin biosynthetic genes such as CHS (At5g13930), F3H (At3g51240) and LDOX (At4g22880) in antiAtGLR1.1 lines. The accumulation of these three anthocyanin biosynthetic genes were validated by qRT-PCR ( FIG. 5 ), in plants grown independently of the microarray experiments, but under the identical conditions.
[0079] The microarray and qRT-PCR data were highly correlated. CHS catalyzes the committal step in the pathway leading to the synthesis of anthocyanin. The subsequent steps include a conversion of naringenin chalcone to naringenin by CHI, and hydroxylations of niringenin by F3H and flavonoid 3′ hydroxylase (F3′H). NADPH-dependent DFR leads to the production of leucoanthocyanidins, which are the least common intermediates in anthocyanin and proanthocyanidin biosynthesis. There were observed increases in several genes involved in flavonoid biosynthetic pathways including two chalcone isomerases (At3g55120, At5g5270) and a flavonoid synthase (FLS, At5g08640).
[0080] Several anthocyanin biosynthetic genes are regulated by distinct MYB TFs, such as PAP1, PAP2 and TRANSPARENT TESTA 2 (TT2 formerly MYB123. The transcripts of MYB-related TFs, PAP1 (At1g56650) and PAP2 (At1g66390) significantly increased, by approximately 5.5 and 3.2-fold (+2.77 and +1.6 log2/ratio), respectively, in the two independently transformed antiAtGLR1.1 lines. The accumulation of several transcripts in antiAtGLR1.1 lines may be explained by the elevation in PAP1, namely two chalcone isomerases (At3g55120, At5g05270), an anthocyanin 5-0-glucosyltransferase (5GT At4g14090) and a glutathione S-transferase (GST; At5g17220). Conversely, overexpression of PAP1 resulted in decreases in a raffinose synthase family glycosyl hydrolase (RSFGH, At5g20250) and gibberellin-regulated protein 1 (GASA1, At1g75750), thus the decreased accumulation of these latter transcripts in the antiAtGLR1.1 plants might be explained by the increased expression of PAP1.
[0081] Total anthocyanins were determined in antiAtGLR1.1 plants to test if there was a corresponding increase in the metabolites, total anthocyanins increased (200%) in antiAtGLR1.1 lines when compared with WT ( FIG. 3 ). Increased expression of anthocyanin biosynthetic genes and increased total anthocyanins in antiAtGLR1.1.I plants are consistent with results from other studies that show that elevated levels of endogenous Suc combined result in increased anthocyanins (Deikman and Hammer, 1995 Plant Physiol. 108: 47-57; Martin et al., 2002; Mita et al., 1997. Plant J. 11: 841-851; Tsukaya et al. 1991. Plant Physiol. 97: 1414-1421; Nikiforova et al. 2003. Plant J. 33: 633-650).
[0082] The references recited herein are incorporated herein in their entirety, particularly as they relate to teaching the level of ordinary skill in this art and for any disclosure necessary for the commoner understanding of the subject matter of the claimed invention. It will be clear to a person of ordinary skill in the art that the above embodiments may be altered or that insubstantial changes may be made without departing from the scope of the invention. Accordingly, the scope of the invention is determined by the scope of the following claims and their equitable Equivalents.
[0000]
TABLE 1
Summary of transcript accumulation in two independently transformed antiAtGLR1.1
lines compared with wild-type in leaves of 30-day-old plants.
Average
Gene Family
accumulation
or Pathway
Gene name
Locus ID
(log 2 /ratio)
Carbon metabolism
C metabolism-Suc
Sus
At5g20830
+0.80
C metabolism-Suc
ATB2/AtbZIP1 1
At1g75390
+1.26
C metabolism-Suc
SFP1*
At5g27350
+1.00
C metabolism-Suc
SFP-member
At3g05400
+2.86
C metabolism-Suc
SFP-member
At3g05160
+0.67
cell wall
cellulose synthase
At4g16590
+1.70
cell wall
cellulose synthase
At4g23990
+2.35
cell wall
cellulose synthase
At5g17420
+1.24
cell wall
pectinesterase
At2g43050
+1.48
cell wall
pectinesterase
At3g10720
−0.91
cell wall
pectinesterase
At3g59010
+1.12
cell wall
pectinesterase
At4g33220
−0.74
cell wall
arabinogalactan-protein
At1g68725
+0.76
cell wall
arabinogalactan-protein
At5g60490
+2.04
cell wall
arabinogalactan-protein
At5g10430
+1.03
cell wall
arabinogalactan-protein
At5g03170
+1.51
Lignin biosynthesis and regulation
lignin
cytochrome P450
At1g74540
+1.21
lignin
CCOMTL2
At1g67990
+1.62
lignin
CAD
At4g34230
+0.68
lignin
CAD
At1g09500
+0.64
lignin
PrD
At5g22630
+0.66
lignin
KAT/GT
At1g77670
+0.69
lignin
laccase
At2g38080
+1.20
lignin
laccase
At2g29130
+0.86
lignin
laccase
At2g40370
+1.20
lignin
laccase
At3g09220
+0.60
lignin
laccase
At5g05390
+1.01
lignin
laccase
At5g60020
+0.68
lignin
peroxidase
At5g42180
+2.89
lignin
peroxidase
At5g05340
+0.90
lignin
DIR11
At2g22900
+0.67
lignin
DIR6
At4g23690
+1.16
lignin
MYB61
At1g09540
+0.97
lignin
MYB20
At1g66230
−0.95
Lipid (oil) biosynthesis and mobilization
Lipid regulation
PPCK1
At1g08650
−0.79
Lipid regulation
PDC
At5g01320
+0.86
Lipid regulation
PDC
At4g33070
+0.76
Lipid metabolism
-ketoacyl-CoA synthase
At2g46720
+0.83
Lipid metabolism
-ketoacyl-CoA synthase
At3gl0280
+0.82
Lipid transport
lipid transfer protein, LTP4
At5g59310
+2.97
Lipid transport
lipid transfer protein, LTP6
At3g08770
+0.73
Lipid transport
lipid transfer protein
At3g51590
+2.86
Lipid transport
lipid transfer protein
At2g44300
+0.68
Lipid
plastid-lipid assoc. protein
At1g51110
+0.85
Lipid
GDSL-motif lipase/hydrolase
At2g31540
+0.91
Lipid
GDSL-motif lipase/hydrolase
At1g29660
+0.85
Lipid
GDSL-motif lipase/hydrolase
At3g04290
+0.69
Lipid
GDSL-motif lipase/hydrolase
At1g74460
+0.83
Lipid
GDSL-motif lipase/hydrolase
At1g28570
+0.83
Lipid
GDSL-motif lipase/hydrolase
At2g42990
+1.15
Lipid
GDSL-motif lipase/hydrolase
At2g23540
+1.12
Lipid
esterase/lipase/thioesterase
At1g08310
−1.04
Lipid
esterase/lipase/thioesterase
At1g54570
+0.96
Lipid
extracellular lipase 6, EXL6
At1g75930
+1.93
Lipid, JA
allene oxide cyclase
At3g25770
+1.78
Lipid, JA
allene oxide cyclase
At3g25760
+1.21
Lipid, JA
allene oxide cyclase
At3g25780
+1.19
Lipid, JA
OPR2
At1g76690
+0.81
Lipid, JA
allene oxide cyclase
At1g13280
+0.78
Lipid, JA
path.-respon. -dioxygenase
At3g01420
+0.97
Lipid, JA
OPR1
At1g76680
+0.87
Anthocyanin and flavonoid?? biosynthesis
anthocyanin
CHS
At5g13930
+2.20
anthocyanin
F3H
At3g51240
+1.56
anthocyanin
LDOX
At4g22880
+1.49
anthocyanin
PAP1
At1g56650
+2.77
anthocyanin
PAP2
At1g66390
+1.60
anthocyanin-related
chalcone isomerase
At3g55120
+0.64
anthocyanin-related
chalcone isomerase
At5g05270
+0.88
anthocyanin-related
FLS
At5g08640
+1.70
anthocyanin-related
5GT
At4g14090
+1.20
anthocyanin-related
GST
At5g17220
+1.85
anthocyanin-related
RSFGH
At5g20250
−0.61
anthocyanin-related
GASA1
At1g75750
−0.61
1 Abbreviated as in the text.
|
This invention relates to compounds for improving plant growth and characteristics, improved modified plants, processes for obtaining the same, and improved methods of obtaining plant products, and specifically those concerning AtGLR1.1.
| 2 |
[0001] The present application is a continuation of provisional patent application Ser. No. 60/897,264, filed by Rebecca Michelle Power, San Diego, Calif. on Jan. 25, 2007, entitled “Personal Exercise Equipment Covers”
CROSS REFERENCE TO RELATED APPLICATIONS
[0002] 6,547,703 Isometric Exercise Swiss ball, April 2003
[0003] 6,712,745 Exercise Fitness Ball Cover, March 2004
BACKGROUND OF THE INVENTION
[0004] 1. Field of the Invention
[0005] This invention relates generally to covers with coverage and accessory attachment capabilities, more specifically to protective fitness accessories, and particularly to a cover for the purpose of covering and protecting an exercise Swiss ball in a securable and releasable fashion with the ability to attach and detach extraneous personal fitness equipment.
[0006] 2. Description of Prior Art
[0007] Inflatable, unbreakable exercise Swiss balls have been the growing trend in personal physical fitness, rehabilitation, and core strength training. These exercise Swiss balls are made of synthetic vinyl, plastic, or solid foam rubber. Because they are semi-non-porous, they can harbor sweat from users, leading to a slippery surface, an unpleasant odor, bacteria, and a feeling of uncleanliness. Thus, there is a need to keep the equipment and its users protected from sweat.
[0008] For people who incorporate fitness balls into their daily fitness routines and are concerned with the level at which they are perceived to be clean, there is a need for a solution which does not compromise the full range of motion used in the latest exercises such as wall squats, an exercise in which the exercise Swiss ball is placed between a wall and a users back while the user slowly bends and straightens his or her legs while his or her back rolls along the vertical circumference of the exercise Swiss ball, and the like.
[0009] Thus, there is a need for a fitted cover that conforms to the exercise Swiss ball without compromising its functionality of core strength training. There is a need to protect the ball during its use and a need to protect the user from a ball that may have been used by many people prior. A washable and dryable cover provides a solution to germs on the ball as perceived by the end user. The cover needs to stay secure around the ball without falling off through the range of motion during use. The washable cover provides a solution to a slippery surface while also making a fashion statement or an advertising medium. A dryable cover protects against moist bacterial breeding grounds.
[0010] In order to hang dry the exercise cover without compromising the integrity of the fabric, an external loop or incorporated grommet made out of any material attached to the cover is needed. Hanging of the cover on a hook can cause unnecessary stretching and kinking of a small area of the fabric.
[0011] People who own exercise Swiss balls at their homes or offices, or the like, are often faced with storage dilemmas with respect to gravity. Exercise Swiss balls, alone, are often placed on the floor or a stand. There is a need for a way in which to store balls by hanging them from the ceiling or wall, or easily carrying them from place to place.
[0012] For people who add a resistance training component to core strength training, there is a need for many people, to build and/or maintain the strength in their torso and limbs. Many people isolate their workouts through the utilization of various pieces of exercise equipment. This can wastes time and money. There is a need for a means of attaching fitness training accessories such as resistance bands, to an exercise Swiss ball during its use, solving both the needs of core strength exercises and resistance exercises.
[0013] Many gyms prohibit guests from bringing purses and bags on the workout floor. That said, another problem faced by people who exercise in the gym is that they do not have a place to keep personal belongings such as keys, phones, workout journals, meal supplements, PDAs, MP3s, iPods and the like close at hand. There is a need to provide accessible storage for these items during one's workout. Since some of these items can have some sort of lanyard, hook or clip attached to them, a ring for attaching these items or a pocket for storing these items will ensure that one's personal belongings are secured together at one time.
[0014] Referencing U.S. Pat. No. 6,712,745 for an Exercise Fitness Ball Cover, March 2004, There is an excess of material in the design if it were to cover an area greater than one half the surface of the exercise Swiss ball. Because of the claim that the cover device has one perimeter, it is evident that there will be an area in which all of the excess material is gathered, causing a lack of uniformity. While this serves the utility for simple exercises during which the ball is intended to stay stationary, this excess material will cause an interruption in uniform smoothness in those exercises involving a full 360 degree rotation on the ball.
[0015] In further reference to 6,712,745 . . . . If the area containing the cord and the excess gathered fabric were positioned to one side of the ball during an exercise requiring rotation, the weight of the excess material and cord would compromise the symmetry of the exercise Swiss ball, and defeat the purpose of the exercise. Because the utility of the aforementioned device does not adequately allow for full range of motion exercises without compromising the symmetry and smoothness of the exercise Swiss ball, there is a need for a device with the utility to accommodate said exercise functions.
[0016] Referencing U.S. Pat. No. 6,547,703 for an Isometric Exercise Swiss ball, April 2003. Because the construction of the aforementioned design is comprised of two hemispherical pieces of fabric designed to cover the entire surface of the exercise Swiss ball, it is necessary for the exercise Swiss ball to be deflated prior to engaging in the equipment's use. This can take time and requires the use of additional equipment for inflating. For example, a gymnasium or physical training or rehabilitation center has several pre-inflated exercise Swiss balls available to its guests. The Isometric Exercise Swiss ball does not lend itself utility in these and other similar situations. Thus, there is a need to provide coverage for exercise Swiss balls with the option of attaching additional fitness accessories without the need to deflate and inflate the ball upon use. Additionally, the shape is not flexible enough for fitting various sizes of balls securely.
[0017] In further reference to 6,712,745 and 6,547,703 . . . . Fully encompassing an exercise Swiss ball without the ability to see the inside ball can present a problem for theft management departments of organizations offering the use of their exercise Swiss balls. The aforementioned designs can lend themselves to possibility of theft, whereby the thief make can conceal the exercise Swiss ball as his or her own. Thus, there is a need to cover the exercise Swiss ball, while also allowing for the partial visibility of the exercise Swiss ball in order to reduce the risk of theft.
[0018] In a final reference to 6,712,745 and 6,547,703 . . . . The aforementioned inventions are spherical in shape and the range of the objects which may be covered uniformly by said inventions are limited. Thus there is a need to minimize the number of covering devices an individual bring for fitness protection, accessorizing, and trend-setting. There is a need for a cover that not only fits an exercise Swiss ball, but also can be folded flat into a rectangle to neatly cover other pieces of exercise equipment including, but not limited to: gym mats, yoga mats, exercise steps, weight benches.
SUMMARY
[0019] The present invention is a cover for covering an exercise Swiss ball. The cover is comprised of a rectangular piece of fabric secured at its shortest sides, or a tubular piece of fabric into which the exercise Swiss ball is inserted and covered at its centermost and widest circumference. The cover can then be cinched at its two perimeters, thereby securing it to the exercise Swiss ball. The ball is covered and the user protected throughout a full 360 degree forward and backward rotation, and a variable side to side rotation of up to, but not limited to, 180 degrees. This rotation is accomplished without interference from excess material or touching the bare surface of the exercise Swiss ball. Variable side coverage will depend upon the width and stretch capability of the fabric used, as well as the degree to which the user has cinched the device's perimeters.
[0020] In addition, the present invention covers an inflated exercise Swiss ball by means of a cover either rectangular or tubular in shape. In the case of the rectangular shape, the length is of the device is slightly greater that the circumference of the exercise Swiss ball. In the case of the tubular shape, the circumference of the device is slightly greater than the circumference of the exercise Swiss ball. In most cases, the width of the cover is not greater than the diameter of the exercise Swiss ball, and never is the width of the device greater than one half of the circumference of the exercise Swiss ball. The two perimeters of the cover are equipped with drawstrings for securing and releasing of the device to and from the exercise Swiss ball.
[0021] The present invention provides a medium for advertising or personal expression, beyond that of an exercise Swiss ball alone. Company logos, sassy phrases, patterns and the like my be printed, embroidered, silk-screened, or the like onto the fabric of the cover.
[0022] And finally, the cover is equipped with one ring or grommet attached on each perimeter. The rings can be made of metal, plastic, elastic or fabric, and they are attached through a reinforced button-hole sized incision near the openings through which the drawstrings are drawn. The purpose of the rings is to allow for the easy attachment or detachment of exercise resistance bands, phones, workout journals, meal supplements, PDAs, MP3s, iPods and the like. When the cover is fully cinched around the exercise Swiss ball, the rings in the lateral openings can be utilized to attach or detach the resistance bands. Through the use of a hook, lanyard, or clip the resistance bands or are fastened to or unfastened from the device. When the cover is not in use with the exercise Swiss ball, the utility of the rings allows for the device to be hung on a hook without the risk of stretching or creating a kink in the fabric.
[0023] Because the present invention is tubular in shape with two perimeters, it can easily slide around a fully inflated exercise Swiss ball and be tightened with the ability to see the exercise Swiss ball inside through either of its lateral closures, thereby reducing the possibility of exercise Swiss ball theft. Furthermore, while the shape of the invention fits an exercise Swiss ball, it can also be folded flat into a rectangle to neatly cover other pieces of exercise equipment including, but not limited to: gym mats, yoga mats, exercise steps, weight benches, and the like.
BRIEF DESCRIPTION OF THE DRAWINGS
[0024] FIG. 1 shows the rectangular to tubular design of the cover for an exercise Swiss ball, constructed in accordance with the present invention.
[0025] FIG. 2 is a frontal view of the cover for covering an exercise Swiss ball, constructed in accordance with the present invention.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
[0026] As illustrated in FIG. 1 , the exercise Swiss ball cover is constructed from a rectangular piece of fabric in which the direction of stretch, if any, runs parallel with the short ends of the fabric. At the long sides of the rectangle, drawstring capabilities are constructed for the purpose of-cinching, stretching and securing the cover to the exercise Swiss ball. The shortest ends of the rectangle are fastened together by any means such as stitching (preferably), ties, zippers, fasteners, Velcro, or the like. The exercise Swiss ball cover can then slide over the ball to form a cylinder of material that hugs the perimeter of the ball. The drawstrings on both open ends of the cylinder of material can then be pulled, stretching the fabric taut over the exercise Swiss ball. The open ends of the cover for the exercise Swiss ball are intended to face outward from the sides of the user during its use, as illustrated in FIG. 2 , thus allowing the user to have a protective lining between the exercise Swiss ball and himself or herself during a full range of forward and backward motion and a considerable tilt up to 90 degrees right or left.
[0027] The exercise Swiss ball cover in an unused state will have a circumference of approximately 80 inches and a width of approximately 30 inches to accommodate a 65 centimeter exercise Swiss ball. For a 75 centimeter exercise Swiss ball, the circumference of the cover in an unused state will measure approximately 88 inches with a width of approximately 33 inches. For a 55 centimeter exercise Swiss ball, the circumference of the cover in an unused state will measure approximately 72 inches with a width of 27 inches. The circumference and the width will vary with the amount of stretch afforded by the fabric used, and the present invention is versatile enough to fit a range of sizes of exercise Swiss balls. Although many of the utility claims of the present invention can be achieved with any type of flaccid material or fabric, a moisture-absorbent or moisture-repellent, fashionable, stretch fabric is preferred.
[0028] The exercise Swiss ball cover of the present invention further includes a means of securing and releasing the device about an exercise Swiss ball. The preferred method is an elastic cord approximately ⅛″ in diameter and 80″ in length that has been threaded through the hemmed perimeters of the cover. The present invention contains two perimeters. Accordingly, two ribbons, strings, elastic cords, or the like are needed to secure the device to the exercise Swiss ball. The two ends of the ribbons, strings, elastic cords, or the like at each perimeter of the device are then secured by means of a cord-stopper, bow, knot, or the like.
[0029] The exercise Swiss ball cover adds the capability of performing integrated resistance exercises. The cover is comprised of a rectangular piece of fabric secured at its shortest sides, or a tubular piece of fabric into which the exercise Swiss ball is inserted and covered at its centermost and widest circumference. The cover can then be cinched at its two perimeters, each equipped with drawstrings, thereby securing the device to the exercise Swiss ball. Once the device is cinched, the excess drawstrings can be tucked inside the snug area between the exercise Swiss ball and the cover. Each perimeter is also equipped with small rings or grommets through which hooks may be temporarily attached for the purpose of adding resistance bands to a workout, with the ball acting as the point from which resistance is drawn. Additionally, the rings or grommets can be used to attach hooks for temporarily hanging small personal belongings during certain workouts which may not require full symmetry of weight. Pockets in the fabric may also be incorporated to serve this purpose.
[0030] The exercise Swiss ball for this present invention's intended use is substantially spherical in shape, and the cover includes the centermost and widest perimeter/circumference of the exercise Swiss ball. Variable side coverage will be dependent upon stretch and width of fabric and how tight the drawstring is pulled. A stretch polyester fabric cover has the advantage of drying quickly, whereas a stretch cotton fabric will be more absorbent of moisture. The cover can be made out of either or any type of fabric, depending upon the user's preference. An organic blend of fabric may appeal to a more organic concerned with a soft feel or more natural sweat protection.
[0031] The exercise Swiss ball cover is noted as a fabric that is substantially tubular, or becomes tubular upon connection of the rectangular shaped fabric's shortest sides. The perimeters of the tubular fabric cover are equipped with drawstrings made functional by folding over and stitching a hem along the device's two perimeters. The drawstrings along each perimeter are capable of being secured upon cinching of cover's perimeters and released prior to removal from the exercise Swiss ball. Securing and releasing of the drawstrings may be in the form of a cord-stopper, a bow, or knot, or the natural tension which occurs by the cinching of fabric upon a cord, string, ribbon, elastic, or the like.
[0032] The exercise Swiss ball cover, as described in the present invention is dependent upon the width and stretch of the fabric used. Notably, the exercise Swiss ball cover made from a fabric with a greater width and or greater stretch capability will cover a greater portion of the exercise Swiss ball. Coverage is also dependent upon the degree to which the device's drawstrings are pulled by the user. Notably, the cover will cover a greater surface area of the exercise Swiss ball in a more taut fashion, as the drawstring is pulled tighter by the user. Rings or grommets are secured into the lateral closures of the device for the option of attaching resistance exercise bands or other small otherwise unsecured personal belongings. These rings or grommets also allow for the cover to hang alone, and even better, allows for the exercise ball to be hung in its cover, creating a storage area that is not dependent upon gravity. That is, the ball no longer has to take up space on the floor.
[0033] The fabric used in the present invention will be either tubular or become tubular in its transformation into the device. The rectangular shaped fabric becomes tubular through stitching, zippers, Velcro, or the like, the length is of the cover is slightly greater that the circumference of the exercise Swiss ball. With the pre-made tubular fabric, the circumference of the cover is slightly greater than the circumference of the exercise Swiss ball. In most cases, the width of the exercise Swiss ball cover is not greater than the diameter of the exercise Swiss ball, and never is the width of the cover greater than one half of the circumference of the exercise Swiss ball. The two perimeters of the cover are equipped with drawstrings for securing and releasing of the device to and from the exercise Swiss ball. The perimeters form the lateral closures to which the personal belonging compatible rings or grommets made of plastic, metal, or the like are secured through button-hole-like openings.
[0034] The present invention in designed to cover and protect an exercise Swiss ball substantially spherical in shape, at its centermost and widest perimeter/circumference, due to its tubular design. The fabric cover is substantially tubular, or becomes tubular upon connection of the rectangular shaped fabric's shortest sides. The perimeters of the cover are equipped with drawstrings made functional by hemming fabric along the device's two perimeters. The drawstrings along each perimeter are capable of being secured upon cinching of the cover's perimeters and released prior to removal from the exercise Swiss ball. Securing and releasing the drawstrings may be in the form of a cord-stopper, a bow, or knot, or the natural tension which occurs by the cinching of fabric upon a cord, string, ribbon, elastic, or the like. The degree to which the exercise Swiss ball is covered is dependent upon the width and stretch of the fabric used. Notably, a cover made from a fabric with a greater width and or greater stretch capability will cover a greater portion of the exercise Swiss ball. Additionally, the coverage is dependent upon the degree to which the cover's drawstrings are pulled by the user. Notably, the cover will protect a greater surface area of the exercise Swiss ball in a more taut fashion, as the drawstring is pulled tighter by the user.
[0035] To use the present invention, the user should place both arms through the tubular fabric and grab the ball, allowing the cover to slide over the ball, forming a belt about the greatest and centermost perimeter of the exercise Swiss ball. The cover can then be flattened out, and the cords on each side should be pulled tightly to stretch the fabric of the cover. Two holes where the cover is gathered or cinched will expose the exercise Swiss ball on opposite sides in a symmetrical fashion. The user can then has the option to attach personal items such as key, phone, portable music, workout journal, coin purse, hand towel, or resistance exercise bands to the rings, creating a personal portable workout station for home, office, gym, or physical training.
[0036] When the cover is removed from the ball, it can be folded flat, or evenly draped over a workout bench for added protection. The cover can be washed. The present invention can be made of any fabric, although a stretch polyester blend allows for the quickest drying time, as dry environments have a tendency to be more resistant to the breeding of bacteria. The cover provides a new medium for advertising and personal expression.
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An exercise Swiss ball cover with the capability of performing integrated resistance exercises and temporarily store personal belongings. The cover is a fabric rectangle secured at its shortest sides, or a fabric tube, into which the exercise Swiss ball is inserted and covered at the centermost, widest circumference. There are two perimeters, each having a small ring or grommet to attach and detach exercise accessories and personal belongings. The cover is cinched at its two perimeters to secure the cover to the exercise Swiss ball. It provides a 360 degree forward and backward rotation capability and a variable lateral rotation of up to 180 degrees without interference from excess material or the bare surface of the exercise Swiss ball. Variable side coverage depends upon stretch and width of fabric used. The cover can be folded into a flat rectangle, making it suitable to neatly drape over a workout bench.
| 0 |
FIELD OF THE INVENTION
This invention is directed generally to a pneumatic transmission system for transmitting a carrier between two points. Specifically, this invention relates to a system for braking a carrier in a pneumatic transmission system, as the carrier approaches its destination point. In one aspect, this invention relates to a transmission system having at least one open terminal or station, one blower to transmit the carrier toward its destination point, and a valve which is closed for a predetermined period of time after the blower has been deactivated, to thereby slow the carrier as the carrier approaches its destination point.
BACKGROUND OF THE INVENTION
Pneumatic transmission systems are widely known and are used to transmit articles from a first place to a second place which is remote from the first place. Pneumatic transmission systems usually include at least two stations, a tube or conduit extending between the two stations, and a carrier positioned within the tube so as to be delivered by pneumatic pressure. The pressure can be a superatmospheric pressure or a subatmospheric pressure.
A common use for a pneumatic transmission system is in drive-in bank teller facilities where business is conducted via a carrier transmitted between the bank and the remote drive-in terminal. Other uses include sending documents between different floors in a building, or from one office to another office located some distance apart.
An example of a conventional pneumatic transmission system that used a pair of blowers is shown in FIG. 1. A first station 30 and a second station 35 are connected by a transmission tube 40. A first blower 10 is located at the first station 30 and can pressurize the air behind a carrier 45, thereby creating enough differential pressure (ΔP) across the carrier 45 to push the carrier 45 upwardly from station 30, then along the horizontal section of the tube 40 to the second station 35. Similarly, the second blower 20, which is located at the second station 35, can pressurize the air behind the carrier 45 and send the carrier 45 in the opposite direction toward the first station 30. In one such system, the blowers were a pair of vacuum cleaner motors which were physically and electrically isolated from each other so that each blower 10 and 20 was operated independently of the other blower. The first blower 10 can be turned on by actuating a first mechanical switch 15, sending a carrier 45 from the first station 30 to the second station 35. The second blower 20 can be turned on by actuating a second mechanical switch 25 to send a carrier 45 from the second station 35 to the first station 30. If a first carrier 45 was inserted in the first station 30 and the blower 10 was turned on and then a second carrier 45 was inserted in the second station 35 and the blower 20 was turned on while the first carrier 45 was in transit, thereby placing two carriers in the transmission tube 40 simultaneously, the movements of the two carriers 45 would be blocked until one of the blowers 10 or 20 was turned off, at which time both carriers would proceed in the direction dictated by the blower which remained on.
In many pneumatic transmission systems, the carrier would travel through the tube and impact a stop device once it had reached its intended destination. In such systems the carrier can travel at speeds of 15-20 feet/second or higher, and the impact of the carrier against the stop device can cause great wear on both the carrier and the system as well as damage the contents of the carrier.
One method for obviating the high velocity impact between the carrier and the stop device has employed the use of an air cushion adjacent to the receiving terminal, as illustrated in FIG. 2. The air cushion is created by pneumatically sealing the receiving terminal 50 (making it a closed terminal) and providing a vent 65 (or check valve) in the tube 75 a short distance from the receiving terminal 50 such that when the carrier 70 passes the vent 65 in an approach to the receiving terminal 50, a trapped column of air is created in the approach leg 55 of the tube 75 which serves to decelerate or "cushion" the carrier 70 as the carrier 70 makes its final approach to the receiving terminal 50. The check valve 65 is opened to the atmosphere either directly, or through a conduit 60 as shown. However, such an air cushion system requires that the receiving terminal have a door capable of pneumatically sealing the terminal. The system operator must then manually open the terminal door in order to retrieve the carrier from the system. Alternatively, a complicated mechanism can be provided to automatically open the terminal door upon the arrival of the carrier. However, such mechanisms are often costly and prone to mechanical failures at inopportune times.
This form of operation is well known in the art of pneumatic systems. However, slowing down a carrier is not this simple when the destination station is an open air station. There is no dead column of air when the station is open to the atmosphere because the air in front of the carrier is exhausted out of the open station. Therefore, there is no pressure build up in front of the carrier and there is no slowing force to act upon the carrier.
Other attempts to resolve the high impact problem have included the use of other trigger means to shut off the stream of air. These alternative trigger means include such items as a photocell, a timing device, a limit switch, a spring catch, and combinations thereof.
An alternative system in which a carrier is decelerated prior to entering an open terminal is disclosed in U.S. Pat. No. 4,180,354 to Greene. U.S. Pat. No. 4,180,354 discloses a transmission system in which the pressurized air behind the carrier is routed principally through a check valve positioned near the open terminal to allow the carrier sufficient time to decelerate before discharging into an open terminal. An adjustable valve allows some air to continue to push the carrier to the terminal. A secondary air line adjacent to the open terminal draws in the air from the main transmission line and reroutes it to the blower, thus avoiding the blowing of air through the open terminal. The carrier is decelerated by simply choking off most of the air behind it at a point near the open terminal so that the carrier ejects with a minimum speed from the transmission line into the open terminal. The above cited system is a way to slow a carrier as it approaches an open destination terminal. However, this system requires multiple routing conduits and an adjustable valve to achieve the desired result.
Still another alternative system in which a carrier is decelerated prior to entering an open terminal is disclosed in U.S. Pat. No. 4,984,939 to Foreman et al. This patent discloses the use of one pressure blower and one vacuum blower, wherein the vacuum blower is operated at an equal or greater capacity than the pressure blower. The pressure blower and vacuum blower are attached to the transmission conduit by air tubes at different locations along the transmission conduit. In this system, a carrier is sent from a first station to a second station by activating the pressure blower at a certain capacity to create a ΔP across the carrier thereby moving it out of the first station, through the transmission conduit and toward the second station. The vacuum blower is attached to the transmission conduit at some point near the second station. As the carrier approaches the second station, the carrier is slowed by the counterflow of air due to the vacuum blower. The vacuum blower sucks air out of the transmission conduit behind the carrier at an equal or greater capacity than the pressure blower, which reverses the ΔP across the carrier and slows the carrier as the carrier makes its final approach to the open terminal.
As mentioned above, this system requires multiple transmission conduits and precise timing in order to operate effectively.
Yet another alternative system in which a carrier is decelerated prior to entering an open terminal is disclosed in U.S. Pat. No. 5,584,613 to Greene et al. This patent discloses the use of a first blower to transmit a carrier toward its destination point while a second opposing blower is activated for a predetermined period of time while the first blower remains on, to create an air block. The thus established air block slows the carrier as it approaches its destination point. The opposing blowers are positioned in a supply/exhaust branch circuit which is attached to a first station. In this system, a carrier is sent from the first station to a second station by activating the first blower at an established capacity to create a ΔP across the carrier, thereby moving it out of the first station, through the transmission conduit and toward the second station. As the carrier approaches the second station, the second opposing blower is activated, thus the carrier is slowed by the air block created by the operation of the opposing blowers. The air block creates a situation where the ΔP across the carrier in the transport conduit decreases, and is preferably reversed, to thereby slow the carrier as the carrier makes its final approach to the second station. The stress placed on the blowers due to their opposing efforts can, however, impact the life expectancy of the blowers.
Conventional pneumatic transmission systems are also used in multistation configurations, such as in a hospital. In these systems, one central station, a laboratory for example, sends a carrier to any one of many receiving stations such as nurse stations. The cargo inside the carrier in these systems can be fragile. Therefore, it is advantageous to allow the carrier to enter the open stations at a low rate of speed in order to maintain the integrity of the cargo. Conventional multistation pneumatic transmission systems currently have to use a slide gate at each station in order to achieve this result. The slide gate is a combination of a door and a motor, which is activated as the carrier enters the particular station. Upon approach of the carrier, the motor is activated and the slide gate positions itself inside the transmission conduit. The slide gate effectively closes the transmission conduit in front of the carrier, thereby forming a dead column of air in front of the carrier. The carrier is slowed as it falls on the dead column of air, and finally comes to rest on the slide gate. The slide gate is then removed from the transmission conduit, allowing the carrier to drop into the open station.
The problems associated with the above described conventional multistation pneumatic transmission systems include, among other things, the cost of numerous slide gates and the lack of reliability due to the use of additional moving parts.
BRIEF SUMMARY OF THE INVENTION
The present invention is a new and advantageous system and method for braking a carrier in a pneumatic transmission system as the carrier approaches its destination terminal. The pneumatic transmission system of the present invention includes at least a first station and a second station, a transport conduit connected to each of the first and second stations, a supply/exhaust branch conduit connected to the first station, a motor driven blower and a valve positioned in the supply/exhaust branch conduit, a controller, and a sensor associated with the transport conduit at a location a predetermined distance away from the second station.
The present invention can be implemented in a multistation pneumatic transmission system. The use of the present invention would eliminate the need for slide gates at all of the receiving stations as described above with respect to a conventional multistation pneumatic transmission system.
The blower is activated to move a carrier from the first station to the second station via the transport conduit. The sensor detects the presence of the carrier in the transport conduit as the carrier passes the sensor location and the sensor then signals the controller. The controller receives the signal from the sensor and, in turn, deactivates the blower and closes the valve for a predetermined amount of time, to thereby create an air block in the transport tube behind the carrier. The air block creates a situation where the (ΔP) across the carrier in the transport conduit decreases, and is preferably reversed, to thereby slow the carrier as the carrier makes its final approach to the second station.
A method for braking a carrier, in a pneumatic transmission system, as the carrier approaches a receiving station includes the steps of activating a first blower for moving air in a first direction to thereby transmit the carrier from a transmitting station toward the receiving station via a transport conduit, sensing the presence of the carrier at a location along the transport conduit, and, upon sensing the presence of the carrier at the location, deactivating the blower and closing a valve for a predetermined time, for creating an air block in the transport tube behind the carrier, thereby decreasing, and preferably reversing, the ΔP across the carrier.
BRIEF DESCRIPTION OF SEVERAL VIEWS OF THE DRAWINGS
FIG. 1 is a block diagram illustrating a conventional pneumatic transmission system utilizing a pair of vacuum cleaner motor blowers.
FIG. 2 is an illustration of a conventional braking system used when the destination station is closed to the atmosphere.
FIG. 3 is a schematic illustration of a pneumatic transmission system containing an embodiment of a carrier automatic braking system in accordance with the present invention.
FIG. 4 is a schematic illustration of a pneumatic transmission system containing a preferred embodiment of a carrier automatic braking system in accordance with the present invention.
DETAILED DESCRIPTION OF THE INVENTION
FIG. 3 illustrates a pneumatic transmission system containing an embodiment of a carrier automatic braking system in accordance with the present invention. The present system comprises a station 100 and a station 101 connected by a substantially airtight transport tube 140, which is open to the atmosphere at station 101, with a blower assembly 200 being positioned within a supply/exhaust branch 120 which is connected to station 100. The supply/exhaust branch 120 includes a conduit 125 which is substantially airtight and a vent/inlet 170 which is open to the atmosphere and can provide air from the atmosphere to the pneumatic transmission system or can allow the exhaust of air from the pneumatic transmission system to the atmosphere. Conduit 125 does not have to be of a similar internal diameter as tube 140 because no carrier is transported therethrough, only air. The blower assembly 200 is comprised of a substantially airtight blower housing 205, show in phantom, which has a first port 210 and a second port 215 in one end. A solenoid valve 220 is mounted to the end of blower housing 205 such that, when actuated, the solenoid shaft 255 at least partially retracts into solenoid housing 250, thereby blocking port 210 with valve disk 260, and preventing air flow through port 210. The present invention, however, is not limited to a solenoid valve. A pair of vacuum cleaner motor blowers 105 and 110 are positioned in a blower tube 225 in series with each other, meaning the vacuum cleaner motor blowers 105 and 110 are within the same air flow path. Furthermore, the vacuum cleaner motor blowers 105 and 110 are spatially separated from each other within the blower tube 225. Blower tube 225, and thus the vacuum cleaner motor blowers 105 and 110, are disposed within blower housing 205. Blower tube 225 is substantially open on one end and is substantially closed on the other end except for communication with port 215. The supply/exhaust branch 120 is connected to station 100 at one end and open to the atmosphere at vent/inlet 170 for supplying or exhausting air. Station 100 can be a closed station, meaning that it can be sealed by closing a door 115 so that, except for the supply/exhaust branch 120, it is substantially closed to the atmosphere during transport of a carrier 130. Station 101 can be either a closed station with a vent or a station which is open to the atmosphere during transport of the carrier 130, but it is shown as an open station for the purpose of this embodiment. The carrier 130 is capable of being filled with items to be transferred and is inserted at either station for transfer to the other station.
The transport tube 140, which is connected to station 100 at one end and to station 101 at its other end, is of sufficient internal diameter such that the carrier 130 can be transmitted therethrough. Transport tube 140 can have any spatial orientation and can include curved portions, straight portions, vertical portions, and horizontal portions, dependent upon the circumstances under which the system is going to be used. For example, the approach leg 145 is shown as a curve from a horizontal direction to a vertical downward direction. However, this approach leg 145 can also remain horizontal or curve in a vertical upward direction as it connects with station 101. The transport tube 140 and the carrier 130 can have nearly any desired dimension and cross section, dependent on the system needs. The transport tube 140 can include any transmission line of any crosssectional form having a pneumatic channel formed therethrough.
To send the carrier 130 from station 100 to station 101, the first motor blower 105 is activated during the transfer phase of the cycle to intake air through the vent/inlet 170 and to apply pressurized air to the carrier 130, which creates a ΔP across the carrier 130 and moves the carrier 130 upwardly, out of station 100, and then horizontally through the tube 140 toward station 101. The motor blower 105 can generate approximately 5 psig behind the carrier 130. Likewise, to send the carrier 130 from station 101 to station 100, the second motor blower 110 would be activated instead of the first motor blower 105, to exhaust air through the vent/inlet 170, thereby creating at least a partial vacuum in the tube 140 on the station 100 side of the carrier 130, while the station 101 side of the carrier 130 remains at 0 psig because it is open to the atmosphere. This ΔP across the carrier 130 generates a force moving the carrier 130 in the opposite or station 100 direction.
In order to send the carrier 130 from station 100 to station 101, the carrier 130 is placed in the tube 140 and the door 115 is shut and sealed. The first motor blower 105 is then activated. This can be done by an operator actuating a switch 155, which is coupled to a controller 165. The controller 165 is coupled to the first motor blower 105 and to the second motor blower 110 for selective activation of the blowers 105 and 110. When switch 155 is actuated, the switch 155 sends a control signal to the controller 165. The controller 165 receives the control signal from the switch 155 and provides a control signal to the first motor blower 105, to thereby activate the first motor blower 105. The controller 165 is also coupled to a sensor 150 which is positioned near or on the transmission tube 140. The sensor 150 does not need to be in physical contact with the transmission tube 140, but it must be positioned such that it is able to sense the carrier 130 as the carrier passes a predetermined location in the transmission tube 140 related to the approach of the carrier 130 to the station 101. The present invention is not limited to an electrical coupling, or even a physical connection between the controller 165 and its peripherals.
First motor blower 105 blows air through supply/exhaust branch 120 and conduit 125 to the first station 100 and creates a ΔP across the carrier 130, thus moving it towards station 101. The motor blowers used in this embodiment can be standard vacuum cleaner motor blowers such as Model No. 115923 manufactured by Ametek Lamp. Vacuum cleaner motor blowers 105 and 110 are substantially equal in size and in output capacity, although mounted in opposite directions. These vacuum cleaner motor blowers 105 and 110 are capable of operating at approximately 23000 RPM and of generating approximately 124 CFM.
As the carrier 130 moves through the tube 140, it reaches the portion of the tube 140 where it is detected by the sensor 150. The sensor 150 detects the presence of the carrier 130 as it passes a predetermined location in the transmission tube 140 and provides a control signal to the controller 165 indicative of that detection. The controller 165 receives this control signal from the sensor 150 and provides a control signal to first motor blower 105 to thereby deactivate the first motor blower 105, to solenoid valve 220 to thereby actuate solenoid valve 220 thus blocking port 210, and to start the timer 160. The timer 160 can be an external peripheral device or it can be integrated in the controller 165. In this embodiment, timer 160 is preferably a Model No. RTE B21 manufactured by IDEC. An air block is created in conduit 125, and thus in pneumatic tube 140, by the blocking of port 210 by solenoid valve 220.
Once the air block is on, a finite amount of air remains in the tube 140 between the carrier 130 and the station 100 because no additional air can get by solenoid valve 220 and through port 210 in either direction. As the carrier 130 continues to move through the tube 140 toward the station 101, the volume of the portion of the tube 140 between the air block and the carrier 130 increases, and as that volume increases, the air pressure in the tube 140 behind the carrier 130 decreases because the amount of air between the air block and the carrier 130 remains substantially constant. The pressure on the station 101 side of the carrier 130, however, is substantially constant at 0 psig because the station 101 is open to the atmosphere. Therefore, as the pressure between the air block and the carrier 130 decreases as the carrier 130 moves through the final approach section 145 of the tube 140, the carrier 130 slows down due to the decreasing ΔP across the carrier 130. In this embodiment, the carrier 130 reaches a point along the tube 140 where the pressure behind the carrier 130 decreases to a value less than the 0 psig in front of the carrier 130. This reversal of the ΔP across the carrier 130 creates a force in the direction of station 100, thereby further slowing the carrier 130 as the carrier 130 approaches station 101. When the predetermined time has elapsed, as noted by the timer 160, the controller 165 deactivates the solenoid valve 220, thereby opening port 210 and allowing free flow of air through conduit 125 and tube 140.
In order to send the carrier 130 from station 101 to station 100 an operator activates the second motor blower 110. This activation is accomplished by an operator actuating a switch 175, which is coupled to the controller 165. When switch 175 is actuated, the switch 175 sends a control signal to the controller 165. The controller 165 receives the control signal from switch 175 and provides a control signal to the second motor blower 110, to thereby activate the second motor blower 110. The motor blower 110 intakes air from the transport tube 140 and exhausts that air through vent/inlet 170 which lowers the pressure in the transport tube 140 and creates a ΔP across the carrier 130 moving it towards station 100.
As the carrier 130 moves through the tube 140, it reaches the portion of the tube 140 where it is detected by the sensor 151. The sensor 151 detects the presence of the carrier 130 as it passes a predetermined location in the transmission tube 140 and provides a control signal to the controller 165 indicative of that detection. The controller 165 receives this control signal from the sensor 151 and provides a control signal to the motor blower 110 to thereby deactivate motor blower 110, to solenoid valve 220 to thereby activate solenoid value 220, and to start the timer 160. Now the solenoid valve 220 is blocking port 210 thereby creating an air block in the conduit 125 and tube 140, as described above.
Once the air block is on, a finite amount of air remains in the tube 140 between the carrier 130 and the station 100 because no additional air can get through the air block created by valve disk 260 blocking port 210. As the carrier 130 continues to move through the tube 140 toward the station 100, the volume of the portion of the tube 140 between the air block and the carrier 130 decreases, and as that volume decreases, the air pressure in the tube 140 in front of the carrier 130 (station 100 side) increases because the amount of air between the air block and the carrier 130 remains substantially constant and it is being compressed into a smaller volume. The pressure on the station 101 side of the carrier 130, however, is substantially constant at 0 psig because the station 101 is open to the atmosphere. Therefore, the ΔP across the carrier 130 decreases as the carrier 130 moves toward the station 100 and the carrier 130 slows down due to the decreasing ΔP across the carrier 130.
The carrier 130 reaches a point along the tube 140 where the pressure in front of the carrier 130 increases to a value greater than the 0 psig behind of the carrier 130. This reversal of the ΔP across the carrier 130 creates a force in the direction of station 101, thereby further slowing the carrier 130 as the carrier 130 approaches station 100. When the predetermined time has elapsed, as noted by the timer 160, the controller 165 deactivates the solenoid valve 220.
FIG. 4 illustrates a pneumatic transmission system containing a preferred embodiment of a carrier automatic braking system in accordance with the present invention.
The present system comprises a station 300 and a station 301 connected by a substantially airtight transport tube 340, which is open to the atmosphere at station 301, with a blower assembly 400 being positioned within a supply/exhaust branch 320 which is connected to station 300. The supply/exhaust branch 320 includes a conduit 325 which is substantially airtight and a vent/inlet 370 which is open to the atmosphere and can provide air from the atmosphere to the pneumatic transmission system or can allow the exhaust of air from the pneumatic transmission system to the atmosphere. Conduit 325 does not have to be of a similar internal diameter as tube 340 because no carrier is transported therethrough, only air. Conduit 325 is attached at one end to port 410 in blower housing 405 and at its other end to check/relief valve 212. A second conduit 214 connects check valve 212 to station 300. Check valve 212 also communicates with tube 340 directly, through port 245, and comprises leaf 216, which is adapted to cover port 218 in certain air flow situations. The blower assembly 400 is comprised of a substantially airtight blower housing 405, shown in phantom, which has a first port 410 and a second port 415 in one end. A solenoid valve 420 is mounted to the end of blower housing 405 such that, when actuated, solenoid shaft 455 at least partially retracts into solenoid housing 450, thereby blocking port 410 with valve disk 460, and preventing air flow through port 410. The present invention, however, is not limited to a solenoid valve. A pair of vacuum cleaner motor blowers 305 and 310 are positioned in a blower tube 425 in series with each other, meaning the vacuum cleaner motor blowers 305 and 310 are within the same air flow path. Furthermore, the vacuum cleaner motor blowers 305 and 310 are spatially separated from each other within the blower tube 425. Blower tube 425, and thus the vacuum cleaner motor blowers 305 and 310, are disposed within blower housing 405. Blower tube 425 is substantially open on one end and is substantially closed on the other end except for communication with port 415. The supply/exhaust branch 320 is connected to station 300 at one end and open to the atmosphere at vent/inlet 370 for supplying or exhausting air. Station 300 can be a closed station, meaning that it can be sealed by closing a door 315 so that, except for the supply/exhaust branch 320, it is substantially closed to the atmosphere during transport of a carrier 330. Station 301 can be either a closed station with a vent or a station which is open to the atmosphere during transport of the carrier 330, but it is shown as an open station for the purpose of this embodiment. The carrier 330 is capable of being filled with items to be transferred and is inserted at either station for transfer to the other station.
The transport tube 340, which is connected to station 300 at one end and to station 301 at its other end, is of sufficient internal diameter such that the carrier 330 can be transmitted therethrough. Transport tube 340 can have any spatial orientation and can include curved portions, straight portions, vertical portions, and horizontal portions, dependent upon the circumstances under which the system is going to be used. For example, the approach leg 345 is shown as a curve from a horizontal direction to a vertical downward direction. However, this approach leg 345 can also remain horizontal or curve in a vertical upward direction as it connects with station 301. The transport tube 340 and the carrier 330 can have nearly any desired dimension and cross section, dependent on the system needs. The transport tube 340 can include any transmission line of any crosssectional form having a pneumatic channel formed therethrough.
To send the carrier 330 from station 300 to station 301, the first motor blower 305 is activated during the transfer phase of the cycle to intake air through the vent/inlet 370 and to apply pressurized air to the carrier 330, which creates a ΔP across the carrier 330 and moves the carrier 330 upwardly, out of station 300, and then horizontally through the tube 340 toward station 301. The motor blower 305 can generate approximately 5 psig behind the carrier 330. Likewise, to send the carrier 330 from station 301 to station 300, the second motor blower 310 would be activated instead of the first motor blower 305, to exhaust air through the vent/inlet 370, thereby creating at least a partial vacuum in the tube 340 on the station 300 side of the carrier 330, while the station 301 side of the carrier 330 remains at 0 psig because it is open to the atmosphere. This ΔP across the carrier 330 generates a force moving the carrier 330 in the opposite or station 300 direction.
In order to send the carrier 330 from station 300 to station 301, the carrier 330 is placed in the tube 340 and the door 315 is shut and sealed. The first motor blower 305 is then activated. This can be done by an operator actuating a switch 355, which is coupled to a controller 365. The controller 365 is coupled to the first motor blower 305 and to the second motor blower 310 for selective activation of the blowers 305 and 310. When switch 355 is actuated, the switch 355 sends a control signal to the controller 365. The controller 365 receives the control signal from the switch 355 and provides a control signal to the first motor blower 305, to thereby activate the first motor blower 305. The controller 365 is also coupled to a sensor 350 which is positioned near or on the transmission tube 340. The sensor 350 does not need to be in physical contact with the transmission tube 340, but it must be positioned such that it is able to sense the carrier 330 as the carrier 300 passes a predetermined location in the transmission tube 340 related to the approach of the carrier 330 to the station 301. The present invention is not limited to an electrical coupling, or even a physical connection, between the controller 365 and its peripherals.
First motor blower 305 blows air through conduit 325 and into check/relief valve 212. The air flow into check/relief valve 212 exerts pressure onto leaf 216, thereby causing leaf 216 to cover port 218. With port 218 blocked, air flows out of check/relief valve 212, through a second conduit 214, to the first station 300, and creates a ΔP across the carrier 330, thus moving it towards station 301. The rotor blowers used in this embodiment can be standard vacuum cleaner motor blowers such as Model No. 115923 manufactured by Ametek Lamp. Vacuum cleaner motor blowers 305 and 310 are substantially equal in size and in output capacity, although mounted in opposite directions. These vacuum cleaner motor blowers 305 and 310 are capable of operating at approximately 23000 RPM and of generating approximately 124 CFM.
As the carrier 330 moves through the tube 340, it reaches the portion of the tube 340 where it is detected by the sensor 350. The sensor 350 detects the presence of the carrier 330 as it passes a predetermined location in the transmission tube 340 and provides a control signal to the controller 365 indicative of that detection. The controller 365 receives this control signal from the sensor 350 and provides a control signal to first motor blower 305 to thereby deactivate the first motor blower 305, to solenoid valve 420 to thereby actuate solenoid valve 420 thus blocking port 410, and to start the timer 360. The timer 360 can be an external peripheral device or it can be integrated in the controller 365. In this embodiment, timer 360 is preferably a Model No. RTE B21 manufactured by IDEC. An air block is created in conduit 325, and thus in tube 340, by the blocking of port 410 by solenoid valve 420.
Once the air block is on, a finite amount of air remains in the tube 340 between the carrier 330 and the station 300 because no additional air can get by solenoid valve 420 and through port 410 in either direction. As the carrier 330 continues to move through the tube 340 toward the station 301, the volume of the portion of the tube 340 between the air block and the carrier 330 increases, and as that volume increases, the air pressure in the tube 340 behind the carrier 330 decreases because the amount of air between the air block and the carrier 330 remains substantially constant. The pressure on the station 301 side of the carrier 330, however, is substantially constant at 0 psig because the station 301 is open to the atmosphere. Therefore, as the pressure between the air block and the carrier 330 decreases as the carrier 330 moves through the final approach section 345 of the tube 340, the carrier 330 slows down due to the decreasing ΔP across the carrier 330. In this embodiment, the carrier 330 reaches a point along the tube 340 where the pressure behind the carrier 330 decreases to a value less than the 0 psig in front of the carrier 330. This reversal of the ΔP across the carrier 330 creates a force in the direction of station 300, thereby further slowing the carrier 330 as the carrier 330 approaches station 301. When the predetermined time has elapsed, as noted by the timer 360, the controller 365 deactivates the solenoid valve 420; thereby opening port 410 and allowing free flow of air through conduit 325, second conduit 214, and tube 340. Upon opening of solenoid valve 420, leaf 216 in check valve 212 is free to open, thereby allowing free flow of air through port 218.
In order to send the carrier 330 from station 301 to station 300 an operator activates the second motor blower 310. This activation is accomplished by an operator actuating a switch 375, which is coupled to the controller 365. When switch 375 is actuated, the switch 375 sends a control signal to the controller 365. The controller 365 receives the control signal from switch 375 and provides a control signal to the second motor blower 310, to thereby activate the second motor blower 310. The motor blower 310 intakes air from the transport tube 340 and exhausts that air through vent/inlet 370 which lowers the pressure in the transport tube 340 and creates a ΔP across the carrier 330 moving it towards station 300. Air propelled by motor blower 310 entering check/relief valve 212 from tube 340 holds leaf 216 in check/relief valve 212 open, thereby allowing free flow of air through port 218. Virtually no air flow occurs through tube 340 between port 218 and station 300, through station 300, or through second conduit 214, since the air flow will find the path of least resistance, which is through port 218.
As the carrier 330 moves through the tube 340, it reaches the portion of the tube 340 where port 218 is located. After carrier 330 passes port 218, the pressure in the tube 340 on the station 300 side of carrier 330 increases, thereby decreasing, and preferably virtually eliminating, the ΔP across carrier 330. The carrier 330 free falls into station 300.
While preferred embodiments of the present invention has been described, with respect to certain preferred embodiments, it should be apparent to those skilled in the art that it is not so limited. Various other modifications may be made without departing from the spirit and scope of the invention. It is intended that the following claims be interpreted to embrace all such variations and modifications.
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A pneumatic transmission system having a carrier automatic braking system contains a transport conduit having a first end and a second end and being capable of permitting the transfer of a carrier therethrough, a first station for sending and receiving a carrier located on one end of the transmission conduit, and a second station for sending and receiving a carrier located on the other end of the transmission conduit. A motor blower, capable of moving a volume of air through a conduit, is enclosed within a supply/exhaust branch which is connected to one of the stations. A valve, capable of closing, to thereby create an air block in the supply line, is also disposed within the supply/exhaust branch. The motor blower blows air to move the carrier from one station to the other. The valve is activated, after deactivating the motor blower, when the carrier is detected at some predetermined location along the transport conduit. The valve closing creates an air block within the supply/exhaust branch which prohibits air from entering or exiting the conduit on the air block side of the carrier as the carrier moves along the transport conduit. The change in differential pressure across the carrier slows the carrier as it approaches its destination station.
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This is a continuation of co-pending application Ser. No. 08/901,118, filed Jul. 28, 1997, now U.S. Pat. No. 5,951,028.
BACKGROUND OF THE INVENTION
1. Field of the Invention
This invention relates to the field of roller skates and, particularly, to an improved skate with canted, large diameter wheels.
2. Prior Art
Various designs of roller skates have been developed over the years. At the present time, “in-line” skates are particularly popular. This type of skate has a plurality of small-diameter wheels aligned in a longitudinal direction beneath the sole of the skater's foot. A number of advantages are claimed for this design of a skate. However, the small diameter of the wheels inherently limits the speed that can be achieved and limits the use of the skates to relatively smooth surfaces.
Among alternative skate designs, skates with large-diameter wheels have been proposed for over a century. For example, U.S. Pat. No. 89,833 discloses a skate with a single wheel of large diameter for use in skating on fields and other uneven surfaces. This skate, and many similar prior art designs, places the wheel to the outside of the skater's foot. While this allows a lower center of gravity than if the wheel were to be located entirely below the skater's foot, undue strain is placed on the skater's ankles because of the lateral offset between the center line of the skater's foot and the point of contact between the wheel and the ground. One solution to this problem is to mount the wheel at an angle with respect to vertical so that the point of contact with the ground will be directly below the skater's foot. Such a design for a single-wheeled skate is shown, for example, in U.S. Pat. No. 2,931,012.
Single-wheeled skates are, of course, inherently unstable. A design for a skate with two large diameter wheels is shown in U.S. Pat. No. 3,885,804 to Cudmore. In this design, two large, canted, equal-sized wheels are mounted con axles extending outwardly from a rigid sole-plate. As disclosed by Cudmore, the canted wheels contact the ground directly beneath the center line of the sole-plate. The wheels are dished with their concave sides facing toward the sole-plate so that a portion of the sole-plate extends into the wheel concavities to permit the sole-plate to be positioned very close to the ground. Cudmore's design provides a reasonably stable skate in comparison to many of the prior art designs; however, development of the present invention has yielded improved stability and responsiveness over the design of Cudmore. Furthermore, the dished wheels used by Cudmore to achieve a low center of gravity inherently limit the ability to turn sharply since the outside surfaces of the wheels will contact the ground when the skate leans in a sharp turn. The present invention overcomes this disadvantage by positioning the wheels so that dishing is not necessary to achieve an acceptably low center of gravity.
SUMMARY OF THE INVENTION
The present invention is a two-wheeled roller skate with canted wheels. In a preferred embodiment, the axle for the forward wheel is located well forward of the ball of the foot, approximately in line with the skater's toes. The axle for the rear wheel is located at the rear of the skater's heel. The wheels are canted so that the front wheel contacts the ground slightly outside of the center line of the skater's foot and the rear wheel contacts the ground slightly inside of the center line. This contact geometry permits the use of a relatively small diameter front wheel and thereby allows the sole of the skate to be positioned close to the ground. In plan projection, the axles are preferably non-parallel in order to provide steering correction. The amount of steering correction desirable will depend on the skater's skill and the nature of the skating activity. In alternative embodiments, the present invention incorporates novel braking mechanisms.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 is a perspective view of the roller skate constructed in accordance with the present invention.
FIG. 2 is a side elevational view of the roller skate of FIG. 1 .
FIG. 3 is a partial bottom plan view of the roller skate of FIG. 1 .
FIG. 4 is a partial front elevational view of the roller skate of FIG. 1 .
FIG. 5 is a partial rear elevation view of the roller skate of FIG. 1 .
FIG. 6 is a partial side elevation view of an alternative embodiment of the present invention illustrating a braking mechanism.
FIG. 7 is a cross-sectional view taken along line 7 — 7 of FIG. 6 .
FIG. 8 is a perspective view of an other alternative embodiment of the present invention.
FIG. 9 is a partial side elevational view of the roller skate of FIG. 8 .
FIG. 10 is a side elevational view of yet another alternative embodiment of the present invention.
FIG. 11 is a side elevational view of still another alternative embodiment of the present invention.
FIG. 12 is a side elevational view of a further alternative embodiment of the present invention.
DETAILED DESCRIPTION OF THE INVENTION
In the following description, for purposes of explanation and not limitation, specific details are set forth in order to provide a thorough understanding of the present invention. However, it will be apparent to one skilled in the art that the present invention may be practiced in other embodiments that depart from these specific details. In other instances, detailed descriptions of well-known methods and devices are omitted so as to not obscure the description of the present invention with unnecessary detail.
FIG. 1 is a perspective view of a skate 10 constructed in accordance with the present invention. Skate 10 comprises a boot 12 to which are attached a front wheel 14 and a rear wheel 16 . The front wheel 14 carries tire 15 and rear wheel 16 carries tire 17 . In a preferred embodiment, the outside diameter of front tire 15 is about five inches and that of rear tire 17 is about seven inches. The invention is not limited in this regard and other sized or equal-sized wheels/tires may be used. In some embodiments, such as illustrated in FIG. 12, the front wheel/tire may have a larger diameter than the rear.
Skate 10 is intended for the right foot of the skater, thus wheels 14 and 16 are mounted to the outside of boot 12 . It is to be understood that a corresponding skate is also provided for the left foot of the skater, which is generally a mirror image of skate 10 . As will be more apparent in the discussion that follows, wheels 14 and 16 are canted so that tires 15 and 17 contact the ground directly beneath boot 12 rather than to the outside thereof.
Boot 12 is generally constructed in the same manner as boots used with. conventional in-line skates. Accordingly, details of boot 12 will not be discussed herein. Wheels 14 and 16 may be machined or cast using a suitable metal or plastic material. Tires 15 and 17 may be made of a natural or synthetic rubber material and may be solid, foam-filled or pneumatic. Tires 15 and 17 may also be made of urethane plastic as has become standard practice for in-line skate wheels.
FIG. 2 is an inside elevation view of skate 10 . A sole plate or chassis 18 is attached to the bottom of boot 12 to provide structural support for wheels 14 and 16 . Alternatively, boot 12 and chassis 18 could be an integral structure. The axle supporting front wheel 14 is located well forward of the ball of the skater's foot, either ahead of or in line with the skater's toes. The axle supporting rear wheel 16 is located generally below the skater's heel.
Referring now to FIG. 3, chassis 18 is shown in bottom plan view. When projected in plan view, the axles of wheels 14 and 16 are generally perpendicular to the center line of the skate. It has been found, however, that superior skating performance is achieved with slight “toe-in” of the front wheel and/or “toe-out” of the rear wheel as indicated by the arrows in FIG. 3 . This provides a desirable steering correction to counteract the tendency of the skate. to steer outwardly due to the offset geometiy of the wheel-to-ground contact patches as described below. It has been determined that neutral handling (i.e., the situation where the skate tracks straight ahead while coasting) is best achieved with the rear wheel parallel to the skate center line and the front wheel toed in at about 2°.
For more experienced skaters, who desire power plus control and greater. hill-climbing ability, a larger toe-in angle up to about 3° or 4° is preferred at the front wheel. This causes the left skate to steer slightly to the right and the right skate to steer slightly to the left and allows the skater to cover a greater distance with each push-off. The optimum configuration for all-around skating has been found to be a toe-out angle at the rear wheel of about 1-1.5° and an equal amount of toe-in angle at the front wheel.
Each skater, depending upon experience and the nature of the terrain to be traversed, may prefer a slightly different adjustment of wheel angles. Indeed, the desirable range of wheel angles extends from 0° to about 5°. Therefore, it may be useful to provide a manual adjustment for toe-in of the front wheel and/or toe-out of the rear wheel within this range.
FIGS. 4 and 5 are front and rear elevational views, respectively, of skate 10 . Projected in this plane, it can be seen that the axles of the front and rear wheels are substantially parallel. It is important to observe that front tire 15 contacts the ground to the outside of the center line of the skate, whereas rear tire 17 contacts the ground to the inside of the center line of the skate . The lateral offset of the front and rear contact patches is approximately equal at about ½ inch from the center line. In an alternative embodiment, such as that shown in FIG. 12, the front contact patch may be inside of the center line and the rear contact patch to the outside of the center line. This would be the case particularly when the front wheel has a larger diameter than the rear.
In an alternative embodiment, such as that shown in FIG. 12 where the front wheel has a larger diameter than the rear wheel, the front contact patch may be inside of the center line and the rear contact patch to the outside of the center line (the opposite relationship to that shown in FIGS. 3-5) axis of the skate. Referring back to FIG. 3, it can be seen that the roll axis is angled outwardly from the longitudinal center line of the skate. This geometry contributes to the stability of the skate at rest by distributing the skater's weight laterally with respect to the center line.
FIGS. 6 and 7 illustrate an optional braking mechanism for use with the present invention. Skate 30 includes rear wheel 32 and rear tire 33 . Wheel 32 includes an annular braking surface 34 . A lever 36 is pivotally connected to chassis 38 at pivot 40 . A relatively small diameter wheel 42 is mounted at the rear end of lever 36 and contacts the ground surface traversed by skate 30 . Alternatively, the rear end of lever 36 may have a simple skid for contacting the ground instead of wheel 42 .
The forward end of lever 36 operatively engages brake lever 44 , which is pivotally coupled to chassis 38 at pivot 46 . Brake shoe 48 is rigidly attached to brake lever 44 with rivets or other suitable fasteners. Brake lever 44 is biased away from braking surface 34 by means of spring 50 . To engage the brake while skating, the skater simply rotates the skate on which braking is desired about the axis of the rear wheel by shifting the skater's body weight. This causes lever 36 to rotate on pivot 40 and bear down on brake lever 44 . This, in turn, urges brake shoe 48 into contact with braking surface 34 . The amount of braking force applied is directly related to the amount by which skate 30 is rotated about the axis of rear wheel 32 . It should be noted that this braking mechanism also has a beneficial stabilizing effect on skate 30 since it inherently limits the amount by which the skate can rotate about the axis of the rear wheel and thus helps prevent the skater from falling backwards.
The braking system shown in FIGS. 6 and 7 is not ideally suited to use on uneven terrain. An alternative braking system is illustrated in FIG. 8 . Here, brake actuation is effected by a pair of hand grips 60 coupled to respective skates 62 . Each of hand grips 60 communicates with its respective skate by means of cable 64 , which may be like a conventional bicycle brake cable for mechanical actuation of the brake. Alternatively, hand grips 60 may incorporate a hydraulic reservoir, in which case, hydraulic pressure is communicated through cable 64 to a hydraulic slave cylinder in skate 62 .
FIG. 9 illustrates a hydraulic braking mechanism for skate 62 . Hydraulic cable 64 communicates with brake caliper 66 , which is rigidly mounted to chassis 68 . Brake shoes (not shown) within caliper 66 exert a clamping force on brake disc 70 in a manner similar in operation to automotive disc brakes.
FIG. 10 illustrates an alternative embodiment of the present invention. Skate 80 has a front wheel 82 similar to that of the previously discussed embodiments. However, rear wheel 84 is substantially larger in diameter, which is desirable for speed skating. In the illustrated embodiment, rear wheel 84 has a diameter of approximately 10 inches. To accommodate a wheel of this size, the axle is located behind the skater's heel, thereby obviating the need to elevate the skater's foot higher above the ground.
FIG. 11 illustrates a further embodiment of the present invention that is a variation of the embodiment shown in FIG. 10 . Skate 90 has a large diameter rear wheel 94 as in the previously discussed embodiment. In this embodiment, however, front wheel 92 is located forward of the skater's toe, which is desirable for high speed skating. Front wheel 92 may have a fixed location on skate 90 or a manual adjustment may be provided so that the skater can locate the axle of the front wheel longitudinally at a desired position within a range of adjustment.
It will be recognized that the above described invention may be embodied in other specific forms without departing from the spirit or essential characteristics of the disclosure. Thus, it is understood that the invention is not to be limited by the foregoing illustrative details, but rather is to be defined by the appended claims.
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A two-wheeled roller skate with canted wheels has an axle for the forward wheel located well forward of the ball of the foot. The axle for the rear wheel is located at the rear of the skater's heel. The wheels are canted so that the front and rear wheels contact the ground on the opposite sides of the center line of the skater's foot. In plan projection, the axles are preferably non-parallel in order to provide steering correction. The amount of steering correction desirable will depend on the skater's skill and the nature of the skating activity. In alternative embodiments, the present invention incorporates novel braking mechanisms.
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INCORPORATION BY REFERENCE TO ANY PRIORITY APPLICATIONS
Any and all applications for which a foreign or domestic priority claim is identified in the Application Data Sheet as filed with the present application are hereby incorporated by reference under 37 CFR 1.57.
BACKGROUND
1. Field
The present disclosure generally relates to ring protection devices which can be used to at least partially encase a user's ring.
2. Description of the Related Art
For a large number of people, a ring carries a high amount of sentimental and/or monetary value. In many cases, rings are worn with a high frequency over a long period of time. It can be nearly impossible to consistently wear a ring while also preventing the ring's exposure to severe damage (via direct contact by liquid, solid, and gases) or loss. These sometimes daily activities include showering, cleaning dishes, and exercise, amongst many others. Given the value of a ring, owners often times either decide to keep the ring on, exposing the ring to further damage. In the alternative, if the user decides to frequently remove the ring from their hand in order to avoid damage, the ring is then exposed to a higher likelihood of loss. In fact, there are at least hundreds of thousands of individuals that purchase insurance policies to protect against damage and/or loss to their rings for this exact reason.
SUMMARY
Disclosed herein in certain embodiments is a ring protection device. In some embodiments, the ring protection device can comprise a shell configured to at least partially encase a ring, and a hinge mechanism configured to move the shell between an open position and closed position.
In some embodiments, the shell can be formed of a rigid material. In some embodiments, the shell can include a clasp mechanism to strengthen the shell when in the closed position. In some embodiments, the ring protection device can further comprise a tracking device mechanism. In some embodiments, the shell can completely engulf the entire ring.
Also disclosed herein is a ring protection device for protecting a ring worn on a human finger which can comprise a shell configured to at least partially encircle the ring when the ring is being worn, and a sealing layer connected to the shell, wherein said sealing layer is configured to contact human skin in order to reduce liquid access to the ring when the ring is being worn.
In some embodiments, the shell can be formed of a rigid material. In some embodiments, the shell can be configured to not contact the ring.
In some embodiments, the ring protection device can further comprise a hinge mechanism configured to move the shell between an open position and closed position. In some embodiments, the ring protection device can further comprise a clasp mechanism to strengthen the shell when in the closed position.
In some embodiments, said shell can comprise a housing compartment which can be configured to protect a portion of the ring that houses one or more primary stones of the ring. In some embodiments, said housing compartment can be removable from a rest of the shell. In some embodiments, the housing compartment can be a first housing compartment, and the first housing compartment can be replaceable with a second housing compartment. In some embodiments, the first housing compartment can have a size or a material that is different from a size or a material of the second housing compartment.
Also disclosed herein is a ring protection device for protecting a ring worn on a human finger which can comprise a shell configured to at least partially encircle the ring while it is being worn, the shell comprising a housing compartment configured to protect a portion of the ring that houses one or more primary stones of the ring, and a sealing layer connected to the shell, wherein said sealing layer is configured to contact human skin in order to reduce liquid access to the ring.
In some embodiments, said sealing layer can be further configured to prevent movement of the ring protection device on the user's finger due to activity or outside contact.
BRIEF DESCRIPTION OF THE DRAWINGS
FIGS. 1A-C illustrate perspective views of an embodiment of a ring protection device.
FIGS. 2A-E illustrate an embodiment of a ring protection device in different positions and from different points of view.
FIGS. 3A-D illustrate components of an embodiment of a ring protection device in different positions and from different points of view.
DETAILED DESCRIPTION
Some embodiments described herein relate to a ring protection device for protecting a person's ring during active or passive conduct or activities. Some embodiments allow the user to protect people and/or fragile material from the sharp edges of the user's ring. Some embodiments relate to a ring protection device that allows a ring owner to protect and/or track his or her ring while not wearing it. Some embodiments allow the ring protection device to be easily put on by one hand of a user.
Embodiments of a ring protection device that may be worn by an individual in order to protect the ring and gem from being damaged, dinged, scratched, or lost, especially during active conduct, are disclosed herein. Embodiments of the disclosed ring protection device can effectively protect the ring from outside contact while simultaneously limiting liquid, such as grease, water, and other liquid chemicals, from entering its perimeter. In some embodiments, the device can have liquid, air, or powder tight sealing. Embodiments of the ring protection device can also be designed to fit comfortably on the user's finger, even during movement based activities. Further, embodiments of the ring protection device can be configured to generally stick on a user's finger, so it doesn't come off during showering or sweating.
Embodiments of the disclosed ring protection device can be used to protect and/or track a ring when the user removes it from his or her finger. Embodiments of the ring protection device can prevent the loss of the ring by alarming (e.g. lights, sounds, or vibration) the user when the ring is a specific distance away and can also prevent damage by protecting the rim from undesired contact. This may be advantageous to deter theft of the device, and therefore the ring.
Described herein are various embodiments of a ring protection device that greatly decreases the risk of damage or loss to a ring, and often times, a valuable ring. The ring can be an annulus. Furthermore, the ring can be a jewelry ring made from various materials such as gold, platinum, silver, jewels, crystals, and stones.
FIGS. 1A-C show an embodiment of a ring protection device 100 . The ring protection device 100 can include a shell, casing or layer 102 . The shell 102 can be made from a protective material, such as plastic, metal or ceramic, though the type of material is not limiting. In some embodiments, the protective material can be rigid or semi-rigid such that the shell does not substantially deform under a load. In some embodiments, the protective material can have slight give to absorb impacts. For example, protective material can have an elastic modulus of at least 1 GPa, though the elastic modulus is not limiting. Furthermore, the protective material can have a relatively high hardness, though the hardness is not limiting. In some embodiments, the protective material can also be transparent or translucent. In some embodiments, the protective material can be opaque. In some embodiments, the protective material can be transparent/translucent in some portions and opaque in other. In some embodiments, shell 102 can completely, substantially, or at least partially encircle, encase, encapsulate or cover the ring 110 . For example, the shell 102 can be an annulus or generally annular, and the shape of the shell 102 is not limiting. The annulus may be continuous or may not be continuous.
Some embodiments of the ring protection device 100 include a hinge 104 and/or clasp mechanism 106 that aids the device 100 in moving back and forth from an open to closed position. For example, the annulus may have gaps, breaks or discontinuities. The annulus may have two or more discontinuities to form two or more segments of the annulus. The segments can be separate components. The segments can be coupled together with a hinge 104 and/or clasp mechanism 106 . For example, a hinge 104 can be coupled to a first segment 103 and a second segment 105 at a discontinuity so that the first 103 and second segments 105 can rotate about the discontinuity. A clasp mechanism 106 can be coupled to a first segment 103 adjacent to a discontinuity and the clasp mechanism 106 can be removably coupled to a second segment 105 to lock and unlock the first and second segment 103 / 105 together. The hinges 104 and clasp mechanisms 106 can be used interchangeably on the device 100 , and the position and attachment parts are not limiting.
The shell 102 can have an opening or slot 108 on an inside of the shell 102 . In some embodiments, the shell 102 can have an annular dome shape. In some embodiments, the shell 102 can have an annular slot 108 on an inside of the annular shell 102 . The slot 108 can be sized to have a ring 110 disposed therein, though the size is not limiting. In some embodiments, the slot 108 can contain at least one lock clip to hold a ring 110 in place.
The ring protection device 100 can include a sealing layer 112 coupled to the shell 102 . The coupling of the sealing layer 112 to the device 100 is not limiting and mechanical and/or chemical coupling can be used. In some embodiments, the sealing layer 112 can be adjacent to the slot 108 . For example, the sealing layer 112 can be on an inner most surface of the shell 102 . As such, the sealing layer 112 can be sandwiched between the shell 102 and a user's finger and/or can be sandwiched between the shell 102 and the ring 110 . Furthermore, the sealing layer 112 can be adjacent to both sides of the slot 108 . Therefore, the sealing layer 112 can include two separate portions. In some embodiments, the sealing layer 112 can be substantially continuous around the annulus of the shell 102 . Thus, the sealing layer 112 can be an annulus, or generally an annulus. In some embodiments, the sealing layer 112 may not be substantially continuous around the annulus of the shell 102 . The sealing layer 112 can be configured to reduce liquid access to the ring 110 . Thus, in use, the slot 108 can be substantially fluidly (e.g., liquidly) isolated from outside of the shell 102 . The sealing layer 112 can be formed from a material that can elastically deform to provide a good seal between the shell 102 and the user's finger. For example, the sealing layer 112 can be a polymer, rubber, foam, or foam-like material, and the type of material is not limiting. Furthermore, the sealing layer 112 can be adapted to function with the hinge 104 and/or clasp mechanism 106 (e.g., fasteners). For example, the sealing layer 112 can have discontinuities similar to that of the shell 102 .
The shell 102 can also include a housing compartment 114 configured to encircle, encase, encapsulate or cover a portion of the ring 110 that houses one or more stones. Since the portion of the ring 110 that houses the stone tends to be larger than the rest of the ring 110 , the housing compartment 114 can be larger (e.g. thicker, wider, and/or taller) than the rest of the shell 102 . Furthermore, as described above, the sealing layer 112 can also be attached to the housing compartment 114 of the shell 102 . The housing compartment 114 can be configured to be separated from the rest of the shell 102 .
The ring protection device 100 can also include a protecting layer configured to contact the ring 110 . For example, the protecting layer can be within the slot 108 and/or the housing compartment 114 . The protecting layer can be or formed from foam, foam-like material, shape-memory foam, or elastic material, though the type of material is not limiting. The protecting layer may deform to form fit to the ring 110 .
The ring protection device 100 can be symmetrical or asymmetrical. For example, some users may wear the ring 110 adjacent to or near a knuckle. The ring 110 may be configured to be worn adjacent to or near a knuckle of the user's finger. For example, the ring protection device 100 may be asymmetrical such that a side of the ring protection device 100 (e.g., shell 102 , sealing layer 112 ) closest to the user's knuckle may be configured and/or shaped differently than a side of the ring protection device 100 furthest form the user's knuckle. Other portions of the ring protection device 100 may be asymmetrical such as to conform to a finger.
The ring protection device 100 can also include one or more light bulbs, such as LEDs (light emitting diodes) or fluorescence, in order to help see both the ring protection device 100 and the ring 110 itself. The number and type of light bulbs is not limiting.
The ring protection device 100 can be used to encase the ring 110 while the user is not wearing the ring 110 . The ring protection device 100 can include one or more tracking devices, such as GPS, to help the user keep track of the location of his or her ring 110 . The type of tracking device is not limiting.
FIG. 2A shows a front cross-sectional view of an embodiment of a ring protection device 100 in an open position with a hinge mechanism incorporating a single hinge 104 .
FIG. 2B shows a side cross-sectional view of an embodiment of a ring protection device 100 shown in FIG. 2A in which neither the shell 102 nor the sealing layer 112 contacts the user's ring band.
FIG. 2C shows the front cross-sectional view of an embodiment of a ring protection device 100 shown in FIG. 2A in which the shell 102 is in a closed position and is configured to contact the ring band for further stability.
FIG. 2D shows a cross sectional view of an embodiment of a ring protection device 100 that uses one possible type of a clasp mechanism 106 with a male and female end. The female clasp end is shown as 106 on the left, and the male clasp end is shown as 106 on the right. The female clasp end could be located on either the first segment 103 or the second segment 105 , and the male clasp end could be located on the opposite segment as the female clasp end.
FIG. 2E shows a side cross-sectional view of an embodiment of a ring protection device 100 with a hinge 104 or clasp 106 line when the device is in the closed position. As the cross section segment cuts down the center of device 100 , the lighter gray shade in FIG. 2E indicates an actual cut through of device 100 , while the dark shade indicates a side view of device 100 which is not a cut through.
FIGS. 3A-D show a further embodiment of a ring protection device 100 . As shown in FIGS. 3A-B , and described above, the ring protection device 100 can have a generally annular shape. FIG. 3A illustrates an embodiment of a ring protection device 100 in a closed configuration. FIG. 3B illustrates an embodiment of the ring protection device 100 of FIG. 3A in an open configuration. As shown, in some embodiments the shell 102 can be split into three segments 302 , 304 , and 307 . In some embodiments, the shell 102 can be split into more than three segments, and the number of segments is not limiting. Each of segments 302 / 304 can attach to housing segment 307 which can be connected to the housing compartment 114 . In some embodiments, the segments 302 / 304 can then attach to one another through a clasp mechanism 106 . In some embodiments, the clasp mechanism 106 can be part of segments 302 / 304 . As shown in FIG. 3B , where the device 100 is opened, both segments 302 / 304 can rotate away from each other. Accordingly, a ring 110 can be inserted through the opened clasp mechanism 106 and inserted into slot 108 . In some embodiments, the segments 302 / 304 can rotate about hinges 104 so that they are generally about 90, 100, 110, 120, 130, 140, 150, 160, 170, or 180° apart, though this angle is not limiting. In some embodiments, each of the segments 302 / 304 / 307 can be generally ¼ of a circle, ½ of a circle, or ¾ of a circle.
In FIGS. 3A-B , the segments 302 / 304 contain a gap 320 in the shell 102 . The underlying sealing layer 112 can fill the gap 320 in the shell 102 and/or segments 302 / 304 . In some embodiments, the segments 302 / 304 can extend fully around the outside of the sealing layer 112 and eliminate the gap 320 . Accordingly, in some embodiments the sealing layer 112 may not be visible when the ring is in the closed position on a finger. In some embodiments, the sealing layer 112 can extend over the edge of the clasp mechanism 106 . In some embodiments, the sealing layer 112 can be thicker in some portions of the device 100 and thinner in others. For example, the sealing layer 112 can be thinner below the housing compartment 114 than around the segments 302 / 304 approximately 90° away in the closed position.
FIGS. 3C-D illustrate more detailed viewpoints of different components of embodiments of ring protection device 100 .
FIG. 3C illustrates an embodiment of a housing segment 307 having a pair of hinges 104 located underneath the housing compartment 114 . In some embodiment, the hinges 104 can be generally snap hinges, configured to remain in certain locations, though the type of hinge 104 is not limiting. In some embodiments, the housing segment 307 can contain a sealing layer 112 . In some embodiments, the housing compartment 114 can be generally centered between hinges 104 . In some embodiments, the housing compartment 114 is not centered between hinges 104 . In some embodiments, other types of rotational connections can be used between segment 307 and segments 302 / 304 , and the type or means of rotation is not limiting. In some embodiments, the sealing layer 112 in the housing segment 307 and segments 302 / 304 can overlap when the hinges 104 are closed, thereby creating a generally seamless 360 degree seal on a user's finger.
In some embodiments, the housing compartment 114 can be decorated to include colors or patterns. In some embodiments, the housing compartment 114 can be generally rectangular shaped. However, the shape of the housing compartment 114 is not limiting. For example, the housing compartment 114 can be generally round, generally circular shaped, or generally triangular shaped. In some embodiments, the housing compartment 114 can be configured to retain a specific sized stone on a ring 110 . In some embodiments, the housing compartment 114 can have generally smooth corners so as not to injure a user. In some embodiments, the housing compartment 114 can be configured to fit within the hinge 104 , as shown in FIGS. 3A-B . In some embodiments, the inside of the housing compartment 114 can contain the sealing layer 112 to protect a ring 110 . In some embodiments, the housing compartment 114 can be integrally formed with the housing segment 307 . In some embodiments, the housing compartment 114 can be attached, either removably or non-removably, from the housing segment 307 . In some embodiments, the shell 102 can consist of the housing segment 307 only, and can be attached or molded to a sealing layer 112 that can wrap up to 360 degrees around the user's finger. In some embodiments, the shell 102 can be attached (e.g., overmolded) directly to the sealing layer 112 with the use of a hinge 104 or a clasp 106 . The attachment technique is not limiting. In yet other embodiments, the shell 102 can consist of segments 302 / 304 only, and can be attached or molded to a sealing layer 112 that can wrap up to 360 degrees around the user's finger.
FIG. 3D illustrates an embodiment of a clasp 106 . In some embodiments, the clasp 106 is a portion of a larger segment (see segments 302 / 304 in FIG. 3A ). In some embodiments, the clasp 106 can also be its own segment. As shown, the clasp can contain a button 306 , or other actuating mechanism, which can release the clasp 106 . The clasp 106 can contain a male 314 and female 312 component. The button 306 can be located on either component. In some embodiments, the female component 312 can be configured to receive and retain the male component 314 . However, a person having skill in the art would understand that different configurations of clasps could be used, such as those including hooks, magnetics, or frictional holding, and the type of clasp is not limiting. In some embodiments, the sealing layer 112 in the segments 302 / 304 can extend into the clasp 106 and can overlap when the clasp 106 is closed, thereby creating a generally seamless seal on a user's finger.
Some embodiments have been described in connection with the accompanying drawings. The figures are drawn to scale, but such scale should not be limiting, since dimensions and proportions other than what are shown are contemplated and are within the scope of the disclosed inventions. Distances, angles, etc. are merely illustrative and do not necessarily bear an exact relationship to actual dimensions and layout of the devices illustrated. Components can be added, removed, and/or rearranged. Further, the disclosure herein of any particular feature, aspect, method, property, characteristic, quality, attribute, element, or the like in connection with various embodiments can be used in all other embodiments set forth herein. Additionally, it will be recognized that any methods described herein may be practiced using any device suitable for performing the recited steps.
While various embodiments of the innovation have been described, it will be apparent to those of ordinary skill in the art that many more embodiments and implementations are possible within the scope of the innovation. Accordingly, the innovation is not to be restricted except in light of the attached claims, or claims that may be presented in the future, and their equivalents.
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Embodiments of the present disclosure are directed to a ring protection device. The ring protection device can have a shell layer to at least partially encase a ring. The ring protection device can have a shell layer containing a housing segment. The segments of the shell layer can be connected to other segments via a hinge mechanism. The shell segments and hinge mechanism can be configured to encase a ring and protect it from damage. The shell layer can be connected to a sealing layer to aid the ring protection functionality. The hinge mechanism can be opened and closed to insert and remove a ring into the ring protection device.
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BACKGROUND OF THE INVENTION
The present invention generally relates to welding and more particularly, to a welding torch employing a welding wire as a consumable electrode.
Commonly, when a consumable electrode is employed for a welding torch, electric current is fed to the electrode through a contact member held in contact with said electrode. In that case, a large amount of servicing of the welding torch has been required owing to the resultant severe abrasion or wear of the contact member. In order to cope with the problem as described above, there has conventionally been proposed an arrangement as shown, for example, in FIGS. 1 through 3.
More specifically, in the known welding torch in FIGS. 1 through 3, first and second abrasion-resistant guide members 3a and 3b are provided along an electrode passage in a torch body 1' so as to be spaced apart from each other. An abrasion resistant guide block 3c having a thickness smaller than the width of the electrode is provided at one side of the electrode passage between the guide members 3a and 3b. An electrode 25 is held between the guide block 3c and a contact member 7' having a thickness exceeding the width of the electrode. Electrode 25 is delivered while being fed with the electric current through the contact member 7', in order to perform the welding operation. Accordingly, the contact member 7' is merely formed with a deep groove as shown in FIG. 2 even if it is worn out. Thus welding operations may be performed without hindrance.
Incidentally, in an arc welding, the so-called stick phenomenon often takes place wherein the electrode tip adheres to an item to be welded (not shown) during arc starting or during welding. In this case, resistance heating represented by I 2 R is produced in the electrode between the contact member 7' and the top of the electrode 25, i.e., between the current feeding position and welding position at the electrode tip. Thus, the electrode is extremely softened and therefore weak. In connection with the above, although the delivery of the electrode is arranged to be properly interrupted through detection, for example, of short-circuit current, the delivery of the electrode is seldom suspended immediately when the electrode tip has been fused onto the item to be welded. Namely, even after the electrode tip has been fused onto the item to be welded, the electrode in its extremely softened state is still delivered, to a certain extent, onto the items to be welded. In the above case, since the second abrasion-resistant guide member 3b is disposed adjacent electrode 25 between the end of the electrode 25 and the contact position between the contact member 7' and the end of electrode 25 as shown in FIG. 1, the extremely softened electrode section delivered towards guide member 3b is deformed by the member so as to create an enlarged section which resists further movement through the second abrasion resistant guide member. This so-called stick phenomenon, as shown in two-dotted chain lines in FIG. 3, prevents further feeding of the electrode in many cases. In such a case, it is a general practice to start the torch again after cutting off the electrode tip automatically or manually upon formation of the stick phenomenon. However, the electrode cannot be fed towards the item to be welded due to presence of the enlarged electrode section adjacent the entrance of the second abrasion-resistant guide member 3b as described above. Accordingly, it has been necessary for the operator to grasp the electrode tip with cutting pliers or the like and pull the electrode in the direction of X1 thereby drawing the enlarged electrode section through member 3b. However, since the space between the end of the welding torch and the item being welded is normally selected to be approximately 10 through 30 mm, the torch must be moved away from the item in the direction of X'2 a sufficient distance to allow removal of the seized electrode portion, thus resulting in inferior operability. Although sintered porcelain, which is superior in abrasion resistance and heat resistance, is normally used as the guide members, the mechanical strength of such sintered porcelain is not so high. Thus, there are cases where the guide members are damaged during forced removal of the seized electrode portion as described above, thus resulting not only in economic disadvantage, but the necessity of replacement of the guide member. Furthermore, in the arc welding operation using a consumable electrode, molten metal particles at high temperatures, i.e. the so-called sputter, are generally scattered. In a welding torch having such a construction as shown in FIG. 1 through FIG. 3, the sputter tends to enter through an opening or the like into the passage of the electrode wire or sliding groove portion of the contact member, so that delivery of the electrode wire or movement of the contact member may be interfered with. In the conventional welding torch as described above, a cover member may be used to prevent the sputter from entering the passage of the electrode wire and sliding groove portion of the contact member. However, in this case, it is difficult to manufacture a cover member to be applied to a narrow portion, thus requiring high manufacturing cost. In addition, even when the cover member is provided, maintenance of the torch tip end portion cannot be effected sufficiently, thus resulting in poor operability. Meanwhile, in the case where the so-called gas shielded arc welding is effected with the use of the conventional welding torch as described above, it is impossible to carry out welding in small spaces due to the large size at the forward end of the welding torch, with a difficulty in forming a passage for the shielding gas towards the item to be welded.
SUMMARY OF THE INVENTION
Accordingly, an essential object of the present invention is to provide an improved welding torch compact in size and efficient in operation, which prevents interference of the feeding of the electrode wire by sputter which has a passage for maintaining a stable shielding gas flow, and which is capable of resuming welding by cutting off an end portion of the electrode wire even when such end portion is fused onto an item to be welded.
Another important object of the present invention is to provide a welding torch of the above described type which is simple in construction, and can be readily manufactured on a large scale at low cost.
In accomplishing these and other objects, according to one preferred embodiment of the present invention, there is provided a welding torch which includes a contact member constituted by a power feeding member formed therein with a through-opening for passing a consumable electrode wire therethrough and a cylindrical support member for supporting the power feeding member, and a fixed guide member for guiding the electrode wire. The guide member is inserted, at its free end portion, into the contact member, and a power feeding connecting member is provided at a base portion of a torch body for the welding torch which is connected to the support member of said contact member through a flexible connecting member. A cylindrical member is provided which covers a portion from the base portion extending of the torch body to the flexible connecting member and a base portion of said contact member. Support pins are provided on the cylindrical member to confront each other for supporting said contact member so as to be tiltable in a plane including an axis of the electrode wire and also, to be restricted in a direction generally intersecting at right angles with said plane. A gas nozzle is detachably mounted on a free end portion of the support member of said contact member, and a shielding gas passage is formed to extend from the base portion of the torch body to the inner portion of the gas nozzle. A pressure means is provided for urging the contact member and the gas nozzle towards the electrode wire as one unit.
By the arrangement according to the present invention as described above, an improved welding torch highly efficient in operation has been advantageously presented.
BRIEF DESCRIPTION OF THE DRAWINGS
These and other objects and features of the present invention will become apparent from the following description taken in conjunction with the preferred embodiment thereof with reference to the accompanying drawings, in which:
FIG. 1 is a fragmentary side sectional view of a main portion of a conventional welding torch (already referred to),
FIG. 2 is a fragmentary cross sectional view taken along the line II--II of FIG. 1 (already referred to),
FIG. 3 is a fragmentary side sectional view showing on an enlarged scale, a lower portion of the welding torch of FIG. 1 (already referred to),
FIG. 4 is a side sectional view of an improved welding torch according to one preferred embodiment of the present invention,
FIGS. 5 to 7 are fragmentary cross sections respectively taken along lines V--V, VI--VI, and VII--VII in FIG. 4,
FIG. 8 is a side elevational view showing a welding torch according to another embodiment of the present invention, and
FIGS. 9 to 11 are fragmentary cross sections respectively taken along lines IX--IX, X--X, and XI--XI in FIG. 8.
DETAILED DESCRIPTION OF THE INVENTION
Before the description of the present invention proceeds, it is to be noted that like parts are designated by like reference numerals throughout the accompanying drawings.
Referring now to the drawings, there is shown in FIGS. 4 through 7, a welding torch WA according to one preferred embodiment of the present invention.
In FIGS. 4 through 7, the welding torch WA generally includes a torch body 1 coaxially formed with a central bore or through-opening 101 along its axis. An abrasion-resistant guide tube 2 is provided which is detachably accommodated in said through-opening 101 and formed with a bore 2a, for example, of a circular cross section. Another abrasion-resistant guide block 3 coaxially formed with a through-opening 301 generally along the axis thereof is provided, said guide block 3 being, for example, detachably mounted at the forward end portion of the torch body 1 in a direction of X1.
The torch body 1, guide tube 2 and guide block 3 constitute a fixed guide member 4 for guiding an electrode wire 25.
The welding torch WA further includes a support member 5 in a cylindrical configuration and a power feeding member 6 of an electrically conductive material, having a through-bore 601 coaxially formed generally along its axis and also a hole 602 with a bottom, which opens in the direction of X2. The above power feeding member 6 is, for example, threaded onto the end portion of the support member 5 in the direction of X1. The support member 5 and the power feeding member 6 constitute a contact member 7 composed of an electrically conductive material, for example, an alloy of copper or copper group, and in the interior of said contact member 7, the free end of the fixed guide member 4 is inserted.
At the base portion of the torch body 1, there is provided a flange portion 102, which is held between a power feeding connecting member 11 and an intermediate member 12 through insulating members 8 and 9 of suitable shapes. The support member 5 for supporting the power feeding member 6 and the intermediate member 12 are connected to each other by a flexible connecting member 13, for example, by a strand wire made of copper or copper group alloy and formed into a cylindrical configuration. Meanwhile, a cylindrical member 14 including members 141 and 142 is supported at the base portion side of the torch body 1 so as to cover flexible connecting member 13 and the base portion of the contact member 7. Moreover, the support member 5 is pivotally supported with respect to the cylindrical member 14. For example, as shown in FIG. 5, the second cylindrical member 142 formed by an electrically insulating material supports the support member 5 through confronting support pins 15, while said support member 5 is in contact with the opposed faces 151 of the support pins 15 so as to be positioned in directions of Z, with a resilient air-tight member 16, for example, an "O" ring being provided between the cylindrical member 142 and the support member 5. The torch body 1 is suitably supported by a mounting member 18 (FIG. 4) through an electrically insulating member 17 disposed in the X2 direction side.
The welding torch WA of FIGS. 4 to 7 is further provided with a pressure means 19 constituted, for example, by a plate spring 191 supported, at its one end, on the torch body 1 by a support piece 192, with the other end of said plate spring 191 contacting an electrically insulating member 193 provided on the support member 5. On the free end of the support member 5, there is detachably mounted a gas nozzle 21 which is constituted, for example, by a nozzle 211 of an electrically insulative material and another nozzle 212 made of a metallic material. The gas nozzle 21 and the contact member 7 are normally urged counterclockwise about the support pins in FIG. 4 as one unit, by the pressure means 19. The guide member 4 is formed with one or more bores 22, while the support member 5 is also provided with two or more bores, for example, four bores 23 radially formed at approximately equal intervals in a circumferential portion of the support member 5. Through said bores 22 and 23 and a cylindrical space 24, the passage of the electrode wire 25 is communicated with the inner space of the gas nozzle 21. The power feeding connecting member 11 is further formed with a bore 110, through which said power feeding connecting member 11 is connected to a power feeding device (not particularly shown).
In the above arrangement, the electrode wire 25 is fed in the direction of X1 by a feeding apparatus (not shown) while suitable electric power for welding is fed to the contact member 7 through the power feeding device (not shown) after said electrode wire 25 has reached the through-bore 601 of the power feeding member 6, and thus, welding is carried out by feeding the electrode wire 25, with the shielding gas being caused to flow out through the gas nozzle 21. In the embodiment as shown in FIG. 4, the shielding gas is fed by utilizing the passage for the electrode wire 25, and flows into the interior of the gas nozzle 21 through the bore 22, cylindrical space 24 and bores 23.
In the above case, the contact member 7 is urged in the direction of Y2 by the pressure means 19 and thus, the end portion of the contact member 7 is pivoted counterclockwise in FIG. 4 about the support pins 15 to come into contact with the electrode wire 25. Namely, the electrode wire 25 to be fed in the direction of X1 by a feeding apparatus (not shown) is restricted by the guide block 3, and is fed to a welding position through sliding contact with the tip end member of the contact member 7, i.e., the power feeding member 6. Incidentally, the portion of the power feeding member 6 equivalent to the power feeding position thereof is gradually worn off as the welding operation proceeds, but since the member 6 supported by the support member 5 is urged in the direction of Y2 by the pressure means 19, said member 6 is always held in contact with the electrode wire 25, irrespective of abrasion of the member 6 so as to feed the electric power for welding positively in a steady state.
Furthermore, owing to the arrangement that the gas nozzle 21 is supported at the free end of the contact member 7, with said gas nozzle 21 and contact member 7 being arranged to rotate in one unit about the support pins 15, a cylindrical space 26 defined by the gas nozzle 21 and the contact member 7 may be maintained in a predetermined configuration at all times, regardless of abrasion of the power feeding member 6. When said cylindrical space 26 within the gas nozzle 21 is maintained under the constant state as described above, the stream of the shielding gas is naturally held at a constant state for making it possible to effect a uniform welding.
It is to be noted here that, the electrode wire 25 restricted by the fixed guide member, particularly by the guide block 3 is fed to a predetermined position in the direction of Y, irrespective of wearing of the power feeding member 6, but on the contrary, the gas nozzle 21 and the contact member 7 are pivoted as one unit in the direction of Y2 about the support pins 15 as the power feeding member 6 is gradually abraded, and there is a possibility that the axis of the electrode wire 25 goes out of alignment with respect to the axis of the stream of the shielding gas discharged from the gas nozzle 21. However, since the distance between the power feeding member 6 and the item to be welded (not shown) are generally set in the range of approximately 10 to 30 mm, while the shielding gas discharged from the gas nozzle 21 is of a laminar flow in an annular shape which may be directed to a comparatively large area including the welding point, there is no tendency that the gas shielding effect is substantially altered, even if the axis of the stream of the shielding gas is not in alignment with the axis of the electrode wire.
Moreover, since the through-bore 601 of the power feeding member 6 is gradually abraded in the direction of Y1 as the welding proceeds, a space tends to be formed at the upper portion of the through-bore 601, i.e. in the direction of Y2, in correspondence to the amount of the above abrasion. It is possible that, as the space becomes larger, sputter caused during the arc welding scatters in the direction of X2, but, owing to the fact that the electrode wire 25 is fed in the direction of X1 at all times during the welding operation, such sputter as described above is carried outwardly through the space at the upper portion of the through-bore 601 as the electrode wire 25 is delivered. Meanwhile, since the power is fed, with the approximate semi-circular portion in the direction of Y1 of the through-bore 601 being normally held in sliding contact with the electrode wire 25, the sputter cannot enter the feed portion. It is to be noted that, although it is advantageous to form at least the end portion of the power feeding member 6 into a spherical convex shape since the sputter is hard to adhere onto such spherical convex portion and may be readily removed even upon adhesion thereonto, the shape of said end portion may be altered to other configurations, for example, to a truncated cone shape.
Thus, power feeding is not affected by sputter at all, with the guide member 4 being advantageously covered by the contact member 6 and cylindrical member 14, etc., and therefore, there is no possibility that sputter enters the feeding passage of the electrode wire 25.
As described above, since the sputter does not interfere with the feeding of the electrode wire or does not hinder the power feeding, while the welding operation similar to that under the early stage may be performed, even if the contact member is worn out to a certain extent, uniform welding may be effected for a long period of time, which feature is particularly effective for automatic welding equipment. Incidentally, when the tip end of the electrode wire has fused onto the welding item during arc start or during welding, the electrode wire is fed, to some extent, to the side of the welding item as described earlier. In this case, in the torch according to the present invention, no inconvenience is caused, because the contact member 6 may be properly pivoted about the pins 15 for displacement. Moreover, since the abrasion-resisting guide member like the conventional one is not disposed on the side of the welding item beyond the power feeding position, the undesirable seizing of molten electrode, as in a conventional torch, does not take place. Accordingly, even when the electrode wire has been fused onto the welding item being welded, the welding operation may be immediately restarted by simply cutting the tip of the electrode wire.
Additionally, since the support member 5 is arranged to contact the opposed faces 151 of the support pins 15 so as to be positioned with respect to the direction of Z, power may be fed under a steady state, in cooperation with the provision of the guide block 3.
Reference is made to FIG. 8 through FIG. 11 showing a welding torch WB according to another embodiment of the present invention, in which like parts in FIGS. 4 through 7 are designated by like reference numerals for brevity of description. In this embodiment, the guide tube 2 described as employed in the arrangement of FIGS. 4 to 7 is omitted, and the power feeding connecting member 11B and the cylindrical member 14B are positioned to each other by a positioning member 271, for example, a key member in the rotating direction, and supported as one unit by a clamping member 281, for example, by a nut. Meanwhile, the intermediate member 12B and the cylindrical member 14B are mutually positioned by a positioning member 272, for example, a key member in the rotating direction, and supported as one unit by a clamping member 282, for example, a cap nut. The torch body 1B extends generally axially through the intermediate member 12B and is supported to be integral with said intermediate member 12B by a clamping member 283, for example, an adapter threaded into the end portion of the intermediate member 12B in the direction of X2.
Around the outer periphery at the base portion of the torch body 1B, there is provided a groove 29, which is coupled with grooves 291 (FIG. 10) axially extending at the peripheral portion of the torch body 1B so as to be in communication with the cylindrical space 24 defined by the torch body 1B and the support member 5. The power feeding connecting member 11B is formed, for example, with a connecting port 31 for the shielding gas (FIG. 11), and this connecting port 31 is in communication with the groove 29 provided at the outer periphery of the torch body 1B by a through-bore 32 extending through a suitable member. Meanwhile, the support member 5 is pivotally supported by the support pins 15 at the free end, i.e. the end portion in the direction of X1 of the cylindrical member 14. In the embodiment as shown, the support pins 15 should preferably be made of an electrically insulative material. Onto the cylindrical member 14B, there is threaded a bush 192B of an electrically insulative material, while an adjusting screw 193B is threaded onto said bush 192B, with a compression spring 191B being disposed between said adjusting screw 193B and the support member 5. In the above structure for the pressure means 19B, the adjusting screw 193B is locked by a nut 194B, after properly adjusting the rotating force of the contact member 7 with respect to the support pins 15 through rotation of the adjusting screw 193B. In the above arrangement, since air-tight members 161, 162 and 163 are properly provided between the power feeding connecting member 11B and the cylindrical member 14B, and also between said cylindrical member 14B and the intermediate member 12B as shown, the shielding gas supplied from the connecting port 31 is caused to flow into the welding position through the through-bore 32, grooves 29 and 291, cylindrical space 24, through-bores 23 and 231 and the annular space 26 of the gas nozzle 21B. It is needless to say that the above arrangement may further be so modified that the groove 29 is provided in the inner periphery of the intermediate member 12B.
By the arrangement of FIGS. 8 through 11, it is possible to effect fine adjustments of the state of contact between the electrode wire 25 and the contact member 7, even during welding operation.
In the embodiment as described earlier with respect to FIGS. 4 to 7, the guide tube 2 employed therein may be made of a wire material having a suitable cross section such as circular or rectangular shape and formed into a generally cylindrical configuration, while the cross section of the electrode wire may also be formed into a non-circular shape, for example, a rectangular configuration.
Meanwhile, it is preferable to electrically insulate the consumable electrode wire 25 from the torch body 1, for example, by coating an electrically insulating material onto the outer periphery of the guide tube 2. When the guide tube 2 is provided as described above, the electrode wire 25 may be smoothly guided by replacing the guide tube with a new one according to the abrasion of such guide tube, and if the guide tube, guide member and power feeding member are respectively arranged to be detachable, it becomes possible to embody welding torches suitable for electrode wires in various configurations, by replacing the above members with those having through-bores corresponding to required electrode wires.
Nevertheless, the guide tube 2 may be omitted depending on necessity as in the embodiment of FIGS. 8 to 11.
Moreover, in the foregoing embodiments, since the fixed guide member 4, contact member 7 and gas nozzle 21 are supported generally coaxially, the forward end portion of the welding torch may be made compact for application thereof even to welding portions in narrow and small spaces.
Furthermore, if the torch body, support member, contact member, and cylindrical member, etc. are arranged to be forcibly cooled by suitable means, various parts of the welding torch are not subjected to high temperatures for facilitation in handling and longer servicing life of the welding torch.
As is clear from the foregoing description, according to the present invention, it is so arranged that the contact member and the gas nozzle are supported as one unit for pivotal movement about the support pins with respect to the fixed guide member. Thus, the stream of shielding gas directed to the welding spot has a gas shielding effect equal to that at the initial state even when the power feeding member is abraded during welding operation, and thus, uniform welding may be effected. Meanwhile, owing to the arrangement that the fixed guide member, the contact member and the gas nozzle are disposed generally coaxially, the welding torch, particularly the forward end portion thereof, is made compact in size for efficient application to welding portions in small spaces. Moreover, since the arrangement is free from entry of sputter during feeding of the electrode wire, there is no possibility that the smooth delivery of the electrode is hindered. Since the contact member is positioned in the direction of Z by the support pins in cooperation with the arrangement that the power is fed, with the electrode wire and the contact member being held in sliding contact by the pressure means at all times, not only the power feeding is effected under a steady state, but also the alignment of the electrode wire is generally constant for positive welding. Furthermore, since the contact member may be properly displaced pivotally, while said contact member formed with the through-hole 601 is made of an electrically conductive material, there is no possibility that the undesirable seizing of the molten electrode takes place as in the conventional arrangements, even when the tip of the electrode has fused onto the item being welded. Accordingly, during the adhesion, the welding may be restarted simply by cutting the electrode tip portion while the electrode is being fed, with a consequential favorable operability.
Although the present invention has been fully described by way of example with reference to the accompanying drawings, it is to be noted here that various changes and modifications will be apparent to those skilled in the art. Therefore, unless otherwise such changes and modifications depart from the scope of the present invention, they should be construed as included therein.
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A gas shielded arc welding torch is described which uses a consumable electrode wire. A cylindrical support member carries a guide tube for guiding the electrode wire through the torch. An electrical contact member is pivotably mounted at the end of the torch and includes a bore through which the wire passes. A spring biases the contact member into constant engagement with the electrode wire. A gas nozzle is mounted on the cylindrical support member and is movable with the contact member to provide a uniform, constant-dimensioned shielding gas passage around the contact member regardless of the movement thereof.
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The present invention lies in certain hydrophilic cyclodextrin derivatives which enable effective oral administration of sex hormones, particularly testosterone, progesterone, and estradiol.
Condensation products of beta-cyclodextrin with propylene oxide or epichlorohydrin from water-soluble complexes with testosterone and other substances, such as progesterone and estradiol. Sublingual administration of tablets of these complexes leads to effective absorption and entry of these hormones into the systemic circulation, followed by only gradual elimination. Other cyclodextrin derivatives, a non-ionic detergent, or other modes of administration were ineffective by comparison.
Therapeutic use of sex hormones is required in the treatment of a number of diseases, including lack of natural hormones. However, effective treatment is difficult since these steroids are absorbed only slowly from the gastrointestinal tract and are rapidly cleared from circulating blood by the liver. Numerous attempts have been made to circumvent these problems, including the administration of huge doses of natural hormones, preparation of lipophilic pro-drugs of natural hormones which are injected intramuscularly and synthesis of analogs of natural hormones. The last approach resulted in preparations which are active but side effects were often significant.
The rationale of the present approach is to rely on physiological doses of natural hormones and to chemically modify additives of the pharmaceutical preparation in order to improve absorption of the hormone. The establishment of efficient and fast absorption would enable the use of a sublingual or rectal route of entry by which steroids would be protected from immediate metabolism by the liver.
From a practical point of view, various carbohydrates and chemically derivatized carbohydrates were used to solubilize or to disperse steroids in order to obtain a suitable drug form. In Example 1, post, there are a number of carbohydrates tested for solubility purposes. It was established that only solutions of testosterone in those cyclodextrin derivatives which are highly water soluble were effective. Furthermore, it was necessary that these preparations be kept in the mouth for several minutes (i.e., were administered sublingually). All other preparations lacked any activity.
The finding that a combination of testosterone, progesterone, or estradiol with hydroxypropyl-beta-cyclodextrin or with poly-beta-cyclodextrin is active only when absorbed from the oral cavity and not from the gastrointestinal tract is in accordance with the fast metabolism of sex hormones by the liver. The half-lives of these hormones in circulation are estimated to be only several minutes. The sublingual route is known to be less immediately affected by liver metabolism than entry from the gastrointestinal tract. Furthermore, possible metabolism of the drug by intestinal tissue, a phenomenon only recently appreciated, is avoided.
It was of interest to estimate the rates of elimination of testosterone administered by the sublingual route. The results are summarized in FIG. 1; testosterone's half-life in serum is about seventy minutes. The same figure also indicates that the same methods enable effective oral administration of progesterone and 17-beta-estradiol. In the therapeutic experiments which involved progesterone and 17-beta-estradiol, it was found that progesterone thus administered was eliminated from serum at a rate similar to that of testosterone, whereas elimination of estrogens was much slower. The experiments in Example 1 were performed on an adult male A, described in Example 2.
The effectiveness described entry of sex hormones into the systemic circulation of man due to the combination of high dissolution power of hydrophilic derivatives of cyclodextrins, the non-aggregated structure of their complexes with steroids, and to their low toxicity and irritancy of mouth tissue. To establish that this effectiveness is achieved by other similar compounds, we synthesized and evaluated the following additional preparations: (1) poly-alpha-cyclodextrin, (2) poly-gamma-cyclodextrin, (3) hydroxypropyl-alpha-cyclodextrin, (4) hydroxypropyl-gamma-cyclodextrin, and (5) trihydroxy-dioxadodecanyl-beta-cyclodextrin. These compounds were prepared in the same manner as the compounds detailed above the proper cyclodextrin and epichlorohydrin (compound 1 and 2 above) or propylene oxide (compounds 3 and 4 above) or 1,4-butanediol diglycidyl ether (compound 5 above). All of these compounds were tested for solubilization of testosterone, progesterone, and estradiol. These results are summarized in FIGS. 2, 3, and 4. These results indicate that all additional beta-cyclodextrin derivatives and all gamma-cyclodextrin derivatives are effective additives. Various glycosylated cyclodextrins, which can be obtained by either enzymatic or chemical methods and are as hydrophilic as above compounds, can also be expected to give positive results. On the other hand, none of the alpha-cyclodextrin derivatives studied achieved solubilization comparable to those obtained with the above compounds. Also, a sample of polyvinylpyrrolidone (average molecular weight 40,000) was used as a solubilizer in the above experiments, and proved to be ineffective.
Toxicity: The lack of untoward effects of poly-beta-cyclodextrin and of hydroxypropyl-beta-cyclodextrin was established by a study of laboratory mice (C57BL/6J strain, males; labelled "B") and on mice (white NIH random breed; labelled "W").
Intraperitoneal route: Compounds were applied in isotonic saline and animals were followed for at least a week after injection.
Poly-beta-cyclodextrin: (1) One B mouse, 15.35 g/kg; one B mouse, 10.7 g/kg; one mouse died after one day; (2) four W mice, 10 g/kg; all mice alive.
P.O. toxicity protocol: Three groups of B mice were used. One group ("Control") was used as a control, the second group ("Poly-BCD") was given (as the only source of liquid) a solution of poly-beta-cyclodextrin (1%) in water, and the third group ("HPBCD") was given (as the only source of liquid) a solution of hydroxypropyl-beta-cyclodextrin (1%) in water. The experiment was conducted for sixteen weeks; there were no deaths. Each week the weight change of the groups of mice was recorded. After sixteen weeks the mice were killed and the tissues were examined by a pathologist; serum was also collected and its cholesterol content was measured.
Weight changes of mice during the experiment are summarized in FIG. 5. Upon termination of the experiment, all mice were found substantially free of pathological changes except one of the controls. The data on this mouse were not included in the results given in Table 2. The livers of mice of the hydroxypropyl-beta-cyclodextrin group had slightly higher average weights than those of the other groups; nevertheless, no pathology was detected there. The cholesterol concentration in plasma did not differ significantly; i.e., average values of the three groups differed between themselves less than the standard deviations.
Material Information Disclosure
German Pat. No. 895,769 (1953)--complexes of drugs with cyclodextrins.
U.S. Pat. No. 2,827,452 Schlenk et al.--formation of complexes with alpha, beta, and gamma cyclodextrins.
Japanese Pat. No. 82130914 (Aug. 13, 1982)--describes the use of cyclodextrin crosslinked with epichlorohydrin to complex penicillin G.
U.S. Pat. No. 3,453,259 Parmerter et al.--describes ethers of cyclodextrins with 2,3-epoxy alcohols or halohydrins which may be used as "complexing agents in order to form inclusion compounds and complexes with various chemicals and materials in ways which are similar to those which are known relative to cyclodextrins."
U.S. Pat. No. 3,459,731 Gramen et al.--claims ethers of cyclodextrins with ethylene oxide and propylene oxide which may be used as various inclusion compounds.
U.S. Pat. No. 3,420,788 Solms--describes cyclodextrins crosslinked with epichlorohydrin and other bifunctional reagents.
British Pat. No. 1,244,990 (Sept. 2, 1977)--describes derivatives of cyclodextrin with poly-functional reactants, such as epichlorohydrin, formaldehyde, diepoxybutane, phosphorus oxychloride. These derivatives can be used in the separation of mixtures of substances or to protect unstable substances against oxidation, decomposition, etc.
DESCRIPTION OF THE FIGURES
FIG. 1. Serum level of sex steroid hormones after sublingual administration of tablets containing (on left): testosterone (10 mg) in the form of its hydroxypropyl-beta-cyclodextrin complex; (on right): progesterone (10 mg) and estradiol (0.5 mg) in the same complexed form; tested on subject described in Table 1.
FIG. 2. Solubilization of testosterone by poly-vinylpyrrolidone (PVP), poly-alpha-cyclodextrin (PACD), by trihydroxydioxadodecanyl-beta-cyclodextrin (HODBCD), by poly-gamma-cyclodextrin (PGCD), poly-beta-cyclodextrin (PBCD), and by hydroxypropyl-beta-cyclodextrin (HPBCD). On right is shown limited solubilization of testosterone (note one order difference in the y-axis scale) by alpha, beta, and gamma-cyclodextrins.
FIG. 3. Solubilization of progesterone by cyclodextrins and their derivatives. For abbreviations cmp. FIG. 2.
FIG. 4. Solubilization of estradiol by cyclodextrins and their derivatives. Abbreviations are the same as in FIG. 2.
FIG. 5. Weight changes of treated and control groups of mice. Control n=5, poly-beta-cyclodextrin n=6, hydroxypropyl-cyclodextrin n=5.
DETAILED DESCRIPTION OF THE INVENTION
Therapeutic use of sex hormones is required in the management of a number of diseases, including lack of natural hormones, many of them prominent in aging. The administration of sex hormones may be used also in manipulating the menstrual cycle resulting in birth control and premenstrual tension syndrome. These steroids are absorbed slowly from the gastrointestinal tract and are rapidly cleared from circulating blood by the liver. A mode of therapy relies on hydrolyzable derivatives of hormones which are dissolved in an oil and injected intramuscularly; alternatively, these derivatives may be transformed into a form suitable for implantation.
This invention discloses that rapid and complete dissolution of sex hormone preparations in the mouth, as achieved by hydrophilic cyclodextrin derivatives, enables an effective entry of these hormones into systemic circulation of a man and that elimination of these hormones from the circulation is only gradual. Only a specific type of dissolution of hormones is effective for this entry; dissolution aided by cyclodextrins themselves, hydrophobic cyclodextrin derivatives, or detergents did not enable effective entry.
In an inclusion complex of a sex hormone with one member of the group consisting of hydroxypropyl-beta-cyclodextrin and poly-beta-cyclodextrin a daily dosage is administered in the amount of 0.1-25 mg (buccal).
The following examples illustrate the claimed invention:
EXAMPLE 1
A number of carbohydrates, their chemical derivatives, and detergents were used to solubilize or to disperse testosterone, and the resulting drug forms were tested on a male with hypopituitary conditions. Results on effective additives and several related ones are given in Table 1, below.
Three of the additives were derivatives of beta-cyclodextrin. Beta-cyclodextrin is a product of enzymatic degradation of starch and contains seven glucose units joined in a circle by alpha 1→4 glycosidic bonds. Heptakis-2,6-di-O-methyl-beta-cyclodextrin (Table 1) is a derivative of beta-cyclodextrin, is more soluble in water and is a better solubilizer than the parent compound (Pitha, Life Sci., 29:307-311, 1981). Hydroxypropyl-beta-cyclodextrin and poly-beta-cyclodextrin are formed by condensation of beta-cyclodextrin with propylene oxide or with epichlorohydrin, respectively. The former contains one cyclodextrin moiety per molecule and has on the average of about one hydroxypropyl group per glucose unit (estimated from integral values of characteristic peaks in NMR spectra). Poly-beta-cyclodextrin is an oligomeric species; for the present invention a soluble preparation with an average molecular weight of 5600 was used. Both hydroxypropyl-beta-cyclodextrin and poly-beta-cyclodextrin are highly soluble in water (e.g., 40% solutions W/W are easily obtainable) and thus greatly differ from beta-cyclodextrin itself (saturated solution contains about 2% W/W). These compounds and their complexes with drugs, when obtained by freeze-drying of the solutions, are white, non-hydroscopic powders suitable for direct tableting. Tween 80, which was also evaluated in the present experiments (see Table 1), is a commercial nonionic detergent (monooleate of polyoxyethylenesorbitan) which efficiently solubilizes steroids into water and is relatively non-toxic.
TABLE 1______________________________________Effects of Solubilizers on Testosterone Bioavailability* Testosterone in Serum (ng/100 ml)** At 2 hr afterTreatment Basal treatment______________________________________Testosterone (10 mg) in form 330 330of its heptakis-2,6-di-O-methyl-beta-cyclodextrincomplex; dry powder admini-stered sublinguallyTestosterone (10 mg) solubi- 370 430lized by Tween 80 (25% W/W inwater); the solution wasadministered sublinguallyTestosterone (14 mg) in form 240 1270of its poly-beta-cyclodextrincomplex; the solution wasadministered sublinguallyTestosterone (10 mg) in form 210 1020of its hydroxypropyl-beta-cyclodextrin complex; tabletwas administered sublinguallyTestosterone (10 mg) in form 530 480of its hydroxypropyl-beta-cyclodextrin complex; drymaterial in hard gelatincapsule was swallowed______________________________________ *Subject defined in Example 2 **Assays performed by Bioscience Laboratories, Inc., Columbia, MD.
The effective absorption of sex hormones is a highly selective phenomenon (Table 1). Complexes of testosterone with beta-cyclodextrin were found relatively ineffective (results not shown). Heptakis-2,6-0-dimethyl-beta-cyclodextrin also had only marginal effects on the absorption of sex steroids from the oral cavity (Table 1). Additionally, this compound has slight toxicity. Dissolution of steroids by detergent (Tween 80) was ineffective as a means of improving the absorption of these hormones (Table 1).
Hydroxypropyl-beta-cyclodextrin and poly-beta-cyclodextrin effectively supported absorption of steroids from the oral cavity. The effectiveness achieved in this manner was impressive compared to other methods. Oral administration of 20 times higher doses of testosterone in conventional tablets led only to peak values of 300-900 ng/100 ml of testosterone in serum. Addition of polyethylene glycol derivatives only moderately improved this situation. The effective agents differ from the others in Table 1 in two points which contribute to the differences in effectiveness. While the ability of hydroxypropyl-beta-cyclodextrin and poly-beta-cyclodextrin to form complexes with drugs is about the same as other beta-cyclodextrins, these agents themselves and their complexes are much more soluble in water. Furthermore, compared to detergents the effective cyclodextrin derivatives do not form mycelles in which a steroid would dissolve; a single modecule of steroid is inserted into the beta-cyclodextrin cavity, and thus retains the potential for fast and mechanistically simple release of hormones. These features indicate that effective absorption of drugs from the oral cavity is primarily dependent on a speedy and effective dissolution of a drug in the saliva and then on barrier-free transfer from the solution to the oral tissue.
EXAMPLE 2
Subject J.P.: Caucasian male, 50 years old with hypopituitary condition which occurred and was diagnosed at the age of 47. Supplement of 200 μg of L-thyroxine, which J.P. receives daily, results in serum levels of 6 mcg/100 ml (cmp normal 5-12 mcg/100 ml) in intervals between testosterone supplementation the level of testosterone in serum was about 200 ng/100 ml (cmp normal 260-1120 ng/100 ml).
The effectiveness of this treatment is shown in Table 1.
TABLE 2______________________________________Average Weight (g) ± Standard Deviation (% of body weight)Treatmentorgan control poly-BCD HPBCD______________________________________lungs 0.20 ± 0.02 (0.63) 0.18 ± 0.02 (0.51) 0.18 ± 0.03 (0.50)liver 1.55 ± 0.16 (4.90) 1.84 ± 0.19 (5.30) 2.04 ± 0.04 (5.70)heart 0.17 ± 0.02 (0.54) 0.18 ± 0.02 (0.51) 0.20 ± 0.02 (0.55)kid- 0.47 ± 0.05 (1.50) 0.53 ± 0.06 (1.50) 0.51 ± 0.04 (1.40)neysspleen 0.10 ± 0.01 (0.32) 0.11 ± 0.03 (0.31) 0.10 ± 0.01 (0.28)# of 4 6 5aminals______________________________________
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The administration of sex hormones, particularly testosteorne, progesterone and estradiol in the form of their complexes or inclusions with specific derivatives of cyclodextrins by the sublingual or buccal route results in effective transfer of these hormones into the systemic circulation, followed by only gradual elimination. To be effective in the above mode of administration, the derivatives of cyclodextrins must carry one or several substituents, each containing one or several hydroxy groups. Specially preferred are the following complexes: hydroxypropylbeta-cyclodextrin and poly-beta-cyclodextrin.
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CROSS REFERENCE TO RELATED APPLICATIONS
This is a continuation of application Ser. No. 08/044,586; filed Apr. 7, 1993 now abandoned.
BACKGROUND OF THE INVENTION
1. Field of the Invention
This invention relates generally to the transdermal delivery of medicament and, more specifically, to an apparatus for the iontophoretic and ultrasonic delivery of medication across the skin or other biological tissue.
2. Prior Art
Iontophoresis has existed for several centuries as a means for applying medication locally through a patient's skin and for delivering medicaments to the eyes and ears. The application of an electric field to the skin is known to greatly enhance the skin's permeability to various ionic agents. The use of iontophoretic techniques has obviated the need for hypodermic injection of certain medicaments, thereby eliminating the concomitant problems of trauma, pain and risk of infection to the patient.
Iontophoresis involves the application of an electromotive force to drive or repel oppositely charged ions through the dermal layers into the area to be treated; either into the surrounding tissues for localized treatment or into the circulatory system for systemic treatment. Positively charged ions are driven into the skin at the anode while negatively charged ions are driven into the skin at the cathode. Studies have shown increased skin penetration of drugs at anodic or cathodic electrodes regardless of the predominant molecular ionic charge. This effect is mediated by polarization and osmotic effects. Regardless of the electrical charge on the medicament employed, two electrodes are used in conjunction with the patient's skin to form a closed circuit to promote the penetration or absorption of the medicament through the skin underlying the working electrode.
One readily observed benefit of transdermal iontophoretic drug delivery is the increased efficacy of the drugs delivered in this fashion. U.S. Pat. No. 5,160,316, to the instant inventor, incorporated herein by reference, describes the use of a multichannel dispersive electrode. Each channel is driven by separate electronic circuits to assure wide dispersion and enhanced penetration of medicament. Such wide field electrodes not only can cover a wide area of body without succumbing to "tunneling effects" but provide sufficient skin penetration to function as a systemic drug delivery system. A co-pending patent application by the present inventor describes a user-friendly iontophoretic system to deliver nicotine as a device to help people quit smoking or, alternatively, to provide established smokers with a noncarcinogenic smokeless cigarette.
Prior art iontophoretic systems have not proved useful for delivery of insulin via the transdermal route. Such a system would be extremely important in the management of diabetic patients and in decreasing the long term complications of diabetes. The patient would be freed from multiple injections of insulin and strict dietary controls which are the mainstay of current therapy of Diabetes Mellitus. It is believed that improved control of intraday glucose fluctuations will significantly decrease the long term complications of diabetes such as blindness and renal failure. Improved control of diabetic pregnancy and children will enhance and prolong life. An iontophoretic insulin delivery system must employ an electrode that avoids current flowing along the path of least resistance into a lesion or skin rupture, resulting in a localized burn.
The foregoing problems are solved by the present invention by providing an improved iontophoretic medicament applicator and combining this iontophoretic dispersion electrode with ultrasonic enhancement of penetration. Ultrasonic fields can readily be generated in the skin underlying an electrode by means of oscillator circuits applying a high frequency voltage waveform to piezoelectric crystals (i.e. quartz) mounted on the dispersive application electrode. It is the nature of piezoelectric crystals to convert electrical oscillations to vibration by means of crystal lattice elongation. Numerous materials such as ceramics (barium titanate), and variations of lead zicornate-lead titanate exhibit good piezoelectric properties and can be mounted on such an electrode. A preferred manufacture of a pliant contouring electrode producing low energy ultrasonic fields utilizes a sheet of Kynar™ polyvinelidene fluoride film that exhibits piezoelectric properties when energized yet retains pliability, stability and absence of toxicity. Such laminates of piezo film are known in the art and have already been manufactured. A bending motion (analogous to bimetallic action of thermostats) can be generated in response to an applied voltage where the top film expands while the bottom contracts. Alternating voltage creates film vibration in phase with applied oscillator output. For higher energy applications multiple mounted piezoelectric crystals or ceramic elements on a flexible iontophoretic sheet will be preferable.
SUMMARY OF THE INVENTION
Surprisingly, the instant inventor has discovered that combining a multichannel iontophoretic electrode with ultrasonic enhancement greatly improves transdermal penetration of larger molecules such as insulin or other peptide. Ultrasound applied to the skin has been shown to enhance skin penetration by (a) disrupting the protective keratin layer; and (b) forming micro-droplets that can readily be charged. A transdermal delivery system combining ultrasound and iontophoresis may be adapted to incorporate percutaneous infrared based glucose sensor technology with the ultrasonic-iontophoretic driver electrode in a biofeedback configuration. Such a system can be worn by a suffering diabetic. The sensor monitors the tissue glucose level, and if it exceeds a specified level the unit will begin to drive insulin through the skin until a normal glucose level is reestablished.
The improved iontophoretic applicator may also be suitable for treatment of large areas of skin where the ultrasonic component of the medicament driver electrode will further enhance the penetration of substances like antibiotic, antifungal, or growth factors when driven into a burn eschar to promote healing and minimize infection.
It is, therefore, a primary object of this invention to describe the construction of a driver electrode that combines the multichannel iontophoretic electrode with piezoelectric ultrasonic application elements into a combined structure which when linked with electrophoretic and ultrasonic driver circuits create a system for greatly enhanced skin penetration of medications, hormones, peptide and other therapeutic substances.
It is an additional object of the present invention to provide an improved iontophoretic medicament applicator that can be used to treat a large dermal area.
It is another object of the present invention to provide a more efficient iontophoretic medicament applicator by coupling the iontophoretic applicator electrode with piezoelectric ultrasonic elements at the site of iontophoretic application.
It is still another object of the present invention to provide an improved iontophoretic medicament applicator that is driven by reusable circuit and ultrasonic sources and comprises a disposable skin contacting surface that contains an iontophoretic dispersion electrode open cell medicament reservoir in contact with the skin surface.
It is a feature of the present invention that the iontophoretic medicament applicator for large dermal areas employs a multichannel electrodispersive matrix to drive the ionic medicament from the matrix or pad into the skin area.
It is another feature of the present invention that the iontophoretic medicament applicator for large dermal areas employs a carrier matrix with the medicament dispersed therewithin in combination with an adhesive layer to facilitate fastening to the patient's skin.
It is a further feature of the present invention that the iontophoretic medicament applicator for large dermal areas employs a conductive matrix and a carrier matrix with the medicament dispersed therewithin and which are sufficiently flexible to conform to the contours of the body area being treated.
It is still another object of the present invention to provide a disposable iontophoretic medicament applicator which employs an absorbent, inert material that is non-corrosive to contain the medicament or therapeutic agent.
It is yet another feature of the present invention that the disposable iontophoretic medicament applicator and the neutral electrode array and active electrode array are integrated into a single band type device to be worn about an extremity providing for comfort and electrical contact with skin. The ultrasonic crystal sources are preferably within close proximity to the dispersive iontophoretic electrodes while the power source and control circuitry for the ultrasonic drivers and the current limited drivers for the iontophoretic components are mounted on a band-type device as a control structure similar to that of a large watch.
It is yet another feature of the present invention that it provide a needleless transcutaneous drug delivery system in which the multichannel iontophoretic dispersion electrode together with the ultrasonic elements can comprise a flexible sheet with remote power and control circuits joined to the flexible sheet by ribbon cabling for treatments requiring higher power densities, higher dosing or treatment of specific areas such as burns, infection or special anatomic areas such as oral gums.
It is yet another object of this invention to describe a system for which overcomes biological boundaries against diffusion by means of the synergistic combination of multichannel iontophoresis and ultrasonic enhancement.
It is another object of the invention to provide a system for painless, controlled and safe delivery of drugs, peptide and other substances through the skin or mucous membrane.
It is an advantage of the present invention that the iontophoretic medicament applicator for large dermal areas improves the efficacy of topical agents and reduces the risk of harmful side effects that may occur with oral systemic treatment techniques.
It is another advantage of the present invention that the disposable iontophoretic medicament applicator for difficult to treat areas conducts the electrical current to the tissue through the solution into which the medicament is dissolved.
It is still another advantage of the present invention that the improved disposable iontophoretic medicament applicator has a low production cost, is safe to use and increases the efficacy of the medicament employed.
It is another feature of this invention that this wide area iontophoretic electrode is further enhanced by the adhesion of multiple ultrasonic elements corresponding to each dispersion electrode channel to further enhance the applied and iontophoretically driven medicament.
It is still another feature of this combined system that the array of ultrasonic elements each generating (30 khz-60 khz) may be driven and energized by circuitry in either serially, in parallel, or a combination of each, or even in multiplex fashion depending on energy sources and level of miniaturization and portability.
It is still another feature that the ultrasonic field in lower energy applications can be generated by incorporating a commercially available piezo film (i.e. Kynar PVDF film).
A preferred embodiment may be worn like a wide watch band with the electronics and power source will be mounted thereon in a manner similar to a large watch. The inner surface of this band will contain the active and grounding multichannel dispersive electrode. The ultrasonic elements are to be placed within this band in close proximity to each electrode channel. The inner surface may be an adhesive, an open cell material, insulin or other peptide-impregnatedhydrogel or other similar matrix. This inner band surface containing the medicament will be disposable and contain a specified amount of desired medicament.
These and other objects, features and advantages are obtained by the improved iontophoretic medicament applicator of the present invention. Various embodiments of the invention can be used to treat large dermal areas, localized areas or small and difficult to reach areas, and even include a "watch band" type of a systemic drug delivery system.
This system readily lends itself to systemic delivery of medication under the control of a physiological sensor connected to the delivery system in a biofeedback configuration. Delivery of nitroglycerin based on heart rate sensing; delivery of blood pressure medication based on blood pressure sensing; and ultimately, the transdermal delivery of insulin by means of the iontophoretic-ultrasonic system regulated and controlled by a similarly noninvasive glucose sensor.
BRIEF DESCRIPTION OF THE DRAWINGS
The objects, features and advantages of the invention will become apparent upon consideration of the following detailed disclosure of the invention, especially when it is taken in conjunction with the accompanying drawings wherein:
FIG. 1 is a top plan view of one embodiment of the improved multichannel iontophoretic applicator combined with several of the plurality of ultrasonic elements which can be used to treat large dermal areas.
FIG. 2 is a top, somewhat schematic, plan view of a miniaturized embodiment of the improved iontophoretic-ultrasonic delivery system combined with a sensor (eg; tissue glucose, blood pressure, or heart rate sensors) to form a biofeedback system for intelligent and controlled drug delivery. This system can be worn as a "watch band" on an extremity.
FIG. 3 is a block circuit diagram of the iontophoretic-ultrasonic (ionosonic) medicament applicator's electrical control circuit used in conjunction with above applicators either as a separate power and control unit or integrated into a single unit if market demand justifies the costs of such miniaturization.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT
An ionosonic applicator electrode, generally indicated at the numeral 10, is shown in FIG. 1. The applicator electrode 10 forms a closed circuit through the patient's body when current is applied which promotes the penetration or absorption of an ionic medicament contained in a layer 18 of the working electrode 10. The polarity of the working electrode 10 is selected based upon the pelarity of the medicament to be administered. The electrode 10 preferably comprises a flexible sheet or film forming a conductive matrix 15 having a current distributing conductive layer, such as a metallic foil, a conductive rubber or resin film, carbon film or other conductive coating or electro-dispersive material. The conductive matrix 15 is flexible so that it may be contoured to the body area on which it is placed and still cover a relatively wide area. Matrix 15 has a medicament carrying layer 18 attached to it, such as by an adhesive. The medicament carrying layer 18 is preferably formed from a porous material about 1/4 of an inch thick which can be a honeycombed sponge-like material with vertical cells to minimize cross flow or lateral dispersion of the medicament. The grounding electrode (not shown) employed with the multichannel electrode 14 must also cover an-area similarly large in size to the area covered by electrode 14.
A ribbon connector (not shown) connects an electrical power source (not shown) to the multichannel electrode 14 and delivers the electrical current by means of the multiconnectors 19 to the lead wires 16 that form the individual electrically conductive channels in the conductive matrix 15. Since the material of construction is flexible, the electrode 10 may be folded over a rigid supporting substrate above the connectors 19 to insure that a good electrical connection is made with the ribbon connector. Each channel in the iontophoretic array 14 preferably carries no more than 1 milliamps. The amount of current that flows to each channel is controlled by the control circuit (shown in FIG. 3) to prevent a tunneling effect from occurring. This prevents the flow of current along the path of least resistance through a lesion or skin rupture, for example, resulting in a burn to the patient at that location. The multichannel electrode 14 can employ a circuit pattern etched such as by laser or photoetching onto, for example, a metal coated Mylar® plastic sheet with each channel isolated to facilitate dispersion over a broad surface area.
Each channel formed by the lead wires 16 can be electrically driven simultaneously or in a sequential multiplex fashion. The use of simultaneous or parallel electrical current to each lead wire 16 in the array 14 would be employed, for example, in the application of medicament to burns where a wide area of dispersion is required. The iontosonic applicator greatly improves the skin penetration by the medicament to actively deliver the medicament to either a wide regional area or to a specific lesion.
Ultrasonic elements 11 made of piezoelectric crystal elements are mounted on this flexible electrode by means of a suitable adhesive such as Silastic™ brand of silicone adhesive. Driving oscillator connections 12 to the crystals can be photoetched onto a polymer sheet (eg; metalized Mylar™) with perforations on the sheet which facilitate mounting of the ultrasonic elements. This electrode can be effective in moving Insulin across skin, as well as antibiotics, antifungal, anti-inflammatory, blood pressure medication and cardiotropic drugs; either as direct drive, logic control timer drive or more elegantly as biofeedback control configuration. It is also effective in the treatment of wide field dermatological conditions, such as eczema, psoriasis and acne. It is also effective for ionic retention of skin hydrating media to facilitate skin hydration in cosmetic applications and in dermal exfoliation to drive medication into the skin in order to inflame the skin and cause the peeling of the external skin layer to stimulate reformation of collagen and collagen growth factors. The ionosonic applicator may also prove useful for driving Minoxidil™ or related compounds into the scalp to enhance hair growth and/or ameliorate baldness. The construction of ultrasonic elements can be piezo-electric crystals, ceramics or distributed segments of Kynar™ PVDF piezo film.
The open-celled sponge-like material in the medicament carrying layer 18 should be inert to the medicament or treatment agent being employed, as well as being noncorrosive and stable. Suitable materials include plastic pads, such as polyethylene, paper or cotton, porous ceramics, open-celled porous polytetrafluoro ethylene, other inert plastics, and open-celled silicone rubber, preferably with vertically aligned medicament-containing cells or tubes.
FIG. 3 shows a block circuit diagram of the iontophoretic medicator electrical control circuit suitable for use with the ionosonic applicator of FIG. 1 and the miniaturized ionosonic applicator diagrammed in FIG. 2. The control circuit, generally indicated at 30, may be either integrated with the electrode, as shown in FIG. 2, or boxed separately to drive the applicator electrode as shown in FIG. 1. The control circuit is equipped with a power source 31 which may be either a battery or an isolated wall source.
The control box 30 is provided with a clock-operated timer switch 32 to preset the length of iontophoretic treatment mediated by the integral CPU. Once the length of time has been selected, a voltage multiplier is utilized to provide the current to iontophoretically drive the medicament into the patient's skin. The current is set and administered until the end of the treatment period. When the clock 32 signals the end of the treatment period, the electrical current to the electrode 10 is gradually terminated by a ramping down of the current to the patient to avoid abrupt change. Ribbon cable (not shown) provides a flexible connection to the multichannel neutral and active electrodes as indicated in FIG. 3, as well as delivering oscillator power for the piezoelectric crystals 11 mounted on the applicator electrode 10. Internal circuit board controls allow for frequency adjustment, adjustment of maximum current per iontophoretic channel (not to exceed 0.6 to 1.2 ma range),and internal control that will shut down any iontophoretic channel electrically performing outside a "normal" range of encountered biological impedance.
FIG. 3 shows the block circuit diagram of the large area iontophoretic medicator control circuit employed with the multichannel iontophoretic applicator of FIG. 2. An isolated current loop generator is employed to feed current to the individual channels in the multichannel electrode via the plurality of individual current loops. Each current loop drives one band or channel in the multichannel electrode. It has been found that 0.6 milliamps current flowing to each channel used within a wide field dispersion grounding electrode, such as that shown in FIG. 1, provides a safe level for operating the iontophoretic device. This level of current avoids the tunnelling effect of current flowing along the path of least resistance and concentrating in, for example, a lesion or skin rupture, resulting in a burn to the patient. This permits current to be distributed over the large area of the multichannel electrode to drive medicament through a patient's skin over a large dermal area. Depending upon the electrode configuration, this current level can vary from about 0.1 to about 1.2 milliamps. The novel introduction of distributed ultrasonic piezoelectric elements combined with the iontophoretic multi electrodes described above greatly enhances the rate of penetration of many molecules. The use of ionosonic applications to administer insulin transdermally now becomes feasible.
While the invention has been described above with references to specific embodiments thereof, it is apparent that many changes, modifications and variations in the materials, arrangements of parts and steps can be made without departing from the inventive concept disclosed herein. For example, in employing the multichannel iontophoretic electrode of the present invention, it is possible to employ a biofeedback control of its operation to disperse, for example, more cardiovascular medication during periods of increased physiological demands, such as during exercise or an angina attack, by linking the penetration of nitroglycerine with heart rate; the physiological indicator of oxygen demand by the heart. In the latter instance, a sensor electrode would measure the increased demand and signal the controller 30 to stimulate more delivery of the transdermal medication, in this case, nitroglycerine (commercially available under the trade name Nitropaste). This type of a biofeedback coupled with ionosonic application provides an active system for percutaneous nitroglycerine delivery which is an improvement over existing passive percutaneous delivery systems. The present invention creates a further improvement in transdermal penetration of medicament over prior purely iontophoretic delivery system by introducing ultrasonic drivers at the site of iontophoretic penetration.
Alternate applications also exist in hormonal therapy, for example in the administration of insulin or steroids based on blood sugar levels and diurnal cycles, as appropriate. The large area multichannel electrode shown in FIG. 1 can also be adapted for use in dental anaesthesia in the form of a bite block, burn treatment and for the treatment of baldness, such as by the transdermal administration of Minoxidil®. Additionally, a conductive gel can also be used to impregnate the porous medicament carrying medium to increase the physical stability and the tissue adhering characteristics of the electrode. Or, a medicament may be dispersed in conductive gel and a layer of the gel serve as the medicament carrying layer.
Accordingly, the spirit and broad scope of the appended claims is intended to embrace all such changes, modifications and variations that may occur to one of skill in the art upon a reading of the disclosure. All patent applications, patents and other publications cited herein are incorporated by reference in their entirety.
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An improved apparatus for the iontophoretic-ultrasonic (ionosonic) transdermal delivery of medication across the skin or other biological membrane so the medication can be absorbed by the adjacent tissues and blood vessels. The apparatus can be adapted for large dermal area application or for a smaller area of application, depending on the choice of specific electrode employed. The apparatus comprises a multichannel iontophoretic applicator electrode. Multiple piezoelectric elements are mounted on the ionotophoetic electrode. The combination of ultrasonic vibration and iontophoresis creates a significant improvement in the penetration of medicament in contact with the skin or mucous membrane underlying the electrode. Drug delivery systems employing biofeedback such as the transcutaneous delivery of insulin based on tissue glucose are outlined based on this ionosonic technology.
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BACKGROUND OF THE INVENTION
This invention relates to a braking hydraulic pressure control valve used in a dual-circuit brake system wherein braking hydraulic pressure generated in a master cylinder is delivered to each of the left-and right rear-wheel-brakes of a vehicle through a pair of mutually independent conduit circuits.
It is commonly practiced in vehicles that a master cylinder is connected to each wheel cylinder disposed on the left-and right rear wheels by a pair of mutually independent conduit circuits for delivering the braking hydraulic pressure generated in the master cylinder due to operation of a brake operation member to the wheel cylinders independently from each other.
The applicant of this invention recently developed a control valve for controlling the braking hydraulic pressure delivered to the left-and right rear wheels in a dual-circuit brake system, wherein valve pistons of a pair of proportioning valves were parallelly disposed in a housing and one biasing device was shared by both valve pistons. In this control valve, the biasing device comprises (a) a guide rod swingably retained at one end thereof with a pivot pin, at a position middle of the pair of valve pistons, (b) a transmission or sliding member provided with a cylindrical portion slidably fitted on the guide rod and an action portion abuttable on rear ends of the valve pistons, (c) a compression coil spring anchored between the transmission member and the guide rod for constantly imparting biasing force to the rear ends of the valve pistons, and (d) a stopper projection extended from one end of the guide rod on the side thereof retained by the pivot pin for being fitted with a predetermined clearance into a stopper hole formed in parallel with the valve pistons within the housing so as to limit the swinging of the guide rod within a minute angular range from a straight center line passing the axis of the pivot pin and parallel to the axes of the valve pistons.
In this braking hydraulic pressure control valve, resilient force of one spring is equally distributed by a transmission member to a pair of valve pistons and an ununiformity of operational stroke between the pair of the valve pistons owing to errors in manufacturing can be absorbed by the swinging of a minute angle of the transmission member and the guide rod. And when one of the pair of independent conduit circuits is damaged, the transmission member is straight linearly moved on a retaining member which has been blocked of swinging exceeding a predetermined range. It causes the valve piston receiving the hydraulic pressure from the normal conduit circuit to compress the coil spring by itself, so the hydraulic pressure in the normal conduit circuit advantageously becomes two times as high as when the both conduit circuits are normal before the hydraulic pressure control begins to take place. Besides, the guide rod may be attached to the housing or a member secured thereto with a simple pivot pin and the transmission member is allowed to be slidably fitted on the outside of the guide rod of bar shape, which makes the manufacturing of the two members quite easy.
SUMMARY OF THE INVENTION
The primary object of this invention is to provide a braking hydraulic pressure control valve maintaining the above-mentioned effects and in addition further compact in size.
According to the invention there is provided a hydraulic pressure control valve for a dual-circuit brake system with a pair of independent conduit circuits for each wheel cylinder on left-and right rear wheels of a vehicle so as to deliver a braking hydraulic pressure generated in a master cylinder by operation of a brake operation member, the control valve being provided with a pair of valve pistons, for controlling the braking hydraulic pressure delivered to each wheel cylinder on the left-and right rear wheels, disposed in a housing parallelly and in such a manner as to be projected at the rear end thereof out of the housing while being imparted with biasing force directed inwards the housing by a biasing device, the biasing device comprising (a) a cover of container shape secured to the housing in such a state as to cover a surface thereof at which rear ends of the pair of valve pistons are projected outwards, (b) a guide rod attached, at one end portion thereof to the cover with a pivot pin, at a position middle between the pair of valve pistons, for being rotatable in a parallel direction to a plane including axes of the pair of valve pistons, (c) a sliding member provided with a cylindrical portion slidably fitted on the guide rod and an action portion abuttable on the rear ends of the pair of valve pistons, (d) a spring for imparting the pair of valve pistons biasing force via the sliding member by means of urging the sliding member onto the valve pistons, and (e) stopper means disposed on the cover for limiting the movement of the guide rod within a predetermined angular range from a straight center line passing an axis of the pivot pin and parallel to the axes of the pair of valve pistons, whereby when either one of the pair of independent conduit circuits is damaged one valve piston which receives braking hydraulic pressure from the normal conduit circuit rotates the guide rod as far as it abuts on the stopper means and pushes the sliding member back along the rotated guide rod resisting the biasing force of the spring before the control of the braking hydraulic pressure begins to take place.
As the guide rod, in this structure, is pivotally supported by the cover, the space conventionally required for attaching the guide rod onto the housing in the middle of the two valve pistons can be eliminated, which allows to narrow the distance between the two valve pistons. This structure provides advantages of: diminished transverse dimensions of the control valve as measured across the length thereof; reduced weight and manufacturing costs thereof; and decreased mass thereof contributing to reduction in space required for attaching the same to the vehicle.
Another object of this invention is to provide a hydraulic pressure control valve composed of as small number of parts as possible, each of which is easy to be manufactured.
Still another object of this invention is to provide an easy assemblable hydraulic pressure control valve.
Another object of this invention is to provide a hydraulic pressure control valve containing a biasing device which can be incorporated in advance as a subassembly within a cover at a removed status from the valve housing.
Another object of this invention is to provide a hydraulic pressure control valve having a biasing device which allows checking of the biasing load thereof before being attached to the valve housing.
Another object of this invention is to provide a hydraulic pressure control valve wherein the valve piston is smoothly movable so as to be able to stably control the braking hydraulic pressure.
Still another object of this invention is to provide a hydraulic pressure control valve wherein adjustment of the biasing force is possible.
Other objects and features necessary for attaining the above-mentioned objects will be naturally understood from the careful study of the undermentioned description in conjunction with the appended claims and drawings.
BRIEF DESCRIPTION OF THE DRAWING
FIG. 1 is an elevational view of an embodiment of a hydraulic pressure control valve, with an essential part being illustrated in section;
FIG. 2 is a transverse sectional bottom view of an essential part of the hydraulic pressure control valve;
FIGS. 3-5 are respectively a perspective view of a cover, a guide rod, and a sliding member of the hydraulic pressure control valve;
FIGS. 6 and 7 are respectively a transverse sectional bottom view and an axial elevational sectional view of an essential part of another embodiment of the hydraulic pressure control valve;
FIGS. 8-9 are respectively a perspective view of a sliding member and a guide rod shown in FIGS. 6 and 7;
FIGS. 10 and 11 are respectively a transverse sectional bottom view and an axial elevational sectional view of an essential part of another embodiment of the hydraulic pressure control valve; and
FIG. 12 is a perspective view of a sliding member shown in FIGS. 10 and 11.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
Referring to the appended drawings preferred embodiments will be described in detail hereinunder.
In two independent pressure chambers 14, 16, a first and a second, in a master cylinder 10 an equal hydraulic pressure is produced in response to depressing of a brake pedal 12. The hydraulic pressure produced in the first pressure chamber 14 is led through a conduit 18 to an inlet port 22 of a braking hydraulic pressure control valve 20, for being further led via an outlet port 24 and a conduit 26 to a wheel cylinder 28 of a left side front wheel and on the other hand via an outlet port 30 to a wheel cylinder 32 of a right side rear wheel. The hydraulic pressure produced in the second pressure chamber 16 is similarly led, by way of one inlet port and two outlet ports, disposed at symmetrical positions to the inlet port 22 and the outlet ports 24, 30, as well as conduits 36, 38 to a wheel cylinder 40 of a right side front wheel and a wheel cylinder 42 of a left side rear wheel. Those ports however are not illustrated, with the right half of FIG. 1 at the upper portion thereof being indicative of an external view of an attaching portion of the control valve 20.
The control valve 20 includes a pair of mutually parallel P valves 43, 44, whose two valve pistons 46, 48 are respectively biased by a biasing device 50.
The valve piston 46 is accommodated in a stepped bore 54 formed in a housing 52 for being slidably fitted through a central hole formed in a sleeve 56 which is threaded into an opening of the stepped bore 54 so as to project out of the sleeve 56 at the rear end thereof, that is, lower end in FIG. 1. The sleeve 56 is provided on the side faced an inlet chamber 66 of the P valve 43 with a recess portion having an oil seal 58 for ensuring the oil tightness between the sleeve 56 and the valve piston 46. In the recess portion a seal cover 60 is secured so as to cover the oil seal 58. On a step formed on the internal surface of the stepped bore 54 a valve seat 62, an elastic body of a cap shape, is mounted. Close contact with and separation from the valve seat 62 of a valve 64 of the valve piston 46 executes communication and interruption between the inlet chamber 66 and an outlet chamber 68. Another stepped bore provided with a sleeve, an oil seal, and a valve seat similarly to the above is symmetrically disposed to the stepped bore 54, not being illustrated, though.
On the bottom surface of the housing 52, i.e., the side where the rear end of the valve pistons 46, 48 are projected, a cover 70 of a container shape is secured in such a manner as to envelop the bottom surface and the biasing device 50. The securing or fastening of the cover 70 is made by a pair of bolts 75 inserted through a pair of bolt holes 74 formed at suitable places in a flange 72 thereof (see FIG. 3). On the internal wall surface of the cover 70 on the portion near the housing 52 (the upper portion in FIG. 1 which will be called hereinafter upper portion) a pair of recesses or notches 76, 76 of U-shape are formed face-to-face in the middle of the two valve pistons 46, 48. This U-shape notch 76 is open upwards, but not open through the cover 70, still leaving thin wall portion as clearly illustrated in FIG. 3.
In the notches 76, 76 a pivot pin 80 for rotatably supporting a guide rod 78 is carried as shown in FIG. 2 via a pair of cylindrical bearings 82, 82 fitted on either end thereof. The guide rod 78 is provided on one end thereof with a head 84, a kind of projection projected in a radial direction, formed integrally, and it is supported by the pivot pin 80 pierced through the head 84 thereof rotatably in a parallel direction to a plane including the axes of the valve pistons 46, 48, the other end (free end) of the guide rod 78 being confronted with a predetermined distance to either stopper 86 disposed face-to-face on the internal wall surface of the lower portion in the cover 70. The two stoppers 86 consist of two side portions of an internal surface of a blind hole formed in a bottom wall of the cover 70 and function to restrict the rotation of the guide rod 78, when the angle formed by the axis of the guide rod 78 and a straight line passing the axis of the pivot pin 80 and parallel to the axes of the valve pistons 46, 48 has reached a predetermined value, by abutting the same so as not to allow further rotation thereof. On this guide rod 78 a sliding member 90 having a cylindrical portion 88 which is provided with a stepped portion 92 on the external surface thereof is fitted. On the stepped portion 92 one end of a compression coil spring 94 which is wound about the cylindrical portion 88 is abutted to urge the same. The other end of the spring 94 is received by a seat plate 96 fixed on the free end of the guide rod 78, which seat plate 96 is carried by a snap ring 98 fitted in an annular groove formed on the guide rod 78. A large diametered portion 100 on the upper end of the cylindrical portion 88 accommodates the head 84 of the guide rod 78 therein and is provided with, on diametrically opposite wall portions as shown in FIG. 5, a pair of U-shaped notches 102, 102 open upwards. These notches 102, 102 respectively have such a width as to receive the bearing 82 therein with a minute clearance inbetween and a bottom portion with an identical radius of curvature with the radius of the bearing 82, so that the sliding member 90 may be prevented from rotating about the axis of the guide rod 78. The depth of the U-shaped notch 102 is determined such that an internal stepped portion 104 of the cylindrical portion 88 does not interfere with the bearing 82 when it is in contact with the head 84 of the guide rod 78. From the large diametered portion 100 of the cylindrical portion 88 an action portion 106 is projected in the radial direction thereof, which abuts at either end portion thereof the rear end (lower end) of the valve pistons 46, 48 for imparting the biasing force of the coil spring 94 to the pair of valve pistons 46, 48.
Operational function of the hydraulic pressure control valve 20 of such a structure will be described next.
Depressing of the brake pedal 12 generates an equal braking hydraulic pressure in each of the first pressure chamber 14 and the second pressure chamber 16 of the master cylinder 10. The hydraulic pressure produced in the first pressure chamber 14 is delivered via the conduit 18 and the inlet port 22 to the inlet chamber 66 for being further delivered via the outlet port 24 connected thereto and the conduit 26 to the wheel cylinder 28 on the left side front wheel; and the hydraulic pressure in the inlet chamber 66 is also delivered via the outlet chamber 68, the outlet port 30, and the conduit 108 to the wheel cylinder 32 on the right side rear wheel. The hydraulic pressure thus transmitted to the wheel cylinders (28, 32) function to brake the vehicle wheels. Just similarly the hydraulic pressure produced in the second pressure chamber 16 of the master cylinder 10 is delivered to the wheel cylinders 40, 42 on the right side front wheel and the left side rear wheel for the same purpose.
The hydraulic pressure delivered to the inlet chamber 66 and the outlet chamber 68 is continuously raised in response to the depressing of the brake pedal 12. As the pushout force affecting the valve piston 46 however overcomes, when the above hydraulic pressure is so raised as to exceed a predetermined value, the biasing force of the biasing device 50 owing to the action of the hydraulic pressure in the outlet chamber 68, the valve 64 is moved so as to seat on the valve seat 62. Communication between the inlet chamber 66 and the outlet chamber 68 is interrupted once herewith, but further rising of the hydraulic pressure in the inlet chamber 66 separates the valve 64 from the valve seat 62, which raises as a result the hydraulic pressure in the outlet chamber 68. The rising of the hydraulic pressure in the outlet chamber 68 forces the valve 64 to seat on the valve seat 62 again. Repetition of this type movement of the valve 64 constitutes the well known hydraulic pressure controlling or reducing action.
Although both valve pistons 46, 48 are so designed as to be equal in their stroke (shift) amount, it can not necessarily be ensured that both are finished completely equal because of inevitable errors of some kinds such as those in manufacturing. When one valve piston, for example, the valve piston 48 on the right side in FIG. 1 is already seated on the valve seat the other valve piston 46 may not be seated yet on the valve seat 62. On such an occasion the amount of projection of the valve piston 46 becomes larger than that of the other valve piston 48 because of continued increasing of the hydraulic pressure in the outlet chamber 68, and the sliding member 90 and the guide rod 78 are counterclockwise, in FIG. 1, rotated at this time up to a position where the biasing forces acting on both valve pistons 46, 48 are equalized so as to rectify the imbalance of forces acting on both pistons, which will make the braking pressure to both rear wheels equal. At this time the guide rod 78 does not abut on the stopper 86, because the clearance between the two members is so determined in advance.
In the event of an oil leakage in one of the two circuits, for example on the conduit 34, the hydraulic pressure produced in the master cylinder 10 is led through the conduit 18 to the inlet port 22 alone. When the hydraulic pressure in the outlet chamber 68 exceeds the predetermined value, the push-out force only of the valve piston 46 affects the action portion 106 of the sliding member 90. So the sliding member 90 and the guide rod 78 under the influence of the push-out force only from the valve piston 46 are rotated largely in the counterclockwise direction, in FIG. 1, and the end portion of the guide rod 78 will consequently abut on the stopper 86 so as to prevent the sliding member 90 and the guide rod 78 from being further rotated. The valve 64 is not at this stage seated on the valve seat 62. When the push-out force of the valve piston 46 overcomes the biasing force, due to further continued rising of the hydraulic pressure in the outlet chamber 68, the valve piston 46 is therefore pushed outside while sliding downwards the sliding member 90 so as to be seated at the valve 64 thereof on the valve seat 62. Then the well known hydraulic pressure controlling action is initiated at this stage, when the hydraulic pressure in the outlet chamber 68 is raised almost two times as high as at the normal time, because only the valve piston 46 receives all of the biasing force of the coil spring 94 at this time. Therefore, the initial value of the hydraulic pressure controlling delivered to the wheel cylinder 32 of the right side rear wheel is almost two times as high as at the normal time.
Incidentally, the control valve 20 is greatly featured in that the biasing device 50 for biasing the valve pistons 46, 48 is mounted on the cover 70. It is allowable indeed that the biasing device 50 is mounted on the housing. When the biasing device is mounted on the housing an extra space for placing a pivot to support the same must be kept on the housing. As this pivot is placed in the middle of a pair of valve pistons it inevitably requires to widen the distance between the valve pistons, which consequently enlarges the width of the control valve itself, namely size larging of the control valve. Contrary to this type, disposition of the pivot on the cover which will dispense with that space, allowing the control valve to be compacted in size. Another merit of mounting the biasing device on the cover 70 resides in that the disposition of the stopper 86 on the cover 70, on which the pivot pin 80 is also mounted, greatly contributes to enhancing relative dimensional precision between the stopper and the guide rod because of elimination of the assembling errors when the control valve is assembled, and allowing advantageously to check the precision before assembling while it is impossible in a case wherein the biasing device is mounted on the housing. Furthermore, the stopper 86 is formed in the neighborhood of the bottom of the cover 70 where the distance from the pivot pin 80 as the rotation center of the guide rod 78 is the greatest so that the allowed rotation range for the guide rod 78 may be determined more precisely.
The above described control valve 20 is provided with further features as mentioned hereunder.
As the U-shaped notches 76 for retaining the pivot pin 80 are allowed to be formed simultaneously with the formation of the cover 70 by means of die casting or the like method, machining for making the bores to pierce the pivot pin 80 can be eliminated. As the U-shaped notches 76 are open upwards for allowing the pivot pin 80 press-fittedly pierced through the head 84 of the guide rod 78 to be rightly positioned only by being put thereinto in a direction perpendicular to the axis of the pivot pin 80, otherwise necessitated positioning parts required when the pin is slidably pierced through the hole are all eliminated. All of those stated above are helpful in diminishing man-hours and cost for assembling the control valve, and in improving the assembling quality. Another advantage of the U-shaped notches 76 lies in that they are formed on the inner side of the wall of the cover 70 not to be cut open to the outer side, which allows high performance of sealing and dispensing of otherwise needed parts and work of sealing, and also allows axial positioning of the pivot pin 80 without any positioning parts even when the pin 80 is slidably pierced through the guide rod 78.
The guide rod 78 is provided with the head 84, as mentioned earlier, radially projecting, which may be abutted on the internal stepped portion 104 of the sliding member 90. On the other end of the guide rod 78 the seat plate 96 for receiving one end of the coil spring 94 is attached. Between this seat plate 96 and the external stepped portion 92 of the cylindrical portion 88 the coil spring 94 is set. This type structure allows the guide rod 78, the sliding member 90, and the spring 94 can be put together into the biasing device 50 as a sub-assembled part. And the coil spring 94 can also be given a preload, which allows imparting a desired set load only by slightly compressing it when the control valve 20 is assembled. Such circumstances have brought about a great deal of efficiency raising to the assembly of the control valve. As checking whether the preload imparted to the coil spring 94 is agreeable with the predetermined value and adjustment of the thus imparted preload by means of inserting a spacer shim(s) are made easy to carry out, it has become possible to give a stable biasing force to the control valve and to prevent variation of performance among many P valves manufactured.
As the necessitated amount of compression for the coil spring 94 when it is assembled into a control valve 20 is small, there is little fear that the valve pistons 46, 48 are imparted force in inclined direction against the axis thereof when the control valve 20 is assembled in comparison to a case wherein the coil spring 94 is compressed by screwing up of the bolt from its natural length. Particularly when the valve piston 46 is made of a soft metal such as an aluminum alloy deformation or scar due to prying function which are liable to take place between the valve piston 46 and the sleeve 56 can be evaded so as to maintain the functional features of the P valve. The present structure wherein the coil spring 94 is allowed to swing or rotate together with the guide rod 78 and the sliding member 90 prevents the coil spring 94 from receiving bending load so as not to produce difference of the biasing force to the pair of valve pistons in comparison to a case wherein one end of the coil spring 94 is anchored to the cover 70.
The sliding member 90 is provided with a pair of U-shaped notches 102, 102, which function for positioning or anti-rotation of the sliding member 90 itself by accommodating the bearings 82, 82 therein. Although there is an idea of attempting to stably position the sliding member 90 through engagement of the action portion 106 thereof and the valve pistons 46, 48, it may adversely affect the stable operation of the valve pistons 46, 48 because of possible prying force applied on the valve pistons 46, 48. Particularly when the valve pistons 46, 48 are made of a soft metal such as an aluminum alloy they are liable to have scratches or abnormal wearing. The above-mentioned structure of the control valve 20 does not allow the valve pistons to take part in the positioning of the sliding member 90, which prevents the occurrence of the disadvantages stated above for maintaining the control performance of the control valve 20 and meritoriously ensures simple configuration of the action portion 106.
Another embodiment of this invention will be described with reference to FIGS. 6-9.
In this embodiment a head 112 of a guide rod 110 is made into a hexagonal prism shape and the internal side of a large diametered portion 118 of a cylindrical portion 116 which is a part of a sliding member 114 is made into a hexagonal fitting hole 119 so as to accommodate the head 112 therein. This mode structure is for preventing mutual relative rotation between the two members. On the other end of the guide rod 110 a male screw 111 is formed as can be seen in FIG. 9. On this male screw 111 a nut 120 having a stepped portion 113 on the external surface thereof is threaded. The stepped portion 113 of the nut 120 receives a seat plate 122 thereon, on which one end of a coil spring 124 is abutted. In this embodiment the spring 124 is gradually compressed by means of screwing up of the nut 120, so the preload applied to the spring 124 can be advantageously adjusted at a desired value by suitably measuring it in the course of gradual increase thereof. When the nut 120 has been exactly positioned, the male screw 111 on the guide rod 110 is squashed or crushed through a hole 126 formed through the wall of the nut 120 so as to surely position the nut 120. It will completely eliminate varying of the biasing force of the spring 124 through the life of the control valve. Besides, the sliding member 114 is fitted in by the head 112 of the guide rod 110 for being well protected from relative rotation between the two when the nut 120 is screwed up.
According to FIGS. 10-12 showing still another embodiment, on the upper end of a guide rod 127 an annular groove is formed, in which a snap ring 128 projecting in a outward-radial direction is put for preventing a sliding member 134 from being got rid of. The snap ring 128 functions as a projection corresponding to the head 84 previously referred to in its effect. A pivot pin 130 is directly carried by a cover 132 without the help of a bearing. On the other end of the guide rod 127 a projection 138 with a larger diameter is formed on which a seat plate 140 of ring shape is engaged, and a coil spring 136 is anchored between the seat plate 140 and the sliding member 134. In this embodiment, too, the biasing device consisting of the guide rod 127, the sliding member 134, and the coil spring 136 can be put together in advance as a subassembly. The coil spring 136 imparted a preload is put in place together with the cover 132 by being slightly compressed so as to get a desired preload, which has largely improved the assembling efficiency of the hydraulic control valve. Besides, the formation of the annular groove for preventing the getting rid of the sliding member 134 in place of the head projecting radially has largely facilitated the manufacturing of the guide rod 127.
This invention can be applied, in addition to the so-called P valve described above, to a so-called L valve, a limited valve, which is provided with a pair of valve pistons, one end thereof being projected outside, such that a hydraulic pressure of constant force can be produced, regardless of rising of the hydraulic pressure supplied, in response to the biasing force imparted to the valve pistons.
The above description is concerned only to preferred embodiments by way of example, not for limiting the invention to those. It goes without saying that this invention can be varied and modified in many ways within the spirit and scope thereof.
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A hydraulic pressure control valve for a dual-circuit brake system of a vehicle. In this control valve a pair of valve pistons for controlling the braking hydraulic pressure delivered to each of rear wheel brakes are disposed in a housing parallelly and imparted with biasing force directed inwards of the housing by one biasing device. The biasing device is assembled or set within a cover of cup-shape such that the biasing device has been given a preload substantially equal to a biasing force necessary for the control valve before the cover is fixed to the valve housing. The biasing device includes a swingable guide rod attached at one end thereof to the cover with a pivot pin, a sliding member slidably fitted on the guide rod, and a compression spring disposed between the sliding member and a free end of the guide rod for biasing the sliding member toward the pivoted end of the guide rod. The guide rod is provided with a projection for stopping axial movement of the sliding member due to the biasing force of the spring. When the cover is attached to the valve housing the sliding member abuts on ends of the valve pistons and consequently is separated from the projection for transmitting the biasing force of the spring to the valve pistons.
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RELATED APPLICATIONS
[0001] This application is a continuation-in-part of U.S. patent application Ser. No. 14/689,945, filed on Apr. 17, 2015 which claims the benefit of the U.S. Provisional Patent Application Ser. No. 61/982,235 filed on Apr. 21, 2014.
FIELD OF THE DISCLOSURE
[0002] The present disclosure is directed to a foam mattress with improved features related to its construction, transportation and cleaning.
BACKGROUND
[0003] Although the traditional spring mattress is the dominant category of mattresses sold within the United States, both latex foam mattresses and visco-elastic (memory) foam mattresses have been sold in the U.S. as specialty-category mattresses.
[0004] Both latex and memory foams have benefits and drawbacks in mattress construction and design. Latex foam has a very quick recovery rate (i.e., is “bouncy”), is highly breathable and can be produced using natural or synthetic materials. If natural materials are used, the mattress can be marketed as such, adding to its desirability in the marketplace. Nonetheless, latex foam mattresses have the highest average return rate of any type of mattress sold in the U.S.—usually due to the resonant “bouncing” that the user feels on a latex foam mattress and/or inadequate pressure relief
[0005] The market for memory foam mattresses was built nearly single-handedly by Tempur-Pedic through novel marketing techniques, such as an association with space-age technology and the image of a handprint “stuck” in the foam top layer after the hand is removed. Due to its slow recovery (or memory), visco-elastic memory foam was marketed as an aid for pressure relief and to enable isolation of one sleeper from another because the foam does not translate vibration. But memory foam mattresses also have a somewhat high return rate, often due to complaints such as: 1) “getting stuck” (i.e., not being able to turn over when changing sleeping positions); 2) overheating (the foam is not highly breathable and the contouring causes the foam to closely hug large portions of the body limiting air flow); and 3) not being conducive for comfort during sex because of the tendency to “get stuck.”
[0006] Further, both latex and memory foam are expensive materials. Manufacturers often use them only for the top layer(s) of a mattress, often referred to as the comfort layer(s). The comfort layer(s) are usually 1-5″ thick and typically consist of 1-3 different foam types laminated together. Beneath these layer(s), regular polyurethane foam is typically used to provide some support and to increase mattress thickness. Some newer “hybrid” mattresses use pocketed spring coils instead of polyurethane foam. To combat the “stuck” feeling of memory foam, some manufacturers have developed quick-response memory foam. Other manufacturers use thinner layers of memory foam (atop poly foam) to limit the depth that user can sink into the foam. A few manufacturers have put latex foam underneath the memory foam to benefit from the quick return (i.e. bounce) that the latex foam provides. But this solution may not solve the problems noted above where memory foam is the top layer of the mattress.
[0007] Accordingly, there is a need for a novel foam mattress construction that couples the contouring pressure relief of memory foam with quick-recovery of latex foam that prevents users from getting “stuck” in the memory foam and improves the springiness of the mattress. Such an arrangement will benefit from the breathability and bounciness of latex foam while mitigating the resonant bouncing and poorer pressure relief characteristics of latex foam.
BRIEF DESCRIPTION OF THE FIGURES
[0008] The accompanying figures, where like reference numerals refer to identical or functionally similar elements throughout the separate views, together with the detailed description below, are incorporated in and form part of the specification, and serve to further illustrate embodiments of concepts that include the claimed invention, and explain various principles and advantages of those embodiments.
[0009] FIG. 1 is a cross-section view of a three-layer mattress in accordance with some embodiments.
[0010] FIG. 2 is a cross-section view of a four-layer mattress in accordance with some embodiments.
[0011] FIG. 3 is a cross-section view of a five-layer mattress in accordance with some embodiments.
[0012] FIGS. 4A and 4B are perspective views of a rolled-up mattress in accordance with some embodiments.
[0013] FIGS. 5A and 5B are perspective views of a mattress with a removable cover in accordance with some embodiments.
[0014] FIGS. 6A and 6B are perspective views of a mattress with a removable cover in accordance with some embodiments.
[0015] FIGS. 7A, 7B and 7C are perspective views of a mattress with a button-down cover in accordance with some embodiments.
[0016] Skilled artisans will appreciate that elements in the figures are illustrated for simplicity and clarity and have not necessarily been drawn to scale. For example, the dimensions of some of the elements in the figures may be exaggerated relative to other elements to help to improve understanding of embodiments of the present invention.
[0017] The apparatus and method components have been represented where appropriate by conventional symbols in the drawings, showing only those specific details that are pertinent to understanding the embodiments of the present invention so as not to obscure the disclosure with details that will be readily apparent to those of ordinary skill in the art having the benefit of the description herein.
DETAILED DESCRIPTION
[0018] I. Definitions
[0019] In this disclosure, the listed terms will be defined as follows:
[0020] Density of a foam is its mass per unit volume. Density may be measured in pounds per cubic foot (pcf).
[0021] IFD is Indentation Force Deflection, which is a method for determining the firmness, and load bearing capacity of foam. IFD measures the load required to depress a 50 square inch compression platen into a foam specimen. IFD is usually reported at 25% deflection of the specimen's height and is measured in pounds. IFD may be measured with ASTM D3574-11 Test B 1 .
[0022] Airflow is a measure of the air permeability of a foam and is measured in cubic feet per minute (cfm). Airflow may be measured with ASTM D3574-11 Test G.
[0023] Recovery is a measure of how quickly a foam returns to original shape after being displaced and is measured in seconds. Recovery is typically used to measure the memory effect of visco-elastic foams. Recovery may be measured with ASTM D3574-11 Test M.
[0024] Rebound is measure of the elasticity of a foam and is measured as a percentage. A steel ball is dropped on a foam specimen, and the percentage height it rebounds (relative to drop height) is measured. Rebound may be measured with ASTM D3574-11 Test H
[0025] Support Factor (SF) is the ratio of 65% IFD over 25% IFD and is a unitless measurement. SF is a measure of the “deeper” support of a foam, and is an indicator as to whether a foam will bottom out or not. SF may be measured with ASTM D3574-11 Test B 1 .
[0026] Tg is the glass transition temperature of the foam. It is a property of all foams but is most relevant with memory foams because memory foams have a Tg within the range of normal ambient temperature (40° F.-80° F.). Tg is the point at which a foam transitions from stiff to pliable. Below Tg, a foam is stiff. Above Tg, a foam is pliable. The transition in mechanical properties can be dramatic, even with but a few degrees change in temperature. Tg, may be measured with dynamic mechanical analysis (DMA) or thermal stress analysis (TSA).
[0027] Latex foam is any high resilience foam where: i) a rebound may be greater than 40%; ii) airflow may be greater than 3.5 cfm; and iii) recovery may be less than 0.5 seconds. Latex foam may be natural latex, styrene butadiene rubber (SBR), polyurethane or any blend of the above foams.
[0028] Latex-like foam is any foam intended to simulate the mechanical properties of latex foam—(i) a rebound may be greater than 40%; ii) airflow may be greater than 3.5 cfm; and iii) recovery may be less than 0.5 seconds—but with polyurethane, polyethylene or other non-natural or non-SBR resins or any blend of the above foams. In the alternative, latex-like foam may have the following properties: (i) a rebound may be greater than 35%; and ii) airflow may be 4 cfm or greater.
[0029] Memory foam is any polyurethane foam with a low rebound, delayed recovery and a temperature-sensitive response. More specifically: i) the rebound may be from 1-2%; ii) the recovery may be greater than 1 second; and iii) the temperature-sensitive response may be the foam softening in response to body heat and having a Tg between 40° F. and 80° F. In the alternative, memory foam may have the following properties: (i) the rebound may be 1% or less; ii) the airflow may be 2 cfm or greater; (iii) the recovery may be about 6 seconds; and iv) the temperature-sensitive response may be the foam softening in response to body heat and having a Tg of 50° F. or less.
[0030] Transition foam is any polyurethane foam of modified visco-elastic polyurethane foam without a “memory foam” feature. Transition foam may have the following properties: (i) the rebound may be about 10%; and ii) the airflow may be 1.5 cfm or more.
[0031] II. Mattress Length and Width
[0032] The mattresses described herein may be of any suitable length and width, including without limitation U.S. or non-U.S. standard sizes such as King, Queen, Full, Twin, Extra Long, California King, Youth and Crib.
[0033] III. The Three-Layer Mattress
[0034] Turing to FIG. 1 , shown is cross-section of a three-layer mattress 100 with a cover 110 . The cross-section of the depth of the mattress 100 includes a first layer 120 , a second layer 130 and a third layer 140 .
A. First Embodiment
[0035] In a first embodiment, the total depth 180 of the mattress 100 may be 9.5 inches. The first layer depth 150 of the mattress 100 may be 1.5 inches. The second layer depth 160 of the mattress may be 1.5 inches. The third layer depth 170 of the mattress may be 6.5 inches.
[0036] In this first embodiment, the first layer 120 is a layer of latex foam. The first layer 120 may consist of C1 latex from Mountain Top Foam and may have the physical properties shown in Table 1.
[0000]
TABLE 1
Potential
Target
Tolerance
Unit
Test Method
Range
Unit
Density
3.3
±0.2
pcf
n/a
2 to 4
pcf
25% IFD
12
±1
lb
ASTM D3574-11 Test B 1
6 to 18
lb
Airflow
>4
minimum
cfm
ASTM D3574-11 Test G
>2
cfm
Recovery
<0.5
maximum
seconds
ASTM D3574-11 Test M
<1
seconds
Rebound
65
±5
%
ASTM D3574-11 Test H
>40
%
Support
3
±0.1
n/a
ASTM D3574-11 Test B 1
>2
n/a
Factor
Tg
n/a
[0037] In Table 1, the rightmost two columns demonstrate potential ranges of physical properties related to the first layer 120 .
[0038] The second layer 130 is a layer of memory foam. The second layer 130 may consist of 4 lb Visco memory foam and may have the physical properties shown in Table 2.
[0000]
TABLE 2
Potential
Target
Tolerance
Unit
Test Method
Range
Unit
Density
4.0
±0.1
pcf
n/a
2 to 6
pcf
25% IFD
10
±1
lb
ASTM D3574-11 Test B 1
6 to 18
lb
Airflow
>2
minimum
cfm
ASTM D3574-11 Test G
>1
cfm
Recovery
3
±1
seconds
ASTM D3574-11 Test M
>1
seconds
Rebound
2
maximum
%
ASTM D3574-11 Test H
<5
%
Support
2.2
±0.1
n/a
ASTM D3574-11 Test B 1
<2.6
n/a
Factor
Tg
60
±2
° F.
DMA
40 to 80
° F.
[0039] In Table 2, the rightmost two columns demonstrate potential ranges of physical properties related to the second layer 130 .
[0040] In the mattress industry, two important parameters used to describe a foam are IFD and SF. Standard test protocols specify the test specimen size and loading regime for these parameters, which creates measurement consistency. Such test protocols may be found in ASTM D3574-11.
[0041] IFD is an indication of foam firmness and indicates how much force a foam pushes back with when a user pushes into it. Industry norms use 25% IFD numbers as a basis for comparison—so an IFD 8 foam (8 pounds of push-back) feels softer than a IFD 20 foam (20 pounds of push-back).
[0042] SF represents the “deeper” support of a foam, and is an indicator as to whether a foam will bottom out or not. SF is the ratio of the 65% IFD to the 25% IFD—the ratio of the force required to depress a sample to 65% of its original height to the force required to depress a sample to 25% of its original height (the standard IFD measurement). SF illustrates how much a single type of foam pushes back the more the user pushes into it. Thus, a foam with a SF of 3 and an IFD of 8 pushes back with 24 pounds force upon 65% compression, while an IFD 8 foam with a SF of 2 only pushes back with 16 pounds at 65% compression.
[0043] A linear “spring” foam generally has a SF of 2.6. Latex and latex-like foam typically have a higher SF (approximately 3.0-3.3). Memory foam typically has a lower SF (approximately 2.0-2.2). These differences are quite significant in the overall feel of the mattress.
[0044] In the mattress industry, it has been a widely accepted rule of thumb that the top layers of foam should have the lowest SF to reduce pressure points, and that the SF should increase as one moves down into the layers. By having the first layer 120 being comprised of a latex or latex-like foam and placed on top of the second layer 130 being comprised of memory foam, the commonly-held rule regarding SF is inverted. Nonetheless, a successful experience for the mattress user is achieved because the foam layers of the bed act as a series of springs. This arrangement eliminates the “stuckness” of memory foam while retaining the pressure relief and motion isolation of the memory foam. At the same time, this arrangement benefits from the breathability and bounciness of latex or latex-like foam while mitigating the resonant bouncing and poorer pressure relief characteristics of latex or latex-like foam.
[0045] The third layer 140 adds overall support and depth for the mattress and may consist of 1.8 pcf conventional polyurethane foam and may have the physical properties shown in Table 3.
[0000]
TABLE 3
Potential
Target
Tolerance
Unit
Test Method
Range
Unit
Density
1.8
±0.1
Pcf
n/a
1 to 4
pcf
25% IFD
32
±3
Lb
ASTM D3574-11 Test B 1
15 to 50
lb
Airflow
>4
minimum
Cfm
ASTM D3574-11 Test G
>2
cfm
Recovery
<0.5
maximum
Seconds
ASTM D3574-11 Test M
<1
seconds
Rebound
50
±5
%
ASTM D3574-11 Test H
>40
%
Support
1.9
±0.1
n/a
ASTM D3574-11 Test B 1
1.5 to 3.5
n/a
Factor
Tg
n/a
[0046] In Table 3, the rightmost two columns demonstrate potential ranges of physical properties related to the third layer 140 .
B. The Second Embodiment
[0047] In a second embodiment, the total depth 180 of the mattress 100 may range from 1 to 22 inches. The first layer depth 150 of the mattress 100 may range from 0.25 to 5 inches. The second layer depth 160 of the mattress may range from 0.25 inches to 5 inches. The third layer depth 170 of the mattress may range from 0.5 to 12 inches.
[0048] The second embodiment is similar to the first embodiment in that the first layer 120 is latex or latex-like foam and the second layer 130 is memory foam. The third layer 140 may be any of the following: i) latex foam; ii) latex-like foam; iii) polyurethane visco-elastic “memory” foam; iv) conventional polyurethane foam; v) HR (high resilience) polyurethane foam; or vi) any other polyurethane, polyethylene or polyester Foam.
[0049] IV. The Four-Layer Mattress
[0050] Turing to FIG. 2 , shown is cross-section of a four-layer mattress 200 with a cover 210 . The cross-section of the depth of the mattress 200 includes a first layer 220 , a second layer 230 , a third layer 240 and a fourth layer 250 .
A. The First Embodiment
[0051] The total depth 295 of the mattress 200 may range from 1 to 22 inches. The first layer depth 260 of the mattress 200 may range from 0.25 to 5 inches. The second layer depth 270 of the mattress may range from 0.25 inches to 5 inches. The third layer depth 280 of the mattress may range from 0.25 to 5 inches. The fourth layer depth 290 of the mattress may range from 0.25 to 12 inches.
[0052] The first layer 220 may be latex or latex-like foam. The second layer 230 , third layer 240 and fourth layer 250 may be any of the following: i) latex foam; ii) latex-like foam; iii) polyurethane visco-elastic “memory” foam; iv) conventional polyurethane foam; v) HR (high resilience) polyurethane foam; or vi) any other polyurethane, polyethylene or polyester foam. In one embodiment, at least one of the second layer 230 , third layer 240 and fourth layer 250 is memory foam. In one embodiment, at least one upper layer has a SF higher than a layer below that upper layer.
B. The Second Embodiment
[0053] In a second embodiment, the total depth 295 of the mattress 200 may be approximately 9.5 inches±0.5 inches. The first layer depth 260 of the mattress 200 may be approximately 1.5 inches±0.125 inches. The second layer depth 270 of the mattress may be approximately 1.5 inches±0.125 inches. The third layer depth 280 of the mattress may be approximately 1.5 inches±0.125 inches. The fourth layer depth 290 of the mattress may be approximately 5 inches±0.125 inches.
[0054] In the second embodiment, the first layer 220 may be a latex-like foam. The first layer 220 may have the physical properties shown in Table 4.
[0000]
TABLE 4
Target
Tolerance
Unit
Test Method
Density
3.5
±0.2
pcf
n/a
25% IFD
13
±2
lb
ASTM D3574-11 Test B 1
Airflow
>4
minimum
cfm
ASTM D3574-11 Test G
Recovery
n/a
Rebound
>35
minimum
%
ASTM D3574-11 Test H
Support Factor
2.5
±0.2
n/a
ASTM D3574-11 Test B 1
Tg
n/a
[0055] The second layer 230 may be a layer of memory foam. The second layer 230 may consist of visco-elastic memory foam and may have the physical properties shown in Table 5.
[0000]
TABLE 5
Target
Tolerance
Unit
Test Method
Density
3.5
±0.2
pcf
n/a
25% IFD
15
±2
lb
ASTM D3574-11 Test B 1
Airflow
>2
minimum
cfm
ASTM D3574-11 Test G
Recovery
6
±2
seconds
ASTM D3574-11 Test M
Rebound
<1
maximum
%
ASTM D3574-11 Test H
Support Factor
2.2
±0.2
n/a
ASTM D3574-11 Test B 1
Tg
<50
maximum
° F.
DMA
[0056] The third layer 240 may be a layer of transition foam. The third layer 240 may consist of modified visco-elastic polyurethane foam without a “memory foam” feature and may have the physical properties shown in Table 6.
[0000]
TABLE 6
Target
Tolerance
Unit
Test Method
Density
2.5
±0.1
pcf
n/a
25% IFD
26
±2
lb
ASTM D3574-11 Test B 1
Airflow
>1.5
minimum
cfm
ASTM D3574-11 Test G
Recovery
n/a
Rebound
10
±2
%
ASTM D3574-11 Test H
Support Factor
2
±0.2
n/a
ASTM D3574-11 Test B 1
Tg
n/a
[0057] The use of this third layer 240 may provide a more seamless transition between the second layer 230 and the fourth layer 250 and increases long-term durability of the mattress.
[0058] The fourth layer 250 may consist of polyurethane foam. This layer adds overall support and depth for the mattress and may consist of 1.8 pcf conventional polyurethane foam and may have the physical properties shown in Table 7.
[0000]
TABLE 7
Target
Tolerance
Unit
Test Method
Density
1.8
±0.1
pcf
n/a
25% IFD
36
±3
lb
ASTM D3574-11 Test B 1
Airflow
>4
minimum
cfm
ASTM D3574-11 Test G
Recovery
n/a
Rebound
n/a
Support Factor
2
±0.2
n/a
ASTM D3574-11 Test B 1
Tg
n/a
[0059] . The Five-Layer Mattress
[0060] Turing to FIG. 3 , shown is cross-section of a five-layer mattress 300 with a cover 305 . The cross-section of the depth of the mattress 300 includes a first layer 310 , a second layer 315 , a third layer 320 , a fourth layer 325 and a fifth layer 330 .
[0061] The total depth 360 of the mattress 300 may range from 1.25 to 22 inches. The first layer depth 335 of the mattress 300 may range from 0.25 to 5 inches. The second layer depth 340 of the mattress may range from 0.25 inches to 5 inches. The third layer depth 345 of the mattress may range from 0.25 to 5 inches. The fourth layer depth 350 of the mattress may range from 0.25 to 5 inches. The fifth layer depth 355 of the mattress may range from 0.25 to 12 inches.
[0062] The first layer 310 may be latex or latex-like foam. The second layer 315 , third layer 320 , fourth layer 325 and fifth layer 330 may be any of the following: i) latex foam; ii) latex-like foam; iii) polyurethane visco-elastic “memory” foam; iv) conventional polyurethane foam; v) HR (high resilience) polyurethane foam; or vi) any other polyurethane, polyethylene or polyester Foam. In one embodiment, at least one of the second layer 315 , third layer 320 , fourth layer 325 and fifth layer 330 is memory foam. In one embodiment, at least one upper layer has a SF higher than a layer below that upper layer.
[0063] VI. Mattress Transportation
[0064] Moving a mattress is a cumbersome task. For example, queen-sized mattresses can weigh up to 100 pounds, and are typically floppy with poor affordance for carrying. They are difficult to get through doorways, down stairs and into cars. As such, many people will discard mattresses when they move because the burdens and costs of moving a mattress are too great.
[0065] Turing to FIG. 4A , shown is a mattress system 400 with two features that facilitate moving so that mattresses are not discarded and have greater long-term value to their owner. The mattress body 405 incorporates straps 410 , 412 , 414 integrated into the design that hold the mattress in an easily transportable shape once rolled up or folded. The straps may be webbing, string or any other material with high tensile strength. The straps may tie, have buckles or incorporate any other fasteners 420 , 422 , 424 that enable the straps to hold the mattress together. The user manually rolls up and/or folds the mattress, and the straps are located in a convenient place such that once rolled, the mattress may easily be strapped together. By integrating the straps, the rolling and strapping process is easier and ensures that all users have the proper materials at hand to roll the mattress for transport.
[0066] Turing to FIG. 4B , shown is another view of the mattress system 400 . In addition to the straps 410 , 412 , 44 , the mattress body 405 has integrated backpack, shoulder and/or hand straps 420 , 430 installed via a securing mechanism 440 that allow the mattress body 405 to be readily carried by one or more people on their shoulders and/or back. This greatly facilitates portability, increasing the odds that an owner will take their mattress with them to their new home and be able to do so with minimal hassle.
[0067] In another embodiment, the cinch straps and carrying straps are part of a separate “wrap” or bag rather than integrated into the mattress.
[0068] VII. Integrated Mattress Washable Pad
[0069] Mattresses are expensive investments that often become stained with sweat and/or other bodily fluids. Even when used with sheets and a mattress pad (a separately-purchased cover that is used to protect the mattress), mattresses become stained. In nearly all cases, the cover of the mattress itself is not washable other than through spot cleaning. A limited number of mattresses (often futon-style) may have a cover that completely zips off and can be laundered, but this is often a cumbersome process because it requires a lot of manipulation of the heavy mattress. Staining of mattresses limits their resale value and can prevent people from giving a mattress to friends when they decide to move town or upgrade to a different mattress.
[0070] Turing to FIG. 5A , shown is a mattress system 500 including a mattress body 510 and of a removable section of a detachable mattress cover 520 that protects the primary mattress cover from stains and that can be washed or replaced with a new one in order to “refresh” the mattress. In this embodiment, the mattress cover 520 covers the entire top of the mattress body 510 and is secured to the mattress body 510 by a securing mechanism 530 . It may be reversible to quickly provide a clean top surface, and it may have different colors from the mattress body 510 in order to better hide stains.
[0071] The securing mechanism 530 may be secured at approximately the same depth all around the mattress body 510 and may consist of hook and loop fasteners, zippers, buttons, snaps, ties or any combination thereof.
[0072] Turing to FIG. 5B , shown is a mattress system 505 including a mattress body 510 and a removable section of a detachable mattress cover 550 that protects the primary mattress cover from stains and that can be washed or replaced with a new one in order to “refresh” the mattress. In this embodiment, the mattress cover 550 covers a portion of the top of the mattress body 510 and is secured to the mattress body 510 by a securing mechanism 540 . The mattress cover 550 may be located in the area most likely to absorb bodily fluids (in the region from the head to the upper thigh). It may cover just the top of the mattress body 510 so it can be easily removed and laundered. It may be reversible to quickly provide a clean top surface, and it may have different colors from the primary mattress in order to better hide stains.
[0073] The securing mechanism 540 may be secured at approximately the same depth around the mattress body 510 to best secure the mattress cover 550 The securing mechanism 540 may consist of hook and loop fasteners, zippers, buttons, snaps, ties or any combination thereof.
[0074] Turing to FIGS. 6A and 6 B, shown is a mattress system 600 with a removable mattress pad 610 that surrounds a portion of the mattress body 510 . The mattress pad 610 may be placed in the area most likely to absorb bodily fluids (in the region from the head to the upper thigh). It may cover just the top of the mattress body 510 so it can be easily removed and laundered. It may be reversible to quickly provide a clean top surface, and it may have different colors from the primary mattress in order to better hide stains.
[0075] Turing to FIG. 7A , shown is a mattress system 700 with a removable mattress pad 730 . It is secured to the mattress body 510 via a button 710 attached to the mattress body 510 and a button hole 720 installed in the mattress pad 730 . Turning to FIG. 7B , shown is a mattress system 704 where the mattress pad 730 is attached to the mattress body (not shown) by means of the button 710 attached to the mattress. Turning to FIG. 7C , shown is a mattress system 706 where the mattress pad 750 is attached to a portion of the mattress body 760 via a button 710 attached to the mattress body 760 . The mattress pads 730 , 750 may be reversible to quickly provide a clean top surface, and may have different colors from the primary mattress in order to better hide stains.
[0076] In the foregoing specification, specific embodiments have been described. However, one of ordinary skill in the art appreciates that various modifications and changes can be made without departing from the scope of the invention as set forth in the claims below. Accordingly, the specification and figures are to be regarded in an illustrative rather than a restrictive sense, and all such modifications are intended to be included within the scope of present teachings.
[0077] The benefits, advantages, solutions to problems, and any element(s) that may cause any benefit, advantage, or solution to occur or become more pronounced are not to be construed as critical, required, or essential features or elements of any or all the claims. The invention is defined solely by the appended claims including any amendments made during the pendency of this application and all equivalents of those claims as issued.
[0078] Moreover in this document, relational terms such as first and second, top and bottom, and the like may be used solely to distinguish one entity or action from another entity or action without necessarily requiring or implying any actual such relationship or order between such entities or actions. The terms “comprises,” “comprising,” “has”, “having,” “includes”, “including,” “contains”, “containing” or any other variation thereof, are intended to cover a non-exclusive inclusion, such that a process, method, article, or apparatus that comprises, has, includes, contains a list of elements does not include only those elements but may include other elements not expressly listed or inherent to such process, method, article, or apparatus. An element proceeded by “comprises . . . a”, “has . . . a”, “includes . . . a”, “contains . . . a” does not, without more constraints, preclude the existence of additional identical elements in the process, method, article, or apparatus that comprises, has, includes, contains the element. The terms “a” and “an” are defined as one or more unless explicitly stated otherwise herein. The terms “substantially”, “essentially”, “approximately”, “about” or any other version thereof, are defined as being close to as understood by one of ordinary skill in the art. The term “coupled” as used herein is defined as connected, although not necessarily directly and not necessarily mechanically. A device or structure that is “configured” in a certain way is configured in at least that way, but may also be configured in ways that are not listed.
[0079] The Abstract of the Disclosure is provided to allow the reader to quickly ascertain the nature of the technical disclosure. It is submitted with the understanding that it will not be used to interpret or limit the scope or meaning of the claims. In addition, in the foregoing Detailed Description, it can be seen that various features are grouped together in various embodiments for the purpose of streamlining the disclosure. This method of disclosure is not to be interpreted as reflecting an intention that the claimed embodiments require more features than are expressly recited in each claim. Rather, as the following claims reflect, inventive subject matter lies in less than all features of a single disclosed embodiment. Thus the following claims are hereby incorporated into the Detailed Description, with each claim standing on its own as a separately claimed subject matter.
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A foam mattress in which a layer of latex or latex-like foam placed above two layers of memory foam is described. This construction of the mattress provides the contouring pressure relief that a visco-elastic foam provides with a top surface with quick recovery (a latex-like “bounce”) that prevents people from getting “stuck” in the visco-elastic foam and improves the springiness of the mattress. The mattress may also include straps and cinches to aid in transportation of the mattress. The mattress may also include removable covers that aid in keeping the mattress clean.
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TECHNICAL FIELD
[0001] The present invention relates to a novel compound having a xanthine oxidase inhibitory activity and a method for manufacturing the same as well as a xanthine oxidase inhibitor containing the compound as an active ingredient.
[0002] In particular, the present invention relates to a pyrazole derivative useful as a therapeutic agent or a preventive agent for diseases associated with xanthine oxidase such as gout, hyperuricemia, tumor lysis syndrome, urinary calculi, hypertension, dyslipidemia, diabetes, cardiovascular diseases such as arteriosclerosis or heart failure, kidney diseases such as diabetic nephropathy, respiratory diseases such as chronic obstructive pulmonary disease, inflammatory bowel diseases or autoimmune diseases.
BACKGROUND ART
[0003] Xanthine oxidase is an enzyme catalyzing the conversion of hypoxanthine to xanthine and further to uric acid in nucleic acid metabolism.
[0004] A xanthine oxidase inhibitor inhibits uric acid synthesis to reduce a level of uric acid in the blood with respect to the action of xanthine oxidase. That is, a xanthine oxidase inhibitor is effective as a therapeutic agent for hyperuricemia and various diseases caused by hyperuricemia. On the other hand, there are gouty arthritis and gouty tophus called gout as a clinical condition caused as a result of deposition of urate crystals after prolonged hyperuricemia. In addition, hyperuricemia is considered to be important as a factor of lifestyle diseases associated with obesity, hypertension, dyslipidemia and diabetes or metabolic syndromes, and recently, it has been clarified that hyperuricemia is a risk factor of renal damage, urinary calculi and cardiovascular diseases according to epidemiological surveys (Guideline for the Management of Hyperuricemia and Gout, 2nd edition). Further, a xanthine oxidase inhibitor is expected to be useful for the treatment of diseases associated with active oxygen species by the active oxygen species generation inhibitory activity, for example, for the treatment of cardiovascular diseases through the vascular function-improving action (Circulation. 2006; 114: 2508-2516).
[0005] Allopurinol and febuxostat are clinically used as a therapeutic agent for hyperuricemia, but allopurinol has been reported to have a side effect such as Stevens-Johnson syndrome, toxic epidermal necrolysis, hepatic disorder and renal dysfunction (Nippon Rinsho, 2003; 61, Suppl. 1: 197-201).
[0006] As a compound having a xanthine oxidase inhibitory activity, for example, there have been reported a phenyl pyrazole derivative (Patent Documents 1 to 3), and a triaryl carboxylic acid derivative (Patent Documents 4 to 7), and the like, such as a pyrazole derivative in which the central aromatic ring is a benzene ring. In addition, there has been reported a pyrazole derivative which is a central bicyclic hetero ring such as a 6-indolepyrazole derivative (Patent Documents 8).
[0007] On the other hand, in Non-Patent Documents 1 and 2, a pyrazole carboxylic acid derivative having a pyridine ring in the center is reported.
CITATION LIST
Patent Literature
[0000]
PTL 1: Japanese Unexamined Patent Application Publication S59-95272
PTL 2: International Publication No. 98/18765
PTL 3: Japanese Unexamined Patent Application Publication H10-310578
PTL 4: International Publication No. 2007/043457
PTL 5: International Publication No. 2007/097403
PTL 6: International Publication No. 2008/126770
PTL 7: International Publication No. 2008/126772
PTL 8: International Publication No. 2011/043568
Non-Patent Literature
[0000]
NPL 1: Bioorganic Medicinal Chemistry Letters, 2006, Vol. 16(21), p. 5616-5620
NPL 2: Bioorganic Medicinal Chemistry Letters, 2006, Vol. 16(21), p. 5687-5690
SUMMARY OF INVENTION
Technical Problem
[0018] An object of the present invention is to provide a novel compound having a xanthine oxidase inhibitory activity. Further, an object of the present invention is to provide a compound having an excellent uric acid lowering action. In addition, an object of the present invention is to provide a compound useful as a therapeutic agent or a preventive agent for diseases associated with xanthine oxidase such as gout, hyperuricemia, tumor lysis syndrome, urinary calculi, hypertension, dyslipidemia, diabetes, cardiovascular diseases such as arteriosclerosis or heart failure, kidney diseases such as diabetic nephropathy, respiratory diseases such as chronic obstructive pulmonary disease, inflammatory bowel diseases or autoimmune diseases.
Solution to Problem
[0019] As a result of earnest studies on compounds having xanthine oxidase inhibitory activity, the inventors have completed the present invention based on the findings: that a compound represented by the following formula (I)
[0000]
[0000] i.e., a pyrazole derivative which has a tricyclic triaryl structure and has as the central ring a pyridine ring possessing one nitrogen atom and substituted with a cyano group, has xanthine oxidase inhibitory activity; further that it has novel xanthine oxidase inhibitory activity accompanied by an excellent uric acid lowering effects; and further that it has sustained xanthine oxidase inhibitory activity that enables particularly excellent uric acid lowering effect over a long period of time. In addition, the inventors have completed the present invention based on the finding that the pyrazole derivative can be a good therapeutic or prophylactic agent for gout, hyperuricemia, tumor lysis syndrome, urinary calculus, hypertension, dyslipidemia, diabetes, cardiovascular diseases such as arteriosclerosis or heart failure, renal diseases such as diabetic nephropathy, respiratory diseases such as chronic obstructive pulmonary disease, inflammatory bowel diseases, autoimmune diseases, or the like.
[0020] The present invention is a compound represented by the following formula (I):
[0000]
[0000] wherein:
A represents a C 6-10 aryl group or a heteroaryl group, wherein the aryl group or heteroaryl group may be unsubstituted or substituted with 1 to 3 groups Q which are the same or different from one another and selected from the group consisting of a halogen atom, —CN, —NO 2 , a C 1-6 alkyl group, a C 3-7 cycloalkyl group, a C 1-6 halogenoalkyl group, a phenyl group, —CH 2 —O—R 2 , —O—R 2 , —O—C 1-6 halogenoalkyl, —O-benzyl, —O-phenyl, —O—CO—R 2 , —NR 3 R 4 , —NH—CO—R 2 , —CO 2 —R 2 , —CO—R 2 , —CO—NR 3 R 4 , —NH—SO 2 —R 2 , —CO-aryl, —S—R 2 , —SO 2 —C 1-6 alkyl, and —SO 2 -phenyl;
X, Y, and Z represent CR 5 or a nitrogen atom, wherein one of X, Y, and Z represents a nitrogen atom and the remaining two represent CR 5 ;
R represents a hydrogen atom or a C 1-6 alkyl group;
R 1 represents a hydrogen atom, an amino group, or a C 1-6 alkyl group;
R 2 represents a hydrogen atom or a C 1-6 alkyl group;
R 3 and R 4 are the same or different from each other and are a hydrogen atom or a C 1-6 alkyl group, where R 3 and R 4 may be taken together to form with the nitrogen atom to which they are attached a nitrogen-containing saturated monocyclic heterocycle; and
R 5 represents a hydrogen atom, a halogen atom, or a C 1-6 alkyl group;
or a pharmaceutically acceptable salt thereof.
[0021] The present invention is also a pharmaceutical composition comprising a compound represented by the above formula (I), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
[0022] The present invention is also a xanthine oxidase inhibitor comprising a compound represented by the above formula (I), or a pharmaceutically acceptable salt thereof, as an active ingredient.
[0023] The present invention is also a therapeutic or prophylactic agent for diseases associated with xanthine oxidase, such as gout, hyperuricemia, tumor lysis syndrome, urinary calculus, hypertension, dyslipidemia, diabetes, cardiovascular diseases such as arteriosclerosis or heart failure, renal diseases such as diabetic nephropathy, respiratory diseases such as chronic obstructive pulmonary disease, inflammatory bowel diseases, or autoimmune diseases, comprising a compound represented by the above formula (I), or a pharmaceutically acceptable salt thereof, as an active ingredient.
[0024] Furthermore, the present invention is a compound represented by the following formula (II) which can be used as an intermediate in the manufacture of the compound represented by the above formula (I):
[0000]
[0000] wherein:
A represents a C 6-10 aryl group or a heteroaryl group, wherein the aryl group or heteroaryl group may be unsubstituted or substituted with 1 to 3 groups Q which are the same or different from one another and selected from the group consisting of a halogen atom, —CN, —NO 2 , a C 1-6 alkyl group, a C 3-7 cycloalkyl group, a C 1-6 halogenoalkyl group, a phenyl group, —CH 2 —O—R 2 , —O—R 2 , —O—C 1-6 halogenoalkyl, —O-benzyl, —O-phenyl, —O—CO—R 2 , —NR 3 R 4 , —NH—CO—R 2 , —CO 2 —R 2 , —CO—R 2 , —CO—NR 3 R 4 , —NH—SO 2 —R 2 , —CO-aryl, —S—R 2 , —SO 2 —C 1-6 alkyl, and —SO 2 -phenyl;
X, Y, and Z represent CR 5 or a nitrogen atom, wherein one of X, Y, and Z represents a nitrogen atom and the remaining two represent CR 5 ;
R represents a hydrogen atom or a C 1-6 alkyl group;
R 1 represents a hydrogen atom, an amino group, or a C 1-6 alkyl group;
R 2 represents a hydrogen atom or a C 1-6 alkyl group;
R 3 and R 4 are the same or different from each other and are a hydrogen atom or a C 1-6 alkyl group, where R 3 and R 4 may be taken together to form with the nitrogen atom to which they are attached a nitrogen-containing saturated monocyclic heterocycle; and
R 5 represents a hydrogen atom, a halogen atom, or a C 1-6 alkyl group;
R 6 represents a protective group of a carboxyl group; and
W represents a halogen atom, a methanesulfonyloxy group, a p-toluenesulfonyloxy group, a trifluoromethanesulfonyloxy group, or a cyano group.
[0025] Furthermore, the present invention is a compound represented by the following formula (III) which can be used as an intermediate in the manufacture of the compound represented by the above formula (I):
[0000]
Wherein,
[0026] X, Y, and Z represent CR 5 or a nitrogen atom, wherein one of X, Y, and Z represents a nitrogen atom and the remaining two represent CR 5 ;
R represents a hydrogen atom or a C 1-6 alkyl group;
R 1 represents a hydrogen atom, an amino group, or a C 1-6 alkyl group;
R 5 represents a hydrogen atom, a halogen atom, or a C 1-6 alkyl group;
R 6 represents a protective group of a carboxyl group;
V represents a halogen atom, a methanesulfonyloxy group, a p-toluenesulfonyloxy group, a trifluoromethanesulfonyloxy group, a hydroxyl group, or a benzyloxy group; and
W represents a halogen atom, a methanesulfonyloxy group, a p-toluenesulfonyloxy group, a trifluoromethanesulfonyloxy group, or a cyano group.
[0027] Furthermore, the present invention is a compound represented by the following formula (IV) which can be used as an intermediate in the manufacture of the compound represented by the above formula (I):
[0000]
[0000] wherein:
A represents a C 6-10 aryl group or a heteroaryl group, wherein the aryl group or heteroaryl group may be unsubstituted or substituted with 1 to 3 groups Q which are the same or different from one another and selected from the group consisting of a halogen atom, —CN, —NO 2 , a C 1-6 alkyl group, a C 3-7 cycloalkyl group, a C 1-6 halogenoalkyl group, a phenyl group, —CH 2 —O—R 2 , —O—R 2 , —O—C 1-6 halogenoalkyl, —O-benzyl, —O-phenyl, —O—CO—R 2 , —NR 3 R 4 , —NH—CO—R 2 , —CO 2 —R 2 , —CO—R 2 , —CO—NR 3 R 4 , —NH—SO 2 —R 2 , —CO-aryl, —S—R 2 , —SO 2 —C 1-6 alkyl, and —SO 2 -phenyl;
X, Y, and Z represent CR 5 or a nitrogen atom, wherein one of X, Y, and Z represents a nitrogen atom and the remaining two represent CR 5 ;
R 2 represents a hydrogen atom or a C 1-6 alkyl group;
R 3 and R 4 are the same or different from each other and are a hydrogen atom or a C 1-6 alkyl group, where R 3 and R 4 may be taken together to form with the nitrogen atom to which they are attached a nitrogen-containing saturated monocyclic heterocycle; and
R 5 represents a hydrogen atom, a halogen atom, or a C 1-6 alkyl group; and
X 2 represents a halogen atom, a methanesulfonyloxy group, a p-toluenesulfonyloxy group or a trifluoromethanesulfonyloxy group.
Advantageous Effects of Invention
[0028] The present invention provides a novel compound having a high inhibitory activity of xanthine oxidase and a method for manufacturing the same compound. Further, the compound by the present invention is useful as a therapeutic agent or a preventive agent for diseases associated with xanthine oxidase in particular such as gout, hyperuricemia, tumor lysis syndrome, urinary calculi, hypertension, dyslipidemia, diabetes, cardiovascular diseases such as arteriosclerosis or heart failure, kidney diseases such as diabetic nephropathy, respiratory diseases such as chronic obstructive pulmonary disease, inflammatory bowel diseases or autoimmune diseases.
DESCRIPTION OF EMBODIMENTS
[0029] Terms used alone or in combination in the present specification will be explained below. Unless otherwise stated, the explanation of each substituent shall be common to each site. It should be noted that when any variable occurs in any number of constituents, its definition is independent in each constituent. In addition, combinations of substituents and variables are permissible only if such combinations result in chemically stable compounds.
[0030] “Xanthine oxidase” is used both in a broad sense that it is an enzyme for catalyzing an oxidation reaction from hypoxanthine to xanthine and further to uric acid and in a narrow sense that it is an oxidase type xanthine oxidoreductase which is one of the enzymes that catalyze the same reaction. In the present invention, unless otherwise specified, “xanthine oxidase” is collectively called an enzyme which catalyzes an oxidation reaction from hypoxanthine to xanthine and further to uric acid. Among the xanthine oxidoreductase which is responsible for this reaction, two types of oxidase type oxidoreductase and dehydrogenase type oxidoreductase are present and both types are included in the xanthine oxidase of the present invention. Unless otherwise specified, “xanthine oxidase” in “xanthine oxidase inhibitory activity”, “xanthine oxidase inhibitor” and the like also has the same meaning as defined above.
[0031] For the purpose of the present invention, an “aryl group” means a group formed by removing one of the hydrogen atoms bonded to an aromatic hydrocarbon ring. C 6-10 aryl groups include, for example, phenyl, naphthyl, indenyl, tetrahydronaphthyl, indanyl, azulenyl groups, and the like.
[0032] For the purpose of the present invention, a “heteroaryl group” means a 3- to 10-membered monocyclic or bicyclic heterocyclic ring system of aromatic character which contains 1 to 5 heteroatoms selected from the group consisting of oxygen, sulfur, and nitrogen atoms. The “3- to 10-membered monocyclic or bicyclic heterocyclic ring system of aromatic character” refers to a monovalent group derived by the removal of a hydrogen atom from a 3- to 10-membered monocyclic or bicyclic aromatic heterocycle and having 1 to 5 heteroatoms selected from the group consisting of oxygen, sulfur, and nitrogen atoms. In the case of a bicyclic heteroaryl group, if one of the rings is an aromatic ring or an aromatic heterocycle, the other ring may have a ring structure which is not aromatic. The numbers of the respective heteroatoms and their combination in such a heteroaryl group are not particularly limited as long as they can form part of a ring of a predetermined number of members and exist chemically stably. Such heteroaryl groups include, for example, pyridyl, pyrazyl, pyrimidyl, pyridazinyl, furyl, thienyl, pyrazolyl, 1,3-dioxaindanyl, isoxazolyl, isothiazolyl, benzofuranyl, isobenzofuryl, benzothienyl, indolyl, isoindolyl, chromanyl, benzothiazolyl, benzimidazolyl, benzoxazolyl, pyranyl, imidazolyl, oxazolyl, thiazolyl, triazinyl, triazolyl, furazanyl, thiadiazolyl, dihydrobenzofuryl, dihydroisobenzofuryl, dihydroquinolyl, dihydroisoquinolyl, dihydrobenzoxazolyl, dihydropteridinyl, benzoxazolyl, benzisoxazolyl, benzodioxazolyl, quinolyl, isoquinolyl, benzotriazolyl, pteridinyl, purinyl, quinoxalinyl, quinazolinyl, cinnolinyl, tetrazolyl groups, and the like.
[0033] For the purpose of the present invention, a “halogen atom” means a fluorine, chlorine, bromine, or iodine atom.
[0034] For the purpose of the present invention, an “alkyl group” means a monovalent saturated linear or branched aliphatic hydrocarbon group. C 1-6 alkyl groups include, for example, methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, isopropyl, isobutyl, s-butyl, t-butyl, isopentyl, 2-methylbutyl, neopentyl, 1-ethylpropyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl, 1-ethylbutyl, 2-ethylbutyl, t-pentyl, isohexyl groups, and the like.
[0035] For the purpose of the present invention, an “alkylene group” means a divalent saturated linear or branched aliphatic hydrocarbon group having 1 to 6 carbon atoms. C 1-6 alkylene groups include, for example, methylene, ethylene, n-propylene, isopropylene, n-pentylene, n-hexylene groups, and the like.
[0036] For the purpose of the present invention, a “cycloalkyl group” means a cyclic saturated hydrocarbon group. C 3-7 cycloalkyl groups include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl groups, and the like.
[0037] For the purpose of the present invention, a “halogenoalkyl group” means an alkyl group substituted with one or more halogens. C 1-6 halogenoalkyl groups include, for example, trifluoromethyl, difluoromethyl groups, and the like.
[0038] For the purpose of the present invention, a “nitrogen-containing saturated monocyclic heterocycle” means a 5- to 8-membered saturated or partially unsaturated monocyclic heterocycle which contains one nitrogen atom and may further contain one heteroatom selected from the group consisting of nitrogen, sulfur, and oxygen atoms, and includes, for example, pyrrolidine, piperidine, piperazine, azepane, diazepane, azocane, morpholine, thiomorpholine, tetrahydropyridine rings, and the like.
[0039] In the foregoing “nitrogen-containing saturated monocyclic heterocycle,” a sulfur atom, which is a ring atom, may be oxidized to form an oxide or a dioxide, or a nitrogen atom may be oxidized to form an oxide.
[0040] In the present invention, a “protective group of a carboxyl group” is, for example, a general protective group of a carboxyl group, which is described in PROTECTIVE GROUPS IN ORGANIC SYNTHESIS, THIRD EDITION, John Wiley & Sons. Inc. Examples of the protective group include methyl group, ethyl group, isopropyl group, heptyl group, t-butyl group, methoxymethyl group, methylthiomethyl group, methoxyethoxymethyl group, methoxyethyl group, benzyl group, t-butyldimethylsilyl groups, and the like.
[0041] In the foregoing formula (I), A represents a C 6-10 aryl group or a heteroaryl group, wherein the aryl group or heteroaryl group may be unsubstituted or substituted with 1 to 3 groups Q which are the same or different from one another and selected from the group consisting of a halogen atom, —CN, —NO 2 , a C 1-6 alkyl group, a C 3-7 cycloalkyl group, a C 1-6 halogenoalkyl group, a phenyl group, —CH 2 —O—R 2 , —O—R 2 , —O—C 1-6 halogenoalkyl, —O-benzyl, —O-phenyl, —O—CO—R 2 , —NR 3 R 4 , —NH—CO—R 2 , —CO 2 —R 2 , —CO—R 2 , —CO—NR 3 R 4 , —NH—SO 2 —R 2 , —CO-aryl, —S—R 2 , —SO 2 —C 1-6 alkyl, and —SO 2 -phenyl;
[0042] Although specific examples of the “aryl group” and the “heteroaryl group” are as defined above, preferred “aryl groups” or “heteroaryl groups” for A include phenyl, pyridyl, pyrazyl, pyrimidyl, furyl, thienyl, isoxazolyl, isothiazolyl, benzofuranyl, benzothienyl, benzothiazolyl, benzimidazolyl, benzoxazolyl, pyranyl, imidazolyl, oxazolyl, thiazolyl, triazinyl, triazolyl, benzoxazolyl, benzisoxazolyl groups, and the like, and more preferred are phenyl and thienyl groups.
[0043] A may be unsubstituted or substituted with 1 to 3 groups Q which are the same or different from one another and selected from the group consisting of a halogen atom, —CN, —NO 2 , a C 1-6 alkyl group, a C 3-7 cycloalkyl group, a C 1-6 halogenoalkyl group, a phenyl group, —CH 2 —O—R 2 , —O—R 2 , —O—C 1-6 halogenoalkyl, —O-benzyl, —O-phenyl, —O—CO—R 2 , —NR 3 R 4 , —NH—CO—R 2 , —CO 2 —R 2 , —CO—R 2 , —CO—NR 3 R 4 , —NH—SO 2 —R 2 , —CO-aryl, —S—R 2 , —SO 2 —C 1-6 alkyl, and —SO 2 -phenyl. In the case where A is substituted with Q, the number of Q is preferably 1 or 2. It is preferred that A is unsubstituted or substituted with group(s) Q selected from the group consisting of a halogen atom, a C 1-6 alkyl group, a C 3-7 cycloalkyl group, a C 1-6 halogenoalkyl group, a phenyl group, —O—R 2 , and —O—C 1-6 halogenoalkyl. It is more preferred that A is unsubstituted or substituted with group(s) Q selected from the group consisting of a halogen atom, a methyl group, and a methoxy group. As the halogen atom, a fluorine atom is preferred.
[0044] Particularly preferred A can be represented, for example, by the following structural formulae.
[0000]
[0045] In the foregoing formula (I), R represents a hydrogen atom or a C 1-6 alkyl group. Although specific examples of the “C 1-6 alkyl group” are as defined above, preferred “C 1-6 alkyl groups” include methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, isopropyl, isobutyl, s-butyl, t-butyl, isopentyl, 2-methylbutyl, neopentyl, 1-ethylpropyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl, 1-ethylbutyl, 2-ethylbutyl, t-pentyl, isohexyl groups, and the like. R is more preferably a hydrogen atom or a methyl group, and particularly preferably a hydrogen atom.
[0046] In the foregoing formula (I), R 1 represents a hydrogen atom, an amino group or a C 1-6 alkyl group. Although specific examples of the “C 1-6 alkyl group” are as defined above, preferred “C 1-6 alkyl groups” include methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, isopropyl, isobutyl, s-butyl, t-butyl, isopentyl, 2-methylbutyl, neopentyl, 1-ethylpropyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl, 1-ethylbutyl, 2-ethylbutyl, t-pentyl, isohexyl groups, and the like. R 1 is more preferably a hydrogen atom, an amino group or a methyl group, and particularly preferably a hydrogen atom.
[0047] In the foregoing formula (I), R 2 represents a hydrogen atom, an amino group or a C 1-6 alkyl group. Although specific examples of the “C 1-6 alkyl group” are as defined above, preferred “C 1-6 alkyl groups” include methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, isopropyl, isobutyl, s-butyl, t-butyl, isopentyl, 2-methylbutyl, neopentyl, 1-ethylpropyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl, 1-ethylbutyl, 2-ethylbutyl, t-pentyl, isohexyl groups, and the like. R 2 is more preferably a hydrogen atom or a methyl group, and particularly preferably a methyl group.
[0048] In the foregoing formula (I), R 3 and R 4 are the same or different from each other and are a hydrogen atom or a C 1-6 alkyl group, where R 3 and R 4 may be taken together to form with the nitrogen atom to which they are attached a nitrogen-containing saturated monocyclic heterocycle. Although specific examples of the “C 1-6 alkyl group” and the “nitrogen-containing saturated monocyclic heterocycle” are as defined above, preferred “C 1-6 alkyl groups” include methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, isopropyl, isobutyl, s-butyl, t-butyl, isopentyl, 2-methylbutyl, neopentyl, 1-ethylpropyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl, 1-ethylbutyl, 2-ethylbutyl, t-pentyl, isohexyl groups, and the like, and preferred “nitrogen-containing saturated monocyclic heterocycles” include pyrrolidine, piperidine, piperazine, azepane, diazepane, azocane, morpholine, thiomorpholine, tetrahydropyridine rings, and the like. More preferred as R 3 , R 4 , and “nitrogen-containing saturated monocyclic heterocycles” are a hydrogen atom, a methyl group, pyrrolidine, piperidine, piperazine, and morpholine, and particularly preferred are a hydrogen atom, a methyl group, and morpholine.
[0049] In the foregoing formula (I), X, Y, and Z represent CR 5 or a nitrogen atom, wherein one of X, Y, and Z represents a nitrogen atom and the remaining two represent CR 5 . The three cases where each one of X, Y, and Z is a nitrogen atom can be represented by the following structural formulae. Among these, the one where Y is a nitrogen atom is preferred.
[0000]
[0050] R 5 includes a hydrogen atom, a halogen atom, or a C 1-6 alkyl group, and a hydrogen atom is preferred.
[0051] In the foregoing formula (I), as a combination of A, Q, R, R 1 , R 2 , R 3 , R 4 , R 5 , X, Y, and Z, a combination of preferred groups, each of which is described above, is preferred, and a combination of groups which are described as more preferred is more preferred. A combination where A and R 1 in the structure of formula (I) of the combination of groups which are described as more preferred are replaced by particularly preferred groups is particularly preferred.
[0052] The compounds of the present invention are those that exhibit excellent xanthine oxidase inhibitory activity. In addition, the compounds of the present invention have excellent uric acid-lowering effects. Furthermore, the compounds of the present invention have prolonged sustained uric acid-lowering effects.
[0053] Specific examples of preferred compounds can include the following compounds.
[0000] Compound No. Structure Name 1 1-(4-cyano-5-phenylpyridin-2- yl)-1H-pyrazole-4-carboxylic acid 2 1-[4-cyano-5-(4- methoxyphenyl)pyridin-2-yl]-1H- pyrazole-4-carboxylic acid 3 1-[4-cyano-5-(2- ethoxyphenyl)pyridin-2-yl]-1H- pyrazole-4-carboxylic acid 4 1-[4-cyano-5-(2- methylphenyl)pyridin-2-yl]-1H- pyrazole-4-carboxylic acid 5 1-[4-cyano-5-(2- fluorophenyl)pyridin-2-yl]-1H- pyrazole-4-carboxylic acid 6 1-[4-cyano-5-(2- chlorophenyl)pyridin-2-yl]-1H- pyrazole-4-carboxylic acid 7 1-[4-cyano-5-(2- methoxyphenyl)pyridin-2-yl]-1H- pyrazole-4-carboxylic 8 1-{4-cyano-5-[2- (trifluoromethyl)phenyl]pyridin-2- yl}-1H-pyrazole-4-carboxylic acid 9 1-{4-cyano-5-[2- (trifluoromethoxy)phenyl]pyridin- 2-yl]-1H-pyrazole-4-carboxylic acid 10 1-[4-cyano-5-(3- methylphenyl)pyridin-2-yl]-1H- pyrazole-4-carboxylic acid 11 1-[4-cyano-5-(3- fluorophenyl)pyridin-2-yl]-1H- pyrazole-4-carboxylic acid 12 1-[4-cyano-5-(3- chlorophenyl)pyridin-2-yl]-1H- pyrazole-4-carboxylic acid 13 1-[4-cyano-5-(3- methoxyphenyl)pyridin-2-yl]-1H- pyrazole-4-carboxylic acid 14 1-[4-cyano-5-(4- methylphenyl)pyridin-2-yl]-1H- pyrazole-4-carboxylic acid 15 1-[4-cyano-5-(4- chlorophenyl)pyridin-2-yl]-1H- pyrazole-4-carboxylic acid 16 1-[4-cyano-5-(4- hydroxyphenyl)pyridin-2-yl]-1H- pyrazole-4-carboxylic acid 17 1-[4-cyano-5-(2-ethoxy-6- fluorophenyl)pyridin-2-yl]-1H- pyrazole-4-carboxylic acid 18 1-[4-cyano-5-(2-fluoro-6- methoxyphenyl)pyridin-2-yl]-1H- pyrazole-4-carboxylic acid 19 1-[4-cyano-5-(2-fluoro-3- methoxyphenyl)pyridin-2-yl]-1H- pyrazole-4-carboxylic acid 20 1-[4-cyano-5-(2,3- difluorophenyl)pyridin-2-yl]-1H- pyrazole-4-carboxylic acid 21 1-[4-cyano-5-(thiophen-3- yl)pyridin-2-yl]-1H-pyrazole-4- carboxylic acid 22 1-[4-cyano-5-(3- methylthiophen-2-yl)pyridin-2- yl]-1H-pyrazole-4-carboxylic acid 23 1-[4-cyano-5-(furan-3- yl)pyridin-2-yl]-1H-pyrazole-4- carboxylic acid 24 1-[4-cyano-5-(3-methoxypyridin- 4-yl)pyridin-2-yl]-1H-pyrazole-4- carboxylic acid 25 1-[4-cyano-5-(pyridin-3- yl)pyridin-2-yl]-1H-pyrazole-4- carboxylic acid 26 1-(4-cyano-5-phenylpyridin-2- yl)-3-methyl-1H-pyrazole-4- carboxylic acid 27 1-(4-cyano-5-phenylpyridin-2- yl)-3-(propan-2-yl)-1H-pyrazole- 4-carboxylic acid 28 1-(4-cyano-5-phenylpyridin-2- yl)-3,5-dimethyl-1H-pyrazole-4- carboxylic acid 29 1-[4-cyano-5-(4- fluorophenyl)pyridin-2-yl]-1H- pyrazole-4-carboxylic acid 30 1-[4-cyano-5-(3- ethoxyphenyl)pyridin-2-yl]-1H- pyrazole-4-carboxylic acid 31 1-[4-cyano-5-(3- propoxyphenyl)pyridin-2-yl]-1H- pyrazole-4-carboxylic acid 32 1-[4-cyano-5-(2,4- difluorophenyl)pyridin-2-yl]-1H- pyrazole-4-carboxylic acid 33 1-[4-cyano-5-(2-fluoro-4- methylphenyl)pyridin-2-yl]-1H- pyrazole-4-carboxylic acid 34 1-[4-cyano-5-(2-fluoro-5- methylphenyl)pyridin-2-yl]-1H- pyrazole-4-carboxylic acid 35 1-[4-cyano-5-(2,5- difluorophenyl)pyridin-2-yl]-1H- pyrazole-4-carboxylic acid 36 1-[4-cyano-5-(2-fluoro-3- methylphenyl)pyridin-2-yl]-1H- pyrazole-4-carboxylic acid 37 1-[4-cyano-5-(4-fluoro-3- methylphenyl)pyridin-2-yl]-1H- pyrazole-4-carboxylic acid 38 1-[4-cyano-5-(2,3- dimethylphenyl)pyridin-2-yl]-1H- pyrazole-4-carboxylic acid 39 1-[4-cyano-5-(3-fluoro-4- methylphenyl)pyridin-2-yl]-1H- pyrazole-4-carboxylic acid 40 1-[4-cyano-5-(3-chloro-4- fluorophenyl)pyridin-2-yl]-1H- pyrazole-4-carboxylic acid 41 1-[4-cyano-5-(3-chloro-2- fluorophenyl)pyridin-2-yl]-1H- pyrazole-4-carboxylic acid 42 1-[5-(4-carboxyphenyl)-4- cyanopyridin-2-yl]-1H-pyrazole- 4-carboxylic acid 43 1-{4-cyano-5-[4- (trifluoromethyl)phenyl]pyridin-2- yl}-1H-pyrazole-4-carboxylic acid 44 1-{4-cyano-5-[4- (trifluoromethoxy)phenyl]pyridin- 2-yl}-1H-pyrazole-4-carboxylic acid 45 1-{4-cyano-5-[3- (trifluoromethyl)phenyl]pyridin-2- yl}-1H-pyrazole-4-carboxylic acid 46 1-{4-cyano-5-[3- (difluoromethoxy)phenyl]pyridin-2- yl}-1H-pyrazole-4-carboxylic acid 47 1-[4-cyano-5-[4-(propane-2- yl)phenyl]pyridin-2-yl}-1H- pyrazole-4-carboxylic acid 48 1-{4-cyano-5-[3-(propane-2- yl)phenyl]pyridine-2-yl}-1H- pyrazole-4-carboxylic acid 49 1-[4-cyano-5-(4-fluoro-2- methylphenyl)pyridin-2-yl]-1H- pyrazole-4-carboxylic acid 50 1-[4-cyano-5-(4-fluoro-2- methoxyphenyl)pyridin-2-yl]-1H- pyrazole-4-carboxylic acid 51 1-[4-cyano-5-(4-chloro-3- methylphenyl)pyridin-2-yl]-1H- pyrazole-4-carboxylic acid 52 1-{4-cyano-5-[4-propan-2- yloxy)phenyl]pyridin-2-yl}-1H- pyrazole-4-carboxylic acid 53 1-[5-(4-tert-butylphenyl)-4- cyanopyridin-2-yl]-1H-pyrazole- 4-carboxylic acid 54 1-[4-cyano-5-(4- phenoxyphenyl)pyridin-2-yl]-1H- pyrazole-4-carboxylic acid 55 1-{4-cyano-5-[4- (methoxymethyl)phenyl]pyridin-2- yl}-1H-pyrazole-4-carboxylic acid 56 1-{4-cyano-5-[3-(propane-2- yl)phenyl]pyridine-2-yl}-1H- pyrazole-4-carboxylic acid 57 1-[4-cyano-5-(naphthalen-2- yl)pyridin-2-yl]-1H-pyrazole-4- carboxylic acid 58 1-[4-cyano-5-(4-methoxypyridin- 3-yl)pyridin-2-yl]-1H-pyrazole-4- carboxylic acid 59 1-{4-cyano-5-[6- (dimethylamino)pyridin-3- yl]pyridin-2-yl}-1H-pyrazole-4- carboxylic acid 60 1-[4-cyano-5-(5-fluoropyridin-3- yl)pyridin-2-yl]-1H-pyrazole-4- carboxylic acid 61 1-[5-(1-benzothiophen-3-yl)-4- cyanopyridin-2-yl]-1H-pyrazole- 4-carboxylic acid 62 1-[4-cyano-5-(pyridin-4- yl)pyridin-2-yl]-1H-pyrazole-4- carboxylic acid 63 1-{4-cyano-5-[4- (methylsulfanyl)phenyl]pyridin-2- yl}-1H-pyrazole-4-carboxylic acid 64 1-{4-cyano-5-[4-(morpholine-4- yl)phenyl]pyridine-2-yl}-1H- pyrazole-4-carboxylic acid 65 1-[4-cyano-5-(4- phenylphenyl)pyridine-2-yl]-1H- pyrazole-4-carboxyic acid 66 1-{5-[4-(benzyloxy)phenyl]-4- cyanopyridine-2-yl}-1H-pyrazole- 4-carboxylic acid 67 1-{4-cyano-5-[3- (dimethylamino)phenyl]pyridine-2- yl}-1H-pyrazole-4-carboxylic acid 68 1-[5-(4-aminophenyl)-4- cyanopyridine-2-yl]-1H-pyrazole- 4-carboxylic acid 69 1-[4-cyano-5-(4- methanesulfonamidophenyl)pyridine- 2-yl]-1H-pyrazole-4-carboxylic acid 70 1-(4-cyano-5-{4-[(morpholine-4- yl)carbonyl]phenyl}pyridine-2-yl)- 1H-pyrazole-4-carboxylic acid 71 1-[5-(4-acetophenyl)-4- cyanopyridin-2-yl]-1H-pyrazole- 4-carboxylic acid 72 1-[4-cyano-5-(3- nitrophenyl)pyridin-2-yl]-1H- pyrazole-4-carboxylic acid 73 1-[5-(4-benzoylphenyl)-4- cyanopyridin-2-yl]-1H-pyrazole- 4-carboxylic acid 74 1-[4-cyano-5-(4- methanesulfonylphenyl)pyridin-2- yl]-1H-pyrazole-4-carboxylic acid 75 1-(5-cyano-6-phenylpyridin-3- yl)-1H-pyrazole-4-carboxylic acid 76 1-[5-cyano-6-(2- fluorophenyl)pyridin-3-yl]-1H- pyrazole-4-carboxylic acid 77 1-[5-cyano-6-(2,4- difluorophenyl)pyridin-3-yl]-1H- pyrazole-4-carboxylic acid 78 1-[5-cyano-6-(2-fluoro-4- methylphenyl)pyridin-3-yl]-1H- pyrazole-4-carboxylic acid 79 1-[5-cyano-6-(2-fluoro-5- methylphenyl)pyridin-3-yl]-1H- pyrazole-4-carboxylic acid 80 1-[5-cyano-6-(2,5- difluorophenyl)pyridin-3-yl]-1H- pyrazole-4-carboxylic acid 81 1-[5-cyano-6-(2,3- difluorophenyl)pyridin-3-yl]-1H- pyrazole-4-carboxylic acid 82 1-[5-cyano-6-(4-fluoro-3- methylphenyl)pyridin-3-yl]-1H- pyrazole-4-carboxyic acid 83 1-[5-cyano-6-(3-fluoro-4- methylphenyl)pyridin-3-yl]-1H- pyrazole-4-carboxylic acid 84 1-[5-cyano-6-(2-fluoro-5- methoxyphenyl)pyridin-3-yl]-1H- pyrazole-4-carboxylic acid 85 1-(6-cyano-5-phenylpyridin-2- yl)-1H-pyrazole-4-carboxylic acid 86 1-[6-cyano-5-(2- fluorophenyl)pyridin-2-yl]-1H- pyrazole-4-carboxylic acid 87 1-[6-cyano-5-(2-fluoro-4- methylphenyl)pyridin-2-yl]-1H- pyrazole-4-carboxylic acid 88 1-[6-cyano-5-(2-fluoro-5- methylphenyl)pyridin-2-yl]-1H- pyrazole-4-carboxylic acid 89 1-[6-cyano-5-(2-fluoro-5- methylphenyl)pyridin-2-yl]-1H- pyrazole-4-carboxylic acid 90 1-[6-cyano-5-(2,4- difluorophenyl)pyridin-2-yl]-1H- pyrazole-4-carboxylic acid 91 1-[6-cyano-5-(2-fluoro-5- methoxyphenyl)pyridin-2-yl]-1H- pyrazole-4-carboxylic acid 92 1-[6-cyano-5-(3- methylphenyl)pyridin-2-yl]-1H- pyrazole-4-carboxylic acid 93 1-[6-cyano-5-(3- ethoxyphenyl)pyridin-2-yl]-1H- pyrazole-4-carboxylic acid 94 1-[6-cyano-5-(4-fluoro-3- methylphenyl)pyridin-2-yl]-1H- pyrazole-4-carboxylic acid 95 1-[6-cyano-5-(2,6- difluorophenyl)pyridin-2-yl]-1H- pyrazole-4-carboxylic acid 96 1-[6-cyano-5-(2-fluoro-6- methoxyphenyl)pyridin-2-yl]-1H- pyrazole-4-carboxylic acid 97 3-amino-1-(4-cyano-5- phenylpyridin-2-yl)-1H-pyrazole- 4-carboxylic acid 98 3-amino-1-[4-cyano-5-(2- fluorophenyl)pyridin-2-yl]-1H- pyrazole-4-carboxylic acid 99 3-amino-1-[4-cyano-5-(4- fluorophenyl)pyridin-2-yl]-1H- pyrazole-4-carboxylic acid 100 3-amino-1-[4-cyano-5-(4- chlorophenyl)pyridin-2-yl]-1H- pyrazole-4-carboxylic acid 101 3-amino-1-[4-cyano-5-(3- methylphenyl)pyridin-2-yl]-1H- pyrazole-4-carboxylic acid 102 3-amino-1-[4-cyano-5-(3- methoxyphenyl)pyridin-2-yl]-1H- pyrazole-4-carboxylic acid 103 3-amino-1-[4-cyano-5-(2- fluoro-4-methylphenyl)pyridin-2- yl]-1H-pyrazole-4-carboxylic acid 104 3-amino-1-[4-cyano-5-(2- fluoro-5-methylphenyl)pyridin-2- yl]-1H-pyrazole-4-carboxylic acid 105 3-amino-1-[4-cyano-5-(2,4- difluorophenyl)pyridin-2-yl]-1H- pyrazole-4-carboxylic acid 106 3-amino-1-[4-cyano-5-(4- fluoro-3-methylphenyl)pyridin-2- yl]-1H-pyrazole-4-carboxylic acid 107 3-amino-1-[4-cyano-5-(2- fluoro-5-methoxyphenyl)pyridine- 2-yl]-1H-pyrazole-4-carboxylic acid
Comp. No. denotes compound number in the above tables.
[0054] Of these compounds, more preferred are compounds 1, 2, 5, 6, 7, 10, 13, 14, 15, 16, 19, 20, 21, 22, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 41, 42, 43, 44, 47, 48, 50, 51, 52, 53, 54, 55, 57, 59, 61, 63, 64, 65, 66, 68, 69, 70, 71, 73, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, and 107, and further preferred are compounds 1, 5, 10, 14, 19, 21, 33, 97, and 98.
[0055] In the compound represented by the foregoing formula (II) which can be used as an intermediate in the manufacture of the compounds represented by the foregoing formula (I) of the present invention, the definitions of A, Q, R, R 1 , R 2 , R 3 , R 4 , R 5 , X, Y, and Z are the same as those in the foregoing formula (I). W represents a halogen atom, a methanesulfonyloxy group, a p-toluenesulfonyloxy group, a trifluoromethanesulfonyloxy group, or a cyano group. W is more preferably a halogen atom or a cyano group, and particularly preferably a cyano group. R 6 represents a carboxyl-protecting group. The definition of the carboxyl-protecting group is as set out above, and it is preferably a methyl, ethyl, or benzyl group.
[0056] Further, in the compound represented by the foregoing formula (III) which can be used as an intermediate in the manufacture of the compounds represented by the foregoing formula (I) of the present invention, the definitions of R, R 1 , R 5 , X, Y and Z are the same as those in the foregoing formula (I). V represents a halogen atom, a methanesulfonyloxy group, a p-toluenesulfonyloxy group, a trifluoromethanesulfonyloxy group, a hydroxyl group, or a benzyloxy group. V is preferably a halogen atom, a trifluoromethanesulfonyloxy group, a hydroxyl group, or a benzyloxy group. W represents a halogen atom, a methanesulfonyloxy group, a p-toluenesulfonyloxy group, a trifluoromethanesulfonyloxy group, or a cyano group. W is more preferably a halogen atom or a cyano group, and particularly preferably a cyano group. R 6 represents a carboxyl-protecting group. The definition of the carboxyl-protecting group is as set out above, and it is preferably a methyl, ethyl, or benzyl group.
[0057] In the compound represented by the foregoing formula (IV) which can be used as an intermediate in the manufacture of the compounds represented by the foregoing formula (I) of the present invention, the definitions of A, Q, R 2 , R 3 , R 4 , R 5 , X, Y, and Z are the same as those in the foregoing formula (I). X 2 represents a halogen atom, a methanesulfonyloxy group, a p-toluenesulfonyloxy group or a trifluoromethanesulfonyloxy group. A halogen atom is preferable.
<General Synthetic Methods>
[0058] Compounds of formula (I) of the present invention and intermediates can be synthesized according, for example, to any of the synthetic methods as described below. It should be noted that, in each formula, A, R, R 1 , Q, X, Y, and Z are as defined for formula (I). In addition, the reagents, solvents, etc. shown in chemical formulae as conditions are merely illustrative, as mentioned also in the text. If necessary, each substituent may be protected with an appropriate protecting group and may be deprotected at an appropriate stage. It should be noted that, as appropriate protecting groups and methods for their removal, protecting groups of each substituent which are widely used in the art and known methods, for example those described in PROTECTIVE GROUPS in ORGANIC SYNTHESIS, THIRD EDITION, John Wiley & Sons, Inc., may be employed.
[0059] In addition, when abbreviations are used for substituents, reagents, and solvents in the text or in tables, they stand for the following.
DMF: N,N-dimethylformamide
[0060] THF: tetrahydrofuran
Ph: phenyl
TFA: trifluoroacetic acid
Synthetic Method (A)
Synthesis of Compound (A-2)
[0061]
[0000] (In the formulae, X 1 and X 2 represent leaving groups) Leaving groups represented by X 1 and X 2 include a halogen atom, a methanesulfonyloxy group, a p-toluenesulfonyloxy group, a trifluoromethanesulfonyloxy group, and the like. This reaction is a method for synthesizing compound (A-2) by lithiation or sodiation of the 4-position of the pyridine of compound (A-1) using base, followed by formylation using a formylating agent. Bases include lithium diisopropylamine (LDA) prepared from diisopropylamine and n-butyllithium, and the like. Formylating agents include N,N-dimethylformamide (DMF), N-formylmorpholine, and the like. This reaction is carried out by reacting compound (A-1) with an equivalent amount or a small excess of a base in an inert solvent at −78° C. to 0° C., then adding an equivalent amount or an excess of formylating agent, and allowing them to react for normally 0.5 to 5 hours. It is preferred that this reaction is performed under an inert gas atmosphere such as nitrogen. Solvents here include, though not particularly limited, for example, ethers such as diethyl ether, tetrahydrofuran (THF), 1,4-dioxane, 1,2-dimethoxyethane, and 1,2-diethoxyethane, or a mixed solvent thereof, and the like.
Synthesis of Compound (A-4)
[0062]
[0000] (In the formulae, X 1 and X 2 represent leaving groups, and Y 1 represents —B(OH) 2 or —B(OR 7 )OR 8 , wherein R 7 and R 8 are the same or different from each other and represent C 1-6 alkyl groups, or R 7 and R 8 are taken together to represent a C 1-6 alkylene group.) This reaction is a method for synthesizing compound (A-4) by coupling compounds (A-2) and (A-3). The leaving groups represented by X 1 and X 2 include a halogen atom, a methanesulfonyloxy group, a p-toluenesulfonyloxy group, a trifluoromethanesulfonyloxy group, and the like. This reaction is carried out by using equivalent amounts of compounds (A-2) and (A-3) or by using either one in excess and allowing them to react in an inert solvent in the presence of a base and a palladium catalyst between room temperature and heating under reflux for normally 0.5 to 2 days. It is preferred that this reaction is performed under an inert gas atmosphere such as nitrogen. Solvents here include, though not particularly limited, for example, aromatic hydrocarbons such as benzene, toluene, and xylene, ethers such as diethyl ether, tetrahydrofuran (THF), 1,4-dioxane, 1,2-dimethoxyethane, and 1,2-diethoxyethane, halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane, and chloroform, alcohols such as methanol, ethanol, 2-propanol, and butanol, N,N-dimethylformamide (DMF), N-methylpyrrolidone, dimethyl sulfoxide (DMSO), water, or a mixed solvent thereof, and the like. Bases include sodium hydroxide, potassium hydroxide, lithium hydroxide, inorganic salts such as sodium carbonate, potassium carbonate, cesium carbonate, and tripotassium phosphate, metal alkoxides such as sodium ethoxide and sodium methoxide, or solutions obtained by diluting these bases with water etc., and the like. As the palladium catalyst, tetrakis(triphenylphosphine)palladium, dichlorobis(triphenylphosphine)palladium, palladium chloride-1,1′-bis(diphenylphosphino)ferrocene, or the like is preferred.
Synthesis of Compound (A-5)
[0063]
[0000] (In the formulae, X 2 represents a leaving group.) Leaving groups represented by X 2 include a halogen atom, a methanesulfonyloxy group, a p-toluenesulfonyloxy group, a trifluoromethanesulfonyloxy group, and the like. This reaction is a conversion reaction of the formyl group into a cyano group and is carried out by reacting the aromatic aldehyde derivative represented by the above formula (A-4) with hydroxylamine. As the hydroxylamine, such as the hydrochloride may be used; in that case, however, it is preferred that an appropriate basic substance is added. In addition, it is possible to accelerate the reaction by adding 1.0 to 3.0 equivalents of acetic anhydride, acetyl chloride, trichloroacetyl chloride, and the like. The amount of hydroxylamine or its salts used in this reaction is normally 1 or more equivalents and preferably 1.0 to 2.0 equivalents. When a basic substance is used, 1.0 to 3.0 equivalents relative to the salt of hydroxylamine are used. As the basic substance used, a carboxylate such as sodium formate, potassium formate, or sodium acetate, a carbonate such as potassium carbonate, sodium carbonate, or sodium hydrogencarbonate, or an organic amine base such as triethylamine, pyridine, or 4-aminopyridine is used. The reaction is carried out by allowing the reactants to react in an inert solvent in the presence of a base between room temperature and heating under reflux for normally 0.5 hours to 3 days. It is preferred that this reaction is performed under an inert gas atmosphere such as nitrogen. Solvents used in this reaction include solvents such as acetic acid, formic acid, toluene, benzene, pyridine, ethyl acetate, dichloromethane, 1,2-dichloroethane, chloroform, carbon tetrachloride, diethyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, 1,2-diethoxyethane, N,N-dimethylformamide (DMF), N-methylpyrrolidone, dimethyl sulfoxide (DMSO), methanol, ethanol, and 2-propanol.
Synthesis of Compound (A-7)
[0064]
[0000] (In the formulae, R 6 represents a carboxyl-protecting group and X 2 represents a leaving group.) The leaving groups represented by X 2 include a halogen atom, a methanesulfonyloxy group, a p-toluenesulfonyloxy group, a trifluoromethanesulfonyloxy group, and the like. This reaction is carried out by using equivalent amounts of compounds (A-5) and (A-6) or by using either one in excess and allowing them to react in a reaction inert solvent in the presence of a base catalyst between room temperature and heating under reflux for normally 0.5 to 3 days. It is preferred that this reaction is performed under an inert gas atmosphere such as nitrogen. Solvents here include, not particularly limited, for example, aromatic hydrocarbons such as benzene, toluene, and xylene, ethers such as diethyl ether, tetrahydrofuran (THF), 1,4-dioxane, 1,2-dimethoxyethane, and 1,2-diethoxyethane, halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane, and chloroform, N,N-dimethylformamide (DMF), N-methylpyrrolidone, dimethyl sulfoxide (DMSO) or a mixed solvent thereof, and the like. Bases include sodium hydride, sodium hydroxide, potassium hydroxide, lithium hydroxide, inorganic salts such as sodium carbonate, potassium carbonate, cesium carbonate, metal alkoxides such as sodium ethoxide and sodium methoxide, or an organic amine base such as triethylamine, N-ethyl-N,N-diisopropylamine (DIPEA) or 1,8-diazabicyclo[5.4.0)-7-undecene (DBU), and the like.
Synthesis of Compound (A-8)
[0065]
[0000] (In the formulae, R 6 represents a carboxyl-protecting group.) This synthetic method is a method for synthesizing the compound (A-8) of the invention by deprotecting the protecting group R 6 of compound (A-7) using an acid or a base etc.
[0066] This reaction is carried out by allowing compound (A-7) to react with an equivalent amount or an excess of acid or base in an inert solvent between room temperature and heating under reflux for normally 0.5 to 5 days. It is preferred that this reaction is performed under an inert gas atmosphere such as nitrogen. Solvents here include, though not particularly limited, for example, aromatic hydrocarbons such as benzene, toluene, and xylene, ethers such as diethyl ether, tetrahydrofuran (THF), 1,4-dioxane, 1,2-dimethoxyethane, and 1,2-diethoxyethane, halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane, and chloroform, alcohols such as methanol, ethanol, 2-propanol, and butanol, N,N-dimethylformamide (DMF), N-methylpyrrolidone, dimethyl sulfoxide (DMSO), water, or a mixed solvent thereof, and the like. Acids include inorganic acids such as hydrogen chloride, hydrogen bromide, sulfuric acid, nitric acid, phosphoric acid or a solution of the acids diluted with water or organic solvents. Bases include sodium hydroxide, potassium hydroxide, lithium hydroxide, inorganic salts such as sodium carbonate, potassium carbonate, cesium carbonate, and tripotassium phosphate, metal alkoxides such as sodium ethoxide and sodium methoxide, or solutions obtained by diluting these bases with water etc., and the like.
[0067] Compound (A-7), for example, can be synthesized also according to the Synthetic Method (B) described below.
Synthetic Method (B)
Synthesis of Compound (B-1)
[0068]
[0000] (In the formulae, X 1 and X 2 represent leaving groups. R 9 and R 10 are the same or different from each other and represent C 1-6 alkyl groups, or R 9 and R 10 are taken together to represent a C 1-6 alkylene group.) Leaving groups represented by X 1 and X 2 include a halogen atom, a methanesulfonyloxy group, a p-toluenesulfonyloxy group, a trifluoromethanesulfonyloxy group, and the like. This reaction is carried out by allowing compound (A-2) to react with an equivalent amount or an excess of alcohol or trialkyl orthoformate in an inert solvent in the presence of an acid between room temperature and heating under reflux for normally 0.5 to 2 days. As the acid here, a Brønsted acid such as hydrogen chloride, trifluoroacetic acid, tosylsulfonic acid, or camphorsulfonic acid, a Lewis acid such as trimethylsilyl trifluorosulfonate or trifluoroborane, or the like is used. Solvents used in this reaction include, for example, aromatic hydrocarbons such as benzene, toluene, and xylene, ethers such as diethyl ether, tetrahydrofuran (THF), 1,4-dioxane, 1,2-dimethoxyethane, and 1,2-diethoxyethane, halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane, chloroform, and carbon tetrachloride, alcohols such as methanol, ethanol, and 2-propanol, or a mixed solvent thereof, and the like.
Synthesis of Compound (B-2)
[0069]
[0000] (In the formulae, R 6 represents a carboxyl-protecting group, and X 1 and X 2 represent leaving groups. R 9 and R 10 are the same or different from each other and represent C 1-6 alkyl groups, or R 9 and R 10 are taken together to represent a C 1-6 alkylene group.) Leaving groups represented by X 1 and X 2 include a halogen atom, a methanesulfonyloxy group, a p-toluenesulfonyloxy group, a trifluoromethanesulfonyloxy group, and the like. This reaction is carried out by using equivalent amounts of compounds (B-1) and (A-6) or by using either one in excess and allowing them to react in an inert solvent in the presence of a base catalyst between room temperature and heating under reflux for normally 0.5 hours to 3 days. It is preferred that this reaction is performed under an inert gas atmosphere such as nitrogen. Solvents here include, though not particularly limited, for example, aromatic hydrocarbons such as benzene, toluene, and xylene, ethers such as diethyl ether, tetrahydrofuran (THF), 1,4-dioxane, 1,2-dimethoxyethane, and 1,2-diethoxyethane, halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane, and chloroform, N,N-dimethylformamide (DMF), N-methylpyrrolidone, dimethyl sulfoxide (DMSO) or a mixed solvent thereof, and the like. Bases include sodium hydride, sodium hydroxide, potassium hydroxide, lithium hydroxide, inorganic salts such as sodium carbonate, potassium carbonate, cesium carbonate, sodium hydride, metal alkoxides such as sodium ethoxide and sodium methoxide, or an organic amine base such as triethylamine, N-ethyl-N, N-diisopropylamine (DIPEA) or 1,8-diazabicyclo(5.4.0)-7-undecene (DBU), and the like.
Synthesis of Compound (B-3)
[0070]
[0000] (In the formulae, R 6 represents a carboxyl-protecting group and X 1 represents leaving groups. R 9 and R 10 are the same or different from each other and represent C 1-6 alkyl groups, or R 9 and R 10 are taken together to represent a C 1-6 alkylene group.) This synthetic method is a method for synthesizing compound (B-3) by cyanation of compound (B-2). Leaving group represented by X 1 includes a halogen atom, a methanesulfonyloxy group, a p-toluenesulfonyloxy group, a trifluoromethanesulfonyloxy group, and the like. In this reaction, cyanation is carried out by converting the aromatic dialkoxy acetal derivative represented by the above formula (B-2) into an aldehyde derivative via deprotection reaction and subsequently reacting it with hydroxylamine. This reaction is a conversion reaction of the formyl group into a cyano group and is carried out by reacting the aromatic aldehyde derivative represented by the above formula (A-4) with hydroxylamine. As the hydroxylamine, salts such as the hydrochloride may be used; in that case, however, it is preferred that an appropriate basic substance is added. In addition, it is possible to accelerate the reaction by adding 1.0 to 3.0 equivalents of acetic anhydride, acetyl chloride, trichloroacetyl chloride, and the like. The amount of hydroxylamine or its salts used in this reaction is normally 1 or more equivalents and preferably 1.0 to 2.0 equivalents. When a basic substance is used, 1.0 to 3.0 equivalents relative to the salt of hydroxylamine are used. As the basic substance used, a carboxylate such as sodium formate, potassium formate, or sodium acetate, a carbonate such as potassium carbonate, sodium carbonate, or sodium hydrogencarbonate, or an organic amine salt such as triethylamine, pyridine, or 4-aminopyridine is used. The reaction is carried out by allowing them to react in an inert solvent in the presence of a base between room temperature and heating under reflux for normally 0.5 hours to 3 days. It is preferred that this reaction is performed under an inert gas atmosphere such as nitrogen. Solvents used in this reaction include solvents such as acetic acid, formic acid, toluene, benzene, pyridine, ethyl acetate, dichloromethane, 1,2-dichloroethane, chloroform, carbon tetrachloride, diethyl ether, tetrahydrofuran (THF), 1,4-dioxane, 1,2-dimethoxyethane, 1,2-diethoxyethane, N,N-dimethylformamide (DMF), N-methylpyrrolidone, dimethyl sulfoxide (DMSO), methanol, ethanol, and 2-propanol or a mixed solvent thereof.
Synthesis of Compound (A-7)
[0071]
[0000] (In the formulae, R 6 represents a carboxyl-protecting group and X 1 represents a leaving group. And Y 1 represents —B(OH) 2 or —B(OR 7 )OR 8 , wherein R 7 and R 8 are the same or different from each other and represent C 1-6 alkyl groups, or R 7 and R 8 are taken together to represent a C 1-6 alkylene group.) This reaction is a method for synthesizing compound (A-7) by coupling compounds (B-3) and (A-3). The leaving groups represented by X 1 include a halogen atom, a methanesulfonyloxy group, a p-toluenesulfonyloxy group, a trifluoromethanesulfonyloxy group, and the like. This reaction is carried out by using equivalent amounts of compounds (B-3) and (A-3) or by using either one in excess and allowing them to react in an inert solvent in the presence of a base and a palladium catalyst between room temperature and heating under reflux for normally 0.5 to 2 days. It is preferred that this reaction is performed under an inert gas atmosphere such as nitrogen. Solvents here include, though not particularly limited, for example, aromatic hydrocarbons such as benzene, toluene, and xylene, ethers such as diethyl ether, tetrahydrofuran (THF), 1,4-dioxane, 1,2-dimethoxyethane, and 1,2-diethoxyethane, halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane, and chloroform, alcohols such as methanol, ethanol, 2-propanol, and butanol, N,N-dimethylformamide (DMF), N-methylpyrrolidone, dimethyl sulfoxide (DMSO), water, or a mixed solvent thereof, and the like. Bases include sodium hydroxide, potassium hydroxide, lithium hydroxide, inorganic salts such as sodium carbonate, potassium carbonate, cesium carbonate, and tripotassium phosphate, metal alkoxides such as sodium ethoxide and sodium methoxide, or solutions obtained by diluting these bases with water etc., and the like. As the palladium catalyst, tetrakis(triphenylphosphine)palladium, dichlorobis(triphenylphosphine)palladium, palladium chloride-1,1′-bis(diphenylphosphino)ferrocene, or the like is preferred.
Synthetic Method (C)
Synthesis of Compound (C-2)
[0072]
[0000] (In the formulae, R 6 represents a carboxyl-protecting group. X 1 , X 2 and X 3 represent leaving groups.) The leaving groups represented by X 1 , X 2 and X 3 include a halogen atom, a methanesulfonyloxy group, a p-toluenesulfonyloxy group, a trifluoromethanesulfonyloxy group, and the like. This reaction is carried out by using equivalent amounts of compounds (C-1) and (A-6) or by using either one in excess and allowing them to react in an inert solvent in the presence of a base between room temperature and heating under reflux for normally 0.5 hours to 3 days. It is preferred that this reaction is performed under an inert gas atmosphere such as nitrogen. Solvents here include, though not particularly limited, for example, aromatic hydrocarbons such as benzene, toluene, and xylene, ethers such as diethyl ether, tetrahydrofuran (THF), 1,4-dioxane, 1,2-dimethoxyethane, and 1,2-diethoxyethane, halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane, and chloroform, N,N-dimethylformamide (DMF), N-methylpyrrolidone, dimethyl sulfoxide (DMSO) or a mixed solvent thereof, and the like. Bases include inorganic salts such as sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, sodium hydride, metal alkoxides such as sodium ethoxide and sodium methoxide, or an organic amine base such as triethylamine, N-ethyl-N,N-diisopropylamine (DIPEA) or 1,8-diazabicyclo(5,4,0)-7-undecene (DBU), and the like.
Synthesis of Compound (C-3)
[0073]
[0000] (In the formulae, R 6 represents a carboxyl-protecting group and X 1 and X3 represents a leaving group. And Y 1 represents —B(OH) 2 or —B(OR 7 )OR 8 , wherein R 7 and R 8 are the same or different from each other and represent C 1-6 alkyl groups, or R 7 and R 8 are taken together to represent a C 1-6 alkylene group.) This reaction is a method for synthesizing compound (C-3) by coupling compounds (C-2) and (A-3). The leaving groups represented by X 1 and X 3 include a halogen atom, a methanesulfonyloxy group, a p-toluenesulfonyloxy group, a trifluoromethanesulfonyloxy group, and the like. This reaction is carried out by using equivalent amounts of compounds (C-2) and (A-3) or by using either one in excess and allowing them to react in an inert solvent in the presence of a base and a palladium catalyst between room temperature and heating under reflux for normally 0.5 to 2 days. It is preferred that this reaction is performed under an inert gas atmosphere such as nitrogen. Solvents here include, though not particularly limited to, for example, aromatic hydrocarbons such as benzene, toluene, and xylene, ethers such as diethyl ether, tetrahydrofuran (THF), 1,4-dioxane, 1,2-dimethoxyethane; and 1,2-diethoxyethane, halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane, and chloroform, alcohols such as methanol, ethanol, 2-propanol, and butanol, N,N-dimethylformamide (DMF), N-methylpyrrolidone, dimethyl sulfoxide (DMSO), water, or mixed a solvent thereof, and the like. Bases include sodium hydroxide, potassium hydroxide, lithium hydroxide, inorganic salts such as sodium carbonate, potassium carbonate, cesium carbonate, and tripotassium phosphate, metal alkoxides such as sodium ethoxide and sodium methoxide, or solutions obtained by diluting these bases with water etc., and the like. As the palladium catalyst, tetrakis(triphenylphosphine)palladium, dichlorobis(triphenylphosphine)palladium, palladium chloride-1,1′-bis(diphenylphosphino)ferrocene, or the like is preferred.
Synthesis of Compound (C-4)
[0074]
[0000] (In the formulae, R 6 represents a carboxyl-protecting group. X 3 represents a leaving group.) This synthetic method is a method for synthesizing compound (C-4) by cyanation of compound (C-3). The leaving group represented by X 3 includes a halogen atom and the like. This reaction is a reaction that replaces the leaving group X 3 with a cyano group, and is carried out by reacting the above formula (C-3) with a cyanating reagent. This reaction is carried out by using equivalent amounts of compound (C-3) and the cyanating reagent or by using either one in excess and allowing them to react in an inert solvent, optionally in the presence of a base and a palladium or copper catalyst, between room temperature and heating under reflux for normally 0.5 hours to 2 days. It is preferred that this reaction is performed under an inert gas atmosphere such as nitrogen. As the cyanating reagent used, a cyanating reagent such as potassium cyanide, sodium cyanide, copper cyanide, or zinc cyanide is used. The amount of the cyanating reagent is normally 1 or more equivalents and preferably 1.0 to 2.0 equivalents. When a basic substance is used, 1.0 to 3.0 equivalents relative to compound (C-3) are used. As the basic substance used, a carboxylate such as sodium formate, potassium formate, or sodium acetate, a carbonate such as potassium carbonate, sodium carbonate, or sodium hydrogencarbonate, or an organic amine salt such as triethylamine, pyridine, or 4-aminopyridine is used. Solvents used in this reaction include solvents such as acetic acid, formic acid, toluene, benzene, pyridine, ethyl acetate, dichloromethane, 1,2-dichloroethane, chloroform, carbon tetrachloride, diethyl ether, tetrahydrofuran (THF), 1,4-dioxane, 1,2-dimethoxyethane, 1,2-diethoxyethane, N,N-dimethylformamide (DMF), N-methylpyrrolidone, dimethyl sulfoxide (DMSO), or a mixed solvent thereof. As the palladium catalyst, tetrakis(triphenylphosphine)palladium, dichlorobis(triphenylphosphine)palladium, palladium chloride-1,1′-bis(diphenylphosphino)ferrocene, or the like is preferred. As the copper catalyst, copper iodide or the like is preferred.
Synthesis of Compound (C-5)
[0075]
[0000] (In the formulae, R 6 represents a carboxyl-protecting group.) This synthetic method is a method for synthesizing the compound (C-5) of the invention by deprotecting the protecting group R 6 of compound (C-4) using an acid or a base etc.
[0076] This reaction is carried out by allowing compound (C-4) to react with an equivalent amount or an excess of acid or base in an inert solvent between room temperature and heating under reflux for normally 0.5 to 5 days. Solvents here include, though not particularly limited, for example, aromatic hydrocarbons such as benzene, toluene, and xylene, ethers such as diethyl ether, tetrahydrofuran (THF), 1,4-dioxane, 1,2-dimethoxyethane, and 1,2-diethoxyethane, halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane, and chloroform, alcohols such as methanol, ethanol, 2-propanol, and butanol, N,N-dimethylformamide (DMF), N-methylpyrrolidone, dimethyl sulfoxide (DMSO), water, or a mixed solvent thereof, and the like. Acids include inorganic salts such as hydrogen chloride, hydrogen bromide, sulfuric acid, nitric acid, phosphoric acid or a solution of the acids diluted with water or organic solvents. Bases include sodium hydroxide, potassium hydroxide, lithium hydroxide, inorganic salts such as sodium carbonate, potassium carbonate, cesium carbonate, and tripotassium phosphate, metal alkoxides such as sodium ethoxide and sodium methoxide, or solutions obtained by diluting these bases with water etc., and the like.
Synthetic Method (D)
Synthesis of Compound (D-2)
[0077]
[0000] (In the formulae, X 4 represents a leaving group.) This synthetic method is a method for synthesizing compound (D-2) by halogenating compound (D-1). The leaving group represented by X 4 includes iodine, bromine, and chlorine atoms. This reaction is carried out by reacting compound (D-1) with an equivalent amount or an excess of halogenating agent in an inert solvent between 0° C. and heating under reflux for normally 0.5 hours to 3 days. It is preferred that this reaction is performed under an inert gas atmosphere such as nitrogen. Solvents here include, though not particularly limited, for example, aromatic hydrocarbons such as benzene, toluene, and xylene, ethers such as diethyl ether, tetrahydrofuran (THF), 1,4-dioxane, 1,2-dimethoxyethane, and 1,2-diethoxyethane, halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane, and chloroform, ethyl acetate, water, or a mixed solvent thereof. Halogenating agents include chlorine, bromine, N-chlorosuccinimide, N-bromosuccinimide, N-iodosuccinimide, water, or a mixed solvent thereof, and the like.
Synthesis of Compound (D-4)
[0078]
[0000] (In the formulae, X 4 and Y 2 represent a leaving groups.) This synthesis method is a method for synthesising the compound (D-4) by reacting compounds (D-2) and ((D-3). The leaving group represented by X 4 includes an iodine atom, a bromine atom, a chlorine atom, and the leaving group represented by Y 2 includes halogen atom, a methanesulfonyloxy group, a p-toluenesulfonyloxy group, a trifluoromethanesulfonyloxy group, and the like. This reaction is carried out by using equivalent amounts of compounds (D-2) and (D-3) or by using either one in excess and allowing them to react in an inert solvent in the presence of a base between room temperature and heating under reflux for normally 0.5 hours to 3 days. It is preferred that this reaction is performed under an inert gas atmosphere such as nitrogen. Solvents here include, though not particularly limited, for example, aromatic hydrocarbons such as benzene, toluene, and xylene, ethers such as diethyl ether, tetrahydrofuran (THF), 1,4-dioxane, 1,2-dimethoxyethane, and 1,2-diethoxyethane, halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane, and chloroform, N,N-dimethylformamide (DMF), N-methylpyrrolidone, dimethyl sulfoxide (DMSO), pyridine, ethyl acetate or a mixed solvent thereof, and the like. Bases include inorganic salts such as sodium hydride, sodium hydride, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, metal alkoxides such as sodium ethoxide and sodium methoxide, or an organic amine base such as triethylamine, N-ethyl-N,N-diisopropylamine (DIPEA) or 1,8-diazabicyclo(5.4.0)-7-undecene (DBU), pyridine, and the like.
Synthesis of Compound (D-5)
[0079]
[0000] (In the formulae, R 6 represents a carboxyl-protecting group and X 4 represents a leaving group.) This reaction is a method for synthesizing compound (D-5) by coupling compounds (D-4) and (A-6). The leaving group represented by X 4 includes an iodine atom, a bromine atom and a chlorine atom. This reaction is carried out by using equivalent amounts of compounds (D-4) and (A-6) or by using either one in excess and allowing them to react in an inert solvent in the presence of a base, a copper catalyst, and a ligand between room temperature and heating under reflux for normally 0.5 hours to 3 days. It is preferred that this reaction is performed under an inert gas atmosphere such as nitrogen. Solvents here include, though not particularly limited, for example, aromatic hydrocarbons such as benzene, toluene, and xylene, ethers such as diethyl ether, tetrahydrofuran (THF), 1,4-dioxane, 1,2-dimethoxyethane, and 1,2-diethoxyethane, halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane, and chloroform, N,N-dimethylformamide (DMF), N-methylpyrrolidone, dimethyl sulfoxide (DMSO), ethyl acetate or a mixed solvent thereof, and the like. Bases include inorganic salts such as sodium hydride, sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, metal alkoxides such as sodium ethoxide and sodium methoxide, or an organic amine base such as triethylamine, N-ethyl-N,N-diisopropylamine (DIPEA) or 1,8-diazabicyclo(5.4.0)-7-undecene (DBU), and the like. Copper catalysts include copper chloride, copper bromide, copper iodide, copper oxide, and the like. Ligands include proline, trans-N,N′-dimethylcyclohexane-1,2-diamine, N,N-dimethylaminoacetic acid, 1,10-phenanthroline, and the like.
Synthesis of Compound (D-6)
[0080]
[0000] (In the formulae, R 6 represents a carboxyl-protecting group.) This synthetic method is a method for synthesizing compound (D-6) by debenzylation of compound (D-5). This reaction is carried out by allowing compound (D-5) to react in an inert solvent in the presence of a palladium catalyst under a hydrogen gas atmosphere between room temperature and heating under reflux for normally 0.5 to 2 days. Solvents here include, though not particularly limited, for example, aromatic hydrocarbons such as benzene, toluene, and xylene, ethers such as diethyl ether, tetrahydrofuran (THF), 1,4-dioxane, 1,2-dimethoxyethane, and 1,2-diethoxyethane, halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane, and chloroform, alcohols such as methanol, ethanol, 2-propanol, and butanol, N,N-dimethylformamide (DMF), N-methylpyrrolidone, dimethyl sulfoxide (DMSO), ethyl acetate or a mixed solvent thereof, and the like. As the palladium catalyst, palladium-carbon, palladium hydroxide, palladium black, or the like is preferred.
Synthesis of Compound (D-8)
[0081]
[0000] (In the formulae, R 6 represents a carboxyl-protecting group. R 11 represents an unsubstituted or substituted C 1-9 alkylsulfonyl group or an unsubstituted or substituted phenylsulfonyl group. Z 1 represents a leaving group.) This synthetic method is a method for synthesizing compound (D-8) by sulfonyl-esterification of the phenolic hydroxyl group of compound (D-6). Sulfonyl groups represented by R 11 include methanesulfonyl, trifluoromethanesulfonyl, p-toluenesulfonyl groups, and the like. The leaving group represented by Z 1 includes a halogen atom, a methanesulfonyloxy group, a p-toluenesulfonyloxy group, a trifluoromethanesulfonyloxy group, and the like. This reaction is carried out by using equivalent amounts of compounds (D-6) and (D-7) or by using either one in excess and allowing them to react in an inert solvent in the presence of a base between 0° C. and heating under reflux for normally 0.5 hours to 2 days. It is preferred that this reaction is performed under an inert gas atmosphere such as nitrogen. Solvents here include, though not particularly limited to, for example, aromatic hydrocarbons such as benzene, toluene, and xylene, ethers such as diethyl ether, tetrahydrofuran (THF), 1,4-dioxane, 1,2-dimethoxyethane, and 1,2-diethoxyethane, halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane, and chloroform, N,N-dimethylformamide (DMF), N-methylpyrrolidone, dimethyl sulfoxide (DMSO), pyridine, ethyl acetate or a mixed solvent thereof, and the like. It is preferred that this reaction is performed under an inert gas atmosphere. Bases include inorganic salts such as sodium hydride, sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, sodium hydrogen carbonate, or an organic amine base such as triethylamine, N-ethyl-N, N-diisopropylamine (DIPEA) or 1,8-diazabicyclo(5.4.0)-7-undecene (DBU), pyridine, and the like.
Synthesis of Compound (D-9)
[0082]
[0000] (In the formulae, R 6 represents a carboxyl-protecting group. R 11 represents an unsubstituted or substituted C 1-9 alkylsulfonyl group or an unsubstituted or substituted phenylsulfonyl group. Y 1 represents —B(OH) 2 or —B(OR 7 )OR 8 , wherein R 7 and R 8 are the same or different from each other and represent C 1-6 alkyl groups, or R 7 and R 8 are taken together to represent a C 1-6 alkylene group.) This reaction is a method for synthesizing compound (D-9) by coupling compounds (D-8) and (A-3). The sulfonyl group represented by R 11 includes a methanesulfonyl group, a trifluoromethanesulfonyl group, a p-toluenesulfonyl group, and the like. This reaction is carried out by using equivalent amounts of compounds (D-8) and (A-3) or by using either one in excess and allowing them to react in an inert solvent in the presence of a base and a palladium catalyst between room temperature and heating under reflux for normally 0.5 to 2 days. It is preferred that this reaction is performed under an inert gas atmosphere such as nitrogen. Solvents here include, though not particularly limited, for example, aromatic hydrocarbons such as benzene, toluene, and xylene, ethers such as diethyl ether, tetrahydrofuran (THF), 1,4-dioxane, 1,2-dimethoxyethane, and 1,2-diethoxyethane, halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane, and chloroform, alcohols such as methanol, ethanol, 2-propanol, and butanol, N,N-dimethylformamide (DMF), N-methylpyrrolidone, dimethyl sulfoxide (DMSO), water, or a mixed solvent thereof, and the like. Bases include sodium hydroxide, potassium hydroxide, lithium hydroxide, inorganic salts such as sodium carbonate, potassium carbonate, cesium carbonate, and potassium phosphate, metal alkoxides such as sodium ethoxide and sodium methoxide, or solutions obtained by diluting these bases with water etc., and the like. As the palladium catalyst, tetrakis(triphenylphosphine)palladium, dichlorobis(triphenylphosphine)palladium, palladium chloride-1,1′-bis(diphenylphosphino)ferrocene, or the like is preferred.
Synthesis of Compound (D-10)
[0083]
[0000] (In the formulae, R 6 represents a carboxyl-protecting group.) This synthetic method is a method for synthesizing the inventive compound (D-10) of the invention by deprotecting the protecting group R 6 of compound (D-9) using an acid or a base etc. This reaction is carried out by allowing compound (D-9) to react with an equivalent amount or an excess of acid or base in an inert solvent between room temperature and heating under reflux for normally 0.5 to 5 days. Solvents here include, though not particularly limited, for example, aromatic hydrocarbons such as benzene, toluene, and xylene, ethers such as diethyl ether, tetrahydrofuran (THF), 1,4-dioxane, 1,2-dimethoxyethane, and 1,2-diethoxyethane, halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane, and chloroform, alcohols such as methanol, ethanol, 2-propanol, and butanol, N,N-dimethylformamide (DMF), N-methylpyrrolidone, dimethyl sulfoxide (DMSO), water, or a mixed solvent thereof, and the like. Acids include inorganic salts such as hydrogen chloride, hydrogen bromide, sulfuric acid, nitric acid, phosphoric acid or a solution of the acids diluted with water or organic solvents. Bases include sodium hydroxide, potassium hydroxide, lithium hydroxide, inorganic salts such as sodium carbonate and potassium carbonate, metal alkoxides such as sodium ethoxide and sodium methoxide, or solutions obtained by diluting these bases with water etc., and the like.
[0084] Hereinafter, salts described as preferred compounds and pharmaceutically acceptable salts thereof among compounds represented by the foregoing formula (I) include, though not particularly limited as long as they are pharmaceutically acceptable salts, for example, salts with inorganic acids such as hydrogen chloride, hydrogen bromide, sulfuric acid, nitric acid, phosphoric acid, and carbonic acid; salts with organic acids such as maleic acid, fumaric acid, citric acid, malic acid, tartaric acid, lactic acid, succinic acid, benzoic acid, oxalic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, acetic acid, trifluoroacetic acid, and formic acid; salts with amino acids such as glycine, lysine, arginine, histidine, ornithine, glutamic acid, and aspartic acid; salts with alkali metals such as sodium, potassium, and lithium; salts with alkaline earth metals such as calcium and magnesium; salts with metals such as aluminum, zinc, and iron, salts with organic oniums such as tetramethylammonium, choline, etc.; and salts with organic bases such as ammonia, propanediamine, pyrrolidine, piperidine, pyridine, ethanolamine, N,N-dimethylethanolamine, 4-hydroxypiperidine, t-octylamine, dibenzylamine, morpholine, glucosamine, phenylglycyl alkyl ester, ethylenediamine, N-methylglucamine, guanidine, diethylamine, triethylamine, dicyclohexylamine, N,N′-dibenzylethylenediamine, chloroprocaine, procaine, diethanolamine, N-benzylphenylamine, piperazine, and tris(hydroxymethyl)aminomethane.
[0085] Furthermore, the compounds represented by formula (I) and salts thereof encompass various hydrates and solvates.
[0086] The foregoing various pharmaceutically acceptable salts of the compounds represented by formula (I) can be appropriately produced based on the ordinary skill in the art.
[0087] The compounds of the present invention also include the stereoisomers, the racemates, and all possible optically active forms of the compounds represented by formula (I).
[0088] The compounds represented by formula (I) of the present invention and pharmaceutically acceptable salts thereof have particularly excellent xanthine oxidase inhibitory activity. In view of their excellent xanthine oxidase inhibitory activity, the compounds represented by formula (I) of the present invention and pharmaceutically acceptable salts thereof will be useful as xanthine oxidase inhibitors.
[0089] The compounds represented by formula (I) of the present invention and pharmaceutically acceptable salts thereof can be used as pharmaceuticals for the treatment or prophylaxis of diseases associated with xanthine oxidase, such as gout, hyperuricemia, tumor lysis syndrome, urinary calculus, hypertension, dyslipidemia, diabetes, cardiovascular diseases such as arteriosclerosis or heart failure, renal diseases such as diabetic nephropathy, respiratory diseases such as chronic obstructive pulmonary disease, inflammatory bowel diseases, or autoimmune diseases, to which they are clinically applicable as xanthine oxidase inhibitors.
[0090] The compounds represented by the foregoing formula (I) and pharmaceutically acceptable salts thereof can be made into a pharmaceutical composition together with a pharmaceutically acceptable carrier and/or diluent. The pharmaceutical composition can be formed into various dosage forms to be administered orally or parenterally. Parenteral administration includes, for example, intravenous, subcutaneous, intramuscular, transdermal, or rectal administration.
[0091] Formulations containing one or more than one of the compounds represented by formula (I) of the present invention or salts thereof as an active ingredient are prepared by using carriers, excipients, and other additives that are commonly used in drug formulation. Carriers and excipients for drug formulation may be solid or liquid and include, for example, lactose, magnesium stearate, starch, talc, gelatin, agar, pectin, acacia gum, olive oil, sesame oil, cacao butter, ethylene glycol, etc. and other commonly used ones. Administration may be in the form of oral administration via tablets, pills, capsules, granules, powders, liquid preparations, etc. or in the form of parenteral administration via injections such as intravenous and intramuscular injections, suppositories, transdermal preparations, etc.
[0092] In general, a dosage of the compound represented by formula (I) of the present invention or a pharmaceutically acceptable salt thereof in the range of 0.01 to 1000 mg can be administered per adult per day, at one time or divided into several times, though the dosage varies depending on the type of disease, the route of administration, the symptoms, age, sex, and body weight of the patient, etc. However, since the dosage varies under various conditions, there are some cases where an amount lower than the above described dosage is sufficient and others where a dosage exceeding the above described range is needed.
EXAMPLES
[0093] The present invention will be described below based on specific examples; however, it is not limited to these examples.
[0094] Structures of isolated novel compounds were confirmed by 1 H NMR and/or mass spectrometry using a single quadrupole instrumentation equipped with an electrospray source, or other appropriate analytical methods.
[0095] For compounds for which 1 H NMR spectra (400 MHz, DMSO-d 6 or CDCl 3 ) were measured, their chemical shifts (δ:ppm) and coupling constants (J:Hz) are shown. As for the results of mass spectrometry, M + +H, i.e., a measured value observed as a value of compound's molecular mass (M) to which a proton (H + ) is added, is shown. It should be noted that the following abbreviations respectively stand for the following. s=singlet, d=doublet, t=triplet, q=quartet, brs=broad singlet, m=multiplet.
[0096] On the compounds synthesized according to the methods of the following examples, further analyses were performed by high-performance liquid chromatography (HPLC) analysis and by mass spectrometry using Time Of Flight-Mass Spectroscopy (TOF-MS) equipped with an electrospray ion source.
[0097] The retention time (in min) of a compound in HPLC analysis under the following analytical conditions is shown as HPLC retention time.
Measurement Conditions of HPLC
[0098] Measurement device: Hewlett-Packard 1100HPLC
Column: Imtakt Cadenza CD-C18 100 mm×4.6 mm 3 μm
UV: PDA detection (254 nm)
Column temperature: 40 degrees centigrade
Gradient conditions:
[0099] Solvent: A: H 2 O/acetonitrile=95/5
0.05% TFA (trifluoroacetic acid)
[0101] B: H 2 O/acetonitrile=5/95
0.05% TFA (trifluoroacetic acid)
[0103] Flow rate: 1.0 mL/min
[0104] Gradient:
0 to 1 min, Solvent B: 2%, Solvent A: 98% 1 to 14 min, Solvent B: 2% to 100%, Solvent A: 98% to 0% 14 to 17 min, Solvent B: 100%, Solvent A: 0% 17 to 19 min, Solvent B: 100% to 2%, Solvent A: 0% to 98%
[0109] As for the results of mass spectrometry, together with the value of “M + +H” observed by the device and analytical conditions given below (Obs. Mass: i.e., an observed value of compound's molecular mass (M) to which a proton (H + ) is added) and the calculated value of “M + +H” (Pred. Mass), the compositional formula (Formula) calculated from the observed value of “M + +H” is also shown.
Measurement Conditions of TOF-MS
[0110] Mass spectrometer: Shimadzu LCMS-IT-TOF
LC: Prominence
[0111] Column: Phenomenex Synergi Hydro-RP 4.0 mm×20 mm 2.5 μm
UV: PDA detection (254 nm)
Flow rate: 0.6 mL/min
Column temperature: 40 degrees centigrade
Detection voltage: 1.63 kV
Gradient conditions:
[0112] Solvent: A: H 2 O/acetonitrile=95/5
0.1% HCOOH
[0114] B: H 2 O/acetonitrile=5/95
0.1% HCOOH
[0116] Flow rate: 0.5 mL/min
[0117] Gradient:
0 to 0.2 min, Solvent B: 2%, Solvent A: 98% 0.2 to 2.5 min, Solvent B: 2% to 100%, Solvent A: 98% to 0% 2.5 to 3.8 min, Solvent B: 100%, Solvent A: 0% 3.8 to 4.0 min, Solvent B: 100% to 2%, Solvent A: 0% to 98% 4.0 to 5.0 min, Solvent B: 2%, Solvent A: 98%
Reference Example
Synthesis of 5-bromo-2-chloropyridine-4-carbaldehyde (reference example compound)
[0123] After a solution prepared by dissolving 10.6 mL of diisopropylamine in 100 mL of THF was cooled to −78° C., 22.7 mL of n-butyllithium was added thereto slowly dropwise. After the reaction solution was stirred for 1 hour, a solution obtained by dissolving 9.7 g of 5-bromo-2-chloropyridine in 50 mL of THF was added slowly dropwise, and the reaction solution was stirred for another hour. Afterwards, 10 mL of N,N-dimethylformamide (DMF) was added dropwise. After this mixed solution was stirred for 1 hour at −78° C., 30 mL of 2 M hydrochloric acid was added, and temperature was raised slowly to room temperature, followed by stirring for 30 minutes at room temperature. Water was added to the reaction mixture, which was then extracted with ethyl acetate. The organic layer was washed with brine, then dried and concentrated in vacuo. 10 mL of dichloromethane was added to the residue, purification was carried out by a conventional method to obtain 3.23 g of 5-bromo-2-chloropyridine-4-carbaldehyde. In addition, after the filtrate was concentrated in vacuo, the residue was purified by silica gel chromatography (hexane:ethyl acetate=9:1) to give 6.34 g of 5-bromo-2-chloropyridine-4-carbaldehyde.
[0124] 1 H-NMR (400 MHz, CDCl 3 ) δ (ppm): 7.72 (1H, s), 8.68 (1H, s), 10.30 (1H, s).
Example 1
Synthesis of 1-(4-cyano-5-phenylpyridin-2-yl)-1H-pyrazole-4-carboxylic acid (compound No. 1) (synthetic method (A))
[0125] (1) To a suspension prepared by adding 8.80 g of 5-bromo-2-chloropyridine-4-carbaldehyde, 5.36 g of phenylboronic acid, and 11.06 g of potassium carbonate in 100 mL of a mixed solution of 4-dioxane/water=4/1, 924 mg of tetrakis(triphenylphosphine)palladium was added, and the resultant reaction mixture was heated at 80° C. for 5 hours under a nitrogen atmosphere. Water was added to the reaction mixture, which was then extracted with ethyl acetate. The organic layer was washed with brine, then dried and concentrated in vacuo to give 10.80 g of 2-chloro-5-phenylpyridine-4-carbaldehyde.
[0126] 1 H-NMR (400 MHz, CDCl 3 ) δ (ppm): 7.3-7.42 (2H, m), 7.50-7.60 (3H, m), 7.81 (1H, d, J=0.6 Hz), 8.61 (1H, d, J=0.6 Hz), 9.99 (1H, s).
[0127] ESI/MS m/e: 218.0, 220.0 (M + +H, C 12 H 8 ClNO).
[0128] (2) To a suspension prepared by adding 10.80 g of 2-chloro-5-phenylpyridine-4-carbaldehyde, 5.56 g of hydroxylamine monohydrochloride, and 5.44 g of sodium formate to 100 mL of formic acid, 12.2 g of acetic anhydride was added, and the resultant reaction mixture was heated at 100° C. for 2 hours under a nitrogen atmosphere. 100 mL of water was added and purification was conducted by conventional means to give 6.34 g of 2-chloro-5-phenylpyridine-4-carbonitrile.
[0129] 1 H-NMR (400 MHz, CDCl 3 ) δ (ppm): 7.27 (1H, s), 7.5-7.6 (5H, m), 7.67 (1H, s), 8.63 (1H, s).
[0130] ESI/MS m/e: 215.0, 217.0 (M + +H, C 12 H 7 ClN 2 ).
[0131] (3) A reaction mixture prepared by suspending 3.22 g of 2-chloro-5-phenylpyridine-4-carbonitrile, 2.31 g of ethyl 1H-pyrazole-4-carboxylate, and 3.11 g of potassium carbonate in 40 mL of dimethyl sulfoxide was heated at 120° C. for 2.5 hours under a nitrogen atmosphere. 50 mL of water was added and purification was conducted by conventional means to give 3.97 g of ethyl 1-(4-cyano-5-phenylpyridin-2-yl)-1H-pyrazole-4-carboxylate.
[0132] 1 H-NMR (400 MHz, DMSO d 6 ) δ (ppm): 1.31 (3H, t, J=8.0 Hz), 4.28 (2H, q, J=8.0 Hz), 7.55-7.62 (3H, m), 7.70-7.72 (2H, m), 8.32 (1H, s), 8.43 (1H, s), 8.86 (1H, s), 9.05 (1H, s) ESI/MS m/e: 319.1 (M + +H, C 18 H 14 N 4 O 2 ).
[0133] (4) To a solution prepared by dissolving 3.97 g of ethyl 1-(4-cyano-5-phenylpyridin-2-yl)-1H-pyrazole-4-carboxylate in 30 mL of a mixed solution of tetrahydrofuran/methanol=1/1, 30 mL of 6 M hydrochloric acid was added, and the resultant reaction mixture was heated at 80° C. for 48 hours. Purification was conducted by conventional means to give 3.71 g of 1-(4-cyano-5-phenylpyridin-2-yl)-1H-pyrazole-4-carboxylic acid.
[0134] 1 H-NMR (400 MHz, DMSO d 6 ) δ (ppm): 7.54-7.62 (3H, m), 7.70-7.72 (2H, m), 8.26 (1H, s), 8.41 (1H, s), 8.85 (1H, s), 8.98 (1H, s), 12.91 (1H, s).
[0135] HPLC Retention Time: 10.48 min.
[0136] Obs Mass (M + +H): 291.0880
[0137] Pred Mass (M + +H): 291.0877
[0138] Formula (M): C 16 H 10 N 4 O 2
Examples 2 to 70
[0139] Using the above reference example compound as the starting material, compound Nos. 2 to 70 were synthesized in the same manner as in Example 1.
[0000] HPLC Comp. Retention Obs Mass Pred Mass Ex. No. Time (M + + H) (M + + H) Formula (M) 1H NMR 2 2 10.53 321.0975 321.0982 C17H12N4O3 3 3 11.21 335.1136 335.1139 C18H14N4O3 4 4 10.92 305.1021 305.1033 C17H12N4O2 5 5 10.43 309.0772 309.0782 C16H9N4O2F 400 MHz (DMSO d6) 7.41-7.50 (1H, m), 7.54-7.63 (2H, m), 7.72 (1H, d, J = 4.0 Hz), 8.26 (1H, s), 8.49 (1H, s), 8.79 (1H, s), 9.00 (1H, s), 12.93 (1H, brs). 6 6 10.89 325.0486 325.0487 C16H9N4O2Cl 400 MHz (DMSO d6) 7.46-7.50 (1H, m), 7.54-7.63 (2H, m), 7.72 (1H, d, J = 4.0 Hz), 8.26 (1H, s), 8.49 (1H, s), 8.79 (1H, s), 9.00 (1H, s), 12.93 (1H, brs). 7 7 10.52 321.0971 321.0982 C17H12N4O3 400 MHz (DMSO d6) 3.80 (3H, s), 7.14 (1H, t, J = 8.0 Hz, 8.0 Hz), 7.24 (1H, d, J = 8.0 Hz), 7.43 (1H, d, 8.0 Hz), 7.53 (1H, t, J = 8.0 Hz), 8.24 (1H, s), 8.38 (1H, s), 8.72 (1H, s), 8.97 (1H, s), 12.89 (1H, s). 8 8 11.03 359.0745 359.0750 C17H9N4O2F3 9 9 11.31 375.0701 375.0700 C17H9N4O3F3 10 10 11.25 305.1027 305.1033 C17H12N4O2 400 MHz (DMSO d6) 2.31 (3H, s), 7.36-7.38 (1H, m), 7.47-7.50 (3H, m), 8.24 (1H, s), 8.38 (1H, s), 8.82 (1H, s), 8.96 (1H, s), 12.93 (1H, brs). 11 11 10.61 309.0778 309.0782 C16H9N4O2F 400 MHz (DMSO d6) 7.39-7.44 (1H, m), 7.55-7.57 (1H, m), 7.61-7.67 (2H, m), 8.25 (1H, s), 8.43 (1H, s), 8.87 (1H, s), 8.97 (1H, s), 12.93 (1H, brs). 12 12 11.30 325.0474 325.0487 C16H9N4O2Cl 400 MHz (DMSO d6) 7.61-7.68 (3H, m), 7.81 (1H, s), 8.24 (1H, s), 8.40 (1H, s), 8.85 (1H, s), 8.95 (1H, s), 12.91 (1H, s). 13 13 10.59 321.0979 321.0982 C17H12N4O3 400 MHz (DMSO d6) 3.84 (3H, s), 7.11-7.14 (1H, m), 7.25-7.27 (2H, m), 7.50 (1H, t, J = 8.0 Hz, 8.0 Hz), 8.24 (1H, s), 8.39 (1H, s), 8.85 (1H, s), 8.96 (1H, s), 12.90 (1H, brs). 14 14 11.29 305.1030 305.1033 C17H12N4O2 400 MHz (DMSO d6) 2.40 (3H, s), 7.40 (2H, d, J = 8.0 Hz), 7.60 (2H, d, J = 8.0 Hz), 8.24 (1H, s), 8.38 (1H, s), 8.82 (1H, s), 8.96 (1H, s), 12.92 (1H, brs).
Ex. denotes Example and Comp. No. denotes Compound Number in the above table including all the following tables.
[0000]
HPLC
Comp.
Retention
Obs Mass
Pred Mass
Ex.
No.
Time
(M + + H)
(M + + H)
Formula (M)
1H NMR
15
15
11.41
325.0485
325.0487
C16H9N4O2Cl
400 MHz (DMSO d6) 7.67 (2H, d,
J = 8.0 Hz), 7.74 (2H, d, J = 8.0 Hz),
8.25 (1H, s), 8.42 (1H, s), 8.85 (1H, s),
8.97 (1H, s), 12.92 (1H, brs).
16
16
8.64
307.0816
308.0826
C16H10N4O3
17
17
11.26
353.1047
353.1044
C18H13N4O3F
400 MHz (DMSO d6) 1.23 (3H, t,
J = 8.0 Hz), 4.07-4.15 (2H, m), 7.03 (1H, t,
J = 8.0 Hz), 7.09 (1H, d, J = 8.0 Hz),
7.52-7.58 (1H, m), 8.25 (1H, s), 8.47 (1H,
s), 8.78 (1H, s), 8.98 (1H, s), 12.95 (1H,
brs).
18
18
10.61
339.0877
339.0888
C17H11N4O3F
400 MHz (DMSO d6) 3.81 (3H, s),
7.06 (1H, t, J = 8.0 Hz), 7.11 (1H, d, J = 8.0 Hz),
7.55-7.61 (1H, m), 8.25 (1H, s), 8.47 (1H,
s), 8.77 (1H, s), 8.98 (1H, s), 12.95 (1H,
brs).
19
19
10.33
339.0880
339.0888
C17H11N4O3F
400 MHz (DMSO d6) 3.92 (3H, s),
7.14-7.17 (1H, m), 7.32-7.41 (2H, m),
8.25 (1H, s), 8.47 (1H, s), 8.82 (1H, s),
8.97 (1H, s), 12.95 (1H, brs).
20
20
10.64
327.0682
327.0688
C16H8N4O2F2
21
21
10.25
297.0435
297.0441
C14H8N4O2S
400 MHz (DMSO d6) 7.61-7.62 (1H, m),
7.81-7.83 (1H, m), 8.13-8.14 (1H, m),
8.23 (1H, s), 8.36 (1H, s), 8.94 (2H, s),
12.95 (1H, brs).
22
22
10.77
311.0594
311.0597
C15H10N4O2S
23
23
9.76
281.0658
281.0669
C14H8N4O3
400 MHz (DMSO d6) 7.13-7.14 (1H, m),
7.93 (1H, t, J = 4.0 Hz), 8.22 (1H, s),
8.33 (1H, s), 8.39 (1H, m), 8.93 (1H, s),
8.96 (1H, s), 12.88 (1H, brs).
24
24
6.46
322.0921
322.0935
C16H11N5O3
25
25
6.25
292.0813
292.0829
C15H9N5O2
26
26
11.17
305.1024
305.1033
C17H12N4O2
27
27
12.78
333.1335
333.1346
C19H16N4O2
400 MHz (DMSO d6) 1.15 (6H, d,
J = 8.0 Hz), 3.55 (1H, q, J = 8.0 Hz),
7.54-7.62 (3H, m), 7.69-7.71 (2H, m),
8.32 (1H, s), 8.82 (1H, s), 8.87 (1H, s),
12.74 (1H, s).
28
28
11.33
319.1180
319.1190
C18H14N4O2
29
29
10.60
309.0771
309.0782
C16H9N4O2F
30
30
11.33
333.0993
333.0993
C18H14N4O3
31
31
12.17
349.1291
349.1295
C19H16N4O3
32
32
10.68
327.0678
327.0688
C16H8N4O2F2
400 MHz (DMSO d6) 7.34-7.38 (1H, m),
7.54-7.60 (1H, m), 7.72-7.78 (1H, m),
8.26 (1H, s), 8.48 (1H, s), 8.83 (1H, s),
8.99 (1H, s), 12.93 (1H, s).
33
33
11.22
323.0928
323.0939
C17H11N4O2F
400 MHz (DMSO d6) 2.42 (3H, s),
7.24 (1H, d, J = 8.0 Hz), 7.30 (1H, d, J = 8.0 Hz),
7.53 (1H, t, J = 8.0 Hz), 8.25 (1H, s),
8.45 (1H, s), 8.80 (1H, s), 8.98 (1H, s),
12.90 (1H, s).
34
34
11.18
323.0923
323.0939
C17H11N4O2F
400 MHz (DMSO d6) 2.37 (3H, s),
7.32-7.36 (1H, m), 7.40-7.44 (2H, m),
8.25 (1H, s), 8.46 (1H, s), 8.81 (1H, s),
8.98 (1H, s), 12.92 (1H, s).
35
35
10.56
327.0691
327.0688
C16H8N4O2F2
400 MHz (DMSO d6) 7.47-7.58 (2H, m),
7.61-7.66 (1H, m), 8.27 (1H, s), 8.50 (1H,
s), 8.87 (1H, s), 8.99 (1H, s), 12.92 (1H,
brs).
36
36
11.21
323.0934
323.0939
C17H11N4O2F
400 MHz (DMSO d6) 2.33 (3H, s),
7.29-7.33 (1H, m), 7.43-7.52 (2H, m),
8.25 (1H, s), 8.46 (1H, s), 8.81 (1H, s),
8.98 (1H, s), 12.91 (1H, s).
37
37
11.39
323.0925
323.0939
C17H11N4O2F
400 MHz (DMSO d6) 2.33 (3H, s),
7.38 (1H, dd, J = 8.0 Hz, 12.0 Hz), 7.56-7.60 (1H,
m), 7.64 (1H, d, J = 12.0 Hz), 8.25 (1H, s),
8.40 (1H, s), 8.83 (1H, s), 8.97 (1H, s),
12.92 (1H, s).
38
38
11.52
319.1190
319.1190
C18H14N4O2
400 MHz (DMSO d6) 2.07 (3H, s),
2.33 (3H, s), 7.17 (1H, d, J = 8.0 Hz), 7.25 (1H, t,
J = 8.0 Hz), 7.35 (1H, d, J = 8.0 Hz),
8.25 (1H, s), 8.42 (1H, s), 8.67 (1H, s),
8.98 (1H, s), 12.91 (1H, s).
39
39
11.41
323.0932
323.0939
C17H11N4O2F
400 MHz (DMSO d6) 2.32 (3H, s),
7.44-7.56 (3H, m), 8.25 (1H, s), 8.40 (1H,
s), 8.84 (1H, s), 8.96 (1H, s), 12.92 (1H, s).
40
40
11.42
341.0243
341.0247
C16H8N4O2FCl
400 MHz (DMSO d6) 7.67 (1H, dd,
J = 8.0 Hz, 12.0 Hz), 7.73-7.77 (1H, m),
8.01 (1H, dd, J = 4.0 Hz, 8.0 Hz), 8.25 (1H,
s), 8.42 (1H, s), 8.87 (1H, s), 8.97 (1H, s),
12.91 (1H, brs).
41
41
11.23
343.0403
343.0393
C16H8N4O2FCl
42
42
8.41
335.0766
335.0775
C17H10N4O4
400 MHz (DMSO d6) 7.85 (2H, d,
J = 8.0 Hz), 8.12 (2H, d, J = 8.0 Hz),
8.26 (1H, s), 8.44 (1H, s), 8.89 (1H, s),
8.98 (1H, s), 13.07 (2H, brs)
43
43
11.62
359.0743
359.0750
C17H9N4O2F3
400 MHz (DMSO d6) 7.93-7.99 (4H, m),
8.26 (1H, s), 8.45 (1H, s), 8.89 (1H, s),
8.98 (1H, s), 12.90 (1H, brs).
44
44
11.88
375.0697
375.0700
C17H9N4O3F3
400 MHz (DMSO d6) 7.61 (2H, d,
J = 8.0 Hz), 8.85 (2H, d, J = 8.0 Hz),
8.26 (1H, s), 8.43 (1H, s), 8.88 (1H, s),
8.98 (1H, s), 12.90 (1H, brs).
45
45
11.48
359.0745
359.0750
C17H9N4O2F3
400 MHz (DMSO d6) 7.84 (1H, t,
J = 8.0 Hz), 7.93 (1H, d, J = 8.0 Hz),
8.03 (1H, d, J = 8.0 Hz), 8.11 (1H, s), 8.26 (1H,
s), 8.44 (1H, s), 8.92 (1H, s), 8.98 (1H, s),
12.94 (1H, brs).
46
46
10.83
357.0798
357.0794
C17H10N4O3F2
400 MHz (DMSO d6) 7.35 (1H, t,
J = 72 Hz), 7.37 (1H, m), 7.55-7.68 (3H,
m), 8.26 (1H, s), 8.43 (1H, s), 8.88 (1H, s),
8.98 (1H, s), 12.92 (1H, s).
47
47
12.55
333.1340
333.1346
C19H16N4O2
400 MHz (DMSO d6) 1.26 (6H, d,
J = 8.0 Hz), 2.99 (1H, q, J = 8.0 Hz),
7.47 (2H, d, J = 8.0 Hz), 7.63 (2H, d, J = 8.0 Hz),
8.24 (1H, s), 8.39 (1H, s), 8.83 (1H, s),
8.97 (1H, s), 12.90 (1H, brs).
48
48
12.50
333.1341
333.1346
C19H16N4O2
400 MHz (DMSO d6) 1.26 (6H, d,
J = 8.0 Hz), 3.00 (1H, q, J = 8.0 Hz),
7.41-7.45 (1H, m), 7.50-7.52 (2H, m),
7.75 (1H, s), 8.25 (1H, s), 8.39 (1H, s),
8.86 (1H, s), 8.98 (1H, s), 12.91 (1H, brs)..
49
49
11.01
323.0934
323.0939
C17H11N4O2F
400 MHz (DMSO d6) 2.20 (3H, s),
7.22 (1H, td, J = 4.0 Hz, 8.0 Hz), 7.31 (1H, dd,
J = 4.0 Hz 12.0 Hz), 7.42 (1H, dd, J = 8.0 Hz,
12.0 Hz), 8.24 (1H, s), 8.43 (1H, s),
8.71 (1H, s), 8.97 (1H, s), 12.91 (1H, brs).
50
50
10.74
339.0872
339.0888
C17H11N4O3F
400 MHz (DMSO d6) 3.82 (3H, s),
6.97-7.01 (1H, m), 7.17-7.20 (1H, m),
7.47-7.51 (1H, m), 8.24 (1H, s), 8.39 (1H,
s), 8.71 (1H, s), 8.96 (1H, s), 12.90 (1H, s).
51
51
12.19
339.0629
339.0643
C17H11N4O2Cl
400 MHz (DMSO d6) 2.42 (3H, s),
7.54-7.57 (1H, m), 7.63-7.65 (1H, m),
7.69-7.70 (1H, m), 8.24 (1H, s), 8.40 (1H,
s), 8.83 (1H, s), 8.96 (1H, s), 12.90 (1H,
brs).
52
52
11.89
349.1290
349.1295
C19H16N4O3
53
53
13.00
347.1495
347.1503
C20H18N4O2
54
54
12.55
383.1141
383.1139
C22H14N4O3
400 MHz (DMSO d6) 7.12-7.24 (5H, m),
7.46 (2H, dd, J = 8.0 Hz), 7.72 (2H, d, J = 8.0 Hz),
8.24 (1H, s), 8.39 (1H, s), 8.84 (1H, s),
8.96 (1H, s).
55
55
10.31
335.1135
335.1139
C18H14N4O3
56
56
12.92
363.1446
363.1452
C20H18N4O3
57
57
11.91
341.1030
341.1033
C20H12N4O2
58
58
5.93
322.0920
322.0935
C16H11N5O3
59
59
6.32
335.1243
335.1251
C17H14N6O2
60
60
8.63
310.0723
310.0735
C15H8N5O2F
400 MHz (DMSO d6) 8.20-8.24 (1H, m),
8.27 (1H, s), 8.50 (1H, s), 8.79-8.81 (2H,
m), 8.95 (1H, s), 9.00 (1H, s), 12.94 (1H, s).
61
61
11.44
347.0580
347.0597
C18H10N4O2S
400 MHz (DMSO d6) 7.45-7.51 (2H, m),
7.70-7.73 (1H, m), 8.14-8.16 (1H, m),
8.21 (1H, m), 8.28 (1H, s), 8.49 (1H, s),
8.90 (1H, s), 9.01 (1H, s), 12.92 (1H, s).
62
62
5.78
292.0817
292.0829
C15H9N5O2
63
63
11.31
337.0749
337.0754
C17H12N4O2S
400 MHz (DMSO d6) 2.49 (3H, s),
7.40 (2H, d, J = 8.0 Hz), 7.59 (2H, d, J = 8.0 Hz),
8.18 (1H, s), 8.32 (1H, s), 8.77 (1H, s),
8.90 (1H, s), 12.86 (1H, s).
64
64
9.99
376.1395
376.1404
C20H17N5O3
400 MHz (DMSO d6) 3.24 (4H, t, J = 4.0 Hz),
3.76 (4H, t, J = 4.0 Hz), 7.13 (2H, d,
J = 8.0 Hz), 7.59 (2H, d, J = 8.0 Hz),
8.23 (1H, s), 8.33 (1H, s), 8.81 (1H, s), 8.95 (1H,
s), 12.88 (1H, s).
65
65
12.61
367.1192
367.1190
C22H14N4O2
400 MHz (DMSO d6) 7.40-7.44 (1H, m),
7.50-7.53 (2H, m), 7.77-7.83 (4H, m),
7.90-7.92 (2H, m), 8.26 (1H, s), 8.43 (1H,
s), 8.91 (1H, s), 8.99 (1H, s).
66
66
12.49
397.1290
397.1295
C23H16N4O3
400 MHz (DMSO d6) 5.21 (2H, s), 7.23 (2H,
d, J = 8.0 Hz), 7.34-7.50 (5H, m), 7.66 (2H, d,
J = 8.0 Hz), 8.24 (1H, s), 8.36 (1H, s),
8.81 (1H, s), 8.96 (1H, s), 12.86 (1H, s).
67
67
8.46
334.1281
334.1299
C18H15N5O2
400 MHz (DMSO d6) 2.97 (6H, s),
6.89-6.95 (2H, m), 6.99 (1H, s), 7.37 (1H, t,
J = 8.0 Hz), 8.25 (1H, s), 8.37 (1H, s),
8.85 (1H, s), 8.97 (1H, s).
68
68
7.10
306.0974
306.0986
C16H11N5O2
400 MHz (DMSO d6) 5.62 (2H, s), 6.71 (2H,
d, J = 8.0 Hz), 7.39 (2H, d, J = 8.0 Hz), 8.21 (1H,
s), 8.27 (1H, s), 8.75 (1H, s), 8.92 (1H, s),
12.84 (1H, s).
69
69
8.57
384.0774
384.0761
C17H13N5O4S
400 MHz (DMSO d6) 3.10 (3H, s), 7.38 (2H,
d, J = 8.0 Hz), 7.69 (2H, d, J = 8.0 Hz), 8.25 (1H,
s), 8.39 (1H, s), 8.83 (1H, s), 8.96 (1H, s),
10.13 (1H, s), 12.89 (1H, s).
70
70
8.23
404.1347
404.1353
C21H17N5O4
400 MHz (DMSO d6) 3.51-3.77 (8H, m),
7.63 (2H, d, J = 8.0 Hz), 7.79 (2H, d, J = 8.0 Hz),
8.26 (1H, s), 8.44 (1H, s), 8.88 (1H, s),
8.99 (1H, s).
Example 71
Synthesis of 1-[4-cyano-5-(3-methylsulfonylphenyl)pyridin-2-yl]-1H-pyrazole-4-carboxylic acid (compound No. 71) (synthetic method (B))
[0140] (1) A reaction mixture prepared by suspending 5.51 g of 5-bromo-2-chloropyridine-4-carbaldehyde, 26.5 g of trimethyl orthoformate, and 4.75 g of p-toluenesulfonic acid monohydrate in 50 mL of methanol was heated at 70° C. for 4 hours. Water was added to the reaction mixture, which was then extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogencarbonate solution and brine, then dried, and concentrated in vacuo to give 5.48 g of 5-bromo-2-chloro-4-(dimethoxymethyl)-pyridine.
[0141] 1 H-NMR (400 MHz, CDCl 3 ) δ (ppm): 3.39 (6H, s), 5.46 (1H, s), 7.57 (1H, s), 8.49 (1H, s).
[0142] (2) A reaction mixture prepared by suspending 5.33 g of 5-bromo-2-chloro-4-(dimethoxymethyl)-pyridine, 2.33 g of ethyl 1H-pyrazole-4-carboxylate, and 4.14 g of potassium carbonate in 50 mL of dimethylformamide was heated at 90° C. for 7 hours under a nitrogen atmosphere. After the reaction mixture was cooled to room temperature, water was added to the reaction mixture, which was then extracted with ethyl acetate. The organic layer was washed with brine, then dried, and concentrated in vacuo to give a crude product of ethyl 1-(5-bromo-4-(dimethoxymethyl)pyridin-2-yl)-1H-pyrazole-4-carboxylate.
[0143] A mixture prepared by first suspending the crude product obtained above in 25 mL of formic acid and then adding 2.78 g of hydroxylamine monohydrochloride was heated at 70° C. for 30 minutes under a nitrogen atmosphere. After the formation of an oxime was confirmed, a reaction mixture prepared by adding 2.72 g of sodium formate and 10.2 g of acetic anhydride to the above mixture was heated at 110° C. for 15 hours. After the reaction mixture was cooled to room temperature, 25 mL of water was added, followed by washing with 100 mL of water to give 2.26 g of ethyl 1-(5-bromo-4-cyanopyridin-2-yl)-1H-pyrazole-4-carboxylate.
[0144] 1 H-NMR (400 MHz, CDCl 3 ) δ (ppm): 1.38 (3H, t, J=8.0 Hz), 4.35 (2H, q, J=8.0 Hz), 8.14 (1H, s), 8.29 (1H, s), 8.71 (1H, s), 8.97 (1H, s).
[0145] (3) A reaction mixture prepared by suspending 80.3 mg of ethyl 1-(5-bromo-4-cyanopyridin-2-yl)-1H-pyrazole-4-carboxylate, 75.0 mg of 3-(methylsulfonyl)phenylboronic acid, 10.2 mg of palladium chloride-1,1′-bis(diphenylphosphino)ferrocene, and 106.1 mg of tripotassium phosphate in 0.8 mL of a mixed solvent of 1,4-dioxane/water=3/1 was heated at 90° C. for 15 hours under a nitrogen atmosphere. After the reaction mixture was cooled to room temperature, 2 mL of water and 4 mL of ethyl acetate were added, followed by stirring. The organic phase was concentrated and dried in vacuo to give a crude product of ethyl 1-[4-cyano-5-(3-methylsulfonylphenyl)pyridin-2-yl]-1H-pyrazole-4-carboxylate.
[0146] A reaction mixture prepared by dissolving the crude product obtained above in 0.8 mL of a 4 M solution of hydrochloric acid in 1,4-dioxane and adding 0.2 mL of 6 M hydrochloric acid was heated at 100° C. for 14 hours. The reaction mixture was cooled to room temperature and then concentrated to give a crude product of 1-[4-cyano-5-(3-methylsulfonylphenyl)pyridin-2-yl]-1H-pyrazole-4-carboxylic acid. This was purified by reversed phase HPLC to give 18.1 mg of 1-[4-cyano-5-(3-methylsulfonylphenyl)pyridin-2-yl]-1H-pyrazole-4-carboxylic acid.
[0147] 1 H-NMR (400 MHz, DMSO d 6 ) δ (ppm): 3.30 (3H, s), 7.89 (1H, dd, J=8.0 Hz, 8.0 Hz), 8.09 (1H, d, J=8.0 Hz), 8.11 (1H, d, J=8.0 Hz), 8.27 (2H, s), 8.46 (1H, s), 8.95 (1H, s), 9.00 (1H, s), 12.91 (1H, s).
[0148] HPLC Retention Time: 8.60 min.
[0149] Obs Mass (M + +H): 369.0645
[0150] Pred Mass (M + +H): 369.0652
[0151] Formula (M): C 17 H 12 N 4 O 4 S
Examples 72 to 74
[0152] Using the above reference example compound as the starting material, compound Nos. 72 to 74 were synthesized in the same manner as in Example 71.
[0000]
HPLC
Comp.
Retention
Obs Mass
Pred Mass
Ex.
No.
Time
(M + + H)
(M + + H)
Formula (M)
1H NMR
72
72
10.15
334.0575
334.0582
C16H9N5O4
400 MHz (DMSO d6) 7.91 (1H,
dd, J = 8.0 Hz, 8.0 Hz), 8.19 (1H,
d, J = 8.0 Hz), 8.27 (1H, s),
8.42 (1H, d, J = 8.0 Hz), 8.47 (1H, s),
8.60 (1H, s), 8.95 (1H, s),
9.01 (1H, s).
73
73
11.53
395.1138
395.1139
C23H14N4O3
400 MHz (DMSO d6)
7.58-7.62 (2H, m), 7.70-7.74 (1H, m),
7.79-7.81 (2H, m),
7.90-7.95 (4H, m), 8.27 (1H, s),
8.47 (1H, s), 8.93 (1H, s), 9.00 (1H,
s).
74
74
9.61
333.0964
333.0982
C18H12N4O3
400 MHz (DMSO d6) 2.66 (3H,
s), 7.87 (2H, d, J = 8.0 Hz),
8.15 (2H, d, J = 8.0 Hz), 8.27 (1H, s),
8.45 (1H, s), 8.90 (1H, s),
8.99 (1H, s).
Example 75
[0153] Synthesis of 1-(5-cyano-6-phenylpyridin-3-yl)-1H-pyrazole-4-carboxylic acid (compound No. 75) (synthetic method (C))
[0154] (1) A reaction mixture prepared by suspending 255 mg of 2,3-dibromo-5-fluoropyridine, 168 mg of ethyl 1H-pyrazole-4-carboxylate, and 207 mg of potassium carbonate in 2 mL of dimethyl sulfoxide was heated at 120° C. for 2 hours under a nitrogen atmosphere. Water was added to the reaction mixture, which was then extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogencarbonate solution and brine, then dried, and concentrated in vacuo to give a crude product of ethyl 1-(5,6-dibromopyridine)-1H-pyrazole-4-carboxylate. This was purified by column chromatography (hexane/ethyl acetate=9/1) to give 164 mg of ethyl 1-(5,6-dibromopyridine)-1H-pyrazole-4-carboxylate.
[0155] 1 H-NMR (400 MHz, CDCl 3 ) δ (ppm): 1.39 (3H, t, J=8.0 Hz), 4.36 (2H, q, J=8.0 Hz), 8.15 (1H, s), 8.37 (1H, d, J=4.0 Hz), 8.43 (1H, s), 8.72 (1H, d, J=4.0 Hz).
[0156] ESI/MS m/e: 373.9, 375.9, 377.9 (M + +H, C 11 H 10 Br 2 N 3 O 2 ).
[0157] (2) A suspension was prepared by adding 82.0 mg of ethyl 1-(5,6-dibromopyridine)-1H-pyrazole-4-carboxylate, 29.3 mg of phenylboronic acid, and 60.5 mg of potassium carbonate were suspended in 1.5 mL of a mixed solution of 1,4-dioxane/water=4/1. A reaction mixture prepared by adding 12.6 mg of tetrakis(triphenylphosphine)palladium to the suspension was heated at 80° C. for 7 hours under a nitrogen atmosphere. Water was added to the reaction mixture, which was then extracted with ethyl acetate. The organic layer was washed with brine, then dried, and concentrated in vacuo to give a crude product of ethyl 1-(5-bromo-6-phenylpyridin-3-yl)-1H-pyrazole-4-carboxylate. This was purified by column chromatography (hexane/ethyl acetate=3/1) to give 82.2 mg of ethyl 1-(5-bromo-6-phenylpyridine-3-yl)-1H-pyrazole-4-carboxylate.
[0158] ESI/MS m/e: 372.0, 374.0 (M + +H, C 17 H 15 BrN 3 O 2 ).
[0159] (3) A reaction mixture prepared by suspending 82.2 mg of ethyl 1-(5-bromo-6-phenylpyridin-3-yl)-1H-pyrazole-4-carboxylate and 31.3 mg of copper (I) cyanide in 1.5 mL of dimethylformamide was heated at 160° C. for 6 hours under a nitrogen atmosphere. After the reaction mixture was cooled to room temperature, insoluble matter was removed by filtration through celite, and water was added to the filtrate, which was then extracted with ethyl acetate. The organic layer was washed with brine, then dried, and concentrated in vacuo to give a crude product of ethyl 1-(5-cyano-6-phenylpyridin-3-yl)-1H-pyrazole-4-carboxylate. This was purified by column chromatography (hexane/ethyl acetate=3/1) to give 54.2 mg of ethyl 1-(5-cyano-6-phenylpyridin-3-yl)-1H-pyrazole-4-carboxylate.
[0160] ESI/MS m/e: 319.1 (M + +H, C 18 H 15 N 4 O 2 ).
[0161] (4) A reaction mixture prepared by suspending 54.2 mg of ethyl 1-(5-cyano-6-phenylpyridin-3-yl)-1H-pyrazole-4-carboxylate was suspended in 1.0 mL of a mixed solution of tetrahydrofuran/methanol=1/1 and adding 0.2 mL of 2 M sodium hydroxide aqueous solution was heated at 50° C. for 2 hours under a nitrogen atmosphere. 0.2 mL of 2 M hydrochloric acid was added to the reaction mixture, which was then extracted with ethyl acetate. The organic layer was washed with brine, then dried, and concentrated in vacuo to give a crude product of 1-(5-cyano-6-phenylpyridine-3-yl)-1H-pyrazole-4-carboxylic acid. This was purified by reversed phase HPLC to give 6.35 mg of 1-(5-cyano-6-phenylpyridine-3-yl)-1H-pyrazole-4-carboxylic acid.
[0162] 1 H-NMR (400 MHz, DMSO d 6 ) δ (ppm): 7.58-7.59 (3H, m), 7.89-7.91 (2H, m), 8.22 (1H, s), 8.97 (1H, d, J=4.0 Hz), 9.27 (1H, s), 9.50 (1H, d, J=4.0 Hz), 12.93 (1H, brs).
[0163] HPLC Retention Time: 9.76 min
[0164] Obs Mass (M + +H): 291.0875
[0165] Pred Mass (M + +H): 291.0877
[0166] Formula (M): C 16 H 10 N 4 O 2
Examples 76 to 84
[0167] Using the above ethyl 1-(5,6-dibromopyridine-1H-pyrazole-4-carboxylate as the starting material, compound Nos. 76 to 84 were synthesized in the same manner as in Example 75.
[0000]
HPLC
Comp.
Retention
Obs Mass
Pred Mass
Ex.
No.
Time
(M + + H)
(M + + H)
Formula (M)
1H NMR
76
76
9.57
309.0772
309.0782
C16H9N4O2F
400 MHz (DMSO d6) 7.34-8.00 (4H,
m), 8.23 (1H, s), 9.01 (1H, d, J = 4.0 Hz),
9.27 (1H, s), 9.53 (1H, d, J = 4.0 Hz),
12.86 (1H, brs).
77
77
9.97
327.0685
327.0688
C16H8N4O2F2
78
78
10.35
323.0937
323.0939
C17H11N4O2F
79
79
10.34
323.0940
323.0939
C17H11N4O2F
80
80
9.92
327.0688
327.0688
C16H8N4O2F2
81
81
9.94
327.0691
327.0688
C16H8N4O2F2
82
82
10.84
323.0934
323.0939
C17H11N4O2F
83
83
10.93
323.0949
323.0939
C17H11N4O2F
84
84
9.76
339.0889
339.0888
C17H11N4O3F
Example 85
Synthesis of 1-(6-cyano-5-phenylpyridin-2-yl)-1H-pyrazole-4-carboxylic acid (compound No. 85) (synthetic method (D))
[0168] (1) A suspension prepared by adding 2.73 g of 2-cyano-3-hydroxypyridine to 60 mL of a mixed solution of acetonitrile/water=5/1 was cooled to 0° C. A reaction mixture prepared by adding 4.85 g of N-bromosuccinimide slowly to the suspension was stirred for 2 hours under a nitrogen atmosphere. Water was added to the reaction mixture, which was then extracted with ethyl acetate. The organic layer was washed with brine, then dried, and concentrated in vacuo to give 5.39 g of a crude product of 6-bromo-2-cyano-3-hydroxypyridine.
[0169] (2) A reaction mixture prepared by first suspending 5.39 g of 6-bromo-2-cyano-3-hydroxypyridine and 4.71 g of potassium carbonate in 60 mL of dimethylformamide and then adding 4.66 g of benzyl bromide was heated at 60° C. for 12 hours. After the reaction mixture was cooled to room temperature, 60 mL of water was added and purification was conducted by conventional means to give 4.73 g of 3-benzyloxy-6-bromo-2-cyanopyridine.
[0170] 1 H-NMR (400 MHz, CDCl 3 ) δ (ppm): 5.26 (2H, s), 7.24 (1H, d, J=8.0 Hz), 7.36-7.44 (5H, m), 7.57 (1H, d, J=8.0 Hz)
[0171] (3) A reaction mixture prepared by first suspending 2.64 g of 3-benzyloxy-6-bromo-2-cyanopyridine, 1.44 g of ethyl 1H-pyrazole-4-carboxylate, 98 mg of copper iodide and 2.29 g of potassium carbonate were suspended in 20 mL of toluene and then adding 236 mg of trans-N,N′-dimethylcyclohexane-1,2-diamine was heated at 100° C. for 12 hours under a nitrogen atmosphere. After the reaction mixture was cooled to room temperature, water was added thereto, which was then extracted with ethyl acetate. The organic layer was washed with brine, then dried, and concentrated in vacuo. The crude product obtained was separated and purified by silica gel column chromatography to give 1.30 g of ethyl 1-(5-benzyloxy-6-cyanopyridin-2-yl)-1H-pyrazole-4-carboxylate.
[0172] (4) A reaction mixture prepared by first suspending 1.39 g of ethyl 1-(5-benzyloxy-6-cyanopyridin-2-yl)-1H-pyrazole-4-carboxylate was suspended in 30 mL of a mixed solution of tetrahydrofuran/ethanol=1/1 and then adding 409 mg of palladium/carbon (10% wt) was stirred at room temperature for 14 hours under a hydrogen atmosphere. The reaction mixture was filtered, and the filtrate was concentrated in vacuo to give 1.02 g of ethyl 1-(6-cyano-5-hydroxypyridin-2-yl)-1H-pyrazole-4-carboxylate.
[0173] (5) A mixture prepared by suspending 46 mg of ethyl 1-(6-cyano-5-hydroxypyridin-2-yl)-1H-pyrazole-4-carboxylate in 1 mL of dichloromethane and adding 35 mg of N,N-diisopropylethylamine was added, followed by cooling to 0° C. A reaction mixture prepared by adding 76 mg of trifluoromethanesulfonic anhydride to the suspension was stirred at room temperature for 4 hours under a nitrogen atmosphere. Water was added to the reaction mixture, which was then extracted with ethyl acetate. The organic layer was washed with brine, then dried, and concentrated in vacuo. The crude product obtained was separated and purified by silica gel column chromatography to give 45.3 mg of ethyl 1-[6-cyano-5-(trifluoromethylsulfonyloxy)pyridin-2-yl]-1H-pyrazole-2-carboxylate.
[0174] 1 H-NMR (400 MHz, CDCl 3 ) δ (ppm): 1.40 (3H, t, J=8.0 Hz), 4.37 (2H, q, J=8.0 Hz), 8.00 (1H, d, J=8.0 Hz), 8.15 (1H, s), 8.39 (1H, d, J=8.0 Hz), 8.98 (1H, s).
[0175] (6) A reaction mixture prepared by first suspending 46.8 mg of ethyl 1-[6-cyano-5-(trifluoromethylsulfonyloxy)pyridin-2-yl]-1H-pyrazole-2-carboxylate, 17.6 mg of phenylboronic acid, and 7.8 mg of palladium chloride-1,1′-bis(diphenylphosphino)ferrocene-dichloromethane complex were suspended in 1.0 mL of 1,2-dimethoxyethane and then adding 0.12 mL of 1 M potassium carbonate aqueous solution was heated at 80° C. for 3 hours under a nitrogen atmosphere. Water was added to the reaction mixture, which was then extracted with ethyl acetate. The organic layer was washed with brine, then dried, and concentrated in vacuo to give a crude product of ethyl 1-(6-cyano-5-phenylpyridin-2-yl)-1H-pyrazole-4-carboxylate.
[0176] A reaction mixture prepared by first suspending the above crude product in 1.5 mL of a mixed solution of tetrahydrofuran/methanol=2/1 and then adding 0.24 mL of 2 M sodium hydroxide aqueous solution was heated at 50° C. for 4 hours. After the reaction mixture was cooled to room temperature, 0.24 mL of 2 M hydrochloric acid were added, followed by extraction with ethyl acetate and concentration in vacuo. The crude product obtained was purified by reversed phase HPLC to give 18.8 mg of 1-(6-cyano-5-phenylpyridin-2-yl)-1H-pyrazole-4-carboxylic acid.
[0177] 1 H-NMR (400 MHz, DMSO d 6 ) δ (ppm): 7.56-7.61 (3H, m), 7.70-7.71 (2H, d, J=4.0 Hz), 8.25 (1H, s), 8.30-8.37 (2H, m), 8.97 (1H, s), 12.95 (1H, s).
[0178] HPLC Retention Time: 10.40 min.
[0179] Obs Mass (M + +H): 291.0874
[0180] Pred Mass (M + +H): 291.0877
[0181] Formula (M): C 16 H 10 N 4 O 2
Examples 86 to 96
[0182] Using as a raw material the ethyl 1-[6-cyano-5-(trifluoromethylsulfonyloxy)pyridine-2-yl]-1H-pyrazole-2-carboxylate obtained above in (5) of Example 85, compound Nos. 86 to 96 were synthesized in the same manner as in Example 85.
[0000]
HPLC
Comp.
Retention
Obs Mass
Pred Mass
Ex.
No.
Time
(M + + H)
(M + + H)
Formula (M)
1H NMR
86
86
10.37
309.0776
309.0782
C16H9N4O2F
400 MHz (DMSO d6) 7.41-7.50 (2H,
m), 7.61-7.69 (2H, m), 8.26 (1H, s),
8.36 (2H, s), 8.99 (1H, s), 12.95 (1H, s).
87
87
11.15
323.0931
323.0939
C17H11N4O2F
400 MHz (DMSO d6) 2.42 (3H, s),
7.27 (2H, dd, J = 24.0 Hz, 8.0 Hz),
7.54 (1H, dd, J = 8.0 Hz, 8.0 Hz),
8.26 (1H, s), 8.33 (2H, s), 8.98 (1H, s),
12.94 (1H, s).
88
88
11.10
323.0939
323.0939
C17H11N4O2F
400 MHz (DMSO d6) 2.37 (3H, s),
7.32-7.45 (3H, m), 8.26 (1H, s),
8.34 (2H, s), 8.99 (1H, s), 12.94 (1H, s).
89
89
10.51
309.0780
309.0782
C16H9N4O2F
400 MHz (DMSO d6) 7.45 (2H, dd,
J = 8.0 Hz, 8.0 Hz), 7.77 (2H, dd,
J = 4.0 Hz, 8.0 Hz), 8.26 (1H, s),
8.30-8.36 (2H, m), 8.98 (1H, s).
90
90
10.60
327.0677
327.0688
C16H8N4O2F2
400 MHz (DMSO d6) 7.35 (1H, td,
J = 8.0 Hz, 4.0 Hz), 7.57 (1H, td,
J = 8.0 Hz, 4.0 Hz), 7.76 (1H, td,
J = 8.0 Hz, 8.0 Hz), 8.26 (1H, s),
8.35 (2H, s), 8.99 (1H, s), 12.93 (1H, s).
91
91
10.55
339.0885
339.0888
C17H11N4O3F
92
92
11.16
305.1038
305.1033
C17H12N4O2
400 MHz (DMSO d6) 2.41 (3H, s),
7.37-7.38 (1H, m), 7.45-7.49 (3H, m),
8.25 (1H, s), 8.29-8.35 (2H, m),
12.91 (1H, s).
93
93
11.24
335.1134
335.1139
C18H14N4O3
400 MHz (DMSO d6) 1.36 (3H, t,
J = 8.0 Hz), 4.11 (2H, q, J = 8.0 Hz),
7.10 (1H, dd, J = 8.0 Hz, 4.0 Hz),
7.22-7.25 (3H, m), 7.48 (1H, t,
J = 8.0 Hz), 8.25 (1H, s), 8.28-8.36 (2H,
m), 12.91 (1H, s).
94
94
11.28
323.0943
323.0939
C17H11N4O2F
400 MHz (DMSO d6) 2.33 (3H, s),
7.37 (1H, t, J = 8.0 Hz), 7.57-7.59 (2H,
m), 7.63 (1H, d, J = 8.0 Hz), 8.25 (1H, s),
8.29-8.34 (2H, m), 12.91 (1H, s).
95
95
10.40
327.0688
327.0688
C16H8N4O2F2
400 MHz (DMSO d6) 7.40 (2H, t,
J = 8.0 Hz), 7.67-7.75 (1H, m), 8.27 (1H,
s), 8.39-8.46 (2H, m), 9.00 (1H, s),
12.93 (1H, s).
96
96
10.55
339.0884
339.0888
C17H11N4O3F
400 MHz (DMSO d6) 3.82 (3H, s),
7.06 (1H, t, J = 8.0 Hz), 7.12 (1H, d,
J = 8.0 Hz), 7.58 (1H, q, J = 8.0 Hz),
8.25 (1H, s), 8.29-8.35 (2H, m),
8.98 (1H, s), 12.90 (1H, s).
Examples 97 to 107
[0183] Using the above reference example compound as the starting material, compound Nos. 97 to 107 were synthesized in the same manner as in Example 1.
[0000]
HPLC
Comp.
Retention
Obs Mass
Pred Mass
Ex.
No.
Time
(M + + H)
(M + + H)
Formula (M)
1H NMR
97
97
10.26
306.0978
306.0986
C16H11N5O2
400 MHz (DMSO d6) 7.54-7.60 (3H,
m), 7.66-7.69 (2H, m), 8.03 (1H, s),
8.68 (1H, s), 8.74 (1H, s).
98
98
10.22
324.0897
324.0891
C16H10FN5O2
400 MHz (DMSO d6) 5.92 (2H, brs),
7.39-7.48 (2H, m), 7.58-7.65 (2H, m),
8.08 (1H, s), 8.69 (1H, s), 8.73 (1H, s),
12.73 (1H, brs).
99
99
10.39
324.0894
324.0891
C16H10FN5O2
100
100
11.20
340.0587
340.0596
C16H10ClN5O2
400 MHz (DMSO d6) 5.92 (2H, brs),
7.64-7.72 (4H, m), 8.03 (1H, s), 8.67 (1H,
s), 8.74 (1H, s).
101
101
10.98
320.1133
320.1142
C17H13N5O2
400 MHz (DMSO d6) 2.40 (3H, s),
5.90 (2H, brs), 7.34-7.36 (1H, m),
7.44-7.47 (3H, m), 8.01 (1H, s), 8.67 (1H,
s), 8.72 (1H, s), 12.71 (1H, brs).
102
102
10.32
336.1088
336.1091
C17H13N5O3
103
103
10.97
338.1044
338.1048
C17H12FN5O2
400 MHz (DMSO d6) 2.41 (3H, s),
5.91 (2H, brs), 7.19-7.31 (3H, m),
7.47-7.52 (1H, m), 8.06 (1H, s), 8.68 (1H,
s), 8.69 (1H, s), 12.71 (1H, brs).
104
104
10.91
338.1036
338.1048
C17H12FN5O2
105
105
10.43
342.0791
342.0797
C16H9F2N5O2
106
106
11.10
338.1056
338.1048
C17H12FN5O2
107
107
10.33
354.0983
354.0997
C17H12FN5O3
Example 108
[0184] The xanthine oxidase inhibitory activity was measured for the compounds synthesized according to the above Examples.
(1) Preparation of Test Compounds
[0185] After a test compound was dissolved in DMSO (manufactured by Sigma Co.) so that the concentration is 20 mM, the test compound was prepared and used at a desired concentration at the time of use.
(2) Measurement Method
[0186] The evaluation of the xanthine oxidase inhibitory activity of the compounds of the present invention was conducted by partially modifying the method described in the literature (Method Enzymatic Analysis, 1, 521-522, 1974). The present evaluation is based on the oxidase type xanthine oxidase inhibitory activity evaluation. That is, a xanthine (manufactured by Sigma Co.) solution prepared at 10 mM in advance using a 20 mM sodium hydroxide solution was adjusted to 30 μM using a 100 mM phosphate buffer solution, and 75 μL/well of each solution was added into a 96-well plate. Aliquots (1.5 μL/well) of each test sample, which was diluted with DMSO so that the concentration is 100 times the final concentration, were added into a 96-well plate, and after mixing, the absorbance at 290 nm was measured by a microplate reader SPECTRA MAX Plus 384 (manufactured by Molecular Devices, LLC). Subsequently, oxidase type xanthine oxidase (derived from buttermilk, supplied by Calbiochem Novabiochem Corp.) was prepared at 30.6 mU/mL using a 100 mM phosphate buffer solution and 73.5 μL/well of each solution was added. Immediately after mixing, the change in absorbance at 290 nm was measured for 5 minutes. The enzyme activity when DMSO was used instead of a test compound solution was defined as 100%, the inhibitory rate of the test compounds was calculated and the 50% inhibitory concentration with respect to oxidase type xanthine oxidase was calculated by fitting to the dose-response curve.
[0187] The results are shown in the following table. Note that the symbols (+, ++, +++) in the table represent inhibitory activity values as shown below.
[0188] 10.0 nM≦IC 50 : +
[0189] 5.0 nM≦IC 50 <10.0 nM: ++
[0190] 1.0 nM≦IC 50 <5.0 nM: +++
[0000]
Compound
Inhibitory
Number
Activity
1
+++
2
+++
3
++
4
++
5
+++
6
+++
7
+++
8
+
9
+
10
+++
11
++
12
++
13
+++
14
+++
15
+++
16
+++
17
++
18
++
19
+++
20
+++
21
+++
22
+++
23
++
24
+
25
+
26
+
27
+
28
+
29
+++
30
+++
31
+++
32
+++
33
+++
34
+++
35
+++
36
+++
37
+++
38
+++
39
+++
40
++
41
+++
42
+++
43
+++
44
+++
45
++
46
++
47
+++
48
+++
49
+
50
+++
51
+++
52
+++
53
+++
54
+++
55
+++
56
++
57
+++
58
+
59
+++
60
+
61
+++
62
+
63
+++
64
+++
65
+++
66
+++
67
++
68
+++
69
+++
70
+++
71
+++
72
+
73
+++
74
+
75
+
76
+
77
+
79
+
80
+
81
+
82
+
83
++
84
++
85
+
86
++
88
+
89
+
90
+
91
++
92
+
93
+
94
+
95
++
96
+
97
+++
98
+++
99
+++
100
+++
101
+++
102
+++
103
+++
104
+++
105
+++
106
+++
107
+++
Example 109
Hypouricemic Effect
Normal Mice
[0191] To 7 to 8-weeks-old Crlj:CD1-type male mice (Charles River Laboratories Japan, Inc.), test compounds suspended in 0.5% methylcellulose solution were administered by gavage using a feeding needle. Blood was taken from the heart at 6, 16, and 24 hours after the administration, after which the serum was separated. Blood uric acid levels were measured by the uricase method on an absorptiometer (Hitachi Autoanalyzer 7180) using a uric acid measurement kit (Autosera SUA: Sekisui Medical), and the percentage of hypouricemic effect was determined according to the following equation.
[0000] Percentage of hypouricemic effect (%)=(Level of uric acid of the control animal−Level of uric acid of the test compound-administered animal)×100/Level of uric acid of the control animal.
[0192] In this test, the excellent hypouricemic effects of the inventive compounds were confirmed. For example, the compounds of compound Nos. 1, 5, 10, 14, 19, 21, and 33 showed the percentage of hypouricemic effect of 70% or more 6 hours after oral administration of 1 mg/kg.
[0193] From the above results, it was shown that the compounds of the present invention have a strong hypouricemic effect.
Example 110
Hypouricemic Effect
Normal Rats
[0194] A test compound suspended in a 0.5% methylcellulose solution was administered to 8 to 9 week-old Sprague-Dawley male rats (Japan Charles River Co.) by oral gavage administration using a feeding needle. After the blood was collected from the tail vein at 6 hours and 24 hours after administration, the plasma was separated. The level of uric acid in the blood sample was measured by uricase method using an absorption spectrometer as well as a uric acid determination kit (L type Wako UA F: Wako Pure Chemical Industries, Ltd.). The percentage of hypouricemic effect was determined by the following expression:
[0000] Percentage of hypouricemic effect (%)=(Level of uric acid of the control animal−Level of uric acid of the test compound-administered animal)×100/Level of uric acid of the control animal.
[0195] The compound of compound No. 1 showed a hypouricemic effect of 70% or more at the dose of 1 mg/kg at 6 hours and 24 hours after administration. Also, the compounds of compound No. 97 and 98 showed a hypouricemic effect of 50% or more at the dose of 10 mg/kg at 6 hours and 24 hours after administration. From these results, it was shown that the compounds of the present invention have a strong and lasting hypouricemic effect.
Example 111
Hypouricemic Effects
Cebus apella Monkeys
[0196] To Cebus apella monkeys, test compounds suspended in 0.5% methylcellulose solution were administered by gavage into the stomach through the nasal cavity using a disposable catheter and a syringe. Blood was taken from the saphenous vein at 4 hours and 24 hours after the administration, after which the plasma was separated. The level of uric acid in the blood was measured using a uric acid measurement kit (L type Wako UA F: Wako Pure Chemical Industries, Ltd.) by the uricase method using an absorption spectrometer and the percentage of hypouricemic effect was determined by the following expression:
[0000] Percentage of hypouricemic effect (%)=(Level of uric acid of the control animal−Level of uric acid of the test compound-administered animal)×100/Level of uric acid of the control animal.
[0197] The compound of compound No. 1 showed a hypouricemic effect of 50% or more at the dose of 1 mg/kg at 4 hours and 24 hours after administration. From these results, it was shown that the compounds of the present invention had a strong and lasting hypouricemic effect also in Cebus apella monkeys.
Example 112
Hypouricemic Effect
Beagle Dogs
[0198] The hypouricemic effect of the compound (I) in beagle dogs was confirmed. A test compound suspended in a 0.5% methyl cellulose solution was orally administered by gavage to beagle dogs (Kitayama Labes). Blood was drawn from the cephalic vein at 24 hours after administration and plasma was separated. The level of uric acid in the plasma sample was measured using an LC-MS/MS method and the percentage of hypouricemic effect was determined by the following expression:
[0000] Percentage of hypouricemic effect (%)=(Level of uric acid of the control animal−Level of uric acid of the test compound-administered animal)×100/Level of uric acid of the control animal.
[0199] The compound of compound No. 1 showed a hypouricemic effect of 50% or more at the dose of 3 mg/kg at 24 hours after administration.
[0200] From these results, the compounds of the present invention were shown to have a strong and lasting hypouricemic effect in dogs.
[0201] In view of the above results, the inventive compounds of the present invention can be expected to exert potent hypouricemic effects even when they are administered once a day or at longer intervals. Clinically, in the treatment or prophylaxis of hyperuricemia and various diseases, particularly chronic diseases, resulting therefrom, it is important to continually lower uric acid levels, and the present invention can be expected to exert excellent effects on such diseases.
INDUSTRIAL APPLICABILITY
[0202] The compounds represented by the foregoing formula (I) of the present invention and pharmaceutically acceptable salts thereof have xanthine oxidase inhibitory activity, and can be used as therapeutic or prophylactic agents for diseases associated with xanthine oxidase, particularly gout, hyperuricemia, tumor lysis syndrome, urinary calculus, hypertension, dyslipidemia, diabetes, cardiovascular diseases such as arteriosclerosis or heart failure, renal diseases such as diabetic nephropathy, respiratory diseases such as chronic obstructive pulmonary disease, inflammatory bowel diseases, autoimmune diseases, or the like, to which they are clinically applicable as xanthine oxidase inhibitors.
|
Provided are a compound expressed by formula (I) or a pharmacologically permissible salt thereof, as well as a drug or drug composition that contains this compound as an active ingredient, having a xanthine oxidase inhibiting effect that is very useful for treating or preventing diseases that are contributed to by xanthine oxidase, such as gout, hyperuricemia, tumor lysis syndrome, urinary tract stones, hypertension, dyslipidemia, diabetes, cardiovascular disease such as heart failure and arterial sclerosis, renal disease such as diabetic near opacity and the like, respiratory disease such as chronic obstructive pulmonary disease and the like, autoimmune diseases such as inflammatory bowel disease, and the like. [In the formula, A, X, Y, Z, R, and R 1 have the meaning set forth in claim 1 ].
| 2 |
CROSS REFERENCE TO RELATED APPLICATION
This application is a continuation-in-part of U.S. Ser. No. 08/697,648 filed Aug. 27, 1996, now U.S. Pat. No. 5,766,400.
FIELD OF THE INVENTION
This invention relates to the fabrication of waterproof, waterproof/breathable, windproof (with or without vapor permeable/moisture vapor transfer) apparel involving a post- or a pre-lamination process in order to provide a water tight seam. More specifically, this invention teaches the formation of leakproof welded fabric seams for non-containable fabrics such as those used in a firefighter's gloves.
BACKGROUND OF THE INVENTION
To date liners for apparel and footwear have been assembled by the stitch and seam method whereby two layers are joined by a stitch pattern creating a seam. Waterproofing the seam was accomplished by taping and gluing the seam. However taped and glued, stitched seams tend to fail when subjected to stress from repeated use.
U.S. Pat. No. 4,847,918 issued to Sturm discloses a flexible fire retardant and heat insulating glove that is mounted within and cemented to a flexible, water tight, vapor permeable plastic glove. A flexible reinforcement element having the outline of the plastic glove, with fingers somewhat longer than the fingers of the plastic glove, is cemented to one face of the plastic glove in substantial registry therewith. The fingers of the reinforcement element were extended beyond the fingers of the plastic glove to provide securement tabs. These securement tabs are stitched or tacked to the tips of the fingers of a reversed leather glove and reinforcement element.
U.S. Pat. No. 5,036,551 issued to Daily et al. concerns elastomeric composite fabrics which have a layered construction and are made of a microporous polymeric membrane, water vapor permeable polymer, and an elastomeric thermoplastic non-woven material. The elastomeric composite fabrics provide barrier properties with water vapor permeability and find utility in articles which conform about another object.
U.S. Pat. No. 5,123,119 issued to Dube concerns a two component, waterproof, breathable glove and the corresponding methods of forming the glove. A homogenous membrane in regard to its permeability characteristics is attached to a fabric. The membrane is tacky on one surface and wear resistant on the other surface. Using a contoured mold and foam forms, the layers for the inner liner are cut and are thermowelded or bonded together to form a three dimensional inner shell of a glove. Then the formed inner shell is attached to an outer glove shell by conventional methods.
U.S. Pat. No. 5,234,523 issued to Battreall discloses a method for laminating a gas permeable layer onto a preformed substrate by forming a laminate precursor comprising a substrate and a gas permeable layer in which a layer of adhesive is positioned between the gas permeable layer and a substrate surface. A layer of water is formed on the surface of the gas permeable layer and the wetted surface is contacted by a preheated platen and superheated steam is ejected onto the gas permeable layer causing the adhesive to cure and bond the gas permeable layer to the substrate.
U.S. Pat. No. 5,294,258 issued to Jarrel et al. concerns a breathable laminate which comprises at least two porous webs laminated together with a porous adhesive matrix, preferably a random fibrous adhesive pattern having a coat weight of between 1.5 and 12 grams per square meter. The two or more porous webs comprise woven or non-woven materials and the resulting breathable fabric or laminate has good hand flexibility. Breathable fabric is adhered to the foam by such random adhesive patterns of similar coat weights. Coating widths of up to 80 inches or more are produced in a slot die, with motors and pumps controlled to maintain consistent, uniform coat weights regardless of coat widths and substrate speeds selected.
U.S. Pat. No. 5,366,801 to Bryant et al. describes a coating which when applied to fabrics enhances the thermal characteristics of the coated fabric. The coating includes integral and leak-resistant microcapsules filled with phase change material or plastic crystals that have specific thermal properties at predetermined temperatures.
A disclosure of Toshiichi Osako describes an arctic glove comprised of a cloth material on the outside, waterproof materials in the middle layer and a woven or knit material on the inside. The three layers are bonded together with adhesives in a dotted state.
U.S. Pat. No. 5,569,507 to Goodwin et al. discloses a laminated seam with outer tabs formed by heat sealing a membrane-backed composite layer to itself with a continuous layer applied as a hot melt to a fabric front layer. The heat and pressure of the heat sealing is said to penetrate the fibers in the fabric of the composite with the adhesive to form a leakproof seal impenetrable by viruses.
As far as applicant is aware, there is no teaching or suggestion of obviousness in the prior art respecting the present invention method of producing a synthetic film membrane and substrate fabric laminate or an outer substrate fabric, substrate fabric and synthetic film membrane laminate for application as a liner for clothing and footwear as described herein. More particularly, there is no teaching or suggestion of utilizing the laminates disclosed herein in a manner which forms a seal in non-containable fabrics such as NOMEX® or KEVLAR® which are used in a firefighter's gloves to make them heat resistant.
SUMMARY OF THE INVENTION
The present invention addresses the seam assembly of a non-containable fabric laminated to a synthetic membrane, such as, for example, a firefighter's glove comprising a NOMEX® or KEVLAR® aramid fiber shell laminated inside a breathable/waterproof synthetic membrane or bladder. Such firefighter's gloves are typically made with an outer leather covering over the membrane and a cotton or other fabric liner inside the aramid fiber shell. Before the present invention, it was difficult to form a leakproof, watertight seam at the outer edges of the aramid fiber/membrane. The membrane had to be assembled separately and then cemented in place over the aramid fiber glove if taping and cementing were to be avoided.
By "non-containable" it is meant that the fabric cannot be thoroughly penetrated by suitable adhesives using practicable temperatures and pressures and bonding conditions to form a leakproof seal completely through the fiber layer to the membrane, either because the fabric is too thick and/or because the interstices of the fabric do not connect through the fabric layer to allow molten adhesive to flow through. An example of a non-containable fabric is aramid fabric obtained under the trade designations NOMEX®, KEVLAR® or the like. Thus, the invention is described with reference to non-containable fabrics that cannot be adequately seamed to form a leakproof seal using the methodology described in U.S. Pat. No. 5,569,507. However, there is no reason that the present invention cannot also be used to seal containable fabrics as well.
According to the present invention, the membrane is laminated to the fiber layers and the fiber/membrane laminates are welded together using a thermoplastic joiner film and RF welding techniques. The fiber layers are precut to have a common edge when overlaid, so as to place the common edges in register with each other. The membranes are positioned over the topmost and under the bottommost fiber layers so as to be opposite outer faces of the fiber layers. The membranes are larger than the fiber layers and extend outwardly of the common edges. The joiner film is positioned between the fabric layers so as to be opposite the inner faces of the fabric layers, and the assembly is welded together so as to fuse the fiber layers with the joiner layer inside the common edges, and so as to fuse the membranes together with the joiner layer outside the common edges. The membranes and the joiner film are continuous across the width of the seam so as to form a leakproof seal across the fabric edges. The fiber layers and the membrane can be pre-laminated prior to the welding step, but they are preferably welded to each other during the same welding step during which the joiner film is melted.
In one aspect, then, the present invention provides a fabric seam for forming a leakproof seal between non-containable fabric composites. The fabric seam includes first and second parallel fabric sections finished to have at least one matching edge, an inner seam portion extending inwardly from the matching edges, and an outer seam portion extending outwardly from the matching edges. The inner seam portion includes opposing inner faces of fabric sections secured to a parallel thermoplastic joiner film and parallel outer faces secured to first and second synthetic membranes. The outer seam portion includes the first and second synthetic membranes secured together on opposite sides of the joiner film. The synthetic membranes and joiner film are continuous between the inner and outer seam portions to form a seal therebetween.
The fabric sections are preferably made of aramid fibers. The thermoplastic joiner film is a polyolefin, polyurethane or the like. The outer seam can be finished or cut to terminate at a distance spaced from the matching edges. Positioning tabs can be formed to extend outwardly from the matching edges. The joiner film preferably terminates adjacent to an inner edge of the inner seam. If desired, positioning tabs can be formed in the joiner film to extend inwardly from the inner edge of the inner seam.
In another aspect, the present invention provides a method for forming a leakproof seal between non-containable fabric composites. The method includes the steps of: (a) finishing first and second fabric sections to have at least one matching fabric edge; (b) overlaying a first synthetic membrane parallel with the first fabric section wherein the first synthetic membrane extends beyond either side of the matching edge; (c) overlaying the first fabric section parallel with a thermoplastic joiner film extending beyond either side of the matching edge; (d) overlaying the joiner film parallel with the second fabric section with the matching edge thereof in register with the matching edge of the first fabric section; (e) overlaying the second fabric section parallel with a second synthetic membrane extending beyond either side of the matching edge; and (f) welding adjacent the matching fabric edges to form a seam securing the fabric sections to the joiner film on one side of the matching edges and securing the synthetic membrane to the joiner film on the other side of the matching edges. The method is particularly applicable to being used with non-containable fibers such as aramid, which cannot be adequately penetrated by a thermoplastic to form a leakproof seal with the application of practicable pressures and temperatures. The finishing step can include the step of finishing the fabric sections along the matching edge. For example, the method can include the step of precutting the joiner film along a contour spaced inwardly from the matching edges. If desired, the precutting step can form positioning tabs extending inwardly from the seam. The method can also include tearing excess joiner film away from an inner edge of the seam.
The method can also include the step of removing excess joiner film and synthetic membrane along an outer edge of the seam. For example, the excess joiner film and synthetic membrane can be removed by die cutting or manually cutting away the materials. If desired, the cutting can form positioning tabs extending outwardly from the seam. Preferably, the welding step (e) secures the first and second synthetic membranes to the respective first and second fabric sections along the matching edges thereof. For example, each membrane can be fused to the respective fabric section in the seam along an outer face of the fabric section extending inwardly from the matching edge, and fused to the matching edge along a transverse dimension thereof. If desired or necessary, the method can include the step of inserting tie layers between the first and second fabric sections and the respective first and second synthetic membranes prior to the welding step.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 is an exploded cross sectional view of a composite fabric seam assembly according to the present invention.
FIG. 2 is a cross sectional view of the assembly of materials of FIG. 1 in relation to a welding bar and platen prior to RF welding.
FIG. 3 is a cross sectional view of the seam formed by welding as shown in FIG. 2
FIG. 4 is a cross sectional view of the seam of FIG. 3 following finishing the outer edge of the seam.
FIG. 5 is a plan view of the arrangement of FIG. 2 showing the weld rod in relation to the fabric edges for a mitten.
FIG. 6 is a plan view of a mitten assembled according to FIG. 4.
DETAILED DESCRIPTION OF THE INVENTION
The present invention is a method of producing prefabricated, multi-layered flexible products eliminating traditional post-construction techniques for clothing and apparel made of non-containable fibers, such as producing a liner using sewn seams which must be taped and glued for waterproof application. In this invention, the method can be used to weld together laminates which are produced through conventional means by adhering substrate non-containable fabric material to a synthetic film membrane and/or separate sheets of substrate non-containable fabric material and synthetic film membrane, to form the prefabricated, multi-layered flexible product. The laminates or separate sheets are placed in a parallel configuration with the center sheet being the thermoplastic joiner film, with or without adhesive properties. The joiner film and the synthetic film membranes extend outwardly beyond edges of the substrate non-containable fabric material. These are then assembled by using a radio frequency (RF) welding process at the perimeter of the outer edge of the desired pattern of the article, outlining a specific form such as a glove or mitten. Welding the layers together produces a seam comprising an inner seam portion and an outer seam portion. The inner seam portion extends inwardly from the fabric edges and comprises the fabric layers joined together at the joiner film on the inside and the outer membrane joined to outer faces of the fabric sections. The outer seam comprises the membranes fused together at the joiner film layer and the membranes are continuous from the inner seam across the otherwise exposed edges of the fabric to the joiner film.
With reference to FIG. 1, the fabric pieces cut into gloves 10, 20 or other shapes are overlaid and underlaid with their respective membranes 30, 40. A thermoplastic joiner film 50 is sandwiched between the glove shapes 10, 20 and is positioned so as to straddle the edges 65 of the glove shapes 10, 20 (see FIG. 2). Outwardly of the edges 65, the ends 70 of the membranes 30, 40 are in contact with the joiner film 50. Preferably, the inner end 75 of the joiner film 50 is precut to match a contour of the desired shape of the edges 65. The joiner film 50 can be in the form of a tape or a design pattern similar to the configuration of the edges 65. For example, a glove which needs to be welded only at the perimeter to create a welded seam, only requires the joiner film 50 at that same perimeter. In order to prevent film waste or stripping after the product has been welded, the joiner film 50 is precut to the inner dimensions of the welding die, so that after welding, the joiner film 50 is not found inside the glove, and therefore no stripping is necessary. Then, after the glove is die cut outside the weld as discussed in more detail below, the glove is finished in the usual fashion.
An optional mesh fabric layer 45 (see FIG. 1) can be used to reinforce the inner and outer tabs formed in the joiner layer 50. If the optional layer 45 is used in this manner, additional welding time should be allowed to let the joiner film 50 flow through the layer 45 and bond to the adjacent glove shape 20.
If desired, a conventional tie layer (not shown) can be used between the membranes 30, 40 and the respective fabric layers of the glove shapes 10, 20. The tie layer is preferably water-based since solvent-based tie layers generally result in weaker bonds. The tie layer should also preferably be thermoplastic to flow and join with the joiner film as opposed to a thermoset which cannot adequately flow to seal well with the joiner film.
For straight seams, joiner film 50 is held in place relative to the ends 70 of the membrane using guide pins (not shown) which are received in holes 78 of each layer. After the weld is accomplished, the ends 70 being held by the pins are cut and removed and the product is finished per design. See FIGS. 3 and 4.
If the product can be turned inside out, the joiner film 50 can be stripped away to easily form an end 75 after the weld has been accomplished. The excess joiner film 50 which is stripped away can be recycled for re-use. For using the stripping away method, the product should be small, in case the excess joiner film cannot be configured for further use to keep waste of the joiner film 50 to a minimum.
With reference to FIGS. 2 and 5, the assembled substrate layers are shown placed on a platen 80 underneath a welding rod 85. In an embodiment shown in FIG. 2, the platen 80 and the welding bar 85 are contoured or stepped with inner end 86 and region 88 raised and depressed with respect to outer end 87 and outer region 89, respectively. Alternatively, the platen 80 and the welding rod 86 can be flat, or one of the platen 80 and welding rod 85 can be contoured or stepped and the other flat. The press is conventionally leveled prior to use in RF sealing. The platen 80 can be heated, for example, to 150° F. to help avoid shifts in temperature of the die 85 in contact with the material being heat sealed. The material to be heat sealed is compressed between the die 85 and the platen 80, preferably at a pressure of from about 15 to about 20 psi. This allows the die or welding rod 85 to be closed firmly against the material to be heat welded, and as the joiner film 50, any tie layer (not shown) and membranes 60, 70 heat up from the applied RF power, the die 85 is allowed to sink in to create a molecular bond of the fabric layers 10, 20 and the membranes 60, 70 with the joiner film 50.
As is known in the art, heat is produced by the reaction of the plastic to the high frequency energy from the RF generator relayed through the die 86. The amount of heat depends on the quantity of RF power applied to the die 85 and the reactivity of the materials to be welded. The pressure applied to the die 85 can be supplied by a pneumatic or hydraulic press. The time of the RF welding is controlled by electronic timers built into the control circuits of the operating press (not shown). RF machines typically include a pre-seal timer, which allows the press to supply full and even pressure on the materials prior to the RF power being applied; a heat seal timer to control the length of time the RF power is applied to the materials; and a dwell or cool timer which is used to allow the material time to set while there is still pressure on the materials.
With reference to FIG. 3, the product following RF sealing is illustrated. The thermoplastic joiner film 50 has melted and filled into voids in the non-containable fabric to form a seal between the fabric layers 10, 20, as well as between the membranes 30, 40. At the same time, the membranes 30, 40 are fused to the outer surfaces of the respective fabric layers 10, 20. The membranes 30, 40 are continuous between the welds to the fabric layer 10, 20, to the welds with the joiner film 50 covering the edges 65. Thus, the double welding of the membranes 30, 40 forms a leakproof seal. The membranes 30, 40 can also weld to the otherwise exposed edges 65 of the fabric section 10, 20 for additional seam strength. In contrast to other welding techniques, however, the joiner film 50 serves to anchor the fabric layers 10, 20 together. This anchoring of the fabric layers 10, 20 to the joiner film S0 serves to minimize stress at the double welds of the membranes 30, 40 so that the seam is stronger and less likely to fail from repeated stress of the seam. The anchoring serves to avoid overstressing the membranes 30, 40 when there is stress on the seam, thereby contributing to the durability of the seam.
Following the RF welding, the article is finished, for example, by die cutting or manually cutting an outer edge of the seam to form a finished edge 95 as shown in FIGS. 4 and 6.
EXAMPLE 1
A thermoplastic sheet was used as a joiner film between non-containable fabric layers and outer waterproof/breathable layers according to the principles of the present invention. The joiner film was a 16 mil polyester aromatic polyurethane blown film having a Shore A hardness of 83, obtained from Stevens Urethane, a division of JPS Elastomerics Corp. under the trade designation ST 1528-83A. Each non-containable fabric layer was KEVLAR® fireproof fabric having a weight of 8 ounces/yard. The outer membrane was 1 mil (30 g/m 2 ) polyurethane obtained under the trade designation FILM 55FR from Proline Textile (Perone, France).
The joiner film was die cut to remove the center portion of the sheet in the pattern of a glove having perimeter dimensions just inside the expected sewn perimeter line of the actual glove, but leaving a tab of material projecting inwardly at the tip of each finger toward the hand and wrist region of the glove. The tabs were sized and positioned to provide means within the seam that could be used for attaching an inner liner, i.e. inner tabs.
Two glove shapes were cut from the KEVLAR® fabric with a perimeter about 1/8-inch larger than that of the cutout in the joiner film to provide an overlap.
Two pieces were cut from the FILM 55FR material in the shape of rectangles with dimensions just outside the greatest dimensions of the glove pattern. The die cut joiner film layer was positioned between the KEVLAR® glove layers, and the FILM 55FR was positioned on the top and under the bottom, above and below the respective upper and lower KEVLAR® glove layers, by means of guide pins between each of the layers.
A radio frequency (RF) welding tool was fastened to the upper platen of a Thermatron 10 kw RF welding machine equipped with a 25-in. by 40-in. bed plate and a 20-in. by 30-in. upper heated platen. The RF welding tool was in proper registration with a foot fixture having the guide pins that register the fabric layers and joiner film directly underneath inside the press of the welding machine. The registration was such that the welding line of the tool followed the perimeter of the glove pattern, falling just inside the perimeter of the KEVLAR® by 1/8-inch and just outside the KEVLAR® layer perimeter by 1/8-inch, and dead center on the die cut shape of the joiner film, so that the welding captured just the edge of the joiner film between the edges of the KEVLAR® layers and a 1/8-inch overlap of the outer membrane layers outside the KEVLAR® layers to join with the joiner film.
The RF welding machine was turned on, the pre-seal time set to 2 seconds, the seal time set to 9 seconds, and the cool timer set to 4 seconds. The low pressure air on the 4-in. diameter cylinder of the RF welding machine was set to 120 psig and the power setting to 27.0 relative (on the high side of the power curve). The platen heater was set to heat the upper platen to a temperature of 110° F. The ram adjustment was not set, allowing the upper platen to completely bottom out on the materials in the press.
The press cycle was initiated to close the press and allow the cycles through pre-seal, seal and cool. The press was opened to obtain the five layers welded in the shape of the glove pattern. The assembly was removed and moved to a clicker cutting device having a foot fixture that matched the foot fixture device used in the bottom or bed plate of the RF welding machine. The foot fixture of the clicker cutter had guide pins identical to those in the RF welding machine to maintain proper registration. A steel rule die having the shape of the glove was fastened to the upper platen of the clicker cutting tool. The line of the steel rule die followed the line of the RF welding tool except for tabs that extended outwardly from the hand region and the tips of the fingers, i.e. outer tabs. The clicker cutter was a standard 25 ton type designed to force the steel rule die through the material, cutting a line along the glove pattern, hitting the material in the middle of the weld (except at the outer tabs) between the joiner film and the outer membrane layers, just outside the perimeter of the KEVLAR® layers.
Once the material was registered with the clicker and the cutting tool, the press was closed and then opened to remove the two pieces. The waste was separated from the glove product. The glove product had inner tabs inside the end of each finger for attachment of a standard cotton or knit shell inside the glove, and outer tabs at the end of each finger and from the sides of the hand region for attachment of a standard leather shell.
EXAMPLE 2
Example 1 is repeated using an additional mesh type fabric with the joiner film to reinforce and strengthen the tabs. The seal time is increased to about 19 seconds to allow additional time for the molten polyurethane to penetrate and flow through the additional mesh layer and bond with the KEVLAR® layers.
EXAMPLE 3
Example 1 is repeated using 8 ounce/yard NOMEX® fireproof fabric in place of the KEVLAR® materials. All other materials and processing steps are unchanged, and the result is the same as in Example 1
Various changes and modifications to the above illustrative embodiments will become obvious to those skilled in the art in view thereof. All such changes and modifications are intended to be embraced by the scope and spirit of the claims which follow.
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A prefabricated multi-layered flexible product which can be used as a liner for an outer shell or as a stand-alone product. A substrate fabric material is placed in parallel with a synthetic film membrane to form a two ply laminate with excess membrane at an edge thereof. A pair of the laminates are overlaid with the substrate fabrics opposing each other with the fabric edges aligned, and a thermoplastic film is strategically placed in between the layers to enhance bonding between the fabric layers and the excess membranes. The laminate(s) and/or separate sheets of above materials are assembled by using a radio frequency welding process and then out into two or three dimensional forms, which in their bonded state form either a prefabricated component liner or a prefabricated stand-alone product. The form may be a glove, sock, shirt, boot/shoe, hat, jacket, pant, etc.
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BACKGROUND OF THE INVENTION
This invention relates to the treatment of water by the controlled introduction of antibacterial substances and by the control of parameters which affect the effectiveness of the substances. More specifically, this invention relates to an apparatus for controlling the chlorine residual and the pH of water in a swimming pool.
Swimming pools provide a great deal of recreational pleasure. The pleasure derived from a swimming pool is substantially dependent upon the quality of the water in the pool. To assure comfort and safety to swimmers using the pool, it is absolutely essential that the water be properly treated chemically. Chemical treatment of swimming pool water primarily involves two pool water tests-- one for chlorine, the other for pH.
Since its introduction into water treatment, chlorination has become a universally accepted method for active disinfection of water and both public and private swimming pools rely on chlorine to sterilize the pool of bacteria and maintain water purity. A chlorine residual must be maintained in the pool water for effective sterilization. If too little chlorine is supplied to the water, not all bacteria will be removed from the water, and the swimming pool will not be safe for swimming. For this reason chlorine in excess of that required for complete sterilization is generally supplied, resulting in a chlorine residual in the pool water. A good average chlorine residual is 1.0 parts per million (ppm); however the pool may effectively have a residual chlorine level as low as 0.6 ppm or as high as 2.0 ppm.
The retention of chlorine residual in swimming pool water is the key to an effective bacteriacidal function. Chlorine escapes into the atmosphere from the open pool water and is consumed by its sterilizing action in an amount proportional to the level of bacteria present in the swimming pool. The quantity of chlorine required to completely sterilize the water in the swimming pool is referred to as the chlorine demand. Chlorine demand of a pool is affected by several factors. The bather load will affect chlorine demand as each swimmer entering the pool uses some of the chlorine residual. Therefore, more swimmers require more chlorine be added to the pool water. Higher water temperatures tend to exhaust chlorine more rapidly. Rain showers and high winds introduce atmospheric contaminants into the pool and dilute its chemical system, creating a greater demand for chlorine. Direct sunlight accelerates the dissipation of chlorine and foliage such as trees, shrubs, flowers and grass in the pool area contribute algae spores, leaves, pollen and associated wastes which stress the pool's chemical system.
Swimming pools may be chlorinated manually by administering a granular form of organic concentrate directly into the pool, but the most common way to introduce chlorine into the pool water is through a chlorinator. A conventional chlorinator receives a continuous flow of water which passes through a container of chlorine. In the past, it has been necessary to periodically perform a manual test on the pool water to check for proper chlorine supply. The test involves the taking of a sample of pool water by hand and adding an indicator substance which provides an indication of chlorine concentration. The pool side test for chlorine establishes the average demand rate and confirms that the necessary level of chlorine residual for effective bacteria control is being maintained. The pool side test for chlorine is usually made using a conventional test reagent, such as o-toludine. While the test should be run often at periodic intervals, all too often the test is not performed due to forgetfulness or inattentiveness.
Proper pH control is essential to the correct operation of a pool as the microbicidal activity of chlorine is pH dependent. The pH value of the swimming pool water expresses its acid-alkali ratio. A desirable pH range for pool operation is pH 7.4 to pH 7.6, slightly basic. Lower pH values tend to accelerate the loss of chlorine and cause excessive eye irritation, corrosion of metal components and possible etching of the pool's interior. Higher pH values slow the microbicidal function of chlorine and can produce scale formation on the pool interior, piping and heater coils.
In addition, some nitrogen, in the form of ammonia, is in the pool water at all times from sources such as human wastes. Chlorine in the pool water may combine with the nitrogen to form other chemical compounds called "chloramines". The formation of chloramines is accelerated as the pH goes to 7.0 or lower. The formation of such compounds is retarded by keeping the pH in the desired slightly basic range. Chloramines may cause eye discomfort to swimmers using the pool a great deal and extensive chemical treatment may be necessary to remove chloramines from the water, assuring its comfort for swimming.
The most frequent adjustment required is to lower the pH of pool water. Left uncorrected, the water in a swimming pool has a tendency to rise in pH due to the introduction of foreign matter. To lower the pH level, strong liquid acids such as muriatic acid have been used. Strong acids of this type are potentially dangerous and are hazardous when being handled. Acid may be added to swimming pool water in several different ways. One approach is to dump a quantity of acid in the swimming pool periodically. The addition of acid to pool water in this manner does lower pH, but the change is abrupt, causing an excessive loss of chlorine in a broad area where the acid is released. A second approach is to use an acidifier connected into a flow line of the circulation system of the pool to constantly supply acid to the pool. This method can result in the addition of too much acid to the pool, driving the pH below the desired range.
It is apparent that present water treatment methods for swimming pools are extremely haphazard and leave much to be desired from a safety and health standpoint. It is further apparent that coordinated control of both chlorine residual and pH without the continual performance of tests is highly desirable.
SUMMARY OF THE INVENTION
In accordance with one aspect of the present invention, an apparatus for automatically controlling a chlorinator supplying chlorine to water in a swimming pool is provided. The apparatus includes an analyzer which produces an electrical signal functionally related to the chlorine residual that is in a liquid sample from the swimming pool. A controller periodically introduces a liquid sample into the analyzer and initiates operation thereof, resulting in the production of the electrical signal. A comparator is coupled to the analyzer and detects the existence or non-existence of a desired level of chlorine residual in the liquid sample based upon the electrical signal produced by the analyzer. The comparator also provides an output signal indicative of the existence or non-existence of the desired level of chlorine residual. A feed control regulates the chlorinator, supplying chlorine to the swimming pool water, in response to the output signal from the comparator to adjust the introduction of chlorine into the swimming pool as needed.
In accordance with a more specific aspect of the present invention, a reagent control device is coupled to the controller and introduces a chlorine reagent substance into the analyzer along with the liquid sample from the swimming pool. Also, the analyzer includes a sample cell into which the liquid sample from the swimming pool is introduced and retained while being analyzed, a light source disposed proximate the sample cell to project light thereon from one side, and a photocell disposed on the side of the sample cell opposite the light source to receive the light passing through the sample cell in the contained liquid sample. The controller includes a timer for initiating sampling and analyzing of the liquid sample on a preselected periodic interval with a state controller coupled to the timer sequencing and coordinating the analysis of the liquid sample within the period of operation defined by the timer. A motor driven plunger is controlled by the controller and draws a liquid sample into the sample cell of the analyzer and expels the liquid sample therefrom at the conclusion of the analysis. A storage element retains the output signal from the comparator over the interval of time between periodic introduction of liquid samples into the analyzer, thereby maintaining the setting of the feed control.
In accordance with another aspect of the invention, there is provided an apparatus for regulating the introduction of a water purification substance and a pH compensation substance into a reservoir of water to maintain a desired pH level therein. An analyzer produces a first electrical signal functionally related to the amount of liquid purification substance present in a first liquid sample from the resevoir and also produces a second electrical signal functionally related to the pH of a second liquid sample from the reservoir. A controller coordinates the taking and analyzing of liquid samples at periodic intervals with reagent introduction means coupled to the controller for entering first and second reagents into the analyzer along with first and second liquid samples. Finally, means responsive to each of the first and second electrical signals from the analyzer enables the introduction of an additional amount of liquid purification substance into the reservoir and also enables the introduction of an additional amount of pH compensation substance.
More specifically, in this aspect of the present invention, timing means supplies timing signals to the controller to initiate the taking of the first and second liquid samples and enables the operation of the analyzer at preselected periodic intervals, and a mechanically actuated piston draws a liquid sample into the analyzer in response to signals from the controller. Operation of the mechanically actuated piston and the reagent introduction means are sequenced by a state controller, which sequencing takes place within the period of enabled operation defined by the timing means.
Even more specifically, the means for enabling the introduction of additional purification substance and pH compensating substance includes a comparator coupled to the analyzer for determining the existence of a desired residual amount of the purification substance and a desired pH level, and for producing signals indicative thereof. Also, feed control means operably connects to the comparator and is responsive to the signals produced by the comparator to regulate the introduction of additional water purification substance and pH compensating substance into the reservoir of water. A storage element couples between the comparator and the feed control means to store the signals from the comparator and continuously present them to the feed control means over the interval of time between the taking of liquid samples.
BRIEF DESCRIPTION OF THE DRAWINGS
In order to appreciate the manner in which the aboverecited advantages and features of the invention are attained and to appreciate and understand others in detail, a more particular description of the invention may be had by reference to specific embodiments thereof which are illustrated in the appended drawings, which drawings form a part of this specification. It is to be noted, however, that the appended drawings illustrate only typical embodiments of the invention and therefore are not to be considered limiting of its scope, for the invention may admit to further equally effective embodiments.
In the drawings:
FIG. 1 is a pictorial view of swimming pool and its associated equipment to which the automatic chlorine and pH control apparatus according to the present invention is connected.
FIG. 2 is a schematic representation of the control system for the automatic chlorine and pH control apparatus shown in FIG. 1.
FIG. 3 is schematic representation of the fluid system internal to the automatic chlorine and pH control apparatus shown in FIG. 1.
FIG. 4 is a front elevation view of the automatic chlorine and pH control apparatus of the present invention.
FIG. 5 is a rear elevation view of the fluid system of the automatic chlorine and pH control apparatus of the present invention.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT
Shown in the embodiment of FIG. 1 is a reservoir of water referred to as a swimming pool 10 having conduits 12 and 14 communicating with the interior body of water held therein. Conduit 12 provides a path for discharge flow circulation from swimming pool 10 and connects to a skimmer 16. Pool water flows from skimmer 16 to a pump 18 which circulates the swimming pool water through the system. From pump 18, pool water is passed through a filter 20 and into a return conduit 22 which supplies pool water to a heater 24 for heating the pool water before it is returned to swimming pool 10 through conduit 14.
Return conduit 22 includes a T-joint 26 which permits a portion of the pool water passing through filter 20 to be siphoned off into inlet conduit 28 which leads to the automatic chlorine and pH control apparatus 30 of the present invention. A first outlet conduit 32 communicates between automatic chlorine and pH control apparatus 30 and an acidifier 34. A second outlet conduit 36 communicates between the automatic chlorine and pH control apparatus 30 and a chlorinator 38. Both acidifier 34 and chlorinator 38 operate in a conventional manner. Pool water passing through acidifier 34 and chlorinator 38 merges to form one stream of water at connecting joint 40 that is passed through conduit 42 back into the main stream of water from swimming pool 10 between skimmer 16 and pump 18.
In general, automatic chlorine and pH control apparatus 30 performs individual tests for the chlorine residual and pH level of the water contained in swimming pool 10 and, based on the results of the analyses performed, control apparatus 30 directs pool water through acidfier 34 and/or chlorinator 38. If both chlorine residual and pH level are within the desired range, control apparatus 30 prevents pool water from flowing through both acidifier 34 and chlorinator 38. Automatic chlorine and pH control apparatus 30 performs a chlorine residual and pH level analysis intermittently at timed intervals. Preferably, an analysis will be performed every eight hours. If by such analyses, control apparatus 30 determines that either additional chlorine or acid should be supplied to the pool water, the appropriate piece of equipment, acidifier 34 or chlorinator 38, will be enabled and its product will be continuously supplied to the pool water until the next test, preferably for a period of eight hours.
Referring now to FIG. 2, a schematic diagram of the control system for the automatic chlorine and pH control apparatus of the present invention is shown. The control system can be divided into the basic functional blocks of power supply, timer, controller, analyzer, comparator and feed control. Each portion of the control system will be discussed in detail in the description which follows.
With further reference to FIG. 2, the power supply 44 of the control system will now be discussed wherein input power for the control apparatus 30 is introduced at input terminals 46 and 48 having connected thereto a stepdown transformer 50. The output voltage of transformer 50 is rectified by a diodes bridge 52 having diodes 53, 54, 55 and 56, which supply current to the +17 volt busline 58. A filter capacitor 60 is connected between the +17 volt busline 58 and ground potential.
Connected to busline 58 is a +8 volt regulator 62 which supplies part of the required system voltage needed for the various electronic components. Regulator 62 supplies 8 volt power to the control system, and busline 58 supplies +17 volt power to the system including exhaust solenoid valve 64, chlorine reagent solenoid valve 66 and pH reagent solenoid valve 68.
The timing means 70 generates timing signals which regulate the operation of the control apparatus 30. Oscillator 72, an astable multivibrator of conventional design, having a pair of inverters 74 and 76 connected in series, supplies a square wave output having a period, preferably of 1.75 seconds. A variable resistor 78 connects to the junction of inverters 74 and 76 and also connects to the junction formed by resistor 81 and capacitor 82. Capacitor 82 further connects to the output of inverter 74, and resistor 80 further connects to the input of inverter 76. A detailed discussion relating to the theory of operation and design of multivibrators of this type may be had by reference to the publication, RCA COS/MOS Integrated Circuit Manual, Technical Series CMS-271, page 89.
The square wave output produced by oscillator 72 is fed to the input 84 of binary counter 86 which is a 14 bit counter capable of making a total of 16,384 binary counts. A count is made with every cycle of the square wave output oscillator oscillator 72 which, as hereinbefore mentioned, is preferably 1.75 seconds. The cycling on and off of automatic chlorine and pH control apparatus 30 is controlled by binary counter 86. Binary counter 86 cycles the control apparatus by activating enabling flip-flop 88, permitting transistor 90 to supply power to lamp 92 and permitting decade counter 94 to count up.
The 1.75 second period of oscillation of oscillator 72 results in binary counter 86 advancing through the total number of binary counts once every eight hours, supplying an output signal on output line 96 to enabling flip-flop 88. Enabling flip-flop 88 is a "D" type having its input tied to voltage regulator 62. When binary counter 86 supplies a signal to flip-flop 88, indicating that an eight hour period has elapsed, flip-flop 88 is clocked to a "set" condition, thereby releasing the reset input 95 on decade counter 94 and turning on lamp 92 through inverter 98, resistor 100 and transistor 90.
In the event that it is desired to perform an analysis at some time other than at the eight hour interval point, a push button switch 102 is provided. Push button switch 102 connects to flip-flop 88 and is operable to force flip-flop 88 to assume a set condition, causing the above described operation to result.
It is seen in the embodiment of FIG. 2 that oscillator 72 and binary country 86 form timing means 70 for periodically activating the automatic chlorine and pH control apparatus to perform chlorine residual and pH level analyses. It can be further seen that the timing means 70 is effective through enabling flip-flop 88 to perform this function. The period between samplings can be altered by changing the frequency of oscillation 72 or selecting a different output of binary counter 86.
Sequencing of control apparatus 30 functions is carried out by a controller 104. The basic element of the controller 104 is decade counter 94 which has ten output lines and advances one count with each clock pulse input. Each count represents a new state and is designated by the particular output line of that count going "high". Input clock pulses to decade counter 94 are received from binary counter 86. In the preferred embodiment shown in FIG. 2, a new clock pulse is supplied to decade counter 94 every twenty-eight seconds. Decade counter 94 also includes a "clock out" feature which supplies a signal via clock output line 106 to enabling flip-flop 88 to reset flip-flop 88, causing decade counter to be disabled and lamp 92 to be extinguished.
Quad input Nor gate 108 receives input signals from decoded outputs 0, 2, 5, and 7 of decade counter 94. The output of Nor gate 108 connects to Nor gate 110, which in turn connects to transistor 114 through resistor 112. A second quad input Nor gate 116 connects to decade counter 94 and receives input signals from decoded output 1, 4, 6, and 9. The output of quad input Nor gate 116 connects to an inverter 118, which in turn connects to driver circuit 120.
Referring further to FIG. 2, a one-shot 122 is connected to decade counter 94 and is triggered by an output signal appearing on decoded output 2. One-shot 122 includes capacitor 124 and resistor 126, which together form an RC network. One-shot 122 detects the presence of decade counter 94 in state 2 and produces a pulse of a duration determined by the RC time constant of capacitor 124 and resistor 126 at the output of one-shot 122. Another one-shot 128, which is identical to one-shot 122, connects to decoded output 7. One-shot 128 includes a capcitor 130 and a resistor 132. One-shot 128 operates in the same manner as one-shot 122, producing a pulse of a defined duration at its output.
Further shown in the embodiment of FIG. 2 is a colorimetric analyzer 134 which performs the chlorine residual and pH test. The analyzer 134 includes a sample cell 136 which receives a metered amount of swimming pool water and reagent. The manner in which pool water and reagent are introduced into sample cell 136 will be discussed fully in connection with the embodiment of FIG. 3. Lamp 92 directs a light beam through sample cell 136 and onto photoelectric cells 138, 140, 142 and 144 which connect to the +8 volt busline 146. Each photocell connects to a resistor forming a separate voltage divider. As shown, photocells 138, 140, 142 and 144 connect to resistors 148, 150, 152 and 154 respectively. It will be apparent that as the color of the solution contained in sample cell 136 changes the amount of light permitted to pass through to the photocells will vary. As the light striking the photocells changes, the resistance values of the photocells change, altering the transfer ratios of the voltage dividers. Therefore, the voltage developed by each voltage divider is dependent upon the amount of light striking its respective photocell, which in turn depends upon the transparency of the solution contained within sample cell 136.
Connected to each photocell is a separate voltage comparator 156, 158, 160 or 162. Comparator 156 connects to the junction formed by photocell 138 and resistor 148 and receives on one input lead the voltage developed across resistor 148. A second input lead to comparator 156 connects to a variable resistor 164. In a similar manner, a first lead of comparator 158 connects to photocell 140 and resistor 152, and a second lead connects to a variable resistor 166. Comparator 160 connects to photocell 142 and resistor 152 with the second input lead for comparator 160 connecting to a variable resistor 168 and to a resistor 170 which is in series with a calibration potentiometer 172. Comparator 162 connects to photocell 144 and resistor 154 with a first input lead and connects to a variable resistor 174 and to a resistor 176, which is in series with another calibration potentiometer 178, with a second lead.
Each voltage comparator functions to detect the existence of a voltage supplied from its respective photocell and resistor combination, which either equals or exceeds the voltage value set by its respective variable resistor. Each comparator provides a two-state output signal, that is, a voltage of either ground potential or of supply voltage potential. Upon the voltage from a respective photocellresistor combination reaching the value set by the respective variable resistor, the output voltage present at the output terminal of the comparator switches to the opposite level.
Voltage comparator 162 serves to detect the existence or non-existence of a predetermined desired chlorine residual level. Calibration potentiometer 178 which connects to comparator 162 through resistor 176, as previously described, provides a reference voltage which corresponds to the the desired level of chlorine residual to be maintained in the pool water. Calibration potentiometer 172 provides a similar reference voltage which represents the desired pH level.
In the preferred embodiment shown, comparator 156 serves to detect the occurence of an error in the introduction of reagent into sample cell 136 with the output signal from comparator 156 being applied to one input of Nor gate 180. Comparator 158 also serves as an error detector, monitoring lamp 92 for the existence of a burned-out bulb, and its output signal is applied to the other input of Nor gate 180. Nor gate 180 provides a signal to flip-flop 182 when either comparator indicates an error. Comparator 160 detects the existence or non-existence of a desired pH level, supplying an output signal to a flip-flop 184. Comparator 162 detects the existence or non-existence of a desired level of chlorine residual, and its output signal is applied to a flip-flop 186.
Flip-flop 186 receives a clock signal from decade counter 94 when it moves into state 4, causing the information as to the existence or non-existence of the desired level of chlorine residual to be stored in flip-flop 186. The clock signal supplied to flip-flop 186 is denoted by the designation "F/F clock 1". Flip-flops 182 and 184 receive a common clock signal from decade counter 94, which clock signal is generated when decade counter 94 moves into state 8 and is denoted by the notation "F/F clock 2". When "F/F clock 2" occurs, the information present at the input lead of each flip-flop is entered therein and stored.
Connected to flip-flop 182 is an inverter 188 which serves to buffer the output signal from flip-flop 182. Resistor 190 connects to inverter 188 and to the base of transistor 192. A lamp 194 connects between the +17 volt buslines 58 and the collector of transistor 192 providing an alarm indicator that is turned on whenever transistor 192 is driven into conduction. Transistor 192 can be driven into conduction by the output of flip-flop 182 whenever an error condition is detected. Thus, there can be an alarm indication whenever there has been a failure of lamp 92, as detected by comparator 158, or no reagent has been entered into sample cell 136, as detected by comparator 156.
Flip-flops 184 and 186 have inverters 196 and 198 receiving the contents stored therein. A resistor 200 connects to inverter 196 and to a driver circuit 202. Similarly, resistor 204 and driver 206 connect to inverter 198. Driver circuits 202 and 204 are preferably Darlington amplifiers. Driver 202 controls solenoid 208 which regulates the flow of water to the acidifier 34. An indicator lamp 210 provides a visual indication that the acidifier 34 is in operation. In an identical manner, driver circuit 109 operates a solenoid valve 212 to control chlorinator 38 operation. An indicator lamp 214 is also provided to give an indication that the chlorinator 34 is enabled.
The combination of lamp 92, sample cell 136 and photocells 138, 140, 142, 144 form analyzer means 134 which periodically receives a liquid sample and is periodically enabled via enabling flip-flop 88 to perform an analysis on the sample. Comparators 156, 158, 160 and 162 form comparator means 155 for providing output signal indication of chlorine residual and pH level. Flip-flops 182, 184 and 186 form storage means 185 for retaining the output signal from the comparator means 155 over the period of time in which the analyzer means 134 is inactive. Drivers 202, 206 and solenoid valves 210, 214 form feed control means 205 for regulating acidifier and chlorinator operation.
As shown in FIG. 2 driver circuit 216 connects between one-shot 122 and chlorine reagent solenoid valve 66, and driver circuit 218 connects in a similar manner between one-shot 128 and pH reagent solenoid valve 68. When decade counter 94 moves into state 2, a pulse is supplied from one-shot 122 to driver circuit 216 which momentarily opens solenoid valve 66, permitting a metered amount of chlorine reagent to be entered into sample cell 136 along with a liquid sample from the swimming pool. Similarly, one-shot 128 produces an output pulse to driver 218 upon the entry of decade counter 94 into state 7, causing driver circuit 218 to momentarily open solenoid valve 68 permitting a predetermined amount of pH reagent to enter sample cell 136 along with a new liquid sample. Both driver circuit 216 and driver circuit 218 are preferably Darlington amplifiers.
As illustrated in FIG. 2, motor 220 is connected to the primary side of step-down transformer 50 at terminals 222 and 224. Between terminal 224 and motor 220 is a relay switch 226 which is closed upon the energization of relay coil 228 connected to the +17 busline 58 and a limit switch 230. Limit switch 230 detects the angular positioning of motor 220 and includes contacts 232 and 234. Energization of relay coil 228 can result from the operation of transistor 114 or driver circuit 120.
Referring now to FIG. 3, a fluid system for handling the fluid flow within automatic chlorine and pH control apparatus 30 is schematically shown. Swimming pool water enters the apparatus at input conduit 236, as denoted by the arrow, and a first tap-off 238 directs the pool water to pH reagent solenoid valve 68. A second tap-off 240 connects acidifier control solenoid valve 242 to the supply of pool water entering inlet conduit 236. A chlorinator control solenoid valve 244 also connects to tap-off 240 and supplies swimming pool water to the chlorinator when opened.
Chlorine reagent solenoid valve 66 connects between pH reagent solenoid valve 68 and sample cell 136. When neither pH reagent solenoid valve 68 or chlorine reagent solenoid valve 66 is activated, sample cell input 246 is placed in fluid communication with tap-off 238 and input conduit 236. The exhaust outlet 248 of sample cell 136 connects to an exhaust solenoid valve 250 which directs exhaust fluid to acidifier fluid line 252.
In FIG. 3, sample cell 136 is shown as a mechanically actuated syringe having a piston 254 movable therein. A connecting rod 256 attaches to piston 254 and extends through one end of sample cell 136. Connecting rod 256 further attaches to a pivot arm 258 by a clevis with a push rod 262 connecting to the opposite end of pivot arm 258 by a clevis 264, causing pivot arm 258 to pivot about pin 266. Reciprocating movement of push rod 262 produces a similar reciprocating movement of piston 254. Withdrawal of connecting rod 256 from sample cell 136 causes a liquid sample from input conduit 236 to be introduced into the interior of sample cell 136 through sample cell input 246.
pH reagent solenoid valve 68 also communicates with pH reagent bottle 268 via conduit 270. During the withdrawal of connecting rod 256 from sample cell 136, pH reagent solenoid valve 68 can be momentarily actuated to place sample cell input 246 in fluid communication with pH reagent bottle 268. As a result, a metered amount of pH reagent is introduced into sample cell 136 along with the liquid sample from input conduit 236. Chlorine reagent solenoid valve 66 communicates with chlorine reagent bottle 272 via conduit 274 and can be momentarily actuated to introduce a metered amount of chlorine reagent into sample cell 136 along with a liquid sample from input conduit 246.
Expulsion from sample cell 136 of the liquid solution contained therein is through exhaust solenoid valve 64. When sample cell 136 is to be emptied, push rod 262 pivots pivot arm 158 causing connecting rod 256 to move into sample cell 136 advancing piston 254 and pushing the contained liquid out exhaust outlet 248. Simultaneously with the inward movement of connecting rod 256, exhaust solenoid valve 64 is opened, permitting the liquid solution in sample cell 136 to be exhausted through acidifier fluid line 252.
Acidifier control solenoid valve 242 and chlorine control solenoid valve 244 are independently controllable such that one or the other, or both may be opened. When chlorine control solenoid valve 244 is opened, the chlorinator is placed in fluid communication with input conduit 236, thereby causing the chlorinator to supply chlorine to the swimming pool. Similarly, when acidifier control solenoid valve 242 is opened, the acidifier is placed in fluid communication with input conduit 236 resulting in additional acid being added to the swimming pool water.
Referring now to FIGS. 4 and 5, the automatic chlorine and pH control apparatus 30 is shown. Specifically, FIG. 4 shows a front elevation view of the apparatus, and FIG. 5 shows a rear elevation view of the apparatus.
First, with reference to FIG. 4, the sample cell 136 referred to in FIGS. 2 and 3 is shown in detail with the photocells 138, 140, 142, 144 mounted on the side thereof with exhaust outlet 248 and sample cell input 246, connecting to sample cell 136. The mechanical linkage comprising connecting rod 256, pivot arm 258 and push rod 262 connects to rotor 276 driven by a motor (not shown) such that when the rotor 276 rotates, push rod 262 reciprocates, producing linear movement of connecting rod 256.
Sample cell 136 and the mechanical linkage described mount to chassis 278 which includes upper and lower support members 280 and 282. Also mounting to chassis 278 is a printed circuit board 284 which carries the control system of the apparatus of the present invention. pH reagent bottle 268 is carried on one side of chassis 278, while chlorine reagent bottle 272 is carried on the other. Also shown in this view are connecting conduits 270 and 274, as well as input conduit 236, acidifier fluid line 252 and chlorine fluid line 286.
FIG. 5 illustrates in detail the fluid system described in FIG. 3. The fluid system mounts to chassis 278 as do motor 220, transformer 50 and calibration potentiometers 172, 178. In the illustration of the fluid system, the reference numerals refer to like components as in FIG. 3. In FIG. 5, tap-off 238 and tap-off 240 are shown as T-fittings, and input conduit 236, acidifier fluid line 252, chlorine fluid line 286 and the conduits 270, 274 are preferably flexible plastic lines.
In operation, after the automatic chlorine and pH control apparatus 30 of the present invention is connected into the circulation system of the swimming pool by inlet conduit 28 and outlet conduits 32, 36, the unit is provided with electrical power from a 110-volt outlet. Electrical power is immediately supplied to +17 volt busline 58 which causes the "power on" lamp 300 to light up and oscillator 72 to immediately begin supplying squarewave pulses to binary counter 86, causing the counter to begin advancing in count. Assuming that binary counter 86 was initially reset, a period of approximately eight hours will elapse before an output signal is supplied over output line 96 to clock enabling flip-flop 88, turning on lamp 92. Alternatively, if it is desired to make an immediate test of chlorine and pH, push button switch 102 may be closed, overriding binary counter 86 and setting enabling flip-flop 88.
With flip-flop 88 in the set condition, decade counter 94 counts the pulses supplied from binary counter 86, which pulses arrive every twenty-eight seconds. Initially, assuming that decade counter 94 is in a reset condition, the 0 state of decade counter 94 will present a signal through Nor gate 108 and Nor gate 110 which will turn on transistor 114. Current is drawn from +17 volt busline 58 through relay coil 228 and contact 232 of limit switch 230 resulting in relay coil 228 becoming energized and relay switch 226 closing, supplying power to motor 220. Energization of motor 220 causes rotor 276 to turn, pulling push rod 262 and causing pivot arm 258 to pivot counterclockwise. This counterclockwise movement of pivot arm 258 causes connecting rod 256 to be urged from within sample cell 136. This movement, of course, causes piston 254 to move within sample cell 136 causing a liquid sample to be drawn into the cell. Motor 220 remains energized until contact is made with limit switch 230, signifying that piston 254 has been fully moved within sample cell 136, opening contact 232, thereby de-energizing relay coil 228. The second contact 234 of limit switch 230 then closes.
Decade counter 94 receives another pulse from binary counter 86 at the end of the next twenty-eight second interval that causes decade counter 94 to move into state 1. Upon this change of state, transistor 114 is turned off and driver circuit 120 is activated. Driver circuit 120, as previously described, opens exhaust solenoid valve 64, and at the same instant, motor 220 is again energized producing further rotation of rotor 276. Further rotation of rotor 276, of course, causes pivot arm 258 to rotate clockwise urging piston 254 back through sample cell 136 with like motion continuing until limit switch 230 is contacted, at which time the motor 220 is de-energized. Exhaust solenoid valve 64 remains open until decade counter 94 moves into the next state.
The discussion just given with regard to the operation of the system during states 0 and 1 of decade counter 94 describes a "washing out" function. This preliminary washing out of the sample cell removes contaminants which might alter the results of the analysis to be performed later.
Upon the receipt of the next clock pulse from binary counter 86, decade counter 94 moves into state 2, at which time transistor 114 is again turned on causing motor 220 to become energized. Motor 220 acts upon rotor 276 to cause piston 254 to be drawn through sample cell 136 in the manner previously described with piston 254 drawing another liquid sample into sample cell 136. One-shot 122 supplies a pulse of predetermined duration to driver circuit 216 opening chlorine reagent solenoid valve 66 to permit a metered amount of chlorine reagent to enter sample cell 136 along with the liquid sample.
The chlorine reagent to be used in the apparatus of the present invention can be any chemical reagent which is sensitive to chlorine concentration and which can show a color change proportional to the concentration of chlorine in a liquid sample. Since chlorine is an active bleaching agent, an effective chlorine reagent is one which is colored, with the color being bleached out by the chlorine in the liquid sample. The degree of bleaching and, as a result, the color and transparency of the liquid sample as compared to a predetermined reference can then be utilized as a measure of the chlorine content of the liquid sample. Typical chlorine reagents found particularly effective for use in the apparatus of the present invention include methyl orange and phenophthalein. The apparatus of the present invention is preferably calibrated to detect at color change a chlorine residual of 1 ppm. The above materials turn completely clear with a chlorine residual of 3 ppm.
Decade counter 94 advances to state 3 with the next pulse. Upon the occurence of passage into this state, transistor 144 is turned off, and the system assumes a quiescent condition to provide an additional twenty-eight second interval in which the chlorine reagent can mix with the liquid sample and fully react.
As the mixture within sample cell 136 reacts, the color of the solution changes due to chlorine bleaching of the chlorine reagent. Depending upon the amount of chlorine residual present in the liquid sample, the solution will have a certain degree of transparency which will of course, affect the amount of light striking photocell 144. At the conclusion of the reaction and upon the solution reaching a stable condition, photocell 144 in combination with resistor 154 outputs a constant voltage to comparator 162. Comparator 162 compares the voltage from photocell 144 and resistor 154 with a reference voltage determined by calibration potentiometer 178 along with variable resistor 174 to detect the existence of a voltage from the analyzer 134 which exceeds the reference voltage and to produce a voltage at its output indicative thereof. The comparator 162 produces a two level output voltage that is compatible with the digital flip-flop 186. The detection result, in the form of a "high" or "low" logic output, from comparator 162 is presented to flip-flop 186. When decade counter 94 receives the next pulse from binary counter 86, sending decade counter 94 into state 4, a clock signal will be supplied to flip-flop 186, causing the detection result to be stored therein.
At the same time flip-flop 186 is being supplied with the clock signal, that same signal is also being supplied to Nor gate 116 which activates driver circuit 120, opening exhaust solenoid valve 64 and at the same time energizing motor 220. Piston 254 is again caused to move back through sample cell 136 exhausting the reacted solution contained therein. From the schematic diagram in FIG. 3, it will be observed that the contents of sample cell 136 are exhausted through acidifier fluid line 252 and are fed into the swimming pool. The chlorine reagents referred to above are not detrimental to humans, and are fed into the pool only in minute quantities. However, if it is not desired to permit the reacted solution to be fed back into the pool, the discharge of the exhaust solenoid valve 64 could be directed to a separate reservoir container.
The next two pulses from binary counter 86 send decade counter 94 into state 5 and then state 6 with the operation of these two states being the same as that which occurs during states 0 and 1. That operation is, of course, the "washing out" of sample cell 136 to rid it of any contaminants which might affect the analysis to be next performed for pH level.
As decade counter 94 moves into state 7, motor 220 is again energized causing piston 254 to be urged through sample cell 136 drawing a liquid sample thereinto. At the same time that the liquid sample is being drawn into the sample cell, one-shot 128 activates driver circuit 218 causing pH reagent solenoid valve 68 to open permitting a metered amount of pH reagent to enter sample cell 136 along with the liquid sample.
The pH reagent can be any chemical reagent which is sensitive to pH within the predetermined range selected for the swimming pool. This chemical reagent can be one which demonstrates a color range of characteristic color within this pH range, but not above. By observing this color change or characteristic color through the apparatus of the present invention, it is then possible to obtain a result which dictates the addition or non-addition of acid to the swimming pool. A very suitable pH reagent has been found to be cresol red. This material goes through a gradual color change of yellow-red-purple through the pH range desirably maintained in the swimming pool water. For example, the reagent is colorless at pH 6.8, pink at pH 8.3 and purple at pH 9.4. Triggering of the apparatus can therefore be easily calibrated to this color change.
After the pH reagent and liquid sample mix and react, resulting in a change of color of the liquid sample, a voltage is supplied to a comparator 160 from photocell 142 that is functionally related to the color the liquid sample and hence the pH thereof. Comparator 162 detects the existence of a desired pH by comparing the voltage with a reference voltage from resistors 168 and 170, and produces an output signal indicative thereof, which signal is a twolevel signal compatible with digital flip-flop 184.
When decade counter 94 moves into state 8 at the occurrence of the next pulse from binary counter 86, a clock signal is supplied to flip-flop 184 causing it to store the detection result therein. This clock signal, denoted F/F clock 2, is also supplied to flip-flop 182 which stores the alarm detection results available from comparators 156 and 158.
The next pulse from binary counter 86 sends decade counter 94 into state 9 resulting in a signal being supplied to Nor gate 116, which again activates driver circuit 120 to open exhaust solenoid valve 64, permitting the reacted solution present in sample cell 136 to be exhausted leaving the cell empty. Also, as mentioned above with regard to the chlorine reagents, the pH reagent can be discharged back into the pool without danger, or if so desired, a separate reservoir can receive the reacted solution from sample cell 136. Also, a pulse is produced by decade counter 94 and is supplied to flip-flop 88 via output line 106 forcing enabling flip-flop 88 to become reset inhibiting decade counter 94 and extinguishing lamp 92.
Flip-flops 182, 184 and 186 energized, however, and the information stored therein is continuously suppled to circuitry external to them. Specifically, flip-flop 186 supplies a continuous signal to driver circuit 206 causing chlorine control solenoid valve 212 to be maintained in an open or closed position over the following eight hour interval before analyzer operation is again permitted. Similarly, flip-flop 184 supplies a signal to driver circuit 202 causing acidifier control solenoid valve 208 to maintain the acidifier in an opened or closed position until the next analysis. Finally, flip-flop 182 supplies a signal to produce an alarm indication via lamp 194.
The foregoing description has been a discussion of one entire cycle of the operation of automatic chlorine and pH control apparatus 30. At the conclusion of a cycle of operation, oscillator 72 and binary counter 86 continue to operate. When binary counter 86 again times out an eight hour period, a new analysis will be performed for both pH and chlorine residual. At that time, the condition set in flip-flops 184 and 186 can be changed to reflect an updated condition.
Components for the preferred embodiments of the chlorine and pH control apparatus include:
______________________________________POWER SUPPLYTransformer 50 Stancor RT-202Diodes 53, 54, 55, 56 1N 916Capacitor 60 1000 microfaradsVoltage Regularor 62 Fairchild 7808UCTIMERVariable resistor 78 5-6 megaohmsResistor 80 15 megaohmsCapacitor 82 0.1 microfaradInverters 74, 76 Motorola MC14049CPBinary Counter 86 Motorola MC14020CPCONTROLLERDecade Counter 94 Motorola MC14017CPNor gate 108, 116 Motorola MC1402CPNor gate 110 Motorola MC1401CPInverter 118 Motorola MC14049CPOne Shot 122, 128 National MM 74 G 221 NCapacitor 124, 130 ITT 4.7 mfResistor 126, 132 Comprehensive 82 k ohmsANALYZERPhotocell 138, 140, 142, 144 Quantrol Z 240AResistors 148, 150, 152, 154 1000 OhmsInverter 98 Motorola MC14049CPResistor 100 10,000 OhmTransistor 90 Texas Instruments A572222COMPARATORComparator 165, 158, 160, 162 National Semiconductor LM 339Potentiometers 164, 166, 168, 172 174, 178 2000 OhmsResistors 170, 176 2700 OhmsNor gate 180 Motorola MC14001CPSTORAGEFlip-flop 182, 184, 186 Motorola MC14013CPFEED CONTROLInverters 196, 198 Motorola MC14040CPResistors 200, 204 10,000 OhmsDriver 202, 206 Darlington AmplifierSolenoid 208 Asco US82617Solenoid 212 Asco USX8210A20MISCELLANEOUSTransistor 192, 114 Texas Instruments A572222Resistor 190 10,000 OhmsInverter 188 Motorola MC14049CPFlip-flop 88 Motorola MC14013CPDriver 120, 216, 218 Darlington amplifiersResistor 112 10,000 OhmMotor 220 Dayton 3M287Limit Switch 230 Micro-Switch 311SM3Relay 228 Potter & Brunsfield KA5DYSolenoid 64, 66, 68 64-Asco US 8262C13 66-68 Skinner C4R180______________________________________
While the present invention has been described primarily with regard to the foregoing preferred embodiments, it should be apparent that the present invention can be subject to various modifications within the scope of the present invention. Accordingly, the present invention cannot be limited to the embodiments above, but must be construed as broadly as any and all equivalents thereof.
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Control apparatus for swimming pools to automatically regulate chlorinator and acidifier operation, thereby maintaining a desired chlorine residual and pH level. A first liquid sample from a swimming pool along with a chlorine reagent substance and a second liquid sample from the pool along with a pH reagent are sequentially introduced into a sample cell with a light source projecting light through the sample cell onto first and second photoelectric cells. The first photocell produces a signal having a magnitude that is directly proportional to the chlorine residual in the first liquid sample, and the second photocell produces a signal functionally related to the pH level of the second liquid sample. First and second comparators connected to the first and second photoelectric cells detect whether the chlorine residual or the pH level of the pool water is above or below a prescribed value and supply a two-state output signal which represents the existence or non-existence of the prescribed level of chlorine residual or pH in the liquid samples. Flip-flops store the detection results and supply signals to driver circuits which initiate or inhibit chlorinator and acidifier operation. A timing circuit periodically enables system operation with a state controller sequencing system operation.
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FIELD OF THE INVENTION
The present invention relates generally to the area of quality control for recombinant agents to be used in gene therapy. More specifically, the invention concerns an assay which can be used to assess the percentage of defective vector in a vector stock, where the vector encodes a therapeutic gene. Most specifically, the invention concerns a method for assessing the percentage of adenovirus containing a non-functional p53 gene in an adenovirus stock containing wild-type p53 to be used for clinical gene therapy.
DESCRIPTION OF RELATED ART
Current treatment methods for cancer, including radiation therapy, surgery and chemotherapy, are known to have limited effectiveness. For example, lung cancer alone kills more than 140,000 people annually in the United States. Recently, age-adjusted mortality from lung cancer has surpassed that from breast cancer in women. Although implementation of smoking-reduction programs has decreased the prevalence of smoking, lung cancer mortality rates will remain high well into the 21st century. The rational development of new therapies for lung cancer will depend on an understanding of the biology of lung cancer at the molecular level.
It is well established that a variety of cancers are caused, at least in part, by genetic abnormalities that result in either the over expression of one or more genes, or the expression of an abnormal or mutant gene or genes. For example, in many cases, the expression of oncogenes is known to result in the development of cancer. "Oncogenes" are genetically altered genes whose mutated expression product somehow disrupts normal cellular function or control (Spandidos et at., 1989).
Many oncogenes studied to date have been found to be "activated" as the result of a mutation, often a point mutation, in the coding region of a normal cellular gene, known as a "proto-oncogene." These mutations result in amino acid substitutions in the expressed protein product. This altered expression product exhibits an abnormal biological function that contributes to the neoplastic process (Travali et al., 1990). The underlying mutations can arise by various means, such as by chemical mutagenesis or ionizing radiation. A number of oncogenes and oncogene families, including ras, myc, neu, raf, erb, src, fms, jun and abl, have been identified and characterized to varying degrees (Travali et al., 1990; Bishop, 1987).
During normal cell growth, it is thought that some growth-promoting proto-oncogenes are counterbalanced by growth-constraining tumor suppressor genes. Several factors may contribute to an imbalance in these two forces, leading to the neoplastic state. One such factor is mutations in tumor suppressor genes (Weinberg, 1991).
One important tumor suppressor is the cellular protein, p53, which is a 53 kD nuclear phosphoprotein that controls cell proliferation. Point mutations in the p53 gene and allele loss on chromosome 17p, where the p53 gene is located, are among the most frequent alterations identified in human malignancies. The p53 protein is highly conserved through evolution and is expressed in most normal tissues. Wild-type p53 has been shown to be involved in control of the cell cycle (Mercer, 1992), transcriptional regulation (Fields et al., 1991), and induction of apoptosis (Yonish-Rouach et al., 1991, and, Shaw et al., 1992).
Various mutant p53 alleles are known in which a single base substitution results in the synthesis of proteins that have altered growth regulatory properties and, ultimately, lead to malignancies (Hollstein et al., 1991). In fact, the p53 gene has been found to be the most frequently mutated gene in common human cancers (Hollstein et al., 1991; Weinberg, 1991), and is particularly associated with those cancers linked to cigarette smoke (Hollstein et al., 1991; Zakut-Houri et al., 1985). The over-expression of mutated p53 in breast tumors has been documented (Casey et al., 1991).
One of the most interesting aspects of gene therapy for cancer relates to utilization of tumor suppressor genes, such as p53. It has been reported that transfection of wild-type p53 into certain types of breast and lung cancer cells can restore growth suppression control in cell lines (Casey et al., 1992). Although direct DNA transfection is not an efficient means for introducing DNA into patients' cells, these results serve to demonstrate that supplying tumor suppressors to cancer cells may be an effective treatment method if improved means for delivering tumor suppressor genes are developed.
Gene delivery systems applicable to gene therapy for tumor suppression and killing are currently being investigated and developed. Virus-based gene transfer vehicles are of particular interest because of the efficiency of viruses in infecting actual living cells, a process in which the viral genetic material itself is transferred to the target cell. Some progress has been made in this regard as, for example, in the generation of retroviral vectors engineered to deliver a variety of genes. Adenovirus vector systems have recently been proven successful in vitro and in animal studies in certain gene transfer protocols.
As the methods and compositions for gene therapy of cancer are improved, clinical treatments are becoming possible. This will require the large scale production of vector stocks. Such large scale production involves generating large amounts of sample vector stock from a "pioneer" vector stock arbitrarily designated as having 100% activity. Concerns arise over the loss of activity in this "scale-up." Clearly, quality control analysis of sample vector stocks will be a necessary step before any treatment regimen is undertaken. For example, it will be necessary to ensure that a sample vector stock contains sufficient active vector to mediate the intended therapeutic effect.
An important consideration expressed by the National Institutes of Health (NIH) Recombinant DNA Advisory Committee (RAC) and Federal Drug Administration (FDA) is the biological significance of these mutations in the final clinical stock. While it is highly unlikely that such mutant vectors would pose any risk to the patient or to those coming in contact with the patient, regulatory agencies will require a quality control analysis for clinical vector preparations. The NIH RAC has stated that the most important quality control aspect is biologic function. Thus, there is a need for an assay that evaluates the percentage of defective vectors in vector stocks for therapeutic use.
There remains, therefore, a clear need for the development of a quality control assay that evaluates the amount of defective or therapeutically inactive vector in a clinical vector stock and the concomitant loss of biologic activity in clinical vector stocks.
SUMMARY OF THE INVENTION
The present invention addresses the foregoing need by providing an assay for measuring the quality of vector preparations for therapeutic use. Specifically, a method for determining the percentage of defective or therapeutically inactive vectors in a sample vector stock is disclosed. It is envisioned that the method of the present invention can be utilized to quantitate loss of biological activity in a variety of therapeutic vector preparations.
In a general embodiment, the present invention provides a method of determining the percentage of defective vectors in a vector stock which is genetically engineered to contain an effector gene that inhibits tumor cell growth, induces tumor cell apoptosis or kills tumor cells. The method comprises the following steps:
a) contacting rumor cells with a vector stock under conditions permitting the introduction of vectors into tumor cells;
b) incubating tumor cells under conditions permitting growth of the cells;
c) assessing tumor cell growth after a sufficient period of time;
d) comparing the tumor cell growth with the growth of cells when contacted with one or more test standard stocks comprising positive control vectors carrying a functional effector gene and negative control vectors not carrying a functional effector gene.
Therefore, in a general sense, the first aspect of the present invention involves contacting rumor cells with a vector stock under conditions which allow importation into the tumor cells of the vector stock. The vector stock may be composed of a virion or plasmid that will infect the particular tumor cells of interest under conditions sufficient to permit such infection. The vector may contain various regulatory elements such as promoters and/or enhancers. The stock will contain from 0 to 100% functional effector gene. Specific examples of such vector stocks include but are not limited to viral vectors such as adenovirus, retrovirus, vaccinia virus, and adenoassociated virus. The tumor cell being contacted will be a target, subject to infection by, the particular vector stock employed for each particular assay. Examples of preferred tumor cells are lung, colon, breast, pancreas, prostate, head and neck, and skin cancer cells.
In a preferred embodiment, the present invention provides that vectors of the test standard stock lacking a functional effector gene, i.e., negative control vectors, encode a luciferase gene. An indicator gene is one that provides evidence of its successful incorporation into a vector. For instance, in a particularly preferred embodiment of the present invention, the indicator gene utilized is the luciferase gene which provides visual evidence of its incorporation. Conditions sufficient to allow infection of tumor cells with vector stock vary with the particular tumor cells and vectors employed in the assay. Such conditions are well known in the art.
Generally, the second aspect of the present invention involves incubating tumor cells under conditions permitting growth of the cells. Sufficient incubation time varies with the particular tumor cell and vector stock combination being assessed. A preferred period sufficient to allow tumor cell growth is between 2 and 10 days. In a preferred embodiment, utilizing an adenovims vector stock and SAOSLM tumor cells (American Type Culture Collection, Rockville, Md.), sufficient growth inhibition occurs in 3 to 5 days.
In a general sense, the third aspect of the present invention involves assessing tumor cell growth after a sufficient period of time. Growth can be assessed by cell counting techniques well known in the art.
Finally, the fourth aspect of the present invention generally involves comparing the growth of rumor cells infected with vector stock to standard test stocks comprising vectors containing known amounts of vector carrying a functional effector gene, i.e. , positive control vectors, and negative control vectors. Functional effector gene refers to the therapeutic gene of interest which is theoretically contained in some amount in the vector stock being tested. Such effector genes include tumor suppressor genes, anti-sense constructs and toxins.
In a more preferred embodiment, the present invention provides that the vectors claimed are adenovirus vectors. Further, these adenovirus vectors can be contained within infectious adenovirus particles.
In yet another preferred embodiment, the therapeutic effector gene chosen to be incorporated into vector is a tumor suppressor. A particularly effective effector gene is the wild-type p53 gene.
In still another preferred embodiment, the percentage of statistically significant detectable defective vectors is between 0.5 and 10%. A most preferred embodiment dictates the percentage of statistically significant detectable defective vectors is greater than 0.5%.
Another embodiment of the present invention provides a kit comprising at least one receptacle which contains a test standard stock. The test standard stock or stocks included within the kit contain known percentages of defective vector compositions. In a preferred embodiment the defective vector composition or compositions are made up of vector incorporating the luciferase gene. In another preferred embodiment the kit may also have included a receptacle which contains a functional effector gene. In a preferred embodiment, the functional effector gene is the wild-type p53 tumor suppressor gene. In a most preferred embodiment, the kit includes receptacles of test standard stock mixtures containing vectors preparations encoding indicators genes in the percentages of 0%, 0.1%, 0.5%, 1.0%, 2.0%, 5.0%, 10%, 20% and 100%.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1. Growth curves for SAOS-LM cells after incubation with medium, Adp53 and Adp53 containing varying amounts of Adluc. Each point represents the mean ISD for triplicate dishes.
FIG. 2. Expansion of the growth curves from FIG. 1. Each point represents the mean ISD for triplicate dishes.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
Gene therapy is becoming a viable approach for the treatment of cancer. As the problems with target specificity, transfer and expression levels are solved, therapeutic gene constructs will become common tools for treating neoplastic disease.
Evaluation of vector stocks for use in gene therapy will be required for both safety and efficacy reasons. Molecular means for the analysis of vector stocks are not practical at this point in time; thus, reliance must be placed on biologic function. One way of standardizing biologic function is to produce test standard stocks of the therapeutic vector that mimic the biologic activity of vector stocks containing various percentages of defective vectors. It is potentially hazardous to create defective vectors containing mutated therapeutic genes to standardize evaluative assays. For example, a mutated p53 gene could be potentially harmful. Therefore, an assay has been developed for determining the percentage of defective vector in a sample vector stock which utilizes a surrogate for defective vector.
According to the present invention, an assay is provided which measures diminution of wild-type function in a vector stock using defective vector. This defective vector represents a vector that has lost function during generation of the vector stock. In its most basic form, the defective vector is simply a vector without any inserted therapeutic gene but may also include an inactive or mutated therapeutic gene. The defective vector has no therapeutic effect on tumor cells because it expresses no therapeutic gene. In order to mimic the existence of defective vector, it is possible to mix a known defective vector, i.e. , a negative control vector, with wild-type vector-effector stocks, i.e. , positive control vectors. In a preferred example, such a negative control vector expresses an indicator gene like the luciferase gene (Adluc). Adluc serves as an indicator of the percentage of defective vector in the test stock.
VECTORS: The vectors that can be tested according to the disclosed assays may vary considerably. The vectors may be standard expression vectors that contain one or more effector genes and regulatory elements required for expression of the effector gene in cells. The regulatory elements will comprise at least a promoter and may also include structures that enhance the transcription of the effector gene (enhancers). The regulatory elements may include structures that permit expression of the effector in a limited class of cells (cell-specific promoters).
Where standard expression vectors are used, various methods for their introduction into cells will be employed. For example, the vectors may be encapsulated in liposomes, conjugated to targeting agents, attached to microparticles or otherwise modified to permit uptake or introduction into target cells. It also is contemplated that naked DNA may, in some instances, be sufficiently transported across cell membranes to be used in gene therapy. Whatever the transfer mechanism of choice or the form of the vector, an assay designed to test the activity of the vector stock will employ that mechanism.
Another form of vector is a viral vector. Viral vectors have been developed from a variety of different virus systems including adenovirus, herpesvirus, retrovirus, vaccinia virus and adeno-associated virus. These vectors have two advantages over standard expression vectors. First, the vectors can be engineered to replicate and encapsidate like infectious virus DNA. This permits the normal targeting and entry system of the virus to be usurped. In addition, the regulatory elements of the virus often are compatible with the gene expression machinery of the cells they infect. Of course, both host range and regulatory elements may be modified for a particular purpose.
EFFECTOR GENE: The effector gene encoded by the vector may be any gene that confers some detectable biologic activity on a tumor cell. Typically, the activity is growth inhibition, stimulation of programmed cell death (apoptosis) or direct cell killing. Various effector genes will have one or more these activities. For example, some tumor suppressor genes will inhibit the growth of tumor cells while others will restore normal programmed cell death of cells. p53 is a classic example of a tumor suppressor. Other tumor suppressors include RB, APC, DCC, NF-1, NF-2, WT-1, MEN-I, MEN-II, BRCA1, VHL, FCC and MCC. Oncogenes are appropriate targets for antisense constructs and include ras, myc, neu, raf, erb, src, fms, jun, trk, ret, gsp, hst, bcl and abl. Toxin genes or genes that block essential cells functions may inhibit the growth of minor cells or kill the cells outright. Toxins include cholera toxin, pertussis toxin, diphtheria toxin, tetanus toxin, ricin, endotoxin. Genes that render cells sensitive to an outside agent such as a cell surface antigen or thymidine kinase also will permit killing of cells.
CELLS: In theory, any tumor cell should be amenable to this sort of analysis. Of course, the tumor must be susceptible to the effector gene used. For toxins or genes that render cells susceptible to an outside agent, almost any cell will work. Antisense constructs and tumor suppressor will have to be tested with particular ramors to assess susceptibility. Lung, breast, colon, head & neck, pancreas, osteosarcoma and prostate tumor cells are exemplary of the cells that will be susceptible to treatment with the tumor suppressor p53.
ASSAY CONDITIONS: The conditions under which the assay is conducted will vary from assay to assay. For example, the condition under which treated cells are incubated and the time of incubation will vary depending on the particular assay. Where growth of cells is the assay read-out, the conditions and time period will vary according to the requirements of the cells involved. Where cell killing is the assay read-out, the conditions and time period will depend on the conditions and time necessary for the effector gene to kill cells. For other effector activities such as growth in soft agar or colony formation, the appropriate conditions, times and additional treatments will be clear to the skilled artisan.
SENSITIVITY: A sample vector stock will contain millions and sometimes trillions of vectors. An assay based on biological activity has a limited ability to identify defective vectors that exist at very low percentages. Depending on the particular kind of vector, the rumor cells being treated and the assay read-out, the threshold for statistically significant results will vary. Those of skill in the art can determine the sensitivity threshold of an assay simply by generating a series of test standard stocks.
For example, one will mix varying percentages of the negative control vector with a positive control vector (e.g., a sample of the pioneer vector stock) arbitrarily designated as having 100% activity. Of course, activity is defined relative to the vector-gene construct being tested. For instance, 100% activity of the positive control stock may be defined in terms of varying degrees of minor cell death, growth inhibition, apoptosis, or in terms of expression of an encoded gene. With some percentage of negative control vector added to the positive control stock, there will be statistically significant difference between the behavior (growth, killing, etc. ) of cells treated with the positive control and the various positive-negative standard stock mixtures. This minimum statistically significant difference is the sensitivity level of the assay.
KITS: It will be desirable to provide kits for particular vector systems that contain, at a minimum, a negative control vector. Typically, these negative control vectors will encode a marker gene, like luciferase, that permits the user to monitor the amount of negative control vector that is in a test vector stock. Such kits also may contain trays or dishes suitable for culture of cells, dilution buffers and chambers, cells for propagation of the negative control vector, media and instructions.
ADENOVIRUS-p53: In a preferred embodiment, the assay is designed to measure the tumor suppression activity of an adenovirus-p53 construct (Adp53). While the mutation rate for viral vectors is not documented, the error rate for an adenovims DNA polymerase is not expected to be higher than that for a mammalian DNA polymerase. Thus, it is possible that in a preparation of 10 10 adenoviral particles there could be as many as 10 4 copies of inactive or mutant p53 expressing adenoviruses.
The identification of mutant vectors by molecular means such as PCR is neither practical nor sufficient for this purpose. Moreover, since there is no assay for cell transformation mediated by mutant p53 by itself, it would be necessary to develop an assay to detect a cooperative event with another oncogene such as ras(2). Such assays are difficult to quantirate. Furthermore, many cells are not responsive to such a combination of genes. Also, this type of assay would also require as a positive control a mutant p53 vector. This has been prohibited by the RAC because of its potential hazard.
Specifically, the assay compares the activity of a pioneer stock of Adp53 vector with the activity of newly produced sample stocks. The pioneer stock of Adp53 is defined as mediating cell death in 100% of SAOS cells (human osteosarcoma cell line with a homozygous p53 deletion) at an MOI of 50:1 on the 5th day of culture. Such pioneer stocks eliminate tumors in vivo in an orthotopic model of human lung cancer growth in nude mice (Fujiwara et al., 1994; Zhang et at., 1993). By adding increasing amounts of defective vector to the pioneer stock (i.e., a stock of positive control vector), it is possible to mimic a sample stock with varying amounts of defective Adp53. The sample Adp53 is then tested for its ability to kill SAOS cells in 5 days and the growth curve compared to curves generated by test stocks with varying percentage of defective vector.
EXAMPLE
DETERMINATION OF THE PERCENTAGE OF DEFECTIVE VECTOR IN A SAMPLE LOT OF ADP53 ADENOVIRUS VECTOR STOCK
SAOS-LM cells (SAOS cell variant lung metastasis) were inoculated at 10 6 cells per 60 mm culture dish. Dishes were then incubated at 37° C. overnight. The cells were counted prior to virus infection. Cells were infected at an MOI of 50:1. Groups included Adp53 pioneer, Adp53 stock containing 0.1%, .5%, 1%, 5%, 10%, and 20% Adluc (reconstituted positive controls), and the test lot of Adp53. All groups were set up in triplicate. Cells were counted daily (two counts per dish) for 5 days. The experiment was performed 3 times.
The results are shown in FIG. 1 and FIG. 2. FIG. 1 shows the profound inhibition of SAOS cells by Adp53 pioneer stock and the lesser inhibition where defective vector has been added. Statistically significant and reproducible differences can be measured by day 3 of the assay and is clearer at day 5. FIG. 2, for example, on day 3 the mean cell count was 25±4 (±S.D.) for Adp53 pioneer stock, and the mean cell count for Adp53 with 1% defective vector was 36±4. This difference is significant at the p<0.02 level. The limit of sensitivity for the assay appears to be 1% as the differences for 0.5% and 0.1% defective vector are not statistically significant. Thus the presence of 1% defective vector in a preparation is biologically significant and detectable reproducibly by this assay.
In conclusion, the development of a biologic standard combined with a surrogate for p53 mutant vector has resulted in the development of a sensitive bioassay for inactive vector. While the compositions and methods of this invention have been described in terms of preferred embodiments, it will be apparent to those of skill in the art that variations may be applied to the composition, methods and in the steps or in the sequence of steps of the method described herein without departing from the concept, spirit and scope of the invention. More specifically, it will be apparent that certain agents that are both chemically and physiologically related may be substituted for the agents described herein while the same or similar results would be achieved. All such similar substitutes and modifications apparent to those skilled in the art are deemed to be within the spirit, scope and concept of the invention as defined by the appended claims.
The following references, to the extent that they provide exemplary procedural or other details supplementary to those set forth herein, are specifically incorporated herein by reference.
LITERATURE CITED
Bishop, Science, 235 305-311, 1985,
Casey, G., Lo-Hueh, M., Lopez, M. E., Vogelstein, B., and Startbridge, E. J., Growth suppression of human breast cancer cells by the introduction of a wild-type p53 gene. Oncogene 6: 1791-1797, 1991.
Fields et at., Science, 249: 1046-1049, 1990.
Fujiwara, T., Grimm, E. A., Mukhopadhyay, T., Zhang, W. W., Owen-Schaub, L., and Roth, J. A. Induction of chemosensitivity in human lung cancer cells in vivo by adenovirus-mediated transfer of the wild-type p53 gene. Cancer Res. 54: 2287-2291, 1994.
Hollstein, M., Sidransky, D., Vogelstein, B., and Harris, C., p53 mutations in human cancers. Science, 253: 49-53, 1991.
Mercer, W. E., Cell cycle regulation and the p53 rumor suppressor protein. Critic. Rev. Eukar. Gene Express, 2: 251-263, 1992.
Spandidos et al., J. Pathol, 157:1-10, 1989.
Travali et al., FASEB, 4:3209-3214, 1990.
Weinberg, R. A., Tumor suppressor gene. Science, 254: 1138-1145, 1991.
Yonish-Rouach et al., Nature, 352:345-347, 1991.
Zhang, W. W., Fang, X., Mazur, W., French, B. A., Georges, R. N., and Roth, J. A. High-efficiency gene transfer and high-level expression of wild-type p53 in human lung cancer cells mediated by recombinant adenovirus. Caner Gene Therapy, 1993. (in press)
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The present invention relates generally to the area of quality control for recombinant agents to be used in gene therapy. Specifically, the invention concerns an assay used to identify the percentage of defective or therapeutically inactive vector in a vector stock.
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CROSS-REFERENCE TO RELATED APPLICATION(S)
None.
BACKGROUND OF THE INVENTION
The present invention relates to a volleyball apparatus, and in particular to a training apparatus used for volleyball practice.
Members of a volleyball team must practice several ball-striking moves to hone skills. Some practice is acquired during team practices, but many times further practice is required whereby drills are carried out. In these instances, the balls become strewn throughout the court and the practicing individual or others must retrieve the balls, which wastes time. This method of practice also wastes gymnasium space since only one or two players are benefitting from the court time. In addition, players are confined to only practice where the volleyball court is set up in the gymnasium.
Other training devices were previously described such as in Crist, U.S. Pat. No. 5,062,646. This apparatus, however, is fixed to a wall preventing it from being portable. Even though the Crist device is collapsible, it can not be completely removed from the gymnasium and stored in another convenient location.
BRIEF SUMMARY OF THE INVENTION
The invention is a volleyball training apparatus. The apparatus has a frame with front and back support members that extend vertically. A first net is attached to and extends between the front support members. A second net is attached to and extends between the back support members and creates a pocket behind the first net.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 a is one embodiment of the volleyball training apparatus invention.
FIG. 1 a is the training apparatus with the second net removed.
FIG. 2 shows the second net of FIG. 1 a.
FIGS. 3 a and 3 b are end views of the frame showing the preferred positioning of the wheels.
FIGS. 4 a and 4 b are top views of the left lower side of the frame showing preferred positions of frame components in the setup and collapsed states.
FIG. 5 is an exploded side view showing the basic components of the frame.
FIG. 6 shows another embodiment of the invention.
FIGS. 7 a - 7 c show the second net used in FIG. 6 .
DETAILED DESCRIPTION
FIG. 1 a shows the preferred embodiment of training apparatus 10 . Training apparatus 10 includes frame 12 (formed by front posts 14 , back posts 16 , front poles 18 , back poles 20 and 22 , net stabilizers 24 a and 24 b , coupler 26 , end bars 28 a and 28 b , cross bars 30 a and 30 b , hinges 32 , supports 34 , cross stabilizers 36 , stabilizing bars 38 , fasteners 40 , pole mounts 42 with pegs 44 a and 44 b , sleeves 46 , and set screws 48 ), first net 50 , second net 52 (with edges 54 , 56 , and 58 , and panels 60 and 62 ), ball release 64 , wheel supports 66 , and wheels 68 .
Front posts 14 and back posts 16 are located at each comer of frame 12 . Front poles 18 stack on front posts 14 , back poles 20 stack on back posts 16 , and back poles 22 stack on back poles 20 . Net stabilizers 24 a and 24 b attach at the tops of back poles 22 . Coupler 26 connects net stabilizers 24 a and 24 b . End bars 28 a and 28 b extend from front posts 14 to back posts 16 . Cross bar 30 a extends between end bars 28 a , cross bar 30 b extends between end bars 28 b . Cross bars 30 a and 30 b are attached to end bars 28 a and 28 b by hinges 32 . Supports 34 extend vertically between and attach to end bars 28 a and 28 b . Cross stabilizers 36 extend diagonally between cross bars 30 a and 30 b and intersect with each other. Stabilizing bars 38 extend diagonally between end bar 28 a and cross bar 30 a and end bar 28 b and cross bar 30 b . Stabilizing bars 38 may extend toward the front or back of frame 12 from either side of cross bars 30 a and 30 b . Fasteners 40 secure connections between each of the components. Pole mounts 42 are attached to cross bar 30 b . Pegs 44 a and 44 b extend vertically from pole mounts 42 . Sleeves 46 slide over front poles 18 , and set screws 48 fix sleeves 46 to front poles 18 .
First net 50 attaches to eyes (or loops) 70 at the top and bottom of sleeves 46 and extends between them. Second net 52 attaches at the ends of edge 54 to eyes 70 at the top of sleeves 46 ; ends of edge 56 attach to net stabilizers 24 a and 24 b near the attachment to back poles 22 ; and edge 58 remains unattached on the backside of frame 12 . Panel 60 of second net 52 hangs loosely between front poles 18 and back poles 20 and 22 , such that second net 52 forms a large pocket behind first net 50 . Panel 62 drapes behind panel 60 . Ball release 64 is located within the pocket of panel 60 of second net 52 . Wheel supports 66 connect to end bars 28 b and support wheels 68 .
When in use, training apparatus 10 is set up as shown and can be positioned on any suitable surface. The height of first net 50 is adjusted by moving sleeves 46 up or down along front poles 18 . Sleeves 46 are secured in the desired position by tightening set screws 48 . First net 50 can be set to an adjustable height such as from about six feet to over nine feet.
FIG. 1 b shows training apparatus 10 with second net 52 removed. This provides a simpler view of apparatus 10 in the course of assembly or disassembly.
FIG. 2 is the preferred embodiment of second net 52 . Second net 52 includes edges 54 , 56 , and 58 , panels 60 and 62 , and position 72 . Second net 52 is about 9 feet 4 inches wide and about 17 feet tall. Edge 56 is positioned about 9 feet 4 inches from edge 54 . Edge 56 is positioned on net stabilizers 24 a and 24 b (FIG. 1 ). Position 72 is located about 9 feet 4 inches from edge 54 . In an alternate embodiment of the invention second net 52 can be attached to back poles 20 at position 72 .
A player practices various shots by hitting a volleyball over first net 50 , and training apparatus 10 provides a realistic setting. Second net 52 catches the volleyballs hit over first net 50 . Second net 52 is positioned about twelve feet above the ground, so that it will block almost all volleyballs as they are hit over first net 50 . The volleyballs come to rest in the pocket formed by panel 60 of second net 52 . Edge 54 of second net 52 could be positioned at any height above the floor along front posts 14 and front poles 18 as long as second net 52 is long enough to form a pocket within panel 60 for catching and keeping the volleyballs. The pocket can also be formed from two separate nets instead of one single net. Volleyballs are easily retrieved from the pocket of second net 52 .
Ball release 64 makes retrieving volleyballs from the pocket of second net 52 more convenient. In one embodiment, ball release 64 is comprised of a tubular piece of cloth that tapers from a larger opening, attached to second net 52 , to a smaller opening, which hangs below the larger opening when loosened to allow volleyballs to drop through, and a drawstring around the smaller opening. When the drawstring cinches the smaller opening closed, the pocket of second net 52 is level. Volleyballs are emptied from the pocket by loosening the drawstring, which allows the tubular cloth to drop down and let volleyballs to pass through.
In a second embodiment, ball release 64 is comprised of a square cloth attached to the pocket of second net 52 . The cloth is permanently attached along one side to second net 52 and detachably connected along the remaining sides by Velcro fasteners or some other suitable means. When all sides of ball release 64 are attached, the volleyballs are collected in the pocket of second net 52 . To release the volleyballs, the detachable sides are released and the volleyballs will fall through the resulting opening.
Two components of the preferred embodiment of the invention prevent spiked volleyballs from undergoing a slingshot action which propels the volleyball back over first net 50 . The first is net stabilizers 24 a and 24 b connected by coupler 26 . If a volleyball is spiked over first net 50 and into second net 52 without net stabilizers 24 a and 24 b with coupler 26 , back poles 20 and 22 tend to bow and flex causing second net 52 to act as a slingshot. With net stabilizers 24 a and 24 b connected together by coupler 26 attached in place, this effect is greatly reduced. Preferably, net stabilizers 24 a and 24 b are made of PVC pipe and the ends are attached to the top of back poles 22 in the following manner. D-loops are attached near the top of back poles 22 , and net stabilizers 24 a and 24 b have openings, which are perpendicular to the length of the tubes, drilled at one end of each tube. The components are attached by slipping a bolt through the openings of 24 a and 24 b and the D-loops on back poles 22 and securing the bolt in place.
The slingshot effect is further reduced by panel 62 of second net 52 . Panel 62 drapes behind panel 60 , which is the section of second net 52 where the volleyball is hit into. The added netting further prevents the volleyball from being tossed back over first net 50 .
FIGS. 3 a and 3 b show the preferred manner of planting apparatus 10 so that it does not roll during use. FIGS. 3 a and 3 b include front post 14 , back post 16 , front pole 18 , back pole 20 , end bars 28 a and 28 b , support 34 , wheel support 66 , and wheels 68 . FIG. 3 b further includes chain 74 .
FIG. 3 a shows apparatus 10 with wheels 68 positioned such that apparatus 10 is mobile. When wheel support 66 with wheels 68 is locked in a position along side end bar 28 b , wheels 68 are on the floor and front post 14 and back post 16 are lifted off the floor. Apparatus 10 can be rolled to a desired location.
FIG. 3 b shows apparatus 10 with wheels 68 positioned such that apparatus 10 is planted on the floor. To operate, one end of wheel support 66 is lifted from the floor and attached to chain 74 , which causes the other end of wheel support 66 to pivot relative to end bar 28 b . In this position, wheels 68 no longer touch the floor and front post 14 and back post 16 now touch the floor. Apparatus 10 is planted in position and will not move during use.
Once practice is finished, training apparatus 10 is collapsible for easy portability and storage. First net 50 and second net 52 are detached from frame 12 . Net stabilizers 24 a and 24 b with coupler 26 detach from back poles 22 and coupler 26 disconnects net stabilizer 24 a from 24 b . Front poles 18 and sleeves 46 are disconnected from front posts 14 , and back poles 22 are disconnected from back poles 20 , which are in turn disconnected from back posts 16 . Front poles 18 are placed on pegs 44 a and back poles 20 and 22 are placed on pegs 44 b for storage. Stabilizing bars 38 slide along cross bars 30 a and 30 b and attach to pins 40 a. This allows end bars 28 a and 28 b , front posts 14 , and back posts 16 to pivot around hinges 32 such that end bars 28 a and 28 b will be essentially parallel to cross bars 30 a and 30 b , and frame 12 will be essentially flat. Training apparatus 10 is easily rolled and requires a minimal amount of space for storage. If desired, all fasteners 40 could be removed and the parts disassembled for even more compact storage, however, this requires more time and effort for disassembly and reassembly.
FIGS. 4 a and 4 b illustrate how frame 12 collapses for storage. FIGS. 4 a and 4 b include end bar 28 b , cross bar 30 b , hinge 32 , stabilizing bar 38 , pole mount 42 with pegs 44 a and 44 b , and wheel support 66 . FIG. 4 b additionally includes arrow 76 .
FIG. 4 a shows the position of each part while apparatus 10 is setup for use. While setup, cross bar 30 b extends perpendicularly from end bar 28 b , and end bar 28 b , cross bar 30 b , and stabilizing bar 38 form a right triangle.
FIG. 4 b shows the position of each part while apparatus 10 is collapsed for storage. Stabilizing bar 38 is disconnected from cross bar 30 b , and as cross bar 30 b pivots at hinge 32 relative to end bar 28 b , the end of stabilizing bar 38 slides along cross bar 30 b in the direction shown by arrow 76 and is connected to pin 40 a . Cross bar 30 b is no longer perpendicular to end bar 28 b , and the frame becomes more compressed, which allows it to fit through a doorway for storage in a storage room, for example.
FIG. 5 shows how basic parts of frame 12 assemble. FIG. 5 shows frame 12 which includes front post 14 with tubing 14 a , back post 16 with tubing 16 a , front pole 18 , back pole 20 with tubing 20 a , back pole 22 , end bars 28 a and 28 b , and support 34 .
To assemble, front pole 18 slides over tubing 14 a and stacks on to front post 14 . The diameter of front post 14 and front pole 18 are equal, while the diameter of tubing 14 a is smaller. Back pole 20 slides over tubing 16 a to fit the same way onto back post 16 , and back pole 22 fits over tubing 20 a to fit onto back pole 20 .
Preferred dimensions for some of the components of frame 12 are as follows. The width of frame 12 is about 43 inches. Front and back posts 14 and 16 are about 38 inches long with tubing 14 a and 16 a about 15 inches long. Front pole 18 is about 60 inches long. Back pole 20 is about 46 inches long with tubing 20 a about 6 inches long. The length of back pole 22 is about 60 inches.
FIG. 6 shows another embodiment of the invention, which is generally similar to FIG. 1 a , with the following exceptions. First, net stabilizers 24 a and 24 b and coupler 26 are not used. Second, second net 52 includes only panel 60 . Third, the upper comers of panel 60 are connected to eyes or hooks 80 at the upper ends of back poles 22 . Fourth, wheels 68 are mounted on the bottom ends of front posts 14 and back posts 16 , and wheel supports 66 are eliminated. Fifth, stabilizing bars 38 extend toward the back of frame 12 from cross bars 30 a and 30 b.
FIGS. 7 a , 7 b , and 7 c show more details regarding second net 52 shown in the embodiment of FIG. 6 . In the embodiment shown in FIGS. 7 a - 7 c ball release 64 is in a form of a square aperture 100 which is covered by a square flap 102 . A hook and loop fastener (such as Velcro) material 104 is positioned around opening 100 to hold flap 102 in place. Fastener 104 is preferably sewn in place around the edge of opening 100 .
Grommets 106 are positioned in each of the four corners of second net 52 for connection to hooks 70 and 80 .
In a preferred embodiment, second net 52 is approximately 9 foot 4 inches square. The forward edge of opening 100 is approximately 30 inches from front edge 54 of second net 52 . Opening 102 is approximately 12 inches by 12 inches in dimension and is centered at approximately equal distances from the left and right edges of second net 52 . Flap 102 is slightly larger in dimension than the size of opening 100 .
Although the present invention has been described with reference to preferred embodiments, workers skilled in the art will recognize that changes may be made in form and detail without departing from the spirit and scope of the invention.
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A collapsible frame supports a first and second net useful for practicing various volleyball maneuvers. The first net is attached such that it acts as a standard volleyball net and the second net is attached behind the first net such that it catches and holds volleyballs hit over the first net. The entire apparatus can be disassembled making it convenient for storing and portable to any desired location.
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FIELD OF THE INVENTION
The present invention generally relates to an apparatus and method to adjust the dimensions of thermoplastic components following passage of the component through final processing in a fixture. The invention particularly relates to an apparatus for maintaining tolerances on thermoplastic components that are post-form extruded. In addition, the invention relates to a process for maintaining product tolerances for post-form extruded thermoplastic materials.
BACKGROUND OF THE INVENTION
Numerous products in the market today are extruded thermoplastics. Such products include vinyl siding, picture frames, tubing, rain gutters and down spouts to name just a few. Thermoplastics such as polyvinyl chloride offer significant advantages in the market place because of their ease of use in forming the product, the finished product's durability and capacity to handle extremes of temperature as well as the ability to color and texturize the product to suit consumer demands. For purposes of example only, the issue of dimensional quality control will be discussed in the context of post-form extruding thermoplastics into a wide variety of vinyl siding styles, textures and colors. Dimensional quality control utilizing the method and apparatus described herein can be applied to a wide variety of products.
Products such as vinyl siding must be manufactured to exacting tolerances in order to withstand the extremes of temperature found in many regions of the country and throughout the world. In addition, the siding must be resistant to moisture, be able to resist damaging impacts from hail, rocks and other objects launched by lawnmowers and even balls and toys thrown by children. Vinyl siding that does not meet design specifications can be poor fitting and consequently aesthetically unappealing thereby leading to product recalls and significant consumer dissatisfaction. Vinyl siding with features that do not mate well because the siding fails to meet design specifications will result in a product that can be very difficult for the installer to attach to the building, or attach to the building without an unsightly fit.
Two commonly employed techniques for producing vinyl siding are profile extrusion and post-form extrusion. Profile extrusion utilizes an extrusion machine to heat powdered thermoplastic resin, typically poly-vinyl chloride, and under great pressure, forces it out of a die in the desired cross-section profile. Though very effective at producing high quality products with dimensional stability, it is a relatively slow process with feed rates in the range of 1.5 to 6 meters per minute (5 to 15 feet per minute). As with nearly all production lines, the speed of production is critical in order for the business to be profitable.
The technique that is most commonly employed for production of vinyl siding is post-form extrusion. With post-form extrusion, thermoplastic resin is heated to temperatures around 200° C. and forced under pressures of as much as 13.8 Kilopascals (2000 pounds per square inch) from an extrusion device. The extruded thermoplastic is then formed into a flat sheet and may undergo other processes such as embossing or cooling before being fed into a water cooled fixture that is commonly referred to as a calibrator. The calibrator serves to bend and twist the flat sheet into the desired profile as the flat sheet is pulled through the calibrator by the haul-off machine at the end of the production line.
The fixtures used to form the flat sheet into the final cross section are machined to very exacting tolerances with internal surfaces that are ground to a mirror finish and are typically plumbed with communicating passages for application of a vacuum source to pull the moving flat sheet against the upper surfaces of the calibrator. Pulling the sheet against the upper surface of the calibrator facilitates increased processing speed by reducing the prospect for jamming and binding of the thermoplastic material against the bottom surface of the calibrator as it moves at speeds of up to 50 meters per minute (165 feet per minute).
As the flat sheet moves into the calibrator it is shaped and formed into the desired cross section. Increasing demand for vinyl siding has prompted manufacturers to seek ways to economically increase their productivity. One way to increase productivity is to increase the haul off machine rate thereby increasing the rate at which resin must be fed into the extruder. Increasing the haul-off rate can have the unintended consequence of changing the dimension of the finished product. Different production lines utilizing nearly identical calibrators can also have different tensions placed on the sheet being pulled through the production equipment. Likewise, varying extrusion device temperature ranges and even varying resin mixtures particularly when coupled with different pull rates can have subtle, yet palpable, impacts on the dimensional integrity of the vinyl siding features.
Accordingly, a substantial need exists for a methodology that can be utilized to adjust the dimensions of features of the post-form extruded vinyl siding after the siding exits the calibrator and before the thermoplastic has had an opportunity to fully set in its final form. A further need exists for a low cost and functional apparatus that can simply and efficiently be utilized to adjust the dimensions of critical features of a post-form extruded product, such as vinyl siding after it exits the calibrator.
SUMMARY OF THE INVENTION
This invention pertains to an apparatus and a method for using the apparatus to adjust to product specifications the dimensions of post-form extruded vinyl siding after the product has exited the calibrator fixture. This invention is not limited to vinyl siding applications and can be utilized on any thermoplastic component that is post-form extruded. This summary will be limited to discussion of vinyl siding applications in order to clearly illustrate the functionality of the apparatus and method of the present invention.
Thermoplastic products have become increasingly popular due to the ease of forming the thermoplastic resin into a finished product, the product's durability and the ability to produce the products in a variety of textures and colors. As previously noted, this invention pertains to an apparatus and method that can be employed in any setting that utilizes thermoplastics in a post-form extrusion process. The numerous attributes of thermoplastic materials have contributed to the substantial increase in the market share that vinyl siding, has experienced over other home siding products during the past several years. Maintaining the finished product within design specification tolerances is critical and requires a concerted effort on the part of the engineer designing and building the fixture/calibrator as well as the process engineer who oversees the vinyl siding production line. Failure to maintain product quality through dimensional control can have catastrophic effects on market success based solely on the ease or difficulty of product installation in the field. If the installers of the vinyl siding find the product difficult to install because of poor design or the inability to maintain product within tolerances, they will seek to install another vendor's product.
Post-form extrusion of vinyl siding generally begins with the introduction of a thermoplastic resin, generally polyvinyl chloride, into an extruder. The extruder augers the resin into contact with the barrel of the extruder generating heat and transitioning the powdered resin to a viscous fluid with considerable resistance to flow. Heater bands strapped to the barrel of the extruder raise the temperature of the resin to approximately 176° C. (350° F.). The highly viscous extruded thermoplastic is then fed into a flat sheet die where it is compressed into a planar sheet and maintains the temperature at which it exited the extruder. Following the flat sheet die which produces a typical cross sectional dimension of from 0.76 mm to 1.5 mm (0.03 to 0.06 inches) in thickness the thermoplastic sheet is pulled through the embossing rolls for imprinting of the grain texture upon the surface of the vinyl siding panels. After passing between the embossing rolls the thermoplastic is pulled through a set of cooling rolls that lowers the temperature to around 115° C. (240° F.). From the cooling rolls the thermoplastic sheet enters the calibrator, or water fixture, which imparts the final desired cross section to the panel.
The calibrator is a precision machined fixture with ultra smooth mirror finish internal surfaces for easing the thermoplastic resin through the many folds and bends encountered within the fixture. In addition to the ultra-smooth surfaces, the calibrator incorporates a series of communicating channels for connection to a vacuum source at surface ports on the calibrator. The communicating channels also open at inlets to the mirror finish surfaces. The vacuum inlets assist in pulling the flat sheet material toward the outer geometry of the calibrator through a reduction in air pressure thereby reducing the prospect for jamming or clogging of the polyvinyl chloride in the calibrator.
Even though the fixtures are precision machined to within a few thousandths of an inch, the thickness of key features on the post-form extruded panel can change from one run to the next, or even during the same run, depending upon the rate at which the product is pulled through the calibrator, the temperatures that are maintained on the ancillary equipment such as the flat sheet die and even the specific mixture of resin that is employed. These parameters all conspire to alter the final dimension of product features exiting the calibrator.
We have found that to maintain the dimensions that are specified for the vinyl siding, particularly on the panel's critical locking feature, a post-form adjustment mechanism is extremely beneficial. Accordingly, the present invention is directed to an apparatus for attachment to the calibrator and for further adjusting, as necessary, the dimension of specified features of the vinyl siding as the profiled feature exits the calibrator.
The apparatus is comprised of a member precisely mounted to the fixture, generally with dowel pins. The member is further comprised of an outer member with a first and a second leg, and an inner member, the inner member slidably mounted between the first leg and the second leg of the outer member. The inner and outer members are comprised of an upper surface and a shaping means opposed the upper surface for altering the dimensions of the panel extruded from the calibrator. The inner member further includes a plate overhanging at least one of the outer members and is detachably secured to the upper surface of the inner member with screws or other suitable attachment means.
Extending outwardly individually from each inner and outer member is a finger. The fingers are machined to coincide with a specific feature, or portion of a feature, of the vinyl siding panel such that any change in the position of any of the fingers will result in a change in the configuration or dimension of the vinyl panel as it is passes from the calibrator.
With the outer members rigidly attached to the calibrator, the inner member can be slidably adjusted up or down through the use of a screw or other adjustment mechanism that is threaded through the plate overhanging the outer member. The screw, or other adjustment mechanism, contacts the upper surface of the rigidly secured outer member and urges the inner member to move either up or down through the translation of force across the overhanging plate which is detachably secured to the inner member. As the thumbscrew or other adjustment mechanism is rotated the protruding finger opposite the upper surface moves up or down and interferes with the profile of the not yet fully set thermoplastic crossing its surface. If, for example, the finger of the inner member protrudes into the locking feature of the extruded vinyl panel, the finger can be utilized to open or close the gap that exists in the locking feature potentially saving the production run of panel from being scrapped if the locking feature dimensions do not fall within product tolerances.
Accordingly, a substantial need exists for a methodology that can be utilized to adjust the dimensions of features of the post-form extruded vinyl siding after the siding exits the calibrator and before the thermoplastic has had an opportunity to fully set in its final form. A further need exists for a low cost apparatus that can simply and efficiently adjust the dimension of critical features of a post-form extruded product, such as vinyl siding after it exits the calibrator.
Reference is now made in detail to the preferred embodiments of the invention, examples of which are illustrated in the accompanying drawings.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 is a perspective view of a calibrator lock adjuster embodying features of the present invention in its operational position connected to a calibrator in accordance with an embodiment of the present invention;
FIG. 2 is a perspective view of a calibrator lock adjuster embodying features of the present invention in isolation;
FIG. 3 is a cross sectional view taken along line 3 — 3 of FIG. 1 of a calibrator lock adjuster embodying features of the present invention engaging a post-form extruded vinyl siding panel;
FIG. 4 is a cross sectional view taken along line 4 — 4 of FIG. 2 embodying features of the present invention including dowel holes, attachment screws, an overhanging plate, inner and outer members and a thumbscrew;
FIG. 5 is a cross sectional view taken along line 5 — 5 of FIG. 2 illustrating the relationship between the inner and outer members and orientation of the screw and dowel pin holes in an embodiment of the present invention.
DETAILED DESCRIPTION OF THE INVENTION
The present invention is directed to an apparatus and a method for using the apparatus to adjust the dimensions of features of a thermoplastic product that has been extruded from a fixture.
The unique adjustment device of the present invention corrects for deviations from product specification for components, such as vinyl siding, that passes through a fixture, or what is commonly referred to in the industry as a calibrator. The present invention will be discussed in the context of a company that produces a wide variety of vinyl siding styles, textures and colors. The invention, however, could be applied to a production line that produces any number of different products that may have demanding specifications for their product that could benefit from adjustment of the dimensions of the component following departure from the calibrator.
The calibrator is a precision machined fixture with typical tolerances of ±0.51 mm (0.020 inch) and generally separates into an upper and lower half that are bolted or clamped together when the extrusion line is in operation. When setting up the extrusion line for production of the vinyl siding the thermoplastic resin is heated in the extruder to about 176° C. (350° F.) through friction generated heat in the barrel of the extruder and with heater bands wrapped around the barrel.
Once the heated thermoplastic exits the barrel of the extruder it is pulled through a flat sheet die where it assumes a planar configuration and remains at a temperature of approximately 176° C. (350° F.). From the flat sheet die, the heated thermoplastic is routed to embossing rolls that provide texture and then onto cooling rolls that lower the temperature of the thermoplastic to approximately 115° C. (240° F.). The cooling rolls serve to extract heat from the thermoplastic thereby hardening the material before entry into the calibrator. The calibrator separates into an upper and lower section. When setting up the process to begin a production run of a vinyl siding product, the calibrator upper and lower sections are separated and the embossed and flattened thermoplastic sheet is laid atop the upper surface of the lower section of the calibrator. The calibrator upper section is then placed over the flat sheet and either bolted or clamped into position. The leading end of the flat sheet is then fed into the haul off machine which begins the process of pulling the extruded material though the calibrator to form the desired profile for the vinyl siding or other product.
The upper and lower internal surfaces of the calibrator are polished to a mirror finish facilitating passage of the thermoplastic flat sheet through the calibrator at speeds approaching 50 meters per minute (165 feet per minute). The calibrator also employs a series of communicating internal channels for delivery of reduced air pressure to several inlets in the upper section of the fixture. These reduced air pressure inlets within the calibrator upper section serve to pull the thermoplastic material progressing through the calibrator to the upper polished surface thereby eliminating excessive friction on the lower surface and possible jamming or clogging of the calibrator. The reduced air pressure is provided by a vacuum pump connected to lines attached to ports on the exterior surface of the upper section of the calibrator. The ports are in turn connected to the communicating channels within the calibrator.
After exiting the calibrator, the vinyl siding has been turned and shaped in the calibrator to form the desired vinyl siding profile. When the siding product exits the calibrator the temperature of the thermoplastic has dropped to approximately 38° C. (100° F.) and has lost considerable malleability. Nonetheless, there is still a very limited opportunity to redress any deviations from product specifications before the thermoplastic fully hardens.
As shown in FIGS. 1 and 3 , attached to the calibrator, typically with the assistance of precision machined dowel pins is an adjustment member 10 . The adjustment member has considerable utility as a final opportunity to alter the dimension of a feature of the vinyl siding product 12 . As the vinyl siding 12 exits the calibrator 14 the feature 16 with the critical dimension requiring adjustment travels past the adjustment member 10 modifying the position of the feature 16 being contacted. During the set up stage when the thermoplastic flat sheet 18 is positioned between the calibrator upper section 20 and the calibrator lower section 22 , the flat sheet 18 is simultaneously directed into and through the adjustment member 10 so that when production commences the profiled vinyl siding feature 16 that is being adjusted is in contact with or in very close proximity to the adjustment member contact surfaces. The contact surfaces will be discussed in more detail below.
As shown in FIGS. 4 and 5 , the adjustment member 10 is comprised of an inner and outer member, the inner member 26 is slidably inserted between the two legs 30 , 32 of the outer member 36 . Both the inner and outer member are preferably machined from stainless steel. As depicted in FIGS. 2 and 3 , the inner and outer members 26 , 36 are preferably J-shaped in configuration with an upper generally planar surface 40 and lower outwardly extending fingers 42 , 43 , 44 . The outwardly extending fingers 42 , 43 , 44 can be configured as necessary to introduce the desired correction to the feature being adjusted, however, as depicted in FIG. 3 the preferred embodiment for adjusting the feature 16 on vinyl siding panels is an elliptical crown 50 . The elliptical crown 50 in the preferred embodiment is polished to a mirror finish in order to provide an ultra-smooth surface over which the vinyl siding panel may rapidly advance and receive dimensional correction.
As shown in FIG. 2 , resting atop and detachably secured to the upper surface of the inner member is a plate overhanging at least one of the outer members. The overhanging plate 52 is secured to the inner member by screws 54 or any other suitable attachment means. As depicted in FIGS. 4 and 5 , disposed through the overhanging plate 52 is a threaded hole 56 into which is threaded a thumbscrew 58 or any other suitable means for urging vertical displacement between the inner and outer members 26 , 36 . Preferably the thumbscrew 58 would have fine threads with a shallow pitch to enhance the control over the displacement of the inner member 26 . As shown in FIG. 4 , the thumbscrew 58 is threaded through the overhanging plate 52 and is placed into contact with the base 60 of an unthreaded hole 62 in the outer member. As the thumbscrew 58 is turned, the tip 64 of the thumbscrew 58 contacts the base 60 and applies a force to the base 60 . Since the outer member 36 is rigidly secured to the calibrator 14 , preferably by precision ground dowel pins placed into dowel pin holes 70 , the force applied by the tip 64 of the thumbscrew 58 will not alter the outer member's 36 position. Instead, the application of force through the thumbscrew tip 64 against the stationary outer member 36 urges the inner member 26 to move from a first position to a second position resulting in displacement D.
The location of the second position for the inner member 26 and its associated outwardly extending finger 43 will typically be determined by calculating the difference between the dimension of the vinyl siding feature 16 as measured at the production line and subtracting that value from the product specification dimension. For example, if the gap of the locking feature 16 of the panel 12 was measured on the production line at 0.35 inches and the product specification dimension was 0.38 inches, the thumbscrew would be turned an appropriate number of turns to correspond with the difference in values, i.e., 9.7 mm−8.9 mm=0.8 mm (0.38 inches−0.35 inches=0.030 inches). When the thumbscrew 58 is rotated an amount corresponding to 0.8 mm (0.030 inches) in displacement D, the crown 50 on the finger 43 would separate the locking feature 16 by 0.8 mm (0.030 inches) as needed to satisfy product specifications.
As a second example, if the locking feature 16 gap is 9.7 mm (0.38 inches) and the product specification dictates a 9.2 mm (0.36 inches) separation, the gap is too wide by 0.5 mm (0.020 inches). In that situation, the thumb screw 58 would be turned an amount corresponding to a lesser displacement of 0.5 mm (0.020 inches) lower thereby closing the gap of the locking feature 16 by the requisite displacement. This repositioning of the thermoplastic feature is possible because the thermoplastic is still malleable at the exit point of the calibrator as it has not cooled to the set point of the material.
While the present invention has been described in connection with the preferred embodiment thereof, it will be understood many modifications will be readily apparent to those skilled in the art, and this application is intended to cover any adaptations or variations thereof. It is manifestly intended this invention be limited only by the claims and equivalents thereof.
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An apparatus and method to adjust the dimensions of thermoplastic components following passage of the component through final processing in a fixture. The invention particularly relates to an apparatus for maintaining product tolerances on thermoplastic components that have undergone post-form extrusion. In addition, the invention relates to a method for maintaining product tolerances on post-form extruded thermoplastic materials.
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FIELD OF THE INVENTION
[0001] The present invention relates to a construction tools, in particular a drill bit for retaining a core drilled from a material and a core retaining device.
BACKGROUND OF THE INVENTION
[0002] In many construction situations there is a need to drill a hole in a material, e.g. concrete from a floor or wall. A core drill bit, also referred to as a circular drill bit or hole-saw, is commonly used for such purpose. The drilling process results in a concrete core being separated from the material, which can fall from the drill bit and cause damage or injury.
[0003] U.S. Pat. No. 6,881,016 (May) discloses a core retainer having a base plate releasably attached to a concrete floor from which a concrete core is to be removed. A brake assembly atop the plate includes a plurality of brake pads for contact with the interior of the core drill bit. The retainer is configured to fit within the core drill bit and either rotate with the core drill bit or be stationary relative thereto. Upon drilling, the plate and separated core fall toward the floor below. This movement is translated to the brake assembly by the linkage such that the brake pads engage the inner circular wall of the core drill bit at a sufficient pressure allowing for the separated core to be retained within the core drill bit.
SUMMARY OF THE INVENTION
[0004] According to one aspect, the present invention provides an improved core retaining device for use with a core drill bit. The core drill bit is adapted for cutting a core from a material and comprises a proximal cutting portion and a distal portion. The core retaining device comprises: a core attachment mechanism for releasably connecting the core retaining device to the core of the material; a bearing connected to the core attachment mechanism allowing the drill bit to rotate while the core attachment mechanism remains statically connected to the core; and a biasing arrangement operably connecting between the drill bit and the core via the bearing, axially biasing the core in the direction of the distal portion of the drill bit.
[0005] It should be understood that when terms such as connected, connecting, attached, attaching, fastened, fastening and the like are used herein the specification and claims, it is meant to denote either of a direct or indirect connection, etc. I.e. there may be one or more intermediate components, without deviating from the intention of the term connected, etc.
[0006] In some embodiments, the device further comprises at least a pair of extensions extending essentially laterally outboard from the drill bit.
[0007] In some embodiments, the core attachment mechanism comprises an attachment plate.
[0008] According to another aspect, the present invention provides an improved core drill bit comprising: a proximal cutting portion; a distal portion comprising at least a pair of apertures; and the core retaining device as defined above.
BRIEF DESCRIPTION OF THE DRAWINGS
[0009] The invention may be more clearly understood upon reading of the following detailed description of non-limiting exemplary embodiments thereof, with reference to the following drawings, in which:
[0010] FIG. 1 is a schematic side sectional view of an embodiment of a core retaining device and core drill bit of the present invention;
[0011] FIG. 2 is a schematic side sectional view of the embodiment of FIG. 1 showing the device and bit after a core material has been cut;
[0012] FIG. 3 is a schematic side sectional view of another embodiment of the present invention; and
[0013] FIG. 4 is a front sectional schematic view of yet another embodiment of the present invention;
[0014] FIG. 5 is a side sectional schematic view of yet another embodiment of the present invention; and
[0015] FIG. 6 is an isometric view of a portion of a biasing arrangement of the embodiment.
[0016] The figures are intended to aid in understanding the invention and components illustrated therein may not necessarily be drawn to scale.
DETAILED DESCRIPTION OF THE INVENTION
[0017] In the following detailed description of the invention, reference is made to the drawings in which reference numerals refer to like elements, and which are intended to show by way of illustration specific embodiments in which the invention may be practiced. It is understood that other embodiments may be utilized and that structural changes may be made without departing from the scope and spirit of the invention.
[0018] In many instances, the same reference numbers may be used for similar components, despite modifications thereto, in the various embodiments described below. For the sake of brevity, description details of certain components which are known in the art are omitted.
[0019] FIGS. 1 and 2 show an embodiment of a core retaining drill bit 10 comprising a core retaining device 12 for cutting a core 200 ( FIG. 2 ) from a material 202 (e.g. concrete). Drill bit 10 is of a generally typical hole-saw configuration and comprises a proximal portion 14 and a distal portion 16 . Proximal portion 14 comprises at least one cutting tooth, and typically a plurality of cutting teeth 18 . Optionally or alternatively drill bit 10 comprises a cutting edge made up of, for example, numerous very small diamonds (not shown). Distal portion 16 comprises a pair of apertures 20 .
[0020] Core retaining device 12 comprises a biasing arrangement including a pair of spools 22 mounted on distal portion 16 , each spool adjacent to one of apertures 20 . Each spool 22 comprises a spring-loaded ratchet mechanism (not seen) with a setting lever 24 to set the ratchet mechanism in a ratcheting or release position.
[0021] Core retaining device 12 further comprises a pair of cables 26 and a plate or elongated member 28 dimensioned to fit within the confines of drill bit 10 and disposed therein. One end of each of cables 26 is fastened or attached to one of spools 22 and the other end of each of the cable is attached or fastened to elongated member 28 , typically at or close to the ends of the member. The spring loaded ratchet mechanisms associated with spools 22 are designed to upwardly bias cables 26 .
[0022] Each spool 22 typically comprises a base 30 whereat the spools are fastened or attached to distal portion 16 of drill bit 10 , for example, by a bolt/nut set 32 or any other appropriate fastening/attachment means (e.g. rivets, welding, etc). According to some embodiments, core retaining device 12 comprises more than two spools 22 , two cables 24 , etc, for example, spaced apart in a circular pattern on top of distal portion 16 of drill bit 10 .
[0023] Core retaining device 12 also comprises a bearing 34 disposed at the center of elongated member 28 . Bearing 34 is attached to a core attachment mechanism 36 comprising, for example, an anchor 38 and a bolt 40 adapted to fasten to core 200 of material 202 . The number of attachment mechanisms 36 (and/or their size or design) depends on the size (weight) of core 200 and in the embodiment illustrated in FIGS. 1 and 2 there is one attachment mechanism. Bearing 34 , which will not be described in further detail as such bearings are known, allows elongated member 28 to spin along with drill bit 10 , when operated, relative to attachment mechanism 36 , which is static with core 200 .
[0024] FIG. 3 shows a further embodiment of the invention wherein there is a core attachment mechanism, now designated 36 a, which is designed for a relatively larger sized core 200 a than core 200 . Core attachment mechanism 36 a comprises an attachment plate 50 which is attached to bearing 28 and also to core 200 a, respectively. Attachment plate 50 can be in a variety of configurations, but typically in the form of a strip or a disk.
[0025] To attach/fasten attachment plate 50 to core 200 a there are a plurality of anchors 38 and bolts 40 ; a set of two are illustrated. If core 200 a is large (heavy) enough to warrant it, according to particular embodiments, core attachment mechanism 36 a comprises additional anchors 38 and bolts 40 which may be disposed juxtaposed linearly, in particular attachment plate 50 is in the form of a strip. On the other hand, if attachment plate 50 is disk shaped, anchors 38 and bolts 40 may be disposed in a circular pattern.
[0026] According to some embodiments, also illustrated in FIG. 3 , the base, now designated 30 a, comprises an extension 31 extending laterally out beyond bit 10 . Extension 31 serves a safety backup purpose in case the drill bit detaches and falls from the drill (not seen), or the drill falls. In such a case the bit and core retainer would be held by the base's extension 31 which would have fallen onto material 202 .
[0027] Operation:
[0028] With cables 26 suitably unwound from spools 22 , core attachment mechanism 32 , 32 a is attached/fastened to core 200 , 200 a so that bearing 28 is above the center point of the core. Upon cutting, drill bit 10 will spin into the material 202 and surround core 200 , 200 a . This action would have a tendency to provide slack to cables 26 , however the bias of the ratchet mechanism takes up this slack and the cables wind up on their respective spools 22 , preventing core 200 from potentially slipping out of drill bit 10 (see FIG. 2 ).
[0029] Although attachment member 36 , which attaches core retaining device 12 to material 202 (and what will become core 200 , 200 a ), need remain static with the core, due to bearing 34 , spools 22 , cables 26 and elongated member 28 are free to spin along with drill bit 10 during cutting.
[0030] When core 200 , 200 a has been completely removed from material 202 , the drill (not shown), along with bit 10 and core 200 , 200 a can be distanced from the opening left by the removed core, at which point core retaining device 12 can be released from the core by removing core attachment mechanism 36 , 36 a.
[0031] FIGS. 4-6 show a further exemplary embodiment of the invention wherein the biasing arrangement is disposed within the confines of drill bit 10 . Similarly to the above embodiments, the biasing arrangement operably connects between the drill bit and core 200 via bearing 34 . The biasing arrangement includes a windable connection element such as a coil able flat sheet 60 (although other such elements could be used, for example one or more cables). Coilable flat sheet 60 is wound on a rod 62 which is biased to rotate so as to tend to pull core 200 in the direction of distal portion 16 of drill bit 10 (i.e. biasing the core away from the material 202 ). Such biasing is typically constituted, for example, by a spring (not shown). Coil able flat sheet 60 is attached to member 28 , however, it should be understood that, as with the aforementioned embodiments, bearing 34 could be connected to the sheet (or cables 26 ) by various means, or even directly connected. Rod 62 is attached to drill bit 10 by a fastening element 64 . The effect of the biasing is similar to the result illustrated in FIG. 2 .
[0032] Without intention to limit, the embodiment shown in FIGS. 4-6 is typically suited to cores smaller than those, for example, that the embodiment shown in FIG. 3 is suited.
[0033] Operation of the drill bit 10 is similar to as described above. Upon cutting, drill bit 10 will spin into the material 202 and surround core 200 . This action would have a tendency to provide slack to the windable connection element (e.g. sheet 60 ), however the bias imposed on rod 62 takes up this slack and the windable connection element winds up on the rod, preventing core 200 from potentially slipping out of drill bit 10 .
[0034] It should be understood that the above description is merely exemplary and that there are various embodiments of the present invention that may be devised, mutatis mutandis, and that the features described in the above-described embodiments may be used separately or in any suitable combination.
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A core retaining device for use with a core drill bit, the bit adapted for cutting a core from a material. The core retaining device comprises: a core attachment mechanism for releasably connecting the core retaining device to the core; a bearing connected to the core attachment mechanism allowing the drill bit to rotate while said core attachment mechanism remains statically connected to the core; and a biasing arrangement operably connecting between the drill bit and the core via the bearing, axially biasing the core away from the material preventing the core from slipping from the drill bit.
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RELATED APPLICATIONS
This application claims the benefit of U.S. Provisional Patent Application 60/560,981, filed on Apr. 12, 2004.
FIELD OF THE INVENTION
This invention relates generally to the manufacture of circular metal tanks from steel coils shipped to site straight from the steel mill.
BACKGROUND OF THE INVENTION
The prior art describes a variety of methods for the construction of circular metal tanks used in storage of solids or liquids. For instance, U.S. Pat. No. 2,751,672, issued to Reed, describes the fabrication of circular tanks from a series of metal sheets which are bolted together. This method of assembly requires a large amount of manual labour, a complicated tank support structure, and is unsuitable for producing tanks for storage of liquids due to the massive number of bolt holes requiring hydraulic seals to prevent the leakage of any stored liquid.
U.S. Pat. No. 4,121,747, issued to McFatter, describes the construction of circular storage tanks from strip metal wound in a helical path in which the tank is built upwardly. The metal strip is fed to a support assembly arranged circularly on a base, and the upper edge of the strip that is fed to the support assembly is aligned with the lower edge of the helical turn immediately thereabove so that the edges are spaced apart in a vertical plane from each other and then “butt” welded together. This invention teaches away from the bending of metal strip edges and sees no potential advantage in doing so. This technique for tank fabrication suffers from the following disadvantages:
a) satisfactory alignment of metal strips ahead of a butt welder is difficult; b) slight misalignment of the metal strips, especially for thinner metal thicknesses, can cause weak welds and/or leaks due to insufficient metal-to-metal contact; and c) there is no provision for reinforcement of metal strips to prevent their deformation (e.g. bulging due to pressure on lower metal strips in a tall liquid storage tank.
U.S. Pat. No. 3,863,479 to Lipp describes the fabrication of metal tubes and tanks from helical metal coils using severe folded bends from adjacent coils. Lipp suffers from the following disadvantages:
a) the tanks are unsuitable for storage of liquids since perfect hydraulic seals at the mechanical bends cannot be guaranteed; b) the method is unsuitable for hard-to-bend metals, especially for higher carbon steels, due to the severity of the bends and lack of stress relief (e.g. annealing) after bending resulting in potential metal cracking and subsequent loss of strength and hydraulic seals; c) the thickness of usable metal is limited due to the severity of the bends, which may result in cracking and subsequent loss of strength and hydraulic seals; and d) there are no reinforcing corrugations in the coils to prevent bulging, which is especially problematic since the thickness of the metal that may be used is limited, as discussed in point (c) above.
SUMMARY OF THE INVENTION
The invention relates to a method for manufacturing a circular metal tank, from an elongated sheet of metal. The upper and lower longitudinal edges of the metal sheet are bent to produce a first “L” bend and a second “chair” bend, respectively. The sheet of metal is moved in a helical trajectory such that the second bend comes into proximity above the first bend. The second bend and the first bend are welded together such that the wall of the cylindrical tank is formed. The first and second bends cooperate to form a helical roller track on the outside of the tank. The tank is supported and rotated about its longitudinal axis on a plurality of rollers that engage the roller track. As the tank is rotated and the metal sheet is welded to the bottom thereof, the tank moves upwards on said rollers.
The metal sheet can optionally be corrugated to reinforce the walls of the tank and to prevent bulging.
The bending of the longitudinal edges of the metal sheet achieves the following:
easier alignment of adjacent portions of the metal sheet which results in stronger welds and therefore improved hydraulic seals and increased structural strength; the first and second bends cooperate to form roller tracks that allow the tank to be supported and positioned on rollers as the tank is being manufactured; the bends themselves also act to reinforce the tank walls; welding of the bends serves to stress relieve or anneal the bent metal, thereby preventing cracks in the metal which may result in leaks and/or compromise the structural integrity of the tank.
BRIEF DESCRIPTION OF THE DRAWINGS
The invention itself both as to organization and method of operation, as well as additional objects and advantages thereof, will become readily apparent from the following detailed description when read in connection with the accompanying drawings, wherein:
FIG. 1 a shows a small circular tank production system according to the present invention;
FIG. 1 b show a medium size circular tank production system according to the present invention;
FIG. 1 c shows a large size circular tank production system according to the present invention;
FIG. 2 shows inclined adjacent loops of the metal strip supported on rollers;
FIGS. 3 a , 3 b & 3 c show a bender/corrugator;
FIGS. 4 a , 4 b & 4 c show cross sections of alternate embodiments of the metal strip after it has been bent and/or corrugated;
FIG. 5 a shows a welding pre-aligner;
FIG. 5 b shows a motorized double roller with adjustable top wheel;
FIGS. 6 a & 6 b show a roller track formed by adjacent unwelded second and first bends of the metal strip;
FIG. 7 shows a roller track formed by adjacent second and first bends of the metal strip in combination with a double roller with adjustable bottom wheel;
FIG. 8 a shows a welding positioner;
FIG. 8 b shows a motorized double roller with adjustable bottom wheel;
FIGS. 9 a & 9 b show a welder;
FIG. 10 shows a weld between adjacent loops of the metal strip as viewed from the inside of the tank;
FIGS. 11 a & 11 b show a roller track engaged by a single roller;
FIG. 12 shows a single free roller assembly;
FIG. 13 shows a decoiler assembly; and
FIGS. 14 a & 14 b show the wall of a tank formed according to the present invention.
DETAILED DESCRIPTION OF INVENTION
FIGS. 1 a , 1 b & 1 c show a top view of the cylindrical tank 10 being constructed according to the present invention. The major components are identified as follows:
The Decoiler 20 unravels a coiled metal sheet 30 and feeds it into a Bender/Corrugator 40 . The Bender/Corrugator 40 creates first and second bends to the longitudinal edges of the metal sheet and optionally imparts single or multiple waveform reinforcing corrugations along the length of the decoiled metal sheet 30 . Welding Pre-aligner 50 “gross” positions adjacent edges of metal sheet 30 after it exits the Bender/Corrugator 40 and ahead of the Welding Positioner 60 . Welding Positioner 60 “fine” positions adjacent edges of the metal sheet 30 after it exits the Welding Pre-Aligner 50 and before it enters the Welder Assembly 70 . Welder Assembly 70 welds (e.g. by fillet weld) adjacent edges of the metal sheet 30 . Support System 80 which is a structure having rollers and positioners (e.g. Welding Pre-aligner 50 and Welding Positioner 60 ) that guide and support the metal sheet 30 , before and after it is welded, along a helical trajectory. Single Rollers 100 make up part of the Support System 80 . They may be motorized or un-motorized rollers and operate to support and position the metal sheet 30 that forms the wall of the tank 10 while it is being constructed. Motorized or un-motorized double rollers 110 and motorized double rollers 111 also make up part of the Support System 80 . Double rollers 110 & 111 operate to support and position the metal sheet 30 that forms the wall of the tank 10 while it is being constructed. Vertical Coil Seam Welder 120 may be manual or automatic and is operative to join (e.g. butt weld) adjacent ends of metal sheets 30 in order to connect two consecutive metal sheets 30 .
FIG. 2 illustrates a typical sequence of single rollers 100 and double rollers 110 & 111 showing adjacent portions of the metal sheet 30 inclined so that the sheet 30 follows a helical path. The image of FIG. 2 is drawn as if it they were flat and unwound (e.g. “Mercator” projection) seen from the interior view. The ends 32 and 34 of the metal sheet 30 are connected to one another although they appear on opposite sides of the Figure.
FIG. 3 a illustrates a bender/corrugator 40 which creates a first “L” bend 42 along the upper longitudinal edge 36 and a second “chair” bend 44 along the lower longitudinal edge 38 of the metal sheet 30 . In the preferred embodiment of the invention the first bend 42 forms what will be termed in the document an L-shaped bend with an angle of between 45 and 135 degrees with the metal sheet 30 and has a width of between 5 and 100 mm, (depending on the thickness of the metal, the type of metal, and the size of the tank 10 ). In the preferred embodiment the second bend 44 has a horizontal portion 46 that is between 5 mm and 100 mm wide and a vertical portion 48 that is between 5 mm and 150 mm.
FIG. 3 b illustrates a bender/corrugator 40 which creates a first “L” bend along the upper longitudinal edge 36 and a second “chair” bend along the lower longitudinal edge 38 plus a single corrugated bend 130 on the metal sheet 30 .
FIG. 3 c illustrates a bender/corrugator 40 which creates a first “L” bend along the upper longitudinal edge 36 and a second “chair” bend along the lower longitudinal edge 38 plus a double corrugated bend 135 on the metal sheet 30 .
FIG. 4 a illustrates the cross section of the metal sheet 30 after it is output from the FIG. 3 a bender/corrugator 40 .
FIG. 4 b illustrates the cross sections of the metal sheet 30 at various stages as it passes through the bender/corrugator 40 of FIG. 3 b.
FIG. 4 c illustrates the cross sections of the metal sheet 30 at various stages as it passes through the bender/corrugator 40 of FIG. 3 c.
FIG. 5 a illustrates the welding pre-aligner 50 , which is operative to gross position adjacent edges of the metal sheet 30 . The pre-aligner 50 has horizontal adjustable rollers 140 —roller 150 pushes the upper edge 36 of the lower unwelded part of the metal sheet 30 (not shown) in the exterior direction (i.e. from the inside of the tank 10 towards the outside) whereas roller 145 pushes both the upper edge 36 of the lower part of the metal sheet 30 and the lower edge 38 of the upper part of the metal sheet 30 in the exterior direction. The pre-aligner 50 additionally has horizontal roller adjustors 165 and 166 to regulate the horizontal positioning of rollers 145 and 150 . The pre-aligner 50 operates in conjunction with a double roller 110 described in more detail below.
FIG. 5 b , shows double roller 110 in isolation. The double roller 110 may be used alone or as part of a welding pre-aligner 50 . The double rollers are also used at other points during the construction of the tank 10 , as shown in FIGS. 1 and 2 . Generally, the double rollers 110 may be motorized or free-rolling. In the preferred embodiment of the present invention the double rollers 110 of the welding pre-aligner 50 and the double rollers 111 of the welding positioner 60 are motorized to aid in the accurate positioning and welding of the metal sheet 30 . In addition, in the embodiment in FIG. 5 b , the double roller 110 has rollers 115 and 117 that are adjustable. Rollers 115 and 117 can be simultaneously horizontally adjusted while the upper roller 115 can also be vertically adjusted upwards or downwards.
FIGS. 6 a and 6 b illustrate the roller track 160 formed by an adjacent “L” bend 42 and chair bend 44 of the unwelded upper and lower edges 36 , 38 of metal sheet 30 . As shown in these figures, the roller track 160 has two opposing roller track sides. The first roller track side is formed by the portion of metal sheet 30 that is continuous with bend 42 and upper edge 36 . The opposing second roller track side is formed by an opposing vertical portion 48 that is continuous with the chair bend 44 . As shown in FIGS. 11 a and 11 b and as discussed below, the space between the roller track sides accommodates one or more rollers that engage the roller track. By engaging the roller track these rollers support and rotate the tank wall as it is being constructed. In the preferred embodiment of the invention the first bend 42 forms an angle of between 45 and 135 degrees with the metal sheet 30 and has a width of between 5 and 100 mm, (depending on the thickness of the metal, the type of metal, and the size of the tank 10 ). In the preferred embodiment the second bend 44 has a horizontal portion 46 that is between 5 mm and 100 mm wide and a vertical portion 48 that is between 5 mm and 150 mm.
Referring to FIG. 5 b , the roller track 160 (shown in isolation in FIGS. 6 a - b ) is supported underneath by roller 119 (on which the “L” bend along the upper longitudinal edge rests) while roller 118 pushes downwards (on the chair bend along the lower longitudinal edge).
FIGS. 7 & 8 b show double roller 111 in isolation. Double roller 111 may also be used as part of a welding positioner 60 . Double rollers 111 are motorized. In the preferred embodiment of the present invention the double rollers 110 (see FIGS. 1 , 2 and 5 b ) of the welding pre-aligner 50 are also motorized to aid in the accurate positioning and welding of the metal sheet 30 . In addition, in the embodiment in FIGS. 7 & 8 b , the double roller 111 has rollers 115 and 117 that are adjustable. Rollers 115 and 117 can be simultaneously horizontally adjusted while the lower roller 117 can also be vertically adjusted upwards or downwards. Referring to FIGS. 7 and 8 b , the roller track 160 (shown in isolation in FIGS. 6 a - b ) is supported underneath by roller 117 (on which the “L” bend along the upper longitudinal edge rests) while roller 115 pushes downwards (on the chair bend along the lower longitudinal edge).
Engagement of the track 160 by motorized double rollers 110 and/or 111 provides both support for the tank 10 as it is being constructed and means to advance the metal sheet 30 in a helical fashion.
FIG. 8 a illustrates the welding positioner 60 , operative to fine position the adjacent edges of the metal sheet 30 (not shown) for welding. Horizontal adjustable roller 170 pushes the lower edge of the upper part of metal sheet 30 in the exterior direction (i.e. from the inside of the tank 10 towards the outside) and roller 175 pushes the upper edge of the lower part of metal sheet 30 in the exterior direction. Adjustors 180 regulate the horizontal positioning of rollers 170 , 175 and therefore the edges of the metal sheet.
Referring to FIGS. 4 , 6 a - b , 7 , 9 a - b and 11 , it will be clear to those skilled in the art that the upper and lower longitudinal edges 36 , 38 of the metal sheet 30 can be bent in a variety of configurations to create alternate track 160 shapes (e.g. non-right angle bends) which still permit the tank 10 to be moved and supported by, for example, engagement with double rollers 110 and/or 111 , or single rollers 100 . In addition, a variety of corrugation configurations may be used.
FIGS. 9 a and 9 b illustrate a welder 70 applying a continuous weld 200 (e.g. fillet weld) to the groove between the “L” bend along the upper longitudinal edge 36 and a second “chair” bend along the lower longitudinal edge 38 of the metal sheet 30 . FIG. 10 illustrates the weld 200 as viewed from the interior of the tank 10 .
FIGS. 11 a and 11 b illustrate a welded roller track 160 engaged by a single roller 100 . Single rollers 100 are used throughout the support system 80 (see FIG. 1 ) to support the tank 10 while allowing it to be easily rotated as the metal sheet 30 is welded and advanced in a helical fashion to produce the tank wall. As seen in the figures, the roller 100 is received between the roller track sides. Referring again to FIGS. 1 a , 1 b and 1 c , the support system 80 may comprise as many or as few single rollers 100 and double rollers 110 & 111 as are deemed necessary depending on the height and size of the tank 10 , and the size and thickness of the metal sheet 30 .
Referring again to FIGS. 1 a , 1 b and 1 c , the support system 80 may comprise as many or as few single rollers 100 and double rollers 110 & 111 as are deemed necessary depending on the height and size of the tank 10 , and the size and thickness of the metal sheet 30 .
FIG. 12 illustrates a single roller 100 supported by a support member 210 of the support system 80 . Support members 210 and rollers 100 , 110 and 111 such as these are arranged in a circular fashion (see FIG. 1 ) to support the tank 10 as it is being built. In the preferred embodiment of the invention the single rollers 100 are tiltable (i.e. the roller 100 can be tilted away from vertical alignment towards the centre of the tank 10 while maintaining contact with the roller track 160 (see FIG. 11 ) to maintain fine control of tank diameter. Further, in the preferred embodiment, the height of the single rollers 100 is adjustable (e.g. by a double threaded height adjuster 220 ) in order to provide control of the shape and incline of the helical winding of the metal sheet 30 .
FIG. 13 illustrates a decoiler 20 that unwinds the coiled metal sheet 30 so that it can be incorporated into the tank.
FIGS. 14 a and 14 b show the wall of a tank 10 produced according to the present invention from one or more helically wound metal sheets 30 welded continuously longitudinally and at vertical sheet-to-sheet seams. As more of the metal sheet 30 is added to the bottom of the tank 10 , the tank is rotated about its longitudinal axis such that it advances gradually in an upward direction. The top edge 230 and the bottom edge 240 of the tank 10 in FIG. 14 a are cut to form circumferential edges each lying in a plane parallel to the ground as shown in FIG. 14 b (obviously, whether the circumferential edges are parallel to the ground or some other point of reference is a matter of design choice). After completion of the welding and cutting of the bottom edge 240 , the tank can be lowered to the ground by reversing the rotation along the single and double rollers (see FIGS. 1 and 2 ). Any number of prior art techniques can be used to finish or cut the top edge 230 and the bottom edge 240 of the circular tank 10 and to weld and seal them to, for example, a concrete base.
SUMMARY
The invention disclosed herein may be conveniently summarized, at least in part, with reference to the following enumerated statements:
Statement 1. The invention includes a method for manufacturing a circular metal tank, comprising the steps of: providing an elongated sheet of metal; bending said sheet of metal along an upper longitudinal edge thereof to produce a first bend; bending said sheet of metal along a lower longitudinal edge thereof to produce a second bend; moving said sheet of metal in a helical trajectory such that said second bend comes into proximity above said first bend; welding said second bend to said first bend to form a wall of said tank, said wall having a continuous, helical weld; wherein said first and second bends cooperate to form a helical roller track on an outside of said tank; and wherein said tank is supported on a plurality of rollers that engage said roller track; and wherein said tank is rotated about its longitudinal axis on said rollers such that said tank moves upwards as said sheet of metal, is welded to a bottom thereof.
Statement 2. The invention includes the method of Statement 1 wherein said elongated sheet of metal is a coiled sheet of metal which is decoiled prior to said bending steps.
Statement 3. The invention includes the method of Statement 1 wherein said first bend is an “L”-bend and said second bend is a chair-bend.
Statement 4. The invention includes the method of Statement 1 wherein said metal sheet is corrugated before said welding step.
Statement 5. The invention includes the method of Statement 1 wherein prior to said welding step adjacent portions of said first and second bends are gross positioned and then fine positioned.
Statement 6. The invention includes the method of Statement 1 wherein at least one of said rollers is motorized and said tank and said metal sheet are moved by means of said motorized roller.
Statement 7. The invention includes the method of Statement 1 wherein said metal sheet is made of one of aluminum, galvanized steel, stainless steel, carbon steel.
Statement 8. The invention includes the method of Statement 1 wherein said first bend forms an angle of between 45 and 135 degrees with a body of said metal sheet.
Statement 9. The invention includes the method of Statement 1 wherein said first bend has a width of 5 mm to 100 mm.
Statement 10. The invention includes the method of Statement 1 wherein a width of a horizontal portion of said second bend is between 5 mm to 100 mm.
Statement 11. The invention includes the method of Statement 1 wherein a width of a vertical portion of said second bend is between 5 mm to 150 mm.
Statement 12. The invention includes the method of Statement 1 wherein a top of said tank is cut so as to create an upper circumferential edge which is parallel to the ground.
Statement 13. The invention includes the method of Statement 1 wherein a bottom of the tank is cut during operation to create a lower circumferential edge which is parallel to the ground.
Statement 14. The invention includes a system for manufacturing a circular metal tank, wherein the system comprises a decoiler for decoiling a coiled sheet of metal; a bender/corrugator for introducing a first bend along an upper longitudinal edge of said metal sheet and a second bend along a second longitudinal edge of said metal sheet; a support system having rollers for moving said metal sheet along a helical trajectory, supporting said tank and for rotating said tank about its longitudinal axis as said metal sheet is added to a bottom edge of said tank; a welding positioner for positioning said second bend proximate and above said first bend; a welder for welding said first and second bends together to form a circular wall of said tank; wherein said first and second bends cooperate to form a helical roller track on an outside of said tank; and wherein said tank is supported on said rollers that engage said roller track.
Statement 15. The invention includes the system of Statement 14 further comprising a vertical coil seam welder for butt-welding an end of a first coiled metal sheet to an end of a second coiled metal sheet before said metal sheet pass through said bender/corrugator.
Statement 16. The invention includes the system of Statement 14 further comprising a welding pre-aligner for gross positioning said first and second bends before said first and second bends are positioned by said welding positioner.
Statement 17. The invention includes the system of Statement 14 wherein said first bend is an “L”-bend and said second bend is a chair-bend.
Statement 18. The invention includes the system of Statement 14 wherein said bender/corrugator additionally corrugates said metal sheet.
Statement 19. The invention includes the system of Statement 14 wherein at least one of said rollers is motorized and said tank and said metal sheet are moved by means of said motorized roller.
Statement 20. The invention includes the system of Statement 14 wherein said metal sheet is made of one of aluminum, galvanized steel, stainless steel, carbon steel.
Statement 21. The invention includes the system of Statement 14 wherein said first bend forms an angle of between 45 and 135 degrees with a body of said metal sheet.
Statement 22. The invention includes the system of Statement 14 wherein said first bend has a width of 5 mm to 100 mm.
Statement 23. The invention includes the system of Statement 14 wherein a width of a horizontal portion of said second bend is between 5 mm to 100 mm.
Statement 24. The invention includes the system of Statement 14 wherein a width of a vertical portion of said second bend is between 5 mm to 150 mm.
Statement 25. The invention includes the system of Statement 14 further comprising means for cutting a top of said tank so as to create an upper circumferential edge which is parallel to the ground.
Statement 26. The invention includes the system of Statement 14 further comprising means for cutting a bottom of the tank to create a lower circumferential edge which is parallel to the ground.
While this invention has been described with reference to illustrative embodiments, this description is not intended to be construed in a limiting sense. Various modifications of the illustrative embodiments, as well as other embodiments of the invention, will be apparent to persons skilled in the art upon reference to this description. It is therefore contemplated that the appended claims will cover any such modifications or embodiments as fall within the true scope of the invention.
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A method for manufacturing a circular metal tank, from an elongated sheet of metal. The upper and lower longitudinal edges of the metal sheet are bent to produce a first “L” bend and a second “chair” bend, respectively. The sheet of metal is moved in a helical trajectory such that the second bend comes into proximity above the first bend. The second bend and the first bend are welded together such that the wall of the cylindrical tank is formed. Welding of the bends serves to stress relieve or anneal the bent metal, thereby preventing cracks in the metal which may result in leaks and/or compromise the structural integrity of the tank. The first and second bends additionally cooperate to form a helical roller track on the outside of the tank. The tank is supported and rotated about its longitudinal axis on a plurality of rollers that engage the roller track.
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CROSS REFERENCE TO RELATED APPLICATIONS
[0001] This application claims priority to provisional application Ser. No. 62/353,319 titled Towel Bar with Integrated Robe Hook, filed on Jun. 22, 2016, the entire contents of which are hereby incorporated by reference.
FIELD OF THE INVENTION
[0002] This invention relates to the field of bathroom accessories. More particularly, it relates to wall-mounted bathroom accessories including towel bars, towel rings, and robe hooks.
BACKGROUND OF THE INVENTION
[0003] Bathroom accessories are commonly used for convenience to store towels or garments. For example, a typical bathroom includes a wall-mounted towel bar along with a robe hook. Bath towels and hand towels are commonly stored on the towel bar, while robes or additional towels are commonly hung from the robe hook. Therefore, a homeowner typically needs to utilize multiple, wall-mounted bathroom accessories.
[0004] In addition to towel bars and robe hooks, many bathrooms are also equipped with other accessories such as soap dishes, soap dispensers, tumbler holders, toothbrush holders, mirrors, and the like. Each one of these bathroom accessories requires an additional fastener to secure the accessory to the bathroom wall. Each fastener creates a hole in the wall and requires time and labor for installation.
[0005] Smaller bathrooms have limited, available wall space, thereby making it difficult for homeowner to find multiple places on their walls for each, desired accessory. As a result, many homeowners elect to install only some of their desired accessories and forego the rest. For example, the robe hook is commonly foregone in exchange for the more-popular towel bar, and, thus, when a need arises for a convenient bathroom robe hook, the homeowner is deprived of the robe hook experience.
[0006] Furthermore, a homeowner may not install robe hooks in their bathroom because the robe hooks may be seldom-used. A homeowner may not want to clutter a bathroom wall with unused accessories, and, thus, detract from the aesthetic appeal of the wall. As a result, when a need arises for a convenient bathroom robe hook, the homeowner is again deprived of the robe hook experience.
[0007] Some homeowners elect to use temporary hooks that attach to the top of a door or suction cup the side of a glass wall. These types of temporary solutions allow the homeowner to easily conceal the hook when not in use, but these solutions offer little utility for heavy items, such as wet towels or large robes, which may cause damage to the door and wall finish.
[0008] What is therefore needed is a bathroom accessory that allows a homeowner to minimize the amount of time and holes in the wall necessary for installation of various bathroom accessories. What is further needed is a towel bar and a robe hook that minimizes the amount of wall space necessary for installation of both accessories. Lastly, what is needed is a robe hook that is secured to the wall, yet easily concealable when not in use.
SUMMARY AND OBJECTS OF THE INVENTION
[0009] A wall-mounted bathroom accessory, such as a towel bar or towel ring, includes a first base configured for attaching to and extending from a wall. A second base may also be attached to the wall horizontally apart from the first base. A first and second receiver in each of the first base and second base, respectively, horizontally oppose one another on a common horizontal plane. The first and second receivers receive a straight and linear bar to form a towel bar. A shaft slidably engages one of a distal ends of the bar and the first base. Both by sliding, the shaft can extend a distance away from one of the first base as determined by the user, and the bar can also slidingly retract into one of the bar and the first base.
[0010] The shaft may be spring-loaded such that it “pops” out of the first base or bar once depressed. The shaft may also have a twisted engagement, such as threaded or bayonet style engagement, with either base or the bar. The shaft may also extend from any one of the first base, second base, or either end of the bar. A cap on a distal end of the shaft can provide a decorative feature and also provide a stop to prevent an object, such as a hanger, from sliding off of the shaft. The cap extends away from either the first base or the second base when the shaft is extended, and the cap draws towards either the first base or the second base when the shaft is retracted. The shaft may extend and retract perpendicular from the bar or may extend and retract in the same axis as the bar.
[0011] In another embodiment, the wall-mounted bathroom accessory may be formed of a first base that attaches to a vertical wall. A first receiver formed in the first base forms an orifice. Either a bar or a ring can be inserted into the orifice of the receiver to form a wall-mounted towel ring. A shaft extends from the first base and manually articulates to a vertical position to form a hook and also manually articulates to a horizontal position to eliminate the hook.
[0012] The shaft may extend from and also articulate from either the end of the bar or from the first base.
[0013] In either embodiment, the shaft can be retained in an extended or articulated vertically position by a detent to hold it in place.
[0014] Additional features and advantages of the invention will become apparent to those skilled in the art upon consideration of the following detailed description of the illustrated embodiment exemplifying the best mode of carrying out the invention as presently perceived. It is intended that all such additional features and advantages be included within this description and be within the scope of the invention.
BRIEF DESCRIPTION OF THE DRAWINGS
[0015] The present disclosure will be described hereinafter with reference to the attached drawings, which are given as non-limiting examples only, in which:
[0016] FIG. 1 is a perspective view of a towel bar according to the present invention with robe hooks in a retracted and concealed position.
[0017] FIG. 2 is a sectional view of a base of the towel bar of FIG. 1 along section line AA with the robe hook in a retracted position.
[0018] FIG. 3 is a sectional view of the base of FIG. 2 , with the robe hook in an extended position.
[0019] FIG. 4 is a sectional view of the base of FIG. 2 , with the robe hook in an extended position with an added support bushing for the extended robe hook.
[0020] FIG. 5 is a perspective view of a towel bar with a robe hook in the extended position.
[0021] In the drawings, some structural or method features may be shown in specific arrangements and/or orderings. However, it should be appreciated that such, specific arrangements and/or orderings may not be required. Rather, in some embodiments, such features may be arranged in a different manner and/or order than shown in the illustrative figures attached. Additionally, the inclusion of a structural or methodological feature in a particular figure is not meant to imply that such feature is required in all embodiments and, in some embodiments, may not be included or may be combined with other features.
[0022] Corresponding reference characters in the drawings indicate corresponding parts throughout the several views. The exemplification set out herein illustrates embodiments of the invention, and such exemplification is not to be construed as limiting the scope of the invention in any manner.
DETAILED DESCRIPTION
[0023] FIG. 1 shows a towel bar 10 according to the invention. The towel bar 10 includes a straight bar 12 that is connected to a base 14 on each distal end 26 , 28 of the bar 12 . While a straight bar 12 is shown, the bar 12 may be formed in any, other shape such as a curved bar. The bar 12 may also be in the form of a ring and require only a single base 14 to support the ring. In such an embodiment, the ring would attach to the base 14 in similar fashion as the bar 12 attaches to the base 14 .
[0024] The bar 12 is used to support a towel (not shown) or similar article draped over the bar 12 at about the middle portion 30 of the bar 12 . The distal ends 26 , 28 of the bar 12 are supported by each base 14 , respectively. The distal ends 26 , 28 of the bar 12 are inserted into a receiver 22 . The distal ends 26 , 28 may be held within the receivers 22 , with either a frictional fit or by attachment of each base 14 to a wall, while the bar 12 is supported by the receivers 22 . Alternatively, a set screw 24 may be located in each receiver 22 and tightened to prevent the bar 12 from rotating or otherwise moving to further secure any objects on the bar 12 .
[0025] Each base 14 includes a pedestal 18 attached to a column 20 . The receiver 22 sits atop the column 20 . While the pedestal 18 , column 20 , and receiver 22 are formed into columnar and round shapes, they can be made into polygonal shapes as well. Other polygonal shapes include pyramidal, rectilinear, or abstract shapes. The abstract shapes may mimic things such as water, trees, animals, or any, other known object. The overall purpose of the base 14 is, simply, to support the bar 12 in a position that is offset from the pedestal 18 to accommodate for an object to be hung from the bar 12 at a distance from a wall.
[0026] Alternatively, the base 14 may be mounted to a wall without any bar 12 . In this configuration, the base 14 would not require a receiver 22 . The base 14 can then act as a robe hook with a retractable and extendable extension as described below.
[0027] FIGS. 2 and 3 show a sectional view of the base 14 described above. In the sectional view, the inside of the base 14 is shown with a robe hook 48 in a retracted position within an internal cavity 38 of the base 14 . The robe hook 48 is formed by a piston 34 that travels within the internal cavity 38 into a retracted position as shown in FIG. 2 and may be extended into an extended position as shown in FIG. 3 .
[0028] The piston 34 may be retracted or extended by manipulation of a cap 16 fastened to an end of a shaft 32 . In the extended position, as shown in FIG. 3 , the piston 34 butts up against the receiver 22 forming a positive stop. In the retracted position, the cap 16 is pressed such that the piston is driven into the internal cavity 38 towards the pedestal 18 until the cap engages the receiver 22 . This sliding engagement of the piston 34 and the internal cavity 38 can also be supplemented with a spring within the internal cavity 38 . In such a configuration, a spring may be used to urge the piston 34 into the extended position when a user manipulates the cap 16 . The spring may be in the form of a compressed coil spring, rubber spring, foam spring, or air spring. The purpose of such a spring is to assist in the extension of the piston into the extended position when a user activates the robe hook 48 by manipulating the cap 16 .
[0029] The piston 34 may also be extended with a threaded engagement such that rotating the robe hook 48 in one direction, i.e. counter clockwise, extends the shaft 32 from the internal cavity 38 , thereby placing the robe hook 48 in the extended position. Rotating the robe hook 48 in the opposite direction, i.e. clockwise, retracts the shaft 32 back into the internal cavity 38 .
[0030] Preferably, the robe hook 48 is extended and retracted by simply pulling and pushing on the cap 16 , respectively. A frictional fit of the piston 34 with the internal cavity 38 may be used to help keep the robe hook 48 in the desired position. A bushing 42 , as shown in FIG. 4 , may also be used to help stabilize the shaft 32 as it is pushed or extended into and from the internal cavity 38 . The bushing 42 may either add friction to the sliding engagement of the shaft 32 or reduce the frictional fit.
[0031] When installing the base 14 to a wall, first, a retainer 44 may be secured. The piston 34 may be inserted into the internal cavity through access 40 in the pedestal 18 . A threaded engagement 36 may be used to attach the piston 34 to the shaft 32 . This assembly technique may also be used to manufacture the base 14 . After the piston 34 is threaded to the shaft 32 , the pedestal may be secured to the wall-mounted retainer 44 (see FIG. 2 for example). The retainer 44 may be used to conceal the use of any fasteners as the fasteners are hidden from view.
[0032] As shown in FIG. 1 , after a first base 14 is attached to a wall with a retainer 44 , the distal end 26 of the bar 12 may be inserted into the receiver 22 . The opposing distal end 28 of the bar 12 may then be inserted into the receiver 22 of the other base 14 . The base 14 may then be attached to the wall in similar fashion, thereby securing the towel bar 10 to the wall.
[0033] Looking to FIG. 5 , the robe hook 48 is shown with the cap 16 and shaft 32 in the extended position. Once extended, the shaft may support an object such as a hanger, and the cap 16 may support a hung garment or towel.
[0034] The figures and descriptions provided herein may have been simplified to illustrate aspects that are relevant for a clear understanding of the herein described devices, systems, and methods, while eliminating, for the purpose of clarity, other aspects that may be found in typical devices, systems, and methods. Those of ordinary skill may recognize that other elements and/or operations may be desirable and/or necessary to implement the devices, systems, and methods described herein. Because such elements and operations are well-known in the art, and because they do not facilitate a better understanding of the present disclosure, a discussion of such elements and operations may not be provided herein. However, the present disclosure is deemed to inherently include all such elements, variations, and modifications to the described aspects that would be known to those of ordinary skill in the art.
[0035] References in the specification to “one embodiment,” “an embodiment,” “an illustrative embodiment,” etc., indicate that the embodiment described may include a particular feature, structure, or characteristic, but every embodiment may or may not necessarily include that particular feature, structure, or characteristic. Moreover, such phrases are not necessarily referring to the same embodiment. Further, when a particular feature, structure, or characteristic is described in connection with an embodiment, it is submitted that it is within the knowledge of one skilled in the art to affect such feature, structure, or characteristic in connection with other embodiments, whether or not explicitly described. Additionally, it should be appreciated that items included in a list in the form of “at least one A, B, and C” can mean (A); (B); (C); (A and B); (A and C); (B and C); or (A, B, and C). Similarly, items listed in the form of “at least one of A, B, or C” can mean (A); (B); (C); (A and B); (A and C); (B and C); or (A, B, and C).
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A towel bar includes a retractable and extendable robe hook. The robe hook may be formed in a wall-mounted first base joined by a towel bar to a wall-mounted second base. A shaft may be extended from the base to reveal the robe hook. When extended, the robe hook provides a location from which objects may be hung. When not needed, the robe hook may be pushed into the base and reside within an internal cavity, thereby concealed from view.
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The present invention relates to road vehicles with all-wheel drive, for example automotive vehicles having two axles in which all four wheels on the two axles are driven, or multiple-axle vehicles in which all the axles have drive wheels thereon. In such vehicles, it is customary to connect not only the wheels on any one axle by a differential, but also the respective drive axles among each other in their driven relationship to the engine or, respectively, a transmission between the engine and the drive shafts by differentials.
BACKGROUND
All-wheel drive vehicles are known, and have the advantage that, under difficult operating conditions, such as snow, ice, sand or the like, the traction available for the vehicle is substantially improved. In order to avoid starting difficulties of the vehicle if the wheels slip or are difficult to turn, it has been customary to provide lock-up elements for one or all of the differentials; the rear wheels, particularly, were often supplied with locking-type differentials in which the respective wheels are securely connected together so that spin of one wheel with respect to another is eliminated. Non-slip or low-slip differentials or lock-up differentials may be used in the position of any of the differentials in the drive system.
Lock-up differentials, or low-slip or non-slip differentials have a disadvantage; critical operating conditions may occur upon application of braking, so that the control of the vehicle can be impaired. This is particularly so if, in addition to the four-wheel drive and the no-slip or locking differentials, the vehicle has an automatic brake control system (ABS) in which the braking pressure, typically hydraulic pressure, applied to the respective wheels is controlled in accordance with slip of the wheels. Such ABSs are well known.
THE INVENTION
It is an object to improve the traction available to the wheels of an all-wheel drive vehicle, and more particularly of an all-wheel drive vehicle which is equipped with an automatic brake control or an anti-lock braking system.
Briefly, a traction control system is provided which includes wheel speed sensors applied to the respective wheels of the vehicle which generate output signals representative of individual wheel speed. The brakes associated with the wheels are then controlled in such a manner that, if the speed of any one wheel is sensed to differ markedly from the speeds of the other wheels, that particular wheel receives braking pressure, so that, in effect, the wheel is locked against spinning by its brake, thus permitting the differential, or other differentials, to apply full traction to the other wheels which are coupled to the differential.
The braking pressure may be applied to more than one wheel, and the reference speed may be derived from a reference speed generator already present in an ABS, or from the speed of one or more of the other wheels, or a composite thereof.
The system has the advantage that it is easily applied, and does not require any modification of standard differentials. Additionally, the undesirable secondary effects of no-slip or lock-up differentials with respect to overall vehicle performance are avoided.
Upon starting, the same effect is obtained as a complete differential lock-up. Thus, excellent traction is available for all the wheels which do not spin, or have a tendency to spin. All the wheels are controlled to receive the appropriate drive power, and the slip of any one of the wheels is appropriately controlled, thus providing for excellent lateral guidance and avoidance of application of yawing torques. Excellent traction is also available at the front wheels of a four-wheel drive vehicle. The use and installation of an anti-wheel block system is standard, well known, and does not introduce any mechanical difficulties in the construction of gearing, transmission and differentials, and is substantially less expensive than the provision of non-slip or low-slip differentials.
It is known to apply control of slippage of driven wheels. The present invention is not specifically related to this feature but, rather, to an electronic alternative for low-slip or non-slip or lock-up differentials in an all-wheel drive vehicle.
The control of the drive slip is carried out in well-known manner. Preferably, the signals of the various transducers on the wheels provide a reference value, corresponding approximately at least to vehicle speed, to provide a simulated speed reference value. The level of the speed reference is, preferably, derived from the transducers of the wheels at one side of the vehicle, and increase in speed is applied as the reference value with some time delay to the system or to the control of the other wheels.
The situation may occur that all wheels of a four-wheel drive vehicle will slip, and, under such conditions, the system would apply the brakes to all the four wheels. In order to prevent excessive forces and torques from arising, the engine is controlled to reduce torque if all wheels are slipping, for example by reducing fuel input, or other engine operating parameters, such as, for example, fuel injection timing (which may apply both to gasoline as well as Diesel engines) or ignition timing.
In accordance with a preferred feature of the invention, application of braking pressure to stop wheel slip is carried out only up to a predetermined speed limit, so that braking of a wheel, which has a speed substantially in excess of the reference speed, is inhibited at reference speed levels beyond a predetermined limit. Thus, the application of braking pressure to the slipping wheel can, thus, be modified or entirely disabled. It is also possible to modify engine parameters, in the direction to reduce torque of the engine, particularly upon slippage of all the wheels by merely controlling fuel supply.
DRAWINGS
FIG. 1 is a schematic block diagram of an all-wheel vehicle traction control system;
FIG. 2 is a schematic hydraulic arrangement controlling the braking system for wheels of the vehicle; and
FIG. 3 is a fragmentary diagram of FIG. 2, and illustrating a modification.
FIG. 4 is a detail of the block diagram of FIG. 1.
DETAILED DESCRIPTION
The traction system for a four-wheel drive vehicle is schematically shown in FIG. 1. The vehicle has four wheels 1a, 1b, 1c, 1d, in which wheels 1a, 1b may be the front wheels, and wheels 1c, 1d the rear wheels. The wheels are connected to respective drive axles which are interconnected by respective differentials 4, 5. The engine 2, typically an internal combustion engine (ICE), is coupled to a transmission 3 via a usual clutch, which may be mechanical or hydraulic (not shown). The transmission 3 applies its output to a drive differential 3a which, in turn, is coupled to the drive shafts 4a, 5a which apply tractive effort to the differentials 4, 5, respectively, for then driving the wheels.
Wheel speed sensors 1a'-1d', as well known in the art, and of any suitable construction, are connected to the respective wheels 1a-1d. The output wheel speed signals are applied to an electronic system ES shown as a unit or block 6. The electronic system recognizes if one or more of the wheels should slip, that is, have a speed substantially in excess of the wheel speed of another wheel, or a group of other wheels, and provides an output signal to a hydraulic brake control block 7. The hydraulic brake control block 7 can be the standard braking system of the vehicle, controlled by the unit 6. Pressurized brake fluid, derived from a pressure source 28, described in detail with reference to FIG. 2, is supplied via respective pressure lines 8 to the brakes of the wheels 1a-1d. Thus, pressurized brake fluid or other braking control can be applied to the respective wheels to prevent slipping or spinning of any one, or more of the wheels. If the electronic system 6 should determine that all the wheels are spinning, that is, if the speeds of all the wheels are high with respect to a reference level, the system provides, by simple comparison of signal levels with a reference, as well known, by use of a comparator, applies a signal over a control line 9 to the engine 2 in a direction to control the engine 2 to decrease output engine torque, for example, by changing the position of a throttle, the characteristics of fuel injection, or the like.
The hydraulic system 7-10-28 is shown in greater detail in FIG. 2: The braking system 10 (FIGS. 1, 2) is constructe in form of the well-known twin-braking circuit. It has a hydraulic tandem main braking cylinder. The braking cylinder is formed within a housing 11, and includes a stepped cylinder 12 in which two pistons 13, 14 are located. The forward or front piston 13 is located by a resetting spring 15 against a shoulder 16 formed in the cylinder, and positioned within a working fluid chamber 17, to which a first braking circuit I is connected. The rest position of the piston 13 is shown in FIG. 2; in this position, the piston 13 is connected through a duct 18 formed in the housing with a refill chamber 19. The forward region of the main braking cylinder thus forms a closed braking circuit. Piston 13 has an inclined surface between two piston areas shown at 13a, forming a camming surface, against which a cam follower 20a operating a switch 20 is engaged.
The second piston 14, operated behind the front piston 13, is operable within a larger step of the cylinder 12 and defines a chamber 21 to which a second braking circuit II is connected. Piston 14 is constructed in ring form, and completed by the end surface 22a of a push rod 22 passing through the ring piston 14. The effective surface acting on the ring piston, thus, is formed by the facing end surface of the piston 14 and by the surface 22a of the push rod 22. The push rod 22, which is stepped, can be operated together with a control valve 23 by the brake control pedal 25 via a brake operating plate 24. The control valve 23 is so constructed that in its two possible terminal positions, chamber 21 is connected either with a relief chamber, namely the supply chamber 19, or with a pressure source 28. Pressure source 28 includes a pump 26 and a pressure reservoir 27. The pump 26 of pressure source 28 is driven by a motor 29, energized when a pressure responsive 30 senses that the pressure within the pressure reservoir 27 has dropped below a predetermined pressure level. The pressure supply unit 28 is well known.
The tandem braking circuit shown in FIG. 2 is merely an example of one type of braking circuit to which the present invention can be applied; different types of tandem or two-circuit main braking systems may be used, and the particular type of cylinder here shown is merely an illustration for better understanding of the construction of a positioning element which is operatively coupled to the control valve 23.
Control valve 23 has a control slider 31 which is operated from the brake pedal plate 24 via a coupling spring 32. The control slider 31 has comparatively long slider surfaces, so that, even if the braking pressure from pump 26 should fail, full excursion of the braking pedal can still supply brake fluid, by operating the brake to the final limit position, and thereby causing operation of the brake push rod or plunger 22 which, initially, will operate freely, but later on will carry along the ring piston 14 by a coupling, not specifically shown. Structures of this type are well known.
The control slider 31 is pressed by a biassing spring 33 towards the right--with reference to FIG. 2--in its starting position, in engagement with the plunger 34 on the pdeal plate 24 under control of the spring 32.
The braking system with which the present invention is particularly suitable is an anti-brake lock, automatic braking system ABS, and the control of brake fluid to the respective braking cylinders is effected by 3/3 magnetic valves 35, 36, 37 which, in dependence on the control signals applied from an automatic braking system, provide for increased braking pressure being applied to the brake cylinders of any one of the wheels, maintenance of braking pressure, or drainage of braking pressure, as well known.
The control slider 31 has one end terminal 39. At that terminal 39, a controllable operating element 40 is engaged. The controllable operating element 40 is illustrated, in FIG. 2, as a pull-in magnet or solenoid, formed as a solenoid coil 41. The solenoid coil 41 has a winding 42 and an armature 43. Upon energization of the winding with current of any desired and predetermined wave form, in which amplitude, frequency, or pulse repetition rate is controllable, armature 43 is pulled in to the magnet in similar manner, and, by coupling to the terminal 39, moves the control slider 31 along. A connecting link 43a coupled the armature 43 to the terminal 39 of the slider 31.
OPERATION
Control slider 31 can be operated by two different control energy sources:
(1) Control slider 31 can be pushed by the push rod 34 from pedal plate 24, operated by the operator of the vehicle upon engagement of the brake pedal 25.
(2) In addition, the control slider 31 may be operated by electrical energization of the positioning element 40, that is, by energizing the terminals of solenoid 41 with electrical signals.
In either case, the control slider 31 is pushed towards the left, thus controlling admission of pressurized brake fluid, that is, braking energy, via a pressure inlet 44 on the control valve 23 through a ring groove 45 and a central through-bore 46 on the slider 31 into the pressure chamber 31, and from there first into the braking circuit II. By suitable spring setting, the pressure will act on the piston 13 and generate pressure in the chamber 17 so that the braking pressure will also become effective in the braking circuit I. Thus, without operation of the braking pedal 25 at all, the brakes can be operated by the positioning element 40 and valves 35-37 can apply braking pressure to the respective brakes of the wheels to control slip of the wheels.
Embodiment of FIG. 3: The system is identical to that of FIG. 2, except that the positioning element 40 has been replaced by a hydraulic working cylinder 47, which has a positioning piston 48, controlled by a magnetic valve 49 which, upon electrical energization of the magnetic valve, controls the piston via hydraulic pressure to shift its position. and The shifted position is applied over a piston rod 48a to the engagement point 39 of the control slider 31. A connecting plate 50 is the link between the piston rod 48 and the terminal point 39 of the control slider of the valve 23. The magnetic valve 49 is electrically energized similar to the solenoid 41 by electrical signals applied to terminals 51. The operation of the braking valves, thus, is effected indirectly by the hydraulic positioning unit 47 and magnetic valve 49.
The electrical signals being supplied to the valves 35-37 can be of any suitable and desired type, for example in clock pulses, pulses with different current levels, different pulse repetition rates, pulse-pulse gap duty cycles and the like, in order to obtain suitable time-current functions and control the actual braking effort at the respective wheels, so that the slip at the wheels will be appropriately controlled. The electronic system 6, which furnishes these signals to the valves 35-37, respectively, can be readily designed to provide suitable output signals depending on operating requirements of the vehicle as such.
The switch 20 is used to switch over, automatically, application of brake fluid between the valves 1a', 1b', associated with the braking circuit I to the braking circuit II in case of failure of the braking circuit I, for example by leakage. This system of automatic change-over is well known, and a similar arrangement can, likewise, be used for change-over of braking fluid from the braking circuit I to the braking circuit II. The broken-line hydraulic connections are as well known return lines for the pressure fluid. The broken line shown in FIG. 3 is an illustration of a drain, which can be connected as shown, or connected to another suitable drain line connection.
Various changes and modifications may be made, and features described herein may be used with any of the others within the scope of the inventive concept. The specific valve and the control arrangement shown in FIGS. 2 and 3 are merely illustrative. In FIG. 4 the unit 6 is shown in greater detail. The four lines coming from the sensors 1a'-1d' are connected to a unit 60 in which a reference-signal is generated from these speed-signal which equals the vehicle speed. This is done in known manner by increasing the reference-signal in dependence of the sensor-signals only delayed. This reference signal is fed to the comparators 61 in which the sensor-signals are compared with this reference signal and in which control-signals for the valves 7 or 35-37 are generated. The control-signals are also fed to an AND-Gate 62 which generates a control signal if all control signals are present. This signal is fed via line 9 to the engine 2 to decrease the torque of the engine. The control signals to the valves 7 and the engine 2 are cut off if the vehicle-speed is above a given level. This is done in unit 63 which generates a cut off signal when this level is reached. This signal inhibits the AND-gate 62 and gates 64 in the lines to the valves 7.
As illustrated in FIG. 1, the hydraulic unit 7 of the brake system 7 applies braking pressure to the wheels 1a . . . 1d individually. FIG. 2 is slightly different in that, for example, the wheels of a braking circuit, e.g. the front wheels, are individually controlled by valves 35, 36, through braking circuit I, at brake lines 1a', 1b', whereas the rear wheels are commonly controlled by a single valve 37, through a brake line II'. The respective brake valves 35, 36, 37 which operate at a slow speed, that is, which do not slip, can be disabled from the electronic system 6 by merely connecting the valve of the respective circuit, e.g. valves 35, 36, to the drain line of the anti-skid braking system, so that no braking effort will be applied by those respective valves, thus reducing loading on the engine 2. Only those wheels, or that wheel which spins will be subjected to braking so that the wheel which spins is braked permitting more tractive effort to be applied to the other wheels. The control of the respective valves 35, 36, 37 can readily be effected by suitable connecting lines from the unit 6, in dependence on relative sensed velocities.
If the speed differential between any one of the wheels and the other wheels as sensed in the unit 6 is such that the respective electrical coil 41, or magnet 49 at terminals 51 is energized, braking pressure is applied. The wheels which should not have braking pressure applied at that time are then connected to the drain line. The logical connection can readily be instrumented by a simple logic network, constructed in accordance with Boolean algebra, as well known and standard in logic control systems.
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To prevent spinning of wheels in all-wheel vehicles, a traction control system is used which, in its simplest form, may use existing wheel speed sensors. If any one, or more, or all of the wheel speed sensors provide output signals representative of spinning of a wheel, for example by providing output signals representative of a substantially higher speed than other wheels, or higher than a reference--indicating that all wheels are spinning--an output signal is generated by the electronic control unit (6) which, in turn, controls application of the wheel brake to the respective wheel, thus preventing its spinning. Spinning of any one wheel, of course, causes loss of traction at another one due to the effect of the normally interposed differentials (4, 5, 3a). Thus, the system provides a simple, electronically controlled "differential lock-up", responsive only to speed of spinning wheels, without modification of the differentials as such, by applying the external wheel brakes, selectively, to those wheel or wheels which are spinning.
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CROSS-REFERENCE TO RELATED APPLICATION(S)
This application claims priority under 35 U.S.C. §119(e) of the U.S. Provisional Patent Application Ser. No. 61/317,407, filed Mar. 25, 2010 and titled “Systems, Devices, and Methods of Energy Management and Property Security,” which is hereby incorporated by reference in its entirety for all purposes.
FIELD OF THE INVENTION
The present invention relates to the field of energy and property management. More specifically, the present invention relates to monitoring and/or controlling energy saving and property safety using disclosed devices and methods.
BACKGROUND OF THE INVENTION
Unattended appliances, such as heating or cooking devices, are able to cause fire and/or others disasters. A typical appliance does not automatically shut off its power when the user is away or the appliance is unattended.
SUMMARY OF THE INVENTION
Systems and devices for and methods of energy management, property security and fire hazard prevention are provided herein. The systems, devices and methods disclosed herein are able to be centralized, computerized and expandable. In some embodiments, the devices and systems are capable of automatically reducing energy consumptions and green house gases emissions and minimizing losses of property due to fire, theft, and vandalism. In some other embodiments, the device, the system, and method include automatic systems, devices and methods for saving standby and operation powers, deterring nonusers, assisting authorities, as well as reducing and detecting fire or other security hazards. In some embodiments, the systems, devices and methods do not need to program a remote thermostat or other controllable devices. In some embodiments, the systems, the devices, and the method do not need to switch on and off an alarm or any other types of security devices.
In a first aspect, a method of fire hazard prevention comprises providing one or more occupancy sensors in a property electrically or communicatively coupled with a gateway processor, sensing an occupancy status of the property using the one or more occupancy sensors, and adjusting one or more appliances according to the occupancy status of the property. In some embodiments, the adjusting comprises disabling the one or more appliances when the occupancy status is negative. In other embodiments, the adjusting comprises enabling the one or more appliances when the occupancy status is positive. In some other embodiments, the method further comprises sensing one or more characteristics of a flame and actuating alarm when the one or more characteristics of the flame are sensed. In some embodiments, the method further comprises notifying an authority or a user when the one or more characteristics of the flame are sensed. In other embodiments, the notification comprises location related information. In other embodiments, the method further comprises setting up a timer to disable a fire hazard prevention function for a predetermined period. In some other embodiments, the method further comprises sensing battery voltage level of one or more battery-powered devices using a voltage sensor, wherein each of the one or more battery-powered devices contains a unique identifier, sending recurring low battery warnings with the unique identifier from the one or more battery-powered devices when detect a low battery condition, translating the identifier into user-understandable device information, and presenting the device information to the user. In some other embodiments, the method further comprises generating the unique identifier based on a device address on a network. In some embodiments, the adjusting comprises adjusting all of the appliances together when the occupancy status in the property changes. In other embodiments, the adjusting comprises adjusting each appliance individually when the occupancy status in the respective area of the appliance changes. In some other embodiments, the method further comprises recording a detection result of the one or more occupancy sensors. In some embodiments, the method further comprises backing up the detection result at a location away from the property. In other embodiments, the method further comprises adjusting a thermostat setting, an illumination level, or a combination thereof. In some other embodiments, the method further comprises sensing an environmental condition. In some embodiments, the environmental condition comprises an illumination level. In other embodiments, the method further comprises preventing frozenness of a water pipe by adjusting a thermostat setting to a predetermined temperature. In some other embodiments, the method further comprises profiling an environmental condition to generate a preference.
In a second aspect, a method of energy management and property security comprises sensing absence of a person in a property using one or more occupancy sensors, reducing energy supply to an appliance when sensing the absence of a person, and notifying a user, an authority, or both when sensing and judging presence of a nonuser. In some embodiments, judging presence of the nonuser comprises sensing a person at the property at a time defined as absence of a person and the person fails to enter correct password within a predetermined time period. In other embodiments, the method further comprises profiling the user's activities using machine learning to determine the time defined as absence of a person. In some other embodiments, the method further comprises requesting to enter a password. In some embodiments, the notifying comprises informing a physical address or a location. In other embodiments, the method further comprises sensing one or more characteristics of a flame and actuating alarm when the one or more characteristics of the flame are sensed.
In a third aspect, a system for energy management, property security, fire hazard prevention or fire hazard detection comprises a gateway processor, one or more occupancy sensors coupling with the gateway processor, and one or more load control devices to control one or more appliances coupled with the system. In some embodiments, the gateway processor consults with a computer-readable user schedule. In other embodiments, the system further comprises a portal website coupled with the gateway process to perform a scheduling task, a backup task, or a combination thereof. In some other embodiments, the system further comprises a firewall coupled with the gateway processor. In some embodiments, the system further comprises one or more sensors capable of sensing a characteristic of a flame. In other embodiments, the system further comprises one or more sensors capable of sensing one or more environmental conditions. In some other embodiments, the one or more environmental conditions comprise an illumination level.
In a fourth aspect, a gateway processor comprises one or more central processor units (CPU), one or more transceivers electrically coupled with the CPU, and one or more computer-readable medium storing a user's schedule, a first set of computer instructions or programs profiling a user's activity and creating the schedule, a second set of computer instructions or programs associating a device with one or more occupancy sensors in accordance with physical locations of the one or more occupancy sensors, a third set of computer instructions or programs translating unique device identifier or designation into device name or location, a fourth set of computer instructions or programs profiling an environmental condition and generating a preference, or a combination thereof. In some embodiments, the gateway processor further comprises at least one occupancy sensor suitable to detect presence or absence of one or more persons. In other embodiments, the gateway processor further comprises a firewall. In some other embodiments, the gateway processor further comprises a user input/output interface. In some embodiments, the computer-readable medium stores a fifth set of computer instructions or programs to perform authority or user notifications. In other embodiments, the computer-readable medium further stores data received from the one or more occupancy sensors, data related to system activities, data of acceptable lowest temperature, information of deployed location, or a combination thereof. In other embodiments, the gateway processor further comprises a buzzer or beeper.
In a fifth aspect, a managed electric or electronic appliance comprises a load control element to control an amount of power delivered, wherein the load control element communicatively couples with a gateway processor and electrically couples with an AC power source and an electric or electronic load coupled with the load control element. In some embodiments, the electric or electronic load comprises a cooking or heating element. In other embodiments, the appliance further comprises a meter to measure the electricity consumed by the electrical or electronic load, a processor coupled with the meter to accumulate the electricity consumption data, and a computer-readable storage medium coupled with the processor to store the accumulated electricity consumption data.
BRIEF DESCRIPTION OF THE DRAWINGS
Embodiments will now be described by way of examples, with reference to the accompanying drawings which are meant to be exemplary and not limiting. For all figures mentioned herein, like numbered elements refer to like elements throughout.
FIG. 1 illustrates a system for energy management, property security and fire hazard prevention according to some embodiments.
FIG. 2 illustrates a method of automatically reducing both standby and operation power consumptions and preventing fire hazards, when detecting the absence of a user, according to some embodiments.
FIG. 3 illustrates a method of detecting an unexpected event according to some embodiments.
FIG. 4 illustrates a method of enabling an appliance according to some embodiments.
FIG. 5 illustrates a method of sensing and warning of a hazardous situation according to some embodiments.
FIG. 6 illustrates a method of sensing a low battery situation according to some embodiments.
FIG. 7 illustrates a flowchart of a method of using the energy management, property security and fire hazard prevention system/device according to some embodiments.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT
Throughout this disclosure, the word “property” is used as a generic term to include any tangible or intangible, movable or unmovable object, place or facility. The word “user” is able to include an individual or a group of individuals, who have the rights to access, operate, employ, consume, transfer or exchange the property. The word “nonuser” is able to include an individual or a group of individuals, who do not have the rights to access, operate, employ, consume, transfer or exchange the property.
Throughout this disclosure, the word “internet” or “Internet” is used as a generic term to include any system interconnecting networks of computerized devices, including but not limited to the Wide Area Network based on TCP/IP and commonly known as “Internet” (with a capital “I”), Cellular or PCS systems based on radio communication technologies.
Throughout this disclosure, the term “local area network” or “LAN” includes a network connecting computerized devices within a limited area. A LAN is able to include either wired or wireless means to connect computerized devices. A LAN is able to include Home Area Network (HAN) where it is implied that the limited area includes a home.
Throughout this disclosure, the noun “schedule” includes a computer-readable data regarding a user's activities at various day, date or time. A schedule is able to be accessible through internet, recorded in a computing device on a LAN, created through profiling a user's activities using machine learning, other techniques, or any combinations thereof.
In some embodiments, the devices, the systems, and the methods are able to be used in residential, commercial, industrial or other properties. A residential deployment is given as an example in FIG. 1 .
FIG. 1 shows a system 100 for energy management, property security and fire hazard prevention in accordance with some embodiments. In some embodiments, the system 100 includes a calendar/schedule portal website 101 , which is configured to render or store a user calendar, a user's schedule data, or any other type of application or mechanism to track time or events and which is able to be coupled with the internet 102 . In some embodiments, the system 100 includes a support portal website 120 , which is configured to store offsite records, to support services, to create or host user webpage(s) and which is able to be coupled with the internet 102 . The calendar/schedule portal website 101 and the support portal website 120 are able to be integrated as one website or are able to be separate websites. The system 100 is applicable to, but not limited by, the use of a calendar/schedule portal website 101 , the use of a support portal website 120 , or the integration thereof. A person of ordinary skill in the art will appreciate that the portal website 101 , the support portal website 120 , or a combination thereof is able to electronically/electrically/communicatively couple with a gateway processor 104 of the system 100 .
In some embodiments, the system 100 comprises a gateway processor 104 comprising one or more transceivers 150 , one or more storage media 152 (e.g., computer-readable medium, hard disk, and flash memory), and one or more central processor unit (CPU) 154 . The gateway processor 104 is able to render or store additional computer-readable user calendar, schedule data, or any other type of application or mechanism to track time or events. In some embodiments, the gateway process 104 comprises the portal website 101 , the support portal website 120 , or a combination thereof.
The one or more transceivers 150 are able to perform uplink, downlink, or both communications. The uplink communication is able to communicate with the support portal website 120 , the calendar/schedule portal website 101 or other internet-enabled devices. The downlink communication is able to communicate with other device(s) on one or more LAN(s) 106 . The one or more storage media 152 are able to store instructions or computer programs, which are able to comprise an html locator link to a particular destination on the World Wide Web, user preferences and/or selections, default settings from pre-programming and/or profiling, event and/or sensor records, or any combinations thereof. The gateway processor 104 is also able to store the physical address or location (which is able to be defined by any type of locator information, such as longitude and latitude) wherein the system 100 is deployed.
The gateway processor 104 is able to be the only node bridging between or otherwise coupling the LAN 106 and devices out of the LAN 106 . The gateway processor 104 is able to access the existing user calendar or schedule data from the calendar/schedule portal website 101 . The gateway processor 104 is able to comprise a firewall 156 against unauthorized access to the LAN 106 by allowing only recognized communications from or to one or more predetermined communication ports. The gateway processor 104 is able to comprise a buzzer or beeper.
In some embodiments, the system 100 includes one or more occupancy sensors 109 , as nodes of the LAN 106 , responsive to motion, heat, sound, pressure, magnetism, vibration, substance, reflection or other physical stimulus associated with or caused by human bodies or human activities, to detect occupancy. The system 100 is able to utilize one or more sensors including infrared, ultrasonic, acoustic, optical, magnetic, chemical, thermo, seismic or a combination thereof. A person of ordinary skill in the art will appreciate that any other type of sensors are applicable so long as the sensing device is able to sense the occupancy of a predetermined and/or a random location.
In some embodiments, the occupancy sensor 109 is able to share the same housing with the gateway processor 104 or is able to be in another device on the LAN 106 . In other embodiments, the occupancy sensor 109 is able to stand alone as a discrete device. In the embodiments that the occupancy sensor 109 is implemented as a standalone device, the occupancy sensor 109 is able to further comprise a transceiver 160 to facilitate communications on the LAN 106 . In some embodiments, the occupancy sensor 109 comprises a transceiver 160 and sensor 158 to detect a person. In other embodiments, the occupancy sensor 109 comprises a transceiver 160 and sensor 158 configured to detect a person regardless of if the person is in standstill or in motion.
In some embodiments, the system 100 includes a digital fire sensor 110 to detect smoke, carbon monoxide or other substances from a flame. Smoke, carbon monoxide, and/or other substances from a flame are able to be characteristics of the flame. A person of ordinary skill in the art will appreciate that any physical conditions, chemical substances generated by a flame that are able to be detected/sensed are able to be the characteristics of the flame, such as heat, light, smoke, and electromagnetic emissions. The digital fire sensor 110 is able to serve as a node of the LAN 106 . In some embodiments, the system 100 includes a digital thermometer and/or light sensor 112 , which is able to serve as a node of the LAN 106 .
In some embodiments, the system 100 includes a safe stove 121 comprising a heating or cooking element 174 (e.g., rice cooker), a load control element 172 and a transceiver 170 , and which is able to be a node on the LAN 106 . The load control element 172 is able to be electrically connected between an AC power source and the heating or cooking element 174 . The load control element 172 is also able to electrically couple with the transceiver 170 to supply, withdraw, vary, limit, or regulate amount of power delivered to the heating or cooking element 174 , in accordance with requests received through the transceiver 170 . A person of ordinary skill in the art will appreciate that the load control element 172 is able to perform various controlling motions to the heating and/or cooking element 174 . In some embodiments, the safe stove 121 further comprises a meter, a processor, and/or a computer-readable medium. The meter is able to measure the electricity consumed by coupled electrical or electronic load. The processor is able to accumulate the power consumption information over time. The computer-readable medium is able to store the accumulated power consumption data. However, a conventional stove and a separate device (e.g., a smart controller), which comprises a transceiver 170 and a load control element 172 , are also able to function together as a safe stove 121 . The system 100 is applicable to but not limited by either a standalone safe stove 121 or a stove coupled with a device comprising a transceiver 170 and a load control element 172 .
In some embodiments, the system 100 integrates a transceiver 170 and a load control element 172 into any electrical or electronic device, where a safe stove 121 is part of an illustrative example. In other embodiments, the system 100 comprises a discrete smart controller comprising a transceiver 170 and a load control element 172 . In some other embodiments, the system 100 comprises a discrete smart controller comprising a transceiver 170 , a load control element 172 , a meter, a processor and a computer-readable medium. A person of ordinary skill in the art will appreciate that there are multiple possible combinations and locations for the transceiver 170 , electric or electronic load 174 , load control element 172 , any kind of meter, processor and computer-readable medium. All the possible combinations and locations are within the scope of some of the embodiments.
As a node on the LAN 106 , the system 100 is able to comprise a power source 111 (such as managed power strip or managed wall outlet) including a transceiver, a load control element and one or more electrical outlet receptacles or sockets. The power source 111 is able to further comprise a meter, a processor, and a computer-readable medium. The meter is able to measure the electricity consumed by coupling with electrical or electronic devices 114 . The processor 104 is able to accumulate the date or information of the power consumption over time. The computer-readable medium 152 is able to store the accumulated power consumption data.
In some embodiments, the power source 111 (e.g. managed power strip) is able to communicate with the gateway processor 104 and supply electricity to or withdraw (reduce) supply of electricity from the electrical outlet receptacles. In some embodiments, a set of electrical/electronic devices 114 (e.g., entertainment equipment) is plugged into the electrical outlet receptacles of the power source 111 (e.g., managed power strip) and is able to be controlled by the power source 111 , according to the requests from the gateway processor 104 .
In some embodiments, the system 100 includes a smart lighting fixture 113 , which comprises a transceiver, a dimmer, and a lighting load. In some embodiments, the smart lighting fixture 113 is a node on the LAN 106 . In other embodiments, a conventional lighting fixture and a separate device, which comprises a transceiver and a dimmer, are also able to function together as a smart lighting fixture 113 . The system 100 is applicable to but not limited by either a standalone lighting fixture 113 or a lighting fixture coupled with a device comprising a transceiver and a dimmer. The separate device (e.g., smart dimmer) or smart lighting fixture 113 is able to further comprise a meter, a processor and a computer-readable medium. The meter is able to measure the electricity consumed by a coupled electrical or electronic load. The processor is able to be configured to accumulate the power consumption data/information over time. The computer-readable medium is able to store the accumulated power consumption data. The system 100 is applicable to but not limited by either a standalone smart lighting fixture 113 or a lighting fixture coupled with a smart dimmer.
In some embodiments, the system 100 includes a HVAC (Heating, Ventilating and/or Air Conditioning) coupled with smart thermostat 105 , as a node on the LAN 106 . In other embodiments, the system 100 includes a smart motorized shading 108 (such as blinds or drapery for windows), comprising a transceiver, a motor and a load controller, which is able to be another node on the LAN 106 . A person of ordinary skill in the art will appreciate that any other devices (e.g., electrical devices, electronic devices, and mechanical devices) are able to be included in the system 100 .
In some embodiments, the system 100 includes a smart siren 107 which is able to be a node on the LAN 106 . The LAN 106 is able to be embodied with any wireless networks (such as ZIGBEE ® and WI-FI ®) and/or any wired networks (such as HOMEPLUG ® and Ethernet). The network topology is able to be mesh, star or any other type of configuration. The LAN 106 is able to use a Smart Energy profile, other standards or proprietary applications. The system 100 is able to utilize but not be limited to a plurality of network protocols, topologies, standards or applications.
In some embodiments, the LAN 106 allows the nodes to send and receive data packets with each others, directly or having one or more intervening nodes to route the data packets. For clarity, the following illustrations will use arrows to represent the communications between nodes of the LAN 106 without showing the LAN 106 and the connectivity of the LAN 106 .
The disclosure herein includes exemplary processes and methods of the present technology to provide a plurality of services to the user. While some embodiments are able to implement all or some of the following processes and methods, some other embodiments of the technology are able to implement additional processes and methods. Not all the exemplary processes and methods are required for the technology to function, and the user is able to configure the inventive system to provide only some of the functions. All components disclosed herein are optional. The technology is applicable but not limited to the automated pause, continuation, or expandability.
FIG. 2 shows a method 200 to automatically reduce both standby and operation power consumptions in terms of electricity, natural gas or other energies, as well as to prevent fire hazards in accordance with some embodiments. In some embodiments, the method is referred as Off Method. When the user leaves a property, the occupancy sensor 109 is able to detect the absence of person and send a Person Absent message 201 to the gateway processor 104 immediately or after a predetermined time delay elapses. Immediately or after another predetermined time delay elapses, the gateway processor 104 is able to send a Power Off command 202 to the safe stove 121 and other devices. The sensed signal of the absence of the person in the property is able to be determined that the occupancy status is negative. The sensed signal of the presence of the person in the property is able to be determined that the occupancy status is positive. Upon receiving the Power Off command 202 , the power source 111 is able to withdraw (reduce) electricity supply completely from the device 114 . By doing so, a television (TV) and other entertainment equipment no longer consume standby powers, while the power source 111 itself is able to become only partially powered just enough to be able to respond to further communications with the gateway processor 104 . Upon receiving the Power Off command 202 , the smart lighting fixture 113 is able to withdraw the electricity from the light bulbs of the smart lighting fixture 113 , in order to eliminate the operation power consumption, and is able to only supply limited power to the transceiver. Upon receiving the Power Off command 202 , the safe stove 121 is able to withdraw electricity completely from the heating element, to avoid fire hazards caused by unattended cooking.
The gateway processor 104 is also able to send a predetermined low temperature setting to the smart thermostat 105 , to adjust the heating setup to a lowest acceptable temperature just enough to prevent water pipes from freezing in order to minimize the natural gas consumption of the HVAC (part of 105 ). The smart thermostat (part of 105 ), upon receiving the lowered temperature setting 226 , is able to adjust the heating setup accordingly.
The above “Off Method” is able to be completed in few seconds or less, to save both the standby and operation powers in electricity, natural gas or other energies, automatically, as well as to prevent fire hazards.
The user is able to elect to disable this process entirely, without impairing the functionality of the system 100 . The user is able to elect to enable or disable this process for selected appliance or equipment. For example, the user is able to set up a timer to temporarily disable this process for the safe stove and/or to allow slow cooking to continue when the user is away. After the predetermined time delay elapses, this process is able to automatically restart to save energies and to prevent fire hazards.
FIG. 3 shows a method 300 to automatically assist the authorities and the user, and to deter nonusers, for property security according to some embodiments. The method 300 includes detecting the presence of a person, consulting the user's calendar, schedule, or any other type of application or mechanism that tracks time, judging the person as a nonuser, alerting or otherwise assisting the authorities and the user, and deterring nonusers. In some embodiments, the method is referred as Unexpected Method. When detecting the change from absence of a person from a property to presence of a person 119 to the property, the occupancy sensor 109 is able to immediately send a Person Present message 203 to the gateway processor 104 . Then the gateway processor 104 is able to send a Schedule Request command 204 to the calendar/schedule portal website 101 , in order to determine whether the user is expected to be at the property at a given time. The occupancy sensor 109 is able to compute the latest schedule based on the corresponding response 205 from the calendar/schedule portal website 101 , its local information, or both.
Based on the resulted latest schedule, the gateway processor 104 is able to judge that the user is not expected to be present in the property according to the user's schedule, set up a timer with predetermined delay, and request the person present in the property to provide a password within the specified time period. The gateway processor 104 is able to generate an audio signal with the buzzer or beeper. The gateway processor 104 is able to send an Unscheduled Entry alert 206 to the user by voice, electronic mail, text message or any combinations thereof, and provide the user registered street address or physical location. By doing so, the system is able to determine if the person present in the property is indeed the user. This is able to result if the user failed to update his or her calendar or schedule or did not maintain a computer-readable calendar or schedule. In an example when the person 119 failed to enter a correct password before timeout or if the gateway processor 104 does not receive a correct password before the timer elapses, the gateway processor 104 is able to immediately notify the authorities and/or the user with the user registered street address or physical location of the property by one or more phone calls, messages, emails, or any other type of communication means. The gateway processor 104 is also able to send an Invasion Alarm 208 to the siren 107 and the smart motorized shading (blinds or drapery) 108 .
To deter the unauthorized person 119 ( FIG. 3 ), upon receiving the Invasion Alarm 208 , the siren 107 is able to sound. To assist the authorities, the smart motorized shading 108 is able to open up or otherwise move the blinds or drapery, such that the interior of the property is able to be seen from the exterior of the property via the windows of the property, in order to permit authorities to view the property from outside. This alarm condition is able to continue until the user returns and enters the correct password.
The gateway processor 104 is able to record all the related events with timestamps to assist any follow-up investigations and is able to send a copy of the record to a support portal website 120 for off-site backup. The above automatic procedure Unexpected Method is able to assist the authorities and the user and is able to deter nonusers, without the need for the user to arm an alarm, to disarm an alarm or to maintain additional calendar or schedule. The user is able to elect to disable this method, without impairing the functionality of the system, especially when the user wishes neither to maintain any computer-readable schedule nor to remember any password.
FIG. 4 shows a method 400 of automatically returning the appliances to their normal states and become responsive to usual operations for the convenience of users in accordance with some embodiments. The method 400 is able to judge the detected person as the user, to access environmental sensors, to manage appliances accordingly and automatically for the user's comfort, needs, profile, data or instructions using preprogramming or profiling mechanisms, according to some embodiments. In some embodiments, the method is referred as On Method.
When detecting the change from absence of a person in a property to presence of a person 119 in the property, the occupancy sensor 109 is able to immediately send a Person Present message 203 to the gateway processor 104 .
If the above Unexpected Method is not disabled by the user, the gateway processor 104 is able to send a Schedule Request command 204 to the calendar/schedule portal website 101 , in order to determine whether the user is expected to be at the property at a given time. The gateway processor 104 is able to compute the latest schedule based on the corresponding response 205 from the calendar/schedule portal website 101 , its local information, or both. In this case, the user is expected to be present in the property according to the user's schedule. Thus, the gateway processor 104 is able to judge the person as the user and is able to automatically send a Supply Power message 212 to the power source 111 and the safe stove 121 .
If the above Unexpected Method is disabled, the gateway processor 104 is able to directly send a Supply Power message 212 to the power source 111 and the safe stove 121 . Upon receiving the message 212 , the power source 111 is able to supply electricity to the set of devices 114 . The set of devices 114 returns to standby from powered down and is then ready to respond immediately to any actuations by the user.
Additionally, the gateway processor 104 is able to send a Read Environment command 210 to the digital thermometer and light sensor 112 . Based on the received temperature and illumination data 209 , the gateway processor 104 is able to send a Temperature Adjustment command 214 to the smart thermostat (part of 105 ) to turn on the air conditioner or the heater based on the temperature of user's preference. Based on the received temperature and illumination data 209 , the gateway processor 104 is able to separately send a Brightness Request command 228 to the smart lighting fixture 113 , specifying a certain percentage of full brightness of the illumination, such as 100%, 70%, 50%, and 0%.
Upon receiving the message 212 , the safe stove 121 is able to close the switch and have the user-controlled heating or cooking element return from powered down to functional and responsive to user controls.
The above (On Method) is able to automatically return the appliances back to normal, thereby causing the appliances to be ready to respond to the user, and also to manage the lighting, temperature and other environmental conditions for the user. The user is able to elect to disable this method, without impairing the functionality of the system, especially when the user has already disabled the Off Method.
FIG. 5 shows a method 500 of sensing a fire using redundancy or backup operations, to alert the fire department and the user automatically and to assist the authorities, regardless of the location of the user in accordance with some embodiments.
In some embodiments, the method 500 comprises sensing a fire using redundancy or backup operations, to alert the fire department and the user, to alert or otherwise assist the authorities, regardless of the user's location, according to some embodiments. In some embodiments, the method 500 is referred as Alarm Method. The disclosed methods/devices are able to perform redundancy or backup operations to detect fire dangers by checking all suitable sensors just in case any of those sensors fails to detect a fire.
As soon as the smoke and carbon monoxide sensor 110 detects smoke, the sensor 110 is able to send a Smoke Alert 215 to the gateway processor 104 . At the same time, the thermometer and light sensor 112 is able to separately send an Extreme Temperature alert 217 with the temperature data to the gateway processor 104 . Upon receiving only the earlier one of the two alerts 215 and 217 , the gateway processor 104 is able to send a Fire Alarm 218 immediately to the siren 107 and the motorized shading 108 . The gateway processor 104 is able to immediately call the fire department and the user and provide the registered user street address or physical location of the property.
The siren 107 is able to sound an alarm to draw attentions, and the motorized shading 108 is able to open the shading to allow the authorities to see through the window.
The gateway processor 104 is able to record all the related events with timestamps to assist any follow-up investigations and is able to send a copy of the record to a support portal website 120 for off-site backup.
The above Alarm Method is able to utilize all available sensors to detect fire, in terms of smoke, carbon monoxide, illumination, temperature or other substances or radiations from a flame, and alert the authorities and the user with all available means, including phone calls, siren and other means, regardless of the location of the user. The Alarm Method is also able to assist the authorities on any follow-up investigation with recorded data. The user is able to elect to disable this method, without impairing the functionality of the system, especially when the user wishes to use another emergency system.
If there are no sensors on the LAN suitable to detect substances or radiations from a flame, the fire detection service is able to pause until such a sensor become available. Once a sensor is added into the system, the sensor is able to automatically identify itself to the gateway processor 104 . The gateway processor 104 is then able to continue the fire detection service. The technology (e.g. the system 100 ) is applicable but not limited to the availability of such a sensor, the fire detection service, or both.
FIG. 6 shows a method 600 of assisting the user to replace an exhausted battery in a node of the network in accordance with some embodiments. In some embodiments, the method 600 comprises sensing a low battery situation, and advising the user which battery to change. In some embodiments, the method is referred as Battery Method.
In some embodiments, both the occupancy sensor 109 and the thermometer and light sensor 112 are battery powered. As the battery for occupancy sensor is expiring (voltage level has decreased), the occupancy sensor 109 is able to set up a recurring timer to send a periodical Low Battery warning 219 to the gateway processor 104 . A unique identifier of the particular occupancy sensor, such as a data link layer address, is able to be included as part of the warning 219 . Any type of identifier or designation is within the scope of embodiments contemplated herein.
The gateway processor 104 is able to translate the unique device identifier into user-understandable device name and/or location, and forward the Low Battery warning 219 to the user. The user is able to replace battery for the occupancy sensor 109 based on the device name and/or location included in the voice, electronic mail, or text message. Thus in some embodiments, the user does not have to identify which node is having the low battery condition in a system wherein multiple battery-powered nodes are used.
As soon as a new battery is installed, the occupancy sensor 109 is able to cancel the recurring timer and stop sending the Low Battery warning 219 to the gateway processor 104 . The user is able to no longer receive the forwarded message 219 .
The above Battery Method is able to help the user to identify which battery to be replaced. The user is able to elect to disable this method, without impairing the inventive system, especially when the user wants to periodically replace the batteries before expiration.
The user is able to access the system disclosed herein from any internet-enabled computing devices with virtual or physical user input/output interface, such as a personal computer, smart phone, digital assistant, or a combination thereof. The gateway processor 104 is also able to comprise a virtual or physical user input/output interface to be used as the user interface during registration, setup procedure, password entry, or other situations.
The gateway processor 104 is able to store default settings, like the highest temperature before fire alarm, lowest temperature before water pipes freeze, and any other default settings to minimize setup procedure. The gateway processor 104 is also able to store program and/or other computer-readable data to assist the user to register and to setup the system 100 with a support portal website 120 .
During the registration or setup procedure, the user is able to specify unique account name/password combination(s) to allow one or more users to access the technology system. The user is able to provide information to enable the technology to access the user's computer-readable calendar(s), schedule(s) or other information stored on the calendar/schedule portal website 101 . The user is also able to enter the street address or physical location of the deployed location to allow the technology to provide the address or physical location to the authorities and the user upon fire emergencies, unauthorized entries or other events. The user is able to enter temperature, illumination or other preferences for automated environmental controls or is able to have the technology to profile the existing environmental conditions in order to generate the preferences. The user is able to elect to have the fire hazard reduction, fire hazard detection, energy management, property security, or any combinations thereof provided by the system 100 and/or the methods described herein. The system 100 is able to store those user information and elections in the support portal website 120 , the calendar/schedule portal website 101 , the gateway processor 104 , or any combination thereof.
The devices and methods disclosed herein are applicable but not limited to the use of the internet 102 . If there is no internet 102 connection, the system is still able to perform fire prevention, fire detection, energy management, property security, or any combination thereof.
FIG. 7 illustrates a flowchart of a method 700 of using the energy management, property security and fire hazard prevention system/device in accordance with some embodiments. The method 700 is able to begin in Step 702 . In Step 704 , occupancy status of a pre-selected property is sensed. Sensing of the occupancy status is able to be performed using any sensors capable of sensing the presence of human beings or animals, such as motion sensors and/or ultrasonic sensors. When the sensor senses the presence of a human being or an animal, the system 100 ( FIG. 1 ) is able to determine that the occupancy status is positive. When the sensor senses the absence of a human being or an animal, the system 100 is able to determine that the occupancy status is negative. At step 706 , one or more environmental conditions are able to be sensed. Any sensors are able to be selected to be used for sensing. For example, if an environmental condition to be sensed is fire, a fire sensor is able to be used. The fire sensor is able to sense one or more characteristics of a flame, such as carbon dioxide, carbon monoxide, temperature, and/or smoke. At Step 708 , one or more device conditions are able to be sensed. Any sensors are able to be selected to be used for sensing. For example, if the battery power is to be checked, a voltage sensor is able to be used. At Step 710 , the results of the sensing described above are responded. For example, when the occupancy status is determined to be negative, the system 100 is able to cut-off power supply or to lower the power supply to the appliance. When the environmental condition sensor senses hazardous condition occurring in/near the property, the system 100 is able to send out notification or warnings. When the device condition sensor senses low in battery power, the system 100 is able to notify the user to change the batteries. In Step 712 , the method is able to be stopped.
The devices and methods disclosed herein are applicable to but not limited by the devices illustrated in the above examples. The system is expandable and is able to have more or less nodes in the networks. Further, a node in the system is able to be an integration of one or more devices illustrated above.
The devices and methods disclosed herein are applicable to but not limited by systems for fire hazard avoidance, fire hazard detection, energy management, property security, or any combination thereof.
The devices and methods disclosed herein are able to utilize but not limited by a locating engine, which is able to associate a node of the LAN(s) with one or more occupancy sensors 109 in a system with a plurality of other occupancy sensors 109 . A node is able to be associated with one or more occupancy sensors 109 when they are physically located in the same area in the property. Based on the location association information, the system is able to perform “fine-grained” services, which enable, disable or adjust appliances or equipment for each area separately and depending on whether a user is present in the area. “Coarse-grained” services are able to enable, disable or adjust appliances or equipment in the property as a whole depending on whether a user is present in the property. The devices and methods disclosed herein are applicable but not limited to fine-grained, coarse-grained services or any combinations thereof. The term “withdraw” energy used herein is able to include reduce, control, stop, and halt energy supply. The property disclosed herein is able to include any properties including cars, factories, warehouse, and banks.
Some of the above-described functions are able to be composed of instructions that are stored on storage media (e.g., computer-readable medium). The instructions are able to be retrieved and executed by the processor. Some examples of storage media are volatile or non-volatile memory devices, tapes, disks, and the like. The instructions are operational when executed by the processor to direct the processor to operate in accord with the invention.
It is noteworthy that any hardware platform suitable for performing the processing described herein is suitable for use with the technology. The terms “computer-readable storage medium” and “computer-readable storage media” as used herein refer to any medium or media that participate in providing instructions to a CPU for execution and/or in providing space to a CPU for storage. Such media are able to take many forms, including, but not limited to, non-volatile media, volatile media and transmission media. Non-volatile media comprise, for example, flash memory, optical or magnetic disks, such as a fixed disk. Volatile media include dynamic memory, such as system RAM. Transmission media include coaxial cables, copper wire and fiber optics, among others, including the wires that comprise one embodiment of a bus. Transmission media are also able to take the form of acoustic or light waves, such as those generated during radio frequency (RF) and infrared (IR) data communications.
To utilize the systems and devices for and methods of energy management, property security and fire hazard prevention, a user is able to initiate the system when he/she leaves the property, set a schedule for a timed, regular, or recurring performance, or allow the system to automatically initiate itself at a predetermined condition, such as upon detecting the entrance of a human or animal.
In operation, one or more occupancy sensors monitor the presence of humans or animals in a property and send the information of the monitoring to a processing unit. The processing unit processes the information to determine the occupancy status of the property and send the data processed to be stored, to generate notification information, or to generate a control signal to control/regulate the power of one or more appliance, such as cooking devices and/or electronic equipments.
The above description is illustrative and not restrictive. Many variations of the invention will become apparent to those of skill in the art upon review of this disclosure. The scope of the invention should, therefore, be determined not with reference to the above description only, but instead should be determined with reference to the appended claims along with their full scope of equivalents.
It will be further understood that the methods of the invention are not necessarily limited to the discrete steps or the order of the steps described. To the contrary, the present descriptions are intended to cover such alternatives, modifications, and equivalents as can be included within the spirit and scope of the invention as defined by the appended claims and otherwise appreciated by one of ordinary skill in the art.
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Systems and devices for and methods of energy management, property security and fire hazard prevention are provided. The systems, devices and methods are able to be centralized, computerized, and expandable. The devices and systems are capable of automatically reducing energy consumptions and minimizing losses of property caused by fire, theft, and vandalism using monitoring sensors (e.g., occupancy sensors) and computer software and equipments.
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STATEMENT OF GOVERNMENT INTEREST
The invention described herein may be manufactured and used by or for the Government of the United States of America for governmental purposes without the payment of any royalties thereon or therefor.
BACKGROUND OF THE INVENTION
The present invention relates to methods of recovering devices from a fluid medium, and more particularly to recovering buoys from water by using a grapnel deployed from a helicopter or ship.
Heretofore, recovery of a buoy from the water by a helicopter has been extremely difficult requiring the lowering of a man from the helicopter to attach a line to the buoy. Recovery of mine countermeasures gear, as well as buoys, has generally been accomplished exclusively by ship. Buoys are generally secured in position by a chain or cable which connects the buoy to an anchor. Current recovery techniques involve maneuvering a ship alongside the buoy to be recovered and hooking it with a shepherd's hook, or deploying a small boat to tow a line to the buoy. Other methods have used hooks towed behind a boat to hook the buoy mooring cable to move the buoy to a new location. In higher sea states (sea state three and higher) it is extremely difficult and hazardous to recover buoys, and it is an established fact that ships cannot recover buoys in sea states exceeding sea state three due to the hazard to personnel.
Since buoys are used extensively as navigational aids and as markers for the location of various underwater objects, it is desirable to have a method for recovering and relocating buoys without manual intervention, with its attendant risks.
SUMMARY OF THE INVENTION
Accordingly, the present invention provides a method and apparatus for recovering buoys by helicopter or by ship, even in high sea states. The buoy recovery gear uses floats and kites rigged as depressors and diverters. A sweep-wire is fitted between the kites with a grapnel attached to it. The grapnel is then towed underwater from the helicopter or ship to engage a grapnel receiving ring previously attached to a buoy mooring cable, and the buoy is then hauled from the water.
OBJECTS OF THE INVENTION
It is therefore an object of the present invention to provide for recovering buoys by a helicopter.
A further object of the present invention is to provide for recovering buoys without manual intervention.
Another object of the present invention is to provide for recovering buoys by ships in sea state three and above.
Still another object of the present invention is to provide an attachment to buoy mooring cables to facilitate the recovery of buoys.
Yet another object of the present invention is to provide for recovering buoys while reducing the hazard to personnel.
A still further object of the present invention is to provide for engaging a buoy mooring cable under the surface of the water at a predetermined depth.
Another object of the present invention is to provide for recovering and relocating buoys at nominal cost.
BRIEF DESCRIPTION OF THE DRAWINGS
Other objects and many of the attendant advantages of the present invention will be readily apparent as the invention becomes better understood by reference to the following detailed description with the appended claims, when considered in conjunction with the accompanying drawings, wherein:
FIG. 1 is a pictorial view of the deployment of the buoy recovery gear;
FIG. 2 is a pictorial view of the buoy recovery gear after engagement with the buoy mooring cable;
FIG. 3(a) is a top view of the grapnel receiving ring;
FIG. 3(b) is a side view of the grapnel receiving ring of FIG. 3(a).
DESCRIPTION OF THE PREFERRED EMBODIMENT
Referring now to the drawings, wherein like reference characters designate like or corresponding parts throughout the several views, FIG. 1 shows a tow vehicle 10 such as a helicopter, ship or the like, to which is connected the buoy recovery gear. The buoy 12 to be recovered is connected by a buoy mooring cable 14 to an anchor 16 which holds the buoy in its position. A grapnel receiving ring 18 is attached to the buoy mooring cable 14 beneath the surface of the water and held in place between two wedge stops 19.
The buoy recovery gear has a first float 20 which is connected by a tow cable 22 to the tow vehicle 10. A kite 24 rigged as a depressor is connected to the first float 20 by line 26. A second float 32 is connected to a diverter 30 by line 34. A sweep wire 28 is run between depressor 24 and diverter 30 so that when towed, the sweep wire will make contact with the buoy mooring cable 14 beneath the grapnel receiving ring 18. A grapnel 36 is attached to the sweep wire 28 midway but slightly nearer diverter 30 between the depressor 24 and the diverter 30 in such a manner that when the sweep wire slips across the buoy mooring cable 14, the grapnel will slide up cable 14 and engage the grapnel receiving ring 18.
As the buoy recovery gear is towed through the water by the tow vehicle 10, the sweep wire 28 is maintained at such a depth by the depressor 24 so that it will cross the buoy mooring cable 14 below the grapnel receiving ring 18. Diverter 30 maintains a separation between first float 20 and second float 32 so that the sweep wire is assured of crossing buoy mooring cable 14.
Referring now to FIG. 2, after the sweep wire 28 crosses and contacts the buoy mooring cable 14, they will slide against each other until grapnel 36 contacts the cable and slides up it to engage the grapnel receiving ring 18. At this point the tow vehicle 10 can start to winch in the buoy recovery gear and the buoy 12 with its associated components to complete the buoy recovery operation.
Referring now to FIG. 3(a) and 3(b), the grapnel receiving ring 18 has a tubular ring 40. A collar 42, which lies in a plane parallel to and concentric with the ring 40, is connected to the ring by four struts 44 to form a rigid structure. As previously described, the grapnel receiving ring 18 is attached to a buoy mooring cable by wedge stops 19 that grapnel 36 can securely engage the receiving ring.
Therefore, it is apparent that the disclosed method for recovering buoys is a simple technique employing currently available equipment which can be used by helicopters or ships without manual intervention and, therefore, without hazard to personnel, even in high sea states where such recovery was previously not possible.
Obviously, other embodiments and modifications of the present invention will readily come to those of ordinary skill in the art having the benefit of the teachings presented in the foregoing description and the drawings. It is, therefore, to be understood that this invention is not to be limited thereto and that said modifications and embodiments are intended to be included within the scope of the appended claims.
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The recovery of buoys by a helicopter or a ship is accomplished by sweeping a grapnel therefrom underwater until it engages a suitable receptacle attached to the buoy mooring cable. Once engaged, the buoy is then winched aboard the helicopter or ship.
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PRIOR RELATED APPLICATIONS
[0001] Not applicable.
FEDERALLY SPONSORED RESEARCH STATEMENT
[0002] Not applicable.
REFERENCE TO MICROFICHE APPENDIX
[0003] Not applicable.
FIELD OF THE INVENTION
[0004] The invention relates to phytoceutical formulations used to treat a variety of diseases. The formulations are particular combinations of plants and have synergistic effect in combination. Principles for selecting beneficial formulations are provided.
BACKGROUND OF THE INVENTION
[0005] The academic study of medicinal plants for the treatment of diverse diseases has been nearly as pervasive as the study of Western medicines—The active principles from many traditional medicines have been extracted from plants, the curative agents identified and their mechanisms of action determined. Plant based medicines are typically well tolerated, with less severe side effects as well as a smaller range of side effects. However, despite the excellent medicinal qualities of many plants, they are individually insufficient to take chronic degenerative diseases into remission. In contrast, while synthetic drugs can be highly effective, their use is often hampered by severe side effects. What is needed in the art are better treatment regimes with improved patient tolerance, while providing sufficient efficacy.
SUMMARY OF THE INVENTION
[0006] A number of known beneficial plants were classified according to their capacity to enhance the three main elements that support overall health: Energy (E), Bio-intelligence (I) and Organization (O). A synergistic effect is expected when all three categories of herbs (E, I, O) are included in a formulation, preferably at least two or three or four plants from each category. Thus, one embodiment of the invention provides a method of selecting additional disease treating formulations according to these principles. Three examples of formulations prepared in this way are provided and additional formulations are being prepared and tested.
[0007] Another embodiment of the invention provides an effective, natural composition for treating circulatory diseases. The composition can be used alone, or can be combined with simultaneous use of one or more pharmaceutical compositions. It can be used for the treatment of diabetic lesions, obliterative arteriosclerosis, Leriche syndrome (aorto-iliac obliteration), Buerger's disease (thromboangiitis obliterans), thrombophlebitis, chronic venous insufficiency, varicose veins, varicose ulcers, hemorrhoids, and the like.
[0008] Another embodiment of the invention provides a composition for the treatment of feminine endocrine diseases that can be used alone or combined with pharmaceuticals. It provides an effective medicine for diseases such as Polycystic Ovary Syndrome, ovarian cysts, fibrocystic breast condition, uterine fibroids, dysfunctional uterine hemorrhage, female infertility, premenstrual syndrome, amenorrhea, and the like.
[0009] Another embodiment of the invention provides a composition for chronic skin disorders. It can be used alone or combined with pharmaceuticals, and can be used to treat diseases such as psoriasis, dermatitis, skin infections, shingles (herpes zoster), boils, eczema, rash, acne or burn, and the like.
DETAILED DESCRIPTION OF THE FIGURES
[0010] FIG. 1 shows representative examples of diabetic foot lesions treated with the herbaria of Table 1.
[0011] FIG. 2 shows representative examples of PCOS treated with the herbaria of Table 2.
[0012] FIG. 3 shows representative examples of psoriasis treated with the herbaria of Table 3.
DETAILED DESCRIPTION OF THE INVENTION
[0013] “Pharmaceutically acceptable excipients” is used herein according to art accepted meanings, and includes those ingredients needed to formulate a medicine for mammalian use, including the use of gelatin capsules.
[0014] “Synergistic” or “synergy” is used herein to mean that the effect is more than its additive property. In preferred embodiments, the synergy is at least 1.5, 2, 5, or 10 fold.
[0015] By use of “plants,” what is meant herein is that the plant (or that portion with medicinal activity) is used whole, ground, or as an extract. Also included are purified active ingredients and derivatives thereof. However, it is believed that the best efficacy of plants used herein is achieved with the use of the entire plant or its extracts, rather than with the use of isolated active ingredients.
[0016] Further, although plants are named here according to commonly used nomenclature, with improving taxonomy plants are often reclassified. Whenever a plant is referenced, it includes related species with similar active ingredients.
[0017] The following examples are illustrative only and should not serve to unduly limit the invention.
EXAMPLE 1
Plant Characteristics—Circulatory Disorders
[0018] Angelica sinensis (Dong Quai or Angelica, also Angelica Archangelia, Angelica Pubescens and Angelica Sylvestris ) contains terpenes (terpenes, mainly β-phellandrene, with β-bisabolene, β-caryophyllene, β-phellandrene, α- and β-pinene, limonene, linalool, borneol, acetaldehyde, menthadienes, and nitromenthadienes), macrocyclic lactones (including tridecanolide, 12-methyl tridecanolide, pentadecanolide), phthalates (such as hexamethylphthalate), coumarins (especially flirocoumarin glycosides such as marmesin and apterin), angelicin and byakangelicin derivatives (osthol, umbelliferone, psoralen, bergapten, imperatoren, xanthotoxol, xanthotoxin, oxypeucedanin and more), as well as various sugars, plant acids, flavonoids, and sterols.
[0019] Acanthopanax senticosus (Russian Ginseng, Siberian Ginseng, Eleuthero, Devil's Shrub, Touch-me-not, Wild Pepper, Shigoka, Acantopanacis senticosus ) contains terpenoids (oleanolic acid), glycosides (Eleutheroside A (daucosterin), B1, C-G, I, K, L, M), phytosterols (β-sitosterol), coumarins (Eleutheroside B1 and B3, isofraxidine), polysaccharides (eleutherans), volatile oils, caffeic acid, coniferyl aldehyde, and sugars. Eleuthero has been shown to bind to estrogen, progestin, and mineralocorticoid receptors, and stimulate T-lymphocyte and natural killer cell production. It has activity anti-platelet aggregation activity similar to aspirin, as well as antioxidant activity. Russian Ginseng contains at least 40 active ingredients.
[0020] Rhaponticum carthamoides (Leuzea, or Maral Root) contains a mixture of compounds called, “levseins.” Levseins represents a complex of more than 10 ecdysterones including 20-beta-ecdysterone, makisterone C, 24-dehydromakisterone A, carthamosterone, polypodyne B and ajugasterone C. Researchers extracted and purified various ecdysteroids from Rhaponticum and found that the ecdysteroids increased the mass of the developing quails in a dose-dependent manner, with the rate of increase proportional to the ecdysteroids content. The Soviets manufactured a synthetic version of this powerful substance for their athletes with great success. Soon after, the U.S. version called Mesobolin circulated on the underground market for a long time. Incorporation of this phytomedicine in a composition provides at least 10 active principles in a single therapeutic.
[0021] Panax ginseng (Chinese ginseng, panax , ren shen, jintsam, ninjin, Asiatic ginseng, Japanese ginseng, Oriental ginseng, Korean red ginseng) main active components are ginsenosides (Ra1, Ra2, Rb1, Rg1, Rd, Re, Rh1, Rh2, Rh3, F1, F2, F3) and panoxosides, which have been shown to have a variety of beneficial effects, including anti-inflammatory, antioxidant, and anticancer effects. Results of clinical research studies demonstrate that Panax ginseng may improve psychological function, immune function, and conditions associated with diabetes. Studies indicate that Panax ginseng enhances phagocytosis, natural killer cell activity, and the production of interferon; improves physical and mental performance in mice and rats; causes vasodilation; increases resistance to exogenous stress factors; and affects hypoglycemic activity. It stimulates hepatic glutathione peroxidase, and the phytosterols inhibit prostaglandin synthesis. Also it displays vascular activity because the saponins act like calcium antagonists in the vasculature. The incorporation of this phytomedicine provides at least 86 active principles in a single therapeutic.
[0022] Panax quinquefolius (American Ginseng, Anchi, Canadian Ginseng, Five Fingers, Ginseng, American, North American Ginseng, Red Berry, Ren Shen, Tienchi) is related to Panax ginseng , but is a distinct species with higher levels of ginsenoside Rb1 and without ginsenoside Rf. Ginsenoside Rb1 is believed to limit or prevent the growth of new blood vessels, making it useful to treat tumors. Research suggests that several of ginseng's active ingredients also have a beneficial influence on platelet aggregation. It also demonstrates an anti-atherosclerotic action, apparently mediated by a correction in the imbalance between prostacyclin and thromboxane. Other studies that have found panaxynol or the lipophilic fraction to be the most potent anti-platelet agent in ginseng, chiefly due to an inhibition of thromboxane formation. This possibly occurs via regulation of cGMP and cAMP levels and prolongation of the time interval between the conversion of fibrinogen to fibrin. Ginsenosides have also been shown to be relatively potent platelet activating factor antagonists. It has antioxidant, anti-inflammatory, and hypolipidemic effects. The incorporation of this phytomedicine into a composition provides at least 206 active principles in a single therapeutic.
[0023] Pfaffia paniculata (Suma, Brazilian Ginseng, Pfaffia , Para Toda, Corango-acu; also Hebanthe paniculata, Gomphrena paniculata, G. eriantha, Iresine erianthos, I. paniculata, I. tenuis, P. eriantha, Xeraea paniculata ) contains active glycosides (beta-ecdysone and three ecdysteroids), pfaffic acids, phytosterols (sitosterol and estimasterol). It also contains saponins. Its germanium content probably accounts for its properties as an oxygenator at the cellular level, and its high iron content may account for its traditional use for anemia. This herb increases oxygenation at the cellular level, and it also has anabolic activity at the muscular and cardiac levels by improving the contraction of the miocardia and diminishing arrhythmias and stabilizing the membranes of cardiac cells. The incorporation of this phytomedicine provides 44 active principles in a single therapeutic.
[0024] Rhodiola rosea (Golden Root, Roseroot) consists mainly of phenylpropanoids (rosavin, rosin, rosarin (specific to R. rosea ), phenylethanol derivatives (salidroside, rhodioloside, tyrosol), flavanoids (catechins, proanthocyanidins, rodiolin, rodionin, rodiosin, acetylrodalgin, tricin), monoterpenes (rosiridol, rosaridin), triterpenes (daucosterol, beta-sitosterol), and phenolic acids (chlorogenic and hydroxycinnamic, gallic acids). It also contains organic acids (gallic, caffeic, and chlorogenic acids) and β-Tyrosol. There are many species of Rhodiola, but it appears that the rosavins are unique to R. Rosea , and it is the preferred species. Its therapeutic properties include a strong estrogen binding property. It also has properties of vasodilatation by activation of mu-opiate receptors in heart muscle, and it is a hypolipidemic, diminishing cholesterol and triglyceride levels. The incorporation of this phytomedicine provides at least 20 active principles in a single therapeutic.
[0025] Echinacea angustifolia or purpurea (Black Sampson, Purple Coneflower, Rudbeckia , Missouri Snakeroot, Red Sunflower) contains alkaloids (Isotussilagine, tussilagine), amides (echinacein, isobutylamides), carbohydrates (echinacin, polysaccharides (heteroxylan and arabinogalactan), inulin, fructose, glucose, pentose), glycosides (echinacoside), terpenoids (Germacrane), Cichoric acid, betaine, methyl-para-hydroxycinnamate, vanillin, phytosterols, and volatile oils. Echinacea has been the subject of hundreds of clinical and scientific studies which have primarily used an extract of the root and aerial portions of the botanical. The rich content of polysaccharides and phytosterols in Echinacea are what make it a strong immune system stimulant. The sesquiterpene esters also have immuno-stimulatory effects. Echinacin has also been found to possess anti-fungal and antibiotic properties. This component of Echinacea also has cortisone-like actions which can help promote the healing of wounds and helps to control the inflammatory reactions. The incorporation of this phytomedicine into compositions provides at least 70 active principles in a single therapeutic.
[0026] Ganoderma lucidum (Reishi, also G. tsugae, G. valesiacum, G. oregonense, G. resinaceum, G. pfezfferi, G. oerstedli , and G. ahmadii ) is an edible fungus containing bitter triterpenoids (ganoderic acid), β-D-glucan, coumarins, alkaloids and ergosterols. It has vasodilator effect and is useful in the treatment of angina. It is hypolipidemic and anti-artherotic. It contains at least 32 active principles.
[0027] Grifola frondosa (Maitake, Dancing Mushroom; also G. sordulenta, Polyporus umbellatus and Meripilus giganteus ) contains the primary polysaccharide, β-D-glucan in the 1.3 and 1.6 forms. It also contains alpha glucan, lipids, phospholipids, and ergosterol. Animal studies suggest maitake may lower serum cholesterol and triglycerides. Beta-D-glucan is also recognized as an effective immuno-stimulator. This substance increases the activity of macrophages and other immunocompetent cells that destroy tumor cells. The substance also improves the immunological efficiency of these cells by increasing production of cytokines IL-1, IL-2 and lymphokines. The final result is an increase of the defenses against infectious diseases. The incorporation of this phytomedicine provides at least 6 active ingredients for therapeutic use.
[0028] Hydrastis canadensis (golden seal, yellow root, turmeric root) contains mainly isoquinoline alkaloids (xanthopuccine, berberine, hidrastine, hidrastanine, beta-hydrastine, canadine and canadaline). These confer anti-inflammatory, bacteriostatic, bacteriocidal, and vasodilator effects. In general, its antibacterial action is directed to metabolic inhibition, inhibition of the formation of enterotoxins, and inhibition of bacterial adhesion. It produces vasodilatation by inhibiting smooth muscle contraction, and inhibiting platelet aggregation. This plant provides at least 34 active principles for therapeutic use.
[0029] Petiveria alliacea (Anamú, Apacin, Apacina, Apazote De Zorro, Aposin, Ave, Aveterinaryte, Calauchin, Chasser Vermine, Congo Root, Douvant-douvant, Emeruaiuma, Garlic Guinea Henweed, Guine, Guine, Guinea, Guinea hen leaf, Gully Root, Herbe Aux Poules, Hierba De Las Gallinitas, Huevo De Gato, Kojo Root, Kuan, Kudjuruk, Lemtewei, Lemuru, Mal Pouri, Mapurit, Mapurite, Mucura-caa, Mucura, Mucuracaa, Ocano, Payche, Pipi, Tipi, Verbena Hedionda , Verveine Puante, Zorrillo) contains Allantoin, Arborinol, Arborinoliso Astilbin, Benzaldehyde, Benzoic-acid Benzyl-2-hydroxy-5-ethyl-trisulfide, Coumarin, Dibenzyl Trisulfide, Engeletin, alpha Friedelinol, Isoarborinol, Isoarborinol-acetate, Isoarborinol-cinnamate, Isothiocyanates, Kno3, Leridal, Leridol, Leridol-5-methyl Ether, Lignoceric Acid, Lignoceryl Alcohol, Lignoceryl Lignocerate, Linoleic Acid Myricitrin, Nonadecanoic Acid, Oleic Acid, Palmitic Acid, Pinitol, Polyphenols, Proline,trans-n-methyl-4-methoxy, Senfol, β-Sitosterol, Stearic Acid, Tannins, and Trithiolaniacine. Its therapeutic activities include anti-inflammatory, immune-stimulant and antimicrobial effects. This phytomedicine provides about 25 active principles.
[0030] Sutherlandia frutescens (Cancer Bush, also Sutherlandia Microphylla ) contains L-canavanine, pinitol, GABA (gamma aminobuteric acid), and asparagine. In addition, novel triterpenoid glucoside known as “SU1” has been isolated and characterized. The therapeutic indications include anti-inflammatory, antioxidant, immuno-modulador, and vasodilator effects. This phytomedicine provide at least 5 active principles.
[0031] Tabebuia avellanedae (Pau d'arco, Ipê, Lapacho, Tahuari, Taheebo, Trumpet Tree, Tabebuia Ipê, Tajy; also T. ipe, T. nicaraguensis, T. schunkeuigoi, T. serratifolia, T. altissima, T. palmeri, T. impetiginosa, T. heptaphylla, Gelseminum avellanedae, Handroanthus avellanedae, H. impetiginosus, Tecoma adenophylla, Tec. avellanedae, Tec. eximia, Tec. impetiginosa, Tec. integra, Tec. ipe ) extracts contain diverse quinone derivatives and a small quantity of benzenoids and flavonoids, including beta-lapachone, xyloidone, tabebuin, quercetin, tecomine, and steroidal saponins. One important ingredient is lapachol, a derivative of which was patented in 1975. It has anti-inflammatory and antibacterial effects. The incorporation of this phytomedicine into a composition provides at least 32 active principles in a single therapeutic.
[0032] Uncaria tomentosa (Cat's Claw, Peruvian Cat's Claw, Samento, Saventaro, Una de Gato, also Uncaria guianensis ) has several alkaloids including pentacyclic oxindole alkaloids (POA) (isomitraphylline, isopteropodine, mitraphylline, pteropodine, speciophylline, uncarine F), tetracyclic oxindole alkaloids (TOA) (isorynchophylline, rynchophylline), glycosides (triterpenic quinovic acid glycosides), hirsutine, tannins, catechins, phytosterols (beta-sitosterol, campesterol, stigmasterol), triterpenes, polyphenols, flavanols and oligomeric proanthocyanidins (OPC). It is an immune-stimulant, an anti-inflammatory, vasodilator, and antioxidant. In laboratory testing, rynchophylline displays an ability to inhibit platelet aggregation and thrombosis, suggesting that cat's claw may be useful in preventing strokes and reducing the risk of heart attack by lowering blood pressure, increasing circulation, inhibiting formation of plaque on arterial walls and formation of blood clots in the brain, heart and arteries. This phytomedicine provides at least 10 active ingredients.
[0033] Petiveria Alliacea (Anamú, Apacin, Apacina, Apazote De Zorro, Aposin, Ave, Aveterinaryte, Calauchin, Chasser Vermine, Congo Root, Douvant-douvant, Emeruaiuma, Garlic Guinea Henweed, Guine, Guine, Guinea, Guinea hen leaf, Gully Root, Herbe Aux Poules, Hierba De Las Gallinitas, Huevo De Gato, Kojo Root, Kuan, Kudjuruk, Lemtewei, Lemuru, Mal Pouri, Mapurit, Mapurite, Mucura-caa, Mucura, Mucuracaa, Ocano, Payche, Pipi, Tipi, Verbena Hedionda , Verveine Puante, Zorrillo) contains Allantoin, Arborinol, Arborinoliso Astilbin, Benzaldehyde, Benzoic-acid Benzyl-2-hydroxy-5-ethyl-trisulfide, Coumarin, Dibenzyl Trisulfide, Engeletin, alpha Friedelinol, Isoarborinol, Isoarborinol-acetate, Isoarborinol-cinnamate, Isothiocyanates, Kno3, Leridal, Leridol, Leridol-5-methyl Ether, Lignoceric Acid, Lignoceryl Alcohol, Lignoceryl Lignocerate, Linoleic Acid Myricitrin, Nonadecanoic Acid, Oleic Acid, Palmitic Acid, Pinitol, Polyphenols, Proline,trans-n-methyl-4-methoxy, Senfol, β-Sitosterol, Stearic Acid, Tannins, and Trithiolaniacine. Its therapeutic activities includes anti-inflammatory, immuno-stimulant and antimicrobial. This phytomedicine provides about 25 active principles.
[0034] Angelica sinensis (Dong quai or Angelica, also Angelica archangelia , Angelica pubescens and Angelica sylvestris ) contains terpenes (terpenes, mainly β-phellandrene, with β-bisabolene, β-caryophyllene, β-phellandrene, α- and β-pinene, limonene, linalool, borneol, acetaldehyde, menthadienes and nitromenthadienes), macrocyclic lactones (including tridecanolide, 12-methyl tridecanolide, pentadecanolide), phthalates (such as hexamethylphthalate), coumarins (especially furocoumarin glycosides such as marmesin and apterin), angelicin and byakangelicin derivatives (osthol, umbelliferone, psoralen, bergapten, imperatoren, xanthotoxol, xanthotoxin, oxypeucedanin and more), as well as various sugars, plant acids, flavonoids, and sterols. These components have vasodilator activity, increase coronary flow and are antithrombotic. The incorporation of this phytomedicine into compositions provides at least 70 active principles in a single therapeutic.
[0035] Crataegus oxyacantha (Hawthorn, see also C. monogyna ) contains mainly flavonoids (such as flavonoglycosyls, hyperoside, rutin, flavonol, kaempferol, quercetin) and oligomeric procyanadins (1-epicatechol), which relax arterial expansion to decrease peripheral vascular resistance. Also contains amines (phenyletylamine, tyramine, O-methoxyphenethylamine), flavone (apigenin, luteolin) derivatives, vitexin glycosides, tannins, saponins, and cyanogenetic glycosides. The incorporation of this phytomedicine into a composition provides at least 52 active principles in a single therapeutic plant.
[0036] Croton lechleri (Dragon's blood, Sangre de Grado, Sangre de Agua; also C. draconoides, C. palanostigma, C. erythrochilus C. salutaris, and C. gossypifolius ) produces a distinctive red exudate from its trunk containing a considerable amount of secondary plant metabolites, the majority of which are hydrolyzing flavonoids, proanthocyanidins (mainly catechin, epicatechin, gallocatechin and/or galloepicatechin), as well as taspine. Other components include the dihydrobenzofuran lignan, six simple phenols and their derivatives, three steroids, non-saturated fatty acids, diterpenoids (hardwickiic acid, bincatriol, crolechinol, crolechinic acid, coberine A, coberine B), and diterpenoids. It heals wounds and ulcers of vascular origin. Incorporation of this phytomedicine into a composition provides at least 23 active principles in a single therapeutic.
[0037] Ginkgo biloba (Ginkgo) contains ginkgolides, bilobalides, bioflavones and flavone glycosides. Flavone glycosides include quercetin, 3-methylquercetin and kaempferol. Quercetin, myrcetin and the rest of the flavonoid fraction of the extract have antioxidant and free radical scavenger effects. The flavonoids diminish infiltration by neutrophils and increase blood flow. Their antioxidant properties and membrane stabilizing activity increase the tolerance to hypoxia. They improve cellular metabolism and protect against the damage caused by ischemia. Ginkgolide B is a powerful inhibitor of platelet activating factor (PAF), binding to its membrane receptors, and antagonizing platelet aggregation. Similarly, it has anti-inflammatory effect by decreasing vascular permeability, and has vasodilator activity by inhibiting the liberation of thromboxane B2 and prostaglandins. Controlled double blind clinical studies conclusively demonstrate the effectiveness of Gingko biloba in treating peripheral arterial insufficiency. The incorporation of this phytomedicine into a composition provides at least 59 active principles in a single therapeutic.
[0038] Hydrocotyle asiatica (Gotu Kola, Bramhi, Pennywort, Marsh Penny, Pennywort; also Hydrocotile asiatica asiatica ) contain terpenoids (triterpenes, asiaticoside, brahmoside and brahminosidea, (saponin glycosides) aglycones, asiaticentoic acid, centellic acid, centoic acid and madecassic acid), sesquiterpenes (caryophyllene, trans-B-farnesene), volatile oils (Germacrene D), alkaloids (hydrocotylin), flavones (Quercetin, kaempferol, sesquiterpenes, stigmasterol, and sitosterol), and vallerine, fatty acids, resin, and tannins. It is used to treat chronic venous insufficiency, varicose veins, and venous hypertension. Incorporation of this phytomedicine in a composition provides at least 59 active principles in a single therapeutic.
[0039] Ruscus aculeatus (Butcher's Broom, Box Holly, Jew's Myrtle, Knee Holly, Kneeholm, Pettigree, Sweet Broom) contains as primary active ingredients the steroidal saponins (ruscogenin and neoruscogenin), but other constituents have been isolated, including flavonoids, tetracosanoic acid, chrysophanic acid, sitosterol, campesterol, stigmasterol, triterpenes, coumarins, sparteine, tyramine, and glycolic acid. Its ingredients reduce vascular permeability, have anti-elastic properties and are vasoconstrictors. The incorporation of this phytomedicine in a composition provides at least 28 active agents.
[0040] Vaccinium myrtillus (European blueberry or bilberry, closely related to American blueberry, cranberry, and huckleberry) contains anthocyanosides such as: cianadins, malvidins, petunidins and peonidins. Other ingredients include arbutin, asperuloside, astragalin, beta-amyrin, caffeic-acid, catechin, chlorogenic-acid, cyanadin-3-O-arabinoside, dihydroxycinnamic-acid, epicatechin, epigallocatechin, epimyrtine, ferulic-acid, gallic-acid, gallocatechin, hydroquinone, hyperoside, isoquercitrin, lutein, coumaric-acids, m-hydroxybenzoic-acid, monotropein, myrtillin, myrtillol, myrtine, neomyrtillin, protocatechuic-acid, quercetins, quinic-acid, resinic-acid, syringic-acid, ursolic-acid, and vanillic-acid. Evidence suggests that anthocyanosides may benefit the retina, as well as strengthen the walls of blood vessels, reduce inflammation, and stabilize collagen containing tissues. The anthocyanosides improve the activity of enzymes lactic dehydrogenase, glucose-6-phosphatase and phosphoglucomutase, each involved in processes of vascular damage. They reduce the arterial deposits and stimulate the production of vasodilators, like prostaglandin (PG12), thus protecting the vascular wall. Anthocyanosides have strong antioxidant properties, as well. The incorporation of this phytomedicine into a composition provides at least 63 active principles in a single therapeutic.
EXAMPLE 2
Composition—Circulatory Disorders
[0041] A particularly preferred composition is shown in Table 1. Ratios reflect the concentration of active ingredient over the natural state, and the amounts provided are mg of extract. Obviously, the amount should be increased where the strength is reduced, and vice versa.
TABLE 1 Herbaria Active Agent Ratio Amount (mg) Energy enhancers Eleutherococcus senticosus root extract 5:1 53.53 Rhaponticum carthamoides root extract 12:1 3.85 Panax ginseng root extract 5:1 10.71 Panax quinquefolius root extract 5:1 32.12 Pfaffia paniculada (Suma) root extract 4:1 21.41 Rhodiola rosea root extract 5:1 9.64 Bio-Intelligence modulators Echinacea angustifolia root extract 6:1 1.34 Echinacea purpurea root extract 6:1 1.34 Ganoderma lucidum extract 6:1 32.12 Grifola frondosa extract 10:1 12.85 Hydrastis canadensis root extract 5:1 38.54 Petiveria alliacea 1:1 64.24 Sutherlandia frutescens 1:1 64.24 Tabebuia avellanedae bark extract 4:1 40.15 Uncaria tomentosa root extract 10:1 16.06 Organization improvers Angelica sinensis root extract 5:1 64.24 Crataegus oxyacantha fruit extract 5:1 42.83 Croton lechleri bark resin extract 10:1 10.71 Ginkgo biloba leaf extract 50:1 19.49 Hydrocotyle asiatica plant extract 5:1 64.24 Ruscus aculeatus root extract 5:1 57.82 Vaccinium myrtillus fruit extract 5:1 38.54 Total 700 mg
EXAMPLE 3
Plant Characteristics—Female Endocrine Disorders
[0042] Panax quinquefolius The active principles responsible for its therapeutic effects are triterpensaponides, of which more than 25 different types have been identified. These are denominated protopanaxadiols (ginsenosides Rc, Rd, Rb1, Rb2) and protopanaxatriols (ginsenosides —Re, —Rf, —Rg1, etc.). Panax also contains hydrosoluble polysaccharides (panaxans A-U) and polyacetylenes (ginsenosides A-K, panaxynol and panaxatriol). These substances confer energizing properties because they increase ATP synthesis. On the other hand they reduce the secretion of prolactin by increasing dopaminergic activity or by activating dopamine receptors at the anterior hipophysis level. Prolactin is a hormone involved in the appearance of anovulatory cycles and dysfunctional uterine hemorrhages, menorrhea, mammary fibrocystic condition, and cyclic mastalgy. The reduction of this hormone explains the recovery in the treatment of uterine dysfunctional hemorrhages, Polycystic Ovary Syndrome (PCOS), Ovary Cysts, fibromyomatous uteri, and infertility.
[0043] Pfaffia paniculata Its most important active principles are: Beta-ecdysone and three glycoside ecdysteroids, six different pfaffic acids, phytosterols and nortriterpenic glycosides. These substances are energizing through an increase in ATP synthesis and oxygenation at the cellular level. Also, its phytosterols act as hormone originators, and have demonstrated effectiveness in the management of diverse conditions associated with hormone imbalance, such as: premenstrual syndrome, dysmenorrhea, infertility, dysfunctional uterine hemorrhages, and menopause.
[0044] Rhodiola rosea See above.
[0045] Astragalus membranaceus (Huang-Qi) This plant contains three main types of active principles. Isoflavones, which act as anti-oxidants; astragalans which act as immune-stimulants and anti-inflammatory by stimulating the phagocytic activity of macrophages, of the cytotoxic response of T and NK lymphocytes and of the production and activity of interferon; and astragalans which act as modulators of the hypothalamus-hypofisis-adrenal axis response.
[0046] Echinacea See above.
[0047] Dioscorea villosa (Rheumatism root, huesos del dialo, Yuma, Yam, Wild Yam, Chinese Yam, Mexican Yam, raiz china, and colic root) contains steroid sapogenins (dioscine, dioscorin and diosgenine) as the main active principles. Diosgenine can change into ecdysone, pregnenolone, and progesterone, thus, diosgenine is a hormonal precursor, which contributes to the neuroendocrine system's modulation. On the other hand, diosgenine has demonstrated its important pro-apoptotic effects, in the therapy of benign and malign tumors, including mamrnary and ovarian cysts, and uterine fibroids.
[0048] Ganoderma lucidum and Grifola frondosa The main active principles of these mushrooms are sterols and beta-proteoglucans which bestow anti-inflammatory and immune-modulating properties, because they increase the phagocytotic capacity of macrophages and increase the production and lifespan of CD4 lymphocytes.
[0049] Tabebuia avellanedae contains diverse substances derived from quinones, such as Alfa and Beta lapachone [2-hydroxi-3-(3-metil-2-butenil)-1,4-naftoquinona] and cyclopentane dialdehydes. These confer important anti-inflammatory, pro-apoptotic, antimitotic and cytostatic effects, in treating benign and malign tumors including mammary and ovarian cysts as well as uterine fibroids.
[0050] Uncaria tomentosa See above.
[0051] Vitex agnus castus (Chaste Tree or chaste berry) An essential oil is extracted from the fruit of this plant, two iridoid glycosides (aucubine and agnuside); a flavone (casticine, which seems to be the primary active principle) and 3 minor flavonoids derived from kaempferol and quercetin. These active principles act on the anterior hypofisis dopaminergic-D2 receptors, modulating prolactin secretion. This hormone is implicated in the appearance of anovulatory cycles and dysfunctional uterine hemorrhages, menorrhea, mammary fibrocystic condition, and cyclic mastalgy. Vitex agnus castus modulates the secretion of LH from the hypofisis, which act on the ovary, starting up the luteal phase and progesterone secretion. Therefore, Vitex benefits dysfunctional uterine hemorrhages, premenstrual syndrome, PCOS, infertility, ovary cysts, menopause, and fibromyomatous uteri.
[0052] Hydrocotile asiatica See above. Also, the active principles include pentacyclic triterpene saponins. The major active principles are asiaticosides and madecassosides. Other minor saponins are the centelloside, brahmosides, brahminosides and Hydrocotile asiatica saponins B, C and D. Mucopolysaccharides are the core components of the cellular matrix. The biochemical action of these active principles reduce the levels of lysosomal enzymes associated with the degradation of mucopolysaccharides. On the other hand, the active agents act on the fibroblasts of the connective tissue, modulating collagen synthesis and inhibiting inflammatory processes. This diminishes the fibrosis processes important to fibrocystic mammary and uterine conditions.
EXAMPLE 4
Composition—Female Endocrine Disorders
[0053] A particularly preferred composition is shown in Table 2.
TABLE 2 Herbaria II Amount Active Agent Ratio (mg) Energy enhancers Rhodiola rosea root extract 5:1 8.16 Panax quinquefolius root extract 4:1 67.97 Pfaffia paniculada (Suma) 4:1 54.37 Bio-Intelligence modulators Astragalus membrenaceus root extract 5:1 73.41 Echinacea angustifolia 6:1 20.39 Echinacea angustifolia radix 6:1 3.40 Echinacea purpurea 6:1 20.39 Echinacea purpurea radix 6:1 3.40 Dioscorea villosa 4:1 125.74 Ganoderma lucidum extract 6:1 36.25 Grifola frondosa mushroom extract 10:1 21.75 Tabebuia avellanedae 4:1 67.97 Uncaria tomentosa 10:1 24.47 Vitex agnus castus 5:1 57.09 Organization improvers Hydrocotile asiatica asiatica 5:1 65.25 Total 650
EXAMPLE 5
Plant Characteristics—Dermal Disorders
[0054] Lepidium meyenii (Maca) Its major active principles are: alkaloids (Macaridina, Lepidiline A and B); benzyl-isotiocyanate and glucosinolates; macamides; Beta-ecdysone and phytosterols. These substances activate ATP synthesis which confers energizing properties.
[0055] Rhaponticum carthamoides See above.
[0056] Panax ginseng The active principles responsible for its therapeutic effects are triterpensaponides of which more than 25 different types have been identified. These include protopanaxadiols (ginsenosides Rc, Rd, Rb1, Rb2) and protopanaxatriols (ginsenosides -Re, -Rf, -Rg 1, etc.). Panax also contains hydrosoluble polysaccharides (panaxans A-U) and polyacetylenes (ginsenosides A-K, panaxynol and panaxatriol). These substances confer energizing properties because they increase ATP synthesis.
[0057] Rhodiola rosea See above. Also, the active principles in this plant (phenylpropanoids, phenylethanol derivatives, flavonoids, monoterpenes and phenolic acids) activate the synthesis of ATP in mitochondria and stimulate reparative energy processes.
[0058] Andrographis paniculata (King of Bitters, Chirettta, Kalmegh and Kiryat) Primary active principles associated with Andrographis are: flavonoids, glucosides and diterpenic lactones (andrographolides). These substances offer immuno-modulator and anti-inflammatory properties. Even though their precise mechanism of action is not known, studies suggest that they stimulate the immune systems and activate macrophages.
[0059] Angelica sinensis contains alkyl phthalides (Ligustilide); terpenes, phenylpropanoids (ferulic acid) and benzenoids. These substances stimulate the immune system's actions, through diverse lymphokines and have an anti-inflammatory effect by inhibiting 5-lipoxygenase and elastase, as well as selectively inhibiting 12-(S)-HHTrE production, a marker of cyclo-oxygenase activity.
[0060] Astragalus membranaceus See above. Also, Astragalus membranaceus inhibits 5-lipoxygenase and elastase, which indicates that it is valuable in the management of skin pathologies involving chronic inflammation, such as psoriasis.
[0061] Echinacea See above.
[0062] Hydrastis canadensis The most important active principles of Hydrastis are isoquinoline alcaloides (Berberina, hydrastina, Hidrastanina, Canadina, Canadalina) which award anti-inflammatory, and immuno-modulating properties. Berberine inhibits activating protein 1 (AP-1), a key factor in transcription the inflammation. It also exerts a significant inhibitory effect on lymphocyte transformation, so its anti-inflammatory action seems to be due to the inhibition of DNA synthesis in the activated lymphocytes or to the inhibition of the liberation of arachidonic acid from the phospholipids of the cellular membrane. It also has immuno-modulating properties by increasing the production of immunoglobulins G and M and stimulating the phagocytotic capacity of macrophages.
[0063] Ganoderma lucidum The main active principles of this mushroom are sterols and beta-proteoglucans that bestow anti-inflammatory and immune-modulating properties by increasing the phagocytotic capacity of macrophages and raising production and lifespan of CD4 lymphocytes.
[0064] Uncaria tomentosa see above.
[0065] Equisetum arvense (Horse tail) This plant contains abundant mineral salts particularly silicic acids and silicates. It also contains phytosterols, phenolic acids, flavonoids (mainly quercetin glycosides and apigenine) and saponins (equisetonin). These active principles block the liberation of arachidonic acid, which diminishes inflammation and reduces the proliferation of keratinocytes, as well as inducing G2/M arrest in keratinocytes. The action mechanism is in part due to the inhibition of mitotic kinase activity of p34cd2 and perturbation of cyclin B1 levels.
[0066] Hydrocotile asiatica See above.
[0067] Tabebuia avellanedae contains diverse quinone derivatives such as alpha and beta-lapachone, cyclopentane dialdehydes and a small quantity of benzenoids and flavonoids, including, xyloidone, tabebuin, quercetin, tecomine, and steroidal saponins. These compounds inhibit keratinocyte growth and offer anti-inflammatory and antibacterial effects, which are of great importance in the treatment of psoriasis.
[0068] Shilajit (Mumiyo) Mumiyo is a natural complex substance, whose active principles are carboxylic acids: (hydroxylated derivatives of Benzoic, Phenylacetic and Hippuric acids), fulvic and humic acids, minerals and amino acids. Of Mumiyo's known properties, the most important ones are its ability to reduce excessive inflammatory reactions and stimulate tissue regeneration. Oral intake of Mumiyo has been used to treat burns, trophic non-healing wounds, eczema, and other skin diseases, such as psoriasis. It has been established that fulvic/humic acids stimulate respiration and oxidative phosphorylation in liver mitochondria, increase mechanical resistance of collagen fibers, activate human leucocytes, reduce excessive inflammatory reactions, and stimulate tissue regeneration.
[0069] Shark cartilage This natural compound reduces psoriatic plaque vascularization. It inhibits the proliferation of endothelial cells, competitively blocking the Endothelial Growth Factor at the receptor level. It also inhibits tyrosine EGF and EGF-2 dependant phosphorylation as well as the increase of FCE induced permeability. Shark cartilage also induces endothelial cell apoptosis, by inducing caspase 3, 8 and 9 activation, and the liberation of cytochrome c from the mitochondria to the cytoplasm. Shark cartilage also induces fibrinolitic activity by increasing the secretion, activity and affinity of Tissue Plasminogen Activator (tPA) for endothelial cells. It also inhibits extracellular matrix degradation, by inhibiting matrix metalloproteinases MMP-2, MMP-7, MMP-9, MMP-12 and MMP-13. It also stimulates production of angiostatin.
[0070] Schizandra chinensis The major active principles of Schizandra (also known as Wuweizi and Wurenchum) are lignans called schizandrines. These substances have known hepato-protective and hepato-regenerative properties. It maintains the integrity of hepatocyte cellular membranes; increases hepatic levels of ascorbic acid; inhibits NADPH oxidation; inhibits lipid peroxidation at the hepatic microsomal level as well as formation of hepatic malondialdehyde; diminishes production of carbon monoxide at the hepatic level; has an inductor effect in the enzymatic anti-toxic microsomal hepatic cytochrome P-450; increases biliary flow and the excretion of toxic substances; promotes recovery of hepatic functions; induces mRNA formation for the Hepatocyte Growth Factor (HGF); encourages the proliferation of the hepatocyte's endoplasmic smooth reticula, and accelerates the proliferation of hepatocytes; increases ornithine decarboxylase activity as well as the mitotic index, facilitates DNA synthesis and hepatic proteins; increases levels of glutathione, glutathione reductase and glucose-6-phosphate, improving the regeneration capacity of the liver.
[0071] Silybum marianum (Milk Thistle) The active principles of this plant are flavonolignans, including silibine, silicristine and silidianine and isosilibinin collectively known as sylimarin. This compound has the highest grade of hepato-protective, hepato-generating, and anti-inflammatory activity. The mechanisms which explain its hepato-protector characteristics are diverse and include anti-oxidation, lipid anti-peroxidation, detoxification increase through a competitive inhibition with toxic substances, as well as protection against the depletion of glutathione. One of the mechanisms that can explain its hepato-regenerative properties is the increase in protein synthesis, obtained thanks to a significant boost in the formation of ribosomes, DNA synthesis and proteins at the hepatic level, because the active principles join a specific polymerase receptor, stimulating ribosome formation. Its anti-inflammatory effect is due to the stabilization of the mastocytes, the inhibition of neutrophils, a strong inhibition of leucotriene (LT) synthesis and formation of prostaglandins. Sylimarin inhibits intestinal beta-glucuronidase enzymes, thus improving glucoronization, which is an important step in hepatic detoxification. More corporal toxins are removed via glucoronization than through other detox pathways.
[0072] Picrorhiza kurroa The most important active constituents are iridoid glycoside picrosides I, II, III and kutkoside, known collectively as kutkin. Though less well researched than Silybum , it appears to have similar applications and mechanisms of action. When compared with Silybum , the curative efficacy of Picrorhiza was found to be similar, or in many cases superior, to the effect of Silybum. Picrorrhiza possesses significant antioxidant activity, by reducing lipid peroxidation and free radical damage. Like sylimarin, it has also an effect on liver regeneration. Picrorrhiza also offers anti-inflammatory effects, inhibiting the infiltration of pro-inflammatory cells. One of its minor components, apocynin exhibits powerful anti-inflammatory effects, without affecting beneficial activities such as phagocytosis, chemotaxis or humoral immunity.
[0073] Smilax spp. (sarsaparilla) Its main active principles are: phytosterols, Steroid Saponins, Phenolic acids, Flavonoids and minerals. These substances adhere to toxins inside the gastrointestinal tract, this way reducing their absorption by the circulatory stream. On the other hand it improves the hepatic and renal excretory functions, facilitating the removal of toxic substances and waste found in cells, blood vessels and lymphatic system. Also, phytosterols block prostaglandin synthetase action, explaining its anti-inflammatory action and use to treat psoriasis.
[0074] Vaccinium myrtillus Angiogenesis appears to be a fundamental inflammatory response early in the pathogenesis of psoriasis and significant abnormalities of vascular morphology and vascular endothelial growth factor (VEGF) play a crucial role in the vascularization of psoriatic plaques. During inflammatory skin diseases such as psoriasis, the skin initiates angiogenesis through VEGF and the active principles of this plant (anthocyanosides, flavonoids, quercetin, tannins, iridoids and phenolic acids) significantly inhibit VEGF expression by the human keratinocytes, reducing the psoriatic plaque's angiogenesis.
EXAMPLE 6
Composition-Dermal Disorders
[0075] A particularly preferred composition is shown in Table 3.
TABLE 3 Herbaria Active Agent Ratio Amount (mg) Energy enhancers Rhaponticum carthamoides root extract 6:1 0.72 Rhodiola rosea root extract 5:1 9.66 Szchisandra chinensis 5:1 16.10 Bio-Intelligence modulators Angelica sinensis 5:1 32.20 Astragalus membranaceus root extract 5:1 48.30 Echinacea angustifolia 6:1 8.05 Echinacea angustifolia radix 6:1 1.34 Echinacea purpurea 6:1 8.05 Echinacea purpurea radix 5:1 1.61 Ganoderma lucidum mushroom extract 6:1 35.78 Hydrastis canadensis 5:1 19.32 Lepidium meyenii 5:1 48.30 Panax ginseng root extract 5:1 16.10 Silibum marianum 5:1 28.98 Shark Cartilage extract 4:1 93.92 Tabebuia avellanedae 4:1 67.08 Uncaria tomentosa 10:1 14.49 Organization enhancers Equisetum arvense 5:1 22.54 Fulvic Acid -Shilajit 65% 1:1 13.95 Hydrocotile asiatica 5:1 42.94 Picrorhiza kurroa (Standardized 4% Kutkin) 5:1 32.20 Smilax officinialis 5:1 72.45 Vaccinium mirtyllus 5:1 16.10 Total 650
EXAMPLE 7
Tolerance Studies
[0076] A multicentric, retrospective study was made on 100 healthy volunteers with the intention of evaluating patient tolerance and side effects of the herbaria combination. A capsule containing 700 mg of the herbaria of Table 1 was administered to each participant three times per day for five days. During that period they were evaluated by a physician, who registered any finding or symptom reported by each subject. The average age of the participants was 37.4 years with a SD of 8.2 years. Gender was 55% female, 45% male. The average weight of the subjects was 70 kilos with a SD of 12.3 kilos. No undesirable effects were observed in 96% of the subjects. Four (4%) subjects reported minor undesirable effects.
[0077] The study showed that herbaria were well tolerated-only minor symptoms were reported by 4 of the 100 subjects. These results showed the non-toxicity of the herbaria, demonstrating that the formulation is safe. Similar results have been obtained for the PCOS and Psoriasis formulations.
EXAMPLE 8
Clinical Studies
[0078] To evaluate the efficacy of the combination, 110 patients affected with diverse degrees of lesions of the diabetic foot, were studied by means of retrospective, multicentric, and descriptive study for two year duration. Of these patients, 50 had grade III-V lesions, and were diagnosed for surgical amputation of the affected area. The patients were treated as above, with ten 700 mg capsule of herbaria three times a day, but the treatment was continued on an as needed basis for times ranging from 1.5 months to 10 months. The data is summarized in Table 4.
TABLE 4 Diabetic Foot Lesion Study Number of Clinical QoL* Treatment Patients Improvement Improvement tolerance Other 110 80.9% 86.4% 97.3% Amputation (89 patients) (95 patients) (107 patients) avoided in 80% of the cases diagnosed for surgery *QoL is Quality of Life
[0079] It is significant to note that the herbaria treatment prevented amputation in 40 patients (80% of the population) who were already diagnosed for surgical removal of portions of the foot. In contrast, in the usual course of standard medical treatment, almost 100% of these patients could have expected to have a partial or complete amputation. Thus, these superior results are quite unexpected and clearly demonstrate the novel and non-obvious qualities of the formulation.
[0080] Likewise, 129 patients with chronic varicose ulcers were evaluated. The treatment (six 700 mg capsules three times a day) improved ulcers in 79% of the population, and remission was achieved in 21% of the population in only two months (Table 5). The systemic treatment also significantly improved the most frequent symptoms (cramps 71.4%, pain 78%, and edema 88.7%). In contrast, most patients with chronic varicose ulcers do not achieve remission under existing pharmaceutical treatments and have high risk of amputation.
TABLE 5 Chronic Varicose Ulcer Study Number of Clinical QoL Treatment Remission Patients Improvement Improvement tolerance time 129 79% 81.2% 99.2% 2 months (102 patients) (105 patients) (128 patients) in 21% of all patients
[0081] In a study of 35 patients with Polycystic Ovary syndrome (PCOS), the treatment improved pelvic pain in all 20 symptomatic patients, menstrual disorder (amenorrhea, dysmenorrhea, menometrorrhea, oligomenorrhea) in all 22 symptomatic patients, asthenia and cephalea in all 17 symptomatic patients, as well as acne and hirsutism in 8 of 9 symptomatic patients. Pelvic echo sonograms revealed that 29 patients (82.9%) experienced a total disappearance of cysts, while another 6 (17.2%) showed a decrease in cyst size. In contrast, most patients with PCOS do not achieve symptomatic relief without surgical intervention, and very few, if any, have a complete disappearance of cysts (Table 6). The dosage was six 650 mg capsules three times a day.
TABLE 6 Polycystic Ovary Syndrome Study Number of Clinical Cyst QoL Treatment Patients Improvement Disappearance Improvement tolerance 35 100% 82.9% 100% 100% (29 patients)
[0082] Similarly, in a study of 123 patients with severe psoriasis, clinical remission was observed in 77% of the patients, and almost two thirds of the patients achieved clinical improvement in less than 45 days (Table 7). In contrast, most patients with severe psoriasis do not achieve remission, but only symptomatic relief with existing pharmaceutical approaches. The dosage was seven 650 mg capsules three times a day.
TABLE 7 Severe Psoriasis Study Number of Clinical QoL Treatment Remission time Patients Improvement Improvement tolerance ≦45 days 123 77.2% 66.3% 100% 82.9% (95 patients) (102 patients)
[0083] In conclusion, these results indicate that synergistic combinations of phytoceuticals, scientifically chosen from each category of herbal tonics described in the next section, is suprisingly effective!
EXAMPLE 9
Principles for Selecting Synergistic Combinations
[0084] In order to expand the range of formulations encompassed by the invention, we have categorized beneficial plants into one of three groups, each of which should be present for synergistic effect. The classifications are Energy, Bio-Intelligence and Organization. Plants classified under Energy are associated with ATP synthesis (such as the Krebs cycle, oxidative phosphorylation, beta-oxidation, etc.). Plants classified under Bio-Intelligence are those that regulate the neuroendocrine and immunological systems and cellular processes, thus controlling the interactions between the various systems in the body. Finally, plants classified under Organization are those that relate to the structure and function of specific organs. Combinations of plants from these three classification groups have synergistic effect because they address each necessary component of cellular and organic health—in effect they provide the triangle on which healing is fully supported.
[0085] A large group of plants were classified (along with some vitamins, etc.) according to this system, based on what is known in the literature about their active ingredients and mode of action. The classification is presented in Table 8. Table 8 is representative only: based on the criterion described herein, additional plants can easily be categorized as their mode of action is elucidated.
TABLE 8 Plant Categories Energy Bio-Intelligence Organization Acantopanacis senticosus Agaricus blazei Angelica sinensis Ajuga turkestanica Aloe vera Buplerum chinense Codonopsis pilosula Andrographis paniculata Cimicifuga racemosa Cordyceps sinensis Annona muricata Chitin fiber Cornu Cervi pantotrichum Aralia mandschurica Chondroitin sulphate Ilex paraguariensis Astragalus membranaceus Crataegus oxyacantha L-arginine Beta 1.3 glucan Croton lechleri Lepidium meyenii Beta 1.6 glucan Curcubita pepo Ocimum sanctum Camelia sinensis Curcuma longa Panax ginseng C oriolus versicolor Dioscorea villosa Panax quinquefolius Echinacea angustifolia Equisetum arvense Pfaffia paniculata Echinacea purpurea Eucommia bark Ptychopetalum olacoides Ganoderma lucidum Fructus ligustri lucidum Rhaponticum carthamoides Grifola frondosa Fructus lycii Rhodiola rosea Hydrastis Canadensis Fulvic acid Schizandra chinensis Lactoferrin Gentiana lutea Ubiquinone (Coenzime Q10) Lentinus edodes Ginkgo biloba Lobostomon trigonus Glucosamine Morinda citrifolia Glycyrrhiza glabra Petiveria alliacea Gynostemma Polygonum multiflorum radix Harpagophytum procumbens Radix apeoniae alba Herba epimedii Radix polygalae Hydrocotile asiatica Shark cartilage Linum usitatissimum Sutherlandia frutescens Minerals Tabebuia avellanedae Mumiyo Turnera aphrodisiaca Opuntia ficus indica Uncaria tomentosa Picrorhiza kurroa Valeriana officinalis Plants enzymes Vitex agnus castus Ptycopetalum olacoides Pygeum africanum Rhamnus purshiana Ruscus aculeatus Salix alba Sargassum fusiforme Sena alejandrina Serenoa repens Silibum marianum Smilax china Solamun nigrum Tribulus terrestris Ulmus fulva Urtica dioica Uva ursi Vaccinium myrthillus Viburnum spp Vitamins
[0086] An illustrative example of synergy in medicinal plants is an in vitro study that demonstrates how the activity of herbal Berberine alkaloids is strongly potentiated by the action of herbal 5′-methoxyhydnocarpin (5′-MHC). It shows a strong increase of accumulation of berberine in the cells in the presence of 5′-MHC, indicating that this plant compound effectively disabled the bacterial resistance mechanism against the berberine antimicrobial, thus showing the synergy of both substances. Stermitz F R, et al., Synergy in a medicinal plant: antimicrobial action of berberine potentiated by 5′-methoxyhydnocarpin, a multidrug pump inhibitor. Proc Natl Acad Sci USA. 2000 Feb. 15; 97(4):1433-7.
[0087] We expect to further demonstrate synergistic effect on a molecular scale by studying the gene expression profile changes in response to various plant ingredients and combinations thereof. Experiments are already underway demonstrating the expression profile in response to the formulations. We will be aided in this work because researchers have already begun studying the expression profiles of various medicinal plants, thus providing a database of knowledge from which to build. E.g., Gohil, et al., mRNA Expression Profile of a Human Cancer Cell Line in Response to Ginkgo Biloba Extract: Induction of Antioxidant Response and the Golgi System, Free Radic Res. 2001 December; 33(6):831-849.
[0088] We may also test combinations of plants for synergistic effects by using the mouse model for diabetic lesions, as described in Mastropaolo, et al., Synergy in Polymicrobial Infections in a Mouse Model of Type 2 Diabetes Infection and Immunity, September 2005, p. 6055-6063, Vol. 73, No. 9. Briefly, obese diabetic mouse strain BKS.Cg-m +/+ Leprdb/J are injected subcutaneously with mixed cultures containing Escherichia coli, Bacteroides fragilis , and Clostridium perfringens . Progression of the infection (usually abscess formation) is monitored by examining mice for bacterial populations and numbers of white blood cells at 1, 8, and 22 days post-infection. Various plant ingredients and combinations thereof can be used to show a synergistic effect. Further, the model can be used to show synergy when the formulations of the invention are combined with existing pharmaceuticals, such as antibiotics.
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Phytoceutical compositions for the prevention and treatment of circulatory disorders, feminine endocrine disorders, and dermal disorders. A specific combination of extracts of plants is taught, as well as principles for varying the formulations based on categorizing plants into one of three groups, Energy, Bio-Intelligence, and Organization and selecting several plants from each group. Such combinations have synergistic effects, with minimal side effects.
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CROSS REFERENCE TO RELATED APPLICATION
This application is a divisional of Ser. No. 09/772,603 filed Jan. 30, 2001.
FIELD OF THE INVENTION
This invention relates to a new protein derived from hydrolyzed bovine IgG concentrate that has independent characteristics significantly different from the protein that it was derived from, and which, by itself, can be used as an effective antimicrobial.
BACKGROUND OF THE INVENTION
There is a continuing effort and need for improved antimicrobials and antivirals which can be used with mammals, including humans, and domestic livestock, in order to modulate their immune system to improve their overall health and, for livestock, weight gain and efficiency. There have been some efforts in the past to use antibodies as immune system modulators.
Antibodies can be orally, intravenously or otherwise administered to a subject animal. This process is generally referred to in the art as passive transfer. The antibodies to be transferred generally are derived from milk, colostrum, serum, egg yolk and even monoclonal antibodies from hybridomas. An example of passive transfer occurs when maternal antibodies are passively transferred to newborn mammals through the placenta and during nursing through colostrum and milk. By this method, the young animals obtain protection and natural immunity against harmful antigens in the environment. Similarly, for developing avians, reptiles and other egg laying animals, egg yolk is the source of maternal antibodies.
Recently, therapeutic studies have successfully exploited oral administration of antibodies for the treatment of some infectious diseases. By a process of vaccination, animals can be immunized against specific microorganisms and other antigens. In addition, increased titers of antibodies can be obtained by a process of hyperimmunization. High amounts of specific antibodies can be obtained by immunizing animals with specific antigens and isolating the antibodies from the egg yolk, milk, colostrum or blood serum/plasma.
There are five distinct classes of antibodies which are also called immunoglobulins (Ig). The most abundant is IgG. The other four are IgM, IgA, IgD, and IgE. These antibodies combine with the antigen and act to neutralize or counter the effects of the antigen introduced into the animal. They accomplish this result by binding to the antigen, thereby neutralizing it and preventing it from binding to other specific cell receptors. The main immunoglobulin present in egg yolk is called IgY, which is similar to IgG, but possess considerable temperature and acid resistance.
Egg and milk preparations serve as a practical source of antibodies suitable for consumption by animals. In fact, egg yolks, for example, can contain as much as 100 mg of antibody, and large numbers of antibody-laden eggs can be produced in a relatively short period of time. Since vaccination of an animal can be used to develop such increased antibody titers in milk and eggs, such immunized milk and eggs can be fed to subject animals whereby antibodies are passively transferred to the subject animals to confer immunity and protection against microorganisms. Antibodies can be used not only to fight off pathogenic antigens or other foreign molecules, but can be used, as described herein, to neutralize naturally-occurring proteins, and thereby modulate that protein's normal physiological effect on the animal's system.
While in the past, bovine and porcine blood serum has been orally administered to aid domesticated livestock and the like in weight gain and overall health, to date, no one has isolated from the serum those fractions which provide specific desired benefits.
It goes without saying that an unexpected and unique advantage of isolation of protein fractions causing specific benefits would be the ability to dose precisely, and the ability to regulate specific responses of living cells to microbial agents such as bacteria and virus.
It is a primary objective of this invention to achieve specific protein fraction isolation and dosing with it to provide bacterial and viral resistance.
SUMMARY OF THE INVENTION
A unique, new protein isolate from the IgG fraction, which is an acid hydrolyzed IgG fraction that has been heat treated for from 15 minutes to 1 hour at a temperature of from 35° C. to 40° C. to unfold and modify the protein, making it antimicrobial in a manner not achievable by the original, untreated and unisolated IgG concentrate.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 shows the effect of acid treatment on the normal antigen-antibody activity of bovine IgG.
FIG. 2 shows the effect of the acid treatment of the invention on the molecular weight of the acid soluble fraction of bovine IgG protein.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT
A new protein has been discovered as a result of a plan to acid hydrolyze bovine IgG concentrate, using, for example, hydrochloric acid. This protein has independent characteristics that are significantly different from the protein that it was derived from. In addition to its significant physical characteristics, the bioactivity of the protein, when used against seven enteric bacterial strains, shows that the new protein is bacterial static when incorporated into bacterial media that are appropriate for the test organisms. The growth of the test organisms, for example, has been reduced from 47.5% to 99.9% compared with controls. In tissue cultures that had been impregnated with the test protein and infected with four selected virus strains, the test protein reduced virus growth from 95% to 100% compared with the controls.
The invention provides for the first time a method where an essentially pure protein was separated from Bovine IgG concentrate which, when the protein was evaluated using the SDS-Page electrophoresis, was shown to produce an intact protein that had a significantly different molecular weight than the starting material, but yet appears to be an intact, nearly pure protein.
The derived protein tested negative to a standard antigen-antibody reaction that is consistent with Bovine IgG concentrate. The protein was destroyed when heat denatured. This protein, when tested with 3 strains of pathogenic E. Coli, 2 strains of Salmonella, one of Pasteurella and Streptococcus was bacterial static. When the same material was tested against 4 virus strains, it was viral static. This data will be provided below in the examples.
Also, as demonstrated in the examples, the bovine IgG concentrate, when sterile filtered and tested to determine if the intact bovine IgG protein was bacteria static like the acid treated soluble fraction, showed the whole protein concentrate was not bacteria static.
Briefly, the starting material is a commercially-available IgG fraction sold by American Protein Corporation, Ames, Iowa, under the trademark NUTRAGAMMAX™.
The starting material from which the IgG fraction is concentrated may be derived from bovine or porcine blood, colostrum or egg or whey. Preferably, it is bovine blood serum.
The initial concentrate is acid hydrolyzed slightly at elevated temperature in the first step of preparation of the new treated and isolated protein. Acid hydrolysis occurs for from about 15 minutes to about 1 hour at a temperature of from 35° C. to 40° C. Acid hydrolysis can occur with any inorganic acid, but is preferably hydrochloric, phosphoric or sulfuric acid at a range of from about 0.1 normal to about 0.2 normal. When this occurs, the concentrate turns quite viscous initially, and thereafter, upon neutralization back to a pH of about 7, becomes substantially less viscous. Thereafter, the material is centrifuged, and the supernatant contains the desired fraction of the present invention. This desired fraction is known to have a molecular weight of about 55,000, and can be used in liquid form, spray dried, or used with a suitable carrier, depending upon how and to whom it is dosed.
In use with domesticated livestock animals, it has been found that an amount should be dosed sufficient to provide a dosage of about 0.25 mg/ml of volume in the mammal's gut. Multiple dosing can occur with up to 5 grams/day. While the testing below-given is with respect to domesticated livestock, it can be used effectively as well on humans, as earlier indicated.
EXAMPLES
The following examples indicate bioactivity for humans as well as other mammalian species. They are offered to further illustrate but not limit the invention. Applicants intend to have the full range of equivalency allowed under the law with respect to the specification disclosure.
Sprayed dried bovine IgG concentrate was dissolved in 0.1N HCL at 35° C. for 15 minutes. The solution was centrifuged at 10K to remove the insoluble material. The solution was filtered through a filter series to 0.2 um. The resulting solution was tested for sterility by incubation in BHI for 48 hours at 37C. Stock cultures of the test organisms were grown to 10 10 per ml and used as the test bacteria. Three dilutions of the test protein were tested along with controls with each dilution inoculated with 10 3 organisms/ml. The samples were inoculated at 37C. for 14 to 18 hours, and the growth was counted using standard plate count methods.
Tissue culture cell lines were developed; VERO cells for human poliovirus as a model for enteric virus production, MDBK cells for herpes virus type 1 as a model for respiratory virus production, MA-104 cells for porcine (OSU strain) and human (WA strain) rotavirus as a model of viruses in neonates and young humans and animals. The test protein was included in the media for the tissue cultures, and the test virus was inoculated on the tissue culture including the controls. The plates were read when there was evidence of virus growth. The cultures were frozen and thawed three times, and the cell debris was removed with slow speed centrifugation. The amount of virus was then determined and compared with the controls.
The results from the acid treatment showed no antigen-antibody activity with the soluble protein after HCL treatment, FIG. 1 .
The effect on the molecular weight of the acid soluble fraction of the bovine IgG protein can be seen in FIG. 2 . In FIG. 2 , band 1 shows the molecular weight of the concentrate itself. Band 2 shows the bovine globulin unreduced before acid treatment. Band 3 shows reduced bovine globulin. Band 4 shows bovine globulin plus hydrochloric acid unreduced, and band 5 shows reduced bovine globulin and acid hydrolyzation. A strong band in columns 4 and 5 at 55,000 can be seen.
The amino acid profile of the test protein before and after acid treatment is reported in Table 1. The results indicate that the test protein unexpectedly changed in amino acid profile after acid treatment. This demonstrates that the test protein not only lost confirmational structure as noted in FIGS. 1 and 2 , but also amino acid profile which would change functionality.
The bacterial static impact of the test protein prepared as described above and as illustrated in FIG. 2 is shown in the following test results.
The hydrochloric acid treated and isolated IgG fraction was heated for 15 minutes at temperatures varying within the range of 35° C. to 40° C., thereafter neutralized, centrifuged, and the supernatant drawn off. This supernatant is approximately 35% of the pure bovine IgG concentrate.
It was tested in standard challenge tests with regard to its ability to reduce the bacterial growth, as illustrated in Table 1.
In particular, the test system occurred as follows:
The selected bacteria (see Table 2) were grown in TSB overnight to about 1×10 9 /mL. The test medium was prepared with working stock concentrations of the test protein. The tubes were seeded with 1000 bacteria per mL and incubated at 37° C. for 20-24 h. The cultures were sampled and standard plate counts were performed.
TABLE 1
MG AMINO
%
AMOUNT
AMOUNT
ACID/g OF
AMINO
AMINO ACID
MW
(In Mm)
(In mg/L)
SAMPLE
ACID
(ACIDIFIED)
HYP
131.1
0
0
0
0.00
ASP
133.1
0.015
1.9965
0.249138964
0.02
SER
105.1
0.013
1.3663
0.170497654
0.02
GLU
147.1
0.017
2.5007
0.312057003
0.03
GLY
75.07
0.01
0.7507
0.093678247
0.01
HIS
155.2
0
0
0
0.00
TAU
125.1
0
0
0
0.00
ARG
174.2
0.006
1.0452
0.130428272
0.01
THR
119.1
0.01
1.191
0.148622342
0.01
ALA
89.09
0.019
1.69271
0.21122966
0.02
PRO
115.1
0.01
1.151
0.143630828
0.01
CYS
240.3
0
0
0
0.00
TYR
181.2
0.005
0.906
0.113057802
0.01
VAL
117.1
0.01
1.171
0.146126585
0.01
MET
149.2
0
0
0
0.00
LYS
182.6
0.012
2.1912
0.27343516
0.03
ILE
131.2
0.005
0.656
0.081860837
0.01
LEU
131.2
0.013
1.7056
0.212838175
0.02
PHE
165.2
0.006
0.9912
0.123689727
0.01
TOTAL
19.31511
2.410291255
0.24
(NON-ACIDIFIED)
HYP
131.1
0
0
0
0.00
ASP
133.1
0.048
6.3888
7.627507163
0.76
SER
105.1
0.059
6.2009
7.40317574
0.74
GLU
147.1
0.058
8.5318
10.18600764
1.02
GLY
75.07
0.036
2.70252
3.226504298
0.32
HIS
155.2
0.012
1.8624
2.223495702
0.22
TAU
125.1
0
0
0
0.00
ARG
174.2
0.022
3.8324
4.575453677
0.46
THR
119.1
0.046
5.4786
6.540830946
0.65
ALA
89.09
0.042
3.74178
4.46726361
0.45
PRO
115.1
0.033
3.7983
4.53474212
0.45
CYS
240.3
0
0
0
0.00
TYR
181.2
0.018
3.2616
3.893982808
0.39
VAL
117.1
0.045
5.2695
6.291189112
0.63
MET
149.2
0.005
0.746
0.890639924
0.09
LYS
182.6
0.036
6.5736
7.848137536
0.78
ILE
131.2
0.014
1.8368
2.192932187
0.22
LEU
131.2
0.043
5.6416
6.735434575
0.67
PHE
165.2
0.019
3.1388
3.747373448
0.37
TOTAL
69.0054
82.38467049
8.24
TABLE 2
THE % REDUCTION OF BACTERIAL GROWTH
AFTER TREATMENT WITH THE TEST PROTEIN
CONTROL MEDIA
SUPERNATANT 0.25
SUPERNATANT 0.12
SUPERNATANT 0.06
TEST
NUTRIENTS
MG/ML OF TEST
MG/ML OF TEST
MG/ML OF
BACTERIA
TO GROW
PROTEIN
PROTEIN
TEST PROTEIN
E. COLI 055
0%
97%
34%
0%
E. COLI 0111
0%
91%
15%
15%
E. COLI 0157:H7
0%
89%
29%
22%
SALMONELLA
0%
96.5%
87.5%
54.5%
TYPHIMURIUM
SALMONELLA
0%
75.4%
57.5%
47%
JAVIANAI
PASTEURELLA SP.
0%
47.5%
47.5%
0%
STREPTOCOCCUS
0%
99.9%
99.9%
99.5%
SUIS
It can be seen that the test protein significantly reduced the growth of all the test organisms with the least effect shown against pasteurella species.
Similar challenges using the following protocol were tested against viruses in vitro. In particular, the ability of acid digested test protein preparations to inhibit the production of virus in vitro were tested. Four virus-cell systems were tested under this program: Human poliovirus on vero cells as a model of enteric virus production; bovine herpesvirus type 1- MDBK cells as a model of respiratory virus production; and porcine (OSU strain) and human (WA strain) rotavirus on MA-104 cells as a model of viruses which are common problems in neonates and young humans and animals. The basic design of the experiments was simple: A small inoculum (˜1000 TCID) of each virus on cells in unsupplemented medium was used as control, and the same inoculum on cells in medium supplemented with 3%, 1.5% or 0.75% of each acid digested (dissolved) test protein preparation. The cultures were run until significant indication of viral infection was observed in the unsupplemented cultures. The cultures were then frozen and thawed three times, the cell debris removed by low speed centrifugation, and the amount of virus assessed. All experiments were run in duplicate. This system was chosen to minimize the effects of the test protein preparations on measurement of the virus. This method gives a fairer comparison of the amount of virus produced than earlier methods we have used. Under other systems we have experienced inhibition of the detection of virus by the preparations under test.
Table 3 shows the results of this testing.
TABLE 3
THE PERCENT REDUCTION OF IN VITRO VIRAL GROWTH
AFTER TREATMENT WITH THE TEST PROTEIN
TEST PROTEIN
VIRUS
CONTROL
@ 3% OF MEDIA
POLIO VIRUS
0%
92%
BOVINE HERPES VIRUS
0%
90%
PORCINE ROTOVIRUS (OSU)
0%
100%
STRAIN
HUMAN ROTOVIRUS
0%
100%
The test protein significantly stopped the infection rate of virus particles compared to the controls. Importantly, when the intact bovine IgG concentrate was evaluated for viral static capacity, it was negative.
In a chicken feeding test the IgG concentrate, as described above, was compared with a controlled plasma and a negative control. Chicks fed the acid-treated plasma at 4% of the ration gained significantly (P<0.05) faster compared with the controls.
In follow-up tests, the IgG concentrate was tested against a pair of E - Coli bacteria. An antibiotic, gentamicin, sensitive parent and mutation that was resistant to the antibiotic were used to test the growth-inhibiting effects of the new protein. The summary of the results are shown in the following Table 4.
TABLE 4
% REDUCTION OF BACTERIAL GROWTH
AFTER TREATMENT WITH THE TEST PROTEIN
SENSITIVE
RESISTANT
RESISTANT
SENSITIVE
STRAIN PLUS
STRAIN PLUS
STRAIN PLUS
STRAIN
TEST PROTEIN
TEST PROTEIN
ANTIBIOTIC
0
97%
97%
0
The results on Table 4 show that the IgG concentrate treated and isolated as herein described controls the rate of growth of both the resistant and the sensitive strain of E - Coli , and that the resistant strain's growth was not restricted in the presence of the antibiotic.
This is a significant development because of the antibiotic resistance that has been developing since antibiotics have been used over a long period of time. This finding strongly suggests that the mode of action of this concentrate is significantly different from that of antibiotics in general, and specifically gentamicin.
From the above it can be seen that the invention accomplishes at least all of its stated objectives.
|
A new protein derived from acid hydrolyzed IgG concentrate which has a molecular weight of about 55,000, and is activated by heat within the defined narrow temperature range provides resulting product that has a protective mechanism for bacterial and viral invasion of living cells.
| 0 |
This is a continuation of application Ser. No. 09/250,033, filed Feb. 12, 1999, which claims the benefit of U.S. Provisional Application Serial No. 60/076,618, filed Mar. 3, 1998.
FIELD OF THE INVENTION
The present invention is generally related to the manufacture of information recording disks and, more particularly, to the manufacture of protective films used to protect the recording layer of information recording disks.
BACKGROUND OF THE INVENTION
Information recording disks such as magnetic recording disks used, for example, in “hard disks,” compact disks, etc. have a structure where a recording layer is formed on the surface of a substrate which is made of a metal or dielectric material. In one process for making a magnetic disk used in a hard disk, a substrate of aluminum (Al), or other suitable metal or dielectric material is first coated with a nickel-phosphorus (NiP) layer. Next, an undercoat metal film of suitable material (such as CoCrTa) is deposited on a surface of the substrate and then a recording layer made from a thin magnetic film of suitable material is deposited on the metal film layer. The recording disk is completed by the depositing of a protective layer over the recording layer.
The protective layer must be composed of a durable film which has lubricating properties in order to shield the recording layer from impact and harsh environments. For example, sputtered carbon films (carbon films which have been deposited by sputtering) have been commonly used as protective layers. Chemical vapor deposition (CVD) of carbon has also been used to provide the protective layer. For ease of description, a protective layer consisting of carbon shall be referred to herein as a carbon protective layer.
With the recording density of hard disks continuing to increase, it has become necessary to provide carbon protective layers having a reduced thickness as compared to those conventionally used in the past. Greater recording density means less space between the sectors on the hard disk. When the space between sectors is reduced, the distance between the recording head and the magnetic recording layer must also be reduced. Currently available hard disks have a recording density of 1.6 gigabytes per square inch. Because the carbon protective layer is deposited on the magnetic recording layer, the thickness of the carbon protective layer must be reduced in order to minimize the distance between the recording head and the magnetic recording layer. Current commercial embodiments use films of between about 100-150 A. This is expected to be reduced to 50-100 A.
FIG. 13 is a schematic plan view of a conventional plasma CVD film deposition chamber. The deposition chamber 6 is equipped with a pumping system 61 , a process gas delivery system 62 for introducing a process gas into the film deposition chamber 6 , plasma generating means 63 forming a plasma by providing energy to the process gas which has been introduced by the process gas delivery system, and a transfer system (not shown) used to transfer a substrate 9 inside the deposition chamber 6 .
The process gas delivery system 62 is designed to introduce an organic compound gas such as methane (CH 4 ) into the interior region of the deposition chamber 6 . The plasma generating means 63 is designed to form a plasma by providing high frequency rf energy to the process gas, and is comprised of a high frequency power source 633 for supplying high frequency electrical power by way of a matching box 632 to a high frequency electrode 631 . When plasma of a gas such as methane is formed, the gas in the plasma decomposes resulting in a thin film of carbon being deposited on the surface of the substrate 9 . The deposited layer of carbon is then polished to a prescribed thickness.
Carbon films may be broadly divided into amorphous carbon films and crystallized carbon films. Crystallized carbon films are generally made of graphite, but some have a lattice structure similar to a diamond and are referred to as diamond-like carbon (DLC) films. In the manufacture of carbon films by plasma enhanced CVD using a hydrocarbon compound gas such as methane, when energy is provided by the collision of negative ions, a reduction in C—H bonds and C covalent bonds in the plasma occur which results in more C single bonds thereby resulting in a film having a diamond lattice structure.
A drawback associated with conventional film deposition apparatuses used to form carbon protective layers is that during the deposition process the carbon, used to provide the protective layer on the hard disk, is also deposited on the exposed surfaces inside the deposition chamber. As the carbon film buildup increases within the deposition chamber, the film separates as a result of internal stresses, gravity, etc., resulting in undesirable carbon particles being released inside the deposition chamber. These undesirable particles adhere to the surface of the substrates inside the chamber, forming protrusions on the surface of the protective layer, resulting in local irregularities in film thickness which can cause head crashes or signal errors.
FIG. 14 is an exploded, cross-sectional view of the surface of an information recording disk and a device used to detect defects on the surface of the disk. When the carbon protective layer is deposited with the particles adhering on the substrate surface, protrusions 902 are formed as shown. The particles and the protrusions resulting therefrom can have a diameter in the range of between about 0.1 to 0.5 microns.
To detect the presence of such protrusions, a glide height test is performed after the carbon protective layer is deposited on the magnetic recording layer. The glide height test is a test in which a tip 904 of a detector 903 , as shown in the dashed outline in FIG. 14, is used to scan the carbon protective layer 901 while being held a predetermined distance above the surface of the protective layer. In present applications, the distance d is set at 1 micro-inch. When the tip 904 contacts a protrusion 902 a short circuit is generated within a detection circuit (not shown) which provides an indication that the hard disk contains a protrusions of sufficient size to make the hard disk defective.
In conventional film deposition apparatuses, a considerable amount of carbon particles may be produced by the separation of the carbon film deposited on the exposed surfaces in the processing chamber which, in turn, cause many carbon particles to contaminate the surfaces of substrates. It is difficult to remove all the protrusions and smooth the substrate in subsequent processing steps. Furthermore, when large protrusions are deposited by the accumulation of carbon particles, attempts to remove the protrusions can lead to problems such as scratches or pitting on the surface of the substrate. Such scratches or pitting might pass the glide height test, but often are considered defects in subsequent certifying tests (i.e. recording and playback tests). A drawback associated with conventional film deposition apparatuses has thus been the inability to reduce the incidence of product defects.
SUMMARY OF THE INVENTION
The aforementioned and related drawbacks associated with conventional film deposition apparatuses are substantially reduced or eliminated by the thin film deposition apparatus of the present invention. The thin film deposition apparatus of the present invention includes an undercoat deposition chamber which deposits a layer of chromium to a substrate to be treated, a magnetic layer deposition chamber which provides a layer of CoCrTa, or other suitable material, on the previously deposited chromium layer which acts as a magnetic recording layer, a protective layer deposition chamber which provides a layer of carbon over the previously deposited magnetic recording layer to act as a protection layer and a holding chamber which temporarily holds the resulting information recording disk upon completion of the processing steps. The protective layer deposition chamber includes a system which removes excess carbon particle buildup from within the chamber by selectively introducing heated plasma and oxygen gas into the interior region of the chamber. The heated plasma and oxygen interact with excess carbon particles, resulting in the formation of a gas which is expelled from the interior of the protective layer deposition chamber by a pumping system. The holding chamber is used to maintain the newly formed information recording disks while the excess carbon particles, generated by the protective layer deposition process, are removed from the interior region of the deposition chamber in order to prevent the information recording disk from being damaged.
By providing a mechanism to remove excess carbon buildup from the protective layer deposition chamber, irregularities on the surface of the information recording disks are eliminated or substantially reduced. The removal of information recording disk irregularities results in enhanced signal accuracy and recording disk integrity.
An advantage of the present invention is that it provides a protective film layer having a planar surface and enhanced protective characteristics.
Another advantage of the present invention is that it effectively prevents unwanted carbon particle buildup from within the deposition processing chambers.
Yet another advantage of the present invention is that is increases information recording disk fabrication yields.
A feature of the present invention is that it uses plasma cleaning to effectively remove excess carbon buildup from within film deposition chambers.
Another feature of the present invention is that it provides the ability to remove treated substrates from respective deposition chambers before plasma cleaning of the respective chambers begins.
BRIEF DESCRIPTION OF THE DRAWINGS
The aforementioned and related advantages and features of the present invention will become apparent from the following detailed description of the invention, taken in conjunction with the following drawings, where like reference numerals represent like elements, in which:
FIG. 1 is a schematic plan view of the thin film deposition apparatus according to a first embodiment of the present invention;
FIG. 2 is a schematic cross-sectional side view of the carriage upon which the substrate manufactured by the film deposition apparatus of the present invention is placed;
FIG. 3 is a schematic side view of a portion of the structure for moving the carriage according to the present invention.
FIG. 4 is a schematic side view of a portion of the structure for moving the carriage according to the present invention;
FIG. 5 is a schematic diagram of the control system for transferring the thin film deposition apparatus of the present invention;
FIG. 6 is a schematic cross-sectional plan view of a magnetic deposition chamber of the present invention;
FIG. 7 is a schematic plan view of the protective layer deposition chamber of the present invention;
FIGS. 8A-8C depict movement of disks through deposition chambers and holding chambers of the present invention;
FIG. 9 is a time line representing the operations occurring during the dwell time;
FIG. 10 is a graph illustrating the reduction of carbon particle buildup when using the protective layer deposition chamber of the present invention;
FIG. 11 is a schematic plan view of a film deposition apparatus according to a second embodiment of the present invention;
FIG. 12 is a schematic plan view of a film deposition apparatus according to a third embodiment of the present invention;
FIG. 13 is a schematic plan view of a conventional plasma CVD film deposition chamber;
FIG. 14 is an exploded cross-sectional view of the surface of an information recording disk and a device used to detect defects on the surface of the disk.
DETAILED DESCRIPTION OF THE INVENTION
The thin film deposition apparatus of the present invention will now be described with reference to FIGS. 1 through 12. FIG. 1 is a schematic plan view of a thin film deposition apparatus according to a first embodiment of the present invention. As shown in FIG. 1, the thin film deposition apparatus includes a series of substrates 9 contained within a cassette 110 . The substrates 9 are mounted inside a loading chamber 1 by the arm 111 of a mounting robot 11 . The mounting robot 11 sequentially places the substrates 9 onto a plurality of carriages 90 which sequentially translate the substrates through the thin film deposition apparatus. A directional control mechanism (not shown) is employed to control the direction of travel of the carriage 90 . Directional rotation chambers 3 are used to rotate the direction of substrate travel ninety degrees (90°). A more complete description of the directional control mechanism is provided in Japanese Laid-Open Patent Application 8-274142 which is assigned to the same assignee as the present invention, and is incorporated fully herein by reference.
After an individual substrate 9 has been loaded onto the carriage 90 by the mounting robot 11 , the substrate is transferred through gate valve 10 into a process chamber 4 where the substrate is heated to a prescribed temperature. In one embodiment, the substrate is heated to a temperature of about 230° C. After being heated, the substrate 9 is transferred through another gate valve 10 into a first film deposition chamber 51 where a chromium (Cr) undercoat layer is deposited on the substrate 9 .
After the undercoat layer had been deposited, the substrate is transferred to a first magnetic film deposition chamber 52 where a layer of magnetic material, such as CoCrTa, is deposited on the undercoat layer to form the recording layer of the information recording disk. Although described above as a single processing step, the recording layer can be deposited in two or more processing steps according to the present invention. As further illustrated in FIG. 1, in the two layer deposition process, after the CoCrTa layer is deposited on the undercoat layer in the first magnetic film deposition chamber 52 , the substrate 9 is transferred to a second undercoat film deposition chamber 53 where a second undercoat layer of Cr is deposited on the substrate, followed by a second layer of CoCrTa being deposited on the second undercoat layer of Cr in the second magnetic film deposition chamber 54 . Although the magnetic recording layer has been described as being CoCrTa, other materials such as CoCrPt and CoCrPtTa may also be used as magnetic recording layers. After the completion of either the single layer process or the multi-layer process described above, the substrate is then transferred to protective film deposition chamber 6 where a protective layer of carbon is deposited on the magnetic recording layer to complete the fabrication of the information recording disk.
After the final processing steps have been completed, the resulting information recording disk is then transferred to an unloading chamber 2 where a recovery robot 21 removes the finished information recording disk from the carriage 90 and places it into a cassette 210 for removal from the thin film deposition apparatus.
The system used to transfer the substrates through the thin film deposition apparatus, and the structure and operation of each of the processing chambers will now be described. FIG. 2 is a schematic cross-sectional side view of the substrate carriage 90 of the present invention. As shown in FIG. 2, the substrate carriage 90 is comprised of a substantially rectangular-shaped member having an upper block portion 906 and a lower block portion 907 . An insulator block portion 905 , made from a suitable material is interposed between the upper block portion and the lower block portion. The upper block portion 906 includes a pair of plate shaped members ( 95 a , 95 b ) each having a generally circular carriage opening ( 90 a , 90 b ) formed therein. The two carriage openings have a diameter that is larger than the diameter of the substrate 9 . A narrow channel opening is present on the bottom ( 208 , 209 ) of carriage openings 90 a and 90 b , respectively, for maintaining a holding pawl 91 (hereinafter referred to as bottom edge holding pawl). Channels are present along the left ( 210 , 214 ) and right portions ( 212 , 216 ) of the respective carriage openings for maintaining side holding pawls 92 therein. The tips of the bottom edge holding pawls 91 are located on a perpendicular line passing through the center of the mounted substrate in order to hold the substrate 9 along the center of its bottom edge.
The side holding pawls 92 on the left ( 210 , 214 ) and right ( 212 , 216 ) edges (hereinafter, side edge holding pawls) of the members ( 95 a , 95 b ) are constructed in such a fashion that the side edge holding pawls 92 contact the side edges of the substrate 9 . The movement of the side edge holding pawls 92 are controlled by plate springs which are opened and closed by opening/closing rods 93 . When a substrate 9 is placed on a carriage 90 , the tip of arm 111 is inserted into the substrate opening to hold the substrate 9 and situate the substrate relative to the carriage opening 90 a as shown in dashed outline. At this point, the opening/closing rods 93 are in the open position thereby causing the side edge holding pawls 92 to be in a position away from the substrate. The arm 111 then moves the substrate 9 onto the bottom edge holding pawl 91 . Next, the opening/closing rods 93 are placed in the closed position, thereby causing the side edge holding pawls 92 to contact the sides of the substrate 9 and maintain the position of the substrate 9 within the carriage opening 90 a.
When the substrate 9 is removed from the carriage 90 , the operation of the carriage elements are exactly the reverse of those described above. As the side edge holding pawls 92 are opened by the movement of the opening/closing rods 93 , the arm 111 for holding the substrate 9 ascend slightly inside the carriage opening 90 a . The arm 111 then moves horizontally to retract the substrate 9 from the carriage 90 . The substrate 9 is transferred to/from the carriage 90 by being moved horizontally. As shown in FIG. 2, several small magnets (hereinafter, referred to as carrier side magnets) 94 are situated along the bottom edge of the carriage 90 and are arranged by alternating the opposite poles of the magnets. A magnetic coupling roller 97 is arranged along the bottom of the carriage 90 , with a housing 96 (FIG. 3) interposed between the carrier side magnets 94 and the coupling roller 97 . The magnetic coupling roller 97 is made from rod-shaped members having spirally extending magnets (hereinafter, referred to as roller side magnets) 971 formed on the outer circumference thereof. The roller side magnets 971 are comprised of a pair of magnets ( 971 a , 971 b ) having opposing polarities. The magnetic coupling roller 97 is disposed in such a way that the roller side magnets 971 a , 971 b face the carrier side magnets 94 with the housing 96 being interposed therebetween. The housing 96 is formed from a highly permeable material which allows the carrier side magnets 94 and the roller side magnets 971 to be magnetically coupled through the diaphragm 96 . Those skilled in the art will appreciate that other mechanisms for translating the carriage could also be employed.
The structure of an individual portion of the directional control mechanism will now be described with reference to FIGS. 3 and 4. FIG. 3 is a schematic side view of a portion of the mechanism for moving the carriage 90 , and FIG. 4 is a schematic side view of a portion of the mechanism for moving the carriage 90 . As shown in FIG. 3, the carriage 90 is placed on a main roller 951 that rotates about a horizontal axis. Auxiliary rollers 952 rotate about an axis perpendicular to the main roller 951 , and are in contact with the bottom of the carriage 90 . Auxiliary rollers 952 press on either side of the bottom portion of the carriage 90 to prevent the carriage from rotating.
As shown in greater detail in FIG. 4, housing 96 separates the magnetic coupling roller 97 and the carrier side magnets 94 . Two magnetic coupling worm gears ( 97 a , 97 b ) are mounted on rod 972 in the housing 96 . A gear 974 is provided on the rod 972 . A drive rod 973 having a gear 975 , which engages gear 974 , is also present within the housing 96 . The drive rod 973 is perpendicular to rod 972 , and is connected to a drive motor 98 . Bearings ( 916 , 977 ) allow rotation of drive rod 973 . When the drive motor 98 is actuated, the drive rod 973 rotates causing the gears 974 and 975 to rotate. This rotation causes magnetic coupling roller 97 , to rotate. When the magnetic coupling roller 97 rotates, the roller side magnets ( 971 a , 971 b ) rotate. Rotation of the roller side magnets 971 is equivalent to a plurality of small magnets with alternating magnetic poles in series, moving in the horizontal direction. As such, the carriage side magnets 94 coupled to the roller side magnets ( 971 a , 971 b ) move in a linear fashion along with the rotation of the roller side magnets ( 971 a , 971 b ), resulting in the linear movement of the carriage 90 .
FIG. 5 is a schematic diagram of the control system for transferring disks through the thin film deposition apparatus of the present invention. Individual units of the aforementioned magnetic coupling roller 97 , connecting rod 972 , drive rod 973 , drive motor 98 , and associated parts are located in each of the chambers 1 , 2 , 3 , 4 , 51 , 52 , 53 , 54 , 6 , 7 and 8 . Controller 99 which controls the entire system for translating disks through the system sends signals to the respective drive motors 98 located in each of the aforementioned chambers, allowing each drive motor 98 and the corresponding carriage 90 to be independently controlled.
The specific structure of the processing chambers, used in the thin film deposition apparatus of the present invention, will now be described. First, the substrates 9 are heated to a temperature of between about 100-130° C. in preheat chamber 4 (FIG. 1 ). This causes degassing of the substrates, i.e., the release of any occluded gas in the substrate. When a film is deposited without degassing the substrate, gas bubbles may develop in the film during subsequent deposition, causing the film surface to become rough as a result of the bubbling. The preheating chamber 4 is equipped with a gas feeding system (not shown) which introduces an inert gas, such as nitrogen, into the interior of the preheating chamber, and heating means for heating the substrate 9 being transferred. Any suitable heating mechanism, such as an infrared lamp, may be used as the heating means. It is most practical to control the operation of the heating means in such a way as to allow the drop in thermal capacity, which occurs when the preheating chamber 4 is empty, to be corrected. Heating conditions which avoid changes in the temperature inside the preheating chamber 4 when the preheating chamber is empty should be experimentally determined beforehand and maintained. For example, in one embodiment, when the heating means is an infrared lamp, the temperature within the preheating chamber is constant when the heating means is operated at about 80% power. When new carriages are transferred into the preheating chamber, the heating means may then be returned to full power.
Undercoat layer deposition chambers 51 and 53 and magnetic layer deposition chambers 52 and 54 will now be described. Undercoat layer deposition chambers 51 and 53 and the magnetic layer deposition chambers 52 and 54 , respectively, deposit undercoat layers or magnetic layers by performing a sputtering process. The structure of the undercoat layer and magnetic layer depositing chambers are very similar, the primary difference being the target materials. Thus, for ease of description, a magnetic layer deposition chamber will be described and shall apply equally to the undercoat layer deposition chamber. FIG. 6 is a schematic cross-sectional plan view of the magnetic layer deposition chamber 52 . Magnetic layer deposition chamber 52 comprises a pumping system 55 to evacuate the interior of the chamber, a gas delivery system 56 for introducing plasma gas into the interior of the chamber, a sputter target 57 which is exposed to the plasma formed in the interior of the chamber, a sputtering power supply 58 for applying a discharge voltage to the target 57 and a magnet system 59 located behind target 57 . The pumping system 55 is equipped with one or more vacuum pumps, such as a roughing pump and a cryopump, capable of reducing the pressure within the interior of the magnetic layer deposition chamber 52 to about 10 −9 torr. The gas delivery system 56 is designed to allow a prescribed amount of a gas, such as argon, to be introduced as the plasma gas. The sputtering power supply 58 is designed to generate a voltage in the range between about −300 to −500 V to be applied to the target 57 in order to sustain a plasma. The magnet system 59 is used to produce a magnetron discharge and consists of a center magnet 591 , a peripheral magnet 592 in the form of a ring around the center magnet 591 and a plate-shaped yoke 593 , linking the center magnet 591 and the peripheral magnet 592 . The target 57 is fixed by means of an insulating block 571 to the magnetic layer deposition chamber 52 . The magnetic layer deposition chamber 52 is electrically grounded.
After a suitable amount of the plasma gas is introduced by the gas delivery system 56 , the interior of the magnetic layer deposition chamber 52 is maintained at a prescribed pressure by the pumping system 55 , and the sputtering power supply 58 is actuated. As a result, a plasma is formed and confined by the magnetic field to a region adjacent to the surface of target 57 . As is well known, this causes sputtering from the target 57 , and the material released from the target 57 is deposited on substrate 9 resulting in the formation of the prescribed magnetic layer on the surface of the substrate 9 . In one embodiment of the present invention, the target 57 consists of CoCrTa, which results in a CoCrTa layer being deposited on the surface of the substrate 9 . As may be seen in FIG. 6, targets 57 , magnet systems 59 and sputtering power supplies 58 are provided on either side of the substrate in order to form magnetic layers on both sides of the substrate 9 . Also shown in FIG. 6, the targets 57 are somewhat larger than the substrate 9 . In one embodiment, carriage 90 moves inside the magnetic layer deposition chamber 52 so that two substrates 9 are sequentially located in front of the targets 57 . That is, the forward substrate 9 is first located in front of the targets 57 , where a film is deposited thereon. The forward substrate is then advanced a prescribed distance, allowing the rear substrate 9 , contained on the carriage 90 , to be positioned in front of the targets 57 so that a magnetic film is deposited on the rear substrate. FIG. 7 is a schematic plan view of the protective layer deposition chamber 6 of the present invention. The deposition chamber of FIG. 7 employs plasma-enhanced chemical vapor deposition (CVD) to deposit a carbon film. The protective layer deposition chamber 6 comprises a pumping system 61 for evacuating the interior of chamber 6 , and a gas delivery system 62 for introducing a processing gas into the interior of the chamber. A plasma (P) is formed to provide energy to the processing gas introduced by the gas delivery system. The pumping system 61 is equipped with a vacuum pumping system, such as a turbo-molecular pump, to establish and maintain a pressure of about 10 −7 torr within the chamber. The gas delivery system 62 is designed to introduce a processing gas, such as methane and hydrogen, at a prescribed flow rate. Alternate processing gases such as C 2 H 4 or C 2 H 6 may also be used.
Plasma is formed within chamber 6 by applying a high frequency rf energy to the processing gas that has been previously introduced. Specifically, the plasma is generated by a high frequency electrode 631 located within the protective film depositing chamber 6 , and a high frequency power source 633 for supplying power through a matching network 632 to the high frequency electrode 631 . High frequency electrode 631 has a hollow interior 650 , with a plurality of apertures 651 in the front surface thereof. Gas delivery system 62 is connected to electrode 631 at node 652 such that the processing gas entering the hollow interior 650 of electrode 631 will be uniformly discharged through the apertures 651 at a prescribed rate. Electrode 631 is mounted on insulating block 634 to the protective film deposition chamber 6 . The protective film deposition chamber 6 is electrically grounded. High frequency power source 633 supplies electrical power at a frequency of about 13.56 MHz, resulting in an output of 500 W to electrode 631 . The resulting high frequency electric field results in a high frequency plasma discharge being produced in the processing gas. In the plasma, the decomposition of the methane results in the deposition of carbon on the surface of the substrate 9 , forming a carbon protective film on the substrate. According to the first embodiment of the present invention, a bias voltage is applied to the substrate 9 during the deposition of the carbon film. The bias voltage causes ion collisions with the substrate by extracting ions from the plasma.
As shown in greater detail in FIG. 7, a negative DC power supply 641 and a second high frequency power source 642 are provided outside the protective film deposition chamber 6 , and are coupled to deposition chamber 6 by a switch 643 . Wire 644 passes through the wall and into deposition chamber 6 . A resilient contact 645 is provided at the tip of the wire 644 and contact 645 is coupled to the upper block 906 (FIG. 2) of the carriage 90 to provide that the negative DC voltage or high frequency voltage is applied through the carriage 90 to the substrate 9 . When high frequency voltage is applied, suitable capacitance is provided between the second high frequency power source 642 and the substrate 9 , and high frequency rf energy is applied by means of the capacitance to the substrate 9 . As a result of the interaction between the rf energy that had been applied to the plasma, a negative self bias voltage is produced at the substrate 9 . The negative DC voltage or negative self bias voltage extracts positive ions from the plasma to produce collisions with the substrate 9 . As specific examples of the negative DC power source 641 and the second high frequency power source 642 , an output of about −150 V may be used as the negative DC power source 641 , while an output of about 13.56 MHz 50 W may be used as the high frequency power source 642 .
The operating parameters used in one embodiment of the protective film deposition chamber 6 are outlined in Table 1 below.
TABLE 1
CH 4 gas
20 cc/min
Hydrogen gas
100 cc/min
Pressure inside protective film
2 Pa
deposition chamber
High frequency power
13.56 MHZ 400 W (x2)
Film depositing speed
10-15 A/sec
Film depositing speed
3.5-5 sec
High frequency electrode 631 is large enough to provide plasma adjacent to two substrates 9 , thereby allowing deposition of a carbon film simultaneously on the two substrates contained within the carriage 90 . High frequency electrodes 631 , and associated structures are provided on both sides of the two substrates 9 , allowing the carbon protective film to be simultaneously deposited on both sides of the two substrates.
A feature provided by the thin film deposition apparatus of the present invention is that deposition chamber 6 is adapted to form oxygen plasma. Gas delivery system 62 of the protective film deposition chamber 6 allows oxygen (O 2 ) gas to be selectively introduced into the chamber. The formation of the oxygen plasma is used to prevent unwanted carbon formation inside the deposition chamber 6 . In the deposition chamber of the present invention, the carbon film deposited on the exposed surfaces inside the chamber is removed by the oxygen plasma.
Specifically, when oxygen gas is introduced to form an oxygen plasma, an abundance of oxygen ions is produced in the plasma. Carbon film deposited on the exposed surfaces of the protective film deposition chamber contains hydrogen. That is, the film contains C—C bonds as well as C—H bonds. When such a carbon film comes into contact with oxygen ions, the C—C bonds or C—H bonds are broken down as follows:
O 2→ 20 + (or 20 − )
(C—C)+4 O + (or 4 O − ) → 2 CO 2 (or 2 CO+O 2 )
(C—H)+2 O + (or 2 O − ) → CO+H 2 O
The CO 2 , CO, O 2 and H 2 O produced by the reactions are all gases, and are evacuated from the interior of the deposition chamber 6 by vacuum pump system 61 , thereby allowing the carbon film to be removed from the interior surfaces deposition chamber 6 .
The following are exemplary operating conditions for the removal of unwanted carbon from the interior surface of the process chamber.
TABLE 2
Oxygen flow rate
150 cc/min
Pressure inside chamber
15 Pa
High frequency power
13.56 MHz 500 W (x2)
Pumping system speed
6,000 L/min
When the oxygen cleaning process is performed under the conditions of Table 2, carbon film is removed at a rate of about 600 A/min.
In accordance with the present invention, substrate 9 is removed from deposition chamber 6 and transferred to holding chamber 7 during the oxygen plasma removal process. In the present embodiment, holding chamber 7 is a vacuum chamber with its own vacuum pumping system 61 , but with no processing equipment. Holding chamber 7 is separably maintained at an atmosphere pressure of about 5×10 −1 torr by vacuum pumping system 61 . The substrate 9 is transferred to holding chamber 7 during the oxygen cleaning process by the control unit 99 of the transferring system. As described above with respect to FIG. 5, control unit 99 independently controls each of the drive motors 98 , allowing independent control. Substrates 9 are thereby removed from deposition chamber 6 during the oxygen cleaning.
The time period from when two processed substrates are unloaded from a carriage 90 in the unloading chamber 2 until two substrates 9 are unloaded from a subsequent carriage 90 is considered the dwell time. The dwell time is determined by the longest time period required to execute the operations of the various chambers. Generally, the magnetic film deposition in the magnetic film deposition chambers 52 and 54 take the longest amount of time, so that the time required for magnetic film deposition and for transferring the substrates to the next chamber is the dwell time. In other words, the dwell time is the longest process time (PT) plus the transfer time (TT). When the time taken in the move to the next chamber differs depending on the chamber, the one taking the most time is the TT, and the dwell time is PT+TT. The carriages 90 are delayed in those chambers where the process or transfer times are shorter than the PT or TT.
During processing, each carriage 90 simultaneously moves to the next processing chamber at the end of the dwell time. In other words, the control unit 99 (FIG. 5) of the transferring system operates in such a way that all drive motors 98 are actuated by the transmission of simultaneous drive signals when the PT time has elapsed and the carriages 90 are all moved simultaneously to the next chamber by the TT time. As previously described, when a carriage 90 reaches the protective film deposition chamber 6 , a carbon protective film is deposited on the substrate by plasma CVD. When the deposition of the carbon protective film is completed, the control unit 99 actuates the drive motor 98 of the protective film deposition chamber 6 and the drive motor 98 of holding chamber 7 , resulting in the carriage 90 being moved from the protective film deposition chamber 6 (FIG. 8 a ) to holding chamber 7 (FIG. 8 b ). At this time, the control unit 99 does not actuate any drive motor 98 other than the drive motors 98 of the protective layer depositing chamber and the holding chamber, and no carriage 90 other than the carriage 90 moving between the protective layer deposition chamber and the holding chamber is actuated. After the carriage is placed in holding chamber 7 , the holding chamber 7 is closed, and the gas delivery system 62 in deposition chamber 6 is switched on. Oxygen gas is thus introduced into deposition chamber 6 allowing oxygen cleaning of the chamber as described above.
Next, the control unit 99 of the transferring system sends drive signals to all the drive motors 98 causing the carriages 90 to move to subsequent chambers. As shown in FIG. 8 (c), the next carriage 90 is moved into the protective film deposition chamber 6 , and the carriage 90 present within chamber 7 is moved to chamber 8 before being transferred to the unloading chamber 21 .
As may be seen from the aforementioned description, the oxygen cleaning process may be carried out after every time a carbon protective film is deposited in deposition chamber 6 . In the preferred embodiment, the oxygen cleaning process is carried out after each carbon deposition to prevent the buildup of carbon on the exposed interior surfaces of the deposition chamber 6 . No substrate is present within deposition chamber 6 during the oxygen cleaning and no substrates are exposed to the oxygen plasma.
According to the first embodiment of the present invention, there is one holding chamber 7 used in the thin film deposition apparatus. This is related to the processing capacity of the protective film deposition chamber 6 . In the present embodiment, the time for the carbon deposition in chamber 6 , the time for the carriage 90 to move from chamber 6 to holding chamber 7 and the time for the oxygen cleaning process are added together resulting in the aforementioned PT+TT.
FIG. 9 is a time line representing the operations occurring during the dwell time. FIG. 9 a depicts an exemplary dwell time in the magnetic layer depositing chambers 52 and 54 , while FIG. 9 b depicts the dwell time in the deposition chamber 6 and holding chamber 7 . In an apparatus having a processing capacity of 450 substrates per hour, the dwell time is 16 seconds ((60×60)/(450/2)=16). As shown in FIG. 9 a , the 16 second dwell time used in the magnetic film deposition chambers 52 and 54 is based on a total of 16 seconds, where the time for the deposition of a film (SP 1 ) on the first substrate 9 on a carriage 90 is 5.5 seconds. The time (tr′) for the carriage 90 to move in the chambers 52 and 54 in order to deposit a film on the second substrate is one second. The time for the deposition of a film (SP 2 ) on the second substrate is 5.5 seconds, and the time for simultaneously moving all the carriages 90 (TT) is four seconds. In the protective film deposition chamber 6 and the holding chamber 7 , as shown in FIG. 9 b , the CVD is five seconds, the tr′ is four seconds, the (as) is three seconds and the TT is four seconds, the same as above. Thus, the processing capacity of the protective film deposition chamber 6 is doubled in the present embodiment. The oxygen cleaning step can thus be performed after every carbon film deposition with no drop in productivity.
FIG. 10 is a graph illustrating the reduction of carbon particle buildup when using the protective layer deposition chamber of the present invention. In a test performed by the inventors, the thin film deposition apparatus, as described above, was used to deposit a carbon protective film on a substrate having a diameter of 3.5′. The number of particles with a diameter of 1 micron or more remaining on the surface of the substrate was then determined. The vertical axis of FIG. 10 indicates the number of particles, while the horizontal axis indicates the number of days since the protective film deposition chamber was first operated. A carbon film deposition chamber with a processing capacity of about 10,000 substrates per day was used. As seen in FIG. 10, 100 particles were produced in a conventional apparatus after one day of operation, and this number increased rapidly thereafter. When this many particles are produced, a large number of protrusions such as those shown in FIG. 14, are deposited on the substrate, resulting in a high probability of glide height test failures.
In contrast, in the protective layer deposition chamber of the present invention, the number of particles was limited to a few over four days of processing. If there were any protrusions caused by this number of particles, they could be completely removed by a tape burnishing process before the glide height test is administered, which would result in no glide height test failures.
In accordance with another embodiment of the present invention, the holding chamber 7 may be located before the protective film deposition chamber 6 . In such a case, after the completion of the process prior to carbon deposition, a carriage 90 is moved into holding chamber 7 and the deposition chamber 6 is empty. Carbon removal is then performed in deposition chamber 6 and the carriage in holding chamber 7 is then moved to the deposition chamber 6 . The protective film is then deposited in the second half of the cycle. After processing is completed at each station, all of the gate valves 10 are open, and all the carriages moved to the next chamber. Carriage 90 is thus again located in the chamber 7 and the deposition chamber 6 is empty. The aforementioned operations are then repeated.
When there are a plurality of protective film deposition chambers, there is a corresponding increase in the number of holding chambers. Each holding chamber 7 may be located either before or after each deposition chamber 6 . In another embodiment, holding chamber 7 is separated from deposition chamber 6 . In this embodiment, the protective layer deposition chamber can be emptied by simultaneously moving only the carriages located in the chambers between the holding chamber 7 and the deposition chamber 6 . When holding chamber 7 is located next to the protective film deposition chamber 6 , the structure of the control system is made more simple as there are fewer drive motors that need to be independently driven in order to empty the protective film deposition chambers.
The thin film deposition apparatus according to a second embodiment of the present invention will now be described with reference to FIG. 11 . FIG. 11 is a schematic plan view of a film deposition apparatus according to a second embodiment of the present invention. The second embodiment differs from the first embodiment in that the holding chamber 7 has been replaced with a second protective film deposition chamber 60 . The two protective film deposition chambers 6 , 60 have the same structure as that depicted in FIG. 7 . That is, they are used to deposit protective films by plasma CVD using a composite gas of methane and hydrogen, and a carbon film deposited on the exposed surfaces inside the chambers can be removed by oxygen plasma.
According to the second embodiment of the present invention, when a carriage 90 is transferred to the first deposition chamber 6 , the carriage 90 is removed from the second deposition chamber 60 , leaving chamber 60 empty. At this time, a mixed gas of methane and hydrogen is introduced into the first deposition chamber 6 , to deposit a carbon protective film on the substrate 9 . At the same time, oxygen gas is introduced into the empty second deposition chamber 60 thereby removing any carbon inside chamber 60 . The protective film deposition treatment and the carbon removal treatment are completed in less than one dwell period. Once the protective layer deposition and the carbon removal treatment have been completed, the gate valve 10 between the first deposition chamber 6 and the second deposition chamber 60 is opened, and the drive motors for chamber 6 and chamber 60 are actuated to move the substrate in the first deposition chamber 6 to the second deposition chamber 60 . In the next cycle, all of the gate valves 10 are open and all of the drive motors are operated to move all the carriages to the subsequent chambers. As a result, a subsequent carriage 90 is again positioned in the first deposition chamber 6 and the second deposition chamber 60 is empty. Thus, carbon is deposited in the first and second deposition chambers 6 and 60 , respectively. There is no time wasted such as through tracking operations in the holding chambers 7 . One unit of dwell time is fully used to execute film deposition and carbon removal. Accordingly, there is no need to double the carbon protective film depositing capacity as is required in the first embodiment, making the second embodiment to the present invention suitable for situations where it would be difficult to double the film-making capacity.
For the operation of the apparatus according to the second embodiment of the present invention, carbon film of half the desired thickness may be deposited in the first deposition chambers 6 , and the remaining half of the film may be deposited in the second deposition chamber 60 . The carriage 90 moves to chamber 60 before half of one unit of dwell time has elapsed.
FIG. 12 is a schematic plan view of a thin film deposition apparatus according to a third embodiment of the present invention. In this embodiment, there are no carriages 90 present in the directional chambers 3 adjacent to the loading chamber 1 and between the magnetic film deposition chamber 54 and the protective film deposition chamber 6 . In the embodiment illustrated in FIG. 12, the drive motors 98 (FIG. 3) are not independently controlled as in the first and second embodiments, but instead are operated simultaneously at the same dwell time.
In operation, after one unit of dwell time has elapsed, all of the carriages 90 move to the next processing chamber in the process flow, resulting in the preheating chamber 4 and the first protective film deposition chamber 6 being empty. As described above, the carbon removal process is performed using oxygen plasma in the empty first protective film deposition chamber 6 . While the carbon removal process is being performed on the first protective film deposition chamber 6 , a carriage 90 is conveyed into the second protective film deposition chamber 60 , where a carbon film is deposited onto the previously deposited layer.
After one unit of dwell time has elapsed, the first undercoat film deposition chamber 51 and the second protective film deposition chamber 60 are empty. Accordingly, the carbon removal process is performed in the second protective film deposition chamber 60 while a carbon protective film is being deposited in the first protective film deposition chamber 6 . The protective film deposited in the first and second protective film deposition chambers are deposited in the same manner and have the same thickness as provided in the second embodiment of the present invention. After five units of dwell time have elapsed, one complete process cycle has been completed.
In the third embodiment of the present invention, the carriages are simultaneously controlled, not independently controlled; thus, the structure of the transferring system control unit 99 can be simplified.
The foregoing detailed description of the invention is provided for the purpose of illustration and description and is not intended to be exhaustive or to limit the invention to the precise embodiments disclosed. Many modifications and variations of the disclosed invention are possible in light of the above teaching. For example, thermal CVD can be used to deposit the protective layer instead of plasma CVD. Accordingly, the scope of the present invention is to be defined by the claims appended hereto.
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An apparatus for manufacturing information recording disks is disclosed. The apparatus includes a deposition chamber for providing an undercoat layer to a substrate to be treated, a deposition chamber for providing a magnetic recording layer on the substrate, a deposition chamber for providing a protective layer over the recording layer and a holding chamber for removing the resulting information recording disk upon completion of the process steps. The deposition chamber which provides the protective layer includes a system which selectively introduces heated plasma and oxygen into the interior of the deposition chamber to clean the interior surfaces of the chamber while the apparatus is in use. The heated plasma and oxygen interact with any excess protective layer material, resulting in the formation of a gas which is removed from the interior of the deposition chamber by a pumping system. The holding chamber is used to remove and maintain the processed information recording disk while the interior of the deposition chamber is being cleaned.
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This is a continuation in part of application Ser. No. 820,379, filed Jan. 14, 1992, now U.S. Pat. No. 5,227,166.
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to feed additives for ruminants. More specifically, the present invention relates to a feed additive composition comprising a biologically active substance that is coated with a coating composition which is stable in the rumen of the ruminant and released in the abomasum or subsequent digestive tract. This ability makes it possible for the biologically active substance to be digested in the abomasum and subsequent digestive tract.
2. Description of the Background Art
In ruminant animals, such as cattle or sheep, the direct oral administration of biologically active substances, such asamino acids and vitamins, causes most of the substances to be decomposed by microorganisms in the rumen; thus they are not effectively utilized.
Accordingly, it is important to pass the biologically active substances through the rumen without decomposition by microorganisms to allow the biologically active substances to be effectively digested and absorbed in the abomasum and subsequent digestive tract. Such an ability would make an impact in the fields of feeds, nutrient preparations and veterinary drugs for ruminant animals.
It was proposed in the past to coat ruminant animal feed additives containing biologically active substances with protective substances, such as fatty acids, hardened animal oils and hardened vegetable oils. However, particles coated with these fats and oils are stable, not only in the rumen, but also in the abomasum and subsequent digestive tract making the biologically active substances difficult to be released in the abomasum and subsequent digestive tract.
For this reason, methods were proposed that added substances propelling the release of the biologically active substances in the abomasum and its subsequent digestive tract that contained such protective substances. In these methods, the biologically active substances are granulated and dispersed in coating materials or coated with coating materials.
The Japanese Laid-Open Patent Publication No. 168351/85 proposes a method of dispersing a biologically active substance in a protective substance which comprises granulating a biologically active substance containing at least 20% by weight of calcium carbonate and at least 10% by weight of a substance selected from the group consisting of monocarboxylic acid, a hardened oil and fat. Furthermore, Japanese Laid-Open Patent Publication No. 195653/86 proposes a process for dispersing a biologically active substance in coating materials composed of at least 10% by weight of a substance selected from the group consisting of a monocarboxylic acid, a hardened oil and fat, and at least 20% by weight to not more than 50% by weight of an insoluble salt of an acid which is more weakly acidic than hydrochloric acid.
As the method of coating with coating materials, for example, Japanese Laid-Open Patent Publication No. 317053/88 describes a method which comprises coating a biologically active substance with a coating material containing the protective substance composed of a monocarboxylic acid, hardened oil, lecithin, and a glycerin fatty acid ester.
However, the method of dispersing a biologically active substance in a coating materials requires that the content of the biologically active substance be considerably decreased in order to retain the protectiveness because the substance is present near the surface of the particle. In view of the fact that the time of passing from rumen to abomasum is between 10 hours to several days, it is difficult to keep the biologically active substances that are present near the surface stable as it passes through the rumen. Furthermore, when the substance is coated with a coating material composed of lecithin, a glycerin fatty acid ester and an oil or a fat, the coated layer has insufficient strength and its protectiveness is diminished. In addition, lecithin and a glycerin fatty acid ester are expected to have an emulsification action of the oil and fat in the small intestine, but because of the length of time required to pass through the small intestine, the property to release the biologically active substances is still not sufficient.
Another method proposed utilizes the difference in pH between the rumen and the abomasum by coating with a polymer which is insoluble in the environment of the rumen but is soluble in the strongly acidic abomasum. Since an organic solvent used for both the coating and the coating agent becomes expensive, this procedure is not a fully satisfactory means.
In view of the foregoing problems, the need exists to provide a method that protects a biologically active substance stably in the rumen of a ruminant animal and yet allows efficient digestion and absorption in the abomasum and subsequent digestive tract.
The present invention provides for such a biologically active substance that can effectively be digested and absorbed by ruminant animals and be safe and economical. Thus, the above objectives have been achieved.
SUMMARY OF THE INVENTION
The present invention provides in one embodiment, a feed additive for ruminants comprising a core containing a biologically active substance and coating composition placed on the surface of the core.
The coating composition comprises lecithin, at least one inorganic substance which is stable under neutral conditions and soluble under acidic conditions, and at least one substance selected from the group consisting of straight-chain or branched-chain saturated or unsaturated monocarboxylic acids having 14 to 22 carbon atoms, salts thereof, hardened vegetable oils, hardened animal oils, and waxes.
In another embodiment, the present invention relates to a feed additive as describe above, wherein the lecithin is used in an amount of from 0.1% to 20% by weight and the inorganic substance is used in an amount from 0.1 to 10% by weight, based on the weight of the coating composition.
In yet another embodiment, the present invention relates to the feed additive described above wherein the inorganic substance is carbonate or a calcium salt of pyrophosphoric acid.
A further embodiment relates to a feed for ruminants that comprises the feed additive described above.
Various other objects and advantages of the present invention will become apparent from the following detailed description of the invention.
DETAILED DESCRIPTION OF THE INVENTION
The present invention relates to a feed additive comprising a core containing a biologically active substance which is coated with coating materials containing lecithin, inorganic substances which are stable under neutral conditions but soluble under acidic conditions, and at least one substance selected from the group consisting of straight-chain or branched-chain saturated or unsaturated monocarboxylic acids having 14 to 22 carbon atoms or salts thereof, hardened vegetable oils, hardened animal oils, and waxes. Such a feed additive dually provides excellent stability in the rumen and excellent dissolution in the abomasum and its subsequent digestive tract.
The feed additive for ruminants of this invention contain lecithin and inorganic substances in the coating materials which are stable under neutral conditions but soluble under acidic conditions. By utilizing the fact that the inside of the abomasum is acidic, the action of the inorganic substances and the emulsification action of fatty acids and hardened oils by lecithin in the small intestine leads to the property of releasing the biologically active substances in the abomasum and its subsequent digestive tract and the synergistic effect makes the dissolving property good. Furthermore, the addition of the inorganic acid salts increases the strength of the coating layer.
In the present invention, the biologically active substances are selected from at least one material from the group consisting of known nutrients, feeds containing them, drugs, such as amino acids and derivatives thereof, hydroxy homologous compounds of amino acids, proteins, hydrocarbons, vitamins and veterinary medicines.
Specifically, they include amino acids such as lysine, methionine, tryptophan and threonine, amino acid derivatives such as N-acylamino acid and N-hydroxymethylmethionine calcium salt, and lysine hydrochloride, hydroxy homologous compounds of amino acids such as 2-hydroxy-4-methylmercaptobutyric acid and salts thereof, powders of natural nutrients such as grain powders, feathers and fish powder, proteins such as casein, corn proteins and potato proteins, carbohydrates such as starch, cane sugar and glucose, vitamins and substances having a similar function such as vitamin A, vitamin A acetate, vitamin A palmitate, vitamins B, thiamine, thiamine hydrochloride, riboflavin, nicotinic acid, nicotinic acid amide, calcium pantothenate, choline pantothenate, pyridoxine hydrochloride, choline chloride, cyanocobalamine, biotin, folic acid, p-aminobenzoic acid, vitamin D 2 , vitamin D 3 and vitamin E, antibiotics such as tetracyclic antibiotics, amino glycoside antibiotics, macrolide-type antibiotics, polyether-type antibiotics, insecticides such as negfon; vermicides such as piperazine, and hormones such as estrogen, stibestrol, hexestrol, tyroprotein and goitrogen.
There is no particular restriction in the preparative method of a core containing a biologically active substance. As required, a binder or a filler may be added and granules, preferably particles close to spherical in shape, are prepared by a known granulating method such as extrusion granulation, fluidized granulation, or stirring granulation.
Examples of the binder are cellulose derivatives such as hydroxypropylcellulose, methyl cellulose, or sodium carboxymethylcellulose, vinyl derivatives such as polyvinyl alcohol or polyvinylpyrrolidone, gum arabic, guaiac gum and sodium polyacrylate. Starch, proteins and crystalline cellulose may be used as the filler. If required, a specific gravity adjusting agent may be added such as calcium carbonate, calcium phosphonate and talc.
The coating materials for coating a core containing the biologically active substance comprises lecithin, at least one inorganic substance which is stable under neutral conditions, but soluble under acidic conditions and at least one substance selected from the group consisting of straight-chain or branched-chain saturated or unsaturated monocarboxylic acids having 14 to 22 carbon atoms, or salts thereof, hardened vegetable oils, hardened animal oils, and waxes.
Examples of monocarboxylic acids include myristic acid, palmitic acid, stearic acid, oleic acid, linoleic acid, and behenic acid. Salts of these may also be used. Examples of hardened vegetable oils include hardened palm oil, hardened soybean oil, hardened rapeseed oil, and hardened castor oil. Examples of hardened animal oils are hardened beef tallow and hog fat. Examples of waxes are carnauba wax and beeswax, natural waxes, synthetic waxes, and paraffin waxes.
Lecithin used in the invention is not required to be pure. Preferably, it may be prepared from soybean and egg yolk as materials.
Examples of the inorganic substance which are stable under neutral conditions and soluble under acidic conditions include magnesium carbonate, calcium carbonate, calcium phosphate, calcium pyrophosphate and mixtures thereof. Carbonates such as magnesium carbonate, calcium carbonate, and the calcium salt of pyrophosphoric acid are more preferred.
Other important inorganic substances within the invention are calcium hydrogen phosphate hydrates, CaHPO 4 .X H 2 O, such as calcium hydrogen phosphate dihydrate, CaHPO 4 .2 H 2 O; calcium dihydrogen pyrophosphate, CaH 2 P 2 O 7 ; magnesium pyrophosphate, Mg 2 P 2 O 7 ; magnesium hydrogen phosphate hydrates, MgHPO 4 .X H 2 O; aluminum phosphate, AlPO 4 ; magnesium hydroxide, Mg(OH) 2 ; aluminum hydroxide, Al(OH) 3 ; ferrous oxide, FeO; manganese oxide, MnO; zinc oxide, ZnO; sodium hydrogen carbonate, NaHCO 3 ; and ferric oxide, Fe 2 O 3 .
The coating composition of this invention is such that in all coating materials, it comprises 0.1 to 20% by weight of lecithin, 0.1 to 10% by weight of the inorganic substance which is stable under neutral conditions and soluble under acidic conditions, preferably 1 to 10% of lecithin and 1 to 10% of the inorganic substance. If the amount of lecithin in the coating materials exceeds 20% by weight, the strength of the coating layer is decreased and the protectiveness in the rumen is reduced. If the amount of lecithin is less than 0.1% by weight, the emulsification action is insufficient, and the dissolving action in the abomasum and its subsequent digestive tract decreases. If the amount of the inorganic substance which is stable at neutrality and soluble under acidic conditions exceeds 10% by weight, the protectiveness in the rumen decreases. If it is below 0.1% by weight, the action of the inorganic substance inside of the abomasum is insufficient.
The ruminant animal feed additive composition of this invention is characterized by the fact that the core containing the biologically active substance is coated with the coating composition.
The amount of the coating materials used to coat core substances is not restricted in any particular manner. It should be as little as possible because the amount of the biologically active substance is large. But it should be the amount in which the coating material can fully protect the biologically active substance in the rumen. Usually, it is coated in an amount of 10 to 300 parts by weight, preferably 15 to 150 parts by weight, per 100 parts by weight of the cores containing the biologically active substance.
There is no particular restriction on the method of coating either. It can be coated by an ordinary method such as a method of fluidized-bed coating, pan coating or melt coating.
The present invention will be illustrated by the following examples and comparative examples without being deemed limitative thereof.
EXAMPLES
The methods below were used in the following examples to evaluate the utility of the ruminant animal feed additive.
Stability in the rumen
About 2 g of the prepared sample was put in a 200 ml Erlenmeyer flask. 100 ml of the Mc Dougall buffer solution corresponding to the rumen juice was put in the container, and shaken for 48 hours at a temperature of 39° C. After shaking, the amount of the biologically active substance dissolved was analyzed, and the stability in the rumen was calculated.
The amount of amino acids dissolved in the biologically active substances in the examples were analyzed by liquid chromatography.
Mc Dougall buffer solution
The following reagents were dissolved in 1000 ml of water.
Sodium hydrogen carbonate: 7.43 g
Disodium phosphate 12-hydrate: 7.00 9
Sodium chloride: 0.34 g
Potassium chloride: 0.43 g
Magnesium chloride hexahydrate: 0.10 g
Calcium chloride: 0.05 g
Dissolving Property in the abomasum
After the stability test, the shaken sample was recovered and washed, and further put into a 200 ml Erlenmeyer flask. 40 ml of a Clark-Lubs buffer solution corresponding to the abomasum juice was added and shaken for 3 hours at 39° C.
After shaking, the amount of the biologically active substance dissolved was analyzed and the dissolving property in the abomasum was calculated.
Clark-Lubs buffer solution
A buffer solution obtained by dissolving the following reagents in 1000 ml of water. Potassium chloride: 3.73 g Hydrochloric acid: 2.1 ml.
Dissolving Property in the small intestines
After the dissolving property inside the abomasum was tested, the shaken sample was recovered, and further put into a 200 ml Erlenmeyer flask. 100 ml buffer solution corresponding to a small intestine juice was added and shaken for 24 hours at 39° C. After shaking, the amount of the biologically active substance dissolved was analyzed, and the dissolving property in the small intestines was calculated.
EXAMPLE 1
A kneader was charged with 325 g of L-lysine hydrochloride, 172.5 g of talc, 2.5 g of sodium carboxymethylcellulose and 135 g of water. They were kneaded and then by using an extruder having a screen with an opening size of 1.5 mm, a cylindrical granule was obtained. The granule obtained was molded by using a spherical granule producing machine (Marumerizer, Fuji Paudal Co., Ltd.) to obtain a granule similar to a spherical shape. The resulting spherical granule was dried by fluidized-bed dryer to obtain a core containing L-lysine hydrochloride.
The coating material prepared, which is 5 parts by weight of lecithin (soybean lecithin, manufactured by WAKO Pure Chemical Industries, Ltd.-food additive-was used) and 5 parts by weight of magnesium carbonate, was dispersed per 90 parts by weight of melted hardened beef tallow. The coating material was used in an amount of 67 parts by weight per 100 parts of the cores (the rate of coating 40%). The fluidized-bed coater (New Marumeizer, Fuji Paudal Co., Ltd.) was used.
The coated particles were subjected to the above evaluation tests and the results were as follows:
The dissolving rate in the rumen was 9%, the dissolving rate in the abomasum was 39%, and the dissolving rate in the small intestines was 40%.
EXAMPLE 2
The preparation was conducted in the same manner as in Example 1 except that in Example 2 calcium carbonate was used instead of magnesium carbonate.
The coated particles were subjected to the above evaluation tests and the results were as follows:
The dissolving rate in the rumen was 4%, the dissolving rate in the abomasum was 46%, and the dissolving rate in the small intestines was 36%.
EXAMPLE 3
The preparation was conducted in the same manner as in Example 2 except that in Example 3, the coating material was used in an amount of 43 parts by weight per 100 parts of the cores (the rate of coating 30%).
The coated particles were subjected to the above evaluation tests and the results were as follows:
The dissolving rate in the rumen was 12%, rate in the abomasum was 20%, and the dissolving rate in the small intestines was 58%.
EXAMPLE 4
The preparation was conducted in the same manner as in Example 2 except that in Example 4, the coating materials contain 10 parts by weight of lecithin and 5 parts by weight of calcium carbonate and was used in an amount of 33 parts by weight (the rate of coating 25%).
The coated particles were subjected to the above evaluation tests and the results were as follows:
The dissolving rate in the rumen was 19%, the dissolving rate in the abomasum was 46%, and the dissolving rate in the small intestines was 32%.
EXAMPLE 5
The preparation was conducted in the same manner as in Example 2 except that in Example 5, the coating materials contain 2 parts by weight of lecithin and 10 parts by weight of calcium carbonate and was used in an amount of 25 parts by weight (the rate of coating 20%).
The coated particles were subjected to the above evaluation tests, and the results were as follows:
The dissolving rate in the rumen was 14%, the dissolving rate in the abomasum was 31%, and the dissolving rate in the small intestines was 35%.
EXAMPLE 6
The preparation was conducted in the same manner as in Example 3 except that in Example 6, calcium pyrophosphate was used instead of calcium carbonate.
The coated particles were subjected to the above evaluation tests and the results were as follows:
The dissolving rate in the rumen was 7%, the dissolving rate in the abomasum was 49%, and the dissolving rate in the small intestines was 32%.
EXAMPLE 7
A kneader was charged with 375 g of D,L-methionine, 120 g of talc, 5 g of sodium carboxymethylcellulose and 150 g of water, and they were kneaded. The mixture was processed by using an extruder having a screen with an opening size of 1.5 m.m to obtain a cylindrical granule. The resulting granule was formed by a spherical shaping apparatus (Marumerizer, Fuji Paudal Co., Ltd.) to make a granule similar to a spherical shape. The spherical granule was dried by fluidized-bed dryer to obtain a core containing D,L-methionine.
The coating material prepared, which is 5 parts by weight of lecithin and 5 parts by weight of magnesium carbonate, was dispersed per 90 parts by weight of melted hardened beef tallow. The coating material was used in an amount of 43 parts by weight per 100 parts by weight of the core (the rate of coating 30%). The fluidized-bed coater (New Marumerizer) was used.
The coated particles were subjected to the above evaluation test and the results were as follows:
The dissolving rate in the rumen was 17%, the dissolving rate in the abomasum was 20%, and the dissolving rate in the small intestines was 60%.
EXAMPLE 8
The preparation was conducted in the same manner as in Example 7 except that in Example 8, calcium carbonate was used instead of magnesium carbonate.
The coated particles were subjected to the above evaluation tests and the results were as follows:
The dissolving rate in the rumen was 15%, the dissolving rate in the abomasum was 26%, and the dissolving rate in the small intestines was 59%.
EXAMPLE 9
The preparation was conducted in the same manner as in Example 8 except that in Example 9, the coating materials contain 10 parts by weight of lecithin and 2 parts by weight of calcium carbonate and was used in an amount of 33 parts by weight (the rate of coating 25%).
The coated particles were subjected to the above evaluation tests and the results were as follows:
The dissolving rate in the rumen was 21%, the dissolving rate in the abomasum was 38%, and the dissolving rate in the small intestines was 37%.
COMPARATIVE EXAMPLE 1
The preparation was conducted in the same manner as in Example 1 except that in this Example, the coating materials contain 10 parts by weight of calcium carbonate.
The coated particles were subjected to the above evaluation tests, and the results were as follows:
The dissolving rate in the rumen was 5%, the dissolving rate in the abomasum was 15%, and the dissolving rate in the small intestines was 16%.
COMPARATIVE EXAMPLE 2
The preparation was conducted in the same manner as in Example 3 except that in this Example, the coating materials contain 30 parts by weight of lecithin.
The coated particles were subjected to the above evaluation tests and the results were as follows:
The dissolving rate in the rumen was 71%, the dissolving rate in the abomasum was 27%, and the dissolving rate in the small intestines was 1%.
COMPARATIVE EXAMPLE 3
The preparation was conducted in the same manner as in Example 8 except that in this Example, the coating materials contain 30 parts by weight of calcium carbonate.
The coated particles were subjected to the above evaluation tests, and the results were as follows:
The dissolving rate in the rumen was 82%, the dissolving rate in the abomasum was 10%, and the dissolving rate in the small intestines was 3%.
The superior properties of feed additives of the present invention disclosed in examples 1 through 14 that are compared to the comparative examples of the prior art are summarized below in Tables 1-3.
TABLE 1__________________________________________________________________________ Example 1 2 3 4 5 6__________________________________________________________________________Biologically active L-lysine L-lysine L-lysine L-lysine L-lysine L-lysinesubstance hydro- hydro- hydro- hydro- hydro- hydro- chloride chloride chloride chloride chloride chlorideCores 100 100 100 100 100 100(parts by weight)Coated layer 67 67 43 33 25 43(parts by weight)Compositionof the coatinglayer (%)Beef tallow 90 90 90 85 88 90Lecithin 5 5 5 10 2 5Magnesium 5 -- -- -- -- --carbonateCalcium -- 5 5 5 10 --carbonateCalcium -- -- -- -- -- 5pyrophosphateDissolvingrate (%)Corresponding 9 4 12 19 14 7to the rumenCorresponding 39 46 20 46 31 49to the abomasumCorresponding 40 36 58 32 35 32to the smallintestines__________________________________________________________________________
TABLE 2__________________________________________________________________________ Example Comparative Example 7 8 9 1 2 3__________________________________________________________________________Biologically active D,L- D,L- D,L- Lysine Lysine D,L-substance Methio- Methio- Methio- hydro- hydro- Methio- nine nine nine chloride chloride nineCores 100 100 100 100 100 100(parts by weight)Coated layer 43 43 33 67 43 43(parts by weight)Compositionof the coatinglayer (%)Beef tallow 90 90 88 90 70 70Lecithin 5 5 10 -- 30 --Magnesium 5 -- -- -- -- --carbonateCalcium -- 5 2 10 -- 30carbonateDissolvingrate (%)Corresponding 17 15 21 5 71 82to the rumenCorresponding 20 26 38 15 27 10to theabomasumCorresponding 60 59 37 16 1 3to the smallintestines__________________________________________________________________________
TABLE 3______________________________________ EXAMPLE 10 11 12 13 14______________________________________Biologically Lysine- Methio- Lysine- Lysine- Lysine-active substance HCl nine HCl HCl HClCores (parts 100 100 100 100 100by weight)Coated layer 33 33 25 33 33(parts by weight)Composition ofthe coatinglayer (%)Beef tallow 90 90 90 90 90Lecithin 5 5 5 5 5CaHPO.sub.4.2H.sub.2 O 5CaH.sub.2 P.sub.2 O.sub.7 5Mg(OH).sub.2 5NaHCO.sub.3 5Fe.sub.2 O.sub.3 5Thickness of 60 15 50 30 40the film (μm)Dissolving rate (%)Corresponding 10 11 22 28 15to the rumenCorresponding 14 11 16 15 18to the abomasumCorresponding 59 60 41 51 46to the smallintestines______________________________________
All publications disclosed herein are incorporated by reference. Obviously, numerous modifications and variations of the present invention are possible in light of the above teachings. It is therefore to be understood that within the scope of the appended claims, the invention may be practiced otherwise than as specifically described herein.
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The present invention relates to a biologically active substance that is stable in the rumen of ruminants and released in the abomasum and its subsequent digestive tract. The biologically active substance has the additional properties of being digested and absorbed with good efficiency.
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BACKGROUND OF THE INVENTION
[0001] 1. Field of the Invention
[0002] The present invention relates to an improved cushioning system for athletic footwear which provides a large deflection for cushioning the initial impact of footstrike, a controlled stiffness response, a smooth transition to bottom-out and stability, and more specifically to a system which allows for customization of these response characteristics by adjustment of the orientation of a single bladder in a resilient foam material.
[0003] 2. Description of Related Art
[0004] Basketball, tennis, running, and aerobics are but a few of the many popular athletic activities which produce a substantial impact on the foot when the foot strikes the ground. To cushion the strike force on the foot, as well as the leg and connecting tendons, the sole of shoes designed for such activities typically include several layers, including a resilient, shock absorbent layer such as a midsole and a ground contacting outer sole or outsole which provides both durability and traction.
[0005] The typical midsole uses one or more materials or components which affect the force of impact in two important ways, i.e., through shock absorption and energy dissipation. Shock absorption involves the attenuation of harmful impact forces to thereby provide enhanced foot protection. Energy dissipation is the dissemination of both impact and useful propulsive forces. Thus, a midsole with high energy dissipation characteristics generally has a relatively low resiliency and, conversely, a midsole with low energy dissipating characteristics generally has a relatively high resiliency. The optimum midsole should be designed with an impact response that takes into consideration both adequate shock absorption and sufficient resiliency.
[0006] One type of sole structure in which attempts have been made to design appropriate impact response are soles, or inserts for soles, that contain a bladder element of either a liquid or gaseous fluid. These bladder elements are either encapsulated in place during the foam midsole formation or dropped into a shallow, straight walled cavity and cemented in place, usually with a separate piece of foam cemented on top. Particularly successful gas filled structures are disclosed in U.S. Pat. Nos. 4,183,156 and 4,219,945 to Marion F. Rudy, the contents of which are hereby incorporated by reference. An inflatable bladder or barrier member is formed of an elastomeric material having a multiplicity of preferably intercommunicating, fluid-containing chambers inflated to a relatively high pressure by a gas having a low diffusion rate through the bladder. The gas is supplemented by ambient air diffusing through the bladder to thereby increase the pressure therein and obtain a pressure that remains at or above its initial value over a period of years. (U.S. Pat. Nos. 4,340,626, 4,936,029 and 5,042,176 to Marion F. Rudy describe various diffusion mechanisms and are also hereby incorporated by reference.)
[0007] The pressurized, inflatable bladder insert is incorporated into the insole structure, in the '156 patent, by placement within a cavity below the upper, e.g., on top of a midsole layer and within sides of the upper or midsole. In the '945 patent, the inflatable bladder insert is encapsulated within a yieldable foam material, which functions as a bridging moderator filling in the irregularities of the bladder, providing a substantially smooth and contoured surface for supporting the foot and forming an easily handled structure for attachment to an upper. The presence of the moderating foam, however, detracts from the cushioning and perception benefits of the gas inflated bladder. Thus, when the inflated bladder is encapsulated in a foam midsole, the impact response characteristics of the bladder are hampered by the effect of the foam structure. Referring to FIG. 5 of the '945 patent for example, the cross-section of the midsole shows a series of tubes linked together to form the gas filled bladder. When the bladder is pressurized its tendency is to be generally round in cross-section. The spaces between those bladder portions are filled with foam. Because the foam-filled spaces include such sharp corners, the foam density in the midsole is uneven, i.e., the foam is of higher density in the corners and smaller spaces, and lower density along rounded or flatter areas of the bladder. Since foam has a stiffer response to compression, in the tighter areas with foam concentrations, the foam will dominate the cushioning response upon loading. So instead of a high deflection response, the response can be stiff due to the foam reaction. The cushioning effects of the bladder thus may be reduced due to the uneven concentrations of foam. In addition, the manufacturing techniques used to produce the sole structure formed by the combination of the foam midsole and inflated bladder must also be accommodating to both elements. For example, when encapsulating the inflatable bladder, only foams with relatively low processing temperatures can be used due to the susceptibility of the bladder to deform at high temperatures. The inflated bladder must also be designed with a thickness less than that of the midsole layer in order to allow for the presence of the foam encapsulating material completely therearound. Thus, there are manufacturing as well as performance constraints imposed in the foam encapsulation of an inflatable bladder.
[0008] A cushioning shoe sole component that includes a structure for adjusting the impact response of the component is disclosed in U.S. Pat. Nos. 4,817,304 to Mark G. Parker et al. The sole component of Parker et al. is a viscoelastic unit formed of a gas containing bladder and an elastomeric yieldable outer member encapsulating the bladder. The impact resistance of the viscoelastic unit is adjusted by forming a gap in the outer member at a predetermined area where it is desired to have the bladder predominate the impact response. The use of the gap provides an adjustment of the impact response, but the adjustment is localized to the area of the gap. The '304 patent does not disclose a way of tuning the impact response to optimize the response over the time of footstrike through the appropriate structuring of both the bladder and encapsulating material.
[0009] A cushioning system for a shoe sole which uses a bladder connected only along its perimeter and supported in an opening in resilient foam material, is disclosed in U.S. Pat. No. 5,685,090 to Tawney et al., which is hereby incorporated by reference. The bladder of Tawney et al. has generally curved upper and lower major surfaces and a sidewall that extends outward from each major surface. The angled sidewalls form a horizontally orientated V-shape in cross-section, which fits into a correspondingly shaped groove in the opening in the surrounding resilient foam material. Portions of the top and bottom of the bladder are not covered with the foam material. By forming the bladder without internal connections between the top and bottom surfaces, and exposing portions of the top and bottom surfaces, the feel of the bladder is maximized. However, the '090 patent does not disclose a way of tuning the impact response through design of both the bladder and foam material.
[0010] One type of prior art construction concerns air bladders employing an open-celled foam core as disclosed in U.S. Pat. Nos. 4,874,640 and 5,235,715 to Donzis. These cushioning elements do provide latitude in their design in that the open-celled foam cores allow for a variety of shapes of the bladder. However, bladders with foam core tensile members have the disadvantage of unreliable bonding of the core to the barrier layers. One of the main disadvantages of this construction is that the foam core defines the shape of the bladder and thus must necessarily function as a cushioning member at footstrike which detracts from the superior cushioning properties of air alone. The reason for this is that in order to withstand the high inflation pressures associated with such air bladders, the foam core must be of a high strength which requires the use of a higher density foam. The higher the density of the foam, the less the amount of available air space in the air bladder. Consequently, the reduction in the amount of air in the bladder decreases the benefits of cushioning. Cushioning generally is improved when the cushioning component, for a given impact, spreads the impact force over a longer period of time, resulting in a smaller impact force being transmitted to the wearer's body.
[0011] Even if a lower density foam is used, a significant amount of available air space is sacrificed which means that the deflection height of the bladder is reduced due to the presence of the foam, thus accelerating the effect of “bottoming-out.” Bottoming-out refers to the failure of a cushioning device to adequately decelerate an impact load. Most cushioning devices used in footwear are non-linear compression based systems, increasing in stiffness as they are loaded. Bottom-out is the point where the cushioning system is unable to compress any further. Compression-set refers to the permanent compression of foam after repeated loads which greatly diminishes its cushioning properties. In foam core bladders, compression set occurs due to the internal breakdown of cell walls under heavy cyclic compression loads such as walking or running. The walls of individual cells constituting the foam structure abrade and tear as they move against one another and fail. The breakdown of the foam exposes the wearer to greater shock forces, and in the extreme, to formation of an aneurysm or bump in the bladder under the foot of the wearer, which will cause pain to the wearer.
[0012] Another type of composite construction prior art concerns air bladders which employ three dimensional fabric as tensile members such as those disclosed in U.S. Pat. Nos. 4,906,502, 5,083,361 and 5,543,194 to Rudy; and U.S. Pat. Nos. 5,993,585 and 6,119,371 to Goodwin et al., which are hereby incorporated by reference. The bladders described in the Rudy patents have enjoyed commercial success in NIKE, Inc. brand footwear under the name Tensile-Air®. Bladders using fabric tensile members virtually eliminate deep peaks and valleys. In addition, the individual tensile fibers are small and deflect easily under load so that the fabric does not interfere with the cushioning properties of air.
[0013] One shortcoming of these bladders is that currently there is no known manufacturing method for making complex-curved, contoured shaped bladders using these fabric fiber tensile members. The bladders may have different levels, but the top and bottom surfaces remain flat with no contours and curves.
[0014] Another disadvantage is the possibility of bottoming-out. Although the fabric fibers easily deflect under load and are individually quite small, the sheer number of them necessary to maintain the shape of the bladder means that under high loads, a significant amount of the total deflection capability of the air bladder is reduced by the volume of fibers inside the bladder and the bladder can bottom-out.
[0015] One of the primary problems experienced with the fabric fibers is that these bladders are initially stiffer during initial loading than conventional air bladders. This results in a firmer feel at low impact loads and a stiffer “point of purchase” feel that belies their actual cushioning ability. The reason for this is because the fabric fibers have a relatively low elongation to properly hold the shape of the bladder in tension, so that the cumulative effect of thousands of these relatively inelastic fibers is a stiff feel.
[0016] The tension of the outer surface caused by the low elongation or inelastic properties of the tensile member results in initial greater stiffness in the air bladder until the tension in the fibers is broken and the effect of the air in the bladder can come into play.
[0017] Another category of prior art concerns air bladders which are injection molded, blow-molded or vacuum-molded such as those disclosed in U.S. Pat. No. 4,670,995 to Huang; U.S. Pat. No. 4,845,861 to Moumdjian; U.S. Pat. Nos. 6,098,313, 5,572,804, and 5,976,541 to Skaja et al.; and U.S. Pat. No. 6,029,962 to Shorten et al. These manufacturing techniques can produce bladders of any desired contour and shape including complex shapes. A drawback of these air bladders can be the formation of stiff, vertically aligned columns of elastomeric material which form interior columns and interfere with the cushioning benefits of the air. Since these interior columns are formed or molded in the vertical position and within the outline of the bladder, there is significant resistance to compression upon loading which can severely impede the cushioning properties of the air.
[0018] Huang '995 teaches forming strong vertical columns so that they form a substantially rectilinear cavity in cross section. This is intended to give substantial vertical support to the air cushion so that the vertical columns of the air cushion can substantially support the weight of the wearer with no inflation (see '995, Column 5, lines 4-11). Huang '995 also teaches the formation of circular columns using blow-molding. In this prior art method, two symmetrical rod-like protrusions of the same width, shape and length extend from the two opposite mold halves to meet in the middle and thus form a thin web in the center of a circular column (see Column 4, lines 47-52, and depressions 21 in FIGS. 1 - 4 , 10 and 17 ). These columns are formed of a wall thickness and dimension sufficient to substantially support the weight of a wearer in the uninflated condition. Further, no means are provided to cause the columns to flex in a predetermined fashion, which would reduce fatigue failures. Huang's columns 42 can be prone to fatigue failure due to compression loads, which force the columns to buckle and fold unpredictably. Under cyclic compression loads, the buckling can lead to fatigue failure of the columns.
[0019] Prior art cushioning systems which incorporate an air bag or bladder can be classified into two broad categories: cushioning systems which focused on the design of the bladder and its response characteristics; and cushioning systems which focused on the design of the supporting mechanical structure in and around the bladder.
[0020] The systems that focused on the air bladder itself dealt with the cushioning properties afforded by the pneumatics of the sealed, pressurized bladder. The pneumatic response is a desirable one because of the large deflections upon loading which corresponds to a softer, more cushioned feel, and a smooth transition to the bottom-out point. Potential drawbacks of a largely pneumatic system may include poor control of stiffness through compression and instability. Control of stiffness refers to the fact that a solely pneumatic system will exhibit the same stiffness function upon loading. There is no way to control the stiffness response. Instability refers to potential uneven loading and potential shear stresses due to the lack of structural constraints on the bladder upon loading.
[0021] Pneumatic systems also focused on the configuration of chambers within the bladder and the interconnection of the chambers to effect a desired response. Some bladders have become fairly complex and specialized for certain activities and placements in the midsole. The amount of variation in bladder configurations and their placement have required stocking of dozens of different bladders in the manufacturing process.
[0022] Having to manufacture different bladders for different models of shoes adds to cost both in terms of manufacture and waste.
[0023] Certain prior pneumatic systems generally used air or gas in the bladder at pressures substantially above ambient. To achieve and maintain pressurization, it has been necessary to employ specially designed, high-cost barrier materials to form the bladders, and to select the appropriate gas depending on the barrier material to minimize the migration of gas through the barrier. This has required the use of specialty films and gases such as nitrogen or sulfur hexafluoride at high pressures within the bladders. Part and parcel of high pressure bladders filled with gases other than air or nitrogen is added requirement to protect the bladders in the design of the midsole to prevent rupture or puncture.
[0024] The prior art systems which focused on the mechanical structure by devising various foam shapes, columns, springs, etc., dealt with adjusting the properties of the foam's response to loading. Foam provides a cushioning response to loading in which the stiffness function can be controlled throughout and is very stable. However, foam, even with special construction techniques, does not provide the large deflection upon loading that pneumatic systems can deliver.
SUMMARY OF THE INVENTION
[0025] The present invention pertains to a sole component for footwear incorporating a sealed, fluid containing chamber and resilient material to harness the benefits of both a pneumatic system and a mechanical system, i.e., provide a large deflection at high impact, controlled stiffness response, a smooth transition to maximum deflection and stability. The sole component of the present invention is specifically designed to optimally combine pneumatic and mechanical structures and properties. The sealed, fluid containing chamber can be made by sealing an appropriately shaped void in the resilient material, or forming a bladder of resilient barrier material.
[0026] Recognizing that resilient material, such as a foamed elastomer, and air systems each posses advantageous properties, the present invention focuses the design of cushioning systems combining the desirable properties of both types, while reducing the effect of their undesirable properties.
[0027] Foamed elastomers as a sole cushioning material possesses a very desirable material property: progressively increasing stiffness. When foamed elastomers are compressed the compression is smooth as its resistance to compression is linear or progressive. That is, as the compression load increases, foamed elastomers become or feel increasingly stiff. The high stiffness allows the foamed elastomers to provide a significant contribution to a cushioning system. The undesirable properties of foamed elastomers include limitations on deflection by foam density, quick compression set, and limited design options.
[0028] Gas filled chambers or bladders also possess very desirable properties such as high deflection at impact and a smooth transition to bottom-out. The soft feel of a gas filled bladder upon loading is the effect of high deflection, which demonstrates the high energy capacity of a pneumatic unit. Some difficulties of designing gas filled bladder systems include instability and the need to control the geometry of the bladder. Pressurized bladders by their very nature tend to take on a shape as close to a ball, or another round cross-section, as possible. Constraining this tendency can require complex manufacturing methods and added elements to the sole unit.
[0029] In the past these two types of structures were used together but were not specifically designed to work together to exhibit the best properties of each system while eliminating or minimizing the drawbacks.
[0030] This is now possible due to the specially designed single chamber, pear-shaped, or taper-shaped bladder that can be used in a variety of locations and configurations in a midsole. The tapered shape has at least one planar major surface and a contoured surface, which is contoured from side to side and front to back. This contoured surface, when used with a resilient material, such as a foamed elastomer, provides a smooth stiffness transition from the resilient material to the bladder and vice-versa. The single chamber tapered bladder can be used in a variety of locations and configurations in a midsole to provide desired response characteristics. Only one bladder shape is required to be stocked which will significantly reduce manufacturing costs.
[0031] The present invention provides the best of pneumatic and mechanical cushioning properties without high pressurization of the air bladder. The air bladder used in the present invention is simply sealed with air at ambient pressure or at a slightly elevated pressure, within 5 psi (gauge) of ambient, and does not require nitrogen or specialized gases. Since the bladder is pressurized to a very low pressure if at all, the air bladder of the present invention also does not require a special barrier material. Any available barrier material can be used to make the bladder, including recycled materials which presents another substantial cost advantage over conventional pressurized bladders. Against the prevailing norm of pressurization, the cushioning system of the present invention is engineered to provide sufficient cushioning with an air bladder sealed at ambient pressure.
[0032] The single chamber air bladder of the present invention can be formed by blow-molding or vacuum forming with the bladder sealed from ambient air at ambient pressure or at slightly elevated pressure. Because high pressurization is not required, the additional manufacturing steps of pressurizing and sealing a pressurized chamber are not required. Minimizing complexity in this way will also be less expensive resulting in a very cost-effective system that provides all of the benefits of more expensive specially designed pneumatic systems.
[0033] When a cushioning system is loaded, the desired response is one of large deflection at initial load or strike to absorb the shock of the greatest force, and a progressively increasing stiffness response to provide stability through the load. The overall stiffness is controlled primarily by the density or hardness of the resilient material—the foam density or hardness when a foamed elastomer is used. Because of the smoothly contoured transition areas of the foam material and air bladder interface, foam densities are even and high concentrations are eliminated. The gentle slopes and contours of the tapered air bladder provide gradual transitions between the foam material and air bladder responses. Thus, because of the shape of the air bladder, the response to a load can be controlled by its placement. Placing the tapered, for example, pear-shaped air bladder at ambient or very low pressure under the area of greatest force of the wearer's foot affords greater deflection capacity than current systems, which employ high pressurization. This is due to the relatively large volume of the tapered air bladder, in combination with the lack of internal connections or structure within the interior area of the bladder, allowing for a relatively large deflection upon load. For example, when the pear shape is used, the larger, more bulbous end of the pear shaped bladder will deflect more than the narrower end. With this parameter in mind, rotation and movement of the air bladder can provide very different cushioning characteristics, which can mimic the effect of more complex and expensive foam structures within a midsole. In this way the air bladder and foam material work in concert to provide the desired response.
[0034] These and other features and advantages of the invention may be more completely understood from the following detailed description of the preferred embodiments of the invention with reference to the accompanying drawings.
BRIEF DESCRIPTION OF THE DRAWINGS
[0035] [0035]FIG. 1 is an exploded perspective view of a footwear sole in accordance with the present invention showing air bladders placed in the heel and metatarsal head areas.
[0036] [0036]FIG. 2A is a top plan view of the sole of FIG. 1 shown with the air bladders positioned in the foam midsole material.
[0037] [0037]FIG. 2B is a top plan view of an alternative embodiment of the footwear sole of FIG. 1 in which an air bladder is rotated in its orientation to provide a specific response.
[0038] [0038]FIG. 3A is a cross-section taken along line 3 A- 3 A of FIG. 2A.
[0039] [0039]FIG. 3B is a cross-section taken along line 3 B- 3 B of FIG. 2B.
[0040] [0040]FIG. 4 is a cross-section taken along line 4 - 4 of FIG. 2A.
[0041] [0041]FIG. 5 is a side elevational view of the heel air bladder shown in the top-load configuration.
[0042] [0042]FIG. 6 is an end elevation view of the air bladder of FIG. 5.
[0043] [0043]FIG. 7 is a bottom plan view of the air bladder of FIG. 5.
[0044] [0044]FIG. 8A is a cross-section taken along line 8 - 8 of FIG. 7.
[0045] [0045]FIG. 8B is a cross-section similar to that of FIG. 8A and shown with a representation of midsole foam material to illustrate the smooth transition of stiffness during footstrike.
[0046] [0046]FIG. 9A is a cross-section taken along line 9 - 9 of FIG. 7.
[0047] [0047]FIG. 9B is a cross-section similar to that of FIG. 9A and shown with a representation of midsole foam material to illustrate the smooth transition of stiffness during footstrike.
[0048] [0048]FIG. 10 is a side elevational view of the calcaneus air bladder shown in the top-load configuration.
[0049] [0049]FIG. 11 is an end elevation view of the air bladder of FIG. 10.
[0050] [0050]FIG. 12 is a bottom plan view of the air bladder of FIG. 10.
[0051] [0051]FIG. 13 is a cross-section taken along line 13 - 13 of FIG. 12.
[0052] [0052]FIG. 14 is a cross-section taken along line 14 - 14 of FIG. 12.
[0053] [0053]FIG. 15 is an exploded assembly view of the cushioning system shown in FIG. 1 with other elements of a shoe assembly.
[0054] [0054]FIG. 16A is an exploded perspective view of another embodiment of a heel chamber in accordance with the present invention.
[0055] [0055]FIG. 16B is a cross-section taking along line 16 B- 16 B of FIG. 16A, with the heel chamber sealed.
[0056] [0056]FIG. 16C is a cross-section taken along line 16 C- 16 C of FIG. 16A, with the heel chamber sealed.
[0057] [0057]FIG. 17A is a diagrammatic cross-section of a sealed chamber illustrating film tensioning and internal pressure when no force is applied to the sealed chamber.
[0058] [0058]FIG. 17B is a diagrammatic cross-section of a sealed chamber illustrating film tensioning and internal pressure when light force is applied to the sealed chamber.
[0059] [0059]FIG. 17C is a diagrammatic cross-section of a sealed chamber illustrating film tensioning and internal pressure when increasing force is applied to the sealed chamber.
[0060] [0060]FIG. 17D is a diagrammatic cross-section of a sealed chamber illustrating film tensioning and internal pressure when high force is applied to the sealed chamber.
DETAILED DESCRIPTION OF THE INVENTION
[0061] Sole 10 of the present invention includes a midsole 12 of an elastomer material, preferably a resilient foam material and one or more air bladders 14 , 16 disposed in the midsole. FIGS. 1 - 4 illustrate a cushioning system with a bladder 14 disposed in the heel region and a bladder 16 disposed in the metatarsal head region, the areas of highest load during footstrike. The bladders are used to form sealed chambers of a specific shape. In an alternate embodiment a sealed chamber can be formed from a void in an elastomeric chamber that is sealed with a separate cover material. The shape of the chambers and their arrangement in the elastomeric material, particularly in the heel region, produces the desired cushioning characteristics of large deflection for shock absorption at initial footstrike, then progressively increasing stiffness through the footstrike.
[0062] The preferred shape of the bladder is a contoured taper shaped outline, preferably pear-shaped, as best seen in FIGS. 5 - 14 . This shape was determined by evaluating pressures exerted by the bottom of a wearer's foot. The shape of the air bladder matches the pressure map of the foot, wherein the higher the pressure, the higher the air-to-foam depth ratio. The shape of the outline is defined by the two substantially planar major surfaces in opposition to one another and in generally parallel relation: a first major surface 18 and a second major surface 20 . These surfaces each have a perimeter border 22 , 24 respectively which define the shape of the bladder so that bladder 14 has a larger rounded end 27 and tapers to a more pointed narrow end 29 . Narrow end 29 has a width substantially less than the maximum width of larger rounded end 27 so that major surfaces 18 and 20 take on a generally pear-shaped outline. Second major surface 20 has substantially the same outline as first major surface 18 but is smaller in surface area by approximately 50%. At the rounded end 27 of the bladder, first major surface 18 and second major surface 20 are only slightly offset as seen in FIGS. 7 - 8 . At narrow end 29 of the bladder, the point of second major surface 20 is further apart from the corresponding point of first major surface 18 than at the rounded end. First major surface 18 and second major surface 20 are symmetric about a longitudinal center line 31 of the bladder. These major surfaces are connected together by a contoured sidewall 26 , which extends around the entire bladder. Sidewall 26 is preferably integral with first major surface 18 and second major surface 20 , and if the bladder is formed of flat sheets, i.e., vacuum molded, a substantial portion of sidewall 26 is formed from the same sheet making up second major surface 20 . Even in a blow-molded bladder, the seam is located such that the sidewall appears to be formed on the same side of the seam as the second major surface.
[0063] As best seen in FIGS. 7, 8A and 9 A, the longitudinal spacing between the rounded end of second major surface 20 and the rounded end of first major surface 18 is less than the longitudinal spacing between the pointed end of second major surface 20 and the pointed end of first major surface 18 . This distance is covered in a contoured manner by sidewall 26 as best seen in FIGS. 5 - 9 A so as to provide a long, smoothly sloped contour at the pointed end of the bladder and a shorter, smoothly sloped contour at the rounded end. This results in a bladder that has a substantially flat side where major surface 18 is disposed, and a substantially convex side where major surface 20 is disposed. Bladder 14 has one axis of symmetry, i.e., the longitudinal axis, and is asymmetrical in all other aspects. This seemingly simple, articulated shape of the air bladder provides a multitude of possible variations depending on the desired cushioning response to load. Also as seen in the Figures, the major surfaces are connected to one another only by the sidewalls. The major surfaces are devoid of any internal connections.
[0064] As seen in FIGS. 1 , 2 A-B and 3 A-B, the orientation of the bladder in the foam material can be varied to attain differing cushioning properties. Air bladder 14 can be oriented in the resilient foam material with its longitudinal axis generally aligned with the longitudinal axis of the midsole as shown in FIG. 2A, which will provide overall cushioning and lateral support for a wide range of wearers. Alternatively, air bladder 14 can be oriented with its longitudinal axis rotated with respect to the longitudinal axis, toward the lateral side, of the midsole as shown in FIG. 2B. With the bladder rotated in this manner, more foam material is present in the medial side of the midsole thereby creating a simulated medial post since the foam material will dominate the response to a load in the medial portion and thereby feel stiffer than the response in the lateral side which will be dominated by the air bladder's deflection. More support is provided on the medial side to stabilize the medial side of the sole and inhibit over-pronation during footstrike. By adjusting the orientation of the air bladder in this manner, the response characteristics of the cushioning system can be customized. The orientations shown in FIGS. 2A and 2B are intended to be exemplary, and other orientations are contemplated to be within the scope of the invention.
[0065] Another possible adjustment to the air bladder's orientation is the determination of which side of the air bladder faces upward. When bladder 14 is positioned in resilient foam material 12 in the orientation shown in FIGS. 1 and 3A, the convex side of the bladder is cradled in the foam, and the flat side faces upward and is not covered with foam, thereby providing more cushioning, i.e. greater deflection of the bladder, and a smooth transition from the feel of the bladder to the stiffer feel of the foam upon loading. The orientation of FIG. 3A in which the mostly planar surface of the bladder is loaded, is referred to herein as the top loaded condition.
[0066] It is possible to turn bladder 14 over and orient it in the foam so that the substantially flat side, containing major surface 18 , faces downward and the convex side, containing major surface 20 , faces upward, FIG. 3B, so that a foam material arch above the bladder takes the load. This orientation is referred to herein as the bottom loaded condition in which a layer of foam material is disposed over the convex side of the bladder. The bottom loaded condition provides a stiffer response than the top loaded condition since more foam material is present between the heel and the bladder to moderate the feel of the bladder's deflection. Additionally, a structural arch is formed. This results in a stronger support for the heel region during footstrike.
[0067] Similarly, air bladder 16 which is illustrated to be in the metatarsal head region of the midsole affords different cushioning properties depending on its orientation. Air bladder 16 also has a first major surface 28 , which is generally planar, and a second major surface 30 , which is also generally planar and is smaller in surface area than first surface 28 . The second surface has a surface area approximately 25% to 40% of the surface area of the first surface. These surfaces are generally parallel to one another and are defined by first perimeter border 32 and second perimeter border 34 which are connected by a sidewall 36 , similar to sidewall 26 of air bladder 14 . Because of the relatively small size of second surface 30 , sidewall 36 has a relatively flat slope, in other words, when placed in resilient foam material the transition from air bladder to foam response is very gradual with air bladder 16 .
[0068] Air bladder 16 is shown placed in the resilient foam midsole in a top loaded configuration, but as with air bladder 14 , it could be turned over to provide a different response to load. The orientation of air bladder 16 with its longitudinal axis aligned with the direction of the metatarsal heads of a wearer as shown in FIG. 2A will provide the desired cushioning response for a wide variety of wearers. However, the orientation can be rotated as explained above to achieve customized responses.
[0069] The line FS in FIG. 2A, which will be referred to as footstrike line FS, illustrates the line of maximum pressure applied by the foot of a wearer to a shoe sole during running by a person whose running style begins with footstrike in the lateral heel area (rear foot strikers). The line FS is a straight line generalization of the direction that the line of maximum pressure follows for rearfoot strikers. The actual line of pressure for a given footstrike would not be precisely along straight line FS, but would generally follow line FS. As seen in this Figure, footstrike line FS starts in the lateral heel area, proceeds diagonally forward and towards the medial side as it proceeds through the heel area (pronation), turns in a more forward direction through the forward heel and arch areas, and finally proceeds through the metatarsal, metatarsal head and toe areas, with the foot leaving the ground (toe off) adjacent the area of the second metatarsal head.
[0070] [0070]FIGS. 8B and 9B illustrate how the midsole foam material and the shape of bladder 14 accomplishes smooth transition of stiffness as the foot of the wearer proceeds through footstrike in the heel area towards the forefoot. At initial footstrike, the foot contacts the rear lateral heel area where the midsole is formed entirely of foam material (F 1 ) to provide a firm, stable, yet shock-absorbing effect. As footstrike proceeds medially and forwardly, the amount of foam material (F 2 ) underlying the foot gradually decreases and the thickness of bladder 14 gradually increases because of the smooth, sloped contour of sidewall 26 in the medial side area (BSM). In this area, the effect of the more compliant bladder 14 gradually takes greater effect for shock absorbing and gradually decreasing the stiffness of the midsole, until an area of maximum bladder thickness and minimum foam thickness (F 3 ) is reached. The maximum bladder thickness occurs in the side-to-side center area (BC) of bladder 14 , which underlies the calcaneous of the foot. In this manner, maximum deflection of bladder 14 , minimum stiffness and maximum shock attenuation is provided under the calcaneous.
[0071] As footstrike proceeds medially past center area BC, sidewall 26 has a smooth contour that decreases the thickness of bladder 14 in the lateral side area (BSL) of the bladder so that the thickness of the foam (F 4 ) gradually increases to again provide a smooth transition from the more compliant effect of bladder 14 to the more stiff, supportive effect of the foam material. When footstrike reaches the medial side of the front heel area, the full thickness of foam F 5 is reached to provide the maximum supportive effect of the foam material. As seen by comparing FIG. 2A to FIG. 2B, the supportive effect of the foam material in the medial heel front area can be maximized by angling the front bladder 14 toward the lateral side as shown in FIG. 2B. Such angling places more foam material, as compared to bladder 14 in FIG. 2A, in the medial front heel area. This orientation is preferred for a shoe designed to restrict over-pronation during running.
[0072] A smooth transition from the effect of the bladder to the effect of the foam material also occurs as footstrike proceeds forward from the rear heel area toward the forefoot area. This transition is accomplished in a similar manner to the transition from the medial to lateral direction by smoothly sloping the forward sidewall of bladder 14 in the forward bladder area BF, and by reducing the overall width of bladder 14 as it extends from its larger rounded end 27 to its more pointed narrow end 29 . In this manner, the thickness of bladder 14 gradually decreases and the thickness of the foam material F 6 gradually increases until the full thickness of the foam material is reached in front of bladder 14 .
[0073] An alternative method of making the cushioning component is to mold the resilient material, such as a foam elastomer, with a void in the shape of the taper shaped bladder and sealing off the void to form a sealed chamber. Any conventional molding technique can be used, such as injection molding, pour molding, or compression molding. Any moldable thermoplastic elastomer can be used, such as ethylene vinyl acetate (EVA) or polyurethane (PU). This alternative method, as well as an alternative configuration for the sealed chamber within the foam material is illustrated in FIGS. 16A, 16B, and 16 C. When a foam elastomer is molded with an insert to provide the void, the foam surrounding the insert will flow and form a skin during the molding process. At the conclusion of the molding process the insert is removed, and the opening which allowed removal of the insert is sealed, such as by the attachment of the outsole, a lasting board, or another piece of resilient material, such as a sheet of thermoplastic urethane 19 , as illustrated in FIGS. 16 A-C. The skin formed from the molding process acts like air bladder material and seals the air in the void, without the need for a separate air bladder. If a closed cell foam material is used, skin formation would not be required. The sealed chamber provides a comparable cushioning effect as having an ambient air filled air bladder surrounded by the foam. This manufacturing method is economical as no air bladder materials are required. Also, the step of forming the separate air bladder is eliminated.
[0074] As seen in FIGS. 16A to 16 C, an alternate sealed chamber 14 ′ is configured for use in the heel area of sole 10 ′. As with bladder 14 , sealed chamber 14 ′ has a contoured tapered shape, and is orientated in the heel area to match with the pressure map of the foot, wherein the higher the pressure, the higher the air to foam depth ratio. Sealed chamber 14 ′ has two substantially planar major surfaces in opposition to one another and in a generally parallel relation: a first major surface 18 ′ and a second major surface 20 ′. These surfaces each have a perimeter border 22 ′, 24 ′, respectively, which define the shape of the bladder so that bladder 14 has a first rounded end 27 ′ and tapers slightly to a flat end 29 ′. A contoured sidewall 26 ′ connects the major surfaces between their respective perimeters 22 ′ and 24 ′.
[0075] Sealed chamber 14 ′ accomplishes smooth stiffness transition from the lateral to medial direction, and from the rear to forward direction in a manner similar to bladder 14 . Comparing FIGS. 9B and 16C, it is seen that a slope contour from bottom surface 24 ′ and along sidewalls 26 ′ is similar on both the medial and lateral sides of sealed chamber 14 ′ as with bladder 14 . Thus, proceeding from heel strike in the lateral rear area and moving towards the medial rear area, the smooth transition of stiffness described above is accomplished. Since the perimeter borders 22 ′ and 24 ′ do not taper inwardly as much as the perimeter borders of bladder 14 , smooth stiffness transition proceeding from the rear of sealed chamber 14 ′ forward is accomplished by varying the slope from bottom surface 20 ′ forward along sidewall 26 ′ in a manner different from bladder 14 . As seen in FIG. 16B, the bottom of sealed chamber 14 ′ tapers upwardly at a greater rate in the forward direction, from bottom surface 20 ′ through sidewall 26 ′ than the upward taper of the bottom in bladder 14 , as seen in FIG. 8B. The more rapid upward taper compensates for the lack of narrowing of sealed chamber 14 ′, so as to increase the amount of foam material underlying the bladder as foot strike moves in the forward direction in a proper gradual rate.
[0076] Stiffness can be controlled by adjusting the orientation of the air bladders. For instance, placing the air bladders directly under the calcaneus in the top loaded orientation results in less initial stiffness during footstrike and more later stiffness than when the bladder is placed under the calcaneus in the bottom loaded orientation with foam between the calcaneus and the bladder. Overall stiffness response is controlled primarily by material density or hardness. For the top loaded configuration, increasing foam density or hardness increases the latter stiffness. For the bottom load condition, increasing foam density or hardness increases the middle and latter stiffness. The stiffness slope is also determined by volume, with large air bladders having lower stiffness and therefore more displacement upon loading. This is due to the larger air volume in a single chamber allowing a gradual pressure increase as the bladder volume decreases during compression. Overall stiffness can also be adjusted by varying the size of the larger first major surface 18 , 18 ′. As will be discussed later, as pressure is applied to the bladder or sealed chamber, the exposed major surface 18 , 18 ′ undergoes tensioning. If the area of the major surface 18 , 18 ′ is increased, the amount of tension the surface undergoes decreases so that stiffness also decreases.
[0077] A preferred foam material to use is a conventional PU foam with a specific gravity or density in the range of 0.32 to 0.40 grams/cm 3 , preferably 0.36 grams/cm 3 . Another preferred foam material is conventional EVA with a hardness in the range of 52 to 60 Asker C, preferably 55 Asker C. Alternatively, a solid elastomer, such as urethane or the like, could be used if the solid elastomer is compliant or shaped to be compliant. Another material property relevant to the sole construction is the tensile stress at a given elongation of the elastomeric material (modulus). A preferred range of tensile stress at 50% elongation is between 250 and 1350 psi.
[0078] When bladder 14 , or sealed chamber 14 ′, is incorporated in the heel area of a midsole an appropriate amount of shock attenuation is provided when the open internal volume of the chamber is between about 10 cubic centimeters and 65 cubic centimeters. For such bladders, the substantially flat major surfaces 18 , 18 ′ could be in the range of about 1,200 mm 2 to 4,165 mm 2 . For example, when a bladder with a volume of 36 cubic centimeters is used, the pressure ranges from ambient 0 psi to 35 psi when bladder 14 is compressed to 95% of its original volume.
[0079] Another advantage of the sole structure of the present invention is the manner in which bladder 14 accomplishes smooth, progressive stiffening by the combination of film tensioning and pressure ramping. Enhanced shock attenuation is also accomplished by minimizing the structure under the areas of greatest pressure to allow for greater maximum deflection while the bag is progressively stiffening. FIGS. 17A through 17 D illustrate the film tensioning and pressure ramping in the chamber devoid of internal connections.
[0080] [0080]FIG. 17A diagrammatically illustrates bladder or sealed chamber 14 within an elastomeric material 13 . Bladder 14 has a flat primary surface 18 and a secondary major surface 20 with its tapered sides. In FIG. 17A, no pressure is applied to the bladder and the tension To along primary surface 18 is zero. The pressure inside the bladder likewise is ambient and for ease of reference will be indicated as P 0 being zero.
[0081] [0081]FIG. 17B diagrammatically illustrates a small amount of force being applied to bladder 16 . For example, a person standing at rest and an external force F 1 representing the external force applied by a calcaneous of the heel to bladder 14 . As seen in this FIG. 17B, force F 1 causes primary surface 18 to bend downward a certain degree, reducing the volume within bladder 14 , and thereby increasing the pressure to a pressure P 1 . The bowing of primary surface 18 also causes tension in primary surface 18 to increase to T 1 . While not illustrated in these diagrams, material 13 also compresses when forces F-F 3 are applied. The combination of increasing pressure within bladder 16 and the compression of the foam material 13 by the downward force helps to stabilize the foam material walls.
[0082] [0082]FIG. 17C diagrammatically illustrates increasing calcaneal force F 2 being applied to bladder 16 , for example during walking. As seen therein, the volume of bladder 16 has been reduced further, thereby increasing the pressure within the bladder to P 2 and the tension along primary surface 18 to T 2 .
[0083] [0083]FIG. 17D illustrates maximum calcaneal force F 3 being applied to bladder 16 , for example during running. As seen therein, the volume of bladder 16 has been reduced substantially, thereby substantially increasing the pressure within the bladder to P 3 and the tension along primary surface 18 to T 3 . Since the interior area of the bladder is devoid of internal connection filled with foam, the bladder can compress a significant degree, as seen in FIG. 17D, thereby enhancing the ability of the bladder to absorb shock. While undergoing this deflection, the pressure is ramping up, such as from PO (ambient) to P 3 (greater than 30 psi). The increase in pressure in the bladder, together with the increasing stiffness of the foam material along the sides of the bladder, help stabilize the footbed. The desired objective of maximum deflection for shock absorption, in combination with medial to lateral stability is thus attained with the combination of the appropriately shaped bladder at ambient pressure within an elastomeric material.
[0084] Both air bladders 14 and 16 , and sealed chamber 14 ′ contain ambient air and are configured to be sealed at ambient pressure or slightly elevated pressure, within 5 psi (gauge) of ambient pressure. The low or no pressurization provides sufficient cushioning for even repeated, cyclic loads. Because high pressurization is not required, air bladders 14 and 16 are not material dependent, and correspondingly, there is no requirement for the use of specialized gases such as nitrogen or sulfur hexafluoride, or specialized barrier materials to form the bladders. Avoiding these specialized materials results in significant cost savings as well as economies of manufacture.
[0085] By varying the orientation and placement of the pear-shaped or taper shaped air bladders sealed at ambient pressure or within 5 psi of ambient pressure, it has been found that a variety of customized cushioning responses are attainable.
[0086] The preferred methods of manufacturing the bladders are blow-molding and vacuum forming. Blow-molding is a well-known technique, which is well suited to economically produce large quantities of consistent articles. The tube of elastomeric material is placed in a mold and air is provided through the column to push the material against the mold. Blow-molding produces clean, cosmetically appealing articles with small inconspicuous seams. Many other prior art bladder manufacturing methods require multiple manufacturing steps, components and materials which makes them difficult and costly to produce. Some prior art methods form conspicuously large seams around their perimeters, which can be cosmetically unappealing. Vacuum forming is analogous to blow-molding in that material, preferably in sheet form, is placed into the mold to take the shape of the mold, however, in addition to introducing air into the mold, air is evacuated out to pull the barrier material to the sides of the mold. Vacuum forming can be done with flat sheets of barrier material which can be more cost effective than obtaining bars, tubes or columns of material typically used in blow molding elastomeric. A conventional thermoplastic urethane can be used to form the bladder. Other suitable materials are thermoplastic elastomers, polyester polyurethane, polyether polyurethane, and the like. Other suitable materials are identified in the '156 and '945 patents.
[0087] The cushioning components of the present invention are shown as they would be assembled in a shoe S in FIG. 15. Cushioning system 10 is generally placed between a liner 38 , which is attached to a shoe upper 40 , and an outsole 42 , which is the ground engaging portion of the shoe.
[0088] From the foregoing detailed description, it will be evident that there are a number of changes, adaptations, and modifications of the present invention that come within the province of those skilled in the art. However, it is intended that all such variations not departing from the spirit of the invention be considered as within the scope thereof as limited solely by the claims appended hereto.
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A sole component for footwear combining the desirable response characteristics of a fluid filled chamber and an elastomeric material. The chamber can be formed as a single bladder chamber in contact with an elastomeric midsole, or a single chamber formed by a sealing a void in elastomeric material. The interface between the chamber and elastomeric material is sloped and gradual so that the shape of the chamber and its placement in a midsole determine the combination of response characteristics in the sole component. The chamber has a relatively simple shape with one axis of symmetry with a rounded portion and a narrow portion. Varying the placement of the chamber in the elastomeric material can simulate the impact response of more complex and expensive systems with only a single chamber shape that needs to be stocked. The chamber has a relatively large volume, is devoid of internal connections, and has an internal pressure within 5 psi of ambient pressure, and preferably at ambient pressure. Since air is used as the fluid, no specialized gases are required. No specialized films or bladder materials are required where the chamber is formed as a bladder, since the bladder is not highly pressurized. Manufacture is simplified and design flexibility enhanced with only one type of air chamber.
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CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application is a continuation-in-part of U.S. patent application Ser. No. 12/638,661 filed Dec. 15, 2009, which claims the benefit of U.S. provisional patent application Ser. No. 61/122,616 filed Dec. 15, 2008. The entireties of the aforementioned applications are incorporated herein by reference.
FIELD
[0002] The present invention relates to ultrasonic imaging of biological materials, such as the cornea and natural lens of the eye and, in particular, relates to an ultrasonic scanning apparatuses and methods for positioning and aligning an ultrasonic transducer with respect to an eye component of interest, and for determining speed of sound in a selected region of the eye.
BACKGROUND
[0003] Ultrasonic imaging can be used to make accurate and precise measurements of structures of the eye, such as, for example, the cornea and lens. Such measurements provide ophthalmic surgeons with valuable information that they can use to guide various surgical procedures performed on the eye such as LASIK procedures or lens replacements.
[0004] Ultrasonic imaging of the cornea and lens presents a problem not generally encountered in other types of tissue. The corneal and lens surfaces are necessarily smooth and gently curved in order to perform their optical function of focusing light rays. Because these structures are smooth and regular, ultrasonic energy is reflected only in specific directions. In particular, an ultrasound pulse from a transducer will only be reflected directly back to that transducer when the pulse is reflected substantially at right angles from the corneal or lens surface. This kind of reflective property is call specular reflection. Because of the specular property of these surfaces, it will be appreciated that special care must be taken to align the transducer with the cornea or lens at each position from which an image segment is to be formed. Ultrasonic imaging of large portions of the cornea or lens can be accomplished by scanning the transducer along the component surface while continually adjusting the alignment of the transducer to provide a sequence of pulses that is always directed through the center of curvature of the specular component, thus ensuring normal reflection.
[0005] Corneal and lens imaging and measurement of dimensions require that the scanning motion of the transducer be smooth and precisely aligned. Departures of the transducer axis as small as 5 microns from the pulse's direction through the center of curvature can significantly degrade the resulting image. Mechanisms for performing the requisite scan alignment are described in U.S. Pat. No. 5,331,962, U.S. Pat. No. 6,491,637 and U.S. Pat. No. 6,887,203 which are incorporated herein by reference. Ultrasonic imaging may be used by ophthalmologists for quantitative analysis of laser refractive surgery, implantation of corneal and phakic lenses, implantation of intraocular lenses including accommodative lenses, and specialty procedures such as glaucoma and cataract treatment.
[0006] Except for on-axis measurements, images of eye components behind the iris and their dimensions cannot be determined by optical means. New procedures, such as implantation of accommodative lenses, may provide nearly perfect vision without spectacles or contact lenses. Implantation of accommodative lenses requires precision measurements of the natural lens and its suspensory ligaments for successful lens implantation. Such measurements include, for example, lens width, thickness, volume and location relative to the cornea. Ultrasonic imaging can be used to provide the required accurate images of the natural lens especially where its suspensory ligaments, known as zonules, attach to the ciliary body. The equatorial ends of the lens, the zonules and ciliary body are well off the optical axis, behind the iris and therefore not accessible to optical imaging.
[0007] Optical imaging devices can be used directly to image accessible portions of the interior of an eye. The speed of light in the cornea, aqueous humor, lens and vitreous humor varies from about 23% less than the speed of light in air to about 29% less than the speed of light in air in the lens. Furthermore the speed of light varies significantly throughout the lens depending on age and other factors. This makes optical measurements which depend on the transmission delays and hence actual speed of light difficult to transform from time delays to distance measurements.
[0008] Ultrasonic imaging requires a liquid medium to be interposed between the object being imaged and the transducer, which requires in turn that the eye, the transducer, and the path between them be at all times be immersed in a liquid medium. Many of the principal ultrasonic scanning mechanisms must be therefore submerged in water for long periods.
[0009] The speed of sound in the cornea, aqueous humor and lens is about 5 to 7% higher than the speed of sound in water. Furthermore, the speed of sound varies little throughout the lens even in the presence of cataracts. This makes acoustic measurements, which depend on the transmission delays of acoustic pulses, relatively easy to transform from time delays to distance measurements. So, in addition to being able to see the entire lens, acoustic imaging of the lens is less subject to errors in signal speed than optical imaging which is restricted to that portion of the lens visible through the pupil.
[0010] Normal ultrasonic imaging practice uses a single transducer for both sending ultrasound pulses to and receiving echoes from eye structures. That arrangement captures only those echoes that return directly to the transducer substantially along the transducer axis.
[0011] It is readily demonstrated that specular surfaces only return echoes along the axis of the incident pulse if the incident pulse is directed normal or perpendicular to the surface of the eye component of interest. This behavior has led to the development of ultrasound imaging devices that maintain their incident beam approximately perpendicular to the corneal or lens surface as the incident ultrasound pulses scan the surface. Such a device is described in U.S. patent application Ser. No. 12/347,674, entitled “Components for an Ultrasonic Arc Scanning Apparatus”, filed Dec. 31, 2008 and U.S. patent application Ser. No. 12/418,392 entitled “Procedures for an Ultrasonic Arc Scanning Apparatus” filed Apr. 3, 2009, both of which are incorporated herein by reference. With such a device, the incident pulse beam scans in a plane while directing its axis through a fixed center point. If that center point is at or near the center of curvature of the corneal or lens surface, the incident beam will remain approximately perpendicular to the surface throughout the scan, and ultrasound reflections will be returned to the transducer from all scanned parts of the surface.
[0012] One method of obtaining an image of the posterior surface of a natural or artificial implanted lens was disclosed in U.S. patent application Ser. No. 12/475,322 entitled “Compound Scanning Head for an Ultrasonic Scanning Apparatus”, filed May 29, 2009 which is incorporated herein by reference. This application discloses an ultrasonic arc scanning apparatus with an independently rotatable sector scan head mounted on the carriage of an arc scanning apparatus so as to form a compound scanning head. This invention presents an approach that allows the lens surfaces and cornea surfaces to be imaged at the same time.
[0013] There remains a need for more advanced ultrasonic scanning devices and methods that can rapidly produce a series of comprehensive images of the anterior segment of an eye, other than an arc scanner with a fixed radius of curvature such as described in, for example, U.S. Pat. No. 6,887,203.
SUMMARY
[0014] These and other needs are addressed by the present invention. The various embodiments and configurations of the present invention are directed generally to ultrasonic imaging of biological materials, such as the cornea and lens of the eye, and, in particular, to an ultrasonic arc scanning apparatus that can move its virtual center of curvature, such that its ultrasonic transducer will emit pulses that reflect substantially perpendicularly from any curved specular surface of interest within the eye.
[0015] In one embodiment, a method and imaging device are provided that:
(a) move a first carriage along a linear guide track to generate a first ultrasound scan image of an ocular feature; and (b) move a second carriage along an arcuate guide track to generate a second ultrasound scan image of the ocular feature.
[0018] In another embodiment, a method and imaging device are provided that:
(a) move a first carriage along a linear guide track to displace linearly an ultrasound transducer to image at least one of a tissue and an organ; and (b) move a second carriage along an arcuate guide track to displace arcuately the ultrasound transducer to image at least one of a tissue and an organ.
[0021] In another embodiment, a method and imaging device are provided that:
(a) generate a scan, in proximity to an optical axis of an eye, of at least one of an anterior surface of a cornea, a posterior surface of a cornea, and an anterior surface of a lens; (b) determine, from the scan, a radius of curvature of the least one of an anterior surface of a cornea, a posterior surface of a cornea, and an anterior surface of a lens; (c) uses the radius of curvature of the at least one of an anterior surface of a cornea, a posterior surface of a cornea, and an anterior surface of a lens to centrate on the corresponding surface.
[0025] In another embodiment, a method and imaging device are provided that:
(a) position a focal plane of an ultrasound transducer in proximity to a lens surface, the lens being a part of an eye of a patient, the eye having an optical axis; (b) move the transducer linearly in the plane of the meridian but at right angles to the optical axis, while the transducer is positioned substantially at a first angle above an optical axis to form a first ultrasound image; and (c) move the transducer linearly in the plane of the meridian but at right angles to the optical axis, while the transducer is positioned substantially at a second angle below the an optical axis to form a second ultrasound image.
[0029] In another embodiment, a method and imaging device are provided that:
(a) using an ultrasound transducer, generate a scan, in proximity to an optical axis of an eye, of at least one of an anterior surface of a cornea, a posterior surface of a cornea, and an anterior surface of a lens; (b) determine, from the scan, a radius of curvature of the least one of an anterior surface of a cornea, a posterior surface of a cornea, and an anterior surface of a lens; (c) use the radius of curvature of the at least one of an anterior surface of a cornea, a posterior surface of a cornea, and an anterior surface of a lens to laterally centrate on the corresponding surface; and (d) position a focal plane of the ultrasound transducer in proximity to the at least one of an anterior surface of a cornea, a posterior surface of a cornea, and an anterior surface of a lens to axially centrate on the corresponding surface.
[0034] The above embodiments can perform combined scans wherein an arc scanner transducer can be moved with one or more degrees of freedom so as to image (1) most of the specular surfaces such as a cornea and a lens and (2) many non-specular features, such as the angle between the cornea and iris lying behind the sclera and the zonules attaching the lens, in a rapid, accurate series of scans that minimize patient motion.
[0035] The above embodiments can enable an ultrasonic transducer to be moved in a variety of choreographed motions such that it can be operated to image not only the cornea and lens but also the iris, zonules and ciliary body of the eye, even as the eye being imaged is in the act of accommodating.
[0036] The above embodiments can permit centrating an ultrasonic scanner on a desired specular surface within an eye, such as the anterior and posterior surfaces of the cornea and the anterior and posterior surfaces of the lens.
[0037] In another embodiment, a method and imaging device are provided that:
(a) generate a B scan of anterior and posterior surfaces of a lens of an eye of a patient in proximity to an optical axis of the lens; (b) determine, from the B scan, a first determination of lens thickness substantially along the optical axis of the lens; (c) generate an A scan of anterior and posterior surfaces of the lens in proximity to an optical axis of the lens; (d) move the transducer along the Z-axis and determining a first Z-axis position wherein the amplitude of the A scan is substantially a local maximum at the anterior surface of the lens; (e) move the transducer along the Z-axis and determining a second Z-axis position wherein the amplitude of the A scan is substantially a local maximum at the posterior surface of the lens; (f) generate a second determination of the lens thickness substantially along the optical axis of the lens as the difference between the first and second Z-axis positions; and (g) compare the first and second lens thicknesses and applying the following rule: when the first and second lens thicknesses are within a first degree of accuracy, determining that a lens thickness is verified.
[0045] In another embodiment, a method and imaging device are provided that:
[0046] (a) generate, by an ultrasound transducer, a plurality of scans of a lens at different meridian angles; and
[0047] (b) form, from the plurality of scans, a three dimensional representation of the lens.
[0048] In another embodiment, a method is disclosed for determining a thickness of a selected region of an eye, wherein the selected region is bounded by a first interface and a second interface, comprising: 1) substantially aligning an axis of an ultrasound transducer with a z-axis of a positioning mechanism and at least one of an optical axis of an eye, a visual axis of an eye, and any line passing through both the first interface and the second interface; 2) moving the positioning mechanism and the ultrasound transducer along the z-axis to determine a first z-axis position wherein an amplitude of a first A-scan is substantially a maximum value in proximity of the first interface of the selected region; 3) moving the positioning mechanism and the ultrasound transducer along the z-axis to determine a second z-axis position wherein an amplitude of a second A-scan is substantially a maximum value in proximity of the second interface of the selected region; and 4) subtracting the first axis position from the second z-axis position to determine the thickness of the selected region.
[0049] In another embodiment, a method is disclosed for adjusting a B-scan comprised of a plurality of A-scans wherein at least one acoustic velocity measured for an imaged region of an eye is used to convert an acoustic pulse transit time for an imaged region to a distance between a first interface and a second interface of the imaged region.
[0050] In another embodiment, a system is disclosed for determining a thickness of a region of an eye wherein the region is bounded by a first interface and a second interface, comprising: 1) a positioning mechanism which can be moved back and forth along a z-axis; 2) a scan head that can be positioned by the positioning mechanism; 3) an ultrasound transducer operably connected to the scan head wherein the ultrasound transducer can be positioned to emit ultrasound pulses along a path coincident with the z-axis of the positioning mechanism; 4) a system for determining a position of the positioning mechanism along the z-axis; and 5) a system for receiving reflected ultrasound pulses.
[0051] These embodiments can permit estimating of the on-axis thickness, equatorial diameter, capsule volume and other geometric features of a natural or accommodative lens.
[0052] In another embodiment, a method and imaging device are provided that include a a plurality of acoustic transducer sensors mounted on a common transducer shaft, whereby a center transducer is focused on a point along the axis of the transducer shaft and the others are focused on points at an angle of about 1 to about 15 degrees from the axis of the transducer shaft.
[0053] The above embodiments can allow, for example, real time imaging of a lens as it accommodates and can better enable researchers to develop artificial accommodative lenses as well as assist ophthalmic surgeons to fit and implant accommodative lenses and then subsequently to diagnose their long term performance.
[0054] The following definitions are used herein:
[0055] An acoustically reflective surface or interface is a surface or interface that has sufficient acoustic impedance difference across the interface to cause a measurable reflected acoustic signal. A specular surface is typically a very strong acoustically reflective surface.
[0056] Animate means of or relating to animal life as opposed to plant life.
[0057] Anterior means situated at the front part of a structure; anterior is the opposite of posterior.
[0058] An A-scan is a representation of a rectified, filtered reflected acoustic signal as a function of time, received by an ultrasonic transducer from acoustic pulses originally emitted by the ultrasonic transducer from a known fixed position relative to an eye component.
[0059] An accommodative lens, also known as a presbyopic lens or presby lens, is an artificial intraocular lens that changes its focal distance in response to contraction of the ciliary body. When successfully implanted, an accommodative lens reverses presbyopia, the inability of the eye to change its focal distance from far to near.
[0060] Accuracy as used herein means free from error.
[0061] Aligning means positioning the acoustic transducer accurately and reproducibly in all three dimensions of space with respect to a feature of the eye component of interest (such as the center of the pupil, center of curvature or boundary of the cornea, lens, retina, etcetera).
[0062] The anterior chamber comprises the region of the eye from the cornea to the iris. The anterior segment comprises the region of the eye from the cornea to the back of the lens.
[0063] An aperture refers to the ultrasonic transducer face which may be planar but is commonly shaped as a concave surface so as to form a focal point at a desired location in front of the transducer face.
[0064] An arc scanner is an ultrasound scanning device utilizing a transducer that both sends and receives pulses as it moves along an arcuate guide track, which guide track has a center of curvature whose position can be moved to scan different curved surfaces.
[0065] Arc scanning transducer center of curvature is the same as the center of curvature of the arc scanning guide.
[0066] Auto-centering means automatically, typically under computer control, causing centration of the arc scanning transducer with the eye component of interest.
[0067] A B-scan is a processed representation of A-scan data by either or both of converting it from a time to a distance using acoustic velocities and by using grayscales, which correspond to A-scan amplitudes, to highlight the features along the A-scan time history trace (the latter also referred to as an A-scan vector).
[0068] A canthus is the angular junction of the eyelids at either corner of the eye where the upper and lower eyelids meet.
[0069] Centration means substantially aligning the center of curvature of the arc scanning transducer in all three dimensions of space with the center of curvature of the eye component of interest (such as the cornea, pupil, lens, retina, etcetera) such that rays from the transducer pass through both centers of curvature. A special case is when both centers of curvature are coincident.
[0070] The ciliary body is the circumferential tissue inside the eye composed of the ciliary muscle and ciliary processes. There are three sets of ciliary muscles in the eye, the longitudinal, radial, and circular muscles. They are near the front of the eye, above and below the lens. They are attached to the lens by connective tissue called the zonule of Zinn, and are responsible for shaping the lens to focus light on the retina. When the ciliary muscle relaxes, it flattens the lens, generally improving the focus for farther objects. When it contracts, the lens becomes more convex, generally improving the focus for closer objects.
[0071] Coronal means of or relating to the frontal plane that passes through the long axis of a body. With respect to the eye or the lens, this would be the equatorial plane of the lens which also approximately passes through the nasal canthus and temporal canthus of the eye.
[0072] Fixation means having the patient focus an eye on an optical target such that the eye's optical axis is in a known spatial relationship with the optical target. In fixation, the light source is axially aligned in the arc plane with the light source in the center of the arc so as to obtain maximum signal strength such that moving away from the center of the arc in either direction results in signal strength diminishing equally in either direction away from the center.
[0073] A guide is an apparatus for directing the motion of another apparatus.
[0074] Haptics are little protrusions extending from the outer diameter of some types of artificial lenses. These haptics fix the position of the lens to the ciliary body by protruding into the ciliary sulcus. In the case of accommodative lenses, the haptics enable the lens to accommodate in response to the action of the ciliary body.
[0075] An intraocular lens is an artificial lens that is implanted in the eye to take the place of the natural lens.
[0076] LASIK is a procedure performed on the cornea for correcting refractive errors, such as myopia, hyperopia, and astigmatism. Commonly, an excimer laser selectively removes tissue from the inside of the cornea, after it is exposed, by cutting a thin flap, so as to reshape the external shape of the cornea.
[0077] As used herein, a meridian is a 2-dimensional plane section through the approximate center of a 3-dimensional eye and its angle is commonly expressed relative to a horizon defined by the nasal canthus and temporal canthus of the eye.
[0078] The natural lens (also known as the aquula or crystalline lens) is a transparent, biconvex structure in the eye that, along with the cornea, helps to refract light to be focused on the retina. The lens, by changing shape, functions to change the focal distance of the eye so that it can focus on objects at various distances, thus allowing a sharp real image of the object of interest to be formed on the retina. This adjustment of the lens is known as accommodation. The lens is located in the anterior segment of the eye behind the iris. The lens is suspended in place by the zonular fibers, which attach to the lens near its equatorial line and connect the lens to the ciliary body. The lens has an ellipsoid, biconvex shape whose size and shape can change due to accommodation and due to growth during aging. The lens is comprised of three main parts: namely the lens capsule, the lens epithelium, and the lens fibers. The lens capsule forms the outermost layer of the lens and the lens fibers form the bulk of the interior of the lens. The cells of the lens epithelium, located between the lens capsule and the outermost layer of lens fibers, are generally found only on the anterior side of the lens.
[0079] Ocular means having to do with the eye or eyeball.
[0080] Ophthalmology means the branch of medicine that deals with the eye.
[0081] Optical as used herein refers to processes that use light rays.
[0082] The optical axis of the eye is a straight line through the centers of curvature of the refracting surfaces of an eye (the anterior and posterior surfaces of the cornea and lens).
[0083] Organ means a differentiated structure (as a heart, kidney or eye) consisting of cells and tissues and performing some specific function in an organism.
[0084] Pachymetery or corneal pachymetery is technically referred to as Time Domain Reflectometry ultrasound. A pulse of ultrasonic energy is sent toward the cornea and the time spacing of the returning echoes are used to arrive at corneal thickness.
[0085] Phakic intraocular lenses, or phakic lenses, are lenses made of plastic or silicone that are implanted into the eye permanently to reduce a person's need for glasses or contact lenses. Phakic refers to the fact that the lens is implanted into the eye without removing the eye's natural lens. During phakic lens implantation surgery, a small incision is normally made in the front of the eye. The phakic lens is inserted through the incision and placed just in front of or just behind the iris.
[0086] Positioner means the mechanism that positions a scan head relative to a selected part of an eye. In the present disclosure, the positioner can move back and forth along the x, y or z axes and rotate in the 0 direction about the z-axis. Normally the positioner does not move during a scan, only the scan head moves. In certain operations, such as measuring the thickness of a region, the positioner may move during a scan.
[0087] Posterior means situated at the back part of a structure; posterior is the opposite of anterior.
[0088] The posterior chamber comprises the region of the eye from the back of the iris to the front of the lens.
[0089] The posterior segment comprises the region of the eye from the back of the lens to the rear of the eye comprising the retina and optical nerve.
[0090] Precise as used herein means sharply defined.
[0091] Presbyiopia is typically caused by a loss of elasticity of the natural lens inside the eye. This occurs as part of the ageing process and, although it cannot be ‘cured’, it can be corrected by wearing glasses or implanting an artificial lens.
[0092] The pulse transit time across a region of the eye is the time it takes a sound pulse to traverse the region.
[0093] Purkinje images are reflections of objects from structure of the eye. There are at least four Purkinje images that are visible on looking at an eye. The first Purkinje image (P 1 ) is the reflection from the outer surface of the cornea. The second Purkinje image (P 2 ) is the reflection from the inner surface of the cornea. The third Purkinje image (P 3 ) is the reflection from the outer (anterior) surface of the lens. The fourth Purkinje image (P 4 ) is the reflection from the inner (posterior) surface of the lens. Unlike the others, P 4 is an inverted image. The first and fourth Purkinje images are used by some eye trackers, devices to measure the position of an eye. Purkinje images are named after Czech anatomist Jan Evangelista Purkyn{hacek over (e)} (1787-1869).
[0094] Refractive means anything pertaining to the focusing of light rays by the various components of the eye, principally the cornea and lens.
[0095] Registration as used herein means aligning.
[0096] Scan head means the mechanism that comprises the ultrasound transducer, the transducer holder and carriage as well as any guide tracks that allow the transducer to be moved relative to the positioner. Guide tracks may be linear, arcuate or any other appropriate geometry. The guide tracks may be rigid or flexible. Normally, only the scan head is moved during a scan.
[0097] Sector scanner is an ultrasonic scanner that sweeps a sector like a radar. The swept area is pie-shaped with its central point typically located near the face of the ultrasound transducer.
[0098] A specular surface means a mirror-like surface that reflects either optical or acoustic waves. For example, an ultrasound beam emanating from a transducer will be reflected directly back to that transducer when the beam is aligned perpendicular to a specular surface.
[0099] The ciliary sulcus is the groove between the iris and ciliary body. The scleral sulcus is a slight groove at the junction of the sclera and cornea.
[0100] Tissue means an aggregate of cells usually of a particular kind together with their intercellular substance that form one of the structural materials of a plant or an animal and that in animals include connective tissue, epithelium, muscle tissue, and nerve tissue.
[0101] A track or guide track is an apparatus along which another apparatus moves.
[0102] Ultrasonic means sound that is above the human ear's upper frequency limit. When used for imaging an object like the eye, the sound passes through a liquid medium, and its frequency is many orders of magnitude greater than can be detected by the human ear. For high-resolution acoustic imaging in the eye, the frequency is typically in the approximate range of about 5 to about 80 MHz.
[0103] A vector refers to a single acoustic pulse and its multiple reflections from various eye components. An A-scan is a representation of this data whose amplitude is typically rectified.
[0104] The visual axis of the eye is the line joining the object of interest and the fovea and which passes through the nodal points of the eye.
[0105] Zonules are tension-able ligaments extending from near the outer diameter of the crystalline lens. The zonules attach the lens to the ciliary body which allows the lens to accommodate in response to the action of the ciliary muscle.
[0106] As used herein, “at least one”, “one or more”, and “and/or” are open-ended expressions that are both conjunctive and disjunctive in operation. For example, each of the expressions “at least one of A, B and C”, “at least one of A, B, or C”, “one or more of A, B, and C”, “one or more of A, B, or C” and “A, B, and/or C” means A alone, B alone, C alone, A and B together, A and C together, B and C together, or A, B and C together.
BRIEF DESCRIPTION OF THE DRAWINGS
[0107] FIG. 1 is a schematic of the main elements of a human eye.
[0108] FIG. 2 is a schematic of some of the typical dimensions of the human eye.
[0109] FIG. 3 shows a view of a human crystalline lens showing axes of reference.
[0110] FIG. 4 is a schematic representation of a lens accommodating.
[0111] FIGS. 5A and 5B illustrate two different types of scanning strategies for ultrasonic scanners.
[0112] FIGS. 6A and 6B are a schematic of a prior art compound scanning head on an arc scanning device.
[0113] FIG. 7 illustrates a prior art compact arc scanning head positioning mechanism.
[0114] FIG. 8 is a schematic of a first view of a scan head capable of combined motion.
[0115] FIG. 9 is a schematic of a second view of a scan head capable of combined motion.
[0116] FIG. 10 is a schematic of a third view of a scan head capable of combined motion.
[0117] FIG. 11 is a schematic of a fourth view of a scan head capable of combined motion.
[0118] FIG. 12 is a schematic of a typical eye showing centers of curvature.
[0119] FIG. 13 is a schematic representation of an ultrasonic transducer showing aperture, focal length, depth of focus and lateral resolution.
[0120] FIGS. 14A , 14 B, and 14 C are a schematic representation of a first method for centrating an arc scanner on the posterior surface of a lens.
[0121] FIG. 15 is an alternative schematic representation of a first method for centrating an arc scanner on the posterior surface of a lens.
[0122] FIGS. 16A and 16B are a schematic representation of varying transducer focal length with an arc scanner centrated on the posterior surface of a lens.
[0123] FIGS. 17A , 17 B, and 17 C illustrate a process of centrating an arc scanner whose center of curvature is laterally displaced.
[0124] FIG. 18 illustrates a short B-scan where the center of curvature is laterally displaced.
[0125] FIGS. 19A , 19 B, and 19 C illustrate a process of centrating an arc scanner whose center of curvature is axially displaced.
[0126] FIG. 20 illustrates a short B-scan where the center of curvature is axially displaced.
[0127] FIGS. 21A , 21 B, and 21 C are a schematic representation of a second method for centrating an arc scanner on the posterior surface of a lens.
[0128] FIGS. 22A , 22 B, and 22 C are another schematic representation of a second method for centrating an arc scanner on the posterior surface of a lens.
[0129] FIG. 23 illustrates a method for determining lens volume.
[0130] FIG. 24 is a schematic of a transducer configuration for improving the range of imaging of an ultrasonic arc scanner.
[0131] FIG. 25 is a block diagram of a control architecture for an ultrasound imaging device.
[0132] FIG. 26 is a schematic representation of a third method for centrating an arc scanner on a surface of a cornea.
[0133] FIGS. 27A and 27B illustrate the position of the apparatus to measure thickness and sound speed of a selected region of the eye.
[0134] FIGS. 28A , 28 B, 28 C, 28 D, and 28 E illustrate the movement of the transducer focal plane to measure thickness and sound speed of a selected region of the eye.
[0135] FIGS. 29A , 29 B, 29 C, and 29 D illustrate an actual ultrasound A-scan.
[0136] FIG. 30 is a schematic of an A-scan of the cornea of an eye.
[0137] FIG. 31 is a schematic of an A-scan of the anterior segment of an eye.
[0138] FIG. 32 is a schematic of an A-scan of an eye from cornea to retina.
[0139] FIG. 33 is a schematic of A-scan amplitudes versus distance along a z-axis of a positioner.
[0140] FIG. 34 is a schematic of A-scan amplitudes versus distance along a z-axis of a positioner showing a local maximum.
[0141] FIGS. 35A , 35 B, and 35 C illustrate the form of amplitude versus position of a focused ultrasound transducer.
DETAILED DESCRIPTION
[0142] In the co-ordinate system of the eye as used herein, the x-direction is substantially parallel to the horizontal equator of the eye (canthus to canthus); the z-direction is substantially along the optical axis of the eye; and the y-direction is perpendicular to the x-z plane of the eye (see FIG. 3 ).
[0143] FIG. 1 is a schematic of the main elements of a human eye. The cornea, which is optically transparent, is located at the front of the eye and is located in the anterior chamber. The anterior and posterior surfaces of a normal cornea and the internal layers, such as Bowman's layer, within a normal cornea are specular surfaces. The iris separates the anterior chamber from the posterior chamber. The back of the lens forms the rear of the posterior chamber. The natural lens sits directly behind the iris. Only the central part of the lens, which is behind the pupil, can be seen optically. The anterior and posterior surfaces of a normal lens are specular surfaces. The cornea, iris and lens comprise the main optical refractive components of the eye. The anterior and posterior chambers comprise the anterior segment of the eye. The main volume or posterior segment of the eye lies behind the lens, with the retina and optical nerve at the rear of the posterior segment of the eye. The composition of the eye's aqueous and vitreous humor are very close to that of water with a density of about 1,000 kg/m 3 , and this allows the eye to be a very good medium for the transmission of acoustic energy.
[0144] The optical axis is the line passing through the centers of curvature of the cornea and lens assuming they are centered as they are in a normal eye. The visual axis is the line joining the fixation point and the fovea.
[0145] Optical means are suitable for viewing the anterior chamber and for viewing near the entire central axis of the eye. However, optical means cannot be used to view the portions of the posterior chamber lying far off-axis and behind the iris because light does not penetrate the iris. These portions includes the suspensory ligaments (also known as zonules) and the ciliary body. However, the eye components that cannot be viewed optically, can be viewed with suitably high-frequency acoustic energy because high-frequency acoustic energy does penetrate the iris. As is well-known, acoustic frequencies in the ultrasonic range of about 10 MHz to about 100 MHz can be used to provide very high resolution images of, for example, the cornea and the lens. Ultrasound imaging over the above frequency ranges are described in “Ultrasonography of the Eye and Orbit”, Second Edition, Coleman et al, published by Lippincott Williams & Wilkins, 2006 which is incorporated herein by reference.
[0146] FIG. 2 is a schematic of some of the typical dimensions of the human eye in millimeters and these dimensions apply at least along or near the optical axis.
Thickness of cornea ˜0.5 mm Radius of curvature anterior cornea surface ˜7.7 mm Radius of curvature posterior cornea surface ˜6.8 mm Distance from the front of the cornea to the front of the lens ˜3.3 mm Thickness of lens ˜3.5 mm Radius of curvature anterior lens surface ˜11 mm Radius of curvature posterior lens surface ˜−6.0 mm Equatorial diameter of lens ˜8.5 mm to 10 mm Distance from the rear of the lens to the front of the retina ˜16 mm
[0156] These are representative dimensions of the relaxed eye. The distance from the front of the cornea to the front of the lens along the optical axis and the thickness of lens along the optical axis depend upon accommodation. These values were taken from “Optics of the Human Eye”, D. A. Atchison, G. Smith, Robert Stevenson House, Edinburgh, ISBN 0 7506 3775 7, first printed in 2000.
[0157] The currently accepted acoustic velocities for some eye components, at 37 C, are:
cornea ˜1639 m/s aqueous humor ˜1532 m/s lens ˜1641 m/s cataractous lens ˜1,629 m/s vitreous humor ˜1,532 m/s sclera (range) 1,583 m/s to 1,744 m/s
[0164] These values are from Table 1.1 of “Ultrasonography of the Eye and Orbit”, Second Edition, Coleman et al, published by Lippincott Williams & Wilkins, 2006.
[0165] For comparison, the acoustic velocity (also known as the speed of sound) in water at 37 C is ˜1,520 m/s.
[0166] FIG. 3 shows a schematic representation of a lens showing the axes of reference used herein. This figure shows a cross-sectional view of a lens 301 where the x-axis 302 is the major horizontal axis of the lens and passes through the geometric center of the lens. The width of the lens is defined along the x-axis 302 . The y-axis 303 is the vertical axis and also passes through the geometric center of the lens. The z-axis 304 is orthogonal to the x-axis 302 and y-axis 303 and is also substantially the same as the optical axis of a normal eye. The lens thickness is defined along the z-axis 304 which also passes through the geometric center of the lens 301 .
[0167] The lens 301 has an ellipsoid, biconvex shape. In an adult, the lens has a diameter or horizontal width of approximately 9 millimeters. This is the dimension along the x-axis 302 of FIG. 3 . The lens has a thickness of approximately 3.5 millimeters. This is the thickness along the z-axis 304 of FIG. 3 . The lens has a height of approximately 9 millimeters. This is the height along the y-axis 303 of FIG. 3 .
[0168] If the lens is approximately symmetrical about all three axes, then its volume can be approximated as an ellipsoid with the approximate volume of the lens being given by:
[0000] lens volume=4/3 πa b c
[0169] where
a=the lens half width (major equatorial radius) b=the lens half height (polar radius) c=the lens half thickness (minor equatorial radius)
[0173] The lens is typically not precisely symmetric about the y-plane and so a lens volume estimation method based on imaging the lens using an accurate and precise imaging device should give a more accurate volume of the lens capsule than an ellipsoid volume approximation.
[0174] FIG. 4 is a schematic representation of a lens accommodating. The approximate lens shapes in relaxed mode 401 R and in accommodative mode 401 A are shown. It is commonly believed that when the ciliary muscle 403 A contracts inward, the sulcus 404 A also contracts inward, tension in the zonules 402 A is reduced and this allows the lens 401 A to accommodate which is appropriate for near vision. When the ciliary muscle 403 R expands outward, the sulcus 404 R also expands outward, tension in the zonules 402 R is increased and this allows the lens 401 R to relax which is appropriate for distant vision. The iris 405 R and 405 A and cornea 407 are also shown for reference.
[0175] There are several theories of exactly how a lens accommodates although there are no accurate and precise devices available for measuring an in-situ lens during accommodation to properly verify these theories. For example, when a relaxed eye (focused for distant vision) accommodates, the inside diameter of the ciliary body 403 A contracts which tends to reduce tension in the zonules 402 A which, in turn, allows the lens 401 A to move and change shape. This contraction also reduces the volume of the posterior segment behind the lens and increases the pressure of the vitreous humor. This tends to push the lens forward and change the shape of the lens. If these lens motions and shape changes can be imaged and if the ciliary body and zonules can be imaged during accommodation, then a better understanding of how accommodation works can be gained. This better understanding can lead to better designs for artificial accommodative lenses.
[0176] Once an accommodative lens is implanted or its natural accommodating action restored by, for example, injection of softening agents, an ultrasonic scanner can then be set up to target the region where the lens and the ciliary body are located and/or target the central portion of the lens. The scanner can then be used to generate a series of images that show the ciliary body and lens attachment means responding to the patient focusing at different distances and that show the movement of the central portion of the lens (anterior surface, posterior surface or both) responding to the patient focusing at different distances. If the lens does not accommodate correctly, these images can be used to diagnose the problem areas such as, for example, failure of the haptics of an artificial accommodative lens to function properly, or failure of either anterior lens apex or posterior lens apex to move as the eye attempts to change focus.
[0177] These procedures can be repeated from time to time to detect any movement or degradation of the lens, be it a softened natural lens or an artificial accommodating lens.
[0178] During the development of the scanning device disclosed herein, it was observed that lens diameter, lens thickness, lens shape and the distance between the cornea and lens varied substantially, even over a small sample of subjects.
[0179] FIGS. 5A and 5B illustrate two different types of prior art scanning strategies for ultrasonic scanners capable of imaging most regions of the interior of an eye. FIG. 5A illustrates the arc scanning principle for producing an ultrasonic scan of a component of an eye 501 . In this type of scanner, which is described, for example, in U.S. Pat. No. 7,048,690; U.S. Pat. No. 6,887,203; U.S. Pat. No. 6,491,637; U.S. Pat. No. 6,315,727; U.S. Pat. No. 5,331,962; U.S. Pat. No. 5,293,871; and U.S. patent application Ser. No. 12/347,674, a transducer 503 is moved along an arc guide track 506 whose center of curvature 502 is set approximately at the center of curvature of the eye surface of interest (here shown as the approximate center of curvature of either cornea surface). In FIG. 5A , an ultrasonic transducer 503 is shown in a sequence of positions with the center of curvature of the arc guide 506 at approximately the center of curvature 502 of the cornea (the radii of curvature and the centers of curvature of the anterior and posterior surfaces of the cornea are very close to each other). The transducer 503 is moved in an arc as shown by arrows 504 to produce many acoustic echoes (represented as rays 505 ) as it moves along the arc guide track 506 . The acoustic echoes can then be combined to form a cross-sectional image of the eye features of interest, commonly called a B scan.
[0180] FIG. 5B illustrates the sector scanning principle for producing an ultrasonic image of a particular location with an eye 511 . In this type of hand-held scanner, which is described, for example, in U.S. Pat. No. 6,198,956, an ultrasonic transducer 516 is shown being oscillated about a fixed position 512 , as indicated by arrows 514 , so as to produce many acoustic echoes (represented as rays 515 ). These echoes can then be combined to form of a localized region of interest within the eye. The scanning principle illustrated in this figure is called sector scanning.
[0181] In both the arc and sector ultrasonic scanners, the transducer acts as both the transmitter and receiver of acoustic signals. The transducer emits a short acoustic pulse and then receives the reflected acoustic signal. This technique is described, for example, in U.S. Pat. No. 5,293,871 and in “Ultrasonography of the Eye and Orbit”, Second Edition, Coleman et al, published by Lippincott Williams & Wilkins, 2006.
[0182] A sector scanner can be used to obtain an approximate measurement of the thickness of an eye component such as, for example, the thickness of the cornea or the thickness of the lens along the optical axis. A sector scanner cannot be used to measure the length of specular features that extend laterally, such as, for example, the length of a LASIK scar or lens capsule, because only that small portion of the cornea or lens that is perpendicular to the acoustic beam and reflects acoustic energy back to the transducer is visible to a sector scanner. Thus, to form an image of the entire cornea or lens, a sector scanner must patch together a series of images taken over a period of seconds in which the operator's hand can move and the patient's eye can move. Thus, a sector scanner may be able to make a qualitative image of an accommodating lens but not a quantitatively accurate image.
[0183] An arc scanner, on the other hand, can be used to measure the thickness of an eye component such as, for example, the thickness of the cornea or the thickness of a lens as well as to measure the length of specular features that extend laterally, such as, for example, the length of a LASIK scar or the lateral length of a natural or implanted lens. In an arc scanner, the patient is typically looking downward at approximately 45 degrees from horizontal. This is a preferred position for an arc scanning device. Both arc and sector scanners are discussed on page 35 of “Ultrasonography of the Eye and Orbit” cited above.
[0184] As will be described below, the present invention discloses apparatuses and methods of producing a combined scan in a way that results in superior and accurately measurable images including substantial portions of lateral extent of both anterior and posterior surfaces of the cornea and lens as well as non-specular features of the eye such as the angle between the cornea and iris lying behind the sclera and the zonules attaching the lens.
[0185] FIGS. 6A and 6B are a schematic of a compound scanning head on an arc scanning device which is taken from U.S. patent application Ser. No. 12/475,322. An arc track 601 is shown mounted on a positioning mechanism 602 . An example of a positioning mechanism is described in FIG. 7 . The positioner 602 orients the arc track 601 such that the center of curvature 609 of the arc track 601 is (1) approximately coincident with the center of curvature of an eye surface of interest (in this example, the surface of interest may be a specular surface 607 on or within the cornea); and (2) such that the plane formed by the arc track 601 and its center of curvature 609 is parallel to a section of interest within an eye component being scanned (in this example, the section of interest may be a desired section through a cornea). A transducer housing 604 is shown mounted rigidly on a transducer carriage 603 . A rotatable transducer head 605 is shown mounted on the transducer housing 604 . In this figure, the transducer head is shown in three possible positions: normal (aligned with the axis of symmetry of the transducer housing 604 ), 5 degrees above normal (but still in the plane of the arc track) and 5 degrees below normal (but still in the plane of the arc track). In each position, a transmitted pulse follows a path such as indicated by rays 606 . In the normal position, the projected ray passes through the center of curvature 609 . In any off-normal position, the projected ray would pass slightly above or below the center of curvature 609 .
[0186] The surface 607 or 608 of an eye component (such as, for example, the anterior surface of a cornea, the anterior surface of a natural lens or an incision within a cornea) is shown along with a sealing surface 610 which maintains the surface of the eye in a water bath such as described in FIG. 3 of U.S. patent application Ser. No. 12/347,674. Surface 608 is circular and has a constant radius of curvature with its center of curvature approximately at the location of the center of curvature 609 of the arc track 601 and transducer head 605 when the transducer head 605 is in normal position. Surface 607 is slightly elliptical.
[0187] In the case of surface 608 with its center of curvature always approximately at the location of the center of curvature 609 of the arc track 601 and transducer head 605 , the transmitted pulse will be always be reflected back along its transmission path and a strong received pulse will be captured by the transducer head 605 when in its normal position (aligned with the axis of symmetry of transducer housing 604 ). When the transducer head 605 is not in its normal position (ie it has moved to an angle above or below its normal position), the strength of the received pulse captured by the transducer head 605 will be diminished, diminishing rapidly as the angle increases away from its normal position.
[0188] In the case of slightly elliptical surface 607 with its variable center of curvature, the transmitted pulse will only be reflected back along its transmission path and a strong received pulse captured by the transducer head 605 , when the transducer head rotates into a position where the transmitted pulse reflects normally from the surface 607 . When the transducer head 605 is at any other angle, the strength of the received pulse captured by the transducer head 605 will be diminished, diminishing rapidly as the angle increases away from the angle at which the transmitted pulse reflects normally from the surface 607 .
[0189] Thus, for any eye component surface that is not perfectly circular with approximately the same center of curvature as the arc track, the compound, rotatable head will almost always produce a stronger received pulse than a fixed head with its transducer aligned with the axis of symmetry of the transducer housing.
[0190] FIG. 6B also includes a close-up 611 of the rotatable transducer head 605 with the transducer head in three possible positions: normal (aligned with the axis of symmetry of the transducer housing 604 ), 5 degrees above normal and 5 degrees below normal.
Mechanism for General Acoustic Scanning
[0191] FIG. 7 illustrates a compact arc scan head positioning mechanism which has been disclosed previously in U.S. patent application Ser. No. 12/347,674. FIG. 7 shows an arc scan head assembly comprised of scan head mount structure 710 and arc guide track 709 with ultrasonic transducer 708 mounted on transducer carriage 712 . Transducer carriage 712 may be moved back and forth along arc guide track 709 to perform an arc scan. The scan head assembly is attached to a main positioner arm 715 (shown in a sectional view). The scan head mount structure 710 , arc track 709 , transducer carriage 712 and transducer 708 are operative under water and are sealed from the rear portion of the positioning mechanism by a translational seal 706 and a rotational seal 707 . The translational seal 706 is typically formed by a large rubber membrane that can flex with the small x and y motions required by the positioner, although alternate sealing mechanisms may be employed. The z-axis seal and rotational seal 707 seal against the main positioner arm 715 which can both rotate and move in and out in the z-direction. Translational seal 706 is attached to stationary plate 701 which, in turn, is affixed to the main arc scanner water tank (not shown) which, in turn, is fixed with respect to the patient being scanned. The z-axis and rotational seal 707 , which is shown in close-up view 711 , is typically formed by a circumferential groove type sealing mechanism with the groove facing into the water, although alternate sealing mechanisms may be employed. Available seals allow both rotation and axial translation of the center tube while maintaining a water tight seal. Plate 702 forms a platform for the x- and y-positioning mechanisms. Plate 702 is fixed relative to stationary plate 701 . The scanning head assembly can be moved back and forth axially (the z-direction) by axial piston 703 or another suitable mechanism. The scanning head assembly can be rotated (the beta-direction) about the z-axis by a rotary stepping motor (not shown) or another suitable device. The scanning head assembly can be moved up and down (the y-direction) by piston 705 or another suitable mechanism. The scanning head assembly can be moved from side to side (the x-direction) by piston 704 or another suitable mechanism. The components to the left or rear of stationary plate 701 remain in ambient air while the components to the right or front of stationary plate 701 are in immersed in water when the arc scanner is operational.
[0192] Typically, the scan head assembly is moved in the x-, y-, z- and beta directions to position the scan head assembly with respect to an eye component of interest. Although these motions are typically made rapidly under computer control, scans of the eye are typically not made during positioning. Once the scan head assembly is positioned with respect to the eye component of interest, scans are made by the transducer carriage 712 moving back and forth along the arc guide track 709 . As described in U.S. patent application Ser. No. 12/347,674, the transducer carriage 712 moves along arc guide track 709 on a fluid bearing for smooth operation.
[0193] As described above, the scanning head can be moved back and forth axially (the z-direction); rotated (the beta-direction) about the z-axis; moved up and down (the y-direction); and moved from side to side (the x-direction). It is therefore possible to move the entire scan head in more complex motions by co-ordinating these movements to obtain scans that cannot be obtained by a simple arc scan. However, the mechanisms of the apparatus of FIG. 7 , while suitable for rapid positioning movements, are not well-suited for rapid scanning motions necessary, for example, to obtain multiple images of an eye accommodating in real time. A more suitable device is illustrated in FIGS. 8 , 9 , 10 , and 11 .
[0194] FIG. 8 is a schematic of a first view of a scan head capable of combined motion. The scan head plate 801 replaces scan head mount structure 710 of FIG. 7 . Scan head plate 801 serves as the platform for a computer controlled linear carriage 802 and arc carriage 803 . Linear carriage 802 moves back and forth along linear guide track 804 . Arc carriage 803 moves back and forth along arc guide track 805 . In this view, arc carriage 803 is at the rightmost limit of its travel along arc guide track 805 and linear carriage 802 is also at the rightmost limit of its travel on linear guide track 804 . As can be appreciated, the motions of arc carriage 803 and linear carriage 802 can be controlled independently. For example, arc carriage 803 can move along arc guide track 805 or be parked anywhere along arc guide track 805 while linear carriage 802 moves along linear guide track 804 . As another example, linear carriage 802 can be stationary while arc carriage 803 moves back and forth along arc guide track 805 to execute a pure arc scan. When arc carriage 803 is stationary and linear carriage 802 is moved, this is referred to as a linear scan. When both arc carriage 803 and linear carriage 802 are moved, this is referred to as combined scan. In this configuration, arc carriage 803 is moved along arc guide track 805 by an induction motor as described in U.S. patent application Ser. No. 12/347,674. Arc carriage 803 moves along arc guide track 805 on a fluid bearing which is also described in U.S. patent application Ser. No. 12/347,674. Ultrasound transducer 806 is mounted on arc carriage 803 and the axis of transducer 806 is aligned along the radius of curvature of arc guide track 805 . Linear carriage 802 is moved along linear guide track 804 by a drive motor (not shown) housed in linear drive motor housing 807 . This drive motor moves linear carriage 802 by a belt and pulley system (not shown except for typical pulley housing 808 ). Linear carriage 802 moves along linear guide track 804 on a fluid bearing similar to that used between arc carriage 803 and arc track 805 . In operation, the scan head assembly of FIG. 8 is under water and is sealed from the x, y, z, beta positioner (shown in FIG. 7 ) by a sealing means behind the scan head plate. Thus the entire scanning mechanism is positioned with respect to an eye for scanning by the x, y, z, beta positioner shown in FIG. 7 , while the actual acoustic imaging scan motion is implemented by one or both of the linear and arc carriages 802 and 803 . The scan head assembly disclosed in FIG. 8 allows rapid independent linear and arcuate motion combinations of the transducer such that various scan geometries, explained in subsequent figures, can be implemented to image not only the cornea, iris and anterior lens surface, but also the posterior lens surface, the ciliary body and the zonules that attach the lens to the ciliary body.
[0195] FIG. 9 is a schematic of a second view of a scan head capable of combined motion. In this view, arc carriage 903 is at the leftmost limit of its travel along arc guide track 905 and linear carriage 902 is at the rightmost limit of its travel on linear guide track 904 .
[0196] FIG. 10 is a schematic of a third view of a scan head capable of combined motion. In this view, arc carriage 1003 is at the leftmost limit of its travel along arc guide track 1005 and linear carriage 1002 is also at the leftmost limit of its travel on linear guide track 1004 .
[0197] FIG. 11 is a schematic of a fourth view of a scan head capable of combined motion. In this view, arc carriage 1103 is at the rightmost limit of its travel along arc guide track 1105 and linear carriage 1102 is at the leftmost limit of its travel on linear guide track 1104 .
[0198] FIGS. 7 through 11 illustrate an ultrasonic imaging device that can be accurately and precisely positioned with respect to an eye component and then can rapidly acquire accurate and precise images of various eye components by using a combination of arc scans, linear scans and combined arc and linear scans. As can be appreciated, devices incorporating other scan heads can be built so as to move an acoustic imaging transducer in a variety of trajectories to obtain images of various eye components. Although FIGS. 7 through 11 depict an ultrasound imaging device having an arc carriage supported by a linear carriage, it is to be understood that the arc carriage can be separate from the linear carriage, with each carriage having a separate ultrasound transducer.
Relationship of Transducer Center of Curvature and Focal Plane
[0199] FIG. 12 is a schematic of a typical eye showing centers of curvature. The front of the eye is on the left. The cornea 1201 is represented by its anterior and posterior surfaces whose centers of curvature are approximately shown by points 1212 and 1213 . The lens 1202 is shown by its anterior and posterior surfaces whose centers of curvature are shown by points 1214 (anterior surface center of curvature) and 1211 (posterior surface center of curvature). The position of the retina 1203 relative to the refractory components is also shown.
[0200] Typical values for the thicknesses and radii of curvature for the refractive components of the eye shown in FIG. 12 are:
Thickness of cornea ˜0.5 mm Radius of curvature anterior cornea surface ˜7.7 mm Radius of curvature posterior cornea surface ˜6.8 mm Thickness of lens ˜3.5 mm Radius of curvature anterior lens surface ˜11 mm Radius of curvature posterior lens surface ˜−6.0 mm
[0207] FIG. 13 is a schematic representation of a focused ultrasonic transducer showing aperture, focal length, depth of focus and lateral resolution. The transducer has an aperture 1302 which is slightly concave with radius of curvature 1304 that focuses the acoustic pulses at location 1305 . Thus, the focal length of the transducer is the distance from the center of the transducer face 1302 to the focal point 1305 . The transducer has a depth of focus 1307 and a lateral resolution 1306 . The axial resolution is defined in “Ultrasonography of the Eye and Orbit”, Second Edition, Coleman et al, published by Lippincott Williams & Wilkins, 2006 as:
[0000] Δaxial= c T/ 2
[0208] where
T=the pulse duration, and c=the acoustic velocity of the medium
[0211] For the example of a transducer with a diameter of 5 mm, a focal length of 15 mm, a center frequency of 38 MHz and a one cycle pulse waveform, the axial resolution is about 20 microns.
[0212] Since the focused beam is diffraction limited, the lateral resolution 1306 is usually given by the diameter of the Airy disc:
[0000] Δlateral=1.22 λf/d
[0213] where
λ=the wavelength of the pulse train, f=the focal length of the transducer and d=the diameter of the transducer
[0217] For the example of a transducer with a diameter of 5 mm, a focal length of 15 mm, a center frequency of 38 MHz and a one cycle pulse waveform, the lateral resolution is about 150 microns.
[0218] The depth of focus is given by the relationship:
[0000] Δ f =λ/(4 sin 2 (θ/2))
[0219] where
λ=the wavelength of the pulse train, θ=the half angle subtended by the transducer diameter at the focal point
[0222] For the example of a transducer with a diameter of 5 mm, a focal length of 15 mm, a center frequency of 38 MHz, the depth of focus is about 1,560 microns.
[0223] As can be appreciated, a the transducer with a concave aperture is preferred. In scanning an eye feature of interest, it is typically preferred to place the focal plane of the transducer as close to the feature of interest as possible. As will be seen in later discussions, obtaining a strong, sharp image of an eye feature of interest involves fulfilling 2 conditions: (1) the focal plane must be located near the feature of interest and (2) the transducer pulse must engage the surface of interest substantially normal to the surface. This latter condition can be fulfilled if the pulse wave train passes through both the center of curvature of the transducer arc track guide and the center of curvature of the eye component surface.
A First Method for Centrating
[0224] FIGS. 14A , 14 B, and 14 C are a schematic representation of a first method for centrating an arc scanner on the posterior surface of a lens. In this method, an arc guide track 1401 is positioned so that its center of curvature 1403 is substantially coincident with the center of curvature 1403 of the posterior surface 1402 of a lens. Procedures to accomplish this centration are described in FIGS. 17A , 17 B, and 17 C, and FIGS. 19A , 19 B, and 19 C. Now as the transducer carrier moves along the arc guide track 1401 , its sonic pulses, represented by rays 1404 , 1405 and 1406 , always pass through both centers of curvature 1403 and reflect substantially perpendicularly from the posterior surface 1402 of the lens. As can be seen, the length of the pulse path is also constant for all positions of the transducer as it moves along the arc guide track 1401 . Thus, it is shown that although the arc guide track may be curved to approximate the curvature of the cornea and anterior lens surface, the same arc guide track can be used to focus and image a surface curved with a radius of curvature of opposite sign such as the posterior surface 1402 of a lens. In the method of FIGS. 14A , 14 B, and 14 C, the center of curvature the arc guide track 1401 is coincident with the center of curvature 1403 of the posterior surface 1402 of the lens. To centrate on the anterior surface of the lens or on either surface of the cornea, it is also only necessary to position the center of curvature of the arc guide track coincident substantially on the center of curvature of the eye surface being imaged.
[0225] A scan of the anterior segment can be made in the following way using this method. First, the arc scanner is centrated on the center of curvature of the anterior surface of the lens and a scan is made moving only the transducer carriage along the arc guide track. This scan will be capable of generating an image of a substantial portion of the anterior surface of the lens and also be capable of generating a low resolution scan of the cornea (since the cornea will typically be further away from the focal plane). Second, the arc guide track can be moved away from the eye in the z-direction to centrate on either center of curvature of the surfaces of the cornea and a scan made again by moving only the transducer carriage along the arc guide track. This scan will be capable of generating an image of a higher resolution image of a substantial portion of the cornea (both surfaces and internal structure since these surfaces are close together and all within reasonable focus). Third, the arc guide track can be moved even further away from the eye in the z-direction to centrate on the center of curvature of the posterior surface of the lens and a scan made again by moving only the transducer carriage along the arc guide track. This scan will be capable of generating an image of a substantial portion of the posterior surface of the lens. These scans can be made in rapid succession (typically on the order of about a second each so as to minimize any movement of the eye by the patient). Since the z-axis motion of the transducer is preferably away from the eye, this would minimize any risk of the transducer assembly being inadvertently moved at high speed toward the eye.
[0226] It is noted that, for a transducer of fixed focal length, it is impossible to have the center of curvature of the arc guide track coincident with the center of curvature of three different eye surfaces and be able to place the focal plane of the transducer on each eye surface. Typically, the focal length of the transducer is designed to be inside the cornea when the transducer is centrated on the cornea. In this case, the focal plane of the transducer will not be on the lens surface of interest when the transducer is centrated on the lens surface of interest. This deficiency can be remedied by using dynamic transducer focusing techniques.
[0227] The centration method described in FIGS. 14A , 14 B, and 14 C can be accomplished by an arc scanner apparatus such as described in U.S. patent application Ser. No. 12/347,674.
[0228] In FIGS. 21 and 22 , an alternate method for centrating will be disclosed that does not require substantial coincidence of the center of curvature of the arc guide track with the center of curvature of the eye surface being imaged.
[0229] FIG. 15 is an alternative schematic representation of the above method for centrating an arc scanner on the posterior surface of a lens. The arcuate path 1501 of a transducer face is shown with its center of curvature centrated on the center of curvature 1513 of the posterior surface of a lens 1503 . For reference, the cornea 1502 is shown with its center of curvature 1512 . The center of curvature 1523 of the anterior surface of the lens 1503 is shown and for reference the approximate axial location of the retina 1504 is also shown. Typical dimensions of various eye components are shown in FIG. 2 . In the setup shown in FIG. 15 , an ultrasonic scan will produce a clear image of much of the posterior lens surface and should also produce a partial image of the anterior surface of the lens. The scan may also produce an image of a small region of the cornea on the axis where ultrasonic pulses intercept the cornea at angles near 90 degrees.
Effect of Transducer Focal Length
[0230] As noted above, a transducer with a fixed focal length cannot be optimized for imaging the cornea and lens surfaces, even though the transducer can be centrated on each of the cornea and lens surfaces. This is illustrated in Figured 16 A and 16 B for a transducer centrated on the posterior surface of a lens.
[0231] FIGS. 16A and 16B are a schematic representation of varying transducer focal length with an arc scanner centrated on the posterior surface of a lens. FIG. 16A shows a focused ultrasonic transducer 1602 which moves along an arc guide track 1601 . The transducer 1602 is shown aligned approximately with the optical axis of an eye 1603 represented by a cornea and a lens. The focal point of the transducer 1602 is represented by the end of the line 1605 and, in FIG. 16A , is shown focused outside the eye. The arc guide track and transducer have a center of curvature 1604 which is centrated on the approximate center of curvature of the posterior surface of the lens. Thus the image of the posterior surface of the lens will be out of focus, even though acoustic pulses will reflect approximately normally from the posterior surface of the lens.
[0232] FIG. 16B also shows a focused ultrasonic transducer 1612 which moves along an arc guide track 1601 . The transducer 1612 is shown lined up with the approximate optical axis of an eye 1603 represented by a cornea and a lens. The focal point of the transducer 1612 is longer than that of transducer 1602 in FIG. 16A and is represented by the end of the line 1606 . In FIG. 16B , transducer 1612 is shown focused approximately in the middle of the lens of the eye. The arc guide track and transducer have a center of curvature 1604 which is centrated on the approximate center of curvature of the posterior surface of the lens. The transducer 1612 of FIG. 16B is thus much better suited to imaging the posterior surface of the lens than the transducer 1602 of FIG. 16A which is not focused near the surface of interest, which in FIGS. 16A and 16B is the posterior surface of the lens. As can be appreciated, the transducer 1602 can be designed to provide a sharp image of the lens surfaces or the cornea surfaces but the same fixed focal length transducer cannot provide sharp images of all surfaces with a single focal length transducer. In practice there is another constraint on the design of transducer focal length. The transducer focal length and arc radius of curvature must allow enough space between the transducer and the eyepiece of the arc scanner for this to be accomplished without endangering the patient's eye by the transducer piercing the membrane separating the water in the arc scanner with the water in the replaceable/disposable eyepiece.
Centrating for Lateral Displacement of Center of Curvature
[0233] FIGS. 17A , 17 B, and 17 C illustrate a process of centrating an arc scanner whose center of curvature is laterally displaced from the center of curvature of the eye feature of interest. FIG. 17A shows the arc path 1701 of a transducer face whose center of curvature 1711 is offset laterally from the center of curvature 1703 of an eye component of interest, such as the anterior or posterior surface of a cornea or lens. As the transducer moves along its arc guide track, it sends out ultrasonic pulses such as represented by ray 1705 . These pulses pass through the center of curvature 1711 of the transducer but not the center of curvature 1703 of the eye component of interest. Therefore, rays emitted and received at different angular positions along the arc path of the transducer face will have different transit times to and from the eye surface of interest. The raw B-scan image of the cornea generated before correction for curvature of the arc will appear as a line tilted at an angle to the horizontal as further described in FIG. 18 . This is because rays emitted and received near the top of the arc in FIGS. 17A , 17 B, and 17 C have less far to travel than rays emitted and received near the bottom of the arc in FIGS. 17A , 17 B, and 17 C.
[0234] FIG. 17B shows the arc path 1701 of a transducer face whose center of curvature 1712 is offset laterally from the center of curvature 1703 of an eye component of interest but not as far offset as the center of curvature of the transducer of FIG. 17A . As the transducer moves along its arc guide track, it sends out ultrasonic pulses such represented by ray 1706 . These pulses pass through the center of curvature 1712 of the transducer but not the center of curvature 1703 of the eye component of interest. The rays emitted and received at different angular positions along the arc path of the transducer will have different transit times to and from the eye surface of interest. The raw B-scan generated before correction for arc curvature will show a line tilted at an angle to the horizontal as further described in FIG. 18 but less tilted than the line generated by the transducer of FIG. 17A .
[0235] FIG. 17C shows the arc path 1701 of a transducer face whose center of curvature 1713 is now substantially coincident with the center of curvature 1703 of an eye component of interest. As the transducer moves along its arc guide track, it sends out ultrasonic pulses such represented by ray 1707 . These pulses pass through the center of curvature 1713 of the transducer as well as the center of curvature 1703 of the eye component of interest. The rays emitted and received at different angular positions along the arc path of the transducer will have substantially the same transit times to and from the eye surface of interest. The raw B-scan generated before correction for arc curvature will now show a horizontal line as further described in FIG. 18 .
[0236] In practice only a short scan centered approximately on the optical axis of the eye need be performed to produce a B-scan before correction for arc curvature and the arc guide track positioner can be moved laterally until the scan line is horizontal and this will be the signature that the arc scanner is centrated with no lateral offset. As can be appreciated, this centration adjustment process can be carried out manually or it can be automated and performed under computer control.
[0237] It is noted that the curvature of the arc guide track and the curvature the eye component of interest may not be exactly the same. In practice, the centration process for correcting for lateral displacement may not produce a horizontal line when centrated but it will produce a line with minimal tilt and some curvature. Thus in general, the operator centrates by moving the arc guide track until a substantially symmetric line with minimal tilt and curvature is produced.
[0238] FIG. 18 illustrates a calculated sequence of short B-scans of a locally spherically curved surface with the same curvature as the arc track guide where the centers of curvature are initially laterally displaced. FIG. 18 shows a schematic representation of three raw B-scans generated before correction for arc curvature. The plot shows transit distance (transit time divided by acoustic velocity) for an ultrasonic pulse from the transducer to a curved eye surface and back to the transducer versus angle of the transducer along its arc guide track. Scan 1803 is tilted indicating that the transit times are longer on the positive side of the optical axis and shorter on the negative side of the optical axis. This means that the center of curvature of the transducer is laterally offset from the center of curvature of the eye component surface being measured. As the lateral offset is reduced, the tilt of the scan is also reduces such as shown by scan 1804 . When the lateral offset is reduced to zero and the center of curvature of the transducer is coincident with the center of curvature of the eye component surface being measured, then the scan is a horizontal straight line 1805 . This means that the arc scanner has been centrated with the eye component surface to be imaged.
Centrating for Axial Displacement of Center of Curvature
[0239] FIGS. 19A , 19 B, and 19 C illustrate a process of centrating an arc scanner whose center of curvature is axially displaced. FIG. 19A shows the arc path 1901 of a transducer face whose center of curvature 1911 is offset axially from the center of curvature 1903 of an eye component of interest, such as the anterior or posterior surface of a cornea or lens. As the transducer moves along its arc guide track, it sends out ultrasonic pulses such as represented by ray 1905 . These pulses pass through the center of curvature 1911 of the transducer but not the center of curvature 1903 of the eye component of interest. Therefore, rays emitted and received at different angular positions along the arc path of the transducer will have different transit times to and from the eye surface of interest. The raw B-scan generated before correction for arc curvature will show a curved line as further described in FIG. 20 . This is because rays emitted and received near the center of the arc have a slightly longer distance to travel than rays emitted and received near either the top or bottom of the arc.
[0240] FIG. 19B shows the arc path 1901 of a transducer face whose center of curvature 1912 is offset axially from the center of curvature 1903 of an eye component of interest but not as far offset as the center of curvature of the transducer of FIG. 19A . As the transducer moves along its arc guide track, it sends out ultrasonic pulses such represented by ray 1906 . These pulses pass through the center of curvature 1912 of the transducer but not the center of curvature 1903 of the eye component of interest. The rays emitted and received at different angular positions along the arc path of the transducer will have different transit times to and from the eye surface of interest. The raw B-scan generated before correction for arc curvature will show a curved line as further described in FIG. 20 but less curved than the line generated by the transducer of FIG. 19A .
[0241] FIG. 19C shows the arc path 1901 of a transducer face whose center of curvature 1913 is now substantially coincident with the center of curvature 1903 of an eye component of interest. As the transducer moves along its arc guide track, it sends out ultrasonic pulses such represented by ray 1907 . These pulses pass through the center of curvature 1913 of the transducer as well as the center of curvature 1903 of the eye component of interest. The rays emitted and received at different angular positions along the arc path of the transducer will have substantially the same transit times to and from the eye surface of interest. The raw B-scan generated before correction for arc curvature will now show a straight horizontal line as further described in FIG. 20 .
[0242] In practice only a short scan centered approximately around the optical axis of the eye need be performed to produce a B-scan before correction for arc curvature and the arc guide track positioner can be moved axially until the scan line is not curved and this will be the signature that the arc scanner is centrated with no axial offset. As can be appreciated, this centration adjustment process can be carried out manually or it can be automated and performed under computer control.
[0243] As noted previously, the curvature of the arc guide track and the curvature the eye component of interest may not be exactly the same. In practice, the centration process for correcting for axial displacement may not produce a straight line when centrated but it will produce a line with minimal curvature. Thus in general, the operator centrates by moving the arc guide track until a line with minimal curvature is produced.
[0244] If an arc scanner is set with its center of curvature both laterally and axially displaced from the center of curvature of an eye component of interest, then the raw B-scan generated before correction for arc curvature will show a tilted curved line. The scanner assembly will then have to be moved both axially and laterally until the tilt and curvature of the raw B-scan generated before correction for arc curvature will show a straight horizontal line at best or at least a line with minimal tilt and curvature. As can be appreciated, this more general centration adjustment process can also be carried out manually or it can also be automated and performed under computer control.
[0245] FIG. 20 illustrates a calculated series of short B-scans of a locally spherically curved surface with the same curvature as the arc track guide where the centers of curvature are initially axially displaced. FIG. 20 shows a schematic representation of three raw B-scans generated before correction for arc curvature. The plot shows transit distance (transit time divided by acoustic velocity) for an ultrasonic pulse from the transducer to a curved eye surface and back to the transducer versus angle of the transducer along its arc guide track. Scan 2003 is curved indicating that the transit times are shorter as the transducer moves on its track in either direction away from the optical axis. This means that the center of curvature of the transducer is axially offset from the center of curvature of the eye component surface being measured. As the axial offset is reduced, the curve of the scan is also reduced such as shown by scan 2004 . When the axial offset is reduced to zero and the center of curvature of the transducer is coincident with the center of curvature of the eye component surface being measured, then the scan is a horizontal straight line 2005 . This means that the arc scanner has been centrated with the eye component surface to be imaged.
A Second Method for Centrating
[0246] FIGS. 21A , 21 B, and 21 C are a schematic representation of a second method for centrating an arc scanner, with the method being illustrated on the posterior surface of a lens. In this method, the center of curvature of an arc guide track is not substantially coincident with the center of curvature of an eye component of interest, such as the anterior or posterior surface of a cornea or lens. However, when centration is achieved in this method, an ultrasound pulse emitted by a transducer on the arc guide track always passes through both the center of curvature of the arc guide track and the center of curvature of an eye component of interest. This condition can be met by moving the entire arc guide track laterally as the transducer is moved along the arc guide track. If the separation of centers of curvatures in the z-direction is “Δz” then the movement of the arc guide track in the x-direction is:
[0000] Δ x=Δz (tan α 1 −tan α 2 )
[0247] where α 1 =the angle between the transducer axis and the horizontal at time t 1
[0248] and α 2 =the angle between the transducer axis and the horizontal at time t 2
[0249] If, as in FIGS. 21A , 21 B, and 21 C, the center of curvature of an arc guide track is closer to the surface of the eye component of interest than the center of curvature of an eye component of interest, then the entire arc guide track is moved laterally in the opposite direction as the transducer is moved along the arc guide track as illustrated in FIG. 21A by arrow 2122 denoting the direction of movement of the arc guide track assembly and arrow 2121 denoting the general direction of movement of the transducer.
[0250] FIG. 21A shows the arc path 2101 of a transducer face whose center of curvature 2105 is closer to the eye surface of interest 2103 than the center of curvature 2104 of an eye component of interest. It is noted, that by design, the center of curvature of the transducer face arc path is the same as the center of curvature of the arc guide track. As the transducer moves along its arc guide track, it sends out ultrasonic pulses such represented by ray 2102 . These pulses pass through the center of curvature 2105 of the transducer arc path 2101 as well as the center of curvature 2104 of the eye component of interest.
[0251] FIG. 21B shows the arc path 2111 of a transducer face whose center of curvature 2115 is closer to the eye surface of interest 2103 than the center of curvature 2104 of an eye component of interest. As the transducer moves along its arc guide track, the entire arc guide track assembly moves in the opposite direction as described above. As the transducer moves along its arc guide track, it sends out ultrasonic pulses such represented by ray 2112 . These pulses pass through the center of curvature 2115 of the transducer arc track 2111 as well as the center of curvature 2104 of the eye component of interest.
[0252] FIG. 21C shows the arc path 2121 of a transducer face whose center of curvature 2125 is closer to the eye surface of interest 2103 than the center of curvature 2104 of an eye component of interest. As the transducer moves along its arc guide track, the entire arc guide track assembly moves in the opposite direction as described above. As the transducer moves along its arc guide track, it sends out ultrasonic pulses such represented by ray 2122 . These pulses pass through the center of curvature 2125 of the transducer arc path 2121 as well as the center of curvature 2104 of the eye component of interest.
[0253] The rays 2102 , 2112 and 2122 are all of slightly differing lengths becoming shorter as the transducer moves along the arc guide track. However, the change in transit time of the transmitted and received ultrasonic pulses can be corrected by the known geometric relationships since the positions of the transducer on the arc guide track and the position of the arc guide track assembly are known accurately at all times. The key point here is that the rays 2102 , 2112 and 2122 all reflect normally off the surface of the eye component of interest. In the case illustrated in FIGS. 21A , 21 B, and 21 C, the arc scanner is able to image the posterior surface of the lens even though the curvature of the posterior lens surface and the curvature of the arc guide track are of opposite sign.
[0254] As an example of the range of motions illustrated in FIGS. 21A , 21 B, and 21 C, the center of curvature of transducer face (R=20 mm) is about 2.466 mm closer to the eye component than the center of curvature of the posterior surface of the lens (R=6 mm).
[0000]
Lateral displacement of arc
Transducer angle with respect
track between adjacent
to the horizontal (degrees)
angular movements (mm)
35.000
0.0000
23.045
0.6775
11.090
0.5656
[0255] FIGS. 22A , 22 B, and 22 C is another schematic representation of representation of a second method for centrating an arc scanner, with the method also being illustrated on the posterior surface of a lens. In this method, the center of curvature of an arc guide track is not coincident with the center of curvature of an eye component of interest, such as the anterior or posterior surface of a cornea or lens. However, when centration is achieved in this method, an ultrasound pulse emitted by a transducer on the arc guide track always passes through both the center of curvature of the arc guide track and the center of curvature of an eye component of interest. This condition can be met by moving the entire arc guide track laterally as the transducer is moved along the arc guide track.
[0256] If the separation centers of curvatures in the z-direction is “Δz” then the movement of the arc guide track in the x-direction is:
[0000] Δ x=Δz (tan α 1 −tan α 2 )
[0257] where α 1 =the angle between the transducer axis and the horizontal at time t 1
[0258] and α 2 =the angle between the transducer axis and the horizontal at time t 2
[0259] If, as in FIGS. 22A , 22 B, and 22 C, the center of curvature of an arc guide track is further away from the surface of the eye component of interest than the center of curvature of an eye component of interest, then the entire arc guide track is moved laterally in the same general direction as the transducer is moved along the arc guide track as illustrated in FIG. 22A by arrow 2222 denoting the direction of movement of the arc guide track assembly and arrow 2221 denoting the direction of movement of the transducer.
[0260] FIG. 22A shows the arc path 2201 of a transducer face whose center of curvature 2205 is further away from the eye surface of interest 2203 than the center of curvature 2204 of an eye component of interest. As the transducer moves along its arc guide track, it sends out ultrasonic pulses such represented by ray 2202 . These pulses pass through the center of curvature 2205 of the transducer arc path 2201 as well as the center of curvature 2204 of the eye component of interest.
[0261] FIG. 22B shows the arc path 2211 of a transducer face whose center of curvature 2215 is further away from the eye surface of interest 2203 than the center of curvature 2204 of an eye component of interest. As the transducer moves along its arc guide track, the entire arc guide track assembly moves in the same direction as described above. As the transducer moves along its arc guide track, it sends out ultrasonic pulses such represented by ray 2212 . These pulses pass through the center of curvature 2215 of the transducer arc path 2211 as well as the center of curvature 2204 of the eye component of interest.
[0262] FIG. 22C shows the arc path 2221 of a transducer face whose center of curvature 2225 is further away from the eye surface of interest 2203 than the center of curvature 2204 of an eye component of interest. As the transducer moves along its arc guide track, the entire arc guide track assembly moves in the same direction as described above. As the transducer moves along its arc guide track, it sends out ultrasonic pulses such represented by ray 2222 . These pulses pass through the center of curvature 2225 of the transducer arc track 2221 as well as the center of curvature 2204 of the eye component of interest.
[0263] The rays 2202 , 2212 and 2222 are all of slightly differing lengths becoming shorter as the transducer moves along the arc guide track. However, the change in transit time of the transmitted and received ultrasonic pulses can be corrected by the known geometric relationships since the positions of the transducer on the arc guide track and the position of the arc guide track assembly are known accurately at all times. The key point here is that the rays 2202 , 2212 and 2222 all reflect normally off the surface of the eye component of interest. In the case illustrated in FIGS. 22A , 22 B, and 22 C, the arc scanner is able to image the posterior surface of the lens even though the curvature of the posterior lens surface and the curvature of the arc guide track are of opposite sign.
[0264] As an example of the range of motions illustrated in FIGS. 22A , 22 B, and 22 C, the center of curvature of transducer face (R=20 mm) is about 3.363 mm further away from the eye component than the center of curvature of the posterior surface of the lens (R=6 mm).
[0000]
Lateral displacement of arc
Transducer angle with respect
track between adjacent
to the horizontal (degrees)
angular movements (mm)
35.000
0.000
23.045
0.9241
11.090
0.7714
Forming an Image of the Anterior Segment of an Eye
[0265] An ultrasound image of the anterior segment of an eye, which includes the cornea, the iris, the sclera, the lens, the ciliary body and the zonules may be imaged by a series of scans in the following way, using the scanning device described in FIGS. 7 through 11 where centration is achieved either by the method of FIGS. 21A , 21 B, and 21 C, or FIGS. 22A , 22 B, and 22 C. Such a scan can image substantial portions of both anterior and posterior cornea as well as substantial portions of the anterior and posterior lens surfaces.
1. the arc scanner is positioned with respect to the center of the eye by manual or computer-controlled means using the x-, y- and beta positioning means described in FIG. 7 . 2. the focal plane of the transducer is placed at or near the posterior lens surface by observing and maximizing the amplitude of an A-scan pulse waveform known to be from the posterior lens surface substantially along the optical axis of the eye 3. A first linear scan is made with the transducer carriage parked at an angle α on the arc guide track (α is typically in the range of 10 to 35 degrees above the optical axis). A second linear scan is made with the transducer carriage parked at an angle −α on the arc guide track. These scans capture sections of the posterior surface of the lens capsule, these sections typically being off the optical axis. 4. the focal plane of the transducer is then retracted so that it is situated near the midpoint of the lens by observing the amplitude of an A-scan substantially along the optical axis of the eye. 5. A combined scan (co-ordinated linear and arcuate motion such as described in FIGS. 21A , 21 B, and 21 C, or FIGS. 22A , 22 B, and 22 C) is then implemented. This scan captures most of the anterior surface of the lens capsule as well as images of the zonules, ciliary body and iris. 6. the focal plane of the transducer is further retracted so that it is situated in the cornea again by observing the amplitude of an A-scan substantially along the optical axis of the eye. 7. An arc scan is then made which captures a sharp image of the cornea and its internal structure as well as additional images of the sclera, iris and anterior lens capsule surface. This scan will typically also image a short section of the posterior lens capsule near the optical axis. 8. Since the above scans are referenced by a common co-ordinate system, they can be readily combined to create a comprehensive image of substantially all of the anterior segment of the eye. 9. This same type of scan can be obtained for several sections (or meridians) through the eye by changing the meridian to be imaged using the beta (rotational) mechanism of the positioner (see FIG. 7 ).
[0275] A series of these anterior segment scans can be carried out by the scanning device described in FIGS. 8 through 11 in about 5 to about 10 seconds so that the patient has little opportunity to move his or her eye.
[0276] As can be appreciated, the steps described above can be performed in a number of different sequences from those described.
Lens Volume
[0277] FIG. 23 illustrates a method for determining lens volume. FIG. 23 shows an anterior cornea surface 2301 and a posterior cornea surface 2302 and their respective centers of curvature 2303 and 2304 . Also shown are an anterior lens surface 2311 and a posterior lens surface 2312 and their respective centers of curvature 2314 and 2313 . The circle 2322 highlights a region where the anterior and posterior lens surfaces come together. The surfaces shown as dotted lines are typically not imaged well or not imaged at all in an ultrasonic scan and therefore have to be estimated. The region 2322 is shown magnified with the hard-to-image surfaces 2323 shown again by dotted lines. As can be appreciated the extent of these hard-to-image surfaces shown is only approximate and depends on the particular patient and on the capabilities of the ultrasonic arc scanner. A possible method for imaging this region of the lens is described in U.S. patent application Ser. No. 12/475,322.
[0278] These hard-to-image surfaces 2323 where the anterior and posterior surfaces of the lens come together can be estimated in at least the following ways:
(1) an estimate of the shape of the hard-to-image surfaces can be made by a qualified ophthalmologist and this shape can be scaled so that it blends with the imaged surfaces of the anterior and posterior lens surfaces. (2) acoustic images of the region where the anterior and posterior lens surfaces come together can be made using advanced methods such as described below. These can be combined with other B-scans of the anterior and posterior surfaces of the lens. (3) plots of anterior and posterior surface angles can be used to estimate the approximate location of the hard-to-image surfaces where the anterior and posterior lens surfaces come together
[0282] The volume of the lens capsule can be determined for example by taking a number of B-scans at different meridian angles and using these to collect a number of points on the anterior and posterior lens surface to form a 3-D representation of the lens. Once a wire frame surface grid is constructed, other points on the lens surface can be approximated by any number of well-known multi-dimensional interpolation methods. The co-ordinates can be used to compute the volume of the lens, for example, if the lens is not a perfect ellipsoid.
Alternate Transducer Configuration
[0283] FIG. 24 is a schematic of a transducer configuration for improving the angular range of imaging of an ultrasonic arc scanner. An arc scanner typically has a maximum included angle through which its transducer moves along its arc guide track. The included angle is typically in the range of about 60 degrees to about 80 degrees. Depending on where the center of curvature of the arc guide track is positioned, the lateral width of an eye component of interest that the scanner can image, may be limited, for example by the eyelid. The transducer configuration illustrated in FIG. 24 will help to extend the lateral range of the image. FIG. 24 shows an arc guide track assembly 2401 on which a transducer carriage 2403 is mounted. The transducer carriage 2403 moves along an arc guide track 2402 during a scan while, as described in FIGS. 21A , 21 B, and 21 C, and FIGS. 22A , 22 B, and 22 C, the arc guide track assembly may also be moved linearly during a “combined” scan. FIG. 24 illustrates three transducers 2411 , 2412 and 2413 mounted on a single transducer shaft 2404 . There can be more than three transducers but typically at least one of the transducers 2412 will have its axis aligned with the axis of the transducer shaft 2404 which in turn is preferably aligned along a radius of curvature of the arc guide track 2402 . The included angle 2424 between adjacent transducers is typically in the range of about 1 degree to about 15 degrees. The center transducer 2412 will typically be used to image a specular surface of interest, such as a cornea or lens surface, while the outside transducers 2411 and 2413 will typically be used to image non-specular components of interest such as the sclera, iris, zonules etcetera. The outside transducers 2411 and 2413 can also provide partial or substantially complete images of the lens surfaces in the region where the anterior and posterior surfaces come together. The pulses emitted and reflected signals received by each transducer may be separate or co-ordinated. Since the exact timing of emitted pulses and the exact location of each transducer is always known, the reflected signals received by each transducer may be reconstructed into a comprehensive image by post-processing or real time processing.
Control and Signal Processing
[0284] FIG. 25 depicts a control and signal processing system for any of the ultrasound imaging device configurations discussed above. The system 2500 includes a sensor array 2508 and controlled device 2512 in signal communication, via duplexed channels 2516 and 2520 , with a computer 2504 .
[0285] The sensor array 2508 includes a host of linear or angular position sensors that, inter alia, track the relative and/or absolute positions of the various movable components, such as the positioning mechanism 602 , arc guide track 601 and transducer carriage 603 , rotatable transducer head 605 , transducer or arc scanner head 605 and 709 , scanner head mount arm 710 , axial piston 703 , piston 704 , piston 705 , linear carriage 802 , arc carriage 803 , a motor to move the arc carriage 803 along the track 805 (not shown), and linear drive motor in the linear drive motor housing 807 . The sensor array can include any suitable type of positional sensors, including inductive non-contact position sensors, string potentiometers, linear variable differential transformers, potentiometers, capacitive transducers, eddy-current sensors, Hall effect sensors, proximity sensors (optical), grating sensors, optical encoders (rotary or linear), and photodioide arrays. Preferred sensor types are discussed in U.S. patent application Ser. No. 12/347,674, which is incorporated herein by this reference.
[0286] The controlled device 2512 is any device having an operation or feature controlled by the computer 2504 . Controlled devices include the various movable or activatable components, such as the positioning mechanism 602 , arc guide track 601 and transducer carriage 603 , rotatable transducer head 605 , transducer or arc scanner head 605 and 709 , scanner head mount arm 710 , axial piston 703 , piston 704 , piston 705 , linear carriage 802 , arc carriage 803 , motor to move the arc carriage 803 along the track 805 (not shown), and linear drive motor in the linear drive motor housing 807 .
[0287] The computer 2504 is preferably a software-controlled device that includes, in memory 2524 , a number of modules executable by the processor 2528 . The executable modules include the controller 2532 to receive and process positioning signals from the sensor array 2508 and generate and transmit appropriate commands to the monitored controlled device 2512 , imaging module 2536 to receive and process A- and B-scan images to produce two-, three- or four dimensional images of selected ocular components or features, and measurement module 2540 to determine, as discussed above, the dimensions and/or volumes of selected ocular components and/or features. The imaging algorithm used by the imaging module 2536 is further discussed in U.S. patent application Ser. No. 12/418,392, which is incorporated herein by this reference.
A Third Method for Centrating
[0288] FIG. 26 is a schematic representation of a third method for centrating an ultrasound scanner on a curved area of interest of an eye, such as, for example, the anterior surface of the cornea 2605 . The posterior surface of the cornea 2608 is shown for reference. In this method, a transducer 2602 travels along a track 2601 . Track 2601 may be a linear or curved track, or any combination thereof. The transducer is positioned in the general area of the area of interest of the eye by another means, such as, for example, visually by an operator. As the transducer 2602 travels along the track, ultrasound pulses represented by ray 2604 are emitted at known transducer positions along the track. As can be appreciated, the length of the pulse path for each ray 2604 can be plotted obtain a geometrically accurate representation of the anterior surface of the cornea 2605 , using known A-scan or B-scan methods. A curve, arc, circle, or ellipse, or other shape 2606 can be fitted to the area of interest of the eye, and the location of the apex and centroid of center of curvature 2607 of curve, arc, circle, or ellipse, or other shape 2606 can be calculated. The process of fitting a curve, arc, circle, or ellipse, or other shape to the area of interest of the eye may be performed using computer techniques, any of which may not require generating an actual geometrically correct plot. Since the position of transducer 2602 is accurately recorded for each ray 2604 , track 2601 can subsequently be moved laterally by positioner 2603 to align the axis of transducer 2602 with the line joining the apex and centroid of the curve, arc, circle, or ellipse, or other shape fitted to the area of interest of the eye 2607 . This substantially achieves lateral centration. Further, track 2601 can be moved axially (along its z-axis) by positioner 2603 to, for example, place the focal plane of transducer 2602 on the anterior surface of the cornea 2605 to substantially achieve axial centration.
[0289] This method can be repeated at one or more meridional positions to centrate the scanner within the x-y plane.
Methods for Determining Thickness and Sound Speed of a Selected Region of the Eye
[0290] In the following, the lens is used as an example of a selected region of the eye to illustrate a method for determining thickness and sound speed of a selected region. The same method may be applied to the cornea, aqueous humor and vitreous humor, any artificial lens and the like, all of which are bounded by acoustically reflective interfaces.
[0291] Typically, the thickness of a lens, measured approximately along its optical axis utilizing an ultrasound technique, can be estimated by either of two known methods:
[0292] (1) by measuring the thickness of the lens directly from an ultrasound B-scan image. The B-scan is constructed from by measuring reflected pulse time of arrivals of many pulses and converting these to distances by using accepted acoustic velocities in water, the cornea, the lens, the vitreous and aqueous humors as described, for example, in “Ultrasonography of the Eye and Orbit”, Second Edition, Coleman et al, published by Lippincott Williams & Wilkins, 2006.
[0293] (2) by measuring the thickness of the lens using an A-scan by setting the ultrasonic transducer with its focal plane inside the lens, preferably near the center, with the transducer axis substantially aligned with the optical axis of the lens, then measuring the time difference between the reflected pulse peak from the posterior surface of the lens and the reflected pulse peak from the anterior surface of the lens. This time difference Δt can be converted to the desired on-axis lens thickness by the formula:
[0000] Δ z=Δt/ 2 c
[0294] where
Δt=measured time difference between the pulses reflected off the anterior and posterior surface Δz is the on-axis lens thickness and c=the accepted lens acoustic velocity
[0298] The factor of 2 arises as the reflected pulse from the posterior surface travels twice the distance across the lens. The pulse transit time across a region is therefore ½ the measured time between the pulses reflected from the anterior and posterior surfaces of the region.
[0299] Both of these methods, which are known, rely on the use either implicitly or explicitly on the accepted acoustic velocity used for the lens to create the B-scan or to convert the pulse transit time difference of an A-scan to a distance measurement. Also both of these methods rely on an image of at least the posterior pole region of the lens capsule which can usually, but not always, be obtained by a simple arc scanner (arcuate guide track only) with its transducer substantially aligned with the optical axis.
[0300] An independent measurement of the lens thickness may be obtained, for example, from a high quality nuclear magnetic resonance scan (“MRI”) of the eye and an accurate measurement taken from the MRI image. This can be compared to the lens thickness determined from either of the two methods described above. Yet another independent measurement of the lens thickness may also be obtained, for example, from a high quality optical image of the eye taken along the optical axis of the eye. This can be compared to the lens thickness determined from either of the two methods described above. Both of these independent methods require corrections which may lead to errors and these measurements would have to be accurate to within about 10 to about 20 microns to be useful.
[0301] A method for determining the thickness of a lens along any line through the lens including the on-axis line (visual or optical on-axis line) is to utilize A-scans and the z-axis positioner. The scanner is positioned so that the transducer can emit pulses along a line through a substantial section of a region of interest such, as for example, the lens of an eye. With the scan head fixed, the positioner is moved back and forth along the z-direction until the anterior surface of the lens is identified and its reflected A-scan signal amplitude is maximized. This corresponds to the focal plane of the transducer being placed on the anterior surface of the lens. The z-axis position of the positioner, z 1 , is recorded. Next, the positioner is moved back and forth along the z-direction until the posterior surface of the lens is identified and its reflected A-scan signal amplitude is maximized. This corresponds to the focal plane of the transducer being placed on the posterior surface of the lens. The z-axis position of the positioner, z 2 , is then recorded. The difference is |z 1 −z 2 |=Δz, where Δz is a direct measurement of the lens thickness. In this method, the transducer holder is aligned with the z-axis of the positioner so that the face of the transducer always moves perpendicularly to the z-axis when the positioner is moved along its z-axis.
[0302] The following figures describe, in more detail, a method for determining the thickness of a selected region of the eye and for determining an accurate measure of average sound speed in the selected region.
[0303] FIGS. 27A and 27B illustrate the position of an apparatus that can measure thickness and sound speed of a selected region of the eye. FIG. 27A shows a positioner arm 2701 rigidly attached to a arcuate guide track 2702 . A transducer carriage 2703 is shown centered on the arcuate guide track 2702 . An ultrasound transducer holder 2704 is rigidly attached to transducer carrier 2703 such that the transducer element emits an ultrasound pulse along a path 2723 that is aligned with the axis of transducer holder 2704 along the z-axis 2721 of the positioner arm 2701 . In this example, the path 2723 of the ultrasound pulse is shown entering an eye 2711 substantially along its visual or optical axis. As will be noted below, the path 2723 of the ultrasound pulse may be at an angle to the visual or optical axis as long as it intersects the two interfaces of the selected region for purposes of determining sound speed of the region. However, it is always preferable to make measurements where the sound pulse is normal to the interfaces so as to minimize refractive errors.
[0304] FIG. 27B shows a close up of the eye illustrating the path 2723 of the ultrasound pulse through the cornea 2731 and the lens 2732 . In this example, the focal plane 2724 of the ultrasound transducer is shown located in the aqueous humor between the cornea 2731 and the lens 2732 . As the positioner arm 2701 is moved back and forth 2722 along its z-axis 2721 , the focal plane 2124 of the transducer moves along the z-axis such that it can cross the two interfaces bounding the region of interest in the eye. As described in FIGS. 28A , 28 B, 28 C, 28 D, and 28 E, the two example interfaces are the anterior and posterior surfaces of a lens.
[0305] FIGS. 28A , 28 B, 28 C, 28 D, and 28 E illustrate the movement of the transducer focal plane to measure thickness and sound speed of a selected region of the eye (a lens in this example). FIG. 28A shows a cornea 2811 and a lens 2812 of an eye with an ultrasound pulse path 2803 passing through the eye. The face 2801 of an ultrasound transducer is shown in relation to the focal plane 2802 of the transducer. The transducer is set up as described in FIGS. 27A and 27B such that the ultrasound pulse path 2803 is aligned to be coincident with the z-axis of the positioner arm. FIG. 28A shows the focal plane 2802 of the transducer behind the posterior surface of lens 2812 in the vitreous humor. In FIG. 28B , the positioner arm has been retracted along its z-axis, moving the focal plane of the transducer into the lens just inside the posterior surface of the lens so that the focal plane has passed across the posterior interface of the lens. As the focal plane is moved, the transducer is emitting a series of ultrasound pulses producing an A-scan with each pulse. In FIG. 28C , the positioner arm has been further retracted along its z-axis, moving the focal plane of the transducer into the center of the lens while continuing to emit a series of ultrasound pulses. In FIG. 28D , the positioner arm has been further refracted along its z-axis, moving the focal plane of the transducer up to the anterior surface of the lens while continuing to emit a series of ultrasound pulses. In FIG. 28E , the positioner arm has been further retracted along its z-axis, moving the focal plane of the transducer past the anterior interface of the lens into the aqueous humor region so that the focal plane has passed across the anterior interface of the lens while continuing to emit a series of ultrasound pulses. The transducer has now generated a series of A-scans as the focal plane 2802 traverses both surfaces of the lens which is the selected region in this example. At the same time, the position of the transducer along the z-axis has been recorded, for example by a magnetic encoding strip on the positioner arm, so that the position of the transducer focal plane is known for each A-scan.
[0306] As can be appreciated, the series of A-scans can be generated as described above by moving the transducer in either direction through the selected region. If the positioner arm has significant back lash when its motion is reversed, then it is preferable to move the positioner arm continuously in either one direction or the other to obtain the most accurate measurements.
[0307] FIGS. 29A , 29 B, 29 C, and 29 D illustrate an clinical ultrasound A-scan. This figure was taken from FIGS. 1.8 and 1 . 9 of “Ultrasonography of the Eye and Orbit”, Second Edition, Coleman et al, published by Lippincott Williams & Wilkins, 2006 and illustrates how an A-scan is generated and interpreted. FIG. 29A is a schematic representation of the main interfaces in an eye that generate strong reflected ultrasound signals. Shown are the surfaces bounding regions of the cornea (C), the aqueous humor (A), the lens (L) the vitreous humor (V) and finally the retina (R). FIG. 29B shows the corresponding reflected A-scan signals from the anterior surface of the cornea (AC), posterior surface of the cornea (PC), the anterior surface of the lens (AL), posterior surface of the lens (PL) and the retina (R). FIG. 29C shows a typical RF ultrasound signal (voltage versus time) where the leftmost signals correspond to reflections from the membrane separating the fluid in the eyepiece from the fluid in the scanner. FIG. 29C shows reflections from the membrane, the corneal and lens surfaces but does not show the reflection from the retina. FIG. 29D shows the rectified A-scan signal of FIG. 29C . Many rectified and filtered A-scans are used to modulate a grayscale that is commonly used to generate a B-scan.
[0308] FIG. 30 is a schematic representation of an A-scan of a cornea of an eye. This illustration shows a typical rectified signal through the cornea as amplitude 12 versus time 11 . Local maximum 1 represents the anterior surface of the cornea, local maximum 2 represents Bowman's layer within the cornea and local maximum 3 represents the posterior surface of the cornea.
[0309] FIG. 31 is a schematic of an A-scan of the anterior segment of an eye. This illustration shows a typical rectified and filtered signal through the anterior segment as amplitude 12 versus time 11 . Local maximum 1 represents the anterior surface of the cornea, local maximum 2 represents Bowman's layer, local maximum 3 represents the posterior surface of the cornea, local maximum 4 represents the anterior surface of the lens and local maximum 5 represents the posterior surface of the lens.
[0310] FIG. 32 is a schematic of an A-scan of an eye from cornea to retina. This illustration shows a typical rectified and filtered signal through the entire interior of an eye as amplitude 12 versus time 11 . Local maximum 1 represents the anterior surface of the cornea, local maximum 3 represents the posterior surface of the cornea, local maximum 4 represents the anterior surface of the lens, local maximum 5 represents the posterior surface of the lens and local maximum 6 represents the surface of the retina. The reflected pulses are shown decreasing in amplitude for interfaces deeper within the eye. This is because the further an acoustic pulse travels, the greater the amplitude attenuation in the acoustic medium. Unless dynamic focusing techniques are used, the reflected signal strength also decreases rapidly as the distance between the interface and transducer focal plane increases.
[0311] FIG. 33 is a schematic of a series of A-scan maximum amplitudes 12 plotted versus distance 11 along a z-axis of a positioner. In this graph, the ultrasound transducer holder axis is accurately aligned with the z-axis of the positioner so that the face of the transducer element always moves perpendicularly to the z-axis when the positioner is moved along its z-axis. As the focal point of the transducer approaches an interface, the maximum signal amplitude increases to a maximum value and then decreases as the focal plane of the transducer passes across the interface. In the example of FIG. 33 , the transducer is moved from an initial position where its focal plane is in front of the anterior surface of the region of interest and is moved until it is beyond the posterior interface of the region of interest. Thus there are two local maximum values 1 and 2 that correspond to interfaces generated by this procedure. The local maximum values are particularly strong when the interfaces are specular. Since the z-position of the positioner is recorded, the difference in z-positions between the first local maximum value 1 and the second local maximum value 2 is a mechanical measurement of the distance between the two interfaces and has the precision of the positioner locator method. For example, if a commercially available magnetic encoder strip is used, the z-position can currently be measured to an accuracy of about 1 micron.
[0312] As can be appreciated, any or all of the A-scans used in the above procedure may be used to measure the time difference between the two interfaces of the region of interest. If many or all A-scans are used, they can be averaged to obtain an even more accurate measurement. If a commercially available 200 MHz A/D converter is used to digitally record each A-Scan, then a time difference between the two interfaces can currently be measured to an accuracy of about 5 nanoseconds.
[0313] Using the above accuracies for distance and time measurements, average sound speed can be measured with an error of no more than about:
[0314] 30 m/s in the cornea
[0315] 5 m/s in the aqueous humor and lens
[0316] 1 m/s in the vitreous humor
[0317] The large error in the cornea is because the width of the cornea is so small, being typically about 0.5 mm.
[0318] Once the distance, Δz, between two interfaces of the region of interest is determined by the mechanical displacement of the z-axis positioner and the time interval, Δt, between two interfaces of the region of interest is determined from A-scans, then the average speed of sound, c, of the region of interest can be determined as c=2 Δz/Δt where Δt is the measured time difference between the pulses reflected off the anterior and posterior surface of the region of interest.
[0319] FIG. 34 is a schematic of A-scan amplitudes 12 versus distance 11 along a z-axis of a positioner showing a local maximum. As the focal point of the transducer approaches an interface, the maximum signal amplitude increases to a maximum value and then decreases as the focal plane of the transducer passes across the interface. Since the measurement is typically made digitally by an A/D converter, the maximum value of any A-scan may not be taken when the focal plane of the ultrasound transducer is exactly at the interface. A more accurate location and amplitude may be computed by fitting the digitally acquired data points 21 with an analytical curve 22 . The analytic curve might be any appropriate function such, as for example, an n-term polynomial determined by a least squares fit to the digital data in the vicinity of the local maximum value, where n is an integer between about 4 and about 20.
[0320] If ‘a’ is the amplitude of the analytic function that is curve fit and ‘z’ is the distance along the z-axis, then the curve fit is of the form:
[0000] a=f ( z )
[0000] when the derivative of the function f′(z)=0, then a=a-max and z=z-max. Then a-max and z-max so obtained can be used as a more accurate representation of the local maximum value and z-max can be used as a more accurate value for the location of the interface.
[0321] FIGS. 35A , 35 B, and 35 C illustrates the form of amplitude versus position of a focused ultrasound transducer. FIG. 35A shows the reflected signal amplitude in the axial half-plane (along the signal path). FIG. 35B shows the reflected signal amplitude in the lateral half-plane (perpendicular to the signal path). FIG. 35C shows a net plot of the signal amplitude for the region of the focal plane of the transducer. As can be seen, the amplitude will be at its highest in the focal region of the transducer. An annular array transducer can be used to move the focal plane of transducer to different regions of the eye and therefore can, with a single transducer, deliver high signal-to-noise reflected signals for selected regions throughout the eye.
[0322] The method disclosed above is described in more detail as follows:
[0000] 1. Select a region (for example, cornea, lens, aqueous humor, vitreous humor) defined by at least two interfaces having acoustically reflective interfaces. The interfaces are preferably specular surfaces such as the anterior and posterior surfaces of the cornea and lens However, the interfaces may be non-specular but acoustically reflective interfaces such as for example the surface of the retina or sclera. The anterior interface is the first interface and the posterior interface is the second interface. Interfaces may be referred from time to time as surfaces.
2. Accurately align the transducer holder with the z-axis of the positioner so that the face of the transducer always moves perpendicularly to the z-axis when the positioner is moved along its z-axis.
3. Select any path thru the region for which the speed of sound is to be measured. A path substantially intersecting the interfaces perpendicularly is preferred. Any other path long enough to get an accurate measurement between the first and second interfaces of the selected region may be used but such a path may give rise to small refractive errors.
4. Position the ultrasound transducer as far back on z-axis as possible or at least with focal plane in front of the first interface; or position the transducer as far forward on z-axis as possible or at least with focal plane behind the second interface. In either case, the focal plane of the transducer should be able to traverse both interfaces defining the selected region during the taking of the measurement.
5. a. Move the transducer assembly along the z-axis with z-axis positioner taking a plurality of A-scans along a path crossing both anterior and posterior interfaces of the selected region.
b. If moving from anterior to posterior, when near the first interface, move the transducer assembly so as to determine a local maximum value of the A-scan amplitude in the vicinity of the first interface. This gives z 1 as determined by the positioner location along the z-axis. When near the second interface, move the transducer assembly so as to determine a local maximum value of the A-scan amplitude in the vicinity of the second interface. This gives z 2 as determined by the positioner location along the z-axis. FIG. 32 illustrates the maximum amplitudes from a plurality of A-scans as a function of distance along the z-axis. c. If moving from posterior to anterior, when near the second interface, move the transducer assembly so as to determine a local maximum value of the A-scan amplitude in the vicinity of the second interface. This gives z 2 as determined by the positioner location along the z-axis. When near the first interface, move the transducer assembly so as to determine a local maximum value of the A-scan amplitude in the vicinity of the first interface. This gives z 1 as determined by the positioner location along the z-axis. d. In making a series of A-scans for this procedure, it is preferable to determine z 1 and z 2 by moving the positioner in one direction along the z-axis so as to avoid mechanical backlash in the z-positioner.
6. Optionally, fit an analytic curve (preferably by the least squares method) to the A-scan data acquired in Step 5 to get a more accurate local maximum value, z 1 max and z 2 max, for z 1 and z 2 . The more accurate value is determined by calculating the local maximum value of the function used for the curve fit. If a=amplitude and z=distance along the z-axis, then a curve fit is of the form:
[0000] a 1 =f ( z 1)
[0326] when f′(z 1 )=0, then a 1 =a 1 max and z 1 =z 1 max
[0327] similarly
[0000] a 2 =f ( z 2)
[0000] when f′(z 2 )=0, then a 2 =a 2 max and z 2 =z 2 max
7. Δz=abs (z 1 −z 2 ) and Δt=abs (t 1 −t 2 )
8. Use any or all A-scans taken during the measurement to get t 1 and t 2 where t 1 is the time of the maximum value of the first interface on each A-scan and t 2 is the time of the maximum value of the second interface on each A-scan. FIG. 31 illustrates an A-scan showing amplitude of reflected signal as a function of time and illustrating peaks corresponding to a first and second interface (for example peaks 4 and 5 are the anterior and posterior interfaces of lens).
9. The speed of sound in the selected region is: c=2 Δz/Δt where Δt is the measured time difference between the pulses reflected off the anterior and posterior surface. The factor of 2 arises as the reflected pulse from the posterior surface travels twice the distance across the lens. The pulse transit time across a region is therefore ½ the measured time between the pulses reflected from the anterior and posterior surfaces of the region.
10. Repeat 1 thru 9 to eliminate unintended eye motion
[0328] A number of variations and modifications of the inventions can be used. For example, a linear scan can be made wherein the transducer carriage is set at a desired angular position along the arc guide track and then the entire arc guide track assembly is moved laterally. This process can be repeated with the transducer carriage set at a different desired angular positions along the arc guide track. This method can generate, for example, detailed images of non-specular features of interest such as such as: the angle between the cornea and iris lying behind the sclera; the zonules attaching the lens; and the sulci formed on the posterior surface of the iris where the anterior and posterior lens surfaces come together. In another scan method, a combined scan can be made where the arc guide track assembly is moved laterally while the transducer carriage moves along the arc guide track. Before the transducer carriage is moved from one end of the arc guide track and after the transducer carriage has reached the other end of the arc guide track, short lateral linear scans can be made. These short linear scans can increase the image quality of non-specular features of interest such as such as: the angle between the cornea and iris lying behind the sclera; the zonules attaching the lens; and the sulci formed on the posterior surface of the iris where the anterior and posterior lens surfaces come together. In another scan technique, the arcuate and linear motions of the transducer can be fully co-ordinated to optimize the angle of the transducer axis relative to an area of interest, such as for example the area where the zonules connect the lens with the ciliary body.
[0329] As will be appreciated, it would be possible to provide for some features of the inventions without providing others. For example, though the embodiments are discussed with reference to an arc scanning device, it is to be understood that the various embodiments may be used with other types of acoustic scanning devices using different transducer motion strategies.
[0330] The present invention, in various embodiments, includes components, methods, processes, systems and/or apparatus substantially as depicted and described herein, including various embodiments, sub-combinations, and subsets thereof. Those of skill in the art will understand how to make and use the present invention after understanding the present disclosure. The present invention, in various embodiments, includes providing devices and processes in the absence of items not depicted and/or described herein or in various embodiments hereof, including in the absence of such items as may have been used in previous devices or processes, for example for improving performance, achieving ease and\or reducing cost of implementation.
[0331] The foregoing discussion of the invention has been presented for purposes of illustration and description. The foregoing is not intended to limit the invention to the form or forms disclosed herein. In the foregoing Detailed Description for example, various features of the invention are grouped together in one or more embodiments for the purpose of streamlining the disclosure. This method of disclosure is not to be interpreted as reflecting an intention that the claimed invention requires more features than are expressly recited in each claim. Rather, as the following claims reflect, inventive aspects lie in less than all features of a single foregoing disclosed embodiment. Thus, the following claims are hereby incorporated into this Detailed Description, with each claim standing on its own as a separate preferred embodiment of the invention.
[0332] Moreover though the description of the invention has included description of one or more embodiments and certain variations and modifications, other variations and modifications are within the scope of the invention, e.g., as may be within the skill and knowledge of those in the art, after understanding the present disclosure. It is intended to obtain rights which include alternative embodiments to the extent permitted, including alternate, interchangeable and/or equivalent structures, functions, ranges or steps to those claimed, whether or not such alternate, interchangeable and/or equivalent structures, functions, ranges or steps are disclosed herein, and without intending to publicly dedicate any patentable subject matter. For example, the steps may be performed in any order and are not limited to the particular ordering discussed herein.
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A method and apparatus are disclosed for generating accurate and precise ultrasonic images of biological materials or animate objects, such as the cornea and lens of the eye, and, in particular, to an ultrasonic scanning apparatus that can position its virtual center of curvature such that its ultrasonic transducer will emit pulses that reflect substantially perpendicularly from a curved specular surface of interest within the eye. This invention can allow real time imaging of a lens as it accommodates and can better enable researchers and ophthalmic surgeons to develop, fit, implant and diagnose performance of artificial lenses including accommodative lenses.
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TECHNICAL FIELD
[0001] The present invention generally relates to the construction of pneumatic tires and more particularly the sidewall area and rim flange protection of a tire.
BACKGROUND OF THE INVENTION
[0002] For many years, tire manufacturers have considered the use of colored sidewalls. One technique known in the art embeds the desired colored compound into the characteristic black sidewall stock of the tire during the extruding or the fabrication of the sidewall and prior to the first stages of tire fabrication or building. The colored compound is normally covered with a thin layer or laminate of black sidewall stock commonly referred to as a cover strip. The tire is subsequently completed in conventional fashion as in the manufacture of a standard black wall tire through the shaping and vulcanization steps. Subsequent to vulcanization, grinding or butting equipment is employed to remove portions of the cover strip and expose the extent of colored compound necessary to achieve the predetermined desired decorative effect. Other ways of adding color to sidewalls have also been proposed. Commercial acceptance of these methods have been limited because of the additional cost associated with the additional processing steps and the increased number of imperfect tires caused by the additional processing.
BRIEF DESCRIPTION OF THE DRAWINGS
[0003] Reference will be made in detail to preferred embodiments of the invention, examples of which are illustrated in the accompanying drawings. The drawings are intended to be illustrative, not limiting. Certain elements in selected ones of the drawings may be illustrated not-to-scale, for illustrative clarity.
[0004] FIG. 1 is a cross-sectional view of a portion of a tire with a removable member and rim flange protector;
[0005] FIG. 2 is a close up view of the removable member and rim flange protector of FIG. 1 ;
[0006] FIG. 3 is a close up view of the removable member and rim flange protector of FIG. 2 shown with an optional flex groove;
[0007] FIG. 4 illustrates a second embodiment of a removable member having a cap and split base cross-section;
[0008] FIG. 5 is a third embodiment of a removable member;
[0009] FIG. 6 is a fourth embodiment of a removable member.
DEFINITIONS
[0010] “Apex” means an elastomeric filler located radially above the bead core and between the plies and the turnup ply.
[0011] “Axial” and “Axially” means the lines or directions that are parallel to the axis of rotation of the tire.
[0012] “Axially Inward” means in an axial direction toward the equatorial plane.
[0013] “Axially Outward” means in an axial direction away from the equatorial plane.
[0014] “Bead” or “Bead Core” generally means that part of the tire comprising an annular tensile member of radially inner beads that are associated with holding the tire to the rim; the beads being wrapped by ply cords and shaped, with or without other reinforcement elements such as flippers, chippers, apexes or fillers, toe guards and chafers.
[0015] “Belt Structure” or “Reinforcement Belts” means at least two annular layers or plies of parallel cords, woven or unwoven, underlying the tread, unanchored to the bead, and having both left and right cord angles in the range from 17E to 27E relative to the equatorial plane of the tire.
[0016] “Breakers” or “tire breakers” means the same as belt or belt structure or reinforcement belts.
[0017] “Bead” or “Bead Core” generally means that part of the tire comprising an annular tensile member of radially inner beads that are associated with holding the tire to the rim.
[0018] “Carcass” means the tire structure apart from the belt structure, tread, undertread over the plies, but including the beads.
[0019] “Circumferential” most often means circular lines or directions extending along the perimeter of the surface of the annular tread perpendicular to the axial direction; it can also refer to the direction of the sets of adjacent circular curves whose radii define the axial curvature of the tread, as viewed in cross section.
[0020] “Cord” means one of the reinforcement strands of which the plies and other cord-reinforced components of the tire are comprised.
[0021] “Green carcass” means the uncured tire carcass prior to the installation of the belt structure and tread.
[0022] “Insert” means the cross-sectionally crescent- or wedge-shaped reinforcement typically used to reinforce the sidewalls of runflat-type tires.
[0023] “Lateral” means a direction parallel to the axial direction.
[0024] “Ply” means a cord-reinforced layer of rubber coated radially deployed or otherwise parallel cords.
[0025] “Radial” and “radially” mean directions radially toward or away from the axis of rotation of the tire.
[0026] “Radial ply structure” means the one or more carcass plies of which at least one ply has reinforcing cords oriented at an angle of between 65° and 90° with respect to the equatorial plane of the tire.
[0027] “Radial ply tire” means a belted or circumferentially-restricted pneumatic tire in which at least one ply has cords which extend from bead to bead are laid at cord angles between 65° and 90° with respect to the equatorial plane of the tire.
[0028] “Shoulder” means the upper portion of sidewall just below the tread edge.
[0029] “Sidewall” means that portion of a tire between the tread and the bead.
[0030] “Tangential” and “tangentially” refer to segments of circular curves that intersect at a point through which can be drawn a single line that is mutually tangential to both circular segments.
[0031] “Tread” means the ground contacting portion of a tire.
[0032] “Tire crown” means the tread, tread shoulders and adjacent portions of the sidewalls.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT
[0033] Referring to FIG. 1 , there is shown the partial cross section of a tire suitable for use as a passenger tire, truck tire for example, but not limited to same. The tire includes a tread portion 110 comprising a ground engaging tread having two outer shoulders 112 and a circumferential belt structure (not shown) located between the shoulders and radially inward of the tread. The tire 100 may further include two bead areas (not shown) and other such common elements as chafers, chippers, and flippers. Elastomeric sidewalls 120 extend radially outward from the bead areas respectively, to the tread shoulders 112 . The tire 100 may further comprise a carcass structure comprising at least one cord reinforced elastomeric ply (not shown) extending outward from each bead area through the sidewalls 112 . The sidewalls may further comprise a rubber projection or rim flange protector 140 , which may be provided on one or both of the sidewalls 120 . The rim flange protector may typically be mounted near the general bead areas 130 of the tire, although not required. The rim flange protector 140 preferably comprises a continuous, circumferential elastomeric projection extending axially outward from a sidewall 120 so that the projection extends radially outward of the rim flange (not shown) of a rim.
[0034] A close-up view of the rim flange protector 140 is shown in FIG. 2 . The rim protector 140 further comprises a groove 150 , which is preferably circumferentially continuous (i.e., circular), although not required. The groove 150 may have any desired configuration, and may for example, comprise a sector or arc-shaped groove. The cross-sectional shape of the groove 150 is preferably “dove-tailed” shape, such that the inner portion 152 of the groove is narrower than the outer portion 154 of the groove. However, the cross-sectional shape of the groove may vary and have straight sidewalls for example. The groove 150 further comprises side portions 156 , 158 which may be shaped complementary to mate with side edges 162 , 164 of a second member 160 . The second member 160 is preferably ring shaped or arc-shaped. The second member 160 may be comprised of a precured elastomeric or rubber member which is assembled to the tire post-cure. The second member 160 may also comprise plastic, metal, alloys, thermoplastic or thermoplastic elastomers. Preferably, the second member 160 is made of polyurethane. More preferably, the second member is made of a polyurethane ring having a hardness greater than the sidewall hardness. For example, in order to further enhance the protective effect of the rim flange protector, the second member preferably has a hardness of 85 or more.
[0035] As shown in FIG. 2 , the second member 160 has an outer cap 166 which is seen by the consumer, and an inner portion 166 which is received in or “snapped into” groove 150 . The inner portion 166 may have an interference fit with groove 150 . The inner portion 166 is complementary shaped to be received in groove 150 . The shape of the outer cap 168 may vary as desired. The outer cap may be larger or smaller as desired, and has a decorative aspect in addition to providing a rim protector feature and may be colored as desired. The outer cap may be decorative, and may be colored as desired for a decorative effect. The outer cap is preferably non-black in color. The decorative cap may additionally comprise one or more lights such as led lights for enhanced visibility. The decorative cap may also comprise highly reflective material or materials which glow in the dark. Further, the outer cap may have identifying indicia such as a trademark or logo. The second member may be a ring shaped member, arc shaped member, or comprise additional shapes as desired.
[0036] FIG. 3 illustrates a second embodiment of the invention which is similar to the embodiment of FIG. 2 , with the addition of a flexible groove 170 . The flexible groove is preferably located adjacent the groove 150 and provides resiliency of the rim flange protector 140 should a shock occur. The flexible groove 170 helps to deter the dislodging of the member from the groove.
[0037] FIG. 4 illustrated a third embodiment of the invention which is similar to the embodiment of FIG. 2 , except that the second member 200 has a different shape. The inner portion of the second member has been split into two or more portions, 202 , 204 . The two or more portions 202 , 204 are received in the groove 150 , and provide a spring like effect in order to help facilitate the retention of the portions 202 , 204 within the groove.
[0038] FIG. 5 illustrates a fifth embodiment of the invention. The rim flange protector 140 comprises two or more grooves, 314 , 318 for receiving two or more projections 306 , 308 of a removable member 300 , therein. The removable member has an elongated outer cap 302 , 304 which may comprise two or more colors. The projections 306 , 308 are preferably dove-tail shaped for snapping into grooves 314 , 318 .
[0039] FIG. 6 illustrates a sixth embodiment of the invention. In this embodiment, the rim flange protector 140 has an outward projection 410 , which is preferably T shaped. A removable member 400 has an outer cap 402 and an inner groove 404 opposite the cap. The inner groove has two opposed retention members 406 , 408 which are held in place onto the tire by the outer lip 412 , 414 . The member is preferably mounted to the tire post cure. The cap 400 may be is threaded onto the outer projection 412 in a circumferential manner, or snapped into place using axial force.
[0040] For all of the above described embodiments, the second member 160 may be mounted into the sidewall prior to closing the mold during the vulcanization of the tire 100 . Preferably, the second member 160 is inserted into the molded in groove 150 after the tire has been vulcanized. In that event, the base portion 166 can be adhered within the groove 150 , respectively, by either the tight fit between the base portion and the groove, or with an adhesive placed within the groove to insure that sufficient adhesive forces can be developed that the second member stays in place. In all of the embodiments described above, the second member 160 can be installed and/or removed from the vulcanized tire at a later time so as to insert another ring for reasons such as styling (using a different color ring or logo) or if the ring is damaged.
[0041] The above described embodiments are not limited to the location near the rim flange. Member 140 may be located anywhere on the sidewall.
[0042] The invention has been illustrated and described in a manner that should be considered as exemplary rather than restrictive in character. It is understood that only preferred embodiments have been shown and described, and that all changes and modifications that come within the scope of the invention are desired to be protected. Undoubtedly, many other “variations” on the techniques set forth hereinabove will occur to one having ordinary skill in the art to which the present invention most nearly pertains, and such variations are intended to be within the scope of the invention, as disclosed herein.
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The invention relates to a pneumatic tire with a toroidal shaped tire carcass having sidewalls and a tread. The tire carcass terminates at opposite bead regions for mounting on a tire rim. The tire has at least one of the sidewalls having a projection of rubber having a groove, and a removable member provided in the groove for forming a decorative or colored rim flange protector.
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BACKGROUND OF THE INVENTION
The present invention relates to UV screening compositions, methods for their preparation and their use. The invention in particular relates to, for example, compositions comprising particulate oxides, their preparation and their use as, for example, paints, plastics, coatings, pigments, dyes and compositions for topical application, in particular, for example, sunscreens.
The effects associated with exposure to sunlight are well known. For example, painted surfaces may become discoloured and exposure of skin to UVA and UVB light may result in, for example, sunburn, premature ageing and skin cancer.
Commercial sunscreens generally contain components which are able to reflect and/or absorb UV light. These components include, for example, inorganic oxides such as zinc oxide and titanium dioxide.
Titanium dioxide in sunscreens is generally formulated as “micronised” or “ultrafine” (20-50 nm) particles (so-called microreflectors) because they scatter light according to Rayleigh's Law, whereby the intensity of scattered light is inversely proportional to the fourth power of the wavelength. Consequently, they scatter UVB light (with a wavelength of from 290 to 320 nm) and UVA light (with a wavelength of from 320 to 400 nm) more than the longer, visible wavelengths, preventing sunburn whilst remaining invisible on the skin.
However, titanium dioxide also absorbs UV light efficiently, catalysing the formation of superoxide and hydroxyl radicals which may initiate oxidations. The crystalline forms of TiO 2 , anatase and rutile, are semiconductors with band gap energies of about 3.23 and 3.06 eV respectively, corresponding to light of about 385 nm and 400 nm (1 eV corresponds to 8066 cm −1 ).
An incident photon is absorbed by titanium dioxide if its energy is greater than the semiconductor band gap Eg shown in FIG. 1 . As a result an electron from the valence band (vb) is promoted into the conduction band (cb) (transition [ 1 ]). If the energy of the incident photon is less than Eg it will not be absorbed as this would require that the electron be promoted to within the band gap and this energy state is forbidden. Once promoted, the electron relaxes to the bottom of the conduction band (transition [ 2 ]) with the excess energy being emitted as heat to the crystal lattice.
When the electron is promoted it leaves behind a hole which acts as a positive particle in the valence band. Both the electron and the hole are then free to migrate around the titanium dioxide particle. The electron and hole may recombine emitting a photon of energy equal to the band gap energy. However, the lifetime of the electron/hole pair is quite long due to the specific nature of the electronic band structure. Thus there is sufficient time (ca. 10 −11 s) for the electron and hole to migrate to the surface and react with absorbed species.
In aqueous environments, the electrons react with oxygen, and the holes with hydroxyl ions or water, forming superoxide and hydroxyl radicals:
TiO 2 +hu → TiO 2 ( e − /h + )→ e − ( cb )+ h + ( vb )
e − ( cb )+O 2 →O 2 .− →HO . 2
h + ( vb )+OH −→ . OH
This has been studied extensively in connection with total oxidation of environmental pollutants, especially with anatase, the more active form [A. Sclafani et al., J. Phys. Chem., (1996), 100, 13655-13661].
It has been proposed that such photo-oxidations may explain the ability of illuminated titanium dioxide to attack biological molecules. Sunscreen titanium dioxide particles are often coated with compounds such as alumina, silica and zirconia which form hydrated oxides which can capture hydroxyl radicals and may therefore reduce surface reactions. However, some TiO 2 /Al 2 O 3 and TiO 2 /SiO 2 preparations exhibit enhanced activity [C. Anderson et al., J. Phys. Chem., (1997), 101, 2611-2616].
As titanium dioxide may enter human cells, the ability of illuminated titanium dioxide to cause DNA damage has also recently been a matter of investigation. It has been shown that particulate titanium dioxide as extracted from sunscreens and pure zinc oxide will, when exposed to illumination by a solar simulator, give rise to DNA damage both in vitro and in human cells [R. Dunford et al, FEBS Lett., (1997), 418, 87-90].
The present invention provides UV screening compositions which address the problems described above and are less liable to produce DNA damage on illumination than conventional sunscreen compositions.
SUMMARY OF THE INVENTION
The present invention accordingly provides UV screening compositions comprising particles which are capable of absorbing UV light, especially UV light having a wavelength below 390 nm, so that electrons and positively charged holes are formed within the particles, characterised in that the particles are adapted to minimise migration to the surface of the particles of the electrons and/or the positively charged holes when said particles are exposed to UV light in an aqueous environment. It is believed that under these circumstances the production of hydroxyl radicals is substantially reduced. Thus the production of hydroxyl radicals may be substantially prevented.
The minimisation of migration to the surface of the particles of the electrons and/or the positively charged holes may be tested by, for example, looking for a reduction in the number of strand breaks inflicted on DNA by light in the presence of particles or UV screening compositions according to the present invention, as compared with the number of strand breaks observed in DNA on treatment with particles used in conventional sunscreen compositions and light, or light alone.
The compositions according to the present invention may find application as paints, plastics, coatings, pigments, dyes and are particularly favoured for use in compositions for topical application, especially, for example, sunscreens.
The average primary particle size of the particles is generally from about 1 to 200 nm, for example about 50 to 150 nm, preferably from about 1 to 100 nm, more preferably from about 1 to 50 nm and most preferably from about 20 to 50 nm. For example, in sunscreens the particle size is preferably chosen to avoid colouration of the final product. For this purpose particles of about 50 nm or less may be preferred especially, for example, particles of about 3 to 20 nm, preferably about 3 to 10 nm, more preferably about 3 to 5 nm.
Where particles are substantially spherical then particle size will be taken to represent the diameter. However, the invention also encompasses particles which are non-spherical and in such cases the particle size refers to the largest dimension.
In a first embodiment the present invention provides UV screening compositions comprising particles which contain luminescence trap sites and/or killer sites. By luminescence trap sites and killer sites will be understood foreign ions designed to trap the electrons and positively charged holes and therefore inhibit migration.
These particles may be, for example, reduced zinc oxide particles, especially reduced zinc oxide particles of from about 100 to 200 nm in size or smaller, for example, from about 20 to 50 nm.
Such reduced zinc oxide particles may be readily obtained by heating zinc oxide particles which absorb UV light, especially UV light having a wavelength below 390 nm, and reemit in the UV in a reducing atmosphere to obtain reduced zinc oxide particles which absorb UV light, especially UV light having a wavelength below 390 nm, and reemit in the green, preferably at about 500 nm. It will be understood that the reduced zinc oxide particles will contain reduced zinc oxide consistent with minimising migration to the surface of the particles of electrons and/or positively charged holes such that when said particles are exposed to UV light in an aqueous environment the production of hydroxyl radicals is substantially reduced as discussed above.
The zinc oxide is preferably heated in an atmosphere of about 10% hydrogen and about 90nitrogen by volume, e.g. at about 800 ° C. and for about 20 minutes.
It is believed that the reduced zinc oxide particles possess an excess of Zn 2+ ions within the absorbing core. These are localised states and as such may exist within the band gap. Transitions [ 1 ] and [ 2 ] may occur as shown in FIG. 1 . However, the electron and hole may then relax to the excess Zn 2+ states (transition [ 3 ]) as shown in FIG. 2 . Thus the electrons and holes may be trapped so that they cannot migrate to the surface of the particles and react with absorbed species. The electrons and holes may then recombine at the Zn 2+ states (transition [ 4 ]) accompanied by the release of a photon with an energy equivalent to the difference in the energy levels.
Alternatively, particles of the present invention may comprise a host lattice incorporating a second component to provide luminescence trap sites and/or killer sites. The host lattice may be preferably selected from oxides, especially, for example, TiO 2 and ZnO, or for example, phosphates, titanates, silicates, aluminates, oxysilicates, tungstates and molybdenates. The second component may, for example, be selected according to criteria such as ionic size. Second components suitable for 5 use according to the present invention may, for example, be selected from nickel, iron, chromium, copper, tin, aluminium, lead, silver, zirconium, manganese, zinc, cobalt and gallium ions. Preferably the second component is selected from iron, chromium, manganese and gallium ions in the 3+state. Preferred particles according to the present invention comprise a titanium dioxide host lattice doped with manganese ions in the 3+state.
The optimum amount of the second component in the host lattice may be determined by routine experimentation. It will be appreciated that the amount of the second component may depend on the use of the UV screening composition. For example, in UV screening compositions for topical application, it may be desirable for the amount of the second component in the host lattice to be low so that the particles are not coloured. In the case of titanium dioxide doped with manganese ions in the 3+state, 0.5% manganese in the titanium dioxide host lattice has been shown to be effective in reducing the rate of DNA damage inflicted by simulated sunlight. However, amounts as low as 0.1% or less, for example 0.05%, or as high as 1% or above, for example 5% or 10%, may also be used.
The dopant ions may be incorporated into the host lattice by a baking technique typically at from 600° C. to 1000° C. Thus, for example, these particles may be obtained in a known manner by combining a host lattice with a second component to provide luminescence trap sites and/or killer sites.
It is envisaged that the mechanism of de-excitation for these particles is as described above for the reduced zinc particles.
In a further embodiment the present invention provides UV screening compositions comprising particles which comprise a population of coated nanoparticles of a metal oxide. The metal oxide is preferably titanium dioxide. The coating is typically a wide band gap material and is preferably a surfactant selected from trioctylphosphine oxide [TOPO] and sodium hexametaphosphate [(NaPO 3 ) 6 ].
The nanoparticles are generally from 1 to 10 nm in size and possibly from 1 to 5 nm in size.
It has been found that the nanoparticles may be obtained by dissolving a titanium salt, preferably titanium (IV) chloride, in an alcohol. The alcohol is 5 generally selected from methanol, ethanol, propanol and butanol. Preferably the alcohol is methanol or propanol. The dehydrating properties of the alcohol may help to inhibit formation of the hydroxide phase. A surfactant is added to bind to the titanium ions and form a surface layer. Typically the ratio of titanium ions to surfactant is 1:1.
The pH of the solution is then monitored while a solution of sodium hydroxide in alcohol, preferably a 1M solution in methanol, is added dropwise until the oxide nanoparticles precipitate. The alcohol is evaporated so that the oxide particles flocculate. The particles may be washed to remove excess surfactant and the remaining alcohol is then evaporated to leave the titanium dioxide nanoparticles as a powder. Preparation of the nanoparticles is generally carried out in an inert atmosphere, preferably an atmosphere of nitrogen or argon. A population of the nanoparticles may then be combined to form the larger particles of the present invention.
On absorption of UV light the electrons and holes produced may be confined to a specific nanoparticle within the particles of the present invention thus minimising migration of the electrons and/or the holes to the surface of the particles. The nanoparticles may also be beneficial in that the rate of recombination of the electrons and holes may be increased. The electrons and holes may recombine with the emission of a photon of energy equal to the band gap as shown in FIG. 3 .
The particles of the present invention may have an inorganic or organic coating. For example, the particles may be coated with oxides of elements such as aluminium, zirconium or silicon. The particles of metal oxide may also be coated with one or more organic materials such as polyols, amines, alkanolamines, polymeric organic silicon compounds, for example, RSi[OSi(Me) 2 xOR 1 ] 3 where R is C 1− C 10 alkyl, R 1 is methyl or ethyl and x is an integer of from 4 to 12, hydrophilic polymers such as polyacrylamide, polyacrylic acid, carboxymethyl cellulose and xanthan gum or surfactants such as, for example, TOPO.
As indicated above, compositions of the invention may be used in a wide range of applications where UV screening is desired, but are particularly preferred for topical application. The compositions for topical application may be, for example, cosmetic compositions, compositions for protecting the hair, or preferably sunscreens. Compositions of the present invention may be employed as any conventional formulation providing protection from UV light.
In compositions for topical application, the metal oxides are preferably present at a concentration of about 0.5 to 10 % by weight, preferably about 3 to 8 % by weight and more preferably about 5 to 7% by weight. Such compositions may comprise one or more of the compositions of the present invention.
The compositions for topical application may be in the form of lotions, e.g. thickened lotions, gels, vesicular dispersions, creams, milks, powders, solid sticks and may be optionally packaged as aerosols and provided in the form of foams or sprays.
The compositions may contain, for example, fatty substances, organic solvents, silicones, thickeners, demulcents, other UVA, UVB or broad-band sunscreen agents, antifoaming agents, moisturizing agents, perfumes, preservatives, surface-active agents, fillers, sequesterants, anionic, cationic, nonionic or amphoteric polymers or mixtures thereof, propellants, alkalizing or acidifying agents, colorants and metal oxide pigments with a particle size of from 100 nm to 20000 nm such as iron oxides.
The organic solvents may be selected from lower alcohols and polyols such as ethanol, isopropanol, propylene glycol, glycerin and sorbitol.
The fatty substances may consist of an oil or wax or mixture thereof, fatty acids, fatty acid esters, fatty alcohols, vaseline, paraffin, lanolin, hydrogenated lanolin or acetylated lanolin.
The oils may be selected from animal, vegetable, mineral or synthetic oils and especially hydrogenated palm oil, hydrogenated castor oil, vaseline oil, paraffin oil. Purcellin oil, silicone oil and isoparaffin.
The waxes may be selected from animal, fossil, vegetable, mineral or synthetic waxes. Such waxes include beeswax, Carnauba, Candelilla, sugar cane or Japan waxes, ozokerites, Montan wax, microcrystalline waxes, paraffins or silicone waxes and resins.
The fatty acid esters are, for example, isopropyl myristate, isopropyl adipate, isopropyl palmitate, octyl palmitate, C 12− C 15 fatty alcohol benzoates (“FINSOLV TN” from FINETEX), oxypropylenated myristic alcohol containing 3 moles of propylene oxide (“WITCONOL APM” from WITCO), capric and caprylic acid triglycerides (“MIGLYOL 812” from HULS).
The compositions may also contain thickeners which may be selected from cross-linked or non cross-linked acrylic acid polymers, and particularly polyacrylic acids which are cross-linked using a polyfunctional agent, such as the products sold under the name “CARBOPOL” by the company GOODRICH, cellulose, derivatives such as methylcellulose, hydroxymethylcellulose, hydroxypropyl methylcellulose, sodium salts of carboxymethyl cellulose, or mixtures of cetylstearyl alcohol and oxyethylenated cetylstearyl alcohol containing 33 moles of ethylene oxide.
When the compositions of the present invention are sunscreens they may be in a form of suspensions or dispersions in solvents or fatty substances or as emulsions such as creams or milks, in the form of ointments, gels, solid sticks or aerosol foams. The emulsions may further contain anionic, nonionic, cationic or amphoteric surface-active agents. They may also be provided in the form of vesicular dispersions of ionic or nonionic amphiphilic lipids prepared according to known processes.
In another aspect the present invention provides a method for preparing the compositions of the present invention which comprises associating the particles described above with a carrier.
In another aspect the present invention provides particles comprising a host lattice incorporating a second component to provide luminescence trap sites and/or killer sites.
In a further aspect the present invention provides particles which comprise a population of coated nanoparticles of a metal oxide.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 shows the absorption of a photon of UV light by titanium dioxide as found in conventional sunscreens.
FIG. 2 shows the absorption of a photon of UV light by reduced zinc oxide particles.
FIG. 3 shows the absorption of UV light by particles of the present invention which comprise at least two coated nanoparticles of titanium dioxide.
FIG. 4 shows relaxation of plasmids caused by illuminated TiO 2 and ZnO and suppression by DMSO and mannitol. In both panels, S, L and R show the migration of supercoiled, linear and relaxed plasmid. The top panel shows the plasmid relaxation found after illumination with sunlight alone for 0, 20, 40 and 60 min (lanes 1 - 4 ) and with 1% anatase (lanes 5 - 8 ) or 1% rutile (lanes 9 - 12 ) TiO 2 for the same times. Lanes 13 - 18 shows illumination with TiO 2 from sunscreen SN8 for 0, 5, 10, 20, 40 and 60 min. The results are typical of those found with various samples. The bottom panel shows illumination with 0.2% ZnO for 0, 10, 20, 40 and 60 min before (lanes 1 - 5 ) or after (lanes 6 - 10 ) adding DMSO; and with 0.0125% sunscreen TiO 2 for 0, 5, 10, 20, 40 and 60 min after adding 200 mM DMSO (lanes 11 - 16 ) or 340 mM mannitol (lanes 1 - 22 ).
FIG. 5 shows the effect of catalase on damage inflicted by illuminated TiO2 and location of lesions in DNA. The top panel shows plasmid DNA which was illuminated (see FIG. 4 ) with sunscreen TiO 2 alone for 0, 20, 40 and 60 min (lanes 1 - 4 ) and for the same times (lanes 8 - 11 ) after adding 2.5 units/μl of catalase (0.1mg/ml of protein). Lanes 5 - 7 show supercoiled, linear and relaxed plasmid. The bottom panel shows illumination with sunscreen TiO 2 as above after adding boiled catalase (lanes 1 - 4 ) or 0.1 mg/ml of bovine serum albumin (lanes 8 - 11 ). The right panel shows a 426 bp fragment of double-stranded DNA labelled at one 5′-end which was illuminated in 0.0125% sunscreen TiO 2 and samples which were analyzed on a sequencing gel. Lanes 1 - 4 show illumination for 0, 20, 40 and 60 min. Lanes 5 - 8 show illumination for the same times followed by treatment with N,N′-dimethylethylenediamine for 30 min at 90° C. before analysis. This reagent displaces many damaged residues from DNA and then cleaves the sugar-phosphate chain, leaving homogeneous, phosphorylated termini with consistent mobility, thus clarifying the spectrum of lesions generated. Lanes 9 - 10 show G and A dideoxy sequencing standards.
FIG. 6 shows the damage inflicted on human cells revealed by comet assays. Row A shows comets obtained using X-rays from a Gavitron RX30 source. The dose rate was 8.9 Gy min 31 1 and cells were exposed on ice for 0, 15, 30 and 60 s, giving comets falling into the five main standard classes shown. 1, class 0; 2, class 1; 3, class II; 4, class III; 5, class IV. Rows B and C show examples of comets obtained using simulated sunlight, MRC-5 fibroblasts and sunscreen TiO 2 (0.0125%). For each exposure, 100 cells were scored, and comets were classified by comparison with the standards (row A). Row B shows no treatment (1); sunlight alone for 20, 40 and 60 min (2-4); and effect of TiO 2 in the dark for 60 min (5). Row C shows sunlight with TiO 2 for 0, 20, 40 and 60 min (1-4); and for 60 min with TiO 2 and 200 mM DMSO (5). The charts summarise results from five independent experiments. D shows that sunlight alone inflicts few strand breaks and/or alkali-labile sites and E that inclusion of TiO 2 catalyses this damage.
FIG. 7 shows a comparison of strand breaks inflicted on DNA by sunlight in the presence of either normal zinc oxide or the zinc oxide of the present invention. Lanes 1 - 4 show illumination with light alone for 0, 20, 40, 60 minutes; lanes 5 - 8 show illumination with normal ZnO (Aldrich) for 0, 10, 20, 40 and 60 minutes; and lanes 9 - 12 show illumination with reduced ZnO for 0, 20, 40 and 60 minutes.
FIG. 8 shows the degradation of DNA irradiated in the presence of manganese doped titanium dioxide. The Figure shows the number of strand breaks per plasmid found during illumination with simulated sunlight at a total intensity between 290 and 400 nm of 6 mWatts/cm 2 . Light alone inflicted significant damage (circles). With anatase titanium dioxide the damage was so severe that it could not be accurately quantified. With rutile titanium dioxide the damage was less (squares), but still severe enough to run off the scale at early times. The presence of manganese reduced this damage considerably. Both 0.1% (triangles) and 0.5% (crosses) manganese had very similar effects, reducing the rate of inflicting damage by about 70%, but an increase to 1% (diamonds) had a very beneficial effect, reducing the damage to undetectable levels at the light doses used.
DESCRIPTION OF THE PREFERRED EMBODIMENTS
The Examples which follow farther illustrate the present invention with reference to the figures.
COMPARATIVE EXAMPLE
Chemical Oxidation by Titanium Dioxide Preparations TiO 2 samples were extracted from over-the-counter sunscreens by washing with organic solvents (methyl cyanide, acetone, chloroform), and their anatase and rutile contents were determined by X-ray diffraction methods. Anatase and rutile standards were obtained from Tioxide Group Services Ltd., Grimsby, UK. TiO 2 concentrations were assayed according to the method of Codell [M. Codell, (1959), Analytical Chemistry of Titanium Metal and Compounds, Interscience, New York] using standards made from pure TiO 2 (Aldrich); the molar extinction coefficient for the complex was assayed as 827 M −1 at 404 nm. The photo-oxidation degradation of phenol by illuminated TiO 2 was monitored using high pressure liquid chromatography [N. Serpone et al., (1996), J. Photochem. Photobiol. A: Chem 94, 191-203] to measure its disappearance, employing isocratic procedures at ambient temperature on a Waters 501 liquid chromatograph equipped with a Waters 441 detector set at 214 nm and a HP 3396A recorder. The column was a Waters μBONDAPAK C-18 reverse phase and the mobile phase was a 50:50 mixture of methanol (BDH Omnisolv grade) and distilled/deionised water. Each sunscreen TiO 2 was illuminated at 0.05% by weight in 58 ml of phenol (200μM in air-equilibrated aqueous media, Ph 5.5; retention time of phenol in the HPLC chromatogram was 5 min) using a 1000-W Hg/Xe lamp and a 365 nm (±10 nm) interference filter, giving a light flux between 310 and 400 nm of ca. 32 mW cm 2−.
Appropriate aliquots (1ml) of the irradiated dispersion were taken at various intervals and filtered through a 0.1 μm membrane to remove the TiO 2 prior to analysis.
Illumination of DNA in Vitro The solar simulator [J. Knowland et al., (1993), FEBS Lett. 324, 309-313] consists of a 250-W ozone-free lamp, a WG 320 filter and a quartz lens, resulting in an estimated fluence between 300 and 400 nm of 12 W m −2 DNA was the plasmid pBluescript II SK + (Stratagene) prepared and analyzed on agarose gels according to [T. Maniatis et al., (1982), Molecular Cloning: A Laboratory Manual, Cold Spring Harbor Laboratory, Cold Spring Harbor, N.Y.]. Relaxed standards were made by depurinating plasmid in 25 mM sodium acetate pH 4.8 at 70° C. for 20 min followed by cleaving with exonuclease III at 37° C. [N. Serpone, (1997), Photochem. Photobiol. A. 104, 1] in 50 mM Tris-HCl, 5 mM CaCl 2 (the Ca 2+ inhibits exonuclease but not cleavage at apurinic sites), 0.2 mM DTT, pH 8; linear standards by cutting with EcoRI. The authentic TiO 2 standards (confirmed by X-ray diffraction to be 100% anatase or 100% rutile) were suspended in water at 2% w/v; ZnO (Aldrich, <1 μm) at 0.4% w/v. 25 μl of each were added to 25 μl of plasmid (2-3 μg of DNA) in 100 mM sodium phosphate pH 7.4 and illuminated as droplets (50 μl) on siliconised microscope slides placed on a brass block embedded in ice. A sunscreen containing only TiO 2 (7% w/v) was vortexed with water and centrifuged. The white pellet was washed 3 times with a mixture of chloroform and methanol (1:1), then with methanol alone, and dried. The powder was suspended in water at 2%, but most quickly settled out, leaving a cloudy supernatant with a TiO 2 content assayed at 0.025% w/v. This was mixed with an equal volume of plasmid DNA in buffer and illuminated. Direct strand breaks were assayed from the conversion of supercoiled plasmid to the relaxed form.
Illumination of DNA in Vivo (Comet Assays)
Human cells (MRC-5 fibroblasts) were illuminated on ice with or without sunscreen TiO 2 (0.0125% w/v). The lens was omitted, giving an intensity similar to that found under the stratum corneum [Knowland, J. et al., (1993), FEBS Lett. 324, 309-313]. Samples were taken at increasing times, kept on ice, and analysed at the same time. For analysis, cells were embedded in low-melting agarose, lysed with 1% Triton X-100, subjected to alkaline gel electrophoresis and stained with ethidium bromide [P. W. Doetsch and R. P. Cunningham, (1990), Mutat. Res. 13, 3285-3304], and classified according to the five main standard classes [V. J. McKelvey-Martin et al., (1993), Mutat. Res. 228, 47-63].
Oxidation of organic materials by hydroxyl radicals from illuminated TiO can be examined conveniently by following the oxidation of a test molecule such as phenol [N. Serpone et al., (1996), J. Photochem. Photobiol. A: Chem. 94, 191-203]. The table below compares the oxidative degradation of phenol by TiO 2 samples from 10 different sunscreens with oxidation catalysed by pure rutile and pure anatase.
TABLE
Photodegradation of phenol by TiO 2 samples
Anatase/rutile
Phenol photodegradation
Relative
Sample
ratio (%)
(mmol h −1 )
rate
SN1 a
50/50
0.008 ± 0.016
1.0
SN2
0/100
0.023 ± 0.008
2.8
SN3
0/100
0.043 ± 0.010
5.2
SN4
54/46
0.043 ± 0.007
5.2
SN5
0/100
0.086 ± 0.015
10.4
SN6
100/0
0.146 ± 0.014
17.6
SN7 a
0/100
0.189 ± 0.008
22.7
SN8
100/0
0.44 ± 0.11
53.3
SN9
63/37
1.11 ± 0.03
134
SN10 b
0/100
1.50 ± 0.04
180
Pure rutile
0/100
3.55 ± 0.12
427
Pure anatase
100/0
31.6 ± 0.8
3803
SN1-10 are over-the-counter sunscreens.
a Also contains Al(OH) 3 .
b Also contains 1.95% ZnO.
All TiO 2 samples oxidise phenol, but activity does not depend solely on crystal type. The most active sample, SN10, also contains ZnO.
Hydroxyl radicals inflict direct strand breaks on DNA, and to test for such damage supercoiled plasmids were illuminated with simulated sunlight and TiO 2. FIG. 4 shows that plasmids were converted first to the relaxed form and ultimately to the linear form, demonstrating strand breakage. Sunlight alone had very little effect, while anatase is more active than rutile, consistent with photochemical comparisons (Table 1 and [A. Sclafani and J. M. Herrmann, (1996), J. Phys. Chem. 100, 13655-13661]. TiO 2 extracted from a sunscreen is also photo-active, and so is pure ZnO. The sunscreen illuminations contain much less TiO 2 than the anatase and rutile ones, suggesting that the sunscreen variety is especially active. Damage was suppressed by the quenchers dimethylsuphoxide (DMSO) and mannitol, suggesting that it is indeed caused by hydroxyl radicals.
FIG. 5 shows (top panel) that damage was very slightly suppressed by catalase, but also (bottom panel) that heat-inactivated catalase and bovine serum albumin have similar effects, suggesting that this limited quenching was due to the protein present rather than to catalase activity. Superoxide dismutase did not suppress the damage either (data not shown). It appears therefore that the strand breaks are not caused by superoxide (O 2 .− ), an active oxygen species formed by reaction between e 31 (cb) and O 2 , and do not depend upon the intermediate formation of hydrogen peroxide by reaction between 2 . OH radicals. Rather, they appear to be due to direct attack by hydroxyl radicals, which is consistent with indications that hydroxyl radicals formed on TiO 2 remain on the surface of the particles. By cleaving end-labelled DNA, other lesions were revealed (right panel), principally at some, but not all, guanine residues. Evidently, DNA damage is not confined to strand breaks.
Comet assays ( FIG. 6 ) show that DNA in human cells is also damaged by illuminated TiO 2 , consistent with endocytosis of TiO 2 . Suppression by DMSO again implies that the damage is caused by hydroxyl radicals. These assays detect direct strand breaks and alkali-labile sites, and reveal the damage attribution to TiO 2.
Thus, illuminated sunscreen TiO 2 and ZnO can cause oxidative damage to DNA in vitro and in cultured human fibroblasts. This has important implications for use of conventional compositions for topical applications. Autoradiographic studies using 65 ZnO have suggested that it passes through rat and rabbit skin, probably through hair follicles, although the chemical form of the 65 Zn detected under the skin (and hence of the form that crosses the skin) is not clear. Some reports have raised the possibility that ZnO and pigmentary TiO 2 pass through human skin, and a recent one suggests that micronised TiO 2 in sunscreens does too [M.-H. Tan et al, Austalas. J. Dermatol, (1996), 37, 185-187]. It is therefore important to characterise the fate and photochemical behaviour of sunscreens, which certainly prevent sunburn, because they are also intended to reduce skin cancers, which have increased rapidly recently.
EXAMPLE 1
Preparation of Reduced Zinc Oxide Particles
The zinc oxide used was supplied by Aldrich. It has a particle size of 100-200 nm and absorbs in the UV below 390 nm and reemits at 390 nm. It was heated in an atmosphere of 10% hydrogen to 90% nitrogen by volume at 800° C. for 20 minutes. Reduced zinc oxide was obtained and was found to absorb in the UV and reemit in the green at 500 nm.
EXAMPLE 2
Comparison of Strand Breaks Inflicted on DNA by Sunlight in the Presence of Either Normal or Reduced Zinc Oxide.
The DNA used was the plasmid pBluescript II SK + (Stratagene) prepared and analyzed on agarose gels according to T. Maniatis et al. [Molecular Cloning: A Laboratory Manual. Cold Spring Harbor Laboratory, Cold Spring Harbor, N.Y. (1982)]. It was illuminated in vitro using a solar simulator [J. Knowland et al, FEBS Lett., 324 (1993) 309-313] consisting of a 250 watt ozone-free lamp, a WG 320 filter and a quartz lens, resulting in an estimated fluence between 300 and 400 nm or 12 Watts.m . 2 . Zinc oxide samples were suspended in water at 0.4% w/v. 25 μl of each suspension was added to 25 μl of plasmid (2-3 μg of DNA) in 100 mM sodium phosphate pH 7.4 and illuminated as droplets (50μl) on siliconised microscope slides placed on a brass block embedded in ice. Direct strand breaks were assayed from the conversion of supercoiled plasmid to the relaxed form, marked S and R on FIG. 7 .
It was observed that illuminated reduced ZnO particles are very much less liable to produce DNA damage than conventional ZnO particles.
EXAMPLE 3
Preparation of Manganese Doped Titanium Dioxide.
Titanium dioxide (25 g) and manganese (II) nitrate (0.8 g) were mixed in deionized water (100 ml). The resulting mixture was ultrasonicated for 10 minutes and then boiled dry. The material produced was fired at 700° C. for 3 hours to give 1% manganese doped titanium dioxide. Titanium dioxide particles with differing dopant levels were prepared in an analogous manner by varying the amount of manganese (II) nitrate.
It is believed that manganese 3+ions (oxidised from manganese 2+during boiling) are incorporated into the surface of the titanium dioxide host lattice.
EXAMPLE 4
Assessment of the Effect of Varying the Percentage of Manganese in a Titanium Dioxide Host Lattice.
The ability of different manganese doped titanium dioxide particles to damage DNA was measured using the plasma nicking assays described in the Comparative Example above.
FIG. 8 shows that simulated sunlight alone inflicted significant damage on DNA as revealed by the generation of strand breaks. As the percentage of manganese in the titanium dioxide host lattice was increased the damage in terms of strand breaks decreased. At a manganese content of 1% the damage was almost prevented and was significantly less than the damage inflicted by light alone.
Thus it is believed that such particles may protect DNA from this particular form of damage. The particles may absorb photons of light which would normally inflict damage and divert their energy into non-damaging processes. The particles may work by photoexcited carrier trapping or by the dopant ions rendering the host lattice p-type. It is believed that these mechanisms may be connected. For particles of less than 20 nm the quantum size effect may also help by shifting the redox potentials.
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A UV screening composition comprising particles which are capable of absorbing UV light so that electrons and positively charged holes are formed within the particles, characterised in that the particles are adapted to minimise migration to the surface of the particles of the electrons and/or the positively charged holes when said particles are exposed to UV light in an aqueous environment.
| 2 |
This application is a continuation application of Ser. No. 08/536,634 filed Sep. 29, 1995, which is now abandoned.
BACKGROUND OF THE INVENTION
The present invention relates to a ball for a ball game such as a soccer ball, or more particularly to a ball of a sewn structure for a ball game, and a manufacturing method thereof.
Hitherto, in a ball for a ball game having an air sealed structure, such as a soccer ball, handball, volleyball, and playground ball, ends of a plurality of leather panels are folded inside, the folded portions are sewn by a thread to form a spherical leather skin layer on the whole, and a rubber bladder of hollow spherical shape is contained in this leather skin layer, which is known as a ball for a ball game having a sewn structure (or known as a sewn ball) (for example, Japanese Unexamined Utility Model Publication No. 136660/1990).
FIG. 1 to FIG. 3 show an example of a soccer ball having a sewn structure, in which twenty hexagonal leather panels 2, 2 . . . and twelve pentagonal leather panels 3, 3 . . . are sewn together end to end by a thread 4 to form a leather skin layer 5, and a bladder 6 of a hollow spherical elastic rubber of small air permeability such as latex and butyl rubber is contained inside. The bladder 6 is inflated with a compressed air through a valve (not shown).
As leather panels 2, 2 . . . , 3, 3 . . . , natural leather or artificial leather is used. Usually on the back side of the leather panels 2, 3, a reinforcing cloth layer 7 is formed by adhering two to four layers of cotton cloth or polyester and cotton blended cloth with latex or other adhesive, and this reinforcing cloth layer 7 is included in the leather panels 2, 3 in the explanations to follow.
On the periphery of the leather panels 2, 2 . . . , 3, 3 . . . , as shown in FIG. 3, multiple sewing holes 8, 8 . . . are provided, and a thread 4 is passed through these sewing holes 8, 8 . . . , and the two leather panels 2, 2 are sewn together. As the thread 4, polyester thread, cotton thread, hemp thread, nylon thread, or the like is used.
Also known is the high shrinkage polyester fiber which shrinks by scores of percent by heat treatment (for example, Japanese Examined Patent Publication No. 40170/1976). This publication discloses a manufacturing method of high shrinkage polyester fiber by drawing polyethylene terephthalate undrawn fiber by 2.5 to 2.9 times in a warm water bath at 60° to 70° C., cooling to 40° C. or less after drawing, feeding into a crimper to crimp, and drying at 45° C. or less after crimping, and such high shrinkage polyester fiber is claimed to shrink by 30% or more in a warm water bath at 70° C. Besides, the high shrinkage polyester shrink yarn is disclosed in Japanese Examined Patent Publications Nos. 40171/1976 and 43931/1977. On the other hand, the wet shrink polyvinyl alcohol (PVA) fiber is known to shrink by scores of percent by water absorption treatment (for example, Japanese Examined Utility Model Publication No. 15353/1988). The wet shrink PVA fiber disclosed in this publication is obtained by spinning PVA of polymerization degree of 300 to 2400 and saponification degree of 90 to 99.9 mol % in ordinary dry or wet process, drawing by 1.5 times or more in an atmosphere at 130° C. or less in moisture absorbing state, and drying, and moreover, after drying, heat treatment may be done in tense state, or in the wet process, scouring process may be done later for removing salts, according to the publication. This wet shrink PVA fiber is known to shrink by 10 to 60% within 30 seconds when immersed in water at 40° C. or less.
Such fiber shrinking by more than 10% by treatment by heating or water absorption is known as self-shrinking yarn. Generally, chemical fibers shrink by heating, but the value is very small, usually about 2 to 3%.
In the sewn structure ball, for example, a soccer ball, the ball sticks to the foot when kicking, and it is easy to exhibit advanced skills in shooting, dribbling and passing, and it excels in game performance, but it is inferior in durability. Similarly, in the handball, volleyball, and playground ball, the sewn ball excels in gripping performance (ease of catching), and is hence easy to control, the trajectory is stable when thrown, not swaying irregularly, and the pain is less if hit against part of the body, but the problem lies in the durability, too. That is, in the sewn ball, as used repeatedly, the sewn portion is expanded as shown in FIG. 4 (called seam opening 11), and the ball is swollen and deformed. For example, when a soccer ball of size No. 5 (initial circumference 685 mm) was used in soccer exercises and games for six months, the circumference was swollen to 705 mm to 710 mm. By contrast, the laminated structure ball excellent in durability (of the same size) was swollen to 700 mm.
The laminated structure ball is manufactured by winding a nylon yarn of about thousands of meters long uniformly on a rubber bladder to form a reinforcing layer to prevent the spherical form from swelling, and laminating a plurality of leather panels thereon through a thin rubber layer, and it is usually called a laminated ball. This laminated ball is extremely excellent in durability because of the reinforcing layer, but the feeling of kicking and contact is poor, and it is inferior in game performance as compared with the sewn ball, and it is exclusively used as an exercise ball or a game ball for low technical level players among school children.
SUMMARY OF THE INVENTION
It is an object of the invention to present a sewn ball enhanced in durability, without sacrificing the high game performance such as gripping and ball control.
According to a first aspect of the present invention, the invention relates to a ball for ball game comprising:
A leather skin layer formed by sewing a plurality of leather panels by a thread, said leather skin layer having a spherical shape; and
a bladder made of an elastomer having a hollow spherical shape, said bladder being accomodated in said leather skin layer, said bladder being provided with a valve for feeding air into said rubber bladder, said bladder being charged with air through said valve;
wherein said thread is made of a self-shrink thread which is subjected to a shrinking treatment after sewing.
In one form of the ball for a ball game of the invention, the self-shrinking thread shrinks by heating.
In this ball for a ball game of the invention the self-shrink thread preferably comprises a high shrinkage polyester fiber.
In another form of the ball for a ball game of the invention, the self-shrink thread shrinks by absorbing water.
In this ball for ball game of the invention, the self-shrinking thread which shrinks by absorbing water preferably comprises wet shrink polyvinyl alcohol fiber.
The leather skin layer of the ball for a ball game of according to one embodiment the invention comprises a plurality of hexagonal leather panels and pentagonal leather panels, and the ball for ball game can be used as a soccer ball or a handball.
The leather skin layer of the ball for a ball game according to a second embodiment of the invention comprises a plurality of almost square leather panels, and the ball for ball game can be used as a volleyball or a playground ball.
According to second aspect of the present invention, the invention relates to a method of manufacturing a ball for a ball game of the invention a said method comprising a step of forming a hollow spherical rubber bladder, a step of sewing a plurality of leather panels into a spherical form with a self-shrink thread to form a leather skin layer, and putting the bladder into the leather skin layer, and a step of shrinking the self-shrink thread by heat.
The self-shrink thread of the present invention is subjected to shrinking treatment after sewing the leather panels to each other. The leather panels are firmly tightened to each other by the shrinked thread, such that opening of a seam in the leather skin layer and swelling of the ball are prevented from occurring.
When the self-shrink thread comprises a thread which shrinks by heating, the self-shrink thread is shrinked by heating after sewing, so that the leather panels can be firmly tightened to each other. The shrinking property of the thread can be kept even if the temperature of the heated thread is returned to ambient temperature.
When the self-shrink thread which shrinks by heating comprises a high shrinkage polyester fiber, a high shrinkage rate can be achieved with a constant rate.
When the self-shrink thread comprises a thread that shrinks upon absorbing water, the thread is shrinked by absorbing rainwater or the like in operative condition or subjected to a treatment of absorbing water forcedly, so that the leather panels are firmly tightened to each other. The shrinkage property of the thread can be kept after absorbing water even if the thread is dried.
When the self-shrink thread comprises a wet shrinkage PVA fiber, a high shrinkage rate can be achieved with a constant rate.
In accordance with the ball of the invention, the game performance such as gripping, ball control and stability of trajectory by kicking or hitting can be maintained in a high state.
BRIEF DESCRIPTION OF DRAWINGS
FIG. 1 is a front view of the ball for ball game illustrating a conventional ball and the present invention;
FIG. 2 is a cross sectioned view taken along lines A--A of FIG. 1;
FIG. 3 is a perspective view illustrating a process of sewing work;
FIG. 4 is a cross sectioned view like FIG. 2 but illustrating a state of opening of a seam;
FIG. 5 is a curve showing a circumference-heating temperature characteristic;
FIGS. 6 and 7 are each curves showing a circumference-number of compressing test characteristic of a soccer ball using a self-shrink thread which shrinks by heating and absorbing water, respectively; and
FIG. 8 is a front view illustrating beach volley ball of the present invention.
DETAILED DESCRIPTION
As shown in FIG. 1 to FIG. 3, a natural leather or artificial leather adhering to a reinforcing cloth layer 7 on its back side is cut, and twenty hexagonal panels 2, 2 . . . , and twelve pentagonal panels 3, 3 . . . are formed, and plural sewing holes 8, 8 . . . are opened in the periphery of the panels, and the panels 2, 2 . . . , 3, 3 . . . are sewn together by a self-shrink thread 9 to form a spherical leather skin layer 5, and a rubber bladder 6 is put therein to prepare a size No. 5 soccer ball 1. The artificial leather is made of polyurethane resin, PVA resin or other resin, which is fashioned after a natural leather.
As the self-shrink thread 9, a high shrinkage polyester fiber which shrinks by heating can be used, for example, Soclatex (registered trademark of Teijin). Heat treatment is done by immersing the soccer ball 1 into 100° C. boiling water, or putting the ball into a heated die. The thread 9 instantly shrinks by 50% when immersed in boiling water without applying tension to the thread (no-load state). At the same time, this thread 9 has a high shrink stress, and, for example, when the shrink thread of the total denier number of 12,000 is put in boiling water to shrink 10%, the tightening force is raised by about 1 kg, and this tightening force is maintained if the temperature is lowered to ordinary temperature. After shrinking, a high strength holding rate is provided.
FIG. 5 shows the result of measurement of the ball circumference (ball girth) after heat treatment at different heating temperatures by fabricating the soccer ball 1 by using a self-shrink thread 9 of 12,000 denier count. As indicated by curve A, at 60° C., the circumference was hardly changed, and at 80° C., the circumference decreased by about 2.6 mm or about 0.4% as compared with that at 60° C. By way of comparison, the circumference of the ball fabricated by using a conventional non-shrink thread (11,500 denier) is indicated by curve B. This conventional ball is free from effects of temperature, and theoretically the curve should be a horizontal line, but actually it was swollen a little (about 0.15%). By using the self-shrink thread 9, it is hence known that the seam is tightened firmly and the circumference of the ball is slightly smaller.
The self-shrink thread 9 shrinks by heating, and firmly tightens the sewn portions of the leather panels 2, 3. By this tightening, partial loosening in sewing, or individual difference in sewing strength by sewing operators is canceled, and a uniform and powerful tightening force is obtained. According to the experiment by the inventors, by measuring the circumference before and after shrinkage treatment in 100 soccer balls and calculating the standard deviation, it was 1.733 before treatment, and 0.966 after treatment. The standard deviation after treatment was about 55% of the value before treatment, which means that the fluctuation range of circumference is narrowed to about half.
FIG. 6 shows the result of a durability test of a soccer ball 1 sewn with self-shrink thread 9, by heating and shrinking for 10 minutes in a thermostatic oven at 80° C. The durability test was done by compressing the ball repeatedly to 33% of its diameter, and after 30,000 times of compression (corresponding to the use for about six months) as indicated by curve A, the circumference was increased from 665 mm to 676 mm, and the increment rate was 1.7%. At this time, an opening of a seam was not observed, and there was no problem in use. On the other hand, curve B indicates the similar compression test result of the ball sewn by conventional non-shrink thread, in which the circumference was increased from 665 mm to 684 mm (increment rate 2.9%). At this time, an opening of a seam was noted in the ball, and there was a problem in use of the ball in a game, e.g. it was not usable. Curve C shows the durability test result of a laminated ball, and the sewn ball of the invention (curve A) presented a durability similar to that of the laminated ball. For the ease of comparison with the ball of the embodiment, the conventional balls of curves B and C were identical in circumference with the ball of the embodiment.
The manufacturing method of the soccer ball of the embodiment is described. As shown in FIG. 3, as the leather panels, a natural leather or artificial leather with a reinforcing cloth layer 7 adhered to the back side is cut, and twenty hexagonal panels 2, 2 . . . , and twelve pentagonal panels 3, 3 . . . are prepared. Plural sewing holes 8 are formed in the periphery of each panel. These panels are hand-sewn by using the self-shrink thread 9, and a spherical leather skin layer 5 is formed.
A rubber bladder 6 is formed by heating and vulcanizing butyl rubber. Simultaneously when forming, a valve for feeding air into the bladder 6 is formed. This bladder 6 is put into the leather skin layer from an unsewn portion left at one side of the leather skin layer 5. A small circular hole 10 (FIG. 1) is formed in the center of one panel 2 of the leather skin layer 5, and the valve of the bladder 6 is positioned at this hole 10, and the peripheral area of the valve is adhered to the back side of the leather skin layer 5. The adhesion between the leather skin layer 5 and bladder 6 is in the valve peripheral area only, and in the other parts, the two are in a separate state. After putting in the bladder 6, the unsewn portion of the leather skin layer 5 is sewn together.
Thus sewn ball 1 is put into a die having a spherical cavity matching with the contour of the ball 1, and is heated for 10 minutes at 80° C. in a state packed with compressed air at specified pressure. As a result, the self-shrink thread 9 shrinks, and the leather panels 2, 3 are bound with a strong tightening force. The heat treatment may be done, aside from the method of using the heating die, for example, by putting the ball in the air for 30 minutes in a thermostatic oven controlled at 80° to 90° C., with the ball internal pressure kept at 0 to 0.3 kg/cm 2 , and a similar shrinking action is obtained.
As the self-shrink thread 9 which shrinks by heating, aside from the high shrinkage polyester fiber, acrylic fiber, acetate fiber, vinylidene fiber, nylon fiber, polyvinyl chloride fiber, polyethylene fiber, and polypropylene fiber may be used by special treatment for drawing and crimping so as to have shrinking action.
In the embodiment, the self-shrink thread 9 refers to the thread which shrinks by heating, but, instead, it is also possible to use other self-shrink thread 9 which shrinks by absorbing water, and therefore the case of using water-absorption type self-shrink thread 9 is explained below. As such self-shrink thread 9, the wet shrink PVA fiber, high shrinkage vinylon known as Cremona (trademark of Kuraray) can be used.
The water-absorption type self-shrink thread 9 instantly shrinks by about 30% in water at ordinary temperature (20° C.). This shrinkage thread 9 also has a high shrink stress, and, for example, if water is absorbed in tensile state by applying a load of 300 g to water absorption shrinkage thread of 12,000 denier, it shrinks more than 10%. The high tightening force by shrinkage is maintained after drying.
TABLE 1______________________________________before absorbing after absorbing shrinkingwater treatment water treatment rate______________________________________ball of 689 mm 682 mm 1.0%embodimentsconventional 690 mm 688 mm 0.3%ball______________________________________
Table 1 shows the result of measurement of circumference by preparing a soccer ball by using self-shrink thread 9 with 12,000 denier, immersing in water, and drying. By way of comparison, the result of the soccer ball using the conventional non-shrink thread (11,500 denier) is also shown. As known from this table, the shrinkage rate of the soccer ball of the embodiment was 1.0%, which was higher than 0.3% shrinkage rate of the conventional soccer ball. Incidentally, the conventional soccer ball also shrank slightly, which was estimated to be shrinkage due to drying of the leather panels.
The self-shrink thread 9 shrinks by absorbing water, and tightens the sewn portions of the leather panels 2, 3 firmly. As a result, partial loosening in sewing, or individual difference in sewing strength by sewing operators is canceled, and a uniform and powerful tightening force is obtained. That is, the same effects as when using the heat shrinkage type self-shrink thread are obtained.
FIG. 7 shows the result of a durability test by preparing the soccer ball 1 by using water-absorption type self-shrink thread 9, and shrinking the self-shrink thread 9 by immersing in water and drying. The durability test conditions are same as in the previous test. As indicated by curve A, after 30,000 times of durability test, the circumference was increased from 670 mm to 683 mm, and the increment rate was 1.9%. At this time, an opening of a seam was not observed, and there was no problem in use. On the other hand, curve B indicates the result of the ball sewn by conventional non-shrink thread, in which the circumference was increased from 670 mm to 688 mm (increment rate 2.7%), and an opening of a seam was noted in the ball, and there was problem in game, and it was not usable. Curve C shows the test result of a laminated ball. The sewn ball of the embodiment (curve A) presented a durability similar to that of the laminated ball. For the ease of comparison with the ball of the embodiment, the conventional balls of curves B and C were identical in circumference with the ball of the embodiment.
The soccer ball 1, in its final process of manufacture, is immersed in water by force to shrink the self-shrink thread 9, and the binding force of the mutual leather panels is reinforced. However, in another method, the soccer ball may be sold to customers without water absorption treatment, and when it is soaked in rainwater or the like during use, the self-shrink thread 9 may be wet to shrink naturally.
In the foregoing embodiments, twenty hexagonal leather panels and twelve pentagonal leather panels are sewn together to form a soccer ball, but the invention may be also applied in the soccer ball prepared by sewing thirty hexagonal leather panels and twelve pentagonal leather panels. It is also applied to the handball having the leather skin layer in the same pattern as the soccer ball. It is also effective to apply in the volleyball, especially beach volleyball and playground ball forming the leather skin layer by sewing twelve or eighteen nearly square panels. FIG. 8 shows a beach volleyball 14 having a leather skin layer 13 sewn by using eighteen slender quadrangular leather panels 12, 12 . . . , laying three panels parallel to form a set, preparing six sets thereof, and arranging into a spherical form so that the array direction of each set may cross orthogonally.
According to the invention, using a self-shrink thread which shrinks by heating or absorbing water as the sewing thread of a ball for a ball game having sewn structure, by shrinking after sewing a ball, the leather panels are bound with a uniform strong tightening force. Accordingly, if used repeatedly, the seam is not opened, and the game performances such as gripping, ball control, and stability of trajectory by kicking or hitting are maintained in a high state, while the touch is soft and pain is less when hitting against part of the body. Moreover, increase of circumference is suppressed, and a stable shape is retained for a long period, and hence, while preventing the swelling tendency which was a defect of a conventional sewn ball, the durability is enhanced notably.
In the invention, if there is individual difference among the sewing operators in the sewing strength of the thread before shrinking, the self-shrink thread shrinks by heating or absorbing water of the leather skin layer after sewing the leather panels, and the difference is canceled, and a uniform and high tightening force is obtained, and a stable durability is realized.
Also according to the invention, by using high shrinkage polyester fiber or wet shrink PVA fiber as the self-shrink thread, a uniform and advanced shrinkage rate is obtained, and the mechanical strength is sufficient, and therefore it is optimum for the ball for a ball game in severe conditions where the ball is exposed to a destructive external force.
Further according to the invention, since the seam is hardly opened after sewing, the grooves formed in the seams are kept for a long period. Hence, the gripping and ball control performance obtained by the seams will not be lost, and it is particularly useful when applied in a soccer ball, handball, volleyball, and playground ball that require such properties.
Though several embodiments of the present invention are described above, it is to be understood that the present invention is not limited only to the above-mentioned embodiments, various changes and modifications may be made in the invention without departing from the spirit and scope thereof.
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A ball for ball game comprising: a leather skin layer formed by sewing a plurality of leather panels by a thread, the leather skin layer having a spherical shape; and a bladder made of an elastomer having a hollow spherical shape, the bladder being accomodated in the leather skin layer, the bladder being provided with a valve for feeding air into the rubber bladder, the bladder being charged with air through the valve; wherein the thread is made of a self-shrink thread which is subjected to a shrinking treatment after sewing.
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CROSS-REFERENCE TO RELATED APPLICATIONS
This application is a continuation of International Application PCT/GB01/04181, with an international filing date of Sep. 19, 2001, published in English under PCT Article 21(2), and is a continuation-in-part of U.S. application Ser. No. 09/936,586, filed Sep. 13, 2001 now U.S. Pat. No. 6,488,960.
FIELD OF THE INVENTION
This invention relates to a controlled-release formulation, and in particular to a formulation of a corticosteroid, suitable for use in the treatment of rheumatoid arthritis.
BACKGROUND OF THE INVENTION
Glucocorticoids, and in particular prednisone and prednisolone, are widely used for the treatment of rheumatoid arthritis. The use of glucocorticoids may be efficacious but has disadvantages, particularly in terms of side-effects such as bone loss.
It appears to be generally recognized that it would be desirable to use low doses of, say, prednisolone, in the treatment of rheumatoid arthritis. While it is clear that low dose oral prednisolone can be efficacious, there is some controversy over what is actually meant by a low dose.
Kirwan, New England J. Med. 333:142-5 (1995), indicates that a daily dosage of 7.5 mg prednisolone is effective. This is supported by Boers et al., The Lancet 350:309-318 (1997). Boers et al. also reports that a typical treatment of rheumatoid arthritis following initial treatment with a non-steroidal anti-inflammatory drug (NSAID) involves a high initial dose and, when the condition is under control, reduced doses, down to a “low maintenance” of 7.5 mg/day.
Gotzsche and Johansen, B. M. J. 316:811-818 (1998), reviews a number of studies of low dose prednisolone in the treatment of rheumatoid arthritis. Most of these studies report doses of at least 7.5 mg. There is one report, but from as long ago as 1967, of a 2.5 mg dose.
It is evident that, in clinical practice, rheumatologists taper the dose of glucocorticoid to as a low a level as they can, before symptoms return. There may be patients who are stable on less than 5 mg prednisolone per day, but there is little or no clinical data to support that such a low dose is actually providing any benefit. This is important, because in many of these patients, prednisolone may be contributing only side-effects. There is no evidence that any dose of prednisolone, lower than those generally used, is effective when given chronically for the treatment of rheumatoid arthritis.
Arvidson et al., Annals of the Rheumatic Diseases 56:27-31 (1997), reports that the timing of glucocorticoid administration in rheumatoid arthritis may be important, in controlling the acute inflammatory aspects of the disease. In the reported study, patients were woken at 2.00 a.m. and given 7.5 mg or 5 mg prednisolone.
U.S. Pat. No. 5,792,496 claims a sustained-release formulation of a glucocorticoid such as prednisone or prednisolone. The formulation comprises 2.5-7 mg of the glucocorticoid and releases at least 90% of the drug during 40-80 minutes, starting about 1-3 hours after the entry of the drug into the small intestine. The intention is that the formulation should be taken immediately before the patient goes to sleep, that the drug should be released during sleep, and that the greatest secretion of cytokines (which occur shortly before waking) should thus be treated most effectively. This is based on the same data as in Arvidson et al., supra, i.e. using doses of 5 or 7.5 mg prednisolone given at 2 a.m.
BRIEF SUMMARY OF THE INVENTION
This invention is based on the discovery that, in a study designed to test the reproducibility of the results reported by Arvidson et al. (and in U.S. Pat. No. 5,792,496), a much lower dosage of the glucocorticoid was also effective. Given the state of the art and the known side-effects of corticosteroids, this increase in their therapeutic index is surprising.
According to the present invention, a unit dosage comprises less than 2.5 mg of prednisolone or an equivalent amount of a corticosteroid. Equivalence is in terms of potency. It will be understood that drugs vary in potency, and that doses can therefore vary, in order to obtain equivalent effects.
Thus, in accordance with the present invention, a controlled-dose formulation of the drug is adapted to release the drug at a predetermined period of time after administration, or at a predetermined time. Advantages of the invention may include enhanced efficacy, reduced side-effects and/or reduced C max . Further or in addition, chronotherapeutic administration allows the use of a reduced level of active material.
DESCRIPTION OF THE INVENTION
The intention behind the invention is that the active ingredient should be released at a predetermined time, e.g. between midnight and 6 a.m., e.g. 2 a.m. and 4 a.m., or a predetermined time after administration. Thus, the user can take the formulation before going to sleep, but have the full value of an effective dosage of the drug during the night, or during sleep, at a dosage that has minimal side-effects. Accordingly, a predominant amount of the active ingredient, e.g. at least 90% by weight, is released at least 2 or 3 hours after administration, and preferably no more than 6, 7 or 8 hours after administration.
Formulations of the invention are intended for the treatment of disorders associated with the release of cytokines, e.g. TNF α, IL-1, IL-2, IL-6 and IL-8. In particular, the invention is suitable for the treatment of inflammatory diseases, including polyarthropathies, and more especially rheumatoid arthritis, asthma, inflammatory bowel disease, chronic obstructive pulmonary disease, psoriasis, psoriatic arthritis, polymyalgia rheumatica and atopic dermatitis. The drug that is used in the formulation may be chosen accordingly. If desired, the active ingredient may be formulated as a pro-drug, so that the active component is released in vivo.
Among active agents that can be used in the invention, examples are glucocorticoids and other corticosteroids, e.g. budesonide, methylprednisolone, deflazacort, fluticasone, prednisone and prednisolone. The appropriate dosage of each such drug depends on its potency.
Equivalent potency in clinical dosing is well known. Information relating to equivalent steroid dosing (in a non-chronotherapeutic manner) may be found in the British National Formulary (BNF), 37 March 1999, the content of which is incorporated herein by reference.
The BNF guidelines are included in the table below. In addition, the proposed clinical dose equivalent to 1 mg of prednisolone when administered in a chronotherapeutic manner is included in the table. More specifically, the following Table is of doses of steroids equivalent to mg of prednisolone and equivalence to 1 mg of prednisolone when administered in a chronotherapeutic manner according to this invention and 1 mg of prednisolone.
Equivalent dose in chronotherapeutic administration
Equal to 5 mg
prednisolone
Equal to
Steroid
(Normal dosing)*
1 mg prednisolone
betamethasone
750
μg
150
μg
cortisone acetate
25
mg
5
mg
deflazacort
6
mg
1.2
mg
dexamethasone
750
μg
150
μg
hydrocortisone
20
mg
4
mg
methyl prednisone
4
mg
0.8
mg
prednisone
5
mg
1
mg
triamcinolone
4
mg
0.8
mg
It is also known (BNF 37 March 1999) from clinical dosing equivalence that doses of triamcinolone, fluticasone and budesonide are broadly similar in nasal administration (110 μg, 100 μg and 200 μg). A chronotherapeutic advantage may be expected upon dosing these drugs.
Corticosteroids such as cortisone acetate and hydrocortisone are less preferred for use in the invention, owing to their systemic side-effects on long-term use. Such compounds, having effect on glucose and mineral metabolism, will be known to those skilled in the art.
The preferred route of administration of a formulation of this invention is oral. However, it will be readily apparent to those skilled in the art that other routes of administration may be used, e.g. having regard to the nature of the condition being treated and the most effective means of achieving delayed release.
The drug may be administered in any conventional formulation that provides delayed release, via any suitable route of administration. Conventional dosing parameters may be adopted, i.e. those which are known to or adapted to the practice of those skilled in the art. The daily dosage (relative to prednisolone) is usually at least 0.25 or 0.5 mg, e.g. 1 to 2 mg, but will be chosen according to the age, weight and health of the subject, and other factors that are routinely considered by the man skilled in the art.
A formulation of the invention may be a unit dosage such as a tablet, capsule, ampoule, vial or suspension. A controlled-release formulation may be in matrix, coating, reservoir, osmotic, ion-exchange or density exchange form. It may comprise a soluble polymer coating which is dissolved or eroded, after administration. Alternatively, there may be an insoluble coating, e.g. of a polymer, through which the active ingredient permeates, as from a reservoir, diffuses, e.g. through a porous matrix, or undergoes osmotic exchange. A further option for a controlled-release formulation involves density exchange, e.g. in the case where the formulation alters on administration, e.g. from microparticles to a gel, so that the active ingredient diffuses or permeates out. Ion-based resins may also be used, the active component being released by ionic exchange, and wherein the rate of release can be controlled by using cationic or anionic forms of the drug. Another type of controlled-release formulation involves pulsed dosing. Further examples are given in U.S. Pat. No. 5,792,496.
An example of a controlled dose of active ingredient is dosing with a tablet containing 1.25 mg prednisolone. In this example, a patient taking a controlled dose of 1.25 mg prednisolone takes the tablet a number of hours before it is due to be released. Time zero on the plot (FIG. 1) denotes the earliest time at which active ingredient is released, probably midnight. The plasma levels achieved by release of the active agent at different times (2, 4 and 6 a.m.) are shown.
It can be seen that the range for C max obtained from the 1.25 mg prednisolone dose is from approximately 20 to 50 ng/ml (total prednisolone which includes protein bound and unbound active) depending on how quickly a patient absorbs the active ingredient. The time to C max or T max is usually between 1 and 3 hours. Where absorption is particularly fast, the C max may be 100 ng/ml total prednisolone or higher (this is not shown on the plot).
The following Study provides the basis of the present invention.
Study Design
The study was an assessor blind comparison of the effects of two doses of prednisolone (1 mg and 5 mg) given at 02.00. Patients stayed the night in hospital but were free to be up and about and to leave the hospital during the day. At 2 a.m. on the appropriate days patients were woken gently, administered the prednisolone, and settled back to sleep. Blood samples and clinical assessments were made at 08.30 and further clinical assessments related to symptoms on the day of drug administration at 12.00 and 08.30 the following day (except the final day when this last assessment was made before departure from the hospital). Patients were admitted on Monday and had a “control” night that evening with no prednisolone but full assessment the following day. On each of the following three nights prednisolone was administered. Patients went home on Friday afternoon but returned the following Monday to repeat the procedure. Allocation to 1 mg or 5 mg prednisolone in the first or second week was by randomization in sealed envelopes. The patient and assessor were not aware of which dose was given.
Outcome
Clinical: Outcome was measured at 08.30 each day for: swollen joint count (n=28); tender joint count (n=28); pain (0.100 mm, VAS). Outcome was measured at 12.00 each day for: morning stiffness (minutes); patient opinion of condition (0-100 mm, VAS); clinician opinion of condition (0-100 mm, VAS). Outcome was measured the following day for: whether the arthritis was worse in the morning or afternoon on the previous day (−1 morning, 0 equal, +1 afternoon).
Serological: Serum samples were obtained at 08.30, kept on ice for up to 1 hour, separated and stored at −70° C. to measure: C-reactive protein (CRP); IL-6 concentration; IL-6 soluble receptor (IL-6sR) concentration; hyaluronate (HA) concentration.
Procedure
Patients acted as their own control and took each dose of prednisolone for three consecutive nights. They were randomly allocated by cards kept in sealed envelopes to either 1 mg prednisolone on three consecutive nights followed by 5 mg on three consecutive nights, or the opposite sequence. The assessor was not aware of the treatment order allocation (and probably remained blind), but no placebo tablets were used and it was possible for a patient to be un-blind.
Patients invited to take part in the study had the following characteristics:
Over 18 years old
Had rheumatoid arthritis by the criteria of the American College of Rheumatology; see Arnett et al., Arthritis Rheum. 31:315-324 (1988)
Had active disease as evidenced by 3 or more swollen and tender joints
Were not taking glucocorticoid medication
Had not had intra-articular glucocorticoid injections in the previous 3 weeks
Had no medical conditions which, in the opinion of the investigator, would contraindicate low dose prednisolone therapy
Informed consent was obtained and the patient prescription written by a doctor not associated with trial evaluation. Medication was dispensed at 2 a.m. on each treatment day after gently waking the patient. The patient was encouraged to settle back to sleep immediately.
On the morning before medication and on each morning on the day of medication, blood samples were taken at 8.30 a.m. and outcome assessments recorded then, and at noon, as indicated above.
Evaluation
Symptoms, signs and laboratory results were compared within and between patients, but the main assessment was visual inspection of the overall pattern of response. Means and standard deviations were used to define variation rates and for calculating trial size for future studies. An overall assessment of practicality and the potential for more frequent (but smaller volume) blood taking was made by discussion amongst the staff and patients involved.
Results
Three patients were able to take part in the study in the time available. One patient (3) was inadvertently given the first dose of treatment in the second week on the first night in hospital. Patient 3 took prednisolone for the next two nights and remained in hospital for a fourth night without prednisolone treatment. This patient's assessments have been included normally in the first week, but in the second week they have been used differently. Here, this patient's results have been included with those of the other patients in accordance with the dose of prednisolone received. This patient's final assessment (no prednisolone the night before) therefore appears as an extra day after the other patients in the study.
The results for 5 mg prednisolone place the patients in this pilot study well within the range of findings published by Arvidson et al. and reinforce the conclusions which can be drawn from that paper.
The results from 1 mg prednisolone raise the possibility that even at this dose there may be an appreciable effect on symptoms. Pain, EMS, patient's opinion and clinician's opinion were statistically significantly reduced, even with only three patients in the study. CRP and IL-6 were reduced significantly on 5 mg prednisolone and there was a tendency for reduction on 1 mg prednisolone.
All patents, patent applications, provisional applications, and publications referred to or cited herein are incorporated by reference in their entirety to the extent they are not inconsistent with the explicit teachings of this specification.
TABLE 1
Mean and 95% confidence intervals for each variable
More
Swollen
Painful
or
Pt
Cln
Day
Dose
Joints
Joints
Pain
Less
EMS
Opn
Opn
CRP
HA
IL-6
IL-6sR
Mean Results
0
0
20.3
21.0
37.7
−1.0
70.0
31.3
34.3
40.5
345.1
44.1
31557.8
1
1
18.7
20.0
26.0
−0.7
55.0
23.7
28.7
35.5
241.9
28.1
31959.9
2
1
18.7
20.3
20.3
−0.7
51.7
26.7
29.3
31.2
320.3
31.1
31468.0
3
1
18.3
20.3
16.7
0.0
40.0
12.7
16.3
25.8
372.5
22.8
30898.9
10
0
12.3
15.3
25.0
−0.3
40.0
24.3
23.3
15.0
396.3
19.3
22937.2
11
5
18.0
19.0
19.7
−0.3
30.0
19.3
27.7
36.6
322.5
30.3
42328.2
12
5
17.3
19.7
15.7
−0.3
20.0
11.7
15.7
31.1
339.5
18.5
35331.6
13
5
14.0
19.7
16.0
−0.7
33.3
13.3
11.7
19.1
193.9
13.8
36172.7
14
0
12.0
9.0
0.0
0.0
0.0
0.0
8.0
19.5
363.5
107.1
32180.5
95% CI Results
0
0
0.7
5.7
24.9
0.0
19.6
20.3
14.1
17.1
213.0
18.1
8838.9
1
1
1.3
7.4
25.2
0.7
9.8
15.4
10.3
23.0
152.3
18.1
10225.5
2
1
3.5
7.7
20.3
0.7
8.6
5.7
10.5
27.5
321.8
32.7
10220.9
3
1
3.6
9.1
16.9
1.1
9.8
12.9
4.6
25.3
96.7
28.4
11329.4
10
0
15.2
19.2
31.8
0.8
48.0
30.2
29.6
22.8
718.7
23.3
27617.3
11
5
3.9
9.1
21.1
1.3
29.4
20.1
13.6
29.1
148.6
24.1
23485.3
12
5
6.5
9.6
15.4
0.7
19.6
11.6
1.7
26.0
221.4
23.6
8919.1
13
5
6.9
10.3
7.8
0.7
6.5
6.2
4.6
18.2
113.3
13.3
7069.5
14
0
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The subject invention concerns a unit dose formulation comprising less than 2.5 mg of prednisolone or an equivalent, equipotent amount of another corticosteroid. One embodiment of a method of the invention concerns once daily administration of the unit dose formulation between midnight and 6 a.m. for the treatment of rheumatoid arthritis.
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FIELD OF THE INVENTION
This invention relates to single or dual chamber pacemakers, and more particularly to a mode of operation wherein one or more blanking periods are determined by measuring inherent noise propagation characteristics of the pacemaker system.
BACKGROUND OF THE INVENTION
In the following description, the term pacemaker refers to all implantable cardiac devices having cardiac pacing and sensing capabilities. Briefly, in these types of devices the sensed signals are fed to a sensing amplifier for amplification and signal conditioning.
This sensing amplifier disables its sensing ability for a brief period following a sensed or a paced event. The time during which sensing is disabled is called a blanking period. The blanking period prevents inappropriate sensing of residual energy by the pacemaker amplifier following an intrinsic event or a pacemaker output pulse. The blanking period may be applied to the same chamber where the event occurs. In dual chamber pacemakers, the blanking period also may be applied to the chamber other than the one in which the event occurs. In this case, the blanking period is called the cross-channel blanking period. There are eight possible blanking periods (See FIG. 1A) in a pacemaker: (1) atrial blanking period after an atrial sense, (2) atrial blanking period after an atrial pace, (3) atrial blanking period after a ventricular sense, (4) atrial blanking period after a ventricular pace, (5) ventricular blanking period after an atrial sense, (6) ventricular blanking period after an atrial pace (7) ventricular blanking period after a ventricular sense, and (8) ventricular blanking period after a ventricular pace. The blanking period is a function of sensing/pacing polarity; sensitivity; pacing amplitude, pulse width, lead maturation, and position of leads. In general, in prior art devices, the durations of these blanking periods was either fixed at the factory, or was one of the adjustable programmer parameters that had to be set by the physician either based on average values obtained from statistical data, or by trial and error.
It is advantageous to provide dual chamber pacemaker with an AMS (Automatic Mode Switching) function, as described for example, in U.S. Pat. No. 5,441,523, incorporated herein by reference. The AMS function switches the pacemaker from a rate-response mode, wherein pacing rate is determined from a physiological pacemaker to a backup pacing rate under certain pre-selected conditions. However, in such a pacemaker an extra long atrial blanking period reduces the sensitivity of the AMS function. In the worst case situation the A-V delay may be equal to or shorter than the atrial blanking period following an atrial event (blanking periods (1) or (2)). Since the A-V delay is followed by a ventricular event, which in turn causes the atrial blanking period to extend still further by a cross channel blanking period (3) or (4). If an intrinsic R-wave occurs before the end of the A-V delay, the atrial blanking period is also extended by blanking period (3). Therefore, fast atrial events associated with atrial tachycardia such as atrial fibrillation or atrial flutter may occur during this extra long blanking period and cannot be sensed by the pacemaker. Accordingly the atrial tachycardia is not detected and the pacemaker does not activate the AMS function to switch from a dual chamber to a ventricular non-tracking mode.
However, if the blanking periods are set to be too short, in channel or cross channel noise may be erroneously sensed as a cardiac event. For example for a short atrial blanking following a ventricular event, a farfield R wave may be sensed improperly as a new ventricular event.
Similarly, if a cross channel ventricular blanking period (5 or 6) is too short, an atrial event may be erroneously interpreted as a ventricular event and ventricular pacing maybe inhibited. If the same ventricular blanking period is too long however, a premature ventricular contraction may occur during this blanking period and a proper A-V delay would not be set up.
Thus, it is clear that the operation of a pacemaker would be vastly improved if the blanking periods can be set accurately and automatically to reflect and compensate for the electrical characteristics of a particular pacemaker system and/or the patient's tissues.
OBJECTIVES AND ADVANTAGES OF THE INVENTION
An objective of the present invention is to provide a pacemaker in which the sensing blanking periods are optimized for a particular patient, pacemaker or both.
A further objective is to provide a pacemaker system in which the blanking periods are determined automatically.
A further objective is to provide a pacemaker system capable of calculating both the in channel and cross channel blanking periods.
Other objectives and advantages of the invention shall become apparent from the following description.
Briefly, a pacemaker system constructed in accordance with this invention includes a pacemaker having means for generating test pulses to a cardiac chamber, and means for sensing cardiac signals corresponding to said pulses, after a preset time period. The time period required for said cardiac signals to decay is measured and this period is used to determine the duration of the in-channel and/or cross channel blanking periods for the pacemaker.
Alternatively, the duration of the blanking periods is determined externally in which case the cardiac response to other stimulation is used as a criteria.
BRIEF DESCRIPTION OF THE DRAWINGS
Further objects, features and advantages of the invention will become apparent upon consideration of the following description, taken in conjunction with the accompanying drawing, in which:
FIG. 1A shows the blanking periods in a prior art dual chamber pacemaker;
FIG. 1 is a block diagram of a pacemaker which embodies the subject invention;
FIG. 2 is a block diagram of the controller of FIG. 1;
FIG. 3 is a state diagram that characterizes the operation of the pacemaker of FIG. 1;
FIG. 4 is a timing diagram showing the relationship between pacing pulses and the corresponding blanking periods in accordance with this invention;
FIG. 5 shows a circuit used to determine the blanking periods in accordance with this invention;
FIG. 6 shows a timing diagram for the circuit of FIG. 5;
FIG. 7 shows a flow chart for the circuit of FIG. 5; and
FIG. 8 shows details of a determinator circuit.
DETAILED DESCRIPTION OF THE INVENTION
Referring now to FIG. 1, a pacemaker 10 constructed in accordance with this invention includes a sensing circuit 12 receiving signals from the heart 14 of a patient and a pacing circuit 16 for generating pacing pulses for the heart 14. A controller 18, which is usually a digital microprocessor receives the signals from the sensor indicative of the electrical activity of the heart, and based on these signals, generates appropriate control signals for the pacing circuit 16.
Pacemaker 10 further includes a telemetry device 20 for selectively exchanging information with an external programmer 22. The pacemaker 10 and programmer 22 jointly form a pacemaker system 24.
Although the invention may be applicable to other types of pacemakers, the pacemaker in FIG. 2 is adapted to operate in a DDDR mode and as such, it receives A-sense and V-sense signals and generates A-pace and V-pace pulses. As shown in more detail in FIG. 2, the controller 18 includes a pacer state machine 24 which generates the pace signals based on the sense signals. In addition, the A- and V-sense signals are also fed to a blanking period calculator 26 which calculates and stores the blanking periods and sends corresponding blanking period signals to the sensory circuit 12.
A preferred embodiment the pacemaker state diagram is shown in FIG. 3. It should be understood that the invention is applicable to pacemakers operating in other modes as well. The PVARP is the Post Ventricular Atrial Refractory Period. An A-sense occurring during this interval is considered to be due to a retrogradely conducted ventricular event and is ignored. A V-sense occurring at any time starts the PVARP.
The API which follows the PVARP is the Atrial Protection Interval and defines the minimum time between an ignored A-sense (i.e., in the PVARP) and the next A-pace. The API is intended to prevent an A-pace being provided during the vulnerable part of the atrial repolarization period, i.e., the relative refractory period during which arrhythmias may be induced.
The Alert which may follow API, is the interval during which A-senses are classified to be P-waves (i.e., of sinus origin) within the correct rate range. Such P-waves are tracked 1:1 by the ventricular channel. The Alert is the remainder of VV interval after the sum of the AV delay plus the PVARP plus the API.
The AV delay which follows an atrial event is intended to mimic the natural P-wave to R-wave interval and is the time between an A-sense (or A-pace) and a V-pace (in the absence of a V-sense).
Importantly, the subject pacemaker further includes means for providing blanking periods in the various sensing channels during either atrial or ventricular activity. More particularly, as shown in FIG. 4, every atrial event (i.e., atrial pace or atrial sense) is followed in the atrial sensing channel by a blanking period. Moreover blanking periods in the atrial sensing channel also follow each ventricular event to inhibit cross-channel noise. In FIG. 4 the blanking periods for atrial sensing following an atrial event are designated as Baa, and the ones following a ventricular event are designated Bav. The corresponding blanking periods for the ventricular channel are also shown in the Figure and are designated as Bvv and Bva, as shown.
As previously described, the present invention pertains to the means of determining and adjusting these blanking periods to insure that the sensing channels operate accurately and reliably. In order to determine these blanking periods, the pacemaker is provided with the blanking period calculator 26. As shown in detail in FIG. 5, the calculator 26 monitors the atrial and ventricular intracardiac signals and generates its own atrial and ventricular test blanking signals Bat, Bvt, respectively.
The calculator 26 includes an atrial noise sensor 106 and a ventricular noise sensor 108. These sensors receive respectively the atrial and ventricular intracardiac signals as shown in FIG. 1. The calculator 26 also includes an atrial pace command generator 102 and a ventricle pace command generator 104. The calculator 26 further includes individual determinator elements 110-116. The operation of the calculator 26 is now described in conjunction with the graphs of FIGS. 4 and 6 and the flow chart of FIG. 7.
Preferably the determination for the various blanking periods is made (or modified) in a physician's office with the patient's pacemaker being coupled to the programmer 22 for initializing or modifying the pacemaker's operation. The programmer 22 provides the physicians with a sequence of steps that are performed to set up various programming parameters. As part of this procedure, the physician may measure and set the pacing signal threshold levels. The blanking periods may be determined and set at the same time as follows. Initially, as shown in FIG. 7, in step S200 the atrium is overdrive paced by issuing appropriate pacing command to generator 102 using a fixed A-V delay of 200 msec. This step is performed to insure that the blanking periods are determined in response to atrial pacing and not an atrial natural pulse. It is believed that blanking periods following a paced pulse in either chamber should be longer than the blanking periods following an intrinsic cardiac event. Therefore, it is safe to apply the blanking periods determined for a paced event to a sensed (intrinsic) event.
Next an atrial test pace signal 300 is generated, as indicated on FIG. 6 (Step 202). Following this signal 300, a shortened atrial test blanking signal Bat is generated by a test blanking generator 118 (FIG. 5) for the atrial sensing channel 25. A similar signal Bvt is generated by generator 118 for the ventricular sensing channel 34 (FIG. 6, Step 204, FIG. 7). These signals are selected to correspond to the time required for the sense amplifier in sensing circuit 12, sensors 106, 108 to settle. For example these test blanking periods may be in the order of 20-30 msec.
Following the test blanking signal Bat, the atrial noise sensor 106 starts monitoring the atrial intracardiac signal. As shown in FIG. 6, typically a variable noise signal 302 is sensed in response to atrial test pace signal 300. Noise signal 302 sensed in the atrium decays after a time duration Tan at which time its peak falls below the sensor threshold level ATH. The output of atrial sensor 106 is fed to determinator 110 which also receives the Bat signal. Determinator 110 measures the time duration Tan by determining the last point in time when the atrial noise sensor receives an input exceeding ATH. This time duration Tan is characteristic of the tissues of heart and other factors.
As shown in FIG. 6, concurrently with the blanking period Bat, a corresponding blanking period Bvt is also generated for the ventricular sensor. Preferably this signal is also in the range of 20-30 msec. At the end of this period, a noise signal 304 is detected by sensing circuit 12. This signal is sensed by ventricular noise sensor 108 and fed to the determinator circuit 114. Determinator circuit 114 also receives the Bvt signal. After a time period Tvn, the ventricular noise signal decays to a peak level below threshold VTH. In order to insure that the blanking period does not exceed the A-V interval, the period Tvn is limited to 80 msec (Tmax). The determinator 114 thus measures the length of signal Tvn.
As shown on FIG. 7, after the signals Tan (i), Tvn (i) are measured, the whole cycle is repeated several times until several values Tan(n), Tvn (n) are obtained. The value of `n` may be for example two. This is illustrated in FIG. 7 by steps S206, S208, S210. At this point, the parameters Tan(n), Tvn(0 . . . n) are analyzed to determine the maximum difference between the respective values. In step S214 a test is conducted to determine if the difference between any two of the parameters Tan is greater than 20 msec. If this difference is less than 20 msec, than the longest Tan (longest) is selected. In step S 216 the blanking period is then calculated or set by adding Bat+Tan (longest)+safety factor. For example the safety factor may be about 15 msec. The parameters Tvn(o . . . n) are analyzed similarly to determine in step S216 for the value Bav. These values are sent to the display of the programmer. (S218).
If in step S214 it is determined that the difference between any two measurement Tan (j) exceeds 20 msec, then in step S220 an error message is sent to the programmer which in response (S222) displays a request that the whole procedure be repeated since the first set of values are unreliable.
After the blanking periods Baa, and Bav are calculated as described above, the ventricle is paced in a manner similar the one described above to obtain the values for Bva and Bvv.
The value of Baa, Bav, Bva, Bvv are transmitted to and displayed by the programmer in step S218. These values may be used as parameters by the pacemaker or may be used as suggested values to the physician as possible programmed values for blanking periods. The value of Bva is not very important and has been included herein for the sake of completeness.
Alternatively, the pacemaker 24 itself may set its own blanking periods to the values determined as described above.
Typically, as shown in FIG. 8, in the sensing circuit for sensing the atrium, the atrial electrode 50 is connected to an amplifier 52. The output of amplifier 52 is fed to a comparator 54. The comparator compares the amplified signal sensed on line 50 with a programmable sensing threshold stored in a memory 56. Signals above this threshold are sent as an A-sense signals by the circuit 12. Sensor 106 includes a peak detector 58 which detects the peaks of the signals senses on line 50. These peaks are fed to a comparator 60. The sensor 106 also includes a divide-by-two circuit 62 which receives the sensing threshold from memory 56 and divides by two. The comparator compares the signals on line 50 with the output of circuit 62 and generates an output when the peaks detected by detector 58 fall below this output. This signal is used to determine the Baa signal as discussed above. The threshold (ATH) may be detected at 50% or less than the programmed sensitivity stored in memory 56. The advantage of this approach is that it can automatically determine a high signal to noise ratio of about 2:1.
In the embodiment described above, the ideal or suggested blanking periods are determined by the pacemaker. Alternatively, the calculation to determine the blanking period in the programmer using telemetered ECG's obtained by the pacemaker. Another alternative would be to perform the calculation on the programmer, using the main timing events (MTEs) only. MTEs are marker generated to indicate senses of intracardiac ECGs. In the case, MTEs are markers of noise senses following a paced event.
Although the invention has been described with reference to several particular embodiments, it is to be understood that these embodiments are merely illustrative of the application of the principles of the invention. Accordingly, the embodiments described in particular should be considered exemplary, not limiting, with respect to the following claims.
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The blanking periods for an implantable cardiac device, such as a pacemaker, is determined by providing an excitation in a cardiac chamber and monitoring the corresponding cardiac activity. For in-channel blanking periods, the response from the same chamber is monitored while for cross-channel blanking period, the other cardiac chamber is monitored. The optimal blanking period is then determined based on the cardiac activity. This period is programmed directly into the device, or transmitted to an external programmer where it is used to provide guidance to a health care professional. The optimal blanking period duration may also be determined using other signals sensed by the programmer, using ECG's or MTE's.
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CROSS-REFERENCE TO RELATED APPLICATIONS
This application is a national stage application of International Application No. PCT/CN2014/076165, filed Apr. 24, 2014 which claims priority to Chinese patent application No. 201310158829.X, entitled “Paper Storage, Printer and Method for Using Multiple Types of Mediums” and filed on May 2, 2013 with the State Intellectual Property Office of China, the disclosure of which is incorporated therein by reference in its entirety.
TECHNICAL FIELD
The present disclosure relates to a paper storage, a printer adopting the paper storage, and a method for using multiple types of mediums.
BACKGROUND
The existing printer includes a printing mechanism and a paper storage fixedly connected with a frame, where a paper roll for printing is placed in the paper storage, and printing paper (i.e. a printing medium) may lead out from the paper roll to be printed by the printing mechanism and outputted to the outside of the printer. Due to the fact that a user needs to use different types of paper rolls depending on a specific case in some scenarios, there is a need for easy replacement of the paper roll in the printer, to improve the work efficiency.
International application Publication No. WO2007111235 provides a printer with a detachable paper storage. As shown in FIG. 1A , a printer 1 ′ includes a body 2 ′, an upper cover 3 ′ and a paper storage 4 ′ for accommodating printing paper, where the upper cover 3 ′ is pivoted with side walls 14 a and 15 a of the body 2 ′ and may be rotatably opened or closed relative to the body 2 ′. A printing head 21 ′ is arranged in the body 2 ′, and a roller 22 ′ is arranged on the upper cover 3 ′, so that when the upper cover 3 ′ is closed relative to the body 2 ′, the printing head 21 ′ tangentially matches with the roller 22 ′.
A first space portion 34 ′ is formed between the side walls 14 a and 15 a of the body 2 ′, and a second space portion 35 ′ is formed between side arms 32 ′ and 33 ′ of the upper cover 3 ′. The paper storage 4 ′ is mounted in a space formed by the first space portion 34 ′ and the second space portion 35 ′. The paper storage 4 ′ includes a first part 4 a and a second part 4 b , where a first slot 45 ′ and a second slot 46 ′ of the second part 4 b match with a first inserting pin 39 ′ and a second inserting pin (not shown) on the body in a plugging manner, and a first inserting tab 40 ′ and a second inserting tab 41 ′ of the second part 4 b match with the side walls 14 a and 15 a of the body 2 ′ in a plugging manner; while clamping detents 51 ′ and 52 ′ of the first part 4 a match with the two side arms of the upper cover 3 ′ in a clamping manner, so that when the upper cover 3 ′ is rotatably opened relative to the body 2 ′, the first part 4 a is accordingly opened. After the paper storage 4 ′ is installed in the printer, as shown in FIG. 1B , a leading end of the printing paper is pulled out from the paper roll and then the upper cover 3 ′ is closed, in this case, the printing paper is pressed between the roller 22 ′ and the printing hear 21 ′ and hence printing can be started. The printer can selectively adopt paper storages having different structural sizes to utilize paper rolls with different outer diameters.
However, the existing printer is defective in that: replacement by a paper roll with a different outer diameter requires for replacement by a paper storage having a different structural size, which requires for installing the first part and the second part of the paper storage respectively, and each time the paper roll is being installed, the upper cover is opened so as to pass the printing paper between the roller and the printing head, thus the operations of replacing the paper roll for such printer are complicated, causing inconvenience in use.
SUMMARY OF THE INVENTION
An object of the present disclosure is to provide a paper storage which is easy to replace and convenient in use. An object of the present disclosure is also to provide a printer adopting the paper storage. An object of the present disclosure is further to provide a method of using multiple types of mediums.
To this end, according to one aspect of the present disclosure, a paper storage is provided and includes: a storage body for accommodating a medium, a medium outlet, and a roller arranged on the storage body, where the medium outlet is configured to discharge the medium accommodated in the storage body after the medium passes by the roller, and an opening opposite to the roller is provided on a wall of the storage body, to allow an external medium processing device to match with the roller through the opening to process the medium.
Further, the paper storage includes a chassis and an upper cover, and the chassis and the upper cover are combined to form the medium outlet.
Further, the roller is arranged on the upper cover and the opening is arranged on the chassis.
Further, the paper storage also includes a paper tearing bar located at the medium outlet and arranged on the chassis.
Further, a guide member configured to limit a position of the medium in a width direction is arranged in the storage body.
Further, the paper storage also includes a clamping structure configured to lock the upper cover and the chassis together when the upper cover is closed relative to the chassis.
Further, the upper cover is pivoted with or detachably connected with the chassis.
Further, a gear in a transmission connection with a driving mechanism of the external medium processing device is arranged at an axial end of the roller.
Further, the paper storage also includes a connection structure configured to connect the storage body with the external medium processing device.
According to another aspect of the present disclosure, a printer is provided and includes: a base and a detachable paper storage as described above, where a printing head assembly is arranged on the base, and a roller of the paper storage is configured to match with a printing head of the printing head assembly at an opening of the paper storage.
Further, the base is provided with a driving mechanism configured to drive the roller to rotate.
Further, the base is provided with a concave portion configured to position the paper storage.
Further, a clamping structure configured to clamp the paper storage and the base together is arranged between the paper storage and the base.
Further, a locking mechanism configured to lock the paper storage is further arranged on the base, and the locking mechanism includes a lock hook configured to match with a core shaft of the roller on the paper storage in a locking manner.
Further, a first elastic element declining toward the paper storage is arranged in the concave portion so that the paper storage always trends to move away from the concave portion.
According to yet another aspect of the present disclosure, a printer is provided and includes: a base and a paper storage detachably connected with the base, where the paper storage includes a chassis and an upper cover which are pivoted with each other through a pivot shaft, where the upper cover is rotatable to be opened or closed relative to the chassis, a roller is arranged on the upper cover, and an opening is arranged on the chassis; a printing head assembly, a driving mechanism configured to drive the roller to rotate, and a concave portion configured to accommodate the paper storage are arranged on the base; a clamping slot configured to clamp the pivot shaft is arranged in the concave portion, and a lock hook configured to lock the core shaft of the roller is arranged on the chassis; and a space configured to accommodate a medium is formed between the upper cover and the chassis when the upper cover is closed relative to the chassis, and the roller matches with a printing head of the printing head assembly at the opening.
The present disclosure also provides a method of using multiple types of mediums including: providing a medium processing system comprising a medium processing device and a plurality of paper storages, and to utilize a different type of medium, combining the paper storage accommodating the type of medium with a base of the medium processing device, wherein the medium is outputted from a medium outlet of the paper storage after passing by a roller of the paper storage, and the medium processing device matches with the roller via an opening of the paper storage to process the medium.
Further, the medium processing system is a printing system, and the medium processing device is a printer.
When the paper storage of the present disclosure is installed on the base of the printer, before the medium in the paper storage is outputted from the medium outlet of the paper storage after passing by the paper storage, the medium is sandwiched between the printing head of the printer and the roller at the opening of the paper storage, is printed by the printing head and then extrudes from the paper storage via the medium outlet of the paper storage. The paper storage can be wholly removed from the printer to detach the paper storage. Therefore, compared with the prior art, the printer adopting the paper storage of the present disclosure eliminates, in replacing the paper storage, the need for respective detachment of various parts of the paper storage and the need for opening of an upper cover of the printer to load the paper roll, thus the problem of the complicated operations of replacing the paper roll and inconvenience in use is avoided.
In addition to the above objects, features and advantages, other objects, features and advantages of the present disclosure will be further described in detail in combination with the accompanying drawings.
BRIEF DESCRIPTION OF THE DRAWINGS
Accompanying drawings, which construct a part of the specification and are used for better understanding of the present disclosure, illustrate some preferred embodiments of the present disclosure, and show principles of the present disclosure in combination with the description below.
FIG. 1A is a structural view of a printer adopting a detachable paper storage provided in International Application Publication No. WO2007111235;
FIG. 1B is a structural section view of the printer shown in FIG. 1A ;
FIG. 2 is a structural section view of a paper storage according to a first embodiment of the present disclosure;
FIG. 3A is a first isometric view of the paper storage according to the first embodiment of the present disclosure, where the upper cover is opened;
FIG. 3B is a second isometric view of the paper storage according to the first embodiment of the present disclosure, where the upper cover is opened;
FIG. 4 is an isometric structural view of the paper storage according to the first embodiment of the present disclosure, where the upper cover is closed;
FIG. 5 is an isometric structural view of the paper storage according to a second embodiment of the present disclosure, where the upper cover is closed;
FIG. 6 is a structural view of a printer according to a first embodiment of the present disclosure;
FIG. 7 is a structural section view of the printer according to the first embodiment of the present disclosure;
FIG. 8 is a structural view of the printer according to the first embodiment of the present disclosure, where the paper storage is separate from a base of the printer;
FIG. 9 is a first view of installing of the paper storage into the printer according to the first embodiment of the present disclosure;
FIG. 10 is a second view of installing of the paper storage into the printer according to the first embodiment of the present disclosure;
FIG. 11 is a partial structural section view of a printer according to a second embodiment of the present disclosure;
FIG. 12 is a first view of installing of a paper storage into a printer according to a third embodiment of the present disclosure; and
FIG. 13 is a second view of installing of a paper storage into a printer according to the third embodiment of the present disclosure.
List of reference numerals
1. Base
2. Paper storage
4. Printing head assembly
5. Roller
7. Elastic hook
8. Elastic slice
11. Left wall
12. Right wall
13. Upper casing
14. Bottom casing
15. Bracket
16. Notch
17. Concave portion
20. Storage body
21. Upper cover
22. Chassis
23. Paper tearing bar
24. Clamping hook
25. Guide member
31. Third connection member
32. Fourth connection member
33. Clamping part
34. Clamping slot
41. Printing head
42. Second elastic element
43. Support plate
51. Core shaft
52. Roller wheel
53. Gear
211. Pivot shaft
221. Left side wall
222. Right side wall
223. Bottom board
224. Opening
225. Inserting slot
312. Clamping member
321. Rotation shaft
322. Locking hook
323. Third elastic element
324. Button
DETAILED DESCRIPTION OF THE EMBODIMENTS
Embodiments of the present disclosure are described in detail below in combination with the accompanying drawings, although the present disclosure can be implemented in various ways defined and covered by the appended claims.
FIG. 2 is structural section view of a paper storage according to a first embodiment of the present disclosure, FIG. 3A is a first isometric view of the paper storage according to the first embodiment of the present disclosure where the upper cover is opened, FIG. 3B is a second isometric view of the paper storage according to the first embodiment of the present disclosure where the upper cover is opened, and FIG. 4 is an isometric structural view of the paper storage according to the first embodiment of the present disclosure, where the upper cover is closed. As shown in FIGS. 2, 3A, 3B and 4 , a paper storage 2 includes a storage body 20 and a roller 5 arranged on the storage body 20 , where the storage body 20 is provided with a medium outlet A and an opening 224 that is opposite to the roller 5 .
The storage body 20 includes an upper cover 21 and a chassis 22 , which are combined in such a way that the medium outlet A is formed. The chassis 22 includes a left side wall 221 , a right side wall 222 and a bottom board 223 , where the left side wall 221 and the right side wall 222 are arranged in parallel to each other, a distance between an inner surface of the left side wall 221 and an inner surface of the right side wall 222 matches with the maximum width of a paper roll, and the bottom board 223 is connected perpendicularly between the left side wall 221 and the right side wall 222 . Preferably, the bottom board 223 has a cross section of an arc shape having a radius matching with the maximum radius of the paper roll. The bottom board 223 is provided with the opening 224 , which has a longitudinal direction extending along a width direction of the paper roll and has a preset width. In other embodiments of the present disclosure, the bottom board 223 may have a cross section of a trapeziform or rectangular shape.
The upper cover 21 is pivoted with or connected detachably with the chassis 22 . In the present embodiment, the upper cover 21 is pivoted with the chassis 22 through a pivot shaft 211 , and may be rotatably opened or closed relative to the chassis 22 . The pivot shaft 211 is located at a side of the chassis 22 away from the opening 224 , and has an axis extending in a direction perpendicular to the left side wall 221 and the right side wall 222 . When the upper cover 21 is closed, a space accommodating the paper roll is formed by the upper cover 21 and the chassis 22 , and the paper roll rolls freely in the space. In this case, a side of the upper cover 21 away from the pivot shaft 211 is opposite to a side of the chassis 22 away from the pivot shaft 211 and is apart from side of the chassis 22 away from the pivot shaft 211 by a predefined distance to form the medium outlet A.
The roller 5 is arranged at a side of the upper cover 21 away from the pivot shaft 211 and has an axis parallel to the axis of the pivot shaft 211 . The roller 5 includes a core shaft 51 , a roller wheel 52 , and a gear 53 , where the core shaft 51 has an axis parallel to the axis of the pivot shaft 211 , and is supported on the upper cover 21 at its both ends, so that the core shaft 51 is rotatable about its own axis. The roller wheel 52 is fixedly arranged on the periphery of the core shaft 51 and extends along the axial direction of the core shaft 51 . The roller wheel 52 has a length larger than the width of the printing paper, and may be made of elastic material such as rubber or plastic. When the core shaft 51 is rotated, the roller wheel 52 is rotated synchronously with the core shaft 51 . When the upper cover 21 is closed, the roller wheel 52 is opposite to the opening 224 on the chassis 22 , in this case, the roller wheel 52 may be located within the chassis 22 , or may pass through the opening 224 on the chassis 22 to be exposed at the external of the paper storage 2 . The gear 53 is fixedly installed on one end of the core shaft 51 , and is transmission connected with a driving mechanism of the printer when the paper storage 2 is installed in the printer. When the gear 53 is driven to rotate by the driving mechanism of the printer, the gear 53 causes the core shaft 51 to rotate, and the roller wheel 52 rotates accordingly.
The paper storage 2 also includes a locking assembly, which is configured to fix the upper cover 21 at a locked position where the upper cover 21 is closed relative to the chassis 22 . In the present embodiment, the locking assembly is embodied as a clamping structure including a clamping hook 24 and a clamping slot (not shown), where the clamping hook 24 is located on one of the chassis 22 and the upper cover 21 , and the clamping slot is located on the other of the chassis 22 and the upper cover 21 . When the upper cover 21 is closed, the clamping hook 24 matches with the clamping slot in a clamping manner, so that the upper cover 21 is fixed at the locked position for closing. When a user pushes the clamping hook 24 , the clamping hook 24 is separated from the clamping slot so that the upper cover 21 is opened. In the present embodiment, the paper storage 2 includes two locking assemblies, which are symmetrically arranged with respect to a middle line between the left side wall 221 and the right side wall 222 of the chassis 22 in the width direction, where two clamping hooks 24 are located at inner sides of the left side wall 221 and the right side wall 222 of the chassis 22 , respectively, and two clamping slots are located on two side walls of the upper cover 21 . Thus, when the upper cover 21 is closed, the two clamping hooks 24 match with the two clamping slots in a clamping manner, so that the upper cover 21 is fixed at the locked position for closing; and to open the upper cover 21 , the clamping hooks 24 are pushed from both sides and hence are separated from the clamping slots, thereby opening the upper cover 21 .
It is noted that in other embodiments of the present disclosure, the locking assembly may include a lock hook and a lock shaft, where the lock hook is pivoted with one of the upper cover 21 and the chassis 22 through a rotation shaft and is rotatable about an axis of the rotation shaft, while the lock shaft is arranged on the other of the upper cover 21 and the chassis 22 , thus, when the upper cover 21 is closed relative to the chassis 22 , the lock hook matches with the lock shaft in a clamping manner to fix the upper cover 21 at the locked position for closing, and when the lock hook is separated from the lock shaft, the upper cover 21 is allowed to be opened relative to the chassis 22 .
The paper storage 2 further includes a connection structure configured to connect the paper storage 2 with the printer. In the present embodiment, the connection structure is a first connection mechanism including a first connection member and a second connection member. Preferably, the first connection member is located at an end of the chassis 22 away from the opening 224 , and the second connection member is located at an end of the chassis 22 close to the opening 224 . Here, the first connection member may be a clamping part or a clamping slot arranged at the outer side of the bottom board 223 of the chassis 22 of the paper storage 2 or at the outer sides of the left side wall 221 and the right side wall 222 of the chassis 22 . When the first connection member is the clamping part, the clamping slot is correspondingly arranged on the printer, and when the first connection member is the clamping slot, the clamping part is correspondingly arranged on the printer, so that the clamping slot matches with the clamping part in a clamping manner. The second connection part may be the lock shaft or the lock hook arranged on the outer sides of the left side wall 221 and the right side wall 222 of the chassis 22 , thus, when the second connection part is the lock shaft, the lock hook is correspondingly arranged on the printer, and when the second connection part is the lock hook, the lock shaft is correspondingly arranged on the printer, so that the lock hook matches with the lock shaft in a locking manner. Therefore, the paper storage 2 is fixedly connected with the printer through the first connection member and the second connection member.
In the present embodiment, the first connection member is a pivot shaft 211 and the second connection member is the core shaft 51 of the roller 5 . When the paper storage is installed in the printer, the core shaft 51 of the roller 5 matches with the lock hook arranged on the printer in a locking manner, to facilitate limiting the relative position of the roller 5 and the printing head of the printer. In other embodiments of the present disclosure, the lock shaft is alternatively arranged on the side wall of the chassis 22 , so that the lock shaft matches with the lock hook arranged on the printer in a locking manner. Therefore, the upper cover 21 of the paper storage 2 may be directly opened to replace the paper roll when the paper storage is installed in the printer, thereby simplifying the operation steps of replacing the paper roll.
Preferably, the paper storage 2 also includes a paper tearing bar 23 of a slice shape located at the medium outlet A, and the paper tearing bar 23 may be fixedly installed on the chassis 22 or the upper cover 21 . By pulling the printing paper forcibly, the printing paper will be torn by the blade of the paper tearing bar 23 . In the present embodiment, the paper tearing bar 23 is fixedly installed on the chassis 22 .
In installing the paper roll, the upper cover 21 is firstly opened, then the paper roll is placed in the chassis 22 , a leading end of the printing paper is drawn out from the paper storage, and finally the upper cover 21 is closed so that the clamping hook 24 on the chassis 22 matches with the clamping slot on the upper cover 21 in a clamping manner, thereby accomplishing the installing of the paper roll. In this case, the printing paper passes by the roller wheel 52 of the roller 5 and is exposed at the opening 224 of the chassis 22 , and the leading end of the printing paper is led out from the medium outlet A of the paper storage 2 .
In the paper storage provided in the present embodiment, the upper cover is pivoted with the chassis and the roller is arranged on the upper cover, so that after the paper roll is installed in the paper storage, the printing paper is discharged from the medium outlet after passing by the roller, and meanwhile the printing paper is exposed at the opening of the chassis. When the paper storage is installed on the printer, the roller on the paper storage matches with the printing head of the printer at the opening of the paper storage, and the printing paper is sandwiched between the roller and the printing head so that printing can be performed on the printing paper by the printing head. To detach the paper storage, the paper storage can be as a whole removed from the printer. Therefore, compared with the prior art, the printer adopting the paper storage of the present disclosure eliminates, in replacing the paper storage, the need for respective detachment of various parts of the paper storage and the need for opening of an upper cover of the printer to load the paper roll, thus the problem of the complicated operations of replacing the paper roll and inconvenience in use is avoided.
It is noted that, in the above embodiment, the upper cover of the storage body is turned over to be opened or closed relative to the chassis in a front-and-rear direction. When the upper cover is closed, the storage body for accommodating the medium is formed by the upper cover and the chassis, and the medium outlet is opposite to the pivoting position. In other embodiments, the upper cover may be laterally turned over to be opened relative to the chassis in a left-and-right direction, and in this case, the medium outlet is located at the side of the pivot shaft on the upper cover. Alternatively, the storage body may be formed in another way or by other parts, without being limited to the upper cover and the chassis as well as the pivot connection between the upper cover and the chassis.
It is noted that, in the above embodiment, the roller is exposed at the opening of the paper storage and is tangential to the printing head. In other embodiments, the printing head may enter into the paper storage through the opening of the paper storage to tangentially match with the roller.
It is noted that, in the above embodiment, the chassis 22 and the upper cover 21 are combined to form the medium outlet A. In other embodiments, an opening may be provided on the surface of the upper cover 21 to form the medium outlet.
FIG. 5 is an isometric structural view of the paper storage according to a second embodiment of the present disclosure, where the upper cover is closed. As shown in FIG. 5 , the second embodiment is different from the previous embodiment in that: the paper storage 2 further includes at least one guide member 25 in the present embodiment, and accordingly at least one inserting slot 225 for installing the guide member 25 is arranged on the bottom board 223 of the chassis 22 .
Here, the guide member 25 is configured to adjust the width of the paper storage 2 , limit the movement of the paper roll placed in the paper storage 2 in an axial direction of the paper roll, and hence prevent the deflected movement of the printing paper. The number of the guide members 25 depends on the alignment manner of the printing paper. When the printing paper is aligned by using one side of the paper storage as a reference plane, one guide member 25 is included in the paper storage 2 , and accordingly several inserting slots 225 are provided on the bottom board 223 of the chassis 22 in the width direction of the paper roll, so that when the guide member 25 is inserted into one of the several inserting slots 225 , a distance between the guide member 25 and the reference plane matches with the width of a certain type of paper roll, thus, the guide member 25 is inserted into the corresponding inserting slot 225 depending on the width of the paper roll in use. When the printing paper is aligned with reference to a center line of the paper storage 2 in the width direction, two guide members 25 are included in the paper storage 2 , and accordingly several inserting slots 225 are provided on the bottom board 223 of the chassis in the width direction of the paper roll, where the inserting slots 225 are divided into groups, each of which includes two inserting slots 225 arranged symmetrically with respect to the center line of the paper storage 2 in the width direction, and a distance between the inserting slots 225 of each group matches with the width of a certain type of paper roll, thus, the two guide members 25 are respectively inserted into the corresponding inserting slots 225 depending on the width of the paper roll in use.
In the present embodiment, the printing paper is aligned with reference to the center line of the paper storage 2 in the width direction, and hence there are two guide members 25 , which match with the corresponding inserting slots 225 on the bottom board 223 in a plugging manner and are both parallel to the left side wall 221 and the right side wall 222 , so that the two guide members 25 , together with the bottom board 223 of the chassis 22 , form a paper accommodating space, and the movement of the paper roll in the paper accommodating space along the axial direction of the paper roll is eliminated. Therefore, the paper storage provided in the present embodiment is applicable to paper rolls of different widths, and hence has improved adaptability to mediums.
FIG. 6 is a structural view of a printer according to the first embodiment of the present disclosure, FIG. 7 is a structural section view of a printer according to the first embodiment of the present disclosure, and FIG. 8 is a view of the printer according to the first embodiment of the present disclosure, where the paper storage is separate from a base of the printer. As shown in FIG. 6 , FIG. 7 and FIG. 8 , a printer includes a base 1 , a paper storage 2 , a printing head assembly 4 , and a second connection mechanism. The printing head assembly 4 and the second connection mechanism are both arranged on the base 1 , and the paper storage 2 is one of those paper storages described in the above embodiments and is detachably connected with the base 1 . After the paper storage 2 is connected with the base 1 , the roller 5 on the paper storage 2 tangentially matches with the printing head 41 of the printing head assembly 4 at the opening of the paper storage.
As shown in FIG. 8 , the base 1 includes a left wall 11 , a right wall 12 , and a bottom casing 14 . The left wall 11 and the right wall 12 are parallel to each other and are spaced by a predefined distance, and a distance between an inner surface of the left wall 11 and an inner surface of the right wall 12 matches with the width of the paper storage 2 . The bottom casing 14 is connected between the left wall 11 and the right wall 12 , and has a cross section of a shape matching with the shape of the cross section of the chassis 22 of the paper storage 2 . The left wall 11 , the right wall 12 and the bottom casing 14 form a concave portion 17 configured to position and accommodate the paper storage 2 .
Preferably, the base 1 further includes an upper casing 13 located between the left wall 11 and the right wall 12 and above the bottom casing 14 , and the upper casing 13 is opposite to a portion of the bottom casing 14 . The concave portion 17 is located at a side of the bottom casing 14 not opposite to the upper casing 13 . Preferably, the base 1 further includes a bracket 15 connected perpendicularly to both the left wall 11 and the right wall 12 and located between the upper casing 13 and the bottom casing 14 .
The printing head assembly 4 is arranged on the base 1 , and is located at the downstream of the concave portion 17 in a printing paper transmission direction. The printing head assembly 4 includes a printing head 41 , at least one second elastic element 42 , and a support plate 43 . The support plate 43 is movably connected with the bracket 15 of the base 1 , and the printing head 41 is fixedly connected with the support plate 43 and located at a side of the support plate 43 away from the bracket 15 . The second elastic element 42 , which may be a pressure spring, a torsion spring or a plate spring, is located between the support plate 43 and the bracket 15 , and has one end connected with the support plate 43 and the other end connected with the bracket 15 . Under the effect of an elastic force applied by the second elastic element 42 , the support plate 43 and hence the printing head 41 always trend to move into the concave portion 17 . The base 1 is also provided with a positioning member (not shown) matching with the support plate 43 , and the support plate 43 of the printing head assembly 4 can be stabilized at a position distant from the bracket 15 by a predefined distance under the limitation by the positioning member.
Preferably, the printer further includes an elastic hook 7 arranged at the outer side of the bottom casing 14 and configured to hang the printer on a waist belt of the user for ease carry.
Preferably, notches 16 are symmetrically arranged on the inner sides of the left wall 11 and the right wall 12 of the base 1 , and openings of the notches 16 are respectively arranged at a side of the left wall 11 and a side of the right wall 12 that are away from the bottom casing 14 . The notch 16 has a width matching with a diameter of the core shaft 51 of the roller 5 of the paper storage 2 , has a length direction extending in an upper-and-down direction, and has a depth direction extending in a thickness direction of the walls. Preferably, the notch 16 has a tapered shape, to smoothly guide the core shaft 51 of the roller 5 into the notch 16 .
The second connection mechanism is arranged on the base 1 , and is configured to connect to the first connection mechanism on the paper storage 2 , so that the paper storage 2 and the base 1 are detachably connected. FIG. 9 is a first view of installing of the paper storage into the printer according to the first embodiment of the present disclosure, and FIG. 10 is a second view of installing of the paper storage into the printer according to the first embodiment of the present disclosure. As shown in FIG. 9 and FIG. 10 , the second connection mechanism includes a third connection member 31 and a fourth connection member 32 .
The third connection member 31 matches with the first connection member of the first connection mechanism on the paper storage 2 . When the first connection member is arranged on the bottom board 223 of the paper storage 2 , the third connection member 31 is arranged on the inner side of the bottom casing 14 of the base 1 , and when the first connection member is arranged on the outer sides of the left side wall 221 and the right side wall 222 of the paper storage 2 , the third connection member 31 is correspondingly arranged on the inner sides of the left wall 11 and the right wall 12 of the base 1 . When the paper storage 2 is installed on the base 1 , the first connection member and the third connection member 31 match with each other in a clamping manner.
In the present embodiment, the first connection member is embodied by the pivot shaft 211 , and the third connection member 31 is arranged on the inner side of the bottom casing 14 and has a groove shape. The third connection member 31 has a depth extending in the thickness direction of the walls, a length extending in a direction perpendicular to the left wall 11 and the right wall 12 , and a cross section of a shape matching with the shape of the cross section of the pivot shaft 211 . When the paper storage 2 is installed on the base 1 , the paper storage 2 is located in the concave portion, and the pivot shaft 211 on the paper storage 2 is clamped in the third connection member 31 on the bottom casing 14 , thereby limiting the movement of a side of the paper storage 2 close to the pivot shaft 211 toward the top and rear of the bottom cashing 14 .
The fourth connection member 32 is configured to match with the second connection member on the paper storage 2 . When the second connection member is embodied as the lock shaft, the fourth connection member 32 includes a lock hook 322 , and when the second connection member is embodied as the lock hook, the fourth connection member 32 is the lock shaft. In the present embodiment, the second connection member is the core shaft 51 of the roller 5 , and the fourth connection member 32 includes the lock hook 322 , a rotation shaft 321 , a third elastic element 323 and a button 324 . The rotation shaft 321 is supported by the left wall 11 and the right wall 12 of the base 1 , the lock hook 322 is pivoted with the base 1 through the rotation shaft 321 , where the lock hook 322 may be fixedly connected with the rotation shaft 321 and hence may be rotated synchronously with the rotation shaft 321 , or alternatively, the rotation shaft 321 may be sheathed in the lock hook 322 so that the lock hook 322 may be rotated about the rotation shaft 321 .
When the pivot shaft 211 of the paper storage 2 matches with the third connection member 31 of the base 1 in a clamping manner, the lock hook 322 may match with the core shaft 51 of the roller 5 in a clamping manner, to fix the position of the paper storage 2 relative to the base 1 . The third elastic element 323 has one end connected with the lock hook 322 and the other end connected with the base 1 . Under the effect of an elastic force applied by the third elastic element 323 , the lock hook 322 always trend to clamp and lock the core shaft 51 of the roller 5 . The button 324 is fixedly connected with the lock hook 322 and located at the outside of the base 1 , and triggering or pressing the button 324 by the user can cause the rotation of the lock hook 322 , so that the lock hook 322 is separated from the core shaft 51 of the roller 5 , thereby allowing detachment of the paper storage 2 from the base 1 .
Specifically the fourth connection member 32 in the present embodiment includes two lock hooks 322 which are integrated and fixedly connected with both ends of the rotation shaft 321 , respectively. The rotation shaft 321 is supported by the left wall 11 and the right wall 12 of the base 1 , and these two lock hooks 322 are rotatable about the axis of the rotation shaft 321 synchronously with the rotation shaft 321 . The third elastic element 323 has one end connected with the base 1 and the other end connected with the lock hooks 323 . The button 324 , which is located at the outside of the upper casing 13 of the base 1 , is connected with an intermediate portion between the two lock hooks 322 . When the pivot shaft 211 of the paper storage 2 matches with the third connection member 31 on the base 1 in a clamping manner, the lock hooks 322 match with the core shaft 51 of the roller 5 in a clamping manner, to fix the position of the paper storage 2 relative to the base 1 . When the user triggers or presses the button 324 , the button 324 causes the rotation of the lock hooks 322 , so that the lock hooks 322 are separated from the core shaft 51 of the roller 5 , thereby allowing detachment of the paper storage 2 from the base 1 .
The procedure of replacing the paper storage in the printer is described below.
To install the paper storage 2 , the pivot shaft 211 of the paper storage 2 is firstly clamped in the third connection member 31 on the base 1 , and then the paper storage 2 is rotated about the pivot shaft 211 so that the paper storage 2 is rotated to approach the printing head 41 . When the paper storage 2 entirely enters into the concave portion 17 , the paper storage 2 is pressed so that the core shaft 51 of the roller 5 on the paper storage 2 pushes the lock hook 322 to rotate by overcoming the elastic force applied by the third elastic element 323 . When the chassis 22 of the paper storage 2 contacts and matches with the bottom casing 14 of the base 1 , the lock hook 323 matches with the core shaft 51 in a clamping manner under the effect of the elastic force applied by the third elastic element 323 , in this way, one end of the paper storage 2 matches with the lock hook 322 in a clamping manner through the core shaft 51 of the roller 5 , and the other end of the paper storage 2 matches with the clamping member 312 on the base 1 in a clamping manner through the pivot shaft 211 , so that the position of the paper storage 2 relative to the base 1 is fixed. Meanwhile, the roller wheel 52 of the roller 5 is tangential to the printing head 41 at the opening of the paper storage, with the printing paper passing through the roller 5 and the printing head 41 .
To detach the paper storage 2 , firstly the button 324 is triggered or pressed, so that the lock hook 322 is rotated to be detached from the core shaft 51 of the roller 5 and the paper storage 2 can be rotated about the pivot shaft 211 , then the paper storage 2 is rotated to be away from the printing head 41 , and the pivot shaft 211 on the paper storage 2 is detached from the third connection member 31 on the base 1 , thereby detaching the paper storage 2 from the base 1 of the printer.
In the use of the printer in the present disclosure, after the paper storage is installed in the paper storage, the printing paper passes by the roller of the paper storage and is exposed at the opening of the paper storage, and the user is allowed to select a paper storage accommodating a corresponding type of paper roll depending on a specific case. The installing and replacing of the paper storage only requires for the matching between the first connection member on the paper storage and the third connection member on the base and between the second connection member on the paper storage and the fourth connection member on the base, as such, the paper storage is locked at a fixed position relative to the base, in this case, the roller of the paper storage tangentially matches with the printing head at the opening of the paper storage, the printing paper within the paper storage is sandwiched between the roller of the paper storage and the printing head at the opening of the paper storage, and printing can be performed on the printing paper by the printing head. Meanwhile, the paper storage can be wholly removed from the printer to detach the paper storage. Therefore, compared with the prior art, the printer in the present disclosure eliminates the need for opening of the upper cover of the printer to load the paper during the replacement of the paper storage and the need for respective detachment of various parts of the paper storage, thus the operations are simplified, and the work efficiency on site is improved.
It is noted that, in the above embodiments, the paper storage is installed on the base through the clamping structure and the locking mechanism. In another embodiment, the user is allowed to press the paper storage into the concave portion by a finger to implement the printing by the paper storage, in this case, the provision of the clamping structure and/or the locking mechanism is eliminated. In still another embodiment, the paper storage and the base match with each other in position by means of an external bracket.
It is noted that the printing head on the base may be replaced by other processing devices such as a scanning head.
FIG. 11 is a partial structural section view of the printer according to a second embodiment of the present disclosure. As shown in FIG. 11 , the present embodiment differs from the preceding embodiment in that: a first elastic element declining toward the paper storage 2 is arranged in the concave portion 17 of the base 1 in the present embodiment, so that the paper storage always trends to move away from the concave portion, where one end of the first elastic element is connected with the concave portion 17 and the other end of the first elastic element is suspended. In the present embodiment, the first elastic element is an elastic slice 8 . In other embodiments, the first elastic element may be of other structural forms such as a pressure spring.
In installing the paper storage 2 , after the pivot shaft 211 on the paper storage 2 matches with the third connection member 31 on the base 1 in a clamping manner, the paper storage 2 is pressed against the elastic force applied by the elastic slice 8 , meanwhile the lock hook 322 is driven against the elastic force applied by the third elastic element 323 , until the lock hook 322 matches with the core shaft 51 of the roller 5 in a clamping manner. In detaching the paper storage 2 , the button 324 is pressed so that the paper storage 2 is automatically rotated about the pivot shaft 211 under the effect of the elastic force applied by the elastic slice 8 , thus the front end of the paper storage 2 is lifted up and hence the paper storage 2 can be easily removed.
With the arrangement of the elastic slice in the base in the present embodiment, when the button is pressed to detach the paper storage, the elastic lice can automatically lift up the paper storage, thereby further simplifying the operation steps of replacing the paper storage.
FIG. 12 is a first view of installing of a paper storage into a printer according to a third embodiment of the present disclosure, and FIG. 13 is a second view of installing of a paper storage into a printer according to the third embodiment of the present disclosure. As shown in FIG. 12 and FIG. 13 , the printer and the paper storage provided in the present embodiment differ from the previous embodiments in that: the first connection member of the paper storage 2 in the present embodiment includes two clamping parts 33 , which are respectively arranged at the outer sides of the left side wall 221 and the right side wall 222 of the chassis 22 and located at a side away from the opening 224 ; and the third connection member of the printer includes two clamping slots 34 , which are correspondingly arranged on the inner surfaces of the left wall 11 and the right wall 12 of the base, and have a depth extending in the thickness direction of the walls.
In installing the paper storage 2 , the clamping parts 33 on the paper storage 2 enter into the openings of the clamping slots 34 on the left wall 11 and the right wall 12 , and when the clamping parts 33 reach the bottoms of the clamping slots 34 , the paper storage 2 is rotated so that the core shaft 51 of the roller 5 enters into the opening of the notch 16 and matches with the lock hooks 322 in a clamping manner, thereby fixing the position of the paper storage 2 relative to the base 1 . In detaching the paper storage 2 , the button 324 is firstly triggered or pressed so that the lock hooks 322 are separated from the core shaft 51 of the roller 5 , then the paper storage 2 is rotated about the clamping parts 33 to lift up the front end of the paper storage 2 , and finally paper storage 2 is moved along the longitudinal direction of the clamping slots 34 to detach the paper storage 2 from the base 1 .
The present disclosure also provides a method of using multiple types of mediums. Herein, a medium processing system is provided and includes one medium processing device and a plurality of paper storages. To utilize a different type of medium, a paper storage accommodating this type of medium is combined with the base of the medium processing device, where the medium is discharged from the medium outlet of the paper storage after passing by the roller of the paper storage, and the medium processing device matches with the roller via the opening of the paper storage for the purpose of processing the medium.
Preferably, the medium processing system is a printing system, and the medium processing device is a printer.
The above medium processing system is advantageous in that: depending on different types of medium processing operations such as the printing operations and scanning operations, paper storages accommodating different mediums may be selectively adopted, and the replacement of the medium is very convenient and rapid.
Some preferred embodiments of the present disclosure have been described as above, but the scope of the present disclosure is not limited thereto, and various modifications and alternations may be made to the present disclosure by those of ordinary skills in the art. Any modifications, equivalent replacements and improvements made without departing from the spirit and principles of the present disclosure fall within the scope of the present disclosure.
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Disclosed are a paper storage and a printer. The paper storage comprises: a warehouse body ( 20 ) for accommodating a medium, a medium outlet (A), and a roller ( 5 ) arranged on the storage body ( 20 ), wherein the medium outlet (A) is configured to discharge the medium accommodated in the storage body ( 20 ) after the medium passes by the roller ( 5 ), and an opening ( 224 ) opposite to the roller ( 5 ) is also arranged on a wall of the storage body ( 20 ), to allow an external medium processing device to match with the roller ( 5 ) through the opening ( 224 ) to process the medium. To replace the paper storage in a printer adopting such paper storage, the need for respective detachment of various parts of the paper storage, and the need for opening of the upper cover of the printer to load the paper roll are eliminated, thereby avoiding the problems of complex operations of replacing the paper roll and inconvenience in use.
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FIELD OF THE INVENTION
The present invention relates to a curved bodied surgical needle and a method of manufacturing the same and more particularly to curved rectangular, round, oval or triangular bodied surgical needles produced from a planar, corrugated or planar and corrugated sheet material.
BACKGROUND OF THE INVENTION
The production of needles from wire stock involves many processes and different types of machinery in order to prepare quality needles. These varying processes and machinery become more critical in the preparation of surgical needles where the environment of intended use is in humans or animals. Some of the processes involved in the production of surgical grade needles include, straightening spooled wire stock, cutting needle blanks from raw wire stock, tapering or grinding points on one end of the blank stock, providing a bore for receiving suture thread at the other end of the blank stock, imparting flat pressed surfaces on opposite sides of the blank by flat pressing a portion of the needle blank to facilitate grasping by surgical instrumentation and the curving of the needle where curved needles are desired. Additional processing may be done to impart flat surfaces substantially perpendicular to the flat pressed portions of the needle blank by side pressing a portion of the needle blank to further facilitate grasping by surgical instrumentation and insertion into humans or animals. Conventional needle processing is, in large part, a labor intensive operation requiring highly skilled labor. Generally, extreme care must be taken to insure that only the intended working of the needle is performed and the other parts of the needle remain undisturbed. Curved rectangular bodied needles have advantages over other needle configurations in many surgical procedures for a variety of reasons including, uniformity of entry depth for multiple sutures and proper "bite" of tissue surrounding the incision or wound. When providing curved bodied needles for surgical procedures, it is desirable for the needles to have a specified cross section and a specified curvature, i.e., a predetermined radius of curvature. The desired cross section and radius of curvature for the finished needle varies with specific applications as is known in the art.
Known methods of forming curved rectangular bodied needles require several separate and distinct operations to be performed on various machinery. The needle blank after having been cut from straightened wire stock must be flat pressed to impart opposed flat surfaces along body portions located between a tapered point end and a drilled end of the needle blanks. After flat pressing to form opposed flat surfaces on the needle blank, the needle can then be taken from the flat press dies to a curving machine to impart the proper curvature to the needle blank. Optionally, the flat pressing and curving of the needle blank may be accomplished in one step with some available curving die equipment. Care must be taken when removing the blanks from the flat press dies and the curving machinery to avoid disturbing the flat surfaces imparted to the needle blank. After the curving and flat pressing the needle blanks, the needle can then be taken from the curving anvil or die to a side press station to impart flat surfaces substantially perpendicular to the opposed flat surfaces previously formed to give the final rectangular cross sectional profile to the needle body. Again, care must be taken during removal of the needle blanks from the curving anvil and during side flat pressing so as to avoid disturbing the previously imparted opposed flat surface and curved portions of the needle blank.
When needles are made of steel or similar resilient materials, the anvil, die or mandrel used to impart curvature to the needle should have a smaller radius than the radius desired in the final needle product. This configuration allows for some springback after the bending operation and insures that the desired radius of curvature is obtained. Disclosure of such features may be found in U.S. Pat. No. 4,534,771. Previously flattened surgical needles improperly positioned on the anvil for curving may result in a deformation of the previously imparted opposed flat surfaces and may have to be reprocessed or discarded.
One disadvantage to the conventional needle forming techniques noted above is that typically only one needle processing operation at a time, such as, for example, wire straightening, blank cutting, sharpening, boring, flat pressing, curving, can be performed on a single piece of machinery. A further disadvantage is the long processing time required to produce such a needle and the high cost associated with forming and transporting the needles between the various machinery. Lastly, a still further disadvantage is the need to readjust numerous pieces of machinery to process needles of varying length and diameters which further increases production tooling down time and production costs. Therefore, a need exists for a surgical needle forming process that is capable of eliminating one or more processing operations such as flat wire straightening, blank cutting, flat pressing, curving, or side pressing needle blanks. It is also desirable to provide a method of forming curved bodied needles which reduces the time required to produce such needles and the associated costs. It is also desirable to provide a process for producing curved bodied needles which decreases material handling demands.
SUMMARY OF THE INVENTION
The present invention provides a curved rectangular, round, oval or triangular bodied surgical needle and a method for producing curved rectangular, round, oval, or triangular bodied surgical needles for use in human or animal surgical procedures. The preferred method of producing a curved rectangular bodied surgical needle according to the present invention includes obtaining a flat or planar rectangular or square material sheet of predetermined composition and dimensions, drilling at least two holes into one edge of the material sheet, grinding one edge opposed to the drilled edge of the material sheet, curving the material sheet, and cutting the material sheet at a point of equal distance between each drilled hole to produce a curved rectangular bodied surgical needle.
The preferred method of producing a curved round bodied surgical needle according to the present invention includes obtaining a rectangular or square material sheet of predetermined composition and dimensions, having opposed corrugated surfaces, drilling at least two holes into one edge of the material sheet, grinding one edge opposed to the drilled edge of the material sheet, curving the material sheet, and cutting the material sheet at a point of equal distance between each drilled hole corresponding to the grooves of the corrugated surface of the material to produce curved round bodied surgical needles.
The preferred method of producing a curved oval bodied surgical needle according to the present invention includes obtaining a rectangular or square material sheet of predetermined composition and dimensions, having opposed corrugated surfaces, drilling at least two holes into one edge of the material sheet, grinding one edge opposed to the drilled edge of the material sheet, curving the material sheet, and cutting the material sheet at a point of equal distance between each drilled hole corresponding to the grooves of the corrugated surface of the material to produce curved oval bodied surgical needles.
The preferred method of producing a curved triangular bodied surgical needle according to the present invention, includes obtaining a rectangular or square material sheet of predetermined composition and dimensions, having one smooth planar surface and one corrugated surface, drilling at least two holes into one edge of the material sheet, grinding one edge opposed to the drilled edge of the material sheet, curving the material sheet, and cutting the material sheet at a point of equal distance between each drilled hole corresponding to the grooves of the corrugated surface of the material to produce curved triangular bodied surgical needles.
Accordingly, it is a primary objective of the present invention to provide a method for producing surgical needles which decreases production time. It is a further object of the present invention to provide a more economical method for producing curved rectangular, round, oval or triangular bodied surgical needles. It is a further object of the present invention to provide a method for producing surgical needles which minimizes potential damage thereto. It is a further object of the present invention to provide a method of producing surgical needles which is compatible with existing surgical suture attachment methods and equipment.
Other objects, features, and advantages of the present invention shall become apparent in view of the following description when considered in connection with the accompanying illustrative drawings.
DESCRIPTION OF THE DRAWINGS
In the drawings which illustrate the best mode presently contemplated for carrying out the present invention:
FIG. 1 is a perspective view of a curved rectangular bodied surgical needle;
FIG. 2 is a perspective view of a sheet of stainless steel material of predetermined dimensions;
FIG. 3 is a perspective view of the material sheet of FIG. 2 having apertures drilled in an edge thereof;
FIG. 4 is a perspective view of the material sheet of FIG. 3 having an edge thereof ground to a surgical point;
FIG. 5 is a side edge view of the material sheet of FIG. 4;
FIG. 6 is a perspective view of the material sheet of FIG. 4 after curvature thereof;
FIG. 7 is a perspective view of the material sheet of FIG. 6 after having been cut into a plurality of surgical needles;
FIG. 8 is a perspective view of a curved round bodied surgical needle;
FIG. 9 is a perspective view of a sheet of corrugated stainless steel material of predetermined dimensions;
FIG. 10 is a perspective view of the corrugated material sheet of FIG. 9 having apertures drilled in an edge thereof between grooves;
FIG. 11 is a perspective view of the corrugated material sheet of FIG. 10 having an edge thereof ground to a surgical point;
FIG. 12 is a side edge view of the corrugated material sheet of FIG. 11;
FIG. 13 is a perspective view of the corrugated material sheet of FIG. 11 after curvature thereof;
FIG. 14 is a perspective view of the corrugated material sheet of FIG. 13 after having been cut into a plurality of surgical needles;
FIG. 15 is a perspective view of a curved triangular bodied surgical needle;
FIG. 16 is a perspective view of a sheet of corrugated and planar stainless steel material of predetermined dimensions;
FIG. 17 is a perspective view of the corrugated and planar material sheet of FIG. 16 having apertures drilled in an edge thereof between grooves;
FIG. 18 is a perspective view of the corrugated and planar material sheet of FIG. 17 having an edge thereof ground to a surgical point;
FIG. 19 is a side edge view of the corrugated and planar material sheet of FIG. 18;
FIG. 20 is a perspective view of the corrugated and planar material sheet of FIG. 18 after curvature thereof;
FIG. 21 is a perspective view of the corrugated and planar material sheet of FIG. 20 after having been cut into a plurality of surgical needles;
FIG. 22 is a perspective view of a curved oval bodied surgical needle;
FIG. 23 is a perspective view of a sheet of stainless steel material of predetermined dimensions; and
FIG. 24 is a schematic diagram of a process for producing curved surgical needles of the present invention.
DESCRIPTION OF THE INVENTION
Referring to the drawings, the preferred embodiment of the curved rectangular bodied surgical needle of the present invention is illustrated and generally indicated as 10 in FIG. 1. The curved rectangular bodied surgical needle of the present invention 10 comprises a body portion 12 which is curved to fall within a range of curvature between 90 and 180 degrees. The needle has a blunt end 14 having an aperture 16 therein suitable for accepting a suture 15 by means of a suitable adhesive, polymeric attachment means, friction fit, or like methods known in the art. Preferably, a suture is attached to the needle 10 by means of a drilled aperture 16 in blunt end 14 which may be crimped to hold the suture 15 but is not intended to be limited thereto. Opposed to blunt end 14 of body portion 12 is a sharpened point 18 suitable for the penetration of human or animal tissue. The curved portion 20 of body portion 12 preferably has a rectangular cross section of predetermined dimensions. The overall size or length of the surgical needle can cover the full range of sizes known to those skilled in the art such as from approximately 5 to 50 millimeters in length but preferably approximately 10 to 47 millimeters in length for greater manageability.
Surgical needle 10 of the present invention may be made from any of the various steels known in the art to be suitable for surgical needles, such as, but not limited to, stainless steels containing chromium. The preferred material for the needles of the present invention are 300 or 400 series stainless steels due to superior strength and durability.
The surgical needles 10 of the present invention are produced using an unique method illustrated in FIGS. 2 through 7.
A material sheet generally indicated as 30 in FIGS. 2 through 7 used in producing curved rectangular bodied surgical needles 10 comprises upper and lower smooth planner surfaces 32 and 34 respectively, point edge 36, blunt edge 38, and side edges 40 and 42. Material sheet 30 is preferably dimensioned between approximately one half and one and one half but preferably approximately 11/16th of an inch in length measuring between point and blunt edges 36 and 38 respectively, between approximately 40 and 60 inches but preferably approximately 48 inches in width measuring between side edges 40 and 42 and between approximately 0.01 and 0.1 of an inch but preferably approximately 0.02 of an inch in thickness measuring between planar surfaces 32 and 34. The dimensions of the material sheet, however, are variable depending on the number of needles to be made per sheet and the desired final dimensions of the surgical needle product. Once the material sheet is obtained in the desired dimensions or cut, honed and/or machined to the desired dimensions, the material sheet is then clamped by a gripping means portion 52, schematically illustrated in FIG. 24, of a machining apparatus, illustrated generally as 50 in FIG. 24. The gripping means portion 52 is designed to move towards a drilling device portion 54 of the machining apparatus 50 for the drilling of an aperture 16 in blunt edge 38 of sheet material 30, and then retract. The gripping means portion 52 then progresses a predetermined distance before again approaching the drilling device portion 54 to drill the next aperture 16 in the blunt edge 38 of sheet material 30. The resulting sheet has apertures or bores 16 drilled in blunt edge 38 at predetermined distances as best illustrated in FIG. 3. The sheet material 30 still clamped by the gripping means portion 52 progresses to a grinding position 56 whereby point edge 36 is ground by preferably a rotating abrasive means so as to form sharpened point 18 as illustrated in FIGS. 4 and 5. The material sheet 30 then progresses to a die stamp or mandrel belt apparatus and sheet material 30 is bent to form a curved portion 20 of the appropriate curvature as illustrated in FIG. 6. At this point, material sheet 30 passes to a cutting apparatus 60 whereby sheet material 30 is cut at a point of equal distance between each drilled aperture as illustrated in FIG. 7. The resultant surgical needle 10 may then be polished and/or electrohoned in order to deburr, soften edges and/or polish the needle which is then ready for any optional point modification, suture attachment, optional lubrication, sterilization and packaging as discussed in greater detail below.
After the curved rectangular bodied surgical needle 10 has been so produced in accordance with the present invention, a suture 15 may be attached by any suitable method currently known to those skilled in the art. Optionally, the curved rectangular bodied surgical needle 10 is lubricated before being sterilized and packaged. It is important to note that any suitable optional point modification, suture attachment means, optional lubrication process, sterilization process, and packaging currently known in the art may be used in accordance with the curved rectangular bodied surgical needle of the present invention.
Referring to the drawings, the preferred embodiment of the curved round bodied surgical needle of the present invention is illustrated and generally indicated as 100 in FIG. 8. The curved round bodied surgical needle 100 of the present invention comprises a body portion 102 which is curved to fall within a range of curvature between 90 and 180 degrees. The needle has a blunt end 104 having an aperture 106 therein suitable for accepting a suture 115 by means of a suitable adhesive, polymeric attachment means, friction fit, or like methods known in the art. Preferably, a suture 115 is attached to the needle 100 by means of a drilled aperture 106 in blunt end 104 which may be crimped to hold the suture but is not intended to be limited thereto. Opposed to blunt end 104 of body portion 102 is a sharpened point 108 suitable for the penetration of human or animal tissue. The curved portion 110 of body portion 102 preferably has a round cross section of predetermined diameter. The overall size or length of the surgical needle can cover the full range of sizes known to those skilled in the art such as from approximately 5 to 50 millimeters in length but preferably approximately 10 to 47 millimeters in length for greater manageability.
Surgical needle 100 of the present invention may be made from any of the various steels known in the art to be suitable for surgical needles, such as, but not limited to, stainless steels containing chromium. The preferred material for the needles of the present invention are 300 or 400 series stainless steels due to superior strength and durability.
The surgical needles 100 of the present invention are produced using an unique method illustrated in FIGS. 9 through 14.
A material sheet generally indicated as 120 in FIGS. 9 through 14 used in producing curved round bodied surgical needles 100 comprises upper and lower corrugated surfaces 122 and 124 respectively, point edge 126, blunt edge 128, and side edges 130 and 132. Material sheet 120 is preferably dimensioned between approximately one half and one and one half inch but preferably approximately 11/16th of an inch in length measuring between point and blunt edges 126 and 128 respectively, between approximately 40 and 60 inches but preferably approximately 48 inches in width measuring between side edges 130 and 132 and between approximately 0.01 and 0.1 of an inch but preferably approximately 0.02 of an inch in thickness measuring between the peaks 119 of upper and lower corrugated surfaces 122 and 124, respectively. The dimensions of the material sheet, however, are variable depending on the number of the needles to be made per sheet and the desired final dimensions of the surgical needle product. Once the material sheet is obtained in the desired dimensions or cut, honed and/or machined to the desired dimensions, the material sheet is then clamped by a gripping means portion 52, schematically illustrated in FIG. 24, of a machining apparatus illustrated generally as 50 in FIG. 24. The gripping means portion 52 is designed to move towards a drilling device portion 54 of the machining apparatus 50 for the drilling of an aperture 106 in blunt edge 128 of sheet material 120, and then retract. The gripping means portion 52 then progresses a predetermined distance before again approaching the drilling device portion 54 to drill the next aperture 106 into blunt edge 128 of sheet material 120. The resulting sheet has apertures or bores 106 drilled in blunt edge 128 at predetermined distances as best illustrated in FIG. 10. The sheet material 120 still clamped by the gripping means portion 52 progresses to a grinding position 56 whereby point edge 126 is preferably ground by a rotating abrasive means so as to form sharpened point 108 as illustrated in FIGS. 11 and 12. The material sheet 120 then progresses to a die stamp or mandrel belt apparatus 58 and sheet material 120 is bent to form a curved portion 110 of the appropriate curvature as illustrated in FIG. 13. At this point, material sheet 120 passes to a cutting apparatus 60 whereby sheet material 120 is cut at a point of equal distance between each drilled aperture corresponding with the grooves 121 of upper and lower corrugated surfaces 122 and 124 respectively, as illustrated in FIG. 14. The resultant surgical needle 100 may then be polished and/or electrohoned in order to deburr, soften edges and/or polish the needle which is then ready for any optional point modification, suture attachment, optional lubrication, sterilization and packaging as discussed in greater detail below.
After the curved round bodied surgical needle 100 has been so produced in accordance with the present invention, a suture 115 may be attached by any suitable method currently known to those skilled in the art. Optionally, the curved round bodied surgical needle 100 is lubricated before being sterilized and packaged. It is important to note that any suitable optional point modification, suture attachment means, optional lubrication process, sterilization process, and packaging currently known in the art may be used in accordance with the curved round bodied surgical needle of the present invention.
It should be noted that curved oval bodied surgical needles 300 illustrated best in FIG. 22 can be produced using the above-described process for producing round bodied needles by varying the corrugation of upper and lower corrugated surfaces 322 and 324 respectively, of sheet material 320 as illustrated in FIG. 23.
Referring to the drawings, the preferred embodiment of the curved triangular bodied surgical needle of the present invention is illustrated and generally indicated as 200 in FIG. 15. The curved triangular bodied surgical needle of the present invention 200 comprises a body portion 202 which is curved to fall within a range of curvature between 90 and 180 degrees. The needle has a blunt end 204 having an aperture 206 therein suitable for accepting a suture 215 by means of a suitable adhesive, polymeric attachment means, friction fit, or like methods known in the art. Preferably, a suture 215 is attached to the needle by means of a drilled aperture 206 in blunt end 204 which may be crimped to hold the suture 215 but is not intended to be limited thereto. Opposed to blunt end 204 of body portion 202 is a sharpened point 208 suitable for the penetration of human or animal tissue. The curved portion 210 of body portion 202 preferably has a triangular cross section of predetermined dimensions. The overall size or length of the surgical needle can cover the full range of sizes known to those skilled in the art such as from approximately 5 to 50 millimeters in length but preferably approximately 10 to 47 millimeters in length for greater manageability.
Surgical needle 200 of the present invention may be made from any of the various steels known in the art to be suitable for surgical needles, such as, but not limited to, stainless steels containing chromium. The preferred material for the needles of the present invention are 300 or 400 series stainless steels due to superior strength and durability.
The surgical needles 200 of the present invention are produced using an unique method illustrated in FIGS. 16 through 21.
A material sheet generally indicated as 220 in FIGS. 16 through 21 used in producing curved triangular bodied surgical needles 200 comprises a lower planner surface 222 an upper corrugated surface 224, point edge 226, blunt edge 228, and side edges 230 and 232. Material sheet 220 is preferably dimensioned between approximately one half and one and one half inches but preferably approximately 11/16th inches in length measuring between point and blunt edges 226 and 228, respectively, between approximately 40 and 60 inches but preferably approximately 48 inches in width measuring between side edges 230 and 232 and approximately 0.01 and 0.1 of an inch, but preferably approximately 0.02 of an inch in thickness measuring between lower planar surface 222 and the peak 219 of corrugated upper surface 224. The dimensions of the material sheet, however, are variable depending on the number of the needles to be made per sheet and the desired final dimensions of the surgical needle product. Once the material sheet is obtained in the desired dimensions or cut, honed and/or machined to the desired dimensions, the material sheet is then clamped by a gripping means portion 52, schematically illustrated in FIG. 24, of a machining apparatus illustrated generally as 50 in FIG. 24. The gripping means portion 52 is designed to move towards a drilling device portion of the machining apparatus 50 for the drilling of an aperture 206 in blunt edge 228 of sheet material 220, and then retract. The gripping means portion 52 then progresses a predetermined distance before again approaching the drilling device portion 54 to drill the next aperture 206 into blunt edge 228 of the sheet material 220. The resulting sheet has apertures or bores 206 drilled in blunt edge 228 at predetermined distances as best illustrated in FIG. 17. The sheet material 220 still clamped by the gripping means portion 52 progresses to a grinding position 56 whereby point edge 226 is ground preferably by a rotating abrasive means so as to form sharpened point 208 as illustrated in FIGS. 18 and 19. The material sheet 220 then progresses to a die stamp or mandrel belt apparatus 58 and sheet material 220 is bent to form a curved portion 210 of the appropriate curvature as illustrated in FIG. 20. At this point, material sheet 220 passes to a cutting apparatus 60 whereby sheet material 220 is cut at equal distances between each drilled aperture corresponding with the grooves 219 of upper corrugated surface 224 as illustrated in FIG. 21. The resultant surgical needle 200 may then be polished and/or electrohoned in order to deburr, soften edges and/or polish the needle which is then ready for any optional point modification, suture 215 attachment, optional lubrication, sterilization and packaging as discussed in greater detail below.
After the curved triangular bodied surgical needle 200 has been so produced in accordance with the present invention, a suture 15 may be attached by any suitable method currently known to those skilled in the art. Optionally, the curved rectangular bodied surgical needle 200 is lubricated before being sterilized and packaged. It is important to note that any suitable optional point modification, suture attachment means, optional lubrication process, sterilization process, and packaging currently known in the art may be used in accordance with the curved triangular bodied surgical needle of the present invention.
It is unexpected that it would be possible to produce the present curved bodied surgical needles in accordance with the method disclosed herein for use in humans and animals due to the small size of the needles required for human and animal surgical use. The cutting of surgical needles from a planar, corrugated and/or planar and corrugated material sheet has been found to be achievable as disclosed herein. The curved bodied surgical needles produced according to the teachings of the present invention are an advantage over needles produced from processes currently known in the art since numerous production steps have been eliminated to decrease the costs of production and lessen the potential for damaging the needle.
Having now described the invention, it should be readily apparent that many variations and modifications may be made without departing from the spirit and scope of the present invention.
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A curved surgical needle and a method for producing the same from a solid sheet of material rather than from coiled wire including the steps of drilling a bore in one edge of the material, grinding an edge opposite the drilled edge to form a sharpened point, curving the material and cutting the material at a point of equal distance between each drilled bored to provide a surgical needle. A suture is then attached to the surgical needle, optionally lubricated, sterilized, and packaged by suitable means known in the art.
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BACKGROUND
Cartons that are used to contain multiple containers, such as beverage containers, often are constructed to be sufficiently durable to withstand shipping, stocking, and transportation to the purchaser's home. At the same time, such sturdy cartons may be difficult to open to access the containers therein. Thus, there is a continuing need for improved cartons that are sufficiently robust yet allow for ready access to the containers therein.
SUMMARY
The present invention is directed generally to a carton that may be used with, for example, cans and bottles of the types used to contain soft drinks, beer and the like. The carton includes various features that provide improved access to the containers therein.
BRIEF DESCRIPTION OF THE DRAWINGS
The description refers to the accompanying drawings in which like reference characters refer to like parts throughout the several views, and in which:
FIG. 1 is a plan view of an exemplary blank from which a carton may be formed, according to the present invention;
FIGS. 2-5 depict enlarged views of various aspects of the exemplary blank of FIG. 1 ;
FIG. 6 is a perspective view of an exemplary carton formed according to the present invention; and
FIGS. 7 and 8 depict various perspective views of the carton of FIG. 6 illustrating removal of a bottle therefrom.
DETAILED DESCRIPTION
The present invention may be best understood by referring to the following figures. For purposes of simplicity, like numerals may be used to describe like features. However, it should be understood use of like numerals is not to be construed as an acknowledgement or admission that such features are equivalent in any manner. It also will be understood that where a plurality of similar features are depicted, not all of such identical features may be labeled on the figures.
According to one aspect of the present invention depicted in FIG. 1 , an exemplary blank 10 for forming a wrap-around carton is provided. The exemplary blank 10 can be folded into a carton that is capable of containing cans or bottles, for example, in two rows of four containers each, as will be discussed below. It will be understood by those of skill in the art that while particular exemplary blanks and cartons are shown and described herein, the various aspects of the present invention may be used with any carton or package, as needed or desired. Thus, numerous blanks and cartons are contemplated hereby.
Still viewing FIG. 1 , the exemplary blank 10 includes a top panel 12 connected to a first angular panel 14 at fold line 16 and a second angular panel 18 at fold line 20 . The first angular panel 14 is connected to a first side panel 22 at fold line 24 . The first side panel 22 is connected to a first bottom panel section 26 at fold line 28 . The second angular panel 18 is connected to a second side panel 30 at fold line 32 . The second side panel 30 is connected to a second bottom panel section 34 at fold line 36 .
The top panel 12 includes one or more opposed finger flaps 38 that may be pressed inward toward the interior of a carton formed from the blank 10 to serve as a gripping feature. The finger flaps 38 may have any suitable shape, for example, circular, rectangular, square, triangular, oval, or any other shape. In the exemplary blank 10 depicted in FIG. 1 , the finger flaps 38 are defined by substantially circular slits 39 and a straight, recessed fold line 40 . If desired, the finger flaps may be separably attached to the top panel 12 along one or more nicks 42 , or other attachment points. A pair of opposed, separably joined thumb flaps 44 defined by arcuate slits 41 and substantially linear fold lines 43 may be located substantially equidistant from the finger flaps 38 . The thumb flaps may be separably joined by one or more nicks 46 or other attachment points.
While particular combination of finger and thumb flaps are provided herein, it will be understood that any combination or configuration of such flaps may be used with the present invention. If desired, the flaps may be substituted by one or more apertures or openings. Additionally, it will be understood that other handle types and geometries are contemplated hereby. It further will be understood by those of skill in the art that more than one handle, opening, or finger or thumb flap may be provided, and that such one or more of such features may be provided in any of the various panels and on any of the sides of the resulting carton. Thus, while certain flap configurations are depicted and described herein, numerous configurations are contemplated hereby.
The top panel 12 of the exemplary blank 10 of FIG. 1 includes a plurality of truncated teardrop shaped openings 48 extending into the first angular panel 14 and the second angular panel 18 . As shown in FIG. 2 , the truncated portion 50 of each opening 48 includes a linear segment 52 and a point 54 at each end 56 of the linear segment 52 . In this example, the openings are configured in two rows, each having four openings. However, the configuration of such openings depends on the number of containers to be supported by the carton. Each opening is dimensioned to receive a neck of a bottle or other container, as will be discussed in greater detail below. Thus, the neck opening may have any suitable shape, for example, a circle, oval, square, rectangle, or any other shape capable of receiving the neck of the container. It will be understood that although such features are shown as being in the top panel, such features may be included in other panels, for example, a side panel, as desired.
Still viewing FIGS. 1 and 2 , an optionally removable tab 58 extends from the truncated portion 50 of each opening 48 through the first angular panel 14 or second angular panel 18 onto the first side panel 22 or second side panel 30 . The tab 58 may have any suitable shape and, in this example, the tab 58 is generally elongated in shape with curved “corners.” In this example, tear lines 60 are zipper cuts to facilitate tearing, and tear line 62 is perforated. Where such a blank is used to form a carton, the tab may be separated partially or completely from the carton to form an enlarged opening to remove a container in the carton. However, other types of fold or tear lines may be used. Thus, for example, lines 60 may be tear lines and line 62 may be a fold line. Where such a blank is used to form a carton, the tab may be separated partially from the carton to form an enlarged opening, and optionally folded away from the carton to remove a container in the carton.
As illustrated in FIGS. 1 and 3 , a heel receptacle 64 extends from the first side panel 22 and second side panel 30 , and into the first bottom panel section 26 and second bottom panel section 34 , respectively. The heel receptacle 64 may be used in a carton formed from the blank 10 to receive the heel or bottom portion of a bottle or other container. Various heel receptacles may be used with the present invention.
In the exemplary heel receptacle 64 depicted in FIGS. 1 and 3 , a substantially linear slit 66 includes a J-cut 68 at each end 70 thereof. A lateral slit 72 extends substantially perpendicularly from about a midpoint of slit 66 . A transverse slit 74 is substantially perpendicular to lateral slit 72 . Angular slits 76 are spaced from and extend angularly away from each J-cut 68 in a direction toward the transverse slit 74 . Angular perforations 78 extend between the angular slits 76 toward the transverse slit 74 . Slits 80 extend between and are spaced from the angular perforation lines 78 and the lateral slit 72 . A plurality of perforations form generally diamond-shaped fold lines or perforation pattern 82 extending between the angular slits 76 across the lateral slit 72 and substantially aligned with fold line 28 or 36 . The various slits and perforated lines define a plurality of pairs of panels 84 , 86 , 88 , and 90 .
As stated above, when the blank 10 is formed into a carton and containers are placed therein, the heel receptacle is used to support the heel of a bottle or other container. In this example, to use the heel receptacle 64 , panels 86 , 88 , and 90 are pivoted toward the interior carton along angular slits 76 and angular perforation lines 78 . When the blank 10 is folded along fold line 28 or 36 , the diamond shaped fold lines 88 allow panels 86 and 90 to fold toward one another. In doing so, flaps 88 and 90 become available to support the heel of a container, for example, a plastic bottle. Flaps 86 also become available to contact the surface of the bottle or container.
Returning to FIG. 1 , the first side panel 22 and the second side panel 30 each include a pair of outer edges 92 . Working from fold lines 24 and 32 , each outer edge 92 includes a first, substantially linear portion 94 that terminates with jot 96 . A second, tapered portion 98 extends angularly from jot 96 towards the adjacent heel receptacle 64 . A third portion 100 extends from the second portion angularly away from the adjacent heel receptacle 64 . A substantially linear fourth portion 102 extends from the third portion 100 and terminates at fold line 28 or 36 . The fourth portion is substantially perpendicular to fold line 28 or 36 . However, it will be understood that various edge patterns and configurations may be used with the present invention, and such patterns and configurations are contemplated hereby.
Still viewing FIG. 1 , the first bottom panel section 26 and the second bottom panel section 34 include features that join the panel sections to form a bottom panel. For example, various locking features may be included. Alternatively, the panel sections may be joined using an adhesive or other fastening material. In the example shown in FIG. 1 , the first bottom panel section 26 also includes a plurality of substantially triangular shaped openings 104 . In this example, the first bottom panel section 26 includes three openings 104 that resemble isosceles triangles having rounded vertices 106 . The base 108 of each opening 104 is substantially parallel to the terminal edge 110 of the first bottom panel section 26 . Although a particular configuration is shown herein, other numbers and shapes of the openings may be used in accordance with the present invention as desired.
The first bottom panel section 26 further includes a plurality of elongated receiving flaps 112 . In this example, the first bottom panel section 26 includes four receiving flaps 112 in a staggered configuration with the substantially triangular shaped openings 104 . However, the number and shape of the receiving flaps may vary, depending on the particular application. As shown in FIGS. 1 and 4 , each receiving flap 112 includes a substantially linear slit 114 having a protrusion 116 extending therefrom. Arcuate cuts 118 extend from the terminal points 120 of the substantially linear cut portion 114 . J-cuts 122 extend away from the arcuate cuts 118 . The elongated receiving flaps 112 further include a somewhat arcuate fold line 124 , in this example, a perforated line, connected to the first bottom panel section 26 . In this configuration, the receiving flaps 112 can be displaced partially from the first bottom panel section 26 and pivoted inward or outward along while remaining connected to thereto.
The second bottom panel section 34 further includes a plurality of cut crease segments 128 separated by substantially trapezoidal shaped flaps 130 . In this example, the blank 10 includes four cut crease segments 128 and three flaps 130 . It will be understood that the number of flaps may vary for a particular application. In one aspect, the number of flaps 130 may correspond to the number of substantially triangular shaped openings 104 , and are spaced to be in alignment with the substantially triangular shaped openings 104 when a carton is formed from the blank 10 .
Each flap 130 is defined by a score line having a first portion 132 substantially parallel to fold line 36 and a pair of angular portions 134 extending away from the ends 136 of the first portion 132 . The angular portions 134 terminate in J-cuts 138 that abut creases 140 of the various cut crease segments 128 . Although a particular flap and cut crease configuration is shown herein, it will be understood that other shapes and configurations are contemplated hereby.
The major edge 142 of the second bottom panel section 34 is defined by a plurality of alternating recessed segments 144 and protruding segments 146 . The number of protruding segments 146 may generally correspond to the number of receiving flaps 112 in the first bottom panel section 26 , and are spaced to be in alignment with the elongated receiving flaps 112 when a carton is formed from the blank 10 . While a particular major edge configuration is shown herein, other configurations are contemplated hereby.
In this example, each protruding segment 146 includes a portion 148 that is substantially linear and substantially parallel to fold line 36 . Each protruding segment 146 further includes edges 150 substantially perpendicular to fold line 36 and that adjoin the substantially linear portion 148 at curved corners 152 . Another pair 154 of substantially linear segments that are substantially parallel to fold line 36 extends from edges 150 toward each other and terminates with a slight curvature to define neck 156 . The neck 156 has a width that is less than the width of the protruding segment 146 . The protruding segment 146 may be joined to the second bottom panel section 34 by a cut crease line 158 . Each recessed segment 144 includes a substantially linear central portion 160 that is substantially parallel to fold line 36 . Angular edges 162 extend therefrom towards neck 156 and meet the substantially linear segments 154 at cut crease line 158 .
To form the blank 10 into a carton 164 (best seen in FIGS. 6 and 7 ), the first bottom panel section 26 and the second bottom panel section 34 are brought towards each other. The blank 10 is folded at fold lines 16 , 20 , 24 , 28 , 32 , and 36 . Each protruding segment 146 is brought into alignment with each receiving flap 112 with the second bottom panel section 34 overlapping the first bottom panel section 26 . Each protruding segment 146 then may be inserted into the corresponding receiving flap 112 , which folds toward the interior of the carton 164 along the arcuate perforated portion 124 . Additionally, the substantially trapezoidal shaped flaps 130 may be directed toward the interior of the carton 164 and inserted into the substantially triangular openings 104 . By doing so, a carton having two open ends is formed. If desired, the first bottom panel section and the second panel section may be glued together using an adhesive or other technique to strengthen the carton further. The terms “glue” and “glued” are intended to encompass any adhesive or manner or technique for adhering materials as are known to those of skill in the art. While use of the terms “glue” and “glued” are used herein, it will be understood that other methods of securing the various panels are contemplated hereby.
FIG. 6 illustrates an exemplary carton formed according to the present invention. In this example, two rows or four containers C are held within the carton 164 . Flaps 86 , 88 , and 90 are directed to the interior 166 of the carton 164 , with the heel H of the base B of each container C resting against flaps 86 and on flaps 88 (see FIG. 8) and 90 . It will be understood that other containers having a base without a heel may be used in accordance with the present invention. The neck N of each container C extends through the openings 48 . The neck N of each container C typically is inserted into the each opening 48 prior to the blank 10 being wrapped around the containers C and formed into the carton 164 .
As illustrated in FIG. 7 , a container C can be easily removed from the carton 164 by using the fingers F and the thumb T of a hand. To do so, a user grasps the tab 58 and pulls the tab away from the carton 164 along tear line 60 and optionally also along tear line 62 . When the user has separated the tab 58 from the carton 164 , the user may discard the removed tab 58 if desired. It will be understood that where line 62 is a fold line, the tab 58 is at least partially pulled away from the carton 164 , and optionally folded along line 62 .
Turning to FIG. 8 , once the tab 58 is removed the user may grasp the container C to be removed and pull the container C through an enlarged opening 168 formed by removing the tab 58 (not shown) adjacent the opening 48 . In this manner, each container may be removed individually while the remaining containers continue to be secured within the carton. Thus, unlike other cartons, the containers may be removed without tearing the carton apart or otherwise destroying the carton.
It will be understood that the exemplary cartons shown herein may be used for cans or other types of cylindrical containers. Some of such cartons and dispensers may be particularly useful for PET bottles having a stubby configuration.
According to the various aspects of the present invention described herein or contemplated hereby, the blank and carton may be formed from a foldable sheet material. In one aspect, the blank is formed from paperboard. In another aspect, the blank may be formed from paperboard having a basis weight of at least about 100 pounds per ream. In another aspect, the blank may be formed from paperboard having a thickness of at least about 0.012 inches. The blank, and thus the carton formed therefrom, also may be constructed from other materials, for example, cardboard or any other suitable material. In the exemplary embodiments discussed above, the blanks are formed from coated solid unbleached sulfate (SUS) board. In general, the SUS board may have a caliper in the range of from about 18 to about 30, for example, 26. If needed or desired, the blank may be laminated to or coated with one or more different or similar sheet-like materials at selected panels or panel sections.
Optionally, one or more panels of the blanks and cartons discussed herein may be coated with varnish, clay, or other materials, either alone or in combination. The coating may then be printed over with product, advertising, and other information or images. The blanks also may be coated to protect any information printed on the blank. The blanks may be coated with, for example, a moisture barrier layer, on either or both sides of the blanks.
It will be understood that in each of the various blanks and cartons described herein and contemplated hereby, a “fold line” can be any substantially linear, although not necessarily straight, form of weakening that facilitates folding therealong. More specifically, but not for the purpose of narrowing the scope of the present invention, a fold line may be a score line, such as lines formed with a blunt scoring knife, or the like, which creates a crushed portion in the material along the desired line of weakness; a cut that extends partially into a material along the desired line of weakness, and/or a series of cuts that extend partially into and/or completely through the material along the desired line of weakness; and various combinations of these features. Where cutting is used to create a fold line, the cutting typically will not be overly extensive in a manner that might cause a reasonable user to consider incorrectly the fold line to be a tear line.
For example, one type of conventional tear line is in the form of a series of cuts that extend completely through the material, with adjacent cuts being spaced apart slightly so that a nick (e.g., a small somewhat bridging-like piece of the material) is defined between the adjacent cuts for typically temporarily connecting the material across the tear line. The nicks are broken during tearing along the tear line. Such a tear line that includes nicks can also be referred to as a slit, since the nicks typically are a relatively small percentage of the subject line, and alternatively the nicks can be omitted from such a slit. As stated above, where cutting is used to provide a fold line, the cutting typically will not be overly extensive in a manner that might cause a reasonable user to consider incorrectly the fold line to be a tear line. Likewise, where nicks are present in a slit (e.g., tear line), typically the nicks will not be overly large or overly numerous in a manner that might cause a reasonable user to consider incorrectly the subject line to be a fold line.
Accordingly, it will be readily understood by those persons skilled in the art that, in view of the above detailed description of the invention, the present invention is susceptible of broad utility and application. Many adaptations of the present invention other than those herein described, as well as many variations, modifications, and equivalent arrangements will be apparent from or reasonably suggested by the present invention and the above detailed description thereof, without departing from the substance or scope of the present invention.
While the present invention is described herein in detail in relation to specific aspects, it is to be understood that this detailed description is only illustrative and exemplary of the present invention and is made merely for purposes of providing a full and enabling disclosure of the present invention. The detailed description set forth herein is not intended nor is to be construed to limit the present invention or otherwise to exclude any such other embodiments, adaptations, variations, modifications, and equivalent arrangements of the present invention.
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A carton for holding containers, such as beverage containers, is disclosed. The carton includes one or more openings in a top wall thereof for receiving necks of containers contained within the carton. One or more at least partially removable tabs are provided in the top wall, whereby the openings can be enlarged for individually removing the containers from the carton. The carton further includes flaps on a bottom panel thereof for retaining heels of the containers. A blank for forming the carton is also disclosed.
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CROSS REFERENCE TO PRIOR APPLICATIONS
This application is a division of Ser. No. 09/354,459, filed Jul. 15, 1999, which claims Benefit of Provisional Application No. 60/093,258 under 35 U.S.C. 119(e), filed Jul. 17, 1998.
CROSS REFERENCE TO RELATED APPLICATIONS
This application is related to a co-pending application entitled Method to Reduce By-Product Deposition in Wafer Processing Equipment and Improved Apparatus, filed Jan. 7, 1998, having a serial No. of 60/070,697.
TECHNICAL FIELD OF THE INVENTION
This invention relates generally to semiconductor manufacturing and more particularly to a method and system for reducing by-product deposition in wafer processing equipment.
BACKGROUND OF THE INVENTION
During the manufacture of semiconductor components, such as integrated circuits, memory chips, and the like, the failure of valves and pumps used in connection with wafer processing equipment is problematic. The failure is often caused by the deposition of by-products, such as by deposition of ammonia chloride (NH 4 Cl). In certain chemical vapor deposition (“CVD”) processes such as chloride-based ammonia reduction CVD processes, ammonia chloride (NH4Cl) is formed by reacting, for example, hydrogen chloride (HCL) with ammonia (NH 3 ). The resulting ammonia chloride may sublimate to a solid and stick to the inside of a wafer processing chamber wall or on the inside of associated valves and pumps. The build up over time of solidified ammonium chloride inside the valves and pumps may cause the valves to leak and the pumps to degrade, and the solidified ammonium chloride may also be transmitted into the process chambers, contaminating the manufacturing processes and reducing their yield.
One attempt at solving such a problem involves placing heaters around the wafer processing chamber or associated pump or conduits to maintain the produced ammonia chloride in a gaseous form to prevent sublimation to a solid form. However, in single wafer processing reactors for chemical vapor deposition of silicon nitride (SiCl 2 H 2 and NH 3 reaction) and titanium nitride (TiCl 4 and NH 3 reaction), process gases from a shower head flow into and through a chamber with high velocity and low temperatures. This flow removes a large amount of heat from inner walls of the reaction system. Because of the removal of heat from the inner walls, heating the outer walls may not be sufficient to prevent sublimation of ammonia chloride to a solid form.
SUMMARY OF THE INVENTION
Accordingly, a need has arisen for an improved method and system for reducing ammonium chloride deposition in wafer processing equipment. The present invention provides a method and system for reducing ammonium chloride deposition in single wafer processing equipment that addresses shortcomings of prior systems and methods.
According to one embodiment of the invention, a method of reducing by-product deposition inside wafer processing equipment includes providing a chamber having a peripheral inner wall and placing a semiconductor wafer within the chamber. The method also includes placing a ring within the chamber proximate the peripheral inner wall and introducing a plurality of reactant gases into the chamber and reacting the gases. The method also includes introducing a heated gas into the chamber through the ring proximate the peripheral inner wall to increase the temperature of the peripheral inner wall.
According to another embodiment of the invention, a method of reducing by-product deposition inside wafer processing equipment includes providing a chamber and placing a semiconductor wafer within the chamber. The method also includes connecting the chamber to a pump through a conduit and placing a heating element within the interior of the conduit to increase a temperature within the conduit. The method also includes introducing a plurality of reactant gases into the chamber and reacting the gases.
Embodiments of the invention provide numerous technical advantages. For example, in one embodiment of the invention, introduction of a heated gas through a ring along the periphery of the inner wall of a chamber inhibits solidification of by-products in water processing, such as ammonia chloride. Such inhibiting reduces degeneration of associated valves and pumps. In addition, the amount of solidified by-product contaminating the manufacturing process is reduced, which increases the yield of the manufacturing process.
Other technical advantages are readily apparent to one skilled in the art from the following figures, descriptions, and claims.
BRIEF DESCRIPTION OF THE DRAWINGS
For a more complete understanding of the present invention and the advantages thereof, reference is now made to the following descriptions taken in connection with the accompanying drawings in which:
FIG. 1 is a graph illustrating a sublimation curve for ammonia chloride;
FIG. 2A is a schematic block diagram illustrating a chemical vapor deposition reactor and associated equipment for wafer processing according to the teachings of the present invention;
FIG. 2B is a schematic cross sectional drawing of a ring for use in the reactor of FIG. 2A;
FIG. 3 is a schematic cross sectional drawing of another embodiment of a wafer processing reactor according to the teachings of the present invention;
FIG. 4 is a schematic cross sectional drawing of a pump and a conduit associated with a wafer processing reactor according to the teachings of the present invention; and
FIG. 5 is a schematic cross sectional diagram of a portion of a conduit according to the teachings of the present invention.
DETAILED DESCRIPTION OF THE INVENTION
Embodiments of the present invention and its advantages are best understood by referring to FIGS. 1 through 5 of the drawings, like numerals being used for like and corresponding parts of the various drawings.
FIG. 1 is a graph illustrating a sublimation curve for an example semiconductor processing by-product, ammonia chloride (NH 4 Cl). The illustrated graph indicates the temperature and pressure conditions at which ammonia chloride changes from a solid into a gas. For example, at 300 Pascals, which is an example pressure at which film formation occurs, ammonia chloride is a gas at temperatures above approximately 180° C. and is a solid at temperatures below approximately 180° C. This curve demonstrates the combination of pressure and temperatures at which ammonia chloride will take a gaseous or solid form, and therefore may be used to ascertain pressures and temperatures at which it is necessary to keep produced ammonia chloride to avoid solidification within a wafer processing system. Although a sublimation curve for ammonia chloride is presented, similar curves exist for other chemicals used in chemical vapor deposition processes.
FIG. 2A is a schematic diagram illustrating a chemical vapor deposition reactor 10 for use in accordance with one embodiment of the present invention. Reactor 10 includes a hermetically sealed chamber 12 , an inlet port 14 for introducing reactants into chamber 12 , a semiconductor support 16 for holding a substrate 18 in chamber 12 , and an outlet port 20 for evacuating chamber 12 . In this embodiment, reactor 10 is a single wafer processing reactor, which processes one wafer at a time. Chamber 12 has an inner peripheral wall 17 . Inlet port 14 is connected to a plurality of reactant gas stores 21 storing reactant gases 22 . Each gas store 21 includes a metering device 24 to control the introduction of reactant gases 22 into chamber 12 . Reactant gases 22 may be otherwise provided to chamber 12 without departing from the teachings of the present invention.
Inlet port 14 is connected to a “shower head” manifold 26 in chamber 12 for dispersing reactant gases 22 across a surface 28 of substrate 18 . Manifold 26 may be connected to a radio frequency source (not explicitly shown) for generating plasma to transfer energy to reactant gases 22 in chamber 12 .
Semiconductor support 16 may include clips or other suitable means for securing substrate 18 over manifold 26 . Substrate 18 may be a wafer, silicon slice, or any other work piece onto which thin films are deposited. A suceptor, or heater 32 , may be included as part of support 16 to transfer thermal energy to reactant gases at surface 28 of substrate 18 . Semiconductor support 16 may be formed from graphite. Heater 32 may be a radio frequency, resistive, or other suitable heater.
Outlet port 20 is connected to a vacuum pump 34 through a conduit 36 . Vacuum pump 34 evacuates and maintains chamber 12 at a desired pressure. An example of a desired pressure is in the range of 0.4 to approximately 8 torr; however, other suitable pressures may be maintained.
In chlorine-based ammonia reduction chemical vapor deposition, for example, reactant gases 22 may include silicon nitride utilizing dichlorosilane (SiCl 2 H 2 ), ammonia, titanium nitride (TiN), and titanium tetrachloride (TiCl 4 ). Reaction of ammonia with hydrogen chloride (HCl) produced from the above reactants forms ammonia chloride (NH 4 Cl). Because of standard operating temperatures and pressures for reactor 10 , this formed ammonia chloride has a tendency to sublimate from gaseous form to a solid form and stick to the walls of chamber 12 , conduit 36 , pump 34 , and associated valves (not explicitly shown). This sublimation problem is particularly acute in single wafer processing systems utilizing shower head manifold 26 , because reactant gases 22 typically flow through shower head manifold 26 at low temperatures and high velocities, resulting in large heat losses within chamber 12 and along inner peripheral wall 17 . To combat the sublimation of formed ammonia chloride to a solid form and deposition of solid ammonia chloride within reactor 10 , pump 34 , conduit 36 , and other elements associated with reactor 10 , but particularly along inner peripheral wall 17 of reactor 10 , a ring 46 is provided within chamber 12 . Ring 46 introduces hot gases 52 along the periphery of inner peripheral wall 17 of chamber 12 to keep the temperature along inner wall 17 at a temperature sufficient to inhibit the produced ammonia chloride from sublimating to a solid form. The introduction of hot gases 52 within chamber 12 , and particularly along inner peripheral wall 17 , provides efficient convective heating that is more effective than heating the exterior of chamber 12 .
FIG. 2B illustrates a cross sectional view of ring 46 along the line 2 B— 2 B of FIG. 2 A. As illustrated, ring 46 is generally circular and includes a plurality of apertures 48 for providing a hot gas into chamber 12 to heat inner wall 17 of chamber 12 ; however, ring 46 may take on any suitable configuration, particularly including configurations that conform to the shape of inner peripheral wall 17 . A hot gas conduit 50 provides a path for hot gases 52 to flow into ring 46 . Hot gases 52 may include any suitable gas for introduction into chamber 12 , including hot purge gases that may be available from other steps of the semiconductor wafer processing process. Particularly suitable gases include hydrogen and nitrogen, because these gases will not interact with reactant gases 22 . Although purge gases may be particularly useful, other gas sources may be utilized without departing from the teachings of the present invention. Thus, the introduction of hot gases along inner peripheral wall 17 increases the temperature of peripheral wall 17 to an extent that would otherwise be difficult using conventional techniques and overcomes heat loss associated with reactant gases 22 flowing through shower head manifold 26 at low temperatures and high velocity. Such increase in temperature inhibits sublimation of produced by-products, such as ammonia chloride, and therefore reduces degradation of associated valves and pumps in addition to reducing contamination of the manufacturing process.
FIG. 3 illustrates a cross sectional schematic of another embodiment of the present invention. A reactor system 110 is analogous to reactor system 10 ; however, instead of utilizing ring 46 to provide hot gases 152 to the interior of a chamber 112 , hot gases 152 are provided directly through a conduit 146 to the underside of a semiconductor support 116 , which in this example is heater 32 . The provided hot gases 152 flare outward towards an inner wall 117 near connection of chamber 112 to an outlet port 120 .
The provision of hot gases 152 underneath semiconductor support 116 is particularly useful in heating a conduit 136 and preventing sublimation of by-products, such as ammonia chloride, to a solid form within a conduit 136 in addition to preventing sublimation of ammonia chloride to a solid form within chamber 112 . Hot gases 152 may include any suitable gas for introduction into chamber 112 , including hot purge gases that may be available from other steps of the semiconductor wafer processing process. Particularly suitable gases include hydrogen and nitrogen, because these gases will not interact with reactant gases 122 . This introduction of hot gases 152 may be combined with the introduction of hot gases 52 , as illustrated in FIG. 2 A.
FIG. 4 illustrates another embodiment of the present invention. Illustrated in FIG. 4 is a reactor 210 analogous to reactor 10 , illustrated in FIG. 1 . Attached to reactor 210 is a conduit 236 leading to a pump 234 . Conduit 236 receives gases from a reactor such as reactor 210 through application of negative pressure by pump 234 . Disposed within conduit 236 is a heating element 250 . Heating element 250 increases the temperature within conduit 236 and pump 234 . In particular, heating element 250 increases the temperature of an inner wall 232 of conduit 236 and an inner wall 238 of pump 234 . Increasing the temperature of inner walls 232 and 238 of conduit 236 and pump 234 , respectively, inhibits solidification of, for example, ammonia chloride on inner walls 232 of conduit 236 and 238 of pump 234 . Heating element 250 may be any suitable heater for increasing the temperature within conduit 236 or pump 234 ; however, according to one embodiment of the invention, heating element 250 is a tungsten halogen lamp.
The introduction of a heating element within the interior of conduit 236 allows more effective heating than heating the exterior of conduit 236 . This more effective heating prevents sublimation of by-product gases to a solid form and therefore reduces degradation of associated valves and pumps in addition to reducing contamination of the manufacturing process. The introduction of a heating element into conduit 236 may be combined with the techniques described in conjunction with FIGS. 2A, 2 B, and 3 to further prevent sublimation of by-product gas.
FIG. 5 illustrates a schematic cross sectional diagram of a portion of a conduit 336 suitable for use with the present invention. According to the embodiment illustrated in FIG. 5, conduit 336 receives hot hydrogen 352 through a conduit 350 from a hot hydrogen source (not explicitly shown). In addition to heating an inner wall 332 of conduit 336 and an inner wall 338 of a pump 334 , hot hydrogen gas 352 provides a hydrogen passivation for, for example, ammonia chloride. Hydrogen passivation of ammonia chloride inhibits formation of ammonia chloride from its constituent elements. Therefore, in addition to preventing the solidification of by-products such as ammonia chloride, use of hot hydrogen 352 prevents the formation of both gas and solid ammonia chloride. To further inhibit the formation of by-products such as ammonia chloride by hydrogen passivation, a platinum catalyst 360 and a heater 354 may be disposed within conduit 332 to generate free hydrogen radicals. In addition, heater 354 may also be added to facilitate generation of free hydrogen radicals. The existence of free hydrogen radicals more efficiently inhibits the formation of ammonia chloride and therefore inhibits formation of solid ammonia chloride on inner walls 332 and 338 .
Although the present invention and its advantages have been described in detail, it should be understood the various changes, substitutions, and alterations can be made therein without departing from the spirit and scope of the present invention as defined by the appended claims.
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A method of reducing by-product deposition inside wafer processing equipment includes providing a chamber having a peripheral inner wall and placing a semiconductor wafer within the chamber. The method also includes placing a ring within the chamber proximate the peripheral inner wall and introducing a plurality of reactant gases into the chamber and reacting the gases. The method also includes introducing a heated gas into the chamber through the ring proximate the peripheral inner wall to increase the temperature of the peripheral inner wall.
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CROSS-REFERENCE TO RELATED APPLICATIONS
This application is a divisional of U.S. application Ser. No. 13/811,957, filed Jan. 24, 2013, which is a Section 371 of International Application No. PCT/CN2011/001223, filed on Jul. 26, 2011, which was published in the Chinese language on Feb. 16, 2012, under International Publication No. WO 2012/019427 A1, and the disclosures of which are incorporated herein by reference.
FIELD OF THE INVENTION
The present invention relates to a novel phthalazinone ketone derivative as represented by formula (I), the preparation methods thereof, the pharmaceutical composition containing the derivative, and the use thereof as a therapeutic agent, especially as the poly (ADP-ribose) polymerase (PARP) inhibitor.
BACKGROUND OF THE INVENTION
Chemotherapy and radiation therapy are two common methods to treat cancer. Both treatments can induce single-stranded and/or double-stranded DNA breakage to produce cytotoxicity, then the targeted tumor cells will die due to chromosomal damage. An important result in response to DNA damage signal is that the signal of the cell cycle in regulation site is activated, the purpose of which is to protect cells from mitosis in the case of DNA damage thereby preventing cell damage. In most cases, the tumor cells exhibit the defects of regulation signal in the cell cycle and have high proliferation rate. So it can be predicted that the tumor cells have specific DNA repair mechanisms, which can respond quickly to repair chromosome damage relevant to proliferation regulation, thereby saving them from cytotoxic effects of some treatment and keep alive.
In the clinical application, the effective concentration of the chemotherapeutical drug or therapeutic radiation intensity can fight these DNA repair mechanism to ensure the killing effect on the target tumor cells. However, the tumor cells can develop tolerance for treatment by enhancing its DNA damage repair mechanisms, and survive from the lethal DNA damage. In order to overcome the tolerance, it is usually necessary to increase the dosage of the therapeutic drug or radiation intensity. This approach will produce adverse effects on the normal tissue nearby the lesions, and then make the treatment course complicated by severe adverse reactions, thereby increasing the risk of treatment. At the same time, the ever-increasing tolerance will reduce the therapeutic effect, so it can be concluded that the cytotoxicity of the DNA damage agents can be improved in the way of tumor cell-specificity by controlling the repair mechanism promoted by the signal of DNA damage.
PARPs (Poly (ADP-ribose) polymerases), characterized by poly ADP-ribosylation activity, are constituted by the superfamily of 18 nucleus enzymes and cytoplasmic enzymes. Such poly ADP-ribosylation effect can adjust the activity of the targeted protein and the interaction between proteins, and regulate other many fundamental biological processes, including DNA repair and cell death. In addition, genomic stability is also associated with the poly ADP-ribosylation (see D'Amours et al. Biochem. J, 1999, 342, 249).
The activity of PARP-1 accounts for about 80% of the total cellular PARP activity. PARP-1, together with PARP-2, which is most similar to PARP-1, are the members having the DNA damage repair capacity in the PARP family. As a sensor and a signaling protein of DNA damage, PARP-1 can detect the DNA damage sites quickly and bond to them directly, and then induce the aggregation of various proteins required for DNA repair, thereby enabling the DNA damage to be repaired. When the cells lack PARP-1, PARP-2 can realize the repair of the DNA damage instead of PARP-1.
Studies have shown that, compared with normal cells, the expression of PARPs protein in solid tumors is generally enhanced. In addition, the tumors (such as breast cancer and ovarian cancer), whose DNA repair related gene is missing (such as BRCA-1 or BRCA-2), show extreme sensitivity to PARP-1 inhibitors. This suggests the potential uses of PARP inhibitors as a single agent in the treatment of a tumor, which can be called triple negative breast cancer (see Plummer, E. R. Curr. Opin. Pharmacol. 2006, 6, 364; Ratnam, et al; Clin. Cancer Res. 2007, 13, 1383). At the same time, because DNA damage repair mechanism is the main mechanism of tumor cells response to the tolerance produced by chemotherapeutic drugs and ionizing radiation treatment, PARP-1 is considered to be an effective target to explore the new methods of cancer therapy.
PARP inhibitors were initially developed and designed using nicotinamide of NAD + , which can be used as PARP catalytic substrate, as a template to develop its analogs. As competitive inhibitors of NAD + , these inhibitors compete with NAD + for PARP catalytic sites, thereby preventing the synthesis of the poly (ADP-ribose) chain. PARP without poly (ADP-ribosylation) modification cannot be dissociated from the DNA damage sites, which will lead other proteins involved in the repair into the damage site, thereby preventing performance of the repair process. Therefore, in the effect of the cytotoxic drugs or radiation, PARP inhibitor will eventually kill tumor cells with DNA damage.
In addition, the NAD + , which is consumed as the PARP catalytic substrate, is the essential factor in the ATP synthesis process of the cells. Under the high level of PARP activity, intracellular NAD + levels will significantly decrease, thereby affecting the intracellular ATP level. Due to lack of intracellular ATP content, the cells cannot achieve programmed ATP-dependent cell death process, and can only turn to necrosis, a special apoptosis process. During the necrosis, a lot of inflammatory cytokines will be released, thereby producing toxic effects on other organs and tissues (Horvath E M et al. Drug News Perspect, 2007, 20, 171-181). Therefore, PARP inhibitors can also be used for the treatment of a variety of diseases related to this mechanism, including neurodegenerative diseases (such as Alzheimer's disease, Huntington's disease, Parkinson's disease), diabetes, concurrent diseases in the ischemia or ischemia-reperfusion process, such as myocardial infarction and acute renal failure, circulatory system diseases, such as septic shock and inflammatory diseases, such as chronic rheumatism, etc (see Tentori L, et al. Pharmacol. Res., 2002, 45, 73-85; Horvath E M et al. Drug News Perspect., 2007, 20, 171; Faro R, et al. Ann. Thorac. Surg., 2002, 73, 575; Kumaran D, et al. Brain Res., 2008, 192, 178).
Currently, a series of patent application have been disclosed on phthalazinone ketone PARP inhibitor, including WO2002036576, WO2004080976 and WO2006021801.
Although there are a series of PARP inhibitors for tumor treatment that have been disclosed, there remains a need to develop new compounds with better efficacy and pharmacokinetics results. After continuous efforts, the present invention designs a series of compounds of formula (I), and finds that the compounds having such structure exhibit an excellent effect and function.
SUMMARY OF THE INVENTION
The present invention is directed to a phthalazinone ketone derivative of formula (I) or a tautomer, enantiomer, diastereomer, racemate, or pharmaceutically acceptable salt thereof, as well as a metabolite, metabolic precursor or prodrug thereof:
wherein:
A and B are taken together with the attached carbon atoms to form a cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein said cycloalkyl, heterocyclyl, aryl or heteroaryl is each independently and optionally substituted with one or more groups selected from the group consisting of alkyl, halogen, hydroxyl, alkoxyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, —C(O)OR 5 , —OC(O)R 5 , —O(CH 2 ) n C(O)OR 5 , —C(O)R 5 , —NHC(O)R 5 , —NR 6 R 7 , —OC(O)NR 6 R 7 and —C(O)NR 6 R 7 ;
R 1 , R 2 , R 3 or R 4 is each independently selected from the group consisting of hydrogen, halogen, alkyl, cyano and alkoxyl, wherein said alkyl or alkoxyl is each independently and optionally substituted with one or more groups selected from the group consisting of halogen, hydroxyl, alkyl and alkoxyl;
D, E, or G is each independently selected from the group consisting of nitrogen atom and C(R 8 );
R 5 is selected from the group consisting of hydrogen, alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein said alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl is each independently and optionally substituted with one or more groups selected from the group consisting of alkyl, halogen, hydroxyl, alkoxyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, carboxyl and alkoxycarbonyl;
R 6 or R 7 is each independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein said alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl is each independently and optionally substituted with one or more groups selected from the group consisting of alkyl, halogen, hydroxyl, alkoxyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, carboxyl and alkoxycarbonyl;
or, R 6 and R 7 are taken together with the attached N atom to form heterocyclyl, wherein said heterocyclyl contains one or more N, O or S(O) m heteroatoms, and said heterocyclyl is optionally substituted with one or more groups selected from the group consisting of alkyl, halogen, hydroxyl, alkoxyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, carboxyl and alkoxycarbonyl;
R 8 is selected from the group consisting of hydrogen, alkyl, halogen, hydroxyl, cyano, alkoxyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, benzyl, —C(O)OR 5 , —OC(O)R 5 , —O(CH 2 ) n C(O)OR 5 , —(CH 2 ) n NR 6 R 7 , —C(O)R 5 , —NHC(O)R 5 , —NR 6 R 7 , —OC(O)NR 6 R 7 and —C(O)NR 6 R 7 , wherein said alkyl, alkoxyl, cycloalkyl, heterocyclyl, aryl, heteroaryl or benzyl is each independently and optionally substituted with one or more groups selected from the group consisting of alkyl, halogen, hydroxyl, alkoxyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, oxo, —C(O)OR 5 , —OC(O)R 5 , —O(CH 2 ) n C(O)OR 5 , —C(O)R 5 , —NHC(O)R 5 , —NR 6 R 7 , —OC(O)NR 6 R 7 and —C(O)NR 6 R 7 ;
m is selected from the group consisting of 0, 1 and 2; and
n is selected from the group consisting of 0, 1 and 2.
A preferable embodiment of the invention relates to a compound of formula (I) or its pharmaceutically acceptable salt, wherein A and B are taken together with the attached carbon atoms to form an aryl, preferably said aryl is phenyl.
Preferably, in the compound of formula (I) or its pharmaceutically acceptable salt, R 1 is hydrogen.
Preferably, in the compound of formula (I) or its pharmaceutically acceptable salt, R 1 is halogen, preferably fluorine atom.
Preferably, in the compound of formula (I) or its pharmaceutically acceptable salt, R 1 is halogen, preferably fluorine atom.
Preferably, in the compound of formula (I) or its pharmaceutically acceptable salt, R 1 , R 2 , R 3 or R 4 is each independently selected from hydrogen atom.
Preferably, in the compound of formula (I) or its pharmaceutically acceptable salt, R 8 is selected from the group consisting of hydrogen, alkyl, halogen, cyano, —C(O)OR 5 , —(CH 2 ) n NR 6 R 7 and —C(O)NR 6 R 7 , wherein said alkyl is optionally substituted with one or more halogen atoms.
Preferably, in the compound of formula (I) or its pharmaceutically acceptable salt, R 8 is trifluoromethyl.
The compound of formula (I) may contain asymmetric carbon atoms, therefore it can exist in the form of optically pure diastereomer, diastereomeric mixture, diastereomeric racemate, a mixture of diastereomeric racemate or as a meso-compound. The present invention includes all these forms. Diastereomeric mixture, diastereomeric racemate or the mixture of diastereomeric racemate can be isolated by conventional methods, such as column chromatography, thin layer chromatography and high performance liquid chromatography.
The equivalent can be understood by an ordinary person skilled in the art that the compound of formula (I) may also have tautomers. The tautomeric forms of the compound (I) include, but are not limited to, the structure represented by the following formula (II):
The compounds of the invention include, but are not limited to, the following:
Exam- ple No. Structure and Name 1 4-[[4-fluoro-3-[3-(trifluoromethyl)-6,8-dihydro-5H- [1,2,4]triazolo[4,3-a]pyrazine-7-carbonyl]-phenyl]methyl]- 2H-phthalazin-l-one 2 4-[[3-(3,4-dihydro-1H-pyrrolo[1,2-a]pyrazine-2-carbonyl)- 4-fluoro-phenyl]methyl]-2H-phthalazin-1-one 3 methyl 7-[2-fluoro-5-[(4-oxo-3H-phthalazin-1- yl)methyl]benzoyl]-3-(trifluoromethyl)-6,8-dihydro- 5H-imidazo[1,5-a]pyrazine-l-carboxylate 4 4-[[3-(6,8-dihydro-5H-imidazo[1,2-a]pyrazine-7-carbonyl)- 4-fluoro-phenyl]methyl]-2H-phthalazin-l-one 5 4-[[4-fluoro-3-[3-(trifluoromethyl)-6,8-dihydro-5H- imidazo[1,5-a]pyrazine-7-carbonyl]phenyl]methyl]-2H- phthalazin-l-one 6 4-[[4-fluoro-3-[1-(hydroxymethyl)-3-(trifluoromethyl)-6,8- dihydro-5H-imidazo[1,5-a]pyrazine-7-carbonyl]phenyl] methyl]-2H-phthalazin-1-one 7 N-ethyl-7-[2-fluoro-5-[(4-oxo-3H-phthalazin-l-yl)methyl] benzoyl]-3-(trifluoromethyl)-6,8-dihydro-5H- imidazo[1,5-a]pyrazine-1-carboxamide 8 7-[2-fluoro-5-[(4-oxo-3H-phthalazin-l-yl)methyl]benzoyl]- 3-(trifluoromethyl)-6,8-dihydro-5H- imidazo[1,5-a]pyrazine-1-carboxylic acid 9 4-[[4-fluoro-3-[1-(methylaminomethyl)-3-(trifluoromethyl)- 6,8-dihydro-5H-imidazo[1,5-a]pyrazine-7- carbonyl]phenyl]methyl]-2H-phthalazin-1-one 10 7-[2-fluoro-5-[(4-oxo-3H-phthalazin-l-yl)methyl]benzoyl]-3- (trifluoromethyl)-6,8-dihydro-5H-imidazo[1,5-a]pyrazine-l- carboxamide 11 4-[[3-[1-bromo-3-(trifluoromethyl)-6,8-dihydro-5H-imidazo [1,5-a]pyrazine-7-carbonyl]-4-fluoro-phenyl]methyl]-2H- phthalazin-l-one 12 4-[[4-fluoro-3-[2-(trifluoromethyl)-6,8-dihydro- 5H-imidazo[1,2-a]pyrazine-7-carbonyl]phenyl]methyl]- 2H-phthalazin-1-one 13 7-[2-fluoro-5-[(4-oxo-3H-phthalazin-l- yl)methyl]benzoyl]-N-methyl-3-(trifluoromethyl)-6,8- dihydro-5H-imidazo[1,5-a]pyrazine-1-carboxamide 14 ethyl 7-[2-fluoro-5-[(4-oxo-3H-phthalazin-1- yl)methyl]benzoyl]-6,8-dihydro-5H- imidazo[1,2-a]pyrazine-3-carboxylate 15 4-[[3-[3-(trifluoromethyl)-6,8-dihydro-5H-[1,2,4] triazolo[4,3-a]pyrazine-7-carbonyl]phenyl]methyl]-2H- phthalazin-l-one 16 4-[[3-(6,8-dihydro-5H-[1,2,4]triazolo[1,5-a]pyrazine-7- carbonyl)-4-fluoro-phenyl]methyl]-2H-phthalazin-1-one 17 4-[[3-(6,8-dihydro-5H-[1,2,4]triazolo[4,3-a]pyrazine-7- carbonyl)-4-fluoro-phenyl]methyl]-2H-phthalazin-1-one 18 4-[[4-fluoro-3-[1-(pyrrolidine-l-carbonyl)-3-(trifluoromethyl)- 6,8-dihydro-5H-imidazo[1,5-a]pyrazine-7-carbonyl] phenyl]methyl]-2H-phthalazin-1-one 19 4-[[4-fluoro-3-[2-(trifluoromethyl)-6,8-dihydro-5H-[1,2,4] triazolo[1,5-a]pyrazine-7-carbonyl]phenyl]methyl]-2H- phthalazin-l-one 20 4-[[4-fluoro-3-[1-(morpholine-4-carbonyl)-3- (trifluoromethyl)-6,8-dihydro-5H-imidazo[1,5-a]pyrazine- 7-carbonyl]phenyl]methyl]-2H-phthalazin-1-one 21 N-methyl-7-[3-[(4-oxo-3H-phthalazin-l-yl)methyl]benzoyl]- 3-(trifluoromethyl)-6,8-dihydro-5H-imidazo[1,5-a] pyrazine-1-carboxamide 22 7-[2-fluoro-5-[(4-oxo-3H-phthalazin-l-yl)methyl]benzoyl]- N,N-dimethyl-3-(trifluoromethyl)-6,8-dihydro-5H- imidazo[1,5-a]pyrazine-1-carboxamide 23 4-[[3-[3-(difluoromethyl)-6,8-dihydro-5H-[1,2,4]triazolo [4,3-a]pyrazine-7-carbonyl]-4-fluoro-phenyl]methyl]-2H- phthalazin-l-one 24 N-(cyclopropylmethyl)-7-[2-fluoro-5-[(4-oxo-3H-phthalazin- l-yl)methyl]benzoyl]-3-(trifluoromethyl)-6,8-dihydro- 5H-imidazo[1,5-a]pyrazine-l-carboxamide 25 7-[2-fluoro-5-[(4-oxo-3H-phthalazin-l-yl)methyl]benzoyl]- 3-(trifluoromethyl)-6,8-dihydro-5H-imidazo[1,5-a]pyrazine- l-carbonitrile 26 4-[[4-fluoro-3-[3-(2,2,2-trifluoroethyl)-6,8-dihydro- 5H-[1,2,4]triazolo[4,3-a]pyrazine-7- carbonyl]phenyl]methyl]-2H-phthalazin-1-one
or pharmaceutically acceptable salts thereof.
This invention relates to a preparation process for a compound of formula (I) or a pharmaceutically acceptable salt thereof, comprising the steps of:
optionally hydrolyzing a compound of formula (IA) to a carboxylic acid, reacting the carboxylic acid with a compound of formula (IB) or a salt thereof in the presence of a condensing agent such as benzotriazole-N,N,N′,N′-tetramethyl urea hexafluorophosphate under an alkaline condition to obtain the compound of formula (I);
wherein:
R a is selected from the group consisting of hydroxyl, halogen and alkoxyl;
A, B, D, E, G and R 1 to R 4 are defined as those in formula (I).
In another aspect, this present invention relates to the use of the compounds of formula (I) or the pharmaceutically acceptable salt thereof in the preparation of the PARP inhibitors.
In another aspect, this present invention relates to a method for inhibiting PARP, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.
In another aspect, this present invention relates to the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof in the preparation of an adjuvant in the treatment of cancer or a medicament causing tumor cells to become sensitive to ionizing radiation or chemotherapy.
In another aspect, this present invention relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof, for use as an adjuvant in the treatment of cancer or causing tumor cells to become sensitive to ionizing radiation or chemotherapy.
In another aspect, this present invention relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof, for use as a PARP inhibitor.
In another aspect, this present invention relates to the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof in the preparation of a medicament for the treatment of cancer, wherein said cancer is selected from the group consisting of breast cancer, ovarian cancer, pancreatic cancer, prostate cancer, liver cancer and colon cancer, wherein said medicament is further co-administered with a therapeutically effective amount of a drug selected from the group consisting of Temozolomide, Adriamycin, Taxol, Cisplatin, Carboplatin, Dacarbazine, Topotecan, Irinotecan, Gemcitabine and Bevacizumab.
In another aspect, this present invention relates to a method for treating cancer, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein said cancer is selected from the group consisting of breast cancer, ovarian cancer, pancreatic cancer, prostate cancer, liver cancer and colon cancer, wherein said compound of formula (I) or the pharmaceutically acceptable salt thereof is further co-administered with a therapeutically effective amount of a drug selected from the group consisting of Temozolomide, Adriamycin, Taxol, Cisplatin, Carboplatin, Dacarbazine, Topotecan, Irinotecan, Gemcitabine and Bevacizumab.
In another aspect, this present invention relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof, for use as a medicament for the treatment of cancer, wherein said cancer is selected from the group consisting of breast cancer, ovarian cancer, pancreatic cancer, prostate cancer, liver cancer and colon cancer, wherein said medicament is further co-administered with a therapeutically effective amount of a drug selected from the group consisting of Temozolomide, Adriamycin, Taxol, Cisplatin, Carboplatin, Dacarbazine, Topotecan, Irinotecan, Gemcitabine and Bevacizumab.
Furthermore, the present invention also relates to a pharmaceutical composition, comprising a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof according to the present invention, and a pharmaceutically acceptable carrier or excipient. The present invention relates to the pharmaceutical composition, for use as a PARP inhibitor, or as an adjuvant in the treatment of cancer or a medicament causing tumor cells to become sensitive to ionizing radiation or chemotherapy, or as a medicament for the treatment of cancer. The present invention relates to the use of the said pharmaceutical composition in the preparation of a PARP inhibitor. The present invention relates to the use of the pharmaceutical composition in the preparation of an adjuvant in the treatment of cancer or a medicament causing tumor cells to become sensitive to ionizing radiation or chemotherapy. The present invention relates to the use of the pharmaceutical composition in the preparation of a medicament for the treatment of cancer, wherein said cancer is selected from the group consisting of breast cancer, ovarian cancer, pancreatic cancer, prostate cancer, liver cancer and colon cancer, wherein said pharmaceutical composition is further co-administered with a therapeutically effective amount of a drug selected from the group consisting of Temozolomide, Adriamycin, Taxol, Cisplatin, Carboplatin, Dacarbazine, Topotecan, Irinotecan, Gemcitabine and Bevacizumab.
DETAILED DESCRIPTION OF THE INVENTION
Unless otherwise stated, the terms used in the specification and claims have the meanings described below.
“Alkyl” refers to a saturated aliphatic hydrocarbon group including C1-C20 straight chain and branched chain groups. Preferably an alkyl group is an alkyl having 1 to 12 carbon atoms. Representative examples include, but are not limited to methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethyl propyl, 1,2-dimethyl propyl, 2,2-dimethyl propyl, 1-ethyl propyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2,3-dimethylpentyl, 2,4-dimethylpentyl, 2,2-dimethylpentyl, 3,3-dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl, 2,3-dimethylhexyl, 2,4-dimethylhexyl, 2,5-dimethylhexyl, 2,2-dimethylhexyl, 3,3-dimethylhexyl, 4,4-dimethylhexyl, 2-ethylhexyl, 3-ethylhexyl, 4-ethylhexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl, n-nonyl, 2-methyl-2-ethylhexyl, 2-methyl-3-ethylhexyl, 2,2-diethylpentyl, n-decyl, 3,3-diethylhexyl, 2,2-diethylhexyl, and the isomers of branched chain thereof. More preferably an alkyl group is a lower alkyl having 1 to 6 carbon atoms. Representative examples include, but are not limited to methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl and etc. The alkyl group may be substituted or unsubstituted. When substituted, the substituent group(s) may be substituted at any available connection point, preferably the substituent group(s) is one or more groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkyxoyl, alkylsulfo, alkylamino, halogen, thiol, hydroxyl, nitro, cyano, cycloalkyl, heterocyclic alkyl, aryl, heteroaryl, cycloalkyoxyl, heterocylic alkyoxyl, cycloalkylthio, heterocylic alkylthio, oxo, —C(O)OR 5 , —OC(O)R 5 , —O(CH 2 ) n C(O)OR 5 , —C(O)R 5 , —NHC(O)R 5 , —NR 6 R 7 , —OC(O)NR 6 R 7 and —C(O)NR 6 R 7 .
“Cycloalkyl” refers to a saturated and/or partially unsaturated monocyclic or polycyclic hydrocarbon group and have 3 to 20 carbon atoms, preferably 3 to 12 carbon atoms, more preferably 3 to 10 carbon atoms. Representative examples of monocyclic cycloalkyl include, but are not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl and etc. Polycyclic cycloalkyl includes the cycloalkyl having spiro ring, fused ring and bridged ring.
“Spiro Cycloalkyl” refers to a 5 to 20 membered polycyclic group with rings connected through one common carbon atom (called as spiro atom), wherein one or more rings may contain one or more double bonds, but none of the rings has a completely conjugated pi-electron system. Preferably a spiro cycloalkyl is 6 to 14 membered, more preferably 7 to 10 membered. According to the number of the common spiro atom, spiro cycloalkyl is divided into mono-spirocyclic ring, di-spirocyclic ring or poly-spirocyclic ring, preferably refers to mono-spirocyclic ring or di-spirocyclic ring. More preferably spiro cycloalkyl is 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/5-membered, or 5-membered/6-membered monocyclic spiro ring. Representative examples of spiro cycloalkyl include, but are not limited to the following groups:
“Fused Cycloalkyl” refers to a 5 to 20 membered polycyclic hydrocarbon group, wherein each ring in the group shares an adjacent pair of carbon atoms with another ring in the group, wherein one or more rings can contain one or more double bonds, but none of the rings has a completely conjugated pi-electron system. Preferably a fused cycloalkyl group is 6 to 14 membered, more preferably 7 to 10 membered. According to the number of carbons in each membered ring, a fused cycloalkyl can be oriented into a bicyclic ring, tricyclic ring, tetracyclic ring or polycyclic ring fused cycloalkyl, preferably fused bicyclic ring or tricyclic ring fused cycloalkyl. More preferably the fused cycloalkyl is a 5-membered/5-membered, or 5-membered/6-membered bicyclic ring fused cycloalkyl. Representative examples of fused cycloalkyl include, but are not limited to, the following groups:
“Bridged Cycloalkyl” refers to a 5 to 20 membered polycyclic hydrocarbon group, wherein any two rings in the group share two disconnected carbon atoms. The rings can have one or more double bonds but have no completely conjugated pi-electron system. Preferably a bridged cycloalkyl is 6 to 14 membered, more preferably 7 to 10 membered. According to the number of membered ring, bridged cycloalkyl is divided into bridged bicyclic ring, tricyclic ring, tetracyclic ring or polycyclic ring, preferably refers to bicyclic ring, tricyclic ring or tetracyclic ring bridged cycloalkyl, more preferably bicyclic ring or tricyclic ring bridged cycloalkyl. Representative examples of bridged cycloalkyl include, but are not limited to the following groups:
The said cycloalkyl can be fused to the ring of aryl, heteroaryl or heterocyclic alkyl, wherein the ring connected with parent structure is cycloalkyl. Representative examples include, but are not limited to indanylacetic, tetrahydronaphthalene, benzocydoheptyl and so on. The said cycloalkyl may be optionally substituted or unsubstituted. When substituted, the substituent group(s) is preferably one or more groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkyxoyl, alkylsulfo, alkylamino, halogen, thiol, hydroxyl, nitro, cyano, cycloalkyl, heterocyclic alkyl, aryl, heteroaryl, cycloalkyoxyl, heterocylic alkyoxyl, cycloalkylthio, heterocylic alkylthio, oxo, —C(O)OR 5 , —OC(O)R 5 , —O(CH 2 ) n C(O)OR 5 , —C(O)R 5 , —NHC(O)R 5 , —NR 6 R 7 , —OC(O)NR 6 R 7 and —C(O)NR 6 R 7 .
“Alkenyl” refers to an alkyl defined as above that have at least two carbon atoms and at least one carbon-carbon double bond. For example, vinyl, 1-propenyl, 2-propenyl, 1-, 2- or 3-butenyl and etc. The alkenyl group may be substituted or unsubstituted. When substituted, the substituent group(s) is preferably one or more group(s) independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkyxoyl, alkylsulfo, alkylamino, halogen, thiol, hydroxyl, nitro, cyano, cycloalkyl, heterocyclic alkyl, aryl, heteroaryl, cycloalkyoxyl, heterocylic alkyoxyl, cycloalkylthio, heterocylic alkylthio, —C(O)OR 5 , —OC(O)R 5 , —O(CH 2 ) n C(O)OR 5 , —C(O)R 5 , —NHC(O)R 5 , —NR 6 R 7 , —OC(O)NR 6 R 7 and —C(O)NR 6 R 7 .
“Alkynyl” refers to an alkyl defined as above that have at least two carbon atoms and at least one carbon-carbon triple bond. For example, ethynyl, 1-propynyl, 2-propynyl, 1-, 2- or 3-butynyl and etc. The alkynyl group may be substituted or unsubstituted. When substituted, the substituent group(s) is preferably one or more group(s) independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkyxoyl, alkylsulfo, alkylamino, halogen, thiol, hydroxyl, nitro, cyano, cycloalkyl, heterocyclic alkyl, aryl, heteroaryl, cycloalkyoxyl, heterocylic alkyoxyl, cycloalkylthio, heterocylic alkylthio, —C(O)OR 5 , —OC(O)R 5 , —O(CH 2 ) n C(O)OR 5 , —C(O)R 5 , —NHC(O)R 5 , —NR 6 R 7 , —OC(O)NR 6 R 7 and —C(O)NR 6 R 7 .
“Heterocyclyl” refers to 3 to 20 membered saturated and/or partially unsaturated monocyclic or polycyclic hydrocarbon group having one or more heteroatoms selected from the group consisting of N, O, or S(O)m (wherein m is 0, 1 or 2) as ring atoms, but excluding —O—O—, —O—S— or —S—S— in the ring, the remaining ring atoms being C. Preferably, heterocyclyl is 3 to 12 membered having 1 to 4 said heteroatoms; more preferably 3 to 10 membered. Representative examples of monocyclic heterocyclyl include, but are not limited to pyrrolidyl, piperidyl, piperazinyl, morpholinyl, sulfo-morpholinyl, homopiperazinyl and so on. Polycyclic heterocyclyl includes the heterocyclyl having spiro ring, fused ring and bridged ring. “Spiro heterocyclyl” refers to 5 to 20 membered polycyclic heterocyclyl with rings connected through one common carbon atom (called as spiro atom), wherein said rings have one or more heteroatoms selected from the group consisting of N, O, and S(O) p (wherein p is 0, 1 or 2) as ring atoms, the remaining ring atoms being C, wherein one or more rings may contain one or more double bonds, but none of the rings has a completely conjugated pi-electron system. Preferably a spiro heterocyclyl is 6 to 14 membered, more preferably 7 to 10 membered. According to the number of common spiro atoms, spiro heterocyclyl is divided into mono-spiro heterocyclyl, di-spiro heterocyclyl or poly-spiro heterocyclyl, preferably refers to mono-spiro heterocyclyl and di-spiro heterocyclyl. More preferably spiro heterocyclyl is 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/5-membered, or 5-membered/6-membered mono-spiro heterocyclyl. Representative examples of spiro heterocyclyl include, but are not limited to the following groups:
“Fused Heterocyclyl” refers to a 5 to 20 membered polycyclic heterocyclyl group, wherein each ring in the group shares an adjacent pair of carbon atoms with another ring in the group, wherein one or more rings can contain one or more double bonds, but none of the rings has a completely conjugated pi-electron system, and wherein said rings have one or more heteroatoms selected from the group consisting of N, O, and S(O) p (wherein p is 0, 1 or 2) as ring atoms, the remaining ring atoms being C. Preferably a fused heterocyclyl is 6 to 14 membered, more preferably 7 to 10 membered. According to the number of membered ring, the fused heterocyclyl is divided into bicyclic ring, tricyclic ring, tetracyclic ring or polycyclic ring fused heterocyclyl, preferably refers to bicyclic ring or tricyclic ring fused heterocyclyl. More preferably fused heterocyclyl is 5-membered/5-membered, or 5-membered/6-membered bicyclic ring fused heterocyclyl. Representative examples of fused heterocyclyl include, but are not limited to the following groups:
“Bridged Heterocyclyl” refers to a 5 to 14 membered polycyclic heterocyclyl group, wherein any two rings in the group share two disconnected atoms, the rings can have one or more double bonds but have no completely conjugated pi-electron system, and the rings have one or more heteroatoms selected from the group consisting of N, O, and S(O) m (wherein m is 0, 1 or 2) as ring atoms, the remaining ring atoms being C. Preferably a bridged heterocyclyl is 6 to 14 membered, more preferably 7 to 10 membered. According to the number of membered ring, bridged heterocyclyl is divided into bicyclic ring, tricyclic ring, tetracyclic ring or polycyclic ring bridged heterocyclyl, preferably refers to bicyclic ring, tricyclic ring or tetracyclic ring bridged heterocyclyl, more preferably bicyclic ring or tricyclic ring bridged heterocyclyl. Representative examples of bridged heterocyclyl include, but are not limited to the following groups:
The said ring of heterocyclyl can be fused to the ring of aryl, heteroaryl or cycloalkyl, wherein the ring connected with parent structure is heterocyclyl. Representative examples include, but are not limited to, the following groups:
The heterocyclyl may be optionally substituted or unsubstituted. When substituted, the substituent group(s) is preferably one or more group(s) independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkyxoyl, alkylsulfo, alkylamino, halogen, thiol, hydroxyl, nitro, cyano, cycloalkyl, heterocyclic alkyl, aryl, heteroaryl, cycloalkyoxyl, heterocylic alkyoxyl, cycloalkylthio, heterocylic alkylthio, oxo, —C(O)OR 5 , —OC(O)R 5 , —O(CH 2 ) n C(O)OR 5 , —C(O)R 5 , —NHC(O)R 5 , —NR 6 R 7 , —OC(O)NR 6 R 7 and —C(O)NR 6 R 7 .
“Aryl” refers to a 6 to 14 membered all-carbon monocyclic ring or a polycyclic fused ring (a “fused” ring system means that each ring in the system shares an adjacent pair of carbon atoms with other ring in the system) group, and has a completely conjugated pi-electron system. Preferably aryl is 6 to 10 membered, such as phenyl and naphthyl. The said aryl can be fused to the ring of heteroaryl, heterocyclyl or cycloalkyl, wherein the ring connected with parent structure is aryl. Representative examples include, but are not limited to, the following groups:
The aryl group may be substituted or unsubstituted. When substituted, the substituent group(s) is preferably one or more groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkyxoyl, alkylsulfo, alkylamino, halogen, thiol, hydroxyl, nitro, cyano, cycloalkyl, heterocyclic alkyl, aryl, heteroaryl, cycloalkyoxyl, heterocylic alkyoxyl, cycloalkylthio, heterocylic alkylthio, —C(O)OR 5 , —OC(O)R 5 , —O(CH 2 ) n C(O)OR 5 , —C(O)R 5 , —NHC(O)R 5 , —NR 6 R 7 , —OC(O)NR 6 R 7 and —C(O)NR 6 R 7 .
“Heteroaryl” refers to a heteroaryl system having 1 to 4 heteroatoms selected from the group consisting of O, S and N as ring atoms and having 5 to 14 annular atoms. Preferably heteroaryl is 5- to 10-membered. More preferably heteroaryl is 5- or 6-membered. The examples of heteroaryl groups include furyl, thienyl, pyridyl, pyrrolyl, N-alkyl pyrrolyl, pyrimidinyl, pyrazinyl, imidazolyl, tetrazolyl, and the like. The said heteroaryl can be fused with the ring of aryl, heterocyclyl or cycloalkyl, wherein the ring connected with parent structure is heteroaryl. Representative examples include, but are not limited to the following groups,
The heteroaryl group may be substituted or unsubstituted. When substituted, the substituent group(s) is preferably one or more groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkyxoyl, alkylsulfo, alkylamino, halogen, thiol, hydroxyl, nitro, cyano, cycloalkyl, heterocyclic alkyl, aryl, heteroaryl, cycloalkyoxyl, heterocylic alkyoxyl, cycloalkylthio, heterocylic alkylthio, —C(O)OR 5 , —OC(O)R 5 , —O(CH 2 ) n C(O)OR 5 , —C(O)R 5 , —NHC(O)R 5 , —NR 6 R 7 , —OC(O)NR 6 R 7 and —C(O)NR 6 R 7 .
“Alkoxyl” refers to both an —O-(alkyl) and an —O-(unsubstituted cycloalkyl) group, wherein the alkyl is defined as above. Representative examples include, but are not limited to, methoxy, ethoxy, propoxy, butoxy, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, and the like. The alkoxyl may be optionally substituted or unsubstituted. When substituted, the substituent is preferably one or more groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkyxoyl, alkylsulfo, alkylamino, halogen, thiol, hydroxyl, nitro, cyano, cycloalkyl, heterocyclic alkyl, aryl, heteroaryl, cycloalkyoxyl, heterocylic alkyoxyl, cycloalkylthio, heterocylic alkylthio, —C(O)OR 5 , —OC(O)R 5 , —O(CH 2 ) n C(O)OR 5 , —C(O)R 5 , —NHC(O)R 5 , —NR 6 R 7 , —OC(O)NR 6 R 7 and —C(O)NR 6 R 7 .
“Hydroxy” refers to an —OH group.
“Halogen” refers to a fluoro, chloro, bromo or iodo atom.
“Amino” refers to a —NH 2 group.
“Cyano” refers to a —CN group.
“Nitro” refers to a —NO 2 group.
“Benzyl” refers to a —CH 2 -(phenyl) group.
“Oxo” refers to an ═O group.
“Carboxyl” refers to a —C(O)OH group.
“Alkoxycarbonyl” refers to a —C(O)O(alkyl) or (cycloalkyl) group, wherein the alkyl and cycloalkyl are defined as above.
“Optional” or “optionally” means that the event or circumstance described subsequently may, but not need to occur, and the description includes the instances of the event or circumstance may or may not occur. For example, “the heterocyclic group optionally substituted by an alkyl” means that an alkyl group may be, but not need to be present, and the description includes the case of the heterocyclic group being substituted with an alkyl and the heterocyclic group being not substituted with an alkyl.
“Substituted” refers to one or more hydrogen atoms in the group, preferably up to 5, more preferably 1 to 3 hydrogen atoms independently substituted with a corresponding number of substituents. It goes without saying that the substituents exist in their only possible chemical position. The person skilled in the art is able to determine if the substitution is possible or impossible without paying excessive efforts by experiment or theory. For example, the combination of amino or hydroxyl group having free hydrogen and carbon atoms having unsaturated bonds (such as olefinic) may be unstable.
A “pharmaceutical composition” refers to a mixture of one or more of the compounds described in the present invention or physiologically/pharmaceutically acceptable salts or prodrugs thereof and other chemical components such as physiologically/pharmaceutically acceptable carriers and excipients. The purpose of a pharmaceutical composition is to facilitate administration of a compound to an organism, which is conducive to the absorption of the active ingredient and thus displaying biologically activity.
m, n and R 5 to R 7 are defined as those in the compounds of formula (I).
Synthesis Method of the Compound in the Present Invention
In order to complete the purpose of the invention, the present invention applies the following technical solution:
A preparation method of a compound of formula (I) of the invention or a pharmaceutically acceptable salt thereof, comprising the steps of:
optionally hydrolyzing a compound of formula (IA) to a carboxylic acid, then reacting the carboxylic acid with a compound of formula (IB) or salt thereof in the presence of a condensing reagent such as benzotriazole-N,N,N′,N′-tetramethyl urea hexafluorophosphate under an alkaline condition to obtain the compound of formula (I);
wherein:
R a is selected from the group consisting of hydroxyl, halogen and alkoxyl;
A, B, D, E, G and R 1 to R 4 are defined as those in the formula (I).
The above condensation reaction is carried out between an acid compound and an amine compound in the presence of a condensing agent under basic condition, wherein the condensing agent is selected from the group consisting of N,N′-dicyclohexylcarbodiimide, N,N′-Diisopropylcarbodiimide and O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (TBTU), preferably O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (TBTU); alkaline condition is provided by an organic or inorganic base, wherein the organic base is selected from the group consisting of diisopropyl ethylamine, pyridine, triethylamine, hexahydropyridine, N-methyl-piperazine, 4-dimethylamino pyridine, etc., preferably diisopropyl ethylamine; wherein the solvent used is selected from the group consisting of toluene, benzene, dichloromethane, tetrahydrofuran, chloroform, N,N-dimethyl formamide, or the mixture of the solvents above, preferably N,N-dimethyl formamide; the reaction temperature is controlled between −80° C. and 100° C., preferably between 0° C. and 60° C.; the reaction time is usually controlled between 1 minute and 72 hours, preferably between 15 minutes and 24 hours.
PREFERRED EMBODIMENTS
The following examples serve to illustrate the invention, but the examples should not be considered as limiting the scope of the invention.
EXAMPLES
The compound's structure was indentified by NMR and/or MS. NMR chemical shifts (δ) were given in 10 −6 (ppm). NMR is determined by a Bruker AVANCE-400 machine. The solvents were deuterated-dimethyl sulfoxide (DMSO-d 6 ), deuterated-chloroform (CDCl 3 ) and deuterated-methanol (CD 3 OD) with tetramethylsilane (TMS) as an internal standard.
MS was determined by a FINNIGAN LCQAd (ESI) mass spectrometer (manufacturer: Thermo, type: Finnigan LCQ advantage MAX).
HPLC was determined on an Agilent 1200DAD high pressure liquid chromatography spectrometer (Sunfire C18 150×4.6 mm chromatographic column) and a Waters 2695-2996 high pressure liquid chromatography spectrometer (Gimini C18 150×4.6 mm chromatographic column).
IC 50 was determined by a NovoStar ELIASA (BMG Co., German);
The thin-layer silica gel used Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate. The dimension of the plates used in TLC was 0.15 mm to 0.2 mm, and the dimension of the plates used in thin-layer chromatography for product purification was 0.4 mm to 0.5 mm.
Column chromatography generally used Yantai Huanghai 200 to 300 mesh silica gel as carrier.
The known starting material of the invention can be prepared by the conventional synthesis method in the prior art, or be purchased from ABCR GmbH & Co. KG, Acros Organics, Aldrich Chemical Company, Accela ChemBio Inc or Dari chemical Company, etc.
Unless otherwise stated in the examples, the following reactions were placed under argon atmosphere or nitrogen atmosphere.
The term “argon atmosphere” or “nitrogen atmosphere” refers to that a reaction flask is equipped with a balloon having 1 L of argon or nitrogen.
In hydrogenation reactions, the reaction system was generally vacuumed and filled with hydrogen, and the above operation was repeated for three times.
Microwave reactions were performed with a CEM Discover-S 908860 microwave reactor.
Unless otherwise stated in the examples, the solution used in following reactions refers to an aqueous solution.
Unless otherwise stated in the examples, the reaction temperature in the following reaction was room temperature.
Room temperature was the most proper reaction temperature, which was 20° C. to 30° C.
The reaction process was monitored by thin layer chromatography (TLC), the system of developing solvent included: A: dichloromethane and methanol system, B: n-hexane and ethyl acetate system, C: petroleum ether and ethyl acetate system, D: acetone. The ratio of the volume of the solvent was adjusted according to the polarity of the compounds.
The elution system for purifying the compounds by column chromatography and thin layer chromatography included: A: dichloromethane and methanol system, B: n-hexane and ethyl acetate system, the ratio of the volume of the solvent was adjusted according to the polarity of the compounds, and sometimes a little alkaline reagent such as triethylamine or an acidic reagent such as acetic acid was also can be added.
Example 1
4-[[4-fluoro-3-[3-(trifluoromethyl)-6,8-dihydro-5H-[1,2,4]triazolo[4,3-a]pyrazine-7-carbonyl]phenyl]methyl]-2H-phthalazin-1-one
2-Fluoro-5-[(4-oxo-3H-phthalazin-1-yl)methyl]benzoic acid 1a (150 mg, 0.50 mmol, prepared according to a known method disclosed by “patent application WO2004080976”) was dissolved in 2 mL of N,N-dimethylformamide, followed by addition of O-(1-benzotriazolyl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (284 mg, 0.75 mmol), 3-(trifluoromethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine hydrochloride 1b (138 mg, 0.60 mmol, prepared according to a known method disclosed by “patent application WO2004080958”) and N, N-diisopropylethylamine (0.2 mL, 1 mmol). After stirring for 12 hours, the reaction mixture was concentrated under reduced pressure and the resulting residue was purified by thin layer chromatography with elution system A to obtain 4-[[4-fluoro-3-[3-(trifluoromethyl)-6,8-dihydro-5H-[1,2,4]triazolo[4,3-a]pyrazine-7-carbonyl]phenyl]methyl]-2H-phthalazin-1-one 1 (25 mg, yield 10.6%) as a white solid.
MS m/z (ESI): 473.2 [M+1]
1 H NMR (400 MHz, CDCl 3 ): δ 10.04 (br. s, 1H), 8.48 (d, 1H), 7.80 (m, 3H), 7.55 (m, 1H), 7.40 (m, 1H), 7.15 (m, 1H), 4.29 (s, 2H), 4.23 (m, 2H), 3.74 (m, 2H), 3.20 (m, 2H)
Example 2
4-[[3-(3,4-dihydro-1H-pyrrolo[1,2-a]pyrazine-2-carbonyl)-4-fluoro-phenyl]methyl]-2H-phthalazin-1-one
Step 1
2-pyrrol-1-yl-ethanamine
Pyrrole 2a (12 g, 17.90 mmol) was dissolved in 150 mL of acetonitrile, followed by addition of 2-chloroethylamine hydrochloride (24.60 g, 21.20 mmol), sodium hydroxide (0.50 g, 4 mmol) and tetrabutyl ammonium hydrogen sulfate (2.40 g, 7 mmol). After stirring for 4 hours under reflux condition, the reaction mixture was heated to 50° C. and reacted for 12 hours. The reaction mixture was concentrated under reduced pressure to obtain 2-pyrrol-1-yl-ethanamine 2b (8 g, yield 41.0%) as a light yellow oil.
Step 2
1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine
2-Pyrrol-1-yl-ethanamine 2b (2 g, 18 mmol) was dissolved in 40 mL of ethanol, followed by addition of formaldehyde solution (40%, 1.5 mL, 18 mmol) and a slow dropwise addition of 1 mL of trifluoroacetic acid. The reaction mixture was heated to 50° C. for 15 minutes, then cooled to room temperature and stirred for 12 hours. The reaction mixture was concentrated under reduced pressure, added with 50 mL of ethyl acetate, washed with saturated sodium bicarbonate solution (50 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to obtain 1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine 2c (1.60 g, yield 72.7%) as a light yellow oil.
Step 3
4-[[3-(3,4-dihydro-1H-pyrrolo[1,2-a]pyrazine-2-carbonyl)-4-fluoro-phenyl]methyl]-2H-phthalazin-1-one
2-Fluoro-5-[(4-oxo-3H-phthalazin-1-yl)methyl]benzoic acid 1a (300 mg, 1 mmol) was dissolved in 3 mL of N,N-dimethylformamide, followed by addition of O-(1-benzotriazolyl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (568 mg, 1.50 mmol), 1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine 2c (210 mg, 1.50 mmol) and N, N-diisopropylethylamine (350 μL, 2 mmol). After stirring for 12 hours, the reaction mixture was concentrated under reduced pressure and the resulting residue was purified by thin layer chromatography with elution system A to obtain 4-[[3-(3,4-dihydro-1H-pyrrolo[1,2-a]pyrazine-2-carbonyl)-4-fluoro-phenyl]methyl]-2H-phthalazin-1-one 2 (15 mg, yield 3.7%) as a white solid.
MS m/z (ESI): 403.1 [M+1]
1 H NMR (400 MHz, CDCl 3 ): δ 10.19 (br. s, 1H), 8.51 (d, 1H), 7.82 (m, 3H), 7.41 (m, 2H), 7.13 (m, 1H), 6.65 (m, 1H), 6.24 (m, 1H), 5.81 (m, 1H), 4.97 (s, 1H), 4.59 (s, 1H), 4.33 (s, 2H), 4.13 (m, 1H), 4.00 (m, 1H), 3.71 (m, 1H), 2.85 (m, 1H)
Example 3
methyl 7-[2-fluoro-5-[(4-oxo-3H-phthalazin-1-yl)methyl]benzoyl]-3-(trifluoromethyl)-6,8-dihydro-5H-imidazo[1,5-a]pyrazine-1-carboxylate
Step 1
methyl 3-(trifluoromethyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazine-1-carboxylate
O-7-tert-butyl-O-1-methyl-3-(trifluoromethyl)-6,8-dihydro-5H-imidazo[1,5-a]pyrazine-1,7-dicarboxylate 3a (600 mg, 1.72 mmol, prepared according to a known method disclosed by “patent application WO2009082881”) was dissolved in 20 mL of a solution of hydrogen chloride in 1,4-dioxane (2 M). After stirring for 5 hours, the reaction mixture was concentrated under reduced pressure and added with 50 mL of dichloromethane. Saturated sodium bicarbonate solution was added dropwise to the reaction mixture until the pH is 8. The organic phase was separated, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to obtain crude methyl 3-(trifluoromethyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazine-1-carboxylate 3b (430 mg) as a white solid. The product was used directly in the next reaction without purification.
Step 2
methyl 7-[2-fluoro-5-[(4-oxo-3H-phthalazin-1-yl)methyl]benzoyl]-3-(trifluoromethyl)-6,8-dihydro-5H-imidazo[1,5-a]pyrazine-1-carboxylate
2-Fluoro-5-[(4-oxo-3H-phthalazin-1-yl)methyl]benzoic acid 1a (300 mg, 1 mmol) was dissolved in 2 mL of N,N-dimethylformamide, followed by addition of O-(1-benzotriazolyl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (568 mg, 1.50 mmol), crude methyl 3-(trifluoromethyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazine-1-carboxylate 3b (300 mg, 1.50 mmol) and N, N-diisopropylethylamine (0.4 mL, 2 mmol). After stirring for 12 hours, the reaction mixture was concentrated under reduced pressure and the resulting residue was purified by thin layer chromatography with elution system A to obtain methyl 7-[2-fluoro-5-[(4-oxo-3H-phthalazin-1-yl)methyl]benzoyl]-3-(trifluoromethyl)-6,8-dihydro-5H-imidazo[1,5-a]pyrazine-1-carboxylate 3 (120 mg, yield 23.0%) as a light yellow solid.
MS m/z (ESI): 530.1 [M+1]
1 H NMR (400 MHz, CDCl 3 ): δ 10.48 (br. s, 1H), 8.52 (d, 1H), 7.87 (m, 3H), 7.43 (m, 2H), 7.30 (m, 1H), 5.02 (m, 2H), 4.34 (s, 2h), 4.17 (m, 2H), 3.99 (m, 2H), 3.00 (s, 3H)
Example 4
4-[[3-(6,8-dihydro-5H-imidazo[1,2-a]pyrazine-7-carbonyl)-4-fluoro-phenyl]methyl]-2H-phthalazin-1-one
Step 1
imidazo[1,2-a]pyrazine
Pyrazin-2-amine 4a (5 g, 52 mmol) was dissolved in a 40% 2-chloroacetaldehyde solution (15 mL, 78 mmol), followed by addition of sodium bicarbonate (6.60 g, 78 mmol). After stirring for 48 hours at 100° C., the reaction mixture was cooled to room temperature, added with 100 mL of a saturated potassium carbonate solution, and extracted with dichloromethane (100 mL×3). The organic phase was combined, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to obtain imidazo[1,2-a]pyrazine 4b (3 g, yield 50.0%) as a brown solid.
MS m/z (ESI): 120.1 [M+1]
Step 2
5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine
Imidazo[1,2-a]pyrazine 4b (500 mg, 4.20 mmol) was dissolved in 5 mL of 2-methoxyethanol, followed by addition of platinum dioxide (100 mg, 0.36 mmol), and the reactor was purged with hydrogen for three times. After stirring for 12 hours, the reaction mixture was filtered. The filtrate was concentrated under reduced pressure to obtain 5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine 4c (200 mg, yield 38.7%) as a yellow oil.
MS m/z (ESI): 124.1 [M+1]
Step 3
4-[[3-(6,8-dihydro-5H-imidazo[1,2-a]pyrazine-7-carbonyl)-4-fluoro-phenyl]methyl]-2H-phthalazin-1-one
2-Fluoro-5-[(4-oxo-3H-phthalazin-1-yl)methyl]benzoic acid 1a (323 mg, 1.08 mmol) was dissolved in 5 mL of N,N-dimethylformamide, followed by addition of O-(1-benzotriazolyl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (614 mg, 1.63 mmol), 5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine 4c (200 mg, 1.63 mmol) and N, N-diisopropylethylamine (0.4 mL, 2.16 mmol). After stirring for 12 hours, the reaction mixture was concentrated under reduced pressure and the resulting residue was purified by thin layer chromatography with elution system A to obtain 4-[[3-(6,8-dihydro-5H-imidazo[1,2-a]pyrazine-7-carbonyl)-4-fluoro-phenyl]methyl]-2H-phthalazin-1-one 4 (10 mg, yield 2.3%) as a white solid.
MS m/z (ESI): 404.1 [M+1]
1 H NMR (400 MHz, CDCl 3 ): δ 10.07 (br. s, 1H), 8.53 (d, 1H), 7.96 (m, 1H), 7.83 (m, 3H), 7.51 (m, 1H), 7.30 (m, 2H), 6.01 (t, 1H), 4.73 (d, 2H), 4.35 (s, 2H), 1.60 (m, 2H), 1.34 (m, 2H)
Example 5
4-[[4-fluoro-3-[3-(trifluoromethyl)-6,8-dihydro-5H-imidazo[1,5-a]pyrazine-7-carbonyl]phenyl]methyl]-2H-phthalazin-1-one
2-Fluoro-5-[(4-oxo-3H-phthalazin-1-yl)methyl]benzoic acid 1a (500 mg, 1.68 mmol) was dissolved in 5 mL of N,N-dimethylformamide, followed by addition of O-(1-benzotriazolyl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (955 mg, 2.52 mmol), 3-trifluoromethyl-5,6,7,8-tetraahydroimidazo[1,5-a]pyrazine hydrochloride 5a (457 mg, 2 mmol, prepared according to a known method disclosed by “patent application WO2009082881”) and N, N-diisopropylethylamine (0.6 mL, 3.36 mmol). After stirring for 12 hours, the reaction mixture was concentrated under reduced pressure and the resulting residue was purified by thin layer chromatography with elution system A to obtain 4-[[4-fluoro-3-[3-(trifluoromethyl)-6,8-dihydro-5H-imidazo[1,5-a]pyrazine-7-carbonyl]phenyl]methyl]-2H-phthalazin-1-one 5 (400 mg, yield 50.5%) as a white solid.
MS m/z (ESI): 472.1 [M+1]
1 H NMR (400 MHz, CDCl 3 ): δ 10.81 (br. s, 1H), 8.49 (m, 1H), 7.79 (m, 3H), 7.42 (m, 2H), 7.08 (m, 1H), 5.00 (m, 1H), 4.64 (m, 1H), 4.32 (m, 2H), 4.16 (m, 3H), 3.75 (m, 1H), 3.49 (s, 1H)
Example 6
4-[[4-fluoro-3-[1-(hydroxymethyl)-3-(trifluoromethyl)-6,8-dihydro-5H-imidazo[1,5-a]pyrazine-7-carbonyl]phenyl]methyl]-2H-phthalazin-1-one
Step 1
[3-(trifluoromethyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazin-1-yl]methanol
Methyl 3-(trifluoromethyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazine-1-carboxylate 3b (315 mg, 1.26 mmol) was dissolved in 10 mL of ethanol, followed by addition of sodium borohydride (240 mg, 6.33 mmol). After stirring for 12 hours, the reaction mixture was added dropwise with 2 M hydrochloric acid until no gas was generated in the reaction mixture. The reaction mixture was concentrated under reduced pressure to obtain the crude [3-(trifluoromethyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazin-1-yl]methanol 6a (230 mg) as a white solid. The product was used directly in the next reaction without purification.
Step 2
4-[[4-fluoro-3-[1-(hydroxymethyl)-3-(trifluoromethyl)-6,8-dihydro-5H-imidazo[1,5-a]pyrazine-7-carbonyl]phenyl]methyl]-2H-phthalazin-1-one
2-Fluoro-5-[(4-oxo-3H-phthalazin-1-yl)methyl]benzoic acid 1a (372 mg, 1.25 mmol) was dissolved in 5 mL of N,N-dimethylformamide, followed by addition of N-hydroxybenzotriazole (85 mg, 0.63 mmol), [3-(trifluoromethyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazin-1-yl]methanol 6a (277 mg, 1.25 mmol), 1-ethyl-(3-dimethyl-aminopropyl) carbodiimide hydrochloride (359 mg, 1.88 mmol) and triethylamine (0.3 mL, 2.5 mmol). After stirring for 12 hours, the reaction mixture was concentrated under reduced pressure and the resulting residue was purified by thin layer chromatography with elution system A to obtain 4-[[4-fluoro-3-[1-(hydroxymethyl)-3-(trifluoromethyl)-6,8-dihydro-5H-imidazo[1,5-a]pyrazine-7-carbonyl]phenyl]methyl]-2H-phthalazin-1-one 6 (400 mg, yield 64.0%) as a white solid.
MS m/z (ESI): 502.2 [M+1]
1 H NMR (400 MHz, CDCl 3 ): δ 10.81 (br. s, 1H), 8.47 (s, 1H), 7.83-7.75 (m, 3H), 7.42-7.36 (m, 2H), 7.14-7.12 (m, 1H), 5.31 (s, 1H), 5.04 (s, 1H), 4.69 (d, 1H), 4.50 (s, 1H), 4.32-4.25 (m, 4H), 4.16-4.10 (m, 1H), 2.05 (s, 1H)
Example 7
N-ethyl-7-[2-fluoro-5-[(4-oxo-3H-phthalazin-1-yl)methyl]benzoyl]-3-(trifluoromethyl)-6,8-dihydro-5H-imidazo[1,5-a]pyrazine-1-carboxamide
Step 1
N-ethyl-3-(trifluoromethyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazine-1-carboxamide
Methyl 3-(trifluoromethyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazine-1-carboxylate 3b (1 g, 4 mmol) was dissolved in 40 mL of ethylamine solution (60%). After stirring at 50° C. for 12 hours, the reaction mixture was concentrated under reduced pressure to obtain the crude N-ethyl-3-(trifluoromethyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazine-1-carboxamide 7a (1.15 g) as a white solid. The product was used directly in the next reaction without purification.
MS m/z (ESI): 263.1 [M+1]
Step 2
N-ethyl-7-[2-fluoro-5-[(4-oxo-3H-phthalazin-1-yl)methyl]benzoyl]-3-(trifluoromethyl)-6,8-dihydro-5H-imidazo[1,5-a]pyrazine-1-carboxamide
2-Fluoro-5-[(4-oxo-3H-phthalazin-1-yl)methyl]benzoic acid 1a (250 mg, 0.84 mmol) was dissolved in 20 mL of N,N-dimethylformamide, followed by addition of O-(1-benzotriazolyl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (480 mg, 1.26 mmol), crude N-ethyl-3-(trifluoromethyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazine-1-carboxamide 7a (242 mg, 0.92 mmol) and N, N-diisopropylethylamine (0.3 mL, 1.68 mmol). After stirring for 12 hours, the reaction mixture was added with 50 mL of H 2 O, and extracted with dichloromethane (50 mL×3). The organic phase was combined, concentrated under reduced pressure, added with 100 mL of ethyl acetate, washed successively with saturated sodium bicarbonate solution (40 mL), saturated sodium chloride solution (40 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and the resulting residue was purified by thin layer chromatography with elution system A to obtain N-ethyl-7-[2-fluoro-5-[(4-oxo-3H-phthalazin-1-yl)methyl]benzoyl]-3-(trifluoromethyl)-6,8-dihydro-5H-imidazo[1,5-a]pyrazine-1-carboxamide 7 (200 mg, yield 43.9%) as a white solid.
MS m/z (ESI): 543.2 [M+1]
1 H NMR (400 MHz, CDCl 3 ): δ 11.38 (br. s, 1H), 8.47 (m, 1H), 7.84 (m, 3H), 7.37 (m, 2H), 7.19 (m, 1H), 5.10 (s, 2H), 4.30 (s, 2H), 4.29 (m, 4H), 3.47 (m, 2H), 1.27 (m, 3H)
Example 8
7-[2-fluoro-5-[(4-oxo-3H-phthalazin-1-yl)methyl]benzoyl]-3-(trifluoromethyl)-6,8-dihydro-5H-imidazo[1,5-a]pyrazine-1-carboxylic acid
Methyl 7-[2-fluoro-5-[(4-oxo-3H-phthalazin-1-yl)methyl]benzoyl]-3-(trifluoromethyl)-6,8-dihydro-5H-imidazo[1,5-a]pyrazine-1-carboxylate 3 (30 mg, 0.057 mmol) was dissolved in 1.5 mL of a mixed solvent of tetrahydrofuran, methanol and water (V/V/V=1:1:1), followed by addition of sodium hydroxide (10 mg, 0.25 mmol). After stirring for 12 hours, concentrated hydrochloric acid was added dropwise to the reaction mixture until the pH was 2. The reaction mixture was extracted with dichloromethane (15 mL×2). The organic phase was combined, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and the resulting residue was purified by thin layer chromatography with elution system A to obtain 7-[2-fluoro-5-[(4-oxo-3H-phthalazin-1-yl)methyl]benzoyl]-3-(trifluoromethyl)-6,8-dihydro-5H-imidazo[1,5-a]pyrazine-1-carboxylic acid 8 (10 mg, yield 34.4%) as a light yellow solid.
MS m/z (ESI): 516.5 [M+1]
1 H NMR (400 MHz, CD 3 OD): δ 8.36 (d, 1H), 7.93 (d, 1H), 7.83 (m, 2H), 7.60 (d, 1H), 7.29 (m, 1H), 6.97 (t, 1H), 4.32 (s, 2H), 3.41 (m, 6H)
Example 9
4-[[4-fluoro-3-[1-(methylaminomethyl)-3-(trifluoromethyl)-6,8-dihydro-5H-imidazo[1,5-a]pyrazine-7-carbonyl]phenyl]methyl]-2H-phthalazin-1-one
Step 1
4-[[3-[1-(chloromethyl)-3-(trifluoromethyl)-6,8-dihydro-5H-imidazo[1,5-a]pyrazine-7-carbonyl]-4-fluoro-phenyl]methyl]-2H-phthalazin-1-one
4-[[4-Fluoro-3-[1-(hydroxy methyl)-3-(trifluoromethyl)-6,8-dihydro-5H-imidazo[1, 5-a]pyrazine-7-carbonyl]phenyl]methyl]-2H-phthalazin-1-one 6 (200 mg, 0.40 mmol) was dissolved in 5 mL of thionyl chloride. The reaction mixture was heated to reflux for 4 hours. The reaction mixture was concentrated under reduced pressure, added with 10 mL of H 2 O, extracted with dichloromethane (10 mL×3). The organic phase was combined, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to obtain 4-[[3-[1-(chloromethyl)-3-(trifluoromethyl)-6,8-dihydro-5H-imidazo[1,5-a]pyrazine-7-carbonyl]-4-fluoro-phenyl]methyl]-2H-phthalazin-1-one 9a (200 mg, yield 96.6%) as a yellow solid.
MS m/z (ESI): 520.1 [M+1]
Step 2
4-[[4-fluoro-3-[1-(methylaminomethyl)-3-(trifluoromethyl)-6,8-dihydro-5H-imidazo[1,5-a]pyrazine-7-carbonyl]phenyl]methyl]-2H-phthalazin-1-one
4-[[3-[1-(Chloromethyl)-3-(trifluoromethyl)-6,8-dihydro-5H-imidazo[1,5-a]pyrazine-7-carbonyl]-4-fluoro-phenyl]methyl]-2H-phthalazin-1-one 9a (372 mg, 1.25 mmol) was dissolved in 5 mL of acetonitrile, followed by addition of 0.6 mL of a 2 M solution of methylamine in tetrahydrofuran and potassium carbonate (159 mg, 1.15 mmol). The reaction mixture was heated to reflux for 6 hours. The reaction mixture was filtered. The filtrate was concentrated under reduced pressure and was purified by thin layer chromatography with elution system A to obtain 4-[[4-fluoro-3-[1-(methylaminomethyl)-3-(trifluoromethyl)-6,8-dihydro-5H-imidazo[1,5-a]pyrazine-7-carbonyl]phenyl]methyl]-2H-phthalazin-1-one 9 (20 mg, yield 10.1%) as a yellow solid.
MS m/z (ESI): 515.2 [M+1]
1 H NMR (400 MHz, CDCl 3 ): δ 11.87 (br. s, 1H), 8.35-8.42 (m, 1H), 7.72-7.81 (m, 3H), 7.35-7.43 (m, 1H), 6.96-7.06 (m, 1H), 5.01-5.02 (m, 1H), 3.99-4.28 (m, 6H), 3.71-3.72 (m, 1H), 3.47 (s, 1H), 2.74 (d, 3H), 2.03-2.05 (m, 1H)
Example 10
7-[2-fluoro-5-[(4-oxo-3H-phthalazin-1-yl)methyl]benzoyl]-3-(trifluoromethyl)-6,8-dihydro-5H-imidazo[1,5-a]pyrazine-1-carboxamide
Step 1
3-(trifluoromethyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazine-1-carboxamide
Methyl 3-(trifluoromethyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazine-1-113 carboxylate 3b (250 mg, 1 mmol) and 10 mL of ammonium hydroxide were added in a 20 mL sealed tube. The reaction mixture was heated to 100° C. and reacted for 3 hours. The reaction mixture was concentrated under reduced pressure to obtain crude 3-(trifluoromethyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazine-1-carboxamide 10a (240 mg) as a white solid. The product was used directly in the next reaction without purification.
MS m/z (ESI): 235.1 [M+1]
Step 2
7-[2-fluoro-5-[(4-oxo-3H-phthalazin-1-yl)methyl]benzoyl]-3-(trifluoromethyl)-6,8-dihydro-5H-imidazo[1,5-a]pyrazine-1-carboxamide
2-Fluoro-5-[(4-oxo-3H-phthalazin-1-yl)methyl]benzoic acid 1a (150 mg, 0.50 mmol) was dissolved in 10 mL of N,N-dimethylformamide, followed by addition of O-(1-benzotriazolyl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (285 mg, 0.75 mmol), crude 3-(trifluoromethyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazine-1-carboxamide 10a (130 mg, 0.55 mmol) and N, N-diisopropylethylamine (0.2 mL, 1 mmol). After stirring for 12 hours, the reaction mixture was added with 50 mL of H 2 O and extracted with dichloromethane (60 mL×3). The organic phase was combined, concentrated under reduced pressure, added with 100 mL of ethyl acetate, washed successively with H 2 O (40 mL) and saturated sodium chloride solution (40 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and the resulting residue was purified by thin layer chromatography with elution system A to obtain 7-[2-fluoro-5-[(4-oxo-3H-phthalazin-1-yl)methyl]benzoyl]-3-(trifluoromethyl)-6,8-dihydro-5H-imidazo[1,5-a]pyrazine-1-carboxamide 10 (50 mg, yield 20.0%) as a white solid.
MS m/z (ESI): 515.1 [M+1]
1 H NMR (400 MHz, CDCl 3 ): δ 8.49 (m, 1H), 7.85 (m, 3H), 7.33 (m, 2H), 7.15 (m, 1H), 5.07 (s, 2H), 4.30 (s, 2H), 4.23 (m, 4H)
Example 11
4-[[3-[1-bromo-3-(trifluoromethyl)-6,8-dihydro-5H-imidazo[1,5-a]pyrazine-7-carbonyl]-4-fluoro-phenyl]methyl]-2H-phthalazin-1-one
Step 1
tert-butyl 3-(trifluoromethyl)-6,8-dihydro-5H-imidazo[1,5-a]pyrazine-7-carboxylate
3-(Trifluoromethyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazine hydrochloride 5a (2.20 g, 8.30 mmol) was dissolved in 20 mL of dichloromethane, followed by addition of triethylamine (4.6 mL, 33.20 mmol) and di-tert-butyl dicarbonate (2.70 g, 12.50 mmol). After stirring for 12 hours, the reaction mixture was added with 50 mL of H 2 O, extracted with dichloromethane (50 mL×3). The organic phase was combined, washed successively with saturated ammonium chloride solution (40 mL) and saturated sodium chloride solution (40 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to obtain tert-butyl 3-(trifluoromethyl)-6,8-dihydro-5H-imidazo[1,5-a]pyrazine-7-carboxylate 11a (2.20 g, yield 91.7%) as a light brown solid.
MS m/z (ESI): 292.1 [M+1]
Step 2
tert-butyl 1-bromo-3-(trifluoromethyl)-6,8-dihydro-5H-imidazo[1,5-a]pyrazine-7-carboxylate
Tert-butyl 3-(trifluoromethyl)-6,8-dihydro-5H-imidazo[1,5-a]pyrazine-7-carboxylate 11a (370 mg, 1.27 mmol) was dissolved in 30 mL of tetrahydrofuran, followed by addition of N-bromosuccinimide (453 mg, 2.54 mmol) under −78° C. After stirring for 1 hour, the reaction mixture was heated to room temperature and reacted for 12 hours. The reaction mixture was added with 50 mL of H 2 O, extracted with ethyl acetate (60 mL×3). The organic phase was combined, washed with saturated sodium chloride solution (40 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to obtain crude tert-butyl 1-bromo-3-(trifluoromethyl)-6,8-dihydro-5H-imidazo[1,5-a]pyrazine-7-carboxylate 11b (510 mg) as a light yellow oil. The product was used directly in the next reaction without purification.
MS m/z (ESI): 372.0 [M+1]
Step 3
1-bromo-3-(trifluoromethyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazine hydrochloride
Crude tert-butyl 1-bromo-3-(trifluoromethyl)-6,8-dihydro-5H-imidazo[1,5-a]pyrazine-7-carboxylate 11b (470 mg, 1.27 mmol) was dissolved in 50 mL of a 2 M solution of hydrogen chloride in 1,4-dioxane. After stirring for 4 hours, the reaction mixture was concentrated under reduced pressure to obtain 1-bromo-3-(trifluoromethyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazine hydrochloride 11c (220 mg, yield 56.5%) as a light yellow oil.
Step 4
4-[[3-[1-bromo-3-(trifluoromethyl)-6,8-dihydro-5H-imidazo[1,5-a]pyrazine-7-carbonyl]-4-fluoro-phenyl]methyl]-2H-phthalazin-1-one
2-Fluoro-5-[(4-oxo-3H-phthalazin-1-yl)methyl]benzoic acid 1a (210 mg, 0.70 mmol) was dissolved in 30 mL of N,N-dimethylformamide, followed by addition of O-(1-N,N,N′,N′-tetramethyluronium hexafluorophosphate (360 mg, 0.95 mmol), 1-bromo-3-(trifluoromethyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazine hydrochloride 11c (214 mg, 0.70 mmol) and N, N-diisopropylethylamine (0.4 mL, 2.10 mmol). After stirring for 12 hours, the reaction mixture was added with 50 mL of H 2 O, extracted with dichloromethane (80 mL×3). The organic phase was combined, concentrated under reduced pressure, added with 100 mL of ethyl acetate, washed successively with saturated sodium carbonate solution (40 mL), H 2 O (40 mL) and saturated sodium chloride solution (40 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and the resulting residue was purified by thin layer chromatography with elution system A to obtain 4-[[3-[1-bromo-3-(trifluoromethyl)-6,8-dihydro-5H-imidazo[1,5-a]pyrazine-7-carbonyl]-4-fluoro-phenyl]methyl]-2H-phthalazin-1-one 11 (185 mg, yield 48.0%) as a white solid.
MS m/z (ESI): 552.0 [M+1]
1 H NMR (400 MHz, CDCl 3 ): δ 8.48 (m, 1H), 7.73 (m, 3H), 7.31 (m, 2H), 7.11 (m, 1H), 4.89 (s, 2H), 4.49 (s, 2H), 4.48 (m, 4H)
Example 12
4-[[4-fluoro-3-[2-(trifluoromethyl)-6,8-dihydro-5H-imidazo[1,2-a]pyrazine-7-carbonyl]phenyl]methyl]-2H-phthalazin-1-one
Step 1
2-(trifluoromethyl)imidazo[1,2-a]pyrazine
Pyrazin-2-amine 4a (5.25 g, 55.20 mmol) was dissolved in 120 mL of ethanol, followed by addition of 3-bromo-1,1,1-trifluoro-propan-2-one 12a (5.7 mL, 55.20 mmol). The reaction mixture was heated to reflux for 16 hours. The reaction mixture was concentrated under reduced pressure, added with 100 mL of ethyl acetate and 100 mL of saturated sodium bicarbonate solution and separated. The aqueous phase was extracted with ethyl acetate (50 mL×3). The organic phase was combined, washed with saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and the resulting residue was purified by silica gel column chromatography with elution system B to obtain 2-(trifluoromethyl)imidazo[1,2-a]pyrazine 12b (2.40 g, yield 22.8%) as a yellow solid.
MS m/z (ESI): 188.0 [M+1]
Step 2
2-(trifluoromethyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine
2-(Trifluoromethyl)imidazo[1,2-a]pyrazine 12b (2.40 g, 12.55 mmol) was dissolved in 100 mL of methanol, followed by addition of Pd—C (10%, 480 mg), and the reactor was purged with hydrogen for three times. After stirring for 12 hours, the reaction mixture was filtered and the filter cake was washed with methanol. The filtrate was concentrated under reduced pressure to obtain 2-(trifluoromethyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine 12c (2.30 g, yield 95.8%) as a yellow oil.
Step 3
4-[[4-fluoro-3-[2-(trifluoromethyl)-6,8-dihydro-5H-imidazo[1,2-a]pyrazine-7-carbonyl]phenyl]methyl]-2H-phthalazin-1-one
2-Fluoro-5-[(4-oxo-3H-phthalazin-1-yl)methyl]benzoic acid 1a (500 mg, 1.68 mmol) was dissolved in 10 mL of N,N-dimethylformamide, followed by addition of O-(1-benzotriazolyl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (830 mg, 2.52 mmol), 2-(trifluoromethyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine 12c (384 mg, 2 mmol) and N, N-diisopropylethylamine (1 mL, 5 mmol). After stirring for 12 hours, the resulting residue was purified by silica gel column chromatography with elution system A to obtain 4-[[4-fluoro-3-[2-(trifluoromethyl)-6,8-dihydro-5H-imidazo[1,2-a]pyrazine-7-carbonyl]phenyl]methyl]-2H-phthalazin-1-one 12 (200 mg, yield 25.0%) as a white solid.
MS m/z (ESI): 472.1[M+1]
1 H NMR (400 MHz, CDCl 3 ): δ 10.29 (br. s, 1H), 8.47 (m, 1H), 7.80 (m, 3H), 7.37 (m, 2H), 7.25 (m, 1H), 6.50 (m, 1H), 4.67 (s, 2H), 4.28 (m, 2H), 4.14 (m, 2H), 3.73 (m, 2H)
Example 13
7-[2-fluoro-5-[(4-oxo-3H-phthalazin-1-yl)methyl]benzoyl]-N-methyl-3-(trifluoromethyl)-6,8-dihydro-5H-imidazo[1,5-a]pyrazine-1-carboxamide
Step 1
N-methyl-3-(trifluoromethyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazine-1-carboxamide
Methyl 3-(trifluoromethyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazine-1-carboxylate 3b (500 mg, 2 mmol) was dissolved in 8 mL of methylamine solution (20% to 30%) was added in a 20 mL sealed tube. After stirring at 60° C. for 6 hours, the reaction mixture was concentrated under reduced pressure to obtain the crude N-methyl-3-(trifluoromethyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazine-1-carboxamide 13a (498 mg) as a white solid. The product was used directly in the next reaction without purification.
MS m/z (ESI): 249.1 [M+1]
Step 2
7-[2-fluoro-5-[(4-oxo-3H-phthalazin-1-yl)methyl]benzoyl]-N-methyl-3-(trifluoromethyl)-6,8-dihydro-5H-imidazo[1,5-a]pyrazine-1-carboxamide
2-Fluoro-5-[(4-oxo-3H-phthalazin-1-yl)methyl]benzoic acid 1a (598 mg, 2 mmol) was dissolved in 10 mL of N,N-dimethylformamide, followed by addition of 1-hydroxybenzotriazole (135 mg, 1 mmol), crude N-methyl-3-(trifluoromethyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazine-1-carboxamide 13a (498 mg, 2 mmol), 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride (573 mg, 3 mmol) and N, N-diisopropylethylamine (774 mg, 6 mmol). After stirring for 12 hours, the reaction mixture was concentrated under reduced pressure, added with 30 mL of H 2 O, extracted with ethyl acetate (50 mL×3). The organic phase was combined, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and the resulting residue was purified by thin layer chromatography with elution system A to obtain 7-[2-fluoro-5-[(4-oxo-3H-phthalazin-1-yl)methyl]benzoyl]-N-methyl-3-(trifluoromethyl)-6,8-dihydro-5H-imidazo[1,5-a]pyrazine-1-carboxamide 13 (650 mg, yield 61.0%) as a white solid.
MS m/z (ESI): 529.1 [M+1]
1 H NMR (400 MHz, CD 3 OD): δ 8.36-8.34 (t, 1H), 7.96-7.94 (d, 1H), 7.86-7.81 (m, 2H), 7.50-7.45 (m, 2H), 7.22-7.15 (dd, 1H), 5.23 (s, 1H), 4.95 (s, 1H), 4.39 (d, 2H), 4.32 (d, 1H), 4.21 (s, 1H), 4.14 (s, 1H), 3.76 (s, 1H), 2.85 (d, 3H)
Example 14
ethyl 7-[2-fluoro-5-[(4-oxo-3H-phthalazin-1-yl)methyl]benzoyl]-6,8-dihydro-5H-imidazo[1,2-a]pyrazine-3-carboxylate
Step 1
ethyl imidazo[1,2-a]pyrazine-3-carboxylate
Pyrazin-2-amine 4a (1 g, 10 mmol) was dissolved in 50 mL of ethylene glycol dimethyl ether, followed by addition of 50 mL of methanol and 3-bromo-2-oxo-propionate (2.30 g, 12 mmol). After stirring for 4 hours at room temperature, the reaction mixture was cooled to 0° C. and stirred for 30 minutes until a solid precipitated. The reaction mixture was filtered, and the filter cake was washed with ether (10 mL×3). The solid was dissolved in 50 mL of anhydrous ethanol and the solution was refluxed for 4 hours. The reaction mixture was concentrated under reduced pressure, added with 100 mL of dichloromethane, washed successively with saturated sodium carbonate solution (40 mL) and saturated sodium chloride solution (40 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to obtain ethyl imidazo[1,2-a]pyrazine-3-carboxylate 14a (0.55 g, yield 28.9%) as a brown solid.
MS m/z (ESI): 192.1 [M+1]
Step 2
ethyl 5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine-3-carboxylate
Ethyl imidazo[1,2-a]pyrazine-3-carboxylate 14a (550 mg, 2.76 mmol) was dissolved in 30 mL of methanol, followed by addition of Pd—C (10%, 100 mg), and the reactor was purged with hydrogen for three times. After stirring for 3 hours, the reaction mixture was filtered and the filtrate was concentrated under reduced pressure to obtain ethyl 5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine-3-carboxylate 14b (480 mg, yield 87.6%) as a yellow oil.
MS m/z (ESI): 196.1 [M+1]
Step 3
ethyl 7-[2-fluoro-5-[(4-oxo-3H-phthalazin-1-yl)methyl]benzoyl]-6,8-dihydro-5H-imidazo[1,2-a]pyrazine-3-carboxylate
2-Fluoro-5-[(4-oxo-3H-phthalazin-1-yl)methyl]benzoic acid 1a (300 mg, 1 mmol) was dissolved in 20 mL of N,N-dimethylformamide, followed by addition of O-(1-benzotriazolyl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (570 mg, 1.50 mmol), ethyl 5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine-3-carboxylate 14b (200 mg, 1 mmol) and N, N-diisopropylethylamine (0.3 mL, 2 mmol). After stirring for 12 hours, the reaction mixture was added with 50 mL of H 2 O, extracted with dichloromethane (80 mL×3). The organic phase was combined, concentrated under reduced pressure, added with 100 mL of ethyl acetate, washed successively with saturated sodium carbonate solution (40 mL), H 2 O (40 mL), saturated sodium chloride solution (40 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and the resulting residue was purified by thin layer chromatography with elution system A to obtain ethyl 7-[2-fluoro-5-[(4-oxo-3H-phthalazin-1-yl)methyl]benzoyl]-6,8-dihydro-5H-imidazo[1,2-a]pyrazine-3-carboxylate 14 (280 mg, yield 58.6%) as a white solid.
MS m/z (ESI): 476.1 [M+1]
1 H NMR (400 MHz, CDCl 3 ): δ 10.53 (br. s, 1H), 8.46 (m, 1H), 7.76 (m, 3H), 7.59 (s, 1H), 7.36 (m, 2H), 7.08 (m, 1H), 4.69 (s, 2H), 4.37 (m, 2H), 4.31 (s, 2H), 4.27 (m, 4H), 1.26 (t, 3H)
Example 15
4-[[3-[3-(trifluoromethyl)-6,8-dihydro-5H-[1,2,4]triazolo[4,3-a]pyrazine-7-carbonyl]phenyl]methyl]-2H-phthalazin-1-one
3-[(4-Oxo-3H-phthalazin-1-yl)methyl]benzoic acid 15a (300 mg, 1.07 mmol, prepared according to a known method disclosed by “patent application WO2004080976”) was dissolved in 10 mL of N,N-dimethylformamide, followed by addition of O-(1-benzotriazolyl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (730 mg, 1.93 mmol), 3-(trifluoromethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine hydrochloride 1b (269 mg, 1.40 mmol) and N, N-diisopropylethylamine (0.9 mL, 5.30 mmol). After stirring for 12 hours, the reaction mixture was added with 15 mL of H 2 O, extracted with ethyl acetate (20 mL×3). The organic phase was combined, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and the resulting residue was purified by thin layer chromatography with elution system A to obtain 4-[[3-[3-(trifluoromethyl)-6,8-dihydro-5H-[1,2,4]triazolo[4,3-a]pyrazine-7-carbonyl]phenyl]methyl]-2H-phthalazin-1-one 15 (100 mg, yield 20.6%) as a white solid.
MS m/z (ESI): 455.1 [M+1]
1 H NMR (400 MHz, CDCl 3 ): δ 10.30 (br. s, 1H), 8.49 (d, 1H), 8.02 (m, 1H), 7.78 (m, 3H), 7.43 (m, 3H), 5.31 (s, 2H), 4.35 (s, 2H), 4.21 (m, 2H), 4.12 (m, 2H)
Example 16
4-[[3-(6,8-dihydro-5H-[1,2,4]triazolo[1,5-a]pyrazine-7-carbonyl)-4-fluoro-phenyl]methyl]-2H-phthalazin-1-one
2-Fluoro-5-[(4-oxo-3H-phthalazin-1-yl)methyl]benzoic acid 1a (360 mg, 1.20 mmol) was dissolved in 10 mL of N,N-dimethylformamide, followed by addition of O-(1-benzotriazolyl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (600 mg, 1.80 mmol), 5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyrazine 16a (150 mg, 1.20 mmol, prepared according to a known method disclosed by “patent application WO2009090055”) and N, N-diisopropylethylamine (0.4 mL, 2.40 mmol). After stirring for 20 hours, the reaction mixture was concentrated under reduced pressure and the resulting residue was purified by thin layer chromatography with elution system A to obtain 4-[[3-(6,8-dihydro-5H-[1,2,4]triazolo[1,5-c]pyrazine-7-carbonyl)-4-fluoro-phenyl]methyl]-2H-phthalazin-1-one 16 (100 mg, yield 21.0%) as a yellow solid.
MS m/z (ESI): 405.1 [M+1]
1 H NMR (400 MHz, CDCl 3 ): δ 10.47 (br. s, 1H), 8.51-8.49 (m, 1H), 7.99-1.77 (m, 4H), 7.42-7.30 (m, 2H), 7.30-7.12 (m, 1H), 4.76 (m, 2H), 4.37-4.28 (m, 4H), 3.77-3.73 (m, 2H)
Example 17
4-[[3-(6,8-dihydro-5H-[1,2,4]triazolo[4,3-a]pyrazine-7-carbonyl)-4-fluoro-phenyl]methyl]-2H-phthalazin-1-one
2-Fluoro-5-[(4-oxo-3H-phthalazin-1-yl)methyl]benzoic acid 1a (170 mg, 0.57 mmol) was dissolved in 10 mL of N,N-dimethylformamide, followed by addition of O-(1-N,N,N′,N′-tetramethyluronium hexafluorophosphate (323 mg, 0.85 mmol), 5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine hydrochloride 17a (100 mg, 0.63 mmol, prepared according to a known method “Journal of Medicinal Chemistry, 2005, 48(1), 141-151”) and N, N-diisopropylethylamine (302 mg, 1.70 mmol). After stirring for 12 hours, the reaction mixture was concentrated under reduced pressure and the resulting residue was purified by thin layer chromatography with elution system A to obtain 4-[[3-(6,8-dihydro-5H-[1,2,4]triazolo[4,3-a]pyrazine-7-carbonyl)-4-fluoro-phenyl]methyl]-2H-phthalazin-1-one 17 (50 mg, yield 21.7%) as a light yellow solid.
MS m/z (ESI): 405.1 [M+1]
1 H NMR (400 MHz, CDCl 3 ): δ 10.87 (br. s, 1H), 8.46-8.45 (m, 1H), 8.18 (s, 1H), 7.80-7.76 (m, 3H), 7.40-7.38 (m, 2H), 7.12-7.07 (m, 1H), 4.79 (m, 2H), 4.31-4.20 (m, 4H), 3.75-3.62 (m, 2H)
Example 18
4-[[4-fluoro-3-[1-(pyrrolidine-1-carbonyl)-3-(trifluoromethyl)-6,8-dihydro-5H-imidazo[1,5-a]pyrazine-7-carbonyl]phenyl]methyl]-2H-phthalazin-1-one
Step 1
pyrrolidin-1-yl-[3-(trifluoromethyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazin-1-yl]methanone
Pyrrolidine (560 mg, 8 mmol), methyl 3-(trifluoromethyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazine-1-carboxylate 3b (400 mg, 1.60 mmol) and 0.4 mL of H 2 O were mixed in a sealed tube. After stirring at 50° C. for 4 hours, the reaction mixture was concentrated under reduced pressure to obtain crude pyrrolidin-1-yl-[3-(trifluoromethyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazin-1-yl]methanone 18a (460 mg) as a light yellow solid. The product was used directly in the next reaction without purification.
MS m/z (ESI): 289.1 [M+1]
Step 2
4-[[4-fluoro-3-[1-(pyrrolidine-1-carbonyl)-3-(trifluoromethyl)-6,8-dihydro-5H-imidazo[1,5-a]pyrazine-7-carbonyl]phenyl]methyl]-2H-phthalazin-1-one
2-Fluoro-5-[(4-oxo-3H-phthalazin-1-yl)methyl]benzoic acid 1a (417 mg, 1.40 mmol) was dissolved in 5 mL of N,N-dimethylformamide, followed by addition of O-(1-N,N,N′,N′-tetramethyluronium hexafluorophosphate (1 g, 2.80 mmol), crude pyrrolidin-1-yl-[3-(trifluoromethyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazin-1-yl]methanone 18a (400 mg, 1.40 mmol) and N, N-diisopropylethylamine (0.7 mL, 4.20 mmol). After stirring for 12 hours, the reaction mixture was concentrated under reduced pressure, added with 20 mL of H 2 O, extracted with ethyl acetate (10 mL×3). The organic phase was combined, washed with saturated sodium chloride solution (10 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and the resulting residue was purified by thin layer chromatography with elution system A to obtain 4-[[4-fluoro-3-[1-(pyrrolidine-1-carbonyl)-3-(trifluoromethyl)-6,8-dihydro-5H-imidazo[1,5-a]pyrazine-7-carbonyl]phenyl]methyl]-2H-phthalazin-1-one 18 (150 mg, yield 18.0%) as a light yellow solid.
MS m/z (ESI): 569.2 [M+1]
1 H NMR (400 MHz, DMSO-d 6 ): δ 12.57 (br. s, 1H), 8.26 (d, 1H), 7.83-7.93 (m, 3H), 7.46-7.50 (m, 2H), 7.26-7.31 (m, 1H), 5.07 (s, 1H), 4.84 (s, 1H), 4.27-4.34 (m, 2H), 4.26-4.27 (m, 1H), 4.07-4.17 (m, 2H), 3.89-3.92 (m, 2H), 3.66-3.68 (m, 1H), 3.48-3.49 (m, 1H), 3.36-3.38 (m, 1H), 1.76-1.91 (m, 4H)
Example 19
4-[[4-fluoro-3-[2-(trifluoromethyl)-6,8-dihydro-5H-[1,2,4]triazolo[1,5-a]pyrazine-7-carbonyl]phenyl]methyl]-2H-phthalazin-1-one
2-Fluoro-5-[(4-oxo-3H-phthalazin-1-yl)methyl]benzoic acid 1a (780 mg, 2.65 mmol) was dissolved in 15 mL of N,N-dimethylformamide, followed by addition of 0-(1-benzotriazolyl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (1.80 g, 4.77 mmol), 2-(trifluoromethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyrazine 19a (560 mg, 2.92 mmol, prepared according to a known method disclosed by “patent application WO2009025784”) and N, N-diisopropylethylamine (1.4 mL, 7.95 mmol). After stirring for 12 hours, the reaction mixture was concentrated under reduced pressure, added with 30 mL of H 2 O, extracted with ethyl acetate (30 mL×3). The organic phase was combined, washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and the resulting residue was purified by thin layer chromatography with elution system A to obtain 4-[[4-fluoro-3-[2-(trifluoromethyl)-6,8-dihydro-5H-[1,2,4]triazolo[1,5-a]pyrazine-7-carbonyl]phenyl]methyl]-2H-phthalazin-1-one 19 (205 mg, yield 16.4%) as a light yellow solid.
MS m/z (ESI): 473.1 [M+1]
1 H NMR (400 MHz, CDCl 3 ): δ 10.67 (br. s, 1H), 8.48 (s, 1H), 7.77 (m, 3H), 7.42 (m, 2H), 7.11 (t, 1H), 5.10 (s, 1H), 4.75 (s, 1H), 4.39 (s, 2H), 4.32 (d, 3H), 3.88 (s, 1H)
Example 20
4-[[4-fluoro-3-[1-(morpholine-4-carbonyl)-3-(trifluoromethyl)-6,8-dihydro-5H-imidazo[1,5-a]pyrazine-7-carbonyl]phenyl]methyl]-2H-phthalazin-1-one
Step 1
7-tert-butoxy carbonyl-3-(trifluoromethyl)-6,8-dihydro-5H-imidazo[1,5-a]pyrazine-1-carboxylic acid
O-7-tert-butyl-O-1-methyl-3-(trifluoromethyl)-6,8-dihydro-5H-imidazo[1,5-a]pyrazine-1,7-dicarboxylate 3a (4.10 g, 12 mmol) was dissolved in a mixed solvent of 15 mL of tetrahydrofuran and methanol (V/V=2:1), followed by addition of 20 mL of a 2 M sodium hydroxide solution. After stirring for 12 hours, the reaction mixture was concentrated under reduced pressure, and 1 M hydrochloric acid was added dropwise with until the pH of the reaction mixture was between 5 and 7. The reaction mixture was filtered and the filter cake was dried in vacuum to obtain 7-tert-butoxycarbonyl-3-(trifluoromethyl)-6,8-dihydro-5H-imidazo[1,5-a]pyrazine-1-carboxylic acid 20a (2 g, yield 50.0%) as a light yellow solid.
MS m/z (ESI): 334.1 [M+1]
Step 2
tert-butyl 1-(morpholine-4-carbonyl)-3-(trifluoromethyl)-6,8-dihydro-5H-imidazo[1,5-a]pyrazine-7-carboxylate
7-Tert-butoxycarbonyl-3-(trifluoromethyl)-6,8-dihydro-5H-imidazo[1,5-a]pyrazine-1-carboxylic acid 20a (330 mg, 1 mmol) was dissolved in 5 mL of N, N-dimethylformamide, followed by addition of O-(1-benzotriazolyl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (756 mg, 2 mmol), morpholine (174 mg, 2 mmol) and N, N-diisopropylethylamine (0.5 mL, 3 mmol). After stirring for 12 hours, the reaction mixture was concentrated under reduced pressure, added with 20 mL of saturated ammonium chloride solution, extracted with dichloromethane (20 mL×3). The organic phase was combined, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and the resulting residue was purified by thin layer chromatography with elution system A to obtain tert-butyl 1-(morpholine-4-carbonyl)-3-(trifluoromethyl)-6,8-dihydro-5H-imidazo[1,5-a]pyrazine-7-carboxylate 20b (400 mg, yield 100.0%) as a yellow solid.
MS m/z (ESI): 405.1 [M−1]
Step 3
morpholino-[3-(trifluoromethyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazin-1-yl]methanone hydrochloride
Tert-butyl 1-(morpholine-4-carbonyl)-3-(trifluoromethyl)-6,8-dihydro-5H-imidazo[1,5-a]pyrazine-7-carboxylate 20b (470 mg, 1.27 mmol) was dissolved in 20 mL of a 2 M solution of hydrogen chloride in 1,4-dioxane. After stirring for 12 hours, the reaction mixture was concentrated under reduced pressure to obtain crude morpholino-[3-(trifluoromethyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazin-1-yl]methanone hydrochloride 20c (300 mg) as a light yellow oil. The product was used directly in the next reaction without purification.
Step 4
morpholino-[3-(trifluoromethyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazin-1-yl]methanone
Crude morpholino-[3-(trifluoromethyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazin-1-yl]methanone hydrochloride 20c (330 mg, 1 mmol) was dissolved in 10 mL of ethyl acetate, followed by addition of potassium carbonate (10 g, 72 mmol). After stirring for 4 hours, the reaction mixture was filtered and the filtrate was concentrated under reduced pressure to obtain crude morpholino-[3-(trifluoromethyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazin-1-yl]methanone 20d (300 mg) as a light yellow solid. The product was used directly in the next reaction without purification.
Step 5
4-[[4-fluoro-3-[1-(morpholine-4-carbonyl)-3-(trifluoromethyl)-6,8-dihydro-5H-imidazo[1,5-a]pyrazine-7-carbonyl]phenyl]methyl]-2H-phthalazin-1-one
2-Fluoro-5-[(4-oxo-3H-phthalazin-1-yl)methyl]benzoic acid 1a (390 mg, 1.30 mmol) was dissolved in 10 mL of N,N-dimethylformamide, followed by addition of O-(1-benzotriazolyl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (983 mg, 2.60 mmol), crude morpholino-[3-(trifluoromethyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazin-1-yl]methanone 20d (400 mg, 1.30 mmol) and N, N-diisopropylethylamine (0.7 mL, 3.90 mmol). After stirring for 12 hours, the reaction mixture was concentrated under reduced pressure and the resulting residue was purified by thin layer chromatography with elution system A to obtain 4-[[4-fluoro-3-[1-(morpholine-4-carbonyl)-3-(trifluoromethyl)-6,8-dihydro-5H-imidazo[1,5-a]pyrazine-7-carbonyl]phenyl]methyl]-2H-phthalazin-1-one 20 (150 mg, yield 20.0%) as a light yellow solid.
MS m/z (ESI): 585.2 [M+1]
1 H NMR (400 MHz, DMSO-d 6 ): δ 12.58 (br. s, 1H), 8.27 (d, 1H), 7.83-7.98 (m, 3H), 7.48-7.50 (m, 2H), 7.27-7.32 (m, 1H), 5.07 (s, 1H), 4.82 (s, 1H), 4.27-4.35 (m, 2H), 4.26-4.27 (m, 1H), 4.07-4.12 (m, 3H), 3.59-3.66 (m, 6H), 3.17-3.18 (m, 2H)
Example 21
N-methyl-7-[3-[(4-oxo-3H-phthalazin-1-yl)methyl]benzoyl]-3-(trifluoromethyl)-6,8-dihydro-5H-imidazo[1,5-a]pyrazine-1-carboxamide
3-[(4-Oxo-3H-phthalazin-1-yl)methyl]benzoic acid 15a (186 mg, 0.67 mmol) was dissolved in 20 mL of N,N-dimethylformamide, followed by addition of 1-hydroxybenzotriazole (98 mg, 0.73 mmol), crude N-methyl-3-(trifluoromethyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazine-1-carboxamide 13a (150 mg, 0.61 mmol), 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride (173 mg, 0.91 mmol) and triethylamine (253 μL, 1.82 mmol). After stirring for 12 hours, the reaction mixture was was concentrated under reduced pressure, added with 50 mL of H 2 O and extracted with ethyl acetate (50 mL×3). The organic phase was combined, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and the resulting residue was purified by thin layer chromatography with elution system A to obtain N-methyl-7-[3-[(4-oxo-3H-phthalazin-1-yl)methyl]benzoyl]-3-(trifluoromethyl)-6,8-dihydro-5H-imidazo[1,5-a]pyrazine-1-carboxamide 21 (280 mg, yield 90.0%) as a light yellow solid.
MS m/z (ESI): 511.2 [M+1]
1 H NMR (400 MHz, CDCl 3 ): δ 11.80 (br. s, 1H), 8.49 (d, 1H), 7.89 (m, 2H), 7.79 (t, 1H), 7.52 (m, 2H), 7.43 (m, 2H), 5.26 (s, 2H), 4.35 (s, 2H), 4.22 (m, 4H), 3.01 (m, 3H)
Example 22
7-[2-fluoro-5-[(4-oxo-3H-phthalazin-1-yl)methyl]benzoyl]-N,N-dimethyl-3-(trifluoromethyl)-6,8-dihydro-5H-imidazo[1,5-a]pyrazine-1-carboxamide
Step 1
tert-butyl 1-(dimethylcarbamoyl)-3-(trifluoromethyl)-6,8-dihydro-5H-imidazo[1,5-a]pyrazine-7-carboxylate
7-Tert-butoxycarbonyl-3-(trifluoromethyl)-6,8-dihydro-5H-imidazo[1,5-a]pyrazine-1-carboxylic acid 20a (330 mg, 1 mmol) was dissolved in 5 mL of N, N-dimethylformamide, followed by addition of 0-(1-benzotriazolyl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (756 mg, 2 mmol), dimethylamine hydrochloride (156 mg, 2 mmol) and N, N-diisopropylethylamine (387 mg, 3 mmol). After stirring for 12 hours, the reaction mixture was concentrated under reduced pressure, added with 50 mL of ethyl acetate, and washed successively with saturated ammonium chloride solution (30 mL) and saturated sodium chloride solution (20 mL×3). The organic phase was combined, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to obtain crude tert-butyl 1-(dimethylcarbamoyl)-3-(trifluoromethyl)-6,8-dihydro-5H-imidazo[1,5-a]pyrazine-7-carboxylate 22a (362 mg) as a light yellow solid. The product was used directly in the next reaction without purification.
MS m/z (ESI): 363.1 [M+1]
Step 2
N,N-dimethyl-3-(trifluoromethyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazine-1-carboxamide hydrochloride
Crude tert-butyl 1-(dimethylcarbamoyl)-3-(trifluoromethyl)-6,8-dihydro-5H-imidazo[1,5-a]pyrazine-7-carboxylate 22a (362 mg, 1 mmol) was dissolved in 3 mL of a 2 M solution of hydrogen chloride in 1,4-dioxane. After stirring for 12 hours, the reaction mixture was concentrated under reduced pressure to obtain crude N,N-dimethyl-3-(trifluoromethyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazine-1-carboxamide hydrochloride 22b (262 mg) as a light yellow solid. The product was used directly in the next reaction without purification.
Step 3
N,N-dimethyl-3-(trifluoromethyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazine-1-carboxamide
N,N-dimethyl-3-(trifluoromethyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazine-1-carboxamide hydrochloride 22b (234 mg, 0.80 mmol) was dissolved in 10 mL of ethyl acetate, followed by addition of potassium carbonate (10 g, 72 mmol). After stirring for 4 hours, the reaction mixture was filtered and the filtrate was concentrated under reduced pressure to obtain crude N,N-dimethyl-3-(trifluoromethyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazine-1-carboxamide 22c (200 mg) as a light yellow solid. The product was used directly in the next reaction without purification.
Step 4
7-[2-fluoro-5-[(4-oxo-3H-phthalazin-1-yl)methyl]benzoyl]-N,N-dimethyl-3-(trifluoromethyl)-6,8-dihydro-5H-imidazo[1,5-a]pyrazine-1-carboxamide
2-Fluoro-5-[(4-oxo-3H-phthalazin-1-yl)methyl]benzoic acid 1a (300 mg, 1 mmol) was dissolved in 5 mL of N,N-dimethylformamide, followed by addition of O-(1-benzotriazolyl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (756 mg, 2 mmol), N,N-dimethyl-3-(trifluoromethyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazine-1-carboxamide 22c (200 mg, 0.80 mmol) and N, N-diisopropylethylamine (0.5 mL, 3 mmol). After stirring for 12 hours, the reaction mixture was concentrated under reduced pressure and the resulting residue was purified by thin layer chromatography with elution system A to obtain 7-[2-fluoro-5-[(4-oxo-3H-phthalazin-1-yl)methyl]benzoyl]-N,N-dimethyl-3-(trifluoromethyl)-6,8-dihydro-5H-imidazo[1,5-a]pyrazine-1-carboxamide 22 (45 mg, yield 11.0%) as a light yellow solid.
MS m/z (ESI): 543.1 [M+1]
1 H NMR (400 MHz, DMSO-d 6 ): δ 12.58 (br. s, 1H), 8.27 (d, 1H), 7.83-7.96 (m, 3H), 7.49-7.51 (m, 2H), 7.27-7.31 (m, 1H), 4.80 (s, 1H), 4.35 (s, 2H), 4.26-4.27 (m, 1H), 4.05-4.07 (m, 1H), 3.66-3.67 (m, 1H), 3.30-3.39 (m, 6H), 2.88-2.97 (m, 2H)
Example 23
4-[[3-[3-(difluoromethyl)-6,8-dihydro-5H-[1,2,4]triazolo[4,3-a]pyrazine-7-carbonyl]-4-fluoro-phenyl]methyl]-2H-phthalazin-1-one
Step 1
2,2-difluoro-N′-pyrazin-2-yl-acetohydrazide difluoroacetate
Pyrazin-2-yl-hydrazine 23a (1 g, 9 mmol) was added in an eggplant-shaped bottle (25 mL), followed by dropwise addition of difluoroacetic anhydride (4 g, 22.98 mmol) at 0° C. After stirring at room temperature for 3 hours, the reaction mixture was concentrated under reduced pressure to obtain crude 2,2-difluoro-N′-pyrazin-2-yl-acetohydrazide difluoroacetate 23b (2 g) as a brown oil. The product was used directly in the next reaction without purification.
Step 2
3-(difluoromethyl)-[1,2,4]triazolo[4,3-a]pyrazine
2,2-Difluoro-N′-pyrazin-2-yl-acetohydrazide difluoroacetate 23b (2 g, 0.01 mol) was dissolved in 10 mL of polyphosphoric acid. After stirring at 140° C. for 7 hours, the reaction mixture was cooled to 50° C. and stirred for another 12 hours. The reaction mixture was poured into 50 mL of ice-water while hot, 30% aqueous ammonia was added dropwise until the pH of the reaction mixture was between 7 and 8, and the solution was extracted with ethyl acetate (30 mL×3). The organic phase was combined, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The resulting residue was dissolved in 30 mL of ethyl acetate and added with activated carbon. After stirring for 30 minutes, the mixture was filtered and the filtrate was concentrated under reduced pressure to obtain 3-(difluoromethyl)-[1,2,4]triazolo[4,3-a]pyrazine 23c (460 mg, yield 30%) as a yellow solid.
MS m/z (ESI): 171 [M+1]
Step 3
3-(difluoromethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine
3-(Difluoromethyl)-[1,2,4]triazolo[4,3-a]pyrazine 23c (460 mg, 2.70 mmol) was dissolved in 10 mL of methanol, followed by addition of Pd—C (10%, 46 mg), and the reactor was purged with hydrogen for three times. After stirring for 3 hours, the reaction mixture was filtered and the filter cake was washed with methanol (10 mL). The filtrate was concentrated under reduced pressure to obtain crude 3-(difluoromethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine 23d (400 mg) as a light yellow oil. The product was used directly in the next reaction without purification.
MS m/z (ESI): 175.0 [M+1]
Step 4
4-[[3-[3-(difluoromethyl)-6,8-dihydro-5H-[1,2,4]triazolo[4,3-a]pyrazine-7-carbonyl]-4-fluoro-phenyl]methyl]-2H-phthalazin-1-one
2-Fluoro-5-[(4-oxo-3H-phthalazin-1-yl)methyl]benzoic acid 1a (685 mg, 2.30 mmol) was dissolved in 10 mL of N,N-dimethylformamide, followed by addition of O-(1-benzotriazolyl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (1.10 g, 3.45 mmol), crude 3-(difluoromethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine 23d (400 mg, 2.30 mmol) and N, N-diisopropylethylamine (1.2 mL, 6.90 mmol). After stirring for 12 hours, the reaction mixture was concentrated under reduced pressure and the resulting residue was purified by thin layer chromatography with elution system A to obtain 4-[[3-[3-(difluoromethyl)-6,8-dihydro-5H-[1,2,4]triazolo[4,3-a]pyrazine-7-carbonyl]-4-fluoro-phenyl]methyl]-2H-phthalazin-1-one 23 (200 mg, yield 20.0%) as a white solid.
MS m/z (ESI): 454.6 [M+1]
Example 24
N-(cyclopropylmethyl)-7-[2-fluoro-5-[(4-oxo-3H-phthalazin-1-yl)methyl]benzoyl]-3-(trifluoromethyl)-6,8-dihydro-5H-imidazo[1,5-a]pyrazine-1-carboxamide
Step 1
tert-butyl 1-(cyclopropylmethylcarbamoyl)-3-(trifluoromethyl)-6,8-dihydro-5H-imidazo[1,5-a]pyrazine-7-carboxylate
7-Tert-butoxycarbonyl-3-(trifluoromethyl)-6,8-dihydro-5H-imidazo[1,5-a]pyrazine-1-carboxylic acid 20a (330 mg, 1 mmol) was dissolved in 5 mL of N, N-dimethylformamide, followed by addition of O-(1-benzotriazolyl)-N,N,N′, N′-tetramethyluronium hexafluorophosphate (756 mg, 2 mmol), cyclopropylmethylamine (142 mg, 2 mmol) and N, N-diisopropylethylamine (0.5 mL, 3 mmol). After stirring for 12 hours, the reaction mixture was concentrated under reduced pressure and added with 50 mL of ethyl acetate and washed successively with saturated ammonium chloride (15 mL×3) and saturated sodium chloride solution (10 mL). The organic phase was collected, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to obtain crude tert-butyl 1-(cyclopropylmethylcarbamoyl)-3-(trifluoromethyl)-6,8-dihydro-5H-imidazo[1,5-a]pyrazine-7-carboxylate 24a (300 mg) as a brown-red oil. The product was used directly in the next reaction without purification.
MS m/z (ESI): 389.1 [M+1]
Step 2
N-(cyclopropylmethyl)-3-(trifluoromethyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazine-1-carboxamide hydrochloride
Crude tert-butyl 1-(cyclopropylmethylcarbamoyl)-3-(trifluoromethyl)-6,8-dihydro-5H-imidazo[1,5-a]pyrazine-7-carboxylate 24a (300 mg, 0.77 mmol) was dissolved in 20 mL of a 2 M solution of hydrogen chloride in 1,4-dioxane. After stirring for 12 hours, the reaction mixture was concentrated under reduced pressure to obtain crude N-(cyclopropylmethyl)-3-(trifluoromethyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazine-1-carboxamide hydrochloride 24b (250 mg) as a light yellow oil. The product was used directly in the next reaction without purification.
MS m/z (ESI): 289.1 [M+1]
Step 3
N-(cyclopropylmethyl)-3-(trifluoromethyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazine-1-carboxamide
N-(cyclopropylmethyl)-3-(trifluoromethyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazine-1-carboxamide hydrochloride 24b (250 mg, 0.77 mmol) was dissolved in 10 mL of dichloromethane, followed by addition of potassium carbonate (320 mg, 2.30 mmol). After stirring for 4 hours, the reaction mixture was filtered and the filtrate was concentrated under reduced pressure to obtain crude N-(cyclopropylmethyl)-3-(trifluoromethyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazine-1-carboxamide 24c (250 mg) as a yellow solid. The product was used directly in the next reaction without purification.
Step 4
N-(cyclopropylmethyl)-7-[2-fluoro-5-[(4-oxo-3H-phthalazin-1-yl)methyl]benzoyl]-3-(trifluoromethyl)-6,8-dihydro-5H-imidazo[1,5-a]pyrazine-1-carboxamide
2-Fluoro-5-[(4-oxo-3H-phthalazin-1-yl)methyl]benzoic acid 1a (300 mg, 1 mmol) was dissolved in 5 mL of N,N-dimethylformamide, followed by addition of O-(1-benzotriazolyl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (756 mg, 2 mmol), crude N-(cyclopropylmethyl)-3-(trifluoromethyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazine-1-carboxamide 24c (250 mg, 0.87 mmol) and N, N-diisopropylethylamine (0.5 mL, 3 mmol). After stirring for 12 hours, the reaction mixture was concentrated under reduced pressure and the resulting residue was purified by thin layer chromatography with elution system A to obtain N-(cyclopropylmethyl)-7-[2-fluoro-5-[(4-oxo-3H-phthalazin-1-yl)methyl]benzoyl]-3-(trifluoromethyl)-6,8-dihydro-5H-imidazo[1,5-a]pyrazine-1-carboxamide 24 (150 mg, yield 30.0%) as a light yellow solid.
MS m/z (ESI): 569.2 [M+1]
Example 25
7-[2-fluoro-5-[(4-oxo-3H-phthalazin-1-yl)methyl]benzoyl]-3-(trifluoromethyl)-6,8-dihydro-5H-imidazo[1,5-a]pyrazine-1-carbonitrile
Step 1
3-(trifluoromethyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazine-1-carbonitrile
3-(Trifluoromethyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazine-1-carboxamide 10a (100 mg, 0.43 mmol) was dissolved in 5 mL of phosphorus oxychloride. The reaction mixture was heated to reflux for 4 hours. The reaction mixture was concentrated under reduced pressure, added with 10 mL of saturated sodium carbonate solution and extracted with ethyl acetate (25 mL×3). The organic phase was combined, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to obtain crude 3-(trifluoromethyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazine-1-carbonitrile 25a (100 mg) as a brown solid. The product was used directly in the next reaction without purification.
MS m/z (ESI): 217.0 [M+1]
Step 2
7-[2-fluoro-5-[(4-oxo-3H-phthalazin-1-yl)methyl]benzoyl]-3-(trifluoromethyl)-6,8-dihydro-5H-imidazo[1,5-a]pyrazine-1-carbonitrile
2-Fluoro-5-[(4-oxo-3H-phthalazin-1-yl)methyl]benzoic acid 1a (210 mg, 0.70 mmol) was dissolved in 5 mL of N,N-dimethylformamide, followed by addition of O-(1-benzotriazolyl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (350 mg, 0.92 mmol), crude 3-(trifluoromethyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazine-1-carbonitrile 25a (100 mg, 0.46 mmol), and N, N-diisopropylethylamine (250 μL, 1.18 mmol). After stirring for 12 hours, the reaction mixture was concentrated under reduced pressure and the resulting residue was purified by thin layer chromatography with elution system A to obtain 7-[2-fluoro-5-[(4-oxo-3H-phthalazin-1-yl)methyl]benzoyl]-3-(trifluoromethyl)-6,8-dihydro-5H-imidazo[1,5-a]pyrazine-1-carbonitrile 25 (50 mg, yield 21.9%) as a white solid.
MS m/z (ESI): 496.6 [M+1]
Example 26
4-[[4-fluoro-3-[3-(2,2,2-trifluoroethyl)-6,8-dihydro-5H-[1,2,4]triazolo[4,3-a]pyrazine-7-carbonyl]phenyl]methyl]-2H-phthalazin-1-one
Step 1
3-(2,2,2-trifluoroethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine
3-(2,2,2-trifluoroethyl)-[1,2,4]triazolo[4,3-a]pyrazine 26a (464 mg, 2.29 mmol, prepared according to a known method “Journal of Medicinal Chemistry, 2005, 48(1), 141-151”) was dissolved in 20 mL of methanol, followed by addition of Pd—C (10%, 200 mg), and the reactor was purged with hydrogen for three times. After stirring for 3 hours, the reaction mixture was filtered and the filtrate was concentrated under reduced pressure to obtain crude 3-(2,2,2-trifluoroethyl)-5,6,7,8-tetrahy dro-[1,2,4]triazolo[4,3-a]pyrazine 26b (480 mg) as a colorless oil. The product was used directly in the next reaction without purification.
Step 2
4-[[4-fluoro-3-[3-(2,2,2-trifluoroethyl)-6,8-dihydro-5H-[1,2,4]triazolo[4,3-a]pyrazine-7-carbonyl]phenyl]methyl]-2H-phthalazin-1-one
2-Fluoro-5-[(4-oxo-3H-phthalazin-1-yl)methyl]benzoic acid 1a (801 mg, 2.69 mmol) was dissolved in 25 mL of N,N-dimethylformamide, followed by addition of 0-(1-benzotriazolyl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (1.27 g, 3.36 mmol), crude 3-(2,2,2-trifluoroethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine 26b (460 mg, 2.24 mmol) and N, N-diisopropylethylamine (0.8 mL, 4.48 mmol). After stirring for 12 hours, the reaction mixture was concentrated under reduced pressure, added with 30 mL of H 2 O and extracted with ethyl acetate (30 mL×3). The organic phase was combined, concentrated under reduced pressure, added with 30 mL of ethyl acetate, washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and the resulting residue was purified by thin layer chromatography with elution system A to obtain 4-[[4-fluoro-3-[3-(2,2,2-trifluoroethyl)-6,8-dihydro-5H-[1,2,4]triazolo[4,3-a]pyrazine-7-carbonyl]phenyl]methyl]-2H-phthalazin-1-one 26 (240 mg, yield 22.1%) as a white solid.
MS m/z (ESI): 486.6 [M+1]
Test Examples
Biological Assays
Example 1
Assay for Determining the Enzyme Activity of PARP
The following in vitro screening assay is used to determine the activity of the compounds of the present invention for inhibiting the enzyme activity of PARP.
The assay described below is to determine the activity of the compounds of the present invention for inhibiting the enzyme activity of PARP by using the Trevigen HT F homologous poly (adenosine diphosphate-ribose) polymerase inhibition assay kit (TREVIGEN HT F homogeneous PARP Inhibition Assay Kit, No. 4690-096-K). The assays are based on the NAD + amount needed to be consumed during the DNA repair process, which is also used in another reaction for catalyzing the substrate without fluorescence activity into molecules with high fluorescence activity. Therefore, the NAD + level in the reaction system can be learned by measuring the enhancement degree of the fluorescence signal, and then the inhibition degree of the test compound on the enzyme activity of PARP was calculated.
The instructions of TREVIGEN HT F homologous poly (adenosine diphosphate-ribose) polymerase inhibition assay kit can be used as reference for the detailed operation of the assays as well as the preparation of the reagents, such as the reaction mixture (reaction mix), cycling reaction mixture (cycling mix), a buffer solution (buffer), and the like.
The procedures for the assay are summarized as follows: The tested compounds were dissolved in dimethylsulfoxide and then diluted with 1× buffer to the concentration desired in the experiment. 25 μL of a 200 nM NAD + solution was added to a 96-well round bottomed plate, followed by the addition of 1 μL of tested compounds solution, and the control of replicate wells were installed. Then 25 pt of the reaction mixture containing DNA, PARP enzyme and reaction buffer was added into each well. After incubating for 30 minutes at room temperature, 50 μL of cycling reaction mixture was added into each well and incubated in the dark at room temperature for 15 to 40 minutes. Then 50 pt of stop solution was added into each well and the fluorescence values of each well were read on an ELISA (Ex544 nm, Em590 nm). The inhibition rate of the test compound on the enzyme activity of PARP could be calculated by the standard curve equation of NAD + .
The IC 50 values of the compounds could be calculated by the inhibition rate at different concentrations.
Example compounds No. IC 50 (PARP-1)/μM 1 0.015 2 0.005 3 0.052 15 0.0023 19 0.0102
Conclusion: The preferable compounds of the present invention have significant inhibition activity on the proliferation inhibition of PARP-1 kinase.
Example 2
Cell Proliferation Inhibition Assay
The following assay is to determine the activity of the compounds of the present invention for inhibiting the proliferation of triple negative phenotype of breast cancer cell line MDA-MB-436 in vitro.
The in vitro cellular assay described below is to determine the activity of the tested compounds for inhibiting the proliferation of triple negative phenotype of breast cancer cell. The inhibition activity is represented by the IC 50 value.
The procedures for the assay are summarized as follows: The MDA-MB-436 cells were seeded to a 96-well cell culture plate at a suitable cell concentration (e.g. 3000 cells/ml medium) by using DMEM F12 with 10% FBS (both purchased from Gibco) as complete medium. Under the conditions of 37° C. and 5% carbon dioxide, the cells were cultured in constant temperature incubator and grew overnight. The tested compounds were dissolved in dimethylsulfoxide and then diluted with culture medium without FBS to the concentration desired in the assays. After the cells adhered to the walls, the cell culture medium was replaced by fresh culture medium, in which the tested compounds at serial concentrations (general 7 to 9 concentrations) were contained. Then the cell plates were cultured for continuously for 72 hours under the conditions of 37° C. and 5% carbon dioxide. 72 hours later, the activity of the tested compounds for inhibiting the cell proliferation was determined by using CCK8 (Cell Counting kit-8, No.: CK04, purchased from Dojindo) method.
IC 50 values of the tested compounds were calculated by the data of inhibition rates of the tested compounds at different concentrations.
Example compounds No. IC 50 (MDA-MB-436)/μM 1 0.0008 3 0.19 5 0.32 7 0.071 10 0.14 12 0.59 13 0.12 15 0.0009 16 0.099 17 0.061 18 0.61 19 0.049 21 0.78 22 0.65 23 0.002 24 0.072 26 0.003
Conclusion: The preferable compounds of the present invention have significantly inhibition activity on the proliferation inhibition of MDA-MB-436 cell.
Pharmacokinetics Assay
Test Example 1
The Pharmacokinetics Assay of the Compounds of Example 7, Example 13 and Example 19 of the Invention
1. Abstract
The compounds of Example 7, Example 13 and Example 19 were administrated intragastrically or by intravenous injection to rats to determine the drug concentration in plasma at different time points by LC/MS/MS method and using SD rats as test animals.
The pharmacokinetic behavior of the compounds of the present invention was studied and evaluated in rats.
2. Protocol
2.1 Samples
Compounds of Example 7, Example 13 and Example 19
2.2 Test Animals
24 Healthy adult SD rats, male and female in half, were purchased from SINO-BRITSH SIPPR/BK LAB. ANIMAL LTD., CO, Certificate No.: SCXK (Shanghai) 2003-0002.
2.3 Preparation of the Tested Compounds
The intragastrical administration group: the right amount of tested compounds were weighed and dissolved in 0.5 mL of DMSO, diluted with physiological saline to 10 mL and prepared to 1.5 mg/mL.
The intravenous injection administration group: the right amount of tested compounds were weighed and added into 0.5% CMC-Na to prepare a 1.5 mg/mL suspension.
2.4 Administration
After an overnight fast, 24 healthy adult SD rats, male and female in half, were administered intragastrically at a dose of 15.0 mg/kg and an administration volume of 10 mL/kg.
2.5 Sample Collection
The intragastrical administration group: blood samples (0.2 mL) were taken from orbital sinus at pre administration and at 0.25 hour, 0.5 hour, 1.0 hour, 1.5 hours, 2.0 hours, 3.0 hours, 4.0 hours, 6.0 hours, 7.0 hours, 9.0 hours, 12.0 hours and 24.0 hours post administration, stored in heparinized tubes and centrifuged for 20 minutes at 3,500 rpm to separate plasma. The plasma samples were stored at −20° C. The rats were fed at 2 hours after administration.
The intravenous injection administration group: blood samples (0.2 mL) were taken from orbital sinus at pre administration and at 2 minutes, 15 minutes, 0.5 hour, 1.0 hour, 2.0 hours, 3.0 hours, 4.0 hours, 6.0 hours, 8.0 hours, 12.0 hours and 24.0 hours post administration, stored in heparinized tubes and centrifuged for 20 minutes at 3,500 rpm to separate plasma. The plasma samples were stored at −20° C.
3. Operation
20 μL of rat blank plasmas taken at various time points after administration were added with 50 μL of internal standard solution and 140 pt of methanol and mixed for 3 minutes by a vortexer. The mixture was centrifuged for 10 minutes at 13,500 rpm. 20 μL of the supernatant was analyzed by LC-MS/MS. The main pharmacokinetic parameters were calculated by software DAS 2.0.
4. Results of Pharmacokinetic Parameters
Pharmacokinetic Parameters of the compounds of the present invention were shown as follows:
Pharmacokinetics Assay (15 mg/kg) Apparent Plasma Area Under Mean Distribution Conc. Curve Residence Clearance Volume oral Cmax AUC Half-Life Time CL/F Vz/F Number bioavailability (ng/mL) (ng/mL*h) t½(h) MRT(h) (l/h/kg) (l/kg) Example 12.9% 971 ± 1400 4495 ± 6671 3.87 ± 4.03 12.7 ± 15.4 15.4 ± 12.4 103 ± 134 7 oral gavage intravenous 34820 ± 15454 0.94 ± 0.26 1.25 ± 0.53 0.52 ± 0.29 0.64 ± 0.19 injection Example 16.8% 3073 ± 719 4298 ± 3252 6.01 ± 2.27 1.87 ± 0.53 4.47 ± 3.78 49.9 ± 52.9 13 oral gavage intravenous 29414 ± 18543 5.05 ± 1.34 0.89 ± 0.44 0.72 ± 0.45 4.70 ± 2.17 injection Example 2335 ± 1652 12557 ± 12372 9.79 ± 4.82 3.50 ± 1.46 3.45 ± 3.21 7.97 ± 5.38 19 oral gavage
Conclusion: The example compounds of the present invention had better pharmacokinetic data and significantly improved pharmacokinetic properties.
Antitumor Effect Assay
Test Example 2
The Assay is to Determine the Antitumor Effect of the Compounds of the Present Invention in Mice
1. Purpose
The therapeutic effect of the compounds of the present invention administered in combination with temozolomide (TMZ) on transplanted tumors of human colon carcinoma SW620 or human breast cancer cells MX-1 in nude mice was evaluated by using BALB/cA-nude mice as test animals.
2. Test Drug
The compounds of Example 1 and Example 19
3. Test Animals
BALB/cA-nude mice, SPF, 16-20 g, female( ) were purchased from SINO-BRITSH SIPPR/BK LAB. ANIMAL LTD., CO. Certificate No.: SCXK(Shanghai) 2008-0016.
4. Experimental Procedures
4.1 Nude mice were adapted to the lab environment for three days.
4.2 The right rib of the nude mice was subcutaneously inoculated with colon carcinoma cells SW620. After tumors grew to 339±132 mm 3 , mice were randomly divided into teams (d0).
Nude mice were subcutaneously inoculated with human breast cancer cells MX-1. After tumors grew to 100 to 200 mm 3 , mice were randomly divided into teams (d0).
4.3 Dosage and dosage regimens were shown in the table below. The volume of tumors and the weight of the mice were measured and recorded for 2 to 3 times per week.
The volume of tumor (V) was calculated by the follow equation:
V= ½× a×b 2
wherein: a, b represents length and width respectively.
The antitumor rate (%)=( C−T )/ C (%)
wherein: T, C represents the tumor volume of the experimental group (tested compounds) and blank control group at the end of the experiment respectively.
5. Dosage, Dosage Regimens and the Results
TMZ
dosage
dosage
Time
antitumor
Compound
cell
(mg/kg)
(mg/kg)
(day)
rate (%)
Example 1 (oral
colon
50
1
44
++
gavage) +
carcinoma
TMZ (oral gavage)
Example 19 (oral
colon
50
10
52
++
gavage) +
carcinoma
TMZ (oral gavage)
Example 19 (oral
breast
50
1
8
+++
gavage) +
cancer
50
3
8
+++
TMZ (oral gavage)
50
10
8
+++
Conlusion: the range of antitumor rate data (%) was shown as follows: “+”: 50%~60%; “++”: 60%~80%; “+++”: 80%~100%. The tested compounds of the present invention administered in combination with temozolomide (TMZ) had significant antitumor rates on colon cancer cell SW620 and human breast carcinoma cell MX-1, which were all higher than 60%.
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A phthalazinone ketone derivative as represented by formula (I), a preparation method thereof, a pharmaceutical composition containing the derivative, a use thereof as a poly (ADP-ribose) polymerase (PARP) inhibitor, and a cancer treatment method thereof are described.
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CROSS-REFERENCES TO RELATED APPLICATIONS
[0001] This application claims the benefit of U.S. Provisional Patent Application Ser. No. 60/913,050, filed Apr. 20, 2007, the entire content of which is herein incorporated by reference.
STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT
[0002] (Not Applicable)
BACKGROUND OF THE INVENTION
[0003] There is a need for support surfaces to provide a therapeutic vibrational action or force to a patient suffering from respiratory ailments. Percussors and vibrators are known to stimulate the expectoration of mucous from the lungs. Vibratory or undulating action applied to the body adjacent the thoracic cavity aids in postural draining or coughing up of sputum and thereby reduces the amount of mucous that lines the inner walls of the alveoli.
[0004] It is commonly regarded that vibrational therapy can provide both percussion and vibration. Vibration, for example, provides approximately 1 to 7 beats per second, while percussion typically provides 7 to 25 beats per second.
[0005] There are support surfaces on the market today that operate a mechanical or pneumatic external device that imparts the vibratory action. Others use many solenoid valves in combination to control and regulate flow, pressurizing and venting of the vibration air cells. Others use a cam action, large diaphragms or alternating action of relatively large size dual valves to move the air in and out of the vibration air cells.
[0006] All the current methods have extensive mechanical and electro-mechanical components such as valves, motors, lever arms, cams, large diaphragms, fluidic connections and the like. They also use finger shaped air cells for the vibratory air cells.
BRIEF SUMMARY OF THE INVENTION
[0007] In an exemplary embodiment, a vibration and modulation system is provided for an array of air cells. The vibration and modulation system includes an air source, a high-pressure reservoir in fluid communication with the air source, and at least one valve coupled between the high-pressure air source and the array of air cells. A control assembly is coupled with the at least one valve and selectively controls a position of the valve to effect a vibratory action in the array of air cells. The air source is preferably a pump, although other sources may be suitable. A size of the high-pressure reservoir is preferably determined based on a total volume of air required to inflate the air cell array to a minimum pressure.
[0008] The control assembly may include a pressure sensor in the high-pressure reservoir that triggers a position of the at least one valve according to a pressure in the high-pressure reservoir. Alternatively, the control assembly may include a check valve with a predetermined cracking pressure disposed between the high-pressure reservoir and the at least one valve. The predetermined cracking pressure is determined according to a desired frequency of vibratory action. In still another variation, the control assembly includes a timing circuit coupled with the at least one valve that controls a position of the at least one valve on a predetermined time interval. In still another alternative arrangement, the control assembly includes a pilot valve coupled with the at least one valve that enables high pressure fluid from the high-pressure reservoir to control a position of the at least one valve.
[0009] In one arrangement, the air source and the high-pressure reservoir are coupled with the at least one valve in parallel.
[0010] The system may additionally include evacuation structure coupled with the air cell array that enables quick deflation of the air cell array. In this context, the evacuation structure may comprise a vent on the at least one valve. The evacuation structure may additionally include a vacuum source coupled with the vent.
[0011] In another exemplary embodiment, a support surface includes an array of air cells, and the described vibration and modulation system coupled with the air cell array, where the vibration and modulation system effects vibratory action on the air cell array. Preferably, when deflated, the air cells are substantially flat. Each of the air cells may additionally include an air cell node including a foam insert disposed in an air sealable container.
[0012] In yet another exemplary embodiment, a vibration and modulation system for an array of air cells for use with a support surface includes an air source, a high-pressure reservoir in fluid communication with the air source, and a multi-position valve coupled between the high-pressure air source and the array of air cells. In a first position, the valve permits air to flow from the high-pressure reservoir to the air cells, and in a second position, the valve evacuates air from the air cells to atmosphere. A control assembly is coupled with the valve and selectively controls a position of the valve to effect a vibratory action in the array of air cells.
BRIEF DESCRIPTION OF THE DRAWINGS
[0013] FIG. 1 is a schematic diagram of a vibration and modulation system according to a first embodiment;
[0014] FIG. 2 is a schematic diagram of a second embodiment;
[0015] FIG. 3 is a schematic diagram of a system including a vacuum source for rapid evacuation of the air cells;
[0016] FIG. 4 shows an exemplary two-dimensional air cell array; and
[0017] FIG. 5 shows an exemplary three-dimensional air cell array.
DETAILED DESCRIPTION OF THE INVENTION
[0018] With reference to FIG. 1 , an exemplary embodiment includes an air source 12 , such as a pump, connected to a high-pressure reservoir 14 , connected to a valve 16 such as a 3-way solenoid valve. A connecting valve 18 connects to the air cells 20 used for vibration and percussion, and a vent port 22 is a vented to atmosphere, which vents the air cells 20 . The air cell array 20 includes small air cells, either generally flat when deflated (two-dimensional) or nodal cylinders or other shape (three-dimensional) connected together in a pattern.
[0019] The vibratory system of the described embodiments can be used and integrated into any support mattress system and hospital bed frame. Alternatively, the system can be a stand-alone system used on any patient on any hospital mattress and bed frame.
[0020] Reservoir
[0021] The reservoir 14 can be any soft sided or hard-sided container of any suitable shape. It is preferably large enough to contain enough pressurized fluid (air, water, etc.) to allow the air cells 20 to quickly inflate. The total volume of air required for the air cells 20 to inflate quickly to a minimum high pressure and the pressure levels in the reservoir 14 determines the reservoir size.
[0022] Air Source
[0023] The air source 12 can be any type of pump (compressor, diaphragm, rotary, etc.) that supplies a sufficient volume of air to keep the reservoir 14 full of pressurized fluid.
[0024] Frequency Control
[0025] The vibration or modulation frequency (beats/sec) is controlled either by pressure or by time.
[0026] Pressure Method
[0027] (a) In one arrangement, a pressure sensor transducer 24 senses the pressure in the reservoir 14 . At certain pressures, the transducer 24 sends a signal to the solenoid valve 16 for it to either open or close, thereby allowing filling of the air cells 20 or venting of the air cells 20 . By changing and setting the desired pressures, the frequency of the vibratory action can be controlled by the caregiver.
[0028] (b) In another arrangement, a check valve 26 is connected between the high-pressure reservoir 14 and the solenoid valve 16 . Check valves have a set cracking pressure (i.e., the valves are held open when a certain pressure is maintained). When the pressure drops below that level, the valve 26 closes again. By choosing the desired check valve 26 with its predetermined cracking pressure, the frequency of pressure variations and therefore the frequency of vibratory action can be controlled.
[0029] Valves
[0030] There are two exemplary methods, both using valves, to control the high-pressure air filling the air cells 20 .
[0031] (a) Solenoid valves, such as a 3-way solenoid valve 16 shown in FIG. 1 , allow the inlet port to pass air (from reservoir 14 ) to the exit port (to the air cells 20 ), and the vent port 22 allows air from the air cells 20 to vent to atmosphere. If the vent port 22 is open, the inlet port to the air cells is closed. The valve 16 opens and closes upon signals, for instance, from a timing circuit 28 . The valve 16 opens and closes its ports using electromagnetic force or the like. The larger the required ports in the valve, the higher the wattage requirement of the valve.
[0032] (b) Pilot valves (not shown) may also be suitable. Since the pressure is high from the reservoir 14 , a pilot valve may be used instead of the typical solenoid valve 16 . With this structure, the high-pressure fluid itself will move the valve instead of the electromagnetic force or the like.
[0033] Timing Method
[0034] A timing circuit or a timing chip 28 can be connected to the solenoid valve 16 . The circuit 28 opens and closes the solenoid valves 16 , which in turn allows the air cells 20 to fill and then to vent within a set period. The timing circuit 28 can have either a fixed on/off period or could be programmed by the user through the use of microprocessors.
[0035] Pressure Reservoir
[0036] The utilization of a pressure reservoir 14 allows for a continuous supply of high pressure to be quickly released, via the valve 16 , to the air cells 20 , allowing very rapid inflation of the air cells 20 . The reservoir 14 avoids complete reliance on the pump 12 to rapidly fill the air cells. If a reservoir was not used, a significantly larger capacity pump would be required to guarantee a sufficient supply of air. An example of a suitable pump is a centrifugal pump known as “Windjammer” made by Ametek. This type of high volume but low pressure blower is widely used in the industry. The supplied air would be most likely be at a lower pressure than the reservoir 14 , but the larger capacity pump 12 would be needed to quickly inflate the air cells. Also, with lower pressure air directly from the pump 12 , the air cells 20 may not reach a high pressure within the short time frame, and this affects the quick venting required to provide the vibratory action. At lower pressures, the venting action would be slower. As can be seen, this high pressure reservoir vibration system is particularly useful in support surfaces that utilize a smaller piston or diaphragm pump with relatively low CFMs.
[0037] In a variation of the first embodiment, with reference to FIG. 2 , the reservoir 14 can have a parallel (Tee) connection 30 between the pump 12 and the valve 16 . This allows air to flow not only from the reservoir 14 , but also from the pump 12 at the same time. This variation might be used, for example, if the size of the reservoir 14 had to be limited.
[0038] Deflation of Air Cells
[0039] As previously mentioned, with a high-pressure reservoir 14 it is possible, in the described embodiments, to quickly deflate the air cells 20 simply by venting through the solenoid valve 16 . If large air cells are desired, or other conditions exist which inhibit the natural venting, however, a vacuum source 32 can be utilized to deflate the air cells. The vacuum source 32 is shown in FIG. 3 .
[0040] Air Cells
[0041] The air cells 20 used for inflation, otherwise known as bladders, have either a 2D or 3D configuration. For the two-dimensional variation, with reference to FIG. 4 , the cells are relatively small circles, oblongs, rectangles or squares. They are generally flat (2D) in the deflated condition. For example, a circular shape might have an OD of 3″ in the deflated condition. A multitude of these small shapes make up an array, with individual circles connected with tubing or passageways between the circles.
[0042] For the three-dimensional shape, with reference to FIG. 5 , each cell is a small node, something like a cylindrical canister. Again these nodes can be connected to form a nodal array as shown. An example of suitable construction is described in U.S. patent application Ser. No. 11/866,602, the contents of which are incorporated by reference. The nodes could have a foam insert 21 inside each one. A vacuum source is used to deflate each node. When the vacuum is turned off, the foam 21 expands and helps to re-inflate each node, causing the vibratory action.
[0043] Whether 2D or 3D, these cell shapes have less volume than the finger cells currently on the market. The smaller volume allows for a more effective and quick control of the air or fluid entering and leaving the air cell. The smaller the volume of the vibrating air cells, the better the percussion or vibration will be, i.e., more beats per second and at higher pressure.
[0044] The air cells can be constructed out of any suitable material such as urethane, supported urethanes, vinyl, and supported vinyl. The air cells are preferably sealed to form an airtight volume. The sealing process could be RF welding, heat or ultrasonic sealing, adhesive or other methods.
[0045] The vibratory air cells are placed under the patient's back around the chest area. They may be used alone or in conjunction with other support surfaces.
[0046] Comparison of Other Inventions
[0047] The exemplary embodiments described herein differ from others in that the reservoir 14 , or accumulator, is used that is at a pressure higher than atmosphere and higher than that developed by a relatively small pump. Typical pressures might be 1 to 8 psi. By utilizing a high-pressure reservoir 14 , smaller solenoid valves 16 can be used, which have smaller opening ports. The high pressure passed through the solenoid valve 16 allows the air cells 20 to inflate very rapidly and to a high pressure. Other systems use air directly from the air source, which passes through valves and then into the air cells. A high-pressure reservoir is not utilized.
[0048] While the invention has been described in connection with what is presently considered to be the most practical and preferred embodiments, it is to be understood that the invention is not to be limited to the disclosed embodiments, but on the contrary, is intended to cover various modifications and equivalent arrangements included within the spirit and scope of the appended claims.
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A vibration and modulation system is provided for an array of air cells. The vibration and modulation system includes an air source, a high-pressure reservoir in fluid communication with the air source, and at least one valve coupled between the high-pressure air source and the array of air cells. A control assembly is coupled with the at least one valve and selectively controls a position of the valve to effect a vibratory action in the array of air cells.
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FIELD OF INVENTION
The embodiments of the present invention relate to a card game. More particularly, a card game adapted for wagering in a casino or similar gaming establishment.
BACKGROUND
As legalized gaming continues to increase in popularity, casinos and related gaming establishments seek to offer new wagering games to entertain their customers. Recently, casinos have been installing large numbers of electronic gaming machines in an effort to retain current patrons and to attract new customers. However, table games provide a different form of entertainment for customers who do not favor, or who need a break from, the often mundane electronic gaming machines. Thus, table games, although seemingly losing popularity, continue to be an integral feature to the success of any casino.
Widely offered table games include Blackjack, Craps, Roulette and Carribean Stud Poker. Unfortunately, the aforementioned table games have been in place for years and no longer exude their initial novelty. In addition, younger gaming patrons desire new and exciting games of chance. Nonetheless, it is important that new table games involve simple rules, traditional gaming indicia, and odds which both the player and the house can accept. Without the aforementioned characteristics, many new table games are likely to be short-lived. Another significant trend in table games is the opportunity to place side wagers having payouts larger than the payouts for the underlying game. For example, some Blackjack tables provide players with a side bet dependent upon the player being dealt Blackjack. If the player places the side wager and is then dealt Blackjack, the dealer causes an electronic wheel, having preestablished award amounts depicted thereon, to spin and stop such that the player wins an award above and beyond that associated with winning the underlying Blackjack game.
The embodiments of the present invention include each of the aforementioned characteristics and also provide a side wager opportunity for players. As a result, the embodiments of the present invention take advantage of the inherent features of currently successful table games.
SUMMARY
Accordingly, the embodiments of the present invention are played with a single deck of standard playing cards on a table similar to Blackjack. The use of more than a single deck is optional. The underlying game disclosed herein is generally analogous to the game of Blackjack. To that end, players attempt to achieve a higher total hand value than a dealer without going over a total hand value of thirty-three (33) as opposed to twenty-one (21). Face cards are worth ten (10), Aces are worth one (1), and the remaining numbered cards two through ten (2-10) are worth their face value. Unlike Blackjack, players are limited to taking a preestablished maximum number of cards (e.g., five).
Players first place a primary wager. The underlying game is dealt with each player and the dealer receiving two initial cards. The dealer receives one face up card and one face down card while the players ideally receive both cards face up. However, the players may receive both cards face down or one face up and one face down. The dealing pattern for the players can take any form desired by the casino operating the game. The initial two cards are dealt in a clockwise fashion starting with a first player to the dealer's most left position with each player and the dealer receiving one card at a time until all have two cards. Thereafter, the first player is engaged by the dealer and plays out the hand by surrendering, hitting, standing or doubling-down. Should the player's total hand value exceed thirty-three (33), the player loses the primary wager. Each successive player is then engaged in a clockwise fashion until each player has completed his or her hand.
Then the dealer completes his or her hand. The dealer must hit any hand value less than twenty-six (26). The dealer must hit his hand as many times as necessary to achieve a total hand value of at least twenty-six (26). The dealer may not take any cards subsequent to achieving a total hand value of twenty-six (26). Once all hands have been completed, the dealer determines which players have won and lost the primary wagers and pays the winners and collects all losing primary wagers. Winning primary wagers are paid even money. Players holding total hand values of exactly thirty-three (33) are paid 3 to 2 on their primary wager.
To add to the excitement level of the game and to entice players to play, the underlying game may also incorporate a side wager based on the initial three cards received during play of the underlying game. In one embodiment, the side wager includes a payout for a three card flush, three card straight, three card straight flush, and three of a kind. The payouts associated with receiving one of the preestablished three card hands are more attractive than the even money odds paid on a winning primary wager. For example, a three card straight may pay 10 to 1 and three of a kind may pay 50 to 1. The larger side wager odds tend to entice players to participate in the optional side wager as a matter of course when playing the underlying game.
The surrender option noted above allows players to surrender one-half of their primary wager immediately after the player has received his or her initial two cards in return for ending that particular play of the underlying game. The surrender option is typically used when a player determines that the value of the initial two cards prevents, or reduces the likelihood of, the formation of a favorable hand. Thus, the player may surrender one-half of the primary wager rather than risking the entire primary wager. Should the player surrender the primary wager with a side wager in place, possible winning side wager hands are resolved independently. Therefore, in the event the two cards surrendered can possibly form a winning side wager hand, the dealer deals a third and final card to evaluate the outcome of the side wager. In the event the two cards held during a surrender cannot possibly result in a winning side wager, the two cards and the side wager are collected by the dealer and the dealer engages the next player.
Players may also double down after the initial two, three or four cards. Doubling-down allows players to double their primary wager in return for receiving a single card (i.e., one hit). As explained later, doubling-down is a very successful option under certain favorable conditions.
In a partially electronic embodiment of the present invention, the dealer uses a keypad located on, or adjacent to, the game table to enter each player's total hand value. The keypad is in communication with a display device which displays the total hand value of each player and the dealer. This partially electronic embodiment eliminates the need for the dealer to re-count each player's total hand value as the dealer engages each player in a clockwise fashion. This embodiment is best suited for games requiring each player to receive all cards face up so that the dealer immediately knows the player's total hand value and may enter the same prior to engaging the next player. The display device is viewable by all players and further adds to the excitement level of the game.
The player's total hand value can also be indicated by a simple marker. For example, a marker similar in size and shape to a wagering chip or token can have player hand values depicted thereon. The marker system, like the electronic display, ensures that the players and the dealer know each hand value at the table.
The embodiments of the present invention may also be facilitated by an electronic gaming machine. The electronic gaming machine eliminates the need for a dealer and is more likely to attract players with little knowledge of the game. In other words, players feel less threatened to play and learn a new game in a completely electronic format. Thereafter, once the player has developed an understanding of the game, the player is more confident and therefore more likely to play the game at a table offering a live version.
Although several embodiments of the present invention have been disclosed, those embodiments and other features, variations and embodiments of the present invention are set forth hereinafter in greater detail.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 illustrates a table layout for practicing the embodiments of the present invention;
FIG. 2 illustrates a display device and keypad for use with a partially electronic embodiment of the present invention;
FIG. 3 illustrates a pay table depicting alternative payout schedules associated with a side wager of a first embodiment of the present invention;
FIG. 4 illustrates a flow chart detailing a sample play of one embodiment of the present invention; and
FIG. 5 illustrates an electronic gaming machine for facilitating a completely electronic version of the embodiments of the present invention.
DETAILED DESCRIPTION
As shown in FIG. 1 , a table layout, generally denoted as reference numeral 100 , has the overall appearance of a conventional Blackjack table. Seven player positions correspond to seven primary wager areas 110 - 1 through 110 - 7 . Also incorporated on the layout 100 are seven side wager areas 120 - 1 through 120 - 7 . A chip rack 125 for holding chips to pay winning wagers and to maintain collected losing wagers is integrated adjacent a dealer area 130 .
While not shown, it is contemplated that a table incorporating the layout 100 may support a card shuffler or card shoe for increasing the speed at which the embodiments of the present invention may be played. Also, while not shown on the layout 100 , it is contemplated that a pay table associated with a side wager may be imprinted directly on the layout 100 or may be displayed in any suitable format on, or near, the table.
FIG. 2 illustrates a display device 150 in electrical communication with a keypad 160 . The display device 150 may be any type of display, such as a liquid crystal display (LCD), light emitting diode (LED) display or video display for displaying numbers and text inputted by means of the keypad 160 . The display device 150 and keypad 160 use a conventional power outlet and electrical cord for receiving power to operate. The display 150 comprises eight (8) sections for displaying each player's total hand value and the dealer's total hand value. In practice, the dealer inputs, using the keypad 160 , each player's total hand value which is then communicated to the display 150 so that the total hand value is displayed in a fashion to identify the total hand value of each player by seat or position number 170 .
The player's total hand value can also be indicated by a simple marker. For example, a marker similar in size and shape to a wagering chip or token can have player hand values depicted thereon. In such an arrangement, the dealer utilizes multiple sets of markers depicting each possible hand value. Each set may be colored differently to correspond to different players. Thus, if a first player's hand value is 25, the dealer places a red chip depicting 25 thereon in proximity to the first player. Then, if a second player's hand value is 30, the dealer places a green chip depicting 30 thereon in proximity to the second player. It is contemplated that the dealer will also mark his or her own hand value. The marker system, like the electronic display, ensures that the players and the dealer are aware of each hand value at the table.
Although up to seven players may participate at a table offering the embodiments of the present invention, the description hereinafter will assume, by way of example, that two players are playing the game. Each player initially places a wager in one of the primary wager areas 110 - 1 through 110 - 7 corresponding to that player's location. Also, each player, if desired, places a wager in a corresponding side wager area 120 - 1 through 120 - 7 . The permissible amounts of the primary and side wager will be determined by the casino offering the game. For example, a casino may allow players to place primary wagers ranging from $10 to $500 and side wagers ranging from $1 to $25. Once the primary and side wagers are placed, the dealer deals the players two cards face up and the dealer two cards with one card face down and one card face up. The pattern of the deal occurs one card at a time to each player and then the dealer in a clockwise fashion until each player and the dealer has two cards.
The dealer then engages a first player positioned to the dealer's most left position. At this point, the player may hit, stand, double-down or surrender as specifically described below.
Hitting requires that the player elect to receive one or more cards to improve the total hand value. The player may take a maximum of three hits resulting in a maximum player hand of five cards. In a first embodiment, all player cards are received face up. Alternatively, other dealing patterns may be used. If the player's total hand value exceeds thirty-three (33) (i.e., the player busts), the primary wager is lost and immediately collected by the dealer.
Standing requires that the player elect to hold the cards dealt and declines any additional cards. Upon receiving the initial two cards, the player will not stand since there is no chance that a third card will exceed the game's maximum total hand value of thirty-three (33). Thus, standing after the initial two cards is not a practical choice. However, after at least three cards have been dealt to the player, standing is a definite option. For example, if the player's initial three cards are face cards, which pursuant to the scoring system comprise a total hand value of thirty (30), the player will likely stand since the odds are that a fourth card will cause the player's total hand value to exceed thirty-three (33) thereby resulting in a losing outcome.
Doubling-down allows the player to double his primary wager in return for a single card (i.e., one hit). The player may double down after receiving the initial two, three or four cards. Doubling-down is best utilized when the player has a hand value that will not exceed thirty-three (33) regardless of the next card's value. In addition, since a standard deck of 52 cards comprises sixteen cards having a value of ten (e.g. (4) Tens, (4) Jacks, (4) Queens and (4) Kings), doubling-down is also best-suited for situations when the player's hand value is within approximately ten to thirteen of thirty-three (33). Therefore, doubling-down is a sound option for players holding hands having values between approximately twenty (20) and twenty-three (23). Often times the casino offering the game may elect to permit doubling-down only on a predetermined range of hand values.
Surrendering is an option that permits players to surrender immediately after receiving their initial two cards. The player surrenders one-half of the primary wager and takes back the other one-half ending the play of the underlying game. Surrendering permits players to discard a partial hand that has a reduced likelihood of winning the primary wager. For example, should a player receive two Aces totaling two, the player may elect to surrender because the odds of receiving three consecutive high cards to significantly improve the hand value are not favorable. Alternatively, surrendering can also be permitted after three or more cards are dealt.
Once the dealer has engaged each player in a clockwise fashion from left to right, the dealer plays his or her hand. First, the dealer reveals the face down card. Then the dealer takes cards (i.e., hits his or her hand) until the dealer's total hand value is twenty-six (26) or more. Unlike the players, the dealer is not limited to taking a predetermined number of cards. Once the dealer's hand total is twenty-six (26) or more, the dealer is prohibited from taking any additional cards. Then the dealer resolves the primary wagers. All ties between the dealer and a player result in a push so that the player neither wins nor loses the primary wager. If the dealer has busted, all non-busting players win their primary wager. Otherwise, the dealer's total hand value is compared to each player's total hand value to determine winning and losing primary wagers. Winning primary wagers are paid even money and players holding total hand values of exactly thirty-three (33) are paid 3 to 2 on their primary wager.
An optional side wager provides players with a chance at a greater payout than that associated with the primary wager. Side wager areas 120 - 1 through 120 - 7 are imprinted on the table layout 100 adjacent each primary wager area 110 - 1 through 110 - 7 . The side wager is based on the initial three cards received by each participating player. As shown in FIG. 3 , side wager pay tables comprise payouts for flushes, straights, straight flushes, and threes of a kind. The maximum payout is provided to a player that receives three initial cards each having a value of three (i.e., three 3s). While three 3s have been chosen to correspond to the maximum payout, since the odds associated with receiving any three of a kind are identical, any three of a kind can be chosen to correspond to the maximum payout. The alternative pay tables shown in FIG. 3 illustrate differing possible payout schemes.
The side wagers are resolved after the first three cards are dealt to the player. If the player has a winning side wager, the player is paid. If the first three cards do not result in a winning side wager, the dealer collects the player's side wager and continues dealing the player's hand. If the participating player elects to surrender his or her primary wager and the player's two cards can possibly result in a winning side wager outcome, the dealer moves the two cards near the side wager area and deals a third card. The side wager is then resolved according to the associated pay table. When the two cards cannot possibly result in a winning side wager outcome, the side wager is lost and immediately collected by the dealer.
FIG. 4 illustrates a flow chart detailing a sample play of one embodiment of the present invention. Although seven players may play the embodiments of the present invention at once, for simplicity, the flowchart is based on a single player. At step 200 , the player places a primary wager and a side wager. At step 201 , the dealer deals the player two cards and the dealer two cards. The dealer's cards are dealt one face up and one face down. Thereafter, the dealer engages the player and the player, at steps 202 , 203 and 204 elects to hit, double-down or surrender, respectively. Should the player elect to double-down at step 203 , the dealer deals the player a third and final card at step 205 . Then, at step 206 , the dealer resolves the player's side wager. Then, at step 207 , the dealer completes the dealer's hand and resolves the player's primary wager at step 208 . If the player surrenders at step 204 , the dealer collects one-half of the player's primary wager at step 209 and at step 210 deals the player a third card. At step 211 , the dealer resolves the player's side wager.
If the player elects to take a hit at step 202 , the dealer resolves the player's side wager at step 212 . Now, the player may again elect to hit, stand or double-down at steps 213 , 214 and 215 , respectively. If the player elects to stand at step 214 , at step 207 , the dealer completes the dealer's hand and, at step 208 , the dealer resolves the player's primary wager. If the player elects to double-down at step 215 the dealer deals a fourth and final card to the player at step 216 . Thereafter, at step 207 , the dealer completes the dealer's hand and, at step 208 , the dealer resolves the player's primary wager.
If the player elects to take a hit at step 213 , the player may again hit, stand or double-down at steps 218 , 214 and 215 , respectively. The player may elect to take a final card at step 218 . Thereafter, at step 207 , the dealer completes the dealer's hand and, at step 208 , the dealer resolves the player's primary wager.
FIG. 5 illustrates an electronic gaming machine, generally designated as reference numeral 300 , of the type that may be used to implement the embodiments of the present invention in an electronic format. The external features of the gaming machine 300 include a display 310 , primary wager selection button 320 , a side wager selection button 330 , a wager button 340 , a card selection button 350 , a stand button 360 , a double down button 370 , a surrender button 380 , a card reader 390 , a coin slot 400 , a bill reader 410 and a credit display 420 . While not shown, the gaming machine can also incorporate a ticket reader and printer for facilitating cashless play.
The operation of the gaming machine 300 is controlled by a microprocessor that communicates with an internal memory device, a display device and external interfaces (e.g., player buttons) of the machine 300 . The microprocessor also incorporates, or communicates with, a random number generator which ensures the randomness of the cards dealt during the play of the electronic embodiment. Since the technology for controlling and operating gaming machines is well known to those skilled in the art, the subtle details are not described herein.
In an electronic format the game may proceed as described hereinafter. A player first inputs a wager by using the coin slot 400 , bill reader 410 or the ticket reader. The wager can either be in the form of a single denomination wager (e.g., $5) or the player may insert a larger amount of money which the machine 300 displays on the credit display 420 so that the player can play on registered credit. On credit, the player first depresses the primary wager selection button 320 to select the primary wager and then uses the wager button 340 to input the amount of the primary wager. Then, if desired, the player depresses the side wager selection button 330 and then uses the wager button 340 to input the amount of the side wager. Once the wagers and corresponding amounts of the wagers have been input, the processor causes the player to receive two cards face up and the simulated dealer to receive two cards with one card face up and one card face down. Then, the player inputs his desired instructions by using the card selection button 350 , the stand button 360 , the double down button 370 or the surrender button 380 . The machine processor is preprogrammed to facilitate any instruction input by the player. Moreover, based on the outcome of the game, the processor causes the player wagers to be resolved and the player to be paid according to a preestablished pay table stored in a memory device of the gaming machine 300 . The payouts can be delivered in coins or may simply be added to the credit total of the player as displayed on the credit display 420 .
In an alternative embodiment, the machine 300 includes a touchscreen display which prompts the player to select the desired wagers, the amounts of the wagers and any instructions (e.g. hit, stand, surrender, double-down). The touchscreen display eliminates the necessity of many of the gaming machine buttons described above thereby simplifying play of the game.
Obviously, many modifications and variations can be effected without departing from the spirit of the invention disclosed herein. It is therefore intended that the scope of the invention be determined solely by the claims appended hereto.
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A wagering card game using a standard deck of playing cards with an objective of achieving a total hand value nearest to thirty-three (33) without going over is disclosed. Players play against a dealer in an attempt to reach a total hand value greater than the dealer but less than thirty-three (33). Players are limited to receiving a maximum number of cards (e.g., five cards). In addition, a side wager provides players with an opportunity to win large payouts. The side wager is dependent upon the initial three cards received by the player. A pay table associated with the side wager comprises payouts for flushes, straights, straight flushes and threes of a kind. In one embodiment of the game, a game table incorporates a display for tracking the players' and dealer's total hand values. In another embodiment, play of the game is facilitated by an electronic gaming machine.
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FIELD OF INVENTION
This invention relates to the shaping of heat deformable material, such as heated glass sheets and, more particularly, to a novel vacuum press.
BACKGROUND OF THE INVENTION
Shaped and tempered glass sheets are widely used as side windows or rear windows in vehicles such as automobiles or the like, and, to be suitable for such application, flat glass sheets must be shaped to precisely defined curvatures dictated by the shape and outline of the frames defining the window openings into which the glass side or rear windows are installed. It is also important that the rear or side windows meet stringent optical requirements and that the windows be free of optical defects that would tend to interfere with the clear viewing therethrough in the viewing area. Any distortion in shaping members that engages a heat softened sheet to help shape the latter is replicated in the major surface of the sheet and may result in an optically deficient surface of the shaped sheet.
One type of commercial production of shaped glass sheets for such purposes commonly includes heating flat glass sheets to their softening point, shaping the heated sheets to a desired curvature and then cooling the bent glass sheets in a controlled manner to a temperature below the annealing range of the glass. During such treatment, a glass sheet is conveyed along a substantially horizontal path that extends through a tunnel-type furnace where the glass sheet is one of a series of sheets that are heated to a deformation temperature of glass and along an extension of the path into a shaping station where each glass sheet, in turn, is engaged by a vacuum mold. The vacuum mold lifts and holds the heat softened glass sheet by suction. At about the same time, a transfer and tempering ring having an outline shape conforming to that desired for the glass sheet, slightly inboard of its perimeter moves upstream into a position below the vacuum mold. The vacuum releases and deposits the glass sheet onto the tempering ring. The tempering ring supports the peripheral edge of the glass sheet while it conveys the glass sheet into a cooling station for rapid cooling.
The vacuum mold is provided with a curved shaping surface that shapes the heat softened glass sheet by suction thereagainst. The molds are generally constructed of a ceramic block or a metal vacuum box. Apertures in the block or the metal shaping plate of the vacuum box connect to a hollow vacuum chamber which communicates with a vacuum source. The mold is covered with a refractory material such as a fiber glass cloth that will not mar or harm the glass at elevated temperatures.
It would be advantageous to construct a vacuum mold with an adjustable shaping surface that can easily change the shaping curvature of the mold without having to replace or disassemble the vacuum mold.
DESCRIPTION OF PATENTS OF INTEREST
U.S. Pat. Nos. 4,052,188 to Seymour; 4,210,435 to Claassen; 4,274,858 to Claassen et al.; 4,319,907 to Pike; and 4,052,185 to Kolakowski disclose bending molds for vertical press bending. The press faces are metal plates covered with a flexible heat-insulating material that will not harm the glass sheet at elevated temperatures. Adjusting bolts are interposed between the shaping surface and a rigid metal backplate used to reinforce the mold face. There is no vacuum engagement by the pressed faced.
U.S. Pat. Nos. 4,260,409 to Reese et al., and 3,634,059 to Miller disclose the use of a solid ceramic press face for shaping the hot glass sheets in a horizontal press-bending apparatus. The ceramic press face is fixed to a rigid baseplate. Due to the nature of the press face, its shaping surface cannot be adjusted or modified to change its curvature other than reshaping the ceramic face. A different ceramic press face is required to form a different glass sheet configuration. In U.S. Pat. No. 3,634,059, apertures are drilled through the ceramic mold to provide airways to a central portion of the mold.
U.S. Pat. Nos. 4,357,156 to Seymour and 4,187,095 to Frank disclose vacuum lifting and shaping apparatuses using a metal box type arrangement. In Seymour, the lifting device is a vacuum platen comprised of a hollow chamber having a flat apertured bottom plate. The hollow interior of the platen is connected to a vacuum source. In Frank, the vacuum lifting device shapes the glass sheet. The vacuum mold is composed of a metal box with a refractory material such as fiber glass covering the apertured shaping surface. Neither patent provides for a way to adjust the configuration of the shaping surface of the vacuum device.
U.S. Pat. Nos. 4,349,375 and 4,277,276 to Kellar et al. teach the shaping of heat softened glass sheets by engaging them against the apertured surface of a deformable vacuum mold and deforming the vacuum mold while maintaining the glass sheet in vacuum engagement thereagainst. The edges of the vacuum chamber are sealed by a hollow metal bar along its non-deforming edge and flexible, longitudinal metal slats or solid neoprene bars along its deformable edge. There are no provisions for internal adjustment of the curvature of the shaping surface. The mold is deformed only by externally positioned pistons or actuating rods.
SUMMARY OF THE INVENTION
The present invention provides for an air tight chamber with easily removable, non-porous, flexible side wall that allows for easy access into the interior of the chamber. A lower wall of the chamber is apertured and a vacuum source is connected to the chamber to permit the lower wall to engage and support a workpiece positioned at the lower wall when a vacuum is drawn through the chamber.
The present invention also provides a vacuum mold for shaping hot glass sheets wherein the mold includes a rigid back plate, a flexible, perforated lower shaping wall, adjustable spacers positioned between the back plate and the shaping wall to maintain them in spaced relation, and easily removable side wall members that seal the vacuum chamber of the mold and allow easy access to the internal adjustable spacers. A fiber glass cloth covers the lower shaping wall. The adjustable spacers include T-shape members rigidly attached to lower shaping wall. A threaded rod is rotatably attached to T-shape member and extends through an aperture in the rigid plate. A first and second nut assembly threaded on the threaded rod captures the adjusting plate therebetween.
In one embodiment of the present invention the removable side walls are the peripheral area of the fiber glass cloth that spans between the rigid plate and shaping wall. This area of the cloth is coated with a heat resistant, impervious material such as heat resistant silicone rubber. The fiber glass cloth which is draped across the shaping wall is secured to the rigid plate by removable clips. To gain access to the adjustable spacers between the rigid plate and shaping wall, the clips are removed, allowing the coated cloth to be pulled back to expose the internal adjustable spacers.
In an additional embodiment of the present invention, a edge of a screen is welded to the periphery of the lower shaping wall with the other edge being detachably secured by clips to the rigid plate, to span the distance therebetween. The screen is coated with a heat resistant, impervious material. A fiber glass cloth is draped across the lower shaping wall and attached to the rigid plate. To gain access to the internal adjustable spacers, the cloth is removed, and the end of the coated screen attached to the rigid plate is unclipped allowing the coated screen to be pulled back to expose the internal adjustable spacers.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 is a fragmentary partly schematic view looking upstream at a typical glass sheet bending apparatus using the vacuum mold which is the subject of this invention.
FIG. 2 is a fragmentary perspective view of the vacuum mold, which is the subject of this invention.
FIG. 3 is a fragmentary view of the vacuum mold in FIG. 2 illustrating an additional embodiment of the invention.
DESCRIPTION OF THE PREFERRED EMBODIMENT
Referring to FIG. 1 of the drawings, an apparatus for treating and shaping sheets of heat softenable material, such as glass, includes a furnace 12 through which glass sheets are conveyed from a loading station (not shown) while being heated to a glass deformation temperature. A cooling station 14 for cooling the curved sheets of glass and an unloading station (not shown) beyond the cooling station 14 are located in end to end relation to the right of the furnace 12. An intermediate or shaping station 16 is disposed between the furnace 12 and the cooling station 14. A sheet transfer means 18 located in the cooling station 14 transfers the shaped and tempered glass sheet downstream for transport to the unloading station.
The furnace 12 includes a horizontal conveyor 20 comprised of longitudinally spaced transversely extending conveyor rolls 22 that define a path of travel which extends through the furnace 12 and the shaping station 16. The rolls 22 of the conveyor 20 are arranged in sections and their rotational speed controlled through clutches (not shown) so that the speed of each conveyor section may be controlled and synchronized in any convenient means.
Often time, the curvatures of automobile windows are similar but not identical. As a result, a different bending mold must be used. The amount of time needed to remove an upper mold for one pattern and install a replacement mold for another pattern of a different radius of curvature is considerable and would interfere with the time that could be used in production. Therefore, it is desirable to have an upper shaping mold capable of producing multiple patterns of different curvatures. In addition, it would be advantageous to have the upper and lower molds large enough to accommodate the production of an entire of family of patterns having the same radius of curvature as taught in U.S. Pat. No. 4,187,095, which teachings are hereby incorporated by reference.
The shaping station 16 comprises a lower shaping mold 24 and an upper shaping mold 26, the latter being the subject of this invention. The mold 26 is covered with a refractory cloth cover 28, such as fiber glass, to insulate the glass from the mold 26. The upper vacuum mold 26 has a rigid upper mounting plate 30 and a flexible apertured lower wall 32. The lower wall 32 is shaped to conform with the shape desired for the glass sheet to be shaped. Referring to FIGS. 1 and 2 as required, the upper vacuum mold 26 which communicates with a source of vacuum (not shown) though an evacuation pipe 34 and a suitable valve (not shown) is suitably connected through upper vertical guide rods 36 to a support frame (not shown) and is vertically movable via a piston arrangement 37 relative to the frame. The evacuation pipe 34 may be connected through a suitable valve arrangement to a source of pressurized air (not shown). The valves for the vacuum line and for the pressure line may be synchronized according to a predetermined time cycle in a manner well known in the art. The lower shaping mold 24 comprises an upper surface 38 which generally complement the shape of lower wall 32 of the upper mold 26. The upper surface 38 is interrupted by intermittently transversely extending grooves 40 which provide clearance for raising and lowering the lower shaping mold 24 between a recessed position below the conveyor rolls 22 and an upper position above the level of the conveyor rolls 22.
Referring to FIG. 2, the lower wall 32 of the upper vacuum mold 26 is connected to the upper mounting plate 30 through a plurality of adjustable connectors 42. T-shape member 44 is fixed to the lower wall 32 in any convenient manner. In the preferred embodiment, the member 44 is welded to the lower wall 32. A clevis member 46 is fitted over the stem section 48 of the T-shape member 44 and rotatably secured thereto by a bolt assembly 50 passing through the clevis 46 and the stem section 48. A threaded rod 52 extends from the clevis 46 through a hole 54 in the upper mounting plate 30 and is secured thereto by nuts 56 and 58. By capturing the upper mounting plate 30 between the nuts 56 and 58, the shape of the lower wall 32 is adjusted for shaping glass and firmly secured through the adjustable connectors 42, e.g. as taught in U.S. Pat. No. 4,052,185 which teachings are hereby incorporated by reference.
In order to seal the open edge area between upper mounting plate 30 and lower wall 32 to form a central vacuum chamber 60, a non-porous, high heat resistant material is used. In the preferred embodiment, the peripheral edge portion 62 of the fiber glass cover 28 is used to seal the chamber 60. The fiber glass cover 28 is drawn across the apertured lower wall 32 with end portion 62 spanning between the plate 30 and wall 32 and is removably fastened to the plate 30 by clamps 64 or any other convenient means. The portion 62 is coated with a heat resistant silicone rubber, e.g. Dow Corning 736 Silastic® RTV, or other heat resistant sealant to prevent airflow therethrough and to form a pliable, vacuum seal. Although not required for the vacuum mold to function, the use of resistant silicone rubber allows the peripheral edge portion 62 to maintain some flexibility. When a vacuum is drawn in the chamber 60 through the evacuating pipe 34, the coated fiber glass cloth seals the space between the plate 30 and the wall 32 so that the air enters the chamber 60 only through the apertured lower wall 32.
To adjust the curvature of the lower wall 32, the rubber impregnate end portion 62 of the fiber glass cover 28 are disconnected from the upper plate 30 and dropped, exposing the internal adjusting connectors 42. With this arrangement, the spacing between the upper mounting plate 30 and the lower wall 32 could be reduced, but still must be large enough to permit the use of suitable adjusting wrenches. The nuts 56 and 58 are loosened and tightened as a pair to increase or decrease the spacing between the upper plate 30 and the lower wall 32.
It has been found that when the shaping station 16 is positioned close to the exit end of the furnace 12, the heat from the furnace 12 tends to breakdown the heat resistant sealant used to coat the portion 62 of the cover 28. To solve this problem, a coated close-weave screen can be used. As shown in FIG. 3 a screen 66 is attached by any convenient means, around the periphery of the lower wall 32 and secured to the upper plate 30 by clamps or other removable means. The screen 66 is then coated with a heat resistant sealant. By removing the clamps, the coated screen can be pulled back to facilitate easy access to the adjustable connectors 42 in the vacuum chamber 60. The uncoated fiber glass cover 28 would cover both the lower wall 32 and the sealant coated screen 66 providing additional protection against the heat from the furnace 12. In practice a coated wire screen, tack welded around the periphery of the lower wall 32 and clamped to the upper plate 32, has been successfully employed to seal the vacuum chamber 60.
As an additional alternative, any heat resistant impervious material, such as heat resistant plastic films can be detachably secured between the upper mounting plate 30 and the lower wall 32 to seal the chamber 60. Metal foils have been successfully used in place of the coated screen 66.
It should be noted that although the specific embodiments of this invention are directed towards a shaping mold for a heat deformable material, such as glass, the teaching of this invention can be applied to any application where a vacuum chamber is used. The form of the invention shown and described in this disclosure represents an illustrative preferred embodiment thereof. It is understood that various changes may be made without the departing from the gist of the invention except insofar as defined the claimed subject matter that follows.
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A vacuum mold for shaping hot glass sheets having a rigid back plate, a flexible perforated lower shaping wall, adjustable spacers positioned between the back plate and shaping wall and easily removable side wall members that seal the vacuum chamber and allow easy access to the internal adjustable spacers. The peripheral edge portions of a refractory cloth which covers the mold is coated with heat resistant silicone rubber to seal the vacuum chamber of the mold.
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CROSS REFERENCE TO RELATED APPLICATIONS
This application is a divisional application of U.S. patent application Ser. No. 13/097,449, for Selectable Filters for a Visual Prosthesis, which claims priority to U.S. Provisional Ser. No. 61/330,098 for Selectable Filter for a Visual Prosthesis filed on Apr. 30, 2010, and is related to U.S. patent application Ser. No. 11/893,260, filed Aug. 15, 2007 for Visor for a Visual Prosthesis, published as 2008/0154336, both of which are incorporated herein by reference in their entirety.
GOVERNMENT RIGHTS NOTICE
This invention was made with government support under grant No. R24EY12893-01, awarded by the National Institutes of Health. The government has certain rights in the invention.
FIELD
The present disclosure is generally directed to neural stimulation and more specifically to a visual prosthetic apparatus for retinal stimulation.
BACKGROUND
As intraocular surgical techniques have advanced, it has become possible to apply stimulation on small groups and even on individual retinal cells to generate focused phosphenes through devices implanted within the eye itself. This has sparked renewed interest in developing methods and apparatuses to aid the visually impaired. Specifically, great effort has been expended in the area of intraocular retinal prosthesis devices in an effort to restore vision in cases where blindness is caused by photoreceptor degenerative retinal diseases such as retinitis pigmentosa and age related macular degeneration which affect millions of people worldwide.
Neural tissue can be artificially stimulated and activated by prosthetic devices that pass pulses of electrical current through electrodes on such a device. The passage of current causes changes in electrical potentials across visual neuronal membranes, which can initiate visual neuron action potentials, which are the means of information transfer in the nervous system.
Based on this mechanism, it is possible to input information into the nervous system by coding the information as a sequence of electrical pulses which are relayed to the nervous system via the prosthetic device. In this way, it is possible to provide artificial sensations including vision.
One typical application of neural tissue stimulation is in the rehabilitation of the blind. Some forms of blindness involve selective loss of the light sensitive transducers of the retina. Other retinal neurons remain viable, however, and may be activated in the manner described above by placement of a prosthetic electrode device on the inner (toward the vitreous) retinal surface (epiretinal). This placement must be mechanically stable, minimize the distance between the device electrodes and the visual neurons, and avoid undue compression of the visual neurons.
In 1986, Bullara (U.S. Pat. No. 4,573,481) patented an electrode assembly for surgical implantation on a nerve. The matrix was silicone with embedded iridium electrodes. The assembly fit around a nerve to stimulate it.
Dawson and Radtke stimulated cat's retina by direct electrical stimulation of the retinal ganglion cell layer. These experimenters placed nine and then fourteen electrodes upon the inner retinal layer (i.e., primarily the ganglion cell layer) of two cats. Their experiments suggested that electrical stimulation of the retina with 30 to 100 uA current resulted in visual cortical responses. These experiments were carried out with needle-shaped electrodes that penetrated the surface of the retina (see also U.S. Pat. No. 4,628,933 to Michelson).
The Michelson '933 apparatus includes an array of photosensitive devices on its surface that are connected to a plurality of electrodes positioned on the opposite surface of the device to stimulate the retina. These electrodes are disposed to form an array similar to a “bed of nails” having conductors which impinge directly on the retina to stimulate the retinal cells. U.S. Pat. No. 4,837,049 to Byers describes spike electrodes for neural stimulation. Each spike electrode pierces neural tissue for better electrical contact. U.S. Pat. No. 5,215,088 to Norman describes an array of spike electrodes for cortical stimulation. Each spike pierces cortical tissue for better electrical contact.
The art of implanting an intraocular prosthetic device to electrically stimulate the retina was advanced with the introduction of retinal tacks in retinal surgery. De Juan, et al. at Duke University Eye Center inserted retinal tacks into retinas in an effort to reattach retinas that had detached from the underlying choroid, which is the source of blood supply for the outer retina and thus the photoreceptors. See, e.g., de Juan, et al., 99 Am. J. Ophthalmol 272 (1985). These retinal tacks have proved to be biocompatible and remain embedded in the retina, with the choroid/sclera, effectively pinning the retina against the choroid and the posterior aspects of the globe. Retinal tacks are one way to attach a retinal array to the retina. U.S. Pat. No. 5,109,844 to de Juan describes a flat electrode array placed against the retina for visual stimulation. U.S. Pat. No. 5,935,155 to Humayun describes a retinal prosthesis for use with the flat retinal array described in de Juan.
Off the shelf miniature cameras used in visual prostheses, or other common miniaturized cameras suitable for mounting in a pair of glasses, have difficulty responding to high intensity lighting conditions and different cameras can have different color responses, which is not ideal. Electronic compensation is not possible in some cases where the camera is saturated. Further electronic compensation requires processing time that can be better allocated to other visual prosthesis functions.
SUMMARY
The present invention is a visual prosthesis including a visor with an embedded camera and an optical filter to limit light entering the lens of the camera. This invention will allow use of custom filters to limit light intensity or certain light frequencies sent to the camera of the visual prosthesis in a variety of brightness conditions which will remove glare. It will allow modification of the color of the light sent to camera of the visual prosthesis to respond to different environments.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 is a schematic view of the visor of the preferred visual prosthesis.
FIGS. 2 and 3 show perspective views of the preferred visor of a visual prosthetic apparatus.
FIG. 4 is a shade wheel for an alternative embodiment.
FIG. 5 is the alternative visor using a shade wheel.
FIG. 6 shows a perspective view of the implantable portion of the visual prosthesis.
FIG. 7 is a side view of the implantable portion of the visual prosthesis.
DETAILED DESCRIPTION
The glasses or visor 1 may have a sliding lens cover 7 that can be placed in front of the camera 3 lens on the visor 1 as shown in FIG. 1 . The camera may be mounted in the bridge of the glasses. The sliding lens cover 7 may be made of dark shade transparent material to limit the intensity of light falling on the camera 3 lens. Based on the ambient light conditions, the user can utilize this feature to limit bright light. The sliding cover 7 material may provide a choice of ND (Normal Density), Graded Neutral Density, normal density plus ultraviolet (ND+UV), Color filters, high contrast filters, or there filters as are commonly known for use for eye glasses. Desired available filters can be combined into a single lens cover and placed linearly side by side. Incorporating a longer sliding travel, each section of filter can come in front of the lens for desired effect.
FIGS. 2 and 3 show two different perspective views of an external portion of a visual prosthetic apparatus according to the present disclosure. ‘External’ is here meant to indicate that the portion is external to the human body, and not implanted therein. The external portion includes the visor 1 and is adapted to be used in combination with an implantable portion 23 , shown in FIGS. 6 and 7 . Turning to FIGS. 2 and 3 , the external portion 1 comprises a frame 2 holding a camera 3 , an external coil arrangement 4 and a mounting system 5 for the external coil arrangement 4 . The external coil arrangement 4 comprises external transmitting and receiving radio-frequency (RF) coils adapted to be used together and communicate with an internal RF coil (later shown in FIGS. 6 and 7 ). The mounting system 5 also encloses the RF circuitry for modulating, demodulating, transmitting, and receiving an RF signal. External coil arrangement 4 and mounting system 5 are connected by a flexible connector 6 .
Alternatively the filter lens cover can be hinged from the top of the frame and flipped down when needed (not shown). Alternatively the lens may be hinged to the side of the camera and flipped sideway when needed (also not shown). Referring to FIGS. 4 and 5 , alternatively the filters can be arranged on a composite circular lens cover in pie chart segment as shown in FIG. 4 . FIG. 5 shows the composite circular lens cover 8 in front of the camera 4 lens. The composite circular lens cover 8 is attached to a bearing at its center and mounted to glasses. The rotating circular lens cover 8 will allow the desired filter section to be placed in front of the camera 3 lens. Another Alternate embodiment is to integrate the actual lens cover mounted into the glasses frame so that it is not visible from the front. The integration can be applicable for both linear travel lens cover ( FIG. 1 ) as well as rotating lens cover ( FIG. 5 ).
FIG. 6 shows a perspective view of an implantable portion 23 of a retinal prosthesis as disclosed. An electrode array 24 is mounted by a retinal tack or similar means to the epiretinal surface. The electrode array 24 is electrically coupled by a cable 25 , which can pierce the sclera and be electrically coupled to an electronics package 26 external to the sclera. Electronic package 26 includes the RF receiver and electrode drivers.
The electronics package 26 can be electrically coupled to the secondary inductive coil 27 . In one aspect, the secondary inductive coil 27 is made from wound wire. Alternatively, the secondary inductive coil may be made from a thin film polymer sandwich with wire traces deposited between layers of thin film polymer. The secondary coil receives power and data from the primary coil 4 which is external to the body. The electronics package 26 and secondary inductive coil 27 are held together by a molded body 28 . The molded body 28 may also include suture tabs 29 . The molded body narrows in a fan tail 31 to form a strap 30 which surrounds the sclera and holds the molded body 28 , secondary inductive coil 27 , and electronics package 26 in place. The molded body 28 , suture tabs 29 and strap 30 are preferably an integrated unit made of silicone elastomer. Silicone elastomer can be formed in a pre-curved shape to match the curvature of a typical sclera. Furthermore, silicone remains flexible enough to accommodate implantation and to adapt to variations in the curvature of an individual sclera. In one aspect, the secondary inductive coil 27 and molded body 28 are oval shaped, and in this way, a strap 30 can better support the oval shaped coil.
The entire implantable portion 23 is attached to and supported by the sclera of a subject. The eye moves constantly. The eye moves to scan a scene and also has a jitter motion to prevent image stabilization. Even though such motion is useless in the blind, it often continues long after a person has lost their sight. By placing the device under the rectus muscles with the electronics package in an area of fatty tissue between the rectus muscles, eye motion does not cause any flexing which might fatigue, and eventually damage, the device.
FIG. 7 shows a side view of the implantable portion of the retinal prosthesis, in particular, emphasizing the fan tail 31 . When the retinal prosthesis is implanted, the strap 30 has to be passed under the eye muscles to surround the sclera. The secondary inductive coil 27 and molded body 28 should also follow the strap under the lateral rectus muscle on the side of the sclera. The implantable portion 23 of the retinal prosthesis is very delicate. It is easy to tear the molded body 28 or break wires in the secondary inductive coil 27 . In order to allow the molded body 28 to slide smoothly under the lateral rectus muscle, the molded body is shaped in the form of a fan tail 31 on the end opposite the electronics package 26 . Element 32 shows a retention sleeve, while elements 33 and 34 show holes for surgical positioning and a ramp for surgical positioning, respectively.
In summary, a visual prosthetic apparatus is provided. The apparatus provides a means for adjusting the light received by the camera. While the invention has been described by means of specific embodiments and applications thereof, it is understood that numerous modifications and variations could be made thereto by those skilled in the art without departing from the spirit and scope of the invention. It is therefore to be understood that within the scope of the claims, the invention may be practiced otherwise than as specifically described herein.
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The present invention is a visual prosthesis including a visor with an embedded camera and an optical filter to limit light entering the lens of the camera. This invention will allow use of custom filters to limit light intensity or certain light frequencies sent to the camera of the visual prosthesis in a variety of brightness conditions which will remove glare. It will allow modification of the color of the light sent to camera of the visual prosthesis to respond to different environments.
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RELATIONSHIP TO PRIOR APPLICATION
This application for U.S. patent is a continuation-in-part of application Ser. No. 24,139, filed Mar. 26, 1979, now U.S. Pat. No. 4,215,104.
FIELD OF THE INVENTION
The present invention relates to a specially configurated multi-scored variously configurated tablet structure constituting a unitary dosage having readily severable sections which may be divided accurately and separated conveniently into multi-sectional sub-dosage units for patient consumption. The score markings are disposed specially such as along the top and bottom surfaces. Additionally, score markings may appear along opposite vertical side surfaces of the tablet.
BACKGROUND OF THE INVENTION
It is well known in the pharmaceutical art that tablets may be formed with a groove or score marking to facilitate breakage of the tablet into sub-dosage units. Typically, these tablets are configurated circularly with a transverse score marking disposed along the top surface of the tablet such that the tablet may be severed into half-sections. One example of such a tablet is that disclosed by Geller, in U.S. Pat. No. 3,883,647. Another example of a tablet having surface score lines and a circular configuration except severable into quarter-sections is the maltese-cross scored tablet disclosed by Languaer in U.S. Pat. No. 3,723,614.
Because of the inherent difficulties of breaking a grooved tablet into accurate predetermined parts, a variety of diverse attempts have been made in the prior art seeking tablet structures which are readily fractured into sub-dosage units by application of moderate manual pressure. One example of such an attempt is that disclosed by Kraus et al., in U.S. Pat. No. 3,336,200, where two half sections having a highly tapered top surface which join at a score line positioned along the diameter of the tablet. These diverse attempts to improve the convenience and accuracy of breaking a grooved tablet into predetermined parts have achieved limited success at best.
Inherently, the problem of breaking a grooved circular tablet resides in the hardness factor which results from tablet forming presses coupled with the small size configuration which does not allow for either ease of handling or breaking. A typical attempt to sever such circular tablet is by means of a sharp knife or related instrument which results more often than not, in facture of the tablet into undesired miniature pieces. In cases where the severing into two pieces is successful, the pressure which is required along the score marking frequently propels both sections from the initial location unless extreme care is used to contain the two pieces during the breaking operation.
In order to overcome the problem of breaking circular tablets because of the hardness factor and small size, prior art attempts have also been made to configurate oblong tablets having score lines disposed transversely along the top surface. One example of such a tablet is that disclosed by Zellers in U.S. Pat. No. 2,052,376. These oblong tablet configurations have also realized limited success in providing a solution to a readily, accurately severable unitary dosage tablet into sub-dosage units. Also, although tablets such as those disclosed by Zellers are oblong in appearance, the transverse cross-sectional configuration thereof is typically cylindrical. This configuration invites disadvantages associated with inclusion of sufficient amounts of active ingredients in a configuration which may be readily consumed without suffering patient discomfort.
One of the well recognized advantages of having a readily dividable tablet is that it permits the administration of a plurality of sub-dosage units thereby avoiding costs for specially preparing an individual tablet for each dosage unit.
It has now been found that by practice of the present invention, unitary dosage tablets may be prepared having specially disposed score markings which permit breakage of the unitary dosage tablet into multi-sectional sub-dosage units in a convenient, accurate manner. Thus, a number of the disadvantages inherent in prior art attempts to provide a solution to tablet breakage into accurate sub-dosage units which may be conveniently consumed by a patient have now been overcome by practice of the present invention.
SUMMARY OF THE INVENTION
The present invention generally stated provides a new, improved multi-scored tablet constituting a unitary dosage having readily severable sections which may be divided accurately and separated conveniently into multi-sectional sub-dosage units.
Generally, tablets of the present invention have score markings disposed selectively along top, bottom, and vertical wall surfaces of a unitary tablet body.
In one general embodiment, the present multi-fractionable tablet has a multi-angular configuration with specially disposed transverse score markings positioned along both the top, and bottom surfaces.
In another general embodiment, the present multi-fractionable tablet has an approximately circular or elliptical vertical wall configuration with two vertical score markings roughly equally positioned along opposite vertical side wall sections of the tablet with intermediately disposed score markings positioned along both the top and bottom surfaces thereof.
In yet another general embodiment, the present multi-fractionable table has an approximately circular or elliptical vertical wall configuration with two transverse score markings disposed along the top surface thereof and defining approximately equal trisectional dosage units in configuration with a longitudinal score marking disposed along the bottom surface of the tablet and defining approximately equal bisectional dosage units.
It is an object of the present invention to provide a multi-fractionable tablet structure prepared in a unitary dosage amount and having score markings disposed selectively such that the tablet may be conveniently fractured into multi-sectional dosage units as desired for patient consumption.
It is also an object of the present invention to provide a multi-fractionable unitary tablet body which may be readily prepared using conventional tablet forming presses, and yet provide a tablet having specially positioned score markings such that the unitary dosage tablet may be readily and conveniently fractured into at least either bisectional or tri-sectional dosage units as desired for patient consumption.
These and other objects and advantages of the present invention will become more readily apparent from the more detailed description of preferred embodiments taken in conjunction with the drawings wherein similar elements are identified by like numerals throughout the several views.
DESCRIPTION OF THE FIGURES
FIG. A is a perspective view of a multi-fractionable pharmaceutical tablet illustrating one embodiment of the present invention;
FIG. B is a top view of the pharmaceutical tablet of FIG. A;
FIG. C is a bottom view of the tablet of FIG. A;
FIG. D is a transverse cross-sectional view of the pharmaceutical tablet of FIG. B taken along sectional lines D--D,
FIG. E is a perspective view of another embodiment multi-fractionable pharmaceutical tablet of the present invention;
FIG. F is a bottom view of the pharmaceutical tablet of FIG. E;
FIG. G is a longitudinal cross-sectional view of the pharmaceutical tablet of FIG. E taken along sectional lines G--G;
FIG. H is a perspective view of yet another embodiment multi-fractionable pharmaceutical tablet of the present invention;
FIG. I is a longitudinal cross-sectional view of the pharmaceutical tablet of FIG. H taken along sectional lines I--I;
FIG. J is a top view of the pharmaceutical tablet of FIG. H;
FIG. K is a perspective view of yet another embodiment multi-fractionable pharmaceutical tablet of the present invention;
FIG. L is a transverse cross-sectional view of the pharmaceutical table of FIG. K taken along sectional lines L--L;
FIG. M is a top view of the pharmaceutical tablet of FIG. K;
FIG. N is a perspective view of yet another embodiment multi-fractionable pharmaceutical tablet of the present invention;
FIG. O is a top view of the pharmaceutical tablet of FIG. N;
FIG. P is a bottom view of the pharmaceutical tablet of FIG. N;
FIG. Q is a perspective view of yet another embodiment multi-fractionable pharmaceutical tablet of the present invention;
FIG. R is a top view of the pharmaceutical tablet of FIG. Q;
FIG. S is a bottom view of the pharmaceutical tablet of FIG. Q;
FIG. T is a perspective view of yet another embodiment pharmaceutical tablet of the present invention;
FIG. U is a top view of the pharmaceutical tablet of FIG. T;
FIG. V is a bottom view of the pharmaceutical tablet of FIG. T;
FIG. W is a perspective view of yet another embodiment pharmaceutical tablet of the present invention;
FIG. X is a top view of the pharmaceutical tablet of FIG. W; and
FIG. Y is a bottom view of the pharmaceutical tablet of FIG. W.
DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS
FIGS. A-D illustrate pharmaceutical table 230 having bevel edge 232 disposed about the bottom peripheral edge thereof with bevel edge 234 disposed about the peripheral edge of top surface 235. These bevel edges may vary as desired and typically range from about 25° to about 50° from the horizontal plane. The side walls of pharmaceutical tablet 230 define an approximate pentagon by wall surfaces 236. On the top surface 235 of tablet 230, there are disposed score 238 and score 240 which originate at one vertical wall edge 242 defining an apex and terminate at oppositely disposed vertical wall edges 244 and 246 respectively, defining base wall 247 of the pentagonal configuration.
Bottom surface 248 of pharmaceutical tablet 230 includes score line 250 which approximately parallels base wall 247.
For consumption purposes, pharmaceutical tablet 230 may be administered as a unitary dosage. In the event a partial dosage is desired, the tablet may be fractured conveniently along score markings 238, while an approximate one-third dosage may be administered by fracturing the tablet respectively along score markings 238 and 240. It will also be appreciated that an approximate one-half dosage may be administered by fracturing the tablet along score markings 250. In the event all of the score lines are used; namely, score lines 238, 240, and 250, it is then possible to provide as many as six multi-fracture dosages.
FIGS. E-G illustrate an embodiment pharmaceutical tablet 252 of the present invention having bevel edge 254, similar to that of tablet 230, disposed about the bottom peripheral edge, with bevel edge 256 correspondingly positioned about the top peripheral edge.
Pharmaceutical tablet 252 is illustrated with hexagonal vertical walls, wall members 258 being approximately equal in length and joined by shorter, parallel walls 260, so as to provide equal trisectional units when fractured along score lines 262 and 264. It will be apparent that parallel walls 260 may be of equivalent length or even longer than wall members 258 if desired. It is preferred to have two of the vertical wall members, such as walls 260, disposed in parallel when comprising the embodiment tablet of FIG. E-G. This feature expedites more effective fracture of this tablet along the top surface 261 by means of score lines 262 and 264 which join the apex where parallel walls 260 unite with wall members 258.
Disposed along the bottom surface 266 of pharmaceutical tablet 252 is score line 268 which joins the two apex sections formed where the respective pairs of wall members 258 unite.
When it is desired to fracture tablet 252 into multi-dosages, fracture may be effected along score lines 262 and 264 which results in up to three multi-dosage portions, or separately along score line 268 which results in two multi-dosage portions. Should one desire, fracture of tablet 252 may be effected along the top and bottom score lines in which case up to six multi-dosage portions result.
FIGS. H-J illustrate an elliptical embodiment pharmaceutical tablet 270 of the present invention having vertical walls 272, top surface 274 with bevel edges 276, and bottom surface 278 with bevel edges 280. The bevel edges are similar in configuration to those of pharmaceutical tablet 230 of FIGS. A-D.
On the top surface of pharmaceutical tablet 270 are two score lines 282 and 284, respectively with intermediately disposed vertical score lines 286 and 288. Score lines 286 and 288 are approximately oppositely positioned along vertical walls 272.
Fracture of the elliptical embodiment pharmaceutical tablet of FIGS. H-J may be effected along score lines 282 and 284 which provides three equal multi-dosage portions, or separately between score lines 286 and 288 which results in two equal multi-dosage portions.
FIGS. K-M illustrate another elliptical embodiment pharmaceutical tablet 290 of the present invention having vertical walls 292, top surface 294 with bevel edges 296, and bottom surface 298 with bevel edges 300. The bevel edges are similar in configuration to those of pharmaceutical tablet 230 of FIGS. A-D.
On the top surface of pharmaceutical tablet 290 is one intermediate score line 302, with two disposed vertical pairs of score lines 304 and 306, and 308 and 310, respectively. One pair of score lines 304 and 306 are approximately oppositely positioned along vertical walls 292 to the second pair of score lines 308 and 310.
Fracture of the elliptical embodiment pharmaceutical tablet of FIGS. K-M may be effected along the two sets of score lines 304 and 306, and 308 and 310 which provides three equivalent multi-dosage portions, or separately along score line 302 which results in two equivalent multi-dosage portions.
FIGS. N-P illustrate yet another elliptical embodiment pharmaceutical tablet 312 of the present invention having vertical walls 314, top surface 316 with bevel edges 318, and bottom surface 320 with bevel edges 322. Again, the bevel edges are similar in configuration to those of pharmaceutical tablet 230 of FIGS. A-D.
On the top surface 316 of pharmaceutical tablet 312 are two score lines 324 and 326, respectively, with intermediately disposed bottom score lines 328.
Fracture of the elliptical embodiment pharmaceutical tablet 312 of FIGS. N-P may be effected along score lines 324 and 326 which provides three equivalent multi-dosage portions, or separately along bottom score line 328 which results in two equivalent multi-dosage portions.
FIGS. Q-S illustrate a circular embodiment pharmaceutical tablet 330 of the present invention having vertical walls 332, top surface 334 with bevel edges 336, and bottom surface 338 with bevel edges 340. Again, the bevel edges are similar in configuration to those of pharmaceutical tablet 230 of FIGS. A-D.
On the top surface 334 of pharmaceutical tablet 330 are two score lines 342 and 344, respectively, with vertical wall score lines 346 and 348 positioned to effect a transverse breakage to that of score lines 342 and 344. Score lines 348 and 346 are approximately oppositely positioned along vertical wall surface 332.
Fracture of the circular embodiment pharmaceutical tablet 330 of FIGS. Q-S may be effected along score lines 342 and 344 which provides three equivalent multi-dosage portions, or separately along score lines 346 and 348 which results in two equivalent multi-dosage portions. Again, should one desire, fracture of tablet 330 may be effected along each of score lines 342-344 346-348 in which case up to six multi-dosage portions result.
FIGS. T-V illustrate another circular embodiment pharmaceutical tablet 350 of the present invention having vertical walls 352, top surface 354 with bevel edges 356, and bottom surface 358 with bevel edges 360. Again, the bevel edges are similar in configuration to those of pharmaceutical tablet 230 of FIGS. A-D.
On the top surface 354 of pharmaceutical tablet 350 are two score lines 362 and 364, respectiely, with vertical wall score lines 366 and 368 positioned to effect a parallel intermediate to that of score lines 362 and 364. Score lines 366 and 368 are approximately oppositely positioned along vertical wall surface 352.
Fracture of the circular embodiment pharmaceutical tablet 350 of FIGS. T-V may be effected along score lines 362 and 364 which provides three equivalent multi-dosage portions, or separately along score lines 366 and 368 which results in two equivalent multi-dosage portions.
FIGS. W-Y illustrate yet another circular embodiment pharmaceutical tablet 370 of the present invention having vertical walls 372, top surface 374 with bevel edges 376, and bottom surface 378 with bevel edges 380. Again, the bevel edges are similar in configuration to those of pharmaceutical tablet 230 of FIGS. A-D.
On the top surface 374 of pharmaceutical tablet 370 is one score line 382 with two bottom score lines 384 and 386 positioned to effect a transverse breakage to that of score line 382.
Fracture of the circular embodiment pharmaceutical tablet 370 of FIG. W-Y may be effected along score line 382 which provides two equivalent multi-dosage portions, or separately along score lines 184 and 186 which results in three equivalent multi-dosage portions. Again, should one desire, fracture of tablet 370 may be effected along side line 382 as well as along score lines 384 and 386 in which case up to six multi-dosage portions result.
The score markings may be at a V-groove angle of about 40° to 65°, and preferably about 45° to 60°, with each V-groove depth being about 1/8 to about 1/3 into the respective depth of the tablet.
The present multi-fractionable tablet structure includes specially positioned score markings for accurate multi-sectional fracture of the tablet.
Tablets of the present invention may be composed of a variety of ingredients such as one or more active pharmaceutical ingredients, fillers, lubricants, carriers, flavoring ingredients or the like as desired. These materials are well known to skilled tablet formulators.
Although it has not been specificially disclosed herein, it will be appreciated that the present multi-fractionable tablet structure may be specially marked with a corporate logo or otherwise colored as desired to reflect particular dosage units being consumed. Also, the present tablet may be coated with suitable materials well known in the tablet formation art.
Having described the present invention with particular reference to the disclosed embodiments, it will be obvious to those skilled in this art, that various changes and modifications may be made therein without departing from the spirit and scope of the invention which is disclosed and claimed herein.
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The invention disclosed provides a multi-fractionable tablet structure initially configurated in a unitary dosage while having readily severable sub-dosage units as components thereof. Score markings are positioned variously about the tablet such as along the top and bottom surfaces thereof. Additionally, score markings may appear along opposite vertical side surfaces of the tablet. Special placement of the score markings readily permits alternatively an accurate equal bisectional or trisectional fracture of the tablet as may be desired for patient consumption.
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BACKGROUND OF THE INVENTION
[0001] 1. Field of the Invention
[0002] The present invention relates to a wheeled vehicle, in particular to an earth-moving vehicle or an excavating vehicle, which is provided with a chassis, an axle that oscillates with respect to the chassis about a longitudinal axis, and a pair of hydraulic cylinders controlled for blocking oscillation of the axle in some operating conditions of the vehicle.
[0003] 2. Description of the Background of the Invention
[0004] In known vehicles of the type just described, the two cylinders are coupled to the chassis on side parts set opposite to one another with respect to the longitudinal axis, extend in a direction transverse to the axle, and comprise respective liners, each of which is connected to the chassis by means of a corresponding fixing device.
[0005] This fixing device comprises a plate welded to the liner of the cylinder and set resting on a side surface of the chassis and a plurality of screws, each of which extends through the plate and is screwed into the chassis.
[0006] In use, the axle exerts on the cylinders a vertical thrust load that is transferred from the plate to the chassis. In optimal conditions, the pull with which the screws are screwed is such that the thrust load is transferred onto the chassis exclusively through the friction present between the side surfaces of the plate and the chassis, which are coupled together by resting against one another, without exerting shear stress on the screws.
[0007] When instead the pull with which the screws are screwed slackens off with passage of time and use of the vehicle, the plate tends to transfer the aforesaid thrust load, no longer directly onto the chassis, but onto the side surface of the screws, thus subjecting the screws themselves to shear stresses, which reduce the life of the screws.
[0008] The purpose of the preferred embodiment is to provide a wheeled vehicle equipped with a chassis, an axle that oscillates with respect to the chassis, and a pair of cylinders for blocking the axle, which will enable the problem set forth above to be solved in a simple and economically advantageous way.
[0009] According to the present invention, a wheeled vehicle includes a chassis; an axle coupled to the chassis to oscillate about a longitudinal axis parallel to a direction of advance of the vehicle; a pair of cylinders disposed between the axle and the chassis for blocking oscillation of the axle; and a fixing assembly for fixing the cylinders to the chassis, the fixing assembly comprising a plate, a plurality of connection screws extending through the plate, at least one annular rest portion affixed in cantilever fashion to one of the chassis and the plate, the annular rest portion surrounding a corresponding one of the plurality of connection screws and defining a shoulder that supports the plate in a radial direction with respect to the axis of the connection screw.
[0010] Preferably, the annular rest portion defines a cylindrical shoulder, which is coaxial to the connection screw, forms part of a bushing fixedly connected to the chassis, and engages a cylindrical seat made in the plate and having a diameter rounding off upwards that of the cylindrical shoulder.
BRIEF DESCRIPTION OF THE DRAWINGS
[0011] [0011]FIG. 1 is a schematic plan view of a preferred embodiment of the wheeled vehicle equipped with an oscillating axle, according to a preferred embodiment of the present invention;
[0012] [0012]FIG. 2 is a schematic and partial front view of the vehicle of FIG. 1;
[0013] [0013]FIG. 3 is a partial, cross-sectional front view of an axle that oscillates with respect to its own chassis for use in a wheeled vehicle including a pair of cylinders for blocking the axle, according to a preferred embodiment of the present invention; and
[0014] [0014]FIG. 4 is an exploded view of some details of FIG. 3, partially sectioned according to the line II-II of FIG. 3 itself.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
[0015] In FIGS. 1 and 2, the reference number 1 designates an earth-moving wheeled vehicle comprising a bottom chassis 2 and a top chassis 55 , which is equipped with a driving cab 58 and an operating arm 59 of a known type, for example an excavating arm, which extends in cantilever fashion from the chassis 55 .
[0016] The chassis 2 , 55 are coupled together by means of a rotating thrust-bearing device 105 (illustrated schematically and partially in FIG. 2), which enables a relative rotation of the bottom and top chassis 2 , 55 themselves about a vertical axis 115 .
[0017] With reference to FIG. 2, the vehicle 1 further comprises a front axle 3 , which carries the front wheels 518 and is coupled to the chassis 2 (in a known way and not described in detail herein) to enable oscillation about a longitudinal axis 4 parallel to a direction of advance of the vehicle 1 and hence to enable the vehicle 1 to adapt to the irregularities of the terrain during the vehicle's advance.
[0018] Oscillation of the axle 3 can be blocked by means of two hydraulic cylinders 5 of a known type, which extend in a direction transverse to the axle 3 itself and each of which comprises a corresponding liner 7 fixed to the chassis 2 and a corresponding rod 9 , which can slide with respect to the liner 7 and is set resting, at its end, against a corresponding axle shaft 10 of the axle 3 . The cylinders 5 define respective rear chambers (not illustrated), which communicate with one another through a pipe and which contain oil, the flow of which from one cylinder 5 to the other through the pipe is controlled by a hydraulic control unit of a known type.
[0019] In FIG. 3, the front axle 3 (partially and schematically illustrated) is coupled to the chassis 2 in a known way (not illustrated) to enable oscillation about a median longitudinal axis 4 , orthogonal to the plane of FIG. 3 and parallel to a direction of advance of the vehicle 1 . The oscillation of the axle 3 with respect to the chassis 2 enables the vehicle 1 to adapt to the irregularities of the terrain during vehicle advance and can be blocked by means of two hydraulic cylinders 5 , of which only one is illustrated in FIG. 3. The cylinders 5 are set on opposite side parts of the chassis 2 , extend along respective vertical axes 6 transverse to the axle 3 , and each cylinder comprises a corresponding liner 7 , fixed to the chassis 2 by means of a fixing device 8 , and a corresponding rod 9 , which can slide axially with respect to the liner 7 between a retracted position and an extended position (illustrated by a dashed line).
[0020] Each rod 9 is set resting against a corresponding axle shaft 10 of the axle 3 and in use receives from this axle shaft 10 an axial thrust S, which is directed upwards and, in use, is transferred, first from the rod 9 to the liner 7 , and then from the latter to the chassis 2 through the device 8 .
[0021] According to what is illustrated in the attached figures, the device 8 comprises a plate 12 , which is fixedly connected to the liner 7 by means of welding and by a plurality of screws 13 (just two of which are illustrated in FIG. 1), which extend along respective axes 14 orthogonal to the axes 4 and 6 .
[0022] Each screw 13 comprises a corresponding head 15 axially coupled to the plate 12 by interposition of a washer 16 , and a corresponding shaft 17 , which extends through the washer 16 , engages with radial play G 1 a corresponding through hole 18 of the plate 12 , and terminates with a threaded stretch 19 , which is screwed into the chassis 2 .
[0023] With particular reference to FIG. 2, the device 8 further comprises, for each screw 13 , a corresponding bushing 21 , which is coaxial to the screw 13 , is fitted about the screw 13 itself with radial play G 2 , and comprises an external radial projection 22 .
[0024] The projection 22 is set resting axially, on one side, against the chassis 2 and, on the other, against the plate 12 , and is delimited radially by an external cylindrical surface 25 welded to the chassis 2 .
[0025] The bushing 21 further comprises two terminal portions 23 , 24 which extend in cantilever fashion from opposite axial parts of the projection 22 . The portion 23 defines a centering appendage, which engages a corresponding centering seat 27 made in the chassis 2 substantially without radial play, while the portion 24 engages a corresponding cylindrical seat 29 , defined by a terminal stretch of the hole 18 , and has a diameter that rounds off downwards that of the seat 29 itself, in such a way as to define a shoulder 30 or external cylindrical surface designed to support the plate 12 in a radial direction with respect to the axis 14 in the absence of a sufficient pull of the screw 13 .
[0026] In use, when the vehicle 1 is new, the pull of each screw 13 is such as to transfer the thrust S from the plate 12 to the chassis 2 through the contact and friction present between a surface 31 axially delimiting the plate 12 and a surface 32 axially delimiting the projection 22 (see FIG. 2) and by means of the welding seam between the projection 22 and the chassis 2 . Consequently, in this optimal operating condition, the plate 12 does not exert shearing forces 12 , either on the bushings 21 on account of the corresponding sizing of the diameters of the shoulder 30 and of the seat 29 , or on the screws 13 thanks to the presence of the play G 1 and G 2 .
[0027] With the passage of time and with use of the vehicle 1 , the pull of the screws 13 can slacken off, in which case the internal surfaces of the seats 29 come to rest on the respective shoulders 30 of the bushings 21 , which start to support the plate 12 in a radial direction with respect to the axes 14 .
[0028] In this operating condition, the thrust S is transferred from the plate 12 to the chassis 2 owing to a shear stress, which, however, is not exerted on the screws 13 , but on the bushings 21 thanks to the coupling between the portions 24 and the seats 29 . The bushings 21 have a diameter much greater than that of the screws 13 , so that they have a resistance to shear stresses that is in general much greater than that of normal screws. The screws 13 continue not to be shear stressed once again on account of the presence of the play G 1 and G 2 .
[0029] Finally, from the foregoing it emerges clearly that in the vehicle 1 described, the presence of the portions 24 between the plate 12 and the screws 13 provides a reliable device 8 with a relatively long life, in so far as it prevents shear stresses on the screws 13 .
[0030] The fact that the portions 24 surround the screws 13 coaxially to the screws 13 themselves enables the screws 13 to support shear stresses in any radial direction with respect to the axes 14 , and not only unidirectional shear stresses directed from below upwards.
[0031] The presence and the conformation of the bushings 21 enable installation of the device 8 in a simple way and appropriate sizing of the diameter of the portions 24 themselves. In particular, the projection 22 enables convenient welding of the bushings 21 to the chassis 2 .
[0032] Finally, from the foregoing it emerges clearly that modifications and variations can be made to the device 8 described herein with reference to the attached figures, without thereby departing from the scope of protection of the present invention.
[0033] In particular, the portions 24 could be other than cylindrical and/or could be integral with one between the chassis 2 and the plate 12 .
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A wheeled vehicle including a chassis; an axle coupled to the chassis to oscillate about a longitudinal axis parallel to a direction of advance of the vehicle; a pair of cylinders disposed between the axle and the chassis for blocking oscillation of the axle; and a fixing assembly for fixing the cylinders to the chassis, the fixing assembly comprising a plate, a plurality of connection screws extending through the plate, at least one annular rest portion affixed in cantilever fashion to one of the chassis and the plate, the annular rest portion surrounding a corresponding one of the plurality of connection screws and defining a shoulder that supports the plate in a radial direction with respect to the axis of the connection screw.
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TECHNICAL FIELD
The present invention relates to a perovskite type complex oxide infrared reflective material and a method of producing the same. The present invention also relates to a coating material and a resin composition containing the infrared reflective material, and further an infrared reflector using the coating material.
BACKGROUND ART
Infrared reflective materials are materials that reflect infrared rays included in sunlight or the like. The infrared reflective materials are used for relaxation of a heat island phenomenon, increase in air conditioning efficiency of buildings in summer, and the like because the infrared reflective materials can reduce the amount of infrared rays absorbed by a ground surface covered with asphalt, concrete, or the like, buildings, and the like.
As such an infrared reflective material, compounds containing chromium such as Cr 2 O 3 , Cu—Cr complex oxides, Fe—Cr complex oxides, Co—Fe—Cr complex oxides, and Cu—Cr—Mn complex oxides as black materials, for example, are known (see Patent Document 1). Compounds not containing chromium including complex oxides of an alkaline earth metal element and manganese such as Ca—Mn complex oxides, Ba—Mn complex oxides, and Ba—Mn complex oxides doped with 4% by weight of titanium dioxide (see Patent Document 2) and a complex oxide of a rare earth element and manganese such as Y—Mn complex oxide (see Patent Document 3) are also known. Compounds such as rod-like titanium oxide (see Patent Document 4) as white materials are also under development.
CITATION LIST
Patent Documents
PATENT DOCUMENT 1: JP 2000-72990 A
PATENT DOCUMENT 2: U.S. Pat. No. 6,416,868
PATENT DOCUMENT 3: JP 2002-038048 A
PATENT DOCUMENT 4: JP 2006-126468 A
SUMMARY OF INVENTION
Problems to be Solved by the Invention
While many of the black infrared reflective materials contain a heavy metal such as Cu, Cr, and Co, use of materials containing such a heavy metal strongly tends to be withheld. Development of materials not using Cr is urgently necessary particularly for concern about the safety. However, a problem is that the complex oxide of an alkaline earth metal element and manganese has a large amount of the alkaline earth metal to be eluted in water, and thus infrared reflectivity is reduced along with elution. In the complex oxide of a rare earth element and manganese, a problem that is pointed out is high cost because of use of an expensive rare earth element as a raw material. Moreover, much more improvement in reflectance on a long wavelength side of an infrared region is demanded of rod-like titanium oxide, which is one of the white infrared reflective materials.
Means for Solving the Problems
With development of a novel infrared reflective material, the present inventors found out that a perovskite type complex oxide containing an alkaline earth metal element and at least one element selected from titanium, zirconium, and niobium has high infrared reflectivity. The present inventors also found out that a complex oxide containing this complex oxide and a manganese element and/or an iron element serves as a black material having sufficient infrared reflectivity. Further, the inventors found out that the two complex oxides have higher infrared reflectivity when a Group IIIa element in the periodic table such as aluminum and gallium and a zinc element are contained in the two complex oxides.
The present inventors also found out that the infrared reflective material can be produced by mixing an alkaline earth metal compound with a compound of at least one element selected from titanium, zirconium, and niobium, and firing a mixture thereof; and in the case where a manganese element and/or an iron element or a Group IIIa element in the periodic table and a zinc element are contained, the infrared reflective material can be produced by further mixing a manganese compound and/or an iron compound or a compound of the Group IIIa element in the periodic table and a zinc compound when the alkaline earth metal compound is mixed with the compound of the at least one element selected from titanium, zirconium, and niobium, and firing the mixture. The inventors found out that because the thus-obtained perovskite type complex oxide is in the form of a powder, the perovskite type complex oxide can be blended with a coating material or a resin composition to be used for various applications, and completed the invention.
Namely, the present invention is an infrared reflective material comprising a perovskite type complex oxide containing at least an alkaline earth metal element and at least one element selected from titanium, zirconium, and niobium. Moreover, the present invention is an infrared reflective material comprising a perovskite type complex oxide further containing a manganese element and/or an iron element in the complex oxide. Further, the present invention is an infrared reflective material comprising a perovskite type complex oxide further containing a Group IIIa element in the periodic table such as aluminum and gallium and a zinc element in the two complex oxides.
Moreover, the present invention is a method of producing the perovskite type complex oxide infrared reflective material, a coating material and resin composition containing the perovskite type complex oxide infrared reflective material, and an infrared reflector onto which the coating material is applied.
Advantages of the Invention
The infrared reflective material according to the present invention is a perovskite type complex oxide containing at least an alkaline earth metal element and at least one element selected from titanium, zirconium, and niobium, and has sufficient infrared reflectivity. Moreover, a black material having sufficient infrared reflectivity is obtained by further containing a manganese element and/or an iron element in this complex oxide. Further, the two perovskite type complex oxides have higher infrared reflectivity when a Group IIIa element in the periodic table such as aluminum and gallium and a zinc element are contained in the two perovskite type complex oxides.
Such an infrared reflective material has high thermal stability and heat resistance because inorganic components stable with respect to heat are used, and has no concern about safety and environmental problems because chromium is not contained. Additionally, the infrared reflective material is resistant to dissolution in water, and reduction in infrared reflectivity caused by elution is small.
For that reason, the infrared reflective material can be used for relaxation of the heat island phenomenon and the like by applying the infrared reflective material to roofs and outer walls of buildings, or applying the infrared reflective material to roads and pavements.
In addition, the infrared reflective material can be produced relatively inexpensively because without using any expensive raw material, and because the infrared reflective material can be produced in the air.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 is an electron micrograph showing a form of particles of Sample g obtained in Example 33;
FIG. 2 is an electron micrograph showing a form of particles of Sample i obtained in Example 35;
FIG. 3 is an electron micrograph showing a form of particles of Sample j obtained in Example 36; and
FIG. 4 is a diagram showing particle size distribution of Sample g obtained in Example 33 (expressed with ▪ in the diagram), and that of Sample i obtained in Example 35 (expressed with ● in the diagram).
DESCRIPTION OF EMBODIMENTS
An infrared reflective material according to the present invention is a perovskite type complex oxide containing at least an alkaline earth metal element, at least one element selected from titanium, zirconium, and niobium, and an oxygen element. Examples of the perovskite type structure include an ABO 3 type structure (wherein A is one or more alkaline earth metal elements, B is at least one element selected from titanium, zirconium, and niobium, and O is an oxygen element); and a layered perovskite type structure (n(ABO 3 ).AO (wherein A, B, and O are the same as those mentioned above, the layered perovskite type structure can be expressed as A n+1 B n O 3n+1 , and has a structure such that an AO layer is interposed between two perovskite units of ABO 3 . Specifically, examples of the layered perovskite type structure include Ca 3 Ti 2 O 7 and Ca 4 Ti 3 O 10 )). For this reason, the content of the alkaline earth metal element and the content of at least one element selected from titanium, zirconium, and niobium are properly adjusted to form desired perovskite type structure. Earth metal element, at least one selected from calcium, strontium, and barium is preferable because those have high infrared reflectivity, and form a complex oxide having a perovskite type structure. Magnesium is an alkaline earth metal element. Because single use of magnesium cannot usually form the perovskite type structure but forms an ilmenite type structure, it is not preferable. However, a complex oxide having a perovskite type structure is obtained by using an alkaline earth metal element other than magnesium, e.g., calcium, strontium, and barium, in combination with a magnesium element as an alkaline earth metal element. In addition, the complex oxide has infrared reflectivity higher than that of those to which magnesium is not added, and has particularly high near-infrared reflectivity. Accordingly, addition of magnesium is preferable. The content of magnesium can be properly set according to desired performance of infrared reflectivity or the like. The atomic ratio of the magnesium element (Mg) to an alkaline earth metal (A) other than magnesium (the ratio of the number of magnesium atoms to the number of alkaline earth metal atoms other than magnesium, and sometimes referred to as a molar ratio) is preferably 1.0×10 −6 ≦Mg/A≦0.20, and more preferably 1.0×10 −6 ≦Mg/A≦0.12. Here, “Mg” designates the number of moles of element of magnesium, and “A” designates the number of moles of element of alkaline earth metal other than magnesium.
The infrared reflective material according to the present invention further contains a Group IIIa element in the periodic table such as boron, aluminum, gallium, and indium in the perovskite type complex oxide containing an alkaline earth metal element, at least one element selected from titanium, zirconium, and niobium, and an oxygen element. Containing of the Group IIIa element in the periodic table is more preferable because infrared reflectivity is higher than that of those to which the Group IIIa element in the periodic table is not added. Containing of at least one selected from aluminum and gallium among the Group IIIa elements in the periodic table is more preferable because particularly high near-infrared reflectivity is obtained. The Group IIIa element in the periodic table may exist on the particle surface of the perovskite type complex oxide and/or within the particles of the perovskite type complex oxide, and preferably exists within the particles of the perovskite type complex oxide. The content of the Group IIIa element in the periodic table can be properly set according to performances such as desired infrared reflectivity. An amount of 0.0005≦Al/B≦1.5 in the atomic ratio (molar ratio) of the Group IIIa element (Al) in the periodic table to the at least one element (B) selected from titanium, zirconium, and niobium is preferably contained. Here, “Al” designates the number of moles of the Group IIIa element in the periodic table, and “B” designates the number of moles of the at least one element selected from titanium, zirconium, and niobium. A value of the atomic ratio (molar ratio) of these Al/B is preferably in the range of 0.0005 to 1.5, because high infrared reflectivity is obtained, more preferably 0.001≦Al/B≦0.45, still more preferably 0.005≦Al/B≦0.35, and most preferably 0.005≦Al/B≦0.25. Due to an insufficient effect of addition, a value of Al/B smaller than 0.0005 is not preferable. Because production of another phase is started, a value of Al/B larger than 1.5 is not preferable.
Moreover, the infrared reflective material according to the present invention further contains a zinc element in the perovskite type complex oxide containing an alkaline earth metal element, at least one element selected from titanium, zirconium, and niobium and an oxygen element or in the perovskite type complex oxide further containing a Group IIIa element in the periodic table. Containing of the zinc element is preferable because infrared reflectivity is higher than that of those to which the zinc element is not added. The zinc element may exist on the particle surface of the perovskite type complex oxide and/or within the particles of the perovskite type complex oxide, and preferably exists within the particles of the perovskite type complex oxide. The content of the zinc element can be properly set according to performances such as desired infrared reflectivity. An amount of 1.0×10 −6 ≦Zn/B≦0.20 in the atomic ratio (molar ratio) of the zinc element (Zn) to the at least one element (B) selected from titanium, zirconium, and niobium is preferably contained. Here, “Zn” designates the number of moles of the zinc element, and “B” designates the number of moles of the at least one element selected from titanium, zirconium, and niobium. A value of the atomic ratio (molar ratio) of these Zn/B is preferably in the range of 1.0×10 −6 to 0.20 because high infrared reflectivity is obtained, more preferably 1.0×10 −6 ≦Zn/B≦0.15, and still more preferably 0.005≦Zn/B≦0.12. Because of an insufficient effect of addition, a value of Zn/B smaller than 1.0×10 −6 is not preferable. Because production of another phase is started or a drastic change in the color of the powder is observed, a value of Zn/B larger than 0.20 is not preferable.
In the case where the infrared reflective material according to the present invention has the ABO 3 type perovskite type structure, the ratio of α/β is usually adjusted so as to be 1 when the content of the alkaline earth metal element is α mol, the total content of the at least one element selected from titanium, zirconium, and niobium, the Group IIIa element in the periodic table, and the zinc element is β mol. A composition wherein 1<α/β≦1.5, namely, the content of the alkaline earth metal element of more than 1 time and not more than 1.5 times is more preferable because the infrared reflective material of the composition has infrared reflectivity higher than that of the composition of α/β=1 and has particularly high near-infrared reflectivity. A still more preferable range is 1<α/β<1.1.
A complex oxide that is a perovskite type complex oxide containing at least an alkaline earth metal element and at least one element selected from titanium, zirconium, and niobium, and does not contain a manganese element and/or an iron element mentioned later is a white material, and has high reflectance. Specifically, when near-infrared reflectivity is represented by reflectance of near infrared rays of sunlight at a wavelength in the range of 700 to 2100 nm (hereinafter sometimes referred to as solar reflectance, which is calculated by multiplying a weighting factor that expresses energy distribution of the sunlight by a spectral reflectance according to JIS R 3106), the solar reflectance is preferably not less than 70%, more preferably not less than 80%, and still more preferably not less than 90%. The whiteness of the complex oxide is preferably not less than 75, more preferably not less than 80, and still more preferably not less than 85, when the whiteness is expressed by a lightness L* value of CIE 1976 Lab (L*a*b* color system) (whiteness is larger as the L* value is larger). Thus, the infrared reflective material according to the present invention can have an increased lightness L* value, and therefore can be used as a white pigment.
Moreover, an a* value and a b* value of the L*a*b* color system determined in the same manner as in the case of the L* value are indices showing hue and saturation. The a* value larger toward the positive side shows that the color is redder, while the a* value larger toward the negative side shows that the color is greener. The b* value larger toward the positive side shows that the color is yellower, while the b* value larger toward the negative side shows that the color is bluer. In the complex oxide, the a* value can suppress redness to be approximately −3 to 10, and the b* value can suppress yellowness to be approximately −1 to 10, for example.
The infrared reflective material according to the present invention further contains a manganese element and/or an iron element in the perovskite type complex oxide containing the alkaline earth metal element, at least one element selected from titanium, zirconium, and niobium, and an oxygen element. Containing of the manganese element and/or the iron element increases blackness. The manganese element and the iron element may exist on the particle surface of the perovskite type complex oxide and/or within particles thereof, and preferably exists within the particles of the perovskite type complex oxide. The content of the manganese element and the iron element can be properly set according to performances such as desired infrared reflectivity and blackness. In the case where the manganese element is contained, an amount of 0.01≦Mn/B≦3.0 in the atomic ratio (molar ratio) of manganese (Mn) to the at least one element (B) selected from titanium, zirconium, and niobium is preferably contained. Here, “Mn” expresses the number of moles of the manganese element, and “B” expresses the number of moles of the at least one element selected from titanium, zirconium, and niobium. A value of the atomic ratio (molar ratio) Mn/B in the range of 0.01 to 3.0 is preferable from the viewpoint of infrared reflectivity and blackness, more preferably 0.05≦Mn/B≦3.0, still more preferably 0.1≦Mn/B≦3.0, and most preferably 0.3≦Mn/B≦3.0. Due to insufficient effect of addition and insufficient blackness, a value of Mn/B smaller than 0.01 is not preferable. Because the alkaline earth metal tends to be easily eluted when a value of Mn/B larger than 3.0, a value of Mn/B larger than 3.0 is not preferable. Moreover, in the case where the iron element is contained, an amount of 0.01≦Fe/B≦1.0 in the atomic ratio (molar ratio) of iron (Fe) to the at least one element (B) selected from titanium, zirconium, and niobium is preferably contained. Here, “Fe” designates the number of moles of the iron element, and “B” designates the number of moles of the at least one element selected from titanium, zirconium, and niobium. A value of the atomic ratio (molar ratio) Fe/B in the range of 0.01 to 1.0 is preferable from the viewpoint of infrared reflectivity and blackness, more preferably 0.05≦Fe/B≦0.8, and still more preferably 0.07≦Fe/B≦0.8. Due to insufficient effect of addition and insufficient blackness, a value of Fe/B smaller than 0.01 is not preferable. Because synthesis as a single phase is impossible, a value of Fe/B larger than 1.0 is not preferable. Both of the manganese element and the iron element can also be contained. From the viewpoint of infrared reflectivity and blackness, it is preferable that the content of the manganese element and that of the iron element be in the above-mentioned respective ranges. In the case where the manganese element and the iron element are contained, as the alkaline earth metal element, at least one element selected from calcium, strontium and barium is preferable because of high infrared reflectivity, and because these can form a complex oxide having a perovskite type structure. A complex oxide having a perovskite type structure is obtained by using an alkaline earth metal element other than magnesium, e.g., calcium, strontium, and barium, in combination with a magnesium element as an alkaline earth metal element. In addition, the complex oxide has infrared reflectivity higher than that of those to which magnesium is not added, and has particularly high near-infrared reflectivity. Accordingly, addition of magnesium is more preferable. The content of magnesium can be properly set according to performances such as desired infrared reflectivity. The atomic ratio (molar ratio) of the magnesium element (Mg) to an alkaline earth metal (A) other than magnesium is preferably 1.0×10 −6 ≦Mg/A≦0.20, and more preferably 1.0×10 −6 ≦Mg/A≦0.12. Here, “Mg” designates the number of moles of element of magnesium, and “A” designates the number of moles of element of alkaline earth metal other than magnesium.
Moreover, the infrared reflective material according to the present invention further contains a Group IIIa element in the periodic table such as boron, aluminum, gallium, and indium in the perovskite type complex oxide containing an alkaline earth metal element, at least one element selected from titanium, zirconium, and niobium, an oxygen element, and a manganese element and/or an iron element. Containing of the Group IIIa element in the periodic table is more preferable because infrared reflectivity is higher than that of those to which the Group IIIa element in the periodic table is not added. Containing of at least one selected from aluminum and gallium among the Group IIIa elements in the periodic table is more preferable because particularly high near-infrared reflectivity is obtained. The Group IIIa element in the periodic table may exist on the particle surface of the perovskite type complex oxide and/or within the particles of the perovskite type complex oxide, and preferably exists within the particles of the perovskite type complex oxide. The content of the Group IIIa element in the periodic table can be properly set according to performances such as desired infrared reflectivity. An amount of 0.0005≦Al/B≦1.5 in the atomic ratio (molar ratio) of the Group IIIa element (Al) in the periodic table to at least one element (B) selected from titanium, zirconium, and niobium is preferably contained. Here, “Al” designates the number of moles of the Group IIIa element in the periodic table, and “B” designates the number of moles of the at least one element selected from titanium, zirconium, and niobium. A value of the atomic ratio (molar ratio) of these Al/B is preferably in the range of 0.0005 to 1.5 from the viewpoint of infrared reflectivity and blackness, more preferably 0.001≦Al/B≦1.3, still more preferably 0.005≦Al/B≦1.0. Due to an insufficient effect of addition, a value of Al/B smaller than 0.0005 is not preferable. Because production of another phase is started or the color of the powder is significantly deviated, a value of Al/B larger than 1.5 is not preferable.
Moreover, the infrared reflective material according to the present invention further contains a zinc element in the perovskite type complex oxide containing an alkaline earth metal element, at least one element selected from titanium, zirconium, and niobium, an oxygen element, a manganese element and/or an iron element, or in the perovskite type complex oxide further containing a Group IIIa element in the periodic table such as boron, aluminum, gallium, and indium. Containing of the zinc element is preferable because infrared reflectivity is higher than that of those to which the zinc element is not added. The zinc element may exist on the particle surface of the perovskite type complex oxide and/or within the particles of the perovskite type complex oxide, and preferably exists within the particles of the perovskite type complex oxide. The content of the zinc element can be properly set according to performances such as desired infrared reflectivity. An amount of 1.0×10 −6 ≦Zn/B≦0.20 in the atomic ratio (molar ratio) of the zinc element (Zn) to the at least one element (B) selected from titanium, zirconium, and niobium is preferably contained. Here, “Zn” designates the number of moles of the zinc element, and “B” designates the number of moles of the at least one element selected from titanium, zirconium, and niobium. A value of the atomic ratio (molar ratio) of these Zn/B is preferably in the range of 1.0×10 −6 to 0.2 because high infrared reflectivity is obtained, more preferably 1.0×10 −6 ≦Zn/B≦0.15, and still more preferably 1.0×10 −6 ≦Zn/B≦0.12. Because of an insufficient effect of addition, a value of Zn/B smaller than 1.0×10 −6 is not preferable. Because production of another phase is started or a drastic change in the color of the powder is observed, a value of Zn/B larger than 0.20 is not preferable.
In the case where the infrared reflective material according to the present invention has the ABO 3 type perovskite type structure, the ratio α/β is usually adjusted so as to be 1 when the content of the alkaline earth metal element is cc mol, and the total content of the at least one element selected from titanium, zirconium, and niobium, the manganese element and/or the iron element, the Group IIIa element in the periodic table, and the zinc element is β mol. A composition wherein 1<α/β≦1.5, namely, the content of the alkaline earth metal element of more than 1 time and not more than 1.5 times is more preferable because the composition has infrared reflectivity higher than that of the composition of α/β=1 and has particularly high near-infrared reflectivity. A still more preferable range is 1<α/β<1.1.
The color of the powder changes to black in the perovskite type complex oxide containing at least an alkaline earth metal element, at least one element selected from titanium, zirconium, and niobium, and a manganese element and/or an iron element. The blackness of the complex oxide is preferably not more than 45, more preferably not more than 40, and still more preferably not more than 32, when the blackness is expressed by a lightness L* value of CIE 1976 Lab (L*a*b* color system), which is the same as mentioned above, (blackness is larger as the L* value is smaller). Thus, the infrared reflective material according to the present invention can have a reduced lightness L* value, and therefore can be used as a black pigment.
In the a* value and the b* value of the L*a*b* color system determined in the same manner as the L* value, the a* value can suppress redness to be approximately 0 to 20, and the b* value can suppress yellowness to be approximately −1 to 10, for example. The infrared reflectivity changes according to the color of the powder. A black powder that easily absorbs the infrared rays has infrared reflectivity relatively smaller than that of a white powder that reflects the infrared rays. From this, the complex oxide containing the manganese element and/or the iron element preferably has the solar reflectance of not less than 10%, more preferably not less than 12%, still more preferably not less than 15%, further still more preferably not less than 20%, and most preferably not less than 25%.
Amounts of the alkaline earth metal, at least one element selected from titanium, zirconium, and niobium, manganese, the iron element, the Group IIIa element in the periodic table, and the zinc element contained in the complex oxide are determined with fluorescent X-ray spectrographic analysis. The amount of oxygen necessary to maintain charge balance based on the valence of those components is calculated. The crystalline structure of the complex oxide can also be checked with X-ray diffraction.
In the infrared reflective material according to the present invention, it is thought that solute atoms form a solid solution and are contained within the particles of the complex oxide or the particle surface of the complex oxide by forming a substitutional solid solution in which solvent atoms on the lattice points of the perovskite type complex oxide (specifically, an alkaline earth metal, atoms of at least one selected from titanium, zirconium, and niobium) are replaced by the solute atoms (specifically, manganese, iron atoms, Group IIIa atoms in the periodic table, or zinc atoms), or by forming an interstitial solid solution in which solute atoms enter the lattice gaps of the perovskite type complex oxide. More specifically, it is imagined that a solid solution is formed in which the solvent atoms of at least one selected from titanium, zirconium, and niobium are replaced by the solute atoms of the manganese and/or the iron, the Group IIIa atoms in the periodic table, or the zinc. The complex oxide preferably maintains the perovskite type structure. In the ABO 3 type structure, at a content of the manganese element in the above-mentioned range of 0.01≦Mn/B≦3.0, X in A:B:O:manganese atoms=1:1-X:3:X is approximately in the range of 0.01 to 0.75 in the atomic ratio (molar ratio). In the case where the iron element is contained, at the above-mentioned content of 0.01≦Fe/B≦1.0, Y in A:B:O:iron atoms=1:1-Y:3:Y is approximately in the range of 0.01 to 0.5 in the atomic ratio (molar ratio). Containing of the manganese element, the iron element, the Group IIIa element in the periodic table, or the zinc element can be checked based on the result of the X-ray diffraction that no peak of a phase other than the complex oxide appears.
Impurities derived from various raw materials may be inevitably mixed in the infrared reflective material according to the present invention. Preferably, Cr is not contained as much as possible. Even if Cr is contained as impurities, the content thereof is not more than 1% by weight. Particularly, the content of Cr 6+ that causes concern about safety is preferably not more than 10 ppm.
The infrared reflective material according to the present invention can have various particle forms and particle sizes by changing production conditions. The particle form may be tabular, granular, approximately spherical, needle-like, and indefinite, for example. Preferably, an average particle size (arithmetic mean value of the largest diameter in one particle) measured from an electron micrograph is approximately 0.02 to 20.0 μm. At an average particle size exceeding 20.0 μm, tinting strength is reduced because the particle size is too large. At an average particle size of less than 0.02 μm, dispersion in a coating material may be difficult. For this reason, the average particle size is preferably 0.1 to 5.0 μm, more preferably 0.2 to 4.5 μm, and still more preferably 0.3 to 4.0 μm.
Moreover, preferably, a BET specific surface area value of the infrared reflective material according to the present invention (single point method according to nitrogen absorption) is approximately 0.05 to 80 m 2 /g. At a BET specific surface area value of less than 0.05 m 2 /g, the particles are coarse, or the particles are mutually sintered and thus tinting strength is reduced. More preferably, the BET specific surface area value is 0.2 to 15 m 2 /g, and still more preferably 0.3 to 5 m 2 /g. The BET specific surface area can be measured by a MONOSORB MS-18 (made by Yuasa-Ionics Company, Limited). From this BET specific surface area value, the average particle size wherein the particle form is regarded to be spherical can be calculated with the following expression 1. Preferably, the average particle size calculated from the BET specific surface area value is approximately 0.02 to 30 μm. However, it may be different from the average particle size calculated from the electron micrograph due to an influence of the particle form, particle size distribution, and the like.
L= 6/(ρ· S ), Expression 1
wherein L is an average particle size (μm), ρ is a density of a sample (g/cm 3 ), and S is a BET specific surface area value of the sample (m 2 /g).
The infrared reflective material according to the present invention can be used for coating materials, inks, plastics, ceramics, electronic materials, and the like. In order to enhance dispersibility in a solvent and a resin to be blended, etc., the particle surface thereof may be coated with an inorganic compound and/or an organic compound when necessary. Examples of the inorganic compound preferably include a compound of at least one selected from silicon, zirconium, aluminum, titanium, antimony, phosphorus, and tin. Silicon, zirconium, aluminum, titanium, antimony, and tin are more preferably a compound of oxide, hydrated oxide, or hydroxide. Phosphorus is more preferably a compound of phosphoric acid or phosphate. Examples of the organic compound include organic silicon compounds, organometallic compounds, polyols, alkanolamines or derivatives thereof, higher fatty acids or metal salts thereof, and higher hydrocarbons or derivatives thereof. At least one selected from these can be used.
The infrared reflective material according to the present invention contains an alkaline earth metal element and at least one element selected from titanium, zirconium, and niobium, and contains a manganese element and/or an iron element, a Group IIIa element in the periodic table such as boron, aluminum, gallium, and indium, and a zinc element when necessary. The alkaline earth metal elements, the manganese element, the iron element, and the like may be eluted in water, and are easily eluted particularly in acidic water. For this reason, in the case where water elution properties need to be controlled, it is effective that the particle surface of the infrared reflective material is coated with an inorganic compound. Examples of such an inorganic compound include a compound of at least one selected from silicon, zirconium, aluminum, titanium, antimony, phosphorus, and tin. Silicon, zirconium, aluminum, titanium, antimony, and tin are more preferably a compound of oxide, hydrated oxide, or hydroxide. Phosphorus is more preferably a compound of phosphoric acid or phosphate. Particularly, oxides, hydrated oxides, or hydroxides of silicon and aluminum are preferable. More preferably, the oxides, hydrated oxides, or hydroxides of silicon (hereinafter sometimes referred to as silica) form high-density silica or porous silica. According to the pH range at the time of silica coating treatment, silica used for coating becomes porous or non-porous (high-density). However, high-density silica easily forms fine coating, and has a high effect of controlling the water elution properties of the infrared reflective material, and therefore is more preferable. For that reason, a first coating layer of high-density silica may exist on the particle surface of the infrared reflective material, and a second coating layer of porous silica or an oxide, hydrated oxide, and hydroxide of aluminum (hereinafter sometimes referred to as alumina) may exist thereon. The silica coating can be observed with an electron microscope. The amount of the inorganic compound to be coated can be set properly. For example, 0.1 to 50% by weight is preferable based on the infrared reflective material, and 1.0 to 20% by weight is more preferable. The amount of the inorganic compound can be measured by an ordinary method such as fluorescent X-ray spectrographic analysis and ICP optical emission spectrometry.
The infrared reflective material according to the present invention can be produced using a conventional method for producing a perovskite type complex oxide. Specifically, the following methods or the like can be used: the so-called solid-phase synthesis method comprising mixing an alkaline earth metal compound with a compound of at least one selected from titanium, zirconium, and niobium, and firing the mixture using an electric furnace, a rotary kiln, or the like; the so-called oxalate method comprising synthesizing an alkaline earth metal with an oxalate of at least one selected from titanium, zirconium, and niobium in a water system, and subsequently firing the mixture; the so-called citrate method comprising synthesizing an alkaline earth metal and a citrate of at least one selected from titanium, zirconium, and niobium in a water system, and subsequently firing the mixture; and the so-called hydrothermal synthesis method comprising mixing an aqueous solution of an alkaline earth metal compound and a compound of at least one selected from titanium, zirconium, and niobium with an alkaline aqueous solution, and performing a hydrothermal process, followed by filtering, washing, and drying. Moreover, in the case where the manganese element and/or the iron element, the Group IIIa element in the periodic table, or the zinc element is contained, the followings can be performed. A manganese compound, an iron compound, a compound of a Group IIIa element in the periodic table, or a zinc compound can be added and mixed at the time of mixing an alkaline earth metal compound with a compound of at least one selected from titanium, zirconium, and niobium. A manganese compound, an iron compound, a compound of a Group IIIa element in the periodic table, or a zinc compound can be added, or mixed at the time of synthesizing oxalate or the like in the water system. Alternatively, a manganese compound, an iron compound, a compound of a Group IIIa element in the periodic table, or a zinc compound can be added or fired at the time of firing a mixture of an alkaline earth metal compound with a titanium compound, or firing a synthesized product.
In the present invention, a solid-phase synthesis method comprising mixing and firing an alkaline earth metal compound and a compound of at least one selected from titanium, zirconium, and niobium is preferable because a perovskite type complex oxide having a proper particle size is obtained. In the case where an alkaline earth metal element other than magnesium as an alkaline earth metal element and a magnesium element are used in combination, a solid-phase synthesis method comprising mixing and firing a compound of such an alkaline earth metal and a compound of at least one selected from titanium, zirconium, and niobium is preferable because a perovskite type complex oxide having a proper particle size is obtained. Moreover, in the case where a manganese element and/or an iron element is contained, a method comprising adding and mixing a manganese compound and/or an iron compound and firing the mixture at the time of mixing an alkaline earth metal compound with a compound of at least one selected from titanium, zirconium, and niobium is preferable because a perovskite type complex oxide having a proper particle size is obtained. Moreover, in the case where a Group IIIa element in the periodic table or a zinc element is contained, a method comprising adding and mixing the Group IIIa compound in the periodic table or a zinc compound, and firing the mixture at the time of mixing an alkaline earth metal compound with a compound of at least one selected from titanium, zirconium, and niobium, or when necessary a manganese compound and/or an iron compound is preferable because a perovskite type complex oxide having a proper particle size is obtained. By adding and mixing a manganese compound, an iron compound, a Group IIIa compound in the periodic table, or a zinc compound at the time of mixing an alkaline earth metal compound with a compound of at least one selected from titanium, zirconium, and niobium, the manganese element, the iron element, the Group IIIa element in the periodic table, or the zinc element easily exists within the particles of the perovskite type complex oxide, and it is preferable.
In the solid-phase synthesis method, oxides, hydroxides, carbonates, and the like can be used as the alkaline earth metal compound, and oxides, hydroxides, carbonates, and the like can be used as the compound of at least one selected from titanium, zirconium, and niobium. Oxides thereof, hydroxides thereof, carbonates thereof, and the like can be used as the manganese compound, the iron compound, the compound of the Group IIIa in the periodic table, or the zinc compound. Next, each of the raw material compounds is weighed, and mixed. A mixing method may be any of a dry blending method comprising mixing raw material compounds in the state of a powder, and a wet blending method comprising mixing raw material compounds in the state of a slurry, and can be performed using the conventional mixers such as stirring mixing machines. Mixing can also be performed using various kinds of grinders, spray driers, granulators, molding machines, and the like at the time of crushing, drying, granulation, and molding. In the case where a manganese compound, an iron compound, a compound of the Group IIIa in the periodic table, or a zinc compound is mixed, and the amounts of these compounds are small, these compounds are made to exist within the particle surface of the compound of at least one selected from titanium, zirconium, and niobium and/or the particles thereof in advance. This is preferable because the solid-phase synthesis reaction is uniformly performed and thus a uniform infrared reflective material is easily obtained. From this, by depositing the manganese compound, the iron compound, the compound of the Group IIIa in the periodic table, or the zinc compound on the particle surface of the compound such as oxides, hydrated oxides, hydroxides, and the like of at least one selected from titanium, zirconium, and niobium in advance, and making these compounds to exist therein or by making these compounds to exist within the particles of such a compound in advance, the manganese element, the iron element, the Group IIIa element in the periodic table, or the zinc element easily exists within the particles of the perovskite type complex oxide, and it is preferable. The method is not particularly limited, and a known method can be used.
Next, the mixture of the raw material compounds is granulated and molded when necessary, and subsequently fired. The temperature of firing may be at least a temperature at which the raw material compounds make a solid-phase reaction. For example, the temperature may be in the range of 1000 to 1500° C. While the atmosphere at the time of firing may be any atmosphere, firing in the air is preferable in order to keep a sufficient infrared reflectivity. At the time of firing, a fusing agent such as sodium chloride and potassium chloride may be added. A firing time can be set properly, and is preferably for 0.5 to 24 hours and more preferably for 1.0 to 12 hours. At a firing time shorter than 0.5 hours, often the reaction does not sufficiently progress. On the other hand, at a firing time longer than 24 hours, hardness of the particles may be increased by sintering, or unusually coarse particles may be produced.
Moreover, in the solid-phase synthesis method, in order to perform the firing reaction more uniformly or in order to make the particle size of the infrared reflective material more uniform, a firing treatment agent (particle size regulating agent) may be added to the mixture of the raw material compounds and fired. As such a firing treatment agent, alkali metal compounds, silicon compounds such as silica and silicate, tin compounds such as tin oxide and tin hydroxide, and the compounds of the Group IIIa elements in the periodic table such as boron, aluminum, gallium, and indium can also be used. However, the firing treatment agent is not limited to these, and various inorganic compounds or organic compounds can be used. While the amount of the firing treatment agent (particle size regulating agent) to be added can be set properly, an amount not to reduce infrared reflectivity is preferable. Particularly, addition of the alkali metal compound to the mixture of the raw material compound and firing is preferable because an infrared reflective material having more uniform particle size is easily obtained. In addition, addition of the alkali metal compound also has an advantage that crushing after firing is relatively easy. Even if the alkali metal compound remains in the obtained infrared reflective material, any adverse influence on infrared reflectivity is not recognized, and the remaining alkali metal compound can be dissolved by rinsing to be removed. As the alkali metal compound, potassium compounds such as potassium chloride, potassium sulfate, potassium nitrate, and potassium carbonate, sodium compounds such as sodium chloride, sodium sulfate, sodium nitrate, and sodium carbonate, and lithium compounds such as lithium chloride, lithium sulfate, lithium nitrate, and lithium carbonate, and the like can be used. The amount of the alkali metal compound to be added in terms of conversion of an alkali metal into an oxide (K 2 O, Na 2 O, Li 2 O, or the like) is preferably 0.01 to 15 parts by weight based on 100 parts by weight of the mixture of the raw material compounds, and more preferably 0.1 to 6 parts by weight.
Crystallinity of the complex oxide is further increased by firing the complex oxide obtained by the method, particularly by the solid-phase synthesis method again. This can suppress water elution properties of the alkaline earth metal elements, the manganese element, and the iron element, and is preferable. The temperature of firing the complex oxide again is preferably in the range of 200 to 1500° C., and more preferably 400 to 1200° C. While the atmosphere at the time of firing the complex oxide again may be any atmosphere, firing in the air is preferable in order to keep a sufficient infrared reflectivity. The time of firing the complex oxide again can be set properly, and is preferably for 0.5 to 24 hours and more preferably for 1.0 to 12 hours.
A conventional surface treatment method used for a titanium dioxide pigment or the like can be used to coat the particle surface of the thus-obtained infrared reflective material with an inorganic compound or an organic compound. Specifically, it is preferable that an inorganic compound or an organic compound be added to a slurry of the infrared reflective material for coating, and more preferable that the inorganic compound or the organic compound be neutralized in the slurry to deposit for coating. Alternatively, the inorganic compound or the organic compound may be added to powder of the infrared reflective material, and mixed for coating.
Specifically, to perform high-density silica coating on the particle surface of the infrared reflective material, first, an aqueous slurry of the infrared reflective material is adjusted at pH of not less than 8 and preferably at 8 to 10 with an alkali compound such as sodium hydroxide, potassium hydroxide, and ammonia, for example. Then, the aqueous slurry is heated to not less than 70° C. and preferably to 70 to 105° C. Next, a silicate is added to the aqueous slurry of the infrared reflective material. As the silicate, various silicates such as sodium silicate and potassium silicate can be used. Addition of the silicate is usually preferably performed over not less than 15 minutes, and more preferably over not less than 30 minutes. Next, after addition of the silicate is completed, further full stirring and mixing are performed when necessary. Then, the slurry is neutralized with an acid while the temperature of the slurry is kept at not less than 80° C. and more preferably at not less than 90° C. Examples of the acid used here include sulfuric acid, hydrochloric acid, nitric acid, phosphoric acid, and acetic acid. These can adjust the pH of the slurry preferably at not more than 7.5 and more preferably at not more than 7 so that the particle surface of the infrared reflective material can be coated with high-density silica.
Moreover, to perform porous silica coating on the particle surface of the infrared reflective material, first, an acid such as sulfuric acid, hydrochloric acid, nitric acid, phosphoric acid, and acetic acid is added to an aqueous slurry of the infrared reflective material to adjust pH at 1 to 4 and preferably at 1.5 to 3. The temperature of the slurry is preferably adjusted at 50 to 70° C. Next, while the pH of the slurry is kept in the range, a silicate and an acid are added to form a coating of porous silica. As the silicate, various silicates such as sodium silicate and potassium silicate can be used. Addition of the silicate is usually preferably performed over not less than 15 minutes, and more preferably over not less than 30 minutes. After addition of the silicate is completed, an alkali compound is added when necessary to adjust the pH of the slurry at approximately 6 to 9. Thus, the particle surface of the infrared reflective material can be coated with porous silica.
On the other hand, to perform alumina coating on the particle surface of the infrared reflective material, preferably, first, a slurry of the infrared reflective material is neutralized at pH of 8 to 9 with an alkali such as sodium hydroxide, and heated to a temperature of not less than 50° C., and next, an aluminum compound and an aqueous acid are added concurrently. As the aluminum compound, aluminates such as sodium aluminate and potassium aluminate can be suitably used. As the aqueous acid, aqueous solutions of sulfuric acid, hydrochloric acid, nitric acid, and the like can be suitably used. The concurrent addition means a method for continuously or intermittently adding a small amount of the aluminum compound and a small amount of the aqueous acid separately to a reactor. Specifically, it is preferable that the aluminum compound and the aqueous acid be simultaneously added over approximately 10 minutes to 2 hours while the pH in the reactor is kept at 8.0 to 9.0. Preferably, after adding the aluminum compound and the aqueous acid, the aqueous acid is further added to adjust the pH at approximately 5 to 6.
Crystallinity of the complex oxide is further increased by firing the complex oxide coated with the inorganic compound or organic compound again. This can suppress water elution properties of the alkaline earth metal elements, the manganese element, and the iron element, and is preferable. The temperature of firing the complex oxide again is preferably in the range of 200 to 1500° C., and more preferably in the range of 400 to 1200° C. While the atmosphere at the time of firing the complex oxide again may be any atmosphere, firing in the air is preferable in order to keep a sufficient infrared reflectivity. The time of firing the complex oxide again can be set properly, and is preferably for 0.5 to 24 hours and more preferably for 1.0 to 12 hours.
The complex oxide obtained by the method can be used in various forms such as powder and a molded body. In the case where the complex oxide is used as powder, it may be properly ground when necessary to adjust the particle size thereof. In the case where the complex oxide is used as a molded body, the powder thereof may be molded into an appropriate size and shape. As a mill, impact mills such as hammer mills and pin mills, grinding mills such as roller mills and pulverizers, and stream mills such as jet mills can be used, for example. As a molding machine, general-purpose molding machines such as extrusion machines and granulators can be used, for example.
Moreover, while the infrared reflective material according to the present invention has sufficient infrared reflectivity, mixing of a compound having other infrared reflectivity or a compound having an infrared shielding (absorption) ability can further enhance infrared reflectivity, or can complement reflective performance at a specific wavelength. As the compound having infrared reflectivity or the compound having an infrared shielding (absorption) ability, those conventionally used can be used. Specifically, examples thereof include inorganic compounds such as titanium dioxide, antimony-doped tin oxide, tungsten oxide, and lanthanum boride, and metal powders such as metallic silver powder and metallic copper powder. Titanium dioxide and metal powder are more preferable. The kind and mixing proportion of the compound having infrared reflectivity or the compound having an infrared shielding (absorption) ability can be properly selected according to application thereof.
Moreover, the infrared reflective material according to the present invention has a color of white or black. Mixing of other pigment to this can further strengthen whiteness or blackness, or can provide the infrared reflective material having a color such as red, yellow, green, blue, and intermediate colors thereof. As the pigment, inorganic pigments, organic pigments, lake pigments, and the like can be used. Specifically, examples of the inorganic pigment include white pigments such as titanium dioxide, zinc white, and precipitated barium sulfate, red pigments such as iron oxide, blue pigments such as ultramarine blue and Prussian blue (potassium ferric ferrocyanide), black pigments such as carbon black, and pigments such as aluminum powder. Examples of the organic pigment include organic compounds such as anthraquinone, perylene, phthalocyanine, azo compounds, and azo methiazo compounds. The kind and mixing proportion of the pigment can be properly selected according to the color and hue.
Next, the present invention is a coating material characterized by containing the infrared reflective material, and the coating material according to the present invention includes a composition called an ink. Moreover, the present invention is a resin composition characterized by containing the infrared reflective material. Moreover, the present invention is an infrared reflector, wherein the coating material prepared by blending the infrared reflective material is applied onto a base material.
The infrared reflective material according to the present invention is contained in resins for coating materials, inks, and plastic molded products such as films. Thereby, a composition using the excellent infrared reflectivity of the infrared reflective material can be obtained. Such coating materials, inks, and resin compositions can contain an arbitrary amount of the infrared reflective material based on the resin. The amount of the infrared reflective material is preferably not less than 0.1% by weight, more preferably not less than 1% by weight, and still more preferably not less than 10% by weight. In addition, a composition forming material used in each field may be blended, and various kinds of additives may be further blended.
In the case where the infrared reflective material is used as the coating material and the ink, specifically, other than a coating film forming material or an ink film forming material, a solvent, a dispersing agent, a pigment, a filler, an aggregate, a thickener, a flow controlling agent, a leveling agent, a curing agent, a crosslinking agent, a catalyst for curing, and the like can be blended. As the coating film forming material, organic components such as acrylic resins, alkyd resins, urethane resins, polyester resins, and amino resins, and inorganic components such as organosilicate, organotitanate, cement, and gypsum can be used, for example. As the ink film forming material, urethane resins, acrylic resins, polyamide resins, salt vinyl acetate resins, chlorinated propylene resins, and the like can be used. Various kinds of resins such as heat-curable resins, resins curable at room temperature, and ultraviolet-curable resins can be used for these of the coating film forming material and the ink film forming material without limitation. Using an ultraviolet-curable resin of a monomer or an oligomer, a photopolymerization initiator and a photosensitizer are blended. The obtained mixture is applied, and irradiated with ultraviolet light to cure the ultraviolet-curable resin. Thereby, without applying thermal load to the base material, a coating film having high hardness and adhesion is preferably obtained.
The coating material according to the present invention can be applied onto a base material to produce an infrared reflector. This infrared reflector can be used as an infrared shielding material and as a thermal insulation material. As a base material, those of various materials and various quality can be used. Specifically, various building materials, civil engineering materials, and the like can be used. The produced infrared reflector can be used as a roof material, a walling material, and a flooring material for houses and factories, and a paving material that forms roads and pavements. The thickness of the infrared reflector can be arbitrarily set according to various applications. For example, in the case where the infrared reflector is used as a roof material, the thickness thereof is usually 0.1 to 0.6 mm, and preferably 0.1 to 0.3 mm. In the case where the infrared reflector is used as a paving material, the thickness thereof is usually 0.5 to 5 mm and preferably 1 to 5 mm. In order to apply the coating material onto the base material, a method for applying or spraying and a method using a trowel are possible. After applying, the coating may be dried, burned, or cured when necessary.
In the case where the infrared reflective material is used as a resin composition, a resin, a pigment, a dye, a dispersing agent, a lubricant, an antioxidant material, an ultraviolet absorbing agent, a light stabilizer, an antistatic agent, a flame retardant, a sanitizer, and the like are kneaded with the infrared reflective material according to the present invention, and are molded into an arbitrary form such as a film form, a sheet form, and a plate form. As the resin, thermoplastic resins such as polyolefin resins, polystyrene resins, polyester resins, acrylic resins, polycarbonate resins, fluororesins, polyamide resins, cellulosic resins, and polylactic resins, and heat-curable resins such as phenol resins and urethane resins can be used. Such a resin composition can be molded into an arbitrary form such as a film, a sheet, and a plate, and can be used as infrared reflectors for industrial uses, agricultural uses, and home uses. The composition can be used also as a thermal insulation material that shields infrared rays.
EXAMPLES
Hereinafter, the present invention will be described using Examples and Comparative Examples, but the present invention will not be limited to those Examples.
Example 1
3.68 g of calcium carbonate CaCO 3 (made by Kojundo Chemical Laboratory Co., Ltd., purity of 99.99%) and 2.94 g of high purity titanium dioxide (PT-301 made by Ishihara Sangyo Kaisha, Ltd., purity of 99.99%) were sufficiently mixed and stirred with an agate mortar. Then, a predetermined amount of the mixture was placed into an alumina crucible, and fired at 1200° C. for 4 hours to obtain calcium titanate (CaTiO 3 ) having a perovskite type structure (Sample A).
The specific surface of Sample A was 1.03 m 2 /g, and the average particle size calculated from the value was 0.72 μm. The content of chromium was not more than a measurement limit of detection.
Example 2
4.02 g of strontium carbonate SrCO 3 (made by Kojundo Chemical Laboratory Co., Ltd., purity of 99.99%) and 2.18 g of high purity titanium dioxide (PT-301 made by Ishihara Sangyo Kaisha, Ltd., purity of 99.99%) were sufficiently mixed and stirred with an agate mortar. Then, a predetermined amount of the mixture was placed into an alumina crucible, and fired at 1200° C. for 4 hours to obtain strontium titanate (SrTiO 3 ) having a perovskite type structure (Sample B) was obtained.
The specific surface of Sample B was 1.33 m 2 /g. The content of chromium was not more than a measurement limit of detection.
Example 3
4.23 g of barium carbonate BaCO 3 (made by Kojundo Chemical Laboratory Co., Ltd., purity of 99.99%) and 1.71 g of high purity titanium dioxide (PT-301 made by Ishihara Sangyo Kaisha, Ltd., purity of 99.99%) were sufficiently mixed and stirred with an agate mortar. Then, a predetermined amount of the mixture was placed into an alumina crucible, and fired at 1200° C. for 4 hours to obtain barium titanate (BaTiO 3 ) having a perovskite type structure (Sample C).
The specific surface of Sample C was 1.39 m 2 /g. The content of chromium was not more than a measurement limit of detection.
Example 4
3.68 g of calcium carbonate CaCO 3 (made by Kojundo Chemical Laboratory Co., Ltd., purity of 99.99%) and 2.94 g of high purity titanium dioxide (PT-301 made by Ishihara Sangyo Kaisha, Ltd., purity of 99.99%) were sufficiently mixed and stirred with an agate mortar. Then, a predetermined amount of the mixture was placed into an alumina crucible, and fired at 1400° C. for 4 hours to obtain calcium titanate (CaTiO 3 ) having a perovskite type structure (Sample D).
The specific surface of Sample D was 0.59 m 2 /g, and the average particle size calculated from the value was 1.23 μm. The content of chromium was not more than a measurement limit of detection.
Example 5
2.79 g of calcium carbonate CaCO 3 (made by Kojundo Chemical Laboratory Co., Ltd., purity of 99.99%) and 3.43 g of zirconium oxide (made by Kojundo Chemical Laboratory Co., Ltd., purity of 99.99%) were sufficiently mixed and stirred with an agate mortar. Then, a predetermined amount of the mixture was placed into an alumina crucible, and fired at 1400° C. for 4 hours to obtain calcium zirconate (CaZrO 3 ) having a perovskite type structure (Sample E). The content of chromium was not more than a measurement limit of detection.
Example 6
3.25 g of strontium carbonate SrCO 3 (made by Kojundo Chemical Laboratory Co., Ltd., purity of 99.99%) and 2.72 g of zirconium oxide (made by Kojundo Chemical Laboratory Co., Ltd., purity of 99.99%) were sufficiently mixed and stirred with an agate mortar. Then, a predetermined amount of the mixture was placed into an alumina crucible, and fired at 1400° C. for 4 hours to obtain strontium zirconate (SrZrO 3 ) having a perovskite type structure (Sample F). The content of chromium was not more than a measurement limit of detection.
Example 7
6.87 g of calcium carbonate CaCO 3 (made by Kojundo Chemical Laboratory Co., Ltd., purity of 99.99%) and 3.65 g of high purity titanium dioxide (PT-301 made by Ishihara Sangyo Kaisha, Ltd., purity of 99.99%) were sufficiently mixed and stirred with an agate mortar. Then, as a fusing agent, 5.26 g of sodium chloride NaCl (made by Kojundo Chemical Laboratory Co., Ltd., purity of 99.99%), and 5.26 g of potassium chloride KCl (made by Kojundo Chemical Laboratory Co., Ltd., purity of 99.99%) were added, and further sufficiently mixed and stirred with the agate mortar. Then, a predetermined amount of the mixture was placed into an alumina crucible, and fired at 1400° C. for 4 hours, and washed with water to obtain calcium titanate (Ca 3 Ti 2 O 7 ) having a layered perovskite type structure (Sample G). The content of chromium was not more than a measurement limit of detection.
Example 8
3.68 g of calcium carbonate CaCO 3 (made by Kojundo Chemical Laboratory Co., Ltd., purity of 99.99%) and 2.93 g of high purity titanium dioxide (PT-301 made by Ishihara Sangyo Kaisha, Ltd., purity of 99.99%), and 0.01 g of aluminum oxide Al 2 O 3 (made by Kojundo Chemical Laboratory Co., Ltd., purity of 99.99%) were sufficiently mixed and stirred with an agate mortar. Then, a predetermined amount of the mixture was placed into an alumina crucible, and fired at 1400° C. for 4 hours to obtain aluminum containing calcium titanate (CaTiO 3 :Al) having a perovskite type structure (Sample H). The atomic ratio (molar ratio) of aluminum and titanium (Al/Ti) was 0.005. The content of chromium was not more than a measurement limit of detection.
Example 9
3.70 g of calcium carbonate CaCO 3 (made by Kojundo Chemical Laboratory Co., Ltd., purity of 99.99%) and 2.86 g of high purity titanium dioxide (PT-301 made by Ishihara Sangyo Kaisha, Ltd., purity of 99.99%), and 0.06 g of aluminum oxide Al 2 O 3 (made by Kojundo Chemical Laboratory Co., Ltd., purity of 99.99%) were sufficiently mixed and stirred with an agate mortar. Then, a predetermined amount of the mixture was placed into an alumina crucible, and fired at 1400° C. for 4 hours to obtain aluminum containing calcium titanate (CaTiO 3 :Al) having a perovskite type structure (Sample I).
The specific surface of Sample I was 0.13 m 2 /g, and the average particle size calculated from the value was 11 μm. The atomic ratio (molar ratio) (Al/Ti) of aluminum and titanium was 0.03. The content of chromium was not more than a measurement limit of detection.
Examples 10 to 16
With respect to calcium carbonate CaCO 3 (made by Kojundo Chemical Laboratory Co., Ltd., purity of 99.99%), high purity titanium dioxide (PT-301 made by Ishihara Sangyo Kaisha, Ltd., purity of 99.99%), and manganese dioxide MnO 2 (made by Kojundo Chemical Laboratory Co., Ltd., purity of 99.99%), the respective amounts described in Table 1 were weighed, and sufficiently mixed and stirred with an agate mortar. Then, a predetermined amount of each mixture was placed into an alumina crucible, and fired at 1400° C. for 4 hours to obtain manganese containing calcium titanate having a perovskite type structure (Samples J to P).
Atomic ratios (molar ratio) (Mn/Ti) of manganese and titanium in Samples J to P were 0.11, 0.25, 0.41, 0.67, 0.96, 1.5, and 2.22 from the results of fluorescent X-ray spectrographic analysis (RIX2100, made by Rigaku Corporation), respectively. The content of chromium in each Sample was not more than a measurement limit of detection. Table 1 shows each specific surface of Samples J, L, N and P, and each average particle size calculated from the value of the specific surface.
TABLE 1
Calcium
Titanium
Manganese
Average
carbonate
dioxide
dioxide
Specific surface
particle size
Sample
(g)
(g)
(g)
(m 2 /g)
(μ/m)
Example 10
J
3.66
2.63
0.32
1.54
0.86
Example 11
K
3.64
2.33
0.63
—
—
Example 12
L
3.62
2.02
0.94
1.03
1.38
Example 13
M
3.61
1.73
1.25
—
—
Example 14
N
3.59
1.43
1.68
0.75
1.86
Example 15
O
3.57
1.14
1.86
—
—
Example 16
P
3.55
0.85
2.16
0.32
4.25
Examples 17 to 20
With respect to calcium carbonate CaCO 3 (made by Kojundo Chemical Laboratory Co., Ltd., purity of 99.99%), high purity titanium dioxide (PT-301 made by Ishihara Sangyo Kaisha, Ltd., purity of 99.99%), and iron sesquioxide Fe 2 O 3 (made by Kojundo Chemical Laboratory Co., Ltd., purity of 99.99%), the respective amounts described in Table 2 were weighed, and sufficiently mixed and stirred with an agate mortar. Then, a predetermined amount of each mixture was placed into an alumina crucible, and fired at 1400° C. for 4 hours to obtain iron containing calcium titanate having a perovskite type structure (Samples Q to T).
Atomic ratios (molar ratio) of iron and titanium (Fe/Ti) in Samples Q to T were 0.12, 0.28, 0.43, and 0.70, respectively from the results of fluorescent X-ray spectrographic analysis (RIX2100, made by Rigaku Corporation). The content of chromium in each Sample was not more than a measurement limit of detection.
TABLE 2
Calcium
Titanium
Iron
Sample
carbonate (g)
dioxide (g)
sesquioxide (g)
Example 17
Q
3.66
2.63
0.29
Example 18
R
3.64
2.32
0.58
Example 19
S
3.62
2.02
0.87
Example 20
T
3.60
1.72
1.15
Example 21
3.59 g of calcium carbonate CaCO 3 (made by Kojundo Chemical Laboratory Co., Ltd., purity of 99.99%), 2.02 g of high purity titanium dioxide (PT-301 made by Ishihara Sangyo Kaisha, Ltd., purity of 99.99%), 0.94 g of manganese dioxide MnO 2 (made by Kojundo Chemical Laboratory Co., Ltd., purity of 99.99%), and 0.01 g of magnesium oxide (made by Kojundo Chemical Laboratory Co., Ltd., purity of 99.99%) were weighed, and sufficiently mixed and stirred with an agate mortar. Then, a predetermined amount of the mixture was placed into an alumina crucible, and fired at 1400° C. for 4 hours to obtain manganese and magnesium containing calcium titanate (CaTiO 3 : Mn, Mg) having a perovskite type structure (Sample U). The atomic ratio (molar ratio) of magnesium to calcium (Mg/Ca) was 0.01, and the atomic ratio (molar ratio) of manganese to titanium (Mn/Ti) was 0.43. The content of chromium was not more than a measurement limit of detection.
Example 22
3.62 g of calcium carbonate CaCO 3 (made by Kojundo Chemical Laboratory Co., Ltd., purity of 99.99%), 2.02 g of high purity titanium dioxide (PT-301 made by Ishihara Sangyo Kaisha, Ltd., purity of 99.99%), 0.94 g of manganese dioxide MnO 2 (made by Kojundo Chemical Laboratory Co., Ltd., purity of 99.99%), and 0.01 g of α-alumina α-Al 2 O 3 (made by Kojundo Chemical Laboratory Co., Ltd., purity of 99.99%) were weighed, and sufficiently mixed and stirred with an agate mortar. Then, a predetermined amount of the mixture was placed into an alumina crucible, and fired at 1400° C. for 4 hours to obtain manganese and aluminum containing calcium titanate (CaTiO 3 : Mn,Al) having a perovskite type structure (Sample V).
The specific surface of Sample V was 0.50 m 2 /g, and the average particle size calculated from the value was 2.86 μm. The atomic ratio (molar ratio) of manganese to titanium (Mn/Ti) was 0.43, and the atomic ratio (molar ratio) of aluminum to titanium (Al/Ti) was 0.007. The content of chromium was not more than a measurement limit of detection.
Example 23
In Example 22, the same procedure as that of Example 22 was performed except that 0.01 g of α-alumina was changed into 0.02 g, to obtain manganese and aluminum containing calcium titanate (CaTiO 3 : Mn,Al) having a perovskite type structure (Sample W). The atomic ratio (molar ratio) of manganese to titanium (Mn/Ti) was 0.43, and the atomic ratio (molar ratio) of aluminum to titanium (Al/Ti) was 0.014. The content of chromium was not more than a measurement limit of detection.
Example 24
In Example 22, the same procedure as that of Example 22 was performed except that 0.03 g of gallium oxide (made by Kojundo Chemical Laboratory Co., Ltd., purity of 99.99%) was used instead of 0.01 g of α-alumina, to obtain manganese and gallium containing calcium titanate (CaTiO 3 :Mn,Ga) having a perovskite type structure (Sample X). The atomic ratio (molar ratio) of manganese to titanium (Mn/Ti) was 0.43, and the atomic ratio (molar ratio) of gallium to titanium (Ga/Ti) was 0.014. The content of chromium was not more than a measurement limit of detection.
Example 25
3.59 g of calcium carbonate CaCO 3 (made by Kojundo Chemical Laboratory Co., Ltd., purity of 99.99%), 1.43 g of high purity titanium dioxide (PT-301 made by Ishihara Sangyo Kaisha, Ltd., purity of 99.99%), 1.56 g of manganese dioxide MnO 2 (made by Kojundo Chemical Laboratory Co., Ltd., purity of 99.99%), and 0.01 g of α-alumina α-Al 2 O 3 (made by Kojundo Chemical Laboratory Co., Ltd., purity of 99.99%) were weighed, and sufficiently mixed and stirred with an agate mortar. Then, a predetermined amount of the mixture was placed into an alumina crucible, and fired at 1400° C. for 4 hours to obtain manganese and aluminum containing calcium titanate (CaTiO 3 :Mn,Al) having a perovskite type structure (Sample Y).
The specific surface of Sample Y was 0.74 m 2 /g, and the average particle size calculated from the value was 1.88 μm. The atomic ratio (molar ratio) of manganese to titanium (Mn/Ti) was 1.01, and the atomic ratio (molar ratio) of aluminum to titanium (Al/Ti) was 0.01. The content of chromium was not more than a measurement limit of detection.
Example 26
3.64 g of calcium carbonate CaCO 3 (made by Kojundo Chemical Laboratory Co., Ltd., purity of 99.99%), 1.16 g of high purity titanium dioxide (PT-301 made by Ishihara Sangyo Kaisha, Ltd., purity of 99.99%), 1.27 g of manganese dioxide MnO 2 (made by Kojundo Chemical Laboratory Co., Ltd., purity of 99.99%), and 0.19 g of α-alumina α-Al 2 O 3 (made by Kojundo Chemical Laboratory Co., Ltd., purity of 99.99%) were weighed, and sufficiently mixed and stirred with an agate mortar. Then, a predetermined amount of the mixture was placed into an alumina crucible, and fired at 1400° C. for 4 hours to obtain manganese and aluminum containing calcium titanate (CaTiO 3 : Mn,Al) having a perovskite type structure (Sample Z). The atomic ratio (molar ratio) of manganese to titanium (Mn/Ti) was 1.25, and the atomic ratio (molar ratio) of aluminum to titanium (Al/Ti) was 0.25. The content of chromium was not more than a measurement limit of detection.
Example 27
3.60 g of calcium carbonate CaCO 3 (made by Kojundo Chemical Laboratory Co., Ltd., purity of 99.99%), 1.87 g of high purity titanium dioxide (PT-301 made by Ishihara Sangyo Kaisha, Ltd., purity of 99.99%), 0.94 g of manganese dioxide MnO 2 (made by Kojundo Chemical Laboratory Co., Ltd., purity of 99.99%), and 0.15 g of zinc oxide ZnO (made by Kojundo Chemical Laboratory Co., Ltd., purity of 99.99%) were sufficiently mixed and stirred with an agate mortar. Then, a predetermined amount of the mixture was placed into an alumina crucible, and fired at 1400° C. for 4 hours to obtain manganese and zinc containing calcium titanate (CaTiO 3 : Mn, Zn) having a perovskite type structure (Sample a). The atomic ratio (molar ratio) of manganese to titanium (Mn/Ti) was 0.77, and the atomic ratio (molar ratio) of zinc to titanium (Zn/Ti) was 0.08. The content of chromium was not more than a measurement limit of detection.
Example 28
3.31 g of strontium carbonate SrCO 3 (made by Kojundo Chemical Laboratory Co., Ltd., purity of 99.99%), 2.48 g of zirconium oxide (made by Kojundo Chemical Laboratory Co., Ltd., purity of 99.99%), and 0.19 g of manganese dioxide MnO 2 (made by Kojundo Chemical Laboratory Co., Ltd., purity of 99.99%) were sufficiently mixed and stirred with an agate mortar. Then, a predetermined amount of the mixture was placed into an alumina crucible, and fired at 1400° C. for 4 hours to obtain manganese containing strontium zirconate (SrZrO 3 :Mn) having a perovskite type structure (Sample b). The atomic ratio (molar ratio) of manganese to zirconium (Mn/Zr) was 0.11. The content of chromium was not more than a measurement limit of detection.
Example 29
3.31 g of strontium carbonate SrCO 3 (made by Kojundo Chemical Laboratory Co., Ltd., purity of 99.99%), 2.48 g of zirconium oxide (made by Kojundo Chemical Laboratory Co., Ltd., purity of 99.99%), 0.19 g of manganese dioxide MnO 2 (made by Kojundo Chemical Laboratory Co., Ltd., purity of 99.99%), and 0.01 g of α-alumina α-Al 2 O 3 (made by Kojundo Chemical Laboratory Co., Ltd., purity of 99.99%) were sufficiently mixed and stirred with an agate mortar. Then, a predetermined amount of the mixture was placed into an alumina crucible, and fired at 1400° C. for 4 hours to obtain manganese and aluminum containing strontium zirconate (SrZrO 3 :Mn,Al) having a perovskite type structure (Sample c). The atomic ratio (molar ratio) of manganese to zirconium (Mn/Zr) was 0.11, and the atomic ratio (molar ratio) of aluminum to zirconium (Al/Zr) was 0.006. The content of chromium was not more than a measurement limit of detection.
Example 30
7.18 g of calcium carbonate CaCO 3 (made by Kojundo Chemical Laboratory Co., Ltd., purity of 99.99%), 2.83 g of titanium dioxide (TTO-55A made by Ishihara Sangyo Kaisha, Ltd., titanium dioxide having aluminum hydroxide existing on a particle surface (Al/Ti=0.03)), 3.12 g of manganese dioxide MnO 2 (made by Kojundo Chemical Laboratory Co., Ltd., purity of 99.99%), and 0.02 g of α-alumina α-Al 2 O 3 (made by Kojundo Chemical Laboratory Co., Ltd., purity of 99.99%) were weighed, and sufficiently mixed and stirred with an agate mortar. Then, a predetermined amount of the mixture was placed into an alumina crucible, and fired at 1200° C. for 4 hours to obtain manganese and aluminum containing calcium titanate (CaTiO 3 :Mn,Al) having a perovskite type structure (Sample d).
The atomic ratio (molar ratio) of manganese to titanium (Mn/Ti) was 1.01, and the atomic ratio (molar ratio) of aluminum to titanium (Al/Ti) was 0.040. Calcium was 1 mol based on 1 mol of the total amount of titanium, manganese, and aluminum.
Example 31
7.48 g of calcium carbonate CaCO 3 (made by Kojundo Chemical Laboratory Co., Ltd., purity of 99.99%), 2.79 g of titanium dioxide (TTO-55A made by Ishihara Sangyo Kaisha, Ltd., titanium dioxide having aluminum hydroxide existing on a particle surface (Al/Ti=0.03)), 3.07 g of manganese dioxide MnO 2 (made by Kojundo Chemical Laboratory Co., Ltd., purity of 99.99%), and 0.02 g of α-alumina α-Al 2 O 3 (made by Kojundo Chemical Laboratory Co., Ltd., purity of 99.99%) were weighed, and sufficiently mixed and stirred with an agate mortar. Then, a predetermined amount of the mixture was placed into an alumina crucible, and fired at 1200° C. for 4 hours to obtain manganese and aluminum containing calcium titanate (CaTiO 3 : Mn,Al) having a perovskite type structure (Sample e).
The atomic ratio (molar ratio) of manganese and titanium (Mn/Ti) was 1.01, and the atomic ratio (molar ratio) of aluminum to titanium (Al/Ti) was 0.040. Calcium was 1.06 mol based on 1 mol of the total amount of titanium, manganese, and aluminum.
Example 32
7.67 g of calcium carbonate CaCO 3 (made by Kojundo Chemical Laboratory Co., Ltd., purity of 99.99%), 2.76 g of titanium dioxide (TTO-55A made by Ishihara Sangyo Kaisha, Ltd., titanium dioxide having aluminum hydroxide existing on a particle surface (Al/Ti=0.03)), 3.03 g of manganese dioxide MnO 2 (made by Kojundo Chemical Laboratory Co., Ltd., purity of 99.99%), and 0.02 g of α-alumina α-Al 2 O 3 (made by Kojundo Chemical Laboratory Co., Ltd., purity of 99.99%) were weighed, and sufficiently mixed and stirred with an agate mortar. Then, a predetermined amount of the mixture was placed into an alumina crucible, and fired at 1200° C. for 4 hours to obtain manganese and aluminum containing calcium titanate (CaTiO 3 : Mn,Al) having a perovskite type structure (Sample f).
The atomic ratio (molar ratio) of manganese to titanium (Mn/Ti) was 1.01, and the atomic ratio (molar ratio) of aluminum to titanium (Al/Ti) was 0.040. Calcium was 1.10 mol based on 1 mol of the total amount of titanium, manganese, and aluminum.
Example 33
2.87 g of calcium carbonate CaCO 3 (made by Kojundo Chemical Laboratory Co., Ltd., purity of 99.99%), 1.13 g of titanium dioxide (TTO-55A made by Ishihara Sangyo Kaisha, Ltd., titanium dioxide having aluminum hydroxide existing on a particle surface (Al/Ti=0.03)), 1.25 g of manganese dioxide MnO 2 (made by Kojundo Chemical Laboratory Co., Ltd., purity of 99.99%), and 0.01 g of aluminum hydroxide Al(OH) 3 (made by Kojundo Chemical Laboratory Co., Ltd., purity of 99.99%) were weighed, and sufficiently mixed and stirred with an agate mortar. The obtained mixture was made into a slurry with water, and subsequently was evaporated to dryness. Next, the obtained solid was ground with an agate mortar. Then, a predetermined amount of the mixture was placed into an alumina crucible, and fired at 1200° C. for 4 hours to obtain manganese and aluminum containing calcium titanate (CaTiO 3 : Mn,Al) having a perovskite type structure (Sample g).
The atomic ratio (molar ratio) of manganese to titanium (Mn/Ti) was 1.01, and the atomic ratio (molar ratio) of aluminum to titanium (Al/Ti) was 0.040.
Example 34
In Example 33, the same procedure as that of Example 33 was performed except that 1.11 g of titanium dioxide (TTO-55N made by Ishihara Sangyo Kaisha, Ltd.) not having aluminum hydroxide existing on the particle surface was used instead of titanium dioxide having aluminum hydroxide existing on the particle surface, and 0.04 g of aluminum hydroxide Al(OH) 3 (made by Kojundo Chemical Laboratory Co., Ltd., purity of 99.99%) was used. Thus, manganese and aluminum containing calcium titanate (CaTiO 3 : Mn,Al) having a perovskite type structure (Sample h).
The atomic ratio (molar ratio) of manganese to titanium (Mn/Ti) was 1.01, and the atomic ratio (molar ratio) of aluminum to titanium (Al/Ti) was 0.040.
Example 35
In Example 33, the same procedure as that of Example 33 was performed except that 0.31 g of potassium carbonate K 2 CO 3 (made by Kishida Chemical Co., Ltd., purity of 99.5%) was added to the slurry of the mixture, and subsequently evaporated to dryness. Thus, manganese and aluminum containing calcium titanate (CaTiO 3 : Mn,Al) having a perovskite type structure (Sample i).
The atomic ratio (molar ratio) of manganese to titanium (Mn/Ti) was 1.01, and the atomic ratio (molar ratio) of aluminum to titanium (Al/Ti) was 0.040.
Example 36
In Example 33, the same procedure as that of Example 33 was performed except that 0.17 g of lithium carbonate Li 2 CO 3 (made by Kishida Chemical Co., Ltd., purity of 99.99%) was added to the slurry of the mixture, and subsequently evaporated to dryness. Thus, manganese and aluminum containing calcium titanate (CaTiO 3 : Mn,Al) having a perovskite type structure (Sample j) was obtained.
The atomic ratio (molar ratio) of manganese to titanium (Mn/Ti) was 1.01, and the atomic ratio (molar ratio) of aluminum to titanium (Al/Ti) was 0.040.
Example 37
7.00 g of calcium carbonate CaCO 3 (made by Kojundo Chemical Laboratory Co., Ltd., purity of 99.99%), 2.46 g of titanium dioxide (TTO-55A made by Ishihara Sangyo Kaisha, Ltd., titanium dioxide having aluminum hydroxide existing on a particle surface (Al/Ti=0.03)), 3.04 g of manganese dioxide MnO 2 (made by Kojundo Chemical Laboratory Co., Ltd., purity of 99.99%), 0.03 g of aluminum hydroxide Al(OH) 3 (made by Kojundo Chemical Laboratory Co., Ltd., purity of 99.99%), and 0.53 g of tin dioxide SnO 2 (made by Kojundo Chemical Laboratory Co., Ltd., purity of 99.99%) were weighed, and sufficiently mixed and stirred with an agate mortar. Then, a predetermined amount of the mixture was placed into an alumina crucible, and fired at 1200° C. for 4 hours to obtain manganese, aluminum, and tin containing calcium titanate (CaTiO 3 :Mn,Al,Sn) having a perovskite type structure (Sample k).
The atomic ratio (molar ratio) of manganese to titanium (Mn/Ti) was 1.12, the atomic ratio (molar ratio) of aluminum to titanium (Al/Ti) was 0.040, and the atomic ratio (molar ratio) of tin to titanium (Sn/Ti) was 0.11.
Example 38
7.07 g of calcium carbonate CaCO 3 (made by Kojundo Chemical Laboratory Co., Ltd., purity of 99.99%), 2.51 g of titanium dioxide (TTO-55A made by Ishihara Sangyo Kaisha, Ltd., titanium dioxide having aluminum hydroxide existing on a particle surface (Al/Ti=0.03)), 3.07 g of manganese dioxide MnO 2 (made by Kojundo Chemical Laboratory Co., Ltd., purity of 99.99%), 0.03 g of aluminum hydroxide Al(OH) 3 (made by Kojundo Chemical Laboratory Co., Ltd., purity of 99.99%), and 0.44 g of zirconium dioxide ZrO 2 (made by Kojundo Chemical Laboratory Co., Ltd., purity of 99.99%) were weighed, and sufficiently mixed and stirred with an agate mortar. Then, a predetermined amount of the mixture was placed into an alumina crucible, and fired at 1200° C. for 4 hours to obtain manganese, aluminum, and zirconium containing calcium titanate (CaTiO 3 :Mn,Al,Zr) having a perovskite type structure (Sample 1).
The atomic ratio (molar ratio) of manganese to titanium (Mn/Ti) was 1.12, the atomic ratio (molar ratio) of aluminum to titanium (Al/Ti) was 0.040, and the atomic ratio (molar ratio) of zirconium to titanium (Zr/Ti) was 0.11.
Example 39
7.19 g of calcium carbonate CaCO 3 (made by Kojundo Chemical Laboratory Co., Ltd., purity of 99.99%), 2.78 g of titanium dioxide (TTO-55A made by Ishihara Sangyo Kaisha, Ltd., titanium dioxide having aluminum hydroxide existing on a particle surface (Al/Ti=0.03)), 3.12 g of manganese dioxide MnO 2 (made by Kojundo Chemical Laboratory Co., Ltd., purity of 99.99%), 0.03 g of aluminum hydroxide Al(OH) 3 (made by Kojundo Chemical Laboratory Co., Ltd., purity of 99.99%), and 0.04 g of silicon dioxide SiO 2 (made by Kojundo Chemical Laboratory Co., Ltd., purity of 99.99%) were weighed, and sufficiently mixed and stirred with an agate mortar. Then, a predetermined amount of the mixture was placed into an alumina crucible, and fired at 1200° C. for 4 hours to obtain manganese, aluminum, and silicon containing calcium titanate (CaTiO 3 :Mn,Al,Si) having a perovskite type structure (Sample m).
The atomic ratio (molar ratio) of manganese to titanium (Mn/Ti) was 1.03, the atomic ratio (molar ratio) of aluminum to titanium (Al/Ti) was 0.040, and the atomic ratio (molar ratio) of silicon to titanium (Si/Ti) was 0.021.
Example 40
Sample g obtained in Example 33 was suspended in pure water, and subjected to ultrasonic dispersion for 10 minutes to prepare a slurry.
This slurry was heated. While the slurry was kept at 75° C., under stirring, 10% by weight of sodium silicate as SiO 2 was added to the slurry over 60 minutes. Then, the slurry was stirred for 30 minutes at 90° C. Then, 2% sulfuric acid was added over 80 minutes until the pH of the slurry reached 8. A preset temperature was set at 60° C., and subsequently the slurry was matured for 60 minutes.
Next, the pH of the slurry was adjusted at 9. Then, at the slurry temperature of 60° C., 2% by weight of sodium aluminate as Al 2 O 3 and sulfuric acid were added simultaneously over 60 minutes. The slurry was matured for 30 minutes, and subsequently filtered, washed, and dried to obtain manganese and aluminum containing calcium titanate (CaTiO 3 :Mn,Al) having a perovskite type structure and coated with 10% by weight of silica in a first layer and 2% by weight of alumina in a second layer (Sample n).
Example 41
A predetermined amount of Sample n obtained in Example 40 was placed into an alumina crucible, and fired again at 700° C. for 1 hour to obtain manganese and aluminum containing calcium titanate (CaTiO 3 :Mn,Al) having a perovskite type structure and coated with silica and alumina (Sample o).
Example 42
A predetermined amount of Sample g obtained in Example 33 was placed into an alumina crucible, and fired again at 900° C. for 4 hours to obtain manganese and aluminum containing calcium titanate (CaTiO 3 :Mn,Al) having a perovskite type structure (Sample p).
The BET specific surface area value was 1.23 m 2 /g.
Example 43
A predetermined amount of Sample g obtained in Example 33 was placed into an alumina crucible, and fired again at 800° C. for 2 hours to obtain manganese and aluminum containing calcium titanate (CaTiO 3 :Mn,Al) having a perovskite type structure (Sample q).
Comparative Example 1
Titanium dioxide made by Ishihara Sangyo Kaisha, Ltd. (white material for near-infrared reflection) was used as Comparison Sample r.
Comparative Example 2
2.94 g of yttrium oxide Y 2 O 3 (made by Kojundo Chemical Laboratory Co., Ltd., purity of 99.99%) and 2.27 g of manganese dioxide MnO 2 (made by Kojundo Chemical Laboratory Co., Ltd., purity of 99.99%) were sufficiently mixed and stirred with an agate mortar. Then, a predetermined amount of the mixture was placed into an alumina crucible, and fired at 1200° C. for 4 hours to obtain yttrium manganate (YMnO 3 ) (Comparison Sample s).
Comparative Example 3
Commercially available infrared reflective oxide black materials Pigment Black 17 <Cr2O3> and Pigment Black 27 <(Co,Fe)(Fe,Cr)2O4> were used as Comparison Sample t and Comparison Sample u, respectively.
As the results of X-ray diffraction of Samples (A to Z, and a to q) obtained in Examples, except Sample f, only a compound corresponding to each composition could be identified, and it was found that the composition is a single phase.
The samples obtained in Examples and Comparative Examples (A to I, and r) were sufficiently ground with an agate mortar. Then, each of the samples was placed into an aluminum ring having a diameter of 30 mm, and press molded at a load of 9.8 MPa. The color of the powder was measured with a whiteness meter NW-1 (made by Nippon Denshoku Industries Co., Ltd.). The results were shown in Table 3.
Moreover, each of the samples obtained in Examples and Comparative Examples (A to I, and r) was placed into a dedicated cell, and the spectral reflectance (reflectance of light at a wavelength of 350 to 2100 nm) was measured with an ultraviolet visible near-infrared spectrophotometer V-570 (made by JASCO Corporation, using a Spectralon <made by Labsphere Inc.> as a standard reflecting plate). Next, according to JIS R 3106, the solar reflectance (reflectance of near infrared rays of the sunlight at a wavelength in the range of 700 to 2100 nm) was calculated, and shown in Table 3.
It was found that Samples A to I obtained in Examples have the L* value of not less than 75, and have sufficient whiteness. It was also found that Samples A to F, H, and I have the L* value of not less than 90, which is approximately the same or more than that of Comparison Sample r, and have high whiteness. In addition, Samples A to F, H, and I show a hue in which the a* value is approximately −3 to 10, and the b* value is approximately 1 to 10. These show that the present invention can be used as a white material.
It was also found that the solar reflectances of Samples A to I obtained in Examples all are higher than that of Comparison Sample r, the relative value is 109 to 124 wherein the solar reflectance of Comparison Sample r is 100, and Samples A to I all have sufficient infrared reflectivity. It was also recognized that containing of aluminum improves the solar reflectance.
TABLE 3
Relative value
wherein
solar reflectance
Solar reflectance
(700 to 2100 nm)
Color of powder
(700 to 2100 nm)
of Sample p
L*
a*
b*
(%)
is “100”
Sample A
94.6
2.7
1.9
82.8
109
Sample B
97.0
0.0
3.0
85.7
113
Sample C
98.7
−2.2
4.5
87.3
115
Sample D
94.0
1.5
1.9
84.0
111
Sample E
98.2
−2.6
1.8
93.6
124
Sample F
96.3
−1.3
3.3
92.1
122
Sample G
78.8
9.4
9.8
87.5
116
Sample H
94.0
1.6
2.0
91.7
121
Sample I
93.8
2.1
4.2
92.0
122
Comparison
94.4
−2.4
2.0
75.9
100
Sample r
The color of the powders of Samples obtained in Examples and Comparative Examples (J to Z, a to c, and s to u) was measured by the method, and the results were shown in Table 4. Moreover, the solar reflectance (reflectance of near infrared rays of the sunlight at a wavelength in the range of 700 to 2100 nm) was calculated by the method, and shown in Table 4.
Samples J to P obtained in Examples (manganese containing calcium titanate) have sufficient blackness. Particularly Samples K to P show the L* value of not more than 40 and a hue in which the a* value is approximately 0 to 20, and the b* value is approximately −1 to 10. These show that the present invention is used as a black material. It was also found that the solar reflectances of Samples J to P all are higher than that of Comparison Sample u, a relative value is 117 to 249 in Samples K to P wherein the solar reflectance of Comparison Sample u is 100, and Samples J to P all have sufficient infrared reflectivity. Moreover, it was found that Samples K to M bear comparison with Comparison Samples s and t, and are a black material having high infrared reflectivity.
Moreover, Samples Q to T (iron containing calcium titanate) obtained in Examples have sufficient blackness, and the L* value is not more than 40. In addition, Samples Q to T show a hue in which the a* value is approximately 0 to 10, and the b* value is approximately 1 to 5. These show that the present invention can be used as a black material. Although the solar reflectances of Samples Q to T did not exceed that of Comparison Sample u, Samples Q to T have an advantage that they do not contain chromium. Particularly, it was found that Sample Q has approximately the same solar reflectance and blackness as those of Comparison Sample u.
In manganese containing calcium titanate, improvement in the solar reflectance was recognized by containing magnesium, aluminum, gallium, and zinc in Samples U to Z and a.
Also in strontium zirconate, it was confirmed that blackness could be obtained by containing manganese, and that the solar reflectance could be improved by containing aluminum.
TABLE 4
Relative value
wherein solar
Solar
reflectance
reflectance
(700 to
(700 to
2100 nm)
Color of powder
2100 nm)
of Sample s
L*
a*
b*
(%)
is “100”
Sample J
41.2
16.7
19.5
70.7
284
Sample K
34.7
15.1
9.9
62.0
249
Sample L
31.0
9.0
3.3
52.1
209
Sample M
28.1
4.4
0.3
43.8
176
Sample N
28.1
1.6
−0.6
36.8
148
Sample O
29.1
1.1
0.1
33.0
133
Sample P
29.3
0.0
0.1
29.1
117
Sample Q
28.5
7.3
2.1
23.2
93
Sample R
26.1
2.1
1.2
14.5
58
Sample S
26.7
1.2
1.1
13.8
55
Sample T
30.4
2.2
4.1
16.1
65
Sample U
30.3
7.9
2.1
57.3
230
Sample V
31.4
8.4
2.3
59.6
239
Sample W
30.8
8.5
2.3
59.6
239
Sample X
28.7
7.5
1.7
58.9
237
Sample Y
28.9
0.0
−0.6
48.4
194
Sample Z
26.7
6.7
1.9
49.3
198
Sample a
32.9
9.6
5.5
57.3
230
Sample b
24.8
3.7
2.0
20.7
83
Sample c
26.0
6.2
3.6
28.0
112
Comparison Sample s
23.7
−3.9
−7.8
40.8
164
Comparison Sample t
24.9
4.3
0.9
36.6
147
Comparison Sample u
24.1
3.6
0.6
24.9
100
Using Samples (d to f) obtained in Examples, the solar reflectances (reflectance of near infrared rays of the sunlight at a wavelength in the range of 700 to 2100 nm and reflectance of the sunlight at a wavelength in the range of 300 to 2100 nm) were calculated by the method, and shown in Table 5. The color of the powders of Samples d to f was measured by the method, and the results were shown in Table 6.
It was found that the solar reflectance of Sample e (manganese and aluminum containing calcium titanate wherein α/β=1.06) is approximately 104 as a relative value wherein the solar reflectance of Sample d (manganese and aluminum containing calcium titanate wherein α/β=1.00) is 100, and Sample e is a black pigment having higher infrared reflectivity. On the other hand, although the solar reflectance of Sample f (manganese and aluminum containing calcium titanate wherein α/β=1.10) was high, production of other phase was recognized.
TABLE 5
Solar
Solar
Relative value wherein
reflectance
reflectance
solar reflectance (300
(700 to
Relative value wherein solar
(300 to
to 2100 nm) of Sample
2100 nm)
reflectance (700 to 2100 nm)
2100 nm)
d is “100”
(%)
of Sample d is “100”
Sample d
32.7
100
47.4
100
Sample e
33.7
103
49.1
104
Sample f
34.8
106
51.2
108
TABLE 6
Color of powder
L*
a*
b*
Sample d
26.6
2.1
−0.5
Sample e
25.9
4.7
−0.1
Sample f
26.3
5.7
0.9
Using Samples (g to j) obtained in Examples, the solar reflectance (reflectance of near infrared rays of the sunlight at a wavelength in the range of 700 to 2100 nm) was calculated by the method, and shown in Table 7.
Comparing Sample g with Sample h, it was found that Sample g using titanium dioxide in which aluminum hydroxide is made to exist on the particle surface of titanium dioxide in advance has higher solar reflectance and higher infrared reflectivity.
The solar reflectance of Sample i (to which a potassium compound was added) and that of Sample j (to which a lithium compound was added) were approximately the same as that of Sample g (to which no potassium compound nor lithium compound was added).
FIGS. 1 to 3 show electron micrographs of Samples g, i, and j. It was found that Samples i and j have a particle size more uniform than that of Sample g. FIG. 4 shows the result obtained by measuring particle size distribution of Sample i and Sample g with an image processing apparatus (LUZEX AP, made by Seishin Enterprise Co., Ltd.). It was found that Sample i (shown with ● in the diagram) has particle size distribution narrower than that of Sample g (shown with ▪ in the diagram). In addition, it was found that the average particle size of Sample i is 1.23 μm and smaller than that of average particle size of Sample g, which is 1.65 μm.
TABLE 7
Solar reflectance (700 to 2100 nm)
(%)
Sample g
46.1
Sample h
25.3
Sample i
46.0
Sample j
46.2
Using Samples (k to m) obtained in Examples, the solar reflectances (reflectance of near infrared rays of the sunlight at a wavelength in the range of 700 to 2100 nm and reflectance of the sunlight at a wavelength in the range of 300 to 2100 nm) were calculated by the method, and shown in Table 8.
It was found that Samples k to m are a black pigment having infrared reflectivity higher than that of Comparison Sample u (Pigment Black 27 <(Co,Fe)(Fe,Cr)2O4>).
TABLE 8
Relative value
Relative value
wherein solar
wherein solar
reflectance (300 to
reflectance (700 to
Solar reflectance
2100 nm) of
Solar reflectance
2100 nm) of
(300 to 2100 nm)
Comparison Sample
(700 to 2100 nm)
Comparison
(%)
u is “100”
(%)
Sample u is “100”
Sample k
27.3
140
37.7
151
Sample l
31.0
159
44.1
177
Sample m
27.6
142
38.5
155
Comparison
19.5
100
24.9
100
Sample u
Using Sample g obtained in Example 33, a predetermined amount of Sample g was mixed with Comparison Sample r (titanium dioxide white material for near-infrared reflection) to obtain a mixture. As a comparison, a predetermined amount of commercially available carbon black (Comparison Sample v, made by Kojundo Chemical Laboratory Co., Ltd.) and a predetermined amount of Comparison Sample r were mixed to obtain a comparison mixture. The solar reflectances of these mixtures (reflectance of near infrared rays of the sunlight at a wavelength in the range of 700 to 2100 nm and reflectance of the sunlight at a wavelength in the range of 300 to 2100 nm) were calculated by the method, and shown in Table 9. Moreover, the color of the powder of the mixture was measured by the method, and the result was shown in Table 10.
When Comparison Sample r (titanium dioxide) is mixed with Sample g, as the proportion of Comparison Sample r is higher, the solar reflectance is gradually increased while the L* value is gradually increased. The same result is obtained even when Comparison Sample r (titanium dioxide) is mixed with carbon black (Comparison Sample v). However, comparing Samples having the L* value of 72 to 74, it was found that the solar reflectance is higher in those in which Sample g is mixed.
TABLE 9
Relative value
wherein solar
Relative value
Mixed
Mixed
Mixed
reflectance
wherein solar
proportion
proportion of
proportion of
Solar
(300 to 2100 nm)
Solar
reflectance (700
of Sample
Comparison
Comparison
reflectance
of
reflectance
to 2100 nm) of
g (% by
Sample v (%
Sample r (%
(300 to
Sample g is
(700 to
Sample g is
weight)
by weight)
by weight)
2100 nm)
“100”
2100 nm)
“100”
100
0
0
32.0
100
46.1
100
70
0
30
37.8
118
50.6
110
50
0
50
42.4
133
54.0
117
20
0
80
53.4
167
61.8
134
10
0
90
59.4
186
66.1
143
5
0
95
65.6
205
70.6
153
0
50
50
35.6
111
34.8
75
0
20
80
37.1
116
36.2
79
0
10
90
42.4
133
41.4
90
0
5
95
50.2
157
49.4
107
0
0
100
75.9
237
77.8
169
TABLE 10
Mixed
Mixed
proportion
Mixed proportion
proportion
of Comparison
of Comparison
of Sample g
Sample v
Sample r
Color of powder
(% by weight)
(% by weight)
(% by weight)
L*
a*
b*
100
0
0
26.6
2.1
−0.5
70
0
30
37.4
1.1
−1.5
50
0
50
46.3
0.6
−1.8
20
0
80
63.6
−0.5
−2.3
10
0
90
72.5
−0.9
−2.1
5
0
95
80.6
−1.5
−1.5
0
50
50
57.8
−1
−0.5
0
20
80
62.9
−1.2
−0.2
0
10
90
67.0
−1.1
0.1
0
5
95
74.3
−1.5
−0.1
0
0
100
90.4
−3
0.6
The water elution properties of Sample L obtained in Example 12 and that of calcium manganate (Ca 2 MnO 4 ) prepared with a method described below were evaluated using the following method.
5 g of each sample was placed into a 500-ml aqueous solution adjusted at pH of 3 with hydrochloric acid. While the pH was kept at 3 using a pH controller (FD-02, made by Tokyo Glass Kikai Co., Ltd.), sampling was performed after 10 minutes, 40 minutes, 120 minutes, and 330 minutes. Each sampled slurry was filtered with a membrane filter (A045A047A, made by ADVANTEC) to recover a filtrate. The concentration of calcium ion included in the recovered filtrate was measured with a multi-ICP optical emission spectrometer (made by Varian Technologies Japan Ltd., 730-ES type). Table 11 shows values obtained by subtracting an initial value from the concentration of calcium ion after 40 minutes, from that after 120 minutes, and from that after 330 minutes where the concentration of calcium ion after 10 minutes is the initial value.
It was confirmed that the amount of Sample L in Example 12 to be eluted in water was significantly smaller than that of calcium manganate, and Sample L has high water elution resistance.
Method for Preparing Calcium Manganate
5.03 g of calcium carbonate CaCO 3 (made by Kojundo Chemical Laboratory Co., Ltd., 99.99%) and 2.18 g of manganese dioxide MnO 2 (made by Kojundo Chemical Laboratory Co., Ltd., 99.99%) each were weighed, and sufficiently mixed and stirred with an agate mortar. Then, a predetermined amount of the mixture was placed into an alumina crucible, and fired at 1200° C. for 4 hours to synthesize calcium manganate (Ca 2 MnO 4 ).
TABLE 11
Concentration of calcium ion
(ppm)
Sample L
Ca 2 MnO 4
After 40 minutes
3
287
After 120 minutes
5
621
After 330 minutes
10
1189
Table 12 shows the results of solar reflectance at 700 to 2100 nm in Sample g and n to q obtained in Examples. Moreover, Table 13 shows the results obtained by evaluating water elution properties of Samples g, o, and p by the method.
It was found that the solar reflectances of Samples n to q bear comparison with that of Sample g. It was also confirmed that the amount of calcium to be eluted in water in Samples g, o, and p was significantly smaller than that of Sample g in Example 33, and Samples g, o, and p have high water elution resistance.
TABLE 12
Solar reflectance (700 to 2100 nm) (%)
Sample g
46.1
Sample n
45.5
Sample o
40.5
Sample p
43.8
Sample q
43.7
TABLE 13
Concentration of calcium ion
(ppm)
Sample g
Sample n
Sample o
After 10 minutes
21
4
5
After 40 minutes
32
5
14
After 120 minutes
55
6
25
After 240 minutes
70
9
37
Further, Table 14 shows the results obtained by evaluating water elution properties of Samples g, p, and q obtained in Examples by the following method.
5 g of each sample was placed into a 500-mL of a hydrochloric acid aqueous solution adjusted at 0.2 mol/L (concentration; 10 g/L). The slurry was stirred for 2 hours while the temperature thereof was kept at 40° C. Then, the slurry was filtered with a membrane filter (A045A047A, made by ADVANTEC) to recover a filtrate. The concentration of calcium ion included in the recovered filtrate was measured with a multi-ICP optical emission spectrometer (made by Varian Technologies Japan Ltd., 730-ES type) (first measurement).
Next, the powder that remained on the membrane filter was dried at 60° C. for 2 hours, and again placed into a 500-mL hydrochloric acid aqueous solution adjusted at 0.2 mol/L (concentration; 10 g/L). Stirring for 2 hours at 40° C. was performed. The powder and a filtrate were recovered using the membrane filter. The concentration of calcium ion in the filtrate was measured with the above-mentioned ICP optical emission spectrometer (second measurement).
Subsequently, this operation was repeated, and the concentration of calcium ion was measured 4 times in total. Table 14 shows difference values obtained by subtracting the measured values of the concentration of calcium ion in Sample p from the measured values of the concentration of calcium ion in Sample g and difference values obtained by subtracting the measured values of the concentration of calcium ion in Sample q from the measured values of the concentration of calcium ion in Sample g.
As a result, it was confirmed that the amount of calcium to be eluted in water in Samples p and q was smaller than that of Sample g, and Samples p and q have high water elution resistance.
TABLE 14
Difference value of concentration of calcium ion
(ppm)
Sample p
Sample q
First measurement
27
9
Second measurement
19
14
Third measurement
17
2
Fourth measurement
22
20
It was confirmed that Samples A to Z and a to q obtained in Examples are powder, and can be blended with a coating material or a resin composition.
INDUSTRIAL APPLICABILITY
The infrared reflective material according to the present invention is a perovskite type complex oxide containing at least an alkaline earth metal element and at least one element selected from titanium, zirconium, and niobium, and containing a manganese and/or an iron element, a Group IIIa element in the periodic table, a zinc element, and the like when necessary. The infrared reflective material has sufficient infrared reflectivity, and in addition, has excellent characteristics such as high thermal stability and heat resistance, and no concern about safety and environmental problems. Accordingly, the infrared reflective material according to the present invention can be used for various infrared reflective applications.
Particularly, because the infrared reflective material is resistant to dissolution in water and reduction in infrared reflectivity caused by elution is small, the infrared reflective material can be used for relaxation of the heat island phenomenon or the like, for example, by applying the infrared reflective material onto roofs and outer walls of buildings, by using the infrared reflective material as a resin composition for films and sheets, or by applying the infrared reflective material onto roads and pavements.
|
An infra-red reflective material is a perovskite-like multiple oxide which includes at least an alkaline-earth metal and at least one type of element selected from a group of titanium, zirconium and niobium, and further, if necessary, manganese and/or iron, an element belonging to the IIIa group of the periodic table such as aluminum and gallium, etc., or zinc, etc., has sufficient infra-red reflective power, is excellent in thermal stability and heat resistance, and does not raise concerns on safety and environmental issues. The infra-red reflective material can be produced by, for example, mixing an alkaline-earth metal compound and a titanium compound and further, if necessary, a manganese compound and/or an iron compound, a compound belonging to the IIIa group of the periodic table, or a zinc compound in predetermined amounts, and firing the mixture. The produced multiple oxide is powdery and can be mixed with paint or a resin composition so as to be used for various purposes such as painting a roof or an outside wall of a building, a road, or a foot path in order to reduce the heat island phenomenon.
| 2 |
This application claims priority to U.S. Provisional Application Ser. No. 61/167,776, filed Apr. 8, 2009.
BACKGROUND OF THE INVENTION
The present invention relates to a stackable low depth tray for storing and transporting beverages containers, such as bottles.
Plastic bottles are widely used as containers for soft drinks and other beverages. These bottles are often stored and transported in trays, particularly plastic trays having side walls, end walls and dividers defining pockets between the side walls and end walls. There are many known tray designs that are referred to as “low depth” trays in which the side walls, end walls and dividers are lower than the height of the stored bottles, and in which the bottles support the weight of additional trays and bottles stacked thereon.
One known type of low-depth tray had sidewalls and dividers all at the same height. In later versions of this tray, a portion of the dividers was lowered to reduce weight. This height of the side walls and dividers was the nest stop for empty crates stacked thereon in both a column (i.e. trays aligned) and cross stack (i.e. each row of trays is ninety degrees relative to the row of trays below it, or the trays are longitudinally aligned and longitudinally offset by 50%).
In the known trays, the bottom ribs of the tray base extend down approximately 0.1″ further than the sidewall. Raising the bottom edge of the sidewalls in this manner makes it easier for a delivery person to get a hand truck blade under a stack of crates to move them. As a result, the sidewalls of stacked empty crates do not rest on each other. It is the bottom ribs extending down from the base that rest on top of the dividers when stacked. One problem with this raised side wall design is that empty stacks are not as stable because the footprint is much smaller stacking on dividers only.
Later generation trays improved on this design by adding ribs on the outside of the walls to capture the sidewall of the crate above and also widening the lower part of the castle to capture the bottom ribs of the crate above.
In another tray, the side walls between the columns and the dividers are lowered for more visibility. As a result, the side walls do stack on the top of the side walls of the tray below. In this design, the columns are taller in order to better support bottles with a portion of reduced diameter between the base and a mid-portion of the bottle. One problem with this design is that the taller columns extend into the handle area of the tray above, in both a column stack and a cross stack position. In order to accommodate the handle, the columns are aggressively tapered on the outside face of the columns on the perimeter of the tray. However, the center columns still do not accommodate the handle in a longitudinal cross-stack arrangement. Also, this design results in corner columns that are more fragile because they include the aggressive taper on two sides.
SUMMARY OF THE INVENTION
A tray for storing and transporting bottles according to one embodiment of the present invention includes a base and a plurality of interior columns extending upwardly from the base, including a center interior column. A plurality of side columns extend upwardly along sides of the tray, including two noncenter side columns and a center side column on each side of the tray, each center side column between the two noncenter side columns. Corner columns are at corners of the tray. The center side columns and the corner columns have outer ledges defining a nesting height of the tray, such that the side walls of a similar tray nested thereon would contact and rest on the outer ledges of the center side columns and the corner columns. The noncenter side columns do not include an outer ledge at the nesting height.
According to another, independent feature of the present invention, exterior surfaces of opposing noncenter side columns on opposite sides of the tray are spaced from one another by a distance less than that by which exterior surfaces at the first height of opposing center side columns on opposite sides of the tray. In other words, the noncenter side columns are offset inwardly relative to adjacent columns. This accommodates the handle of a tray stacked thereon in a ninety-degree cross-stacked configuration.
According to another, independent feature of the present invention, exterior surfaces of the end columns are offset inwardly relative to the respective adjacent corner columns. This accommodates the handle of a tray nested thereon in a column stack configuration.
According to another, independent feature of the present invention, the center interior column and the center side columns include spaced apart halves, defining a passage therethrough. The halves of the center interior column are spaced further apart than the halves of the center side columns in order to accommodate the handle cross-stacked longitudinally thereon.
These and other features of the application can be best understood from the following specification and drawings, the following of which is a brief description.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 is a perspective view of a tray according to one embodiment of the present invention.
FIG. 2 is a side perspective view of the tray.
FIG. 3 is a bottom perspective view of the tray.
FIG. 4 is a bottom perspective view of the tray.
FIG. 5 is a side view of the tray.
FIG. 6 is an end view of the tray.
FIG. 7 is a perspective of the tray with a similar tray column stacked thereon.
FIG. 8 is a perspective of the tray with the similar tray cross-stacked ninety degrees thereon.
FIG. 9 is an end view of the trays of FIG. 8 .
FIG. 10 is a section view through the trays of FIGS. 8 and 9 .
FIG. 11 shows the tray with the similar tray cross-stacked longitudinally thereon.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT
A tray 10 according to one embodiment of the present invention is shown in FIG. 1 . The tray 10 includes a base wall 12 . A plurality of longitudinal dividers 14 a and a plurality of lateral dividers 14 b (or, together “dividers 14 ”) extend outward from a plurality of interior columns 20 a , 20 b which, together with the base walls 12 , longitudinal dividers 14 a and lateral dividers 14 b define a plurality of bottle receiving pockets. The interior columns include a center interior column 20 a and two noncenter interior columns 20 b arranged generally along a longitudinal centerline of the tray 10 .
The lateral dividers 14 b each connect one of the interior columns 20 with one of a plurality of side columns 22 a , 22 b positioned along a side edge of the tray 10 . The side columns 22 a , 22 b (collectively “side columns 22 ”) center side columns 22 a and noncenter side columns 22 b . The tray 10 further includes four corner columns 24 extending upwardly from the corners of the tray 10 . End columns 26 extend upwardly from ends of the tray 10 , between the corner columns 24 .
Side walls 28 on each side of the tray 10 define outer ledges 30 a , 30 b adjacent the center side columns 22 a and noncenter side columns 22 b , respectively. The side walls 28 further define outer ledges 32 adjacent the corner columns 24 . Exterior surfaces 34 b of the noncenter side columns 22 b adjacent the outer ledges 30 b are offset inwardly relative to the exterior surfaces 34 a of the center side columns 22 a adjacent the outer ledges 30 a and relative to the exterior surfaces 36 of the corner columns 24 adjacent the outer ledges 32 . The outer ledges 30 a of the center side columns 22 a and the outer ledges 32 of the corner columns 24 define the nesting height, and the outer ledges 30 b of the noncenter side columns 22 b are slightly lower than the nesting height. Alternatively, the outer ledges 30 b of the noncenter side columns 22 b could be eliminated.
At the ends of the tray 10 , an end wall 46 defines outer ledges 42 at the nesting height adjacent exterior surfaces 44 of the corner columns 24 . The end wall 46 also defines an outer ledge 48 below the nesting height adjacent an exterior surface 51 of the end column 26 . The exterior surface 51 of the end column 26 is offset inwardly relative the exterior surfaces 44 of the corner columns 24 . A handle 49 is defined by a downwardly open recess formed in the end wall 46 below the end column 26 .
The center side columns 22 a are split to define a lateral passage 50 therethrough, which is aligned with a lateral passage 52 through the center interior column 20 a . As shown in FIG. 2 , the lateral passage 52 through the center interior column 20 a is wider than the lateral passage 50 through the center side columns 22 a , such that the interior surfaces 54 of the center interior column 20 a are offset away from center relative to the interior surfaces 56 of the center side columns 22 a . The lateral divider 14 b aligned with the center interior column 20 a is at the same height as a lower surface 58 of the lateral passage 52 through the center interior column 20 a , which is below the nesting height. The lower surface 60 of the lateral passage 50 through the center side columns 22 a is at the nesting height, continuous with the outer ledges 30 a of the center side columns 22 a.
As a result, only the outer ledges 30 a and lower surface 60 of the lateral passage 50 of the center side columns 22 a and the outer ledges 32 , 42 of the corner columns 24 are at the nesting height. Considering the tray 10 as two sets of 2×2 pockets, this creates nesting stops only at the four corners of each of the sets of four pockets. This provides stable, consistent nesting in a column stack and in cross-stack (longitudinal or lateral).
Further, within each set of 2×2 pockets, if one considers the split center interior column 20 a and the center side columns 22 a as two separate columns each, then the non-corner columns along the perimeter of each 2×2 set (i.e. end column 26 , noncenter side columns 22 b , and one half of the center interior column 20 a ) are each offset inwardly relative to its adjacent “corner columns” (now also considering the split center side columns 22 a as “corners” within each 2×2 set). The offset end column 26 provides clearance for the handle 49 of a similar tray column stacked thereon. The offset noncenter side columns 22 b provide clearance for the handle 49 of a similar tray cross-stacked laterally (i.e. 90 degrees) thereon. The offset halves of the center interior column 20 a provide clearance for the handle 49 of a longitudinally cross-stacked similar tray.
FIGS. 3 and 4 are bottom perspective views of the tray 10 . The base 12 includes a plurality of interconnected ribs 58 generally defining the lowermost plane of the tray 10 . The lowermost edge of the side walls 28 and end walls 46 are spaced slightly above the lowermost plane of the ribs 58 . Additionally, a channel 60 is formed laterally through the center of the ribs 58 (i.e. aligned with the center lateral divider 14 b ) to provide another surface that is in the same plane as the lowermost edges of the side walls 28 and end walls 46 . These are the bottom nesting surfaces of the tray 10 , i.e. the surfaces that contact the nesting stop surfaces at the nesting height of the tray 10 nested below. Thus, these lower perimeter surfaces of the trays 10 support the trays 10 in any nesting configuration, rather than the ribs 58 which are spaced inwardly from the perimeter. This provides increased stability of the stacked trays 10 . The ribs 58 also form cone-shaped bottle-cap receiving recesses 62 , which receive the bottle-caps of bottles in a tray 10 stacked therebelow when the trays are loaded. The cone-shaped recesses 62 increase the stability of the stacked, loaded trays 10 .
FIG. 5 is a side view of the tray 10 . Again, the outer ledges 30 a and 32 are at the nesting height, while the outer ledges 30 b and longitudinal dividers 14 a (and lateral dividers 14 b , FIG. 2 ) are spaced slightly below the nesting height. As a result, all of the contact with the upper tray 10 is only on the surfaces that are at the nesting height. Also, as shown, the ribs 58 of the base 12 extend downwardly slightly further than the side walls 28 (and end walls 46 , FIG. 3 ). The channel 60 through the center of the base 12 provides another surface at the same height as the side walls 28 and end walls 46 .
FIG. 6 is an end view of the tray 10 . As shown, the outer ledge 48 adjacent the end column 26 is slightly lower than the outer ledges 42 , 32 of the corner columns 24 , which are at the nesting height.
FIG. 7 shows the tray 10 with a similar tray 10 ′ column stacked thereon. The side walls 28 ′ and end walls 46 ′ rest on the outer ledges 30 a , 32 , 42 of the lower tray 10 . The offset end column 26 of the lower tray 10 nests in the handle 49 ′ of the upper tray 10 ′.
FIG. 8 shows the tray 10 with the similar tray 10 ′ cross stacked ninety degrees thereon. In this configuration, one side wall 28 ′ of the upper tray 10 ′ rests on the lower surfaces 60 of the passages 50 through the center side columns 22 a of the lower tray 10 . The other side wall 28 ′, shown in FIG. 9 , rests on the outer ledges 42 of the corner columns 24 of the lower tray 10 .
FIG. 10 is a section view through a portion of the trays 10 , 10 ′ of FIGS. 8 and 9 . Because the outer surface 34 b of the noncenter side column 22 b is offset inwardly, the noncenter side column 22 b can nest behind the handle 49 ′ of the upper tray 10 ′. The side wall 28 ′ of the upper tray 10 ′ is received within the passage 50 through the center side column 22 a . The end wall 46 ′ of the upper tray 10 ′ rests on the outer ledge 30 a of the center column 22 a of the lower tray 10 .
FIG. 11 shows the two trays 10 , 10 ′ in a longitudinally cross-stacked configuration. The end wall 46 ′ of the upper tray 10 ′ is received within the passages 50 , 52 of the center side columns 22 a and the center interior column 20 a and rests on the outer ledges 30 a of the center side columns 22 a . The side walls 28 ′ of the upper tray 10 ′ rest on the outer ledges 32 of the lower tray 10 .
In accordance with the provisions of the patent statutes and jurisprudence, exemplary configurations described above are considered to represent a preferred embodiment of the invention. However, it should be noted that the invention can be practiced otherwise than as specifically illustrated and described without departing from its spirit or scope.
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A tray for storing and transporting bottles according to one embodiment of the present invention includes a base and a plurality of corner columns and side columns extending upwardly from the base, including center side columns. The center side columns and the corner columns having outer ledges defining a nesting height of the tray, such that the side walls of a similar tray nested thereon would contact and rest on the outer ledges of the center side columns and the corner columns. According to another, independent feature of the present invention, the noncenter side columns are offset inwardly relative to adjacent columns. This accommodates the handle of the tray in a ninety-degree cross-stacked configuration. As another optional feature, end columns are offset inwardly relative to adjacent corner columns in order to accommodate the handle of a similar tray nested thereon.
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This application is a continuation-in-part of application Ser. No. 07/678,897 filed Mar. 28, 1991, now U.S. Pat. No. 5,153,020, the disclosure of which is hereby incorporated by reference and which is a continuation of application Ser. No. 07/367,322, filed Jun. 20, 1989, which is a continuation-in-part of application Ser. No. 211,494 filed Jun. 24, 1988, now U.S. Pat. No. 4,911,946, the disclosure of which is hereby incorporated by reference.
SUMMARY OF THE INVENTION
In accordance with the present invention, carbohydrate particles comprising starch granules selected from the group consisting of taro (from Colocasia esculenta), Saponaria vaccaria, Amaranthus retroflexus (Pigweed), Maranta arundinacea, Wheat B and buckwheat starches display fat-like mouthfeel characteristics when the hydrated particles have a substantially spheroidal shape and a mean particle size distribution ranging from about 0.1 microns to 4 microns, with less than about 2% of the total number of particles exceeding 5 microns in diameter. These starches are characterized by small granule sizes (i.e., taro (1.4-4.0 microns), Saponaria vaccaria (0.5-1.6 microns), Amaranthus retroflexus (0.75-1.25 microns); buckwheat (1.3-12 microns)) and are particularly suitable for crosslinking with phosphorous oxychloride and according to other methods to provide stable cream substitutes. The dispersion of macrocolloidal particles can replace all or a portion of the fat or cream in food products such as ice cream, yogurt, salad dressings, mayonnaise, cream, cream cheese, other cheeses, sour cream, sauces, icings, whipped toppings, frozen confections, milk, coffee white and spreads.
DETAILED DESCRIPTION OF THE INVENTION
EXAMPLE 1
In this example, small granule starches were stabilized by cross-linking with tannic acid to produce cream substitutes. Specifically an aqueous starch suspension (17 g starch/28 ml water) was heated in a water bath to 45° C., with stirring, and the pH was adjusted with 1 N NaOH (pH 8-11.4). After crosslinking was achieved (1-6 hours), the suspension was neutralized to pH=6.5 to 7.00, and twice centrifuged with 200 ml of water (5000 rpm for 10 min.), and either dried in a vacuum oven or freeze dried for storage.
Amaranth starch treated as described above (2% w/w, pH=11.4, 2 hours) gave a slightly off-white powder. The taste of its aqueous suspensions was rated as being creamy by a sensory panel. The stabilized starch displayed higher thermal stability as demonstrated by a differential scanning calorimetry (DSC) endotherm (T g ) at 70.94° C. The cross-linked starch had an improved water holding capacity (up to 10.20 g). Cross-linking of a similar suspension at pH=8 for 1 hour gave a stabilized product with T g 69.7° C. and average particle size of 1.66 microns.
Wheat B starch treated as described above gave a creamy suspension, whose water holding capacity was up to 4.980 g.
EXAMPLE 2
In this example, cross-linking was performed as described in Example 1 using Tamarind extract instead of tannic acid as cross-linking agent. Crosslinking of Amaranth starch according to the above procedure (2% w/w, pH=8, 1 hour) gave a creamy-tasting product with T g of 73.97° C. and a water holding capacity of 9.780 g. Wheat B starch according to the above procedure (2% w/w, pH=8, 1 hour) gave a creamy-tasting product with T, of 89.29° C. and water holding capacity of 4.601 g.
EXAMPLE 3
In this example, cross-linking was performed as described in Example 1 using Tamarind seed powder instead of tannic acid as cross-linking agent. Crosslinking of Amaranth starch according to the above procedure (2% w/w, pH=8, 2 hr) gave a creamy-tasting, off-white product with T g of 65.91° C. and water holding capacity of 10.13 g. When the same procedure was conducted for 6 hours, the resulting product had a T g of 68.49° C. and water holding capacity of 9.612 g.
EXAMPLE 4
In this example, Amaranth starch granules were stabilized by cross-linking with ortho-phosphoric acid. Specifically, an aqueous Amaranth starch suspension (17 g starch/28 ml water) was heated in a water bath to 45° C. with stirring, and the pH was adjusted with 1 N NaOH (pH 8-11.4). After crosslinking was achieved (1-6 hours), the suspension was neutralized to pH=6.5 to 7.00, and twice centrifuged with 200 ml of water (Sorvall 5000 rpm for 10 minutes), and either dried in a vacuum oven or freeze dried for storage. The treated Amaranth starch above (2% w/w, 2 hours) gave a slightly off-white powder. The taste of its aqueous suspensions was rated to be creamy by a sensory panel. The stabilized starch displayed higher thermal stability as demonstrated by DSC endotherm (T g ) at 78.07° C.
EXAMPLE 5
In this example, Amaranth starch granules were stabilized by cross-linking with phosphorous oxychloride. Specifically, an aqueous starch suspension (10 parts starch in 24 parts water and 1 part sodium chloride) was heated in a water bath to 40° C., with stirring, and the pH was adjusted with 1 N NaOH (pH 11.6). After cross-linking was achieved (1-8 hours), the suspension was neutralized to pH=5.2 with 20% aqueous HCl, and twice centrifuged with 200 ml of water (5000 rpm for 10 minutes), and either dried in a vacuum oven or freeze dried for storage.
Amaranth starch treated as described above (2% w/w, 2 hr) gave a slightly off-white powder. The taste of its aqueous suspensions was rated to be creamy by a sensory panel. The stabilized starch displayed higher thermal stability as demonstrated by a DSC endotherm (T g ) at 80.41° C. and average particle size of 0.96 microns.
EXAMPLE 6
In this example, starch was stabilized by heat treatment to produce cream substitutes. An aqueous suspension of starch (17 g starch/28 ml water) was heated in a water bath at different temperatures (50-80° C.) for 3 hours. The product was isolated as described in Example 1 above. Specifically, an aqueous Amaranth suspension heated to 70° C., gave a slightly off-white powder. The taste of its aqueous suspensions was rated creamy by a sensory panel. The stabilized starch displayed higher thermal stability as demonstrated by a DSC endotherm (T g ) at 75.37° C., and had a water holding capacity of 8,619 g. The average particle diameter was 1.74 μm. A sample heated to 80° C. showed a T g at 81.61° C.
An aqueous Wheat B suspension treated according to the above procedure and heated to 70° C., gave a slightly off-white powder. The taste of its aqueous suspensions was rated creamy by a sensory panel. The stabilized starch displayed higher thermal stability as demonstrated by a DSC endotherm (T g ) at 78.5° C., and had a water holding capacity of 5.1 g. The average particle diameter was 1.05 microns. A sample heated to 65° C. showed a T g of 70.7° C. and had a water holding capacity of 5.7 g.
An aqueous Taro starch suspension treated according to the above procedure and heated to 70° C., gave a slightly off-white powder. The taste of its aqueous suspensions was rated creamy by a sensory panel. The stabilized starch displayed higher thermal stability as demonstrated by a DSC endotherm (T g ) at 85° C., and had a water holding capacity of 10.28 g.
An aqueous buckwheat starch suspension treated according to the above procedure and heated to 80° C., gave a slightly off-white powder. The stabilized starch displayed higher thermal stability as demonstrated by the fact that the DSC thermogram showed no transition up to about 95° C.
An aqueous Arrow root (Maranta arundinacea) starch suspension treated according to the above procedure and heated to 70° C., gave a slightly off-white powder. The taste of its aqueous suspensions was rated creamy by a sensory panel. The stabilized starch displayed higher thermal stability as demonstrated by a DSC endotherm (T g ) at 78° C.
The foregoing specific examples are provided for purposes of illustration only and it will be apparent to one of ordinary skill in the art that many changes and modifications can be made thereto. Therefore, the scope of the invention is to be limited solely by the appended claims.
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A fat substitute is disclosed which comprises water-dispersible macrocolloid particles composed of starch materials selected from the group consisting of taro, Saponaria vaccaria, Amaranthus retroflexus, Maranta arundinacea, Wheat B and buckwheat, which particles have a substantially spheroidal shape and a particle size distribution effective to impart the substantially smooth organoleptic character of an oil-and-water emulsion.
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[0001] This is a Non-Provisional Application claims priority to and the benefit of Italian Patent Application No. 102015000086616 filed on Dec. 22, 2015, the content of which is incorporated by reference in its entirety.
[0002] The present invention relates to a novel hydrated crystalline form (form B) and the amorphous form of Olaparib.
BACKGROUND OF THE INVENTION
[0003] PARP (poly ADP-ribose polymerase) inhibitors with a phthalazinone structure are known, in particular as BER (base excision repair) inhibitors.
[0004] WO 2005/053662 discloses the use of said inhibitors for the treatment of tumor cells with an HR (homologous recombination) dependent DNA DSB (double-strand break) repair deficiency. In particular it describes the use of said compounds for tumors presenting a deficiency of phenotype BCRA1 and/or BCRA2, such as ovarian, breast or prostate cancer.
[0005] Olaparib (4-[3-(4-cyclopropanecarbonyl-piperazine-1-carbonyl)-4-fluorobenzyl]-2H-phthalazin-2-one), described in U.S. Pat. No. 7,449,464, is a PARP inhibitor used in the treatment of tumors, in combination with radiotherapy or chemotherapy.
[0006] Two crystalline forms of Olaparib, defined as form A and form L, are known in the literature. A solvated form of form A is also known.
[0007] Form A is described in U.S. Pat. No. 8,247,416. The crystalline form A of Olaparib has an XRPD spectrum (λ=1.5418 Å) containing the most intense peaks at 2θ=10.5, 12.0, 14.0, 17.8, 21.1, 21.7, 22.3, 24.3, 26.1, 29.2.
[0008] The solvated crystalline form A, also described in U.S. Pat. No. 8,247,416, can be obtained by maturation and crystallization from different solvents. The XRPD spectrum (λ=1.5418 Å) of Olaparib as solvated form A has characteristic peaks at 2θ=7.0-7.5, 10.1-10.6, 15.1-15.6, 18.5-19.0, 21.0-21.5, 24.8-25.3, 27.0-27.5.
[0009] Form L, disclosed in US 2010/286157, has an XRPD spectrum (λ=1.5418 Å) containing the most intense peaks at 2θ=10.4, 13.6, 14.4, 17.2, 17.5, 18.8, 23.0, 25.1.
[0010] Particular crystalline forms of Olaparib can possess advantageous properties in terms of their solubility and/or stability and/or bioavailability and/or impurity profile and/or filtration characteristics and/or drying characteristics and/or their ability to be handled and/or micronized and/or preparation of solid oral forms.
DESCRIPTION OF THE INVENTION
[0011] The present invention relates to the preparation and characterization of a novel crystalline form (hydrated form B) and the amorphous form of Olaparib.
DESCRIPTION OF FIGURES
[0012] FIG. 1 : Infrared spectrum of Olaparib amorphous form.
[0013] FIG. 2 : DSC curve of Olaparib amorphous form.
[0014] FIG. 3 : XRPD pattern of Olaparib amorphous form.
[0015] FIG. 4 : Infrared spectrum of Olaparib crystalline form B.
[0016] FIG. 5 : DSC curve of Olaparib crystalline form B.
[0017] FIG. 6 : XRPD pattern of Olaparib crystalline form B.
[0018] FIG. 7 : 1 H-NMR spectrum of the hydrated crystalline form of Olaparib (form B) in d 6 -DMSO.
[0019] The amorphous form of Olaparib has better solubility in various organic solvents and in water than crystalline forms A and L of Olaparib. The amorphous form of Olaparib is stable if exposed to the moisture in the air, and is not hygroscopic.
[0020] The amorphous form of Olaparib is obtained from a suitable polar solvent such as methanol, dimethyl sulfoxide, dimethyl formamide, dimethyl acetamide, acetic acid and water, or from a suitable mixture thereof. Dimethyl sulfoxide, dimethylformamide or water is preferably used.
[0021] The amorphous form of Olaparib can be obtained by adding a solution of Olaparib in a polar solvent to an anti-solvent.
[0022] Olaparib in crystalline form is dissolved in a polar solvent such as methanol, dimethyl sulfoxide, dimethyl formamide, dimethylacetamide or acetic acid, preferably dimethyl sulfoxide, dimethylformamide or acetic acid, and more preferably dimethylsulfoxide or dimethylformamide, at a temperature ranging between 16° C. and 100° C., preferably between 20° C. and 70° C., and more preferably between 25° C. and 70° C.
[0023] The solution of Olaparib is added to an anti-solvent, preferably a polar protic anti-solvent such as water, at a temperature ranging between −10° C. and 50° C., preferably between −10° C. and 30° C., and more preferably between −10° C. and 25° C.
[0024] The resulting suspension is left under stirring for a time ranging between 0 and 5 hours, preferably between 10 minutes and 2 hours, and more preferably between 10 minutes and 40 minutes, at a temperature ranging between −20° C. and 50° C., preferably between −10° C. and 30° C., and more preferably between −10° C. and 25° C.
[0025] The suspension is filtered and the solid washed with an anti-solvent, preferably a polar protic anti-solvent such as water. The resulting solid is dried at low pressure at a temperature ranging between 0° C. and 70° C., preferably between 20° C. and 60° C.
[0026] The amorphous form of Olaparib has an IR spectrum, DSC curve and XRPD pattern as shown in FIGS. 1, 2 and 3 respectively.
[0027] In particular, the amorphous form of Olaparib has:
an IR spectrum comprising absorption peaks at ±1.5 cm −1 ; a DSC curve comprising an exothermic peak at 184.9° C. and an endothermic peak at 210.8° C.
[0030] Preparation of the Hydrated Crystalline Form of Olaparib (Form B):
[0031] The hydrated crystalline form of Olaparib (form B) exhibits better solubility in various organic solvents and in water than the crystalline forms of Olaparib A and L. The novel crystalline form is a hydrated form with a water content ranging between 3% and 7%. The water content aids the solubility of Olaparib in water. The hydrated crystalline form of Olaparib (form B) is stable to air and heat for a long time ( 30 days) and, when exposed to a water-saturated environment, maintains its original physicochemical characteristics.
[0032] The hydrated crystalline form of Olaparib (form B) is crystallized from a crystalline form of Olaparib (form A, form L or solvated form A) by a suitable polar solvent or a suitable mixture of polar solvents, such as carboxylic acids, amides and/or water.
[0033] The hydrated crystalline form of Olaparib (form B) can be obtained by adding a solution of Olaparib in a polar solvent to an anti-solvent, or adding an anti-solvent to a solution of Olaparib in a polar solvent.
[0034] The crystalline Olaparib is dissolved in a polar solvent such as acetic acid, propionic acid, butyric acid, valeric acid, dimethyl sulfoxide, dimethylformamide or dimethyl acetamide, preferably acetic acid, propionic acid, dimethylsulfoxide or dimethyl formamide, and more preferably acetic acid, dimethylsulfoxide or dimethylacetamide, at a temperature ranging between 20° C. and 100° C., preferably between 20° C. and 70° C., and more preferably between 35° C. and 70° C.
[0035] The solution of Olaparib is added to an anti-solvent, preferably a polar protic anti-solvent such as water, at a temperature ranging between −10° C. and 50° C., preferably between 0° C. and 30° C., and more preferably between 10° C. and 25° C.
[0036] Alternatively, an anti-solvent, preferably a polar protic anti-solvent such as water, is added to the Olaparib solution at a temperature ranging between - 10 ° C. and 50° C., preferably between 0° C. and 30° C., and more preferably between 10° C. and 25° C.
[0037] The resulting suspension is left under stirring for a time ranging between 1 and 48 hours, preferably between 5 minutes and 24 hours, and more preferably between 10 minutes and 18 minutes, at a temperature ranging between 0° C. and 50° C., preferably between 10° C. and 40° C., and more preferably between 10° C. and 30° C.
[0038] The suspension is filtered and the solid washed with an anti-solvent, preferably a polar protic anti-solvent such as water. The resulting solid is dried at low pressure at a temperature ranging between 0° C. and 70° C., preferably between 20° C. and 60° C.
[0039] Alternatively, crystalline form B of Olaparib can be obtained from the amorphous form of Olaparib and a suitable mixture of polar solvents.
[0040] The amorphous form of Olaparib is treated with a polar solvent such as water, acetic acid, propionic acid, butyric acid, valeric acid, dimethylsulfoxide, dimethyl formamide or dimethyl acetamide, preferably acetic acid, propionic acid, dimethyl sulfoxide or dimethylformamide, and more preferably acetic acid, dimethylsulfoxide, dimethyl acetamide or a mixture thereof, at a temperature ranging between 20° C. and 100° C., preferably between 20° C. and 70° C., and more preferably between 35° C. and 70° C.
[0041] The resulting suspension is left under stirring for a time ranging between 1 and 48 hours, preferably between 5 minutes and 24 hours, and more preferably between 10 minutes and 18 minutes, at a temperature ranging between 0° C. and 50° C., preferably between 10° C. and 40° C., and more preferably between 10° C. and 30° C.
[0042] The suspension is filtered and the solid washed with an anti-solvent, preferably a polar protic anti-solvent such as water. The resulting solid is dried at low pressure at a temperature ranging between 0° C. and 70° C., preferably between 20° C. and 60° C.
[0043] The hydrated crystalline form of Olaparib (form B)has an IR spectrum, DSC curve and XRPD pattern as shown in FIGS. 4, 5 and 6 respectively. In particular, hydrated crystalline form B of Olaparib has:
an IR spectrum comprising absorption peaks at 3513, 3163, 1681, 1651, 1438, 1222, 1012, 810, 773, 587±1.5 cm −1 ; a DSC curve comprising an exothermic peak at 141.5° C. and an endothermic peak at 210.5° C. An XRPD pattern comprising the following peaks: (2θ): 6.36 (29), 6.80 (14), 8.26 (13), 12.61 (65), 13.64 (10), 15.00 (100), 15.81 (14), 16.38 (17), 16.64 (13), 17.90 (16), 18.61 (20), 18.85 (15), 19.64 (37), 20.00 (19), 21.96 (31), 22.93 (35), 26.07 (30), 26.78 (22). A Karl Fisher value ranging between 3% and 7%.
EXAMPLES
[0048] The IR spectra were recorded with a Perkin Elmer spectrum 1000 IR instrument, sample preparation as KBr pellet. The spectrum was recorded by performing 16 scans at a resolution of 4 cm −1 .
[0049] The DSC curves were recorded with a Perkin Elmer Pyris 1 instrument; 3-5 mg of material was used to prepare the samples. The scans were conducted at the rate of 10° C. a minute.
[0050] The NMR spectra were recorded with a Varian Mercury 300 instrument in DMSO at 25° C., 16 scans being performed.
[0051] The XRPD spectra were recorded with a Bruker D2 instrument using the following parameters: Wavelength CuKα (λ=15419 Å)—Energy 30 KV—Stepsize: 0.02°—2θ Range: 2.6°-40°.
Example 1
[0052] Olaparib (1.0 g) is suspended in 3 ml of DMSO, and the suspension is heated at 60° C. until completely dissolved. The solution is poured into water (30.0 mL) at 0° C.
[0053] The resulting mixture is maintained under stirring for 30 minutes at 0° C., and filtered through a Büchner funnel to obtain 1.0 g of a white solid, which is dried in oven under vacuum for 10 h. The product (amorphous form) has an IR spectrum, DSC curve and XRPD pattern as shown in FIGS. 1-3 respectively.
Example 2
[0054] Olaparib (2.0 g) is suspended in 6 ml of DMF, and the suspension is heated at 60° C. until completely dissolved. The solution is poured into water (60.0 mL) at 0° C.
[0055] The resulting mixture is maintained under stirring for 30 minutes at 0° C., and filtered through a Büchner funnel to obtain 1.2 g of a white solid, which is dried in oven under vacuum for 1 h. The product (amorphous form) has an IR spectrum, DSC curve and XRPD pattern as shown in FIGS. 1-3 respectively.
Example 3
[0056] Olaparib (2.0 g) is suspended in 6 ml of acetic acid, and the suspension is heated at 50° C. until completely dissolved. The solution is poured into water (60.0 mL) at 0° C.
[0057] The resulting mixture is maintained under stirring for 16 h at 25° C., and filtered through a Büchner funnel to obtain 2.0 g of a white solid, which is dried in oven under vacuum for 24 h. The product (crystalline form B) has an IR spectrum, DSC curve, XRPD pattern and 1 H-NMR spectrum as shown in FIGS. 4-7 respectively.
Example 4
[0058] Olaparib (2.0 g) is suspended in 6 ml of acetic acid, and the suspension is heated at 50° C. until completely dissolved. Water (60.0 mL) is added by dripping at 0° C. The resulting mixture is maintained under stirring for 16 h at 25° C., and filtered through a Büchner funnel to obtain 2.0 g of a white solid, which is dried in oven under vacuum for 24 h. The product (crystalline form B) has an IR spectrum, DSC curve, XRPD pattern and 1 H-NMR spectrum as shown in FIGS. 4-7 respectively.
Example 5
[0059] The amorphous form of Olaparib obtained in example 1 (1.0 g) is suspended in 10 ml of a 3/7 mixture of acetic acid/water. The suspension is maintained under stirring for 16 h at 25° C., and filtered through a Büchner funnel to obtain 0.9 g of a white solid, which is dried in oven under vacuum for 24 h. The product (crystalline form B) has an IR spectrum, DSC curve, XRPD pattern and 1 H-NMR spectrum as shown in FIGS. 4-7 respectively.
Example 6
[0060] Olaparib form A (2.0 g) is suspended in 60 ml of water and seeded with Olaparib form B. The suspension is maintained under stirring at 25° C. for 7 days. The suspension is filtered through a Bëchner funnel to obtain 2.0 g of a white solid, which is dried in oven under vacuum for 24 h. The product (crystalline form B) has an IR spectrum, DSC curve, XRPD pattern and 1 H-NMR spectrum as shown in FIGS. 4-7 respectively.
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Disclosed are a novel crystalline form and an amorphous form of Olaparib, and the process for their preparation.
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BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to rodeo equipment. More particularly, the present invention relates to a safety device for remotely releasing a bull rope from an animal.
2. Problems in the Art
In a bull riding contest at a rodeo, a bull is trained to buck while a rider attempts to remain on the bull for a specified period of time. The rider is allowed to hold on to the bull with one hand via a bull rope or rigging. When the specified time period has expired or the rider is thrown from the animal, the rider will attempt to let go of the bull rope or saddle rigging to become separated from the animal.
A typical prior art bull rope is comprised of a rope which can be wrapped around the chest of the animal immediately behind the front legs. A typical prior art bull rope is comprised of a tweed rope with a loop in one end and a handle formed between the two ends. A bull rider will wrap the bull rope around the chest of the animal and insert the end of the bull rope through the loop in the other end. The rider then pulls the rope toward the handle and holds on to the end of the rope to secure the rope to the bull. Since the object of bull riding is to stay on the bull, bull riders want a very secure and tight bull rope. Riders typically wear leather gloves. To tightly secure the bull rope, bull riders will spread rosin on their gloves and on the rope. The rope is then wrapped tightly around the riders hand and wrist with the rosin helping to secure the bull rope. When the rider is thrown or the specified time period has expired, the rider will attempt to let go of the rope in order to dismount from the animal.
Occasionally, when a rider is thrown from the animal, the rider's hand remains secured to the bull rope because of the tight grip described above. When this happens, the rider may be dragged by the arm along side of the animal at which time the rider can be stepped on, kicked, or otherwise injured. Once a bull rider is thrown without releasing this secure grip, the bull riders is almost helpless until a rodeo clown or other person is able to release the grip. This situation has resulted in serious injuries, including many which are crippling and even fatal. Another effect of this problem is that riders tend to practice less than desired because of the risk of getting hurt. The lack of practice add further to the danger of the sport.
It can be seen that the rider has a significant incentive to tightly secure one hand to the bull rope or saddle rigging as securely as possible in order to remain on the animal for the specified period of time. Unfortunately, as the grip on the bull rope becomes more secure, it is harder for the rider to release the hand from the animal when thrown. It can also be seen that there is a need for safety devices in this very dangerous sport. One prior art approach attempts to stop the animal from bucking after the specified time period has elapsed to protect the rider. U.S. Pat. No. 3,733,530 issued to Labart uses a radio controlled latch attached to a bucking strap to remotely release the bucking strap from the animal. While this device may help to calm the animal, the device does not help the riders release their hands from the bull rope or saddle rigging. As a result, a rider may still be hung up on the animal even after the bucking strap is released. So, regardless of whether the animal stops bucking, the rider is still in danger when one hand is caught in the bull rope. Many riders have been injured even after the bucking strap has been released since the animals commonly continue to buck. So it can be seen that while this particular prior art device may help calm the animal, a separate and unrelated problem still exists--a rider's hand being hung up in the bull rope. The prior art does not teach, suggest, or even acknowledge a solution to this hazard. There is no known prior art device which allows the rider to quickly become detached from the animal after being thrown while at the same time allowing the rider to tightly secure one hand to the animal.
FEATURES OF THE INVENTION
A general feature of the present invention is the provision of a remote release safety device which secures a bull rope to a rodeo animal.
A further feature of the present invention is the provision of a remote release safety device which is used on the bull rope of a rodeo animal so that the bull rope can be released from the animal after a rider is thrown.
A further feature of the present invention is the provision of a remote release safety device which includes an electrically actuated fastening device to allow a bull rope to be remotely released from an animal.
A further feature of the present invention is the provision of a remote release safety device having a radio receiver for receiving a radio signal from a transmitter for remotely releasing the device from a rodeo animal.
A further feature of the present invention is the provision of a remote release safety device for use on bull ropes of rodeo animals in order to prevent injuries and deaths to riders.
These as well as other features of the present invention will become apparent from the following specification and claims.
SUMMARY OF THE INVENTION
The remote release safety device of the present invention is used by rodeo participants to attach a bull rope to an animal in such a way that the bull rope can be remotely released if the rider is thrown from the animal and cannot release his hand from the bull rope. The invention is comprised of a buckle release device which is actuated when a radio signal is received by a receiver. The receiver receives signals from a transmitting device controlled by a person other than the rider. When the rider is thrown from the animal and is unable to let go of the bull rope, the transmitter can be activated which causes the remote buckle release device to release the bull rope which allows the rider to safely separate from the animal.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 is a perspective view of a bull rider riding a bull.
FIG. 2 is a perspective view of the bull rope and remote release safety device of the present invention.
FIG. 3 is a block diagram of the present invention.
FIGS. 4-6 are cross sectional views of the present invention showing the internal workings of the present invention.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT
The present invention will be described as it applies to its preferred embodiment. It is not intended that the present invention be limited to the described embodiment. It is intended that the invention cover all alternatives, modifications, and equivalences which may be included within the spirit and scope of the invention.
FIG. 1 shows a bull rider 10 riding a bull 12 while using a bull rope 14 of the present invention. Attached to the bull rope 14 is a releasable latching mechanism 16 which can not be seen in FIG. 1, since it is positioned underneath the bull. The bull rope 14 is preferably comprised of a tweed rope and is wrapped around the chest of the bull 12 immediately behind the front legs. A bull rider 10 will grasp the rope 14 near the portion of the rope on the bull's back to tightly secure the rider's hand to the bull rope 14. The rope wraps around the chest of the animal and is held together by inserting the end of the rope 14 through a loop and then holding on to the end while also wrapping the rope around the hand of the rider.
The bull rope 14 will remain secured to the bull 12 until the end of the rope is released by the rider or the buckle release device 16 of the present invention is released.
FIG. 2 shows the bull rope 14 with the remote buckle release device 16 of the present invention. The bull rope 14 is comprised of a tweed rope with a loop (not shown) at one end. A remote buckle release device 16 is also connected to the rope 14. As shown in FIG. 2, the bull rope 14 is attached to the remote release device 16 by a pair of loops 18 inserted through first and second eyebolts 20 and 22. FIG. 2 shows the eyebolt 22 in the released position, with a dotted line showing where it attaches to the remote latch 16.
FIG. 2 also shows a remote transmitting device 24 which is used to transmit a signal to the remote release device 16. When the buckle release device 16 receives the appropriate signal from the remote 24, it releases the bull rope 14 from the bull 12.
FIG. 3 is a block diagram of the remote buckle release device 16. FIG. 3 shows the transmitting device 24 and the remote buckle release device 16. The transmitting device 24 includes a conventional radio transmitter 26 and a conventional antenna 28. When the transmitter 24 is activated, it transmits a signal via the antenna 28. The receiver 30 within the buckle release device receives the transmitted signal via the antenna 31. The receiver 30 is preferably a 2-channel receiver. When a signal is received by the receiver 30, a control signal is sent to an electrical actuator (e.g., servo 32) which actuates a buckle mechanism and releases the bull rope 14. Of course, the block diagram of FIG. 3 shows only one possible configuration for the present invention, as any number of configurations are possible. For example, rather than radio signals, other signals could be used such as light signals, sonic signals, etc. The receiver antenna 31 is preferably contained within the housing of the buckle release device 16, although an external antenna could also be used. The antenna 31 shown in FIG. 4 is a 20 inch wire antenna which is glued to the inside surface of the housing 34 of the device 16.
FIGS. 4-6 show detailed views of the releasable latch 16 of the present invention. The latch 16 is enclosed in a housing 34 which includes a lid 36 secured to the housing 34 by screws 38. The first threaded eyebolt 20 is rigidly secured to the housing 34 by a nut 40. Disposed within the housing 34 is a battery 42, the receiver 30, the antenna 31, a servo motor 32, and a latching assembly 44. The battery 42 supplies power to the transmitter 30 and the servo 32. The servo 30 acts to control the operation of the servo 32. The servo 32, in turn, controls the latching assembly 44.
As best shown in FIG. 5, the servo 32 is secured to the housing 34 by a pair of servo mounts 46. A layer of padding 48 is placed between the housing 34 and the servo 32 to secure the servo 32. The servo 32 includes a shaft 50 rigidly coupled to an arm 52 which is rotatably coupled to a servo extension rod 54. By activating the servo 32, the extension rod 54 will move generally back and forth. As shown in FIG. 6, the rod 54 is rotatably coupled to a slip locking pin 56. The slip locking pin 56 is rotatably mounted to a mount 58 so that the locking pin 56 is rotatably mounted relative to the housing 34 between a latched (FIG. 6) and an unlatched position (not shown). A cylindrical chamber 62 having opened and closed ends 64 and 66, respectively, is formed by a steel tube 68. A locking pin spring 60 is disposed between the locking pin 56 and the tube 68 to bias the locking pin in the latched position shown in FIG. 6. When the remote releasably latch 16 of the present invention is latched, the eyebolt 22 is disposed partially within the cylindrical chamber 62. A chamber spring 70 is disposed in the cylinder 62 to press against eyebolt 22. The spring 70 functions to press the eyebolt tightly against the locking pin 56 as well as ensure that the eyebolt 22 will exit the chamber 62 when desired. The eyebolt 22 is securely held within the chamber 62 by the locking pin 56 which is partially inserted in a hole 72 in the eyebolt 22.
The remote buckle release device 16 of the present invention operates as follows. When preparing a bull 12 or other rodeo animal for a contest, the bull rope 14 including the remote buckle release device 16 is attached to the bull 12 by wrapping the rope 14 around the chest of the bull 12 immediately behind the front legs. The rope is tightened to the desired tension by the rider by inserting the end of the rope 14 through a loop, pulling the rope 14 up, and wrapping the rope around the rider's hand so that the rope is very securely attached. The latching mechanism 44 will be in the position shown in FIGS. 4-6.
When the bull 12 is in the chute, the rider 10 is mounted on the bull 12 while grasping the bull rope 14. When the chute opens and the bull 12 starts to buck (FIG. 1), the bull rider 10 rides the bull 12 until a specified time period has expired or until the bull rider 10 is thrown from the bull 12. If the rider 10 is thrown from the bull 12, the rider 10 will attempt to release his hand from the bull rope 14 in order to escape from the bull 12 and avoid injury. In the unfortunate but common event that the bull rider 10 cannot separate his hand from the bull rope 14 after being thrown, another person can release the bull rope 14 using the remote control 24. When the person activates the transmitter 26 by pressing a button, a radio signal is transmitted and received by the receiver 30 within the buckle release device 16. The receiver 30 then sends a trigger signal to an electrical actuator such as servo 32. The servo 32 will then rotate causing the servo extension rod 54 to rotate the locking pin 56. When the locking pin 56 has rotated far enough, the pin 56 will no longer be inserted in the hole 72 in the eyebolt 22. At this point, the eyebolt 22 will pull out of the chamber 62 due to the tension on the bull rope 14 and also due to the pressure from the spring 70. When the eyebolt 22 exits the chamber 62, bull rope 14 will be released from the bull 12 which in turn releases the bull rider's hand and allows the rider 10 to escape from the bull 12 without injury. The entire process starting from when the person activates the transmitter 26 to the time when the bull rope 14 is released, takes place in a fraction of a second, giving the rider 10 the opportunity to escape before being injured. To use the bull rope 14 again, a user simply inserts the eyebolt 22 into the chamber 62 where the locking pin 56 will lock the eyebolt in place.
Although the present invention has been described as a device for use with a bull rope 14, the invention is not limited to that particular use. For example, the invention could be used as a remote release device for a saddle rigging used with saddle broncos.
The preferred embodiment of the present invention has been set forth in the drawings and specification, and although specific terms are employed, these are used in a generic or descriptive sense only and are not used for purposes of limitation. Changes in the form and proportion of parts as well as in the substitution of equivalents are contemplated as circumstances may suggest or render expedient without departing from the spirit and scope of the invention as further defined in the following claims.
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A remote release device is adapted to secure a bull rope around the chest of a rodeo bull. The release device includes a radio receiver which receives signals transmitted from a remote transmitter and causes a latching mechanism to release the bull rope from the bull. The transmitter is activated by a person when the bull rider is thrown and is unable to let go of the bull rope. In this way, the bull rider avoids injury.
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BACKGROUND OF THE INVENTION
[0001] 1. Field of Invention
[0002] This invention pertains to a method and an apparatus that forms ablated features in substrates such as by laser ablation of polymer substrates for inkjet print head applications.
[0003] 2. Description of the Related Art
[0004] The laser ablation of features on polymer materials using a mask and imaging lens system is well known. In this process, features on the mask are illuminated with laser light. The laser light that passes through the transparent features of the mask is then imaged onto the substrate such as a polymeric film where the ablation process occurs.
[0005] [0005]FIG. 1 illustrates a basic layout of a conventional excimer laser machining system 10 . Typically, the system 10 is controlled by a computer 12 with an interface to the operator of the system. The computer 12 controls the firing of the pulsed laser system 24 and a low speed, low resolution servo system 14 . The function of the servo system 14 is to position the mask 16 and substrate chuck 18 for proper registration of the laser milled pattern with respect to other features on the substrate 19 prior to ablation of substrate 19 . For this purpose, a vision system (not shown) is often interfaced to the computer system. The servo system 14 or computer 12 may control an attenuator module 20 , to vary the amount of UV radiation entering the system. Alternatively, the laser pulse energy may be varied by adjusting the laser high voltage or a control set point for energy, maintained by the laser's internal pulse energy control loop.
[0006] The UV beam path is indicated in this figure with arrows 22 (not intended to be actual ray paths, which are not typically parallel) which show the flow of UV energy within the system. The UV power originates at the pulsed excimer laser 24 . The laser 24 typically fires at 100-300 Hz for economical machining with pulses that have a duration of about 20-40 nanoseconds each. The typical industrial excimer laser is 100-150 watts of time average power, but peak powers may reach megawatts due to the short duration of the pulse. These high peak powers are important in machining many materials.
[0007] From the output end of the laser, the UV energy typically traverses attenuator 20 ; however, this is an optional component not present in all laser machining systems. The attenuator 20 performs either or both of two possible functions. In the first function, the attenuator 20 compensates for the degradation of the optical train. The attenuator 20 thus used, allows the laser to run in a narrow band of pulse energies (and hence a restricted range of high voltage levels), allowing for more stable operation over the long term. With new optics in the system, the attenuator 20 is set to dissipate some of the power of the laser. As the optics degrade and begin to absorb energy themselves, the attenuator 20 is adjusted to provide additional light energy. For this function, a simple manual attenuator plate or plates can be used. The attenuator plates are typically quartz or fused silica plates with special dielectric coatings on them to redirect some of the laser energy toward an absorbing beam dump within the attenuator housing.
[0008] The other possible function of the attenuator 20 is for short term control of laser power. In this case, the attenuator 20 is motorized with either stepper motors or servo system, and the attenuator is adjusted to provide the correct fluence (energy per unit area) at the substrate for proper process control.
[0009] From the attenuator 20 , the UV energy propagates to a beam expansion telescope 26 (optional). The beam expansion telescope 26 serves the function of adjusting the cross sectional area of the beam to properly fill the entrance to the beam homogenizer 28 . This has an important effect on the overall system resolution by creating the correct numerical aperture of illumination upon exit from the homogenizer. Typical excimer laser beams are not symmetric in horizontal vs. vertical directions. Typically, the excimer beam is described as “top hat-gaussian,” meaning that between the laser discharge direction (usually vertical), the beam profile is “top hat” (initially relatively flat and dropping off sharply at the edges). In the transverse direction, the beam has a typical intensity profile that looks qualitatively gaussian, like a normal probability curve.
[0010] The expansion telescope 26 allows some level of relative adjustment in the distribution of power in these directions, which reduces (but does not completely eliminate) distortion of the pattern being imaged onto the substrate 19 due to the resolution differences in these two axes.
[0011] Between the expansion telescope 26 and homogenizer 28 is shown a flat beam folding mirror 30 . Most systems, due to space limitations, will contain a few such mirrors 30 to fold the system into the available space. Generally, the mirrors may be placed between components, but in some areas, the energy density or fluence can be quite high. Therefore, mirror locations are carefully chosen to avoid such areas of high energy density. In general, the designer of such a system will try to limit the number of folding mirrors 30 in order to minimize optics replacement cost and alignment difficulty.
[0012] The UV light next enters the beam homogenizer 28 . The purpose of the homogenizer 28 is to create a uniformly intense illumination field at the mask plane. It also determines the numerical aperture of the illumination field (the sine of the half angle of the cone of light impinging on the mask), which as stated above, has an impact on overall system resolution. Since certain parts of the excimer beam are hotter than others, uniform illumination requires that the beam be parsed into smaller segments which are stretched and overlaid at the mask plane. Several methods for this are known in the art, with some methods being based on traditional refractive optics, e.g., as disclosed in U.S. Pat. Nos. 4,733,944 and 5,414,559, both of which are incorporated herein by reference. The method may also be based on diffractive or holographic optics, as in U.S. Pat. No. 5,610,733, both of which patents are incorporated by reference, or on continuous relief microlens arrays (described in “Diffractive microlenses replicated in fused silica for excimer laser-beam homogenizing”, Nikoladjeff, et. al, Applied Optics, Vol 36, No. 32, pp. 8481-8489, 1997).
[0013] From the beam homogenizer 28 the light propagates to a field lens 32 , which serves to collect the light from the homogenizer 28 and properly couple it into the imaging lens 34 . The field lenses 32 may be simple spherical lenses, cylindrical lenses, anamorphic or a combination thereof, depending on the application. Careful design and placement of field lenses 32 are important in achieving telecentric imaging on the substrate side of the lens 32 .
[0014] The mask 16 is typically placed in close proximity to the field lens 32 . The mask 16 carries a pattern that is to be replicated on the substrate 19 . The pattern is typically larger (2 to 5 times) than the size of the pattern desired on the substrate 19 . The imaging lens 34 is designed to de-magnify the mask 16 in the course of imaging it onto the substrate 19 . This has the desired property of keeping the UV energy density low at the mask plane and high at the substrate plane. High de-magnification usually imposes a limit on the field size available at the substrate plane.
[0015] The mask 16 may be formed from chromium or aluminum coated on a quartz or fused silica substrate with the pattern being etched into the metallic layer by photolithography or other known means. Alternatively, the reflecting and/or absorbing layer on the fused silica mask substrate 16 may comprise a sequence of dielectrics layers, such as those disclosed in U.S. Pat. Nos. 4,923,772 and 5,298,351, both of which are incorporated herein by reference.
[0016] The purpose of the imaging lens 34 is to de-magnify and relay the mask pattern onto the substrate 19 . If the pattern is reduced by a factor of M in each dimension, then the energy density is raised by M 2 multiplied by the transmission factor of the imaging lens 34 (typically 80% or so). In its simplest form, the imaging lens 34 is a single element lens. Typically, the imaging lens 34 is a complex multi-element lens designed to reduce various aberration and distortions in the image. The imaging lens 34 is preferably designed with the fewest elements necessary to accomplish the desired image quality in order to increase the optical throughput and to decrease the cost of the imaging lens 34 . Typically, the imaging lens 34 is one of the most expensive parts of the beam train.
[0017] As noted above, the imaging lens 34 creates a de-magnified image of the pattern of the mask 16 on the substrate 19 . Each time the laser fires, an intense patterned area is illuminated on the substrate 19 . As a result, etching of the substrate material results at the illuminated areas. Many substrate materials may be so imaged, especially polymeric materials. Polyimides available under various trade names such as Kapton™ and Upilex™ are the most common for microelectronic applications and inkjet applications.
[0018] The system 10 described in FIG. 1 is a “typical” system. For non-demanding applications, the system can be further simplified and still produce ablated parts, but with some sacrifice in feature tolerances, repeatability, or both. It is not unusual for systems to make some departure from this typical architecture, driven by the particular needs of the application.
[0019] There are many applications for laser ablation of polymeric materials. Some applications or portions thereof are not demanding in terms of tolerances, e.g., electrical vias, and the emphasis is on small size, high density features and low cost. Other applications require very demanding tolerances and repeatability. Examples of the latter applications are fluid flow applications such as inkjet print head nozzle manufacture and manufacture of drug dispensing nozzles. In these demanding applications, the requirements for exact size, shape, and repeatability of manufacture are much more stringent than the simpler conductive path features provided by a microelectronic via. The detailed architecture of the system is critical to obtaining tight tolerances and product repeatability. In addition, process parameters and the optical components all play important roles in obtaining the tightest possible tolerances, down to the sub-micron level.
[0020] As mentioned above, the invention relates to the formation of nozzles for inkjet print head applications and other fluid flow applications. During the firing of a thermal inkjet print head, a small volume of ink is vaporized. The vaporized ink causes a droplet of ink to shoot through an orifice (i.e., the nozzle) which is directed at the print media. The quality of thermal inkjet printing is dependent upon the characteristics of the orifice. Critical attributes of the orifice include the shape and surface condition of the bore.
[0021] One important aspect for fluid flow applications is the slope of the via walls. Vias made in the conventional manner have very steep wall slopes, with the slope dependent upon the incident radiation fluence (energy per unit area), and to a lesser extent, the number of laser pulses used to create the feature. Using conventional methods, very little can effectively be done to control or shape the via wall slope. One method is controlling the energy distribution of the radiation hitting the substrate. In a projection imaging system, this can be accomplished by placing ring shaped apertures on the masks such as described in U.S. Pat. No. 5,378,137. However, the mask features used to create the hole profiles must be very small (sub-resolution for the imaging system), or they may be imaged into the ablated hole or via. The disadvantage of this method is that the small mask features can easily be damaged and also add difficulty and expense to the mask making process.
[0022] In a typical inkjet print head made currently in the industry, small ablated orifices or vias are made in the polymer film substrate at a concentration of about 300 or more ablated orifices per inch. The size of the orifices may vary depending upon the particular application, but generally have an exit diameter less than about 35 microns. The entrance orifice diameter is typically less than 100 microns, with an average entrance diameter of about 50 microns to about 60 microns being more typical. The objective of the invention described herein is to provide additional control over the shape of the orifice in addition to the traditional process controls of mask features, fluence, laser shots, and so forth in controlling the detailed shape of the orifice.
[0023] In addition to the ring-mask method described above, another method of shaping the orifice wall angle is to displace the beam using an optical method. This can be accomplished, for example, by spinning a flat or wedge-shaped optical element between the mask and projection lens. Such a method is described in U.S. Pat. No. 4,940,881. Placing a spinning element between the mask and the projection lens has the effect of moving the image in a circular orbit. This motion changes the ablated feature profile by moving the incident light at the surface of the substrate. The disadvantage of the method of U.S. Pat. No. 4,940,881 is that the radius of the orbit cannot be easily changed during the machining cycle. If the optical elements are wedge-shaped, as described in U.S. Pat. No. 4,118,109, the method also has the disadvantage that the angle of the beam is altered during the orbit, which limits the smallest possible beam displacement and complicates process control. An additional limitation is that hole wall slope profiles are limited to concave geometry (see FIG. 6), when used in conjunction with a conventional laser mask (e.g. one with simple apertures in the reflecting or absorbing coating for each ablated feature), except at very low fluences.
[0024] An apparatus and method for controlling an ablated orifice shape using two rotating optical elements is described in co-pending U.S. patent application Ser. No. 09/197,127,entitled “LASER ABLATED FEATURE FORMATION DEVICE” filed on like date herewith, and incorporated by reference herein. The invention of copending U.S. patent application Ser. No. 09/127,127 has the advantage over U.S. Pat. No. 4,940,881 in that the profile of the hole wall can be altered by controlling the relative rotational velocities and phase angle between the two rotating optical elements. In this manner, any desired hole profile (i.e., concave, convex or straight) can be obtained without requiring a complicated mask structure.
[0025] Yet another method for moving the image on the substrate utilizes a movable mirror between the mask and the projection lens. The mirror can be tilted in such a manner that the image moves in a prescribed orbit, thereby moving the incident light at the substrate. A major disadvantage of this method is the limited sensitivity of control, since a small tilt of the mirror can be a rather large displacement of the apparent mask position. Further, such mirrors must be of a minimum thickness to insure sufficient mechanical stability and flatness of the reflecting surface. This in turn, makes for a rather large inertia, and limits the bandwidth or highest speed of the device. When the system bandwidth is limited, it places limits on the scan patterns that can be effectively used to shape the holes.
[0026] An alternative to optically or mechanically moving the mask image is to actually move the substrate. This has a disadvantage, however, that the motion of the substrate must be very precise. The requirement for high precision is due to the fact that the projection lens of the ablation system shrinks the projection mask image down to the substrate to concentrate the laser energy. Consequently, the tolerances on the motion profile also shrink proportionately. This approach usually has the same inertial problems as the tilting mirror approach discussed above, except that the problem is further aggravated by additional mass of the substrate holders and motion stages used in typical automated systems.
[0027] As can be seen, there are multiple ways by which the profile of a laser ablated feature may be controlled to some degree. However, it can also be seen that the currently available methods have limitations which restrict their usefulness. What is needed, therefore, and what is provided by the present invention, is an apparatus and method for controlling the profile of laser ablated features which is very flexible in allowing the creation of multiple types of orifice profiles, while at the same time providing accurate and repeatable results. In the present invention, the mask itself is continually moved according to a prescribed set of coordinates for each and every laser pulse. The detailed trajectory of this motion has a strong influence on the final ablated hole shape. The ability to change the hole geometry without any additional optical element is a powerful yet flexible process parameter. Moving the mask itself within a certain prescribed trajectory can change the geometry of the ablated feature in a desirable fashion, including convex, concave and straight-walled features.
SUMMARY OF THE INVENTION
[0028] The present invention provides a method of improving the geometry of laser ablated features. In the method of the invention, the mask is moved at high speed and high resolution during the ablation process in a plane perpendicular to the optical axis of the system, thereby causing the image to move in a like way and change the geometry of the ablated feature on the substrate. The mask can be moved in any desired pattern, such as a circular pattern, spiral pattern, or more general scan pattern to create the desired shape of the wall slope of the ablated feature. The ablated feature can be made oval by moving the mask in an elliptical orbit during the machining cycle.
[0029] In one broad respect, this invention provides a process useful for ablating features in a substrate, comprising: irradiating the substrate with radiation that has passed through a mask to form an ablated feature in the substrate, wherein the mask is orbited perpendicular to the optical axis during formation of the feature thereby forming a selected wall shape.
[0030] The process of this invention may be employed to ablate a variety of materials. For instance, the process may be used to etch or expose patterns in organic or inorganic photoresist during semiconductor fabrication using a variety of radiation sources such as X-rays and ultraviolet light including deep ultraviolet light. The process of this invention can be employed to ablate features in substrates that either completely traverse the substrate, i.e., holes or vias, or features with a given depth which is less than the total depth of the substrate, often described as a “blind” feature.
[0031] In yet another broad respect, this invention provides an apparatus useful for making holes in a substrate, comprising: a radiation source; a mask positioned between the radiation source and a substrate to be irradiated with radiation from the radiation source, wherein the mask is capable of moving perpendicular to the system optical axis when the substrate is being irradiated such that a different feature shape is formed than would have been formed if the mask were not orbited.
[0032] As used herein, the term “laser feature” includes holes, bores, vias, nozzles, orifices and the like, and may be fully ablated through the substrate or only partially through the substrate (“blind” features).
BRIEF DESCRIPTION OF THE DRAWINGS
[0033] [0033]FIG. 1 illustrates a typical laser machining system employing a mask for irradiating a substrate.
[0034] [0034]FIG. 2 illustrates a laser machining system using a compound mask motion device during the ablation process.
[0035] [0035]FIG. 3 illustrates one possible system hardware architecture for controlling motion of the mask.
[0036] [0036]FIG. 4 illustrates trigger feedback to the servo control system.
[0037] [0037]FIG. 5 illustrates the time difference between a laser pulse and when the mask is in position.
[0038] [0038]FIG. 6 illustrates different bore profiles which may be created with the present invention.
[0039] [0039]FIG. 7 illustrates a laser shot pattern which may be created using the present invention for creating a nozzle having an axis which is non-orthogonal to the substrate surface.
[0040] [0040]FIG. 8 illustrates nozzle arrays in which the longitudinal axes of arrays of nozzles are inclined in predetermined directions, for the purpose of directing fluids exiting the nozzle arrays and controlling the relative direction of the exiting fluids.
DETAILED DESCRIPTION OF THE INVENTION
[0041] As discussed above, FIG. 1 illustrates the basic layout of a conventional excimer laser machining system 10 , including servo system 14 control of mask 16 , substrate chuck 18 and attenuator 20 . As noted above, in the typical system 10 of FIG. 1 servo system 14 is a low speed, low resolution system which functions to properly register mask 16 and substrate 19 prior to ablation of substrate 19 . Servo system 14 does not move during the ablation process and only provides gross movement of mask 16 and substrate 19 (movements on the order of several millimeters) to align mask 16 and substrate 19 .
[0042] In contrast to the machining system of FIG. 1, the mask 16 used in the practice of the present invention is capable of moving at high speeds and high resolution in a plane perpendicular to the optic axis of the system during irradiation of the substrate. FIG. 2 schematically represents this concept of a laser system including a high speed active mask scanning subsystem 48 integrated with laser control which is “piggybacked” onto the low speed servo system 14 . The light from the beam conditioning optics (which may consist of the components described in FIG. 1 of attenuator, beam expansion, homogenization, and field lenses, as appropriate for the application) sufficiently overfills the features on the mask 16 so that mask motions on the order of approximately +/−100 microns or less (caused by high speed scanning subsystem 48 ) can be achieved within the homogeneous region of the illumination field. The light passing through the mask is then imaged by imaging lens 24 , onto the fixed substrate 19 . It will be appreciated by those skilled in the art that the schematic illustration of FIG. 2 is non-limiting, and other control systems may also be suitable.
[0043] A mask used in the practice of laser ablation is well known. One representative example of a type of mask which can be used in the practice of this invention is described in U.S. Pat. No. 5,378,137, incorporated herein by reference. Typically, a mask comprises a clear, fused quartz substrate having a thin opaque or reflective layer. The opaque material may be a layer of chrome that has been sputtered onto the substrate, an ultraviolet enhanced coating, or any other suitable reflective or otherwise opaque coating, such as multi-layer dielectric coatings. The reflective or opaque coating on the mask is patterned such that it comprises a series of apertures or other structures through which the light passes, ultimately illuminating the substrate. Each aperture of the mask corresponds to a resulting feature in the substrate.
[0044] The type of laser employed will be a function of the substrate to be ablated. For instance, the polymer film used to make inkjet print heads and electronic packaging applications is typically a polyimide, such as Kapton™ and Upilex™, having a thickness of approximately 2 mils. For these applications an excimer laser is commonly employed, such as KrF excimer (248 nanometers), or XeCl excimer (308 nanometers). Alternatively, for features larger than about 35 microns, a TEA CO 2 laser may be used to ablate polyimides. In general, the excimer laser commonly produces a pulse width of about 30 nanoseconds, which is very fast on the time scale of laser repetition rate and mask motion. The power of the laser may be selected depending on number and type of optical components in the system to deliver a fluence at the substrate in the range from about 400 to about 1000 or more millijoule/cm 2 .
[0045] In the practice of this invention, when the substrate is a polymer such as a polyimide film, the polymer may be provided from a reel and positioned on the substrate stage in the laser system. The laser is then repeatedly pulsed for a predetermined amount of time to ablate the polymer to form a pattern of ablated features. A variety of factors affect the geometry of the feature, including use of structures in the mask, laser power, fluence, number of laser pulses, and so forth, in addition to the mask trajectory of this invention. The finished polymer is then removed, with fresh polymer being positioned on the stage.
[0046] The mask 16 movement can be achieved in variety of ways. As described above, the mask 16 can be mechanically moved through the use of an electromechanical servo motor or its equivalent which is connected, directly or indirectly, to the mask. Such a servo system is adequate for low speed, low resolution motion, such as initial alignment of the mask 16 and substrate 19 . However, such a servo system is not useful for providing the high speed, high resolution movements necessary in the laser machining operation due to the typically high system inertia and other factors, which are discussed in greater detail below.
[0047] For high speed, high resolution movement, the mask 16 is connected to a piezoelectric material or apparatus, such as a linear or rotary piezoelectric micropositioner, which is “piggybacked” onto low speed servo system 14 . Representative, non-limiting examples of such micropositioners are available from Physik Instrumente. Such micropositioners may have typical resolutions of 0.1 μm, having varying travel ranges, rotary angle speeds, and velocity ranges. The aforementioned mechanisms can be readily connected to the mask using conventional techniques.
[0048] The mask scanning system hardware architecture is illustrated in FIG. 3. This is one representative and non-limiting architecture. Referring to FIG. 3, the laser machining system is usually controlled by a computer or microcontroller 12 , which includes an ablation system controller 50 and a laser controller 52 which controls the laser light source 24 . Both ablation system controller 50 and laser controller 52 communicate with a real time servo controller 54 that manages the x,y motion of the laser mask 16 , through x-axis and y-axis micropositioning motion stages 62 , 64 , respectively. A position feedback system 60 sends real time position information back to the real time servo controller 54 (referred to as “closed loop” control). Possible feedback devices include, but are not limited to LVDT sensors, strain gauge sensors, capacitive sensors, and inductive sensors.
[0049] When the laser source is a high pressure gas discharge laser, such as an excimer or TEA CO 2 laser, then the output characteristics of the laser are highly dependent upon a steady firing or repetition rate. A typical repetition rate may be 200-300 Hz. If the laser is fired at an unsteady repetition rate, the refreshing of the gas between the electrodes may be incomplete or vary from laser shot to laser shot, charging of the high voltage capacitors may vary, and perhaps other undesirable effects. Further, the laser manufacturer typically optimizes the laser for the case of steady firing of the laser. Thus, the need for optimal laser performance in turn places rigorous timing demands on the motion control of the mask micropositioning motion stages 62 , 64 . This is further compounded by the high firing rates of the laser, thereby demanding a relatively high bandwidth for the overall positioning system (consisting of mask 16 , the mask holder, micropositioners 62 , 64 , servo amplifiers 58 , position feedback device 60 , and real time servo controller 54 . The high firing rates of the laser preclude the use of a conventional servo system, as such a system is too slow to provide accurate movement at rates of 200-300 Hz.
[0050] The overall system bandwidth is a function of several system components. In particular, the mechanical system may have some inherent time constant. For example, the position feedback device 60 can affect system bandwidth, and the actuator providing the motion can have some delay. For example, moving a piezo device is similar to charging a capacitor through a resistor, and therefore has some inherent RC time constant. In addition, the power supply for the servo or piezo system usually has some impedance or time constant. Therefore, the overall system performance must be considered as a whole when designing the system, and the components must be selected and tested to provide a motion bandwidth appropriate for the desired repetition rate of the radiation source.
[0051] For a given hardware set, several different control schemes are possible. The least complex way to implement this invention would be to trigger the laser after the motion control system is in position (within some prescribed following error). However, as discussed above, for best laser performance the laser must fire at a steady repetition rate, which would be difficult with this type of control scheme. In addition this type of control scheme would likely not achieve the highest material throughputs, which is an important economic consideration. Any practical control scheme must therefore accommodate the steady firing of the laser in the range of 200-300 Hz, and, at the same time, place the mask within some small tolerance of the desired position when the laser fires to achieve a repeatable laser machining process.
[0052] [0052]FIG. 4 schematically illustrates the concepts associated with the timing of the laser firing and motion control systems. First, the real time servo controller 54 for the mask motion may or may not be connected to the laser trigger source 56 . Laser trigger source 56 determines the laser firing rate with its steady clock output by its connection to the laser controller, 52 . When real time controller 54 is not connected to trigger source 56 , the internal time base of the real time controller 54 generates the sequence of times at which the mask is to be in a desired position. In this case, an external signal (such as from the ablation system controller 50 ) is required to synchronize the start of the laser burst and mask motion. In a preferred embodiment, the real time servo controller 54 is connected to the trigger source 56 , allowing data capture of the actual mask position at time of laser firing (within hardware speed limitations). There are several possible choices of trigger sources, including the internal clock of the real time servo controller 54 , the internal clock of the laser controller 52 , or an external clock.
[0053] [0053]FIG. 5 shows a time sequence of a “burst” of several laser shots, represented by the regularly spaced solid bars. In general, due to propagation delays, servo following errors, system inertia, and other inherent system factors, the time when the mask is in the desired (x,y) position will vary somewhat from the regularly occurring laser pulses. In FIG. 5, the time at which the mask is in position (within a sufficiently small tolerance) is represented by the dashed bars. The time difference between these two is represented by τ. The error in the position of the mask is approximated by the product of τ and the instantaneous velocity of the mask.
[0054] The effect of the mask position error on the final ablated results is reduced by an amount proportional to the demagnification of the imaging lens, which is typically in the range of 2×-5×. For high precision applications, placement errors of the light pattern on the substrate of less than 0.2 microns are desired. Thus, for a 5×demagnification system, this translates to a mask position error of 1 micron or less. With trigger source verification, the actual position of the mask can be calculated within a time period determined by the system propagation delays, the speed of the position feedback device and the speed of data capture. Within these inherent limitations, the mask position can be quantified at the time of laser firing. A laser firing at 250 Hz corresponds to 4 ms between laser shots, while the error in capturing the mask position is typically less than 30 microseconds.
[0055] Different control schemes are possible for use in conjunction with the system architecture described above. However, in the preferred embodiment, a set of position, velocity, and time (“PVT”) vectors are pre-calculated. These vectors include the x,y positions of desired mask locations corresponding to the laser triggering. However, they also contain PVT information for a number of points between the actual laser trigger points. By precalculating these intermediate points in the motion profile, the system performance can be optimized by selecting a trajectory to minimize the resonant frequency of the overall system and its harmonics. The PVT vectors are loaded into the real time servo controller 54 in advance of laser processing. The servo controller 54 continuously adjusts the mask velocity to reach the specified positions at the specified times.
[0056] It will be recognized that such a control system may be operated in either a synchronous manner (where laser firing and high speed movement of the mask are controlled from the same clock source), or in an asynchronous manner (where laser firing and high speed movement of the mask are controlled from independent clock sources). Synchronous operation is preferred for greater accuracy. Also, control systems may use a “closed loop” control, where feedback is provided about the position of mask 16 during the ablation process, or an “open loop” control where no feedback about the position of mask 16 is provided during the ablation process. The preferred “PVT” control system described above uses closed loop control, although open loop systems could also be used.
[0057] The system software is parametric in nature and the preferred embodiment is a multi-threaded software architecture. PVT vectors for the motion trajectory and time interval are read from the ablation controller 50 . Intermediate trajectory points and velocities are calculated in such a way as to make the most efficient mask movement given the system bandwidth. Multiple threads are used to manage the flow of information to the real time servo controller 54 , which is synchronized with the ablation controller 50 . Position feedback system 60 provides data back to the ablation controller 50 .
[0058] [0058]FIG. 6 illustrates how the ablated feature in the substrate can have a straight, concave, or convex wall shape, as measured from the bore axis. The wall shape may be adjusted by selectively controlling the motion of the mask 16 as describe above, which allows material to be ablated at different rates from inside the hole and thereby create different wall shapes. The ability to modify the pattern of laser shots (and thereby shape the wall of the bore) by simply changing the motion of the mask 16 is a powerful and flexible process parameter which has been unavailable heretofore.
[0059] A particularly useful ability of the present invention allows the ablated features to have an axial orientation which is not perpendicular to the surface of the substrate. That is, the axis of the orifice may be tilted with respect to the substrate surface. Such a variable axial orientation of the orifice is achieved by creating a spiraling laser shot pattern (as depicted in FIG. 7), while allowing the center of each circular “orbit” to slowly drift in a prescribed direction during the ablation process. Such a laser shot pattern is not possible with, for example, a single rotating optical element as shown in U.S. Pat. No. 4,940,881 which can only move the light in a circular pattern.
[0060] The ability to create an ablated orifice with a non-orthogonal axis is a significant advance and advantage in fluid flow applications. For example, as shown in FIG. 8, a group of two or more nozzles may be positioned such that the axis of each nozzle is directed toward a common predetermined point. In FIG. 8, individual nozzles 82 are arranged in arrays 84 , 85 , 86 , 87 , with four nozzles 82 per array 84 , 85 , 86 , 87 . In each array 84 , 85 , 86 , 87 , the nozzles 82 are angled toward a common point 88 , 89 , 90 , 91 , respectively, in the center of each array 84 , 85 , 86 , 87 . Such an orientation of the nozzles 82 within each array 84 , 85 , 86 , 87 significantly improves, for example, the ability to control the direction in which a fluid drop is projected through each nozzle 82 . This control thereby allows or prevents, for example, the coalescence of drops after exiting the nozzles 82 . Alternatively, it can control the relative placement of drops of fluid on a target material, such as placement of ink from an inkjet print head on paper, thereby effecting the quality of print. It will be recognized by those skilled in the art that any number of nozzles and arrays may be ablated to achieve the necessary result for a particular application.
[0061] It can be seen from examining FIG. 8 that the axis of at least one nozzle 82 ′ in each of arrays 84 , 85 , 86 , 87 , is aligned with a first common axis 92 , while a second nozzle 82 ″ of each array 84 , 85 , 86 , 87 is aligned with a second common axis 94 . Similarly, each nozzle 82 of each array 84 , 85 , 86 , 87 is aligned with a predetermined common axis. When forming arrays 84 , 85 , 86 , 87 , the nozzles 82 ′ are ablated in one step, nozzles 82 ″ are ablated in a separate step, and so on. The different directional axes of the nozzles 82 are created by simply changing the ablation pattern by altering the motion of the mask in a predetermined manner.
[0062] As noted above, the nozzle arrangement illustrated in FIG. 8 is useful in applications where control of the individual drops exiting the nozzles is desired, for example, to allow or prevent the coalescence of drops after exiting the nozzles 82 . The tendency for individual drops to coalesce or not can be controlled by altering the orientation of the longitudinal axes of the nozzles in each array. Particular uses include print heads for ink jet printers (having nozzles with exit diameters in the range of 8 to 35 microns, and preferably between 10 and 25 microns) and aerosol nozzles plates for applications such as medicinal inhalers (having nozzles with exit diameters of less than about 5 microns diameter and preferably in the range of 0.5 to 3.0 microns).
[0063] The inventive mask orbiting apparatus described herein provides significant advantages over other methods of controlling the wall shape of an ablated feature. In particular the invention allows precise, repeatable placement of individual laser shots in any of a variety of manners. The individual laser shots may be placed in widely varying yet easily controllable patterns to achieve the desired wall shape and axial orientation of the ablated feature.
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This invention concerns a process useful for ablating features from a substrate, including the steps of illuminating the substrate with laser light that has passed through a mask to form an ablated feature in the substrate, wherein the mask is orbited perpendicular to the angle of the laser light during formation of the feature thereby forming a selected wall shape. This invention also concerns an apparatus useful for making holes in a substrate having a radiation source; a mask positioned between the radiation source and a substrate to be irradiated with radiation from the radiation source, wherein the mask is capable of following a trajectory perpendicular to the angle of the radiation.
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This is a continuation of application No. 08/002,480, filed as PCT/GB92/01570 Aug. 27, 1992, which was abandoned upon the filing hereof.
BACKGROUND OF THE INVENTION
This invention relates to biocidal proteins, processes for their manufacture and use, and DNA sequences coding for them. In particular, it relates to antimicrobial proteins isolated from seeds such as those of members of the Brassicaceae, Compositae or Leguminosae families.
In this context, antimicrobial proteins are defined as proteins possessing at least one of the following activities: antifungal activity (which may include anti-yeast activity); antibacterial activity. Activity includes a range of antagonistic effects such as partial inhibition or death.
The Brassicaceae is a large family of herbs and shrubs which grow widely in tropical, sub-tropical and temperate regions. The Family Brassicaceae is also known as the "Cruciferae". Raphanus sativus (radish) belongs to this family and is cultivated widely as a vegetable.
Dahlia belongs to the Compositae and has been extensively cultivated as an ornamental garden plant. A number of hybrids are commercially available, belonging to the Dahlia merckii or Dahlia variablis species. Cnicus benedictus, another Compositae, is a native plant of the Mediterranean regions and was once used as a tonic and a cure for gout.
Lthyrus and Clitoria belong to the Leguminosae family. Lathyrus has been extensively cultivated as an ornamental garden plant, the most widely known being the sweet pea plant, Lathyrus odoratus. The genus Clitoria is less well known to European gardeners; Clitoria ternatea was originally introduced from the East Indies in the 1800s.
Although plants normally grow on substrates that are extremely rich in fungal organisms, infection remains a rare event. To keep out potential invaders, plants produce a wide array of antifungal compounds, either in a constitutive or an inducible manner. The best studied of these are phytoalexins which are secondary metabolites with a broad antimicrobial activity spectrum that are specifically synthesised upon perception of appropriate defence-related signal molecules. The production of phytoalexins depends on the transcriptional activation of a series of genes encoding enzymes of the phytoalexin biosynthetic pathway. During the last decade, however, it has become increasingly clear that some plant proteins can play a more direct role in the control of phytopathogenic fungi. Several classes of proteins with antifungal properties have now been identified, including chitinases, beta-1,3-glucanases, chitin-binding lectins, zeamatins, thionins and ribosome-inactivating proteins.
These proteins have gained considerable attention as they could potentially be used as biocontrol agents. The chitinases and beta-1,3-glucanases have weak activities by themselves, and are only inhibitory to plant pathogens when applied in combination (Mauch et al, 1988, Plant Physiol, 88,936-942). The chitin-binding lectins can also be classified as rather weak antifungal factors (Broekaert et al, 1989, Science, 245, 1100-1102; Van Parijs et al, 1991, Planta, 183, 258-264). Zeamatin is a more potent antifungal protein but its activity is strongly reduced by the presence of ions at physiological concentrations (Roberts and Selitnermikoff, 1990, G Gen Microbiol, 136, 2150-2155). Finally, thionins and ribosome-inactivating proteins are potentially hazardous since they are known to be toxic for human cells (Carrasco et al, 1981, Eur J Biochem, 116, 185-189; Vernon et al, 1985, Arch Biochem Biophys, 238, 18-29; Stirpe and Barbieri, 1986, FEBS Lett, 195, 1-8).
SUMMARY OF THE INVENTION
We have now purified a new class of potent antimicrobial proteins with broad spectrum activity against plant pathogenic fungi and with some antibacterial activity, moderate sensitivity to ions and apparent low toxicity for cultured human cells.
According to the present invention, we provide antimicrobial proteins capable of being isolated from seeds and in particular from members of the Brassicaceae, the Compositae or the Leguminosae families including Raphanus, Brassica, Sinapis, Arabidopsis, Dahlia, Cnicus, Lathyrus or Clitoria.
In further aspects, this invention comprises a vector containing a DNA sequence coding for a protein according to the invention. The DNA may be cloned or transformed into a biological system allowing expression of the encoded protein.
The invention also comprises plants transformed with recombinant DNA encoding an antimicrobial protein according to the invention.
The invention also comprises a process of combating fungi or bacteria whereby they are exposed to the proteins according to the invention.
A new class of potent antimicrobial proteins has been isolated from seeds of the Brassicaceae, the Compositae, and the Leguminosae. Similar proteins may be found in other plant families, genera and species. The class includes proteins which share a common amino acid sequence and which show activity against a range of plant pathogenic fungi.
The antimicrobial proteins isolated from seeds of Raphanus sativus (radish) include two protein factors, hereafter called Rs-AFP1 (Raphanus sativus -Antifungal Protein 1) and Rs-AFP2 (Raphanus sativus-Antifungal Protein 2) respectively. Both are oligomeric proteins, composed of identical 5 kDa subunits. Both proteins are highly basic and have pI values above 10. Similar antifungal proteins have been isolated from other Brassicaceae, including Brassica napus (Bn-AFPs), Brassica rapa (Br-AFPs), Sinapis alba (Sa-AFPs) and Arabidopsis thaliana (At-AFP1).
The antimicrobial proteins isolated from seeds of Dahlia and Cnicus include four protein factors, hereafter called Dm-AMP1 (Dahlia merckii--Antimicrobial Protein 1), Dm-AMP2 (Dahlia merckii--Antimicrobial Protein 2), Cb-AMP1 (Cnicus benedictus--Antimicrobial Protein 1) and Cb-AMP2(Cnicus benedictus--Antimicrobial Protein 2) respectively. The Dm-AMP proteins may be isolated from seed of the Dahlia genus. The Cb-AMP proteins may be isolated from seed of the Cnicus genus. All four proteins are closely related and are composed of 5 kDa subunits arranged as oligomeric structures. All four proteins are highly basic.
The antimicrobial proteins isolated from seeds of Lathyrus and Clitoria include three protein factors, hereafter called Lc-AFP (Lathyrus cicera--Antifungal Protein), Ct-AMP1 (Clitoria ternatea--Antimicrobial Protein 1) and Ct-AMP2 (Clitoria ternatea--Antimicrobial Protein 2) respectively. Lc-AFP may be isolated from seed of the Lathyrus genus. The Ct-AMP proteins may be isolated from seed of the Clitoria genus. All three proteins are composed of 5 kDa subunits arranged as oligomeric structures and are highly basic.
N-terminal amino acid sequence determination has shown that the above proteins isolated from the Brassicaceae, Compositae and Leguminosae are closely related and can be classified as a single protein family. Between the different plant families, the protein sequences are approximately 50% identical. These sequences enable manufacture of the proteins by chemical synthesis using a standard peptide synthesiser.
The antimicrobial proteins are partially homologous to the predicted protein products of the Fusarium-induced genes pI39 and pI230 in pea (Pisum sativum--a member of the Leguminosae family) as described by Chiang and Hadwiger, 1991 (Mol Plant Microbe Interact, 4, 324-331). This homology is shared with the predicted protein product of the pSAS10 gene from cowpea (Vigna unguiculata another legume) as described by Ishibashi et al (Plant Mol Biol, 1990, 15, 59-64). The antimicrobial proteins are also partially homologous with the predicted protein product of gene pI322 in potato (Solanum tuberosum--a member of the Solanaceae family) as described by Stiekema et al, 1988 (Plant Mol Biol, 11, 255-269). Nothing is known about the biological properties of the proteins encoded by genes pI39, pI230, pSAS10 or pI322 as only the cDNA has been studied. However, the pI39, pI230 and pI322 genes are switched on after challenge to the plant by a disease or other stress. It has been proposed that the pSAS10 gene encodes a protein involved in germination. Due to their sequence similarity with the antimicrobial proteins of the invention, the proteins encoded by the pI39, pI230, pSAS10 or pI322 genes may be useful as fungicides or as antibiotics.
The antimicrobial protein sequences show a lower degree of partial homology with the sequences of a group of small α-amylase inhibitors found in the following members of the Gramineae: sorghum (Bloch and Richardson, 1991, FEBS Lett, 279:101-104), wheat (Colitta et al, 1990, FEBS Lett, 270:191-194) and barley (Mendez et al, 1990 Eur J Biochem, 194:533-539). Such proteins, including SIα2 from sorghum and γ-1-purothionin from wheat, are known to inhibit insect α-amylase and are toxic to insect larvae. It is not known if these α-amylase inhibitors show any antifungal or other antimicrobial activity: no other data on their biological activity has been reported. Due to their sequence similarity with the antimicrobial proteins of the invention, the α-amylase inhibitor proteins may be useful as fungicides or as antibiotics.
A third antifungal protein has been isolated from radish seeds, hereafter called Rs-nsLTP (Raphanus sativus non-specific lipid transfer protein). It is a dimeric protein, composed of two identical 9 kDa subunits. Amino acid sequence determination has identified the 43 N-terminal residues of Rs-nsLTP, and has shown it to be homologous with non-specific lipid transfer proteins isolated from other plants (Arondel and Kadet, 1990, Experientia, 46:579-585) but not with the other antimicrobial proteins discussed above. The Rs-nsLTP sequence enables manufacture of the protein by chemical synthesis using a standard peptide synthesiser.
Knowledge of their primary structure, enables the production of DNA constructs encoding the antimicrobial proteins. The DNA sequence may be predicted from the known amino acid sequence or the sequence may be isolated from plant-derived DNA libraries.
Oligonucleotide probes may be derived from the known amino acid sequence and used to screen a cDNA library for cDNA clones encoding some or all of the protein. cDNA clones encoding the Rs-AFPs have been isolated in this way and sequenced. These same oligonucleotide probes or cDNA clones may be used to isolate the actual AFP, AMP or Rs-nsLTP gene(s) by screening genomic DNA libraries. Such genomic clones may include control sequences operating in the plant genome. Thus it is also possible to isolate promoter sequences which may be used to drive expression of the antimicrobial (or other) proteins. These promoters may be particularly responsive to environmental conditions (such as the presence of a fungal pathogen).
DNA encoding the antimicrobial proteins (which may be a cDNA clone, a genomic DNA clone or DNA manufactured using a standard nucleic acid synthesiser) can then be cloned into a biological system which allows expression of the proteins. Hence the proteins can be produced in a suitable micro-organism or cultured cell, extracted and isolated for use. Suitable micro-organisms include Escherichia coli and Saccharomyces cerevisiae. The genetic material can also be cloned into a virus or bacteriophage. Suitable cells include cultured insect cells and cultured mammalian cells. The DNA can also be transformed by known methods into any plant species, so that the antimicrobial proteins are expressed within the plant.
Plant cells according to the invention may be transformed with constructs of the invention according to a variety of known methods (Agrobacterium Ti plasmids, electroporation, microinjection, microprojectile gun, etc). The transformed cells may then in suitable cases be regenerated into whole plants in which the new nuclear material is stably incorporated into the genome. Both transformed monocot and dicot plants may be obtained in this way, although the latter are usually more easy to regenerate.
Examples of genetically modified plants which may be produced include field crops, cereals, fruit and vegetables such as: canola, sunflower, tobacco, sugarbeet, cotton, soya, maize, wheat, barley, rice, sorghum, tomatoes, mangoes, peaches, apples, pears, strawberries, bananas, melons, potatoes, carrot, lettuce, cabbage, onion.
The AFP, AMP and Rs-nsLTP proteins show a wide range of antifungal activity, including anti-yeast activity, and the AMPs are also active against Gram positive bacteria. The proteins are useful as fungicides or antibiotics. Exposure of a plant pathogen to an antimicrobial protein may be achieved by application of the protein to plant parts using standard agricultural techniques (eg spraying). The proteins may also be used to combat fungal or bacterial disease by expression within plant bodies.
All the antimicrobial proteins show surprisingly high activity: they inhibit the growth of a variety of plant pathogenic fungi at submicromolar doses. Antifungal activity of the AMPs is only partially dependent on the ionic conditions. The antifungal effect of the AFPs is not affected by K + ions at physiological concentrations (50 mM). The antifungal effect of Rs-AFP1, but not Rs-AFP2, is antagonised by Ca 2+ at physiological concentrations (1 mM). Rs-nsLTP also inhibits growth of a variety of plant pathogenic fungi, but is less potent and more salt sensitive that the AFPs.
The antimicrobial proteins can be isolated and purified from appropriate seeds, synthesised artificially from their known amino acid sequence, or produced within a suitable micro-organism by expression of recombinant DNA. The proteins may also be expressed within a transgenic plant.
BRIEF DESCRIPION OF THE DRAWING
The invention may be further understood by reference to the drawings, in which:
FIG. 1 shows the cation exchange chromatogram for the Raphanus antifungal proteins and the associated graph of fungal growth inhibition.
FIG. 2A shows the HPLC profile of purified Rs-AFP1.
FIG. 2B shows the HPLC profile of purified Rs-AFP2 and Rs-nsLTP.
FIG. 3 shows the cation exchange chromatogram for the B napus antifungal proteins and the associated graph of fungal growth inhibition.
FIGS. 4A and 4B show the HPLC profile of purified B napus antifungal proteins.
FIG. 5 shows the cation exchange chromatogram for B rapa antifungal proteins and the associated graph of fungal growth inhibition.
FIGS. 6A and 6B show the HPLC profile of purified B rapa antifungal proteins.
FIG. 7 shows the cation exchange chromatogram for S alba antifungal proteins and the associated graph of fungal growth inhibition.
FIGS. 8A and 8B show the HPLC profile of purified S alba antifungal proteins.
FIG. 9 shows the cation exchange chromatogram for A thaliana antifungal protein and the associated graph of fungal growth inhibition.
FIG. 10 shows the HPLC profile of purified A thaliana antifungal proteins.
FIG. 11 shows the cation exchange chromatogram for the basic extract of Dahlia merckii and the corresponding graph of antifungal activity.
FIG. 12 shows the reverse-phase HPLC profile of purified Dm-AMP1 and Dm-AMP2.
FIG. 13 shows the cation exchange chromatogram for the basic extract of Cnicus benedictus and the corresponding graph of antifungal activity.
FIG. 14 shows the reverse-phase HPLC profile of purified Cb-AMP1.
FIG. 15 shows the reverse-phase HPLC profile of purified Cb-AMP2.
FIG. 16 shows the cation exchange chromatogram for the basic extract of Lathyrus and the corresponding graph of antifungal activity.
FIG. 17 shows the reverse-phase HPLC profile of purified Lc-AFP.
FIG. 18 shows the cation exchange chromatogram for the basic extract of Clitoria and the corresponding graph of antifungal activity.
FIG. 19 shows the reverse-phase HPLC profile of purified Ct-AMP1.
FIG. 20 shows the reverse-phase HPLC profile of purified Ct-AMP2.
FIG. 21 shows the amino acid sequences of Rs-AFP1, Rs-AFP2 and the related Brassicaceae proteins.
FIG. 22 shows the amino acid sequences of the Dm-AMPs and the Cb-AMPs.
FIG. 23 shows the amino acid sequences of Lc-AFP and Ct-AMP1.
FIGS. 24A, 24B and 24C show the alignment of the amino acid sequences of Rs-AFP1, Dm-AMP1, the Cb-AMPs, Lc-AFP, Ct-AMP1, sorghum SIα2, wheat γ1 purothionin, and the predicted products of the pea genes pI230 and pI39, of the cowpea gene pSAS10, and of the potato gene p322.
FIGS. 25A and 25B show predicted DNA sequences for the Dm-AMP and Cb-AMP genes.
FIG. 26 shows predicted DNA sequences for the Lc-AFP and Ct-AMP1 genes.
FIG. 27 shows the amino acid sequence of Rs-nsLTP.
FIGS. 28A and 28B show the alignment of the amino acid sequences of Rs-nsLTP and various plant non-specific lipid transfer proteins.
FIG. 29 is a graph of Rs-AFP2 in vivo activity.
FIG. 30 shows the full length cDNA sequence of Rs-AFP1.
FIG. 31 shows the truncated cDNA sequence of Rs-AFP2.
FIGS. 32A and 32B show the full length DNA sequence of PCR assisted site directed mutagenesis of Rs-AFP2.
FIG. 33 shows the expression vector pFRG7.
FIG. 34 shows the expression vector pFRG8.
DESCRIPTION OF THE PREFERRED EMBODIMENTS
The following Example illustrates the invention.
EXAMPLE 1
Antifungal and antibacterial activity assays.
Antifungal activity was measured by microspectrophotometry as previously described (Broekaert, 1990, FEMS Microbiol Lett, 69:55-60). Routinely, tests were performed with 20 μ1 of a (filter-sterilized) test solution and 80 μ1 of a suspension of fungal spores (2×10 4 spores/ml) in half strength potato dextrose broth (1/2PDB). Some tests were performed using a suspension of mycelium fragments in a synthetic growth medium. The synthetic growth medium consisted of K 2 HPO 4 (2.5 mM), MgSO 4 (50 μM), CaCl 2 (50 μM), FeSO 4 (5μM), CoCl 2 (0.1 μM), CuSO 4 (0.1 μM), Na 2 MoO 4 (2μM), H 3 BO 3 (0.5 μM), KI (0.1 μM), ZnSO 4 (0.5 μM), MnSO 4 (0.1 μM), glucose (10 g/l), asparagine (1 g/l), methionine (20 mg/l), myo-inositol (2 mg/l), biotin (0.2 mg/l), thiamine-HCl (1 mg/l), and pyridoxine-HCl (0.2 mg/l). Control microcultures contained 20 μl of sterile distilled water and 80 μl of the fungal suspension.
Unless otherwise stated the test organism was Fusarium culmorum (strain IMI 180420) and incubation was done at 25° C. for 48 hours. Percent growth inhibition is defined as 100 times the ratio of the corrected absorbance of the control microculture minus the corrected absorbance of the test microculture over the corrected absorbance at 595 nm of the control microculture. The corrected absorbance values equal the absorbance at 595 nm of the culture measured after 48 hours minus the absorbance at 595 nm measured after 30 min.
Antibacterial activity was measured microspectrophotometrically as follows. A bacterial suspension was prepared by inoculating soft nutrient agarose (tryptone, 10 g/l; Seaplaque agarose (FMC), 5 g/l). Aliquots (80 μl) of the bacterial suspension (10 5 colony forming units per ml) were added to filter-sterilized samples (20 μl) in flat-bottom 96-well microplates. The absorbance at 595 nm of the culture was measured with the aid of a microplate reader after 30 minutes and 24 hours of incubation at 28° C. Percent growth inhibition was calculated as described above for the antifungal activity assay.
EXAMPLE 2
Extraction of the basic protein fraction from Raphanus sativus seeds.
Ammonium sulphate fractionation of proteins precipitating in the interval of 30 to 70% relative saturation was followed by heat treatment to remove heat-labile proteins, and by isolation of the basic protein fraction (pI>9) by passage over a Q-Sepharose (Pharmacia) anion exchange column equilibrated at pH 9. The detailed methods are described below.
One kg of R sativus seeds (obtained from Aveve, Belgium) was ground in a coffee mill and the resulting meal was extracted for 2 hours at 4° C. with 2 litres of an ice-cold extraction buffer containing 10 mM NaH 2 PO 4 , 15 mM Na 2 HPO 4 , 100 mM KCl, 2 mM EDTA, 2 mM thiourea, and 1 mM PMSF. The homogenate was squeezed through cheesecloth and clarified by centrifugation (30 min at 7,000×g). Solid ammonium sulphate was added to the supernatant to obtain 30% relative saturation and the precipitate formed after standing overnight at room temperature was removed by centrifugation (30 min at 7,000×g). The supernatant was adjusted to 70% relative ammonium sulphate saturation and the precipitate formed overnight at room temperature collected by centrifugation (30 min at 7,000×g). After redissolving the pellet in 400 ml distilled water the solution was heated at 80° C. for 15 min. The coagulated insoluble material was removed by centrifugation (30 min at 7,000×g) and the supernatant was dialyzed extensively against distilled water using tubing (SpectralPor, Spectrum, USA) with a molecular weight cut off of 1,000 Da. After dialysis the solution was adjusted to 50 mM Tris-HCl (pH 9) by addition of the ten-fold concentrated buffer, and subsequently passed over a Q-Sepharose Fast Flow (Pharmacia, Uppsala, Sweden) column (12×5 cm) in equilibrium with 50 mM Tris-HCl (pH 9). The protein fraction passed through the column was dialyzed extensively against distilled water and adjusted to 50 mM sodium N-morpholinoethanesulphonic acid (Na-MES), pH 6, by addition of the ten-fold concentrated buffer.
This material represents the basic heat-stable protein fraction of R sativus seeds. Its further chromatographic purification is described in Example 3.
EXAMPLE 3
Purification of antifungal proteins from R sativus seeds.
The starting material for the isolation of the R sativus antifungal proteins was the basic heat-stable protein fraction extracted from the mature seeds as in Example 2. These proteins were further separated by cation exchange chromatography, as shown in FIG. 1.
About 150 mg of the basic heat-stable protein fraction dissolved in 50 mM sodium MES (pH 6) was applied on a S-Sepharose High Performance (Pharmacia) column (10×1.6 cm) previously equilibrated with the sodium MES buffer. The column was eluted at 2.5 ml\min with a linear gradient of 1000 ml from 0 to 500 mM NaCl in 50 mM sodium MES buffer (pH 6). The eluate was monitored for protein by online measurement of the absorbance at 280 nm (results shown in the lower panel of FIG. 1) and collected in 10 ml fractions. Of these fractions, 20 μl was tested in the microspectrophotometric antifungal activity assay described in Example 1 using either the synthetic growth medium (Medium A: results shown as full lines in the upper panel of FIG. 1) or the same medium supplemented with 1 mM CaCl 2 and 50 mM KCl (Medium B: results shown as dashed lines in the upper panel of FIG. 1).
Upon fractionation, the mixture yielded a broad peak representing the unbound fraction, two well resolved peaks (peak 1 and peak 2) eluting around 100 and 200 mM NaCl respectively, and a group of five non-resolved peaks (peaks 3 to 7) eluting between 250 and 450 mM NaCl. No antifungal activity was associated with the unbound fraction, whereas all bound peak fractions displayed antifungal activity when assayed in medium A. However, tests performed in medium B only indicated growth inhibition for the fractions corresponding to peaks 1 and 2, respectively. It appears therefore that the antifungal activity of these fractions is less salt-dependent than that of the fractions from peaks 3 to 7.
The fractions showing antifungal activity in growth medium B (peaks 1 and 2) were further purified by reversed-phase chromatography. About 1 mg amounts of peak 1 material (FIG. 2A) and peak 2 material (FIG. 2B) were loaded on a Pep-S (porous silica C 2 /C 18 , Pharmacia) column (25×0.93 cm) in equilibrium with 0.1% TFA. The column was eluted at 5 ml/min with a linear gradient of 200 ml from 0.1% trifluoroacetic acid (TFA) to 40% acetonitrile/0.1% TFA. The eluate was monitored for protein by online measurement of the absorption at 214 nm. Five ml fractions of the eluate were collected, vacuum-dried, and finally dissolved in 0.5 ml distilled water of which 10 μl was used in a microspectrophotometric antifungal activity assay.
FIGS. 2A and FIG. 2B show the HPLC profiles of purified peak 1 and peak 2 material respectively. The lower panels show monitoring of the eluate for protein by measurement of the absorbance at 214 nm. Results of the microspectrophotometric antifungal activity assay in medium A (full line) and medium B (dashed line) are shown in the upper panels.
The material from peak 1 yielded a single major peak eluting at 30% acetonitrile and co-eluting with the antifungal activity in both medium A and medium B. The active factor isolated from this peak is called Rs-AFP1 (Raphanus sativus antifungal protein 1). The peak 2 material, on the other hand, resolved into two major peaks eluting at 30% and 33% acetonitrile respectively. The peak eluting at 30% acetonitrile was active in both medium A and medium B, whereas the peak eluting at 33% was active only in medium A. The active factor purified from the 30% acetonitrile peak is called Rs-AFP2 (Raphanus sativus antifungal protein 2), and that from the 33% acetonitrile peak is designated Rs-nsLTP (Raphanus sativus non-specific lipid transfer protein) because of its homology with non-specific lipid transfer proteins isolated from other plant species (see Example 13).
EXAMPLE 4
Purity of the isolated Rs-AFPs.
The purity of the isolated antifungal proteins was verified by native cathodic gel electrophoresis followed by protein staining and in situ detection of antifungal activity using a bio-zymographic technique.
Native cathodic gel electrophoresis and bio-zymography were done as previously described (De Bolle et al, 1991, Electrophoresis, 12, 442-444) with some modifications. Electrophoresis was performed on continuous 10% acrylamide gels containing 60 mM Tris/70 mM MES (pH 7). The electrophoresis buffer consisted of 100 mM L-histidine/41 mM MES (pH 6.5) Gels were cooled at 10° C. during electrophoresis. The samples contained 20% glycerol, 0.0025% methylene blue, and 10 μg of purified Rs-AFP1 or 20 μg of Rs-AFP2. Proteins were detected by silver-staining of a diffusion blot prepared from the gel (Kovarik et al, 1987, Folia Biological, 33, 253-257). The gel was overlaid with a soft agar gel (De Bolle et al, 1991, Electrophoresis, 12, 442-444) containing viable Trichoderma hamatum spores and incubated at 25° C. for 3 days.
Rs-AFP1 and Rs-AFP2 migrate as single protein bands after cathodic gel electrophoresis. Moreover, the antifungal activity co-migrated exactly with the protein bands in the gel. These results indicate that the isolated factors are highly pure and that the antifungal activity is not attributable to minor contaminants.
EXAMPLE 5
Antifungal proteins related to Rs-AFPs from other species of Brassicaceae.
Using the purification procedure described in Example 3, we have isolated antifungal proteins from other Brassicaceae, including Brassica napus, Brassica rapa, S.inapis alba and Arabidopsis thaliana.
FIG. 3 shows the cation exchange chromatogram for antifungal protein isolated from B napus, and the associated graph of fungal growth inhibition (upper panel). FIGS. 5A and 5B show the HPLC profile of the purified B napus antifungal proteins, isolated from peak 1 (Bn-AFP1, FIGS. 5A and peak 2 (Bn-AFP2, FIG. 5B.
FIG. 5 shows the cation exchange chromatogram for antifungal protein isolated from B rapa, and the associated graph of fungal growth inhibition (upper panel). FIGS. 6A and 6B show the HPLC profile of the purified B rapa antifungal proteins, isolated from peak 1 (Br-AFP1, FIG. 6A) and peak 2 (Br-AFP2, FIG. 6B).
FIG. 7 shows the cation exchange chromatogram for antifungal protein isolated from S alba, and the associated graph of fungal growth inhibition (upper panel). FIGS. 8A and 8B show the HPLC profile of the purified S alba antifungal proteins, isolated from peak 1 (Sa-AFP1, FIG. 8A) and peak 2 (Sa-AFP2, FIG. 8B).
FIG. 9 shows the cation exchange chromatogram for antifungal protein isolated from A thaliana, and the associated graph of fungal growth inhibition (upper panel). FIG. 10 shows the HPLC profile of the purified A thaliana antifungal proteins, isolated from peak 1 (At-AFP1).
All these antifungal proteins behave similarly to Rs-AFP1 and Rs-AFP2 with respect to their SDS-PAGE and isoelectric focusing pattern (as described in Example 5).
EXAMPLE 6
Extraction of the basic protein fraction from Dahlia merckii, Cnicus benedictus, Lathyrus cicera and Clitoria ternatea seeds.
Five hundred grams of D merckii or C benedictus or Clitoria ternatea seeds (purchased from Chiltern Seeds, Cumbria, UK) or Lathyrus cicera seeds (from Instituto Botanico Universitade Coimbra, Portugal) were ground in a coffee mill and the resulting meal was extracted for 2 hours at 4° C. with 2 litres of an ice-cold extraction buffer containing 10 mM NaH 2 PO 4 , 15 mM Na 2 HPO 4 , 100 mM KCl, 2 mM EDTA and 1 mM benzamidine. The resulting homogenate was squeezed through cheesecloth and clarified by centrifugation (30 min at 7,000×g). Solid ammonium sulphate was added to the supernatant to obtain 75% relative saturation and the precipitate allowed to form by standing overnight at 4° C. Following centrifugation at 7,000×g for 30 minutes, the precipitate was redissolved in a minimal volume of distilled water and dialyzed extensively against distilled water using benzoylated cellulose tubing (Sigma, St Louis, MO). After dialysis the solution was adjusted to 50 mM NH 4 Ac (pH 9) by addition of the ten-fold concentrated buffer and passed over a Q-Sepharose Fast Flow (Pharmacia, Uppsala, Sweden) column (12×5 cm) equilibrated in 50 mM NH 4 Ac (pH 9). The protein fraction which passed through the column was adjusted to pH 6 with acetic acid.
This material represents the basic (pI>9) protein fraction of the seeds. The fractions were further purified as described in Examples 7, 8, 9 and 10.
EXAMPLE 7
Purification of antimicrobial proteins from Dahlia merckii seeds.
The starting material for the isolation of the D merckii antimicrobial proteins was the basic protein fraction extracted from the mature seeds as in Example 6. Proteins were further purified by cation exchange chromatography of this extract.
Approximately 500 ml of the basic protein fraction was applied to a S-Sepharose High Performance (Pharmacia) column (10×1.6 cm) equilibrated in 50 mM NH 4 Ac, pH 6.0. The column was eluted at 3.0 ml\min with a linear gradient of 50-750 ml NH 4 Ac, pH 6.0 over 325 minutes. The eluate was monitored for protein by online measurement of the absorbance at 280 nm (results shown in the lower panel of FIG. 11) and collected in 10 ml fractions. Samples from each fraction were assayed for antifungal activity as described in Example 1 (results shown in the upper panel of FIG. 11).
Following chromatography, the extract yielded a broad peak of activity eluting at around 250 mM NH 4 Ac. The fractions showing antifungal activity were pooled and further purified by reverse-phase HPLC. About 3 mg amounts of the peak were loaded on a PEP-S (porous silica C 2 /C 18 , Pharmacia) column (25×0.4 cm) equilibrated with 0.1% TFA (trifluoracetic acid). The column was developed at 1 ml/min with a linear gradient of 0.1% TFA to 100% acetonitrile/0.1% TFA over 100 minutes. The eluate was monitored for protein by online measurement of the absorption at 280 nm (results shown in the lower panel of FIG. 12). One ml fractions were collected, vacuum-dried, and dissolved in 0.5 ml distilled water. 10 μfrom each fraction was assayed for antifungal activity (results shown in the upper panel of FIG. 12). The material yielded two well-resolved peaks of activity, eluting at 18% and 22% acetonitrile. These represent the purified proteins Dm-AMP1 and Dm-AMP2 respectively.
EXAMPLE 8
Purification of antimicrobial proteins from Cnicus benedictus seeds.
The procedure described in Example 7 was followed using the basic extract from Cnicus benedictus seeds. Following chromatography on the S-Sepharose High Performance column, the Cnicus extract yielded two peaks of antifungal activity eluting at approximately 250 mM (peak 1) and 500 mM (peak 2) NH 4 Ac (results shown in FIG. 13).
Active fractions were pooled for each peak and further purified on reverse-phase HPLC as described in Example 7. Results for peak 1 are shown in FIG. 14: it yielded an active factor eluting at 18% acetonitrile which is designated Cb-MP1. Similarly peak 2 eluted to a single peak of activity which is designated Cb-AMP2 (results shown in FIG. 15).
EXAMPLE 9
Purification of antifungal protein from Lathyrus cicera seeds.
The procedure described in Example 7 was followed using the basic extract from Lathyrus cicera seeds. Following chromatography on the S-Sepharose High Performance column, the Lathyrus extract yielded a single peak of antifungal activity eluting at approximately 160 mM NH 4 Ac (results shown in FIG. 16).
Active fractions were pooled and further purified on reverse-phase HPLC as described in Example 7. Results for peak 1 are shown in FIG. 18: it yielded an active factor eluting at 22% acetonitrile which is designated Lc-AFP.
EXAMPLE 10
Purification of antimicrobial proteins from Clitoria ternatea seeds.
The procedure described in Example 7 was followed using the basic extract from Clitoria ternatea seeds. Following chromatography on the S-Sepharose High Performance column, the Clitoria extract yielded two partially resolved peaks of antifungal activity eluting between 260 mM and 400 mM NH 4 Ac (results shown in FIG. 18).
Active fractions were pooled for each peak and further purified on reverse-phase HPLC as described in Example 7. Results for peak 1 are shown in FIG. 19: it yielded an active factor eluting at approximately 18% acetonitrile which is designated Ct-AMP1. Similarly peak 2 yielded an active factor eluting at approximately 18% acetonitrile which is designated Ct-AMP2 (results shown in FIG. 20).
EXAMPLE 11
Molecular structure of the purified antimicrobial proteins.
The molecular structure of the purified antimicrobial proteins was further analysed. Sodium dodecyl sulphate polyacrylamide gel electrophoresis (SDS-PAGE) was performed on precast commercial gels (PhastGel High Density from Pharmacia) using a PhastSystem (Pharmacia) electrophoresis apparatus. The sample buffer contained 200 mM Tris-HCl (pH 8.3), 1% (w/v) SDS, 1 mM EDTA, 0,005% bromophenol blue and, unless otherwise stated, 1% (w/v) dithioerythritol (DTE). Proteins were fixed after electrophoresis in 12.5% glutaraldehyde and silver-stained according to Heukeshoven and Dernick (1985, Electrophoresis, 6, 103-112).
The Rs-AFPs were analysed by SDS-PAGE. After reduction with β-mercaptoethanol and modification of the cysteine residues by S-pyridylethylation, both Rs-AFP1 and Rs-AFP2 show single bands with an apparent molecular mass of about 5 kDa. After simple reduction without further cysteine derivatisation, the 5 kDa band is always accompanied by a 16 kDa band at variable yields, which may represent an oligomeric form of the 5 kDa protein resisted during electrophoresis. Unreduced Rs-AFP1 and Rs-AFP2 migrate as single bands of 20 kDa and 17 kDa, respectively. These results show that the native Rs-AFPs are oligomeric proteins, consisting of dimers, trimers or tetramers of the 5 kDa polypeptide. The oligomeric structure appears to be stabilised by disulphide linkages. SDS-PAGE analysis of unreduced Rs-AFP1, Rs-AFP1 reduced and S-pyridylethylated Rs-AFP2 with 200 ng of the proten separated on the gels. Myoglobin fragments were used as molecular weight markers (Pharmacia) with the following sizes: 17 kDa, 14.5 kDa, 8 kDa, 6 kDa, and 2.5 kDa.
SDS-PAGE analysis of Rs-nsLTP after reduction with DTE yielded a single 9 kDa band. The unreduced Rs-nsLTP migrated as a single 18 kDa band. It appears therefore that Rs-nsLTP is a dimeric protein (2×9 kDa) stabilised by disulphide bridges.
Purified Rs-nsLTP, reduced and non-reduced, was analyzed by SDS-PAGE with molecular weight markers of myoglobin fragments described above.
Free cysteine thiol groups of the Rs-AFPs were assessed qualitatively as follows. Hundred μg amounts of reduced or unreduced proteins were dissolved in 6 M guanidinium-Cl containing 100 mM sodium phosphate buffer (pH 7) and 1 mM EDTA. The mixtures were allowed to react with 5,5'-dithionitrobenzoic acid and monitored for release of nitrothiobenzoate as described by Creighton (1989, Protein structure, a practical approach, 155-167). Reduction of the proteins was done by addition of Tris-HCl (pH 8.6) to 100 mM and dithioerythritol to 30 mM, followed by incubation at 45° C. for 1 hour. The proteins were separated from the excess reagents by reversed-phase chromatography on a C 2 /C 18 silica column.
The unreduced Rs-AFPs did not contain free cysteine thiol groups, whereas the reduced proteins did, indicating that all cysteine residues participate in disulphide bonds.
The pI values of Rs-AFP1 and Rs-AFP2 were determined by isoelectric focusing and found to be higher than 10 for both proteins. Isoelectric focusing was performed on precast Immobiline Dry Strips (Pharmacia) rehydrated in 8 M urea, using marker proteins in the pI range from 4.7 to 10.6 (Pharmacia).
When reduced with DTT, Two purified proteins from Dahlia and two purified proteins from Cnicus run as 5/6 kDa bandsupon SDS-PAGE analysis.
In their inreduced form, the purified proteins run as oligomers. Unreduced Dm-AMP1 runs as a 24 kDa protein and Dm-AMP2 as a 17 kDa proteins. Similarly, unreduced Cb-AMP1 runs as a single band of 30 kDa and Cb-AMP2 as a band of 18 kDa.
When reduced with DTT, SDS PAGE analysis three proteins (two proteins purified from Clitoria and one protein purified from Lathyrus) run as 5/6 kDa bands.
In their unreduced form, the purified proteins run as oligomers. Unreduced Ct-AMP1 and Ct-AMP2 run as proteins of approximately 15 kDa whereas unreduced Lc-AFP runs as an approximately 12 kDa protein.
EXAMPLE 12
Amino acid sequencing of the Rs-AFPs and related proteins.
Cysteine residues of the antifungal proteins were modified by S-pyridylethylation using the method of Fullmer (1984, Anal Biochem, 142, 336-341). Reagents were removed by HPLC on a Pep-S (porous silica C 2 /C 18 ) (Pharmacia) column (25×0.4 cm). The S-pyridylethylated proteins were recovered by eluting the column with a linear gradient from 0.1% trifluoroacetic acid (TFA) to acetonitrile containing 0.1% TFA. The resulting protein fractions were subjected to amino acid sequence analysis in a 477A Protein Sequencer (Applied Biosystems) with on-line detection of phenylthiohydantoin amino acid derivatives in a 120A Analyser (Applied Biosystems). Where necessary due to the proteins being blocked, treatment of the S-pyridylethylated proteins with pyroglutamate amino peptidase was done according to the supplier's instructions (Boehringer Mannheim, Mannheim, FRG).
The N-terminal amino acid sequence of Rs-AFP1 and Rs-AFP2 was determined by automated Edman degradation, after treatment with pyroglutamate amino peptidase which cleaves off cyclic N-terminal glutamate residues. FIG. 21 shows the sequence of the first 44 N-terminal amino acids of Rs-AFP1 and of the first 35 residues of Rs-AFP2. The sequences of Rs-AFP1 and Rs-AFP2 differ at only two positions within the first 36 residues. The replacement of a glutamic acid by a glutamine (position 4) and an asparagine by an arginine (position 27) in Rs-AFP2 are consistent with the higher net positive charge of this protein relative to Rs-AFP1, which was previously evidenced by cathodic gel electrophoresis and cation exchange chromatography (FIG. 1). Rs-AFP1 appears to be rich in cysteine and basic amino acids (5 and 9 respectively within the first 45 residues). The molecular mass of Rs-AFP1 calculated on the basis of the partial amino acid sequence (4964 Da) is very close to the value estimated by SDS-PAGE (about 5000 Da) which indicates that the determined sequence encompasses the major part of the protein. However, it is anticipated that Rs-AFP1 contains at least one more cysteine, since the absence of free thiol groups assumes an even number of cysteines.
FIG. 21 also shows the first 23 to 30 N-terminal amino acids of the Rs-AFP-like proteins isolated from other Brassicaceae as described in Example 5 (Bn-AFP1, Bn-AFP2, Br-AFP1, Br-AFP2, Sa-AFP1, Sa-AFP2, At-AFP1 (SEQ ID No: 1 through SEQ ID No: 9). All proteins were treated with pyroglutamate amino peptidase prior to sequencing but the cysteine residues were not modified. Consequently, cysteine residues appear as blanks upon Edman degradation. Amino acids identical to the corresponding amino acids in Rs-AFP1 are shown by dots. It appears therefore that the Rs-AFP-like proteins from other members of the family Brassicaceae are identical or nearly identical to Rs-AFP1 and Rs-AFP2. Br-AFP2 contains an unidentified uncommon amino acid at position 11.
FIG. 22 shows the complete amino acid sequence for the peptides Dm-AMP1, Cb-AMP1 and Cb-AMP2 (SEQ ID NO: 10 through SEQ ID NO: 13). Shown also is the sequence for the first 20 N-terminal amino acids of Dm-AMP2. The sequences for Dm-AMP1 and Dm-AMP2 differ at only one position (position 2) in these first 20 amino acids. Comparing the sequences for Cb-AMP1 and Cb-AMP2, there are three changes. The substitution of an acidic residue (aspartic acid at position 22) in Cb-AMP1 for a neutral asparagine in Cb-AMP2 and the substitution of glutamine at position 23 for a basic lysine are consistent with the higher net positive charge. Similarly, Cb-AMP2 also differs from Dm-AMP1 at two positions although the result is the net gain of two positive charges.
All four proteins show striking similarity to the proteins isolated from seeds of the Brassicaceae family. Alignment of the amino acid sequence for Rs-AFP1 (Raphanus Sativus--Antifungal Protein 1) with the sequence for Dm-AMP1 reveals that they have approximately 50% identical residues.
FIG. 23 shows the complete amino acid sequence for the peptides Lc-AFP and Ct-AMP1 (SEQ ID NO:14 and SEC ID NO:15) Ct-AMP2 is expected to be highly homologous to Ct-AMP1. Both Lc-AFP and Ct-AMP1 are also homologous to the Compositae and Brassicaceae proteins. In particular Ct-AMP1 is very homologous to the Dahlia peptide Dm-AMP1, having 35 identical residues in its sequence.
Homologies can be found between this group of closely related proteins and the products encoded by two pea (Pisum sativum) genes, pI39 and pI230, which are specifically induced by the fungus Fusarium solani(Chiang and Hadwiger, 1991, Mol Plant Microbe Interact, 4, 324-331), and with the protein product of potato (Solanum tuberosum) gene p322 (Stiekema et al, 1988, Plant Mol Biol, 11, 255-269). Nothing is known about the biological properties of the proteins encoded by genes pI39, pI230 or p322. In addition, the Rs-AFP-like/Dahlia/Cnicus/Lathyrus/Clitoria class of antimicrobial proteins show homology to inhibitors of insect gut α-amylases from Sorghum bicolor(Bloch and Richardson, 1991, FEBS Lett, 279, 101-104), and also to γ-purothionins from Triticum aestivum (Colilla et al, 1990, FEBS Lett, 270, 191-194) which inhibit in vitro protein synthesis in cell-free systems (Mendez et al, 1990, Eur J Biochem, 194, 533-539).
FIGS. 24A, B and C show the alignment of the amino acid sequences of Rs-AFP1, Dm-AMP1, the Cb-AMPs, Lc-AFP, Ct-AMP1, the sorghum α-amylase inhibitor SIα2, wheat γ1 purothionin, and the predicted sequences of the mature protein products of the Fusarium-induced pea genes pI230 and pI39, of the cowpea gene pSAS10, and of the potato gene p322. Sequence identities and conserved changes compared with Rs-AFP1 are boxed. Conserved changes are considered as substitutions within the amino acid homology groups FWY, MILV (SEQ ID NO:16) RHK, EDNQ (SEQ ID NO:17), and PAGST (SEQ ID NO:18). Gaps introduced for optimal alignment are represented by dashes (SEQ ID NO:19 through SEQ ID NO:30).
Upon alignment of the sequences, all of the cysteines and most of the glycines appear at conserved positions, suggesting their importance with respect to structure and function of these proteins. Also noteworthy are the conserved aromatic residues at positions 11 and 40.
FIGS. 25A and 25 show one of the possible DNA sequences of the genes encoding Dm-AMP1, Dm-AMP2, Cb-AMP1 and Cb-AMP2 (SEQ ID NO:31 through SEQ ID NO:34). Similarly FIG. 26 shows one of the possible DNA sequences of the genes encoding Lc-AFP and Ct-AMP1 (SEQ ID NO:35 and SEQ ID NO:36). These gene sequences have been predicted from the known amino acid sequences using codons which commonly occur in dicotyledonous plants. The actual gene sequences within the seed may differ due to the degeneracy of the genetic code.
EXAMPLE 13
Amino acid sequencing of Rs-nsLTP.
Amino acid sequencing of the Rs-nsLTP protein was carried out according to the description in Example 12.
FIG. 32 shows the first 43 N-terminal amino acids of Rs-nsLTP (SEQ ID NO:37) of which the cysteine residues were modified by S-pyridylethylation. In FIG. 33 the sequence of Rs-nsLTP is aligned with the N-terminal sequences of non-specific lipid transfer proteins isolated from Spinacia oleracea (So-nsLTP; Bernhard et al, 1990, Plant Physiol, 95, 164-170), Ricinus communis (Rc-nsLTP; Takishima et al, 1986, Biochim Biophys Acta, 870, 248-255), Daucus carota (Dc-nsLTP; Stenk et al, 1991, Plant Cell, 9, 907-921), Hordeum vulgare (Hv-nsLTP; Bernhard and Somerville, 1989, Arch Biochem Biophys, 269, 695-697), and Zea mays (Zm-nsLTP; Tchang et al, 1988, J Biol Chem, 263, 16849-16855). Gaps introduced for optimal alignment of the sequences are indicated by dashes (SEQ ID NO:38 through SEQ ID NO:43). Identical amino acids and conserved substitutions occurring in at least 4 of the 6 sequences are boxed. Conserved changes are considered as substitutions within the amino acid homology groups FWY, MILV, RHK, EDNQ and PAGST. Rs-nsLTP shows 38 to 53% sequence identity with the non-specific lipid transport proteins from other plant sources. Non-specific lipid transport proteins are proteins that can translocate phospholipids or other apolar compounds between two membrane systems. These proteins were previously thought to play a role in the transport of phospholipids from endoplasmic reticulum to cell and organelle membranes (Arondel and Kaden, 1990, Experientia, 46, 579-585). However, recent evidence shows that nsLTPs are located extra-cellularly, making their proposed function in membrane biogenesis unlikely (Sterk et al, 1991, Plant Cell, 3, 907-921).
EXAMPLE 14
Stability of the proteins' antifungal activity.
Tests for antifungal activity were performed with 20 μl samples diluted five-fold with growth medium containing Fusarium culmorum spores, according to the assay method given in Example 1. Untreated control samples consisted of the test proteins at 500 μg/ml in 10 mM sodium phosphate buffer (pH 7). Heat stabiliity tests were performed by heating aliquots of the test proteins for 10 minutes at different temperatures up to 100° C. Reduction of disulphide bridges was done by addition of dithiothreitol at 30 mM and Tris-HCl (pH 8.6) at 300 mM. The reagents were removed by reversed-phase chromatography. For digestions, different proteases were added at 100 μg/ml and incubated at 37° C. for 16 hours. The control treatment containing only the reagents proved negative for antifungal activity after the reversed-phase chromatography step.
The antifungal activity of all the purified proteins tested was resistant to heat treatments at up to 100° C. for 10 minutes. Reduction of their disulphide bonds by dibhiothreitol, however, completely abolished the antifungal activity. These disulphide linkages are essential for biological activity. Treatment of the Rs-AFP proteins with trypsin, chymotrypsin, proteinase K or pronase E reduced the antifungal activity by at least 10-fold.
EXAMPLE 15
Antifungal potency of the proteins.
The antifungal potency of the purified proteins was assessed on different plant pathogenic fungi, using the assay described in Example 1. Growth of fungi, collection and harvest of fungal spores, and preparation of mycelial fragments were done as previously described (Broekaert et al, 1990, FEMS Microbiol Lett, 69:55-60). The following fungal strains were used: Alternaria brassicola MUCL 20297, Ascochyta pisi MUCL 30164, Botrytis cinerea MUCL 130158, Cercospora beticola strain K897, Cladosporium sphaerosperum (K0791), Colletotrichum lindemuthianum MUCL 9577, Fusarium culmorum IMI 180420, Fusarium oxysporum f.sp. pisi IMI 236441, Fusarium oxysporum f.sp. lycopersici MUCL 909, Mycosphaerella fijiensis var fijiensis IMI 105378, Nectria haematococca Collection Van Etten 160-2-2, Penicillium digitatum (K0879), Phoma betae MUCL 9916, pyrenophora tritici-repentis MUCL 30217, Pyricularia oryzae MUCL 30166, Rhizoctonia solani CBS 207-84, Sclerotinia sclerotianum MUCL 30163, Septoria nodorum MUCL 30111, Septoria tritici (K1097D), Trichoderma hamatum MUCL 29736, Trichoderma viride K1127), Verticillium albo-atrum (K0937), Verticillium dahliae MUCL 19210, Venturia inaequalis MUCL 15927.
For C beticola, R solani, S sclerotianum, S nodorum and M fijiensis, mycelial fragments were used as inoculum, whereas all other fungi were inoculated as spores.
Serial dilutions of the antifungal proteins were applied to the fungi, either using growth medium A or medium B. The percent growth inhibition was measured by microspectrophotometry. The concentration required for 50% growth inhibition after 48 h of incubation (IC 50 value) was calculated from the dose-reponse curves. The IC 50 values for the slow growing fungi S nodorum and inaequalis was measured after 5 and 15 days of incubation respectively.
The results for Rs-AFP1 and Rs-AFP2 are summarised in Table 1.
TABLE 1______________________________________ANTIFUNGAL ACTIVITY of Rs-AFP1 and Rs-AFP2 IC.sub.50 (μg/ml) Medium A Medium BFungus Rs-AFP1 Rs-AFP2 Rs-AFP1 Rs-AFP2______________________________________A brassicola 15 2 >100 20A pisi 5 4 >100 50B cinerea 8 2 >100 >100C beticola 2 2 100 3C lindemuthianum 100 3 >100 >100F culmorum 12 2 70 5F oxysporum pisi 30 2 >100 >100F oxysporum 15 2 >100 >100lycopersiciM fijiensis 4 1.5 30 10N haematococca 6 2 >100 30P betae 2 1 20 6P tritici-repentis 3 1.5 30 7P oryzae 0.3 0.4 >100 7R solani 100 >100 >100 >100S sclerotianum 20 >100 >100 >100S nodorum 20 15 100 20T hamatum 2 2 20 4V dahliae 5 1.5 >100 50V inaequalis ND 25 ND >50______________________________________ ND = not determined
The concentration of Rs-AFPS required for 50% growth inhibition in medium A varied from 0.3 82 g/ml to over 100 μg/ml, depending on the test organism. The antifungal potency of Rs-AFP1 is generally slightly lower than that of Rs-AFP2 in medium A. The difference in antifungal potency between Rs-AFP1 and Rs-AFP2 is more pronounced for the tests performed in medium B. Rs-AFP1 only inhibits 4 out of 17 fungi by more than 50% at oncentrations below 100 μg/ml, whereas Rs-AFP2 is inhibitory on 11 out of 18 fungi at this concentration. For some fungi, such as E culmorum and C beticola, the IC 50 value of Rs-AFP2 measured in medium A is comparable to that obtained in medium B. On other fungi, such as F oxysporum f.sp. pisi, the IC 50 value of Rs-AFP2 is increased from 2 μg/ml in medium A to over 100 μg/ml in medium B.
The antifungal potency of the Rs-AFP-like proteins from B napus, B rapa, S alba and A thaliana was compared to that of Rs-AFP1 and Rs-AFP2 using five different test fungi. The results of these experiments are shown in Table 2. With the exception of Br-AFP2, all proteins had specific activities comparable to that of the Rs-AFPs. The fact that Br-AFP2 is on average 20-fold less active than the related species may be related to the observation that Br-AFP2 has an uncommon amino acid at position 11 (see FIG. 21) whereas the Rs-AFPs and related proteins all have an aromatic residue at this position (see FIGS. 24A-C. When tested in medium B, Rs-AFP2 appears to be the most potent protein, especially on the fungus E culmorum.
TABLE 2__________________________________________________________________________Antifungal Activity of Rs-AFP-like proteins from Brassica rapa, Brassicanapus,Sinapis alba and Arabidopsis thalianaFungus Rs-AFP1 Rs-AFP2 Br-AFP1 Br-AFP2 Bn-AFP1 Bn-AFP2 Sa-AFP1 Sa-AFP2 At-AFP1__________________________________________________________________________IC.sub.50 (μg/ml) in medium AA brassicola 15 2 3 75 0.60 1.20 1.2 4.5 10B cinerea 8 2 1.50 >100 2 2 1.8 3.5 3.90F culmorum 12 2 2 38 2.80 2.10 4 2.3 3F oxysporum 15 2 1.80 42 1.30 1.50 6 2.3 3lycopersiciP oryzae 0.3 0.4 0.25 3 0.35 0.25 0.5 0.3 0.25V dahliae 5 1.5 0.80 15 1.20 1 1.5 1.2 1.50IC.sub.50 (μg/ml) in medium BA brassicola >100 20 >100 >100 >100 >100 >100 >100 >100B cinerea >100 >100 >100 >100 >100 >100 >100 >100 >100F culmorum 70 5 19 32 33 40 40 32 35F oxysporum >100 >100 >100 >100 >100 >100 >100 >100 >100lycopersiciP oryzae >100 7 >100 >100 32 8 25 3.8 >100V dahliae >100 50 >100 >100 >100 >100 >100 >100 >100__________________________________________________________________________
The antifungal potency of Rs-nsLTP is shown in Table 3. On most fungi Rs-nsLTP is 10 to 20 fold less potent relative to Rs-AFP2. Rs-nsLTP also appears to be highly salt-sensitive. None of the 13 fungi tested are inhibited by Rs-nsLTP in Medium B at concentrations below 100 μg/ml.
TABLE 3______________________________________Antifungal Activity of Rs-nsLTP IC.sub.50 (μg/ml)Fungus Medium A Medium B______________________________________A brassicola 48 500A pisi 41 700B cinerea 45 680C lindemuthianum 25 >1000F culmorum 20 520F oxysporum 54 >1000lycopersiciF oxysporum pisi 58 900M fijiensis >100 >100N haematococca 100 >1000P betae 18 750P oryzae 10 >1000T hamatum 30 >1000V dahliae 7 135______________________________________
The results for the Compositae proteins are summarised in Table 4.
The concentration of antimicrobial proteins required for 50% growth inhibition in medium A varied from 0.3 μg/ml to over 100 μg/ml, depending on the test organism. In general, the antifungal potency of the proteins was in the order: Cb-AMP2>Cb-AMP1>Dm-AMP1>Dm-AMP2. The differences in activity between the proteins is more pronounced in medium B, with Cb-AMP2 showing the best salt tolerance. Dm-AMP1 and Dm-AMP2 only inhibit the growth of 6 out of 11 fungi by more than 50% at concentrations below 100 μ/ml, whereas the two Cnicus proteins inhibit the growth of 7 out of 8 fungi when assayed in medium B.
Table 5 summarises the results for the antimicrobial proteins isolated from Leguminosae seeds.
These proteins are active, although their activity is somewhat lower than that of the Rs-AFPs and Compositae proteins, especially when assayed in high salt buffer, Medium B. In particular, the activity of Lc-AFP is markedly lower and comparable to the activity of Br-AFP2. The amino acid sequence of Lc-AFP also shows a substitution at position 11 which is normally tryptophan (FIGS. 21 and 23).
The high levels of antifungal activities demonstrated in vitro by each of the purified proteins suggest that they may play a role in the defence of seeds or seedlings against fungal attack.
TABLE 4__________________________________________________________________________ANTIFUNGAL ACTIVITY of the Dm-AMPs and the Cb-AMPs IC.sub.50 (μg/ml) Medium A Medium BFUNGUS Dm-AMP1 Dm-AMP2 Cb-AMP1 Cb-AMP2 Dm-AMP1 Dm-AMP2 Cb-AMP1__________________________________________________________________________A brassicola 1.1 2 ND ND 140 140 NDB cinerea 12 10 5 7 >200 >200 40C beticola 1 3 1.2 1 6 6 5C sphaerospermum 3 3 1 0.35 12 12 8F culmorum 5 3 5 2 8 55 16F oxysporum pisi 2.7 17 ND ND >200 >200 NDP digitatum 2 2 2 1.4 70 50 15P oryzae 5 6 ND ND >200 >200 NDS tritici 1 0.5 0.8 0.5 4 2 2T viride >80 >80 >100 40 >100 >100 >100V albo-atrum 4 2 ND ND ND ND NDV dahliae 0.3 0.6 0.5 1.2 3 4 5__________________________________________________________________________ ND = not determined
TABLE 5__________________________________________________________________________ANTIFUNGAL ACTIVITY of the Ct-AMPs and Lc-AFP IC.sub.50 (μg/ml) Medium A Medium BFUNGUS Ct-AMP1 Ct-AMP2 Lc-AFP Ct-AMP1 Ct-AMP2 Lc-AFP__________________________________________________________________________B cinerea 37 15 80 >150 >150 >200C sphaerospermum 9 3 10 >150 50 >200F culmorum 18 6 20 75 50 >200P digitatum >150 >150 9 >150 >150 >200P oryzae >150 >150 >200 >150 >150 >200S tritici 9 2 37 >150 60 >200T viride >150 >150 >200 >150 >150 >200V albo-atrum 9 3 37 >150 100 >200V dahliae 2 1 20 40 12 >200__________________________________________________________________________
EXAMPLE 16
Effect of ions on antifungal activity.
The effect of ions on the antifungal activity of the Rs-AFPs and Rs-nsLTP was examined in more detail. The IC 50 values of Rs-AFP1, Rs-AFP2 and Rs-nsLTP on F culmorum and T hamatum were measured in five different media. The reference medium was the synthetic growth medium described in Example 1 which contains a total of 2.5 mM monovalent cations and 0.1 mM divalent cations. The four other media contained 10 mM KCl, 50 mM KCl, 1 mM CaCl 2 or 5 mM CaCl 2 in supplement, respectively. For the purpose of comparison, these tests were performed in parallel with β-purothionin, an antifungal protein from wheat seeds (isolated as described in Redman and Fisher, 1969, J Sci Food Agric, 20, 427-432) and Mj-AMP2, an antifungal protein from Mirabilis jalapa seeds (Cammue et al, 1992, J Biol Chem, 267, 2228-2233).
Table 6 shows the results of the antifungal activity assays in the presence of K + and Ca 2+ .
Addition of KCl at up to 50 mM did not affect the antifungal activity of either Rs-AFP1 or Rs-AFP2. CaCl 2 at 1 mM had no effect on Rs-AFP2 but increased the IC 50 value of Rs-AFP1 by about four-fold (ie, Ca 2+ reduced the antifungal activity of Rs-AFP1). CaCl 2 at 5 mM almost completely inactivated Rs-AFP1 while its effect on Rs-AFP2 varied from a slight increase in IC 50 for F culmorum to complete inactivation for T hamatum. Addition of KCl at 50 mM decreases the activity of Rs-nsLTP by more than 30-fold with both test fungi. In comparison, the IC 50 value of β-purothionin
TABLE 6__________________________________________________________________________VARIATIONS IN ANTIFUNGAL ACTIVITYIN THE PRESENCE OF K.sup.+ AND CA.sup.2+ IC50 (μg/ml) Antifungal Reference medium supplement:Fungus protein None 10 mM K.sup.+ 50 mM K.sup.+ 1 mM Ca.sup.2+ 5 mM Ca.sup.2+__________________________________________________________________________F culmorum Rs-AFP1 5 5 6 10 100 Rs-AFP2 3 2 2 2 5 Rs-nsLTP 20 35 >1000 108 >1000 β-purothionin 10 7 4 10 70 Mj-AMP2 4 5 40 50 >100T hamatum Rs-AFP1 7 7 7 30 >100 Rs-AFP2 2 2 3 2 >100 Rs-nsLTP 30 60 >1000 >1000 >1000 β-purothionin 4 3 1.5 4 30 Mj-AMP2 2 2 25 20 >100__________________________________________________________________________
increased by about 7-fold in the presence of 5 mM CaCl 2 . Mj-AMP2 appeared to be highly sensitive to the presence of salts, since its IC 50 values increased by about 10-fold upon addition of either 1 mM CaCl 2 or 50 mM KCl.
These results show that the Rs-AFPs are antagonised by divalent cations. Rs-AFP1 is much more sensitive to the presence of divalent cations than Rs-AFP2. Rs-nsLTP is clearly more salt-sensitive than either Rs-AFP1 or Rs-AFP2. The antagonistic effect of cations appears to be strongly dependent on the test organism.
EXAMPLE 17
Effect of the purified antimicrobial proteins on the growth of the yeast, Saccharomyces cerevisiae.
The purified proteins were tested for their effect on Saccharomyces cerevisiae. The method used was similar to the antifungal assay described in Example 1 except that the growth medium was YPD (10 g/l yeast extract, 20 g/l bactopeptone, 20 g/l glucose) with 0.5% seaplaque agarose.
When assayed at levels of 250 μg/ml, none of the purified Brassicaceae proteins had an effect on the growth of Saccharomyces cerevisiae (strain Sp1). Similarly, Lc-AFP did not inhibit the growth of S cerevisiae (strain JRY188) at a concentration of 200 μg/ml.
The Compositae and Clitoria peptides were active against the growth of S cerevisiae (strain JRY188). These results are shown in Table 7. Of the six peptides, the two Clitoria peptides, Ct-AMP1 and Ct-AMP2 showed the highest level of activity.
TABLE 7______________________________________ACTIVITY OF Dm-AMPs, Cb-AMPs and Ct-AMPs on YEASTProtein IC.sub.50 (μg/ml)______________________________________Dm-AMP1 50Dm-AMP2 50Cb-AMP1 30Cb-AMP2 20Ct-AMP1 18Ct-AMP2 9______________________________________
EXAMPLE 18
Effect of the purified antimicrobial proteins on bacteria.
The antibacterial effect of the purified proteins was assessed on Agrobacterium tumefaciens C58, Alcaligenes eutrophus, Azospirillum brasilense Sp7, Bacillus megaterium ATCC 13632, Erwinia carotovora strain 3912, Escherichia coli strain HB101, Pseudomonas solanacearum strain K60 and Sarcina lutea ATCC 9342, using the assay described in Example 1.
Rs-AFP2 caused 50% inhibition in B megaterium at 200 μg/ml, but had no effect on the other bacteria at concentrations up to 500 82 g/ml.
The Compositae peptides Dm-AMP1, Dm-AMP2, Cb-AMP1 and Cb-AMP2 showed activity only on B megaterium where they inhibited growth to 50% at concentrations of 180, 40, 80 and 32 μg/ml respectively.
Rs-AFP1, Bn-AFPs, Br-AFP2, Sa-AFPs, Ct-AMPs and Lc-AFP had no effect on any of the bacteria at concentrations up to 500 μg/ml.
Results show that in general these proteins possess only weak antibacterial activity.
EXAMPLE 19
Effect of the purified antifungal proteins on cultured human cells.
Human cell toxicity assays were performed either on umbilical vein endothelial cells (Alessi et al, 1988, Eur J Biochem, 175, 531-540) or skin-muscle fibroblasts (Van Damme et al, 1987, Eur J Immunol, 17, 1-7) cultured in 96-well microplates. The growth medium was replaced by 80 μl of serum-free medium (Optimem 1 for endothelial cells or Eagle's minimal essential medium (EMEM) for fibroblasts, both from GIBCO), to which 20 μl of a filter-sterilised test solution was added. The cells were further incubated for 24 hours at 37° C. under a 5% CO 2 atmosphere with 100% relative humidity. The viability of the cells was assessed microscopically after staining with trypane blue (400 mg/1 in phosphate buffered saline, PBS) for 10 minutes. Alternatively, cells were stained with neutral red (56 mg/l in PBS) for 2 hours at 37° C. Cells were lysed in acidic ethanol (100 mM sodium citrate, pH 4, containing 50% ethanol) and scored for release of the dye by microspectrophotometry at 540 nm.
The Rs-AFPs and Rs-nsLTP were evaluated for their potential toxic effects using this assay. When added at up to 500 μg/ml to either cultured human umbilical vein endothelial cells or human skin-muscle fibroblasts, neither Rs-AFP1, Rs-AFP2, nor Rs-nsLTP affected cell viability after 24 h of incubation. In contrast, β-purothionin administered at 50 μg/ml decreased the viability of both cell types by more than 90%.
EXAMPLE 20
Anti-fungal activity of the Rs-AFPs against foliar disease: in vivo test
Rs-AFP2 was tested against the sugarbeet foliar disease Cercospora beticola (strain E897) using the following method.
Sugarbeet plants were grown in John Innes potting compost (No. 1 or 2) in 4cm diameter mini-pots. The protein preparation was formulated immediately prior to use by dissolving in sterile distilled water and diluting to the appropriate concentration. The formulation was applied to the plants as a foliar spray. The spray was applied to maximum discrete droplet retention. Plants were treated with the protein one day prior to inoculation with the disease which was applied as a foliar spray at a concentration of 50000 spores/mi. Plants were kept in an humidity chamber for 48 hours and then transferred to the glasshouse. Disease was assessed following a further incubation of 8 days.
Results are shown in FIG. 29. The commercially available fungicide hexaconazole was used as a standard. Rs-AFP2 gave good control of the disease and the concentration giving 50% control was approximately 15 μM. In comparison hexaconazole gave 50% disease control when applied at approximately 7 μM. This confirms that the protein can act as an effective fungicide in vivo and that its activity is on a molar basis comparable to the chemical standard.
EXAMPLE 21
Molecular cloning of RS-AFP1 and Rs-AFP2 cDNAs
From outdoor grown Raphanus sativus plants, seeds at 6 different developmental stages were collected, frozen in liquid nitrogen and stored at -80° C. After pulverisation, total RNA was extracted from 15 g of a mixture of the 6 different developmental stages, using the method of De Vries et al (1988, Plant Molecular Biology Manual, B6, 1-13) with the exception that 6 ml of a 1:2 phenol:RNA extraction buffer mixture and 2 ml of chloroform were used per g of tissue. Poly (A) + mRNA was purified by affinity chromatography on oligo(dT)-cellulose as described by Siflow et al (1979, Biochemistry 18, 2725-2731) yielding about 10 μg of poly(A) + RNA per g of tissue. Double stranded cDNAs were prepared from 1.5 μg of poly(A) + RNA according to Gubler and Hoffman (1983, Gene 25, 263-269) and ligated to EcoRI/NotI adaptors using the cDNA Synthesis Kit of Pharmacia. The cDNAs were cloned into the lambda ZAPII phage vector (Stratagene) according to the manufacturers instructions. A DNA probe for screening the cDNA library was produced by polymerase chain reaction (PCR) as follows. Two degenerate oligonucleotides were synthesised: OWB15 (5'AAAGAATTCAARYTNTGYSARMGNCC 3')(SEQ ID NO:44) and OWB17 (5'AAAGAATTCRTGNGCNGGRAANACRTARTTRC 3'). (SEQ ID NO:45). OWB15 corresponds to amino acids 2 to 7 of Rs-AFP1 and has a sense orientation. OWB17 corresponds to amino acids 36 to 43 of Rs-AFP1 and has an antisense orientation. Both primers have the AAAGAATTC (i.e. AAA followed by the EcoRI recognition sequence) sequence at their 5' ends. PCR was performed with the Taq polymerase under standard conditions (Sambrook et al, 1989, Molecular Cloning, Cold Spring Harbor Laboratory Press) using OWB15 and OWB17 as amplimers and 25 ng of cDNA as target DNA. The temperature programme included an initial step at 94° C. for 5 min, 30 cycles (94° C. for 1 min; 45° C. for 2 min, 72° C. for 3 min) and a final step at 72° C. for 10 min. The 144 bp PCR amplification product was purified on a 3% agarose (NuSieve, FMC) gel. This PCR product was partially reamplified using the sense degenerate oligonucleotide OWB16 (5'AAAGAATTCGGNACNTGGWSNGGNGTNTG 3')(SEQ ID NO:46) and OWB17. OWB16 also has the AAAGAATTC (SEQ ID NO:47) extension at its 5' end. This 123 bp PCR amplification product was again purified on a 3% agarose (NuSieve, FMC) gel and reamplified by PCR under the same conditions except that the reaction mixture contained 130 μM dTTP and 70 μM digoxigenin-11-dUTP instead of 200 μM dTTP. The digoxigenin-labeled PCR product was purified on a 3% NuSieve agarose gel. About 10,000 plaque forming units of the lambda ZAPII cDNA library were screened with the digoxigenin-labeled PCR product by in situ plaque hybridisation using nylon membranes (Hybond-N, Amersham). Membranes were air-dried and DNA was crosslinked to the membranes under UV light (0.15 J/cm 2 ). Hybridisation was performed for 16 h at 64° C. in 5×SSC, 1% blocking reagent (Boehringer Mannheim), 0.1% N-lauroylsarcosine, 0.02% sodium dodecylsulphate containing 10 ng/ml of heat denatured digoxigenin-labeled probe. Nonspecifically bound probe was removed by rinsing two times 5 min in 2×SSC/0.1% SDS at 25° C. and two times 15 min in 0.1×SSC/0.1% SDS at 60° C. Detection of the probe was done using antidigoxigenin antibodies linked to alkaline phosphatase (Boehringer Mannheim) and its substrate 5-bromo-4-chloro-3-indolyl phosphate (Boehringer Mannheim) according to the manufacturers instructions. Positive plaques were purified by two additional screening rounds with the same probe under the same conditions. Inserts from purified plaques were excised in vivo into the pBluescript phagemid form with the aid of the helper phage R408. The inserts from 22 different positive clones were excised by EcoRI digestion and their sizes compared by agarose gel electrophoresis. Four clones had an insert of approximately 400 bp, the other 18 positive clones contained inserts ranging between approximately 250 and 300 bp. The four clones with the 400 bp inserts and six clones with the smaller inserts were subjected to nucleotide sequence analysis. The clones with the largest insert all had an open reading frame of 80 amino acids corresponding to Rs-AFP1, as could be determined by comparison to the experimental N-terminal amino acid sequences (see Example 12). The 243 bp open reading frames code for the mature Rs-AFP1 (50 amino acids) preceded by a putative 29 amino acid signal sequence obeying the (-1, -3) rule (von Heijne 1985, Mol. Biol. 184, 99-105). These full-length cDNA clones only differed from each other in the length of their 5' and 3' end untranslated regions. Five of the clones with the smallest insert were partially identical to the full-length Rs-AFP1 cDNA clones except that they were truncated at their 5' ends. The remaining clone was identified as a 5' truncated Rs-AFP2 cDNA clone by comparing the deduced and the experimentally determined amino acid sequences. When comparing the full-length Rs-AFP1 cDNA clone pFRG1 (FIG. 30) (SEQ ID NO:48 and SEQ IS NO:49) and the truncated Rs-AFP2 cDNA clone pFRG2 (FIG. 31) (SEQ ID NO:50 and SEQ ID NO:51), it can be seen that the codon usage is slightly different and that the 3' end untranslated region of the Rs-AFP2 cDNA is longer than the one of the Rs-AFP1 cDNA. Finally, both the Rs-AFP1 and the Rs-AFP2 cDNA clones have at least two polyadenylation signals. FIG. 30 shows the nucleotide sequence and the deduced amino acid sequence of the full-length RsAFP1 cDNA clone pFRG1. The putative signal sequence is underlined and the sequence of the mature Rs-AFP1 is boxed. FIG. 31 shows the nucleotide sequence and the deduced amino acid sequence of the 5' truncated Rs-AFP2 cDNA clone pFRG2.
In order to obtain a full-length Rs-AFP2 cDNA, another approach was followed: PCR was performed under standard conditions using the antisense oligonucleotide OWB23 (5'ATAGAATTCGACGTGAGCTTATCATCTTATTATCCG 3') (SEQ ID NO:52) in combination with the M13 universal primer at one hand and the M13 reverse primer at the other hand. The last 30 nucleotides of OWB23 form the inverted complementary sequence of the part of the 3' untranslated region immediately flanking the poly-A tail of pFRG2 (see FIG. 31). This sequence is extended to the 5' end, with the GAATTC EcoRI recognition site preceded by the nucleotides `ATA`. As a template, either 2 μg of total cDNA or 10 5 recombinant phages were used. In both cases, 3 separate reactions were set up. Prior to amplification, phages were lysed by an initial step in the PCR temperature programme of 5 min at 99° C. to liberate the phage DNA. The size of the amplification products was determined by electrophoresis on a 3% agarose (NuSieve, FMC) gel. Products were obtained with sizes corresponding to inserts of 280 to 300 bp. Thus, it can be concluded that no full-length Rs-AFP2 cDNA clones seem to be present in the cDNA library.
EXAMPLE 22
Mutagenesis of Rs-AFP1 cDNA to RS-AFP2 DNA
As can be deduced from the experimentally determined N-terminal sequences (see Example 12) and the nucleotide sequences (see Example 21), Rs-AFP1 and Rs-AFP2 only differ in two amino acids as stated in Example 12. As the antifungal potency of Rs-AFP2 is significantly higher than that of Rs AFP1 (see Table 1) and a full-length cDNA clone of the Rs-AFP2 is not available, the Rs-AFP1 cDNA was transformed into the Rs-AFP2 nucleotide sequence by PCR-assisted site-directed mutagenesis according to the method of E. Merino et al (1992, BioTechniques 12, 508-510). The following oligonucleotides (SEQ ID NO:53 through SEQ ID NO:57) were used: OWB28 (5'CTTGGCCTTTGGCACAACTTC 3'), OWB29 (5'GCTTTCTCAAGTCTAATGCAC 3'), OWB30 (5'AACTCGAGCTGCAGTGTCGACCTATTAACAAGGAAAGTAGC 3'), OWB35 (5'GGAATAGCCGATCGAGATCTAGGAAACAGCTATGACCATG 3'), OWB36 (5'GGAATAGCCGATCGAGATCTAGGA 3').
The first mutation (glutamate into glutamine at position 5 of the mature protein) was introduced by performing PCR with the Pfu polymerase (Stratagene) using OWB35 (this is the M13 universal primer with a 5' tag sequence) and OWB28 (the first antisense mutagenesis primer) as amplimers and 100 ng of the KpnI-digested pFRG1 cDNA as target DNA. MgCl 2 was added to the amplification mixture to a final concentration of 50 mM. The temperature programme included an initial step at 94° C. for 5 min, 30 cycles (94° C. for 1 min, 45° C. for 2 min, 72° C. for 3 min) and a final step at 72° C. for 10 min. In a second step, this PCR product was used as a megaprimer and extended by the Pfu polymerase using 50 ng of the KpnI-digested pFRG1 cDNA as the target DNA. The temperature programme included an initial step at 94° C. for 5 min followed by a 5 cycles extension (94° C. for 1 min, 50° C. for 1 min, 72° C. for 1 min). Then OWB29 (the antisense primer introducing the second mutation, from asparagine to arginine at position 27 of the mature protein) and OWB36 (which is identical to the 5' tag sequence of OWB35) were added, followed by PCR amplification by the Pfu-polymerase as described for the introduction of the first mutation. To get a full-length length Rs-AFP2 nucleotide sequence, the procedure outlined in the second step was repeated though using the oligonucleotide primers OWB36 and OWB30 (which introduces a second stop codon followed by the SalI, PstI and XhoI restriction sites, thus also eliminating the 3' end untranslated region of the Rs-AFP1 cDNA clone pFRG1). The final PCR product was cut with BamHI (occurring in the polylinker of the pBlueScript phagemid pFRG1) and SalI, subcloned in pEMBL18+ (pre-digested with the same restriction enzymes) and subjected to nucleotide sequence analysis. FIG. 33 and B Show the nucleotide sequence and the derived amino acid sequence of the full-length Rs-AFP2 DNA clone pFRG4 obtained by PCR-assisted site-directed mutagenesis of the Rs-AFP1 cDNA clone pFRG1 (SEQ ID NO:58 and SEQ ID NO:59). The putative signal sequence is underlined and the sequence of the mature Rs-AFP2 is boxed.
EXAMPLE 23
Construction of the expression vector pFRG7
The expression vector pFRG7 (FIG. 33; SP=signal peptide, MP=mature protein) contains the full coding region of the Rs-AFP2 DNA flanked at its 5' end by the strong constitutive promoter of the 35S RNA of the cauliflower mosaic virus (Odell et al, 1985, Nature 313, 810-812) with a duplicated enhancer element to allow for high transcriptional activity (Kay et al, 1987, Science 236, 1299-1302). The coding region of the Rs-AFP2 DNA is flanked at its 3' end side by the polyadenylation sequence of 35S RNA of the cauliflower mosaic virus (CaMV35S). The plasmid backbone of this vector is the phagemid pUC120 (Vieira and Messing 1987, Methods Enzymol. 153, 3-11). pFRG7 was constructed as follows: clone pFRG4 which consisted of the Rs-AFP2 DNA (FIG. 37) cloned into the BamHI/SalI sites of pEMBL18+, Boehringer). The 298 bp BamHI/SalI fragment was subcloned into the expression vector pFAJ3002 which was pre-digested with BamHI and SalI. pFAJ3002 is a derivative of the expression vector pFF19 (Timmermans et al, 1990, J. Biotechnol. 14, 333-344) of which the unique EcoRI site is replaced by a HindIII site.
EXAMPLE 24
Construction of the plant transformation vector pFRG8
The expression vector pFRG7 was digested with HindIII and the fragment containing the Rs-AFP2 DNA expression cassette was subcloned into the unique
HindIII site of pBin19Ri. pBin19Ri is a modified version of the plant transformation vector pBin19 (Beyan 1984, Nucleic Acids Research 12, 8711-8721) wherein the unique EcoRI and HindIII sites are switched and the defective nptII expression cassette (Yenofsky et al. 1990, Proc. Natl. Acad. Sci. USA 87: 3435-3439) is introduced. The new plant transformation vector is designated pFRG8 (FIG. 34).
EXAMPLE 25
Plant Transformation
The disarmed Agrobacterium tumefaciens strain LBA4404 (pAL4404)(Hoekema et al, 1983, Nature 303, 179-180) was transformed with the vector pFRG8 using the method of de Framond et al (BioTechnology 1, 262-269).
Tobacco transformation was carried out using leaf discs of Nicotiana tabacum Samsun based on the method of Horsch et al (1985, Science 227, 1229-1231) and co-culturing with Agrobacterium strains containing pFRG8. Co-cultivation was carried out under selection pressure of 100 μg/ml kanamycin. Transgenic plants (transformed with pFRG8) were regenerated on media containing 100 μg/ml kanamycin. These transgenic plants may be analysed for expression of the newly introduced genes using standard western blotting techniques. Plants capable of constitutive expression of the introduced genes may be selected and self-pollinated to give seed. F1 seedlings of the transgenic plants may be further analysed.
__________________________________________________________________________SEQUENCE LISTING(1) GENERAL INFORMATION:(iii) NUMBER OF SEQUENCES: 59(2) INFORMATION FOR SEQ ID NO:1:(i) SEQUENCE CHARACTERISTICS:(A) LENGTH: 44 amino acids(B) TYPE: amino acid(C) STRANDEDNESS: single(D) TOPOLOGY: linear(ii) MOLECULE TYPE: peptide(xi) SEQUENCE DESCRIPTION: SEQ ID NO:1:GlnLysLeuCysGluArgProSerGlyThrTrpSerGlyValCysGly151015AsnAsnAsnAlaCysLysAsnGlnCysIleAsnLeuGluLysAlaArg202530HisGlySerCysAsnTyrValPheProAlaHisLys3540(2) INFORMATION FOR SEQ ID NO:2:(i) SEQUENCE CHARACTERISTICS:(A) LENGTH: 36 amino acids(B) TYPE: amino acid(C) STRANDEDNESS: single(D) TOPOLOGY: linear(ii) MOLECULE TYPE: peptide(xi) SEQUENCE DESCRIPTION: SEQ ID NO:2:GlnLysLeuCysGlnArgProSerGlyThrTrpSerGlyValCysGly151015AsnAsnAsnAlaCysLysAsnGlnCysIleArgLeuGluLysAlaArg202530HisGlySerCys35(2) INFORMATION FOR SEQ ID NO:3:(i) SEQUENCE CHARACTERISTICS:(A) LENGTH: 27 amino acids(B) TYPE: amino acid(C) STRANDEDNESS: single(D) TOPOLOGY: linear(ii) MOLECULE TYPE: peptide(xi) SEQUENCE DESCRIPTION: SEQ ID NO:3:GlnLysLeuCysGluArgProSerGlyThrTrpSerGlyValCysGly151015AsnAsnAsnAlaCysLysAsnGlnCysIleAsn2025(2) INFORMATION FOR SEQ ID NO:4:(i) SEQUENCE CHARACTERISTICS:(A) LENGTH: 27 amino acids(B) TYPE: amino acid(C) STRANDEDNESS: single(D) TOPOLOGY: linear(ii) MOLECULE TYPE: peptide(xi) SEQUENCE DESCRIPTION: SEQ ID NO:4:GlnLysLeuCysGluArgProSerGlyThrXaaSerGlyValCysGly151015AsnAsnAsnAlaCysLysAsnGlnCysIleArg2025(2) INFORMATION FOR SEQ ID NO:5:(i) SEQUENCE CHARACTERISTICS:(A) LENGTH: 30 amino acids(B) TYPE: amino acid(C) STRANDEDNESS: single(D) TOPOLOGY: linear(ii) MOLECULE TYPE: peptide(xi) SEQUENCE DESCRIPTION: SEQ ID NO:5:GlnLysLeuCysGluArgProSerGlyThrTrpSerGlyValCysGly151015AsnAsnAsnAlaCysLysAsnGlnCysIleAsnLeuGluLys202530(2) INFORMATION FOR SEQ ID NO:6:(i) SEQUENCE CHARACTERISTICS:(A) LENGTH: 23 amino acids(B) TYPE: amino acid(C) STRANDEDNESS: single(D) TOPOLOGY: linear(ii) MOLECULE TYPE: peptide(xi) SEQUENCE DESCRIPTION: SEQ ID NO:6:GlnLysLeuCysGluArgProSerGlyThrTrpSerGlyValCysGly151015AsnAsnAsnAlaCysLysAsn20(2) INFORMATION FOR SEQ ID NO:7:(i) SEQUENCE CHARACTERISTICS:(A) LENGTH: 25 amino acids(B) TYPE: amino acid(C) STRANDEDNESS: single(D) TOPOLOGY: linear(ii) MOLECULE TYPE: peptide(xi) SEQUENCE DESCRIPTION: SEQ ID NO:7:GlnLysLeuCysGluArgProSerGlyThrTrpSerGlyValCysGly151015AsnAsnAsnAlaCysLysAsnGlnCys2025(2) INFORMATION FOR SEQ ID NO:8:(i) SEQUENCE CHARACTERISTICS:(A) LENGTH: 26 amino acids(B) TYPE: amino acid(C) STRANDEDNESS: single(D) TOPOLOGY: linear(ii) MOLECULE TYPE: peptide(xi) SEQUENCE DESCRIPTION: SEQ ID NO:8:GlnLysLeuCysGlnArgProSerGlyThrTrpSerGlyValCysGly151015AsnAsnAsnAlaCysArgAsnGlnCysIle2025(2) INFORMATION FOR SEQ ID NO:9:(i) SEQUENCE CHARACTERISTICS:(A) LENGTH: 27 amino acids(B) TYPE: amino acid(C) STRANDEDNESS: single(D) TOPOLOGY: linear(ii) MOLECULE TYPE: peptide(xi) SEQUENCE DESCRIPTION: SEQ ID NO:9:GlnLysLeuCysGluArgProSerGlyThrTrpSerGlyValCysGly151015AsnSerAsnAlaCysLysAsnGlnCysIleAsn2025(2) INFORMATION FOR SEQ ID NO:10:(i) SEQUENCE CHARACTERISTICS:(A) LENGTH: 50 amino acids(B) TYPE: amino acid(C) STRANDEDNESS: single(D) TOPOLOGY: linear(ii) MOLECULE TYPE: peptide(xi) SEQUENCE DESCRIPTION: SEQ ID NO:10:GluLeuCysGluLysAlaSerLysThrTrpSerGlyAsnCysGlyAsn151015ThrGlyHisCysAspAsnGlnCysLysSerTrpGluGlyAlaAlaHis202530GlyAlaCysHisValArgAsnGlyLysHisMetCysPheCysTyrPhe354045AsnCys50(2) INFORMATION FOR SEQ ID NO:11:(i) SEQUENCE CHARACTERISTICS:(A) LENGTH: 20 amino acids(B) TYPE: amino acid(C) STRANDEDNESS: single(D) TOPOLOGY: linear(ii) MOLECULE TYPE: peptide(xi) SEQUENCE DESCRIPTION: SEQ ID NO:11:GluValCysGluLysAlaSerLysThrTrpSerGlyAsnCysGlyAsn151015ThrGlyHisCys20(2) INFORMATION FOR SEQ ID NO:12:(i) SEQUENCE CHARACTERISTICS:(A) LENGTH: 50 amino acids(B) TYPE: amino acid(C) STRANDEDNESS: single(D) TOPOLOGY: linear(ii) MOLECULE TYPE: peptide(xi) SEQUENCE DESCRIPTION: SEQ ID NO:12:GluLeuCysGluLysAlaSerLysThrTrpSerGlyAsnCysGlyAsn151015ThrLysHisCysAspAspGlnCysLysSerTrpGluGlyAlaAlaHis202530GlyAlaCysHisValArgAsnGlyLysHisMetCysPheCysTyrPhe354045AsnCys50(2) INFORMATION FOR SEQ ID NO:13:(i) SEQUENCE CHARACTERISTICS:(A) LENGTH: 50 amino acids(B) TYPE: amino acid(C) STRANDEDNESS: single(D) TOPOLOGY: linear(ii) MOLECULE TYPE: peptide(xi) SEQUENCE DESCRIPTION: SEQ ID NO:13:GluLeuCysGluLysAlaSerLysThrTrpSerGlyAsnCysGlyAsn151015ThrLysHisCysAspAsnLysCysLysSerTrpGluGlyAlaAlaHis202530GlyAlaCysHisValArgSerGlyLysHisMetCysPheCysTyrPhe354045AsnCys50(2) INFORMATION FOR SEQ ID NO:14:(i) SEQUENCE CHARACTERISTICS:(A) LENGTH: 47 amino acids(B) TYPE: amino acid(C) STRANDEDNESS: single(D) TOPOLOGY: linear(ii) MOLECULE TYPE: peptide(xi) SEQUENCE DESCRIPTION: SEQ ID NO:14:LysThrCysGluAsnLeuSerGlyThrPheLysGlyProCysIlePro151015AspGlyAsnCysAsnLysHisCysLysAsnAsnGluHisLeuLeuSer202530GlyArgCysArgAspAspPheXaaCysTrpCysThrArgAsnCys354045(2) INFORMATION FOR SEQ ID NO:15:(i) SEQUENCE CHARACTERISTICS:(A) LENGTH: 49 amino acids(B) TYPE: amino acid(C) STRANDEDNESS: single(D) TOPOLOGY: linear(ii) MOLECULE TYPE: peptide(xi) SEQUENCE DESCRIPTION: SEQ ID NO:15:AsnLeuCysGluArgAlaSerLeuThrTrpThrGlyAsnCysGlyAsn151015ThrGlyHisCysAspThrGlnCysArgAsnTrpGluSerAlaLysHis202530GlyAlaCysHisLysArgGlyAsnTrpLysCysPheCysTyrPheAsp354045Cys(2) INFORMATION FOR SEQ ID NO:16:(i) SEQUENCE CHARACTERISTICS:(A) LENGTH: 4 amino acids(B) TYPE: amino acid(C) STRANDEDNESS: single(D) TOPOLOGY: linear(ii) MOLECULE TYPE: peptide(xi) SEQUENCE DESCRIPTION: SEQ ID NO:16:MetIleLeuVal(2) INFORMATION FOR SEQ ID NO:17:(i) SEQUENCE CHARACTERISTICS:(A) LENGTH: 4 amino acids(B) TYPE: amino acid(C) STRANDEDNESS: single(D) TOPOLOGY: linear(ii) MOLECULE TYPE: peptide(xi) SEQUENCE DESCRIPTION: SEQ ID NO:17:GluAspAsnGln1(2) INFORMATION FOR SEQ ID NO:18:(i) SEQUENCE CHARACTERISTICS:(A) LENGTH: 5 amino acids(B) TYPE: amino acid(C) STRANDEDNESS: single(D) TOPOLOGY: linear(ii) MOLECULE TYPE: peptide(xi) SEQUENCE DESCRIPTION: SEQ ID NO:18:ProAlaGlySerThr15(2) INFORMATION FOR SEQ ID NO:19:(i) SEQUENCE CHARACTERISTICS:(A) LENGTH: 51 amino acids(B) TYPE: amino acid(C) STRANDEDNESS: single(D) TOPOLOGY: linear(ii) MOLECULE TYPE: peptide(xi) SEQUENCE DESCRIPTION: SEQ ID NO:19:GlnLysLeuCysGluArgProSerGlyThrTrpSerGlyValCysGly151015AsnAsnAsnAlaCysLysAsnGlnCysIleAsnLeuGluLysAlaArg202530HisGlySerCysAsnTyrValPheProAlaHisLysCysIleCysTyr354045PheProCys50(2) INFORMATION FOR SEQ ID NO:20:(i) SEQUENCE CHARACTERISTICS:(A) LENGTH: 50 amino acids(B) TYPE: amino acid(C) STRANDEDNESS: single(D) TOPOLOGY: linear(ii) MOLECULE TYPE: peptide(xi) SEQUENCE DESCRIPTION: SEQ ID NO:20:GluLeuCysGluLysAlaSerLysThrTrpSerGlyAsnCysGlyAsn151015ThrGlyHisCysAspAsnGlnCysLysSerTrpGluGlyAlaAlaHis202530GlyAlaCysHisValArgAsnGlyLysHisMetCysPheCysTyrPhe354045AsnCys50(2) INFORMATION FOR SEQ ID NO:21:(i) SEQUENCE CHARACTERISTICS:(A) LENGTH: 50 amino acids(B) TYPE: amino acid(C) STRANDEDNESS: single(D) TOPOLOGY: linear(ii) MOLECULE TYPE: peptide(xi) SEQUENCE DESCRIPTION: SEQ ID NO:21:GluLeuCysGluLysAlaSerLysThrTrpSerGlyAsnCysGlyAsn151015ThrLysHisCysAspAspGlnCysLysSerTrpGluGlyAlaAlaHis202530GlyAlaCysHisValArgAsnGlyLysHisMetCysPheCysTyrPhe354045AsnCys50(2) INFORMATION FOR SEQ ID NO:22:(i) SEQUENCE CHARACTERISTICS:(A) LENGTH: 50 amino acids(B) TYPE: amino acid(C) STRANDEDNESS: single(D) TOPOLOGY: linear(ii) MOLECULE TYPE: peptide(xi) SEQUENCE DESCRIPTION: SEQ ID NO:22:GluLeuCysGluLysAlaSerLysThrTrpSerGlyAsnCysGlyAsn151015ThrLysHisCysAspAsnLysCysLysSerTrpGluGlyAlaAlaHis202530GlyAlaCysHisValArgSerGlyLysHisMetCysPheCysTyrPhe354045AsnCys50(2) INFORMATION FOR SEQ ID NO:23:(i) SEQUENCE CHARACTERISTICS:(A) LENGTH: 47 amino acids(B) TYPE: amino acid(C) STRANDEDNESS: single(D) TOPOLOGY: linear(ii) MOLECULE TYPE: peptide(xi) SEQUENCE DESCRIPTION: SEQ ID NO:23:LysThrCysGluAsnLeuSerGlyThrPheLysGlyProCysIlePro151015AspGlyAsnCysAsnLysHisCysLysAsnAsnGluHisLeuLeuSer202530GlyArgCysArgAspAspPheXaaCysTrpCysThrArgAsnCys354045(2) INFORMATION FOR SEQ ID NO:24:(i) SEQUENCE CHARACTERISTICS:(A) LENGTH: 49 amino acids(B) TYPE: amino acid(C) STRANDEDNESS: single(D) TOPOLOGY: linear(ii) MOLECULE TYPE: peptide(xi) SEQUENCE DESCRIPTION: SEQ ID NO:24:AsnLeuCysGluArgAlaSerLeuThrTrpThrGlyAsnCysGlyAsn151015ThrGlyHisCysAspThrGlnCysArgAsnTrpGluSerAlaLysHis202530GlyAlaCysHisLysArgGlyAsnTrpLysCysPheCysTyrPheAsp354045Cys(2) INFORMATION FOR SEQ ID NO:25:(i) SEQUENCE CHARACTERISTICS:(A) LENGTH: 45 amino acids(B) TYPE: amino acid(C) STRANDEDNESS: single(D) TOPOLOGY: linear(ii) MOLECULE TYPE: peptide(xi) SEQUENCE DESCRIPTION: SEQ ID NO:25:AsnThrCysGluAsnLeuAlaGlySerTyrLysGlyValCysPheGly151015GlyCysAspArgHisCysArgThrGlnGluGlyAlaIleSerGlyArg202530CysArgAspAspPheArgCysTrpCysThrLysAsnCys354045(2) INFORMATION FOR SEQ ID NO:26:(i) SEQUENCE CHARACTERISTICS:(A) LENGTH: 46 amino acids(B) TYPE: amino acid(C) STRANDEDNESS: single(D) TOPOLOGY: linear(ii) MOLECULE TYPE: peptide(xi) SEQUENCE DESCRIPTION: SEQ ID NO:26:AsnThrCysGluHisLeuAlaAspThrTyrArgGlyValCysPheThr151015AsnAlaSerCysAspAspHisCysLysAsnLysAlaHisLeuIleSer202530GlyThrCysHisAspTrpLysCysPheCysThrGlnAsnCys354045(2) INFORMATION FOR SEQ ID NO:27:(i) SEQUENCE CHARACTERISTICS:(A) LENGTH: 47 amino acids(B) TYPE: amino acid(C) STRANDEDNESS: single(D) TOPOLOGY: linear(ii) MOLECULE TYPE: peptide(xi) SEQUENCE DESCRIPTION: SEQ ID NO:27:LysThrCysGluLeuAsnAlaAspThrTyrArgGlyProCysPheThr151015ThrGlySerCysAspAspHisCysLysAsnLysGluHisLeuLeuSer202530GlyArgCysArgAspAspValArgCysTrpCysThrArgAsnCys354045(2) INFORMATION FOR SEQ ID NO:28:(i) SEQUENCE CHARACTERISTICS:(A) LENGTH: 47 amino acids(B) TYPE: amino acid(C) STRANDEDNESS: single(D) TOPOLOGY: linear(ii) MOLECULE TYPE: peptide(xi) SEQUENCE DESCRIPTION: SEQ ID NO:28:ArgHisCysGluSerLeuSerHisArgPheLysGlyProCysThrArg151015AspSerAsnCysAlaSerValCysGluThrGluArgPheSerGlyGly202530AsnCysHisGlyPheArgArgArgCysPheCysThrLysProCys354045(2) INFORMATION FOR SEQ ID NO:29:(i) SEQUENCE CHARACTERISTICS:(A) LENGTH: 48 amino acids(B) TYPE: amino acid(C) STRANDEDNESS: single(D) TOPOLOGY: linear(ii) MOLECULE TYPE: peptide(xi) SEQUENCE DESCRIPTION: SEQ ID NO:29:ArgValCysMetGlyLysSerAlaGlyPheLysGlyLeuCysMetArg151015AspGlnAsnCysAlaGlnValCysLeuGlnGluGlyTrpGlyGlyGly202530AsnCysAspGlyValMetArgGlnCysLysCysIleArgGlnCysTrp354045(2) INFORMATION FOR SEQ ID NO:30:(i) SEQUENCE CHARACTERISTICS:(A) LENGTH: 47 amino acids(B) TYPE: amino acid(C) STRANDEDNESS: single(D) TOPOLOGY: linear(ii) MOLECULE TYPE: peptide(xi) SEQUENCE DESCRIPTION: SEQ ID NO:30:LysIleCysArgArgArgSerAlaGlyPheLysGlyProCysMetSer151015AsnLysAsnCysAlaGlnValCysGlnGlnGluGlyTrpGlyGlyGly202530AsnCysAspGlyProPheArgArgCysLysCysIleArgGlnCys354045(2) INFORMATION FOR SEQ ID NO:31:(i) SEQUENCE CHARACTERISTICS:(A) LENGTH: 150 base pairs(B) TYPE: nucleic acid(C) STRANDEDNESS: both(D) TOPOLOGY: linear(ii) MOLECULE TYPE: cDNA(xi) SEQUENCE DESCRIPTION: SEQ ID NO:31:GAGCTTTGCGAGAAGGCTTCTAAGACTTGGTCTGGAAACTGCGGAAACACTGGACATTGC60GATAACCAATGCAAGTCTTGGGAGGGAGCTGCTCATGGAGCTTGCCATGTTAGAAACGGA120AAGCATATGTGCTTCTGCTACTTCAACTGC150(2) INFORMATION FOR SEQ ID NO:32:(i) SEQUENCE CHARACTERISTICS:(A) LENGTH: 60 base pairs(B) TYPE: nucleic acid(C) STRANDEDNESS: both(D) TOPOLOGY: linear(ii) MOLECULE TYPE: cDNA(xi) SEQUENCE DESCRIPTION: SEQ ID NO:32:GAGGTTTGCGAGAAGGCTTCTAAGACTTGGTCTGGAAACTGCGGAAACACTGGACATTGC60(2) INFORMATION FOR SEQ ID NO:33:(i) SEQUENCE CHARACTERISTICS:(A) LENGTH: 150 base pairs(B) TYPE: nucleic acid(C) STRANDEDNESS: both(D) TOPOLOGY: linear(ii) MOLECULE TYPE: cDNA(xi) SEQUENCE DESCRIPTION: SEQ ID NO:33:GAGCTTTGCGAGAAGGCTTCTAAGACTTGGTCTGGAAACTGCGGAAACACTAAGCATTGC60GATGATCAATGCAAGTCTTGGGAGGGAGCTGCTCATGGAGCTTGCCATGTTAGAAACGGA120AAGCATATGTGCTTCTGCTACTTCAACTGC150(2) INFORMATION FOR SEQ ID NO:34:(i) SEQUENCE CHARACTERISTICS:(A) LENGTH: 150 base pairs(B) TYPE: nucleic acid(C) STRANDEDNESS: both(D) TOPOLOGY: linear(ii) MOLECULE TYPE: cDNA(xi) SEQUENCE DESCRIPTION: SEQ ID NO:34:GAGCTTTGCGAGAAGGCTTCTAAGACTTGGTCTGGAAACTGCGGAAACACTAAGCATTGC60GATAACAAGTGCAAGTCTTGGGAGGGAGCTGCTCATGGAGCTTGCCATGTTAGATCTGGA120AAGCATATGTGCTTCTGCTACTTCAACTGC150(2) INFORMATION FOR SEQ ID NO:35:(i) SEQUENCE CHARACTERISTICS:(A) LENGTH: 141 base pairs(B) TYPE: nucleic acid(C) STRANDEDNESS: both(D) TOPOLOGY: linear(ii) MOLECULE TYPE: cDNA(xi) SEQUENCE DESCRIPTION: SEQ ID NO:35:AAGACTTGCGAGAACCTTTCTGGAACTTTCAAGGGACCATGCATTCCAGATGGAAACTGC60AACAAGCATTGCAAGAACAACGAGCATCTTCTTTCTGGAAGATGCAGAGATGATTTCNNN120TGCTGGTGCACTAGAAACTGC141(2) INFORMATION FOR SEQ ID NO:36:(i) SEQUENCE CHARACTERISTICS:(A) LENGTH: 147 base pairs(B) TYPE: nucleic acid(C) STRANDEDNESS: both(D) TOPOLOGY: linear(ii) MOLECULE TYPE: cDNA(xi) SEQUENCE DESCRIPTION: SEQ ID NO:36:AACCTTTGCGAGAGAGCTTCTCTTACTTGGACTGGAAACTGCGGAAACACTGGACATTGC60GATACTCAATGCAGAAACTGGGAGTCTGCTAAGCATGGAGCTTGCCATAAGAGAGGAAAC120TGGAAGTGCTTCTGCTACTTCGATTGC147(2) INFORMATION FOR SEQ ID NO:37:(i) SEQUENCE CHARACTERISTICS:(A) LENGTH: 43 amino acids(B) TYPE: amino acid(C) STRANDEDNESS: single(D) TOPOLOGY: linear(ii) MOLECULE TYPE: peptide(xi) SEQUENCE DESCRIPTION: SEQ ID NO:37:AlaLeuSerCysGlyThrValAsnSerAsnLeuAlaAlaCysIleGly151015TyrLeuThrGlnAsnAlaProLeuAlaArgGlyCysCysThrGlyVal202530ThrAsnLeuAsnAsnMetAlaXaaThrThrPro3540(2) INFORMATION FOR SEQ ID NO:38:(i) SEQUENCE CHARACTERISTICS:(A) LENGTH: 43 amino acids(B) TYPE: amino acid(C) STRANDEDNESS: single(D) TOPOLOGY: linear(ii) MOLECULE TYPE: peptide(xi) SEQUENCE DESCRIPTION: SEQ ID NO:38:AlaLeuSerCysGlyThrValAsnSerAsnLeuAlaAlaCysIleGly151015TyrLeuThrGlnAsnAlaProLeuAlaArgGlyCysCysThrGlyVal202530ThrAsnLeuAsnAsnMetAlaXaaThrThrPro3540(2) INFORMATION FOR SEQ ID NO:39:(i) SEQUENCE CHARACTERISTICS:(A) LENGTH: 42 amino acids(B) TYPE: amino acid(C) STRANDEDNESS: single(D) TOPOLOGY: linear(ii) MOLECULE TYPE: peptide(xi) SEQUENCE DESCRIPTION: SEQ ID NO:39:GlyIleThrCysGlyMetValSerSerLysLeuAlaProCysIleGly151015TyrLeuLysGlyGlyProLeuGlyGlyGlySerSerGlyGlyIleLys202530AlaLeuAsnAlaAlaAlaAlaThrThrPro3540(2) INFORMATION FOR SEQ ID NO:40:(i) SEQUENCE CHARACTERISTICS:(A) LENGTH: 43 amino acids(B) TYPE: amino acid(C) STRANDEDNESS: single(D) TOPOLOGY: linear(ii) MOLECULE TYPE: peptide(xi) SEQUENCE DESCRIPTION: SEQ ID NO:40:ValAspCysGlyGlnValAsnSerSerLeuAlaSerCysIleProPhe151015LeuThrGlyGlyValAlaSerProSerAlaSerCysCysAlaGlyVal202530GlnAsnLeuLysThrLeuAlaProThrSerAla3540(2) INFORMATION FOR SEQ ID NO:41:(i) SEQUENCE CHARACTERISTICS:(A) LENGTH: 45 amino acids(B) TYPE: amino acid(C) STRANDEDNESS: single(D) TOPOLOGY: linear(ii) MOLECULE TYPE: peptide(xi) SEQUENCE DESCRIPTION: SEQ ID NO:41:ValLeuThrCysGlyGlnValThrGlyAlaLeuAlaProCysLeuGly151015TyrLeuArgSerGlnValAsnValProValProLeuThrCysCysAsn202530ValValArgGlyLeuAsnAsnAlaAlaArgThrThrLeu354045(2) INFORMATION FOR SEQ ID NO:42:(i) SEQUENCE CHARACTERISTICS:(A) LENGTH: 44 amino acids(B) TYPE: amino acid(C) STRANDEDNESS: single(D) TOPOLOGY: linear(ii) MOLECULE TYPE: peptide(xi) SEQUENCE DESCRIPTION: SEQ ID NO:42:AlaLeuAsnCysGlyGlnValAspSerLysAsnLysProCysLeuThr151015TyrValGlnGlyGlyProGlyGlyProSerGlyLeuCysCysAsnGly202530ValArgAspLeuHisAsnGlnAlaGlnSerSerGly3540(2) INFORMATION FOR SEQ ID NO:43:(i) SEQUENCE CHARACTERISTICS:(A) LENGTH: 44 amino acids(B) TYPE: amino acid(C) STRANDEDNESS: single(D) TOPOLOGY: linear(ii) MOLECULE TYPE: peptide(xi) SEQUENCE DESCRIPTION: SEQ ID NO:43:AlaIleSerCysGlyGlnValAlaSerAlaIleAlaProCysIleSer151015TyrAlaArgGlyGlnGlySerGlyProSerAlaGlyCysCysSerGly202530ValArgSerLeuAsnAsnAlaAlaArgThrThrAla3540(2) INFORMATION FOR SEQ ID NO:44:(i) SEQUENCE CHARACTERISTICS:(A) LENGTH: 26 base pairs(B) TYPE: nucleic acid(C) STRANDEDNESS: both(D) TOPOLOGY: linear(ii) MOLECULE TYPE: cDNA(xi) SEQUENCE DESCRIPTION: SEQ ID NO:44:AAAGAATTCAARYTNTGYSARMGNCC26(2) INFORMATION FOR SEQ ID NO:45:(i) SEQUENCE CHARACTERISTICS:(A) LENGTH: 32 base pairs(B) TYPE: nucleic acid(C) STRANDEDNESS: both(D) TOPOLOGY: linear(ii) MOLECULE TYPE: cDNA(xi) SEQUENCE DESCRIPTION: SEQ ID NO:45:AAAGAATTCRTGNGCNGGRAANACRTARTTRC32(2) INFORMATION FOR SEQ ID NO:46:(i) SEQUENCE CHARACTERISTICS:(A) LENGTH: 29 base pairs(B) TYPE: nucleic acid(C) STRANDEDNESS: both(D) TOPOLOGY: linear(ii) MOLECULE TYPE: cDNA(xi) SEQUENCE DESCRIPTION: SEQ ID NO:46:AAAGAATTCGGNACNTGGWSNGGNGTNTG29(2) INFORMATION FOR SEQ ID NO:47:(i) SEQUENCE CHARACTERISTICS:(A) LENGTH: 9 base pairs(B) TYPE: nucleic acid(C) STRANDEDNESS: both(D) TOPOLOGY: linear(ii) MOLECULE TYPE: cDNA(xi) SEQUENCE DESCRIPTION: SEQ ID NO:47:AAAGAATTC9(2) INFORMATION FOR SEQ ID NO:48:(i) SEQUENCE CHARACTERISTICS:(A) LENGTH: 414 base pairs(B) TYPE: nucleic acid(C) STRANDEDNESS: both(D) TOPOLOGY: linear(ii) MOLECULE TYPE: cDNA(ix) FEATURE:(A) NAME/KEY: CDS(B) LOCATION: 16..255(xi) SEQUENCE DESCRIPTION: SEQ ID NO:48:GTTTTATTAGTGATCATGGCTAAGTTTGCGTCCATCATCGCACTTCTTTTT51MetAlaLysPheAlaSerIleIleAlaLeuLeuPhe1510GCTGCTCTTGTTCTTTTTGCTGCTTTCGAAGCACCAACAATGGTGGAA99AlaAlaLeuValLeuPheAlaAlaPheGluAlaProThrMetValGlu152025GCACAGAAGTTGTGCGAAAGGCCAAGTGGGACATGGTCAGGAGTCTGT147AlaGlnLysLeuCysGluArgProSerGlyThrTrpSerGlyValCys303540GGAAACAATAACGCATGCAAGAATCAGTGCATTAACCTTGAGAAAGCA195GlyAsnAsnAsnAlaCysLysAsnGlnCysIleAsnLeuGluLysAla45505560CGACATGGATCTTGCAACTATGTCTTCCCAGCTCACAAGTGTATCTGC243ArgHisGlySerCysAsnTyrValPheProAlaHisLysCysIleCys657075TACTTTCCTTGTTAATTTATCGCAAACTCTTTGGTGAATAGTTTTTATGTAA295TyrPheProCys80TTTACACAAAATAAGTCAGTGTCACTATCCATGAGTGATTTTAAGACATGTACCAGATAT355GTTATGTTGGTTCGGTTATACAAATAAAGTTTTATTCACCAAAAAAAAAAAAAAAAAAA414(2) INFORMATION FOR SEQ ID NO:49:(i) SEQUENCE CHARACTERISTICS:(A) LENGTH: 80 amino acids(B) TYPE: amino acid(D) TOPOLOGY: linear(ii) MOLECULE TYPE: protein(xi) SEQUENCE DESCRIPTION: SEQ ID NO:49:MetAlaLysPheAlaSerIleIleAlaLeuLeuPheAlaAlaLeuVal151015LeuPheAlaAlaPheGluAlaProThrMetValGluAlaGlnLysLeu202530CysGluArgProSerGlyThrTrpSerGlyValCysGlyAsnAsnAsn354045AlaCysLysAsnGlnCysIleAsnLeuGluLysAlaArgHisGlySer505560CysAsnTyrValPheProAlaHisLysCysIleCysTyrPheProCys65707580(2) INFORMATION FOR SEQ ID NO:50:(i) SEQUENCE CHARACTERISTICS:(A) LENGTH: 284 base pairs(B) TYPE: nucleic acid(C) STRANDEDNESS: both(D) TOPOLOGY: linear(ii) MOLECULE TYPE: cDNA(ix) FEATURE:(A) NAME/KEY: CDS(B) LOCATION: 1..108(xi) SEQUENCE DESCRIPTION: SEQ ID NO:50:GGAAATAATAACGCATGCAAGAATCAGTGCATTCGACTTGAGAAAGCA48GlyAsnAsnAsnAlaCysLysAsnGlnCysIleArgLeuGluLysAla151015CGACATGGGTCTTGCAACTATGTCTTCCCAGCTCACAAGTGTATCTGT96ArgHisGlySerCysAsnTyrValPheProAlaHisLysCysIleCys202530TATTTCCCTTGTTAATTCCATAAACTCTTCGGTGGTTAATAGTGTGCGCATA148TyrPheProCys35TTACATATAATTAATAAGTTTGTGTCACTATTTATTAGTGACTTTATGACATGTGCCAGG208TATGTTTATGTTGGGTTGGTTGTAATATAAAAAAGTTCACGGATAATAAGATGATAAGCT268CACGTCGCCAAAAAAA284(2) INFORMATION FOR SEQ ID NO:51:(i) SEQUENCE CHARACTERISTICS:(A) LENGTH: 36 amino acids(B) TYPE: amino acid(D) TOPOLOGY: linear(ii) MOLECULE TYPE: protein(xi) SEQUENCE DESCRIPTION: SEQ ID NO:51:GlyAsnAsnAsnAlaCysLysAsnGlnCysIleArgLeuGluLysAla151015ArgHisGlySerCysAsnTyrValPheProAlaHisLysCysIleCys202530TyrPheProCys35(2) INFORMATION FOR SEQ ID NO:52:(i) SEQUENCE CHARACTERISTICS:(A) LENGTH: 36 base pairs(B) TYPE: nucleic acid(C) STRANDEDNESS: both(D) TOPOLOGY: linear(ii) MOLECULE TYPE: cDNA(xi) SEQUENCE DESCRIPTION: SEQ ID NO:52:ATAGAATTCGACGTGAGCTTATCATCTTATTATCCG36(2) INFORMATION FOR SEQ ID NO:53:(i) SEQUENCE CHARACTERISTICS:(A) LENGTH: 21 base pairs(B) TYPE: nucleic acid(C) STRANDEDNESS: both(D) TOPOLOGY: linear(ii) MOLECULE TYPE: cDNA(xi) SEQUENCE DESCRIPTION: SEQ ID NO:53:CTTGGCCTTTGGCACAACTTC21(2) INFORMATION FOR SEQ ID NO:54:(i) SEQUENCE CHARACTERISTICS:(A) LENGTH: 21 base pairs(B) TYPE: nucleic acid(C) STRANDEDNESS: both(D) TOPOLOGY: linear(ii) MOLECULE TYPE: cDNA(xi) SEQUENCE DESCRIPTION: SEQ ID NO:54:GCTTTCTCAAGTCTAATGCAC21(2) INFORMATION FOR SEQ ID NO:55:(i) SEQUENCE CHARACTERISTICS:(A) LENGTH: 41 base pairs(B) TYPE: nucleic acid(C) STRANDEDNESS: both(D) TOPOLOGY: linear(ii) MOLECULE TYPE: cDNA(xi) SEQUENCE DESCRIPTION: SEQ ID NO:55:AACTCGAGCTGCAGTGTCGACCTATTAACAAGGAAAGTAGC41(2) INFORMATION FOR SEQ ID NO:56:(i) SEQUENCE CHARACTERISTICS:(A) LENGTH: 40 base pairs(B) TYPE: nucleic acid(C) STRANDEDNESS: both(D) TOPOLOGY: linear(ii) MOLECULE TYPE: cDNA(xi) SEQUENCE DESCRIPTION: SEQ ID NO:56:GGAATAGCCGATCGAGATCTAGGAAACAGCTATGACCATG40(2) INFORMATION FOR SEQ ID NO:57:(i) SEQUENCE CHARACTERISTICS:(A) LENGTH: 24 base pairs(B) TYPE: nucleic acid(C) STRANDEDNESS: both(D) TOPOLOGY: linear(ii) MOLECULE TYPE: cDNA(xi) SEQUENCE DESCRIPTION: SEQ ID NO:57:GGAATAGCCGATCGAGATCTAGGA24(2) INFORMATION FOR SEQ ID NO:58:(i) SEQUENCE CHARACTERISTICS:(A) LENGTH: 288 base pairs(B) TYPE: nucleic acid(C) STRANDEDNESS: both(D) TOPOLOGY: linear(ii) MOLECULE TYPE: cDNA(ix) FEATURE:(A) NAME/KEY: CDS(B) LOCATION: 43..282(xi) SEQUENCE DESCRIPTION: SEQ ID NO:58:CCCCGGGCTGCAGGAATTCGCGGCCGCGTTTTATTAGTGATCATGGCTAAGTTT54MetAlaLysPhe1GCGTCCATCATCGCACTTCTTTTTGCTGCTCTTGTTCTTTTTGCTGCT102AlaSerIleIleAlaLeuLeuPheAlaAlaLeuValLeuPheAlaAla5101520TTCGAAGCACCAACAATGGTGGAAGCACAGAAGTTGTGCCAAAGGCCA150PheGluAlaProThrMetValGluAlaGlnLysLeuCysGlnArgPro253035AGTGGGACATGGTCAGGAGTCTGTGGAAACAATAACGCATGCAAGAAT198SerGlyThrTrpSerGlyValCysGlyAsnAsnAsnAlaCysLysAsn404550CAGTGCATTAGACTTGAGAAAGCACGACATGGATCTTGCAACTATGTC246GlnCysIleArgLeuGluLysAlaArgHisGlySerCysAsnTyrVal556065TTCCCAGCTCACAAGTGTATCTGCTACTTTCCTTGTTAATAG288PheProAlaHisLysCysIleCysTyrPheProCys707580(2) INFORMATION FOR SEQ ID NO:59:(i) SEQUENCE CHARACTERISTICS:(A) LENGTH: 80 amino acids(B) TYPE: amino acid(D) TOPOLOGY: linear(ii) MOLECULE TYPE: protein(xi) SEQUENCE DESCRIPTION: SEQ ID NO:59:MetAlaLysPheAlaSerIleIleAlaLeuLeuPheAlaAlaLeuVal151015LeuPheAlaAlaPheGluAlaProThrMetValGluAlaGlnLysLeu202530CysGlnArgProSerGlyThrTrpSerGlyValCysGlyAsnAsnAsn354045AlaCysLysAsnGlnCysIleArgLeuGluLysAlaArgHisGlySer505560CysAsnTyrValPheProAlaHisLysCysIleCysTyrPheProCys65707580__________________________________________________________________________
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Biocidal proteins isolated from seeds have been characterised, in particular proteins isolated from members of the Brassicaceae, Compositae and Leguminosae families including Raphanus, Brassica, Sinapis, Arabidopsis, Dahlia, Cnicus, Lathyrus and Clitoria. The proteins show a wide range of antifungal activity and some are active against Gram-positive bacteria. All share a common amino acid sequence. DNA encoding the proteins has been isolated and incorporated into vectors. Plants transformed with this DNA may be produced. The proteins find commercial application as antifungal or antibacterial agents; transformed plants will show increased disease-resistance.
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FIELD OF THE INVENTION
This invention relates generally to instrumentalities which can fractionate constituent components of substances such as blood, platelets or plasma using cryoprecipitation and a method therefore.
More specifically, the present invention relates to an improved method and apparatus for preparing fibrinogen concentrate. This invention also relates to the preparation of fibrinogen concentrate product which has clinical application as fibrin glue.
BACKGROUND OF THE INVENTION
Sutures have been used as a conventional surgical means for uniting tissues and surgical margins, as hemostatic aids, and for blocking or ligation. However, sutures suffer from many drawbacks. For example, sutures may be incompatible with the tissue, causing fistula or granuloma, sutures may cut through parenchymal and inflammatory tissues, absorbable suture material may disintegrate prematurely and produce dehiscence of the wound, and closely spaced sutures may cause tissue ischemia resulting in necrosis of the wound margins. Suturing is also time-consuming.
In order to overcome the above-mentioned shortcomings of sutures, various attempts at developing suitable substitutes have been made. One goal has been the development of a tissue glue which ensures union of the tissue without causing any damage thereto.
Cyanoacrylate-based substances have been commonly used as a fibrin glue. However, these substances are toxic to the tissue and cannot be absorbed (J. A. Collins, et al., "Cyanoacrylate Adhesives as Topical Hemostatic Aids", Surgery 65, 260-263, 1969). Thus, this type of tissue glue was found to result in the growth of granulated tissue in response to the foreign substance, rejection of the cyanoacrylate, fistula formation and local suppuration.
As early as 1909, it was realized that "fibrin powder" could be utilized to achieve blood clotting and wound healing (H. Matras, "Fibrin Seal: The State of the Art", J. Oral Maxillofac Surg 43, 605-611, 1985). Others later used fibrin tampons and thin fibrin plaques to control bleeding in parenchymal organs (see, e.g., E. G. Grey, "Fibrin as a Hemostatic in Cerebral Surgery", Surg Gynecol Obstet 21, 452-454, 1915). Another attempt involved the uniting of rabbit nerve with chicken plasma and chicken embryo extract (J. Z. Young, et al., "Fibrin Suture of Peripheral Nerves", Lancet 239, 126-128, 1940). Other work involved autologous and homologous rabbit plasma (I. M. Tarlov, et al., "Plasma Clot and Silk Suture of Nerves", Surg Gynecol Obstet 76, 366-369, 1943). In 1944 the first use was made of a combination of fibrinogen and thrombin for anchoring skin grafts, but the results failed to demonstrate a good adhesive effect (see E. P. Cronkite, et al., "Use of Thrombin and Fibrinogen in Skin Grafting", JAMA 124, 976-980, 1944, and R. T. Tedrick, et al., "Fibrin Fixation of Skin Transplants", Surgery 15, 90-93, 1944).
Due to advances in basic research, it is now possible to prepare highly concentrated plasma products and isolate some coagulation factors. Rabbit cryoprecipitate solution and an equal amount of thrombin solution have been used together with fascicular adaptation to reunite a rabbit nerve stump. This procedure was later applied on a human. In the human application, autologous plasma cryoprecipitate solution was first used, but since the clottable substances were found to be insufficient, homologous cryoprecipitate solution from pooled single-donor plasmas was subsequently used to obtain higher concentration for better tensile strength. Later, fibrin glue or sealant became more widely known.
Fibrin glue or sealant was successfully adapted for use in microvascular surgery. Others later combined suturing and sealing when applying the procedure in neurosurgery for extra-intracranial anastamosis, and on the dura repair, satisfactory results were obtained using fibrin sealant.
Fibrin sealant has three components: fibrinogen concentrate, calcium chloride and thrombin. These components mimic the final common pathway of the clotting cascade, i.e. the conversion of fibrinogen to fibrin (see, e.g., R. W. Colman, et al., Hemostasis & Thrombosis (2d ed.), 1987). In vitro, fibrinogen induces adhesion, spreading, and microfilament organization of human endothelial cells. Fibrinogen also has been found to stimulate fibroblast growth. The surface protein of fibroblasts has been found to contain fibronection.
Various publications discuss the clinical applications of fibrin sealant, but only a few mention the binding or tensile strength of the fibrin sealant (see, e.g. Jorgensen, et al., "Mechanical Strength in Rat Skin Incisional Wounds Treated with Fibrin Sealant", J. Surg Research 42, 237-241, 1987 and Bense, et al., "Effect of Fibrin Sealant on the Tensile Strength of Rat Visceral Pleura", Scand J. Thor Cardiovasc Surg 21, 179-180, 1987). Heretofore, there has also been a lack of data concerning the required concentration of fibrinogen for tissue binding and the necessary tensile strength at this fibrinogen concentration for use in various tissues.
In preparing fibrin sealant, thrombin of bovine origin is diluted with calcium chloride, with concentrations dependent on the tissue to be applied and the time of clotting. Equal amounts of fibrinogen concentrate and thrombin diluted in calcium chloride are used for clinical application. When the two components are mixed, thrombin converts fibrinogen to fibrin so that clotting is initiated and the mixture solidified. Meanwhile, in the presence of calcium ions, thrombin activates factor XIII to factor XIIIa. Activated factor XIIIa together with thrombin catalyzes the crosslinkage of fibrin and increases the strength of the clot. During would healing the clot material undergoes gradual lysis and is completely absorbed.
A major application of fibrin sealant is in surgery as a hemostasis aid, especially in thoracic-cardiovascular surgery, and in traumatic surgery (liver or spleen injury). In other areas of medicine, fibrin sealant is used as a tool to facilitate hemostasis, permit tissue fixation, enhance implant material growth, stimulate fibroblast growth and as an embolization material. Applications include orthopedic surgery, neural surgery, periodontal surgery, cerebral surgery, sinus or fistula obturation in proctologic and general surgery, chest surgery and genitourinary surgery, skin grafting in burn patients, punch hair grafting in plastic surgery, closure of corneal incisions in eye surgery, repair of lymph leak in general surgery and in myringoplasty in ear surgery.
Although there are great advantages to using fibrin sealant in clinical medicine, it is prohibited to use the commercially available product from pooled human plasma in the United States because of potential transmission of hepatitis B, acquired immunodeficiency syndrome (AIDS), and other transfusion transmittable diseases. The Food and Drug Administration (FDA) regulations have required that all plasma protein fractions shall receive heat treatment for not less than 10 or more than 11 hours at an attained temperature of 60°+/-0.5° C. to inactivate infectious agents.
Commercially available fibrinogen is prepared from the plasma pooling of a large number of donors, which has high potential for disease transmission. In addition, fibrinogen will not tolerate the ten hours of heating to 60° C. used to inactivate the hepatitis virus in other blood fractions. Studies have indicated that this product was a source of hepatitis transmission (7.8% of post-transfusion hepatitis rate). Under these circumstances, the FDA revoked all licenses for the manufacture of human fibrinogen since Jun. 30, 1978.
In Europe, fibrinogen product is commercially available as a fibrinogen concentrate kit ("Tisseel", Immonu AG, Vienna, Austria) prepared from pooled fresh frozen plasma. The tensile strength for Tisseel is 900/g/cm 2 . Since this commerical fibrinogen concentrate is not available in the United States because it is currently not licensed by the FDA, alternative methods such as chemical precipitation and cryoprecipitation have been used to prepare fibrinogen concentrate.
Fibrinogen is one of the three main protein constituents of plasma. The major constituent, albumin (ALB), occurs in a concentration of approximately four percent. The plasma globulins are present in a concentration of about 2.5 percent and are particularly associated with the processes of immunity. Fibrinogen occurs in much smaller amounts, with its concentration in human plasma being about 0.4 percent.
Several authors have discussed fibrinogen/fibrinogen interaction and fibrinogen interaction with other proteins. Aggregation of fibrinogen at pH 5.7 and low ionic strength (<0.3) has been found. A disulfide bond between fibrinogen molecules in cold-insoluble fibrinogen fraction has been demonstrated. It has been thought that the cold-insoluble precipitate that formed from normal plasma was a reaction between cold-insoluble globulin (CIg), fibrinogen and fibrin.
The plasma proteins can be separately isolated by: 1) organic solvents such as methanol or ethanol at low temperature using Cohn's fractionation, 2) cryoprecipitation, 3) chemical precipitation of plasma with salts such as ammonium sulfate, potassium phosphate, and sodium citrate, and 4) other methods. The solubility of the plasma proteins in these substances decreases in the order of albumin, globulin, and fibrinogen. The latter precipitates first and albumin last upon the addition of increasing amount of the precipitating agent.
1. Ethanol Fractionation (Cohn's fractionation)
In this process, 1,000 to 1,500 liters of 4,000-6,000 human source plasma are pooled and treated sequentially in the cold with various concentrations of ethanol and buffers to precipitate fractions containing different plasma proteins. Fibrinogen is the first material precipitated and harvested at-5° C. with 25% ethanol at a pH of 6.9. Variables determining the precipitation of proteins are ethanol concentration, pH, temperature, ionic strength and protein concentration.
2. Cryoprecipitation
The standard cryoprecipitation method has been primarily used to prepare antihemophilic factor (Factor VIII). Cryoprecipitate also has been known as a source of fibrinogen. The cryoprecipitate method can be also used to prepare fibrinogen concentrate. It is known that some factors might affect the yield of Factor VIII, such as ABO blood grouping, freezing and thawing conditions (see Kasper, et al., "Determinants of Factor VIII Recovery in Cryoprecipitate", Transfusion 15, 312-322, 1975, and Rock, et al., "Variations in Cryoprecipitate Production", Transfusion 17, 50-53, 1977). With respect to Factor VIII preparation, others have studied freezing and thawing conditions (see Brown, et al., "Antihaemophilic Globulin: Preparation by an Improved Cryoprecipitation Method and Clinical Use", Br Med J 2, 79-85, 1967). However, all the factors for cryoprecipitation are not known.
It has been observed that when frozen plasma is thawed in the cold at 4° C., most of the Factor VIII remains in the cold-insoluble precipitate. This precipitate also contains variable amounts of fibrinogen ranging from 100 to 300 mg/single donor unit of cryoprecipitate. It has become routine to prepare anti-hemophilic factor (Factor VIII) and fibrinogen using the cryoprecipitation method in the blood bank using a closed system of plastic bags to maintain the sterility of the product from collection of the whole blood from the donor. See, e.g.: Rousou, et al., "Fibrin Glue: An Effective Hemostatic Agent for Nonsuturable Intraoperative Bleeding", Ann Thorac Surg. 38, 409-410, 1984; Lupinetti, et al., "Cryoprecipitate-Topical Thrombin Glue", J. Thorac Cardiovasc Surg 90, 502-505, 1985; Ness, et al., "Cryoprecipitate as a Reliable Source of Fibrinogen Replacement", JAMA 241, 1690-1691, 1979; Brown, et al., "Antihaemophilic Globulin: Preparation by an Improved Cryoprecipitation Method and Clinical Use", Br Med J 2, 79-85, 1967; Ness, et al., "Fibrinogen in Cryoprecipitate and Its Relationship to Factor VIII (AHF) Levels", Transfusion 20, 93-96, 1980; Carlebjork, et al., "Freezing of Plasma and Recovery of Factor VIII", Transfusion 26, 159-162; Masure, "Human Factor VIII Prepared by Cryoprecipitation", Vox Sang 16, 1-9, 1969, and; Williams, et al., "A New and Improved Method for the Preparation of Autologous Fibrin Glue and Further Applications.", Exhibit Presentation, 71st Annual Clinical Congress of the American College of Surgeons, 1985.
3. Chemical Precipitation
Human fibrinogen can be precipitated from human plasma by ammonium sulfate, polyethylene glycol, plyvinyl-pyrrolidone, and barium/magnesium sulfate. Entering the closed blood bag system for the addition of chemicals opens the system to the potential for bacterial contamination. Small amounts of fibrinogen concentrate solution (0.5-1.9 ml) can be prepared using these methods, but the side effects and safety due to the chemical substances as well as bacterial contamination opportunities are of great concern.
4. Other Methods
Sporadic reports have mentioned the use of the following methods to prepare purified fibrinogen: chromatography, polyelectrolyte fraction technology, recombinant DNA technology and ion exchange chromatography. See C. Th. Smit Sibinga, et al., "Plasma Fractionation and Blood Transfusion", Martinus Nijhoff Publishers, Northland, 1985.
As mentioned above, several methods have been developed for the isolation of purified fibrinogen. However, these have numerous drawbacks that make them inapplicable in clinical use, such as disease transmission (heat treatment intolerable), bacterial contamination (using open system), chemical toxicity and safety, inadequate product volume, time consumption, and cost. Disease transmission is one of the main concerns and the reason the FDA has not approved the commercially prepared fibrinogen concentrate (Tisseel) for use in this country.
Among the methods described previously, the cryoprecipitation method is the simplest and most economic way to make concentrated fibrinogen. Most U.S. blood banks use cryoprecipitate as the fibrinogen (FBG) source for fibrin glue which contains less FBG (260-2,500 mg/dl) compared to Tisseel (7,000-10,000 mg/dl).
Fibrinogen concentrate can be prepared from random single-donor fresh frozen plasma or autologous plasma in sufficient quantity to meet some surgical demand. According to the Standards of the American Association of Blood Banks, fibrinogen concentrate can be currently stored for up to 5 years at -80° C. or at least 5 days at 4° C. until it is needed. Cryoprecipitate contains Factor VIII and fibrinogen and is used to supply fibrinogen in patients with hypofibrinogemia and also as an alternative source of fibrinogen concentrate for fibrin sealant in the United States.
However, traditional cryoprecipitation suffers from problems including the recovery of only small amounts of fibrinogen having low tensile strength when using single-donor cryoprecipitate to prepare fibrin sealant. Further, the fibrinogen concentrates prepared by traditional cryoprecipitation have a concentration range of 260-2,500 mg/dl. This is not an adequate concentration for applying this product as a tissue sealant over highly vascular areas. High fibrinolytic activity over that area breaks down the fibrin clot very quickly. These concentrates have a tensile strength of around 120 gm/cm 2 which is usually not sufficient for surgical applications.
The following patents reflect the state of the art of which applicant is aware insofar as these patents appear germane to the patent process. However, it is respectfully stipulated that none of these patents teach singly nor render obvious when considered in any conceivable combination the nexus of the instant invention as set forth hereinafter.
______________________________________INVENTOR U.S. PAT. NO. ISSUE DATE______________________________________Anderson, et al. 3,920,625 1975Garber, et al. 4,025,618 1977Seufert 4,141,887 1979Shanbrom 4,188,318 1980Rose, et al. 4,627,879 1986______________________________________
None of the prior art resolves the longstanding and vexing problem that comes from the inefficient extraction of fibrinogen. Optimization of fibrin or fibrinogen extraction particularly as outlined hereinafter, allows for the autologous provision of fibrin from an individual immediately prior to surgery such that the fibrin is extracted from the patient and the residual blood components are restored to the individual with no discernable adverse effects that would mitigate against a commencement of the operation.
SUMMARY OF THE INVENTION
The instant invention is distinguished over the known prior art in a multiplicity of ways. For one thing, the yields associated with the apparatus and methodology according to the instant invention provide enhanced quantities and higher quality of fibrin which allows certain prior art difficulties to have been obviated.
In its elemental form, a reservoir forms an interior of the device which receives heat transfer fluid therewithin which is isolated from the material to be fractionated by cryoprecipitation such as blood or plasma not only by a pouch within which the blood or plasma resides, but also by a membrane which is interposed between the blood pouch and which depends into the reservoir. Thus, should the pouch have a hairline fracture, upon thawing the blood, and if the blood contaminates areas outside the pouch, the contamination will be localized to the interior of the membrane which is configured for expeditious dislodgement from its situ overlying and depending within the reservoir. Replacement with a fresh membrane free from contamination is a minor procedure. Thus, one attribute of the invention is the means by which it takes into account the likelihood of a pouch having a fracture.
The reservoir includes means for storing preferably two heat transfer fluids and maintaining those fluids at two ideal temperatures, typically one near -30° C., and the other at 3° C. Upon deployment of the pouch of the material to be fractionated within the membrane, the membrane depends within the reservoir and a first, freezing fluid is directed at the membrane in two distinct manners. A first manner involves raising the liquid level of the heat transfer fluid up around the membrane and the fractionable material within the pouch so that hydrostatic pressure exists on the membrane causing it to collapse so that it conforms to the exterior contour of the pouch. The absence of an air gap between the membrane and the pouch assures that the thermal profile in heat exchange is optimal.
A second manner in which the first freezing fluid thermally contacts the pouch takes the form of a pulsation in which exterior surfaces of the membrane pocket receive the freezing fluid from a nozzle such that the freezing fluid impinges on the membrane pocket and indirectly against the pouch, adding a mixing action from the deceleration of the freezing fluid. An ancillary benefit attends this pulsation. As the blood, platelet or plasma within the pouch starts to freeze, the pulsation maximizes the effect of areas of accelerated freezing and crystallization.
After the freezing step, a second heat transfer fluid is caused to coact against the membrane and pouch, this time, however, heating the contents within the pouch from its cold temperature to a thawed temperature, preferably around +3° C. As before, the liquid level of the heat transfer fluid is raised up around the membrane and contacts the fractionable material within the pouch through the membrane so that hydrostatic pressure exists on the membrane causing it to collapse and conform to the exterior of the pouch. In addition, the nozzles are again caused to coact against the membrane and pouch which in this case allows the kinetic energy to be dissipated by contact directly against the membrane and indirectly against the pouch adding a mixing action from the deceleration of the thawing fluid thereagainst. As before, this type of pulsation serves to knead the contents within the pouch, forcing circulation therewithin and therefore accelerating the thawing process. Ultimately, the center of the thermolabile, transfusible fluid within the pouch will have been thawed prior to the outer periphery especially because there has been pulsing on two major faces of the pouch.
In a preferred form of the invention, two such nozzles are provided one on each side of the pouch and are synchronized to contact the pouch simultaneously, so that equal and opposite forces are experienced on both sides of the pouch, providing forced circulation of the fractionable material as it changes phase. This synchronous pulsing also keeps the pouch stable and free from oscillation.
Another benefit of the forced circulation of both the freezing and thawing fluid within the pouch is that it occurs in a substantially toroidal manner so that there is internal circulation which is simulative of the kneading. By attacking the geometrical center of the bag through the pulsing liquid, the fractionating process will have been accelerated.
Other types of kneading could occur by either different orientation of nozzles in their contacting relationship with the pouch or by other means by which the pouch is manipulated. For example, variously shaped platens can move in jaw-like concert to intermittently squeeze the bag. Other forms of vibratory excitation could also provide the similar benefit.
As the result of the above-described structure and methodology, fluids such as blood, platelets or plasma or even pharmaceutical products can be fractionated and then centrifuged for separation by decanting. Typically less than 6 minutes is required for 250 ml. of plasma to be taken through one change of phase.
OBJECTS OF THE INVENTION
Accordingly, it is a primary object of the present invention to provide a novel and useful device and method for rapidly freezing and thawing fractionable material such as blood, platelets or plasma followed by centrifuging and then decanting for subsequent use, such as in an operation.
A further object of the present invention is to provide a device as characterized above which minimizes the likelihood of contamination should a pouch containing the fractionable material have a fracture therewithin which would be most easily discernible only upon thawing of a once frozen pouch. In the event that such a fracture occurs, a primary object of the present invention is to reinitialize the apparatus of the present invention expeditiously and with minimal downtime caused by the contamination.
A further object of the present invention is to provide a device as characterized above which minimizes the existence of unwanted thermal gradients which may delay the formation of the product when fractionating.
A further object of the present invention is to provide a device as characterized above which benefits from a pulsation coacting against the pouch containing the fractionating material to provide improved circulation thereby accelerating the separation process.
A further object of the present invention is to provide a device as characterized above which does not require the attention of personnel and therefore allows the separating process to be performed with substantially minimal attention.
A further object of the present invention is to provide a device as characterized above which is automated and regulated such that the fractionating process, while unattended provides uniform results.
A further object of the present invention is to provide a device as characterized above which lends itself to mass production techniques, is safe and easy to use, and is extremely durable in construction.
A further object of the present invention is to provide a device as characterized above which substantially shortens the amount of time required for phase change of fractionable fluids contained in pouches especially in emergency situations or involving the requirement of blood for lifesaving situations.
A further object of the present invention is to achieve a method of isolating fibrinogen which can be carried out in blood banks, which follow the Standards of American Association of Blood Banks for preparation conditions in a closed bag system, and which also produces a high yield of fibrinogen capable of producing a clot of high tensile strength.
An additional object is to produce a fibrinogen concentrate for use in fibrin glue and the like, which has increased fibrinogen concentration and increased tensile strength.
Another object is to obtain a fibrinogen concentrate which overcomes the disadvantages of the known prior art.
In accordance with the present invention, fibrinogen concentrate is prepared by a cryoprecipitation method which employs at least two freeze-thaw cycles. A cryoprecipitation method according to the present invention concentrates fibrinogen by the steps of: subjecting fractional material to a freeze-thaw cycle by freezing the fractionable material, and then thawing the frozen fractionable material, subjecting the fractionable material to a second freeze-thaw cycle by freezing and then thawing the frozen plasma and then centrifuging the fractionable material to concentrate cryoprecipitated fibrinogen; and separating the fibrinogen from the remainder of the fractionable material. The fractionable material could be whole blood, plasma or platelets.
A fibrinogen product prepared in accordance with this invention advantageously has a higher concentration and increased volume of fibrinogen (about 4,000-6,000 mg/dl FBG in 3-5 ml) than achieved by conventional cryoprecipitation methods. According to the present cryoprecipitation process, a fibrinogen product can be readily prepared having from about 2-6 times more fibrinogen than the standard cryoprecipitation method.
Viewed from one vantage point, it is an object of the present invention to provide a device for transferring heat with respect to a fractionable product which is stored in a flexible pouch to cryofractionate the product, comprising a housing, suspension means in said housing for receiving the pouch and holding the pouch such that major surface areas of the pouch are accessible, heat transfer means oriented to address the major surfaces of the pouch including at least one heat transfer fluid such that upon contact with said one heat transfer fluid, the fractionable product within the pouch approaches the temperature of the heat transfer fluid, and means for circulating the product in the pouch to minimize thermal gradients within the pouch during heat transfer.
Viewed from a second vantage point, it is an object of the present invention to provide a device for cyclically transferring heat between an article at one temperature and a fluid maintained at another temperature and back again which includes a membrane interposed between the fluid and the article, the membrane isolating the fluid from the article such that the fluid contact with the article is indirect and temperature change passes through the membrane, and means for pulsing the fluid is provided oriented to impinge the article through the membrane, whereby the fluid pulsing means induces thermal circulation into the article for better heat transfer.
Viewed from a third vantage point, it is an object of the present invention to provide a device for rapidly and cyclically freezing and thawing fractionable materials such as blood or plasma for use in an operation as needed which comprises a reservoir adapted to receive heat transfer fluid therewithin and isolated from the fractionable material by a membrane, the membrane interposed between the fractionable material and the reservoir to preclude contact with the heat transfer fluid, and pulsing means to deliver the heat transfer fluid against the fractionable material by pulsing passing through the membrane, the pulsing means and the heat transfer fluid collectively defining a massaging means against the fractionable material to promulgate rapid phase change of the fractionable material by circulating the fractionable material for better heat transfer.
Viewed from a fourth vantage point, it is an object of the present invention to provide a method for rapidly changing phase of fractionable fluid from a liquid state to a frozen state and back again, the steps including pulsing thermal fluid against a pouch containing the fractionable fluid to change the temperature of the fractionable fluid and circulate the fractionable fluid within the pouch as it changes phase and maintaining the thermal fluid at a temperature different from the temperature of the fractionable fluid to allow the fractionable fluid to approach the thermal fluid.
These and other objects will be made manifest when considering the following detailed specification when taken in conjunction with the appended drawing figures.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 is a perspctive view, showing exploded parts of the apparatus according to the present invention.
FIG. 1A is directed to a detail of FIG. 4 along lines 1A--1A in section.
FIG. 2 is a transverse longitudinal sectional view of the apparatus according to the present invention showing a loading or removing cycle.
FIG. 3 is a view similar to FIG. 2 schematically showing the device in operation.
FIG. 4 is a detail of a portion of the FIG. 2 structure.
FIG. 5 is a detail of a portion of the FIG. 3 structure.
FIGS. 6A, 6B, 6C and 6D explain the phenomena of the pulsation and internal circulation according to the instant invention.
FIG. 7 shows a fluid flow schematic.
DESCRIPTION OF PREFERRED EMBODIMENTS
Referring to the drawings now, wherein like reference numerals refer to like parts throughout the various drawing figures, reference numeral 10 is directed to the device for fractionating constituent components from a material using cryoprecipitation according to the present invention.
In essence, the device 10 is formed from a housing 30 having a control panel 12 on one exposed surface thereof and an opening 40a on a top wall 16 and within which a flexible membrane 50 is provided. The membrane 50 occludes an interior 70 of the housing 30 from an exterior. The membrane 50 is removably inserted to depend within the interior 70 so that a pouch P can be removably inserted into the membrane 50 and therefore into the interior 70. The pouch P is then exposed to heat exchange fluid F and fluid pulsation through the membrane 50.
More specifically, the housing 30 from a side view is a substantially rectangular construct having one corner of the rectangular construct truncated or mitered providing an inclined surface upon which a control panel 12 is provided. With reference to FIGS. 1 through 3, the housing 30 includes a bottom wall 2 supported on a surface by means of feet 4 disposed on a bottom surface of wall 2. The bottom wall 2 is preferably substantially rectangular in configuration and planar and has two parallel side edges from which extend two vertical side walls 6 one each on opposed side edge extremities. In addition, a front wall 8 extends up from a front edge of the bottom wall 2. A rear wall 14 extends up from a rear edge of the bottom wall 2 which is parallel to the front wall edge. A top wall 16 is provided which joins the side walls 6 and rear wall 14. Had the front wall 8 been similarly joined with the top wall 16, an orthorhombic rectangular construct would have been provided. Instead, an inclined control panel wall 12 extends from a top edge of the front wall 8 to a forward edge of the top wall 16. Thus, to accommodate the control panel 12, the side walls 6 are truncated at corners adjacent the control panel 12 to complete the housing 30.
The control panel 12 supports a temperature indicator 18 used to indicate the temperature of the heat exchange fluid F in a manner to be described. In addition, a temperature control 20 allows alteration of the temperature of the heat exchange fluid F as reflected by the temperature indicator 18. The control panel 12 also supports a timer 22 indicating the amount of time that the heat exchange fluid F will circulate (in a manner to be described) and a timer control 24 is provided on the panel 12 to alter the amount of time that will define one cycle for the heat exchange processes. If desired, a commercially available digital touch pad could be used for not only the timer and its control but also for the temperature and its control. An on/off switch 26 is operatively coupled to provide power to the device 10 and is also supported on the control panel 12. An indicator 28 is also provided on the control panel 12 and indicates whether or not the device 10 is in the midst of a cycle for fractionating material by cryprecipitation. The indicator 28 may be in the form of a pilot light and/or may include an audible alarm.
As mentioned briefly, the housing 30 includes an opening 40a through which a membrane 50 is provided which occludes the interior 70 defined by the housing walls 2, 8, 12, 16 discussed hereinabove. In essence, the membrane 50 is sufficiently flexible to receive a fractionable thermolabile product such as a pouch P of blood, plasma or platelets therewithin so that it can be cryoprecipitated expeditiously. The membrane 50 is formed from a front panel 32, a rear panel 34, two side panels 36 and a bottom panel 38. The two side panels 36 and bottom panel 38 connect the front and rear panels 32, 34 together respectively at side and bottom edges of the front and rear panels 32, 34 so that an enclosure is provided having an upper opening 40b which is substantially complemental to the opening 40a of the housing 30.
In addition, the membrane 50 preferably includes a skirt 42 of material depending from the bottom panel 38. The skirt 42 has a sleeve 44 at a lowermost extremity of substantially cylindrical configuration and substantially coextensive with the width of both the front and rear panels 32, 34. A hold-down rod 46 is inserted within the sleeve 44 and is used as anchor to offset the effects of buoyancy associated with the heat transfer fluid F to be described hereinafter. The hold-down rod 46 may have a magnetic component which cooperates with another magnet 46a, located on a top surface of a shelf 82 to offset buoyancy. Another version may embody the rod 46 as substantially U-shaped with legs extending upwardly, parallel to the side panels 36.
The topmost portion of the membrane 50 adjacent the opening 40b includes a peripheral flange 48 defining a turnout of the membrane 50. This flange 48 supports a snap-on coupling 60 having an oval configuration which is somewhat complemental to the opening 40b of the flexible membrane 50. The coupling 60 also circumscribes the opening 40a of the housing 30. Coupling 60 can suspend beneath flange 48 or be integrally formed therewith or be bonded thereto. The snap-on coupling 60 has an outer profile of substantially circular configuration, shown best in FIG. 1A, with an opening 62 to define an interior therewithin defining a retention mechanism which adheres to a ridge 64 on the top wall 16 of housing 30.
More specifically, the interior of the coupling 60 is formed from a pair of spaced guide channels 58 which diverge outwardly and which lead to retention channels 56 which diverge inwardly. Two parallel, facing support channels 54 communicate with the retention channels 56 and terminate in an abutment channel 52 which rests on a top surface of ridge 64 that circumscribes the outer periphery of the housing opening 40a. Thus, whereas the coupling 60 defines a recess, the ridge 64 defines a projection with a contour complemental to the snap-on channel 60 for frictional retention therebetween.
The construction thus far enumerated with respect to the snap-on channel 60 and ridge 64 lend themselves to the expeditious removal of the flexible membrane 50 should it become contaminated when a pouch of fractionable thermolabile fluid (such as blood) becomes fractured before or during the cryoprecipitating process and contaminates the interior of the flexible membrane 50. Thus, the ridge 64 defines a male projection complemental to the recess integrally formed on the snap-on coupling 60 and allows rapid replacement.
Attention is now directed to FIGS. 2 and 3 with respect to the operation mechanism by which a pouch P of fractionable material can be inserted into the membrane 50 located within the interior 70 of the device 10 and rapidly cycled between optimal temperatures for cryoprecipitation and then for other subsequent purposes. It is to be noted that the membrane 50 is characterized as one which is extremely flexible and yields to hydrostatic pressure induced by the presence of the heat transfer fluid F on an outside surface thereof so that the pouch P (when placed within the interior of the membrane 50) will have the membrane 50 collapse around the pouch P and conform to the configuration of the pouch P with no air gaps for optimal heat transfer. One suitable material for this membrane 50 is polyetherurethane, although other thin hydrostatically flexible material such as Teflon® would be serviceable.
Comparison between FIGS. 2 and 3 shows the membrane 50 collapsing around the pouch P and conforming to the pouch P in the presence of hydrostatic pressure. More specifically, a sump 80 is provided at a lowermost portion of the device 10 and collects the heat transfer fluid F therewith. Typically, a silicone heat transfer fluid F would be adequate to operate within the contemplated temperature range of typically -30° C. to +37° C. The sump 80 holds the heat transfer fluid F therewithin. An immersion heater 90 elevates the heat transfer fluid F to a substantially constant temperature. Typically the target temperature of the pouch P when heated is 4° C. As mentioned earlier, the temperature of the fluid F can be controlled on the control panel 12 by an appropriate mechanism.
A cooling element 95 is also located in the sump 80 and is operatively coupled to a source of power and the temperature/timer controls 18, 20, 22, 24. This cooling element 95 can maintain the heat transfer fluid F at and below the freezing point of the fractionable material. For blood products, -30° C. is adequate.
A pump 100 is placed above the sump 80 and supported on an intermediate platform 82 supported in the housing 30. The pump 100 includes an inlet 84 which extends into the heat transfer fluid F contained in the sump 80. The inlet 84 delivers the heat transfer fluid F to the pump 100 so that it can be administered on an exterior surface of the membrane 50 (i.e. on a surface of the membrane 50 opposite from that surface of the membrane 50 contacting the pouch P) following the preferred manner. The pump 100 administers heat transfer fluid F to a geometrical center of the pouch P ("through" the membrane 50) by means of a nozzle jet 130. By geometrical center it is meant the surfaces of the pouch P remote from side edges thereof which define a periphery. By the jet 130 impinging on the pouch P along major surfaces thereof and preferably at the geometrical center of the pouch P, the core of the fractionable fluid contained within the pouch P will be rapidly thawed or cooled and effectively circulated in the following manner.
It is preferred that the nozzle jet 130 pulse heat transfer fluid F at the geometrical center of the membrane 50 and pouch P. In order to achieve same, the nozzle 130 has interposed between its outlet and the pump 100 a solenoid valve 120 and a surge chamber 110. The surge chamber 110 is closer to the pump 100 than the solenoid valve 120. In use and operation, as the pump 100 provides continuous fluidic pressure by delivering heat transfer fluid F from the sump 80 through the pump 100 and to a surge chamber 110. Cyclic opening and closing of the solenoid valve 120 provides pulses from the nozzle jet 130 hitting the geometrical center of the pouch P.
The surge chamber 110 is configured in such a manner that increasing fluidic pressure exerted by the pump 100 will be stored as potential energy in the surge chamber 110 whereupon, by opening of the solenoid valve 120, the potential energy within the surge chamber 110 converts immediately to kinetic energy and vents outwardly through the nozzle jet 130. The nozzle jet 130 may have appropriate nozzle geometry such as converging, diverging throat areas to achieve acceleration at its outlet and an appropriate "needle" or "spray" pattern.
In a preferred form of the invention, a pair of nozzles 130, one each disposed on opposite major surfaces of the membrane 50 and therefore the pouch P are provided. One way to achieve two nozzles 130 operating in concert would be to have a solitary pump 100 delivering heat transfer fluid F to both of the nozzles 130 with a manifold delivering to the nozzle jets 130 simultaneously. It is preferred that each nozzle 130 administer a pulse of heat transfer fluid F to the geometrical center of the membrane 50 at the same time, to preclude oscillation or rocking of the membrane 50 back and forth. However, a branch manifold such as just described may provide an unwanted reduction in pressure of the nozzle 130 output. In such an event, a pair of pumps 100 (shown in the drawing FIGS. 2, 3 and 7) along with a pair of surge chambers 110 and solenoid valves 120 are provided, with the firing of the solenoid valves 120 synchronized with electrical means (not shown) to achieve simultaneous firing of the nozzles 130.
It should be noted that multiple jets or jets 130 oriented off-axis from the geometrical center can impart other types of internal kneading of the contents in pouch P when strategically fired. When the jets 130 are staggered and/or fired sequentially, rotary motion or different types of mixing can be effected.
Also vertical oscillatory motion can also be imparted by intermittent actuation of the magnetic pair 46, 46a shown in FIG. 2. Magnet pairs could be located elsewhere within chamber 125, (for example one on the partition 88 and another elsewhere on the membrane 50), to induce other types of motion, as should now be evident. Collectively, the jets 130 and magnets 46, 46a can induce complex motion by operating in concert.
FIG. 3 reflects another preferred scenario for the most expeditious heat transfer of the contents within the pouch P. It is contemplated that the rate at which the heat transfer fluid F contacts the membrane 50 and pouch P is greater than the ability of the heat transfer fluid F to be drained from a weep hole 86 placed through the platform 82 and thence to the sump 80. The distribution of the heat transfer fluid F by means of the nozzles 130 will thus cause accumulation of the heat transfer fluid F within a chamber 125 circumscribing the membrane 50 and defined by partitions 88 (located forward and rearward of the membrane 50) and the side walls 6. Partitions 88 allow the liquid level of heat transfer fluid F to rise to ensconce the membrane 50 and cause the membrane 50 to collapse upon the pouch P by hydrostatic pressure. Even with the presence of heat transfer fluid F within this chamber 125, the nozzle jets 130 are configured to still provide pulsing shocks through the heat transfer fluid F and to the membrane 50 and therefore the pouch P. At least one spillway 92 encourages the heat transfer fluid F, once it has risen to the level of the spillway 92, to re-enter the sump 80 to maintain the temperature of the heat transfer fluid F substantially constant at a target temperature. Note that the weep hole 86 is preferred to communicate with the spillway 92. This beneficially controls the rate at which heat transfer fluid F seeps from the chamber 125.
FIGS. 6A through 6D reflect the various stages in the freeze-thaw cycle for a pouch P of thermolabile, fractionable material. FIG. 6D reflects fractionable material in a pouch P which is not frozen. FIG. 6A reveals a frozen pouch P. FIG. 6A also reflects the scenario when the membrane 50 has already been ensconced in heat transfer fluid F and has constricted around the pouch P and the nozzle jets 130 are continuing to work on the pouch P through the membrane 50. As shown therefore, in FIG. 6A, the pouch P and the membrane 50 have a somewhat rectangular configuration or the exact configuration of the frozen pouch P. The initial thermal pulsing causes a minor indentation at the area of impingement with the nozzle jets 130 and liquid thawed from the pouch P is starting to circulate, as shown by arrows X, between the skin of the pouch P and the frozen fractionable cryoprecipitate material. In FIG. 6B there has been sufficient melting at the core of the pouch P to encourage greater fluid circulation of the fractionable cryoprecitable material such as shown by the arrows Y and when contrasted with the arrows X of FIG. 6A. There is still, however, a core of material C 1 which is substantially shaped like a FIG. "8" in cross-section but the outer fluid is becoming thicker, working and diminishing the size of the frozen core C 1 . FIG. 6C shows the scenario where only a minor frozen core C 2 exists and the fluid migration forces Z are pushing the frozen core C 2 closer to the pulsating center. Finally, FIG. 6D shows the pouch P when it is completely thawed and in a flaccid state.
With the foregoing structure in mind, the following methodology for its utilization should now be more evident. A pouch P of material containing blood, plasma, platelets or the like is initially introduced into the device 10 by placement into the opening 40b of the membrane 50 to achieve a substantially FIG. 6D configuration. With the device turned on, the working heat transfer fluid F collapses the membrane 50 upon the pouch P by raising the liquid level within the chamber 125. Concurrently, the nozzles 130 pulse liquid towards the pouch, through the membrane 50. Because of the internal circulation attending this chilling process, a frozen core, similar to C 2 will occur. As the temperature continues to decrease, the core will enlarge such as shown at C 1 in FIG. 6B and will ultimately solidify. It is desired that the temperature when totally frozen be somewhere between 0° C. and -30° C. Thereafter, the process reverses using a heat transfer fluid F which proceeds to melt the contents of the pouch P as in the sequence described with respect to FIGS. 6A through 6C hereinabove.
Whereas FIGS. 2 and 3 reflect one scenario for heating and cooling heat transfer fluid F contained within a single sump 80, FIG. 7 reflects the realization that for the most rapid cycling, it is more efficient to have separate tanks for the coldest fluid F and hottest fluid F so that there is no downtime in cycling from the freezing process to the heating process consecutively.
As shown in FIG. 7, therefore, two stand pipes 92 are provided one of which is for heating of the heat transfer fluid F which is directed through a valve 140 into a tank 170 within which the heating element 90 is operatively connected. During the heating process, therefore, valve 140 and valve 190 are open allowing the heat transfer fluid F to circulate to the pumps 100 and therebeyond. The valve 180 remains closed isolating the cooling heat transfer fluid F.
Another stand pipe 92 is directed through a valve 150 into a tank 160 within which cooling element 95 is operatively connected.
During the freezing process, therefore, valve 140 is kept open allowing heat transfer fluid F to drain through the stand pipe 92 and into the tank 170. Valve 190 is closed. Valve 180 is opened allowing the circulation of the freezing fluid F to the pump 100 and nozzles 130 therebeyond. Both valves 140 and 150 can be remotely operated as by a solenoid. With the valve 150 and valve 180 closed, the cooling element 95 operatively coupled to a source of power allows the heat transfer fluid F contained within the storage tank 160 to be maintained at an optimal temperature. Typically, this temperature is near -30° C. In any event, the liquid contained in the tank 160 is allowed to be pumped through pump 100 by an open valve 180 and a closed valve 190. In this way, the working heat transfer fluid F does not have to go through the extremes of temperature during each cycle. Also shown in FIG. 7 is the structure mentioned hereinabove where one or two pumps could be used and if one pump were to be used a separate branch for the surge valves 110 and firing solenoid valves 120 are provided.
Also in FIG. 7, another means for massaging the pouch P is suggested. More specifically, a solenoid 155 is operatively coupled to reciprocate a rod and pouch holder 165, which when the pouch P has been grasped by hydrostatic pressure through the membrane 50 will induce circulation within the pouch P. A gear mechanism 157, 159, prehaps coupled to the solenoid holder rod assembly can impart twisting to the pouch P.
Moreover, having thus described the invention, it should be apparent that numerous structural modifications and adaptations may be resorted to without departing from the scope and fair meaning of the instant invention as set forth hereinabove and as described hereinbelow by the claims.
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A method and device for fractionating pouches of cryoprecipitable material including a membrane which provides a barrier within an interior of the device with the membrane receiving the pouches of cryoprecipitable material therewithin. The interior of the device includes a sump having a heat transfer fluid stored therein and maintained at a temperature which is to be achieved by the cryoprecipitable material as it cycles between freezing and thawing. The pouch of material, after placement within the membrane, is exposed (through the membrane) to hydrostatic forces associated with the heat transfer fluid in the sump collapsing the membrane on the pouch while pulsating jets impinge indirectly upon the pouch through the membrane. In this way, as the contents within the pouch change temperature, circulation of the fluid within the pouch occurs for more rapid realization of the cycling target temperatures for the cryoprecipitable material within the pouch. In one form, a single sump includes both a heating and cooling element for cycling the heat transfer fluid. In another form, two separate sumps respectively store "hot" heat transfer fluid and "cold" heat transfer fluid for alternate cycling. After plural cycles, the fractionated component of cryoprecipitable material is centrifuged and then separated.
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CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application claims the benefit under 35 U.S.C. §119(e), to provisional application No. 61/622,847 filed on Apr. 11, 2012, the disclosure of which is incorporated by reference herein in its entirety.
BACKGROUND
[0002] 1. Field
[0003] Embodiments of the present invention relate to bead beaters.
[0004] 2. Background
[0005] Given the complexity of the automation of molecular testing and immunoassay techniques, there is a lack of products that provide adequate performance to be clinically usable in near patient testing settings. Typical molecular testing includes various processes involving the correct dosage of reagents, sample introduction, sample homogenization, lysis of cells to extract DNA and/or RNA, purification steps, and amplification for its subsequent detection. Even though there are central laboratory robotic platforms that automate these processes, for many tests requiring a short turnaround time, the central laboratory cannot provide the results in the needed time requirements.
[0006] The homogenization and/or lysis of a biological specimen is usually the initial step in a testing process such that a suitably purified analyte or analytes can be obtained for molecular testing. Generally speaking there are three main approaches to cell lysis: chemical, enzymatic and physical. These processes may be used alone or in combination, sequentially or in a single step, to achieve a more optimal process. The use of chemical and enzymatic processes can prove problematic as some chemicals used to rupture the cell wall can denature any enzymes present or generate problems in subsequent processes.
[0007] Physical methods for cell rupture include sonication, heating (usually between 90° C.-100° C.), repeated freeze-thawing, creation of rapid and large changes in pressure and mechanical methods. Mechanical methods involve the physical rupture of the cell wall through physical forces such as high-shear forces, grinding, and bombardment of the cell with small particles, often consisting of beads. Mechanical methods of disruption have a number of advantages. They often employ a one-step process, are generally very rapid, are amenable to automation, and have the ability to disrupt solid specimens, such as bone, where the analyte(s) of interests may not be made obtainable without mechanical homogenization.
BRIEF SUMMARY
[0008] Mechanical bead beater systems and methods that can be integrated with a near patient testing system are provided.
[0009] In an embodiment, a system for at least one of homogenization and lysis of a sample includes one or more walls forming an enclosed chamber, a permanent magnet within the enclosed chamber, a magnet guide, and one or more magnets located outside the chamber. The enclosed chamber has an inlet and one or more fluidic connections configured to introduce at least the sample into the chamber. The permanent magnet has a positive pole and a negative pole. The magnet guide is configured to laterally guide the permanent magnet between a first position and a second position. The magnet guide is also configured to maintain a substantially constant orientation of the positive pole and the negative pole of the permanent magnet during the movement. Movement of the one or more magnets outside the chamber changes a magnetic field between the one or more magnets and the permanent magnet. The permanent magnet is configured to move between the first and second positions in response to the changing magnetic field.
[0010] An example method of homogenizing a sample is described. The method includes introducing a sample into an enclosed chamber and actuating one or more magnets located outside the chamber. The magnetic field generated by the one or more magnets induces a force upon a permanent magnet disposed within the chamber, the permanent magnet having a positive pole and a negative pole. The induced force causes the permanent magnet to move. The method further includes laterally guiding the movement of the permanent magnet between a first position and a second position within the chamber. An orientation of the positive pole and the negative pole of the permanent magnet remains substantially constant during the movement. The method further includes homogenizing the sample within the chamber via the movement of the permanent magnet.
[0011] Another example method of homogenizing a sample is described. The method includes introducing a sample into an enclosed chamber and actuating one or more magnets located outside the chamber. The magnetic field generated by the one or more magnets induces a force upon a permanent magnet disposed within the chamber, the permanent magnet having a positive pole and a negative pole. The induced force causes the permanent magnet to move. The method further includes laterally guiding the movement of the permanent magnet between a first position and a second position within the chamber. An orientation of the positive pole and the negative pole of the permanent magnet remains substantially constant during the movement. The movement of the permanent magnet excites a plurality of beads located within the chamber. The method further includes homogenizing the sample within the chamber via the movement of the permanent magnet and the plurality of beads.
[0012] An example method of lysing a sample is described. The method includes introducing a sample into an enclosed chamber and actuating one or more magnets located outside the chamber. The magnetic field generated by the one or more magnets induces a force upon a permanent magnet disposed within the chamber, the permanent magnet having a positive pole and a negative pole. The induced force causes the permanent magnet to move. The method further includes laterally guiding the movement of the permanent magnet between a first position and a second position within the chamber. An orientation of the positive pole and the negative pole of the permanent magnet remains substantially constant during the movement. The method further includes lysing the sample within the chamber via the movement of the permanent magnet.
[0013] Another example method of lysing a sample is described. The method includes introducing a sample into an enclosed chamber and actuating one or more magnets located outside the chamber. The magnetic field generated by the one or more magnets induces a force upon a permanent magnet disposed within the chamber, the permanent magnet having a positive pole and a negative pole. The induced force causes the permanent magnet to move. The method further includes laterally guiding the movement of the permanent magnet between a first position and a second position within the chamber. An orientation of the positive pole and the negative pole of the permanent magnet remains substantially constant during the movement. The movement of the permanent magnet excites a plurality of beads located within the chamber. The method further includes lysing the sample within the chamber via the movement of the permanent magnet and the plurality of beads.
BRIEF DESCRIPTION OF THE DRAWINGS/FIGURES
[0014] The accompanying drawings, which are incorporated herein and form a part of the specification, illustrate embodiments of the present invention and, together with the description, further serve to explain the principles of the invention and to enable a person skilled in the pertinent art to make and use the invention.
[0015] FIG. 1 is a graphical representation of a test cartridge platform, according to an embodiment.
[0016] FIGS. 2A-F display various views of a bead beater system, according to an embodiment.
[0017] FIGS. 3A-C display various other views of the bead beater system, according to an embodiment.
[0018] FIGS. 4A-B display a permanent magnet and magnet covers, according to an embodiment.
[0019] FIGS. 5-8 are diagrams illustrating methods performed by the bead beater system, according to an embodiment.
[0020] FIG. 9 is a graph of Ct values from Bacillus subtilis spores.
[0021] Embodiments of the present invention will be described with reference to the accompanying drawings.
DETAILED DESCRIPTION
[0022] Although specific configurations and arrangements are discussed, it should be understood that this is done for illustrative purposes only. A person skilled in the pertinent art will recognize that other configurations and arrangements can be used without departing from the spirit and scope of the present invention. It will be apparent to a person skilled in the pertinent art that this invention can also be employed in a variety of other applications.
[0023] It is noted that references in the specification to “one embodiment,” “an embodiment,” “an example embodiment,” etc., indicate that the embodiment described may include a particular feature, structure, or characteristic, but every embodiment may not necessarily include the particular feature, structure, or characteristic. Moreover, such phrases do not necessarily refer to the same embodiment. Further, when a particular feature, structure or characteristic is described in connection with an embodiment, it would be within the knowledge of one skilled in the art to effect such feature, structure or characteristic in connection with other embodiments whether or not explicitly described.
[0024] Embodiments described herein relate to a bead beater system for homogenization and/or lysing of a sample. The sample may be a liquid, solid, semi-solid, or a combination thereof. In one embodiment, the bead beater system is integrated with a test cartridge platform. The test cartridge platform includes a network of fluidic channels, a portion of which may couple to the integrated bead beater. The fluidic channels may provide the sample to a bead beater chamber, extract the sample from the bead beater chamber, and/or be used to pressurize or depressurize the bead beater chamber.
[0025] The bead-beater system is designed to use physical disruption of samples by the oscillation of, for example, a permanent magnet within the bead-beater chamber. This physical disruption may in turn be aided by the presence of beads (e.g., inert beads made of glass and/or other materials). In one example, the lysis and/or homogenization process is further optimized through the use of a lysis buffer within the bead beater chamber. In another example, enzymatic lysis is performed by applying heat to the sample. Heating the sample may be performed before the actual bead beating of the sample in some examples. In an embodiment, all the necessary reagents and components of the bead-beater are contained within the test cartridge platform.
[0026] In some embodiments, both the test cartridge platform and the integrated bead beater are designed to be disposable after use. Once the reagents or the sample are placed within the integrated test cartridge, they do not again enter into contact with the external environment or with any part of an external measurement instrument. This feature is important for many laboratories and hospitals to safely dispose of the products after their use.
[0027] The bead-beater chamber itself is designed to be able to process a wide variety of specimens and to disrupt a wide variety of cell types. This is, in part, achieved by the availability of different test cartridge platforms that are specific to each particular specimen/cell type combination. In another example, variable conditions that are controlled by the analyzer, such as the speed and duration of oscillation of the permanent magnet, allow for processing a wide variety of sample types.
[0028] Further details relating to the components of the bead beater system are described herein with references made to the figures. It should be understood that the illustrations of each physical component are not meant to be limiting and that a person having skill in the relevant art(s) given the description herein would recognize ways to re-arrange or otherwise alter any of the components without deviating from the scope or spirit of the invention.
[0029] FIG. 1 illustrates an example test cartridge system into which a bead beater may be integrated, according to an embodiment. Although reference will be made herein to the structure of the example test cartridge system, one of skill in the art will recognize that bead beater embodiments described herein may be used with any number of testing system types and configurations.
[0030] The test cartridge system includes a cartridge housing 102 . Other components may be considered as well for inclusion it the test cartridge system, such as an analyzer module or various active components such as pumps or heaters.
[0031] Cartridge housing 102 includes a variety of fluidic channels, chambers, and reservoirs. For example, cartridge housing 102 may include a plurality of storage chambers 116 which may contain various buffers or other reagents to be used during an assay or PCR protocol. Storage chambers 116 may be pre-filled with various liquids so that the end user will not need to fill storage chambers 116 before placing the test cartridge system into an analyzer. Cartridge housing 102 may further include one or more processing chambers 124 a - b connected to fluidic channels along a side of cartridge housing 102 . Processing chambers 124 a - b may be used for a variety of processing and/or waste applications.
[0032] Samples are introduced into cartridge housing 102 via sample port 114 , according to an embodiment. A user may place a swab completely within sample port 114 and its corresponding chamber 124 b , and subsequently seal the port with a port lid 112 . In another example, sample port 114 receives solid, semi-solid, or liquid samples. In an embodiment, cartridge housing 102 includes more than one inlet to introduce samples.
[0033] The various chambers and channels around cartridge housing 102 may be sealed via the use of covers 118 , 126 , and 128 . The covers may be films capable of sealing the fluid within cartridge housing 102 . In another example, the covers may be plastic panels. In an example, one or more of the covers are transparent. Additionally, one or more of the covers may be thermally controlled for heating portions of housing 102 .
[0034] The integrated test cartridge system allows a user to place a sample into, for example, sample port 114 , then place the test cartridge system into an analyzer. In embodiments, the reaction steps to be performed including, for example, purification, lysing, mixing, binding, labeling and/or detecting can all be performed within the test cartridge system via interaction with the analyzer without any need for the end user to intervene. Additionally, since all of the liquids remain sealed within the test cartridge system, after the test is completed, the test cartridge system may be removed from the analyzer and safely disposed of without contamination of the analyzer.
[0035] The test cartridge system may further include fluidic channels which lead to an inner processing chamber having an opening 132 . In an embodiment, the inner processing chamber is an integrated bead beater chamber disposed within cartridge housing 102 . Although the chamber itself is hidden from view in FIG. 1 , various other components of the system are shown in the exploded view. For example, the bead beater system includes a processing lid 134 that fits over opening 132 . Within the chamber itself, a permanent magnet 138 is disposed along with magnet covers 136 a - b , according to an embodiment. In another example, a single magnet cover may be used to surround permanent magnet 138 . The end of the bead beater chamber is closed using, for example, a panel cover 140 . Each of the components of the bead beater system will be explained in more detail herein.
[0036] FIGS. 2A-F illustrate various views of the bead beater system, according to embodiments. The description of each view is set forth to describe features that may be present on or within the bead beater system, but should not be limiting as to the placement or dimensional properties of the features.
[0037] FIG. 2A provides a perspective view of a bead beater 201 which can be integrated into a test cartridge system, such as example system 100 , according to an embodiment. The outer view of bead beater 201 displays panel cover 140 and processing inlet 132 as described previously. In one example, processing inlet 132 may be placed on a side of bead beater 201 . Processing inlet 132 is configured to accept any type of sample, including liquid, solid, semi-solid, or any combination thereof. Processing inlet 132 leads into an enclosed chamber where the bead beating process takes place. In another example, samples entering processing inlet 132 are lead to a first chamber, and then transferred from the first chamber into a second chamber where the bead beating process takes place.
[0038] On one side of bead beater 201 , fluid inlets 203 a - b are provided to couple with a fluidic system. For example, fluid inlets 203 a - b may couple to channels connecting to any one of storage chambers 116 or processing chambers 124 a - b . In an embodiment, fluid inlets 203 a - b lead into the chamber where the bead beading takes place. As such, fluid inlets 203 a - b may be used for introducing any liquid into the bead beating chamber, extracting any liquid from the bead beating chamber, applying a pressure differential in the bead beating chamber, or any combination thereof.
[0039] External to bead beater 201 , an actuator system 202 is attached to a beam 206 , according to an embodiment. In one example, actuator system 202 is a rotary actuator that applies a rotational force upon beam 206 . Actuator system 202 may receive various signals via coupling 204 . For example, the signals may include power or control signals. Coupling 204 may represent wires, RF signals, or optical signals. Actuator system 202 may rotate beam 206 at any speed within the capabilities of actuator system 202 . In one example, actuator system 202 rotates beam 206 at speeds ranging from 50 RPM to 8000 RPM. In another example, actuator system 202 rotates beam 206 at around 4000 RPM.
[0040] Near either end of beam 206 , external magnets 208 a - b are attached, according to an embodiment. External magnets 208 a - b may have the same polarity or opposite polarities. As beam 206 rotates, external magnets 208 a - b pass by an outside wall of bead beater 201 in an alternating manner. Thus, a changing magnetic field is generated between the rotating external magnets 208 a - b and, for example, a permanent magnet (not shown) disposed within the chamber of bead beater 201 .
[0041] In one embodiment, bead beater 201 may include a cavity through one of the walls of bead beater 201 . The cavity may be covered by a thermally conductive film, such as, for example, an aluminum foil. By heating the thermally conductive film, the contents within the inner processing chamber of bead beater 201 may be heated via the cavity. In another example, one of the walls of the inner processing chamber may be a thermally controlled surface to heat the contents of the inner processing chamber without requiring a cavity. Introducing heat into the inner processing chamber may allow for enzymatic lysis of a sample to occur. In one example, enzymatic lysis may be performed using an applied heat to a sample before the actual bead beating of the sample commences.
[0042] FIG. 2B provides a side cross-sectional view of bead beater 201 along with actuator system 202 , according to an embodiment. The view also illustrates a magnetic beater 214 disposed within an enclosed chamber 212 of bead beater 201 . Both processing inlet 132 and panel cover 140 are shown as well.
[0043] In an embodiment, beam 206 is coupled to actuator system 202 by means of an axle 210 that attaches to the center of beam 206 . As previously described, the rotation of beam 206 alternates the passing of external magnets 208 a - b outside of enclosed chamber 212 . Magnetic beater 214 is a permanent magnet having polarity. In an embodiment, magnetic beater 214 has a positive pole 215 a and a negative pole 215 b . In an example, each pole of magnetic beater 214 faces either substantially towards or away from panel cover 140 .
[0044] As beam 206 rotates, the magnetic force induced upon magnetic beater 214 either attracts or repels magnetic beater 214 . The attraction or repulsion of magnetic beater 214 causes magnetic beater 214 to move back and forth within enclosed chamber 212 . For example, external magnet 208 a has a positive polarity and causes magnetic beater 214 to move away due to a magnetic repulsive force 216 between external magnet 208 a and positive pole 215 a of magnetic beater 214 . Magnetic beater 214 may be pushed against the back wall of enclosed chamber 212 . In another example, permanent magnet may be pushed to a stop position within enclosed chamber 212 before reaching the back wall.
[0045] In one embodiment, one or more walls of enclosed chamber 212 are manufactured from metals having a high thermal conductivity such as aluminum, copper, etc., and can be thermally controlled. Introducing heat into the inner processing chamber may allow for enzymatic lysis of a sample to occur. In one example, enzymatic lysis may be performed using an applied heat to a sample before the actual bead beating of the sample commences.
[0046] FIG. 2C illustrates a situation where beam 206 has rotated to bring external magnet 208 b outside of enclosed chamber 212 . Magnet 208 b may have a negative polarity which induces a magnetic attractive force 218 upon magnetic beater 214 due to the attraction between external magnet 208 b and positive pole 215 a of magnetic beater 214 . Magnetic beater 214 may be pulled up against the inner wall of panel cover 140 . In another example, magnetic beater 214 may be pulled to a stop position within enclosed chamber 212 before reaching panel cover 140 .
[0047] The lateral back and forth movement of magnetic beater 214 is guided by the geometry of enclosed chamber 212 , according to an embodiment. The geometry may be designed to prevent the face of positive pole 215 a and negative pole 215 b from flipping within enclosed chamber 212 . The movement frequency of magnetic beater 214 within enclosed chamber 212 is associated with the rotation speed of beam 206 . Samples placed within enclosed chamber 212 are lysed and/or homogenized by the movement of magnetic beater 214 .
[0048] FIG. 2D illustrates enclosed chamber 212 having a plurality of beads 220 , according to an embodiment. The beads may be included to aid in the homogenization and/or lysing process of a sample within enclosed chamber 212 . The back and forth lateral movement of magnetic beater 214 excites plurality of beads 220 into movement as well. Plurality of beads 220 may range in size from one micron in diameter up to 3000 microns in diameter. Additionally, plurality of beads 220 may be manufactured from various inert materials including plastics, glass, ceramics, and silica.
[0049] FIG. 2E illustrates another embodiment for actuating a set of external magnets 224 a - b . Horizontal beam 222 is connected to a linear actuator (not shown) and lateral back and forth movement of horizontal beam 222 passes external magnets 224 a - b by an outside wall of bead beater 201 in an alternating manner, according to an embodiment. Similarly to the discussion above, each of external magnets 224 a - b may have opposite polarities, causing magnetic beater 214 to move back and forth within enclosed chamber 212 of bead beater 201 . Other alternatives for external magnetic field actuation are also contemplated, such as using an electromagnet to produce an alternating electromagnetic field.
[0050] FIG. 2F illustrates another embodiment of bead beater 201 in which a sensor 226 has been included. Sensor 226 may be used to monitor the rate of movement of magnetic beater 214 within enclosed chamber 212 . The data collected from sensor 226 is helpful for determining whether magnetic beater 214 is in any way obstructed and/or not moving correctly within enclosed chamber 212 . Sensor 226 may be, for example, a magnetic sensor or an optical sensor that identifies movement of magnetic beater 214 .
[0051] FIG. 3A illustrates a view within enclosed chamber 212 of bead beater 201 , according to an embodiment. Magnetic beater 214 is shown surrounded by chamber walls. The geometry of the chamber walls includes lobes 302 and ridges 304 that act as magnet guides, according to an embodiment. Lobes 302 and ridges 304 may be utilized to provide a trefoil or quatrefoil cross-section to the chamber walls. Other arrangements are possible as well for the purpose of guiding the movement of magnetic beater 214 . In one example, a recess 301 is provided to accept panel cover 140 .
[0052] Ridges 304 provide contact points for magnetic beater 214 and prevent magnetic beater 214 from flipping around within enclosed chamber 212 . Additionally, ridges 304 reduce wobbling of magnetic beater 214 as it moves laterally within enclosed chamber 212 . Ridges 304 may be made of the same material as the rest of chamber walls 302 , or may be a softer material, such as Teflon, to reduce mechanical stress on magnetic beater 214 .
[0053] Lobes 302 provide adequate space around magnetic beater 214 for liquid and beads to move while magnetic beater 214 traverses enclosed chamber 212 . The geometry of the chamber walls may include any number of lobes 302 . The curvature and general size of lobes 302 may be chosen so as to reduce any dead volume within enclosed chamber 212 during the movement of magnetic beater 214 . In one example, the volume existing around magnetic beater 214 within enclosed chamber 212 is 1 ml, though other volumes may be considered as well.
[0054] FIG. 3B illustrates the interior of enclosed chamber 212 with magnetic beater 214 removed, according to an embodiment. A protruding element 306 may be included on a back wall of inner chamber 212 to act as a mechanical stop and minimize the contact area of magnetic beater 214 against the back wall. Protruding element 306 protects plurality of beads 220 , if included, from being crushed by magnetic beater 214 . Protruding element 306 may be any suitable shape and/or size to reduce the contact area as magnetic beater 214 is pushed against the back wall. A second protruding element may also be included on the inner wall of panel cover 140 (not shown).
[0055] FIG. 3C illustrates a perspective view of bead beater 201 along with processing lid 134 and panel cover 140 , according to an embodiment. Processing lid 134 may be dimensioned to seal processing inlet 132 so as to prevent any leakage through processing inlet 132 . Panel cover 140 fits into recess 301 to seal the enclosed chamber from the side. In an embodiment, panel cover 140 may be removed in order to remove any objects within the enclosed chamber, such as a permanent magnet.
[0056] FIG. 4A illustrates a side view of components of magnetic beater 214 , according to an embodiment. In an example, magnetic beater 214 includes permanent magnet 138 sandwiched between two magnet covers 136 a - b . Permanent magnet 138 may have a substantially cylindrical shape. Magnet covers 136 a - b may be utilized to protect permanent magnet 138 from any damage due to collisions within the bead beater system. Magnet covers 136 a - b may be made of a compliant material which can absorb the shock caused by magnetic beater 214 colliding with the inner walls or protruding elements 306 of enclosed chamber 212 . Magnet covers 136 a - b may be coupled together via an adhesive or suitable locking mechanism. In another example, a single magnet cover is used or molded around permanent magnet 138 .
[0057] FIG. 4B illustrates another embodiment of magnetic beater 214 . Magnetic covers 136 a - b may include cover protrusions 402 a - b . Cover protrusions 402 a - b may provide the same mechanical stop benefits as described previously for protruding elements 306 .
[0058] FIGS. 5-8 describe example methods to be employed for homogenizing or lysing a sample with or without beads, according to embodiments. It should be understood that methods 500 , 600 , 700 , and 800 describe example operation sequences that can be performed with bead beater 201 , and should not be considered limiting. Any of methods 800 , 900 , 1000 , and 1100 may also include a step of heating the contents within bead beater 201 to perform an enzymatic lysis. In one example, the enzymatic lysis is performed before the bead beating occurs.
[0059] FIG. 5 displays a flowchart of an example method 500 for homogenizing a sample using bead beater 201 .
[0060] At block 502 , at least the sample is introduced into an enclosed chamber. The sample may be introduced, for example, through processing inlet 132 or via fluid inlets 203 a - b . In an embodiment, a solid or semi-solid sample may be provided for homogenization. For example, samples with a high viscosity (e.g. sputum, tissue, bone) are well suited for homogenization to break down complex matrices that hold the cellular components of the sample together.
[0061] At block 504 , one or more magnets disposed outside the enclosed chamber are actuated. The one or more magnets may be rotated by or linearly translated by an outer wall of the enclosed chamber. Additionally, the one or more magnets may have opposite polarities so as to alternate the direction of an induced magnetic field. Alternatively, an alternating electromagnet may be actuated outside of the enclosed chamber.
[0062] At block 506 , a force is induced upon a permanent magnet disposed within the chamber. The force is generated due to either magnetic attraction or repulsion.
[0063] At block 508 , the movement of the permanent magnet is laterally guided between a first position and a second position within the chamber due to the induced magnetic force. The force causes the permanent magnet to move within the chamber in a direction either towards or away from the magnet outside of the chamber walls. The first and second position may correspond to each end of the enclosed chamber. The geometry of the chamber facilitates the lateral movement of the permanent magnet, according to an embodiment.
[0064] At block 510 , the sample is homogenized within the chamber via the movement of the permanent magnet. The homogenized sample may be lysed using bead beater 201 or transferred to another chamber for further processing.
[0065] FIG. 6 displays a flowchart of an example method 600 for homogenizing a sample using bead beater 201 containing a plurality of beads. The included beads act to speed up the process of breaking down the sample.
[0066] At block 602 , at least the sample is introduced into an enclosed chamber. The sample may be introduced, for example, through processing inlet 132 or via fluid inlets 203 a - b . In an embodiment, a solid or semi-solid sample may be provided for homogenization. For example, samples with a high viscosity (e.g. sputum, tissue, bone) are well suited for homogenization to break down complex matrices that hold the cellular components of the sample together.
[0067] At block 604 , one or more magnets disposed outside the enclosed chamber are actuated. The one or more magnets may be rotated by or linearly translated by an outer wall of the enclosed chamber. Additionally, the one or more magnets may have opposite polarities so as to alternate the direction of an induced magnetic field. Alternatively, an alternating electromagnet may be actuated outside of the enclosed chamber.
[0068] At block 606 , a force is induced upon a permanent magnet disposed within the chamber. The force is generated due to either magnetic attraction or repulsion.
[0069] At block 608 , the movement of the permanent magnet is laterally guided between a first position and a second position within the chamber due to the induced magnetic force. The force causes the permanent magnet to move within the chamber in a direction either towards or away from the magnet outside of the chamber walls. The first and second position may correspond to each end of the enclosed chamber. The geometry of the chamber facilitates the lateral movement of the permanent magnet, according to an embodiment.
[0070] At block 610 , a plurality of beads within the chamber are excited by the movement of the permanent magnet. The beads may vary in shape, size and/or material as described previously. The added movement of the beads within the chamber provide further beating of the sample and a more efficient homogenization process.
[0071] At block 612 , the sample is homogenized within the chamber via the movement of the permanent magnet and the plurality of beads. The homogenized sample may be lysed using bead beater 201 or transferred to another chamber for further processing.
[0072] FIG. 7 displays a flowchart of an example method 700 for lysing a sample using bead beater 201 . The objective of cell lysis is to release cellular contents which are required for analysis. Examples of cellular contents include, but are not limited to, DNA, RNA, polypeptides, enzymes, prions, proteins, antibodies, antigens, allergens, and virons.
[0073] At block 702 , at least the sample is introduced into an enclosed chamber. The sample may be introduced, for example, through processing inlet 132 or via fluid inlets 203 a - b.
[0074] At block 704 , one or more magnets disposed outside the enclosed chamber are actuated. The one or more magnets may be rotated by or linearly translated by an outer wall of the enclosed chamber. Additionally, the one or more magnets may have opposite polarities so as to alternate the direction of an induced magnetic field. Alternatively, an alternating electromagnet may be actuated outside of the enclosed chamber.
[0075] At block 706 , a force is induced upon a permanent magnet disposed within the chamber. The force is generated due to either magnetic attraction or repulsion.
[0076] At block 708 , the movement of the permanent magnet is laterally guided between a first position and a second position within the chamber due to the induced magnetic force. The force causes the permanent magnet to move within the chamber in a direction either towards or away from the magnet outside of the chamber walls. The first and second position may correspond to each end of the enclosed chamber. The geometry of the chamber facilitates the lateral movement of the permanent magnet, according to an embodiment.
[0077] At block 710 , the sample is lysed within the chamber via the movement of the permanent magnet. The lysate may be transferred from the chamber to a second chamber via one of fluid inlets 203 a - b.
[0078] FIG. 8 displays a flowchart of an example method 800 for lysing a sample using bead beater 201 containing a plurality of beads. The objective of cell lysis is to release cellular contents which are required for analysis. Examples of cellular contents include, but are not limited to, DNA, RNA, polypeptides, enzymes, prions, proteins, antibodies, antigens, allergens, and virons. The included beads act to speed up the process of tearing the cell walls to release the cellular contents.
[0079] At block 802 , at least the sample is introduced into an enclosed chamber. The sample may be introduced, for example, through processing inlet 132 or via fluid inlets 203 a - b.
[0080] At block 804 , one or more magnets disposed outside the enclosed chamber are actuated. The one or more magnets may be rotated by or linearly translated by an outer wall of the enclosed chamber. Additionally, the one or more magnets may have opposite polarities so as to alternate the direction of an induced magnetic field. Alternatively, an alternating electromagnet may be actuated outside of the enclosed chamber.
[0081] At block 806 , a force is induced upon a permanent magnet disposed within the chamber. The force is generated due to either magnetic attraction or repulsion.
[0082] At block 808 , the movement of the permanent magnet is laterally guided between a first position and a second position within the chamber due to the induced magnetic force. The force causes the permanent magnet to move within the chamber in a direction either towards or away from the magnet outside of the chamber walls. The first and second position may correspond to each end of the enclosed chamber. The geometry of the chamber facilitates the lateral movement of the permanent magnet, according to an embodiment.
[0083] At block 810 , a plurality of beads within the chamber are excited by the movement of the permanent magnet. The beads may vary in shape, size and/or material as described previously. The added movement of the beads within the chamber provide further beating of the cells and lead to a more efficient lysing process.
[0084] At block 812 , the sample is lysed within the chamber via the movement of the permanent magnet and the plurality of beads. The lysate may be transferred from the chamber to a second chamber via one of fluid inlets 203 a - b.
Example
[0085] An Example protocol to be performed using embodiments of bead beater 201 is now discussed. The protocol is an example only and is not limiting on embodiments of the present invention. The lysing efficiency of the bead beater with different bead sizes is analyzed based on DNA detection. It should be understood that the steps recited here provide just one possible example for using the system.
[0086] Bacillus subtilis , known also as the hay bacillus or grass bacillus, is a Gram-positive, catalase-positive bacterium. A member of the genus Bacillus; B. subtilis is rod-shaped, and has the ability to form a tough, protective endospore, allowing the organism to tolerate extreme environmental conditions. Endospores of various Bacillus species are formed in sporulation, a process that is generally induced by reduced levels of nutrients in the environment. Endospores contain an outer spore cortex that is extremely resistant to harsh physical and chemical treatments making it challenging to identify a spore lysis method that can be completed in a few minutes.
[0087] An example protocol for lysing the cells of Bacillus subtilis is adapted from W. Nicholson and P. Setlow, Molecular Biological Methods for Bacillus , New York, John Wiley, pp. 391-450, 1990. In this example protocol, a 100 mL culture of Bacillus subtilis subsp. spizizenii (ATCC 6633) grown in sporulation medium (SM) is vortexed, then separated in two volumes of 50 mL. After centrifugation at 3750 g for 15 minutes, the pellets are washed three to five times with 50 mL sterile cold distilled water, each wash being centrifuged at 3750 g for 15 minutes. The final pellets are re-suspended in 50 mL of sterile cold distilled water. Spore suspensions are treated with DNase to remove external residual DNA, quantified and diluted to a final concentration of 5×10 9 endospores/mL. Serial 10-fold-dilutions are prepared (1×10 4 , 1×10 3 , 1×10 2 , and 10 endospores/mL) in nucleases free water to be used as a starting material in the fluidically integrated magnetic bead beater.
[0088] First, 400 mg of sterile, acid washed glass beads are introduced into the bead beater chamber. Second, a 400 μL endospores dilution is transferred to the bead beater chamber via the processing inlet. The magnets on the outside of the bead beater are rotated at around 4000 RPM for about 1 minute to perform lysis on the cells within the bead beater chamber. Bacterial nucleic acids are released when spores are disrupted by the mechanical action of the bead beater. Nucleic acid extractions remain stable for several months when stored frozen at −80° C. or −20° C. and may be frozen and thawed several times without any significant loss in PCR analytical sensitivity.
[0089] Amplification and detection of DNA from Bacillus subtilis endospores at different starting concentrations is performed on the StepOnePlus™ Real-Time PCR System from Applied Biosystems with the TaqMan® Universal master mix II no UNG, with Taq Gold polymerase (from Applied Biosystems, ref 4440040), according to the manufacturer's instructions. 1.5 μL of prepared lysate is added directly to a qPCR reaction having 1× TaqMan® Universal master mix II no UNG with Taq Gold polymerase, 0.90 μM of each SpoA Bacillus subtilis -specific primer, 0.25 μM of SpoOA TaqMan® probe, and 0.8 mg/mL BSA; in a final volume of 15 μL. In parallel, spores without processing are tested as untreated controls (at the same concentrations). 1.5 μL of distilled water is also added to a qPCR reaction as a negative control. The optimal cycling conditions for maximum sensitivity and specificity are 10 minutes at 95° C. for initial denaturation, then fifty cycles of two steps consisting of 15 seconds at 95° C. and 60 seconds at 60° C. Amplification is monitored during each elongation cycle by measuring the level of fluorescence. Table 1 below provides the SpoOA Bacillus subtilis -specific primers and probe sequence used in the TaqMan® qPCR reaction.
[0000]
TABLE 1
Product
Length
size
Primer
Sequence (5′->3′)
(bp)
(bp)
SpoOA F
ccatcatcgcaaagcagtatt
21
70
SpoOA R
tgggacgccgatttcatg
18
SpoOA
ctcgacgcgagcatcacaagcatt
24
probe
[0090] FIG. 9 provides a graph of the Ct values (number of PCR cycles needed to produce a positive signal) for samples processed with various sizes beads, and untreated samples, at four different B. subtilis starting concentrations. Results are a mean of 10 replicates at each concentration.
[0091] At low Bacillus subtilis concentrations (10 and 1×10 2 endospores/mL), Ct values were lower in the presence of 150-212 μm diameter beads (higher DNA concentration) compared to the <106 μm diameter bead conditions, increasing the sensitivity of the process. At higher concentrations (1×10 3 and 1×10 4 endospores/mL) no difference was observed between the two bead sizes tested. The larger bead size (150-212 μm diameter) consistently produced lower Ct values than the untreated samples for each starting concentration of Bacillus subtilis , while the smaller bead size (<106 μm diameter) produced lower Ct values than the untreated samples only for the higher starting concentrations (1×10 3 and 1×10 4 endospores/mL.) Untreated samples were undetectable at the lowest Bacillus subtilis concentration (10 endospores/mL.)
[0092] The best results in terms of sensitivity and lysis efficiency are observed with the fluidically integrated magnetic bead beater having 150-212 μm diameter silica beads, in this example.
[0093] The foregoing description of the specific embodiments will so fully reveal the general nature of the invention that others can, by applying knowledge within the skill of the art, readily modify and/or adapt for various applications such specific embodiments, without undue experimentation, without departing from the general concept of the present invention. Therefore, such adaptations and modifications are intended to be within the meaning and range of equivalents of the disclosed embodiments, based on the teaching and guidance presented herein. It is to be understood that the phraseology or terminology herein is for the purpose of description and not of limitation, such that the terminology or phraseology of the present specification is to be interpreted by the skilled artisan in light of the teachings and guidance.
[0094] Embodiments of the present invention have been described above with the aid of functional building blocks illustrating the implementation of specified functions and relationships thereof. The boundaries of these functional building blocks have been arbitrarily defined herein for the convenience of the description. Alternate boundaries can be defined so long as the specified functions and relationships thereof are appropriately performed.
[0095] The Summary and Abstract sections may set forth one or more but not all exemplary embodiments of the present invention as contemplated by the inventor(s), and thus, are not intended to limit the present invention and the appended claims in any way.
[0096] The breadth and scope of the present invention should not be limited by any of the above-described exemplary embodiments, but should be defined only in accordance with the following claims and their equivalents.
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A system for at least one of homogenization and lysis of a sample includes one or more walls forming an enclosed chamber, a permanent magnet within the enclosed chamber, a magnet guide, and one or more magnets located outside the chamber. The enclosed chamber has an inlet and one or more fluidic connections configured to introduce at least the sample into the chamber. The permanent magnet has a positive pole and a negative pole. The magnet guide is configured to laterally guide the permanent magnet between a first position and a second position and maintain a substantially constant orientation of the permanent magnet during the movement. Movement of the magnets outside the chamber changes a magnetic field between the one or more magnets and the permanent magnet. The permanent magnet moves between the first and second positions in response to the changing magnetic field.
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BACKGROUND OF THE INVENTION
The present invention relates to a method for preparing indigestible and low-caloric polysaccharides and, more particularly, to a method for preparing heteropolysaccharides preferably suited for indigestible and low-caloric edible materials.
As for the preparation of indigestible polysaccharides, the following methods have been suggested so far: the one to produce edible condensed polymers from an aqueous solution containing saccharides such as glucose or maltose, edible polycarbonic acid and/or edible polyol (Japanese Patent Publication (Examined) No.53-47280); the one to act upon starch or starch derivatives with an edible acid under a particular condition (Japanese Patent Publication (Examined) No.56-29512); and the one to heat up starch or starch hydrolyzates with sugar alcohol and an inorganic acid or organic acid in an anhydrous condition (Japanese Patent Publication No.1-12762). These polymers are generally obtained through polymerizing starch or starch hydrolyzates, saccharides such as glucose or maltose, and edible polycarbonic acid or polyol at a high temperature. Another method to utilize pyrodextrin with indigestibility has also been proposed (Japanese Patent Application No. 63-254540).
The results gained through these prior methods, however, are homopolymers mainly consisting of glucose and have a defect of being apt to be decomposed by amylase.
On the other hand, the research on hetero-oligosaccharides such as fructo-oligosaccharides, galacto-oligosaccharides, and bean oligosaccharides as low-caloric sweetening agents has lead to their commercial supply on the market place.
The inventors of the present application have directed their attention to the fact that these low-caloric oligosaccharides are of heterosaccharides and hit upon a new idea that indigestible polysaccharides may be obtained by converting starch decomposed products into heteropolysaccharides and, on the basis of this new idea, they have successfully come to develop a novel method for preparing heteropolysaccharides.
SUMMARY OF THE INVENTION
Accordingly, an object of the present invention is to materialize such a new idea as mentioned above, that is, to provide a novel method for converting homopolysaccharides obtained from starch decomposed products into heteropolysaccharides indigestible in the human body.
The foregoing object of the invention is accomplished by treating up to polymerize starch decomposition products and in which at least one kind of monosaccharides except glucose, homo-oligosaccharides except gluco-oligosaccharides, and hetero-oligosaccharides with a small amount of an inorganic acid as a catalyst.
In the present specification, the following terms have the following meanings unless otherwise specified herein:
(1) "Maltodextrins" means a general term for starch hydrolyzates in the range of 1 to 20 of DE (the abbreviation of "Dextrose Equivalent", the value representing a hydrolyzaticn degree of starch).
(2) "Corn Syrup Solid" means a general term for starch hydrolyzates powder in the range of 20 to 40 of DE.
(3) "Pyrodextrins" means a general term for the dextrins soluble partially or wholly which are obtained through heating starch alone or with a small amount of acid added as a catalyst at a temperature from 100° to 200° C.
(4) "Soluble Starch" means a starch of low molecular weight obtained through an addition of an oxidizing agent such as sodium hypochlorite to starch in an alkaline suspension condition and then an oxidation of a part of hydroxyl groups in starch.
(5) "Powdering" means a drying and powdering process by spray-drying or vacuum freeze-drying as pretreatment of preparation in order to mix starch decomposition products and other saccharides with a catalyst uniformly and to cause reaction in an anhydrous powder condition.
(6) "Homo-oligosaccharides" means a general term for combination of single monosaccharide, including starch, maltose, cellulose, and the like.
(7) "Hetero-oligosaccharides" means a general term for combination of two or more kinds of monosaccharides, including lactose, sucrose, fructo-oligosaccharide, galacto-oligosaccharide, bean oligosaccharide, and the like.
General kinds of starch obtained from potato, corn, waxy corn, sweet potato, cassaba, and the like are used as raw materials for starch decomposition products which are initial materials employed in the invention. And their DE is preferable in the range of 3 to 40. Pyrodextirn and oxidized starch can be also used.
Preferred examples of starch decomposition products are maltodextrin, corn syrup solid, pyrodextrin, and oxidized starch with DE in the range of 3 to 40. These starch decomposition products can be used singly or in combination with two or more.
The saccharides to be used in the present invention are classified as follows:
(i) monosaccharides (excluding glucose);
(ii) homo-cligosaccharides (excluding gluco oligosaccharide); and
(iii) hetero-oligosaccharides.
Glucose and gluco-oligosaccharide are excluded in the above (i) and (ii) because starch decomposition products are gluco-oligosaccharides and contain a small amount of glucose.
One kind or two kinds among the above saccharides shown in (i) to (iii) can be used together, that is, not only one kind alone among (i) to (iii) can be used, but also two or more kinds among (i) to (iii) can be used together. If using only one specific kind of saccharides belonging to (i), not only one of that kind can be used but also two or more of that kind can be used together.
The saccharides to be used may be monosaccharides such as xylose, arabinose, galactose, mannose, fructose, sorbose, and oligosaccharides such as sucrose, lactose, kestose, nitrose, lactulose, raffinose, stachinose. Moreover, other than single use of sucrose or fructose, such fructo-oligosacharides mixed with sucrose, fructose, glucose, kestose, nistose and the like, and galacto-oligosaccharides mixed with sucrose, raffinose, stachinose and the like can be also used.
Mixture ratio of sacharides to starch decomposition products is in such a wide range as 25 to 300 parts by weight. In consideration of process, however, a preferable mixture ratio of saccharides is in the range of about 25 to 50 parts by weight in case of high DE (i.e., DE over 25) and in the range of about 50 to 75 parts by weight in case of low DE.
As acid to be used as catalyst, inorganic acids including hydrochloric acid, nitric acid, phosphoric acid, etc., particularly diluted hydrochloric acid is preferable when used in an amount below 0.1%, and more preferably 0.03%. A preferable amount of 1% hydrochloric acid to be used is not more than 10%, and 5% on the average.
For carrying out the method in accordance with the invention, material mixtures are dissolved in water to prepare an aqueous solution containing 30 to 50%, preferably 40%, of the material mixtures (heating up is necessary in case of oxidized starch), then an inorganic acid is added and the solution is powdered through spray-drying, vacuum freeze-drying and so on. The powder thus obtained is then heated up at a temperature range of 100° to 200° C. for reaction and polymerization. The time spent for this process is sufficient for the polymerization. The powder of heteropolysaccharides obtained through the mentioned process is then dissolved in water, neutralized and decolorized with the use of activated charcoal, and desalted with ion-exchanger resins, powdered through spray-drying to obtain a powder of refined heteropolysaccharides.
Described hereinafter are preferred examples accompanied by experiments in accordance with the present invention.
In this respect, the indigestible ingredients disclosed in the invention were measured and analyzed in the following method, and it was acknowledged thereby that the produced ingredients were heteropolysaccharides.
Analytical Method for Content of Indigestible Ingredient
A sample of 1 g measured precisely was dissolved in 50 ml of water and whose pH was adjusted to 5.8, then 0.1 ml of alpha-amylase ("Thermamyl 120" produced by Novo Co.) was added and allowed to react at a temperature of 95° C. for 30 minutes. The solution was cooled and adjusted to pH 4.5, then 0.1 ml of amyloglucosidase (produced by Sigma Co.) was added to be allowed to react at a temperature of 60° C. for 30 minutes, and further heated up to 90° C. to complete the reaction. After these processes, the solution was filtered and condensed to 5% to be applied to HPLC (High-Performance Liquid Chromatography), whereby the amount of glucose produced from saccharides was measured. Content of the indigestible polysaccharides was obtained by the following expression:
Content of indigestible polysaccharides (%) =100-(monosaccharides produced % × 0.9)
Acknowledgment Method of Heteropolysaccharides
The solution obtained was dissolved in water, and a part thereof was hydrolyzed with acid and neutralized to be placed in HPLC, and the acknowledgment of heteropolysaccharides was conducted through comparison with the composition of saccharides before the hydrolysis.
Example of experiment 1
A predetermined amount of the materials specified in Table 1 were employed for the process. The results obtained are also shown in Table 1. Note that descriptions in Table 1 respectively represent the following.
Mixing ratio is the one at dry condition (by weight).
SD indicated in drying method means spray-drying in which material mixtures were dissolved to 40% by weight, then 1% hydrochloric acid solution added by 5% to the mentioned mixtures under dry condition and dried up at an inlet-air temperature of 160° C., at an outlet-air temperature of 95° C., and at an atomizer revolution of 14000 r.p.m.
Note that the solutions No.1, No.2, No.12 were of 30% by weight.
FD indicated in drying method indicates vacuum freeze-drying method in which material mixtures were dried up at a freezing temperature of -20° C., and at a table temperature of 40° C., other conditions being the same as in SD.
______________________________________DE5: waxy corn starch hydrolyzed by alpha-amylaseDE25: corn starch hydrolyzed by acidDE35: corn starch hydrolyzed by acidDextrin: potato starch pyrodextrin(British Gum 70E produced by Matsutani Chemicals)Oxidized starch: cassaba (tapioca) starch processed by sodium hypochlorous acid(Stabilose S-10 produced by Matsutani Chemicals)______________________________________
Note that each of the above processes by alpha-amylase, acid heat up dextrin, and sodium hypochlorite was carried out in accordance with the following method:
Hydrolysis by alpha-amylase
2000 Kgs of waxy corn starch was dissolved in 4000 liters of water, Klaistase KD in 3 Kgs was added after being adjusted to pH 5.8 with calcium carbonate, then poured into 500 liters of hot water at a temperature of 85° C. with steam introduced therein to keep the temperature at around 85° C. After the pouring which took 15 minutes, the solution was boiled under a pressure of 1.5 Kg for 10 minutes, then gushed out under normal pressure. After cooling at about 85° C, 2 Kgs of Klaistase KD was further added to the solution, and secondary hydrolysis was carried out while keeping the temperature at 85° C. for 25 minutes. Oxalic acid was then added to the solution and adjusted to pH 4.0 so as to terminate the reaction of alpha-amylase. The solution was refined through known processes of decoloration, filtration, and by ion-exchanger resins to be condensed to 35%, and finally spray-dried to obtain powder of about 1450 Kgs.
Hydrolysis by acid (DE25)
2000 Kgs of corn starch was dissolved in 4000 liters of water, 7 Kgs of oxalic acid was added, then poured into 500 liters of hot water at a temperature of 85° C. with steam introduced therein to keep the temperature at around 85° C. After the pouring which took 25 minutes, the solution was boiled under a pressure of 1.5 Kg for 40 minutes, then gushed out under normal pressure. The pH of the solution was adjusted to 5.5 with calcium carbonate, then the solution was refined through known processes of decoloration, filtration, and by ion-exchanger resins to be condensed to 50%, and finally spray-dried to obtain powder of about 1500 Kgs.
Hydrolysis by acid (DE35)
2000 Kgs of potato starch was dissolved in 4000 liters of water, 8 Kgs of oxalic acid was added, then poured into 500 liters of hot water at a temperature of 85° C. with steam introduced therein to keep the temperature at around 85° C. After the pouring which took 25 minutes, the solution was boiled under a pressure of 1.6 Kg for 50 minutes, then gushed out under normal pressure. The pH of the solution was adjusted to 5.5 with calcium carbonate, then the solution was refined through known processes of decoloration, filtration, and by ion-exchanger resins to be condensed to 45%, and finally spray-dried to obtain powder of about 1400 Kgs.
Pyrodextrin
5000 Kgs of potato starch was put into a Ribbon Mixer, 1% hydrochloric acid in 150 liters was sprayed with stirring and uniformized through a mixer, further allowed to mature in the Ribbon-Mixer. The obtained mixture was preliminarily dried up to a condition containing 3% of water, subsequently put into a Rotary-Kiln-Type converter to be continuously heated at a temperature of 180° C. for two hours. Finally about 4000 Kgs of pyrodextrin was obtained.
Oxidation of starch
1000 Kgs of tapioca starch was dissolved in 1200 liters of water and stirred, then its pH was adjusted to 9.5 with sodium hydroxide solution, and similarly adding with sodium hydroxide solution to keep pH appropriately, and then 200 liters of sodium hypochlorite solution was poured into the above solution for two hours. The temperature kept in the range of 21° to 23° C. for it to react for 5 hours, sodium sulfite solution was added to stop the reaction, then sulfuric acid was added for neutralization. Subsequently, the mixture was washed in water in a normal method and flash-dried to be 900 Kgs of powder.
TABLE 1-1______________________________________Starch HeatingDecompo- Mixing Drying MethodNo sition Saccharides Rate Method °C. hr______________________________________1 DE5 fructose 85:15 SD 140 × 1.02 DE5 sucrose 50:50 SD 140 × 1.03 DE5 fructo-oligo- 50:50 FD 148 × 1.0 saccharides4 DE5 galacto-oligo- 70:30 FD 160 × 2.0 saccharides5 DE25 galactose 90:10 SD 150 × 2.06 DE25 xylose 50:50 SD 140 × 0.57 DE35 fructose 95:5 SD 120 × 0.58 DE35 sucrose 90:10 SD 140 × 1.09 DE35 fructo-oligo- 80:20 SD 120 × 1.0 saccharides10 DE35 70:30 SD 150 × 2.011 dextrin lactose 50:50 SD 150 × 1.012 oxidized galactose 80:20 SD 160 × 2.0starch______________________________________
TABLE 2-2______________________________________Indigestible Product Before AfterNo. Processing Processing Average Weight______________________________________1 12 76 8002 12 71 10003 37 88 12004 17 89 14005 2 80 7006 2 77 6007 0 60 8008 0 65 7009 15 70 55010 23 85 100011 22 90 150012 9 65 2000______________________________________
DESCRIPTION OF THE PREFERRED EMBODIMENTS
EXAMPLE 1
A mixture of 850 gs of starch hydrolyzate of DE3.5 (Pinedex No.100 produced by Matsutani Chemicals) and 150 gs of fructose was dissolved in water to get a 40% solution, then 500 ppm of hydrochloric acid was added, and dried up with a spray-drier (at an inlet air temperature of 160° C., an outlet air temperature of 95° C., and atomizer speed at 14000 r.p.m.).
Subsequently, 500 gs of the powder obtained through the above was placed in an aluminum vat and heated in an oven in order at a temperature of 100° C. for 30 minutes, at a temperature of 140° C. for 30 minutes, and at a temperature of 160° C. for 30 minutes, respectively.
The powder obtained in the above process was then dissolved in water and neutralized with sodium hydroxide, decolorized with activated charcoal, then desalted with ion-exchanger resins and finally spray-dried to obtain 450g of powder. Properties of this powder were as follows:
______________________________________Average molecular weight 5500Decomposition ratio of pancreatin 8.5%Indigestible portion 75.8%______________________________________
EXAMPLE 2
A mixture of 500 gs of starch hydrolyzate of DE8.0 (Pinedex No.100 produced by Matsutani Chemicals) and 500 gs of sugar was dissolved in water to be a 40% solution, then 300 ppm of hydrochloric acid was added, and dried up with a freeze-drier (at an inlet air temperature of -20° C., a table temperature of 40° C.).
Subsequently, 500 gs of the powder obtained through the above was ground and placed in an aluminum vat and heated in an oven in order at a temperature of 140° C. for 30 minutes.
The powder obtained in the above process was then dissolved in water and neutralized with sodium hydroxide, decolorized with activated charcoal, then desalted with ion-exchanger resins and finally spray-dried to obtain 400g of powder. Properties of this powder were as follows:
______________________________________Average molecular weight 8000Decomposition ratio of pancreatin 7.7%Decomposition ratio of invertase 1.3%Indigestible portion 62.8%______________________________________
EXAMPLE 3
A mixture of 2000 Kgs of starch hydrolyzate of DE3.5 (Pinedex No.1 produced by Matsutani Chemicals) and 2000 Kgs of lactose was dissolved in water to be a 40% solution, then 500 ppm of hydrochloric acid was added, and dried up with a spray-dryer (with an inlet air temperature of 170° C., an outlet air temperature of 90° C., and an atomizer speed at 4500 r.p.m.). Then 3900 Kgs of the obtained powder was placed in a Rotary-Kilin-Type converter and continuously heated at a temperature of 160° C. for one hour and a half.
The powder obtained in the above process was then dissolved in water and neutralized with sodium hydroxide, decolorized with activated charcoal, then desalted with ion-exchanger resins and finally spray-dried to be 3000 Kgs of powder. Properties of this powder were as follows:
______________________________________Average molecular weight 3500Decomposition ratio of pancreatin 5.2%Decomposition ratio of invertase 1.2%Indigestible portion 87.8%______________________________________
EXAMPLE 4
A mixture of 800 gs of starch hydrolyzate of DE39 (Pinedex No.100 produced by Matsutani Chemicals) and 200 gs of xylose was dissolved in water to be a 45% solution, then 400 ppm of hydrochloric acid was added, and dried up in the same method as in Example 1.
Subsequently, 800 gs of the obtained powder was put in an aluminum vat and heated in an oven at a temperature of 130° C. for 25 minutes.
The powder obtained in the above process was then dissolved in water and neutralized with sodium hydroxide, decolorized with activated charcoal, then desalted with ion-exchanger resins and finally spray-dried to obtain 650 gs of powder. Properties of this powder were as follows:
______________________________________Average molecular weight 520Decomposition ratio of pancreatin 4.5%Decomposition ratio of invertase 0.8%Indigestible portion 88.4%______________________________________
EXAMPLE 5
A mixture of 600 gs of pyrodextrin (Arabix No.6 produced by Matsutani Chemicals) and 400 gs of galactose was dissolved in water to be a 50% solution, then 500 ppm of hydrochloric acid was added, and dried up in the same method as in Example 2.
Subsequently, 850 gs of the powder obtained was put in an aluminum vat and heated in an oven at a temperature of 150° C. for 40 minutes.
The powder obtained in the above process was then dissolved in water and neutralized with sodium hydroxide, decolorized with activated charcoal, then desalted with ion-exchanger resins and finally spray-dried to obtain 650 gs of powder. Properties of this powder were as follows:
______________________________________Average molecular weight 1600Decomposition ratio of pancreatin 3.5%Decomposition ratio of invertase 0.7%Indigestible portion 90.5%______________________________________
EXAMPLE 6
A mixture of 750 gs of oxidized starch (Stabilose S-10 produced by Matsutani Chemicals) and 250 gs of lactose was dissolved in water to be a 40% solution, then 350 ppm of hydrochloric acid was added, and dried up in the same method as in Example 2.
Subsequently, 750 gs of the powder obtained was put in an aluminum vat and heated in an oven at a temperature of 180° C. for 40 minutes.
The powder obtained in the above process was then dissolved in water and neutralized with sodium hydroxide, decolorized with activated charcoal, then desalted with ion-exchanger resins and finally spray-dried to obtain 600 gs of powder. Properties of this powder were as follows:
______________________________________Average molecular weight 2100Decomposition ratio of pancreatin 7.7%Decomposition ratio of invertase 1.1%Indigestible portion 80.4%______________________________________
Note that the analyzing methods employed in the preferred Examples 1 to 6 were as follows.
Also note that the starch decomposition products employed in the preferred Examples 1 to 6 were respectively produced in the following manner.
Pinedex No.100
Produced in the same condition as for hydrolysis by alpha-amylase (DE5) employed in Example 1 of Experiment except that the time of secondary hydrolysis was changed to 18 minutes.
Pinedex No.1
Produced in the same condition as for hydrolysis by alpha amylase (DE5) employed in Example 1 of Experiment except that the material was corn starch and that the amount of Klaistase KD was changed to 4 Kgs, and the time to 30 minutes.
Pinedex No.6
Produced in the same condition as for hydrolysis by acid (DE5) employed in Example 1 of Experiment except that the time for boiling was changed to 60 minutes.
Arabix No.7
Produced in the same condition as for Pyrodextrin by acid (DE5) employed in Example 1 of Experiment except that the temperature for heating was changed to 170° C.
Decomposition ratio of pancreatin
The same was made to a 10% solution, and at pH 6.5 at a temperature of 37° C., 1% by solid basis of pancreatin (produced by Ishizu Co.) was added to it, and the digestion was conducted for 10 hours, finally the decomposition ratio was expressed by the following equation: ##EQU1##
Decomposition ratio of lactase
The sample to a 10% solution, and at pH 7.3 at a temperature of 37° C., 1% by solid basis of β-galactocidase (produced by Sigma Co.) was added to it, and the digestion was conducted for 10 hours, finally the decomposition ratio was estimated by the following equation: ##EQU2##
Decomposition ratio of invertase
The same was made to a 10% solution, and at pH 4.0 at a temperature of 20° C., 1% by solid basis of invertase (produced by Wako Junyaku Co.) was added to it, and the digestion was conducted for 10 hours, finally the decomposition ratio was obtained through the following equation: ##EQU3##
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A process of preparing indigestible heteropolysaccharides which features dissolving starch decomposition products and at least one kind out of monosaccharides excluding glucose, homo-oligosaccharides excluding gluco-oligosaccharides, and hetero-oligosaccharides into water and to which an inorganic acid was added, then powdering and heating the powder in an anhydrous condition thereof.
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CROSS-REFERENCE WITH RELATED APPLICATIONS
This application claims the benefit of U.S. Provisional Application Ser. No. 60/092,568, filed Jul. 13, 1998.
BACKGROUND OF THE INVENTION
1. Field of the Invention
This invention relates generally to the field of phosphorus chemistry, and is particularly concerned with a novel method for the production of α-keto bisphosphonate esters (carbonylbisphosphonate esters) and the use of these esters in reactions with C, N, O, or P nucleophiles for synthesis of α-functionalized bisphosphonates.
2. Description of Related Art
There are several pathological conditions that involve irregularities in calcium and phosphate metabolism. Such conditions comprise bone related diseases including Paget's disease and osteoporosis, as well as osteolysis in bone metastases. Bone metastases present a major problem in many frequently occurring malignancies. Hypercalcemia, resulting from bone resorption, is a common and very important complication of malignancy, causing distressful symptoms, such as severe pain and spontaneous fractures, and may lead to a metabolic coma and death. Moreover, neoplastic cell-induced osteolysis may determine the localization and growth enhancement of bone tumors. (See, G. R. Mundy, Bone, 8, supp. 1, S9-5 16 (1987); and Calcium in Biological Systems, R. P. Rubin, G. B. Weiss, and J. W. Putney, Jr. eds. Plenum Press, N.Y. (1985). Other pathological conditions cause or result from deposition of calcium and phosphate anomalously in the body, such as rheumatoid arthritis and osteoarthritis.
In some common bone disorders, the balance between the process of resorption and formation remains normal, but the rate of bone turnover is much higher. Most cases of primary hyperparathyroidism, Paget's disease, and thyroxicosis are in this category. In other common diseases such as osteoporosis, there is an imbalance between resorption and formation. Whether increased resorption or impaired formation predominates, however, the consequence is the same, i.e., diminished total bone mass.
Natural pyrophosphates having the structure: ##STR1## are known to be natural regulators of Ca 2+ metabolism at the cellular level. In recent years, many investigators have shown interest in the method of synthesis and biological activity of synthetic analogs of pyrophosphates, namely bisphosphonates and their derivatives. Bisphosphonic acids having the structure: ##STR2## and their derivatives are pyrophosphate analogs in which the oxygen between the two phosphorus atoms is replaced by a carbon.
Bisphosphonates are a class of drugs that have been developed for use in various metabolic diseases of bone, the target being excessive bone resorption and inappropriate calcification and ossification. (M. D. Francis and R. R. Martodam, "The Role of Phosphonates in Living Systems" R. L. Hilderbrand, ed., CRC Press, Boca Raton, Fla., 1983, pp. 55-96; and H. Fleisch, Bone, 1987, 8, Supp. 1, S23-S28). A current theory attributes the biological activity of anti-resorptive bisphosphonates to two design components. One of these components is the so-called "bone-hook" functionality, associated with the bisphosphonate backbone, which is all of the molecule except the R group substituent in the following formula (3): [(HO) 2 P(O)CR(OH)P(O)(OH) 2 ]. This bone-hook functionality is directly responsible for primary hydroxyapatite adsorption. The second design component is the bioactive moiety, R group, which is postulated to modulate the anti-resorptive potency of the drug within a given affinity class. See, Ebetino, F. H., Dansereau, S. M., Bisphosphonate on Bones; Bijvoet, O., Fleisch, H. A., Canfield, R. E., Russell, G., Eds. Elsevier Science B. V. 1995, p. 139-153. Numerous references disclose compositions containing polyphosphonates, in particular bisphosphonates, such as 1-hydroxyethylidenediphosphonic acid (HEDP) having the formula: (HO) 2 P(O)CCH 3 (OH)P(O)(OH) 2 , where the R group in (3) is CH 3 . See, U.S. Pat. Nos. 3,683,080 and 4,230,700 to Francis. See also, U.S. Pat. No. 4,868,164 to Ebetino, et al., which refers to heterocyclic bisphosphonates. HEDP is used in medicine under the name Etidronate (disodium salt of HEDP). HEDP is a useful complexing agent for alkaline earth, transition, and lanthanide metals. HEDP is also used to regulate calcium metabolism in the treatment of Paget's disease, to inhibit formation and growth of calcium oxalate stones in kidneys, and to reduce plaque when added to dental preparations. HEDP has also been suggested for use in treatment of diseases ranging from bone cancer to arthritis (See, Zolotukhina, et al., Russian Chemical Reviews, 1993, 62, 647-659). Numerous other references describe bisphosphonic acids useful for the treatment of osteoporosis and/or arthritis, and are herein incorporated by reference: U.S. Pat. No. 5,104,863 to Benedict, et al.; U.S. Pat. No. 4,267,108 to Blum, et al.; U.S. Pat. No. 4,754,993, to Bosies, et al.; U.S. Pat. No. 4,939,130 to Jaeggi, et al.; U.S. Pat. No. 4,971,958 to Bosies, et al.; DE 40 11 777 to Jaeggi; WO 90/12017 to Dunn, et al.; WP 91/10646 to Youssefyeh, et al.; AU-A-26738/88 to Jaeggi; AU-A-45467/89, assigned to Ciba-Geigy; and U.S. Pat. No. 4,208,401 to Bauman.
The elucidation and further development of structure-activity relationships in the bisphosphonate class of compounds has increasingly flourished during the past few years (See, Ebetino, F. H., et al., supra; and Zolotukhina, et al., supra.) Rational design of new medicinal agents based on bisphosphonates has progressed from simple α-alkyl and α-halo bisphosphonates, to bisphosphonates substituted with a range of heterocyclic and heteroatomic moieties. Bisphosphonate chemistry has yielded an increasing variety of bone-active compounds, including potent anti-resorptive agents that have therapeutic potential in osteoporosis and other diseases of bone metabolism (See, Ebetino, F. H., et al., supra.) Variation in the P-C-P backbone has led to analogs of varied hydroxyapatite affinity, Ca 2+ chelation and anti-mineralization properties.
McKenna, et al., have reported the synthesis of crude carbonylbisphosphonate ester preparations by reaction of the corresponding α-diazo compounds with tert-butyl hypochlorite in formic acid, followed by a second step of pyrolytic distillation at reduced pressure. (See, McKenna, C. E.; Khare, A.; Ju, J. -Y.; Li, Z. -M.; Duncan, G.; Cheng, Y. -C.; Kilkuskie, R. Phosphorus Sulfur, 76:139-142, 1993). However, this method of synthesis suffers from serious defects: 1) The carbonylbisphosphonate esters are obtained in moderate to poor, erratic, yields, particularly due to the instability of the reaction mixture to prolonged heating; 2) An undesirable α-dichlorinated side product is usually formed, which resists attempts at removal; 3) Other impurities are often present, seen by NMR analysis. Furthermore, the vacuum pyrolysis in the second step is difficult to control and is difficult to scale up.
It has also been reported that reaction of carbanion nucleophiles such as Reformatsky reagents with α-keto monophosphonates (4) leads not to the desired α-hydroxy α-alkylated adduct (5) of the present invention, but instead to elimination of the phosphorus moiety forming a carbonyl product (6) and phosphite (7) (See, Breuer, E., The Chemistry of Organophosphorus Compounds; Hartley, F. R., Ed.; John Wiley & Sons: New York, (1996) Vol. 4: 653-730, p.685.) ##STR3##
Hydrates of the impure carbonylbisphosphonate esters, prepared by the previous method of McKenna, et al., are readily formed by treatment with H 2 O, however, the hydrates were not isolated. (See, McKenna, et al., supra.) Prior to the present invention, attempts to regenerate pure carbonylbisphosphonate esters, free of the α,α-dichloro contaminant and other impurities, have been unsuccessful. For example, in the previous method of McKenna, et al., the regeneration of carbonylbisphosphonate esters by evaporation (via heating and low pressure) of the aqueous phase, after extraction with an organic solvent, lead instead to formation of an unwanted product containing both phosphonate and phosphate groups.
It was previously reported that vicinal trioxo compounds can be obtained from corresponding α-diazo compounds through an "oxygen-halogen-insertion" reaction using t-BuOCl in formic acid, acetonitrile and other solvents (See, Regitz, M.; Adolph, H. -G. Liebigs Ann. Chem. 1969, 723, 47-60.) Regitz, et al., proposed that chloro-tertbutyloxy-diacylmethanes are first formed, which decompose spontaneously into tertbutyl chloride and the trioxo product. As described above, an analogous approach led to the synthesis of crude carbonylbisphosphonate esters. (See, McKenna, et al., Phosphorus Sulfur, (1993), supra). The unsatisfactory nature of this method was initially ascribed to inadequate drying of the solvent, or non-optimal solvent. However, reactions carried out according to the previous procedure of McKenna, et al., between diazo MDP esters and t-BuOCl in different, very well-dried solvents, such as: acetonitrile; acetone; ethyl acetate; t-butanol; and CCl 4 , still gave low yields of the desired products and was accompanied by the usual formation of unwanted side products, including α,α-dichlorinated bisphosphonate. (See, McKenna, et al., supra.) The intermediate product expected to be formed in the first step of this procedure, α-chloro-α-alkoxy methylenebisphosphonate, did not decompose spontaneously into the oxo product ( 31 P NMR evidence), and thus required pyrolysis.
Regitz, et al., postulated that interaction between 2-diazo 1,3-oxo compounds and t-butylhypochlorite in alcohols involves intermediate formation of an α-diazonium α-chloro bisphosphonate species and a t-butoxide anion, followed by nucleophilic substitution of the --N 2 + leaving group by an alcohol molecule (S N 2 or S N 1)(See, Regitz, et al., supra.) However, according to this mechanism, the first step, the formation of the α-diazonium α-chloro species and t-butoxide anion, requires release of t-butoxide, a very poor leaving group.
Generally, for efficient transfer of positive chlorine from alkylhypochlorite, an activated species, such as the protonated form of the alkoxide, is desirable as the leaving group. (See, Tassignon, P. S. G., et al., (1995) Tetrahedron Lett., Vol. 43: p.11 863-11 872). Thus, t-butanol is a more reasonable leaving group in this reaction than t-butoxide. In formic acid the solvent provides a proton, but also the wrong nucleophile for carbonylbisphosphonate ester formation, which then must be removed in the inefficient pyrolysis step. The substitution taking place in the second step of this reaction, between the α-diazonium α-chloro bisphosphonate species and a nucleophile, therefore requires a nucleophile able to produce an intermediate that facilely leads to the desired carbonylbisphosphonate ester. Consequently, it appears there is a need for a better nucleophile for this reaction. Moreover, α-hydroxy bisphosphonates possess high affinity for hydroxyapatite and can be highly potent anti-resorptive agents, thus chemistry that generates a methylenebisphosphonate with an α-hydroxy function together with the addition of a R group is particularly desirable.
There continues to be a need for new bone-active agents. Design and synthesis of new bisphosphonates active against bone diseases would be greatly aided by preparative methodology facilitating introduction of the R moiety into the bisphosphonate structure. Such methodology, could also be employed for preparation of bisphosphonates that would be useful in treating many bone and other diseases, such as viral infections, or other health disorders that may be responsive to phosphonate drugs. (See, Zolotukhina, et al., supra.) Indeed, methodology facilitating introduction of a R group moiety into the bisphosphonate structure could be used to prepare any bisphosphonate possessing a particular utility or desirable property requiring introduction of a specific R group.
BRIEF SUMMARY OF THE INVENTION
The present invention solves the above-described problems by providing methods for readily converting α-diazo methylenebisphosphonate esters into substantially pure carbonylbisphosphonate esters in a simple and economical reaction, while suppressing the α,α dichloro by-product. In one embodiment of the invention the process for the preparation of carbonylbisphosphonate comprises: forming a reaction mixture of α-diazo methylenebisphosphonate ester, tert-butylhypochlorite, and a polar aprotic organic solvent; and adding an effective amount of water to the reaction mixture, whereby conversion of the α-diazo methylenebisphosphonate ester to the substantially pure carbonylbisphosphonate is substantially complete. One advantage of the present invention is that it does not require the additional step of heating for conversion to the bisphosphonate ester to be complete. Yet another advantage of the present invention is the resultant high yield of the substantially pure carbonylbisphosphonate esters. In another embodiment of the invention, the carbonylbisphosphonate ester so produced is utilized in ketone reactions with C, N, O, or P nucleophiles providing a versatile pathway for synthesis of α-functionalized bisphosphonates. One of many possible examples is the classical reductive amination of ketone which provides bisphosphonates having the structure: ##STR4## These α-functionalized bisphosphonates could be used in treatment or preventing diseases characterized by irregular calcium and phosphate metabolism, including osteoporosis and arthritis.
These and other features, aspects, and advantages of the present invention will become better understood with regard to the following detailed description and appended claims.
DETAILED DESCRIPTION OF THE INVENTION
The synthetically versatile ketone group in carbonylbisphosphonate esters having the structure: ##STR5## provides a convenient entry to a wide range of new α-substituted bisphosphonates via nucleophilic addition chemistry. R 1 , R 2 , R 3 , and R 4 esterifying group, for example, when each are independently selected from alkyl (preferably having 1 to 24 carbon atoms), aryl (preferably having 6 to 30 carbon atoms), aralkyl (preferable having 7 to 24 carbon atoms) and hydrates thereof, which can serve as protecting groups and that are removable either chemically or metabolically.
One advantage of this approach in preparation of bone actives is that an α-hydroxy group may be generated with introduction of the R group moiety: ##STR6##
Herein we describe a new, mechanism-based approach to the synthesis of carbonylbisphosphonate esters and demonstrate exemplary reactions of these compounds with some C, N, O, and P-containing nucleophiles. This technology provides a versatile pathway to new α-substituted bisphosphonate derivatives and could be readily adapted to drug discovery synthetic strategies including combinatorial methods. Conversion of the product adducts, which are esters, to corresponding acids, could be effected in a variety of ways known to skilled practitioners, for example, from classical acid hydrolysis to much milder silyldealkylation with reagents such as bromotrimethylsilane. (See, McKenna, C. E.; Higa, M. T.; Cheung, N. H.; McKenna, M. -C. Tetrahedron Letters (1977), 155-158; and McKenna, C. E.; Schmidhauser, J. J. Chem. Soc., Chem. Comm. (1979), 739.)
The invention provides a new, rational understanding of the synthesis and reactive chemistry of α-keto bisphosphonate esters. The present invention solves a long standing problem in the synthesis of bisphosphonate derivatives namely, the preparation of pure carbonylbisphosphonate esters. Furthermore, it was surprisingly found that α-keto bisphosphonate esters, prepared in virtually pure form by the new method, readily reacted with a metalated carbanion reagents, e.g., Grignard, to give desired α-hydroxy α-alkylated bisphosphonates, rather than simply elimination products that might be expected by analogy with Breuer, E., supra.
The interaction of α-diazo methylenebisphosphonate esters with t-butylhypochlorite in ethyl acetate in the presence of 1-10 equivalents of water proceeded exothermically at room temperature, about 20° C., with evolution of N 2 , and the reaction mixture was maintained at this temperature by cooling. The reaction formed the desired carbonylbisphosphonate ester in practically quantitative yield, greater than about 90%, within about 1 to 2 minutes after a typical induction period of about 2 to 5 minutes. The above kinetic behavior indicated an autocatalytic character of the reaction, wherein HCl, generated as a reaction product, accelerated the reaction by protonation of the t-butyloxy leaving group. However, an excess of hydrogen chloride product must be avoided, otherwise chlorination of the intermediate product of α-diazonium, α-chloro bisphosphonate may take place, which leads to dichlorinated side products. Thus, the concentration of water in the reaction mixture is crucial to the success of the synthesis. Although an excess of water, relative to the diazo substrate, is essential to eliminate formation of the dichlorinated side product, by providing H 2 O nucleophile to compete with Cl, too large an excess of water will convert the product carbonylbisphosphonate ester to its corresponding hydrate, which may lead to a decomposition pathway, see the scheme below. It is thus very important to remove excess water immediately after the reaction is completed, which occurs when the evolution of N 2 ceases. The removal of excess water can be conveniently effected by adding a suitable reagent that removes water, such as: P 2 O 5 , SOCl 2 , and chlorotrimethylsilane (CTMS). The water trapping reagent CTMS was the preferable reagent for this purpose, as a liquid which reacts quickly with H 2 O forming hexamethyidisiloxane, an inert, volatile organic liquid, along with HCl. After removing the solvent, excess reagents, and by-products in vacuo, substantially pure carbonylbisphosphonate ester was obtained, and used directly in situ in further reactions. ##STR7##
If the water-trapping reagent is omitted, the carbonylbisphosphonate product is converted to its hydrate (methyl and isopropyl carbonylbisphosphonate esters). The hydrates are easily isolated as colorless, crystalline compounds with well defined melting points. Treatment of these pure hydrates with P 2 O 5 or magnesium perchlorate in organic solvents, such as: CH 2 Cl 2 , CHCl 3 , ether, and acetonitrile conveniently regenerate the carbonylbisphosphonate esters.
Tetramethyl carbonylbisphosphonate hydrate readily dissolves in H 2 O, where it decomposes to dimethyl hydrogen phosphonate, a process catalyzed by a base, such as: sodium acetate, and sodium bicarbonate. Other hydrates are also presumed to react according to the following scheme: ##STR8##
On heating, the carbonylbisphosphonate hydrates produce a product, whose NMR and Mass Spectrometry (MS) data are consistent with the products formed according to the following scheme. ##STR9##
On heating, the hydrate 10 loses water to regenerate the carbonylbisphosphonate ester, and also decarboxylates to form dialkylphosphite. The phosphite adds to the carbonyl group of the carbonylbisphosphonate ester, giving an adduct which rearranges to the bisphosphonophosphate 11. To verify this scheme, the reaction between tetraisopropyl carbonylbisphosphonate and dimethyl phosphonate was investigated and is illustrated in the following scheme: ##STR10##
The formation of two products with the O-dimethoxyphosphoryl group (12) and O-diisopropoxyphosphoryl group (13), (12:13; ratio 1:0.75 by 31 P NMR analysis), proved the instability of the intermediate α-hydroxy trisphosphonate, which has three phosphorus atoms connected to the α-carbon atom. Formation of the two products revealed that the migratory aptitude of the dimethoxyphosphoryl group was about 3 times higher than that of the diisopropoxyphosphoryl group in the subsequent rearrangement step. The formation of the compound, the O-diisopropoxyphosphoryl group (13), also demonstrated that nucleophilic phosphorus attacked at the carbon rather than the oxygen of the carbonyl group.
Referring now to the reaction chemistry of the ketones, according to literature cited above, dialkyl acylphosphonates are reported to react with metal carbanion reagents with the formation of carbonylbisphosphonate esters, as a consequence of the elimination of phosphite from the initial addition product. See, Breuer, E., supra. The carbonylbisphosphonate esters of the present invention serve as starting compounds for the synthesis of different α-alkylated, α-hydroxy methylenebisphosphonate derivatives by reaction with Grignard reagents. For example, the tetraisopropyl ester of HEDP was obtained from the reaction of tetraisopropyl carbonylbisphosphonate and methyl magnesium iodide. Other halogens can be substituted for iodine, such as chlorine or bromine. The reactions were carried out in mixed organic-ether solvents and yields of the desired products were from about 40 to 75%. ##STR11##
Wherein R 1 , R 2 , R 3 , and R 4 are each independently selected from an alkyl and aryl group, which group may include a heterocyclic compound. As examples R 1 , R 2 , R 3 , and R 4 are each independently isopropyl and ethyl; R' is alkyl or aryl group, which group may include a heterocyclic compound, as examples R' is methyl, phenyl, or arylalkyl.
It was previously reported that impure esters of carbonylbisphosphonate are converted to the corresponding aryl hydrazones by a standard reaction with aryl hydrazine. (See, McKenna, C. E., et al., supra.) The purer carbonylbisphosphonate esters made by the present invention described herein react smoothly with another nitrogen-containing nucleophile, NH 2 OMe, giving oxime esters. For example, reaction of iPr 4 carbonylbisphosphonate gave the corresponding novel O-methyl oxime product in a 60% yield: ##STR12##
All reactions in these Examples were performed in scrupulously dried glassware under N 2 . All solvents and reagents were of Analytical Reagent (AR) grade quality, purchased from Sigma-Aldrich, Inc. Nuclear Magnetic Resonance (NMR) spectra were recorded on a Bruker AM 360 spectrometer. 1 H and 13 C NMR chemical shifts (ppm) are referenced to tetramethylsilane. 31 P NMR chemical shifts (ppm) are referenced to external 85% H 3 PO 4 . Chemical shifts are reported in ppm. Melting points were recorded on a Thomas Hoover apparatus.
EXAMPLE 1
Synthesis of tetraisopropyl carbonylbisphosphonate
To a solution of tetraisopropyl α-diazo methylenebisphosphonate (74 mg, 0.2 mmol) in 4 ml ethyl acetate (0.14 M H 2 O) cooled by an ice bath (about 10-15° C.) was added at least one equivalent, preferably 1.5 equivalents excess of t-butyl hypochlorite in 2 ml ethyl acetate (0.14 M H 2 O). After about 2 to 5 minutes, N 2 rapidly evolved from the reaction mixture with a corresponding change in the reaction mixture color from colorless to yellow. 1 mM of chlorotrimethylsilane was then added to reaction mixture, and after about 5 minutes, 3 ml of the solvent was removed in vacuo. The resulting solution of carbonylbisphosphonate ester was used in different reactions without additional purification 31 P NMR (ethyl acetate): δ -4.9, the yield of product was approximately 95%.
EXAMPLE 2
Synthesis of tetramethyl carbonylbisphosphonate
By use of the same procedure as described in Example 1, tetramethyl α-diazo methylenebisphosphonate in 4 ml ethyl acetate (0.14 M H 2 O) cooled by an ice bath (10-15° C.) was added a 1.5 excess of t-butyl hypochlorite in 2 ml ethyl acetate (0.14 M H 2 O). After about 2 to 5 minutes, N 2 rapidly evolved with a corresponding change in the reaction mixture color to yellow. 1 mM of chlorotrimethylsilane was added to reaction mixture, and after 5 min, 3 ml of solvent was removed in vacuo. The resulting solution of carbonylbisphosphonate ester was used in different reactions without additional purification. 31 p NMR (ethyl acetate): δ -1.8, the resulting yield of product was approximately 93%.
EXAMPLE 3
Synthesis of tetraethyl carbonylbisphosphonate
By use of the same procedure as described in Example 1, tetraethyl α-diazo methylenebisphosphonate in 4 ml ethyl acetate (0.14 M H 2 O) cooled by an ice bath (10-15° C.) was added a 1.5 excess of t-butyl hypochlorite in 2 ml ethyl acetate (0.14 M H 2 O). After about 2 to 5 minutes, N 2 rapidly evolved with a corresponding change in the reaction mixture color to yellow. 1 mM of chlorotrimethylsilane was added to reaction mixture, and after 5 min, 3 ml of solvent was removed in vacuo. The resulting solution of methylenebisphosphonate was used in different reactions without additional purification. 31 P NMR (ethyl acetate): δ -3.9, the resulting yield of product was approximately 94%.
EXAMPLE 4
Synthesis of hydrate of tetramethyl carbonylbisphosphonate
By use of the same procedure as described in Example 1, tetramethyl α-diazo methylenebisphosphonate in 4 ml ethyl acetate (0.14 M H 2 O) cooled by an ice bath (10-15° C.) was added a 1.5 excess of t-butyl hypochlorite in 2 ml ethyl acetate (0.14 M H 2 O). After about 2 to 5 minutes, N 2 rapidly evolved with a corresponding change in the reaction mixture color to yellow. However, the chlorotrimethylsilane was not added to the reaction mixture to remove the water in the last step. After 5 min, 3 ml of the solvent was removed in vacuo. Crystals of the hydrate were filtrated, and washed with dry ether. 31 P NMR (D 2 O): δ 16.9, the resulting yield of product was about 80%, and the m.p. 97-98° C.
EXAMPLE 5
Synthesis of hydrate of tetraisopropyl carbonylbisphosphonate
By use of the same procedure as described in Example 4, tetraisopropyl α-diazo methylenebisphosphonate in 4 ml ethyl acetate (0.14 M H 2 O) cooled by an ice bath (10-15° C.) was added a 1.5 excess of t-butyl hypochlorite in 2 ml ethyl acetate (0.14 M H 2 O). After about 2 to 5 minutes, N 2 rapidly evolved with a corresponding change in the reaction mixture color to yellow. Again, the chlorotrimethylsilane was not added to the reaction mixture to remove the water in the last step. About 2.5 equivalent volumes of pentane was added to the final solution until hydrate precipitation was induced. After 5 min, 3 ml of the solvent was removed in vacuo. Crystals of the hydrate were filtered, and washed with dry ether. 31 P NMR (D 2 O): δ 14.2, the resulting yield of product was about 20%; m.p. 49 to 51° C.
EXAMPLE 6
Synthesis of tetraisopropyl 1-hydroxy-ethylidenebisphophonate
Using the same reaction as described in Example 5, 2 mmol carbonylbisphosphonate ester was synthesized, but before the solvent was removed in vacuo, an equal volume of dry toluene was added 1:1 to the reaction mixture. 2/3 of the solvent was removed in vacuo, and a toluene solution of the carbonylbisphosphonate ester was added to a 5 ml ether solution of the Grignard reagent (5-fold excess) obtained from Mg and Mel at 5° C. After 10 min, the reaction mixture was diluted with 30 ml ether, washed with 20 ml cold (about 0 to 5° C.) 5% acetic acid and 20 ml water, and dried over Na 2 SO 4 . The solvent was removed in vacuo, and the compound purified by TLC. The yield was about 78%. The volume of eluent acetone to chloroform was 1:5. 31P NMR (CDCl 3 ): δ 19.3; 13 C NMR (CDCl 3 ): δ 71.1, (t, 2 J pc =154 Hz. 1 H NMR (CDCl 3 ): δ 1.6, t, 3 J PH =16 Hz.
EXAMPLE 7
Synthesis of tetraisopropyl hydroxy-phenylmethylenebisphosphonate
The same procedure as described in Example 6 was used, but the Grignard reagent was obtained from bromobenzene and Mg. The yield was about 38%. The compound was purified by TLC (benzene:ethyl acetate, 1:1). 31 P NMR (CDCl 3 ): δ 15.7; 1 H NMR (CDCl 3 ): δ 1.2-1.4 (m, 24H), 3.8 (broad s, 1H), δ 4.75-4.95 (m, 4H), 7.2-7.8 (m, 5H).
EXAMPLE 8
Synthesis of tetraethyl 1-hydroxy-2-phenylithyledenebisphosphonate
The same procedure as described in Example 6 was used, but the Grignard reagent was obtained from benzyl chloride and Mg. The yield was about 48%. The compound was purified by TLC (benzene:ethyl acetate, 1:1). 31 P NMR (CDCl 3 ): δ 19.6. 1 H NMR (CDCl 3 ): δ 3.3 (t, 2H) 3 J PH =13.4 Hz, 3.8 (broad s, 1H), 4.0 to 4.3 (m, 8H).
EXAMPLE 9
Synthesis of tetraisopropyl (O-methylhydroxyimino)methylenebisphosphonate
To 3 mmol of 0-methyl hydroxylamine hydrochloride (in 10 ml methanol) was added 3 mmol of NaOH. After addition, the reaction mixture was stirred for 1 hour. 2 mmol of tetraisopropyl carbonylbisphosphonate in 3 ml ethyl acetate, obtained as described in Example 1, was added, at room temperature, to the reaction mixture. After one day, the solution was filtered, and the solvent removed in vacuo. The compound was purified by column chromatography on silica gel, (acetone:CH 2 Cl 2 , 1:5). The yield of product was about 59%. 31P NMR (CDCl 3 ): dd δ 5.15, 1.95 2 J PP =54.5 Hz. 13 C NMR (CDCl 3 ): δ 23.5, 24.2, 64.0, 72.1, 72.5, dd 149.5, 1 J pc =196 Hz, 1 J pc =141 Hz. 1 H NMR (CDCl 3 ): δ 1.2-1.4 (m, 24H), 4.18 (s, 3H), δ 4.75-4.95 (m, 4H).
The following references, discussed above, are all incorporated herein by reference: G. R. Mundy, Bone, 8, supp. 1, S9-5 16 (1987);, R. P. Rubin, G. B. Weiss, and J. W. Putney, Jr. Calcium in Biological Systems eds. Plenum Press, N.Y. (1985); M. D. Francis and R.R. Martodam, "The Role of Phosphonates in Living Systems" R. L. Hilderbrand, ed., CRC Press, Boca Raton, Fla., 1983, pp. 55-96; H. Fleisch, Bone, 1987, 8, Supp. 1, S23-S28; U.S. Pat. Nos. 3,683,080 and 4,230,700 to Francis; U.S. Pat. No. 4,868,164 to Ebetino, et al.; Zolotukhina, et al., Russian Chemical Reviews, 1993, 62, 647-659; U.S. Pat. No. 5,104,863 to Benedict, et al.; U.S. Pat. No. 4,267,108 to Blum, et al.; U.S. Pat. No. 4,754,993, to Bosies, et al.; U.S. Pat. No. 4,939,130 to Jaeggi, et al.; U.S. Pat. No. 4,971,958 to Bosies, et al.; DE 40 11 777 to Jaeggi; WO 90/12017 to Dunn, et al.; WP 91/10646 to Youssefyeh, et al.; AU-A-26738/88 to Jaeggi; AU-A-45467/89, assigned to Ciba-Geigy; and U.S. Pat. No. 4,208,401 to Bauman; Ebetino, F. H., Dansereau, S. M., Bisphosphonate on Bones; Bijvoet, O., Fleisch, H. A., Canfield, R. E., Russell, G., Eds. Elsevier Science B.V. 1995, p.139-153; McKenna, C. E.; Khare, A.; Ju, J. -Y.; Li, Z. -M.; Duncan, G.; Cheng, Y. -C.; Kilkuskie, R. Phosphorus Sulfur, 76:139-142, 1993; Breuer, E., The Chemistry of Organophosphorus Compounds; Hartley, F. R., Ed.; John Wiley & Sons: New York, 1996; 4: 653-730, p.685; Regitz, M.; Adolph, H. -G. Liebigs Ann. Chem. 1969, 723, 47-60; McKenna, C. E.; Higa, M. T.; Cheung, N. H.; McKenna, M. -C. Tetrahedron Lett. (1977), 155-158; McKenna, C. E.; Schmidhauser, J. J. Chem. Soc., Chem. Comm. (1979), 739; and Tassignon, P. S. G., et al., (1995) Tetrahedron Lett., Vol. 43: p.11 863-11 872.
In a further embodiment of the invention, the carbonylbisphosphonate ester so produced is utilized in ketone reactions with C, N, O, or P nucleophiles providing a versatile pathway for synthesis of α-functionalized bisphosphonates. One of many possible examples is the classical reductive amination of ketone which provides bisphosphonates having the structure: ##STR13## These α-functionalized bisphosphonates could be used in treatment or preventing diseases characterized by irregular calcium and phosphate metabolism, including osteoporosis and arthritis. The carbonylbisphosphonate esters may be reacted with metalated carbanions to form α-substituted α-hydroxy methylenebisphosphonate esters.
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A unique method for the synthesis of substantially pure α-keto bisphosphonate esters and the usage of these esters in reactions with C, N, O, or P nucleophiles for synthesis of α-functionalized bisphosphonates. The method starts with a reaction mixture formed of an α-diazo methanediphosphonate ester, including tert-butylchlorite, a polar aprotic organic solvent, and an effective amount of water. After synthesis is complete, a water trapping reagent may be added to remove any excess water. The present invention provides a versatile pathway to new α-substituted bisphosphonate derivatives and could be readily adapted to combinatorial drug discovery synthetic strategies. The α-keto bisphosphonate esters can be converted to the corresponding acids by acid hydrolysis or mild silyldealkylation.
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BACKGROUND OF THE INVENTION
1. Field of the Invention
This invention describes a method of saving power in an implantable device, such as a pacemaker, which includes RF telemetry functionality.
2. Description of Related Art
Since the allocation of a special frequency band for implantable medical devices using RF telemetry, the so-called MICS (Medical Implantable Communication Service) band, by FCC in the late 1990's, the development of devices including this functionality has really taken off. However, since the battery capacity in an implantable device is very limited, the introduction of a RF transceiver operating at 402-405 MHz becomes a real challenge. If the transceiver operates at 5 mA in the active mode, this might be acceptable since in the normal user scenario the on-time is only a fraction (<0.01%) of the total device life time. A trickier problem is the issue of waking up the RF component from the off state to start communications in a reasonable amount of time without draining the battery.
The most common method of solving this problem today is to introduce the so-called sniff mode. This means that the complete receiver RF portion of the device is turned on for a limited period of time (e.g. 10 milliseconds) during which time the device listens to see if there are any transmitters active in the vicinity wanting to make contact. By duty cycling the on (sniff) time heavily with the off time a considerable power saving can be achieved. For example having the device on for 5 ms consuming 5 mA and then off for 995 ms while consuming only leakage current of maybe 100 nA will lower the average current consumption to only about 25 μA. This is very good in most applications. However, for an implantable device consuming less than 10 μA in total this is unacceptable. Lowering the average power consumption further by decreasing the on time is difficult since a certain time is needed to start up the RF receiver and to receive a message telling the device to start transmitting a response. Increasing the off time is not preferred since the doctor who is trying to get in contact with the device expects a response within a second or two.
An example of the prior art is found in U.S. Pat. No. 4,519,401 issued May 28, 1985.
SUMMARY OF THE INVENTION
According to the present invention there is provided an implantable electronic device, comprising a first radio receiver for receiving telemetry data, said first radio receiver having a wake mode and a sleep mode, and being configured to be in said sleep mode unless woken up by a triggering event; a second radio receiver with very low power consumption compared to said first radio receiver; a control unit coupled to the second radio receiver for periodically turning on the second radio receiver during a listen window to listen for an incoming radio frequency signal indicating an external device wishes to establish contact; an analyzer forming part of the second radio receiver for verifying the properties of an incoming radio signal, said analyzer, in response to receipt of said incoming radio frequency signal, prolonging the listening window to enable reception of a full wake-up message, wherein the prolongation of the listen window is sustained only as long as the properties of the incoming wake-up message match a correct message ; and said analyzer further being configured to place said first radio receiver in the wake mode to receive incoming telemetry data in response to the detection of a full correct wake-up message by the second radio receiver.
The first radio receiver normally forms part of a transceiver for exchanging two-way telemetry data with an external device.
Thus, in accordance with the invention, an implantable device with an RF telemetry transceiver has a separate low power receiver to wake-up the device to save power when an external RF unit wishes to communicate with the implanted device. The normal RF telemetry transceiver is turned off for most of the time except when there is an active telemetry link in operation.
The low power receiver has a simplified architecture to drive down the power consumption to about 200 μA and operates as a wake-up device for the full RF transceiver. Because of the simplicity of the low power receiver it can also be turned on very quickly (less than 200 μs).
For most of the time all the RF functionality in the implantable device is switched off and consumes less than 100 nA of leakage current. Every 1 second the lower power receiver is turned on by the application circuitry for about 0.5 ms to listen to see if there are any outside devices trying to get in contact. If an appropriate signal is received, the listen window is prolonged to enable the reception of a full wake-up message and trigger the turn on of the full-blown MICS transceiver, which starts to transmit and receive. The prolongation of the wake-up receiver's reception window is only sustained as long as the properties of the received message match a correct message. One example of such a property is to use so called Manchester encoding and to turn off the low power receiver as soon as any non-Manchester encoded signal is detected. This leads to additional power saving since the wake-up receiver is turned off immediately as soon as it becomes clear that the message is incorrect instead of receiving a complete wake-up message before checking if the message is correct or not.
With a power consumption of 200 μA from the low power receiver this will give a total average power consumption of 200 nA (100 nA leakage and 100 nA from the low power receiver).
In accordance with another aspect the invention provides a method of saving power in an implantable electronic device having a first radio receiver for receiving telemetry data, said first radio receiver having a wake mode and a sleep mode, and being configured to be normally in said sleep mode, said method comprising periodically listening in a sniff mode for a wake-up signal with a second radio receiver that has very low power consumption compared to said first radio receiver; in response to reception of part of a wake-up signal by said second radio receiver prolonging the sniff mode while the received part of a wake-up signal remains valid until a complete wake-up signal is received; and in response to a complete valid wake-up signal, placing said first radio receiver in the wake mode to receive incoming telemetry data.
BRIEF DESCRIPTION OF THE DRAWINGS
The invention will now be described in more detail, by way of example only, with reference to the accompanying drawings, in which:—
FIG. 1 is a block diagram of an implantable device in accordance with one embodiment of the invention; and
FIG. 2 is a more detailed block diagram of an embodiment of the invention.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT
Referring to FIG. 1 , the simplified receiver comprises an antenna 1 receiving a wake-up signal (common with the MICS band antenna or separate), an amplifier 2 which amplifies the signal, and a comparator/detector 3 that detects the amplified signal if it is above a certain power level.
To further increase the security of the receiver against the device being woken up by noise, the wake-up signal comprises a predetermined coded pattern, which is analyzed in an analyzer 4 to see if it matches the wake-up pattern. Only if the pattern is correct the full transceiver 5 will be turned on by the analyzer 4 . The amplifier 2 , comparator 3 and analyzer 4 form part of a simple very low power receiver 20 , which is periodically turned on during a sniff period to listen for an incoming radio frequency signal by a control unit 21 .
FIG. 2 shows another embodiment where an RF signal is received by a tuned antenna 6 connected to an amplifier 7 , an optional band pass filter 8 , which in turn is connected to a rectifier 9 , connected to a comparator 10 , which is connected to an analyzer 11 . The analyzer 11 is connected to the full high power RF transceiver 12 . The amplifier 7 , the band pass filter 8 , the rectifier 9 , the comparator 10 form part of a simple low power RF receiver circuit 13 . The control block 15 controls the turning on and turning off of the low power receiver 13 .
The full transceiver may use the same antenna as the low power receiver as shown in FIG. 1 or may use a separate antenna as shown in FIG. 2 with antenna 14 shown as a separate entity.
The incoming RF signal picked up by the antenna 6 is fed into the simple receiver circuit 13 . The described solution uses a Manchester encoded On/Off Keying (OOK) modulation scheme, but other modulation schemes such as Frequency Shift Keying (FSK), Phase Shift Keying (PSK), etc. can also be envisioned for those skilled in the art.
The signal picked up by the antenna is amplified by the amplifier 7 , fed into the low power band-pass filter 8 that filters the signal around the chosen wake-up frequency, in or outside the MICS band. The filtered signal is then fed into the rectifier 9 and connected to the comparator 10 as a much lower frequency signal. The comparator 10 acts as a decoder that decodes the incoming RF-signal (if any), and if the level is above the comparators threshold, which can be made programmable, starts to convert the signal into logical ones ‘1’ and zeros ‘0’. The digital signal from the comparator 10 is fed into an analyzer 11 where it checked to see if it is a Manchester encoded signal and if so is compared to a predetermined digital signal pattern and if the incoming signal matches this pattern the analyzer turns on the full RF transceiver, which starts the full RF transmission. If there is no matching Manchester encoded signal detected within the 0.5 ms window the device just goes back to sleep until the next 0.5 ms on time 995.5 ms later.
For greater noise immunity it is an preferable to code the incoming signal using a more sophisticated scheme than one where the presence of signal represents a ‘1’ and absence of signal represents a ‘0’. Examples include pulse width modulation (PWM) where a long presence of a signal in a time slot represents a ‘1’ and a short presence represents a ‘0’. Alternatively the signal may be amplitude modulated using Pulse Position Modulation (PPM) or Pulse Amplitude Modulation (PAM), provided a suitable analyzer 14 is used.
An additional level of security can be achieved by letting the detection of the correct signal within the first 5 ms trigger a prolongation of the low power receiver to allow a longer coding pattern to be used before turning on the full transceiver. In this embodiment the prolongation only continues as long as the received pattern is Manchester code and thus matches the expected properties. However, those skilled in the art will appreciate that the said expected properties can mean any coding pattern as well as the correct pulse width, correct pulse position, correct frequency, correct pulse amplitude etc. This is done even before the digital wake-up message is decoded given the possibility of immediately going back to sleep as soon as the incoming message has the incorrect properties.
The simplicity of the receiver 13 makes it very difficult to achieve very good receiver sensitivity. In order to attain a reasonable wake-up range it can be advantageous to use another frequency band than the MICS band, which is very limited in the allowed output power (maximum 25 μW). Examples of such frequency bands that can be used are the ISM band at 2.45 GHz, the US ISM band at 902-928 MHz, the Short Range devices band at 868 MHz in Europe. These bands all have a much higher power limit than the MICS band.
The described circuitry lends itself to integration in a single chip, for example, using CMOS technology.
It will be appreciated by one skilled in the art that the above description represents an exemplary embodiment, and that many variants within the scope of the appended claims are possible without departing from the scope of the invention.
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An electronic implantable device with a power saving circuit incorporates a radio frequency receiver with high power consumption. The first power radio receiver of high power is normally turned off during a period of inactivity. When an analyzer forming part of a second radio receiver and coupled to the first radio receiver detects a predetermined identification code in a received radio frequency signal received by the second radio receiver, it outputs a signal to turn on the first power receiver.
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CROSS REFERENCE TO RELATED APPLICATIONS
Electric charge pumps have been in use for several generations and a prime example is the battery charger. The difference between the well known battery charger and the herein defined electric charge pump is that the battery charger transfers electric charges from one plate to another within the battery and the electric charge pump transfers charges from an object to the ground or from the ground to an object. The difference in these two systems produces profoundly different results. Metal processing to change or modify the internal structure of a metal is also not new. Examples are carbonizing, annealing, cold working, hot working, alloying, precipition hardening and very rapid cooling from liquid to a solid to obtain an amorphous material. Metal processing while under a high electrical potential can now be added to the list.
Reference is made herein to Rao, et al. U.S. Pat. No. 5,914,088 of June 22, 1999. This apparatus is for continuously annealing amorphous alloy cores with closed magnetic field path. This system utilizes electricity to maintain a magnetic field that in turn causes the cores to retain their amorphous characteristics, it does not utilize a high electric potential to produce a nano crystalline or amorphous structure within said cores.
FEDERAL SPONSORED R & D
No Federal R & D funds were received.
REFERENCE TO MICROFICHE APPENDIX
Microfiche appendix is not required.
BACKGROUND OF THE INVENTION
This invention relates to the removal of or the addition of electric charges while a metal or metal part is at a temperature above the crystallization point and maintaining the surfeit or the deficiency until said metal or metal part has a temperature well below the crystallization point. This is the process that changes the molecular structure of said metal or metal part.
SUMMARY OF THE INVENTION
It is the object of my invention to provide a method to reduce electromagnetic core energy losses by modifying the molecular structure in said core materials.
It is another object of my invention to modify the crystalline structure so as to change the material characteristics such as the ultimate tensile strength, the yield point, the elongation and the fatigue factors.
The aforementioned and other objects of this invention are achieved by the utilization of direct current electric energy applied to an insulated metal or metal part to add or remove electric charges from said part usually with the application of heat energy. When direct electric potential is applied to metal or metal parts insulated from the ground or the opposite charged conductor, negative electric charges are either added or extracted from said metal or parts dependent upon how the connections are made. This connection causes a shortage or excess of electric charges in and on the material or part and when the part is heated to just under the melting point or the material is heated to the molten stage and then cooled to below the recrystallization temperature, while the electric potential is maintained, the internal structure of said material or part is changed. This changed structure, when applied to silicon electric steel cores, used in alternating current devices will reduce the core energy losses significantly. The extent of this change to the metal molecular structure can be controlled by varying the electrical potential/temperature ratios. The crystalline structure change in metallic parts alters many of the physicals of the metal. This stated process has applications in electrical inductance, structural applications and fatigue life of many different parts.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1; this drawing is for very high voltage/potential applications and utilizes a transformer to boost the potential and a bridge rectifier to convert alternating current to pulsating direct current.
FIG. 2; this drawing is for very high voltage/potential applications and utilizes a transformer to boost the potential and a rectifier to convert alternating current to pulsating direct
FIG. 3; this drawing depicts a moderate voltage/potential application wherein the available voltage/potential is adequate without the need for a transformer. This system utilizes a bridge rectifier to convert alternating current to pulsating direct current.
FIG. 4; this drawing depicts a moderate voltage/potential application wherein the available voltage/potential is adequate without the need for a transformer. This system utilizes a rectifier to convert alternating current to pulsating direct current. This system utilizes only one half of the alternating current cycle.
FIG. 5; this system is for moderate and low voltage/potential applications wherein direct current of adequate voltage/potential is available.
DESCRIPTION OF THE PREFERRED EMBODIMENT
Referring to FIG. 1 . This is the higher voltage more effective unit. Part #1 is the material or part to be treated. This part is electrically insulated from the ground and the other conductor and may be inside an oven or may be heated by any number of other methods or may be already in a molten state or of a high temperature depending upon the planned process. Part #1 is connected to either the positive or negative pole of a bridge rectifier #2. The other pole is connected to ground #3. The secondary conductors of transformer #5 are connected to the bridge rectifier and the primary conductors of the transformer #5 are connected to the alternating current power source #4. When an electric potential is applied to a metal or a part and said part is heated to above the crystallization point or the metal is already in the molten state or at a high temperature then either a shortage of electric charges or a surfeit of electric charges is in or on the metal or metal part. When said metal or metal part is cooled to below the crystallization point, while under said electric potential, the molecular structure is changed.
DESCRIPTION OF OTHER EMBODIMENTS
Referring to figure #2. This unit consists of the material or part #1 to be processed and is electrically insulated from the ground and from other conductors. This part or material may be heated in an oven or by any number of other methods and depending upon the planned process may be already in the molten state or at a high temperature. Part #1 is connected to the rectifier #6 which is connected to the secondary of the transformer #5. The other secondary conductor of transformer #5 is connected to ground #3. The primary conductors of transformer #5 are connected to the alternating current source #4. The function of this unit is the same as the unit in
Referring now to figure #3. This unit is for low to moderate voltages and does not utilize a transformer to increase or change voltage. Part #1 is the material or part to be processed. It is insulated from the ground and other electrical conductors and may be heated in an oven or any other available method or may be already in the molten state or at a high temperature depending upon the planned process. Part #1 is connected to either the positive or negative connection of the bridge rectifier #2. The other connector of the bridge rectifier #2 is connected to ground #3. The alternating current connectors on the bridge rectifier are connected to the alternating current power source #4. This unit functions in the same manner as the units in figures #1 and #2.
Referring now to figure #4. This unit is for low to moderate voltages and does not use a transformer to increase or change voltage. Part #1 is the material or part to be processed is insulated from ground and other electrical conductors and may be heated by any number of method. or may already be in the molten state or at a high temperature depending upon the planned process. This part is electrically connected to one connector of a rectifier #6 which in turn is connected to one connector of the alternating current source #4. The other conductor of the alternating current source is connected to ground #3. This unit functions in the same manner as the unit in figure #2 except that the voltage from the power source #4 is adequate and a transformer is not required. As this unit utilizes a standard rectifier instead of a bridge rectifier only one half of the alternating current cycle is utilized.
Referring now to figure #5. This unit is for low voltage applications and does not use a rectifier or a transformer because the power source is direct current and is adequate. Part #1 is the material or part to be processed and is insulated from the ground and other conductors and may be heated by any number of methods or may already be in the molten state or at a high temperature dependent upon the planned process. Part #1 is connected to the direct current source part #7 which has the other conductor connected to the ground #3. This unit functions in the same manner as the other units except a transformer, bridge rectifier and rectifier are not required as the direct current is adequate and is supplied at the source.
MAGNETIC CORE LOSS REDUCTION PROCESSING CONCEPT
When a ferromagnetic material is heated to a temperature significantly above the Curie point and at the same time placed under a positive potential, then cooled while still under the positive potential, the grain structure is changed in such a way as to reduce the ferromagnetic core losses.
TESTING MATERIALS AND EQUIPMENT
(1) One transformer to convert 120 volt house current to 720 and 1200 volts.
(2) Two bridge rectifiers, one 800 volt and one 1200 volt
(3) One propane torch.
(4) Three Styrofoam cups.
(5) One wood Styrofoam cup holder
(6) One wood stake suspension unit.
(7) Modified extension cord with (3) 100 or (3) 200 watt light bulbs in series and with end wires bare for connection to test units.
(8) Twelve each transformer core pieces 0.013 thick×1 ⅛ wide×6 ⅝ long.
(9) One gallon of distilled water.
(10) One probe thermometer.
(11) One electric multa tester
(12) 20 gage copper magnetic wire.
(13) Electrical tape.
(14) Electrical connectors.
(15) Piece of iron tie wire 14 ga.
TEST PREPARATION
(a) Six pieces of transformer are stacked and the upper half is wound with 2 layers of electrical tape, 20 gage copper wire is wound over the electrical tape [65 turns]. A layer of copper wire is then wound over said electrical tape [58 turns]. 1 layer of electrical tape is then wound over the wire turns. This is the control unit.
(b) Each of the remaining pieces, individually, are hung on the iron wire attached to the wooden stake with a small weight attached to the bottom end with iron wire. The iron wire holding the transformer core piece is connected to the transformer high voltage wire through the bridge rectifier and the continuity is checked. The connection to the rectifier is the positive side. The transformer is then plugged in and the core piece is heated with the propane torch to a bright cherry red [about 1000 deg. C ] working slowly from the bottom up to the top. The heating is repeated one more time. After the core piece is cooled it is removed and set aside. Repeat the above for each core piece. These core pieces are then stacked and wound with copper wire the same as the
(c) Three each Styrofoam cups are filled with 200 grams of water. One cup is placed in the cup holder and the other cups are set aside.
(d) the control unit is then connected to the modified extension cord and placed in the cup with the bare metal emerged in the water.
(e) the unit is left over night to acclimatize.
TESTING
In the morning the probe thermometer is placed in the cup with the control unit and the start temperature is recorded. The probe must not touch the core material. The modified extension cord is then plugged in. Every 15 minutes the temperature is recorded and after 5 recordings the thermometer it placed in one of the set aside cups, the extension cord is unplugged and the temperature in the set aside cup is recorded. The difference between the last recorded temperature of the cup with the control or test unit and the temperature in the set aside cup is the temperature increase resulting from core losses. This is repeated for the test unit.
TEST RESULTS
(3) 100 watt bulbs 720 volt positive potential
Date-31 July 1999 controll unit
1 Aug. 1999 test unit
Time
Temp
Time
Temp
9:45 AM
15.0 deg C.
10:45 AM
15.1 deg C.
10:00 AM
15.1 deg. C.
11:00 AM
15.3 deg. C.
10.15 AM
15.4 deg. C.
11:15 AM
15.6 deg. C.
10:30 AM
15.8 deg. C.
11:30 AM
16.0 deg. C.
10:45 AM
16.2 deg. C.
11:45 AM
16.5 deg. C.
11:00 AM
16.7 deg. C.
12:00
17.0 Deg. C.
amb.
15.6 deg C.
amb.
15.7 deg. C.
Delta
1.1 deg. C.
delta
1.3 deg. C.
The temperature increase of 0.2 deg. C of the control unit less than the test unit is attributed to a change from grain oriented to non oriented brought about by heating under 720 volt positive potential. Either the temperature was not high enough or the positive potential was not sufficient.
TEST #2
This is the same as test #1 except that 1200 volt positive potential was used instead of 720 volt positive potential.
Date 3 Aug. control
4 Aug. test
time
temp.
time
temp.
8:00 AM
16.2 deg. C.
8:00 AM
16.2 deg. C.
8:15 AM
16.5 deg. C.
8:15 AM
16.3 deg. C.
8:30 AM
16.9 deg. C.
8:30 AM
16.7 deg. C.
8:45 AM
17.6 deg. C.
8:45 AM
17.4 deg. C.
9:00 AM
18.5 deg. C.
9:00 AM
18.0 deg. C.
9:15 AM
19.4 deg. C.
9:00 AM
18.8 deg. C.
amb.
16.9 deg. C.
amb.
16.8 deg. C.
delta
2.5 deg. C.
delta
2.0 deg C.
Results are a 20% reduction in energy losses.
TEST FOR NEGATIVE POTENTIAL OF 1200 volts.
5 August 19999 Test
Time
Temp.
8:00 AM
16.3 deg. C.
8:15 AM
16.5 deg. C.
8:30 AM
16.9 deg. C.
8:45 AM
17.5 deg. C.
9:00 AM
18.3 deg. C.
9:15 AM
19.1 deg. C.
amb.
17.1 deg C.
Delta = 2.0 deg. C. Same as positive potential.
CORROSION TEST
Both the control and the test units were placed in water then removed from the water and placed on a wire outside and left over night. The results were that the control unit was covered with a red loosely adhered oxide and the test unit was unaffected.
IRON WIRE TEST
A 40 foot length of 14 gage iron wire was suspended from the ceiling, insulated from ground and the resistance was checked. This wire was then heated to a bright cherry red while under 1200 positive potential and allowed to cool. The resistance was again checked and no difference was determined. A 6 inch piece of this wire was cut from the test unit and bent to an angle of 90 degrees over a sharp radius. After 14 double bends the wire parted. A 6 inch test unit of unprocessed wire bending the same as the test piece and this wire parted after 6.5 double bends. An untreated piece of wire 6 inches long was then bent as above and it broke after 4.5 double bends.
ALUMINUM AND COPPER
Both aluminum and copper were subjected to heating under an electrical potential and then checked for electrical resistance. No change in electrical resistance was observed.
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When an electrical potential is applied to a metal or a metallic solution or a metal that is close to the melting point or a metal that is molten the electric charges are either drawn off and the metal has a high positive potential or a surfeit of electric charges are added and the metal has a high negative potential. When the metal is heated and then cooled, under said potential, the internal structure of the metal is changed. The crystal structure can become nano crystaline and or amorphous dependent upon the alloying elements, the potential and the temperature. This process has applications in inductive electrical parts as well as metalic structual materials.
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CROSS-REFERENCE TO RELATED APPLICATIONS
This patent application is the U.S. national phase, under 35 USC 371, of PCT/EP2004/050623, filed Apr. 28, 2004 and published as WO 2005/115756 A1, the disclosures of which are expressly incorporated herein by reference.
FIELD OF THE INVENTION
The present invention is directed to a printing unit for a multicolor web-fed rotary printing press and to a method for operating such a printing unit. A plurality of blanket-to-blanket printing units are arranged vertically one above the other. Each printing unit includes two printing groups which form a blanket-to-blanket location. The printing group cylinders are all mounted in a center frame section. Inking units are mounted in outer frame sections.
BACKGROUND OF THE INVENTION
A printing unit of this general type is discussed in WO 95/24314 A1. Four blanket-to-blanket printing units are arranged vertically, one above another, and can be moved horizontally relative to one another in the area of their blanket-to-blanket printing point. The blanket-to-blanket printing units that are on the same side of a web are each mounted in a shared frame. At least one of said frames can be moved horizontally.
EP 12 64 686 A1 discloses a printing unit with blanket-to-blanket printing units arranged vertically, one above another The printing group cylinders are mounted in a center frame section and the two inking units are mounted in respective outer frame sections. These outer frame sections can be moved horizontally, relative to the center frame section, in order to introduce plate handling devices into the intermediate space, as may periodically be needed.
EP 11 49 694 A1 discloses a printing unit having a multitude of arch-shaped blanket-to-blanket printing units, arranged vertically, one above another. Each such printing unit is comprised of two printing groups that form a blanket-to-blanket printing point. The printing group cylinders of the printing groups are all mounted in a center frame section while the inking units, which are assigned to the printing groups, are mounted in respective outer frame sections. The adjacent frame sections are structured such that their spacing relative to one another is adjustable.
SUMMARY OF THE INVENTION
The object of the present invention is to provide a printing unit for a multicolor web-fed rotary printing press, and to provide methods for operating such a printing press.
The object is attained, in accordance with the present invention with the provision of a printing unit for a multi-color web-fed rotary printing press having a plurality of blanket-to-blanket printing units which are arranged vertically. Each of these printing units is comprised of two printing groups that form a blanket-to-blanket printing location. The printing group cylinders of the printing units are all mounted in a center frame section. Inking units that are assigned to the printing groups are each mounted in outer frame sections. The adjacent frame sections can be adjusted, in terms of their spacing, with respect to each other. Forme and transfer cylinders of each printing group are coupled via a toothed gear connection and are actuated in pairs by their own drive motor. The inking units each have at least one separate drive motor mounted on its assigned outer frame section.
The benefits to be achieved with the present invention consist especially in that in a first aspect, high printing quality is ensured at low cost using a rotary printing press having a compact construction. This is achieved, firstly, in that the printing group cylinders can remain in a fixed, such as, for example, a preset position relative to one another, even when the printing unit is opened, thus insuring excellent reproducibility. Secondly, the quality (doubling) is increased because a plane of connection for the rotational axes of the coordinating transfer cylinders forms an angle that is not equal to 90°, and which is preferably between 77 and 87°, with the plane of the web that is being fed into the respective blanket-to-blanket printing unit. Further, by using finite rubber blankets, which are structured as multipart printing blankets, a rigid mounting of the printing group cylinders in the frame walls can be effected, thereby providing rigidity to the printing press.
This configuration is supported or is made possible by a drive configuration that is specifically adapted to it. To prevent a drive train from extending beyond the point of separation between the printing group cylinders and the inking unit, each blanket-to-blanket printing unit is rotationally actuated by at least one drive motor of its own. This at least one drive motor for each blanket-to-blanket printing unit is independent from the other blanket-to-blanket printing units, and is also independent from the assigned inking units. Each inking unit also has its own independent drive motor for its rotational actuation. Transmission play, in the area of a separable transmission, and a transfer of impacts up to the printing point via the drive train, and resulting from reversal movements in the inking unit, are prevented. In one advantageous embodiment of the present invention, the printing group cylinders can each be separately driven by respective, independent drive motors. However, in order to minimize cost while achieving high quality and variability, in the preferred embodiment of the present invention, coordinating forme cylinders and transfer cylinders are actuated, in pairs, by drive motors that are independent from the motors of other pairs of forme cylinders and transfer cylinders. In this manner, a printing forme change for each individual printing point, using the drive motor that actuates the pair of cylinders, both during print operation and during maintenance and, if applicable, with longitudinal registration, is still possible. In this context, the frame section that accommodates all the printing group cylinders is also advantageous with respect to its simple construction. In this construction, a shared lubricant chamber can be formed for all of the drive trains of the various printing groups.
Of particular advantage, with respect to quality and a compact construction, is the structuring of the printing groups or inking units as printing groups or inking units which are suitable for “waterless offset printing”. No dampening agent supply or dampening unit is provided. Instead, the inks and the printing formes are selected to have corresponding properties suitable for such waterless offset printing.
BRIEF DESCRIPTION OF THE DRAWINGS
Preferred embodiments of the present invention are represented in the accompanying drawings and will be described in greater detail below.
The drawings show:
FIG. 1 a schematic side elevation view of a printing unit in an operational position B; in
FIG. 2 a view similar to FIG. 1 and showing the printing unit in a maintenance position A; in
FIG. 3 a frontal view of a drive configuration in accordance with the present invention; in
FIGS. 4 a and 4 b top plan views of two drive configurations; and in
FIGS. 5 a and 5 b two preferred embodiments of the inking unit in accordance with the present invention.
DESCRIPTION OF THE PREFERRED EMBODIMENTS
Referring initially primarily to FIG. 1 , a printing machine, such as, for example, a web-fed rotary printing press, and especially a multicolor web-fed rotary printing press, has a printing unit 01 , in which a web of material 02 , referred to here as web 02 , can be printed multiple times in sequence, such as, for example, in this case the web 02 can be printed four times. Alternatively, multiple webs can be printed simultaneously a single time or multiple times. The printing unit 01 has multiple blanket-to-blanket printing units 03 arranged vertically, one above another with four such printing units 03 being depicted in FIG. 1 , and which printing units 03 are operable, for double-sided printing in blanket-to-blanket operation. The blanket-to-blanket printing units 03 are each formed by two printing groups 04 , each of which printing groups 04 has cylinders 06 ; 07 . One cylinder is structured as a transfer cylinder 06 and one cylinder is structured as a forme cylinder 07 , as depicted by for example, printing group cylinders 06 ; 07 , and an inking unit 08 . In each case, a blanket-to-blanket printing point 05 is formed between the two transfer cylinders 06 when these two cylinders, in the engaged position depicted in FIG. 1 . The above-described components are indicated with lead lines and only in the uppermost blanket-to-blanket printing unit 03 shown in FIG. 1 . However, the several printing units 03 ; 04 , which are arranged one above another, are essentially identical in structure, especially in the embodiment of the features that are relevant to the present invention.
The forme cylinders and transfer cylinders 07 ; 06 are preferably each structured with a barrel width of at least four vertical printed pages arranged side by side in newspaper format, and especially in broadsheet format. In this manner, a double-width web 02 can be printed with four pages positioned side by side. The forme cylinder 07 can be correspondingly loaded with four printing formes arranged side by side. Advantageously, both of the cylinders 06 ; 07 have a circumference that corresponds essentially to two printed pages in newspaper format, and which are arranged in tandem.
The printing group cylinders 06 ; 07 of the multiple, such as the depicted four blanket-to-blanket printing units 03 , which are arranged one above another, are rotatably mounted in a center frame or panel section 11 , which is, in turn, preferably arranged fixed in its location such as, for example, being secured in plate on a floor 09 of the printing shop, on a stationary support 09 , on a mounting plate 09 or on a mounting frame 09 for the printing unit 01 . The inking units 08 , which are situated on both sides of the blanket-to-blanket printing units 03 , as may also be seen in FIG. 1 , are each mounted in separate frame or panel sections 12 ; 13 , which are, in turn, mounted vertically opposite the center frame section 11 . The frame or panel sections 12 , 13 are movable relative to the floor 09 or the support 09 or the mounting plate 09 or the mounting frame 09 , which is hereinafter referred to as the support 09 . For this purpose, the outer frame sections 12 ; 13 are each mounted in bearing elements 14 ; 16 of the frame sections 12 ; 13 and of the support 09 , which bearing elements 14 ; 16 correspond with one another. These bearing elements 14 ; 16 can be structured as rollers 14 that run on rails 16 , as illustrated in FIG. 1 , or can be configured as sliding or as roller-mounted linear guide elements 14 ; 16 that are allocated to one another.
Preferably, the fixed central frame or panel section 11 , and the movable, outer frame or panel sections 12 ; 13 are structured such that in their operational position B, as depicted in FIG. 1 , they are structured in pairs, the shapes of which pairs essentially complement one another on their facing sides. When these pairs are pushed together, at their lines of separation or their lines of abutment 17 ; 18 they nevertheless form an essentially closed side configuration, as shown in FIGS. 1 and 2 . In this manner, on both the cylinder side and the inking unit side, the greatest possible area for accommodating the bearing can be achieved in the corresponding frame section 11 ; 12 ; 13 . Additionally, requirements with respect to noise, personnel safety and containment of contamination can be met. In order to achieve the most stable mounting possible, with cylinder journals of corresponding strength, the center frame section 11 deviates from a vertical alignment in the area of the cylinder bearing, which is not specifically shown in FIGS. 1 and 2 , and is equipped with corresponding protrusions 19 , as is shown in FIG. 2 , and that accommodate the bearing. The outer frame sections 12 ; 13 have recesses 21 whose shape complements these protrusions 19 , as may also be seen in FIG. 2 . The recesses 21 and the protrusions 19 are formed on the bearing arrangements in the inking unit 08 and the printing group 04 with respect to provision of sufficient or even the greatest possible strength of the enclosure, i.e. at least a minimum strength, through the respective frame.
FIG. 2 shows a maintenance position A of the printing unit in accordance with the present invention on both sides of the printing points 05 The relative position of the inking units 08 , with respect to the printing group cylinders 06 ; 07 , is achieved by moving the frame sections 12 ; 13 that accommodate the inking units 08 laterally. It is also possible to adjust only one side of the assembly to the depicted maintenance position A, while the other side of the printing unit 01 is in the operational position B depicted in FIG. 1 . In principle, the relative positions can also be achieved in another embodiment, in which one outer frame section, 12 or 13 is mounted so as to be fixed in space, while the center section 11 and the other outer frame section 11 , 13 or 12 or even all three frame sections 11 ; 12 ; 13 are mounted so as to be movable with respect to each other.
FIGS. 3 and 4 schematically depict an advantageous drive configuration for the printing group cylinders 06 ; 07 of the printing unit 01 . The journals for the forme cylinders and of the transfer cylinders 07 ; 06 are each non-rotatably connected, at their end surfaces, to toothed gears 22 ; 23 , respectively, and particularly, spur gears 22 ; 23 . These gears, in pairs, form a drive connection. The paired drive is advantageously accomplished by the use of a drive motor 24 via a transmission, and particularly by a speed-reduction transmission, which is situated on one of the two cylinders 06 ; 07 , and particularly on the forme cylinder 07 . Due to its shorter adjustment path, the location of the drive on the forme cylinder 07 contributes to a simple and sturdy construction of the printing unit. In the depicted example, the drive is accomplished via a sprocket wheel 26 on the spur gear 22 , as seen in FIG. 4 a . In another embodiment, as seen in FIG. 4 b , in addition to the spur gear 22 , a second toothed gear 27 can be non-rotatably connected to the forme cylinder journal, and on which second toothed gear 27 the sprocket wheel 26 is actuated. In this embodiment, the spur gears 22 ; 23 , that form the drive connection, can be structured to be evenly toothed to favor the accomplishment an axial relative shiftability to accomplish lateral register, and the second toothed gear 27 and the sprocket gear 26 can be structured to be helically toothed in order to provide rigidity. In principle, it is also possible, with the above-described configurations, to effect the drive first on the transfer cylinder 06 and from there on the forme cylinder 07 . Reference symbols 06 and 07 would then need to be transposed. In a preferred embodiment which is not shown here, and for the purpose of improved attenuation, the output from the drive motor 24 to one of the cylinders 06 ; 07 can take place not via a toothed gear connection, such as a sprocket but instead can take place via a belt and chain drive, such as, for example, via a belt, and especially a toothed belt which meshes with corresponding pulleys. If the drive motor 24 is sufficiently heavy, is large in dimension and/or has an adapter transmission, typically for speed reduction, then the drive motor 24 can also drive coaxially on one of the cylinders 06 ; 07 of each of the pairs of cylinders.
As may be seen by again referring to FIG. 4 , the frame section 11 , together with a cover 28 , preferably forms a lubricant chamber 29 that conceals the cylinder end surfaces, and also conceals the toothed gears 22 ; 23 ; 27 ; or the sprockets 26 . This lubricant chamber 29 preferably extends over the four spur gars 22 ; 23 of a blanket-to-blanket printing unit 03 in its width, and over all four of the vertically arranged blanket-to-blanket printing units 03 in its height. In other words, one shared lubricant chamber 29 exists for all of the printing group cylinders 06 ; 07 of the printing unit 01 .
The blanket-to-blanket printing units 03 are each structured, relative to the intended vertical web path, such that a plane of connection, which is defined by the rotational axes of the coordinating transfer cylinders 06 of each printing unit 03 , in their engaged position, forms an angle α that is not equal to 90°, and which is preferably between 77° and 87°, with respect to the plane of the web 02 that is being fed into the respective blanket-to-blanket printing unit 03 , as is shown by way of example in FIG. 1 . In the engaged position of each printing unit 03 , the rotational axes of the forme cylinders 07 do not lie in the same plane as those of the transfer cylinders 06 . In other words, the blanket-to-blanket printing units 03 are not linear in structure. Instead, they are angular and preferably are arch-shaped. To accomplish this purpose, the cylinders 06 ; 07 are correspondingly mounted in the frame section 11 . As is schematically indicated in FIG. 4 a , by the use of double lines, the journals of the transfer cylinder 06 are mounted in radial bearings 32 , which radial bearings 32 are, in turn, mounted in eccentric bushings 33 to thereby allow adjustment of the transfer cylinder 06 . This mounting can have a overall structure, such as, for example, a three-ring or as a four-ring bearing 32 , 33 . In one preferred embodiment, only one of the transfer cylinders 06 is mounted in this manner, so as to be adjustable, while the other transfer cylinder 06 is fixed. The mounting of the forme cylinders 07 can also be structured in this manner. However, in FIG. 4 a only the radial bearings 31 are shown.
In one preferred embodiment of the present invention, the printing unit 01 is structured as a printing unit 01 for use in dry offset printing, or in other words for waterless or for dampening agent-free offset printing. In this preferred embodiment, the printing unit 01 has no dampening units, and thus is even more compact. In FIG. 1 , the inking units 08 are illustrated in schematic fashion, and can be structured differently in accordance with the demands of the specific printing unit.
In a first embodiment of the present invention, and which is particularly advantageous in terms of its compact construction, the inking units 08 are structured as short inking units 08 , as seen at the top right of FIG. 2 . Such short inking units 08 each have an anilox roller 34 , which dips into an ink tray 36 where it absorbs ink. Excess ink is scraped off the anilox roller 34 by a blade device 37 , such as, for example, by a fountain blade or a fountain sheet. The ink tray 36 and the blade device 37 can preferably be structured as a single component as an ink chamber blade 36 , 37 , which receives its ink from an ink supply by the operation a pump that is not shown in FIG. 2 . The anilox roller 34 preferably has a drive motor 35 that is mechanically independent from the printing group cylinders 06 ; 07 . The ink is taken from the anilox roller 34 by at least one forme roller 38 , and advantageously by two such rollers 38 , as seen in FIG. 2 or by even three such forme rollers 38 , and is transferred to the forme cylinder 07 . Because the cells on the anilox roller 34 essentially define the quantity of ink to be taken up, for each rotation of the anilox roller 34 the overall quantity of ink removed from the ink tray 36 can result either from a relative speed of two rollers or advantageously from the temperature of the ink and/or the temperature of ink-transporting components, such as, for example, the temperature of at least the anilox roller 34 . The anilox roller 34 is rotationally actuated by its own drive motor 35 , which motor 35 is mechanically independent from the printing group cylinders 06 ; 07 , and especially from the forme rollers 38 . With a substantial change in the quantity of ink needed, the anilox roller 34 must, if applicable, be exchanged for another.
In one embodiment of the present invention, that is advantageous in terms of the variability of the quantity of ink, the inking units 08 are structured according to the depictions of FIGS. 5 a and 5 b , for example, as roller inking units 08 . The ink is again applied by multiple forme rollers 38 , such as the two forme rollers 38 depicted in FIGS. 5 a and 5 b , to the printing forme of the forme cylinder 07 . However, in this embodiment the forme rollers 38 do not receive the ink from an anilox roller 34 , but instead receive ink by way of a roller train, which has at least one oscillating cylinder 39 that is provided with a hard surface, and is a so-called distribution cylinder 39 . A roller train that has two distribution cylinders 39 with hard surfaces and with one intermediate roller 41 between them, and which is provided with a soft surface, is advantageous. The distribution cylinder 39 that is distant from the forme cylinder receives the ink, through another intermediate roller 41 , from a film roller 42 which has a hard surface. In accordance with the partitionable printing unit 01 of the present invention, it is provided that the two distribution cylinders 39 are mechanically coupled to one another via a transmission, such as, for example, a wheel train or a belt and chain drive, and are rotationally actuated by a shared drive motor 43 that is mechanically independent from the printing group cylinders 06 ; 07 . Such a drive train is indicated by a dashed line. In one simple embodiment of the present invention, an oscillating axial movement of the two distribution cylinders 39 can be accomplished, from the rotational movement of the two distribution cylinders 39 by the provision of a corresponding transmission which is not specifically shown. However, in one advantageous embodiment of the present invention, the axial movement of the distribution cylinders 39 is produced by the use of at least one other drive motor that is not shown here. The intermediate rollers 41 , and the forme rollers 41 are preferably driven only by friction. The film roller 42 receives ink from a fountain roller 44 , with which it forms a contact gap or point. The fountain roller 44 is rotationally actuated via its own drive motor 46 . The metering of the ink onto the fountain roller 44 can be accomplished in various ways which are not specifically depicted.
In one simple embodiment of the present invention, as seen in FIG. 5 a , the fountain roller is configured as a dipping roller 44 , which roller 44 dips into the ink reservoir of an ink tray 47 . With proper control of the speed of the drive motor 46 , and hence the speed of the fountain roller 44 , the quantity of ink to be transported from the fountain roller, through the gap, to the film roller 42 , can be adjusted.
In one advantageous embodiment of the present invention, as shown in FIG. 5 b , the inking unit 08 is structured as an ink injector system 08 and receives the necessary quantity of ink in a controlled manner through the use of a pump device 48 , which allows a quantity of ink to be applied to the fountain roller 44 in a targeted fashion through the use one or more pumps. Advantageously, the quantity of ink to be applied can be controlled, in zones, for sections of the fountain roller 44 , which fountain roller 44 is divided in an axial direction, which quantity of ink applied to the various zones is achieved with multiple pumps or with multiple, individually controllable valves, or preferably with a combination of the two. In this manner, an ink requirement that differs over a web to be printed can be taken into consideration. The pump or pumps 48 can be structured as piston pumps or as continuously running gear pumps.
As indicated primarily in FIG. 5 , the transfer cylinders 06 each preferably have at least one axially extending opening 49 on their periphery, and especially have a channeled opening 49 , into which the ends of a resilient dressing or packing 51 , which is schematically depicted in FIG. 5 b , can be inserted and which, if applicable, can be fastened in an interior channel. The resilient dressing or packing 51 is advantageously structured as a multipart printing blanket 51 which includes a dimensionally stable base plate, such as, for example, of metal and an elastic layer, such as, for example, of rubber, and which thus may be, for example, a so-called metal printing blanket 51 . Preferably, on the transfer cylinder 06 , which has the width of four printed pages, two such printing blankets 51 are arranged axially side by side. In an advantageous further development, these two axially arranged printing blankets 51 are arranged offset in a circumferential direction with respect to each other, such as, for example offset by 180°. In this manner, and in contrast to rubber sleeves, an exchange of the resilient dressing or packing 51 is possible, without requiring an opening in the panel 11 and without the requirement of corresponding removable radial bearings, also in the panel section 11 . In the operational position B depicted in FIG. 1 , the resilient dressing or packing 51 can be conveniently exchanged from the intermediate space that is formed between the inking units 08 and the printing group cylinders 06 ; 07 . The same applies to accessing a web 02 in the event of problems during threading of the web 02 or following a web tear.
Although it is advantageous for the maintenance position A of the printing unit, as depicted in FIG. 2 , to be assumed in the aforementioned circumstances, such a positioning is not advantageous during routine printing forme changes. As is shown in the lower left corner of FIG. 1 as an example for all of the printing groups 04 , in an advantageous further development of the present invention all the printing groups 04 are assigned printing forme exchange devices 52 or printing forme handling devices 52 . These printing forme exchange devices 52 can advantageously have two guides, on one of which guides the printing forme, and especially the printing plate, can be advanced to the forme cylinder 07 , guided between the inking units 08 . On the other guide, the printing forme to be removed can be withdrawn from the forme cylinder 07 . The guides can also be structured as closed shafts. The printing forme exchange devices 52 or their guides/shafts are connected to the outer frame sections 12 ; 13 and are moved together with the movement of the inking units 08 . For the advancement and the withdrawal of the printing plates, at least one transport element for the printing forme is expediently provided. This at least one transport element has, for example, a drive element, such as, for example, a motor and has an actuated holding element, such as, for example, a frictional surface, a stop, or a suction foot. Thus to accomplish routine printing forme changes, it is not necessary for the printing unit 01 to be placed in its maintenance position A, which would, in turn, require time and, if applicable, would also require an adjustment of settings and a realignment. The printing group cylinders 06 ; 07 , and especially the transfer cylinders 06 that form the printing point 05 , can remain in their positions relative to one another.
Preferably, the printing forme handling device 52 is structured for this purpose such that, when viewed in an axial direction of the forme cylinder 07 , a printing forme can be handled on four sections side by side. This can be accomplished by using correspondingly wide, continuous guides or shafts and by also using at least four transport elements for the sections, or with four guides/shafts, which are arranged side by side, each of which is provided with assigned transport elements.
Everything which has been discussed in the above-description with respect to cylinders 06 ; 07 that have been recited as being four printed pages wide and/or printing forme handling devices 52 can be applied accordingly for cylinders 06 ; 07 which have a width of six printed pages which are arranged axially side by side.
While preferred embodiments of a printing unit for a multicolor web-fed rotary printing press, and a method for operating such a press, in accordance with the present invention, have been set forth fully and completely hereinabove, it will be apparent to one of skill in the art that various changes in, for example, the overall structure of the printing press, the types of webs being printed, and the like could be made without departing from the true spirit and scope of the present invention which is accordingly to be limited only by the appended claims.
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A printing unit, which is a part of a multi-color printing press, has a plurality of double printing units which are arranged vertically one above the other and consist of two printing groups forming a double print position. The printing group cylinders are mounted together in a central stand section. Inking units, which are associated with the printing groups, are mounted in outer stand sections. A distance between adjacent ones of these stand sections is adjustable. Printing and transfer cylinders of each printing group are coupled by a toothed gear wheel connection and are driven in pairs by a separate drive motor. The toothed gear wheels of all of the printing group cylinders are arranged in a common lubricant chamber which is formed by the central stand section and a cover. The inking systems have at least one separate drive motor, which is independent of the printing group cylinders.
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This invention was made during the performance of a contract with the United States Government, Department of the Army. The United States Government has rights to this invention under this patent.
REFERENCE TO RELATED APPLICATION
This application is a division of application Ser. No. 414,730 filed Sep. 27, 1989 now U.S. Pat. No. 5,019,590; which is a continuation of application Ser. No. 108,145 filed Oct. 13, 1987 now abandoned; which is a continuation-in-part of application Ser. No. 943,555 filed Dec. 18, 1986 now abandoned.
BACKGROUND OF THE INVENTION
1. Field of the Invention
This invention is in the field of organic chemistry. More particularly, it relates to a process for the synthesis of oxygen-containing heterocyclic organic compounds, materials formed by this process, and intermediates generated in the process. In one application, this process is used to prepare analogs of the antimalarial agent known as qinghaosu or artemisinin.
2. Background References
In prior copending U.S. patent application Ser. No. 943,555, there is disclosed a multi-step stereospecific synthesis of the oxygen-containing tetracycle artemisinin and a group of its analogs.
We have now found a new process for producing such materials. This new process is characterized by being a more direct route and by achieving the desired analogs in several fewer steps. It is also characterized by improved versatility which permits the synthesis of a wider range of possible analogs.
The present process employs ozonolysis of vinylsilanes to introduce oxygen functionality. A reference of which we are aware which involves ozonolysis of a vinylsilane is that of George Buchi et al., Journal of the American Chemical Society, Vol 100, 294 (1978). This reference illustrates the use of this reaction but effects different rearrangements and arrives at different ring structures than called for herein.
In another aspect, this invention employs unsaturated bicyclic ketones as reactants. References relating to such materials and to methods for forming some of them include W. Clark Still, Synthesis, Number 7, 453-4 (1976); Kazuo Taguchi et al., Journal of the American Chemical Society, Vol. 95, 7313-8 (1973); and E. W. Warnhoff et al., Journal of Organic Synthesis, Vol 32, 2664-69 (1967).
Other art of interest to the present invention relates to the ancient antimalarial natural product known as qinghaosu. The antimalarial qinghaosu has been used in China in the form of crude plant products since at least 168 B.C. Over the last twenty years, there has been an extensive interest in this material. This has led to an elucidation of its structure as ##STR1## The chemical name artemisinin has been applied to the material. This name will be used in this application to identify the material.
The carbons in the artemisinin structure have been numbered as set forth above. When reference is made to a particular location in a compound of this general type, it will, whenever possible, be based on the numbering system noted in this structure. For example, the carbon atoms bridged by the peroxide bridge will always be identified as the "4" and "6" carbons, irrespective of the fact that this invention can involve materials having different bridge-length structures in which these carbons would otherwise be properly numbered.
References to artemisinin and to its derivatives include the May 31, 1985 review article by Daniel L. Klayman appearing in Science, Vol 228, 1049 (1985); and the article appearing in the Chinese Medical Journal, Vol 92, No. 12, 811 (1979). Two syntheses of artemisinin have been reported in the literature by Wei-Shan Zhou, Pure and Applied Chemistry, Vol 58(5), 817 (1986); and by G. Schmid et al., Journal of the American Chemical Society, Vol 105, 624 (1983). Neither of these syntheses employs ozonolysis or the unsaturated bicyclic ketones as set forth herein.
The interest in artemisinin has prompted a desire for an effective and efficient method for its synthesis and for the synthesis of its analogs. It is also of interest to be able to apply such a method to the production of other oxygen-containing tetracycles. The prior application provided one such method. This invention provides an additional method.
STATEMENT OF THE INVENTION
A new process for forming tetracyclic oxygen-containing compounds has now been found. The process is characterized by employing as a reactant an olefinically unsaturated bicyclic bridging ketone having nonenolizable bridgehead moieties for both of its alpha positions (that is, at the positions immediately adjacent to the carbonyl). The process is further characterized by converting this ketone carbonyl to a vinylsilane. This vinylsilane is then subjected to ozonolytic cleavage of its olefinic bond to yield a member of a family of unique carboxyl/carbonyl-substituted vinylsilanes which may in turn optionally be subjected to a wide range of reactions prior to a final ozonolysis/acidification step which, closes the oxygen-containing ring structure. This process can yield desired artemisinin (qinghaosu) analogs and the like in several fewer steps than prior processes. It can also give rise to a variety of artemisinin analogs not easily obtainable with the prior processes. The process is also characterized by permitting control of the stereochemistry of the "1", "4", and "7" centers (as these positions are defined in artemisinin).
Thus, in one aspect this provides a family of new bicyclic bridging ketones of General Formula I ##STR2## wherein m is an integer--either 0 or 1; n is an integer--either 0, 1, 2, 3, or 4; and the various R's are each independently selected from hydrogens, alkyls and substituted alkyls.
In another aspect, this invention provides the corresponding family of vinylsilanes of General Formula II ##STR3## wherein m, n, and the various R's each have the meanings ascribed to them with reference to General Formula I and the three R S 's each are lower hydrocarbyls. These materials can be formed by silylating the ketones of General Formula I.
The alkylene olefinic bond in the vinylsilanes of General Formula II undergoes a suprisingly preferential ozonolytic cleavage (the olefinic bond in the vinylsilane functionality is not significantly attacked) to yield the mixed carbonyl/ester vinylsilanes of General Formula III. ##STR4##
These materials, wherein m, n, the R's, and the R S 's each have the meanings ascribed to them with reference to General Formula II and R E is a protecting esterifying group such as a lower alkyl, constitute another aspect of this invention. The materials of General Formula III are very versatile. Following deprotection of the acid functionality, they can be subjected to further ozonolysis and acid treatment to yield tetracyclic artemisinin analogs directly. Alternatively, with their acid functionality protected, they can have their carbonyl-containing chain extended by classic chain extension techniques such as by the Wittig reaction. These chain extension products can be represented by General Formula IV. ##STR5## In General Formula IV the chain extension is represented by the ##STR6## unit wherein R is a hydrogen, an alkyl or a substituted alkyl and p is an integer of from 0 to 2 subject to the proviso that p plus m has a value not greater than 2. In General Formula IV, the remaining R's and R S 's and R E and m and n have the meanings previously ascribed to them with reference to Formula III.
The chain extension produucts can be deprotected and then can be subjected to ozonolysis and acidification to form the desired tetracyclic structure. In another variation, the acid functionality and the carbonyl functionality can be protected (such as by esterification and by conversion to an acetal or ketal, respectively) and the product then alkylated to add an R F group and deprotected to give a product as shown in General Formula V. ##STR7## In the formula R F is a lower alkyl group or substituted lower alkyl group and the other substituents are as previously defined. This alkylation product is then subjected to ozonolysis and acidification to yield the desired tetracycle.
Of course, one could alter the sequence of these several steps or alternatively employ more than one of these modifications.
As previously noted, the materials of General Formulas III, IV or V can be subjected to ozonolysis and acidification to create a final tetracycle. Such tetracycles are represented by General Formula VI. ##STR8## In this formula, X and Y together can equal a carbonyl oxygen or X can be hydrogen, while Y is selected from hydrogen, hydroxyl, or alkyl ethers; carboxylic esters; carbonates, carbamates, amides and ureas. The various other substituents have the meanings previously ascribed to them.
In a further aspect, the present invention provides the process for forming the claimed tetracycles and their intermediates. This process involves the combination of the several steps outlined above.
In additional aspects, the present invention provides pharmaceutical compositions based on these tetracycle compounds and the use of these compositions to treat malaria and other similar conditions.
Detailed Description of the Invention
BRIEF DESCRIPTION OF THE DRAWING
The present invention will be described with reference being made to the accompanying drawing in which
FIG. 1 is a flow scheme illustrating an overall process in accord with this invention;
FIG. 2 is a flow scheme illustrating additional process steps for varying the X and Y substituents in the materials of the invention; and
FIGS. 3A and 3B are tables of structures of typical reactants employed as starting materials in the present invention.
DESCRIPTION OF PREFERRED EMBODIMENTS
In accord with this-invention, analogs of artemisinin of General Formula VI can be prepared using the general reaction techniques set forth in FIG. 1. Additional variations can be introduced using the techniques of FIG. 2. This reaction sequence proceeds from a bridgehead ketone through a bridgehead vinylsilane through a mixed carbonyl/ester compound to the final tetracycles.
This Description of Preferred Embodiments is arranged in accordance with these various compounds and reactions into the following sections:
1. The Bridgehead Ketones of Formula I
2. The Vinylsilanes of Formula II
3. The Mixed Carbonyl/Ester Vinylsilanes of Formula III
4. The Chain-Extended Vinylsilanes of Formula IV
5. The Derivatized Vinylsilanes of Formula V
6. The Tetracycles of Formula VI
7. The Preparation Process
8. Use of the Tetracycles
9. Examples
1. The Bridgehead Ketones of Formula I
The bridgehead ketones which are employed as intermediates in the synthesis scheme of this invention can be defined structurally by means of General Formula I. In this formula m is an integer--either 0 or 1; n is an integer--either 0, 1, 2, 3, or 4; and the various R's are each independently selected from hydrogens, alkyls and substituted alkyls.
In defining the groups represented by the various R's in General Formulas I-VI, reference is made to the possibility of "substituting" these groups. The limits of this possible substituting can be spelled out in functional terms as follows: A possible substituent is a chemical group, structure or moiety which, when present in the compounds of this invention, does not substantially interfere with the preparation of the compounds or which does not substantially interfere with subsequent reactions of the compounds. Thus, suitable substituents include groups that are substantially inert under the various reaction conditions presented after their introduction such as those of ozonolysis. Suitable substituents can also include groups which are predictably reactive under the conditions to which they are exposed so as to reproducibly give rise to desired moieties.
These possible substituents may from time to be referred to as R* such that R's will be described as including one or more R* substituents. R* can be any substituent meeting the above functional definition. Common R* groups include saturated aliphatic groups including linear and branched alkyls of 1 to 12 carbon atoms such as methyl, ethyl, isopropyl, n-butyl, t-butyl, the hexyls including cyclohexyl, decyl and the like. R* can also include aromatic groups generally having from 1 to 10 aromatic carbon atoms, for example aryls such as quinolines, pyridines, phenyls, naphthyls; aralkyls of up to about 20 total carbon atoms such as benzyls, phenylethyls and the like; and alkaryls of up to about 20 total carbon atoms such as the xylyls, ethylphenyls and the like. These various hydrocarbon structures of the R* substituents may themselves include olefinic carbon-carbon double bonds, subject to the understanding that ozonolysis or oxidative cleavage of this unsaturation may occur if it is present during that reaction; amides, sulfonates, carbonyls, carboxyls, alcohols, esters, ethers, sulfonamides, carbamates, phosphates, carbonates, sulfides, sulfhydryls, sulfoxides, sulfones; and nitro, nitroso, amino, imino, oximino, alpha- or beta-unsaturated variations of the above, and the like, subject to the understanding that many of these functional groups may be subject to attack during the overall reaction sequence and thus may need to be appropriately protected. They can then be deprotected at some later stage as desired.
Returning to the materials encompassed by General Formula I, while any of the possibilities encompassed by the formula are possible, preference is given to materials wherein n is 1 or 2 or 3. Preference is also given to materials wherein the various R's are selected from hydrogen, lower alkyls and substituted lower alkyls. As used herein a "lower" group such as an alkyl is one containing from 1 to about 10 and preferably from 1 to about 4 carbon atoms. Materials wherein at most one or two of the R's in the m methylenes and at most one of the R's in the m methylenes are other than hydrogen are especially preferred.
While General Formula I is a very suitable representation of the bridgehead ketones employed herein, and without any intent to limit the scope of the invention beyond the structure so elaborated, at times it may be helpful to the understanding of this invention to provide structures in which the various substituents are distinguished from one another. To that end, General Formula I* is provided to illustrate the location of the various substituents in the bridgehead ketone materials. Other similar expanded formulas will be provided hereinafter for other products and intermediates of the present invention. It should be appreciated that these more elaborate formulas only represent our present best understanding of the structures of these materials and the most likely stereochemistry to the extent known or reasonably inferred. It is possible that inversions may occur at various optically active centers from time to time which are not reflected in these more detailed structures. These additional materials are considered to be part of this invention and to be included within the more general structures such as General Formula I, etc. ##STR9##
In General Formula I*, m is an integer--either 0 or 1; n is an integer--0, 1, 2, 3, or 4; the m R A1 's, R A2 , R B1 , and the n R C1 's and R C2 's are each independently selected from hydrogens, alkyls and substituted alkyls. These various groups have the preferences set forth with reference to General Formula I, as well.
Among the materials encompassed by General Formulas I and I*, several are known compounds. (See Still, supra, for a disclosure of materials wherein n is 1, m is 1 and all the R's are hydrogen; wherein n is 2, m is 1 and all the R's are hydrogen; wherein n is 3, m is 1 and all the R's are hydrogen; and wherein n is 2, m is 1 and all the R's are hydrogen except for one R C1 , which is a methyl.) The remaining materials are believed to be novel compounds.
The bridgehead ketone materials of General Formulas I and I* can be prepared as follows: When both of the R B substituents are hydrogen, the materials can be prepared by the cyclodialkylation of appropriate enamines. The pyrrolidine enamines are a well-known family of materials whose preparation from commercial cyclic ketones is well documented, and for this reason they are preferred. In a typical representative reaction cyclohexanone is converted to the cyclohexeneamine, which is then reacted with a 1,4-dichlorobut-2-ene to give a bicyclic ketone as shown in Reaction 1. ##STR10##
In consideration of the chain lengths defined by n and m and the locations of the various R groups, the dialkyation agent can be defined by General Formula VII and the enamine by General Formula VIII. In these formulas, the various R groups have the meanings assigned to them in the previous formulas and the Z's each are leaving groups such as halo's, especially chloro's or bromo's. ##STR11##
These dialkylation agents and enamines can also be represented in the convention of General Formula I* as follows: ##STR12##
When considering the possible values of n and m, there are two basic structures for the dialkylation agent and five basic structures for the enamine. FIGS. 3A and 3B are tables that grid these materials with one another to illustrate these feedstocks and the ten basic bicycloketone structures to which they give rise.
The reaction of the dialkylation reagent and the enamine is carried out under effective alkylation conditions. These include anhydrous conditions; an aprotic reaction medium such as dimethylformamide, tetrahydrofuran, or the like; and the general exclusion of oxygen from the reaction vessel such as by an inert gas cap. The reaction is generally promoted by the addition of a base such as an amine or the like, for example a trialkyl amine, and by the presence of a halide alkylation promoter such as an alkali metal iodide. In the reaction, approximately equimolar amounts of the dialkylation reagent and the enamine are employed. A representative preparation taken from Still (supra) is provided in Example 1.
In those cases where the bridgehead ketones have R B substituents other than hydrogen, they can be prepared using the methods set forth by Taguchi et al (supra) and Warnhoff et al (supra). In Taguchi et al saturated bridgehead ketones containing a carboxylic acid functionality at one of the bridgeheads are prepared. The carboxyl group can be used as a point of attachment for other R B substituents as called for. The Warnhoff et al work discloses a method for introducing carboxyl and halo substituents on both of the bridgehead carbons of saturated bicyclic ketones. Again, these groups can serve as active sites for the coupling of other R B groups as desired. With suitable modification, the desired olefinic bond can be introduced into the bicyclic structure.
2. The Vinylsilanes of Formula II
The bicyclic bridgehead ketones of Formula I are converted to the vinylsilanes of Formula II. In Formula II the three R S substituents in the silyl functionality are independently selected from lower hydrocarbyls. Typical hydrocarbyls for this application are lower alkyls, aryls, alkyls and aralkyls. In selecting these three R's, generally two or three of them are methyls. Typical silyl groups include trimethylsilyl, t-butyldimethylsilyl and phenyldimethylsilyl. In preferred silyls, two of the three R S 's are each methyls, and the third is a methyl, ethyl, propyl, butyl, or t-butyl. The various other R's are as described with reference to General Formula I.
Following the conventions set forth defining Formula I*, the vinylsilanes can also be represented by General Formula II*. ##STR13##
The conversion of the ketone to the vinylsilane can be carried out using any of the art-known methods for silylating a carbonyl functionality. In this case a method which proceeds with good efficiency and yield involves the straightforward use of bis(trialkylsilyl) methyllithium. This reagent can be prepared by the method of Grobel and Seebach, Chem. Ber, 110, 852 (1977), in which an alkyl lithium is reacted with the needed bis(trialkylsilyl)methane in an aprotic dry solvent with hexamethylphosphortriamide at low to moderate temperature to yield the desired reagent complex, which can be used to effect the silylation. The silylation is carried out by contacting the ketone and the silylation reagent at about equimolar levels (0.75 to about 1.33 equivalents of silylation complex based on the ketone present) at low temperatures such as -100° C. to about 0° C., once again in an aprotic anhydrous reaction phase. The product of this silyation can be extracted into a nonpolar organic phase and can be worked up by rinsing with water, brine, and the like. The final product can be purified, such as by chromatographic techniques.
3. The Mixed Carbonyl/Ester Vinylsilanes of Formula III
An unexpected and key element of the present invention relates to the formation of the mixed carbonyl/ester vinylsilanes of Formula III (or Formula III*, below) by differential ozonolytic cleavage of the olefinic double bond (instead of the bridging vinylsilane) of Formula II. ##STR14##
The materials of Formulas III and III* have the same substituents described with reference to the vinylsilanes and additionally include an R E group which is a protective esterifying group. Typically, R E is a lower alkyl and especially a methyl but can be any removable carboxyl protecting group as is known in the art.
The ozonolytic cleavage reaction is an adoption of the method described by R. E. Claus and S. L. Schreiber, Org. Syn., 64. 150 (1985). This reaction is carried out at low temperatures in a liquid reaction medium. Ozone is extremely reactive, and it is advantageous to employ low temperatures to avoid side reactions between the ozone and other regions of the vinylsilane molecule. The low temperature can range from a high of about 15° C. to a low equal to the freezing point of the reaction solvent, which can be as low as -100° C. or lower. Excellent results are obtained at dry ice/acetone bath temperatures (-78° C.), and a preferred temperature range is from -100° C. to about -25° C. with most preferred temperatures being in the range of from -70° C. to -80° C.
The reaction solvent employed in this reaction is selected to assure compatibility with the highly reactive ozone. As a general rule, ethers, both linear and cyclic, are to be avoided as they are likely to be converted to peroxides, which present an explosion hazard. The solvents employed are commonly mixtures of polar organics, preferably lower alcohols such as methanol, ethanol, the propanols, and ethylene and propylene glycols; and the liquid esters such as ethyl acetate with halohydrocarbons such as methylene chloride, chloroform, dichloroethylene and the like. Of these solvents, the lower alcohols, especially methanol mixed with halohydrocarbons and especially dichloroethylene, are preferred. In the case shown in FIG. 1 and demonstrated in the examples, an optimum solvent was a 5:1 volume ratio of methylene chloride and methanol, respectively. The solvent plus the presence of an acid acceptor such as alkali metal carbonate or bicarbonate gave best results. This acid acceptor is useful to prevent the alcohol of the reaction medium from combining with an aldehyde of the reaction product. The acid acceptor can be employed to advantage if, as in the case of FIG. 1, this reaction is undesired.
The reaction is carried out by mixing the vinyl silane in the reaction medium and then adding the ozone. The amount of ozone preferably is controlled so that excesses are avoided. Good results are obtained when the amount of ozone is limited to not more than 1.25 equivalents, based on the amount of vinylsilane present, with ozone levels of from about 0.75 to about 1.25 equivalents based on the amount of vinylsilane present being preferred. Lower ozone levels can be used, but are not preferred because of the lower yields which result.
The reaction is very quick, generally being complete in a few minutes. Excellent results are obtained, at times in the range of 15 seconds to about 45 minutes depending upon the rate of ozone delivery.
The product of the ozonolytic cleavage can be worked up and recovered. In the case of sensitive products, the workup is carried out under reductive conditions, for example in the presence of an alkylamine and an anhydride such as acetic anhydride. In cases where the product is less sensitive, the conditions need not be reductive.
The recovered product can then be treated with a strong acid such as a mineral acid and preferably hydrochloric acid to yield the tetracycles of Formula VI. This product can be recovered by extraction into an organic layer which is then washed, dried and, if desired, subjected to column chromatography and the like. The mixed carbonyl/carboxyl material is generally unstable and must be used promptly to avoid yield loss.
4. The Chain-Extended Vinylsilanes of Formula IV
Notwithstanding their reactivity, the vinylsilanes of Formula III are versatile intermediates. The carbonyl-containing arm can be extended using conventional chain-extension techniques such as the Wittig reaction. An embodiment of this reaction is shown in FIG. 1 and in the Examples. This serves to introduce a ##STR15## unit wherein R is a hydrogen, an alkyl or a substituted alkyl and p is an integer of from 0 to 2, subject to the proviso that p plus m has a value not greater than 2. Generally it is preferred if at least one of the R groups and particularly 2 or more of the R groups in the chain extension region is hydrogen(s). It is also preferred if the alkyls and substituted alkyls are lower alkyls. The product of this chain extension has the structure shown in Formula IV. Using the convention of Formula I*, these materials can also be represented by General Formula IV*. ##STR16##
These chain extension products can be deprotected and subjected to ozonolysis and acidification to yield the desired tetracyclic structure. Alternatively, the chain-extension products can be further derivatized as shown below.
5. The Derivatized Vinylsilanes of Formula IV
After protecting the carbonyl group such as an acetal or ketal, these materials can be derivatized to modify their structure and give rise to numerous other substitution patterns. In another variation, the acid functionality and the carbonyl functionality can be protected (such as by esterification and by conversion to an acetal or ketal, respectively) and the product then alkylated to add an R F group and deprotected to give a product as shown in General Formula V and (General Formula V* below). ##STR17## In this formula the R F group is a lower alkyl or substituted lower alkyl.
6. The Tetracycles of Formula VI
The artemisinin analog compounds which are provided by this invention are tetracycles which can be defined structurally by means of General Formula VI (or General Formula VI*, below). ##STR18##
These compounds are formed from the vinylsilane of Formula III, the chain-extended vinylsilane of Formula IV, or the derivatized vinylsilane of Formula V by ozonolysis and acidification. The substituents are the same as described with reference to the prior structures. The product of the ozonolysis and acidification will have X and Y as a carbonyl oxygen. As will be noted, this carbonyl can be reduced and reacted so that X is hydrogen, while Y is selected from hydrogen, hydroxyl, alkyl ethers, carboxylic esters, carbonate, carbamates, amides and ureas.
It will be appreciated that General Formula VI can be written in simplified forms depending whether or not the chain extension and/or alkylation have taken place. Formula VIA represents the tetracyle which is obtained if the product of Formula III is converted directly, VIB results if a chain extension product is converted, and VIC results if an alkylated but not chain extended material is converted. ##STR19##
The ozonolysis reaction is similar to the ozonolytic cleavage reaction. It is carried out at low temperatures in a liquid reaction medium. The low temperature can range from a high of about 15° C. to a low equal to the freezing point of the reaction solvent, which can be as low as -100° C. or lower. Excellent results are obtained at dry ice/acetone bath temperatures (-78° C.), and a preferred temperature range is from -100° C. to about -25° C. with most preferred temperatures being in the range of from -70° C. to -80° C.
The reaction solvent employed in this reaction is again selected to assure comparability with the highly reactive ozone. The solvents employed are polar organics, preferably lower alcohols such as methanol, ethanol, the propanols and ethylene and propylene glycols; and the liquid esters such as ethyl acetate. Mixed solvents may, of course, be used. Of these solvents, the lower alcohols, and especially methanol, are preferred.
The reaction is carried out by mixing the vinyl silane in the reaction medium and then adding the ozone. The amount of ozone preferably is controlled so that excesses are avoided. Good results are obtained when the amount of ozone is limited to not more than 1.25 equivalents, based on the amount of vinylsilane present, with ozone levels of from about 0.75 to about 1.25 equivalents (based on the amount of vinylsilane present) being preferred. Lower ozone levels can be used, but are not preferred because of the lower yields which result from them.
The reaction is very quick, being complete in a few minutes at most. Excellent results are obtained at times in the range of 15 seconds to about 15 minutes, depending upon the rate of ozone delivery.
The ozonolysis reaction product is treated with acid to bring about rearrangement of transitory intermediates and give rise to the desired product tetracycles. This reaction can be carried out in an nonaqueous liquid reaction phase with halohydrocarbons such as chloroform and the like being preferred. The acid employed should be of at least moderate strength as shown by a pKa of from about 5 to about 0.1 and can be an organic or an inorganic acid. Mixtures of acids can be used, if desired. Typical acids include acetic acid; the substituted acetic acids such as trichloroacetic acid, trifluoroacetic acid and the like, and other strong organic acids such as alkyl sulfonic acids and the like. The mineral acids such as the hydrohalic acids, e.g., HCl, HBr, etc., the oxyhalo acids such as HClO 3 and the like; sulfuric acid and phosphoric acid and the like may be used as well but should be checked before use to assure that they do not cause unwanted side reactions.
The rearrangement reaction is merely catalyzed by the acid, thus in principle only a trace amount of acid is needed. However, the use of more than a trace amount of acid may be preferred. In particular, the amount of acid added is generally at least about one equivalent based on the amount of product present. Large excesses are generally not needed, and the preferred amount of acid is from about one to about ten, and especially from about one to about two, equivalents based on the amount of product present. This reaction does not require high temperatures. It will go to completion overnight at room temperature. The reaction may also proceed to completion either more rapidly or more slowly, depending on the acid and solvent system employed. Higher temperatures may be employed, if desired and if it is ascertained that they do not give unacceptable yield losses. Temperatures from about -100° C. to about +50° C. can be used with temperatures of from about -20° C. to about +30° C. being preferred and temperatures of from about 0° C. to about +20° C. being more preferred. As would be expected, times are inversely related to temperature with times in the range of 1 hour to about 24 hours being useful.
The product of the acid-catalyzed rearrangement can be worked up and purified using chromatographic techniques and the like.
To obtain tetracycles where X and Y are other than a carbonyl oxygen, the techniques illustrated in FIG. 2 can be used. As shown in that figure, the carbonyl can be reduced without affecting the reduction-sensitive peroxy group by the use of sodium borohydride as reported by M.-m Liu et al. in Acta Chim Sinica, Vol 37, 129 (1979). This reduction converts the carbonyl into a lactol (hemiacetal where X is hydrogen and Y is hydroxyl). The Y hydroxyl can be converted to an ester by reaction with an appropriate acid anhydride or acid halide or active ester. Typical examples of these reactants include acetic anhydride, propionic anhydride, maleic anhydride and substituted analogs thereof, alkanoyl chlorides, and the like. This reaction is carried out in an aprotic solvent such as an ether or halohydrocarbon (for example, dichloromethane) at a moderate temperature of from about 0° C. to room temperature in from about 0.5 to 5 hours. An ether can also be formed such as by contacting the alcohol with methanol or a R*-CH 2 -OH alcohol corresponding to the remainder of the ether in the presence of a Lewis acid such as BF 3 . The BF 3 is presented as an etherate and forms a complex with the alcohol and effects the ether formation at -10° C. to room temperature in from 0.5 to 5 hours. The added alcohol is a good solvent. A carbonate can be formed from the alcohol such as by reacting it with an organic chloroformate such as an alkyl chloroformate. This is again carried out at -10° C. to room temperature in from 0.5 to 5 hours in an aprotic solvent such as was used in the formation of the ester. All of these products can be recovered using a conventional organic workup.
7. The Preparation Process
The overall preparation process is the combination of the various steps provided as preparations for the various intermediates. This overall process is shown in FIG. 1. The optional steps to form the various X and Y altered materials are given in FIG. 2. The process is given as a specific reaction sequence leading to the preparation of the artemisinin analog (±)-13-,14-desmethylartemisinin and in this regard tracks the examples provided herein. It will be appreciated that by changing the starting materials as has been set forth herein, this process could be used to provide the full range of materials encompassed by General Formulas I-V. For brevity, we have not stressed the stereochemical aspects of the present process and their implications for the structure of the final tetracycle products. However, by design, the process provides a method for directing and controlling the stereochemistry of key ring positions of the final tetracycles. The control of stereochemistry is illustrated diagramatically in FIG. 1 and demonstrated in the Examples.
More particularly, the stereochemistry of the "1" and "7" centers (these centers are numbered according to their positions in artemisinin, as noted previously) is directed by the structure of the bicyclic bridging ketone. The stereochemistry remains intact through the series of reactions and directs the course of the final ozonolysis. The final ozonolysis occurs from the face of the molecule opposite the "1" and "7" substituents. This direction of the course of ozonolysis sets the stereochemistry of the "6" center so that upon the cyclization with acid the stereochemistry of the "4" and "5" centers is controlled.
An example of the possible stereochemistry of tetracycles provided by this invention is illustrated by General Formula VI**. In this formula the various R substituents and X and Y are as previously described. ##STR20##
The present process can provide a direct route to many artemisinin analogs previously described. In that regard, it complements the process disclosed in parent application U.S. Ser. No. 943,555. It also permits the facile synthesis of materials not readily obtainable heretofore. These are the materials of Formulas VI* and VI**, where at least one of the R A1 , R A2 , R C1 and R C2 substituents is other than hydrogen. These materials (and particularly when at least one of R A1 , R C1 , and R C2 is other than hydrogen) are believed to be novel compounds.
7. Use of the Products
The artemisinin analog compounds of this invention all contain the peroxy linkage which can lead to free radical intermediates in vivo; they should have antiprotozoan activities against a broad range of parasites such as Toxoplasma, Leishmania, Trypanosoma, etc., in addition to Plasmodia. In tests they have been demonstrated to have high activity in this application. They offer activity against drug-resistant forms of malaria and can even intervene in cerebral malaria where they can interrupt coma and reduce fever. These materials should also have antihelmenthic activity against such diseases as Schistosoma and Trichinella, etc. (R. Docampo et al., Free Radicals in Biology, Vol. VI, Chapter 8, p. 243, 1984, Academic Press, Inc.). In this application, the compounds are generally compounded into vehicles or carriers known in the art for administration to patients in need of such treatment. The mode of administration can be oral or by injection. Typical vehicles are disclosed in Remington's Pharmaceutical Sciences, Alfonso R. Gennaro, ed., Mack Publishing Company, Easton, Pa. (1985).
For oral administration, the compounds can be prepared as elixirs and suspensions in sterile aqueous vehicles and also can be presented admixed with binders, carriers, diluents, disintegrants and the like as powders, as pills, or as capsules. Typical liquid vehicles include sterile water and sterile sugar syrup. Typical solid materials include starch, dextrose, mannitol microcrystalline cellulose and the like.
For administration by injection, the materials can be presented as solutions/suspensions in aqueous media such as injectable saline, injectable water and the like. They can also be presented as suspensions or solutions in nonaqueous media such as the injectable oils including injectable corn oil, peanut oil, cotton seed oil, mineral oil, ethyl oleate, benzyl benzoate and the like. The nonaqueous media can, in some cases, permit substantial quantities of the medication to be administered as a depot in the patient's fat layer so as to obtain a prolonged release of the agent to the patient.
The materials of this invention are used in fairly large doses. Commonly, dose levels of from about 100 mg/day to as much as 10,000 mg/day are employed. The actual use level will vary depending upon the particular patient's response to the drug and to the patient's degree of affliction. In a particularly preferred utility, they are used against Plasmodia and, in that use, require dosages from 0.1 to 10 times that used with the natural product artemisinin.
The peroxide link presented by all of these compounds and the free radicals it can produce are useful in a range of industrial chemical settings, as well.
8. Examples
The invention will be further described with reference being made to the following examples. These are provided merely to illustrate one preferred mode for carrying out the preparation of the invention and to illustrate several embodiments of the compounds provided by this invention and are not to be construed as a limitation upon the scope of the invention.
EXAMPLE 1
1. The total synthesis of racemic 13,14-desmethylartemisinin 1, as shown in FIG. 1.
The bicyclic ketone 2, available in good yield from cyclohexanone by the method of Still (W. C. Still, Synthesis, 453 (1976)), was treated with bis(trimethylsilyl)methyl lithium to give the diene 3 in 56% yield. The disubstituted double bond of 3 was selectively converted to the ozonide by treatment with ozone in methanol:dichloromethane (1:5, v/v) in the presence of sodium bicarbonate. The crude ozonolysis product was then reacted with Et 3 N/Ac 2 O to afford the esteraldehyde 4 in 43% yield. This unstable aldehyde was used immediately in the reaction with lithium methoxyethyldiphenylphosphine oxide (S. Warren et al, J. C. S. Perkin I, 3099 (1979)) to give a complex diastereomeric mixture of phosphine oxides 5. It was more convenient and efficient to convert 5 without prior purification to the enol ether 6 by treatment of 5 with NaH/THF. Thus, the enol ether 6 was produced from the aldehyde 4 with 54% yield. Ester hydrolysis of 6 gave the acid 7, acidification of which afforded the keto-acid 8, in 54% overall yield from 6. Finally, low temperature ozonolysis of 8 in methanol followed by careful evaporation of solvent gave an intermediate dioxetane which was treated immediately in moist CDCl 3 with CF 3 CO 2 H to give the analog 1 in 33% isolated yield.
Preparation of 10-Trimethylsilylmethylenebicyclo[4.3.1]dec-2-ene (3)
Bis(trimethylsilyl)methyllithium was prepared according to a procedure of Grobel and Seebach (B.Th. Grobel and D. Seebach, Chem. Ber., 110, 852 (1977)); to a solution of bis(trimethylsilyl)methane (2.85 ml, 13.3 mmol) in THF (20 ml) and HMPT (5 ml) at -78° C. was added dropwise via syringe a solution of s-BuLi (7.66 ml of 1.74 M in pentane). The resultant pale green solution was allowed to warm to -40° C. After 8 h at -40° C., the resultant red solution was cooled to -78 ° C. and a solution of bicyclo[4.3.1]dec-2-ene-10-one 2 (2.00 g, 13.3 mmol) in THF (5 ml) was added. The reaction was allowed to warm to -5° C. over 13 h, then stirred with H 2 O (50 ml) and extracted into hexane (2×50 ml). The combined hexane layers were washed with H 2 O (4×100 ml) and brine (100 ml), dried over Na 2 SO 4 and evaporated to give 3.00 g of yellow oil, which was purified via column chromatography with silica gel. After elution with EtOAc/hexane, some starting ketone, 0.35 g, was recovered and the desired diene 3 was isolated as a colorless oil, 1.64 g (56.0% yield).
NMR (400 MHz): delta 5.67 (AB pattern, 2H, --CH═CH--), 5.18 (s, 1H, ═CH(TMS)), 2.85 (bs, 1H, bridgehead H), 2.26 (m, 4H, ═CH--CH 2 --), 2.05 (m, 1H), 1.79-1.55 (m, 3H) 1.41 (s, 1H), 1.28 (m, 1H), 0.07 (s, 9H, SiCH 3 ).
Preparation of Methyl syn-2(3-(2-Acetaldehyde)-2(E.Z)-trimethylsilylmethylenecyclohexyl)acetate (4)
As per Schreiber's procedure (R. E. Claus and S. L. Schreiber, Org. Syn., 64, 150 (1985)), through a stirring suspension of NaHCO 3 (12 mg) in a solution of 10-trimethylsilylmethylenebicyclo[4.3.1]dec-2-ene (400 mg, 1.82 mmol), dry CH 2 Cl 2 (15 ml) and absolute methanol (3 ml) at -78° C. was passed a stream of O 3 /O 2 . The disappearance of starting material was monitored by periodic TLC (SiO 2 in EtOAc/hex) before the mixture was purged with inert gas, allowed to warm to ambient temperature, filtered, diluted with dry benzene (30 ml) and concentrated at reduced pressure to a colorless solution of approximately 10 ml. This concentrate was diluted with dry CH 2 Cl 2 (15 ml) and treated successively with triethylamine (0.39 ml) and acetic anhydride (0.58 ml). After 4 h at ambient temperature, the reaction was stirred with 10% aq. HCl (3 ml) and H 2 O (20 ml). The aqueous layer was separated and extracted with Et 2 O (2×25 ml). The combined organic layers were washed with H 2 O (25 ml), sat. aq. NaHCO 3 (2×30 ml) and brine (2×60 ml), dried over Na 2 SO 4 and evaporated to give a yellow oil, which was purified via column chromatography with silica gel. After elution with EtOAc/hex, the unstable aldehyde 4 was obtained as a colorless oil, 215 mg (43.7% yield) which consisted of a 1:1 mix of E:Z isomers by NMR (90 MHz) and was used immediately.
NMR (90 MHz): delta 9.70 (m, 1H, --CHO), 5.30 (s, 1H, ═CH(TMS)), 3.65 (d, 3H, --CO 2 CH 3 ), 3.50-2.05 (m, 6H), 1.90-1.10 (bm, 6H), 0.12 (d, 9H, SiCH 3 ).
Preparation of Methyl syn-2(3-methoxy-2(E,Z)-butenyl-2-(E,Z)trimethylsilylmethylene)cyclohexyl)acetate (6)
To a solution of diisopropylamine (0.184 ml, 1.31 mmol) in THF (10 ml) at 0° C. was added dropwise a solution of nBuLi (0.821 ml of 1.6 M in hexanes). After 10 min at 0° C., a solution of (1-methoxyethyl)diphenyl phosphine oxide (S. Warren et al, J. C. S. Perkin I, 3099 (1979)) (307 mg, 1.19 mmol) in THF (5 ml) was added via cannula. After 10 min at 0° C., the resultant brick red solution was cooled to -78° C., and a solution of aldehyde 4 (215 mg, 0.796 mmol) in THF (5 ml) was added via cannula. After 1 h at -78° C., the resultant yellow solution was allowed to warm to ambient temperature, stirred with sat. aq. NH 4 Cl (20 ml) and extracted with Et 2 O (2×20 ml). The combined ethereal layers were washed with sat. aq. NH 4 Cl (20 ml, brine (820 ml), sat. aq. NaHCO 3 (2-15 ml) and brine (2×25 ml), dried over Na 2 SO 4 and evaporated to provide 483 mg of yellow foam, from which a purified sample of diastereomeric adduct mixture 5 was obtained and spectrally scrutinized.
NMR (90 MHz): delta 8.25-7.24 (bm, 10H, ArH), 5.75-4.90 (m, 3H, HO--CH), 3.67 (q, 3H, --CO 2 CH 3 ), 3.30 (q, 3H --OCH 3 ), 3.30-0.69 (m, 15H), 0.70 (q, 9H, SiCH 3 ).
The crude adduct mixture 5 was placed in THF (4 ml) and added via cannula to a stirring suspension of NaH (24 mg of an 80% oil dispersion, 0.80 mmol) in THF (8 ml). After 3 h at ambient temperature, the resultant suspension was stirred with sat. aq. NH 4 Cl (15 ml) and hexane (50 ml). The separated organic layer was washed with sat. aq. NH 4 Cl (15 ml) and brine (25 ml), dried over Na 2 SO 4 and evaporated to afford 344 mg of orange oil, which was purified by column chromatography with silica gel. After elution with EtOAc/hexane, enol ether 6 was obtained as a colorless oil, 140 mg (54.3% yield from 4), which was a mix of four diastereomers as reflected in the NMR and TLC (SiO 2 in EtOAc/hexane).
NMR (90 MHz): delta 5.10 (m, 1H, --CH), 4.18 (bm, 1H, --CH(OMe)), 4.48 (m, 3H, OCH 3 ), 3.17-0.90 (m, 15H), 0.07 (d, 9H, SiCH 3 ).
Preparation of syn-2(3(3-Oxobutyl)-2(E,Z)-trimethyl silylmethylenecyclohexyl)acetic Acid (8)
To a solution of ester 6 (90.0 mg, 0.278 mmol) in MeOH (10 ml) was added 6N KOH (0.69 ml, 15 equiv). The solution was heated at reflux for 12 h and allowed to stir at ambient temperature for an additional 12 h. The resultant yellow solution was acidified with sat. aq. NH 4 Cl (35 ml) and extracted with EtOAc (2×20 ml). The combined organic layers were washed with brine (2×30 ml), dried over Na 2 SO 4 and evaporated to give acid 7 as a yellow oil, which was a fairly pure E:Z mix by NMR and used without further purification.
NMR (90 MHz): delta 5.23 (m, 1H, ═CH), 4.26 (bt, 1H, MeO--C═CH), 3.48 (m, OCH 3 ), 3.40-0.90 (m, 15H), 0.07 (d, 9H, SiCH 3 ).
The yellow oil was placed in CH 2 Cl 2 (10 ml) and stirred with silica gel (70-230 mesh) while adding freshly prepared 10% aq. oxalic acid (50 ml). After 2 h at ambient temperature, the solid was filtered off and rinsed with CH 2 Cl 2 (100 ml). The filtrate was concentrated in vacuo to afford a yellow oil, which was purified by column chromatography with silica gel. After elution with HOAc/EtOAc/hexane, ketoacid 8 was obtained as a yellow oil, 77 mg (93.9% yield from enol 7).
NMR (90 MHz): delta 5.23 (d, 1H, ═CH), 3.30-2.30 (m, 6H), 2.13 (s, 3H, COCH 3 ), 2.00-1.00 (bm, 8H), 0.07 (d, 9H, SiCH 3 ).
Preparation of (±)-13,14-desmethylartemisinin (1)
Through a solution of ketoacid 8 (17 mg, 0.057 mmol) in absolute MeOH (2 ml) at -78° C. was passed a stream of O 3 /O 2 until no starting material could be detected by TLC (HOAc/EtOAc/hexane). The resultant pink solution was allowed to warm to ambient temperature and concentrated in vacuo to a yellow foam, which was placed in CDCl 3 (2 ml) After treatment with 10% trifluoroacetic acid in CDCl 3 (20 microliter), the formation of cyclization product 8 was monitored by NMR (90 MHz). After 8.5 h at ambient temperature, the solution was stirred with NaHCO 3 (25 mg), filtered, and evaporated to give 17 mg of yellow oil, which was purified by PTLC with silica gel. After development with 5% EtOAc/CHCl 3 , the major component was isolated and reapplied to PTLC plates for development in 35% EtOAc/hexane. In this manner, (±) 13,14-desmethylartemisinin (1) was isolated as white needles which were recrystallized with EtOAc/hexane to give 4.8 mg, mp 130-130.5° C.
1 H NMR (400 MHz): delta 5.90 (s, 1H, H 5 ), 3.18 (dd, 1H, J=18.3, 7.1 Hz, H 11alpha ), 2.42 (dt, 1H, J=3.5, 3.8 Hz, H 1 )m 2.25 (dd, 1H, J=18.3, 1.3 Hz, H 11beta ), 2.02 (ddd, 1H, J=15.3, 4.9, 2.7 Hz, H 3alpha ), 1.96-1.48 (m, 10H), 1.44 (s, 3H, --CH 3 ). 13 C NMR: delta 168.7, 105.4, 93.2, 78.1, 43.9, 38.4, 36.0, 32.1, 31.6, 30.2, 26.6, 25.5, 25.4, 24.7. IR (KBr) 2925, 1735, 1210, 1005 cm -1 . CIMS ( + NH 4 ) m/e 272 (M+ + NH 4 ), 255 (M+ + H).
Biological Results
The analog 1 was sent to Walter Reed Army Institute of Research (WRAIR) for in vitro testing against P. falciparum using modifications of the procedures of Desjardins et al, 1979, and Milhous et al, 1985, (Desjardins, R. E., C. J. Canfield, D. E. Haynes, and J. D. Chulay, Antimicrob. Angents Chemother., Vol. 16, 710-718 (1979); Milhous, W. K., N. F. Weatherly, J. H. Bowdre, and R. E. Desjardins, Antimicrob. Agents Chemother. Vol. 27, 525-530, 1985.) to assess the intrinsic activity of compound 1 as an anti-malarial drug relative to simultaneous known controls such as chloroquine, mefloquine; pyrimethamine, sulfadoxine, tetracycline, qinghaosu or quinine. Since some anti-malarials are more static than cidal in action, it is necessary to extend the incubation period to assess the effects of such drugs on parasite growth rates. In order to insure exponential parasite growth and maximum uptake of radioisotope throughout the extended incubation, reduced starting parasitemias (0.2%) and reduced red cell hematocrits (1.0%) are required. As a result, drugs which are actively incorporated into erythrocytes (such as chloroquine or qinghaosu) will have slightly lower 50% inhibitory concentrations than in other assay systems employing higher red cell hematocrits. Except for the contribution from the 10% normal pooled human plasma and added 10 -10 M (0.014 ng/ml) PABA, the culture medium is folate-free. The trace amount of PABA insures exponential growth of the sulfonamide-susceptible parasite clone without antagonizing the activity of antifol anti-malarials. Sulfonamides and sulfones are 1,000-10,000-fold more active and DHFR inhibitors are 5-200-fold more active in this medium than in normal RPMI 1640 culture medium.
All test compounds are solubilized in DMSO and diluted 400-fold (to rule out a DMSO effect) in culture medium with plasma for a starting concentration of at least 12,500 ng/ml. Drugs are subsequently diluted fivefold using the Cetus Pro/Pette™ system utilizing a range of concentrations from 0.8 ng/ml to 12,500 ng/ml. Fifty percent inhibitory concentrations are reported in ng/ml.
Table 1 summarizes differences in the susceptibility profiles of the two control P. falciparum clones (Oduola, A. M. J., N. F. Weatherly, J. H. Bowdre, R. E. Desjardins, Thirty-second Annual Meeting, American Society of Tropical Medicine and Hygiene, San Antonio, Tex., Dec. 4-8, 1983) and provides results of testing. The W-2 Indochina P. falciparum clone is resistant to chloroquine, pyrimethamine and sulfadoxine but susceptible to mefloquine. The D-6 African P. falciparum clone is susceptible to chloroquine, pyrimethamine and sulfadoxine but resistant to mefloquine.
TABLE 1______________________________________IN VITRO ED.sub.50 VALUES OF SELECTEDANTIMALARIALS AGAINST TWO STRAINSOF P. FALCIPARUM*Antimalarial MW × 10.sup.-9 M ng/ml × 10.sup.-9 M ng/ml______________________________________Qinghaosu 282 10.99 3.09 7.01 1.97Dihydro- 284 1.68 0.47 1.37 0.38quinghaosuArteether 312 6.00 1.87 3.96 1.23(±)-13,14- 254 82.95 21.06 15.98 4.05Desmethyl-artemisinin (1)Chloroquine 515 11.49 5.91 52.13 26.84Mefloquine 414 53.69 22.22 3.33 1.37______________________________________ *Data obtained by Walter Reed Army Institute of Research (WRAIR) ##STR21## ##STR22##
The data shown in Table 1 indicate that compound 1 is approximately 1/2 as active as the natural product Qinghaosu against the W-2 Indochina strain of P. falciparum. Against this same strain, compound 1 was about three times as potent as the classical antimalarial agent chloroquine. While it can be seen from the table that the antimalarial efficacy of 1 varies with strain, the potency of 1 versus the other five compounds is still in the nanogram range and this is highly significant. These data show that compound 1 is a highly active antimalarial agent.
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A process for synthesizing oxygen-containing polyoxatetracycle compounds and in particular analogs of the antimalarial agent known as qinghaosu or artemisinin is disclosed. The process employs as a reactant an olefinically unsaturated bicyclic bridging ketone having nonenolizable bridgehead moieties for both of its alpha positions. This ketone is converted to a vinylsilane that is subjected to ozonolytic cleavage of its olefinic bond to yield a member of a family of unique carboxyl/carbonyl-substituted vinylsilanes which may in turn optionally be subjected to a wide range of reactions prior to a final ozonolysis/acidification step which closes the oxygen-containing ring structure. The various intermediates are claimed as aspects of this invention as are novel tetracycles and their use as antimalarials.
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BACKGROUND OF THE INVENTION
1. Field of the Invention
This invention relates generally to an independent suspension for use on a motor vehicle. More particularly, the present invention relates to an independent suspension having suspension members arranged to decouple longitudinal and lateral load paths between a wheel support member and a motor vehicle structure.
2. Disclosure Information
Independent suspensions using `A`-shaped control arms are well known in the motor vehicle industry. The design is desirable for its ability to maintain a tire and wheel assembly in a predetermined relationship with a road surface. Two parameters used to measure this relationship are "toe" and "camber". Toe refers to the orientation of the wheel and tire assembly about a vertical axis. "Toe-in" refers to a condition where the leading edge of the tire and wheel assembly has rotated, or turned, inward toward the center of the vehicle. Camber refers to the vertical angle of the tire and wheel assembly relative to the longitudinal plane of the vehicle. As a suspension undergoes dynamic loading, it is desirable to manage toe change to improve the dynamic response of the vehicle. It is also desirable to provide optimal camber change during dynamic loading, especially lateral, of the suspension.
The major source of camber change during dynamic loading occurs due to deformation of the elastomeric bushings used to mount the control arms to the wheel support member and the vehicle structure. The elastomeric bushings common in todays suspensions are necessary to provide isolation from the dynamic loads imparted on the suspension during operation. Typically, when the vehicle encounters bumps, chuckholes etc., the suspension attachment joints must deflect to provide adequate isolation, thus ensuring customer satisfaction. However, suspension designers cannot simply provide large amounts of deflection for isolation purposes, as this could negatively impact the steering handling performance of the vehicle. Thus, in conventional designs, a compromise must be made between isolation the handling performance.
It would therefore be desirable to provide a suspension design capable of decoupling isolation from handling performance such that a suspension could be designed that provided both optimal handling performance as well as sufficient isolation to satisfy customers.
SUMMARY OF THE INVENTION
According to the present invention, a rear suspension apparatus for a motor vehicle is provided for decoupling the lateral and longitudinal load paths from the suspension into a vehicle structure. The rear suspension apparatus comprises a wheel support member having upper and lower ends. The suspension also includes an upper control arm having first and second upper ends pivotably connected to the vehicle structure and an outer upper end connected to the upper end of the wheel support member. The suspension further includes a lower control arm having first and second lower ends pivotably connected to the vehicle structure and an outer lower end connected to the lower end of the wheel support member.
The first and second lower ends of the lower control arm pivot about an axis which is coaxial with respect to a straight line (L1), which extends forwardly, outwardly and upwardly from the second end toward the first end of the lower control arm with respect to a longitudinal axis (LV) of the motor vehicle. The second lower end and the outer lower end of the lower control arm are located on a straight line (L2), which substantially perpendicularly intersects the longitudinal axis (LV) of the motor vehicle.
Similarly, the first and second upper ends of the upper control arm pivot about an axis which is coaxial with respect to straight line (L3), which extends forwardly, outwardly and downwardly from the second upper end toward the first upper end of the upper control arm with respect to the longitudinal axis (LV) of the motor vehicle. The second upper end and the outer upper end of the upper control arm are located on a straight line (L4), which substantially perpendicularly intersects the longitudinal axis (LV) of the motor vehicle.
An advantage of this rear suspension apparatus is to decouple the longitudinal and lateral load paths between the wheel support member and the vehicle structure, thereby allowing for appropriate isolation while providing sufficient lateral load path stiffness to minimize or eliminate undesirable camber and/or toe changes due to compliance of the suspension joints.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 is a perspective view of a rear suspension apparatus located in a motor vehicle structure in accordance with the present invention.
FIG. 2 is a plan view of a rear suspension apparatus according to the present invention.
FIG. 3 is a rear view of a rear suspension apparatus according to the present invention.
FIG. 4 is a partial sectional view of a restricted motion joint for use in a rear suspension apparatus according to the present invention.
FIG. 5 is a partial sectional view of a conventional elastomeric joint for use in a rear suspension apparatus according to the present invention.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT
Referring now to FIG. 1, a suspension for a motor vehicle is shown attached to a subframe, which is a component of the vehicle structure 10. The term "structure" when used in this specification and claims will be understood to refer to either a conventional vehicle chassis having body on frame construction or a conventional unitary chassis and body construction, which may or may not incorporate subframes therein. In any event, the structure makes up a part of the sprung mass of the vehicle and provides a foundation for suspension attachement.
The suspension comprises a wheel support member 12 having upper and lower ends 14, 16 and a rearward portion 17. An axle 18, which may be driven as illustrated, or imaginary on freewheeling axles, extends through a center 20 of the wheel support member 12. Upper and lower control arms 22, 24 and a toe link 26 connect the wheel support member 12 to the vehicle structure 10. It should be noted that only the left of the suspension will be described herein for purposes of simplicity, it being understood that the right side is simply the symmetric opposite of the left.
Referring now to FIGS. 2 and 3, the upper control arm 22 is of the "A-shaped" type, including first and second upper ends 30, 32 for pivotably attaching to the vehicle structure 10. The upper control arm 22 also includes an outer upper end 34 for pivotably attaching to the upper end 14 of the wheel support member 12.
The lower control arm 24 is also of the A-shape type, including first and second lower ends 40, 42 for pivotably attaching to the vehicle structure 10. The lower control arm 24 also includes an outer lower end 44 for pivotably attaching to the lower end 16 of the wheel support member 12.
Being of the A-shape type, both the upper and lower control arms 22, 24 lie in predetermined planes which result in desirable suspension operating characteristics. As illustrated, the lower control arm lies in a plane defined by lines L1 and L2. Line L1 may be determined by drawing a line through centers 50, 52 of the joints disposed on the first and second lower ends 40, 42, respectively. The first and second lower ends 40, 42 are located such that line L1 extends forwardly, outwardly and upwardly from the second lower end 42 toward the first lower end 40 with respect to a longitudinal axis (LV) of the vehicle.
The second line, L2, may be determined by drawing a line through the center 52 of the second lower end 42 and a center 54 of the joint disposed on the outer lower end 44. The second lower end 42 and the outer lower end 44 are located such that an extension of line L2 would substantially perpendicularly intersect the longitudinal axis (LV) of the vehicle. It should be noted that in this regard, the longitudinal axis of the vehicle is not a single line, but contemplates any line lying in a vertical plane oriented longitudinally with respect to the longitudinal dimension of the motor vehicle. The second lower end 42 and the outer lower end 44 are also located such that line L2, when viewed from directly above, lies substantially directly under a line that would extend from the center 20 of the wheel support member 12 inwardly to substantially perpendicularly intersect the longitudinal axis (LV) of the vehicle. In the presently preferred embodiment, this line takes the form of the axle 18.
Similar to the orientation of the lower control arm 24, the upper control arm 22 lies in a plane defined by lines L3 and L4. Line L3 may be determined by drawing a line through centers 60, 62 of the joints disposed on the first and second upper ends 30, 32, respectively. The first and second lower ends 30, 32 are located such that line L3 extends forwardly, outwardly and downwardly from the second upper end 32 toward the first upper end 30 with respect to a longitudinal axis (LV) of the vehicle.
The second line, L4, may be determined by drawing a line through the center 62 of the second upper end 32 and a center 64 of the joint disposed on the outer upper end 34. The second upper end 32 and the outer upper end 34 are located such that an extension of line L4 would substantially perpendicularly intersect the longitudinal axis (LV) of the vehicle. The second upper end 32 and the outer upper end 34 are also located such that line L4, when viewed from directly above, lies substantially directly over the axle 18, like line L2.
The toe link 26 is preferably adjustable in length and includes an inner toe end 70 attached to the vehicle structure 10 and an outer toe end 72 attached to the rearward portion 17 of the wheel support member 12. As illustrated, the toe link 26 extends along a line, L5. Line L5 may be determined by drawing a line through centers 74, 76 of the joints disposed on the inner and outer toe ends 70, 72, respectively. These ends are located such that line L5 extends slightly forward from the inner toe end 70 toward the outer toe end 72. Additionally, it is desirable if, when viewed from the rear, the toe link 26 can be located such that Line L5 is as close as possible to being directly rearward of the axle 18.
The above described novel suspension geometry provides several operating advantages for increased vehicle stability, however, perhaps its greatest advantage lies in its ability to decouple longitudinal and lateral load paths. Decoupling the lateral load path from the longitudinal load path allows the use of stiff or no transational compliance joints in the lateral load path previously unacceptable due to their unacceptable transmissibility of noise and vibration.
In view of this, the presently preferred embodiment makes use of restricted motion joints in the lateral load path. The resulting suspension provides handling performance that customers would describe as crisp, rapid response to steering inputs by the driver. Conventional joints are also used in the longitudinal load path to provide isolation from longitudinal force inputs.
One example of a restricted motion joint contemplated for use in the present invention is a conventional ball joint. A conventional ball joint provides three degrees of rotational freedom and no translational degrees of freedom. Therefore, it is considered rigid from a displacement standpoint and relatively unconstrained from a rotational standpoint. In the present invention a ball joint is preferred for providing the connection of the outer upper end 34 of the upper control arm 22 to the upper end 14 of the wheel support member 12.
FIG. 4 illustrates another example of a restricted motion joint contemplated for use in the present invention known as a cross axis joint 80. A cross axis joint is similar to a rod end in that it allows three rotational degrees of freedom and no translational degrees of freedom. However, there may be a degree of elasticity built into the rotational degrees of freedom to provide some resistance to rotations. The cross axis joint 80 includes a housing 82 having a bore for receiving a race 84. A substantially rigid bushing 86 is disposed within the race 84 and includes a bore therethrough for receiving a threaded fastener for attachment to the vehicle structure. The outer diameter of the housing 82 is sized to allow a press fit relationship within a bore formed in the end a control arm.
In the preferred embodiment, a cross axis joint 80 provides connection at the second upper end 32, the second lower end 42 and the outer lower end 44. Thus, restricted motion joints are located at each of the pivotable connections in the lateral load path. Additionally, the inner and outer toe ends 70, 72 of the toe link 26 include restricted motion joints such as cross axis joint 80.
FIG. 5 illustrates a conventional elastomeric bushing 90 commonly used for suspension attachment. The elastomeric bushing 90 includes an outer sleeve 92 having an outer diameter permitting a press fit relationship with a bore formed in the end of a control arm. An inner sleeve 94 is coaxially disposed within the outer sleeve 92 forming an annular region therebetween which is filled with an elastomeric material 96 having a predetermined durometer. A threaded fastener passes through a bore in the inner sleeve for attachment with the vehicle structure 10. This type of joint permits three degrees of rotational freedom as well three degrees of translational freedom and is very effective for providing vibration isolation. In the present invention, elastomeric bushings 90 provide connection at the first upper end 30 and the first lower end 40. Thus, elastomeric joints are located at each of the pivotable connections in the longitudinal load path to provide isolation from longitudinal forces.
During operation, the primary benefit of decoupling the load paths and the resultant ability to use restricted motion joints comes from the reduction in compliant camber change under lateral loads generated during vehicle maneuvers. The reduction in camber change provides a consistent tire to road interface, resulting in improved static and dynamic lateral acceleration capability. The driver perceives this as a more responsive vehicle to steering inputs. Additionally, the elimination of compliance in the lateral load path provides a suspension that tracks the desired course more quickly and accurately than a suspension with lateral compliance.
The toe change characteristics of the suspension are controlled through the novel implementation of the toe link 26. Dynamic longitudinal loading can cause the suspension to toe in or toe out, which in turn can change the vehicle's natural tendency to understeer or oversteer. The present invention assures desirable toe change under varying longitudinal load conditions. However, the degree of toe out is controlled by the length of the rearward portion 17 of the wheel support member 12. Similarly, when the wheel encounters a bump, the natural tendency again is toward toe out. However, due to the forward skew of the toe link, the suspension actually toes in.
The foregoing description presents one embodiment of the present invention. Details of construction have been shown and described for purposes of illustration rather than limitation. For instance, it should be recognized by those skilled in the art that elastomeric bushings having a very high durometer, or constructed from a rigid material, could be substituted for the cross axis joints described above, while providing the equivalent operability and functionality. Modifications and alterations of the invention will no doubt occur to those skilled in the art that will come within the scope and spirit of the following claims.
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An independent suspension apparatus suitable for use in a motor vehicle capable of decoupling longitudinal and lateral load transfers is described. The suspension includes upper and lower control arms (22, 24), each having first and second ends (30, 32, 40, 42) respectively, being pivotably attached to a vehicle structure. Each of the control arms also includes an outer end (34, 44) for attachment to a wheel support member (12). A toe link (26) is provided for controlling toe change during dynamic loading of the suspension. The upper and lower control arms (22, 24) are arranged so as to provide a decoupling of the longitudinal and lateral load paths between a wheel support member (12) and the vehicle structure (10). This allows the use of restricted motion joints in the lateral load path to reduce camber changes normally resulting from the necessary use of compliant bushings found in the lateral load path.
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[0001] This application claims the benefit of U.S. Provisional Application Ser. No. 60/643,487, filed Jan. 13, 2005, entitled “DIETARY SUPPLEMENT FOR TREATMENT OF LIPID RISK FACTORS,” which application is incorporated herein by reference in its entirety.
BACKGROUND OF THE INVENTION
[0002] The Centers for Disease Control reports that heart disease and stroke—the principal components of cardiovascular disease—are the first and third leading causes of death for both men and women in the United States, accounting for nearly 40% of all deaths. Over 930,000 Americans die of cardiovascular disease each year, which amounts to one death every 34 seconds. In addition, the CDC reported that the cost of heart disease and stroke in the United States was projected to be $368 billion in 2004, including health care expenditures and lost productivity from death and disability.
[0003] It is recognized that one can is to reduce the risk of cardiovascular disease through therapy aimed at lowering the blood lipid levels. Various therapies, including the use of pharmaceutical formulations, are currently extensively used by patients in need. There is a desire to find non-pharmaceutical (e.g. “over the counter”) formulations and supplements to provide assist in the management of lipid risk factors. For example, U.S. Pat. No. 6,632,428 to Zhang, et al. discloses methods and compositions comprising red rice fermentation products that can be used as natural dietary supplements and/or medicaments for the treatment or prevention of hyperlipidemia and associated disorders and symptoms, such as cardiovascular diseases.
SUMMARY OF THE INVENTION
[0004] The present invention provides a dietary supplement for the treatment of lipid risk factors comprising nicotinic acid, pantethine and lemon/orange flavonates. This supplement provides significant benefit in affect on major cardiovascular disease (“CVD”) lipid risk factors, including LDL-C, HDL-C, and Tg. Also described are methods for treatment of lipid risk factors in a person in need thereof, comprising administering a dietary supplement in unit dosage form comprising nicotinic acid, pantethine and lemon/orange flavonates to the person.
[0005] It is believed that provision of the three listed active ingredients in a single unit dose formulation provides substantial benefit in co-action of the active ingredients, as well as convenience to the user. It is particularly advantageous that CVD factor benefits are provided by the present dietary supplement in a non-prescription formulation.
DETAILED DESCRIPTION
[0006] The essential ingredients of the dietary supplement of the present invention comprise nicotinic acid, pantethine and lemon/orange flavonates. All individual ingredients have been clinically tested in randomized clinical trials and have been shown to beneficially and safely improve CVD risk. Nicotinic acid and pantethine have also been shown to improve non-traditional CVD risk factors such as apolipoprotein B, LDL particle size, and Lp(a)-C levels. Lemon/orange flavonates are an excellent source of polymethoxylated flavones (PMFs). Animal and human studies have shown that PMFs lower LDL-C and also likely possess other CVD benefits, such as improved platelet and vascular function.
[0007] It will be appreciated that the actual preferred amounts of active compound in a specific case will vary according to the particular compositions formulated, the mode of application, and the nature of the person being treated. For example, the specific dose for a particular patient depends on the age, body weight, general state of health, on the diet, on the timing and mode of administration, on the rate of excretion, and on medicaments used by the patient.
[0008] In a preferred embodiment, the dietary supplement comprises
a) from about 1 to about 1000 mg Nicotinic Acid, b) from about 1 to about 1000 mg Pantethine, and c) from about 1 to about 1000 mg lemon/orange flavonates.
[0012] In another preferred embodiment, the dietary supplement comprises
a) from about 50 to about 500 mg Nicotinic Acid, b) from about 50 to about 400 mg Pantethine, and c) from about 25 to about 350 mg lemon/orange flavonates.
[0016] In yet another preferred embodiment, the dietary supplement comprises
a) from about 100 to about 350 mg Nicotinic Acid, b) from about 100 to about 300 mg Pantethine, and c) from about 50 to about 250 mg lemon/orange flavonates.
[0020] As a preferred example of a dietary supplement, a tablet is provided that comprises:
a) about 250 mg Nicotinic Acid, b) about 200 mg Pantethine, and c) about 150 mg lemon/orange flavonates.
[0024] The active ingredients as discussed above can optionally be combined with any additional ingredients that do not adversely affect the treatment of lipid risk factors function of the dietary supplement. In a preferred embodiment, the dietary supplement “consists of” the above active ingredients, or in other words does not contain active ingredients other than the above recited three ingredients. A three-active-component formulation is advantageous in providing a simple formula with a minimum potential of adverse interactions with other materials.
[0025] The dietary supplement of the present invention preferably is formulated with one or more nontoxic pharmaceutically acceptable carriers, such as cornstarch, lactose, or sucrose, which do not deleteriously react with the active compounds.
[0026] Preferably, the dietary supplement of the present invention is provided in a format suitable for oral administration, and more preferably in a dry oral administration format. Most preferably, the dietary supplement is provided in tablet form. In an alternative preferred format, the dietary supplement is in a form selected from the group consisting of dragees, lozenges, powders, or capsules.
[0027] In a particularly preferred embodiment, the dietary supplement of the present invention is provided in a sustained release or time release form. For purposes of the present invention the dietary supplement is considered to be “sustained release” or “time release” if the active ingredients are delivered to the bloodstream at a rate that is measurably longer than the rate of a like conventional supplement administration form. Preferably, the active ingredients are delivered to the bloodstream at a rate that is at least about twice as long as the rate of delivery of a like conventional supplement administration form.
[0028] The provision of a dietary supplement in sustained release form finds particular benefit as a convenient dosage form by virtue of eliminating the necessity for dosage several times during the day. Moreover, therapeutic benefits may also be obtained by the sustained release of the active ingredients of the inventive formulation. In one aspect, the sustained-release form beneficially delivers the active agents systemically more slowly, which can improve product tolerability and efficacy. Additionally, it is believed that the sustained release dosage form of the present invention provides superior benefit to like dietary supplements that are not in sustained release form due to the continuous application of the effect of the active ingredient without disadvantageous periods absent the effect of the active ingredient. It is believed that even short time periods absent the effect of the active ingredient have a disproportionately adverse effect in the treatment of lipid risk factors.
[0029] The dietary supplement of the present invention may be provided as a sustained release product in any appropriate manner, such as those known in the pharmaceutical and health product arts.
[0030] According to one preferred embodiment, a matrix such as wax, hydroxypropyl methylcellulose, or the like, is used as a pharmaceutical adjunct, which provides a sustained release of the active constituents of the tablet. According to this preferred embodiment, a sufficient amount of the time release matrix material can be incorporated in the tablet to ensure proper time release tablet.
[0031] A preferred example of a sustained release systems include a proprietary process developed by Innovite, Inc. This process is described at http://www.endur.com/index.cfm?fuseaction=main.about as follows:
Innovite has developed a novel process for impregnating a matrix (vegetable source) with active ingredients. This material is then compressed into tablets having uniform, continuous release rates. This proprietary process uses a cold-extrusion technique that extends stability profiles by eliminating heat, moisture and solvents.
[0033] Alternatively, the active ingredients of the dietary supplement can be provided in a suitable discrete from, such as in particle or granule form, and further provided with an enteric coating that is resistant to disintegration in gastric juices.
[0034] The coated granules can be mixed with optional additives such as antioxidants, stabilizers, binder, lubricant, processing aids and the like. The mixture can be compacted into a tablet which, prior to use, is hard and dry or it can be poured into a capsule.
[0035] Those skilled in the art will also appreciate that the formulations of the present invention may also be encapsulated in other time-release delivery systems such as a liposome delivery system, polysaccharides exhibiting a slow release mechanism, polymer implants or microspheres. In such time release delivery systems, the active compound is suitably protected with differentially degradable coatings, e.g., by microencapsulation, multiple coatings, etc., and such means effect continual dosing of compositions contained therein.
[0036] In use, the dietary supplement as described herein is administered to a person in need of treatment of lipid risk factors. In one method, a unit dose dietary supplement is administered on a substantially daily basis. Preferably, the unit dose dietary supplement is in a time release format. In another method, the unit dose dietary supplement is administered in from about two to about six doses per day.
[0037] In a preferred embodiment, the dietary supplement of the present invention is administered with food.
[0038] All percentages and ratios used herein are weight percentages and ratios unless otherwise indicated. All publications, patents and patent documents cited are fully incorporated by reference herein, as though individually incorporated by reference. Numerous characteristics and advantages of the invention meant to be described by this document have been set forth in the foregoing description. It is to be understood, however, that while particular forms or embodiments of the invention have been illustrated, various modifications can be made without departing from the spirit and scope of the invention.
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A dietary supplement is provided for the treatment of lipid risk factors comprising nicotinic acid, pantethine and lemon/orange flavonates. This supplement provides significant benefit in affect on major cardiovascular disease (“CVD”) lipid risk factors, including LDL-C, HDL-C, and Tg in a non-prescription formulation. Also described are methods for treatment of lipid risk factors in a person in need thereof, comprising administering a dietary supplement in unit dosage form comprising nicotinic acid, pantethine and lemon/orange flavonates to the person.
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FIELD OF USE
This invention is generally in the field of devices for opening vessels of the human body with specific application to percutaneous transluminal coronary angioplasty (PTCA) and stent delivery into a dilated artery.
BACKGROUND OF THE INVENTION
It is well known to use balloon angioplasty catheters for the dilatation of various vessels of the human body and most particularly for opening arteries. It is also well known to place stents into vessels to maintain patency of that vessel. It is also well known to use a balloon catheter for imbedding a stent into the wall of the vessel to maintain vessel patency.
Typical angioplasty balloons are made from non-compliant or semi-compliant plastic which is folded over itself to minimize the catheter cross sectional area during introduction into a patient. These balloons typically have two folds which allow the relatively inelastic plastic of the balloon to be wrapped tightly. During stent delivery, a two-fold balloon applies non-uniform frictional forces to the inside surface of the stent. This can cause a stent which typically has 5 to 9 cells circumferentially disposed in each cylindrical segment of the stent to have some cells expand to a larger size as compared to some other cells. The result of such frictional forces is often seen in stent deployments where cells on one side of the stent are expanded more or less than adjacent cells around the stent's circumference.
SUMMARY OF THE INVENTION
The present invention overcomes the disadvantages of prior art devices by utilizing a balloon with three or more folds to more evenly distribute the frictional forces on the inside of the stent during stent deployment thus improving the uniformity of stent cell expansion.
Ideally one would like to have the same number of balloon folds as the number of stent cells distributed circumferentially around the stent. Twice or half the number of balloon folds as compared to the number of stent cells may also be advantageous.
Although this invention could be used for any vessel of the human body including but not limited to arteries, veins, vascular grafts, biliary ducts, urethras, fallopian tubes, bronchial tubes, etc., the descriptions herein are particularly valuable for coronary artery stenting.
Thus the object of this invention is to improve the uniformity of stent cell expansion during deployment by utilizing a stent delivery balloon with three or more folds.
Another object of this invention is to have the same number of balloon folds as the number of circumferentially distributed stent cells.
Yet another object of this invention is to have exactly twice the number of balloon folds as the number of circumferentially distributed stent cells.
Still another object of this invention is to have exactly half the number of balloon folds as the number of circumferentially distributed stent cells.
These and other objects and advantages of this invention will become apparent to a person of ordinary skill in this art upon careful reading of the detailed description of this invention including the drawings as presented herein.
BRIEF DESCRIPTION OF THE DRAWING
FIG. 1 is a longitudinal cross section of a distal portion of a prior art balloon angioplasty catheter used for stent deployment.
FIG. 2 is an enlarged transverse cross section of the prior art balloon angioplasty catheter at section 2--2 of FIG. 1.
FIG. 3 is longitudinal cross section of a distal portion of a multifold balloon stent delivery catheter.
FIG. 4 is an enlarged transverse cross section of the catheter at section 4--4 of FIG. 3.
FIG. 5 is a longitudinal cross section of a distal portion of a multifold balloon stent delivery catheter which incorporates a protective sheath.
FIG. 6 is a longitudinal cross section of a rapid exchange version of the multifold balloon catheter just proximal to the distal portion where the multifold balloon is located.
DETAILED DESCRIPTION OF THE INVENTION
U.S. Pat. Ser. No. 4,733,665 by Julio C. Palmaz (which is included herein by reference) describes the expansion of a stent by an angioplasty balloon. U.S. patent application Ser. No. 08/061,562 entitled "Multi-Cell Stent with Cells Having Differing Characteristics" (which application is included herein by reference) describes a stent which has at least three cells disposed circumferentially in each cylindrical segment of which the stent is composed.
FIG. 1 shows a longitudinal cross section of a distal portion of a typical angioplasty balloon stent delivery catheter 10 which includes a stent 20 and a balloon angioplasty catheter 15. Near the distal end of the balloon angioplasty catheter 15 is the angioplasty balloon 16 with folds 16A and 16B (see FIG. 2). The balloon 16 is attached at its proximal end to the distal end of the tube 11 and the distal end of the balloon 16 is joined to the distal end of the inner shaft 12 which has a inner guide wire lumen 19 through which the guide wire 30 can move slideably. The annular passageway 17 between the tube 11 and the inner shaft 12 is in fluid communication with the space between the balloon 16 and the inner shaft 12 and is used to inflate and deflate the balloon 16 so as to expand the stent 20 into the wall of a vessel of the human body. A radiopaque marker band 14 fixed to the inner shaft 12 provides a reference for identifying the center position of the balloon and stent.
FIG. 2 is an enlarged transverse cross section of the catheter 10 at section 2--2 of FIG. 1. The two balloon folds 16A and 16B of the balloon 16 are clearly shown. During expansion of the balloon 16, the folds 16A and 16B and other surfaces of the balloon 16 will exert unequal frictional forces against the inside surface of the stent 20 which may cause the five-cell stent 20 to expand non-uniformly. The number of cells disposed circumferentially in a single cylindrical segment of a stent is clearly defined in the cited U.S. patent application Ser. No. 08/661,562. Between three and nine cells per cylindrical segment is typical for a multi-cell stent. Each cell is formed from a series of wire-like struts that are connected together to form a closed perimeter cell.
To provide more uniformity of expansion of each cell in a cylindrical segment of the stent, it would therefore be highly desirable to have a stent delivery balloon with more than two folds.
FIG. 3 is longitudinal cross section of a distal portion of a multifold balloon stent delivery catheter 40 which includes a stent 20 and a multifold balloon angioplasty catheter 50. Near the distal end of the multifold balloon angioplasty catheter 50, the angioplasty balloon 52 with folds 52A, 52B, 52C, 52D, and 52E (see FIG. 4) is attached at its proximal end to the tube 11 and at its distal end to the inner shaft 12 which has a central guide wire lumen 19 through which the guide wire 30 can move slideably. The annular space 17 between the tube 11 and the inner shaft 12 is in fluid communication with the space between the balloon 52 and the inner shaft 12 and is used to inflate and deflate the balloon 52 so as to expand the stent 20 into the wall of a vessel of the human body. A radiopaque marker band 14 fixed to the inner shaft 12 provides a reference for identifying the position of the balloon 52 and stent 20.
FIG. 4 is an enlarged transverse cross section of the catheter 40 at section 4--4 of FIG. 3. The five balloon folds 52A, 52B, 52C, 52D, and 52E of the balloon 52 are clearly shown. During expansion of the balloon 52, the folds 52A, 52B, 52C, 52D, and 52E will tend to exert essentially equal frictional forces against the inside surface of each of the five cells around the circumference of the stent 20 which will cause the stent 20 to expand more uniformly as compared to a balloon that has only two folds.
FIG. 5 is a longitudinal cross section of a distal portion of a multifold balloon stent delivery catheter 60 which incorporates a protective sheath 62 over the angioplasty balloon stent delivery catheter 50 which is identical to that shown in FIGS. 3 and 4. The sheath 62 lies outside of the tube 11 and can be moved slideably with respect to the tube 11 by means located at the proximal end (not shown) of the catheter 60. For a typical stent delivery procedure, the catheter 60 would be advanced with the sheath 62 covering the stent 20 as shown in FIG. 5 until the desired stent placement location is reached. The sheath 62 would then be moved proximally to uncover the stent 20. The balloon 52 would then be inflated to expand the stent 20 against the vessel wall.
It should be understood that the catheters shown in FIGS. 1, 2, 3 and 4 are all shown with each balloon in its compressed state prior to stent deployment. For stent deployment, the balloon is inflated to a pressure that typically is in the range of 3 to 20 atmospheres.
The catheters shown in FIGS. 1, 2, 3 and 4 can be of either the "over-the-wire" type or a "rapid exchange" type both of which are well known in the art of balloon angioplasty. The "over-the-wire type of balloon catheter is characterized by having the central lumen 19 extend for the entire length of the catheter from an entry port (not shown) located at the catheter's proximal end to an exit port at the distal end of the catheter, which exit port is shown in FIGS. 1 and 3. A "rapid exchange" balloon catheter has a guide wire lumen entry port that is situated in a distal half-length of the catheter but proximal to the proximal end of the inflatable balloon.
An alternative embodiment of the present invention utilizes a rapid exchange concept for the balloon catheter. FIG. 6 shows a longitudinal cross section of a portion of the rapid exchange (as opposed to "over-the wire") multifold balloon stent delivery catheter 70 which portion is located just proximal to the multifold balloon 52. The catheter 70 has a dual lumen tube 72 having a balloon inflate/deflate lumen 74 and a second lumen 79 which is blocked near its distal end by the plug 75. The distal end of the lumen 74 enters into an annular passageway 17 which is in fluid communication with the interior of an inflatable angioplasty balloon as illustrated in FIG. 3. The dual lumen tube 72 is joined at its distal end to the proximal end of the outer cylindrical tube 11 which encloses the annular passageway 17. A thin-walled steel tube 78 can be inserted into the distal end of the lumen 79 at the distal end of the dual lumen tube 72 as a reinforcement. The tube 78 forms a fluid tight connection between the distal end of the lumen 79 and the proximal end of the guide wire lumen 19 inside of the inner shaft 12. An entry port 76 allows the guide wire 30 to enter the lumen 79.
The material(s) selected for the tubes 11, 12, 62 and 72 can be Teflon or an elastomer such as polyurethane or polyethylene. The length of the catheters 10, 40, 60, or 70 is typically 20 to 150 cm depending on the vessel into which it is to be used. The diameter of the catheter will typically vary from 1.0 to 3.0 mm depending on its use. The marker band 14 is typically made from a dense metal such as an alloy of tantalum, platinum or gold.
The fluid entry means at the proximal end of over-the-wire or rapid exchange types of catheters is well known in the art of balloon angioplasty catheters. The method for joining the proximal end of the outer sheath 60 to the exterior surface of the dual lumen tube 72 by means of a Tuohy-Borst fitting is also well known in the art of balloon angioplasty catheter.
It should also be understood that the invention described herein can be used with a variety of angioplasty balloon catheters including those with fixed guide wires at their distal end.
Various other modifications, adaptations, and alternative designs are of course possible in light of the above teachings. Therefore, it should be understood at this time that within the scope of the appended claims, the invention may be practiced otherwise than as specifically described herein.
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The present invention utilizes a balloon with three or more folds to more evenly distribute the frictional forces on the inside of a stent during stent deployment thus improving the uniformity of stent cell expansion. Ideally one would like to have the same number of balloon folds as the number of stent cells distributed circumferentially around the stent. Matching the number of balloon folds to the number of cells of each cylindrical segment of the stent provides better size uniformity for the stent cells after they are expanded against the wall or other vessel within a human body.
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[0001] The present application claims the priority of German Patent Application No. 102007048046.8 filed Oct. 5, 2007 under 35 U.S.C. § 119, the disclosure of which is hereby fully incorporated by reference herein.
TECHNICAL FIELD
[0002] The present invention relates to a device and method for delivering a fluid, such as hot-melt adhesive.
BACKGROUND
[0003] In many industrial applications, free-flowing materials (fluids) are delivered with the aid of fluid delivery devices and placed or dispensed onto substrates. The fluids may be adhesives, paints, sealing materials or gases, for example, and the substrates may be sanitary articles, plastic films, furniture or machine parts and the like. Depending on the specific application, the fluids may be delivered in the form of beads, strips or films, for example, or the material may be sprayed, if necessary, with the aid of a gaseous stream that influences the fluid. The fluid delivery devices are connected to a fluid source, for example a container for adhesives, and the fluid is transported with the aid of a pump to a discharge opening that is circular or slot-shaped, for example.
[0004] In some applications, it is advantageous or necessary that the fluid be heated before it is delivered. In the case of spraying methods, it may be advantageous to heat a gas that affects a liquid to be delivered. In many applications, it may be necessary to heat a liquid to be delivered, in particular a fluid hot-melt adhesive prior to delivery and application to a substrate or material. A fluid delivery device with an integrated heat transfer chamber is known from the applicant's patent EP 1 419 826 A2, for example, in which it was proposed that a structure with cavities, made in particular of a sintering material, be disposed in a heat transfer chamber in order to influence the transfer of heat in an advantageous manner.
[0005] There is a need for further improvement of fluid delivery devices which have a heat transfer member. There is therefore a need to optimize the fluid mechanics of heat transfer member for heating or also for cooling a fluid, so that they can be better adapted to changing viscosities of the fluid, for example. There is also a need to reduce the geometrical dimensions of the fluid delivery device as a whole. In many cases, it is also necessary to process and apply temperature-sensitive fluids, particularly hot-melt adhesives or thermoplastic materials which must be gently heated, without causing temporary local overheating and hence detrimental impacts on the properties of the material.
[0006] The object of the present invention is to specify a device and a method for delivering a fluid, and a heat transfer member for a fluid delivery device, which take up relatively little installation space and/or which are suitable for processing temperature-sensitive fluids, particularly hot-melt adhesives, and/or are fluidically optimized, especially with regard to changing viscosities of the fluids.
SUMMARY
[0007] The invention achieves this object, according to a first aspect of the invention, with a device of the kind specified at the outset, in which the heat transfer passage is of a flow cross-section which changes in the flow direction.
[0008] A heat transfer member is fluidically optimized due to the flow cross-section of the heat transfer passage changing in the flow direction of the fluid. Depending on the respective fluid temperature, the viscosity of the fluid changes during heating or cooling. As a result of such change, there is also a change in the flow resistances, flow speeds and shearing forces within the fluid. By virtue of the heat transfer passage having a flow cross-section that changes and is adapted to the respective application conditions, the flow speed and/or shearing forces or other parameters can be adapted or positively affected, depending on the specific application, so that the fluid is gently heated or cooled.
[0009] In one particularly preferred embodiment in which, for example, hot-melt adhesive or other fluid or gases are to be delivered, it is proposed that the heat transfer passage has a flow cross-section which decreases, at least in sections thereof, in the direction of fluid flow. In this way, consideration is given to the fact that the viscosity usually decreases with increasing fluid temperature. Flow cross-sections which decrease in this manner result in a substantially uniform flow resistance and possibly also in uniform flow speed and shearing forces in the fluid.
[0010] Another embodiment of the invention is characterized in that the heat transfer passage is defined by heat transfer surfaces which are arranged in substantially mutually parallel relationship, and the mutual spacing of which decreases in the direction of the intended preferred flow of material. A decreasing flow cross-section is therefore realized with this relatively simple design measure.
[0011] According to another aspect or embodiment of the invention, the heat transfer passage is of a substantially meander-shaped configuration, at least in portions thereof. By means of such a meander-shaped configuration, the design and production of a fluid delivery device can be made especially compact.
[0012] In one embodiment, it is proposed that the heat transfer member comprise a base member through which the heat transfer passage defined by the heat transfer surfaces extends along a curved path disposed between two closure elements. The base member is configured with at least one closure element to receive a heating or cooling element. The fluid thus flows in a meandering manner along a curved path, thus achieving efficient heat transfer within a small installation space. It is advantageous when at least one closure element of the base member, or the base member itself, is adapted to receive a sealing element.
[0013] According to a further aspect, the invention achieves its object in a device of the kind specified at the outset, and/or is advantageously developed, in that the heat transfer member has a plurality of plates which each have at least one respective contact face and are so arranged that the contact faces of two adjacent plates are respectively connected to each other, wherein a continuous heat transfer passage extends through the entirety of the plates in their connected state, and the plates have apertures, in particular through openings, for receiving heating elements.
[0014] Due to the plurality of plates, the heat transfer member has a sandwich construction which provides advantages in production engineering, especially. If so required, the size and thermal capacity of the heat transfer member can be adapted in a simple manner by selecting the appropriate number of plates.
[0015] According to the embodiment of the invention with a meander-shaped configuration of the flow passage, it is proposed that, on at least one face, the plates have an aperture which does not extend completely through the thickness of a plate, and that the apertures have at least one through opening in an end portion of an aperture, which through opening is adapted for the through flow of fluid from one aperture into the aperture in an adjacent plate, so that the entire heat transfer passage is embodied by coupling the apertures. It is advantageous when the plates are adapted with at least one contact face to receive a sealing element. The outer plates of an assembly of plates can preferably be closed by means of closure elements.
[0016] According to one other aspect of the invention, the heat transfer surfaces of the heat transfer member are configured so that a reference output temperature of the fluid can be set, and that the heat transfer surfaces of the heat transfer member are designed with a surface area of such magnitude as to permit the attainment of the reference temperature by a heating temperature of the heat transfer surfaces, which is substantially equal to the reference temperature of the fluid.
[0017] According to an exemplary method of the invention, the reference temperature of the fluid is reached when the fluid flows over the heat transfer surfaces of the heat transfer member, and a heating temperature is substantially equal to the reference temperature of the fluid obtains at heat transfer surfaces.
[0018] By dimensioning the heat transfer passage in the manner of the invention such that, when the fluid is flowing through or has finished flowing through the heat transfer member, the actual or reference temperature of the fluid is substantially equal to the heating temperature of the heat transfer surfaces, i.e., the fluid has reached their surface temperature; particularly gentle heating (or cooling) of the fluid can thus be achieved, which is advantageous in the case of temperature-sensitive fluids, and particularly of thermoplastic adhesives, and any local damage due to overheating is prevented. In other words, by dimensioning the passage in the manner described, the selected surface temperature is so low that overheating or excessive temperature gradients in the fluid are effectively prevented.
[0019] According to one embodiment of the invention, it is proposed that the heat transfer member is essentially produced from a strongly heat-conducting material, such as copper or aluminum. It is particularly advantageous for the production process when the heat transfer passage is produced by wire erosion.
BRIEF DESCRIPTION OF THE DRAWINGS
[0020] The invention shall now be described on the basis of embodiments and with reference to the Figures, in which:
[0021] FIG. 1 shows a side elevation view of a dispensing head according to an embodiment of the invention,
[0022] FIG. 2 shows a view from below of the dispensing head in FIG. 1 ,
[0023] FIG. 3 shows a cross-section of a side elevation view of the dispenser head in FIGS. 1 and 2 , in the sectional plane A-A as shown in FIG. 2 ,
[0024] FIG. 4 shows a cross-sectional view of another embodiment of a heat transfer member;
[0025] FIG. 5 shows a perspective view of an embodiment of a heat transfer member, and
[0026] FIG. 6 shows a cross-sectional view of an embodiment of a heat transfer member with apertures for heating elements.
DETAILED DESCRIPTION
[0027] FIG. 1 shows a device 1 according to an embodiment of the invention for delivering fluid. Device 1 may also be referred to as dispensing head 1 . Fluid, in particular a liquid hot-melt adhesive, is supplied to device 1 through an inlet opening 2 . The fluid flows through a heat transfer member 3 which is fixed to a base member 5 with fasteners 4 . In the embodiment shown, screw connections are provided as fasteners 4 , but other, preferably releasable connections, such as plug connections or the sliding of parts into one another by means of rails, can likewise be considered advantageous. In heat transfer member 3 , the fluid flowing therethrough is brought to a desired, and in particular a selectable reference temperature which is substantially identical to the discharge temperature of the fluid. A control unit 6 is likewise fixed to base member 5 . Control unit 6 cooperates with a valve mechanism and controls the selectably intermittent or continuous delivery of fluid and application of the fluid to a substrate.
[0028] A nozzle arrangement 7 is also fixed to base member 5 . Fluid is received by nozzle arrangement 7 from base member 5 and dispensed through a discharge opening 9 . Nozzle arrangement 5 also has a mouthpiece holder 10 and a mouthpiece 11 , which is fixed to mouthpiece holder 10 with fasteners 8 . Discharge opening 9 may be wholly or partially embodied in mouthpiece holder 10 or in mouthpiece 11 .
[0029] FIG. 2 shows a plan view from below of device 1 in FIG. 1 . It shows inlet opening 2 through which fluid is supplied to device 1 , heat transfer member 3 , base member 5 and nozzle arrangement 7 mounted on base member 5 . Mouthpiece holder 10 is connected to base member 5 by fasteners 13 . The discharge opening 9 of nozzle arrangement 7 is configured as a slot nozzle 9 ′. Mouthpiece 11 extends along the entire length of mouthpiece holder 10 . A cross-sectional plane A-A is positioned substantially symmetrical through device 1 , such that inlet opening 2 , heat transfer member 3 , base member 5 , control unit 6 and nozzle arrangement 7 are shown in cross-section.
[0030] FIG. 3 shows a cross-section of device 1 through sectional plane A-A. The path taken by the fluid until it is delivered to the substrate can readily be seen from the FIG. 3 . After entering through inlet opening 2 , the fluid is fed to heat transfer member 3 . Heat transfer member 3 has a heat transfer passage 14 which has a plurality of parallel subsections defined by two opposite heat transfer surfaces 15 , 16 . In the embodiment shown, heat transfer passage 14 has a meander-shaped configuration which is also shown in FIG. 5 to aid understanding. The flow cross-section of the heat transfer passage is not constant. Due to the changing distance between the heat transfer surfaces, the flow cross-section decreases in the direction of flow.
[0031] Heat transfer member 3 is closed on one side by a closure element 17 and on the opposite side abuts base member 5 . Heat transfer member 3 has apertures 18 on the surfaces which are in contact with closure element 17 and base member 5 . The apertures 18 are configured to receive sealing elements or a sealing material.
[0032] The fluid is fed from heat transfer passage 14 to a through-channel 19 in base member 5 , and passes through the channel 19 to control unit 6 . Control unit 6 has a valve mechanism 20 which is configured to move a valve piston 21 . In the selected orientation of device 1 , valve piston 21 performs a vertical movement and causes closure or opening of a through opening 23 . When valve piston 21 is in the open position, fluid is fed to a discharge passage 25 . Through discharge passage 25 , which in the chosen embodiment is partially disposed in mouthpiece holder 10 and in mouthpiece 11 , fluid is fed to a discharge opening 9 and delivered therethrough onto the substrate.
[0033] Valve mechanism 20 is connected to base member 5 and partially extends into the interior of base member 5 . Sealing elements 22 are provided in apertures and prevent the discharge of fluid at those locations. The nozzle arrangement likewise has apertures 24 which are configured to receive sealing elements or sealing material.
[0034] FIG. 4 shows an alternative embodiment of a heat transfer member 3 , which is connected in an appropriate manner to a base member 5 as shown in FIG. 3 , and which also cooperates functionally with the components thereof. This embodiment has a plurality of individual plates 26 with apertures 14 ′ that are embodied in a surface of the plates and which form a heat transfer passage—in sandwich construction—in that a through opening 27 extending from the surface of apertures 14 ′ through the thickness of plate 26 is provided in a portion of each plate, thus forming a passage for the fluid from one aperture 14 ′ to the next. Heat transfer member 3 is closed on one side by a closure element 17 ′. In the chosen embodiment, a second closure element 28 configured to receive a filter arrangement 20 ′ is provided on the opposite side. Filter arrangement 20 ′ partially extends into the interior of second closure element 28 . A filter element 21 ′ extends in the vertical direction in the heat transfer member 3 oriented as shown. A through opening 23 ′ through which fluid can pass after filtration is connected to a through passage 19 , which is not shown here but corresponds to the one shown in FIG. 3 .
[0035] Plates 26 each have apertures 18 ′ on a contact surface 29 for receiving a sealing element. The second closure element 28 likewise has an aperture 18 ′ for receiving a sealing element. Filter arrangement 20 ′ likewise has an aperture 22 ′ for a sealing element.
[0036] FIG. 5 shows a perspective view of an integral embodiment of a heat transfer member 3 as shown in FIG. 3 . Flow channel 14 is disposed inside heat transfer member 3 and has a meander-shaped configuration. The flow cross-section decreases in the direction of flow—which runs from top to bottom when the heat transfer member 3 is oriented as shown in FIG. 5 . The fluid leaves heat transfer member 3 through an opening 32 . Aperture 18 for receiving a sealing element is embodied in the form of a circumferential groove. Heat transfer member 3 also has through bores 30 through which fasteners 4 (not shown) extend.
[0037] The arrangement of heating elements is shown by way of example in FIG. 6 for an embodiment comprising a plurality of individual plates 26 . In a cross-sectional plane parallel to and in the vicinity of the lateral surfaces of the heat transfer member 3 , plates 26 and second closure element 28 have bores 33 configured to receive fasteners. Closure element 17 ′ has threaded bores 35 in which screws for fixing plates 26 and closure elements 17 ′, 28 can engage with each other. The second closure element 28 and plates 26 also have bores 34 which are configured to receive substantially cylindrical heating elements. Plates 26 are arranged in relation to each other in such a way that bores 33 , 34 of the respective plates are coaxial to each other, with the result that the screws and inserted heating elements can extend through the plates.
[0038] While the present invention has been illustrated by a description of various illustrative embodiments and while these embodiments have been described in some detail, it is not the intention of the Applicants to restrict or in any way limit the scope of the appended claims to such detail. Additional advantages and modifications will readily appear to those skilled in the art. The various features discussed herein may be used alone or in any combination depending on the needs and preferences of the user. This has been a description of illustrative aspects and embodiments the present invention, along with the preferred methods of practicing the present invention as currently known. However, the invention itself should only be defined by the appended claims.
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A device and a method for delivering a fluid, in particular hot-melt adhesive. The device includes a base member having an inlet opening for receiving the fluid from a fluid source and an outlet opening for delivering the fluid to a nozzle arrangement. The nozzle arrangement has a discharge passage with a discharge opening for delivery of the fluid. A heat transfer member heats or cools the fluid and includes a heat transfer passage through which the fluid can flow. The heat transfer passage is of a flow cross-section which changes in the flow direction.
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BACKGROUND OF THE INVENTION
The present invention relates to a movable cover or roof for covering crops such as orchard trees and protecting them from frost damage.
Frost can kill or injure crops and is an especially grave danger in orchards where the fruit itself is exposed during periods of cold weather. Methods of protecting crops against frost include smudge pots, university return stack heaters, liquid fuel heaters and wind machines all of which consume expensive fuel as well as portable covers which act to retain warm air or to block cold drafts. Portable covers may be used to cover individual plants or all the plants on a plot of land to retain warm air and to block cold air radiation.
Protective coverings for agricultural plots found in the prior art include movable protective covering for orchards disclosed in U.S. Pat. No. 1,106,624 to Cadwallader et al. In Cadwallader a framework of static rigging is formed by vertical uprights, carrying guy wires. A flexible fabric covering is extended over the framework by turning large drums located at opposite ends of the framework that operate as take-up reels for the fabric and for the cable which draws the fabric across the crossbars and rollers and along the support wires.
Movable fabric panels are found in U.S. Pat. No. 2,051,643 to Morrison which discloses a cloth house for protecting plants. In Morrison an insect-proof fabric house composed of numerous strips joined edge to edge is supported over a framework of posts, guy wires and supporting cables. Some fabric joints incorporate weight supporting wires and the lowermost edges of the fabric are held fast to a framework by wires within the fabric edge which connect to gourmets located on baseboards of the framework. Morrison's cloth house was improved by adding the transverse cords disclosed in U.S. Pat. No. 2,143,659 to Morrison to the top surface of the house.
Another form of portable plant protection is disclosed in U.S. Pat. No. 3,100,950 to Heuer in which a cover is suspended between or across rows of posts. The cover can be folded back by manually drawing it back in a direction along the row.
While the devices disclosed in the identified patents and other devices in the prior art were satisfactory for their intended use, they were not intended to be adapted for use with lightweight synthetic materials.
Thus there existed a need for a plant protecting cover which could selectably be placed over the crops to protect them or be withdrawn to allow light and water to enter the orchard. Ideally the cover should be easily operated by one man, should be able to be quickly opened or retracted, should be relatively inexpensive to fabricate and should be able to be exposed to the elements for a long period of time without damage. The present invention fulfills these requirements.
SUMMARY OF THE INVENTION
The present invention is embodied in a cover for protecting crops from frost damage. The cover is attached to a permanently installed framework and can be selectively extended to the covering position or withdrawn therefrom by means of a sheet rake which can move outwardly carrying an outer edge of the cover to an outer edge of the framework or inwardly scooping up and holding the cover as it moves inwardly. The sheet rake is propelled by running rigging comprising a plurality of winches that control sets of cables. Each set of cables contain at least one cable pulling the sheet rake and extending the cover over the framework and at least one other cable withdrawing the sheet rake and cover.
The framework comprises rows of posts joined by wires extending at right angles to the rows. The sheet rake moves atop the wires which support it. The winches and running rigging are attached to and support by the posts.
The cover of the invention is lightweight polyethylene film which is easily moved to and withdrawn from the covered position.
The present invention using a cover in two independently moved sections can cover an agricultural plot of about one acre. An operator winches one section into position, then the other section and can position both in about ten minutes. The invention protects from still air radiation frost without burning expensive fuels.
Other features and advantages of the present invention will become apparent from the following detailed description, taken in conjunction with the accompanying drawings, which illustrate, by way of example, the principles of the invention.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 is a plan view of a cover of the invention covering a plot of land having the cover shown only in broken line in order to reveal a framework below the cover;
FIG. 2 is a front elevational view taken substantially in the direction of the arrows 2--2 in FIG. 1;
FIG. 3 is a fragmentary enlarged view of an area substantially enclosed by circular line 3 in FIG. 1 having the cover broken away to show a post and winches;
FIG. 4 is a rear elevational view taken substantially in the direction of the arrows 4--4 in FIG. 3 and showing the post, the winch and cables;
FIG. 5 is a fragmentary enlarged view of an area substantially enclosed by circular line 5 in FIG. 1 showing the winch and a portion of a sheet rake;
FIG. 6 is a left elevational view taken substantially in the direction of the arrows 6--6 in FIG. 5 and showing the post, winch and a sheet rake;
FIG. 7 is a fragmentary sectional view taken substantially in the direction of the line 7--7 in FIG. 1 and showing a transverse cable, the post and the cover;
FIG. 8 is fragmentary sectional view taken substantially along the line 8--8 in FIG. 7;
FIG. 9 is a fragmentary enlarged view of an area substatially enclosed by circular line 9 in FIG. 1 and showing a backstay, static rigging and one post;
FIG. 10 is a full left elevational view taken substantially in the direction of the line 10--10 in FIG. 9 and showing one post and backstay;
FIG. 11 is a sectional view substantially taken along the line 11--11 in FIG. 3.
FIG. 12 is a fragmentary elevational view looking in the direction of the arrow 12 in FIG. 6 and showing the sheet rake.
DESCRIPTION OF THE PREFERRED EMBODIMENT
The present invention resides in a framework 20 permanently installed in an agricultural plot and having a movable cover 22 which can be drawn over the framework to protect crops from damage resulting from still air radiation frost. The cover 22 is supported above the crops, which for the purpose of illustration will be described as fruit trees, by standing rigging 24 comprised of wires supported by upright posts 28. The posts 28 extend above the top of the fruit trees and thereby support both the standing rigging 24, attached to the post tops, and the cover 22 well over the protected fruit trees.
In accordance with the present invention, the flexible cover is supported over the fruit trees by standing rigging 24 while a movable sheet rake assembly 30 extending across and supported by the standing rigging 24 carries the free outer edges of the cover 22 outwardly from the center to the edges of the framework 20. As the sheet rake assembly 30 is drawn back towards the center of the framework 20, it gathers the cover 22 in a series of gathering tines 32 and carries the gathered cover back to the center of the framework. Running rigging 34 drawn by winches 36 and 37 enables one man to quickly and manually extend the cover 22 above the fruit trees or to withdraw the cover.
More particularly, as can best be seen in FIGS. 1 and 2, the standing rigging 24 supporting the cover 22 comprises, in a typical installation, three rows of upright posts 28, a center row 38 and two edge rows 40. The posts 28 are permanently anchored in the earth, for example, in concrete filled holes, and the tops of the posts 28 extend sufficiently above the fruit trees so that no portion of the standing rigging is less than 18 inches above the fruit trees. As is shown in FIGS. 4 and 6 at least one step 82 is provided on each post 28 to enable a laborer to work atop the post.
Each post 28, herein 11/2 inch galvanized steel, is connected to the corresponding post in the adjacent row by a laterally running support wire 42. Typical support wires 42 are 1/8 inch galvanized wire that are attached to the posts as can be seen in FIG. 10 by 1/4 inch eye bolts 43. A transverse cable 44, made of 3/32 inch galvanized steel or other light cable, extends along the center row 38 passing through the top of each post 28 in the row.
The posts 28 are guyed into position by back stays 46. As can best be seen in FIG. 10, each back stay 46 includes the back stay itself made of wire, as well as an eye bolt clamp 48 connecting the stay to the post, a 1/4 inch turnbuckle 50 and a 3 foot long 1/2 inch metal stake 52 that anchors the back stay into the ground. As can best be seen from FIG. 1, the back stays 46 extend perpendicularly outward of the framework 20 except for four back stays attached to posts 28a supporting the running rigging 34. These four posts extend outwardly in a direction opposite to the direction of force which the running rigging 34 applies to the post.
The cover 22 which can overlay the entire framework includes unitary sections of synthethic film stretching along the length of the sheet rake assembly 30 and extending between immediately adjacent rows of posts 28. The cover is made from films of polyethylene, polypropylene, nylon or other materials which form a tough plastic film having excellent fatigue and tear strength. The thickness of the cover is in the range between 4 and 6 mils. In the embodiments shown in FIG. 1, the cover sections are attached to one another at a location near the center of the framework 20 and along row 38. As is shown in FIG. 7, one method of connecting these sections to each other is accomplished by passing the transverse cable 44 through grommets 54 lying near the edges of the sections to be joined. In the illustrated embodiment, the cover 22 lies atop each post 28 in the center row 38 and the transverse cable 44 passes through the cover in the vicinity of each of those posts running from outside the cover to the inside thereof. Thereafter the transverse cable 44 passes through the top portion of the post 28 and thence outwardly of the cover 22 through another grommet 54. The transverse cable 44 is connected to the outermost posts 28b in the center row 38 by an eye bolt 56 and therefore the transverse cable passes only once through the cover in the vicinity of the outermost posts.
The movable portions of the invention comprise, as is shown in FIG. 1, the sheet rake assembly 30, the running rigging 34 and the outward pulling 36 and inward pulling winches 37 that move the running rigging. The sheet rake assembly 30 includes two elongated wooden members that extend across the entire framework 22, transversely to the support wires 42. The sheet rake assembly 30 holds the outer edge of the cover 22 sections between the wooden members. In the illustrated embodiment, and as is best shown in FIG. 6, the sheet rake assembly 30 has a rectangular cross section measuring 2 inches across and 1 inch high and that includes a frame 64 made of a 2"×3/4" piece of wood to which a cap 66, made of a 2"×1/4" piece of wood is joined by counter sunk screws 68. A bottom cover 70, a sheet of 1/8 inch aluminum protects the bottom and reduces friction between the sheet rake assembly 30 and the support wires 42. To increase the ability of the sheet rake assembly 30 to hold the cover, the outermost end of the cover is wrapped around, and is sewn to, a cord 72, typically 3/16 inch polypropylene. The cord 72 is placed on the outer side of the sheet rake assembly 30 defined in this specification and the appended claims as the side opposite the inside of the sheet rake which is the side facing the center of the framework 20, or facing the location at which the cover 22 is permanently attached to the framework.
As can best be seen in FIGS. 1 and 12, a pair of metal tines is attached to the sheet rake assembly 30 in the vicinity of each support wire 42. A scoop tine 73 extends generally inwardly and downwardly from the sheet rake assembly 30 in order to scoop the cover 22 up from the support wires 42 and on to the sheet rake assembly itself, thus preventing the cover from becoming trapped under the sheet rake assembly. The gathering tine 32, describing an arc commencing upwardly and rearwardly of the sheet rake assembly 30, holds the cover atop the assembly as the assembly moves toward the center of the framework 20 collecting the cover as it moves. Both tines are aluminum, have a rounded surface and are about 18 inches in length.
The running rigging 34, referred to above, moves the sheet rake assembly 30 outwardly and inwardly along the support wires 42. As shown in FIG. 1, the running rigging 34 includes four winches 36 and 37 each of which moves three cables 74 and 76. The outward pulling winches 36 take in those cables 74 that move the cover into the covering position by pulling the sheet rake assembly towards the edge rows 40, while the inwardly pulling winches 37 take in cables 76 that pull the cover back to the center. Each winch 36 and 37 the locations of which are described below carries three cables, one connected to the center of the sheet rake assembly and one on each side. The cables attached to the sides of the sheet rake assembly are placed at a suitable distance from the center of the framework 20, so that the pulling force of the cables is distributed uniformly along the length of the sheet rake assembly. The inward pulling center cable 76, as is shown in FIG. 3 and 4, is lead by a block 80, attached on the inward face of the center post 28, to its running position while the inwardly pulling cables connected to the sides of the sheet rake assembly 30 are led by blocks 80a and 80b on the side faces of the center post 28 and by blocks 82a and 82b on the outer running rigging posts 28a to their operating location. The corresponding outward pulling cable blocks have identical but primed numbers in the drawings, thus, one winch 36 or 37 draws three cables and thereby moves the sheet rake assembly 30.
In the embodiment depicted in FIG. 1, each outward pulling two winches 36 is attached to one of the posts 28 in the middle of edge rows 40, while both the inwardly pulling winches 37 are attached to one post 28 in the middle of the center row 38. Suitable winches for use in the invention are single spur gear, half ton winches such as those manufactured by Thern, Inc. of Winona, Wisconsin. The running cable herein is 1/8 inch galvanized steel, 7×19, winch cable having a breaking strength of 2000 pounds.
From the foregoing, it will be appreciated that the protective cover 22 of the invention provides a device that protects agricultural crops from frost damage without the burning of costly fuels. The cover can be quickly moved into position by a single operator who can move the cover 22 over a one acre plot in about ten minutes. The cover 22 can be withdrawn to permit sunlight or rain to enter on the agricultural plot.
While a particular form of the invention has been illustrated and described, it will be apparent that various modifications can be made without departing from the spirit and scope of the invention.
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A retractable cover for protecting agricultural crops against radiation frost. The polyethelene film cover lies atop a static rigging comprised of rows of posts permanently anchored in the earth and wires joining the posts. An elongated sheet rake extending the length of one row is attached to one side of the cover and is adapted to move the cover between a covering position and a retracted position adjacent a location where the cover is connected to the posts. Winch driven cables are used to move the sheet rake.
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BACKGROUND OF THE INVENTION
FIELD OF THE INVENTION
The invention relates to the treatment of waste materials, such as shredder waste (also called Shredderleichtraktion in German) or residues. This waste arises from the recycling of bulky metal scrap by fragmentising using, e.g. a hammer mill. The heavy metal scrap typically is automobile bodies, white goods, light iron, heavy steel, structural steel. The raw material is fed into the hammermill, initially shred, and cleaned magnetically and by eddy currents to produce ferrous and non-ferrous products on separate production lines.
About 75% of old cars are fed into shredder installations for recycling the materials. About 25% of the shredder charge remains as non-recoverable residues and is disposed of mainly in landfill sites. The shortage of landfill capacity has in recent years driven up the costs of properly disposing of these residues. This cost increase, together with the decline in profits, is increasingly resulting in a disposal crisis for the car recycling business. The difficult situation regarding disposal has already led to the closure of shredder plants. This results in a shortage for the steel industry of an important source of raw material for steel manufacture and like processes.
The shredder waste typically comprises metals, plastics, wood and rubber, and depending on the nature of the material being fragmented will also contain copper, aluminium and other elements derived from say stainless steel, and possibly silica.
SUMMARY OF THE INVENTION
It is an object of this invention to provide means for recovering as much as possible of the ingredients of the shredder waste for economic re-use. The waste material may be considered as a source of carbon, i.e. the plastics, wood and rubber, and of metals for the steel works, e.g. aluminium. The copper is of value in smelting or refining. More specifically, the invention provides a method to remove, or substantially reduce, the copper content and/or the SiO 2 from glass or sand to provide a waste material containing the carbon sources and appropriate metals to be added to steel manufacturing furnaces without risk, and a copper enriched component which may be used in smelting or refining.
In one aspect, the invention provides a method of treating the light fraction of fragmented material, the method comprising fragmenting fragmentable material to provide a heavy fraction and a light fraction; characterised by reducing the size of the light fraction to particles of injectable size; mixing the particles with a magnetic substance to provide particles coated with the magnetic substance and particles which are not so coated; subjecting the mixture to magnetic separation; injecting the magnetised particles into the furnace.
One typical shredder waste has the following composition before separation of the heavy fraction (% by weight):
______________________________________Fe (total) 25.4 Fe (2+) 2.74 Fe (met.) 3.86SiO2 30.9 Al2O3 8.5 CaO 5.2MgO 2.5 TiO2 1.36 P 0.13Mn 0.21 Na 1.98 K 0.94Cu 2.81 Pb 0.37 Zn 4.37Cd <0.001 Cr 0.15 Ba 0.28Ni 0.13 Mo <0.05 Co 0.015Sn <0.05 As <0.01 Sb <0.1V 0.006 C 0.13 S 0.83Hg <0.00002______________________________________
Depending on the source the fraction may contain plastic which has entrapped other materials by being subjected to heat and/or pressure. The metal bits must be released from a plastic cover before they can be teased out.
The shredder light fractions are heterogeneous mixtures of plastic, rubber, wood, textile residues, glass, iron and non-iron particles, plastic fibres and inert materials. The non metallic makes up about 25% of the total weight. There are variously sized `balls` of the fine plastic fibres, which enclose small particles of the above-mentioned materials. There are also small iron and non-iron particles in these balls, including copper in the form of small wires, partly in the shape of small rods, as well as in the form of minute pellets or tiny spirals. Some of these small wires have eyes and hooks formations and have become caught up in the fine plastic fibres. Larger pieces are present as well as numerous `agglomerates` composed mainly of minute particles of the above-mentioned materials.
Fine and finest plastic fibres of <1 mm up to a few millimeters in length, in combination with moisture and an observable rust formation on iron particles led to agglomeration in very heterogeneous shapes (pellet, cubes, rod and the like). These shapes can easily be crumbled between the fingers. A large proportion of the powder fraction (micron size) adheres to and forms part of such agglomerates. Some copper and/or metal particles of lengths below 1 mm up to 3 cm in the form of little rods, triangles, spirals or loops are `interwoven` with these agglomerates or have been caught up in the `cocoon`. The largest proportion of these metal particles is however exposed.
The light fraction is reduced in size by comminution or like process to provide an average particle size appropriate to the equipment by which the particles can be injected into a furnace. Usually the particles will have an average particle size below about 8 mm. Comminution may be carried out in a suitable fragmentiser or rotary or pressure mixer.
When the reduced size particles are mixed with magnetic particles, those particles will adhere to the other particles wherever they can. They will adhere preferentially to rough surfaces, typically plastics, fibres, wood, rubber. It has been observed that they will not adhere as easily (if at all) to the smooth surface of copper wire and this difference in properties is an original way of separating copper and SiO 2 from the other materials.
The magnetic material preferably is a millscale, optionally with oil, and a carrier, e.g. water may be provided. Preferably the water content of the magnetic material is about 10 to 25% by weight. The water may be added deliberately or it may be derived from the millscale or the shredder waste or both. Instead of the magnetic mill scale slurry, other magnetic materials in dry or wet form with or without oil content can also be used. For example, blast furnace gas sludge and powders, Bessemer converter sludge and powders can be utilised. Preferably the mixing is carried out in a rotary mixer for at least 1.5 minutes.
Typically the shredder waste mass contains copper and the magnetic separation is carried out so as to remove some of the copper and provide particles having a low content of copper which can be used as a feed charge to a furnace or cement kiln. It is of advantage to add other materials. Examples include flyash and lime. These optional additives may be added before or after the magnetic separation. Preferably the flyash is mixed with the particles for at least two minutes. Calcium oxide is preferably added with the flyash. The flyash preferably has a grain size of about 70 to 90 micron. Instead of fly ash with free CaO contents, burned lime can also be used. If there is not enough moisture present in the shredder waste, which brings about a hydration process, then a proportionate quantity of water should be added.
In other aspects the invention provides a charge for use in a furnace or kiln and obtained from shredder waste light fraction, the charge comprising injectable magnetised particles of coated plastics, wood and rubber; and a method of separating copper and silica from a mixture containing particles derived from shredder waste light fraction, the method comprising adding a magnetic substance to the mixture, subjecting the mixture to magnetic separation and recovering the copper and silica.
DESCRIPTION OF THE DRAWING
In order that the invention may be well understood it will now be described by way of illustration with reference to the following example which is to be read in conjunction with the flow diagram of FIG. 1.
DESCRIPTION OF THE PREFERRED EMBODIMENTS
EXAMPLE
Used car bodies and like materials were treated in a hammermill fragmentiser to provide a heavy fraction useful as scrap metal feedstock, and a light fraction. The latter had the composition indicated above containing copper, aluminium, stainless steel, glass and SiO 2 , e.g. sand; and carbon-containing materials such as plastics, wood and rubber. The light fraction was subjected to a comminution to provide agglomerates containing particles of about 8 mm average length. As a result of this treatment, a quantity of the agglomerates making up the waste is `broken up` or crumbled, to expose some of the metal particles contained within and adhering to these agglomerates. A quantity of mill scale slurry, containing approximately 10-25% proportion of water, was added to the agglomerates and mixed for 1.5 to 2 minutes in a forced action mixer. The fine substances from the waste combine with the moist oily finest particles of the mill scale slurry to form micro-agglomerates which, when looked at with the naked eye, have unequal rounded shapes. When observed through a microscope, it can be seen that these small agglomerates have the shape of a `sea urchin`. It was observed that while the mill scale adhered to the plastics, rubber and wood particles, the lengths of copper wire were uncoated, because the coating medium could not adhere to the smooth surface of the wire.
Approximately 20% (weight per cent) fly ash from a coal-fired power station with approximately 8% CaO was added to this two-component mixture and mixed for approximately 2 minutes to form substantially dry particles. The grain size of the ash is around 70-90 micron.
It was observed under the microscope that few metal laminae in a size of >0.5 mm were present in the newly produced agglomerates. The larger fraction of these scale laminae was lying loose `with cleaned surface`. A large quantity of the copper wires was lying openly visible and free of adherent micro-substances adhering to them. In addition to the copper parts, other metals and steel parts/wires were also exposed. (Some copper wires were intertwined with the `cocoon balls` and could not be freed as a result of mechanical treatment of the mixture). As a result of the mechanical treatment of the mass in the mixer, the sharp-edged small scale laminae have led to a cutting-up or crumbling of a largish number of the cocoon agglomerates. The fine ash particles coated the small agglomerates, consisting of shredder and mill scale substances as well as plastic fibres. The particles were left for two to three days for a hydration process to take place. This was exothermic. It was observed that, after approximately 24 hours, a temperature of up to 45° C. was reached. After 48 hours, the temperature in the heap reached the ambient temperature. The storage took place in covered rooms. The even `soaking` of the heap of debris effected a faster `drying`, i.e. an increased evaporation of moisture. It was possible to reduce the moisture without thermal addition to below 10%.
The mixture, consisting of coated particles and uncoated particles was fed into a conventional magnetic separator. The magnetic substances were easily separated from the non-magnetic ones such as copper, aluminium, special steel, glass, and SiO 2 . According to the chemical analysis, the proportion of copper, in comparison to the shredder raw faction, could be reduced by approximately 60%. The treated mixture has a minimal remaining proportion of copper and SiO 2 . This mix is made up of plastics, wood, rubber and particles of magnetic metal could be added to a blast furnace. Because the atmosphere in the furnace is substantially oxygen-free and the temperature is very high the plastics burned without forming undesired by products.
The separated copper, aluminium, stainless steel and silica were recovered for use in appropriate industrial processes.
While this invention has been described in conjunction with specific embodiments thereof, it is evident that, after reading of the specification, many alternatives, modifications and variations may be suggested to those skilled in the art. Accordingly, the preferred embodiments of the invention as set forth herein, are intended to be illustrative, not limiting. Various changes may be made without departing from the spirit and full scope of the invention as set forth herein and defined in the appended claims to which reference should be made for a complete understanding of the invention.
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Shredder waste light fraction is converted into injectable material by being comminuted to an appropriate size. The copper and/or silica is then separated by magnetic separation so that the material may be injected into a metallurgical furnace or cement kiln.
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RELATIONSHIP TO OTHER APPLICATION
[0001] This application claims the benefit of the filing date of Provisional Patent Application Ser. No. 61/188,916, filed on Aug. 14, 2008, the disclosure of which is incorporated herein by reference.
GOVERNMENT RIGHTS
[0002] This invention was made under contract awarded by National Cancer Institute-National Institute of Health, Contract Number R01-CA100247. The government has certain rights in the invention.
BACKGROUND OF THE INVENTION
[0003] 1. Field of the Invention
[0004] This invention relates generally to diagnostic methods of detecting the characteristics of cancer, and more particularly, to a diagnostic methodology for determining the likelihood of the presence of cancer, or of developing cancer, in response to genomic instability.
[0005] 2. Description of the Related Art
[0006] Increasing attention is focusing on chromosomal and genome structure in cancer research due to the fact that genomic instability plays a principal role in cancer initiation, progression and response to chemotherapeutic agents. The integrity of the genome (including structural, behavioral and functional aspects) of normal and cancer cells can be monitored with direct visualization by using a variety of cutting edge molecular cytogenetic technologies that are now available in the field of cancer research.
[0007] Cytogenetic visualization technologies have traditionally played an important role in cancer research. Both the chromosomal number changes or aneuploidy, and the telomeric deficient mediated chromosomal breakage-fusion-bridge cycle has long been linked to the cancer phenotype and chromosomal instability. Many chromosomal aberrations, particularly translocations or inversions are closely associated with a specific morphological or phenotypic subtype of leukemia, lymphoma or sarcoma. As a result, chromosomal analysis of patient samples has become an essential component of cancer research.
[0008] The identification of a chromosome translocation involving a reciprocal rearrangement of chromosomes 8 and 21 in patients with a form of acute myelogenous leukemia (AML), and the identification of a translocation involving chromosomes 9 and 22 in patients with chronic myeloid leukemia (CML), has initiated more than 100 genes cloned from translocation breakpoints. In the past three decades, over 30,000 cancer cases have been analyzed by chromosomal karyotyping employing one basic visualization method using normal chromosomes as a standard, to search for the correlation between a specific karyotype and a specific type of cancer, which revealed more than 600 acquired, recurrent, balanced chromosome rearrangements. Among these analyses, a great deal of attention has been focused on clonal chromosomal changes in the identification of both primary and secondary abnormalities. These clonal abnormalities, particularly if complex, are significant to neoplasia. As a result, these chromosomal visualization methods have served as an important tool for both cancer research and diagnosis.
[0009] In recent years, extensive research has been performed with molecular probes targeting specific regions of the genome for detecting gene deletions and amplifications. With the development of live images as well as the maturation of FISH related technologies, more direct visualization approaches are available to cancer biology,
[0010] With the completion of the sequencing phase of both human and mouse genome projects, one of the next priorities is the systematic study of genomic structure relative to function as well as abnormalities associated with the cancer phenotype based on recent emerging genomic information. A powerful application of newly available technology is the use of microarrays to correlate specific genes or pathways to types or stages of cancer, particularly when used in conjunction with the tissue micro-dissection method. The challenge for this approach is the complexity of the karyotypical changes that occur and the karyotypical heterogeneity that is associated with cancer cell lines and tumor samples. It is therefore necessary to carefully karyotype the cell lines/tissues being studied before microarray analysis is performed.
[0011] CGH technology has been effective in establishing possible karyotype patterns by pinpointing the gains or loses within specific chromosomal regions. Since CGH data focuses on clonal karyotype changes it could miss non-clonal changes that occur at an early stage of cancer development (this is further discussed in the following section). Similarly, the heterogeneity of tumor samples makes data interpretation difficult with significant exceptions occurring when various samples of the same tumors were analyzed.
[0012] Gene knock out technology has produced a large collection of mouse models that can be used to study genomic aberrations that occur during cancer development. Particularly with the recent development of RNA interference technology, the correlation between different pathways defined by key genes and the genomic structure/function can be analyzed in great detail. The technical challenge for genome structure and function studies by using this approach is to develop a system that can monitor the genome structure and changes caused by these targeted genes. It would be ideal to directly visualize the changes occurring before and after dysfunction of genes that are expected to be involved in the maintenance of the integrity of the genome. Such a direct visualization system will fill the gaps between molecular biology and cytology, between studies using in vitro and in vivo assays, and could be used for comparative analysis between normal and cancer conditions.
[0013] One re-emerging concept in cancer research is that epigenetic events also play an important role in the evolution of cancer. Cancer often displays aberrant methylation of promoter regions, which is linked to the loss of gene function. Such heritable DNA changes are not mediated by altered nucleotide sequences and might involve the formation of transcriptionally repressive chromatin. Visualization methods are urgently needed to study cancer related epigenetic phenomena.
[0014] Traditional strategies in cancer research have been focused on the identification and characterization of the general patterns of genetic aberrations and in particular, key “cancer gene” mutations. The underlying principle has been specific types of cancer are caused by sequential genetic events occurring during “cancer development.” This gene-centric view has dominated the field of cancer research for decades resulting in the concentration of research effort on defining mutated oncogenes, tumor suppressor genes and their molecular pathways.
[0015] Despite the initial success of identifying a number of gene mutations that had a high penetration among certain patient populations, most subsequently identified gene mutations have displayed low frequencies among patients. Further, the list of cancer genes continues to grow, which brings in to question the goals and rationale of continuing to attempt to identify a handful of commonly shared gene mutations in cancer. Clearly, the current concept of cancer is not consistent with the reality of the presence of high degrees of genetic diversity in patients. To solve this dilemma, cancer genome sequencing has been proposed to identify these common cancer genes, based on the assumption that cancer heterogeneity among patients is genetic “noise” and can be eliminated by validation using large patient samples. Unfortunately, this highly anticipated approach is delivering unwanted results.
[0016] In yet another example of heterogeneity, the vast majority of gene mutations are not shared among patients. In light of this disappointing fact, some have suggested shifting from gene identification to pathway characterization, others are searching for non-gene causes including bacterial/viral infections, cancer stem cells, metabolic stress and errors, oxidative stress, aneuploidy, inflammation, tumor/tissue interaction, immuno-deficiency, a large array of epigenetic effects. These different approaches represent essentially the same attempt to find common causative patterns but are now focused on different levels of genetic/epigenetic or cellular organization and their response under all kinds of environmental stress.
[0017] There is a need for a system and method of visualizing different yet closely related major levels of genome structures.
[0018] There is additionally a need for a methodology for illustrating mitotic and meiotic chromatin loops, as well as identifying defective mitotic figures (DMF).
[0019] There is also a need for a new type of chromosomal aberration capable of monitoring condensation defects in cancer and genomic instability.
[0020] There is a further need for a system for characterizing apoptotic related chromosomal fragmentations caused by drug treatments.
SUMMARY OF THE INVENTION
[0021] The foregoing and other needs are fulfilled by this invention which provides, in accordance with a first diagnostic method aspect of the invention, a diagnostic method of determining tumorigenicity of a tissue specimen. In accordance with the invention, there are provided the steps of:
[0022] determining a magnitude of genome diversity in the tissue specimen; and
[0023] diagnosing a likelihood of cancer in response to said step of determining the magnitude of genome diversity.
[0024] In one embodiment of this method aspect, the step of determining the magnitude of genome diversity includes the step of determining the karyotypic heterogeneity in the tissue specimen.
[0025] In a further embodiment, the step of determining the presence of elevated genome diversity includes the step of detecting non-clonal chromosome aberrations (NCCAs). IN some embodiments, the step of detecting NCCAs includes the further step of detecting the frequency of NCCAs. The step of diagnosing is responsive to said step of detecting the frequency of NCCAs.
[0026] In an advantageous embodiment of the invention, the step of detecting NCCAs includes the further step of screening lymphocytes.
[0027] Additionally, in a still further embodiment, the step of determining the presence of elevated genome diversity includes the step of applying Spectral Karyotyping to detect translocations throughout the genome.
[0028] In accordance with a further method aspect of the invention, there is provided a diagnostic method of determining drug resistance of a patient. The further method includes the steps of:
[0029] determining the presence of genome diversity in the tissue specimen; and
[0030] diagnosing the drug resistance of the patient in response to said step of determining the presence of genome diversity.
[0031] Cell death plays a key role for both cancer progression and treatment. In this disclosure the inventors characterize chromosome fragmentation, a new type of cell death that takes place during metaphase where condensed chromosomes are progressively degraded. It occurs spontaneously without any treatment in instances such as inherited status of genomic instability, or it can be induced by treatment with chemotherapeutics. It is observed within cell lines, tumors, and lymphocytes of cancer patients. The process of chromosome fragmentation results in loss of viability, but is apparently nonapoptotic and further differs from cellular death defined by mitotic catastrophe. Chromosome fragmentation represents an efficient means of induced cell death and is a clinically relevant biomarker of mitotic cell death. Chromosome fragmentation serves as a method to eliminate genomically unstable cells. Paradoxically, this process could result in genome aberrations common in cancer. The characterization of chromosome fragmentation may also shine light on the mechanism of chromosomal pulverization.
[0032] Cancer progression represents an evolutionary process where overall genome level changes reflect system instability and serve as a driving force for evolving new systems. To illustrate this principle it must be demonstrated that karyotypic heterogeneity (population diversity) directly contributes to tumorigenicity. Five well characterized in vitro tumor progression models representing various types of cancers were selected for such an analysis. The tumorigenicity of each model has been linked to different molecular pathways, and there is no common molecular mechanism shared among them. The common link of tumorigenicity between these diverse models is elevated genome diversity. Spectral karyotyping (SKY) was used to compare the degree of karyotypic heterogeneity displayed in various sublines of these five models. The cell population diversity was determined by scoring type and frequencies of clonal and non-clonal chromosome aberrations (CCAs and NCCAs). The tumorigenicity of these models has been separately analyzed. As expected, the highest level of NCCAs was detected coupled with the strongest tumorigenicity among all models analyzed. The karyotypic heterogeneity of both benign hyperplastic lesions and premalignant dysplastic tissues were further analyzed to support this conclusion. This common link between elevated NCCAs and increased tumorigenicity suggests an evolutionary causative relationship between system instability, population diversity, and cancer evolution. The present invention reconciles the difference between evolutionary and molecular mechanisms of cancer and suggests that NCCAs can serve as a biomarker to monitor the probability of cancer progression.
[0033] The present invention constitutes a method based on the new usage of a known but previously ignored data system to detect abnormal chromosomes, and is useful for the detection of cancer (both status of individual system instability and its potential response to treatment) as well as understanding the mechanism of cancer progression. There is herein described a new type of mitotic cell death, termed “chromosome fragmentation,” which, as will be described herein, is a consequence of certain cellular stressors such as inherited genomic instability or chemotherapeutic treatment in M phase, and a pathologically related process that results in the breakdown of the chromosomes, elimination of genetic material, and subsequent death of cells. The somatic evolution of cancer is similar to natural evolution with system stability mediated genetic heterogeneity playing a key role.
[0034] The chromosome represents not only the vehicle in which genes are carried but also serves as a genetic framework that controls all genes in a systemic manner. The karyotypic-defined genome is the driving force for cancer evolution and for other types of organismal evolution. Clinical cytogenetic analysis is commonly done in many types of cancers and often serves as a diagnostic and prognostic marker of cancer progression. Clonal events are recorded, but recent evidence shows that nonclonal events provide the diversity that is required for tumor progression and survival in the extremely harsh environment of a tumor. Change on the chromosomal level has the capability of directly altering the regulation of hundreds or possibly thousands of genes. Chromosomal change, including translocations, deletions, duplications, inversions, defective mitotic figures, and fragmentation of chromosomes can serve to increase diversity that is required for cancer progression and evolution.
[0035] The traditional approach of monitoring clonal chromosomal aberrations focuses on the same specific chromosomal changes shared by mitotic figures that are from the same individual or are the same chromosomal changes noted among different individuals. The traditional approach of using clonal aberrations was originally developed for detection in chromosome preparations from patients with leukemia. However, this type of approach is not applicable for solid tumors, because solid tumors display a high degree of heterogeneity and a high degree of genomic diversity (reflected as increased non-clonal aberrations). In addition, clonal aberrations do not display common patterns and are difficult to identify, usually developing only in the later stages of tumor formation.
[0036] The present inventive system focuses on monitoring NCCAs that are detected randomly, as a given NCCA occurs in only a single mitotic figure. Due to their apparent random nature and normally low frequencies. NCCAs have previously been considered as background artifacts. Now with the use of multiple color Spectral Karyotyping that can be used to monitor an entire genome by painting each individual chromosome coupled with the ability to check large numbers of mitotic figures, we have recognized that the occurrence frequency of NCCAs is not random at all and has important implications. For example, data developed by the inventors has demonstrated that NCCAs could actually represent signature changes reflecting the level of increasing genomic instability that precedes and leads to cancer initiation and progression.
[0037] When the genome is unstable (due to defective DNA repair, checkpoint deficiencies, or cell stress that is induced by radiation or environmental chemical carcinogens), there appears to be a significantly increased rate of non-clonal chromosomal changes prior to any clonal aberration formation. This increased frequency of NCCAs reflects the unstable nature of the genome and may actually activate oncogenes or inactivate tumor suppression genes or change the gene expression profile for genes located on translocated chromosomes. Since there are many pathways that can lead to cancer development, and there are many different types of non-clonal chromosomal translocations, it is possible that many different combinations of NCCA events could initiate and/or promote cancer development, thus NCCAs are very likely an indicator of cancer transformation.
[0038] The new diagnostic system disclosed this application is based on two new features. First, there is disclosed herein the concept of using the frequency of NCCAs to monitor genomic instability. Second, there is disclosed the use of Spectral Karyotyping that is capable of detecting all translocations throughout the genome. Two types of new chromosomal aberrations have been characterized. These are DMFs and chromosome fragmentation, which have been overlooked for a several decades. Therefore, the establishment of this previously ignored approach of scoring NCCAs to monitor genomic instability is fundamentally important with practical applications particularly relevant for patients on chemotherapy.
[0039] The inventors herein identify four important practical usages of NCCAs. First, NCCAs have directly been linked to genomic instability by several important experiments. Most significant, it has been found that cancer cells display very high rates of NCCAs correlating with their level of genomic instability. This contention has been verified further through experiments using knock out mice that are engineered to be genomically unstable. These experiments verify that frequencies of NCCAs correlate with the level of overall genomic instability. Additional experimental support has been performed utilizing normal genomes by applying carcinogens that are known to cause instability, as well as using unstable cancer genomes, and also subjecting them to carcinogen treatments. Both of these experiments confirmed the direct correlation between the level of genomic instability and quantitatively measured rates of NCCAs. In all of these experiments, NCCAs represented the indicator of increasing genomic instability and provided the earliest detectable chromosomal changes preceding cancer initiation in solid tumors.
[0040] Recently, there has been renewed interest in cancer genomic changes occurring at the chromosomal level. Study at the chromosomal level is a new trend for cancer research and is now considered the level at which genomic instability is reflected for the majority of cancers. Chromosomal biomarkers also have a distinct advantage primarily due to the fact that chromosomal changes represent an end product of multiple molecular pathways that generate high levels of heterogeneity typically seen in solid tumors. This will result in the ability to perform comparisons regardless of the molecular pathway or degree of heterogeneity. NCCAs are therefore useful to study genomic instability, which is a key feature of cancer development. In accordance with the present invention, genome instability should also contribute to other types of disease.
[0041] Second, NCCAs provide the underlying basis for cancer clonal evolution. This is significant as cancer research has been unable to provide an explanation or a theory for solid tumor progression. One of the most puzzling aspects is the lack of karyotype patterns displayed by similar or the same type of tumor and there is also no pattern of evolution during tumor progression. This has been a focus of intense investigation in the cancer research field, attempting to identify analogous patterns found in hematologically based cancers. NCCAs represent transient chromosomal alterations that ultimately lead to permanent changes that underlie cancer initiation. NCCAs mediate the chromosomal alterations that set off a particular pathway leading to the formation of clonal populations. Since this can occur through a variety of pathways, no common karyolype pattern has been found that leads to a pattern of clonal evolution in solid tumors. The apparent contradiction is that on the one hand, all NCCAs come from the same parental cell, while on the other hand NCCAs are different from the parental cells (some of them can be drastically different). When subsequent new clonal aberrations form, they appear not to be interconnected, however the inconsistent patterns seen in solid tumors can be explained by the occurrence of NCCAs. NCCAs therefore represent the important link between similar cancer phenotypes that display widely varying heterogeneity and are essential to the process of clonal evolution that activates cancer.
[0042] Third, the rate of NCCAs can be easily accessed from patients by screening lymphocytes derived from drawn blood samples rather than direct tissue biopsies. This makes the use of NCCAs a practical and feasible tool. The use of lymphocytes for the purpose of monitoring genetic susceptibility is not new. Lymphocytes have been used to detect chromosomal breakage as a means to correlate increased chromosomal instability in cancer patients. However, the rates of breakage are less reliable than rates of non-clonal translocations. Chromosomal breakage used to predict the likelihood of cancer was successful based on group data, but was not as reliable when used for individual based data. Levels of NCCAs can be used to monitor and establish a genomic instability baseline for each individual (since the genetic background is the same for all of an individual's cells). The use of a system to monitor genomic instability based on the use of NCCAs obtained from patient's lymphocytes is strongly supported by data.
[0043] Fourth, is the practical application of NCCAs as a biomarker capable of monitoring the potential of drug resistance and possible response of patients after chemotherapy. The correlation of high frequencies of NCCAs has been associated with the increased likelihood of drug resistance in cancer patients. The inventors have also surprisingly demonstrated that many of the current available chemotherapies can induce genome instability and thus also induce drug resistance. This new finding is very different from previously known mechanisms of bacterial antibiotic resistance. Therefore, the use of the frequencies and types of NCCAs is an important new method that can now be used to study drug resistance. NCCAs can thus be monitored in each patient to follow the affects of drug or reagent therapy and is a new method that can be used to assess underlying genomic instability and the potential for recurring cancer transformation. High rates of NCCAs are indicative of an unstable genome, the presence of which is a strong indicator of chemotherapy resistance.
[0044] An emerging genome-centric concept on cancer evolution states that overall genome level variation coupled with stochastic gene mutations serve as a driving force of cancer evolution by increasing the cell population diversity. The importance of non-clonal chromosome aberrations (NCCAs) (both structural and numerical) and their dynamic interplay with clonal chromosome aberrations (CCAs) in the immortalization process has been recently demonstrated and supports the genome-centric concept of cancer evolution. Similarly, the pattern of gene mutations within tumors occurs stochastically. These data and the absence of universal gene mutations revealed by recent large scale sequencing efforts reveals that genome dynamics and stochastic cancer evolution and its clinical implications should now be incorporated into the conceptual framework of cancer research.
[0045] Studies on clonal diversity and subsequent clinical outcomes in Barrett's esophagus reinforce the concept that cancer progression occurs through somatic evolution driven by genome instability coupled with an increase in or accumulation of clonal diversity. To date, however, most evolutionary analyses have focused on specific genetic loci rather than the overall genome level diversity. The impact of genetic variation at the genome level is much more profound than at the gene level, as the higher level of organization often constrains lower levels and displays more stable characteristics than lower levels. It is therefore expected that the major form of cellular population diversity is generated by karyotypic heterogeneity reflected as NCCA/CCA cycles (previously described as the waves of clonal expansion with the regeneration of genetic diversity in between) occurring during somatic evolution. It is thus more reliable and easier to measure the degree of diversity at the genome level than at the individual gene level. In addition, it has been a challenge to trace individual genes for most cancer types where there is a high level of genomic heterogeneity.
[0046] Increased NCCAs are associated with multiple genetic and environmental factors including dysfunction of genes that maintain genome integrity, over-expression of onco-proteins, exposure to carcinogens, cells reaching crisis stages prior to immortalization; etc. For a given cell population, elevated NCCAs will directly promote tumorigenicity. This correlation supports the biological significance of NCCAs in cancer formation. Previously, only the immortalization step was extensively shown to have such a correlation. To test the hypothesis further that increased levels of NCCAs directly promote tumorigenicity, it is necessary to link the two events in a simple model system.
[0047] There are a number of in vitro tumorigenicity models available. Most however, focus on the link between tumorigenicity and specific pathways rather than the evolutionary mechanism of tumorigenicity. Accordingly, a large number of pathways have been linked to tumorigenicity without revealing common mechanisms. In light of the discovery by the inventors herein that genome instability mediated somatic cell evolution is the common mechanism in cancer, some of the previously characterized systems have been reexamined with a focus on overall genome diversity rather than specific pathways. The inventors have selected five readily available in vitro models that represent various human and mouse cancer types to confirm that the linkage between increased levels ofNCCAs and tumorigenicity represents a common feature across drastically different models transcending previously characterized molecular pathways.
[0048] In addition, the inventors have demonstrated that five patients with Gulf War Syndrome have displayed significantly higher levels ofNCCAs, which illustrates the practical application ofNCCAs and provides further support to the proof of principle.
[0049] FIG. 1 is a graphical representation of detected levels ofNCCAs in individual patients plotted as a percentage of cells with chromosomal changes for patients that are normal patients or have been diagnosed with cancer or Gulf War Syndrome.
[0050] FIG. 2 is a graphical representation of the average and standard deviation of each group of patients as shown in FIG. 1 .
[0051] In the field of cancer clinical cytogenetics only clonal chromosomal aberrations (CCAs) have been used to systematically characterize or “karyotype” cancers, this method is primarily based on experience with hematology cancers. Solid tumors behave differently than hematologically based cancers. There have been no universal clonal events identified in solid tumors; however NCCAS and unrelated CCAs have been reported. Previously, NCCAs have been disregarded as not significant, making it extremely difficult to reconcile cancer karyotype findings. In contrast, the inventors herein have demonstrated that not only are NCCAS significant but they also explain progressive heterogeneity and chemotherapy resistance. In addition, the quantitative frequencies of these structures can be used as a direct indicator of underlying latent genomic instability and the potential chemotherapy resistance and subsequent cancer transformation. Further, these structures represent fundamental underlying changes that precede cancer initiation and continue to occur during progression that likely represent the earliest detectable changes prior to tumor initiation.
[0052] The concept of NCCAs underlying cancer initiation and progression will change perspectives on certain aspects of cancer research. In particular, according to emerging trends, it is now known that chromosome aberrations can initiate cancer as opposed to being a consequence of cancer as was previously thought, and therefore, the focus will now shift to the examination of chromosomal alterations rather than the monitoring of specific pathways. This approach has more practical application since our system can be used to monitor entire genomes, focusing on the earliest detectable changes. These structures can be applied for diagnostic and prognostic purposes as well as for monitoring drug effects on the genome.
[0053] Spectral karyotyping (SKY) was used herein to compare the degree of karyotypic heterogeneity displayed in various sublines of five in vitro systems, where the cell population diversity was determined by the frequency of NCCAs. The tumorigenicity of these models has been further analyzed to link elevated structural NCCAs and tumorigenicity. In addition, benign hyperplastic lesions (without evidence of carcinoma) were examined and displayed low levels of structural NCCAs. In contrast, premalignant dysplastic tissue of the c-myc transgenic mouse model displayed high levels of NCCAs. Based on the observations that there are many types of karyotypic aberrations, the distribution patterns of structural and numerical NCCAs as well as the contribution of various types of genome level variation to tumorigenicity have also been analyzed, suggesting the importance of using total frequencies of structural NCCAs when monitoring the potential tumorigenicity. Together, our analysis agrees with the proposed model that chromosomal instability produces genetic variation and the more variation there is, the more likely a favorable combination will be produced that will result in a lesion that will produce malignancy/tumorigenecity. Thus, the identified common link between the elevated levels of NCCAs and increased tumorigenicity establishes a strong relationship between genome level diversity and tumorigenicity. Further, this information illustrates the relationship between the general evolutionary mechanism and large numbers of specific molecular mechanisms of cancer.
[0054] In brief, the evolutionary mechanism of cancer is equal to the collection of total number of individual molecular mechanisms. As each individual case often involves different molecular mechanisms and the mechanisms are constantly changing during cancer evolution, it is difficult to predict the status of cancer and the response to treatment based only on tracing specific pathways.
[0055] Another component of the present invention is the characterization of two new structures of NCCAs: defective mitotic figures (DMFs) and chromosome fragmentation. These two markers can also be used as clinical markers of progressive disease as well as to monitor the chemotherapy process.
[0056] It is clear that the new NCCA biomarker can be used; 1) to classify cancer patients in terms of the suitability of chemotherapy (i.e., to classify patients according to likely chemotherapy response and options, as some of the patients will be harmed if their genomes are not stable and they are subjected to chemotherapy); 2) to screen the general population to assess the risk of cancer, and early detection (the inventors have demonstrated that elevated NCCAs can be detected in the initial stages of cancer); 3) to further study the mechanism and patterns of cancer progression from the perspective of genomic instability; and 4) to screen the chemotherapeutical agents and environment insults.
[0057] The basic mechanism underlying these structures (NCCAs) is currently under study. There is an important direct correlation with the underlying genomic instability of cells (specifically tumor cells) that can be used to monitor and predict tumor behavior in clinical specimens. In addition to monitoring theses structures when examining tumor biopsy samples, these structures can also be easily obtained from blood lymphocytes in patients and, are therefore, useful practically to ascertain the inherent level of genomic instability of clinical patients that may be at risk for cancer or are in the initial stages of cancer to determine the likelihood of progression. NCCAs could be useful for clinical evaluation of treatment regimens by giving additional information to the clinician as to the possibility of progression, in addition to the stage of the tumor.
[0058] These structures also readily increase when known genomically destabilizing drugs or reagents are applied to cells of patient samples. Rates of NCCAs, therefore, could be used to determine the effects that a specific drug or chemotherapy agent has on tumor cells, i.e., will the drug in question increase or decrease genomic stability. Additionally, the application of certain chemotherapy agents to patient samples could determine the latent genomic instability level of a patient. The most genomically unstable patients will display the highest NCCA levels when a known destabilizing drug is applied. This process could become a very useful clinical tool for cancer that could also have applications in the toxicology field, as well as to screen chemotherapy agents to determine the extent of drug resistance.
Cell Culture and Chromosome Preparation
[0059] Various stages of cells representing the five models (Table 1) were briefly cultured. The original frozen cell passages used in the previous tumorigenicity studies were short-term cultured. After 2-4 days culture, mitotic cells were harvested for chromosome preparation. Briefly, cells were grown to 70% confluence and treated with colcemid for 4-8 h. Trypsinized cells were harvested and treated with hypotonic solution (0.4% KCL, 10 min at 37° C.), followed by Carnoy's fixation (3:1 of methanol and acetic acid) (three times at 20 min each) and air-dried. The chromosomal slides can be used for SKY immediately or stored at −70° C. for future use.
[0000]
TABLE 1
Types and frequencies of various CCAs
and NCCAs of the seven models analyzed
Cell Lines tissue
Chromosomal
samples
number
CCAs
sNCCAs (%)
Tumorigenicity
The LNCap cell lines
Pd36:
79.17 ± 14.35
der(1)t(1; 15),
30%
Low
der(6)t(4; 6),
der(4)t(4; 6; 10),
der(15)t(15; 1),
der(16)t(16; 6)
Pd69:
90.39 ± 22.43
der(1)t(1; 15),
41.5%
der(6)t(4; 6),
der(4)t(4; 6; 10),
der(15)t(15; 1),
der(16)t(16; 6),
der(13; 13)
Pd125:
88.77 ± 19.97
der(1)t(1; 15),
53%
High
der(6)t(4; 6),
der(4)t(4; 6; 10),
der(15)t(15; 1),
der(16)t(16; 6)
MCF10DCIS.com model
Pd9:
48.35 ± 2.18
der(1)t(1; 2),
5.9%
Low
t(3; 17), t(17; 3),
der(6)t(6; 19),
der(9)t(9; 3; 5),
der(21)t(21; 17)
Pd29:
49 ± 2.03
der(1)t(1; 2),
12%
t(3; 17), t(17; 3),
der(6)t(6; 19),
der(9)t(9; 3; 5),
der(21)t(21; 17),
der(15)t(15; 21),
der(3)t(3; 9)
Pd46:
47.58 ± 4.54
der(1)t(1; 2),
42%
High
der(6)t(6; 19),
der(9)t(9; 3; 5),
der(15)t(15; 21)
MCF10-CSC model
CSC-MCF10A1:
51.25 ± 14.29
der(1)t(1; 13),
24.3%
No
der(3)t(3; 9),
t(3; 17), t(17; 3),
der(6)t(6; 19),
der(9)t(9; 3; 5)
CSC-MCF10A2:
51.82 ± 18.23
der(1)t(1; 13),
30%
No
der(3)t(3; 9),
t(3; 17), t(17; 3),
der(6)t(6; 19),
der(9)t(9; 3; 5)
CSC-MCF10A3:
95.5 ± 22.00
der(1)t(1; 13),
42%
Yes
der(3)t(3; 9),
t(3; 17), t(17; 3),
der(6)t(6; 19),
der(9)t(9; 3; 5)
CSC-MCF10A4:
48.96 ± 7.56
der(1)t(1; 13),
34.8%
No
der(3)t(3; 9),
t(3; 17), t(17; 3),
der(6)t(6; 19),
der(9)t(9; 3; 5)
MCF10-HoxA1 model
HOXA1:
46.55 ± 0.76
der(3)t(3; 9),
15.3%
Yes
der(9)t(5; 3; 9) + 1
Control:
46.5 ± 0.76
der(3)t(3; 9),
5.3%
No
der(9)t(5; 3; 9) + 1
Mouse ovarian cancer model
Pd9:
71.08 ± 3.37
der(10; 10)
9.1%
No
Pd45:
58.6 ± 13.21
der(1)t(1; 2),
30%
der(8)t(8; 16)
Pd91:
57.6 ± 13.89
t(1; 2), t(8; 9),
50%
Yes
t(5; 3), t(3; 2)
MCF10-Rad6B (benign lesion)
MC15
52.17 ± 16.18
der(1)t(1; 2),
4.3%
No
der(1)t(1; 5),
t(3; 17), t(17; 3),
der(6)t(6; 19),
der(9)t(5; 3; 9)
Myc-transgenic mouse model (premalignant dysplastic tissue)
MG2
40.41 ± 5.16
−17
24%
Yes
[0060] For each sample of these models, an average of 50 SKY images were analyzed. For the MCF10-HoxA1 model, in addition to the listed frequency of structural NCCAs, 78% of errors in segregation reflected by the sticking chromosomes were detected in the HoxA1 line, while 14% of errors were detected in the control cell line.
[0061] MCF10A-Rad6B clone 5 cells were derived by stable transfection of Rad6B, a fundamental component of postreplication DNA repair pathway. MCF10-Rad6B clone 5 cells (1×107) were suspended in Matrigel and injected into the mammary fat pads of female immunodeficient nude mice, and lesions from the injection sites were harvested at 70 days. Harvested xenografts were cultured in DMEM/F12 supplemented with 5% horse serum, 10 μg/ml insulin, hydrocortisone and 10 ng/ml EGF to derive MC15. MC15 cells were harvested and chromosomes prepared within 2-4 passages for SKY analysis.
[0062] Chromosome preparation from proliferating mammary glands of MMTV-c-myc transgenic mice Proliferating mammary glands were collected from two virgin female MMTV-c-myc transgenic mice at age of 7 months. Virgin females of this transgenic line of mice spontaneously develop palpable mammary tumors at ages of 7-9 months. The proliferating mammary glands used in this study were collected from an area distant from a palpable tumor, and histology of the glands in the same area showed only proliferating glands without atypia. Proliferating glands were briefly cultured and chromosomes were prepared for SKY analysis.
SKY and Data Analysis
[0063] Following probe denaturation, hybridization and SKY detection, randomly selected mitotic figures were photographed and analyzed by SKY imaging software. Fifty to hundred SKY images were captured for each cell population to identify commonly shared karyotype features and to reveal the karyotypic diversity of these various cell populations. NCCAs were scored by identifying chromosomal numbers, chromosome translocations/large deletions or other types of abnormality detected within a given mitotic cell. There are two steps needed to score frequencies of NCCAs and CCAs. First, a 4% cutoff line is used to identify any specific recurrent karyotypes or CCAs. The frequency of a CCA is determined by calculating the number of cells displaying the same CCA divided by the total cells examined (50-100). Non-clonal karyotypes (NCCAs) are classified as having a frequency lower than 4%. The total frequencies of NCCAs of a given cell population is then calculated by using all cells displaying NCCAs divided by the total cells examined. Both types of CCAs as well as frequencies and types of NCCAs are listed in Tables 1 and 2.
[0000]
TABLE 2
Distribution of various types of structural
NCCAs for MCF10-CSC model
Recorded abnormal
Frequencies
Cell lines
structures
(%)
MCF10A-CSC-1 (# of karyotypes = 53)
t-NCCA
1
1.9%
DMF
7
13.0%
Other abnormal images
5
9.4%
Total
24.3%
MCF10A-CSC-2 (# of karyotypes = 60)
New CCA
der(15; 22)
6.7%
t-NCCAs
3
5.0%
Chr-F
3
5.0%
DMF
6
10.0%
Other abnormal images
6
10.0%
Total
30.0%
MCF10A-CSC-3 (# of karyotypes = 50)
New CCA
der(15; 22)
8.0%
t-NCCAs
5
10.0%
Chr-F
3
6.0%
DMF
10
20.0%
Other abnormal images
3
6.0%
Total
42.0%
MCF10A-CSC-4 (# of karyotypes = 60)
New CCA
der(15; 22)
10.0%
der(13; 22)
5.0%
t-NCCAs
5
8.3%
Chr-F
7
11.6%
DMF
7
11.6%
Other abnormal images
2
3.3%
Total
34.8%
t-NCCA refers to translocated chromosomes.
Chr-F refers to chromosome fragmentation.
[0064] Other abnormal images refer to these previously uncharacterized mitotic aberrations.
In Vivo Tumorigenicity Test
[0065] In earlier studies, it was learned that all cigarette smoke condensate (CSC)-treated MCF10A cells efficiently formed colonies in soft-agar. The inventors then re-established cell lines from the soft-agar colonies and further examined the persistence of their transforming characteristics. The re-established cell lines, when plated after 17 passages without CSC treatment, still formed colonies in soft-agar. To determine whether the cell lines showing transformed characteristics in the anchorage-independent assay can grow in nude mice, we injected four selected CSC-transformed cell lines, MCF10A-CSC1, MCF10A-CSC2, MCF10A-CSC3, and MCF10A-CSC4 into female nude (nu/nu) mice (with 105 cells of each cell line suspended in Matrigel) (BD Biosciences, San Diego, Calif.). Palpable tumors appeared in 20 days and animals were sacrificed in 44 days.
Statistical Analysis
[0066] Ninety-five percent confidence intervals were calculated by combining the lines with the highest and the lowest tumorigenicity for each model. A Student's t-test was then run on this data showing a significant difference in NCCA levels between cells with high and low tumorigenicity (P=0.01791) ( FIG. 5A ). Ninety-five percent confidence intervals of chromosome number were also calculated for each cell line studied ( FIGS. 5B-5F ).
[0067] The reproducibility of NCCA level is very high. Though many factors can influence NCCA frequency including culture conditions and genetic makeup of a given cell line, the frequency of NCCAs is reproducible for a similar group. For example, in the MCF10 breast disease model, duplicates of treated and untreated show a significant difference (P=0.00055) in NCCA frequency when the treated are compared to the untreated, however standard deviation within treatments is quite low (0.00212132 in treated and 0 in untreated). Similarly, when comparing two stages of the immortalization process of the Li-Fraumeni model, duplicates of the earliest stage were similar (SD=0.008485281) and significantly different from the duplicates of later stages of the cell populations (P=0.0034). Similar results were reported regarding the frequencies of NCCAs in ATM−/− mice as well as various cancer cell lines with or without onco-protein expression.
Results
[0068] Molecular characterizations and measured genome diversity for the five models The molecular characterization of these five models has been accomplished by previous studies and the key points are briefly summarized (Table 3, below). To examine genome diversity, multiple color SKY was used to score the level of NCCAs and types of CCAs. The following is detailed information on each model.
The LNCaP Model
[0069] A unique prostate cancer model with three distinctive stages has been developed using sublines of LNCaP cells originally established from a human prostate adenocarcinoma. Within this model, C33 (passage number<33) represents the early stage that is androgen-responsive; C51 (passage 45-70) represents the middle stage with decreased androgen-responsiveness; and C81 (passage 81-120) represents the late stage with androgen-unresponsiveness and increased tumorigenicity, illustrated by a xenograft animal model, where C33 and C81 stage cells of the LNCaP cell model showed differential tumorigenicity when implanted subcutaneously in nude mice. In this model increased genetic aberrations, such as microsatellite instability and allelic loss were observed in later passages, but the karyotypes appeared to be stable throughout the progressive transformation. This illustrates the link between tumorigenicity and increased genetic alterations reflected by microsatellite instability and chromosomal allelic loss.
[0070] Three cell populations representing C33 (pd36), C51 (pd69), and C81 (pd125) were used for SKY analysis. The overall karyotypes of all cells at various passages shared the same set of five altered chromosomes demonstrating the overall stability at the karyotypic level as determined by the presence of stable CCAs ( FIG. 8 ). At pd69, der(13;13) formed as a new transitional CCA, however, it was lost by pd125 (Table 1). Thus there were no specific late passage CCAs. Increased structural NCCAs, on the other hand, represent a significant feature of the transition between early and later passages.
BRIEF DESCRIPTION OF THE DRAWING
[0071] Comprehension of the invention is facilitated by reading the following detailed description, in conjunction with the annexed drawing, in which:
[0072] FIG. 1 is a graphical representation of detected levels of NCCAs in individual patients plotted as a percentage of cells with chromosomal changes for patients that are normal patients or have been diagnosed with cancer or Gulf War Syndrome;
[0073] FIG. 2 is a graphical representation of the average and standard deviation of each group of patients as shown in FIG. 1 ;
[0074] FIGS. 3A , 3 B, 3 C, and 3 D are photographic representations that are useful to illustrate morphologic features of chromosome fragmentation;
[0075] FIGS. 4A , 4 B, 4 C, and 4 D are photographic representations that are useful to illustrate chromosome fragmentation that results in cell death;
[0076] FIGS. 5A , 5 B, 5 C, and 5 D are photographic representations that illustrate TUNEL staining performed on cells undergoing chromosome fragmentation to show negative staining of cells displaying chromosome fragmentation and to illustrate that chromosome fragmentation is not apoptotic;
[0077] FIG. 6 is a graphical representation that illustrates that the chromosome fragmentation rate is associated with genomic instability;
[0078] FIG. 7 is a representation of a model that illustrates the relationship between chromosome fragmentation and other types of cell death;
[0079] FIGS. 8A and 8B illustrate examples of increased levels of NCCAs detected from the late stages of in vitro models coupled with increased tumorigenicity, specifically a karyotype comparison between an early stage (p36) ( FIG. 8A ) and a late stage (p105) ( FIG. 8B ) of the LNCaP cell line;
[0080] FIG. 9A and 9B illustrate example of increased levels ofNCCAs detected from the late stages of in vitro models coupled with increased tumorigenicity, including the comparison between subline MCF10A-CSC-1 ( FIG. 9A ) and CSC-3 ( FIG. 9B ). Both lines share five common types of CCAs as indicated by the blue colored boxes;
[0081] FIGS. 10A , 10 B, and 10 C illustrate examples of increased levels of NCCAs detected from the late stages of in vitro models coupled with increased tumorigenicity, specifically the comparison between the HOXA1 expressed line and the control line generated from MCF10, both of which displayed the same karyotypes with two identical CCAs;
[0082] FIGS. 11A-11F illustrate the distribution of structural and numerical NCCAs; and
[0083] FIG. 12 illustrates the evolutionary mechanism of cancer and its relationship with molecular mechanisms.
DETAILED DESCRIPTION
[0084] There is described in this disclosure a new type of mitotic cell death, termed “chromosome fragmentation,” which is a consequence of certain cellular stressors such as inherited genomic instability or chemotherapeutic treatment in M phase, and a pathologically related process that results in the breakdown of the chromosomes, elimination of genetic material, and subsequent death of cells. This form of cell death is different from typical apoptosis and mitotic catastrophe. It is caspase independent, does not exhibit the typical oligosomal DNA degradation of apoptosis, and is not inhibited by overexpression of Bcl-2. In the case of mitotic catastrophe, classic methods of inducing mitotic catastrophe do not increase levels of chromosome fragmentation detectable by cytogenetic analysis. Chromosome fragmentation, although morphologically similar to, is distinct from S-phase premature chromosome condensation (and chromosome pulverization) as chromosomes undergoing fragmentation are from mitotic, nonreplicating cells. Chromosome fragmentation offers insight into the basis for chromosome pulverization in cases where the genome has been destabilized. Chromosome fragmentation represents a clinically relevant form of cell death, which unlike other types of cell death is clinically identifiable using standard cytogenetic analysis that is commonly performed on tumors, due to its defined morphologic features. Chromosome fragmentation is an important form of non-clonal chromosome aberrations (NCCAs), which are linked to cancer progression. It can serve as a much needed biomarker of induced cell death and genome instability.
Materials and Methods
[0085] Cell culture. Cell lines were used, including HeLa, HCT116, HCT116 p53−/−, HCT116 14-3-3s−/−, H460-neo, H460-Bcl-2, and H1299-v138. HCT116 14-3-3s−/− cells were grown in McCoy's 5A medium; others were grown in RPMI 1640. G418 (400 μg/mL) was used as necessary.
[0086] Induction of chromosome fragmentation. After 3 to 8 h treatment of colcemid, mitotic cells were gently shaken off and resuspended in culture medium containing colcemid. Cells were then treated with doxorubicin or methotrexate at 1 μg/mL for various times.
[0087] Cytogenetic examination. Cells were harvested and cytogenetic slides were prepared using standard protocols. Slides were stained by Giemsa for scoring nuclear structures or stored at −20° C. for further characterization including spectral karyotyping (SKY) and antibody staining. The fragmentation index was determined by dividing the number of cells displaying chromosome fragmentation by the total number of mitotic cells, including cells undergoing chromosome fragmentation.
[0088] Spectral karyotyping analysis. SKY was performed on mitotic spreads as described. Briefly, cytogenetic slides were denatured and hybridized with human painting probes. After washing and spectral karyotyping detection, mitotic structures were captured using a charge coupled device camera.
[0089] Bromodeoxyuridine incorporation and antibody staining. Cells were pretreated for 3 h with colcemid and collected via mitotic shake off. Cells were treated for 6 h with 1 μg/mL doxorubicin, colcemid, 100 μmol/L deoxycytidine, 100 μmol/L bromodeoxyuridine (BrdUrd), and harvested for cytogenetic analysis.
[0090] Antibody staining was performed as described. Cell suspensions were dropped on ice-cold microscope slides followed by washes in cold buffer [10 mmol/L Na2HPO4, 0.15 mol/L NaCl, 1 mmol/L EGTA, and 0.01% NaN3] and buffer [1.0 mmol/L triethanolcomine-HCl (pH 8.5), 0.2 mmol/L NaEDTA (pH 8.0), 25 mmol/L NaCl, 0.05% TweenR20, and 0.1% bovine serum albumin]. Slides were then air dried and primary antibodies were loaded.
[0091] Viability assessment. Viability was assessed using a LIVE/DEAD assay (Invitrogen) according to manufacturer's protocol.
[0092] Terminal deoxyribonucleotide transferase-mediated nick-end labeling staining. Terminal deoxyribonucleotide transferase-mediated nick-end labeling (TUNEL) staining was performed using a kit supplied by Roche. Briefly, mitotic cells were induced to undergo chromosome fragmentation washed thrice in PBS, attached to slides using a Shandon cytospin at 500 rpm for 5 min, fixed in 4% paraformaldehyde, and subjected to TUNEL.
[0093] Caspase inhibition. Caspase activity was inhibited by treatment of HCT116 cells for 12 h with 20 mmol/L z-vad-fmk followed induction of chromosome fragmentation (by concurrent treatment with colcemid and 1 μg/mL doxorubicin) for 6 or 12 h in the presence of or after removal of z-vad-fmk. Following treatment, cytogenetic slides were made and scored.
[0094] Caspase-3 activity. Caspase-3 activity was measured using the caspase-3 colorimetric assay kit from R&D Systems as described. HCT116 cells were treated for 8 h with colcemid with and without z-vad-fmk. Mitotic cells were then shaken off and treated with doxorubicin for an additional 6 and 12 h.
[0095] Western blotting. Analysis was performed as herein described.
[0096] Induction of genomic instability. For induction of genomic instability, H1299-v138 cells were grown at 39° C. for 2 weeks and then grown at 32° C. where cells were photographed and collected daily and cytogenetic preparations were made and analyzed for chromosome fragmentation.
[0097] Induction of mitotic catastrophe. Mitotic catastrophe was induced as described. HCT116 14-3-3−/− cells were treated for up to 72 h with 2 μg/mL doxorubicin and HCT 116 p53−/− cells were treated with 1 μg/mL aphidicolin for up to 96 h were each harvested every 24 h. Cytogenetic preparations and cytospin preparations were made allowing for chromosomal and morphologic analysis.
Results
[0098] Chromosome fragmentation represents a unique phenotype of chromosome aberration. To define chromosome fragmentation, the morphology first is characterized. Fragmented chromosomes are distinct from normal chromosomes prepared by cytogenetic techniques. Chromosomes that are progressively cut into smaller pieces and fragmented chromosomes often show lighter density of Giemsa or 4′,6-diamidino-2-phenylindole (DAPI) staining than normal chromosomes stained in parallel indicating the loss of chromosomal material. Mitotic figures displaying chromosome fragmentation can be grouped into at least three groups, early fragmentation where few chromosomes are broken, midstage fragmentation where a significant number of the chromosomes have been fragmented, and late stage where all or most of the chromosomes have been fragmented, suggesting a progressive process ( FIG. 3A ). Chromosome fragmentation is not the result of the slide preparation, as under identical conditions both normal and fragmented chromosomes coexist within the same cell ( FIG. 3A ). In fact, the variable frequencies of fragmented chromosomes are determined by the specific cell line used and drug treatment before the making of slides ( FIG. 2D ).
[0099] FIGS. 3A , 3 B, 3 C, and 3 D are photographic representations that are useful to illustrate morphologic features of chromosome fragmentation. Chromosomes undergoing fragmentation display many breaks and often seem frayed. In FIG. 3A , Giemsa staining shows chromosome fragmentation is a progressive process with early stages showing few fragmented chromosomes [left, chromosome fragmentation (arrows 110 ); intact chromosomes (arrows 115 )], mid stage with approximately half of the chromosomes fragmented (middle), and late stage with nearly all chromosomes except for one at the top showing degradation (right). In FIG. 3B , there is illustrated evidence that chromosome fragmentation occurs in condensed mitotic chromosomes. Cells undergoing chromosome fragmentation stain positive (left DAPI, right FITC) for phosphorylated H3 (Ser10) both in early (top) and late (bottom) stages. In FIG. 3C , spectral karyotyping images (inverted DAPI right, SKY left)indicate that chromosomes are condensed before fragmentation as fragmented chromosomes retain their chromosomal domains in early and later stages of fragmentation (top and bottom). Additionally, spectral karyotyping images show that single chromosomes can be eliminated via chromosome fragmentation (arrow 116 ). In FIG. 3D , chromosome fragmentation is distinct from S-phase premature chromosome condensation as chromosomes from S-phase cells forced to undergo premature chromosome condensation should show BrdUrd uptake (DAPI left, anti-BrdUrd-FITC right). Cells undergoing chromosome fragmentation (cell on right) do not show incorporation of BrdUrd, whereas S-phase cells (left cell) from the same treatment do.
[0100] FIGS. 4A , 4 B, 4 C, and 4 D are photographic representations that are useful to illustrate chromosome fragmentation that results in cell death. As the rate of chromosome fragmentation increases ( FIG. 4A ), cellular viability decreases ( FIG. 4B ). Viability staining shows that cells undergoing chromosome fragmentation display loss of membrane integrity as ethidium homodimer is able to enter the cell and stain chromosome fragments red ( FIG. 4C ). Viable cells show only green staining. Chromosome fragmentation is induced more efficiently if combinations of chemotherapeutics and microtubule inhibitors are used ( FIG. 4D ). Col, colcemid; dox, doxorubicin; MTX, methotrexate.
[0101] A mitosis-specific event. Chromosome fragmentation was observed at low levels (typically <5% of mitotic cells, depending on specific cell line) in a number of cell lines without any drug treatment. To show that chromosome fragmentation is generated directly from mitotic cells and not from cells in interphase, the population of mitotic cells was increased via shaking off nonadherent mitotic cells and treating with colcemid to arrest them in mitosis and concurrently treating them with the topoisomerase II inhibitor, doxorubicin. Nearly 100% of these mitotic cells showed a degree of chromosome fragmentation within 12 h of this treatment ( FIG. 4D ). When interphase cells were treated with doxorubicin and colcemid that was preceded by a double thymidine block, no chromosome fragmentation was observed for up to 24 h. BrdUrd incorporation was monitored during induction of chromosome fragmentation and no BrdUrd incorporation was observed ( FIG. 1D ), suggesting that despite the morphological similarity of chromosome fragmentation and PCC, they are in fact distinct processes.
[0102] Additional indications that chromosome fragmentation takes place exclusively in mitotic cells include assessment of the phosphorylation status of histone H3 at serine 10. Immunofluorescent staining of phosphorylated H3 (Ser 10), revealed the majority of mitotic cells, fragmented or not, show positive H3 staining, suggesting that these fragments are indeed derived from condensed mitotic chromosomes ( FIG. 3B ). Multiple color spectral karyotyping was then performed to examine the relationship between fragmented and normal chromosomes as spectral karyotyping can precisely identify individual chromosomes. Results from spectral karyotyping analysis ( FIG. 3C ) show that even highly fragmented chromosomes are condensed and have a grouping and localization similar to what would be expected if that chromosome was intact.
[0103] Chromosome fragmentation results in cell death. Fragmented mitotic figures with extensive chromosomal damage would seemingly be incompatible with survival. To test the direct link between fragmentation and cell death, mitotic cells were treated to induce chromosome fragmentation and followed this with calcein AM and ethidium homodimer staining to assess viability. Following treatment, cells were collected and analyzed for viability and the frequency of chromosome fragmentation. It was found that chromosome fragmentation does result in cell death as chromosome fragmentation increases ( FIG. 4A ) as viability decreases ( FIG. 4B ). Additionally, cells were observed that displayed extensive ethidium homodimer labeling of fragmented chromosomes ( FIG. 4C ), further illustrating that chromosome fragmentation directly results in loss of membrane integrity and loss of viability. Therefore, chromosome fragmentation is a form mitotic cell death.
[0104] This process differs from typically described apoptosis. Next, a determination was made whether chromosome fragmentation is a typical apoptotic process. TUNEL staining performed on cells undergoing chromosome fragmentation shows negative staining of cells displaying chromosome fragmentation ( FIG. 5A ) in agreement with previous reports. Cells with typical apoptotic morphology (round clusters of DNA) from the same slides, however, show positive TUNEL staining ( FIG. 5A ) as did positive controls (data not shown). Also, apoptotic oligosomal DNA ladders were not evident after induction of fragmentation (data not shown). Chromosome fragmentation, however, involves strand breaks as evidenced by positive-H2AX staining along chromosomes ( FIG. 5B ). This has been implicated in apoptosis and damage repair signaling.
[0105] FIGS. 5A , 5 B, 5 C, and 5 D are photographic representations that illustrate TUNEL staining performed on cells undergoing chromosome fragmentation to show negative staining of cells displaying chromosome fragmentation and to illustrate that chromosome fragmentation is not apoptotic. Fragmented chromosomes show negative TUNEL staining ( FIG. 5A , arrows 120 , DAPI right, TUNEL left). Typical apoptotic bodies display positive TUNEL results (arrows 125 ) as do positive controls (data not shown). Chromosome fragmentation results in intense −H2AX staining (DAPI left, FITC right), which is an indicator of strand breaks, indicating that despite negative TUNEL staining, there is indeed strand breakage ( FIG. 5B ). Caspase inhibition does not inhibit chromosome fragmentation ( FIG. 5C ). Cells pretreated with broad-spectrum caspase inhibitors and then treated to induce chromosome fragmentation in the continued presence of, or after removal of, caspase inhibitors show similar frequencies of chromosome fragmentation at 6 and 12 h of treatment (top). Notwithstanding that there was no change in the frequency of chromosome fragmentation, levels of caspase-3 activity significantly (6 h, P=0.003479; 12 h, P=0.00007) differed between the cells treated with z-vad-fink and those without (bottom), indicating that activation of the initiator caspase, caspase-3, is not required for chromosome fragmentation. Interestingly, treated cells in the presence of caspase inhibitors tend to exhibit later stages of fragmentation compared with cells removed from caspase inhibition after 12 h of treatment, although total chromosome fragmentation frequencies remain similar. Chromosome fragmentation frequencies were unaltered in H460 cells that overexpress the apoptosis inhibitor Bcl-2 when compared with H460 cells carrying an empty neo vector when chromosome fragmentation is induced once again, indicating that caspase activation and/or mitochondrial membrane permeabilization are not required for chromosome fragmentation to occur (top). Levels of pro- and active caspase-3 are higher in the H-460 neo control compared with H460-Bcl-2-overexpressing cells when fragmentation is induced for 6 and 12 h, as indicated by Western blotting (bottom).
[0106] Mitotic cells were pretreated with the caspase inhibitor z-vad-fmk or with a negative control of z-vad-fmk for a short period then treated with colcemid and doxorubicin and analyzed for frequency of chromosome fragmentation. As shown in FIG. 5C (top), chromosome fragmentation frequencies were not significantly altered upon caspase inhibition. Furthermore, FIG. 5C (bottom) shows that caspase-3 reactivity is largely inhibited when 20 μmol/L zvad-fmk is added. However, levels of caspase-3 activation increase from 6 to 12 h of treatment in the uninhibited cells. Bcl-2 overexpression was also found not to inhibit chromosome fragmentation. Using two variants of the non-small cell lung cancer cell line, H460, the first overexpressing Bcl-2 and the second carrying an empty neo vector, chromosome fragmentation was induced. Both lines showed similar frequency of chromosome fragmentation as indicated in FIG. 5D (top), whereas levels of pro-caspase-3 and activated caspase-3 were increased in the treatments on cells containing the empty neo vectors and levels and activation were decreased or eliminated in cells overexpressing Bcl-2 ( FIG. 5D , bottom). This indicates that unlike apoptosis, Bcl-2 overexpression does not influence frequency of chromosome fragmentation.
[0107] This process differs from typical mitotic catastrophe. If chromosome fragmentation lacks the classic hallmarks of apoptosis perhaps it was mitotic catastrophe. During treatment, cells in culture became large and detached as reported. Cytogenetic analysis coupled with phosphorylated H3 antibody staining indicated that the cells that were undergoing mitotic catastrophe may not be typical mitotic cells. Cells were harvested after 24, 48, and 72 hours and prepared for cytogenetic analysis or as described. Chromosome fragmentation was not observed, indicating that this model of mitotic catastrophe is distinct from chromosome fragmentation. Mitotic shake off was then performed on the HCT116 14-3-3−/− cell line and accumulated mitotic cells were treated to induce fragmentation. Interestingly, HCT116 14-3-3−/− seemed to be resistant to chromosome fragmentation, as very few mitotic figures displayed fragmentation, whereas the parental strain of HCT116 shows drastically increased frequency of fragmentation when the same treatment was applied.
[0108] A second model of mitotic catastrophe induced by aphidicolin treatment in p53 null HCT 116 cells was assessed for chromosome fragmentation. A mitotic fraction of 3.2% at 72 h [compared with over 20% by three-dimensional fluorescence-activated cell sorting (FACS) analysis of DNA content and H3 phosphorylation] and 5.4% at 96 h was observed via our conventional cytogenetic analysis. Chromosome breaks were evident in the majority of chromosome spreads at 96 h. These breaks in contrast to chromosome fragmentation were more regular in size. Most cells do not show extensive breaks as typical chromosome fragmentation does, and when viewed at ×20 magnification these mitotic spreads appear normal. In the case of chromosome fragmentation, normal mitotic spreads are typically discernible from chromosome fragmentation at ×20 magnification. A minority of mitotic cells show some chromosome fragmentation; however, even the total mitotic fraction does not represent the proportion of cells reported as undergoing “mitotic catastrophe.” Further previous reports have failed to show mitotic specific proteins such as MPM2 or phosphorylated H3. Mitotic chromosomes with and without breaks stained intensely positive for phospho-H3 (Ser10); however, a number of cells with no apparent chromosomal condensation showed slight H3 staining indicating that those cells previously identified as mitotic by FACS analysis are not actually mitotic.
[0109] A true mitotic cell death. Chromosome fragmentation is an event that takes place in stressed cells and results in death directly from mitosis, seemingly unlike what has been termed mitotic catastrophe. Chromosome fragmentation seems to be a form of programmed cell death although the possibility remains that chromosome fragmentation is a form of necrosis. Chromosome fragmentation is not a form of apoptotic cell death, as it lacks the morphologic and biochemical markers of apoptosis.
[0110] The process of chromosome fragmentation results in cell death as evidenced by loss of viability in cells undergoing chromosome fragmentation ( FIGS. 4A and 4B ). Further, chromosome fragmentation cannot be induced from cells in other stages of the cell cycle. When cells were blocked in S phase with a double thymidine block, chromosome fragmentation was not apparent, although massive cell death occurred likely due to G2 arrest and subsequent apoptosis induced by the doxorubicin. Furthermore, the lack of BrdUrd incorporation in cells undergoing chromosome fragmentation shows that the chromosomes are not induced to condense during S-phase. Thus, chromosome fragmentation does not represent premature chromosome condensation during S-phase. Rather, chromosome fragmentation is a phenomenon that takes place during mitosis and occurs when chromosomes are damaged either by drug treatment or inappropriate passage of damaged cells through the G2 checkpoint. It should be noted that previous reports have shown spontaneous fragmentation in the ATR knockout model, most likely due to cells entering mitosis with DNA damage and ineffective G2 checkpoint activation. Therefore, chromosome fragmentation is not a unique phenotype of the ATR−/− genotypes, but rather the general feature of unstable genomes.
[0111] Based on the morphologic characterization, chromosome fragmentation might offer insight into the mechanism of the long-described phenomenon of chromosome pulverization. Frequently observed after viral infection and thought to occur from cell fusion, chromosome pulverization has often been linked to the prematurely condensed chromosomes and thus was thought of as occurring in interphase nuclei. The lack of BrdUrd incorporation noted in chromosome fragmentation ( FIG. 3D ) challenges this notion and shows that fragmentation is the likely mechanism of chromosome pulverization in cases of drug treatment or viral infection.
[0112] Nonapoptotic cell death. Chromosome fragmentation lacks many of the hallmark features of apoptosis, including the characteristic pattern of DNA fragmentations detectable by the TUNEL reaction. Caspase activation is also a hallmark of apoptosis. As caspase activation is intimately involved in apoptosis, the inventors herein sought to determine whether chromosome fragmentation was also dependent on caspase activity. These results were not due to cells already undergoing apoptosis as cells were rinsed to remove detached dying or mitotic cells and cultured for 15 h in the presence of the caspase inhibitor, shaken off, and then treated with colcemid and doxorubicin in the continued presence of z-vad-fmk or with z-vad-fmk removed. Although there was strong repression of caspase activation in the presence of z-vad-fmk ( FIG. 5C , bottom), the fragmentation index was not significantly altered, indicating independence of caspase activation in chromosome fragmentation.
[0113] Bcl-2 is an antiapoptotic protein that is commonly overexpressed in tumors. Bcl-2 overexpression inhibits mitochondrial pore opening, cytochrome c release, and subsequent apoptosis. Bcl-2 overexpression was shown not to alter the frequency of chromosome fragmentation when it was induced by drug treatment of mitotic cells, despite the repression of caspase-3 expression and activation detectable in the Bcl-2-overexpressing cells compared with cells expressing an empty neo vector only. Chromosome fragmentation therefore lacks many of the major hallmarks of apoptosis, DNA strand breaks, sensitivity to caspase inhibition, and sensitivity to Bcl-2 overexpression. However, chromosome fragmentation does display double strand breaks as noted by positive -H2AX staining ( FIG. 5B ), which can serve as an early apoptotic sign.
[0114] The present mitotic cell death process differs from previously described mitotic catastrophe. Mitotic catastrophe has been loosely defined as cell death that results from aberrant mitoses. It has been contradictorily suggested to be apoptotic and nonapoptotic, but seems to typically be linked with segregation abnormalities. Not only do the definitions of mitotic catastrophe differ but there is also a lack of morphologic characterization of chromosomes from cells undergoing mitotic catastrophe. It has been strongly suggested that more descriptive terms for mitotic cell deaths be used to avoid the vagueness and confusion of the term “mitotic catastrophe.” Due to the confusion of mitotic catastrophe, and its apparent importance, chromosome fragmentation was assessed in two representative systems of mitotic catastrophe. Cells were induced to undergo mitotic catastrophe according to published reports. Half of the cells were prepared using reported protocols and half were prepared according to standard cytogenetic procedure to score chromosome fragmentation frequency.
[0115] One of the first models of mitotic catastrophe described in human cells is the HCT116 cell line without 14-3-3 function. Cells treated with a low dose of doxorubicin undergo mitotic catastrophe, which was described as a near-steady population of 2N cells, a declining population of 4N cells, and an increase in sub-2N content. Cells were subjected to the same treatment as reported collected and processed by conventional cytogenetic protocols but chromosome fragmentation was not evident although irregularly shaped small nuclei that seem to have condensed chromatin due to their uniform dark staining are quite regular. When cells were stained for phosphorylated H3, only a very small fraction of cells show any positive signal, leading to the conclusion that mitotic catastrophe described in such a system may not truly be mitotic.
[0116] There is no consensus on the exact role of 14-3-3 in mitotic catastrophe. On one hand, 14-3-3 is described as a regulator of the G2 checkpoint that functions with cdc25 to sequester cdc2 in the cytoplasm, whereas other reports suggest that 14-3-3 does not take part in the G2 checkpoint, but rather may serve as an antiapoptotic protein much like survivin. Nevertheless, the mitotic catastrophe shown by the HCT116 14-3-3−/− model is distinct from chromosome fragmentation.
[0117] It is reported that by 72 h of aphidicolin treatment in the HCT116 p53−/− system, more than 20% of cells were mitotic as determined 4N content and positive phospho-H3 staining, whereas 40% of the cells died. A similar number of mitotic figures upon cytogenetic analysis was not observed, although a portion of cells in interphase showed phosphorylation of histone H3 and may represent a portion of the mitotic population described by FACS analysis.
[0118] Mitotic catastrophe is commonly defined as cell death after abnormal or failed segregation. In fact, the mitotic catastrophe generally is not considered a form of cell death, but rather an irreversible trigger of cell death. Further, the Nomenclature Committee on Cell Death realizes the ambiguity of mitotic catastrophe and suggests use of descriptive terms such as “cell death at metaphase” and “cell death preceded by mutinucleation.” Neither model of mitotic catastrophe displays typical chromosome fragmentation in concordant levels to the portion of the cell population dying by mitotic catastrophe. This is likely due to chromosome fragmentation resulting in death directly during mitosis, whereas the majority of cell death due to mitotic catastrophe in the two systems examined takes place after the completion of an abnormal mitosis. Although the mechanistic differences between chromosome fragmentation and mitotic catastrophe are yet to be addressed in depth, importantly they are distinct based on the fact that one is a typical mitotic event and the other does not directly seem to be. Nevertheless, further study is warranted regarding the molecular links between mitotic catastrophe and chromosome fragmentation.
[0119] Linked to genomic instability. Interestingly, it was observed that the frequencies of chromosome fragmentation correlate to levels of genomic instability of a given cell line. Elevated chromosome fragmentation was often detected from cell lines with high level of instability. Such correlation is nicely reflected by the dynamics of a given cell population in that cells are more likely to undergo chromosome fragmentation during the transition from periods of instability to stability. During cancer progression, there are distinct transitional stages of genomic stability as evident by patterns of clonal and nonclonal karyotypic progression. The cell line H1299 v-138 is a line that expresses a temperature-sensitive p53 mutation. This system is genomically unstable at the restrictive temperature (data not shown). Culturing cells at the restrictive temperature results in rapid growth and increased nonclonal chromosome aberrations (NCCA), indicating the presence of an unstable phase. When there is a shift to the permissive temperature, there is a major die off as the cells regain relative genomic stability. As the cells die off, death by chromosome fragmentation is elevated ( FIG. 6 ), indicating that chromosome fragmentation is involved in the elimination of genomically unstable cells. When cells are continuously cultured at the same temperature, there is a dramatically decreased rate of chromosome fragmentation that is highlighted at the permissive temperature when p53 function is restored.
[0120] The transiently increased frequencies of chromosome fragmentation and NCCAs can be achieved by additional drug treatment or even by switching from the restrictive to permissive temperature, demonstrating that genomic instability and the mitotic cell killing are tightly linked possibly by evolutionary selection. When both internal and environmental conditions change (either by dysfunction of p53, or simply by switching the temperature or carcinogen treatment), genomic instability, reflected by increased NCCAs, will lead to cell death reflected by increased chromosome fragmentation frequency, which will in turn reduce the heterogeneity for a given cell population. According to this analysis, the frequency of chromosome fragmentation should be used to monitor the in vivo and in vitro response of chemotherapeutics. The high frequencies of fragmentation often occur after chemotherapy was observed.
[0121] FIG. 6 is a graphical representation that illustrates that the chromosome fragmentation rate is associated with genomic instability. The H1299 v-138 cell line contains a temperature-sensitive p53 mutation with the restrictive temperature being 39° C. and the restrictive temperature being 32° C. H1299 v-138 cells were grown at 39° C. and then shifted to 32° C. During the shift, the cells progressively detached and died over a period of 5 d until few viable cells remained in agreement with previous reports. Upon temperature shift, spontaneous chromosome fragmentation rates increased, then declined, as the number of dying cells and overall genomic instability decreased.
[0122] Paradoxically, the process of fragmentation could also introduce additional heterogeneity. This may occur through the differential elimination of certain chromosomes leading to aneuploidy, a form of NCCA that serves as the driving force of cancer progression. Mitotic figures in which only one or two chromosomes were fragmented ( FIG. 3C ) were frequently observed. These cells are expected to survive but display aneuploidy. In addition, if a cell is undergoing chromosome fragmentation and is not able to complete the process of death, these fragments can be lost and form micronuclei. These can be “stitched” together by various repair complexes, or can result in double minute chromosomes if they are retained and replicated. Thus, incomplete chromosome fragmentation can potentially lead to genomic instability, which, in turn, could lead to genome complexity that drives cancer progression.
[0123] It has herein been shown that during chromosome fragmentation, there is intense −H2AX staining along all chromosomes ( FIG. 5B ). Phosphorylation of H2AX is one of the initial events in the recruitment of repair complexes. If chromosome fragmentation is halted during the process, it is conceivable that repair complexes could be recruited, fragments rejoined, and karyotypically complex chromosomes could be formed. Thus, chromosome fragmentation is a clinically important phenomenon that can result in DNA damage, change in chromosome number, and changes in NCCA levels that increase population diversity. The degree of chromosome fragmentation could also serve as a measurement of induced and spontaneous mitotic death and transient genomic instability. For example, for some patients, chromosome fragmentation has been observed in peripheral lymphocytes even months after chemotherapy is withdrawn. High frequencies of fragmentation have also been observed from the blood of brain tumor patients without any chemotherapy. Obviously, determining the clinical significance of these observations requires more research.
[0124] The question herein raised is what is the clinical significance of chromosome fragmentation? First, all chemotherapeutics tested to this point can generate increased frequencies of chromosome fragmentation. For example, doxorubicin and methotrexate, which exert significantly different effects and cause death by different mechanisms, can induce chromosome fragmentation. This indicates that the initial pathway to trigger the cell death process could be different, but as long as the killing happens in mitotic cells, chromosome fragmentation is a common form of cell death. Second, limited clinical samples were also examined from lymphocyte cultures of cancer patients and chromosomal preparations of primary tumors. Elevated fragmentation is often detected particularly in individuals under chemotherapy (data not shown).
[0125] Although the mechanism of the relationship of chromosome fragmentation with other forms of cell death requires further characterization, the inventors herein propose a model showing the interconnectivity of various forms of cell death ( FIG. 7 ). It is possible that chromosome fragmentation represents progressive degradation of DNA from chromosomes to chromosome fragments to smaller DNA fragments or that it is an initial event that results in the formation of smaller chromosomal fragments that are easier for cells to further digest possibly via apoptotic pathways as the cell dies. An additional possibility is that chromosome fragmentation could represent a form of autophagy, as it has been shown that chromosomes can be enveloped by autophagic vesicles upon intense free radical formation. In fact, for the early fragmented mitotic figures, often one or a few chromosomes were fragmented indicating such a connection. Another challenge is to understand the molecular mechanism of chromosome fragmentation, which molecules are involved in digestion, and how they are activated when the genome is unstable or when the cell is insulted.
[0126] FIG. 7 is a representation of a model that illustrates the relationship between chromosome fragmentation and other types of cell death. Chromosome fragmentation differs from mitotic catastrophe in that cells undergoing chromosome fragmentation commit to death during mitosis, whereas cells dying via mitotic catastrophe die after mitosis.
[0127] FIGS. 8A and 8B illustrate examples of increased levels of NCCAs detected from the late stages of in vitro models coupled with increased tumorigenicity, specifically a karyotype comparison between an early stage (p36) ( FIG. 8A ) and a late stage (p105) ( FIG. 8B ) of the LNCaP cell line. In addition to sharing all four types of CCAs as indicated by the blue colored boxes, there are more NCCAs detected as indicated by the yellow boxes coupled with increased tumorigenicity.
[0128] Increasing level of NCCAs combined with progressing cell passages clearly correlates with increased tumorigenicity. The fact that C33, which exhibits delayed tumor formation also has a relatively high degree of NCCAs (30%), further supporting the notion that increased levels of NCCAs promote tumorigenicity. From an evolutionary viewpoint, the higher the frequency of NCCAs increases the probability of cancer progression in shorter periods of time. Tumorigenicity, can be achieved with lower frequencies of NCCAs but requires longer time frames for the selection process to occur.
The MCF10DCIS.com Model
[0129] MCF10DCIS.com xenograft is a model of human comedo ductal carcinoma in situ. This cell line was cloned from a cell culture initiated from a xenograft lesion obtained after two successive trocar passages of a lesion formed by premalignant MCF10AT cells. Early passage cells display a less invasive capability while the late-passage cells have a more extensive invasive capability. Various passages of this cell line were SKY analyzed to identify karyotype patterns as shown in Table 1.
[0130] The majority of the altered chromosomes were shared among the three passages examined. With passage progression, dynamic NCCAs and CCAs were evident with some CCAs being replaced by others. At passage pd46, in addition to increased NCCAs, even the retained CCAs were not evenly distributed throughout the population indicating a high degree of heterogeneity as the degree of homogeneity drops. At passage pd46, der(15)t(15;21) were newly formed and high levels of NCCAs observed, thus linking these changes to increasingly invasive phenotypes. The mechanism of highly aggressive phenotypes was recently linked to stromal-epithelial interaction.
The MCF10 Model Transformed by Cigarette Smoke Condensate (CSC)
[0131] To exclude the possibility that a specific CCA such as der(15)t(15;21) play a major role in the increased tumorigenicity observed in the MCF10DCIS model, it would be ideal to use cell populations that display different degrees of tumorigenicity and yet share the same marker chromosomes (identical CCAs). Four transformed lines have been generated by treatment with CSC, independent of the MCF10DCIS.com model. Even though all four lines displayed anchorage-independent growth in soft-agar, there was only one line that generated tumors in immunodeficient mice (see tumorigenicity session). Comparison of the karyotypic features of these four transformed lines showed they share six altered chromosomes in common ( FIG. 9 ). Three of the alterations are shared in common with MCF10DCIS indicating the same origin for these two differently transformed systems (Table 1).
[0132] FIGS. 9A and 9B illustrate example of increased levels of NCCAs detected from the late stages of in vitro models coupled with increased tumorigenicity, including the comparison between subline MCF10A-CSC-1 ( FIG. 9A ) and CSC-3 ( FIG. 9B ). Both lines share five common types of CCAs as indicated by boxes 910 . In line CSC-3 with increased tumorigenicity, in addition to ploidy changes, there were many NCCAs detected as indicated by boxes 920 .
[0133] Although the four lines displayed the same sets of altered CCAs, NCCAs occurred at different levels in these lines. Various types of structural and numerical NCCAs are listed in Table 2. As illustrated by the tumorigenic assay of immunodeficient mouse xenografs, only CSC-MCF 10A3 produced tumors in immunodeficient mice. In addition to elevated levels of NCCAs, the average chromosome number was also increased in CSC-MCF10A3. Therefore, in this system, increased ploidy and the frequency of NCCAs were linked to tumorigenicity.
The MCF10 Model Transformed by HOXA1
[0134] To exclude the possibility that ploidy rather than a high degree of diversity contribute to the tumorigenicity that is observed with CSC-MCF10A3, an additional subline was selected with identical karyotypes (and ploidy status) but these lines displayed a diversity of NCCAs. This subline was obtained by spontaneously transforming MCF10 cells by over-expression of HOXA1. Human growth hormone-regulated HOXA1 has been shown to be a mammary epithelial oncogene. HOXA1 stimulates the transcriptional activation of a number of pro-oncogenic molecules including cyclin D1 and Bcl-2 that promotes proliferation and survival. Over-expressed HOXA 1 in human mammary carcinoma cells results in drastically increased tumorigenicity.
[0135] The degree of genome diversity of the cell line over-expressing HOXA1 (stable transfected with HoxA1 expression plasmid) and the control cell line containing vector only (Table 1) were compared. Both the HOXA1 line and the control line shared identical marker chromosomes and the karyotypes were identical ( FIG. 10 ). The major difference was the frequency of defective mitotic figures (DMFs), a new phenotype of chromosome condensation defects and G2-M checkpoint deficiencies. In addition, the frequency of errors in cell division that are related to DMFs was higher in the HOXA1 line ( FIG. 10 ). DMFs represent an ignored karyotypic aberration. The key description of a DMF is its differential condensation among all chromosomes and its genetic consequences causing an increase in population diversity and possibly leading to typical chromosomal aberrations such as aneuploidy, deletion, or translocations. As DMFs are a typical form of NCCA, the high frequencies of DMFs observed from the HOXA1 line indicates a high degree of genome diversity. Thus both the involvement of the HOXA1 oncogene and elevated NCCAs were co-linked to tumorigenicity.
[0136] FIGS. 10A , 10 B, and 10 C illustrate examples of increased levels ofNCCAs detected from the late stages of in vitro models coupled with increased tumorigenicity. This figure shows the comparison between the HOXA1 expressed line and the control line generated from MCF10. Both lines displayed the same karyotypes with two identical CCAs indicated by the boxes 1010 in FIG. 10A . Interestingly, however, the HOXA1 line also displays a much higher level of abnormal mitotic figures (chromosomes are not well condensed), by a arrow 1020 or separated (indicated by arrows 1025 in FIG. 10B . These defective mitotic figures are types of NCCAs.
[0137] FIGS. 11A-11F illustrate the distribution of structural and numerical NCCAs. In FIG. 11A , the distribution of NCCAs across the five cell lines of five in vitro models with the highest tumorigenicity and the five cell lines with the lowest. The bars indicate 95% confidence intervals. The difference between high and low tumorigenicity is significant (P=0.01791, Student's t-test), illustrating the significant relationship between frequencies of NCCAs and tumorigenicity. In FIGS. 11B to 11F , the distribution of chromosome number across the five systems analyzed. The graphs represent average chromosome number, bars indicate 95% confidence intervals. A change in the chromosome number does not associate with increased tumorigenicity in most lines except MCF10-CSC, possibly due to the ploidy. Passages/cell lines with higher tumorigenicity, however, tend to show increased confidence interval widths indicating more variance in chromosome number.
Mouse Ovarian Cancer Model
[0138] Mouse syngeneic ovarian cancer models have been established and have proven to be very useful in the study of temporal molecular and cellular events during neoplastic progression. Primary mouse ovarian surface epithelial cells were isolated and cultured for varying generations. It is known that tumorigenicity (tested in nude mice) rises with increasing passage number. Three representative stages of a parallel experiment were selected for karyotype analysis representing pd9, pd45, and pd91 (Table 1).
[0139] Even at an early stage (passage 9), the karyotypes were clearly no longer normal as the population of cells contained 10% NCCAs and a CCA [der(10; 10)]. This initial CCA was replaced by two new CCAs der(1)t(1; 2), der(8)t(8; 16). Only der(1)t(1; 2) was detected during the later stages, illustrating karyotypic dynamics during in vitro culture. Again, the most prominent feature linking the cell progression stages was the percentage of NCCAs. During early passages NCCAs were detected in only 10% of all cells analyzed. By passage 91, however, NCCAs were detected in almost all cells, even though these cells also contained a four CCAs. Thus, the elevated NCCAs and two clonal aberrations were linked to tumorigenicity. In a parallel experiment, the tumorigenicity of an independent cell culture series was linked to increased numerical NCCAs (aneuploidy) and no recurrent CCAs were detected and distinct remodeling of the actin cytoskeleton and focal adhesion complexes were coupled with down-regulation and/or aberrant subcellular location of E-cadherin and connexin-43.
Tumorigenicity Analysis
[0140] To establish a strong relationship between the level of NCCAs and tumorigenicity, cells with different levels of NCCAs were injected into mice and then comparatively analyzed for tumorigenicity. In most of these models, the tumorigenicity of various stages of the cell populations was previously tested using this assay and the data are readily available. To reduce variation in our analysis, the original frozen cell passages used in the tumorigenicity studies were used in our SKY analysis. Since the relative levels of NCCAs detected should be similar among these cells including those used to test tumorigenicity, the detected occurrence of increased NCCA frequencies should take place prior to injection into animals. As illustrated in FIG. 11 and Table 1, in each model, the highest tumorigenicity was always associated with the highest frequencies of structural NCCAs. Interestingly, in the LNCaP prostate cancer model, compared to early passage cells, the late stage cells with androgen-unresponsiveness, produced tumors two times faster, while the frequencies of NCCAs nearly doubled between early and late stage cells.
[0141] The tumorigenicity of the MCF10A-CSC model was then examined. The control MCF10A cells as well as three of the CSC-transformed cells lines (MCF10A-CSC1, CSC-2, and CSC-4) did not form tumors in the nude mice within 20 days, even though all CSC lines exhibit anchorage-independent growth. Only the MCF10A-CSC3 cell line grew and formed palpable tumors in the nude mice within 20 days. Thus, tumorigenicity is linked to the highest level of genome diversity. In conclusion, for all five models, the highest levels of genome diversity were linked to tumorigenicity.
[0000] Formulation of a Model that Illustrates the Relationship Between Evolutionary Concept and Molecular Mechanisms
[0142] Summarizing of all models that have been analyzed, it is clear that in each case examined (a given experimental model based on a selected cell line, individual animal lesion), a specific or combination of specific molecular pathways can be illustrated and thus linked by molecular analysis. However, there is no common molecular basis or mechanism leading to cancer evolution in general, since no specific form of genomic aberration is universally shared among diverse cancer cases. This is also true at the sequence level, as a recent large scale sequencing project indicated that there are many different genetic combinations or hills at the gene level in the context of the evolutionary adaptive landscape. If we abstract from these seemingly specific and unrelated causes, including a number of known molecular pathways, elevated DMFs, increased ploidy, simple or complex chromosomal translocations, and large scale stochastic changes at the gene level and epigenetic level, the picture of a common mechanism will emerge. That mechanism is karyotypic heterogeneity rather than a specific molecular pathway.
[0143] The present evolutionary explanation of why there is a correlation between elevated NCCAs, genome diversity and tumorigenicity is illustrated in the model shown in FIG. 12 . This figure illustrates the evolutionary mechanism of cancer and its relationship with molecular mechanisms. The evolutionary mechanism of cancer formation is summarized as three key components: 1, system instability; 2, increased system dynamics or population heterogeneity (reflected as an increased probability of a hit of a specific pathway or potential pathways); and 3, natural selection at the somatic cell level. There are many different molecular pathways that can trigger system instability, and it is the unstable system that activates different molecular pathways as the response to system instability. The somatic selection process stochastically favors different packages of genome alterations. The lower left box represents a normal stable state that typically generates infrequent NCCAs and when they do occur will likely go extinct.
[0144] With increased instability, much higher levels of NCCAs occur representing an increasing number of potential genome systems coupled with specific molecular pathways. Each array represents a given molecular pathway, or the so called molecular mechanism. The increased number of pathways (represented by various colored arrows) increases the probability that evolution will proceed at a faster rate progressing much further in selected cell populations with some eventually achieving cancer status (the evolutionary mechanism).
[0145] Based on the concept of cancer evolution and the realization that cancer is a disease of probability, one can understand why elevated genome diversity will lead to the success of cancer evolution regardless of which molecular pathways or mechanisms are involved. This diagram links various molecular mechanisms with the evolutionary mechanism of cancer. It not only can explain the knowledge gaps between basic experiments and clinical findings (in experimental systems, many cancer genes can effectively cause a cancer phenotype, yet, these gene mutations only account for a small portion of the clinical cancer cases), but also focuses attention on the evolutionary mechanism rather than molecular mechanisms. There are large numbers of different molecular mechanisms that for all practical purposes cannot be predicted, in contrast, it would be much more useful to predict the increasing probability of cancer using the evolutionary mechanism. Such relationship between evolutionary mechanism and molecular mechanisms of cancer can simply be stated as follows:
[0000] Evolutionary Mechanism=ΣIndividual Molecular Mechanisms
[0146] This formula offers insight into the relationship between system instability, karyotypic heterogeneity, individual molecular mechanisms and tumorigenicity.
[0147] As illustrated by our model ( FIG. 12 ), the linkage between the elevated degree of NCCAs and tumorigenicity explains the mechanism of cancer in simple evolutionary terms. A stable cell population, with lower degrees of change, translates into a lower probability of cancer formation. Increased system instability, in contrast, results in an increased probability of cancer formation. Our experimental data illustrate the evolutionary mechanism of cancer formation and that system instability is the key causative factor. As we pointed out previously, many genetic, metabolic and environmental elements can contribute to genome system instability, including system dynamics.
[0148] When unstable, the genome system offers a higher probability of change or diversity, reflected as variable karyotypes that offer a greater number of different molecular pathways, which are the material for evolutionary selection as well as a precondition to establish new genome systems.
[0149] The seven examples described above involved both human and mouse cells of different cancer types and the malignant phenotypes have been linked to specific but different precipitating events. These events range from increased microsatellite instability and allelic loss, to chromosome ploidy, different chromosomal translocations and numerical aberrations, to HOXA1 gene and c-Myc expression, and to down-regulation of E-cadherin, as well as centrosome amplification caused by Rad6 and stromal-epithelial interaction (Table 3). For each characterized system, the linkage between a specific pathway or genetic event has been described as a given molecular mechanism. When considering all systems together, however, none of these events can be used to explain all cases. Significantly, the only common link to tumorigenicity is increased levels of NCCAs! Clearly, our correlative observation between increased levels of NCCAs and tumorigenicity supports the causal relationship between system instability reflected by elevated NCCA levels and tumorigenicity. Thus, such a correlation offers an evolutionary mechanism for cancer formation by generating cellular diversity.
[0000]
TABLE 3
Various molecular mechanisms are linked to the increase in NCCAs,
the common feature of the evolutionary mechanism of cancer
Previous findings (molecular
mechanisms: features or
Current common
Cell model
identified pathways
findings
LNCaP
Increased microsatellite instability;
Increased frequencies
gradually lost androgen response;
of NCCAs; increased
Increased tumorigenicity
genome diversity
MCF10DCIS.com
Stromal-epithelial interaction;
Increased frequencies
increasingly invasive phenotypes
of NCCAs; increased
genome diversity
MCF10-CSC
Increased ration of BCL-xL/Bax;
Increased frequencies
increased expression of PCNA,
of NCCAs ploidy;
gadd45; increased tumorigenicity
increased
tumorigenicity in vivo
MCF10-HoxA1
Activation of cdD1 and Bcl-2;
Increased frequencies
increased tumorigenicity
of MDFs; increased
genome diversity
Mouse Ovarian
Change: cytoskeleton and focal
Increased frequencies
adhesion complex, down:
of NCCAs; increased
E-cadherin and connexin-43,
genome diversity
increased tumorigenicity
MCF10-Rad6
Centrosome amplification,
Low level of structural
aneuploidy and transformation;
NCCAs; aneuploidy
benign hyperplastic lesions
Myc-transgenic
Expression of A2 and E2F1;
Increased frequencies
mice
increased tumorigenicity
of NCCAs
[0150] It should be pointed out that the context of the term “mechanism” is very different among academic fields. In molecular biology, for example, mechanism typically refers to a change in a molecule that results in a specific phenotype or other molecular events. The evolutionary meaning of mechanism refers to the generation of cellular heterogeneity, which is the instrument or means of natural selection through population diversity. The evolutionary mechanism is therefore much broader than the molecular mechanism and can be achieved by many different molecular mechanisms or other mechanisms under specific circumstances. For example, different types of stress can trigger system instability. In molecular terms, the stress can be classified into specific molecular actions such as ER stress, metabolic stress, stress resulting from ineffective DNA repair, over-expression of certain oncogenes, etc.
[0151] Irrespective of the type of molecular stress, the system response is not stress specific but displays a common response increasing the level of system dynamics, confirmed by the elevation of NCCAs. Despite the common response of elevated NCCAs, a specific NCCA (or number of NCCAs) will be selected, however the associated molecular pathways will be more or less unpredictable and will continuously change. Each molecular mechanism that generates stress and the response to stress can contribute to or is even equal to the evolutionary mechanism of each specific case. However, the general evolutionary mechanism cannot be sufficiently explained or predicted by individual molecular mechanisms as there is no shared molecular mechanism in all cancer cases. Similarly, the term causative relationship has a different meaning when considering the difference between a single molecular pathway and a complex system.
[0152] In the molecular sense, the causative relationship is defined within an isolated network where molecule A or event A (called cause) leads to B (called effect). In a complex system, however, cause and effect relationships might not be so narrowly defined nor maintain the same meaning as illustrated by experiments. An experimentally defined relationship setup between two parties can be easily changed when additional interactions are included. In fact, complicated interactions are always present in natural settings but are ignored in experimental analyses.
[0153] To analyze complex systems, correlation studies are thus fundamentally important as causative studies among lower level parts of a system in an isolated setting may not be as reliable in the context of a complex system. In contrast, to study the mechanism of cancer evolution (and not individual molecular mechanisms), a general correlative relationship where system instability results in population diversity, and the population diversity provides the necessary pre-condition for cancer evolution to proceed, in fact illustrates the causative relationship between system dynamics and cancer.
[0154] It is likely that many different pathways are stochastically involved and selected when there is elevated instability and genetic diversity, based on the stochastic nature of karyotypic aberrations and the mechanism of cancer evolution. For example, some NCCAs may activate dominant oncogene defined pathways, while others may have various combinations of minor changes that eventually result in the final phenotypes of uncontrolled growth. The link between NCCAs and tumorigenicity in the majority of cancers supports our model.
[0155] The concept herein disclosed predicts that the result of genomic instability (inherited or induced) is the generation of population diversity (evident though clonal diversity or non-clonal diversity or the combination of both) which drives the cancer evolutionary process. Interestingly, the cases we analyzed here represent the tip of the iceberg, as the often hidden link between population diversity and tumorigenicity can be easily found in cancer literature. Although most of these reports focus on specific molecular pathways, including specific oncogenes, tumor suppressor genes, epigenetic regulation, or genes responsible for tissue architecture, most of these aberrations can be linked to overall genome instability resulting in population diversity. This fits well with the genome-centric concept of cancer.
Advantages of Using NCCAs/CCAs to Monitor the Cancer Evolutionary Process
[0156] Initially demonstrated in the in vitro immortalization model, the high level of NCCAs and dynamic interaction between NCCAs and CCAs plays an important role in cellular immortalization. The current study further provides solid evidence that elevated NCCAs are directly linked to tumorigenicity.
[0157] Most recent studies have focused on tracing specific gene mutations or methylation patterns due to the available technologies. However, there are some serious limitations regarding the strategies of gene based evolutionary analysis. First, the current technologies used in genetic analyses are based on a mixture of cell populations that only artificially profiles the most dominant clonal population and ignores the importance of heterogeneity. Second, as illustrated in previous publications, most solid cancers involve progression with high levels of stochastic change, where it is difficult to trace the genetic changes, and only during slow phases (prior to the blastic phase in CML, for example) of limited blood based cancers or solid tumors are some genetic changes traceable.
[0158] Even in blood cancers, it is almost impossible to trace genetic changes in late stages. In addition, according to the theory of orderly heterogeneity and system complexity, it might be more meaningful to trace the higher levels of genetic organization (genome) than the lower gene levels. More importantly, in somatic evolution, macro-evolution is the main mechanism and replacement of various genomes is the driving force of somatic cell evolution. When the genome context changes, even when the gene state is the same, it often does not keep the same biological meaning. For example, in different human pancreatic cancer cell lines, the K-ras gene mutation was linked to very different pathways, possibly due to the different context of genomes. Interestingly, NCCAs and epigenetic programming responding to stimulation of the Ras-MAPK pathway may be a better marker for cancer progression than the upstream mutated oncogenes. Therefore, by focusing on genome diversity, the overall evolutionary potential can be measured based on the karyotypic heterogeneity. Indeed, monitoring the karyotypic level is more effective than monitoring the gene level, as focusing on karyotypic heterogeneity is in fact studying the evolutionary mechanism while focusing on individual genes is studying a single specific molecular mechanism. Thus, the present study offers a new direction that uses the degree of karyotypic heterogeneity to effectively monitor tumorigenicity.
[0159] One issue that needs further analysis is the contribution of specific CCAs in combination with elevated NCCAs. Traditionally, attention has focused on CCAs as only clonal expansion was thought to be important for the accumulation of additional gene mutations. Genome dynamics drive cancer evolution, therefore it would be interesting to study how key CCAs play a role in increasing the population diversity rather than just providing proliferation. In agreement with our previous findings, the current studies favor NCCAs rather than specific CCAs in monitoring genome system variance. However, it is still possible that for specific cases certain CCAs can contribute more to cancer evolution than others. For example, the mutation of p53, which can have many different functions, could be an example of a CCA that increases evolutionary dynamics, in addition to other functions.
[0160] It is thus possible that some powerful CCAs when combined with a certain level of NCCAs, would be most effective in terms of cancer evolution. In fact, consistent with previous publications, we have observed that increased frequencies of complex CCAs (involving multiple translocations within one chromosome) are most frequently detected during the late stage of immortalization and during the formation of drug resistance.
[0161] It should be pointed out that, using a system approach to monitor NCCA/CCA dynamics is not contradictory to studying the function of various cancer genes, similar to not seeing the forest for the trees, these two approaches focus on two levels of genetic organization, and try to address different mechanisms (evolutionary and molecular) of cancer formation. Following decades of effort attempting to understand each molecular mechanism (including oncogenes, tumor suppressor genes, DNA repair genes, genes regulating transcription/RNA splicing/translation/protein modification and protein degradation, genes controlling cell cycle, cell death, cell proliferation and differentiation, cell communication as well as aneuploidy, micro-environments, and immuno-system responses), it seems that the complexity of cancer is too high and that just tracing individual pathways will not lead to understanding the nature of cancer due to the highly dynamic (stochastic and less predictable) features of this disease. There is a need to focus on the system's behavior and its patterns of evolution rather than focusing principally on individual pathways alone. Studying the dynamics of NCCAs/CCAs is just one such example of this approach.
Some Technical Clarifications of Using NCCAs
[0162] The terminology non-clonal aberration is commonly used in the field of cancer cytogenetics. There seems to be no disagreement on the use of this term, but there is a distinct disagreement on their biological significance. The general rule in tumor cytogenetics has been that only clonal chromosomal abnormalities found in tumors were considered significant and should be reported.
[0163] A clone is defined as a cell population derived from a single progenitor. It is common practice to infer a clonal origin when a number of cells have the same or closely related abnormal chromosome complements. In practice, there are two meanings when the clonal aberration is used in cancer cytogenetic. First, it means that they are derived from a common ancestor within a defined time frame; and it also means that they are karyotypically identical or similar to each other. This latter meaning is of importance to cancer research, as technically speaking, all different cancer cells as well as normal cells of one individual must come from a single progenitor cell of a fertilized egg. However, different tumor cells and normal cells of one individual are not considered clones when they display drastically different genetic profiles (only when they share the same marker of abnormal chromosomes). The term “non-clonal” here is used to distinguish the clonal karyotypes rather than refer to cells not derived from a common ancestor.
[0164] Another note of caution is that whether or not an aberration is clonal depends on the time frame of examination and the level at which the study takes place (karyotypic vs. gene). Within a given period, the clonal aberrations can further evolve making it hard to realize that they are derived from a common ancestor. In addition, the concept of clonality can be applied to different levels of genetic organization. Cell populations with the same p53−/− mutation can be referred to as clonal at a specific locus, but they might be considered non-clonal at the karyotypic level.
[0165] To establish a precise scoring system to monitor the level of genome instability is challenging, as there are many different types of genome level alterations. By comparing the type and distribution of aberration frequencies for these model lines, it appears that the proportion of structural NCCAs represents the best biomarker. When NCCAs are used to score the level of heterogeneity, the total frequency of structural and numerical NCCAs should all be included. The structural NCCAs seem to play a more dominant role than numerical NCCAs, at least for the late stage of cancer progression (after transformation) that has been examined in this study. Chromosomal number variation plays an important role prior to the formation of structural NCCAs during the immortalization process of the mouse ovarian model.
[0166] The 4% cutoff of clonal/non-clonal is based on the standard of practice in medical genetics. It would be ideal if more than 100 mitotic figures could be included in the analysis and thereby use 1% as the cutoff line, but this is very time consuming and costly. In fact, a 4% cutoff is also reasonable as illustrated by studies conducted by the inventors herein with large numbers of cell lines and clinical samples.
[0167] For example, when studying the level of genome variations during the in vitro immortalization process, two additional cutoff lines were used (1% and 10%), the overall patterns of punctuated and stepwise phases of karyotypic evolution were the same as the 4% cutoff line (when the genome is unstable, the level of NCCAs often reaches over 20-50%). In the present immortalization model, when the cell population reached the unstable phase, NCCA levels were 100%, regardless of which cut off line was used to separate CCAs and NCCAs. In normal lymphocytes (based on both human and mouse data), the level of structural NCCAs is very low, in the range of 0.1-2%. For the purpose of establishing a baseline of structural and numerical NCCAs in normal individuals, over 100 mitotic figures are often scored. Interestingly, as illustrated by a current study, the differential frequency of NCCAs is more important than the absolute level of NCCAs as for each system tested, there seems to be a baseline of instability. No matter which cutoff line is used; the elevated NCCAs can easily be scored.
[0168] A key point here is the use of NCCAs rather than a given CCA to measure the overall system status and determine how stable a genome system is within a population. The population behavior or stability can be monitored by the degree of population diversity. It is believed that a new direction in cancer research will focus on controlling the process of system evolution, rather than focusing on specific drug targets, as there is no fixed target and just focusing on specific targets does not solve the issue of drug resistance in a dynamic evolving system. During the evolutionary selection process, any given pathway or specific target could become insignificant. Therefore, the apparent disadvantage of monitoring NCCAs in fact is an advantage in terms of monitoring the system status and its usefulness for system control.
[0169] One additional point needs to be clarified, the NCCA/CCA cycles reference herein could be described as clonal expansion and heterogeneity. The waves of dominant NCCAs or specific CCAs reflect the overall status of the stability of a population and the pattern of evolutionary dynamics. In contrast, using clonal expansion and genetic diversity to describe these two phases of population dynamics is not accurate. For example, during the clonal expansion phase, there is clearly genetic diversity. While, during the genetically diverse phase, all the new clones are still generated by clonal expansion. One of the key findings of our karyotypic evolutionary study is that there are two typical types of clonal expansion illustrated by the immortalization model: clonal expansion with a lower level of system instability where expanded clonals share the majority of karyotypic characteristics of the parental cells; and clonal expansion with high levels of system instability where expanded clonals share few or no key karyotypic characteristics.
[0170] Interestingly, by just using a molecular profile such as tracing specific loci using a mixed cell population, drastically different evolutionary phases would not be appreciated. The partial reason that previous cytogenetic studies found the term clonal expansion and genetic diversity accurate is that the contribution of high levels ofNCCAs were disregarded, resulting in easily identified marker chromosomes. From a molecular standpoint, it is easier to use the term clonal expansion in the molecular sense to study specific loci. When a specific locus is not an expansion, it can be called genetic diversity. However, if large numbers of loci were simultaneously monitored, it would be challenging to define the phase of clonal expansion. This is the exact situation when one studies karyotypic evolution based on a single cell within a dynamic cell population. In conclusion, it is useful to describe the change in frequency of the NCCAs or the amount of genetic diversity and also the phenomena of clonal expansion indicated by the types and frequency of CCAs.
Potential Clinical Implications
[0171] With an emphasis on the overall instability of the genome generating clonal diversity of cell populations as a major cause of cancer, this study favors a new approach to cancer research by focusing on the mechanism of cancer evolution rather than focusing on a specific molecular mechanism such as gene mutations or pathway. For the majority of cancer cases that involve multiple cycles of NCCA/CCA interaction, one specific pathway will likely not be successful. Thus more potential available pathways represented by high levels of NCCAs are necessary to develop a successful combination. It is likely that certain CCAs coupled with relatively powerful pathways can speed up the process of cancer evolution by drastically destabilizing the genome or by producing a high level of cell proliferation (such as specific powerful fusion gene mediated tumorigenesis). To complete the entire process of cancer formation, however, an overall high level of diversity is the key. Coupled with elevated levels of population diversity, there could be many pathways or great numbers of combinations of pathways that could lead to cancer through multiple steps.
[0172] The combination of dominant pathways and high level genome dynamics create the most favorable conditions for cancer evolution. Therefore, reduction of factors leading to genome instability and reducing cell population diversity should become new areas of focus for clinical research. For example, the key to cancer prevention and treatment is stabilization of the genome system. When genomes are unstable, blocking one particular aberrant pathway will likely not be successful, as new pathways will eventually emerge.
[0173] It is true that stochastic gene mutations also contribute to population diversity and can be traced in evolutionary studies. Similarly, epigenetic dynamics, as well as copy number variation all contribute to genome level alterations. It is very important to incorporate the degree of diversity at various levels. Our hypothesis that using the frequencies of NCCAs might be inclusive of most of the other types of genetic and epigenetic dynamics seems to be correct and needs to be explored further, as the vast majority of other levels of genetic alterations will lead to karyotypic changes if system evolution occurs. Based on our viewpoint that the karyotype defines a genome system (both the overall expression pattern and the identity of a species), and that cancer evolution is driven by karyotypic mediated macro-evolution, it is anticipated that most cancer cases will have variable karyotypes. In fact, for many cases of leukemia, the seemingly normal karyotypes are only detected during the relatively stable phase of cancer progression. In the blastic phase, for example, karyotypic dynamics are overwhelming. Based on this consideration, this might be an advantage of using the highest level of genetic organization (the genome) to monitor genome system instability and evolution.
[0174] It is noteworthy that increased karyotypic diversity associated with various stages of cancer progression has been previously noted by others. The high level of karyotypic heterogeneity of NIH 3T3 cells has been linked to population diversity and transformation. The literature has also provided ample evidence to support this viewpoint, though the evidence has been largely ignored. For example, many genes or pathways that are linked to genomic instability in fact generate increased karyotypic diversity.
[0175] Interestingly, the link between population diversity and tumorigenicity reconciles the gap between certain experimental findings and clinical data when considering how these powerful oncogenes contribute to cancer. Under experimental conditions, most oncogenes are capable of inducing tumors, as the conditions have been created that increase the probability of cancer progression by using strong promoters and artificial selection. In real clinical cases, these well characterized oncogenes have limited involvement. The combination of strong oncogenes and tumor suppressor genes can significantly increase the probability of cancer progression under experimental conditions further demonstrating the importance of diversity as over or under expression of many oncogenes and tumor suppressor genes are directly or indirectly caused by genome instability.
[0176] Lastly, the present approach to monitoring genome diversity constitutes a valuable concept to develop assays for clinical use. It is known that the lesions in Barrett's esophagus exhibit the unique feature of stasis that allows the establishment of a correlation between stages associated with some key genes (one of the possible reasons is that the pre-cancer phase could be relatively more stable where there are more opportunities for clonal expansion). However, in contrast to Barrett's esophagus, most fast growing tumors exhibit high levels of diversity and dynamic karyotypic evolution, which is more typical of most progressive genomically unstable tumors. Monitoring of the levels of non-recurrent genomic aberrations in these latter types of tumors rather than using the degree of clonal aberrations is a more accurate level of genomic instability and is a practical method of accessing the likelihood of cancer progression. In addition to the potential benefit of using the level of NCCAs to monitor cancer progression and to provide needed tools for early diagnosis, this concept will help us to refocus on overall genomic instability and the generation of population diversity, rather than continue to focus entirely on specific pathways alone.
Conclusion
[0177] Chromosome fragmentation is a clinically relevant mode of mitotic cell death that results in the progressive degradation of chromosomes during mitosis. Chromosome fragmentation is apparently not apoptotic and differs from models of mitotic catastrophe. Interestingly, chromosome fragmentation is intimately linked with genomic instability, serving to remove cells that display an altered genomic system stability, which is commonly seen in cancer progression. Furthermore, as it represents one form of NCCA, chromosome fragmentation could lead to increased genome stability if the process is compromised, which could lead to the increased genome complexity noted in cancer. Although questions still exist about the mechanisms of chromosome fragmentation, this form of cell death needs to be monitored especially in cancer where genome stability plays such a key role in disease progression. In closing, as chromosome fragmentation is a new form of mitotic cell death that is of great importance to cancer treatment.
[0178] Although the invention has been described in terms of specific embodiments and applications, persons skilled in the art may, in light of this teaching, generate additional embodiments without exceeding the scope or departing from the spirit of the claimed invention. Accordingly, it is to be understood that the drawing and description in this disclosure are proffered to facilitate comprehension of the invention, and should not be construed to limit the scope thereof
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A diagnostic method of determining tumorigenicity of a tissue specimen includes the steps of determining a magnitude of genome diversity in the tissue specimen, and diagnosing a likelihood of cancer in response to said step of determining the magnitude of genome diversity. The magnitude of genome diversity includes the determination of karyotypic heterogeneity in the tissue specimen, illustratively by detecting non-clonal chromosome aberrations (NCCAs). The detection of NCCAs includes the detection the frequency of NCCAs, and the diagnosis is responsive to the step of detecting the frequency of NCCAs. Detection of NCCAs advantageously includes the further step of screening lymphocytes. Also, the step of determining the presence of elevated genome diversity includes the step of applying Spectral Karyotyping to detect translocations throughout the genome. The diagnostic method is useful to determine drug resistance of a patient.
| 2 |
TECHNICAL FIELD
The present invention relates to a method and an apparatus for optimizing the die drafts in a series of die drafting operations in performing a wire die draft reduction of elongated rod or wire stock. More particularly, the invention is directed to a computer-based expert system for selecting a preferred die draft schedule, including permissible slip values, for a rod or wire die drafting manufacturing operation.
BACKGROUND OF THE INVENTION
Selection of appropriately sized dies in a die drafting operation has heretofore involved choosing ever smaller die apertures based on the experience or set of experiences of an operator, which are often reduced to a chart or series of approximation calculations.
Most die draft selection techniques rely on standard area reductions between each die to calculate the die draft. This method works well when the selected sizes are based on standard reductions, such as Brown and Sharp size reductions. It may not work well for odd sizes or unusual rod materials. Problems can also arise when drawing non-standard materials or special alloys.
One known method of selecting the various dies is described in "Wire Drawing Practice: Die Drafting," by Bobby C. Gentry, published in Wire Journal, August 1975. This calculation-based approximation technique is based on many years of practice and experience. Since each successive die size calculation relies on previous die size calculations, each calculation must be carefully verified to eliminate errors in the die draft schedule.
A chart or table is prepared from calculations incorporating a fixed ten percent slip rate between the capstan surface velocity ("capstan velocity") and the wire linear velocity ("wire velocity"). An optimal die draft schedule may require repeated adjustment of calculated values. A tenth-gauge reduction table is usually generated, from which the dies are selected. This time-consuming effort is imprecise and expensive, as it may, if erroneous, result in wire breaks which require restringing the rod, and is inherently consumptive of the engineer's valuable time.
As can be readily appreciated, the analysis of hundreds of wire drafting parameters in producing an efficient and effective wire drafting schedule for various rod and wire sizes on a given wire-drafting machine can be an extraordinarily time-consuming task because of the numerous combinations and permutations of the relevant parameters, and may require repeated adjustments, even if slight in magnitude, in order to provide effective and efficient operation of the wire drawing machine or machines.
In view of the foregoing limitations and shortcomings of the prior art methods and apparatus, as well as other disadvantages not specifically mentioned above, it should be apparent that there exists a need in the art to eliminate imprecision and time-consuming trial-and-error methods of die selection. It is, therefore, a primary object of this invention to fulfill that need by providing a computer-based system of selecting dies for a given rod/wire size requirement.
An advantage of the present invention resides in the fact that the intellectual expertise of the skilled engineer and operator are combined in a computer-based application wherein little skill in generating the die draft schedule is required for reliable and economic operation.
SUMMARY OF THE INVENTION
Briefly described, the aforementioned objects are accomplished according to the invention by providing a computer-based expert system with a plurality of databases including available die sizes, drawing machine parameters including capstan velocity (i.e., capstan surface velocity) and number of blocks, standard rod sizes and desired wire sizes.
The method of selecting the dies intervening between the rod input and wire output involves the steps of determining the rod input and wire output sizes; inputting the beginning and ending slip percentages which may involve estimations of these data values; determining the slip increment and dividing by the number of dies less one, where the slip increment is determined by deducting from the beginning slip value the ending slip value and dividing by the number of dies less one; multiplying the capstan velocity by the slip (expressed as a decimal value) to determine the wire velocity; calculating each wire size by the wire velocity; comparing the calculated wire size and the desired wire size; recalculating the calculated and desired wire sizes and outputting the resultant values to the slip increment determining step until the calculated and desired sizes are equal; and listing the wire size, percentage slip, and area reduction according to each of the blocks in the die draft schedule.
The expert system apparatus includes a computer including a memory unit, a control unit, an arithmetic logic unit, and an input/output unit; a program instruction set; a data storage unit including stored data in a plurality of databases; a keyboard or the like for entering data relating to input material size and output wire size, starting and ending slip and a slip increment; at least one controlled communications pathway for exchanging data between said computer and said data storage unit; and a device for outputting said optimized die draft schedule in human cognizable form; the program instruction set being adapted for iterative calculation of a plurality of slip increments according to the formula:
slip increment=(slip start-slip finish)/number of dies-one
and iterative calculation of a plurality of die sizes from the formula:
wire velocity=capstan velocity×slip.
DESCRIPTION OF THE DRAWINGS
With the foregoing and other objects, advantages, and features of the invention which will become hereinafter apparent, the nature of the invention may be more clearly understood by reference to the following detailed description of the invention, the appended claims, and to the several views illustrated in the attached drawings.
FIG. 1 is a simplified block diagram of the expert die draft system;
FIG. 2 is a simplified diagram of the computer shown in FIG. 1;
FIG. 3 is a simplified flow diagram of the expert die draft schedule system;
FIGS. 4A and 4B set forth a subroutine for adapting the program instruction set for use with most conventional wire drafting machines; and
FIG. 5 illustrates die drafting in simplified form.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT
Referring now to FIG. 1, a preferred embodiment of the die draft expert system for optimizing wire drawing die schedules is shown, including a computer 11 adapted to receive input from a keyboard 12, a display unit 13, and/or a printer 14 for output of data in human cognizable form. The computer 11, communicates with one or more databases 15 in a storage unit 16 for exchange of data.
Shown in FIG. 2, the computer 11 is of conventional design; it can be a microprocessor, which includes an Arithmetic Logic Unit ("ALU") 202, a control unit 203 communicating with the ALU 202 and with an I/O function 206. A memory unit 204 communicates with control unit 203 for temporary storage. An accumulator 205 communicating with the ALU 202, control unit 203, and I/O unit 206 is often included for additional temporary storage of data. Computer 11 interactively operates under control of a program instruction set 17, all or part of which may be retained in storage unit 16 or in the computer internal memory unit 204 during operation. These elements may be configured as a personal computer for convenience. One of ordinary skill in the computer programming arts can without unnecessary experimentation prepare the program instruction set from FIGS. 1-4 and the following description.
An illustration of the computer, including such a microprocessor 201, is shown in FIG. 2. ALU 202 performs logical operations such as AND, OR, etc., and arithmetic operations such as addition, subtraction, multiplication, and division. The control unit 203 directs operation of the computer from the memory 204 instructions and executes these instructions. The accumulator 205 is usually included to temporarily store data. The I/O unit 206 handles the input and output operations, sending and receiving signals to and from the microprocessor 201.
The method of the invention is shown more clearly in FIG. 3, an illustrative block diagram of the invention in flow terms, in connection with the apparatus illustrated in FIGS. 1 and 2. Upon initialization at START 101, the display 13 prompts the user at block 102 for input into computer 11 of the rod size, then the output wire size. The input of this and subsequent user supplied data values is accomplished conventionally via keyboard 12. The input order of these two data elements may be reversed; the data is preferably stored in the computer memory unit 204, but may also be written to storage 16 for recall.
As the wire passes over capstans in the drawing machine, the wire is pulled along a predetermined path at a given linear velocity. The wire velocity and the capstan velocity are not equal; the wire travels slower than the capstan surface at all but the final capstan. This difference is called "slip" herein. Starting and ending slip data values for the respective capstans before and after the dies are next selected at block 103; these values may be input by the user at block 114 or predetermined by the program instruction set 17. A typical starting slip data value is fifteen per cent, but this value may vary according to many determinants, including the drawing machine, the wire material being drawn, etc. as known to those of ordinary skill in the art. Alternate values range between about ten percent and about 20 percent. The ending slip data value may also be input by the user or predetermined by the program instruction set 17. A typical ending slip data value is about five percent at the next to final die, with alternate values ranging from about two percent to about ten percent. The total slip is evenly distributed among the capstans save for the last die, for which zero slip is desirable. Again, the program instruction set 17 may be configured such that the starting and ending slip data values may be selected in the reverse order.
The machine specific data must be determined; in a simple configuration of the invention, the program instruction set 17 or storage unit 16 contains this data. In a variant embodiment, it may also be determined by the user where the data is unknown or is not preferred by the operator or engineer. This data includes, for example, the number of dies, the capstan surface velocity or capstan angular velocity and diameter at each capstan, and such other specific drawing machine factors as may be desirable. The drawing machine data is obtained in block 104 if known, or entered by the user at block 113 where not known or not stored. Next, the slip increment and the number of dies required are determined by iterative calculation in block 105, according to Equation 1: ##EQU1##
The wire velocity preceding each die is then determined in block 106 according to Equation 2: ##EQU2## where slip is expressed as a decimal value.
Once the wire velocity is calculated in block 106, the wire size following each die is calculated in block 107 according to Equation 3: ##EQU3## where n represents a given capstan and n-1 represents the preceding capstan.
In block 108, a comparison is made in which the wire size following the final die is compared with the desired wire size; following an affirmative result, i.e., in which the calculated size equals the desired size, the calculated die size values are output in block 112 either to display 13 or printer 14. It is preferred that the die size, percentage slip, and area reduction for each die are listed in columns. Alternatively, the results may also be communicated to the drawing machine area visually or electrically (not shown).
A negative result of the comparison in block 108 leads to a further iteration in the calculation and comparison procedure; blocks 105-108 form a portion of an iterative feedback loop cycle which further includes comparison block 109 plus either slip value decremental block 110 or slip value incremental block 111; the decremental or incremental outputs of blocks 110 or 111 are supplied to block 105 and provide adjustment of the number of dies and the slip data values on successive iterations until the slip increments and number of dies provide the desired degree of reduction and favorable comparison between the calculated wire size and the desired wire size.
In a first illustration of the invention, input of the following rod and wire data values result in the die drafting schedule of Table 1 for a Vaughn wire drawing machine with 10 die blocks.
TABLE 1______________________________________Rod size = 375 milsDesired wire cross section = 100 milsBlock Size (in) % Slip % Area Reduction______________________________________1 375 15.0 0.02 339.7 13.8 18.03 285.7 12.5 29.24 241.0 11.3 28.95 205.2 10.0 27.56 173.5 8.8 28.57 147.0 7.5 28.28 126.5 6.3 26.09 109.5 5.0 25.010 100.0 0.0 16.6______________________________________
In another illustration of the invention, input of the following data values result in the die drafting schedule of Table 2 for a Vaughn wire drawing machine with 13 die blocks.
TABLE 2______________________________________Rod size = 375 milsDesired wire size = 64 milsBlock Size (in) % Slip % Area Reduction______________________________________1 375 15.0 0.02 301.4 14.1 35.43 261.3 13.2 24.84 226.4 12.3 25.05 196.1 11.4 25.06 169.6 10.5 25.27 146.5 9.5 25.38 126.9 8.6 25.09 110.1 7.7 24.710 95.4 6.8 24.811 82.7 5.9 24.812 71.9 5.0 24.513 64.0 0.0 20.7______________________________________
In an enhanced embodiment, certain of the data values may be entered by the user and compared with the optimized values produced by the die draft optimizing system. The comparison of the user-selected die sizes and the computer optimized die schedule provides a convenient reference guide for unusual situations. This enhanced embodiment is especially useful when preparing to draw specially treated rod, unusual rod sizes, or merely different alloys or materials than normal. In this enhanced embodiment, the user is interrogated whether a user-supplied die draft schedule is to be entered; preferably after entry of the rod and wire sizes at block 102. Alternatively, this question may be asked at any of blocks 102-104. (Slip data values are entered at block 103.)
Then the operator is to enter data values for the particular drawing machine at block 114, such as the number of dies and each respective die size for comparison with the computed die draft schedule. Upon completion of the computed die draft schedule, the values are displayed side-by-side on display 13 (and/or output on printer 14) for direct comparison and modification. A subroutine is added to the program instruction set 17 to accomplish this purpose. An example for this subroutine is illustrated in FIGS. 4A and 4B. This subroutine example is limited to 20 dies.
A simplified illustration of the die drafting process is set forth in FIG. 5. A rod or wire of given size enters a die block and is pulled along by a rotatable capstan in a sequence of wire cross section reducing steps. In FIG. 5, C x represents each of a plurality of rotatably driven capstans, each capstan having a progressively faster surface velocity (left to right in FIG. 5) C 1 . . . C n ; D x represents each of a 35, plurality of drawing dies, each having a progressively smaller die section D 1 . . . D n ; and W x represents the wires exiting each of the dies, where W 1 . . . W n are the respective linear velocities of the wire after exiting a given die. Each of the wire sections save the last wire section (W n ) travels at a linear velocity less than the surface velocity of the respective driven capstan, the difference S x here being referred to as slip, expressed as a percentage or as the difference of 1 less the decimal expression of the percentage; a specific slip value is associated with each of the capstans: S 1 . . . S n .
Given capstan surface velocities (or determining the surface velocity from the capstan angular velocity and the capstan diameter) either from a user input or from a database, and given the last die diameter, i.e., the desired wire size, and given the slip (being equally divided among the capstans save the last capstan: C n =W n ),
W.sub.n-1 =C.sub.n-1 ×S.sub.n-1 Equation 4
where S is given as 1 less the percentage slip expressed as a decimal value, the wire linear velocity is equal to the capstan surface velocity time the slip.
Each of the next preceding die sizes can be calculated for each die because the same quantity of rod/wire volume relative to the wire velocity must be distributed along each capstan over a given time, therefore: ##EQU4##
Although certain presently preferred embodiments of the invention have been described herein, it will be apparent to those skilled in the art to which the invention pertains that variations and modifications of the described embodiment may be made without departing from the spirit and scope of the invention. Accordingly, it is intended that the invention be limited only to the extent required by the appended claims and the applicable rules of law.
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An expert system having a computer which can receive input data and from stored data to produce an optimized die draft schedule for a given wire drawing machine. The system is adaptable to store data for a plurality of die drawing machines, producing an optimized die draft schedule for a range of input and output rod/wire sizes on each drawing machine for which the system has stored operating parameters. Alternatively, operating parameters for additional drawing machines can be entered, enabling generation of optimum die draft schedules for most wire drawing machines. An enhanced mode may be made available to enable comparison of computed values and operator estimated values.
| 1 |
FIELD OF THE INVENTION
The field of this invention relates to preparation and setting of blast-furnace slag mud formulations into a wellbore to cement a casing.
BACKGROUND OF THE INVENTION
In the past, casing has been cemented downhole using Portland cement-based materials. The Portland cement is mixed with water or available aqueous solution and circulated to properly spot the material for properly sealing off the outside of the casing from the formation. The Portland cementing systems have generally been provided to well operators by oilfield service companies. These service companies have brought to the well site, mixing equipment and personnel so that the Portland cement can be continuously mixed with water to obtain the proper ratio of cement to water for proper solidification on the casing exterior. More recently, an alternative to Portland cement systems has been developed. This system involves the addition of blast-furnace slag (BFS) to water-based mud for slurry densities in the range of between 10-20 lbs./gal., depending on the mud weight and the requirements applicable to the specific operation. The thickening time of BFS/mud mixtures is controlled by activators and retarders. Activators accelerate hydration of BFS and reduce thickening time and improve early compressive strength development. Some of the more effective activators are alkali materials that increase the mud pH. The addition of BFS and activators to mud has negligible effect on the plastic viscosity, yield point, and gel strength over and above the properties of the original mud. The rheological properties can be further adjusted using chemical thinners or deflocculents, dilution of the mud with water, or a combination of both steps.
BFS/mud mixtures can be activated by thermal energy or chemical activation. Chemically, BFS is similar to Portland cement. It is the residue from ore and other additives developed in a molten state, along with iron in a blast furnace. BFS is discharged from a blast furnace at a temperature between 2500°-2900° F. and quenched as a molten slag to produce a glassy, granular material. Optimization of BFS/mud mixtures puts the solids by volume content at anywhere in the range between 16-45% and reasonably approximates the concentrations of equivalent density Portland cement slurries.
BFS is less reactive than Portland cement. As a consequence, BFS/water-based mud mixtures or BFS/water mixtures must be chemically activated to achieve set in the downhole wellbore environment, and Portland cement/water mixtures usually must be chemically retarded. Chemical activation is simpler and less expensive than retardation. Typically, sodium hydroxide and sodium carbonate are the most widely used activators for BFS/water-based mud mixtures because they are commonly available. Sodium hydroxide has a greater impact on setting time, while sodium carbonate has a greater influence on the manner of set and the compressive strength. Above 80° F., sodium carbonate is used in greater concentrations than sodium hydroxide because there is sufficient thermal energy to reduce setting times, while the higher sodium carbonate concentration aids in the early compressive strength development. In temperatures below 80° F., the sodium hydroxide concentration can be equal or slightly higher than sodium carbonate concentration because of low thermal energy available to activate the slag hydration. Typically, activator concentration in the formulations varies between 2-24 lbs./barrel of slurry for most formulations, depending on the temperature and the amount of retarding material present. Yet another advantage of using BFS/mud mixtures is uniform compressive strength build-up over time in situations where significant temperature differentials exist between top and bottomhole temperatures.
When using BFS/mud mixtures in the field, the BFS is typically mixed with the mud in the mud pits on the rig. Batch mixing in rig pits or mud premix tanks or cement mixers is possible. In some instances, this has required isolation of mud to be used for batch mixing with the BFS. Testing is then separately done on samples of the mixture. Upon completion of the testing, activators, dispersants or other additives were added to the isolated fluid. This was usually done prior to cementing. Use of this procedure involved several operational considerations which could adversely affect the rig equipment and/or the success of the primary cement job. The possible problems all arise from the potential for premature set of the slag-mix slurry, if all of the components are added to the mix mud before the cementing operation is initiated. Generally, according to API procedures, BFS is less abrasive than barite and, therefore, undue wear on pumps and other equipment is not a major problem. In the past, however, concerns about early set-up of the BFS/mud mixture in the surface equipment has been an impediment to successful cementing, especially where there are substantial thermal differences between ambient temperatures at the surface, where the activator is added, and bottomhole temperature, where the activator is to perform. Normally, BFS/mud mixtures were designed to have sufficient thickening time at the downhole temperature to allow slurry placement. In many situations where the downhole temperature exceeds the surface temperature, the mixture thickening time is longer on the surface. This leaves ample time to flush the lines and other surface equipment of residual fluid before it sets. However, in deepwater applications, the slurry surface temperature may be higher than the bottomhole circulating temperature. Therefore, slurries designed at the surface for lower bottomhole temperatures will set faster on the surface. In the past, this has required a dedicated line from the mixing tank to the rig pumps to minimize contamination of surface equipment. Additionally, due to flow variability upon pumping of the BFS/cement slurry, fine tuning of the amount of activator was necessary to account for variations in flowrates, as well as any bottomhole temperature variations. If the batch was premixed in the mud pits, there would be no opportunity to control the rate of addition of activator to the batch blend. Additionally, batch mixing presented uniformity problems as well as the potential that the batch could solidify if pumping problems developed.
In the past, radio tracer injection techniques have been used to facilitate foot-by-foot measurements of Portland cement coverage behind a casing. The principle used was injection of a uniform tracer material with a short half-life to allow measurement of cement placement, mud displacement, and the mixing that takes place at displacement fronts. The injection technique for the radioactive material is illustrated in FIG. 1 of IADC/SPE Paper 14778 entitled "Evaluation of Cementing Practices by Quantitative Radio Tracer Measurements," authored by Kline, et al., delivered in 1986 at the IADC/SPE Conference in Dallas, Tex.
The system illustrated in FIG. 1 has many advantages over the prior techniques which have been used to add activator to the BFS/mud slurry. The apparatus and method illustrated in FIG. 1 deal with the possible risks to rig equipment and the success of the primary cement job, for which no answers were available in the referenced 1993 article by Cowan, the inventor of U.S. Pat. No. 5,058,679, which is discussed in the detailed description below. One of the concerns to the well operator is if attempts are made to continuously mix the activator with the BFS/mud slurry, the operator was required to call out a cementing service company who would bring, at great expense, continuous mixing equipment previously used for Portland cement-based systems to conduct the inline mixing of the BFS with the mud. In order to save rig time and expense, ideas began to develop about using the rig equipment for mixing the BFS with the mud. The economic incentive was to avoid the cost associated with hiring a service company for the mixing operation and to minimize rig time due to delays which could ensue from such an operation with a cementing service company. However, as pointed out by Cowan, the risks of batch mixing in the rig pits and adding a precise amount of activator for the expected downhole conditions created certain risks. For example, where the subsurface temperatures were significantly lower than the surface temperatures, additional activator would have to be added to allow for the lower temperature downhole. However, this would shorten the set-up time for the BFS/mud slurry and create operational problems if the slurry, once activated, was not quickly placed downhole where the expected lower temperature would be encountered. Those skilled in the art appreciated that the pumping of the BFS/mud slurry is not a continuous operation at a smooth flowrate. Upon initial presentation into the casing internals, the mud "free falls" until the casing internals are filled and the mud starts its progress outside of the casing adjacent the formation. At that point, fluid losses could occur due to washouts or high porous segments, as well as resistance to flow can occur, all of which act to put additional resistance on the surface pumping equipment, which in turn induces the rig personnel to alter the operation of the surface pumps to avoid exceeding a predetermined pressure. This results in a slowing down of the flowrate, which in turn can cause problems if a large batch has been mixed in the rig equipment and activator already added. Continuous addition of activator on a real-time basis to reflect the actual operating flowrates directly compensates for flow fluctuations while at the same time minimizing the time between activator injection and final placement. In essence, as soon as the activator is added, the mud is pumped through the cementing head and toward its final destination. If for any reason there is a flow interruption, the surface equipment is essentially free of activated BFS/mud slurry.
Accordingly, the apparatus and method of the present invention have been developed to improve on the systems for activator addition to BFS/mud mixtures. The present invention allows for sensitivity to changing flowrates and pressure conditions downhole during the placement of the BFS/mud mixture. The method of addition also minimizes the risk of line plugging when using surface mud circulating equipment. The activator concentration can be adjusted on a real-time basis and precisely added for the expected downhole temperatures to be encountered, while at the same time minimizing the risk of fouling surface equipment or the inside of the casing.
SUMMARY OF THE INVENTION
The invention provides for metering the pumping rate of BFS/mud mixtures pumped to the cementing head on a rig for sealing off the formation from the casing. Since BFS/mud mixtures require an activation agent, preferably sodium hydroxide is pumped into the flowline to the cementing head. Feedback from the BFS/mud slurry flowrate is fed to the activator injector pump drive system to regulate the addition rate of the activating agent in response to varying conditions, such as mud flowrate. The injection rate target can also be adjusted to compensate for any changes in downhole temperature. The risk of fouling surface equipment and the casing internal diameter is minimized because the activation agent is added very close in time to when the BFS/mud mixture enters the cementing head. Even in situations where the anticipated downhole temperature is significantly lower than the surface temperature, a sufficient amount of activating agent is added for the downhole conditions without fear of fouling the casing internal or the surface pumping equipment.
BRIEF DESCRIPTION OF THE DRAWING
FIG. 1 is a plan view of a skid-mounted assembly illustrating the preferred embodiment of the present invention.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT
As previously stated, traditionally, Portland cement slurried in water has been used as the solidifying agent for sealing off the casing from the formation and to provide mechanical support for the casing. More recently, to replace the Portland cement-based systems, a technique has been developed to use blast furnace slag as the solidifying agent for water-based mud. This procedure is illustrated in U.S. Pat. No. 5,058,679. Typically, these BFS/mud systems require an activation agent to begin the hardening process. Sodium hydroxide and/or sodium carbonate have proven to be effective activating agents for the BFS/mud mixtures. In the preferred embodiment of the present invention, sodium hydroxide 25-50% by weight solution will be used, depending on local weatyher conditions. The apparatus and method of the present invention constitute an improvement over the prior batch systems used for BFS/mud mixtures. As discussed in a recent article appearing in the October 1993 issue of World Oil, entitled "Solidify Mud to Save Cementing Time and Reduce Waste," by K. M. Cowan (also the patentee of U.S. Pat. No. 5,058,796), the prior method of adding activators into a batch mix tank, such as the mud tanks, presented numerous problems with plugging of rig equipment or potentially the casing, particularly if the ambient temperature at the surface where the batch is mixed is substantially higher than the bottomhole temperature. This type of temperature gradient is encountered in offshore wells in deepwater locations. The article concludes that the present technology still makes it difficult to implement the BFS/mud system using exclusively the rig equipment, particularly the active circulating system on the rig. The apparatus and method of the present invention has very simply answered the inquiry made by Mr. Cowan in the article.
The apparatus A of the present invention is illustrated in FIG. 1. In the preferred embodiment, a skid 20 is used to facilitate portability of the significant pieces of equipment involved. On top of skid 20 is BFS/mud inlet 22. The rig pumps (not shown) are used to supply the BFS/mud mixture which has yet to be activated from the mud pits or other rig equipment to the skid 20. Inlet 22 is connected to meter 5 through line 26 which can be isolated using valves 8. Meter 5 is preferably a magnetic flow meter which is capable of handling slurries. For economy, the meter 5 working pressure may be fairly low in the order of about 1000 pounds. However, to avoid over pressure of meter 5, a relief valve 14 can be provided which can be set preferably at or near the working pressure of the meter 5. Downstream of relief valve 14 is inline mixer 7. Between inline mixer 7 and relief valve 14 are connections for activation pumps 1. Two pumps are illustrated on skid 20 which can be operated in unison or with one operating as a backup unit. In the preferred embodiment, an explosion-proof motor 3 is connected to a variable speed motor reducer which in the preferred embodiment can reduce the pump speed with respect to the motor speed by a ratio of approximately 6-1. The speed reducer 2 can vary the ratio to alter the operating speed of the pump 1 responsive to signals received from control panel 15. A source of activation material, preferably 50% caustic soda solution, is connected to the inlets as marked on FIG. 1. Each of the pumps 1 discharge past a bleed valve 11 followed by a block valve 10 and finally a check valve 12. As indicated in FIG. 1, the discharge of pump 1 has an outlet to a pressure switch with the switch 13 mounted on a panel. The pressure switch is electrically tied to motor 3 for shutdown in the event of sudden loss of pressure during operation which would signal a serious leakage of caustic soda. Due to the safety concerns, a rapid shutdown of the caustic supply is desirable in the event of a catastrophic leak. Both the pumps 1 on the skid 20 are similarly equipped.
Downstream of inline mixer 7 which mixes the BFS/mud slurry arriving from inlet 22 with the caustic soda coming from pump 1 is a sample port assembly 19 which allows monitoring personnel to obtain a sample of the activated BFS/mud mixture. Block valves 8 on line 26 allow isolation of the meter 5, relief valve 14, and inline mixer 7. With valves 8 which are disposed upstream of meter 5 and downstream of sample port assembly 19 both closed and a bypass valve 8 on line 24 open, the entire skid 20 operates as essentially as a piece of pipe. During normal operation when caustic soda is added, the valves 8 on line 26 are in the open position while the block valve 8 on the bypass line 24 is closed. The mixture of caustic soda with the BFS/mud slurry exits from outlet 28 and goes to a cementing head (not shown) for pumping down the casing and around the outside of the casing in the normal manner for a cementing operation. The BFS/mud flowrate is indicated on flow indicator controller 4. The flow indicator 4 sends a signal into the electrical control panel 15. Within the panel, in a manner known in the art, the signal from the flow indicator controller 4 is used to generate a signal directed to the variable speed drive 2 to alter the speed of the pump. In the preferred embodiment, the pump 1 is of a positive displacement type where its volume delivery is directly proportional to its operating speed.
In operation, the rig pumps (not shown) are oriented for flow communication with inlet 22 with the block valve 8 on the bypass line 24 closed. Flow through meter 5 creates a signal on controller 4 which in turn regulates pump 1 at a particular speed through manipulation of variable speed drive 2. In this manner, a predetermined addition rate, as determined on control panel 15, of caustic soda is attained by regulating the speed of pump 1 to the flowrate measured on meter 5. Knowing the properties of the BFS/mud slurry mixture coming into inlet 22, the desired rate of addition of caustic soda can be readily determined since the properties of caustic soda are as well also known. The mixture is thoroughly mixed in inline mixer 7 and then exits the skid 20 through outlet 28. It then flows to the cementing head (not shown) down the casing and around the outside of the casing for ultimate cementing between the casing and the formation. It is anticipated that the addition of caustic soda occurs when flow of BFS/mud slurry is initiated. The addition continues at a rate proportional to the flow. During the initial pumping, the BFS/mud mixture, which has just been activated on skid 20, flows generally smoothly until the BFS/mud mixture reaches the bottom of the casing. Thereafter, fluctuations in the flowrate may occur due to resistance to flow offered by the formation around the outside of the casing. Variations in flowrate which occur when rig personnel alter the speed of the rig pumps to avoid increasing pressure beyond a predetermined value are automatically accounted for at the surface by adjustments to the flowrate of caustic soda at pump 1 through the controller 15 acting on a signal received from flowmeter 5. Conveniently, by the time the activated BFS/mud mixture reaches the bottom of the wellbore to come around the casing and go up the casing, most, if not all, of the caustic soda which is necessary for subsequent hardening of the mixture has already been added. Once that point is reached, the pumps 1 are turned off and blocked in and the skid 20 is operated on bypass line 24 by opening the bypass 8 on line 24 and closing the two inline valves 8 on line 26. At this time, a pressure buildup is usually experienced at the rig pump as the BFS/mud mixture is forced upwardly outside the casing adjacent the formation. Since the pressure rating of the meter 5 is only 1000 pounds, it can be effectively blocked in casing valves 8 on line 26 once the condition has occurred where no additional caustic soda is required.
The illustrated system disclosed in FIG. 1 and described above has several advantages. First, it is a compact design which can be used for both onshore and offshore applications. In locations where space is commonly at a premium, a compact design is often helpful. The present invention allows the use of rig pumps and equipment to mix the BFS/mud slurry without fear that the lines will set up if the pumping procedure is interrupted after a batch activation. Batch activation in mud pits or other equipment can present serious concerns of plugging the important rig equipment if pumping problems are encountered after activation. With apparatus A of the present invention, there is no activation until the slurry is about to enter the cementing head. If pumping problems develop, the activated inventory in the surface equipment is negligible.
Variations in the pumping rate are measured by the apparatus of the present invention and real time corrections to the caustic soda addition rate are made in response to such flow fluctuations of the BFS/mud slurry. The system can be entirely isolated once a sufficient amount of caustic soda has been added to the charge of BFS/mud slurry which is to be used in the cementing procedure. Typically, the rig location has a mud engineer whose principal responsibilities are the physical properties of the mud during the drilling operation. The apparatus of the present invention allows the use of the same mud engineer or even rig personnel to monitor the performance. Accordingly, with the compact design of the skid 20, the skid can be made a permanent part of the rig equipment and no incremental personnel are necessary beyond a mud engineer who would be on location in any event during the drilling operation for monitoring of the mud properties. In short, the apparatus and method of the present invention takes the fear out of batch mixing BFS/mud slurries using existing rig equipment. It also provides a greater degree of control and certainty over the consistency and uniformity of concentration of activating caustic soda in the mixture. Since the caustic soda is mixed inline with the flowing BFS/mud mixture, a more uniform consistency can be obtained as opposed to batch mixing in large tanks where the consistency of the permeation of caustic soda within the BFS/mud mixture is unknown or at best uncertain. By continuously adding the caustic soda, the operator is assured of a more consistent hardening of the BFS/mud mixture throughout the zone being cemented.
For added safety, a housing 29 shown in dashed lines can be put over meter 5 and relief valve 14, as well as most of the discharge piping from pump 1 so that in the event any leaks develop, personnel on the rig are protected from burns which could occur from skin contact with 50% caustic soda.
It should be noted that other percentages of caustic soda can be used without departing from the spirit of the invention. Other activators can be used at different concentrations without departing from the spirit of the invention. The proportionality between the measured flowrate and the speed of the pump 1 can be changed to accommodate different concentrations of activator in the BFS/mud slurry or, alternatively, to accommodate different concentrations of activator solutions used so that the ultimate concentration of activator in the finished mixed slurry is in the proper range requirement. The BFS concentration in the mud can also be taken into account when computing the amount of actuator to be added. This is usually determined before a batch of BFS is mixed with the mud in the rig equipment.
Although batch mixing facilitates use of rig mud equipment, continuous BFS/mud mixing is also within the scope of the invention. The desired concentration of BFS in the mud is continuously obtained and the feed rate of BFS is then measured. The activator is then injected continuously in proportion to the BFS feed rate. In this manner, as soon as the BFS/mud mixture is prepared, it is immediately activated and sent directly downhole for placement prior to any risk of set-up. If pumping problems develop, the surface equipment can easily be cleaned out without risk of plugging or set-up.
The advantages of use of the system as described and shown in FIG. 1 allow the rig operator to eliminate the use of a cementing service company with its necessary equipment for the mixing operation. By the use of a simple skid-mounted assembly as shown in FIG. 1, the cementing procedure using BFS/mud slurries can be carried out using rig personnel who can manually or with the aid of rig equipment batch mix the BFS slurry with the mud without the addition of caustic. With the use of the apparatus and method of the present invention, the caustic is only added at the last minute before the BFS/mud slurry goes downhole.
While mixing of two or more fluids inline has been accomplished in the past, such as, for example, in U.S. Pat. Nos. 3,833,718 and 3,827,495, ever since the technology of using BFS/mud solutions has evolved as described in U.S. Pat. No. 5,058,679 and the World Oil article by its inventor Cowan, operators have been struggling with a reliable method that addresses the risks to rig equipment, particularly in applications where the downhole temperature is significantly below the surface temperatures when a batch is mixed with an activating agent. Temperature gradients of 40° F. are possible which require higher actuator concentrations which in turn can limit the time before substantial hardening at surface temperatures to only a few hours. This can be a significant problem for rig operations if any problems develop during the injection procedure for the BFS/mud slurry after it has been activated. Disposal of the activated slurry may be a problem especially in an offshore environment. The apparatus and method of the present invention address and solve this problem.
The foregoing disclosure and description of the invention are illustrative and explanatory thereof, and various changes in the size, shape and materials, as well as in the details of the illustrated construction, may be made without departing from the spirit of the invention.
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The invention provides for metering the pumping rate of BFS/mud mixtures pumped to the cementing head on a rig for sealing off the formation from the casing. Since BFS/mud mixtures require an activation agent, preferably sodium hydroxide is pumped into the flowline to the cementing head. Feedback from the BFS/mud slurry flowrate is fed to the activator injector pump drive system to regulate the addition rate of the activating agent in response to varying conditions, such as mud flowrate. The injection rate target can also be adjusted to compensate for any changes in downhole temperature. The risk of fouling surface equipment and the casing internal diameter is minimized because the activation agent is added very close in time to when the BFS/mud mixture enters the cementing head. Even in situations where the anticipated downhole temperature is significantly lower than the surface temperature, a sufficient amount of activating agent is added for the downhole conditions without fear of fouling the casing internal or the surface pumping equipment.
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This is a continuation of application Ser. No. 657,586, filed Feb. 12, 1976, now abandoned.
BACKGROUND OF THE INVENTION
This invention is directed to a vehicle for transporting large machines such as combines and other large equipment. The inventive concepts are usable in conjunction with self-propelled vehicles or trailers. Although many vehicles have been constructed for transporting such equipment, there have been many problems and disadvantages with those of the prior art.
The trend in farm machinery today is toward more efficient machinery, and this generally means larger machinery. This trend is exemplified by the developments in the field of combines used by farmers to harvest crops. Combines have grown in width beyond the standard 8 foot width allowed for vehicles on public highways during all but certain hours of each day. These over width machines also have wheels that are spaced apart more than 8 feet. The machines are usually transported by trailer, and thus the trailers are also wider than the acceptable width. In most cases, over-wide vehicles can move only during certain hours of each day, and require special permits and escorts even under these circumstances.
When an over width machine is being transported, there is no way to avoid these restrictions. However, in many cases it is advantageous to move the transport vehicles when empty, and presently such movement is subject to the same restrictions as when loaded, because of the over-wide width, loaded or empty. Perhaps one-half of all traveling with these transport vehicles is with them empty, or carrying loads less than 8 feet wide.
In the prior art, transport vehicles such as trailers are built having a width wide enough for the largest machines that they might haul. Thus, they are subject to the same restrictions as the equipment which might be transported upon them.
SUMMARY OF THE INVENTION
It is an object of this invention to provide a new and novel vehicle for carrying wide machinery.
Another object of this invention is to provide such a vehicle that is of variable width.
Still another object of this invention is to provide such a vehicle having a plurality of sections movable between retracted and extended width positions, and means to assure alignment of these sections.
Another object of this invention is to provide such a vehicle whose width can be varied easily by the efforts of only one person.
A vehicle constructed in accordance with the teachings of this invention has a center portion and a pair of side portions flanking the center portion. The running gear (and trailer towing gear) are advantageously attached to the center portion, although this could be altered. The center portion comprises a frame and a plurality of side section support members attached to the frame. Each side section support member is adapted to interact in telescoping relationship with elements of the side sections. Preferably, these side section support members are hollow tubular members. There are sufficient number of side section support members to form runways to receive the wheels of the machinery being carried.
Each side portion comprises a plurality of side sections, arranged along the length of the trailer. Each side section has an outer rail and a plurality of telescoping members that interact with the side section support members on the main frame. The side sections are movable between an inner position, fully retracted to a width preferably less than 8 feet, and a plurality of outer positions spaced outwardly therefrom, the outermost positions providing, for example, a total width of 12 feet, although greater widths can be obtained. The telescoping members form the runways for receiving the wheels of the machine being transported, and must extend sufficiently inward in engagement with the side section support members to be able to withstand the cantilevered load placed upon them by the machinery wheels. The forewardmost side section support member and its corresponding telescoping member are raised with respect to the rest to act as a forward abutment for the machinery wheels. Others can be raised also, to provide a cradle against movement for one or more of the machinery wheels.
Each side section is of such size and weight as to be movable by a single person. In order to insure that the various side sections are easily aligned longitudinally in a particular position, the middle section on each side is provided with a stop means, which is engaged by the flanking front and rear side sections, to halt the outward movement thereof at the same lateral position as the middle side section. A pin through the telescoping members of the middle side section holds all side sections in their innermost position. In their intermediate positions, the weight of the load holds the sections from movement inwardly or outwardly, although locking means could be provided. A means for limiting the amount of full extension is provided for at least the middle side section, and can be a tether or the like attached on the one hand to the center portion of the trailer and on the other hand to the middle side section.
The telescoping members can be of rectangular or circular section, or other tubing or sections that will so telescope together. The center portion of the vehicle advantageously includes heavy longitudinal frame members such as I-beams. The vehicle wheels are of such width as to allow highway access at all times, so the trailer is not restricted in use when not extended. Drive-on ramps are provided at the rear of the trailer, and are adjustable insofar as lateral spacing is concerned, to receive machinery wheels of various spacings.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 is a perspective view of a trailer constructed in accordance with the teachings of the invention, with the side frames in the extended position.
FIG. 2 is a view taken along line 2--2 of FIG. 1, showing the side frames in the retracted position in solid lines and in the extended position in broken lines.
FIG. 3 is a top plan view of the trailer of FIG. 1.
FIG. 4 is a side elevational view of the trailer of FIG. 1.
FIG. 5 is a view taken along line 5--5 of FIG. 4.
FIG. 6 is a view taken along line 6--6 of FIG. 4.
FIG. 7 is an enlarged perspective view showing the relationship between side frame and main frame.
FIG. 8 is an enlarged perspective view of the front trailer support leg.
FIG. 9 is an enlarged perspective view of the side frame stop mechanism.
DESCRIPTION OF THE PREFERRED EMBODIMENT
The following description is directed to a trailer constructed in accordance with the teachings of this invention. However, except for those elements peculiar to trailers alone, the description could also apply to a self-propelled vehicle.
A trailer constructed in accordance with this invention comprises a main portion flanked by a pair of extendable side portions. The main portion comprises basically a main frame 10, and each side portion a plurality of side sections 12, 14, and 16.
Main frame 10 comprises left frame member 20 and right frame member 22, which are of I-beam construction, disposed on either side of a trailer axis. At the front portion of the trailer, where they converge, they are attached together by a pad 24, upon which the towing gear 26 is mounted. A plurality of lateral cross braces 28 are attached between frame members 20 and 22 at the front portion of the trailer. Four sets of dual wheels 32 are mounted on axles attached to the underside of frame members 20 and 22. The maximum distance between the outer surfaces of the wheels (or tires) is less than 8 feet by a sufficient margin to allow the maximum dimension in width of the entire trailer to be 8 feet or less in the retracted position.
Four square tube side support members 36 and a fifth such member 38 extend laterally across the trailer, passing through and welded to frame members 20 and 22. A plurality of square tube runway members 40 are attached to the undersides of main frame members 20 and 22 and extend laterally across the trailer. All these members support the side frames, while also providing cross bracing between the main frame members. Also, the outer ends of members 40 are joined by plates 41 welded thereto (FIG. 7) for reinforcement. A plurality of panels 42 are attached between some of the front and rear main side support members and the adjacent main runway members.
Middle side frame 14 comprises an outside rail 44, of I-beam construction, and a plurality of middle telescoping members 46 of square tube construction attached to the inner surface of outside rail 44 and that closely fit inside main side support members 38, and are slidable therein. The front and rear edges 50 of outside rail 44 are inclined to facilitate movement of the wheels of the machinery being carrier over them during loading and unloading. Panels 42 also assist the machinery wheels in moving over members 36 and 46 during loading and unloading. The upper surfaces of members 36 and 46 are approximately the same height as the uppermost surfaces of wheels 32.
Front side frame 12 comprises an outside rail 52 of I-beam construction, to which are attached a plurality of telescoping members 54 of square tube construction which fit closely inside of runway members 40, and are slidable therein. The upper surface 56 of outside rail 52 is positioned closely beneath the lower surface of outside rail 44. Attached to upper surface 56 is an extension 58, to which is attached a telescoping member 60, which fits closely within side support member 38. In addition to supporting side frame 12, members 38 and 60 halt the forward movement of the machine wheels, as do the rearmost members 36 and 46. The forward wheel of the machinery is also cradled by the forwardmost members 36 and 46, to prevent rearward movement.
Rear side frame 16 comprises an outside rail 72, to which are attached a plurality of telescoping members 74, which fit closely inside runway members 40, and are slidable therein. The upper surface 76 of outside rail 72 fits closely beneath the lower surface of outside rail 44.
Runway members 40 and main support members 36 and 38 have a total width somewhat less than 8 feet, so that the maximum width between the outside rails of the side sections in the retracted position is no more than 8 feet. The length of telescoping members 46, 54, 60 and 74 is maximized, to allow the side frames to be extended outwardly as far as possible, and to insure adequate overlap with the members into which they telescope, for maximum strength. Therefore, as shown in FIG. 2, the inner ends of telescoping members on opposite sides abut in the center when the side frames are fully retracted.
On the bottom surface 80 of outside rail 44 are a pair of L-shaped brackets 82. On the rear surface of outside rail 52 and on the front surface of outside rail 72 are a shoulder 84, aligned with brackets 82. The interaction of brackets 82 with shoulders 84 prevents side frames 12 and 16 from ever being positioned laterally outwardly of side frame 14. As inclined guide surface 86 on bracket 82 assists in the engagement of the two elements. Outward movement of middle side frame 14 is limited by the extension of a chain 90 (FIG. 6), which is attached to a pin 92 welded onto the inside of one of the main side frame support members 36 at the center thereof, and to the inside of the corresponding telescoping member 46. A pin 100 (FIG. 5) through openings in the main support member 36 and corresponding telescoping member 46 locks side frame 14 in its innermost position.
A pair of loading ramps 102 are attachable to the rearmost runway member 40 and/or corresponding telescoping members 74. Ramp support legs 104 extend downwardly from ramps 102, to help support the rear portion of the trailer during loading and unloading.
A swivel jack stand 106 (FIG. 8) is located at the front of the trailer, to support the trailer when it is not attached to the towing vehicle. Stand 106 comprises a mounting bracket 108 attached to frame member 20. A square tube mounting arm 110 is configured to be slidable within bracket 108. Arm 110 has a first pair of holes 112 and in two opposite sides and a second pair of holes 114 in the other sides. Bracket 108 has a pin 116 attached thereto. A stand member 118 is attached perpendicularly to arm 110. A telescoping leg 120 slides inside stand member 118, and is equipped with height adjustment openings 122 through which a pin 124 can pass. A bearing plate 126 completes the mechanism.
Many of the advantages of the invention should become apparent from a consideration of structural features described above. Chief among these are the simplicity and strength of the structure, the low height of the runways, and the inherent cradling of the wheels of the machine being carried plus, of course the simplicity, ease of operation, and effectiveness of the width adjustability concept. Additional advantages are also seen from a consideration of the operation of the apparatus. In its retracted position, the outside rails side frames 12, 14 and 16, on both sides, are in abutting relationship with the outer ends of main side support members 36 and 38 and runway member 40. Pins 100 are in place through one of the telescoping members 40, thus holding middle side frames 14 against outward movement. Because of stops 82, the other side frames 12 and 16 are also held against outward movement.
To extend the side frame, pins 100 are removed, and middle side frame 14 is extended to the desired position, its outward movement being limited by chain 90. Then, side frames 12 and 16 are extended until shoulders 84 engage stops 82. If this is an intermediate position short of full extension, the weight of the machine being transported will prevent additional outward movement. However, additional preventing means, such as pins, could be used to define intermediate positions. With ramps 102 installed, the machine to be transported is driven, pushed, or pulled onto the trailer, until its forward wheel is cradled between the two forwardmost side support members 36 and 38.
When the machine being transported is removed, the trailer is returned to its narrow configuration by first pushing side frames 12 and 16 inwardly, followed by middle side frame 14. Pins 100 are then replaced.
Jack stand 106 is shown in FIG. 8 in position to support the forward portion of the trailer. Arm 110 is insertable into bracket 108, and pin 116 slipped into place to hold it there. Leg 120 is extended to the desired position and held in place by pin 124. When the jack is not needed, arm 110 is removed from bracket 108 and then re-inserted after being rotated 90°, so that leg 120 is parallel to the ground. The jack is held in this position also by pin 116.
Variations and modifications from the above described preferred embodiment may become apparent to those skilled in the art, once having viewed this disclosure. However, the scope of the invention is not limited by this disclosure, but is governed by the breadth of the appended claims.
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A trailer for transporting large machinery such as farm combines and the like. The trailer comprises a main or center portion flanked laterally by side portions, each side portion comprising a plurality of outwardly telescoping sections which form runways to receive the wheels of the machinery. The trailer wheels and towing gear are attached to the main portion. The side sections are extendable to accommodate equipment having a wide wheel-span. Each of the three side sections on each side, can be separately extended or retracted by a single person. An alignment system is provided to facilitate alignment of the three sections. A chain limits the outward extension of the side sections. Locking pins hold the side sections in their inner positions.
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CROSS REFERENCE TO RELATED APPLICATIONS
[0001] This application is a divisional application of U.S. Ser. No. 12/134,592, filed Jun. 6, 2008, the contents of which are hereby incorporated herein by reference.
FIELD OF THE INVENTION
[0002] The present invention relates generally to invasive medical devices, and specifically to the construction of probes for insertion into body organs.
BACKGROUND OF THE INVENTION
[0003] In some diagnostic and therapeutic techniques, a catheter is inserted into a chamber of the heart and brought into contact with the inner heart wall. In such procedures, it is generally important that the distal tip of the catheter engages the endocardium with sufficient pressure to ensure good contact. Excessive pressure, however, may cause undesired damage to the heart tissue and even perforation of the heart wall.
[0004] For example, in intracardiac radio-frequency (RF) ablation, a catheter having an electrode at its distal tip is inserted through the patient's vascular system into a chamber of the heart. The electrode is brought into contact with a site (or sites) on the endocardium, and RF energy is applied through the catheter to the electrode in order to ablate the heart tissue at the site. Proper contact between the electrode and the endocardium during ablation is necessary in order to achieve the desired therapeutic effect without excessive damage to the tissue.
[0005] A number of patent publications describe catheters with integrated pressure sensors for sensing tissue contact. As one example, U.S. Patent Application Publication 2007/0100332, whose disclosure is incorporated herein by reference, describes systems and methods for assessing electrode-tissue contact for tissue ablation. An electro-mechanical sensor within the catheter shaft generates electrical signals corresponding to the amount of movement of the electrode within a distal portion of the catheter shaft. An output device receives the electrical signals for assessing a level of contact between the electrode and a tissue.
SUMMARY OF THE INVENTION
[0006] The embodiments of the present invention that are described hereinbelow provide a novel design of an invasive probe, such as a catheter. The probe comprises a flexible insertion tube, having a distal end for insertion into a body cavity of a patient. The distal tip of the probe is coupled to the distal end of the insertion tube by a coupling member. The coupling member comprises a tubular piece of an elastic material, such as a superelastic alloy, with a helical cut running along a portion of the length of the piece.
[0007] The coupling member permits the distal tip to bend in response to pressure exerted on the distal tip when the distal tip engages tissue in the body cavity. Typically, the bend angle is proportional to the pressure and may be measured in order to determine the force of contact between the probe and the tissue. On the other hand, the width of the helical cut may be chosen so as to inhibit bending of the distal tip beyond a certain angular limit in order to avoid damaging the probe.
[0008] There is therefore provided, in accordance with an embodiment of the present invention, a medical probe, including:
[0009] a flexible insertion tube, having a distal end for insertion into a body cavity of a patient;
[0010] a distal tip, which is disposed at the distal end of the insertion tube and is configured to be brought into contact with tissue in the body cavity; and
[0011] a coupling member, which couples the distal tip to the distal end of the insertion tube and includes a tubular piece of an elastic material having a helical cut therethrough along a portion of a length of the piece.
[0012] In a disclosed embodiment, the elastic material includes a superelastic alloy, and the helical cut subtends an angle between 360° and 720° about an axis of the tubular piece.
[0013] Typically, the coupling member is configured to bend in response to pressure exerted on the distal tip when the distal tip engages the tissue, and the helical cut has a width chosen so as to inhibit bending of the distal tip beyond a predetermined angular limit.
[0014] In some embodiments, the probe includes a position sensor within the distal tip, wherein the position sensor is configured to sense a position of the distal tip relative to the distal end of the insertion tube, which changes in response to deformation of the coupling member. In a disclosed embodiment, the position sensor is configured to generate a signal in response to a magnetic field, wherein the signal is indicative of a position of the distal tip. The probe may include a magnetic field generator within the distal end of the insertion tube for generating the magnetic field. Additionally or alternatively, the probe includes an electrical conductor, which is coupled to a distal side of the position sensor and is curved to pass in a proximal direction around the position sensor and through the insertion tube so as to convey position signals from the position sensor to a proximal end of the insertion tube.
[0015] In some embodiments, the probe includes a pull-wire for use by an operator of the probe in steering the probe, wherein the pull-wire passes through the insertion tube and is anchored at a point in the distal end of the insertion tube that is proximal to the helical cut in the coupling member. Alternatively or additionally, the probe includes a heat-resistant plastic sheath covering at least the coupling member.
[0016] In a disclosed embodiment, the insertion tube, distal tip and coupling member are configured for insertion through a blood vessel into a heart of a patient.
[0017] There is also provided, in accordance with an embodiment of the present invention, a method for performing a medical procedure, including:
[0018] inserting into a body cavity of a patient a probe, which includes a flexible insertion tube and a distal tip, which is disposed at a distal end of the insertion tube, and a coupling member, which couples the distal tip to the distal end of the insertion tube and includes a tubular piece of an elastic material having a helical cut therethrough along a portion of a length of the piece; and
[0019] bringing the distal tip into contact with tissue in the body cavity.
[0020] In a disclosed embodiment, inserting the probe includes passing the probe through a blood vessel into a heart of the patient, and the method includes ablating the tissue with which the distal tip is in contact.
[0021] There is additionally provided, in accordance with an embodiment of the present invention, a method for producing a medical probe, including:
[0022] providing a flexible insertion tube, having a distal end for insertion into a body cavity of a patient, and a distal tip, which is configured to be brought into contact with tissue in the body cavity; and
[0023] coupling the distal dip to the distal end of the insertion tube using a coupling member, which includes a tubular piece of an elastic material having a helical cut therethrough along a portion of a length of the piece.
[0024] The present invention will be more fully understood from the following detailed description of the embodiments thereof, taken together with the drawings in which:
BRIEF DESCRIPTION OF THE DRAWINGS
[0025] FIG. 1 is a schematic sectional view of a heart chamber with a catheter in contact with the heart wall inside the chamber, in accordance with an embodiment of the present invention;
[0026] FIG. 2 is a schematic sectional view of a catheter, in accordance with an embodiment of the present invention; and
[0027] FIG. 3 is a schematic side view of a coupling member, in accordance with an embodiment of the present invention.
DETAILED DESCRIPTION OF EMBODIMENTS
[0028] FIG. 1 is a schematic sectional view of a chamber of a heart 22 , showing an insertion tube 26 of a catheter 20 inside the heart, in accordance with an embodiment of the present invention. The catheter is typically inserted into the heart percutaneously through a blood vessel, such as the vena cava or the aorta. An electrode 28 on a distal tip 24 of the catheter engages endocardial tissue 30 . Pressure exerted by the distal tip against the endocardium deforms the endocardial tissue locally, so that electrode 28 contacts the tissue over a relatively large area. In the pictured example, the electrode engages the endocardium at an angle, rather than head-on. Distal tip 24 therefore bends at an elastic joint 32 relative to the insertion tube of the catheter. The bend facilitates optimal contact between the electrode and the endocardial tissue.
[0029] Because of the elastic quality of joint 32 , the angle of bending of the joint is proportional to the pressure exerted by tissue 30 on distal tip 24 (or equivalently, the pressure exerted by the distal tip on the tissue). Measurement of the bend angle thus gives an indication of this pressure. The pressure indication may be used by the operator of catheter 20 is ensuring that the distal tip is pressing against the endocardium firmly enough to give the desired therapeutic or diagnostic result, but not so hard as to cause undesired tissue damage. U.S. patent application Ser. No. 11/868,733, filed Oct. 8, 2007, whose disclosure is incorporated herein by reference, describes a system that uses a pressure-sensing catheter in this manner. Catheter 20 may be used in such a system.
[0030] FIG. 2 is a schematic, sectional view of catheter 20 , showing details of the distal end of the catheter, in accordance with an embodiment of the present invention. A coupling member 40 forms the joint between distal tip 24 and the distal end of insertion tube 26 . The coupling member has the form of a tubular piece of an elastic material, with a helical cut along a portion of its length, as shown more particularly in FIG. 3 . Typically, the coupling member (along with the distal end of catheter 20 generally) is covered by a flexible plastic sheath 42 . When catheter 20 is used, for example, in ablating endocardial tissue by delivering RF electrical energy through electrode 28 , considerable heat is generated in the area of distal tip 24 . For this reason, it is desirable that sheath 42 comprise a heat-resistant plastic material, such as polyurethane, whose shape and elasticity are not substantially affected by exposure to the heat.
[0031] Catheter 20 comprises a position sensor 44 within distal tip 24 . (In the pictured embodiment, the position sensor is contained within a part of coupling member 40 that is inside the distal tip of the catheter.) The position sensor is connected via a conductor 46 to a processing unit (not shown) at the proximal end of insertion tube 26 . Conductor 46 may typically comprise a twisted-pair cable. Position sensor 44 is configured to sense the position of the distal tip relative to the distal end of the insertion tube. As explained above, this position changes in response to deformation of the coupling member, and the processing unit may thus use the position reading in order to give an indication of the pressure exerted on and by the distal tip.
[0032] For intracardiac operation, insertion tube 26 and distal tip 24 should generally have a very small outer diameter, typically on the order of 2-3 mm. Therefore, all of the internal components of catheter 20 , such as conductor 46 , are also made as small and thin as possible and are thus susceptible to damage due to even small mechanical strains. To avoid damage to conductor 46 when coupling member 40 bends, the conductor is coupled to the distal side of position sensor 44 , as shown in FIG. 2 , rather than to the proximal side, from which the path of the conductor would be shorter. The conductor is then curved to pass in a proximal direction around the position sensor and through insertion tube 26 so as to convey position signals from the position sensor to the processing unit via the proximal end of the insertion tube.
[0033] Position sensor 44 may comprise one or more coils, which are configured to generate signals in response to a magnetic field. These signals are indicative of the position and orientation of distal tip 24 . The magnetic field may be produced by a miniature magnetic field generator 48 within the distal end of the insertion tube. Thus, when coupling member 40 bends, the signals generated by the position sensor change and can be analyzed by the processing unit to determine the pressure on the distal tip. Additional magnetic fields may be generated by field generators (not shown) in fixed locations external to the patient's body. These fields cause position sensor 44 to generate additional signals that are indicative of the position and orientation of distal tip 24 in the fixed frame of reference of the external field generators. These aspects of the operation of position sensor 44 are described in detail in the above-mentioned U.S. patent application Ser. No. 11/868,733. They are outside the scope of the present invention.
[0034] Catheter 20 may comprise a pull-wire 50 for use by an operator in steering the catheter. The pull-wire passes through insertion tube 26 and is anchored at an anchor point 52 in the distal end of the insertion tube. The operator tightens the pull-wire (typically by turning a knob—not shown—at the proximal end of the catheter) in order to bend the distal end of the catheter. When the operator releases the pull-wire, the catheter straightens due to the resilience of the insertion tube. In catheters that are known in the art, the pull-wire is anchored near the distal tip of the catheter. In catheter 20 , however, anchor point 52 is proximal to the helical cut in coupling member 40 , and may be proximal to the coupling member altogether, as shown in FIG. 2 . This relatively proximal positioning of the anchor point means that the pull-wire steers the catheter as a whole, rather than bending the coupling member and distal tip.
[0035] FIG. 3 is a schematic side view of coupling member 40 , in accordance with an embodiment of the present invention. As noted earlier, the coupling member comprises a tubular piece 60 of an elastic material, typically a metal material. For example, the coupling member may comprise a superelastic alloy, such as nickel titanium (Nitinol). For intracardiac applications, the Nitinol tube may typically have a length of 10 mm, with outer diameter 2.0 mm and wall thickness 0.05 mm. Alternatively, in other applications, the tube may have larger or smaller dimensions.
[0036] A helical cut 62 is made along a portion of the length of tubular piece 60 , and thus causes the tubular piece to behave like a spring in response to forces exerted on distal tip 24 . Cut 62 may be made by laser machining of the tubular piece. For the tube dimensions given above, cut 62 is typically opened by the laser to a width of about 0.1 mm. To give the appropriate balance between flexibility and stiffness for intracardiac applications, cut 62 typically subtends an angle between 360° and 720° about the central axis of the tubular piece, as illustrated in FIG. 3 (in which the cut subtends about 540°). Alternatively, larger or smaller angular extents may be used depending on application requirements.
[0037] The spring-like behavior of coupling member 40 extends up to a certain angle of bending of tubular piece 60 , for example, 30°. Above this angle, the sides of cut 62 on the inner side of the bend will come into contact, thereby inhibiting any further bending of the distal tip. The width of the cut may thus be chosen so as to impose a predetermined angular limit on the bending of joint 32 ( FIG. 1 ). This sort of bend limit is useful in preventing damage that may occur to the delicate internal components of catheter 20 due to excessive bending.
[0038] Although the operation and construction of catheter 20 are described above in the context of catheter-based intracardiac procedures, the principles of the present invention may similarly be applied in other therapeutic and diagnostic applications that use invasive probes, both in the heart and in other organs of the body. Furthermore, the principles of the implementation of catheter 20 and coupling member 40 may also be applied to enhance flexibility in catheter designs of other types, such as lasso, helix, and “Pentarray” type catheters. In a helical lasso catheter, for example, resilient elements like coupling member 40 may be incorporated in the helix in order to enhance the ease of use and accuracy of alignment of the lasso in the desired position within the heart.
[0039] It will thus be appreciated that the embodiments described above are cited by way of example, and that the present invention is not limited to what has been particularly shown and described hereinabove. Rather, the scope of the present invention includes both combinations and subcombinations of the various features described hereinabove, as well as variations and modifications thereof which would occur to persons skilled in the art upon reading the foregoing description and which are not disclosed in the prior art.
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A medical probe includes a flexible insertion tube, having a distal end for insertion into a body cavity of a patient, and a distal tip, which is disposed at the distal end of the insertion tube and is configured to be brought into contact with tissue in the body cavity. A coupling member couples the distal tip to the distal end of the insertion tube and includes a tubular piece of an elastic material having a helical cut therethrough along a portion of a length of the piece.
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CROSS-REFERENCE TO RELATED APPLICATIONS
This application is a continuation of International Patent Application No. PCT/FR2006/001988 with an international filing date of Aug. 25, 2006, designating the United States, now pending, and further claims priority benefits to French Patent Application No. 0508956, filed Sep. 1, 2005. The contents of the aforementioned specifications are incorporated herein by reference.
BACKGROUND OF THE INVENTION
1. Field of the Invention
This invention relates to the field of medicine, and more particularly to pharmaceutical compositions and methods for the treatment and prevention of respiratory failure.
2. Description of the Related Art
Living things derive their energy from their surroundings. They remove from their environment substances rich in nutrients or energy, degrading them in the process, and rejecting the remains of the degradation process. Respiration is essential for life. The cells of our body consume oxygen (O 2 ) and emit carbon dioxide (CO 2 ). The respiratory system is responsible for carrying out the gaseous exchange between the organism (the blood) and the surrounding atmosphere. The blood transports the gas between the respiratory system and the cells.
The respiratory system is comprised of two principal elements: a respiratory pump (ribcage, respiratory muscle) intended, like bellows, to take in and let out air from the lungs; and a gas diffuser (airways, lungs) which, on an air cell level, performs the O 2 —CO 2 exchange between the blood and the alveolar air.
Respiratory failure is defined as the incapacity of the respiratory system to perform its role, that is to say to maintain normal hematose (transformation of venous blood, rich in CO 2 , to arterial blood, rich in O 2 ). It can be chronic (slow onset) or acute (sudden onset).
Respiratory failure can have different causes. There are three known major categories of respiratory failure: obstructive syndromes (bronchitis, asthma, cystic fibrosis, etc.); restrictive syndromes (neuromuscular ailments, scolioses, motor disability, excess weight, etc.); and mixed syndromes.
Currently, curative treatment for respiratory failure, besides the treatment of obstructive syndromes by bronchodilators, calls primarily upon mechanical breathing equipment and/or on the supply of oxygen in the case of substantial bronchiole congestion.
All of the proposed solutions therefore refer to processes aimed at increasing the oxygen supply to the body. For example, Japanese Pat. Appl. Publ. No. JP 11-29410 published on Feb. 2, 1999 describes the use of DHA phospholipids for administration in the form of an aerosol, in the treatment of lung disease during acute attacks. The described treatment is not suitable for the long term and is aimed only at improving the oxygen supply to the body in the short term.
Another of the processes described in the art, is aimed at improving the oxygen uptake and its transport in the body by the blood, particularly in the long term.
Currently, no medicine exists which is aimed specifically at the symptomatic prevention of respiratory failure in humans, with proven effectiveness and harmlessness.
It is known that long-chain n-3 fatty acids (n-3 LC-PUFA) such as eicosapentaenoic acid (EPA; 20:5n-3) and docosahexaenoic acid (DHA; 22:6n-3) have multiple effects on cell membranes, in particular, the fluidity of the red corpuscle membranes, and that they are equally likely to act on the vascular contractability and the cardiac rhythm. Thus, the oxygen supply to the body depends on the hemoviscosity, which is linked to the deformability, of the red corpuscles, and on the vasodilatation of the vessels which regulate the peripheral micro-circulation.
The n-3 LC-PUFA are therefore potential agents capable of modulating the oxygenation of tissues and, therefore, of respiration.
It has thus been shown that a daily intake of 3 g of n-3 LC-PUFA (1.8 g of EPA and 1.2 g of DHA) in the form of fish oil, that is to say a dose much higher than the maximum limit of 2 g/day of n-3 LC-PUFA recommended by the AFSSA (Agence Française pour la Sécurité Sanitaire des Aliments˜French Food Standards Agency), leads to an improvement in the maximum respiratory capacity (VO 2max ) of sportsmen solely after significant endurance exertion (80 min at 70% of their VO 2max ). But in the absence of long-lasting physical exertion, taking 3 g/day n-3 LC-PUFA had no effect (Léger C L et al. Cah. Nutr. Diét, XXVII, 2, 1992). This has been confirmed elsewhere; Mickleborough T D et al., Am. J. Respir. Crit. Care Med. 168 (10), 1181-9 (2003) have shown that the daily intake of 3.2 g of EPA and 2.2 g of DHA in the form of fish oil had no effect on the pulmonary function before exertion of elite athletes.
SUMMARY OF THE INVENTION
In one aspect, the invention provides a pharmaceutical composition comprising a pharmaceutically-acceptable excipient and at least one phospholipid of the general formula (I)
wherein one of R 1 or R 2 represents a docosahexaenoyl residue (DHA) and the other represents a saturated or unsaturated acyl residue containing 8 to 24 carbon atoms, or both R 1 and R 2 represent independently and at each occurrence a docosahexaenoyl residue (DHA); and R 3 represents a choline residue, a serine residue, an ethanolamine residue, an inositol residue, a glycerol residue, or hydrogen.
In certain embodiments of the invention, one of R 1 or R 2 represents a docosahexaenoyl residue (DHA) and the other represents a saturated or unsaturated acyl residue selected from a palmitate residue, a stearate residue, an oleate residue, a linoleate residue, or an arachidonate residue.
In certain embodiments of the invention, R 3 represents a choline residue of formula —CH 2 CH 2 N + (CH 3 ) 3 .
In certain embodiments of the invention, the pharmaceutical composition comprises a DHA lecithin.
In certain embodiments of the invention, the pharmaceutical composition comprises a phospholipid of the formula:
In certain embodiments of the invention, the pharmaceutical composition comprises a phospholipid of formula (I) present in partially or fully hydrolysed form.
In certain embodiments of the invention, the pharmaceutical composition is provided in a unit dose comprising an equivalent of 200 mg of DHA.
In certain embodiments of the invention, the pharmaceutical composition is provided in the form of DHA-enriched egg or DHA-enriched egg extracts.
In certain embodiments of the invention, the pharmaceutical composition is provided in a solid or liquid form selected from powder, plain or sugar-coated tablet, capsule, soft capsule, granule, lozenge, suppository, or syrup.
In certain embodiments of the invention, the pharmaceutical composition is provided in the form of a food supplement.
In certain embodiments of the invention, the pharmaceutical composition is an enteral composition.
In certain embodiments of the invention, the pharmaceutical composition is intended for the treatment and/or the prevention of respiratory failure in a patient, particularly in a human.
In other aspects, the invention provides a method for treating or preventing respiratory failure of a patient comprising administering to a patient in need of such treatment or prevention a pharmaceutical composition as described herein.
DETAILED DESCRIPTION OF THE INVENTION
The inventors have now surprisingly shown that an oral supplement of DHA alone in the form of phospholipids at a dose of less than 200 mg/day, allows people with respiratory failure, incapable in their state of performing the least of physical effort for a long duration, to improve, sometimes in a spectacular way, their ability to move. These improvements are linked to the taking of the supplement, disappearing shortly after ceasing to take it, and reappearing on its reintroduction.
In humans, nutritional supplements based on DHA in the form of phospholipids, with the aim of preventing the effects of respiratory failure, have never been described.
Thus, the present invention relates to the use of docosahexaenoic acid (DHA; C22:6 n-3) in the form of phospholipids for the preparation of composition intended for the prevention of respiratory failure.
DHA is a fatty acid from the omega-3 family comprising a carbon chain of 22 carbon atoms and 6 cis-double bonds (C22:6 n-3) with the following formula:
It should be noted that DHA is a fatty acid which has long been known for its protective role towards cardiovascular problems and depression. It is also recommended to pregnant women for the healthy development of the foetus. As a general rule, nutritionists advise the consumption of around 2 mg/kg/day to maintain well-being (Nutritional supplements advised to the French population, Agence Française pour la Sécurité Sanitaire des Aliments, TEC and DOC editions, Paris, 2001). Specific diets also exist, largely based on fish, which enable the DHA content in food to be significantly increased.
Nevertheless, food diets rich in DHA have never shown any particular effects on respiratory failure.
It is, therefore, very unexpected that the inventors have noticed that certain extracts of eggs enriched with DHA, provide a noticeable improvement in the symptoms of respiratory failure.
Moreover, it has been noted that high doses of DHA in the form of fish oils have a tendency to cause bloatedness and diarrhoea, increasing the risk of enteropathy (Burns C. P. et al., Phase I clinical study of fish oil fatty acid capsules for patients with cancer cachexia: cancer and leukemia group B, study 9473, 1999, Clin. Cancer Res. 5(12): 3942-3947).
Thus, the inventors have shown that doses of DHA as low as 200 mg/day are sufficient to give an improvement in the quality of life of people with respiratory failure.
Furthermore, by analysing different parameters of respiratory failure, the inventors realised that DHA-phospholipids from eggs, mainly lecithins, show properties with regard to respiratory failure that are not shown with other forms of DHA, in particular those in the form of triacylglycerides, in their ability to change the fatty acid composition in the red corpuscle membranes.
The subject of the present invention therefore concerns a pharmaceutical composition comprising a pharmaceutically-acceptable excipient and at least one phospholipid of the general formula (I)
wherein one of R 1 or R 2 represents a docosahexaenoyl residue (DHA) and the other represents a saturated or unsaturated acyl residue containing 8 to 24 carbon atoms, or both R 1 and R 2 represent independently and at each occurrence a docosahexaenoyl residue (DHA); and R 3 represents a choline residue, a serine residue, an ethanolamine residue, an inositol residue, a glycerol residue, or hydrogen; as well as methods of treatment and prevention of respiratory failure in a patient, particularly a human, comprising administering the same.
An interesting aspect of the invention resides in the fact that the treatment or the prevention of respiratory failure only requires the administration of an equivalent dose of DHA of between 0.1 and 2.5 mg/kg/day, for an individual of average build of around 75 kg.
An equivalent dose of DHA means the quantity by mass of the DHA residue of formula II:
provided by the phospholipids of formula (I).
A phospholipid of formula (I) is a complex lipid formed from glycerol of which two alcohol groups are esterified by fatty acids (groups R 1 and R 2 ), the third being esterified by phosphoric acid, itself being linked to several compounds (group R 3 ).
Preferably, according to the invention, the docosahexaenoyl (DHA) residue is in position R 2 .
In a particular embodiment of the invention, when one of the groups R 1 or R 2 is an acyl residue, then the acyl residue is selected from a palmitate, stearate, oleate, linoleate or arachidonate residue, but preferably is a palmitate residue.
In another particularly preferred embodiment of the invention, the group R 3 represents a group corresponding to chloine of formula:
—CH 2 CH 2 N + (CH 3 ) 3
Phospholipids, which are suitable according to the invention, are generally found in the form of mixtures of different types of phospholipids of formula (I), and consist particularly of DHA-lecithins, notably phosphorated lipid complexes combined with oils, or predominantly chlonic glycerophospholipids of formula (I). These lecithins are amphoteric, soluble in alcohol, precipitated by acetone and form an emulsion with water. Such lecithins are found most particularly in eggs, which can be enriched or not with DHA.
A method of obtaining DHA-lecithins, notably from eggs of birds, whose feed (diet) has been enriched with DHA, is described, e.g., in the French Pat. Appl. Publ. No. FR 2749133. The DHA lecithins prepared according to this method are particularly suitable for the purposes of use according to the invention.
A preferred embodiment of the invention therefore consists of the use of at least one phospholipid of formula (I) in which the said phospholipid is extracted from eggs, more particularly from eggs enriched with DHA.
Generally, the equivalent dose of DHA, calculated from the body mass and by day is in the range between 0.1 and 2.5 mg/kg/day and more preferably in the range between 0.3 and 2 mg/kg/day. These doses correspond respectively to an average dose of phospholipids of formula (I) calculated from the body mass and by day, in the range respectively between 1 and 70 mg/kg/day, preferably between 3.5 and 50 mg/kg/day and more preferably between 7.5 and 25 mg/kg/day (gross weight of phospholipids).
The phospholipids of formula (I) can be used as they are, that is to say substantially non-associated with other phospholipids or fatty acids. However, due to the fact that it is easier to extract these phospholipids from natural products, the said phospholipids are, more often, used in the form of complexes comprising other phospholipids and/or fatty acids.
According to the invention, the phospholipids of formula (I) can be used in the form of total or partial hydrolysates. These hydrolysates generally consist of free DHA and as necessary, other fatty acids arising from phospholipids of formula (I). Such hydrolysates are obtained by standard methods, for example, by reacting enzymes such as pancreatic phospholipase and pancreatic lipase on the phospholipids of formula (I).
The term “enteral formulation,” as used herein, refers to a composition allowing for the introduction of a reagent by the digestive route. A useable enteral composition according to the invention can assume different forms, and can consist notably of a solid or liquid pharmaceutical composition in the form of a powder, plain or sugar-coated tablets, capsules, soft capsules, granules, lozenges, suppositories, syrups, etc.
Taking into account the fact that the phospholipids of formula (I) previously described show no toxicity to humans, the composition according to the invention can take the form of a food supplement. Such a food supplement is particularly recommended to improve the quality of life of people with respiratory failure, and even for prevention, before the first symptoms of the illness are noticed.
In another particular embodiment of the invention, the composition can be incorporated into a foodstuff, thus enriching it in DHA.
The example given below intends to illustrate the invention in a non-limiting way.
EXAMPLE
The effect of “phospholipid” treatment was evaluated by the administration of a dose of 140 mg/day of DHA in the form of egg yolk powder (10 g/day) containing predominantly, phospholipids in the form of DHA to individuals prone to respiratory insufficiency. It was the tendency to breathlessness that was evaluated during the transition from a resting state to a state of exertion.
State of exertion means, in the current test, the transition from a resting state to exertion proportional to the recognised capacities of the individuals. The improvement was based on the tendency to breathlessness of the individual during the state of exertion.
The placebo used consisted of soft capsules of ethyl ester of DHA (175 mg/day). The esters of fatty acids are slightly less well metabolised than triacylglyceride and phospholipid forms, hence the use of a dose 25% higher for the placebo.
The following procedure was carried out:
5 individuals, 3 women and 2 men, aged between 60 and 83 years, with weights of between 72 and 109 kg and heights of between 145 and 175 cm, received a placebo for 3 weeks. At the end of this supplementation, a check-up of their respiratory insufficiency was carried out.
Then, the 5 individuals received 3 weeks of “phospholipid” treatment and another check-up of their respiratory insufficiency was carried out.
Then, the supplementation of the DHA phospholipid was stopped for 6 weeks at the end of which, a further check-up was performed.
Then, the supplementation was resumed for 3 weeks and a check-up was carried out.
The table below summarises the severity of the respiratory insufficiency of the people before and after supplementation, with the placebo or with the composition according to the invention.
Dyspnoea
After treatment
Before treatment
Placebo
“phospholipids”
Upon
Upon
Upon
Patient
At rest
exertion
At rest
exertion
At rest
exertion
A
++
++
ND
+
+
B
+
++
+
++
0
+
C
0
+
0
+
0
0
D
+
++
+
++
0
0
E
+
++
+
++
0
0
Legend: 0: no respiratory insufficiency; +: mild respiratory insufficiency; ++: severe respiratory insufficiency; ND: not determined
These results show a decrease, even a disappearance, of the tendency to breathlessness of people having received a supplement of DHA phospholipids, whether it be after supplementation in a resting state or in a state of exertion.
These results point towards a DHA phospholipid supplementation improving the quality of life of those with respiratory failure.
It is interesting to note that when the supplementation of DHA phospholipids is stopped, patients revert to their condition as it was before taking the supplements and when supplementation is recommenced, the improvements noticed before stopping the supplements are reproduced. The effect of DHA phospholipid supplementation is therefore transitory and cannot be considered a therapeutic treatment.
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Taught are pharmaceutical compositions comprising at least one phospholipid having at least one docosahexaenoyl (DHA) residue, such as a lecithin-DHA-type phospholipid, and methods for treating or preventing respiratory failure of a patient comprising administering these pharmaceutical compositions to a patient in need of such treatment or prevention.
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This is continuation of application Ser. No. 08/102,303 filed on Feb. 2, 1993, now U.S. Pat. No. 5,390,988, which is a continuation-in-part of application Ser. No. 07/829,927 filed on Feb. 4, 1992, abandoned.
TECHNICAL FIELD
The invention of this document deals broadly with vehicle operation and control systems. More specifically, however, it deals with a pilot device, retrofitable to an ABD control valve system and other systems installed in a car of a train, for effecting generally uniform and substantially instantaneous application and releasing of air brakes among the various cars of the train in which the pilot device is installed. The focus of the invention is a simple and relatively inexpensive device which can be incorporated into existing air brake systems.
BACKGROUND OF THE INVENTION
Air brake systems are known in the prior art and have been used in freight train braking systems for a number of years. For various reasons, it is particularly desirable that the air brakes of multiple cars in a train be applied and released generally uniformly and substantially instantaneously. Among these reasons are to deter and, if possible, eliminate property damage, bodily injury, and even possible loss of life which might occur as a result of non-uniform and/or sequential (that is, "domino effect") application and/or release of brakes among the various cars. Such non-uniform and sequential brake application and/or release can, if it becomes exaggerated, lead to damage of cars, derailment, significant property damage, and even personal injury or loss of life.
A rudimentary air brake comprises a piston housing having a piston disposed reciprocally therein. The piston stem is stepped to accommodate a graduating valve and to provide for engagement, by a shoulder of the piston stem, of a slide valve, both of which are received within the housing. Fluid communication exists between the housing, at a location remote from an end of the housing into which air from a brake pipe is introduced, and an auxiliary reservoir.
During normal operation of the train, air in the brake pipe maintained at a defined pressure enters the piston housing through a port at one end thereof. In this condition, air from the brake pipe engages the face of the piston to move the piston to one end of a throw along which the piston reciprocates. With the piston in this position, known as the charging position, air passes around the circumferential extremity of the piston face and passes throughout the piston housing and into the auxiliary reservoir. The auxiliary reservoir will become charged substantially to the same pressure as that in the brake pipe.
When the engineer desires to activate the air brake, pressure in the brake pipe is decreased by manipulation of an automatic brake valve in the locomotive. The reduction of pressure in the brake pipe is, in turn, sensed at the face of the piston in the housing. As a result, pressure in the auxiliary reservoir will be at a higher level than that in the brake pipe and that sensed at the face of the piston. As a result, the pressure in the auxiliary reservoir will serve to urge the piston within its housing in a direction toward a port through which pressure in the brake pipe is introduced into the housing.
The slide valve is provided with a channel which is, initially, obstructed by the graduating valve seated within a recess formed within the stem of the piston. As the piston face moves, however, it drags the stem and, concurrently, the graduating valve to open a port to allow pressure from the auxiliary reservoir to enter into the channel through the slide valve. The slide valve is, in turn, moved by the piston stem to a location in which the channel through the slide valve is in communication with both the interior of the piston housing (and the auxiliary reservoir), on the one hand, and a pipe to the brake cylinder, on the other. When the brake assembly achieves this configuration, it is said to be in an application position. Air passes from the auxiliary reservoir, through the housing, through a pipe, and into the brake cylinder to urge the brake piston, to overcome a bias, to a location at which the brake will be applied.
Discharge of air within the auxiliary reservoir/piston housing assembly to the brake cylinder will result in a reduction of pressure within the auxiliary reservoir/piston housing assembly. As this occurs, the piston head and attached stem will be urged away from the application position back toward a location intermediate the charging position and the application position. The piston stem, concurrently, drags the graduating valve along with it. The slide valve, however, remains, when the piston is in the lap position, in the same location it occupies when the assembly is in the application position. With this relationship of the various components, pressure will be maintained in the brake cylinder, since the graduating valve obstructs escape of air in the cylinder and its charging pipe through the channel formed in the slide valve. Lap position will continue to be maintained as long as no adjustment to air pressure in the brake pipe is made.
When the engineer desires to release the brake, the automatic brake valve within the locomotive will be manipulated to increase pressure in the brake pipe. This increased pressure acts upon the face of the piston and functions to return the piston to its charging position. As the piston is moved toward its charging position, a shoulder defined within the piston which is intended to engage the slide valve does, in fact, so engage the slide valve. As the slide valve is drawn back to the location it occupies in the charging position, ports are brought into registration with one another through the slide valve, to effect exhaust of the air in the brake cylinder. As the air is exhausted from the cylinder, the brake piston is returned to its withdrawn position to release the brake. It will be understood that the level to which the engineer increases the brake pipe pressure is that at which it was originally maintained (that is, the predetermined pressure maintained at the charging position) at which discussion of the braking cycle initiated.
The discussion of the prior art at this point has been restricted to a train car having an air brake system installed therewithin. It will be understood, however, that when multiple cars comprise the overall train, each individual car will have a substantially identical braking system installed. The braking system of each car is serviced by a common brake pipe extending the length of the train. As will be understood in view of this disclosure, "sequential" application and releasing of brakes of cars along the line will, to some extent, occur. This results from pressure reduction conveyance along the brake pipe and other factors.
It will be understood that the system described hereinbefore is rudimentary. Consequently, any problems inherent in such a system would be exacerbated.
In recognition of the lack of refinements and fine-tuning resulting in less than a perfect air brake system, various attempts have been made to improve upon the basic system. One improved structure is embodied in a component of a freight car braking system known as the ABD control valve. That product is one developed by the Westinghouse Air Brake Co. over twenty-five years ago. That product is described in detail in Westinghouse Air Brake Co.'s INSTRUCTION PAMPHLET G-g-5062-16 of August 1969. It will not, therefore, be discussed in detail herein other than to the extent that it is described in the DETAILED DESCRIPTION OF THE INVENTION portion of this document in illuminating the structure and operation of the present invention. The disclosure of INSTRUCTION PAMPHLET G-g-5062-16 of August 1969 is incorporated herein by reference.
It will be understood that the "SERVICE PORTION" described and illustrated in that Westinghouse document operates generally on the same principles as the basic system described hereinbefore. In the case of the ABD control valve, pressure in the brake pipe is not allowed to pass around the face of the piston in order to effect charging of the auxiliary reservoir. In fact, the face of the piston is sealed by diaphragm, and the air from the brake pipe merely operates on the face of the piston to move slide valves carried by the piston to effect registration of various ports and passageways to charging of the auxiliary reservoir and an emergency reservoir, and other functions. For example, as the piston is moved, a graduating valve carried thereby closes the port of communication between the brake pipe and the auxiliary reservoir as the ABD control valve moves from a charging configuration toward an application configuration.
Having specified these differences, however, it should again be pointed out that the ABD control valve functions substantially on the same principles as the basic system. As a result, initiation and functioning of the braking process are governed by the variation of the brake pipe pressure. Consequently, while some improvements over the basic system are achieved, there are still inherent deficiencies in the ABD control valve. Certainly, it does not provide for generally uniform and substantially instantaneous application and releasing of the brakes of all cars within a train.
It is to these dictates and problems of the prior art that the present invention is directed. It is an adaptor which is able to be used to retrofit an ABD control valve and other braking equipment structures to overcome problems of the prior art.
SUMMARY OF THE INVENTION
The present invention is a braking system applicable for use in railroad trains wherein each car employs an ABD-type control valve as described in Westinghouse Air Brake Co. INSTRUCTION PAMPHLET G-g5062-116 of August 1969. The invention incorporates a block, electro-pneumatic in configuration, which is retrofitable to the fully pneumatic ABD control valve. The block is mounted to the control valve between the service slide valve portion and an accelerated release valve portion of the control valve. The block incorporates a pair of miniature solenoid valves which serve to interrupt and vent air flow in various passages in the control valve. As such, the retrofitable adaptor block accomplishes a "pilot" function.
In view of the nature of the block adaptor, only extremely minor alterations need be made to the basic ABD control valve, and these alterations are merely to permit mounting of the block in accordance with the present invention in a manner so that ports therein are able to be registered with passages in the control valve. It follows that all pneumatic functions of the basic control valve remain substantially unchanged.
In retrofitting an ABD control valve in a manner in accordance with the present invention, an insert to the valve housing would be provided along with gasket material and four replacement bolts. The block adaptor is, in turn, mounted to the insert with ports therein in registration with passages in the adaptor.
The miniature solenoid valves are, of course, actuated electrically. Actuation could be accomplished by one or both of radio/battery or "train wire system" modes. Typically, both modes could be employed to provide back-up operation. Either or both of the modes would be initiated by the engineer at a master control panel in the locomotive. Typically, the controls for the miniature solenoid valves, whether actuation was implemented in a radio/battery mode or a "train wire system" mode, would be slaved to the automatic brake valve. As a result, functioning of the pilot adaptor would automatically be coordinated with the operation of the automatic brake valve to govern operation of the ABD control valve. Consequently, the engineer need not be concerned about performance of multiple functions.
It is an object of the present invention to provide for a retrofit structure, which, when used in combination with an ABD control valve as known in the prior art, effects substantially instantaneous and simultaneous application and release of the brakes of multiple cars of a train. It is also an object of the present invention to provide a structure for accomplishing this objective which is simple and inexpensive.
It is also an object of the present invention to provide structure which will allow the release of a stuck brake. It is also an object of the present invention to provide a structure which will allow a graduated release of the train brake. It is also an object of the present invention to provide a structure which will allow an accelerated direct release of the train brake.
It is also an object of the present invention to allow the continued use of the in-place pneumatic brake system in the event of a malfunction in the electrical transmission system of the retrofit structure. Further, it is an object of the present invention to allow a relatively uniform and instantaneous operation of the electro-pneumatic brake system even though several individual cars dispersed through the train may have inoperative electrical components.
The present invention is thus a structure which effects braking of the cars in a train in an improved fashion over the methods known in the prior art. More specific features and advantages obtained in view of those features will become apparent with reference to the DETAILED DESCRIPTION OF THE INVENTION, appended claims, and accompanying drawing figures.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 is a schematic sectional elevational view of the service portion of an ABD control valve, retrofitted with the pilot device in accordance with the present invention, in charging position;
FIG. 2 is a view similar to FIG. 1 wherein the control valve is in preliminary quick service position;
FIG. 3 is a view similar to FIG. 1 wherein the control valve is in service position;
FIG. 4 is a view similar to FIG. 1 wherein the control valve is in either lap position, stuck brake condition or graduated release position;
FIG. 5 is a view similar to FIG. 1 wherein the control valve is in release and recharge position or in accelerated direct release position.
FIG. 6 is a schematic view illustrating a first control means embodiment; and
FIG. 7 is a schematic view illustrating a second control means embodiment.
DETAILED DESCRIPTION OF THE INVENTION
Referring now to the drawings wherein like reference numerals denote like elements throughout the several views, FIG. 1 illustrates the braking system employing the present invention with components in a charging position. With the various components as indicated in FIG. 1, brake pipe air flows from the locomotive 50 through the line of train cars through axially-aligned brake pipe segments of each car which are in fluid communication with each other. Within each car, a pipe segment diverges from the brake pipe segment to provide air to the control valve at the designated pressure. The air passes from the pipe segment through a combined dirt collector and cut-out cock and into a strainer and chamber b. The brake pipe air, thereafter, flows, in the service portion of the control valve, through choke 27 and passage b1 to a chamber B, a wall of which includes the face of the service diaphragm piston 11. Brake pipe air also passes through chamber C of an accelerated release valve diaphragm piston 29. Passage of brake pipe air to chamber C is through a passage in which is a disposed application solenoid valve S1 and a pressure sensor PS1.
The auxiliary reservoir (not shown) is charged through chamber Y which is connected to the auxiliary reservoir through passage a1. Choke 26 in passage b2 controls the rate at which chamber Y is charged. As a result, Chamber B is charged at a faster rate, and the service diaphragm piston is, thereby, maintained in release position. As a result, the slide valve 13 and graduating valve 12 are also in release position.
Auxiliary reservoir air in chamber Y flows through release solenoid valve S2 to chamber T on the auxiliary reservoir air side of piston 29. As in the case of chambers B and Y, the auxiliary reservoir air pressure is initially lower than the brake pipe air pressure in chamber C because of controlling rates of charging by appropriate choking mechanisms.
Auxiliary air in chamber Y flows to the emergency reservoir (not shown) through aligned ports n, m in the service graduating and service slide valves, respectively, and through passages e4, e2 and e. When fully charged, pressure in the emergency reservoir, auxiliary reservoir, and brake pipe will be equalized. It should be noted that emergency reservoir air in chamber M surrounds accelerated release check valve 30. Accelerated release check valve 30 is shown in a closed position in FIGS. 1-4.
Referring now to FIG. 2, when the engineer moves the automatic brake valve handle 52 in the locomotive to the position corresponding to service position of the ABD control valve, such movement, in addition to accomplishing a number of things to be discussed hereinafter, functions to effect energization of application solenoid valve S1 as a result of valve S1 operation being slaved to manipulation of handle 52. This allows brake pipe air to be exhausted at a controlled rate through exhaust 40. Consequently, a local reduction of brake pipe air from passage b8 and chamber C and from the upper face of service diaphragm piston 11 result. The greater auxiliary reservoir pressure in chamber Y moves the service piston upward to allow service graduating valve 12 to connect the brake pipe air to the quick service volume and exhaust to atmosphere through choke 39.
Continued flow of brake pipe air through chokes 39 and exhaust 40 causes the service diaphragm piston 11 to move to service position, as illustrated in FIG. 3. With piston 11 in this position, auxiliary reservoir air flows past the service graduating valve 12 and through passage c5 and other passages in the control valve to the brake cylinder. A piston in the brake cylinder is biased away from an actuation position, for example, by a coil spring. As auxiliary reservoir air flows to the brake cylinder, it builds up pressure within the cylinder to force the piston, against the bias, to apply the brakes.
Brake pipe air also flows to the brake cylinder through quick service limiting valve 32. Such flow continues until the brake cylinder reaches 10 p.s.i. At that time, the limiting valve closes off further flow of the brake pipe air to the cylinder.
As the various components move to their service positions, egress of air from the emergency reservoir is cut-off by the service slide valve 13 which occludes the emergency reservoir's egress port. Emergency reservoir air, therefore, remains at the pressure to which it was charged previous to movement of the automatic brake valve.
When the desired brake pipe pressure reduction has been completed, manipulation of handle 52 causes, the master controller 52 in the locomotive 50 to function to cause a break in the electric signal initiating movement of the application solenoid valve S1. As a result, venting of brake pipe air through exhaust 40 is terminated. Auxiliary reservoir air continues to flow, however, to the brake cylinder until the pressure in chamber Y is reduced to a level slightly below brake pipe pressure in chamber B. When this occurs, service graduating valve moves to what is known as "lap position" (shown in FIG. 4), and further flow of auxiliary reservoir air to the brake cylinder is cut-off. Emergency reservoir air flow through passage e4 remains precluded by the service slide valve 13.
When the engineer in the locomotive 50 wishes to release the brakes, he moves the automatic brake valve handle 52 to running or release position. This permits brake pipe air to flow into the train line brake pipe. As this movement of the automatic brake pipe handle 52 is accomplished, the master controller 54 is activated to effect energization of release solenoid valve S2. The release solenoid valve S2 moves to the position shown in FIG. 5. The small volume of air trapped in chamber T on the auxiliary reservoir air side of piston 29 is rapidly exhausted to atmosphere through exhaust port 40. Brake pipe air on the opposite face of piston 29 effects immediate movement of the piston to the left, as viewed in FIG. 5. As a result of this movement, accelerated release check valve 30 unseats and permits emergency reservoir air in chamber M which, as will be recalled, remained at the pressure to which it was charged previous to the brake application, to flow through check valve 38 and passages b8 and b1 to chamber B above service piston 11. The brake pipe pressure in chamber B has, again, become greater than the auxiliary reservoir pressure in chamber Y, and the service slide valve is forced to release position. This permits cavity t in the slide valve 13 to connect the brake cylinder to exhaust at a retainer. The brakes are, thereby, released.
As this is occurring, brake pipe air from the locomotive continues to flow through the train line holding the service pistons in release positions while recharging the reservoirs.
It is notable that the release solenoid valve S2 can be energized for a relatively short period of time (i.e., 3 to 4 seconds), and a relatively instantaneous release of brakes will occur. The presence and operation of valve S2 significantly decreases the period of time necessary to effect brake release, and release will occur substantially simultaneously throughout all cars of the train.
When release solenoid valve S2 is de-energized, auxiliary reservoir air is, again, permitted to enter chamber T on the auxiliary reservoir air side of the accelerated release piston 29. When brake pipe pressure and auxiliary reservoir air pressure on opposite sides of piston 29 are nearly equal, check valve 30 automatically returns to its closed position. This occurs as a result of the action of biasing spring 31.
As will be seen in view of this disclosure, the operation of an ABD pneumatic control valve retrofitted in accordance with the present invention will operate substantially in the same manner as will such a valve which has not been retrofitted. Accomplishment of braking and releasing of brake functions, however, will occur substantially more rapidly when the present invention is incorporated than when it is not.
FIG. 4 illustrates the position that solenoid S3 and pressure sensor PS2 occupy in a stuck brake condition. Solenoid S3 and pressure sensor PS2 are located in the manifold of the block adaptor and are connected to brake cylinder passage c1 by means of small tube c1a. FIG. 4 shows the service piston 11 and service slide valve 13 in service lap position, the position in which the vast majority of stuck brakes occur.
As described previously in the BACKGROUND OF THE INVENTION, when the engineer desires to release the brakes, the automatic brake valve will be manipulated to increase pressure in the brake pipe. This increased pressure acts upon the face of the piston and functions to return the piston to its release and charging position. As the piston, together with its slide valve, is moved to release and charging position, ports are brought into registration with one another (through the slide valve) to effect exhaust of the air in the brake cylinder. As the air is exhausted from the cylinder, the brake piston is returned to its withdrawn position to release the brake.
On occasion, due to a slow build-up of the brake pipe pressure on a long train, a car with a defective brake caused by air leakage in the control valve, excessive slide valve friction or other malfunction, may not release. In this situation, the slide valve remains in service lap position, thereby preventing the air in the brake cylinder from exhausting to atmosphere. This, by far, is the most common cause of a stuck brake.
Referring now to FIG. 4, which illustrates the braking system employing the present invention with components shown in an abnormal service lap position, brake cylinder air in passage c5 is out of registration with the exhaust passage leading to the exhaust at the retainer. The precondition for a stuck brake occurs when the initial build up of brake pipe pressure in Chamber B fails to move the service slide valve from service lap position to release and charging position. During this critical period, brake pipe air will continue to flow into Chamber Y below the service piston through passage b2 and slide valve stabilizing breather port o. Any brake pipe leakage past the service slide valve will contribute to the eventual equalization of brake pipe air in chamber B with the auxiliary reservoir air in Chamber Y. In this situation, nothing in the prior art is capable of releasing the brake pneumatically. Subsequent brake pipe reductions will add to the pressure build up in the brake cylinder, resulting in slid flat wheels and possible derailment. Upon visual detection, which is particularly difficult during the hours of darkness, the train must be stopped to allow the air in the brake cylinder to be released manually. At the same time, the brake system of the car must be cut out manually by closing the brake pipe cut-out cock. If the car is safe to move, it must be set out at the next terminal where repairs can be made.
The present invention employs a microprocessor Mp as part of the adaptor package. In conjunction with a computer on the locomotive, the microprocessor continuously monitors the functions of each car's brake system, including a stuck brake condition. The pressure sensor PS2 electronically reports the pressure in the brake cylinder of each car, thus informing the locomotive engineer whether or not the train brakes are applied or released. When the train brakes are in the release mode, a stuck brake condition is quickly and easily detected by the brake cylinder pressure sensor PS2 on the defective car. Since the computer has memorized the location of each car in the train sequentially, the computer allows the engineer to isolate the defective brake for remedial action. By closing a switch on the locomotive, the microprocessor on the specific car will act to energize solenoid S3 which will move to open position, allowing the auxiliary reservoir air to exhaust to atmosphere through exhaust 40. The sudden reduction of auxiliary reservoir air in chamber Y below service diaphragm piston 11 allows the greater brake pipe pressure in chamber B to force the piston and service slide valve 13 to release position (FIG. 5) where exhaust cavity t in the slide valve connects the brake cylinder passages to the exhaust at the retainer. When the brake cylinder pressure drops a predetermined amount (an indication that the service slide valve has returned to release position), the microprocessor will automatically deenergize solenoid valve S3, thus limiting the reduction of auxiliary reservoir air to the minimum level necessary to release the brake.
FIG. 4 also illustrates the position that solenoid S4 and pressure sensor PS2 occupy when in graduated release position. Solenoid S4 and pressure sensor PS2 are located in the manifold of the block adaptor and are connected to brake cylinder passage c1 by means of small tube c1a. FIG. 4 shows the service piston 11 and slide valve 13 in service lap position, which holds air pressure in the brake cylinder following a service brake application. With the service slide valve in lap position, nothing in the prior art will allow a graduated release of the brakes. With the present invention, the engineer can make a graduated reduction of brake cylinder pressure by actuating solenoid S4, which will connect brake cylinder passage c1 to the atmosphere at exhaust 40. This action will allow a graduated release of brake cylinder pressure in controlled increments down to 10 pounds, the setting of the quick service limiting valve 32. The final 10 pounds can be released by actuating solenoid S2, as shown in the normal release and recharge position (FIG. 5). The graduated release feature will provide significant benefits when stopping and when braking on undulating, descending grades.
FIG. 5 illustrates the position that solenoid S4 and pressure sensor PS2 occupy when in accelerated direct release position. When releasing the brake, either pneumatically or electro-pneumatically, all of the air in the brake cylinder must pass to the atmosphere through restricted exhaust choke 25. To facilitate a faster release, solenoid S4 is activated to allow brake cylinder air in passage c1 and c1a to release directly to atmosphere through exhaust 40. The rapid discharge of air through exhaust 40 supplements the exhaust of brake cylinder air through restricted choke 25, thus effecting an accelerated release of the brakes.
Numerous characteristics and advantages of the invention covered by this document have been set forth in the foregoing description. It will be understood, however, that this disclosure is, in many respects, only illustrative. Changes may be made in details, particularly in matters of shape, size, and arrangement of parts without exceeding the scope of the invention. The invention's scope is, of course, defined in the language in which the appended c1aims are expressed.
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A pilot mechanism for improving operation of various functions of the pneumatic brake of a train. The mechanism includes solenoid valves, controllable by either a radio/battery mode of operation or a train wire system mode of operation. The solenoid valves can be interposed in various passages in fluid communication with passages of a conventional ABD control valve, as modified to enable operation of the invention, to permit substantially immediate venting of air in those passages to atmosphere.
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BACKGROUND OF THE INVENTION
This invention relates to a lighting assembly for use as vehicle headlamps.
A variety of vehicle headlamp assemblies are in use or have been proposed. Regardless of what type of headlamp assembly is used, it is necessary to properly aim the headlights to direct the light from the headlights in a specific direction from the vehicle. Proper aim of a headlight ensures that a driver is provided with the optimum lighting conditions while driving.
Traditionally, headlamps were aimed through external mounting arrangements. Such arrangements typically included manipulating adjustment screws to change the position of a headlamp housing. The adjustment screws were typically within a mounting assembly that mounted the headlamp assembly to the body or frame of the vehicle. More recently, internally aimed headlamp assemblies have been introduced. Internally aimed headlamp assemblies include, for example, a housing that is fixedly mounted relative to the frame of the automobile. Adjustment mechanisms are used to alter the position of a reflector and the headlight within the headlamp assembly to appropriately aim the headlight. Although internally aimed headlamp assemblies have advantages compared to externally aimed headlamps, there are also drawbacks.
A significant drawback associated with typical internally aimed headlamp assemblies is that the arrangement of components is relatively complex. Moreover, assembling an internally aimed headlamp is typically relatively complex and time-consuming. There is a need, therefore, for an internally aimed headlamp assembly that is readily and efficiently assembled.
This invention addresses the needs discussed above. Moreover, this invention overcomes the drawbacks associated with typical headlamp assemblies. This invention includes unique snapping engagements among various components of a headlamp assembly that render the manufacturing and assembly process far more economical than previously proposed assemblies.
SUMMARY OF THE INVENTION
In general terms, the invention is a light assembly for use on vehicles. The light assembly includes a housing having a rear portion and a front portion with a channel including two side walls. The channel extends along at least a portion of a peripheral edge on the front portion of the housing. A bezel is received within the housing and has a tab member that engages one of the channel side walls on the housing. A lens has a flange portion that is at least partially received within the channel and the tab member on the bezel engages the flange portion to maintain the flange portion within the channel on the housing. Accordingly, the housing, bezel and lens are all held together by the tab member on the bezel.
The tab member on the bezel is used to hold the lens, the housing and the bezel in place temporarily. An adhesive is provided within the channel on the housing that cures to form a permanent bond between the housing, bezel and lens.
A reflector is supported within the housing for movement relative to the housing, the bezel and the lens. The reflector supports the headlamp bulbs, which are mounted onto the reflector through bulb retainers. The bulb retainers include snapping engagement surfaces that facilitate easy assembly. The reflector is supported within the housing by an adjustment mechanism, which is connected to the reflector through a snapping retainer.
The various features and advantages of this invention will become apparent to those skilled in the art from the following detailed description of the presently preferred embodiment. The drawings that accompany the detailed description can be described as follows.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 is an exploded, perspective view of a headlamp assembly designed according to this invention.
FIG. 2 is a rear elevational view of the embodiment of FIG. 1 when assembled.
FIG. 3 is a cross-sectional view of the embodiment of FIG. 2 taken along the lines 3--3.
FIG. 4 is a partially cross-sectional view of the embodiment of FIG. 2 as seen from the top of the illustration of FIG. 2.
FIG. 5 is a cross-sectional illustration of a preferred engagement between several components of a headlamp assembly designed according to this invention.
FIG. 6 is a partial, cross-sectional view of another feature of a headlamp assembly designed according to this invention.
FIG. 7 is a cross-sectional view of another feature of a headlamp assembly designed according to this invention.
FIG. 8 is a perspective view of a retainer socket designed according to this invention.
FIG. 9 is a cross-sectional view taken along the lines 9--9 in FIG. 8.
FIG. 10 is a cross-sectional view taken along the lines 10--10 in FIG. 8.
FIG. 11 is a perspective view of a bulb retainer designed according to this invention.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT
FIG. 1 is an exploded, perspective view of a headlamp assembly 20. A housing 22 has a generally open front portion and a generally enclosed rear portion. A primary reflector 24 is supported within the housing 22 as will be described in more detail below. A secondary reflector 26 is also included for a turn signal light within the headlamp assembly 20. A bezel 28 is generally received within the open portion of the housing 22. A lens 30 generally covers across the open portion of the housing 22. An elastomer molded close-out seal 32 is received around the periphery of the engagement between the lens 30 and the housing 22.
In the illustrated embodiment two headlight bulbs 34 are included. The headlight bulbs 34 are received through the openings 36 in the primary reflector 24. A pair of bulb retainers 38 maintain the bulbs 34 within the openings 36 so that the bulbs 34 remain fixed relative to the primary reflector 24. Details regarding the retainers 38 will be discussed below.
A pair of openings 40 on the rear portion of the housing 22 provide access to the bulbs 34 from outside of the assembly 20. A pair of caps 42 are received on the rear portion of the housing 22 to close off the openings 40 once the assembly 20 is complete. As will be described in more detail below, the caps 42 are selectively removable to provide access to the bulbs 34.
A turn signal bulb 44 is mounted within an opening 46 on the rear portion of the housing 22. The turn signal bulb 44 also protrudes through an opening 48 on the secondary reflector 26. The secondary reflector 26 is preferably rigidly mounted within the housing 22.
The primary reflector 24 is movably mounted within the housing 22. An adjustment mechanisms includes an adjustor 50, which is a conventional linear actuator device. A shaft having a ball portion 52 extends from the adjustor 50 through an opening 54 in the rear portion of the housing 22 and is received within a ball-retaining socket 56. The ball-retaining socket 56 is snappingly engaged into an opening 58 on the primary reflector 24. Details regarding the snapping engagement between the retainer socket 56 and the opening 58 will be provided below. Similarly, an adjustor 60 includes a ball portion 62 that protrudes through an opening 64 in the rear of the housing 22. The ball portion 62 is received within a retainer socket 66 that snappingly engages the primary reflector 24 at the opening 68.
FIG. 2 illustrates the embodiment of FIG. 1 in an assembled condition as seen from the rear of the housing 22. FIG. 3 is a cross-sectional view taken along the lines 3--3 in FIG. 2. FIG. 4 is a cross-sectional view of the same embodiment as seen from the top of the illustration in FIG. 2. FIGS. 2, 3 and 4 generally illustrate the arrangement of the various components of the assembly 20 when it is in an assembled condition.
An important feature of this invention is the manner in which the assembly 20 is assembled. Specifically, a unique arrangement provides a connection between the bezel 28, the housing 22 and the lens 30. This snapping engagement is highlighted in FIG. 5. The bezel 28 includes a tab member 72 that has a protruding finger portion 73. The tab member 72 snappingly engages the housing 22 and the lens 30. Specifically, the finger portion 73 is snappingly received within an opening 74 on the housing 22 and protrudes through an opening 76 on the lens 30. During the preferred assembly procedure, the bezel 28 is moved relative to the housing 22 such that the finger member 73 rides along the ramped portion 78 on a first sidewall 80 until the finger member 73 snaps into place within the opening 74. A second sidewall 82 on the housing 22 extends generally parallel to the first sidewall 80. The first and second sidewalls 80 and 82 form a channel 83 that preferably extends around the entire periphery of the front portion of the housing 22. Curable, sealing adhesive 84 preferably is disposed within the channel on the housing 22.
After the bezel 28 is snapped into engagement with the housing 22, the lens 30 is then snapped into place. As the lens 30 is moved toward the housing 22 a flange 86 on the lens 30 is moved into the channel between the first and second sidewalls 80 and 82. The finger portion 73 rides along a ramped surface 88 on one end of the flange 86 until the finger portion snappingly engages the opening 76. At this moment, the tab member 72 on the bezel 28 maintains the bezel 28, the housing 22 and the lens 30 in a fixed position relative to each other. In the preferred embodiment, there are three tab members 72 along a bottom portion of the bezel 28 and two tab members spaced along a top portion of the bezel 28. There also are corresponding numbers of openings 74 on the housing 22 and openings 76 on the lens 30, each one for receiving a finger member 73.
The snapping engagement of the bezel 28, the housing 22 and the lens 30 preferably is used for temporarily maintaining those three portions of the assembly in a fixed position relative to each other. The curable adhesive and sealant 84 is then allowed to cure, which permanently fixes the bezel to the housing and the lens, respectively. Those skilled in the art will be able to choose from among commercially available adhesives to realize a permanent connection between the bezel, the housing and the lens that also creates a fluid-tight seal along the interface between the lens and the housing. The elastomer seal 32 preferably engages the lens 30 and the second sidewall 82 on the housing 22 as illustrated in FIG. 5. The elastomer seal provides a second fluid-tight seal around the perimeter of the connection between the lens 30 and the housing 22. In one embodiment, the elastomer seal 32 is not used and the adhesive 84 acts as a sealant for sealing off the interface between the lens and the housing. In the preferred embodiment, however, the channel formed by the two sidewalls 80 and 82 extends around the entire periphery of the housing 22 and the molded close-out seal 32 is received along the entire periphery of the housing 22 and the lens 30.
Referring again to FIGS. 3 and 4, the aim of the lights within the headlamp assembly is adjusted by moving the reflector 24 within the housing 22. It is important to note that the primary reflector 24 is movably supported within the housing 22 solely by the connections between the reflector 24 and the adjustors 50 and 60. The adjustor 50, which is a conventional linear actuator, is used to adjust the horizontal aim of the headlight. A shaft 90 extends out of the adjustor 50. An adjustment screw 92 can be manipulated (i.e., turned) to cause the shaft 90 to move in a fore and aft direction relative to the adjustor 50. As the shaft 90 moves, the ball portion 52 also moves according to the direction arrows shown in FIG. 3, for example. Since the ball portion 52 is snappingly received within the retainer socket 56, which is snappingly engaged to the reflector 24, the reflector 24 moves responsive to movement of the shaft 90 and the ball portion 52. The adjustor 50 can, therefore, be used to adjust the horizontal angle of the aim of the lamp 34. A center line 100 of the lamp aim is schematically illustrated in FIG. 3. Movement of the shaft 90 and the ball portion 52 cause the reflector 24 to move, which results in the center line 100 of the lamp aim moving according to the direction arrows 102 and 104, respectively.
Similarly, adjustor 60 includes a shaft 94 and an adjustment screw 96. Manipulation of the adjustment screw 96 causes the shaft 94 to move in a fore and aft direction relative to the adjustor 60. This motion is schematically illustrated by the direction arrows in FIG. 4, for example. Movement of the shaft 94 causes the ball portion 62 and, therefore, the reflector 24 to move in a generally horizontal plane. Accordingly, the center line 100 of the headlight aim moves according to the direction arrows 106 and 108, respectively.
As seen in FIGS. 1, 2 and 6, the bubble level 70, which is connected to the primary reflector 24, provides an indication of the angular orientation of the center line 100 of the headlamp aim. FIG. 6 illustrates a snapping level cover 120 that includes a tab member 122 that is received within a groove 124 on the housing 22. A snapping engagement member 126 abuts an engagement surface 128 on the housing 122. The placement of the tab member 122 within the groove 124 and the engagement between the snapping member 126 and the surface 128 ensure that the cover 120 does not move in a vertical direction (according to the drawing). A pair of engagement members 130 and 132, which are formed on the housing 22, are nestingly received within corresponding notches in the cover 120 to ensure that the cover 120 does not move in a generally horizontal direction (according to the drawing). When a technician, for example, desires to view the level 70 to ensure proper headlamp aim, the engaging member 126 is pulled generally away from the housing 22 and the entire cover 120 is moved according to the direction arrow 134. To replace the cover 120, the tab 122 is inserted within the groove 124 and the cover 120 is moved in a generally arcuate direction (according to arrow 134) until the snapping engagement member 126 appropriately snaps into position against the engagement surface 128.
Referring now to FIG. 7, another feature of this invention will be described. The caps 42 close off the openings 40 after the headlight assembly has been completed. The housing 22 includes projections 140 and 142 that extend generally outward and away from the rear portion of the housing 22. The caps 42 include a generally arcuate portion 144 that extends across the opening 40. At each end of the generally arcuate portion 144 is an engagement surface 146. The engagement surface 146 is biased against the extensions 140 and 142 because of the curvilinear lip portion 148. The caps 42 preferably are made from an elastomeric material. Accordingly, the configuration of the curvilinear lip portions 148 provides a bias of the engagement surface 146 against the extensions on the housing 22.
Any exterior force on the arcuate portion 144 caused by a fluid that is external to the housing 22 effectively forces the engagement surfaces 146 against the extensions on the housing, thereby enhancing the sealing characteristics provided by the caps 42. In the event that one of the caps needs to be removed to replace a bulb 34, for example, a tab portion 150 can be pulled in a generally arcuate direction (according to the arrow 152) away from the housing 22 to remove the cap 42. The caps 42 ensure a fluid-tight seal on the openings 40 of the housing 22 because any pressure on the caps 42, other than the schematically illustrated generally arcuate motion of the tab member 150, will effectively enhance the sealing characteristics of the caps rather than cause them to be removed from the housing 22.
As mentioned above, the ball portions 52 and 62 of the adjustors 50 and 60 are respectively connected to the primary reflector 24. FIG. 8 illustrates a preferred embodiment of the socket retainer 56. The entire retainer 56 preferably is made of a generally resilient elastomer or plastic material. The retainer 56 snappingly engages the opening 58 on the primary reflector 24. The retainer 56 includes a generally annular ring portion 160. A basket portion 162 extends generally away from the ring portion 160. A flange on the reflector 24 that extends around the opening 58 is received between an engagement surface 164 on the ring portion 160 and engaging tabs 166 on the basket portion 162, respectively. Preferably, four engaging tabs 166 are equally circumferentially spaced around the basket portion 162 in diametrically opposed pairs. The engaging tabs 166 include generally ramped surfaces 168 (shown in FIG. 9) to facilitate moving the basket portion through the opening 58 until the flange on the reflector 24 is engaged within the neck portion 170 on the retainer 56.
The ball portion 52 is snappingly received within the retainer 56 by moving the ball portion through the opening defined by the ring portion 160. A plurality of retaining tab members 172 protrude generally inward within the basket portion 162. In the preferred embodiment, four retaining tabs 172 are equally circumferentially spaced intermittent with the tabs 166. As the ball portion is pushed into the retainer, the retaining tab members 172 flex in a generally radial direction to allow the ball portion 52 to be received within the basket portion 162. After the ball portion has protruded past the retaining tab members 172 they return to a position where they prevent the ball portion 52 from undesirably exiting the basket portion 162.
The ball portion 52 is illustrated in phantom in a received and engaged position in FIG. 10, for example. Accordingly, the resilient engaging tabs 166 and the resilient retaining tab members 172 on the retainer 56 provide a simple, snapping engagement between the ball portion 52 and the opening 58 on the reflector 24. A ball and socket joint is, therefore, provided that facilitates adjusting the position of the reflector 24 within the housing 22. The description of the retainer 56 applies equally to the retainer 66.
An efficient snapping arrangement also preferably is provided for supporting the bulbs 34 on the reflector 24. FIG. 11 illustrates a bulb retainer designed according to this invention. The bulb retainer 38 includes a generally annular ring portion 180. A bottom edge 182 on the ring portion 180 is received against a rear side of the reflector 24. Engaging tab members 184 include an engagement surface 186 that abuts a front surface on the reflector 24. This arrangement is generally illustrated in FIG. 4, for example. As can be appreciated from the drawings, the engaging tab members 184 include a ramped surface that facilitates moving the bulb retainer 38 through the openings 36 in the reflector 24.
The ring portion 180 also includes a plurality of slots 190 that are intermittently spaced with tab portions 192. The bulbs 34 preferably include tabs that are received axially through the slots 190 during an assembly process, for example. The bulb can then be turned so that the tabs on the bulb are tucked beneath the tabs 192 on the ring portion 180. The bulb is then axially aligned within the retainer 38. Abutment surfaces 194 are provided for preventing the bulbs from being pushed too far through the retainers 38. In the preferred embodiment, the bulbs 34 include a base portion 188 that abuttingly engages the engagement tab members 184 and biases them in a generally radially outward direction. The tab members 184 are, therefore, biased into a more solid engagement with the reflector 24. This provides significant advantages in maintaining the position of the bulbs supported on the reflector 24.
The various features of this invention, including the snapping engagement of the bezel to the housing and the lens, the snapping engagement between the ball socket retainer and the reflector, and the snapping engagement between the bulb retainer and the reflector each provide significant advantages compared to other headlamp assemblies. The snapping engagements facilitate economical and relatively simple assembly of a headlamp designed according to this invention.
The foregoing description is exemplary rather than limiting in nature. Variations and modifications to the disclosed embodiment will become apparent to those skilled in the art that do not necessarily depart from the purview and spirit of this invention. Accordingly, the scope of the legal protection accorded to this invention can only be determined by studying the following claims.
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A vehicle headlight assembly includes a snapping engagement between a bezel, a housing and a lens. The snapping engagement positions all three pieces relative to each other during a manufacturing or assembly process. The light bulbs of the headlamp assembly are supported on the internally aimed reflector by bulb retainers that snappingly engage openings in the reflector. The bulbs preferably include housings that bias tab members on the bulb retainers into engagement with the reflector. The reflector is moved within the housing to direct the beam of light from the bulbs. Socket retainers snappingly engage the reflector. Ball members on conventional adjustors are received within the socket retainers so that the adjustors support the reflector within the housing and provide the ability to adjust the angular position of the bulbs and reflector relative to the remainder of the assembly.
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[0001] I claim the benefit under Title 35, United States Code, § 120 to U.S. Provisional Application No. 60/222,857, filed Aug. 4, 2000, entitled PROPYLENE POLYMER HAVING AGREEABLE ODOR CHARACTERISTICS AND SHAPED ARTICLES THEREOF.
BACKGROUND OF THE INVENTION
[0002] 1. Field of the Invention
[0003] The present invention is directed to controlled rheology polymers having improved odor characteristics. More specifically, the present invention is directed to compositions having agreeable odor characteristics comprising a propylene polymer having a melt flow index in the range from 4 to 120 decigrams/minute, di-t-amyl peroxide, and at least one decomposition product thereof.
[0004] 2. Description of Related Art
[0005] The physical properties of polypropylene resins provide several benefits for applications in food, drug, and cosmetic applications. In comparison to polymeric materials such as PET, polypropylene has a lower specific gravity allowing for cost savings in some applications owing to the lower quantity of material required. Good temperature resistance permits polypropylene to be used for “hot filled” liquid containers. Additionally, low moisture vapor transmission makes polypropylene ideal for packaging applications requiring dry environment storage. While the clarity of polypropylene resins do not yet match the clarity offered by polystyrene materials, visual inspection of the packaging contents is still possible. This is an important benefit for some consumer applications and applications such as medical syringes where the ability to perform a visual volume determination is crucial.
[0006] The end use applications for polypropylene are myriad. Polypropylene is often used in consumer applications, such as small appliances (for example, coffee machines and personal coolers). Properties such as lightness, resistance to cracking, thermal resistance, and ease of processing make this material ideal for many uses that directly impact the consumer.
[0007] In the medical industry, polypropylene is perhaps best recognized as the material of choice for disposable syringes. Polypropylene's ability to undergo steam and radiation sterilization without premature degradation is a vital element of this material's success in medical applications. Polypropylene is also used in medical packaging applications such as the storage of intravenous fluids and specimens.
[0008] Ease of processing in blow molding, injection molding, and thermoforming operations makes polypropylene an ideal material for manufacturing the rigid containers often associated with food use. High heat resistance is exploited in applications where precooked meals are supplied in polypropylene containers that are heated in microwave ovens. The polypropylene allows a hot meal to be warmed and served in an inexpensive disposable container that retains its rigidity during the heating cycle.
[0009] Biaxially oriented polypropylene films (BOPP) have seen widespread use in the snack and bakery markets. The low vapor transmission characteristic of polypropylene keeps baked goods moist and fresh in appearance. Snack foods, such as potato chips and chocolate candies, are often packaged in opaque bags manufactured from a combination of BOPP and low oxygen permeability films. Importantly, the high printability of polypropylene films offers the food vendor an opportunity to uniquely label and mark the food product.
[0010] Special requirements regarding safety and performance command a price premium in the resin market. The performance attributes described above for polypropylene permit this resin to be successfully marketed to high-value FDA regulated end uses. Organoleptics present after final manufacture of the resin may affect odor and taste characteristics. These unwanted chemical inclusions have to be carefully controlled. Resin formulations are affected not only by the end user's subjective odor/taste perception but also by regulatory agencies. In the United States, this function is performed by the FDA, which closely regulates the additives that are permitted in food and drug applications. Additives that can negatively impact odor and taste (for example, thioesters) are generally avoided in resin formulations for food applications.
[0011] Many of the end-use applications require resins with specific melt flow characteristics. In most cases, high melt flow material is manufactured from a basic polypropylene resin with low melt flow. This process of rheology modification is usually accomplished through a reactive extrusion technique known as viscosity breaking (vis-breaking). The method of processing a controlled rheology resin involves the extrusion of a polypropylene base resin of known melt flow characteristics in the presence of an organic peroxide. The decomposition of the organic peroxide at extruder temperatures yields a radical species that chemically degrades the polymer backbone in a “beta scission” process. This process can be precisely controlled by adjusting the amount of peroxide added to the resin during extrusion. The consistent and predictable results obtained through this process add an extra degree of flexibility to the manufacturing process. This allows large quantities of low melt flow polypropylene to be tailored to various higher melt ranges.
[0012] The organic peroxide most widely used to produce controlled rheology polypropylene is 2,5-dimethyl 2,5-di-t-butylperoxyhexane (DTBPH). The decomposition of this peroxide yields several organic species as by-products, including t-butyl alcohol (TBA), acetone, methane, as well as others. The FDA regulates TBA. The upper limit of TBA concentration allowed in food grade applications is 100 ppm. TBA has an astringent “chemical” odor that affects the odor and taste characteristics of the final resin. Not only does the TBA affect odor/taste performance, it also impacts the salability of the resin into high-value markets. If TBA is present at concentrations higher than 100 ppm, the polypropylene may not be used in food grade applications, as per FDA regulation (21 CFR 177.1520).
[0013] As an additive, DTBPH is regulated by the FDA. Additionally a special limitation applies for residual TBA. An organic peroxide that does not yield FDA regulated decomposition products, and does not negatively impact the odor/taste characteristics of the propylene polymer, would eliminate the difficulties associated with meeting a TBA target while at the same time offer the polypropylene industry a tool for manufacturing a highly marketable resin.
[0014] U.S. Pat. No. 3,144,436 discloses a process for improving the processability of high molecular weight stereoregular hydrocarbon polymers which comprises treating the said polymer melt in the essential absence of oxygen in a screw extruder, at the temperature of from the polymer melting point to 100° C. above its melting point, with 0.005-0.5 weight percent of a free radical initiator until the melt index of the resulting stereoregular product is increased from the range “no-flow”-10 to 0.1-100, under the conditions of A.S.T.M. Test No. D-1238-57T Condition E, with the amount of oxygen introduced into the polymer during the process being less than 0.2% of the total weight.
[0015] U.S. Pat. No. 3,887,534 discloses a method for modification of crystalline propylene polymer which comprises heating a mixture comprising 100 parts by weight of said polymer and 0.001 to 0.5 part by weight of an aliphatic peroxide at a temperature of from 170° to 280° C. to diminish the molecular weight of said polymer whereby its processability is much improved, said peroxide having a half life time of from 2.0 to 10.0 hours at 130° C. and vapor pressure of not more than 760 mm Hg at 230° C.
[0016] U.S. Pat. No. 3,940,379 discloses a process for the degradation of propylene polymers comprising contacting a propylene polymer exhibiting a first melt flow rate with oxygen or an oxygen-containing gas and an organic or inorganic peroxide; melting and working the resulting mixture in a high shear zone thereby degrading said propylene polymer; and recovering an essentially odor free propylene polymer exhibiting a second melt flow rate higher than said first melt flow rate.
[0017] U.S. Pat. No. 4,271,279 discloses high density polyethylene cross-linked with certain cyclic perketals including a group of novel cyclic perketals. Typical of the novel molecules is 3,6,6,9,9-pentamethyl-3-ethylacetate-1,2,4,5-tetraoxy cyclononane.
[0018] U.S. Pat. No. 4,451,589 discloses a specific class of thermoplastic polymers that are said to exhibit improved processability resulting from initial partial degradation of high molecular weight polymers using a chemical prodegradant present in excess of the amount reacted during pelletization. This class of polymers includes polymers and copolymers of polypropylene and butylene. After pelletizing, the polymer including unreacted prodegradant can be safely handled and shipped without difficulty. When remelted by extruding or the like, the prodegradant in the pellets reacts, further reducing the molecular weight as well as narrowing the molecular weight distribution of the polymer to a point where high capacity production of quality fibers and extruded products can be obtained. The prodegradant is preferably of the type that predictably and controllably affects the polymer molecular properties without being significantly affected by minor fluctuations in the polymer producer's or processor's manufacturing steps. Specific preferred embodiments include 2,5-dimethyl-2,5 bis-(t-butylperoxy) bexyne-3; 3,6,6,9,9-pentamethyl-3-(ethyl acetate)-1,2,4,5-textraoxy cyclononane; α,α′-bis (t-butylperoxy) diispropyl benzene and 2,5-dimethyl-2,5-di (t-butylperoxy) hexane as the prodegradant added in an amount providing an amount of unreacted prodegradant after pelletizing of about 0.01 to 10.0 percent based on the weight of polymer.
[0019] U.S. Pat. No. 4,707,524 discloses small amounts of peroxides that do not decompose to TBA and have a half-life in the range of about 1.0 to 10 hrs. at 128° C. are incorporated in polypropylene by thermal mechanical melting in an extruder. Control of molecular weight and molecular weight distribution is achieved as a function of the amount of peroxide added. The peroxides of choice are 2,2 di(t-amyl) peroxy propane and 3,6,6,9,9 pentamethyl-3 n-propyl-1,2,4,5 tetraoxacyclononane.
[0020] The disclosures of the foregoing are incorporated herein by reference in their entirety.
SUMMARY OF THE INVENTION
[0021] In accordance with this invention, there is provided a dialkyl organic peroxide that offers improved organoleptic performance in comparison to the peroxide traditionally used for the controlled rheology reaction of propylene polymers. This peroxide, di-tertiary-amylperoxide (DTAP) effectively modifies polypropylene yielding higher melt flow resins with improved odor characteristics.
[0022] More particularly, the present invention is directed to a polymer composition comprising a propylene polymer having a melt flow index in the range from 4 to 120 decigrams/minute, di-t-amyl peroxide, and at least one decomposition product of said peroxide, whereby said composition has agreeable odor characteristics.
[0023] In another aspect, the present invention is directed to a method of manufacturing a shaped article comprising the steps of:
[0024] A) mixing a propylene polymer having a melt flow index in the range from to 20 decigrams/minute with a vis-breaking amount of di-t-amyl peroxide,
[0025] B) heating the mixture at a temperature effective to decompose the di-t-amyl peroxide until the melt flow index is in the range of from 4 to 120 decigrams/minute, and
[0026] C) shaping an article comprising a mixture comprising the propylene polymer having a melt flow index in the range from 4 to 120 decigrams/minute, di-t-amyl peroxide, and decomposition products of said peroxide, whereby said article has agreeable odor characteristics.
[0027] In still another aspect, the present invention is directed to an improvement in a method for producing a controlled rheology propylene polymer, wherein the improvement comprises employing a vis-breaking amount of t-amyl peroxide to generate free radicals and produce t-amyl alcohol, whereby the pleasantness of the organoleptic qualities of the polymer is increased.
DESCRIPTION OF THE PREFERRED EMBODIMENTS
[0028] Propylene polymers are successfully used for the manufacture of a great variety of shaped articles. Shaped articles in which the agreeable odor characteristics afforded according to this invention are particularly valuable include food contact and medical applications, such as packaging films, candy wrappers, bottles and containers for foods and pharmaceuticals, and medical syringes, for which the physical properties including lightness, resistance to cracking, and thermal resistance, combined with ease of processing and favorable economics make propylene polymers the materials of choice. Particularly preferred are shaped articles characterized by a high surface to volume ratio, such as films, where agreeable odor characteristics are especially important.
[0029] As used herein, the term “propylene polymer” is intended to include homopolymeric polypropylene and copolymers of propylene with other copolymerizable monomers wherein the major portion, i.e., greater than about 50% by weight of the copolymer is comprised of propylene moieties. Suitable copolymerizable monomers include, for example, ethylene, butylene, 4-methyl-pentene-1, and the like.
[0030] The propylene polymers used in manufacture of shaped articles according to the invention, particularly for packaging applications, are suitably manufactured by controlled rheology techniques where feedstock resins with low melt flow characteristics are modified by a reactive extrusion technique known as viscosity breaking (vis-breaking) to the desired melt flow range. Vis-breaking can be carried out as part of the procedure of compounding the polymer with additives such as antioxidants and colorants, or as a separate process step before or after compounding with additives. A convenient compilation of additives that can be safely used in shaped articles intended for food contact is contained in title 21 of the U.S. Code of Federal Regulations, Pats 170-199, including in particular Part 178, Section 2010, for antioxidants and stabilizers.
[0031] During vis-breaking by reaction of the feedstock resin during extrusion with an organic peroxide, the decomposition of the peroxide yields a trace amount of organic material (organoleptics) that affects the odor and taste characteristics of the finished resin.
[0032] The first step in the controlled rheology reaction is the decomposition of the peroxide. This occurs in a homolytic fashion yielding two alkoxy radicals. The alkoxy radical can itself abstract a hydrogen atom from the polymer or undergo rearrangement. Hydrogen abstraction by an alkoxy group yields t-amyl alcohol (TAA) and TBA for DTAP and DTBPH, respectively.
[0033] Rearrangement of the alkoxy radical yields acetone and an ethyl or methyl radical depending on the starting peroxide. Just as is the case for the alkoxy radical, the alkyl radical is free to abstract a hydrogen from the polypropylene resin. Hydrogen abstraction by an alkyl radical is more pronounced for DTAP owing to a greater tendency to rearrange after decomposition. This forms lower quantities of residual alcohol in the finished polypropylene resin.
[0034] The abstraction of a hydrogen atom from the polymer backbone, either by an alkoxy or an alkyl radical leads to a beta scission rearrangement of the polymer. This reaction shortens the polymer chain length (lower MW) yielding a polymer with higher melt flow characteristics.
[0035] In accordance with this invention, significant improvements in odor have been demonstrated in a series of odor studies conducted on polypropylene processed by reactive extrusion technique with di-t-amyl peroxide selected as the organic peroxide. The improvement in odor is directly related to the molecular structure of the organic peroxide, as shown by comparison of di-t-amyl peroxide with other peroxides.
[0036] In order to achieve improved odor/taste characteristics in the finished polypropylene product, the organoleptics must be either present in lower concentration, bound in the polymer, or intrinsically have more agreeable odor/taste properties.
[0037] DTAP contains a lower active oxygen content than does DTBPH. In order to achieve the same rheological effect a greater quantity of DTAP must be used in comparison to DTBPH. Theoretical active oxygen contents of 9.6 for DTAP vs. 11.02 for DTBPH indicate that it takes approximately 20% more DTAP to achieve the same degree of rheology modification as DTBPH. In practice, the vis-breaking amount of di-t-amyl peroxide is suitably in the range from 200 to 2000 parts by weight per million parts by weight of propylene polymer, and the temperature effective in decomposing di-t-amyl peroxide is suitably in the range from 320° F. (160° C.) to 600° F. (316° C.).
[0038] Since a greater amount of DTAP is required for the vis-break reaction and there are no differences in the finished properties of a CR resin produced using DTAP compared to DTBPH, any improvements in odor/taste must be derived from the odor/taste characteristics of organoleptics. When one compares the odor of TBA and TAA it is readily apparent that TBA has a disagreeable, astringent odor while TAA has a sweet, fruity odor. This difference in the properties of the organoleptic species leads to improved odor/taste in the finished resin.
[0039] An analysis of the physical properties of DTAP reveals some additional benefits of this dialkyl peroxide. DTAP is a liquid at room temperature with a freezing point below −50° C. A low freezing liquid does not require heat traced piping and will not freeze during winter months. The U.S. Department of Transportation classifies DTAP as a OP8 hazard permitting transport and storage in relatively large packages.
[0040] In terms of peroxide reactivity, DTAP and DTBPH show very similar performance owing to the similarity in their 10-hour half-life temperatures. This permits DTAP to be used in an essentially “drop-in” fashion as a substitute for DTBPH and does not require significant changes to the extruder heat profile.
[0041] The advantages and the important features of the present invention will be more apparent from the following example. All parts and percentages are by weight unless otherwise specified.
EXAMPLE
Odor Comparison of Controlled Rheology Resins Containing DTAP or DTBPH
[0042] A series of odor studies was carried out for polypropylene resins vis-broken with di-t-amyl peroxide (DTAP) in one composition and with 2,5-dimethyl,2,5-di-t-butylperoxyhexane (DTBPH), a peroxide used in the prior at to produce controlled rheology polypropylene, in another. A polypropylene resin manufactured by Solvay was chosen as the base resin (MI=12). The extrusion trials were run on vented 53 mm twin screw extruder. The throughput rate was approximately 350 lbs./hr. with barrel temperatures between 390 and 410° F. (199 and 210° C.).
[0043] In a convenient compounding technique, peroxides were added to the extruder as “masterbatch” comprising the liquid peroxide mixed with the base polypropylene resin. The masterbatch was added under a nitrogen purge. Peroxide loadings and the corresponding melt flow data are provided in Table 1.
TABLE 1 Peroxide Loading Sample Peroxide Loading Melt Flow Index Base Resin none 12 DTAP (low break) 500 ppm 33 DTAP (high break) 1200 ppm 55 DTBPH (low break) 400 ppm 36 DTBPH (high break) 700 ppm 49
[0044] Odor studies as per ASTM E544-75/88 were carried out to determine the intensity and hedonic tone of the vis-broken products compared to the baseline polypropylene. The baseline data consist of the “barefoot” resin extruded without organic peroxide. Independent odor evaluations were carried out by St. Croix Sensory, Inc. An odor panel consisting of 10 persons was asked to judge odor characteristics of vis-broken polypropylene. Odor trials were carried out on samples at ambient, 20° C. (68° F.), and elevated, 60° C. (140° F.), temperatures. The results of the odor trials are shown in Tables 2 and 3.
[0045] The Odor Intensity is the relative strength of the odor above the Recognition Threshold (suprathreshold). The intensity of an odor is referenced on the ASTM Odor Referencing Scale described in ASTM E544-75/88, Standard Practice for Referencing Suprathreshold Odor Intensity. The IITRI Dynamic Dilution Binary Olfactometer (Butanol Wheel) is the method St. Croix Sensory uses for the procedure of odor intensity referencing.
[0046] The odor intensity of an odor sample is compared to the odor intensity of a series of concentrations of the reference odorant, which is butanol. An olfactometer delivers the butanol in air to eight glass sniffing ports that make up a series of increasing concentrations of the butanol. The series has an increasing concentration ratio of 2 (binary scale).
[0047] The odor intensity of an odor sample is expressed in parts per million of butanol. A larger value of butanol means a stronger odor, but not in a simple numerical proportion. The average value of the odor evaluation is the reported intensity for the odor sample.
[0048] Hedonic Tone is a measure of the pleasantness or unpleasantness of an odor sample. The hedonic tone is independent of its character. An arbitrary, but common, scale for ranking odors by hedonic tone is the use of a 21 point scale, wherein +10 is “pleasant”, 0 is “neutral”, and −10 is “unpleasant”.
[0049] The assignment of a hedonic tone value to an odor sample by an assessor is subjective to the assessor, who uses personal experience and memories of odors as a referencing scale.
[0050] The average value of the odor evaluation is the reported hedonic tone for the odor sample.
TABLE 2 Results of Odor Trials (Sample Temperatures @ 20° C.) Sample Odor Intensity Hedonic Tone Baseline (unextruded) 25 +1.0 Baseline (extruded) 45 +0.5 DTAP (MI-33) 80 +0.6 DTBPH (MI-36) 110 −0.5 DTAP (MI-55) 150 −0.4 DTBPH (MI-49) 170 −0.5
[0051] [0051] TABLE 3 Results of Odor Trials (Sample Temperature @ 60° C.) Sample Odor Intensity Hedonic Tone Baseline (unextruded) 55 −1.5 Baseline (extruded) 475 −1.9 DTAP (MI-33) 65 −0.5 DTBPH (MI-36) 70 −0.7 DTAP (MI-55) 120 −1.3 DTBPH (MI-49) 140 −1.8
[0052] The odor results clearly show that polypropylene modified with DTAP has improved odor characteristics in both intensity and hedonic tone when compared to polypropylene modified with DTBPH at both trial temperatures.
[0053] In particular, the odor intensity for polypropylene processed to MI 33 with DTAP measured at 20° C. is 30 points lower (80 vs. 110) than that measured for a resin modified to a similar melt flow with DTBPH. In addition, the hedonic tone shows more than a full point improvement towards pleasant (+0.6 vs. −0.5). This improvement is realized even though approximately 20 percent more DTAP is used in the masterbatch formulation in order to achieve a similar break.
[0054] Similar results were observed when vis-breaking was carried out to a greater extent (compare the last two lines of Table 2).
[0055] Results at 60° C. show an interesting change in the human perception of odor. Intensity actually decreases for like samples. For example, the DTAP (MI-33) sample yields an intensity of 80 at 20° C., while at 60° C. the intensity is 65.
[0056] Surprisingly, both the intensity and the hedonic tone of this sample are better (lower intensity, less negative hedonic tone) than the unmodified extruded base resin.
[0057] In view of the many changes and modifications that can be made without departing from principles underlying the invention, reference should be made to the appended claims for an understanding of the scope of the protection to be afforded the invention.
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A polymer composition is disclosed that comprises a propylene polymer having a melt flow index in the range from 4 to 120 decigrams/minute, di-t-amyl peroxide, and at least one decomposition product of said peroxide, whereby said composition has agreeable odor characteristics.
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