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BACKGROUND OF THE INVENTION
The present invention addresses the problem of providing complete protection to plastic bottles from tampering at the mouth of the bottle, and also provides a method of attaching the invention to the bottle cap and then bonding the invention to the plastic bottle by induction, thereby providing a new method of joining plastic to plastic inductively.
Prior art has produced numerous devices that address various aspects of the problem, yet all of them have various drawbacks. Generally, the devices currently in the market place provide very little if any protection. Any person with an ordinary laundry iron can easily remove the foil seal from a plastic bottle, contaminate the contents and then replace the same seal.
The present invention is an improvement over the prior art in that it provides a novel and unique method of frictionally by means of projections and cavities, or adhesively attaching a plastic safety insert inside a screw or snap on cap, where it remains until utilized in the bottling process. It also is an improvement over the prior art in that the invention has a sectioned internal shoulder, enabling the invention to be molded in one piece and still provide expandable projection supports that can be opened to receive and position a safety disc and then can be closed to hold the safety disc. The invention also provides a piece that enables the invention to be bonded to the plastic bottle by the induction method.
SUMMARY OF THE INVENTION
The present invention is a plastic neck insert, consisting of an insert body, a two piece, or a one piece safety disc, a perforated metal weld band or weld coil which is positioned either on the insert or in the bottle. The insert assembly is then positioned inside the screw or snap on cap preferably by projections and cavities on the insert and in the cap. After the tablets, caplets or capsules are placed in the bottle, the cap with the insert assembly is positioned in the bottle. The safety insert is then bonded to the bottle by induction. When the customer twists the cap to open it, the parts that hold the insert in the cap will be broken and an audible sound will be heard. The cap can then be removed leaving the insert bonded to the bottle.
To achieve this, the invention includes an insert molded in plastic, having a rim, an outside shoulder, a perforated metal weld band positioned under the shoulder, a plurality of cavities or projections on the insert top, and an internal shoulder divided into sections. The bottom of the insert has tapered sides and a number of equally spaced tapered projections extending downward in a configuration that provides a horizontal support platform which securely holds the plastic safety disc to the bottom of the sectioned internal shoulder.
For each tapered projection having a disc support configuration, there will be a break in the internal shoulder, this enables the steel mold that creates the disc support configuration to be released.
The insert is then placed in a screw or snap on cap where cavities or projections in the cap engage the projections or cavities on the insert, and frictionally hold the parts together until they are positioned in the bottle. If the insert is placed in a snap on cap, the attachment to the insert may be different as will be shown in the detailed explanation.
Various other features, objects and advantages of the present invention will become obvious to those skilled in the art upon reading the disclosures set forth hereinafter.
BRIEF DESCRIPTION OF THE DRAWING
Referring now to the drawings which illustrate some presently preferred embodiments of the invention wherein:
FIG. 1 is a perspective view partly in section of a safety disc bottle neck insert in accordance with the present invention.
FIG. 2 is a sectional view of the side wall portion of the safety disc bottle neck insert showing the flexible disc support projection in its expanded position.
FIG. 3 is a sectional view of a bottle screw cap showing cap projectons which will hold the safety disc bottle neck insert in the cap.
FIG. 4 is a sectional view of FIG. 1 showing the complete safety disc bottle neck assembly.
FIG. 5 is a sectional view similar to FIG. 4 showing the safety disc bottle neck insert prior to the positioning of the safety disc.
FIG. 6 is a sectional view of another embodiment of the safety disc bottle neck insert in accordance with the present invention.
FIG. 7 is a sectional view of the safety disc bottle neck insert positioned within and attached to the screw cap prior to insertion into the bottle.
FIG. 8 is a sectional view similar to FIG. 7 showing the screw cap and the safety disc bottle neck insert positioned in the bottle prior to induction.
FIG. 9 is a sectional view of another embodiment in accordance with the present invention, showing the sidewall portion of the safety disc bottle neck insert assembled in a snap on cap.
FIG. 10 shows still another embodiment in accordance with the present invention of a snap on cap as seen from below.
FIG. 11 is a sectional view of the snap on cap as shown in FIG. 10 with the safety disc bottle neck insert attached thereto.
FIG. 12 is a perspective view of a two piece molded safety disc in accordance with the present invention.
FIG. 13 is a sectional view of a one piece safety disc similar to the safety disc shown in FIG. 6.
FIG. 14 is a side view of the safety disc bottle neck insert and a cross section of the bottle neck showing still another embodiment in accordance with the present invention.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
Referring to the drawings in which like parts are denoted by the same reference numerals throughout. FIG. 1 shows the preferred embodiment. Numeral 3 designates the tamper proof bottle neck insert, which is comprised of a molded cylindrical plastic piece, having a rim stop 4, an insert cavity 14, an outside shoulder 5, a perforated metal weld band 6, a sectioned internal shoulder 7, a vertical side wall 8, a tapered disc retainer 9, a tapered flexible safety disc support projection 10 having a disc support configuration 11 on its inner wall, a projection tip 12, with a two piece safety disc 13 positioned under the sectioned internal shoulder 7, and above the disc support 11.
FIG. 2, shows a portion of the bottle neck insert 3, with a weld coil 15. The projection tip 12, has been grasped and pulled outward showing the flexible support projection 10, in its open position.
FIG. 3, shows a screw cap 16, screw threads 18, and cap projections 17.
FIG. 4, shows the bottle neck insert 3, with the safety disc 13, being held firmly in place by three of the disc supports 11. Each break in the internal shoulder 7, is next to or above a flexible disc support projection 10.
FIG. 5, shows the bottle neck insert 3 minus the safety disc 13. This view shows the relationship of disc retainer 9, to the flexible disc support projection 10. Disc retainer 9, is contiguous to flexible disc support projection 10, but does not touch it. This allows flexible disc support projection 10, to move independently of disc retainer 9, which remains stationary.
FIG. 6, shows another embodiment of the bottle neck insert 3. Numeral 35 designates a tamper proof bottle neck insert comprising a rim projection 19, a rim stop 4, a weld coil 15, a flexible disc support projection 10, a disc support 11, a disc retainer 9, a sectioned internal shoulder 7, a disc shield 20, a one piece safety disc 21 having a rim 22, and a side wall 23.
The one piece pie-pan shaped safety disc 21, is positioned and held in place at the rim 22, between disc support 11, disc retainer 9, and internal shoulder 7.
To assemble the bottle neck insert 3, the perforated metal weld band 6, is first positioned as a tight fit under and against the outside shoulder 5. Pressure is exerted against the projection tip 12, which moves the flexible safety support projection 10, to the open position as shown in FIG. 2, the two piece safety disc 13, is then positioned and held in place by the tapered disc retainer 9. The flexible safety support projection 10, is then moved to the closed position so that the disc support 11 firmly engages the underside of safety disc 13.
The assembled bottle neck insert 3, is then positioned in the screw cap 16, shown in FIG. 3 by aligning the cap projections 17, of the screw cap 16, with the insert cavities 14, on the bottle neck insert 3, and then frictionally attaching the units together as shown in FIG. 7.
The screw cap 16, with the bottle neck insert 3, positioned within it is then positioned in the mouth of the bottle 24, as shown in FIG. 8. It should be noted that the cap projections 17, of the screw cap 16, and the insert cavities 14, of the bottle neck insert 3, may be reversed. The cap projections 17, can be positioned on the insert as rim projections 19, as shown in FIG. 6, while the female cavities 14, can be molded into the screw cap 16, to frictionally attach the bottle neck insert 3, to the screw cap 16.
The perforated weld band 6, which is in contact with the insert side wall 8, and the bottle wall 24, is now inductively heated and bonds the bottle neck insert 3, to the bottle 24.
As the plastic bottle 24 proceeds along the bottling line after bonding, the screw cap 16, can be twisted counter clockwise to break the cap projections 17, then clockwise to retighten the screw cap 16, to allow the screw cap 16, to be easily removed. The preferred procedure would be to allow the customer to twist and break the cap projectons 17, at the interface between the screw cap 16, and the insert 3. The cap projections 17, will be of such small diameter as to easily allow anyone to break the connecting projections. A distinct crack will be heard upon twisting the screw cap 16 open.
FIG. 9, and FIG. 11, show other embodiments in accordance with the present invention. FIG. 9, shows the bottle neck insert 27, adhesively attached to the pulp-board backing 26, by an adhesive which easily peels away from the bottle neck insert 27. The pulp-board backing 26, is adhesively attached to snap on cap 25 in the conventional manner. Snap on cap 25, and the bottle neck insert 27, have no cap projections 17, or insert cavities 14.
Snap on cap 25, with the bottle neck insert 27 attached, is positioned in a plastic bottle 24, the bottle neck insert 27, is then inductively bonded to the plastic bottle 24. When the customer pulls the snap on cap 25, off the plastic bottle 24, the adhesive attaching the insert 27, to the pulp-board backing 26, having a greater affinity for the pulp-board backing 26, will therefore peel away from the plastic insert 27, and remain adhered to the pulp-board backing 26, inside snap on cap 25.
FIG. 10, shows a snap on cap 85, as viewed from below, having an insert recess 28, molded into it. Bottle neck insert 27, is frictionally attached to snap on cap 85, at the insert recess 28 as shown in FIG. 11, and is then positioned in a plastic bottle 24, then the bottle neck insert 27, is inductively bonded to the bottle 24.
FIG. 12 shows a two piece molded safety disc 29, comprising a disc rise 30, a disc cavity 31, and a disc projection 32. Safety disc 29, is the preferred embodiment to safety disc 13, because when assembled, the disc projection 32, mated with the disc cavity 31, and the disc rise 30, give the safety disc 29, more stability without interfering with its breakaway feature. Once the two piece disc 29, breaks away into the bottle, the disc projections 32, would make it impossible to re-assemble the disc 29.
One piece disc 21, shown in cross section in FIG. 13, shows the pie-pan shaped configuration, the disc rim 22, and the disc side wall 23. If a one piece disc is used in the insert 3, there could be the possibility of a tampering attempt. Disc 21, positioned in insert 35 of FIG. 6, overcomes that. When the safety disc 21 has been pushed into the bottle the flexible safety disc support projection 10, in its normal closed position, prevents the safety disc 21 from being pulled back and repositioned; disc shield 20, positioned under the front portion of the sectioned internal shoulder 7, in front of disc side wall 23, protects safety disc support projection 10, from any tampering. Any attempt at cutting away safety disc support projection 10, would so damage the disc shield 20, and the sectioned internal shoulder 7, that it would be immediately evident to anyone that a tampering attempt had been made.
FIG. 14, shows still another embodiment in accordance with the present invention. The bottle neck insert 34, has no outside shoulder 5. Weld coil 15, or perforated metal weld band 6, is positioned on the outside of the insert 34, up against the insert rim stop 4. Bottle 24, has a recess 33 cut into the bottle mouth in which the weld coil 15, or the perforated metal weld band 6, will rest when the insert 34 is positioned in bottle 24.
The disclosure of the invention described above represents the preferred embodiments of the invention: however, variations, thereof, in the form, construction, and arrangement of the various components thereof and the modified application of the invention are possible without departing from the spirit and scope of the appended claims.
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The present invention provides an audible sound protecting mechanism and a tamper proof disc to prevent and deter persons from implanting contaminated substances into bottles containing capsules, tablets or caplets, removing the contents of the bottle, changing their composition, replacing the contents back into the bottle and restoring the bottle to its original condition so as to appear untouched, for the purpose of doing harm to another person. The safety disc that protects the products is so positioned inside the neck of the bottle, that is is beyond the reach and manipulations of anyone; therefore, if broken, the safety disc cannot be replaced, repaired, or repositioned.
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FIELD OF THE INVENTION
[0001] The invention relates to a method of producing a titanium-suboxide-based coating material as well as a coating material produced according to the method and a sputter target provided there-with.
BACKGROUND OF THE INVENTION
[0002] The technical field of the present invention primarily involves the PVD coating technique, in which titanium dioxide is widely employed as coating material because of its high refraction index. Originally, proceeding from titanium metal as a coating material, a titanium dioxide layer was deposited, via a reactive PVD coating process by the addition of oxygen to the process gases, on a substrate to be coated. However, in coating based on metal targets, problems are posed by the very low coating rates in particular in the DC sputter process frequently used. This will slow down relevant manufacturing processes in the technical application, for example when PVD layer systems are applied for thermal insulation glazing.
[0003] To solve these problems, prior art suggestions consisted in using so-called suboxide targets on the basis of titanium or niobium suboxides.
[0004] These titanium suboxides of the chemical formula Ti n O 2n−1 , with n>2, are called Magneli phases. They have very positive properties as far as the use as a coating material is concerned, such as high corrosion resistance and excellent electric conductivity. Owing to their chemical composition, they are able strongly to accelerate layer production within the scope of the PVD coating technique.
[0005] Methods of producing these titanium-suboxide-based coating materials are known from lots of prior art documents such as DE 100 00 979 C1, U.S. Pat. No. 6,334,938 B2, U.S. Pat. No. 6,461,686 B1 and U.S. Pat. No. 6,511,587 B2. The production methods disclosed therein have in common that titanium dioxide is the starting material from which to proceed in the production of the titanium-suboxide-based coating material or the target as far as PVD-coating-technique is concerned; under reducing conditions, the starting material is transferred into a titanium suboxide either via a thermal sputtering process or corresponding sintering technology.
[0006] Drawbacks reside in the fact that comparatively strong fluctuations result in the stoichiometry of the coating materials thus produced, which is again accompanied with inconstant removal behaviour of the PVD coating material from the target produced. The reason resides in partially differing electric conductivity of the coating material in the case of varying stoichiometric compositions. Another drawback is a lower refraction index.
[0007] Special problems are posed by the influence of the respective oxygen content of the suboxide on the sputtering behaviour. If it fluctuates due to stoichiometric differences in the suboxide composition, this will result in a significant reduction of the sputtering rate. Tests have shown that removal rates of approximately 10 nm/min are obtained in sputter targets produced by reduced titanium dioxide.
[0008] Proceeding from the described prior art problems, it is an object of the invention to specify a method of producing a titanium-suboxide-based coating material as well as a coating material of that type, by the aid of which significantly high sputtering rates of the coating material are obtained without any relevant losses of the refraction index.
[0009] This object is fundamentally implemented by the titanium-suboxide-based coating material, as opposed to the state of the art, being produced starting from a titanium-suboxide base material that is further treated under oxidizing conditions. In doing so, a finely dispersed titanium-dioxide component is produced in situ in the titanium-suboxide base material.
[0010] Examinations of coating materials thus produced have shown that adhesions of titanium dioxide, in particular in the rutile phase thereof, positively affect the sputtering rate of the coating material and the refraction index of the coatings thus produced, provided this titanium-dioxide component is finely dispersedly integrated in a conductive matrix of electrically conductive suboxides such as Ti 3 O 5 , Ti 4 O 7 , Ti 5 O 9 , and Ti 8 O 15 . Thus the electric conductivity is not significantly affected. On the whole, the titanium-suboxide-based coating material produced by the method according to the invention excels by offering special advantages to DC sputtering, namely high electric conductivity, high density, high sputtering rates, good reproducibility, insignificant addition of oxygen as a process gas during sputtering, insignificant tendency of contamination of the target material upon the addition of oxygen as a process gas, high thermal resistance by homogeneous layer structuring in the target production, and a high achievable refraction index of the coatings produced from the coating material.
[0011] Fundamentally, any appropriate sintering process, for instance for the manufacture of a sintered-granulate coating material, suggests itself for the further treatment of the titanium-suboxide base material; however, the titanium-suboxide-based coating material is preferably produced by thermal sputtering of a titanium-suboxide base material, preferably with the aid of a multi-cathode plasma torch by the addition of oxygen. In doing so, the rutile phase of the titanium dioxide, at a proportion of up to maximally 50 percent by weight, is integrated in the titanium-suboxide-based coating material by oxidation of corresponding titanium-suboxide base materials. The rutile content can be controlled by way of the sputtering distance.
[0012] Titanium suboxides of the formula Ti n O 2n−1 , with n=3 to 8, have crystallized as preferred phases in the process.
[0013] Further features, details and advantages of the invention will become apparent from the ensuing description.
DESCRIPTION OF THE PREFERRED EMBODIMENT
[0014] Producing a titanium-suboxide-based target proceeds from a titanium-suboxide base material in the form of a powder of a fineness that may be in a range between 10 and 200 μm. A radiographic, semiquantitative determination of the phase content of this material shows for example the following composition:
Ti 3 O 5 18 percent by weight Ti 4 O 7 26 percent by weight Ti 5 O 9 45 percent by weight Ti 6 O 11 8 percent by weight Ti 7 O 13 5 percent by weight Ti 8 O 15 1 percent by weight
[0021] This sample was observed to contain comparatively well developed crystalline phases with very low amorphous components. Titanium dioxide could not be found so that the sum of crystalline suboxides was assumed to be 100 percent by weight. With only an approximate determination of the Ti n O 2n−1 contents being possible in the quantification, listed above, of the individual suboxides because of the line overlap in the radiographic measurement diagram and because of the partially insignificant contents, the above listed approach results in a total of 103 percent.
[0022] This titanium-suboxide sputtering powder is sputtered thermally by a multi-cathode plasma torch—namely a triplex-II torch. This triplex-II torch is a three-cathode torch in which three stationary electrical arcs are produced.
[0023] That is what distinguishes this device from other thermal-sputtering plasma torches such as conventional single-cathode plasma torches, in which turbulences occur in the plasma jet, leading to the employed powder being worked irregularly. The important time and local fluctuations of the single arc negatively affect the melting behaviour and acceleration of the particles in the plasma beam, which also influences the efficiency of the coating process.
[0024] Upon thermal sputtering with the aid of the described multi-cathode plasma torch (details of which are specified in the specialist essays of Barbezat, G., Landes, K., “Plasmabrenner-Technologien-Triplex: Hohere Produktion bei stabilerem Prozeβ3”, in “Sulzer Technical Review”, edition 4/99, pages 32 to 35; and Barbezat, G., “Triplex II—Eine neue Ära in der Plasmatechnologie”, loc. cit., edition 1/2002, pages 20, 21) uniform, controlled treatment of the titanium-suboxide powder takes place, which is of substantial importance for setting a defined component of titanium dioxide in its rutile modification in situ. It is of decisive importance that the noble gas argon or a mixture of the noble gases argon and helium are used in the operation of the multi-cathode plasma torch for reduction of the titanium-suboxide base material in the torch to be prevented, thus enabling its controlled oxidation by the atmosphere. The coating material thus obtained excels by special chemical homogeneity. This special material nature, including the component, as specified, of rutile finely dispersed in a conductive titanium-suboxide matrix, results in clearly improved ability of sputtering of the coating material as compared to conventional titanium metal targets.
[0025] The following system parameters were used in the plasma sputtering process:
electric current: 450-520 A plasma gas helium: 25-35 SLPM plasma gas argon: 20-30 SLPM sputtering distance: 80-120 mm coating per passage: 20 μm sputtering atmosphere: air
[0032] The coating material in the form of a titanium-suboxide-based sputtering layer, produced as explained above, comprises the following proportional composition, which was again determined semiquantitatively and radiographically:
rutile 41 percent by weight Ti 3 O 15 15 percent by weight Ti 4 O 7 10 percent by weight Ti 5 O 9 9 percent by weight Ti 6 O 11 9 percent by weight Ti 7 O 13 5 percent by weight Ti 8 O 15 11 percent by weight (total of suboxides 59 percent by weight)
[0041] As regards the above table, it is stressed that the listed contents of the titanium-suboxide phases were determined semiquantitatively from the relative peak intensities of the radiographic measurement. Exclusively the crystalline phases were determined and converted to 100 percent by weight. Any definite quantification of the titanium suboxides is not possible, because there may be many combinations with a varying oxygen deficit.
[0042] For verification of the applicability of a titanium-suboxide-based coating material with a finely dispersed rutile component for use in dc-pulse magnetron sputters, PVD coating tests were made and compared to corresponding tests based on conventional Ti 4 O 7 -mixed-oxide targets.
[0043] The following system parameters were used:
target-substrate distance: 90 mm target material: titanium-suboxide coating material with rutile or Ti 4 O 7 mixed oxide, respectively gas flow: 2×100 sccm/purity: 4.8 carrier rate: 0.5 mm/s
[0048] Set as process parameters were:
base pressure: approximately 3×10 −6 mbar substrate temperature: ambient temperature discharge power: 2000-6000 W generator frequency: 100 kHz pulse time: 1 μs mixed-gas flow (Ar: O 2 W9:1): 0-100 sccm/purity: O 2 4.5/Ar 5.0 total pressure: 500 mPa substrate: float glasses 10×10 cm 2 , 5×5 cm 2
[0057] The mixed-gas flow with an addition of O 2 is necessary because of the under-stoichiometry in the coating material. Any modification of discharge voltage will not be found above a certain flow of oxygen, as a result of which there is no unsteady behaviour as usual in the sputtering of metal targets upon transition from the metal to the oxide mode. The ceramic suboxide targets according to the invention ensure more stable process management.
[0058] The following comparative table of the static sputtering rate as and the optical refraction index n for various titanium target materials shows that the inventive ceramic titanium-suboxide-based coating materials with rutile phase offer an optimal compromise of sputtering rate and refraction index.
[0059] The TiO x sputtering layer shows the highest sputtering rate as compared to the Ti 4 O 7 mixed oxide target and the titanium target reactively sputterd in the transition mode. Only the refraction index of the titanium target sputtered in the oxide mode is higher, however at a sputtering rate that is lower by a factor of nearly 12.
TABLE comparison of the static sputter rate a s and the optical refraction index n for various titanium based target materials. Rate a s at 1 W/cm 2 Material [nm/min] n at λ, = 550 nm TiO x sputtering layer 14.8 2.47 Ti 4 O 7 mixed oxide 9.9 2.42 Ti oxide mode 1.2 2.51 Ti transition mode 6.3 2.42
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A method of producing a titanium-suboxide-based coating material comprises the following steps: providing a titanium-suboxide base material; and treating the titanium-suboxide base material under oxidizing conditions for in-situ development of a finely dispersed titanium-dioxide component in the ceramic titanium-suboxide base material.
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CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application is a continuation of U.S. application Ser. No. 10/203,311 filed Aug. 6, 2002, which was a national stage filing under 35 U.S.C. 371 of PCT/GB01/000541 filed Feb. 9, 2001, which International Application was published by the International Bureau in English on Aug. 16, 2001 and claims foreign priority from Great Britain applications 0002979.3 filed Feb. 9, 2000, 0002980.1 filed Feb. 9, 2000, 0002982.7 filed Feb. 9, 2000, and 0002981.9 filed Feb. 9, 2000; each of which is hereby incorporated herein in its entirety by reference.
BACKGROUND OF THE INVENTION
[0002] 1. Field of the Invention
[0003] The present invention relates to identification of genes upregulated by interferon-α (IFN-α) administration. Detection of expression products of these genes may thus find use in predicting responsiveness to IFN-α and other interferons which act at the Type 1 interferon receptor. Therapeutic use of the proteins encoded by the same genes is also envisaged.
[0004] 2. Background of the Invention
[0005] IFN-α is widely used for the treatment of a number of disorders. Disorders which may be treated using IFN-α include neoplastic diseases such as leukemia, lymphomas, and solid tumours, AIDS-related Kaposi's sarcoma and viral infections such as chronic hepatitis. IFN-α has also been proposed for administration via the oromucosal route for the treatment of autoimmune, mycobacterial, neurodegenerative, parasitic and viral disease. In particular, IFN-α has been proposed, for example, for the treatment of multiple sclerosis, leprosy, tuberculosis, encephalitis, malaria, cervical cancer, genital herpes, hepatitis B and C, HIV, HPV and HSV-1 and 2. It has also been suggested for the treatment of arthritis, lupus and diabetes. Neoplastic diseases such as multiple myeloma, hairy cell leukemia, chronic myelogenous leukemia, low grade lymphoma, cutaneous T-cell lymphoma, carcinoid tumours, cervical cancer, sarcomas including Kaposi's sarcoma, kidney tumours, carcinomas including renal cell carcinoma, hepatic cellular carcinoma, nasqpharyngeal carcinoma, haematological malignancies, colorectal cancer, glioblastoma, laryngeal papillomas, lung cancer, colon cancer, malignant melanoma and brain tumours are also suggested as being treatable by administration of IFN-via the oromucosal route, i.e. the oral route or the nasal route.
[0006] IFN-α is a member of the Type 1 interferon family, which exert their characteristic biological activities through interaction with the Type 1 interferon receptor. Other Type 1 interferons include IFN-β, IFN-ω and IFN-τ.
[0007] Unfortunately, not all potential patients for treatment with a Type 1 interferon such as interferon-α, particularly, for example, patients suffering from chronic viral hepatitis, neoplastic disease and relapsing remitting multiple sclerosis, respond favourably to Type 1 interferon therapy and only a fraction of those who do respond exhibit long-term benefit. The inability of the physician to confidently predict the therapeutic outcome of Type 1 interferon treatment raises serious concerns as to the cost-benefit ratio of such treatment, not only in terms of wastage of an expensive biopharmaceutical and lost time in therapy, but also in terms of the serious side effects to which the patient is exposed. Furthermore, abnormal production of IFN-α has been shown to be associated with a number of autoimmune diseases. For these reasons, there is much interest in identifying Type 1 interferon responsive genes since Type 1 interferons exert their therapeutic action by modulating the expression of a number of genes. Indeed, it is the specific pattern of gene expression induced by Type 1 interferon treatment that determines whether a patient will respond favourably or not to the treatment.
SUMMARY OF THE INVENTION
[0008] It has now been found that the human genes corresponding to the cDNA sequences in GenBank assigned accession nos. g4586459, g2342476, g3327161 and g4529886, correspond to a mouse gene upregulated by administration of IFN-α by an oromucosal route or intravenously. These human genes are thus now also designated an IFN-α upregulated gene.
[0009] The proteins corresponding to GenBank cDNAs g4586459, g2342476, g3327161 and g4529886 have previously had no assigned function. These proteins (referred to below as HuIFRG-1, HuIFRG-2, HuIFRG-3 and HuIFRG-4 proteins respectively), and functional variants thereof, are now envisaged as therapeutic agents, in particular for use as an anti-viral, anti-tumour or immunomodulatory agent. For example, they may be used in the treatment of autoimmune, mycobacterial, neurodegenerative, parasitic or viral disease, arthritis, diabetes, lupus, multiple sclerosis, leprosy, tuberculosis, encephalitis, malaria, cervical cancer, genital herpes, hepatitis B or C, HIV, HPV, HSV-1 or 2, or neoplastic disease such as multiple myeloma, hairy cell leukemia, chronic myelogenous leukemia, low grade lymphoma, cutaneous T-cell lymphoma, carcinoid tumours, cervical cancer, sarcomas including Kaposi's sarcoma, kidney tumours, carcinomas including renal cell carcinoma, hepatic cellular carcinoma, nasopharyngeal carcinoma, haematological malignancies, colorectal cancer, glioblastoma, laryngeal papillomas, lung cancer, colon cancer, malignant melanoma or brain tumours. In other words, such proteins may find use in treating any Type 1 interferon treatable disease.
[0010] Determination of the level of HuIFRG-1, HuIFRG-2, HuIFRG-3 or HuIFRG-4 proteins or a naturally-occurring variant thereof, or the corresponding mRNA, in cell samples of Type 1 interferon-treated patients, e.g. patients treated with IFN-α, e.g. such as by the oromucosal route or intravenously, may also be used to predict responsiveness to such treatment. It has additionally been found that alternatively and more preferably, such responsiveness may be judged, for example, by treating a sample of human peripheral blood mononuclear cells in vitro with a Type 1 interferon and looking for upregulation or downregulation of an expression product, preferably mRNA, corresponding to the same gene.
[0011] According to a first aspect of the invention, there is thus provided an isolated polypeptide comprising;
(i) the amino acid sequence of SEQ ID NO: 2, SEQ ID NO:4, SEQ ID NO:6 or SEQ ID NO: 8; (ii) a variant thereof having substantially similar function, e.g. an immunomodulatory activity and/or an anti-viral activity and/or an anti-tumour activity; or (iii) a fragment of (i) or (ii) which retains substantially similar function, e.g. an immunomodulatory activity and/or an anti-viral activity and/or an anti-tumour activity
for use in therapeutic treatment of a human or non-human animal, more particularly for use as an anti-viral, anti-tumour or immunomodulatory agent. As indicated above, such use may extend to any Type 1 interferon treatable disease.
[0015] According to another aspect of the invention, there is provided an isolated polynucleotide, e.g. in the form of an expression vector, which directs expression in vivo of a polypeptide as defined above for use in therapeutic treatment of a human or non-human animal, more particularly for use as an anti-viral, anti-tumour or immunomodulatory agent. Such a polynucleotide will typically include a sequence comprising:
(a) the nucleic acid of SEQ. ID. NO: 1, SEQ ID NO: 3, SEQ ID NO: 5 or SEQ ID NO: 7 or the coding sequence thereof; (b) a sequence which hybridises, e.g. under stringent conditions, to a sequence complementary to a sequence as defined in (a); (c) a sequence that is degenerate as a result of the genetic code to a sequence as defined in (a) or (b); or (d) a sequence having at least 60% identity to a sequence as defined in (a), (b) or (c);
such that the polypeptide encoded by said sequence is capable of expression in vivo.
[0020] In a further aspect, the invention provides a method of predicting responsiveness of a patient to treatment with a Type 1 interferon, e.g. IFN-α treatment (such as IFN-α treatment by the oromucosal route or a parenteral route, for example, intravenously, subcutaneously or intramuscularly), which comprises determining the level of one or more proteins selected from the proteins defined by the sequences set forth in SEQ ID NO: 2, SEQ ID NO:4, SEQ ID NO:6 or SEQ ID NO: 8, and naturally-occurring variants thereof, e.g. allelic variants, or one or more of the corresponding mRNAs, in a cell sample from said patient, e.g. a blood sample, wherein said sample is obtained from said patient following administration of a Type 1 interferon, e.g. IFN-α by an oromucosal route or intravenously, or is treated prior to said determining with a Type 1 interferon such as IFN-α in vitro. Such determining may be combined with determination of any other protein or mRNA whose expression is known to be affected in human cells by Type 1 interferon administration e.g. IFN-α administration.
[0021] The invention also provides:
a pharmaceutical composition comprising the protein defined by the amino acid sequence set forth in SEQ ID NO: 2, SEQ ID NO:4, SEQ ID NO:6 or SEQ ID NO: 8, or a functional variant thereof as defined above, and a pharmaceutically acceptable carrier or diluent; a method of treating a subject having a Type 1 interferon treatable disease, which method comprises administering to the said patient an effective amount of such a protein;
use of such a protein in the manufacture of a medicament for use in therapy as an anti-viral or anti-tumour or immunomodulatory agent, more particularly for use in treatment of a Type 1 interferon treatable disease; a pharmaceutical composition comprising a polynucleotide as defined above and a pharmaceutically acceptable carrier or diluent; a method of treating a subject having a Type 1 interferon treatable disease, which method comprises administering to said patient an effective amount of such a polynucleotide; use of such a polynucleotide in the manufacture of a medicament, e.g. a vector preparation, for use in therapy as an anti-viral, anti-tumour or immunomodulatory agent, more particularly for use in treating a Type 1 interferon treatable disease; a polynucleotide capable of expressing in vivo an antisense sequence to a coding sequence for the amino acid sequence defined by SEQ ID NO: 2, SEQ ID NO:4, SEQ ID NO:6 or SEQ ID NO: 8, or a naturally-occurring variant of said coding sequence, for use in therapeutic treatment of a human or non-human animal and pharmaceutical compositions comprising such a polynucleotide in combination with a pharmaceutically acceptable carrier or diluent; an antibody to the protein defined by the amino acid sequence set forth the in SEQ ID NO: 2, SEQ ID NO:4, SEQ ID NO:6 or SEQ ID NO: 8 for use in therapeutic treatment of a human or animal body and corresponding pharmaceutical compositions.
BRIEF DESCRIPTION OF THE SEQUENCES
[0030] SEQ. ID. No. 1 is the amino acid sequence of human protein HuIFRG-1 and its encoding cDNA.
[0031] SEQ. ID. No.2 is the amino acid sequence alone of HuIFRG-1 protein.
[0032] SEQ. ID. No.3 is the amino acid sequence of human protein HuIFRG-2 and its encoding cDNA.
[0033] SEQ. ID. No.4 is the amino acid sequence alone of HuIFRG-2 protein.
[0034] SEQ. ID. No.5 is the amino acid sequence of human protein HuIFRG-3 and its encoding cDNA.
[0035] SEQ. ID. No.6 is the amino acid sequence alone of HuIFRG-3 protein.
[0036] SEQ. ID. No.7 is the amino acid sequence of human protein HuIFRG-4 and its encoding cDNA.
[0037] SEQ. ID. No.8 is the amino acid sequence alone of HuIFRG-4 protein.
DETAILED DESCRIPTION OF THE INVENTION
[0038] As indicated above, human proteins HuIFRG-1, HuIFRG-2, HuIFRG-3 or HuIFRG-4 and functional variants thereof are now envisaged as therapeutically useful agents, more particularly for use as an anti-viral, anti-tumour or immunomodulatory agent.
[0039] A variant of HuIFRG-1, HuIFRG-2, HuIFRG-3 or HuIFRG-4 protein for this purpose may be a naturally-occurring variant, either an allelic variant or a species variant, which has substantially the same functional activity as HuIFRG-1, HuIFRG-2, HuIFRG-3 or HuIFRG-4 protein and is also upregulated in response to administration of IFN-α, e.g oromucosal or intravenous administration of IFN-α. Alternatively, a variant of HuIFRG-1, HuIFRG-2, HuIFRG-3 or HuIFRG-4 protein for therapeutic use may comprise a sequence which varies from SEQ. ID. No. 2 but which is a non-natural mutant.
[0040] The term “functional variant” refers to a polypeptide which has the same essential character or basic function of HuIFRG-1, HuIFRG-2, HuIFRG-3 or HuIFRG-4 protein. The essential character of HuIFRG-1, HuIFRG-2, HuIFRG-3 or HuIFRG-4 protein may be deemed to be as an immunomodulatory polypeptide. A functional variant polypeptide may show additionally or alternatively anti-viral activity and/or anti-tumour activity.
[0041] Desired anti-viral activity may, for example, be tested for as follows. A sequence encoding a variant to be tested is cloned into a retroviral vector such as a retroviral vector derived from the Moloney murine leukemia virus (MoMuLV) containing the viral packaging signal , and a drug-resistance marker. A pantropic packaging cell line containing the viral gag, and pol, genes is then co-transfected with the recombinant retroviral vector and a plasmid, pVSV-G, containing the vesicular stomatitis virus envelope glycoprotein in order to produce high-titre infectious replication-incompetent virus (Burns et al., Proc. Natl., Acad. Sci. USA 84, 5232-5236). The infectious recombinant virus is then used to transfect interferon sensitive fibroblasts or lymphoblastoid cells and cell lines that stably express the variant protein are then selected and tested for resistance to virus infection in a standard interferon bio-assay (Tovey et al., Nature, 271, 622-625, 1978). Growth inhibition using a standard proliferation assay (Mosmann, T., J. Immunol. Methods, 65, 55-63, 1983) and expression of MHC class I and class II antigens using standard techniques may also be determined.
[0042] A desired functional variant of HuIFRG-1, HuIFRG-2, HuIFRG-3 or HuIFRG-4 protein may consist essentially of the sequence of SEQ ID NO: 2, SEQ ID NO: 4, SEQ ID NO: 6 or SEQ ID NO: 8. A functional variant of SEQ ID NO: 2, SEQ ID NO: 4, SEQ ID NO: 6 or SEQ ID NO: 8 may be a polypeptide which has a least 60% to 70% identity, preferably at least 80% or at least 90% and particularly preferably at least 95%, at least 97% or at least 99% identity with the amino acid sequence of SEQ ID NO: 2, SEQ ID NO: 4, SEQ ID NO: 6 or SEQ ID NO: 8 over a region of at least 20, preferably at least 30, for instance at least 100 contiguous amino acids or over the full length of SEQ ID NO: 2, SEQ ID NO: 4, SEQ ID NO: 6 or SEQ ID NO: 8. Methods of measuring protein identity are well known in the art.
[0043] Amino acid substitutions may be made, for example from 1, 2 or 3 to 10, 20 or 30 substitutions. Conservative substitutions may be made, for example according to the following Table. Amino acids in the same block in the second column and preferably in the same line in the third column may be substituted for each other.
ALIPHATIC Non-polar G A P I L V Polar-uncharged C S T M N Q Polar-charged D E K R AROMATIC H F W Y
[0044] Variant polypeptide sequences for therapeutic use in accordance with the invention may be shorter polypeptide sequences, for example, a peptide of at least 20 amino acids or up to 50, 60, 70, 80, 100, 150 or 200 amino acids in length is considered to fall within the scope of the invention provided it retains appropriate biological activity of HuIFRG-1, HuIFRG-2, HuIFRG-3 or HuIFRG-4 protein. In particular, but not exclusively, this aspect of the invention encompasses the situation when the variant is a fragment of a complete naturally-occurring protein sequence.
[0045] Variant polypeptides for therapeutic use in accordance with the invention may be chemically modified, e.g. post-translationally modified. For example, they may be glycosylated and/or comprise modified amino acid residues. They may also be modified by the addition of a sequence either at the N-terminus and/or C-terminus. Polypeptides for therapeutic use in accordance with the invention may be made synthetically or by recombinant means. Such polypeptides may be modified to include non-naturally occurring amino acids, e.g. D amino acids. Variant polypeptides for use in accordance with the invention may have modifications to increase stability in vitro and/or in vivo. When the polypeptides are produced by synthetic means, such modifications may be introduced during production. The polypeptides may also be modified following either synthetic or recombinant production.
[0046] A number of side chain modifications are known in the protein modification art and may be present in variants for therapeutic use according to the invention. Such modifications include, for example, modifications of amino acids by reductive alkylation by reaction with an aldehyde followed by reduction with NaBH 4 , amidination with methylacetimidate or acylation with acetic anhydride.
[0047] Polypeptides for use in accordance with the invention will be in substantially isolated form. It will be understood that the polypeptides may be mixed with carriers or diluents which will not interfere with the intended purpose of the polypeptide and still be regarded as substantially isolated.
[0000] Polynucleotide Therapy
[0048] As an alternative to administration of HuIFRG-1, HuIFRG-2, HuIFRG-3 or HuIFRG-4 protein, or a functional variant thereof as described above, an isolated polynucleotide may be administered, e.g. in the form of an expression vector such as a viral vector, which directs expression of the desired polypeptide in vivo. Hence, as indicated above, in a further embodiment the invention provides an isolated polynucleotide, which directs expression in vivo of a polypeptide as defined above, which polynucleotide includes a sequence comprising:
(a) the nucleic acid of SEQ. ID. NO: 1, SEQ ID NO: 3, SEQ ID NO: 5 or SEQ ID NO: 7 or the coding sequence thereof; (b) a sequence which hybridises, e.g under stringent conditions, to a sequence complementary to a sequence as defined in (a); (c) a sequence that is degenerate as a result of the genetic code to a sequence as defined in (a) or (b); or (e) a sequence having at least 60% identity to a sequence as defined in (a), (b) or (c)
for use in therapeutic treatment of a human or non-human animal, more particularly for use as an anti-viral, anti-tumour or immunomodulatory agent.
[0053] Preferably, such a polynucleotide will be a DNA. The coding sequence for HuIFRG-1, HuIFRG-2, HuIFRG-3 or HuIFRG-4 protein or a variant thereof may be provided by a cDNA sequence or a genomic DNA sequence. Polynucleotides comprising an appropriate coding sequence can be isolated from human cells or synthesised according to methods well known in the art, as described by way of example in Sambrook et al. (1989) Molecular Cloning: A Laboratory Manual, 2 nd edition, Cold Spring Harbor Laboratory Press.
[0054] Polynucleotides for use in accordance with the invention may include within them synthetic or modified nucleotides. A number of different types of modification to polynucleotides are known in the art. These include methylphosphonate and phosphothioate backbones, addition of acridine or polylysine chains at the 3′ and/or 5′ ends of the molecule. Such modifications may be incorporated to enhance the in vivo activity or life span of the polynucleotide as a therapeutic agent.
[0055] Typically, a polynucleotide for use in accordance with the invention will include a sequence of nucleotides, which may preferably be a contiguous sequence of nucleotides, which is capable of hybridising under selective conditions to the complement of the coding sequence of SEQ. ID. NO: 1, SEQ ID NO: 3, SEQ ID NO: 5 or SEQ ID NO: 7. Such hybridisation will occur at a level significantly above background. Background hybridisation may occur, for example, because of other cDNAs present in a cDNA library. The signal level generated by the interaction between a desired coding sequence and the complement of the coding sequence of SEQ. ID. NO: 1, SEQ ID NO: 3, SEQ ID NO: 5 or SEQ ID NO: 7 will typically be at least 10 fold, preferably at least 100 fold, as intense as interactions between other polynucleotides and the target sequence. The intensity of interaction may be measured, for example, by radiolabelling the nucleic acid selected for probing, e.g. with 32 P. Selective hybridisation may typically be achieved using conditions of low stringency (0.3M sodium chloride and 0.03M sodium citrate at about 40° C.), medium stringency (for example, 0.3M sodium chloride and 0.03M sodium citrate at about 50° C.) or high stringency (for example, 0.03M sodium chloride and 0.003M sodium citrate at about 60° C.).
[0056] The coding sequence of SEQ. ID. NO: 1, SEQ ID NO: 3, SEQ ID NO: 5 or SEQ ID NO: 7 may be modified for incorporation into a polynucleotide as defined above by nucleotide substitutions, for example from 1, 2 or 3 to 10, 25, 50 or 100 substitutions. Degenerate substitutions may, for example, be made and/or substitutions may be made which would result in a conservative amino acid substitution when the modified sequence is translated, for example as shown in the table above. The coding sequence of SEQ. ID. NO: 1, SEQ ID NO: 3, SEQ ID NO: 5 or SEQ ID NO: 7 may alternatively or additionally be modified by one or more insertions and/or deletions and/or by an extension at either or both ends provided it encodes a polypeptide with the appropriate functional activity compared to HuIFRG-1, HuIFRG-2, HuIFRG-3 or HuIFRG-4 protein.
[0057] A nucleotide sequence capable of selectively hybridising to the complement of SEQ. ID. NO: 1, SEQ ID NO: 3, SEQ ID NO: 5 or SEQ ID NO: 7, or at least the coding sequence thereof, will be generally at least 70%, preferably at least 80 or 90% and more preferably at least 95% or 97%, homologous to such a DNA sequence. This homology may typically be over a region of at least 20, preferably at least 30, for instance at least 40, 60 or 100 or more contiguous nucleotides of the said DNA sequence.
[0058] Any combination of the above mentioned degrees of homology and minimum size may be used to define nucleic acids comprising desired coding sequences, with the more stringent combinations (i.e. higher homology over longer lengths) being preferred. Thus for example a polynucleotide which is at least 80% homologous over 25, preferably over 30 nucleotides may be found suitable, as may be a polynucleotide which is at least 90% homologous over 40 nucleotides.
[0059] Homologues of polynucleotide or protein sequences as referred to herein may be determined in accordance with well-known means of homology calculation, e.g. protein homology may be calculated on the basis of amino acid identity (sometimes referred to as “hard homology”). For example the UWGCG Package provides the BESTFIT program which can be used to calculate homology, for example used on its default settings, (Devereux et al. (1984) Nucleic Acids Research 12, p387-395). The PILEUP and BLAST algorithms can be used to calculate homology or line up sequences or to identify equivalent or corresponding sequences, typically used on their default settings, for example as described in Altschul S. F. (1993) J Mol Evol 36:290-300; Altschul, S, F et al. (1990) J Mol Biol 215:403-10.
[0060] Software for performing BLAST analyses is publicly available through the National Center for Biotechnology Information (http://www.ncbi.nlm.nih.gov/). This algorithm involves first identifying high scoring sequence pair (HSPs) by identifying short words of length W in the query sequence that either match or satisfy some positive-valued threshold score T when aligned with a word of the same length in a database sequence. T is referred to as the neighbourhood word score threshold (Altschul et al, supra). These initial neighbourhood word hits act as seeds for initiating searches to find HSP=s containing them. The word hits are extended in both directions along each sequence for as far as the cumulative alignment score can be increased. Extensions for the word hits in each direction are halted when: the cumulative alignment score falls off by the quantity X from its maximum achieved value; the cumulative score goes to zero or below, due to the accumulation of one or more negative-scoring residue alignments; or the end of either sequence is reached. The BLAST algorithm parameters W, T and X determine the sensitivity and speed of the alignment. The BLAST program uses as defaults a word length (W) of 11, the BLOSUM62 scoring matrix (see Henikoff and Henikoff(1992) Proc. Natl. Acad. Sci. USA 89: 10915-10919) alignments (B) of 50, expectation (E) of 10, M=5, N=4, and a comparison of both strands.
[0061] The BLAST algorithm performs a statistical analysis of the similarity between two sequences; see e.g., Karlin and Altschul (1993) Proc. Natl. Acad. Sci. USA 90: 5873-5787. One measure of similarity provided by the BLAST algorithm is the smallest sum probability (P(N)), which provides an indication of the probability by which a match between two nucleotide or amino acid sequences would occur by chance. For example, a sequence is considered similar to another sequence if the smallest sum probability in comparison of the first sequence to the second sequence is less than about 1, preferably less than about 0.1, more preferably less than about 0.01, and most preferably less than about 0.001.
[0062] As indicated above, a polynucleotide for use in accordance with the invention in substitution for direct administration of HuIFRG- 1, HuIFRG-2, HuIFRG-3 or HuIFRG-4 protein or a functional variant thereof may preferably be in the form of an expression vector. Expression vectors are routinely constructed in the art of molecular biology and may, for example, involve the use of plasmid DNA and appropriate initiators, promoters, enhancers and other elements, such as for example polyadenylation signals which may be necessary, and which are positioned in the correct orientation, in order to allow for protein expression. Such vectors may be viral vectors. Examples of suitable viral vectors include herpes simplex viral vectors, replication-defective retroviruses, including lentiviruses, adenoviruses, adeno-associated virus, HPV viruses (such as HPV-16 and HPV-18) and attenuated influenza virus vectors. Other suitable vectors would be apparent to persons skilled in the art. By way of further example in this regard reference is made again to Sambrook et al., 1989 (supra).
[0063] A polynucleotide capable of expressing in vivo an antisense sequence to a coding sequence for the amino acid sequence defined by SEQ. ID. No. 2, or a naturally-occurring variant thereof, for use in therapeutic treatment of a human or non-human animal is also envisaged as constituting an additional aspect of the invention. Again, such a polynucleotide may preferably be in the form of an expression vector. Such a polynucleotide will find use in treatment of diseases associated with upregulation of HuIFRG-1, HuIFRG-2, HuIFRG-3 or HuIFRG-4 protein.
[0064] It will be appreciated that antibodies to HuIFRG-1, HuIFRG-2, HuIFRG-3 or HuIFRG-4 protein and antigen-binding fragments thereof may find similar use.
[0000] Pharmaceutical Compositions
[0065] A polypeptide for use in accordance with the invention is typically formulated for administration with a pharnaceutically acceptable carrier or diluent. The pharmaceutical carrier or diluent may be, for example, an isotonic solution. For example, solid oral forms may contain, together with the active compound, diluents, e.g. lactose, dextrose, saccharose, cellulose, corn starch or potato starch; lubricants, e.g. silica, talc, stearic acid, magnesium or calcium stearate and or polyethelene glycols; binding agents, e.g. starches, arabic gums, gelatin, methyl cellulose, carboxymethylcellulose or polyvinyl pyrrolidone; desegregating agents, e.g. starch, alginic acid, alginates or sodium starch glycolate; effervescing mixtures; dyestuffs; sweeteners; wetting agents, such as lecithin, polysorbates, laurylsulphates; and, in general, non-toxic and pharmacologically inactive substances used in pharmaceutical formulations. Such pharmaceutical preparations may be manufactured in known manner, for example, by means of mixing, granulating, tableting, sugar-coating, or film coating processes.
[0066] Liquid dispersions for oral administration may be syrups, emulsions and suspensions. The syrups may contain as carriers, for example, saccharose or saccharose with glycerine and/or mannitol and/or sorbitol.
[0067] Suspensions and emulsions may contain as carrier, for example a natural gum, agar, sodium alginate, pectin, methyl cellulose, carboxymethylcellulose, or polyvinyl alcohol. The suspensions or solutions for intramuscular injections may contain, together with the active compound, a pharmaceutically acceptable carrier, e.g. sterile water, olive oil, ethyl oleate, glycols, e.g. propylene glycol, and if desired, a suitable amount of lidocaine hydrochloride.
[0068] Solutions for intravenous injection or infusions may contain as carrier, for example, sterile water or preferably they may be in the form of sterile, aqueous, isotonic saline solutions.
[0069] The dose of polypeptide for use in accordance with the invention may be determined according to various parameters, especially according to the substance used; the age, weight and condition of the patient to be treated; the route of administration; and the required regimen. A physician will be able to determine the required route of administration and dosage for any particular patient. A typical daily dose is from about 0.1 to 50 mg per kg, preferably from about 0.1 mg/kg to 10 mg/kg of body weight, according to the activity of the specific active compound, the age, weight and condition of the subject to be treated, and the frequency and route of administration. Preferably, daily dosage levels are from 5 mg to 2 g.
[0070] A polynucleotide for use in accordance with the invention will also typically be formulated for administration with a pharmaceutically acceptable carrier or diluent. Such a polynucleotide may be administered by any known technique whereby expression of the desired polypeptide can be attained in vivo. For example, the polynucleotide may be delivered intradermally, subcutaneously, or intramuscularly. Alternatively, the polynucleotide may be delivered across the skin using a particle-mediated delivery device. A polynucleotide for use in accordance with the invention may be administered by intranasal or oral administration.
[0071] A non-viral vector for use in accordance with the invention may be packaged into liposomes or into surfactant. Uptake of nucleic acid constructs for use in accordance with the invention may be enhanced by several known transfection techniques, for example those including the use of transfection agents. Examples of these agents include cationic agents, for example calcium phosphate and DEAE dextran and lipofectants, for example lipophectam and transfectam. The dosage of the nucleic acid to be administered can be varied. Typically, the nucleic acid is administered in the range of from 1 pg to 1 mg, preferably from 1 pg to 10 □g nucleic acid for particle-mediated gene delivery and from 10 □g to 1 mg for other routes.
[0000] Prediction of Type 1 Interferon Responsiveness
[0072] As also indicated above, in a still further aspect the present invention provides a method of predicting responsiveness of a patient to treatment with a Type 1 interferon, e.g. IFN-α treatment such as IFN-α treatment by an oromucosal route or intravenously, which comprises determining the level of one or more of HuIFRG-1, HuIFRG-2, HuIFRG-3, HuIFRG-4 protein and naturally-occurring variants thereof, or one or more corresponding mRNAs, in a cell sample from said patient, wherein said sample is taken from said patient following administration of a Type 1 interferon or is treated prior to said determining with a Type 1 interferon in vitro.
[0073] Preferably, the Type 1 interferon for testing responsiveness will be the Type 1 interferon selected for treatment. It may be administered by the proposed treatment route and at the proposed treatment dose. Preferably, the subsequent sample analysed may be, for example, a blood sample or a sample of peripheral blood mononuclear cells (PBMCs) isolated from a blood sample.
[0074] More conveniently and preferably, a sample obtained from the patient comprising PBMCs isolated from blood may be treated in vitro with a Type 1 interferon, e.g. at a dosage range of about 1 to 10,000 IU/ml. Such treatment may be for a period of hours, e.g. about 7 to 8 hours. Preferred treatment conditions for such in vitro testing may be determined by testing PBMCs taken from normal donors with the same interferon and looking for upregulation of an appropriate expression product. Again, the Type 1 interferon employed will preferably be the Type 1 interferon proposed for treatment of the patient, e.g. recombinant IFN-α. PBMCs for such testing may be isolated in conventional manner from a blood sample using Ficoll-Hypaque density gradients. An example of a suitable protocol for such in vitro testing of Type 1 interferon responsiveness is provided in Example 6 below.
[0075] The sample, if appropriate after in vitro treatment with a Type 1 interferon, may be analysed for the level of HuIFRG-1, HuIFRG-2, HuIFRG-3 or HuIFRG-4 protein or a naturally-occurring variant thereof. This may be done using an antibody or antibodies capable of specifically binding one or more of HuIFRG-1, HuIFRG-2, HuIFRG-3 or HuIFRG-4 protein and naturally-occurring variants thereof, eg. allelic variants thereof. Preferably, however, the sample will be analysed for mRNA encoding HuIFRG-1, HuIFRG-2, HuIFRG-3 or HuIFRG-4 protein or a naturally-occurring variant thereof. Such mRNA analysis may employ any of the techniques known for detection of mRNAs, e.g. Northern blot detection or mRNA differential display. A variety of known nucleic acid amplification protocols may be employed to amplify any mRNA of interest present in the sample, or a portion thereof, prior to detection. The mRNA of interest, or a corresponding amplified nucleic acid, may be probed for using a nucleic acid probe attached to a solid support. Such a solid support may be a micro-array carrying probes to determine the level of further mRNAs or amplification products thereof corresponding to Type 1 interferon upregulated genes, e.g. such genes identified as upregulated in response to oromucosal or intravenous administration of IFN-α. Methods for constructing such micro-arrays (also referred to commonly as nucleic acid, probe or DNA chips) are well-known (see, for example, EP-B 0476014 and 0619321 of Affymax Technologies N.V. and Nature Genetics Supplement January 1999 entitled “The Chipping Forecast”).
[0000] The Following Examples Illustrate the Invention:
EXAMPLES
Example 1
[0076] Previous experiments had shown that the application of 5 μl of crystal violet to each nostril of a normal adult mouse using a P20 Eppendorf micropipette resulted in an almost immediate distribution of the dye over the whole surface of the oropharyngeal cavity. Staining of the oropharyngeal cavity was still apparent some 30 minutes after application of the dye. These results were confirmed by using 125 I-labelled recombinant human IFN-□1-8 applied in the same manner. The same method of administration was employed to effect oromucosal administration in the studies which are described below.
[0077] Six week old, male DBA/2 mice were treated with either 100,000 IU of recombinant murine interferon α (IFN α) purchased from Life Technologies Inc, in phosphate buffered saline (PBS), 10 μg of recombinant human interleukin 15 (IL-15) purchased from Protein Institute Inc, PBS containing 100 μg/ml of bovine serum albumin (BSA), or left untreated. Eight hours later, the mice were sacrificed by cervical dislocation and the lymphoid tissue was removed surgically from the oropharyngeal cavity and snap frozen in liquid nitrogen and stored at −80° C. RNA was extracted from the lymphoid tissue by the method of Chomczynski and Sacchi (Anal. Biochem. (1987) 162, 156-159) and subjected to mRNA Differential Display Analysis (Lang, P. and Pardee, A. B., Science, 257, 967-971).
[0000] Differential Display Analysis
[0078] Differential display analysis was carried out using the “Message Clean” and “RNA image” kits of the GenHunter Corporation essentially as described by the manufacturer. Briefly, RNA was treated with RNase-free DNase, and 1 μg was reverse-transcribed in 100 μl of reaction buffer using either one or the other of the three one-base anchored oligo-(dT) primers A, C, or G. RNA was also reverse-transcribed using one or the other of the 9 two-base anchored oligo-(dT) primers AA, CC, GG, AC, CA, GA, AG, CG, GC. All the samples to be compared were reverse transcribed in the same experiment, separated into aliquots and frozen. The amplification was performed with only 1 μl of the reverse transcription sample in 10 μl of amplification mixture containing Taq DNA polymerase and α- 33 P dATP (3,000 Ci/mmole). Eighty 5′ end (HAP) random sequence primers were used in combination with each of the (HT11) A, C, G, AA, CC, GG, AC, CA, GA, AG, CG or GC primers. Samples were then run on 7% denaturing polyacrylamide gels and exposed to authoradiography. Putative differentially expressed bands were cut out, reamplified according to the instructions of the supplier, and further used as probes to hybridise Northern blots of RNA extracted from the oropharyngeal cavity of IFN treated, IL-15 treated, and excipient treated animals.
[0000] Cloning and Sequencing
[0079] Re-amplified bands from the differential display screen were cloned in the Sfr 1 site of the pPCR-Script SK(+) plasmid (Stratagene), and cDNA amplified from the rapid amplification of cDNA ends were isolated by TA cloning in the pCR3 plasmid (Invitrogen). DNA was sequenced using an automatic di-deoxy sequencer (Perkin Elmer ABI PRISM 377).
[0000] Identification of Human cDNA
[0080] Differentially expressed murine 3′ sequences identified from the differential display screen were compared with random human expressed sequence tags (EST) present in the dbEST database of GenBank™ of the United States National Center for Biotechnology Information (NCBI). The sequences potentially related to the murine EST isolated from the differential display screen were combined in a contig and used to construct a human consensus sequence corresponding to a putative cDNA.
[0081] One such cDNA was found to correspond to GenBank cDNA sequence g4586459. The corresponding polypeptide sequence is GenBank sequence g4586460, not assigned in GenBank any function.
[0082] Other mouse genes upregulated in lymphoid tissue in response to oromucosal administration of IFN-α as described above have also been found to be upregulated in the spleen of mice in response to intravenous administration of IFN-α. A similar result is anticipated in respect of the mouse gene corresponding to the human gene identified by Genbank cDNA accesssion no. g4586459 when intravenous administration of IFN-α is carried out as described in Example 5 below.
[0083] Furthermore, mRNAs corresponding to human gene analogues of mouse genes found to be upregulated in response to oromucosal and intravenous administration of IFN-α have been found to be enhanced in human peripheral blood mononuclear cells following treatment with IFN-α in vitro. The same result is anticipated for mRNA corresponding to the cDNA as set forth in SEQ ID NO: 1 when human peripheral blood mononuclear cells are treated with IFN-α as described in Example 6 below.
Example 2
[0084] Previous experiments had shown that the application of 5 μl of crystal violet to each nostril of a normal adult mouse using a P20 Eppendorf micropipette resulted in an almost immediate distribution of the dye over the whole surface of the oropharyngeal cavity. Staining of the oropharyngeal cavity was still apparent some 30 minutes after application of the dye. These results were confirmed by using 125 I-labelled recombinant human IFN-□1-8 applied in the same manner. The same method of administration was employed to effect oromucosal administration in the studies which are described below.
[0085] Six week old, male DBA/2 mice were treated with either 100,000 IU of recombinant murine interferon α (IFN α) purchased from Life Technologies Inc, in phosphate buffered saline (PBS), 10 μg of recombinant human interleukin 15 (IL-15) purchased from Protein Institute Inc, PBS containing 100 μg/ml of bovine serum albumin (BSA), or left untreated. Eight hours later, the mice were sacrificed by cervical dislocation and the lymphoid tissue was removed surgically from the oropharyngeal cavity and snap frozen in liquid nitrogen and stored at −80° C. RNA was extracted from the lymphoid tissue by the method of Chomczynski and Sacchi (Anal. Biochem. (1987) 162, 156-159) and subjected to mRNA Differential Display Analysis (Lang, P. and Pardee, A. B., Science, 257, 967-971).
[0000] Differential Display Analysis
[0086] Differential display analysis was carried out using the “Message Clean” and “RNA image” kits of the GenHunter Corporation essentially as described by the manufacturer. Briefly, RNA was treated with RNase-free DNase, and 1 μg was reverse-transcribed in 100 μl of reaction buffer using either one or the other of the three one-base anchored oligo-(dT) primers A, C, or G. RNA was also reverse-transcribed using one or the other of the 9 two-base anchored oligo-(dT) primers AA, CC, GG, AC, CA, GA, AG, CG, GC. All the samples to be compared were reverse transcribed in the same experiment, separated into aliquots and frozen. The amplification was performed with only 1 μl of the reverse transcription sample in 10 μl of amplification mixture containing Taq DNA polymerase and α- 33 P dATP (3,000 Ci/mmole). Eighty 5′ end (HAP) random sequence primers were used in combination with each of the (HT11) A, C, G, AA, CC, GG, AC, CA, GA, AG, CG or GC primers. Samples were then run on 7% denaturing polyacrylamide gels and exposed to authoradiography. Putative differentially expressed bands were cut out, reamplified according to the instructions of the supplier, and further used as probes to hybridise Northern blots of RNA extracted from the oropharyngeal cavity of IFN treated, IL-15 treated, and excipient treated animals.
[0000] Cloning and Sequencing
[0087] Re-amplified bands from the differential display screen were cloned in the Sfr 1 site of the pPCR-Script SK(+) plasmid (Stratagene), and cDNA amplified from the rapid amplification of cDNA ends were isolated by TA cloning in the pCR3 plasmid (Invitrogen). DNA was sequenced using an automatic di-deoxy sequencer (Perkin Elmer ABI PRISM 377).
[0000] Identification of Human cDNA
[0088] Differentially expressed murine 3′ sequences identified from the differential display screen were compared with random human expressed sequence tags (EST) present in the dbEST database of GenBank™ of the United States National Center for Biotechnology Information (NCBI). The sequences potentially related to the murine EST isolated from the differential display screen were combined in a contig and used to construct a human consensus sequence corresponding to a putative cDNA.
[0089] One such cDNA was found to correspond to GenBank cDNA sequence g2342476. The corresponding polypeptide sequence is GenBank sequence g2342477, not assigned in GenBank any function.
[0090] Other mouse genes upregulated in lymphoid tissue in response to oromucosal administration of IFN-α as described above have also been found to be upregulated in the spleen of mice in response to intravenous administration of IFN-α. A similar result is anticipated in respect of the mouse gene corresponding to the human gene identified by Genbank cDNA accesssion no. g2342476 when intravenous administration of IFN-α is carried out as described in Example 5 below.
[0091] Furthermore, mRNAs corresponding to human gene analogues of mouse genes found to be upregulated in response to oromucosal and intravenous administration of IFN-α have been found to be enhanced in human peripheral blood mononuclear cells following treatment with IFN-α in vitro. The same result is anticipated for mRNA corresponding to the cDNA as set forth in SEQ. ID. No. 3 when human peripheral blood mononuclear cells are treated with IFN-α as described in Example 6 below.
Example 3
[0092] Previous experiments had shown that the application of 5 μl of crystal violet to each nostril of a normal adult mouse using a P20 Eppendorf micropipette resulted in an almost immediate distribution of the dye over the whole surface of the oropharyngeal cavity. Staining of the oropharyngeal cavity was still apparent some 30 minutes after application of the dye. These results were confirmed by using 125 I-labelled recombinant human IFN-□1-8 applied in the same manner. The same method of administration was employed to effect oromucosal administration in the studies which are described below.
[0093] Six week old, male DBA/2 mice were treated with either 100,000 IU of recombinant murine interferon α (IFN α) purchased from Life Technologies Inc, in phosphate buffered saline (PBS), 10 μg of recombinant human interleukin 15 (IL-15) purchased from Protein Institute Inc, PBS containing 100 μg/ml of bovine serum albumin (BSA), or left untreated. Eight hours later, the mice were sacrificed by cervical dislocation and the lymphoid tissue was removed surgically from the oropharyngeal cavity and snap frozen in liquid nitrogen and stored at −80° C. RNA was extracted from the lymphoid tissue by the method of Chomczynski and Sacchi (Anal. Biochem. (1987) 162, 156-159) and subjected to mRNA Differential Display Analysis (Lang, P. and Pardee, A. B., Science, 257, 967-971).
[0000] Differential Display Analysis
[0094] Differential display analysis was carried out using the “Message Clean” and “RNA image” kits of the GenHunter Corporation essentially as described by the manufacturer. Briefly, RNA was treated with RNase-free DNase, and 1 μg was reverse-transcribed in 100 μl of reaction buffer using either one or the other of the three one-base anchored oligo-(dT) primers A, C, or G. RNA was also reverse-transcribed using one or the other of the 9 two-base anchored oligo-(dT) primers AA, CC, GG, AC, CA, GA, AG, CG, GC. All the samples to be compared were reverse transcribed in the same experiment, separated into aliquots and frozen. The amplification was performed with only 1 μl of the reverse transcription sample in 10 μl of amplification mixture containing Taq DNA polymerase and α- 33 P dATP (3,000 Ci/mmole). Eighty 5′ end (HAP) random sequence primers were used in combination with each of the (HT11) A, C, G, AA, CC, GG, AC, CA, GA, AG, CG or GC primers. Samples were then run on 7% denaturing polyacrylamide gels and exposed to authoradiography. Putative differentially expressed bands were cut out, reamplified according to the instructions of the supplier, and further used as probes to hybridise Northern blots of RNA extracted from the oropharyngeal cavity of IFN treated, IL-15 treated, and excipient treated animals.
[0000] Cloning and Sequencing
[0095] Re-amplified bands from the differential display screen were cloned in the Sfr 1 site of the pPCR-Script SK(+) plasmid (Stratagene), and cDNA amplified from the rapid amplification of cDNA ends were isolated by TA cloning in the pCR3 plasmid (Invitrogen). DNA was sequenced using an automatic di-deoxy sequencer (Perkin Elmer ABI PRISM 377).
[0000] Identification of Human cDNA
[0096] Differentially expressed murine 3′ sequences identified from the differential display screen were compared with random human expressed sequence tags (EST) present in the dbEST database of GenBank™ of the United States National Center for Biotechnology Information (NCBI). The sequences potentially related to the murine EST isolated from the differential display screen were combined in a contig and used to construct a human consensus sequence corresponding to a putative cDNA.
[0097] One such cDNA was found to correspond to GenBank cDNA sequence g3327161. The corresponding polypeptide sequence is GenBank sequence g3327162, not assigned in GenBank any function.
[0098] Other mouse genes upregulated in lymphoid tissue in response to oromucosal administration of IFN-α as described above have also been found to be upregulated in the spleen of mice in response to intravenous administration of IFN-α. A similar result is anticipated in respect of the mouse gene corresponding to the human gene identified by Genbank cDNA accesssion no. g3327161 when intravenous administration of IFN-α is carried out as described in Example 5 below.
[0099] Furthermore, mRNAs corresponding to human gene analogues of mouse genes found to be upregulated in response to oromucosal and intravenous administration of IFN-α have been found to be enhanced in human peripheral blood mononuclear cells following treatment with IFN-α in vitro. The same result is anticipated for mRNA corresponding to the cDNA as set forth in SEQ. ID. No. 5 when human peripheral blood mononuclear cells are treated with IFN-α as described in Example 6 below.
Example 4
[0100] Previous experiments had shown that the application of 5 μl of crystal violet to each nostril of a normal adult mouse using a P20 Eppendorf micropipette resulted in an almost immediate distribution of the dye over the whole surface of the oropharyngeal cavity. Staining of the oropharyngeal cavity was still apparent some 30 minutes after application of the dye. These results were confirmed by using 125 I-labelled recombinant human IFN-□1-8 applied in the same manner. The same method of administration was employed to effect oromucosal administration in the studies which are described below.
[0101] Six week old, male DBA/2 mice were treated with either 100,000 IU of recombinant murine interferon α (IFN α) purchased from Life Technologies Inc, in phosphate buffered saline (PBS), 10 μg of recombinant human interleukin 15 (IL-15) purchased from Protein Institute Inc, PBS containing 100 μg/ml of bovine serum albumin (BSA), or left untreated. Eight hours later, the mice were sacrificed by cervical dislocation and the lymphoid tissue was removed surgically from the oropharyngeal cavity and snap frozen in liquid nitrogen and stored at −80° C. RNA was extracted from the lymphoid tissue by the method of Chomczynski and Sacchi (Anal. Biochem. (1987) 162, 156-159) and subjected to mRNA Differential Display Analysis (Lang, P. and Pardee, A. B., Science, 257, 967-971).
[0000] Differential Display Analysis
[0102] Differential display analysis was carried out using the “Message Clean” and “RNA image” kits of the GenHunter Corporation essentially as described by the manufacturer. Briefly, RNA was treated with RNase-free DNase, and 1 μg was reverse-transcribed in 100 μl of reaction buffer using either one or the other of the three one-base anchored oligo-(dT) primers A, C, or G. RNA was also reverse-transcribed using one or the other of the 9 two-base anchored oligo-(dT) primers AA, CC, GG, AC, CA, GA, AG, CG, GC. All the samples to be compared were reverse transcribed in the same experiment, separated into aliquots and frozen. The amplification was performed with only 1 μl of the reverse transcription sample in 10 μl of amplification mixture containing Taq DNA polymerase and α- 33 P dATP (3,000 Ci/mmole). Eighty 5′ end (HAP) random sequence primers were used in combination with each of the (HT11) A, C, G, AA, CC, GG, AC, CA, GA, AG, CG or GC primers. Samples were then run on 7% denaturing polyacrylamide gels and exposed to authoradiography. Putative differentially expressed bands were cut out, reamplified according to the instructions of the supplier, and further used as probes to hybridise Northern blots of RNA extracted from the oropharyngeal cavity of IFN treated, IL-15 treated, and excipient treated animals.
[0000] Cloning and Sequencing
[0103] Re-amplified bands from the differential display screen were cloned in the Sfr 1 site of the pPCR-Script SK(+) plasmid (Stratagene), and cDNA amplified from the rapid amplification of cDNA ends were isolated by TA cloning in the pCR3 plasmid (Invitrogen). DNA was sequenced using an automatic di-deoxy sequencer (Perkin Elmer ABI PRISM 377).
[0000] Identification of Human cDNA
[0104] Differentially expressed murine 3′ sequences identified from the differential display screen were compared with random human expressed sequence tags (EST) present in the dbEST database of GenBank™ of the United States National Center for Biotechnology Information (NCBI). The sequences potentially related to the murine EST isolated from the differential display screen were combined in a contig and used to construct a human consensus sequence corresponding to a putative cDNA.
[0105] One such cDNA was found to correspond to GenBank cDNA sequence g4529886. The corresponding polypeptide sequence is GenBank sequence g4529888, not assigned in GenBank any function.
[0106] Other mouse genes upregulated in lymphoid tissue in response to oromucosal administration of IFN-α as described above have also been found to be upregulated in the spleen of mice in response to intravenous administration of IFN-α. A similar result is anticipated in respect of the mouse gene corresponding to the human gene identified by Genbank cDNA accesssion no. g4529886 when intravenous administration of IFN-α is carried out as described in Example 5 below.
[0107] Furthermore, mRNAs corresponding to human gene analogues of mouse genes found to be upregulated in response to oromucosal and intravenous administration of IFN-α have been found to be enhanced in human peripheral blood mononuclear cells following treatment with IFN-α in vitro. The same result is anticipated for mRNA corresponding to the cDNA as set forth in SEQ. ID. No. 7 when human peripheral blood mononuclear cells are treated with IFN-α as described in Example 6 below.
Example 5
[0000] Intravenous Administration of IFN-α
[0108] Male DBA/2 mice are injected intravenously with 100,000 IU of recombinant murine IFN-α purchased from Life Technologies Inc. in 200:1 of PBS or treated with an equal volume of PBS alone. Eight hours later the animals are sacrificed by cervical dislocation and the spleen was removed using conventional procedures. Total RNA was extracted by the method of Chomczynski and Sacchi (Anal. Biochem. (1987) 162, 156-159) and 10.0 :g of total RNA per sample is subjected to Northern blotting in the presence of glyoxal and hybridised with a cDNA probe for the mRNA of interest as described by Dandoy-Dron et al. (J. Biol. Chem. (1998) 273, 7691-7697). The blots are first exposed to autoradiography and then quantified using a Phospholmager according to the manufacturer's instructions.
Example 6
[0000] Testing Type 1 Interferon Responsiveness In Vitro
[0109] Human peripheral blood mononuclear cells (PBMC) from normal donors are isolated on Ficoll-Hypaque density gradients and treated in vitro with 10,000 IU of recombinant human IFN-α2 (intron A from Schering-Plough) in PBS or with an equal volume of PBS alone. Eight hours later the cells are centrifuged (800×g for 10 minutes) and the cell pellet recovered. Total RNA is extracted from the cell pellet by the method of Chomczynski and Sacchi and 10.0 :g of total RNA per sample is subjected to Northern blotting as described in Example 5 above.
[0110] The same procedure can be used to predict Type 1 interferon responsiveness using PBMC taken from a patient proposed to be treated with a Type 1 interferon.
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The present disclosure relates to identification of genes upregulated by interferon-α administration, in particular the human genes corresponding to the cDNA sequences in GenBank designated g4586459, g2342476, g3327161 and g4529886. Determination of expression products of these genes is proposed as having utility in predicting responsiveness to treatment with interferon-α and other interferons which act at the Type 1 interferon receptor. Therapeutic use of the proteins encoded by the same genes is also envisaged.
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TECHNICAL FIELD
The present invention relates in general to measuring instruments, and in particular, to a method and apparatus for ascertaining the gap between opposing parts.
BACKGROUND INFORMATION
In manufacturing quality control, it is often necessary to verify the width of a gap between two adjacent, opposing surfaces. For example, when servicing a computer printer, it is required to optimally set the distance between an end part of a printing head and a surface of a printing medium in order to obtain high quality printing on the printing medium. This distance is called a print gap. It is, therefore desirable to preset the print gap in accordance with the thickness of the recording medium, such as paper.
Currently, print gaps and similar gaps are measured with a plurality of shim or wire gauges (“feeler” gauges). Feeler gauges are thin steel plates of a predetermined thickness. The width of a gap is measured by a feeler gauge by inserting the gauge into the gap and moving the gauge back and forth within the gap. The amount of frictional resistance between the gauge and the opposing surfaces increases as thicker gauges are inserted into the gap. A gauge that is too thin will result in little or no frictional resistance when inserted into the gap. On the other hand, if the gauge is too thick, insertion will be impossible or will be achieved with great difficulty. Thus, it is possible to determine width of the gap by judging the degree of frictional resistance.
Judging the correct amount of frictional resistance is subjective and is dependent on the experience of the operator. Often an inexperienced operator may not be able to repeat the same result because he is relying on his judgment regarding the correct degree of frictional resistance. Furthermore, other operators may not be able to reproduce the results even with the same gauge.
What is needed, therefore, is an inexpensive device to objectively determine whether a gap has been set to the proper tolerances.
SUMMARY OF THE INVENTION
The previously mentioned needs are fulfilled with the present invention. Accordingly, there is provided, in a first form, a feeler gauge which provides an objective means of determining the width of a gap. The feeler gauge comprises a gap measuring element which is insertable into the gap and an indicator coupled to the gap measuring element for automatically indicating when said gap has been set to a predetermined distance. The measuring element comprises two plates which act as a switch in an electrical circuit. When the gap gauge is inserted into a gap of predetermined width, the plates press against each other and current from a power source lights up a light emitting diode. Conversely, when the plates are inserted into a gap that is too wide, the plates do not press against each. The circuit, therefore, is not complete, and the light emitting diode does not light up. Thus, this invention provides an objective, reliable means for confirming the width of a gap. The invention can be used for gaps of different widths by varying the thicknesses of the plates.
These and other features, and advantages, will be more clearly understood from the following detailed description taken in conjunction with the accompanying drawings. It is important to note the drawings are not intended to represent the only form of the invention.
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 conjunction with the accompanying drawings, in which:
FIG. 1 is an isometric view incorporating one embodiment of the present invention;
FIG. 2 is an exploded isometric view of the shim plate unit of one embodiment of the present invention;
FIG. 3 is an electrical schematic diagram of the control unit of one embodiment of the present invention;
FIG. 4 is an isometric view incorporating another embodiment of the present invention;
FIGS. 5A and 5B are cross-section views of the embodiment illustrated in FIG. 2; and
FIGS. 6A and 6B are cross-section views of the embodiment illustrated in FIG. 4 .
DETAILED DESCRIPTION OF THE INVENTION
The principles of the present invention and their advantages are best understood by referring to the illustrated embodiments depicted in FIGS. 1-4 of the drawings, in which like numbers designate like parts. In the following description, well-known elements are presented without detailed description in order not to obscure the present invention in unnecessary detail. For the most part, details unnecessary to obtain a complete understanding of the present invention have been omitted inasmuch as such details are within the skills of persons of ordinary skill in the relevant art.
Turning now to FIG. 1, there is illustrated an isometric view of gap gauge 100 . In this embodiment, gap gauge 100 is a hand held device adaptable for measuring the print gap between a printer head (not shown) and a platen (not shown). Note, however, the present invention is not limited to measuring gaps in printers, but can be used for any other application where a gap needs to be measured. When panel unit 104 is inserted into a print gap, an electrical contact is made sending an electrical current to a suitable indicator, such as a light emitting diode, LED 102 , which provides a visual indication to the user of the magnitude of the gap to be measured. Another, such indicator could be a “beeper” or sound generator chip coupled to a small speaker to provide an audible indication. Such sound generator chips and speakers are commercially available and well known by those who practice the relevant art.
The present invention is designed to measure a particular width with a small amount of tolerance. Thus, gaps of different widths will require separate gauges. However, in several industries, such as computer printers, the width of the gap must be preset to a particular distance. The width of the gap is set by a trial and error method. It is set, then measured. If it is not within a particular tolerance, another attempt is made to set the gap. The steps of setting the gap and then checking the gap by measuring its width is repeated until the gap is within a particular tolerance to a predetermined distance.
The primary components of gap gauge 100 are panel unit 104 and housing unit 106 . Housing unit 106 acts as a handle for gap gauge 100 . Housing unit 106 comprises of enclosure 108 which is made of plastic or another suitable material. Housing unit 106 may be set at an angle relative to panel unit 104 to clear any structure such as a printer cover. Enclosure 108 encloses most of the electronics of the present invention. As will be discussed in reference to FIG. 3, the basic electrical components housed in enclosure 108 is a battery (FIG. 3 ), LED 102 , on/off switch 110 , and the circuitry connecting the components.
In the embodiment illustrated in FIG. 1, panel unit 104 is made from two closely spaced, generally rectangular metal shims (FIG. 2 ). Panel unit 104 is designed to be inserted into the print gap to be checked. If the print gap is the correct width, the shims make contact and complete an electrical circuit (see FIG. 3) which in turn, causes LED 102 to light up. Depending on the embodiment, there may also be a guide installed to help align gap gauge 100 to the print gap to be measured. In this embodiment, which is designed to be used for printers, guide 112 is attached to panel unit 104 to assist in aligning gap gauge 100 into a print gap. Guide 112 is made from plastic or another suitable material. Its dimensions are governed by the dimensions and configuration of the printer head.
FIG. 2 is an exploded view of gap gauge 100 . Shim 202 is a substantially flat metal plate with a small rectangular protrusion 204 at one corner. Shim 202 is used as a base for panel unit 104 (FIG. 1 ). When gap gauge 100 is assembled, protrusion 204 is inserted into slot 212 of housing unit 106 (where it makes electrical contact with the electrical circuitry (not shown) housed in housing unit 106 .
Shim 216 is a flat metal plate that is substantially the mirror image of shim 202 . Shim 216 can be of variable thickness to correspond to the thickness of the gap the particular gap gauge is designed to be measured. Shim 216 also has a small rectangular protrusion 218 , which when assembled, is inserted into slot 214 of housing unit 106 where it makes electrical contact with the electrical circuitry (not shown).
Tape strips 208 a and 208 b are strips of double-sided adhesive tape which adhere shim 202 to shim 216 . Tape strips 206 a and 206 b are strips of electrical insulating tape which act as spacers and keep shim 202 and shim 216 from making electrical contact when panel unit 104 is not in a print gap.
FIG. 3 schematically illustrates a typical electronic arrangement of the present invention. A suitable power supply, such as a replaceable or rechargeable battery 302 supplies power to the electronics of the invention. Battery 302 powers LED 102 when the circuit is closed. On/off switch 110 prevents battery drain by keeping the circuit open when gap gauge 100 is not in use. On/off switch 110 is a typical on/off switch designed to be mounted on a standard electric circuit board. Such on/off switches are common in the marketplace and are well known by those who practice the art. Panel unit 104 is shown in FIG. 3 as another switch because, panel unit 104 operates as a switch. Resistor 301 is provided to limit the current flow and, thus conserve power from battery 302 .
When operating this embodiment, the user first turns gap gauge on by means of on/off switch 110 . The user then uses housing unit 106 (FIG. 1) as a handle to insert panel unit 104 (FIG. 1) into the gap to be measured, for instance, the gap between a printhead and a platen. If the gap is the correct thickness, shim 216 (FIG. 2) will be pressed against shim 202 (FIG. 2) and the electric circuit will be complete.
Referring back to FIGS. 2 and 3, once shim 216 is pressed against shim 202 , the current from battery 302 flows through LED 102 which illuminates indicating to the user that the gap is set at a predetermined distance. Current then flows through on/off switch 110 (which is switched on) and around to a common electrical connection (not shown) in housing unit 106 which is connected to protrusion 218 . The current flows through shim 216 to shim 202 , then to protrusion 204 . Protrusion 204 connects to another common electrical connection (not shown) which is connected, to resistor 301 , then to the negative terminal of battery 302 , thus completing the circuit.
Panel unit 104 acts similar to a spring-loaded electrical switch. Shim 216 is relatively thin compared to shim 202 which is the base. Not only do tape strips 206 a , 206 b , 208 a , and 208 b separate shim 216 from shim 202 , but these strips hold the edges of shim 216 in place. FIG. 5A represents a section view of the embodiment illustrated in FIG. 1 when panel unit 104 is not inserted into a gap. The section was cut at approximately the midpoint of shim 202 and through tape strips 208 a and 208 b . The thicknesses of the shims and strips of tape have been greatly exaggerated for illustration purposes. When the panel unit is not inserted, shim 216 spans between the strips of tape. It does not, therefore, make contact with shim 202 and the electrical circuit (see FIG. 3) is not complete.
FIG. 5B, on the other hand, illustrates how shim 216 deflects when inserted into an appropriate gap between surface 502 and surface 504 . If the gap is at the correct distance, shim 216 will deflect enough so that it makes contact with shim 202 . This contact completes the electrical circuit, thereby causing LED 102 to illuminate. Thereafter, when LED 102 is removed from the gap, shim 216 flexes back to its original shape (illustrated in FIG. 5A) similar to the way a trampoline deflects when there is a load on it and springs back into shape when the load is removed. Once shim 216 has returned to its original shape, the electrical circuit (see FIG. 3) is broken and LED 102 is no longer illuminated.
A second embodiment is illustrated in FIG. 4 which is an exploded isometric view of gap gauge 400 . The second embodiment is similar to the first embodiment except that it uses a t-shaped upper shim, rather than a rectangular shaped plate.
For brevity and clarity, a description of those parts which are identical or similar to those described in connection with the first embodiment illustrated in FIGS. 1-3 will not be repeated here. Reference should be made to the foregoing paragraphs with the following description to arrive at a complete understanding of this second embodiment.
The embodiment shown in FIG. 4 uses an identical housing unit to the first embodiment. The panel unit is different and a mylar film is also used as a cover. In the second embodiment, shim 402 is a substantially flat metal plate with a small rectangular protrusion 404 at one corner. Shim 402 is used as a base for this embodiment. Upper shim 416 is a flat metal plate that is shaped similar to a “t.” Upper arm 419 of shim 416 extends to a length that is substantially the same as the width of base shim 402 . Bottom leg 417 of shim 416 extends from the midpoint of arm 419 to a distance that is substantially the width of base shim 402 . The ends of upper arm 419 and leg 417 thus, are substantially flush with the edges of shim 402 when shim 416 is placed over shim 402 . Additionally, one end of arm 419 has protrusion 418 which when the invention is assembled, is inserted into slot 214 of housing unit 106 where it makes electrical contact with the electrical circuitry (not shown). Shim 416 can be of variable thickness to correspond to the thickness of the gap the particular gap gauge is designed to be measured.
Tape strips 408 a and 408 b are strips of double-sided adhesive tape which adhere shim 402 to shim 416 . Depending whether guide 112 (FIG. 1) is used, tape strip 406 is a strip of electrical insulating tape or a strip of adhesive tape. In any case tape strip 406 acts as a spacer and keeps shim 402 and top arm 419 from making electrical contact when the panel unit is not in a print gap. Tape strip 410 is also a double-sided adhesive tape designed to adhere the lower end of leg 417 to shim 402 . Mylar film 420 is provided to keep dust out of the space between shim 416 and shim 402 . Such mylar film is commercially available in extremely thin thicknesses.
In operation, the panel unit of the second embodiment acts in a similar manner to the panel unit of the first embodiment. Shim 416 is relatively thin compared to shim 402 which is the base. Tape strips 406 , 408 a , 408 b , and 410 separate upper shim 416 from base shim 402 . They secure the edges of shim 416 in place. FIG. 6A represents a section view of the second embodiment illustrated in FIG. 4 when the panel unit is not inserted into a gap. The section view was cut approximately at the midpoint of shim 402 and through tape strips 410 and 406 . The thicknesses of the shims and strips of tape have been exaggerated for illustration purposes. When the panel unit is not inserted into a gap, shim 416 spans between the strips of tape. It does not, therefore, make contact with shim 402 and the electrical circuit is not complete.
FIG. 6B illustrates how shim 416 deflects when inserted into an appropriate gap between surface 602 and surface 604 . If the gap is at the correct distance, shim 416 will deflect enough to make contact with shim 402 . This contact completes the electrical circuit (FIG. 3 ), thereby causing LED 102 (FIG. 1) to illuminate. Thereafter, when the panel unit is removed from the gap, shim 416 flexes back to its original shape (illustrated in FIG. 6A) breaking the electrical circuit.
In sum, the electronic feeler gauge has several substantial advantages over the prior art. Judging the correct amount of frictional resistance is often subjective and is dependent on the experience of the operator. The present invention provides an objective indication when the gap has been adjusted correctly. Thus, the learning curve is greatly reduced and the present invention may be used by more inexperienced technicians. Additionally, more consistent results will be obtained by different operators because of the objectivity introduced by the present invention.
Although the invention has been described with reference to specific embodiments, these descriptions are not meant to be construed in a limiting sense. Various modifications of the disclosed embodiments, as well as alternative embodiments of the invention will become apparent to persons skilled in the art upon reference to the description of the invention. It is therefore, contemplated that the claims will cover any such modifications or embodiments that fall within the true scope of the invention.
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An electronic feeler gauge and a method of using the same which provides an objective means of determining the width of a gap between two surfaces. The gauge comprises a measuring element which is insertable into the gap and an indicator coupled to the measuring element for automatically indicating when the gap has been set to a predetermined distance. The measuring element comprises two plates which act as an electrical switch in an electrical circuit. When the gap gauge is inserted into a gap of predetermined width, the plates press against each other and current from a power source lights up a light emitting diode. Conversely, when the plates are inserted into a gap that is too wide, the plates do not press against each. The circuit, therefore, is not complete, and the light emitting diode does not light up. Thus, this invention provides an objective, reliable means for confirming the width of a gap. The invention can be used for gaps of different widths by varying the thicknesses of the plates.
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CROSS-REFERENCE TO RELATED APPLICATIONS
This application claims foreign priority benefits under 35 U.S.C. §119(a)-(d) from German patent application ser. no. 10 2011 055 292.8 filed Nov. 11, 2011.
TECHNICAL FIELD
The invention relates to an air nozzle, and more particularly to an air nozzle, having a flange intended for the attachment to a vehicle body opening, and including at least one air guiding element via which air flowing through the air nozzle can be deflected, and having pivot stubs which are mounted to the flange whose pivot axis extends substantially parallel to the axis of the air flow through the air nozzle before reaching the air guiding elements, and that the pivot stubs are moveable in a direction parallel to their pivot axis
BACKGROUND OF THE INVENTION
Air nozzles for vehicles are used on a large scale, and due to the large quantities produced and the associated low production costs which are required, it is necessary to carry out a standardization of both the sizes and the types.
On the other hand, different vehicles comprise completely different ventilation situations, so that e.g. a windshield defroster nozzle having a throw distance which is as high as possible has to be constructed totally differently from a legroom air outlet.
In many cases it is desired to influence the outlet of air by the user, for example via a slider, which influences the outlet cross section, or via lamellae, which influence the direction of the outlet of air.
But there are also simpler air nozzles, which are also referred to as air outlets, and which are provided with fixed lamellae and are formed as an integral plastic part, in most cases.
Besides these different requirements which require a considerable variety of production on the part of the manufacturers of air nozzles, automotive manufacturers often proceed to freely locate the desired installation site of the air nozzle.
While typically an installation in a body opening made of sheet steel on the one hand or of sheet aluminum on the other hand does not pose any problems due to the comparatively small difference in thickness of sheet steel and sheet aluminum and as a safe locking is possible through detents known per Se, this does not hold true without further ado for the installation at the dashboard or e.g. at other plastic coverings in a vehicle. There, completely different thicknesses of the base material are used, and sometimes foamed materials are also used, many times for safety reasons, i.e. to keep the risk of injuries as low as possible in case of a possible collision with vehicle passengers.
DE 20 2009 004 949 U discloses an air nozzle comprising a combined screw/lock fastening, wherein the screw is intended to pass through the snap-in tongue.
With the help of the inclined plane at the snap-in tongue a difference in thickness of the installation wall can be compensated. for to a certain extent. However, this compensation is not sufficient to cover the possible installation sites so that in such a nozzle still at least four or five different nozzles of each nozzle type have to be made available in order to cover the possible installation sites.
Pure screw fastening is also possible, as can be seen e.g. from U.S. Pat. No. 6,016,976. In a pure screw fastening it is possible to provide for additional screw holes adjacent to the body opening and to make possible to lock the air nozzle even at an installation from the front side, as is always desired.
However, such additional cutouts in bodies multiply the effort in the production of the body openings and may also pose adjustment and adaptation problems. While in round nozzles that click into place angle errors do not play any role, this does not hold true for screw fastening nozzles as the screw holes have to be in exact alignment with the cutouts for the screws.
For reasons of the simplification of the installment, therefore, snap-lock connections have been desired up to now which are, however, not problem-free either. For instance, DE 102 48 740 A1 (see paragraph [0005] and paragraph [0006]) discusses the problem that protruding snap4n tongues break easily when they are accidentally installed at an angle.
Moreover, snap-in tongues also those comprising slanted planes which should, however, not exceed a certain tilt angle are typically suitable for balancing different thicknesses of metal sheet, but not completely different installation sites.
Furthermore, DE 10 2006 029 733 A1 discloses an air nozzle which has a relatively flat design, on the one hand, and which is also supposed to cover different material thicknesses, on the other hand. For this purpose, a clamping element with different snap-in elements is provided.
Generally, this solution is well suited for covering different wall thicknesses. It is, however, rather intended for flat and therefore lightweight nozzles, while a fine adjustment is slightly overstrained in the application of larger and heavier nozzles, such as lamellar spreader rolling.
Furthermore, it has already been suggested to use an adjustable sliding mechanism for adapting to different wall thicknesses in the bearing housings for air nozzles, which does not only facilitate the adaptation to different material thicknesses of the dashboard or any other installation site but which can also balance an unevenness to a certain extent. Typically, the bearing flange of the bearing housing has a circular shape while the installation site can in part also be at a curved sheet metal. But still a sealing must be guaranteed, which is a problem to a certain extent. For this purpose, a sealant can for instance be introduced before the installation takes place in order to carry out sealing.
However, a further problem is the tendency of the suggested air nozzles to detach due to the permanent vibrations, because if there is a slight play already, the bearing is burdened to an ever increasing extent, until the air nozzle eventually blocks.
OBJECTS AND SUMMARY OF THE INVENTION
In contrast, the invention is still based on the task of creating a cost-effective air nozzle, which can be used more universally, which means that it is also suitable for larger and heavier nozzles and facilitates a permanent safe bearing, also when it comes to different material thicknesses of the installation site.
According to the invention, it is especially favorable if the pivot stubs, of which at least two, preferably three, are mounted at the circumference of the air nozzle, can be moved by inventive bearing elements.
The bearing elements have the dual function of facilitating the pivot movement of the pivot stubs on the one hand, and of facilitating a movement towards the pivot axis, on the other hand.
In an advantageous development of the invention, the bearing elements are formed as screws in order to facilitate an axial displacement corresponding to the pitch of their threads.
It is inventively preferred that the movement in an axial direction takes place subsequent to the pivot movement, in fact when the bearing element is actuated concordantly.
Instead of a screw, the bearing element can also be formed as a journal with a corresponding operating gate, as a slide guide, or e.g. via a stationary axis, which is covered by a sleeve which either comprises a gate itself or is guided by a gate fixed to the air nozzle.
It is especially favorable that the actuation takes place in one go and if in the actuation the pivoting of the pivot stubs takes place first so that, in the installation of the air nozzle, the pivot stub is pivoted from its substantially tangential orientation to the substantially radial direction before it is displaced axially, and finally serves the fixed mounting against the body opening. Therefore, it is provided according to the invention that the pivot stubs are mounted to the flange, namely in particular via special bearing elements, wherein their pivot axis extends substantially parallel to the axis of the air flow through the air nozzle, before reaching the air guiding elements, and wherein the pivot stubs are pivotable, i.e. away from the interior of the air nozzle to the outside.
When installing the air nozzle according to the invention, the pivot stubs remain substantially tangentially to the flange at first, i.e. abut against it or are at least substantially parallel to the outside. Preferably, the pivot stubs are slightly clipped or snap-locked in place or lie flat against that element by friction. Insofar, their position is secured in pivot direction as well as in an axial direction. This securing prevents the pivot stub from unintentionally moving away from its starting position, e.g. in the direction of the air outlet of the air nozzle. Preferably, bearing elements are provided which are formed as screws and, in that position, their screw heads flush with the circumferential part of the flange of the air nozzle.
If any work was done without the aforementioned securing, there was the danger that the screws would move into the outlet direction, especially in case of overhead assembly. Pivoting would then not be possible anymore as the pivot stubs would then be located on the axial height of the body opening and would have to be pushed back again in order to be pivoted.
On the other hand, without the pre-securing in the pivot direction there was the danger that the pivot stubs would swivel out, i.e. would protrude from the air nozzle. Then, an assembly would not be possible as the pivot stubs which are swiveled out have larger dimensions than the body opening.
After inserting the air nozzle with the predetermined position of the pivot stubs, at least one screw forming the bearing element is actuated. Through the actuation of the screw against the resistance of the securing, which can be formed by a slight clipping into place, the pivot stub is first moved in the protruding direction in which it protrudes at an angle of about 900 to the side.
When further tightening the screw, through its thread the pivot stub is axially displaced, i.e. basically in such a way that it moves from behind to the body opening. This is continued until the pivot stub abuts against the body opening from behind.
Preferably, both the pivot stub and the housing of the air nozzle are made of a plastic material which is, at least to some degree, elastic. This leads to a bias favorable for the bearing when the pivot stub abuts against the body opening.
It is especially important that the wall thickness of the body opening can vary in many areas in this type of assembly without having to provide another air nozzle.
Due to the universal usability of the air nozzle, the plurality of air nozzles which needs to be provided is drastically reduced so that only one single type of each air nozzle has to be held ready.
The tightening of the screw corresponds to the thickness of the wall of the body. This can even, for instance, amount to several cm so that the axial actuating path of the pivot stubs has to amount to several cm, too, as the same air nozzle has to be able to be mounted to both a body wall made of sheet metal and a foamed dashboard having a wall thickness of, for instance, 1 or even 2 cm.
It is to be understood that the friction conditions of the clipping-in device, thread and pivot friction of the pivot stub have to be adjusted to the requirements in order to ensure the desired sequence of the three sequences of movements which are succeeding one another.
It is to be understood that the inventive air nozzle is by no means limited to a round air nozzle. Rather, rectangular combination air nozzles comprising a nozzle array of e.g. 20×30 cm can be installed without further ado according to the invention. Such air nozzles are typically provided with several nozzle outlets with different air guiding elements and can further be adjusted with reference to their flow intensity to a significant degree.
The inventive flange can be part of the housing or can be provided separately. It can be ring-shaped i.e. circular for circular air nozzles or L-shaped, and typically the protruding part of the flange is supported by the body opening.
The pivotable pivot angle of the pivot stubs can preferably be limited by stops. The stop in drive direction of the screw must be rigid, as the friction of the screw arranged in the pivot stub must be smaller than the flexibility of this stop.
It is also to be understood that the outer diameter of the flange and the external dimensions of the pivot stubs must be larger than the body opening in order to ensure the desired bearing by clamping the body wall between the flange and the pivot stubs and that the outer diameter of the housing of the air nozzle without the flange or without the protruding part of the flange and when the pivot stubs abut, is smaller than the diameter of the body opening.
According to the invention it is especially favorable if a contact surface is provided at the pivot stub which points in the direction of the air outlet and is insofar intended for the support at the body wall from behind. The broadened contact surface ensures a better distribution of power and a reduced pressure on the body wall which is important when soft materials, such as foamed plastic materials, are used for the body wall.
Further advantages, details and features may be taken from the following description of an embodiment of the invention by means of the figures.
BRIEF DESCRIPTION OF THE FIGURES
FIG. 1 shows a perspective schematic view of a part of an inventive air nozzle in one embodiment;
FIG. 2 shows a back perspective view of the air nozzle;
FIG. 3 shows a perspective view of an inventive pivot stub;
FIG. 4 shows a perspective view of the bearing of the pivot stub according to FIG. 3 which is intended for the installation in the housing of the air nozzle according to the invention;
FIG. 5 shows a perspective view of the front of an assembled air nozzle, with the air guiding elements partially open;
FIG. 6 shows a perspective view of the front of an assembled air nozzle as in FIG. 5 , with the air guiding elements close; and
FIG. 7 shows a rear perspective view of the air nozzle mounted in a body opening.
FIG. 8 shows a back perspective view of the air nozzle as shown in FIG. 2 , with the pivot stubs in another postion.
DETAILED DESCRIPTION
FIG. 1 illustrates a perspective view of an air nozzle 10 in detail. A housing 12 in the form of an outer ring can be seen which—as is given in the comparison in FIG. 2 —is complemented by an inner ring which in turn covers the front side of the outer ring.
FIG. 1 shows the uncovered outer ring 14 . As can be seen, it is provided with a circumferential flange 16 which is formed as a circle in the embodiment illustrated and which extends in a two-dimensional way across a body opening 51
In the outer ring an inner ring is received in a snap-in manner in a way known per se and is rotatable in it. The inner ring is provided with air guiding elements 49 which serve to deflect or—if necessary—reduce the air flowing through the air nozzle.
The housing 12 extends parallel to the discharge direction to the back. As can be seen schematically from FIG. 1 , in this example three pivot stubs 18 , 20 and 22 are mounted in an equal distribution around the periphery of the housing 12 . In the example illustrated, the pivot stubs 18 to 22 are shown in the protruding position. Their pivot position, but also their axial position, can be determined via bearing elements 24 , wherein the bearing elements are formed by three screws 26 , 28 and 30 in the embodiment illustrated, each of the screw heads 32 being illustrated as a cross recess.
The body wall not shown which surrounds the body opening extends between the pivot stubs 18 to 22 and the flange 16 . The axial displacement of the pivot stubs 18 to 22 to the front, i.e. towards the drawing plane, clamps the body wall towards the flange 16 . For this purpose, every pivot stub 18 to 22 is provided with a contact surface 40 which is otherwise broadened slightly relative to the pivot stub 18 to 22 , namely in tangential direction in the position of the pivot stubs illustrated in FIG. 1 .
The contact surface 40 is tapered slightly radially towards the outside—again considered in the position according to FIG. 1 —in order to facilitate an easier abutment When the pivot stubs are swiveled in.
FIG. 2 shows a part of the inventive air nozzle 10 . Here, the inner ring 44 , which is provided with a knurling 46 in the outside, is attached to the outer ring 14 . It extends into the discharge opening 48 of the air nozzle 10 and also covers the flange 16 so that the screw heads 32 (see FIG. 1 ) are covered by the inner ring 44 .
The inner ring 44 is only attached or plugged-in when the assembly of the outer ring has been completed.
FIG. 2 also shows that the pivot stub 18 can occupy two completely different positions which—for reasons of simplicity—are both illustrated in FIG. 2 . In the swiveled-in position 50 , the pivot stub 18 extends substantially in abutment with the housing 12 of the air nozzle 10 . In this position, it is substantially displaced towards the back relative to the other position, i.e. away from the air guiding elements.
In the swiveled-out position 52 the pivot stub 18 extends in a substantially radial manner, i.e. away from the discharge opening 48 of the air nozzle to the outside. By tightening the screw 26 which can be seen in FIG. 1 but is not illustrated in FIG. 2 , the displacement from position 50 to position 52 is implemented. For this purpose, the screw 26 extends through a passage recess 60 in the pivot stub 18 . Here, the screw 26 engages its thread and exerts a pivot force to the pivot stub 18 through the thread friction. The pivot axis 61 extends coaxially through the passage recess 60 .
The pivot movement of the pivot stub 18 is limited by stops. In the swiveled-in position 50 , the pivot stub is adjacent to the housing 12 . It is held in this position by a holding projection 62 . The determination of the position, however, takes place using only low force which is lower than the friction force of the thread engagement between screw 26 and pivot stub 18 .
Accordingly, when turning the screw 26 , the holding position of the pivot stub 18 at the holding projection 62 is released, and the pivot stub 18 can be swiveled freely to the swiveled-out position 52 .
In order to prevent the pivot stub 18 from reaching behind the holding projection 62 in th˜axial front position (corresponding to the swiveled-out position 52 ), an additional locking projection 64 is provided to prevent exactly that from happening.
Opposite the holding projection 62 a stop rib 66 is formed which limits the swivel movement of the pivot stub 18 towards the swiveled-out position 52 . In the embodiment illustrated, the swivel angle between positions 50 and 52 amounts to approximately 100°; it is to be understood, however, that the possible pivot angle can be adjusted to the sizing of the pivot stub 18 and the remaining dimensioning to a large extent.
During the assembly of the air nozzle, inner ring 44 and outer ring 14 are separated. The outer ring 14 is introduced into the body opening at a swiveled-in position 50 of the pivot stubs 18 to 22 . In this position, the pivot stubs 18 to 22 are each also axially determined by the holding projection 62 .
As soon as the desired position of the outer ring 14 of the air nozzle 10 is reached, at least one of the screws 26 to 30 is actuated so that first the pivot stub 18 is transferred to the swiveled-out back position—which is not illustrated in any of the figures—and then to the swiveled-out front position 52 illustrated in FIG. 2 . In this position the body wall is clamped between the contact surface 40 and the flange 16 .
Subsequently, the other pivot stubs are also transferred to the position 52 , and afterwards the inner ring 44 is clipped into place so that the screw heads 32 are covered.
The structure of a pivot stub 18 can be seen from FIG. 3 . Here, a rigidity rib 70 is also shown which serves to improve the rigidity of the pivot stub 18 . The comparison of FIG. 2 and FIG. 3 shows that the inclined section 72 of the contact surface 40 improves the slenderness of. the embodiment in the swiveled-in position 50 .
FIG. 4 shows that the outer ring 14 with the housing 12 and the further parts described herein, except for the pivot stub 18 , can be implemented integrally without further ado. The stop rib 66 extends radially outward and has a solid construction and is additionally stiffened by a block 74 adjacent to the flange. Furthermore, a guide rib 76 is provided opposite the stop rib 66 at the bearing of the pivot stub 18 which comprises a further inclined surface 78 which, at a radial displacement of the pivot stub 18 , pushes this stub from the swiveled-in position 50 to the outside.
Also with regard to the holding projection 62 , FIG. 4 shows that this projection is only formed in a crowned manner at a rib, so that an easy locking is possible, without preventing a swiveling out of the pivot rib when the torque of the screwing force is applied.
It is to be understood that it is possible without further ado according to the invention to automate the assembly of the inventive air nozzle. For instance, insertion of the outer ring 14 with the pre-assembled and swiveled-in pivot stubs 18 to 22 can be done via an assembly robot which can also fasten the screw heads 32 without further ado.
Therefore, the inventive air nozzle allows for an insofar easy assembly suitable for automation, and therefore also for a cost-effective assembly.
While a preferred form of this invention has been described above and shown in the accompanying drawings, it should be understood that applicant does not intend to be limited to the particular details described above and illustrated in the accompanying drawings, but intends to be limited only to the scope of the invention as defined by the following claims. In this regard, the term “means for” as used in the claims is intended to include not only the designs illustrated in the drawings of this application and the equivalent designs discussed in the text, but it is also intended to cover other equivalents now known to those skilled in the art, or those equivalents which may become known to those skilled in the art in the future.
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This invention relates to an air nozzle, comprising a flange intended for the attachment to a vehicle body opening, and comprising at least one air guiding element via which air flowing through the air nozzle can be deflected. Furthermore, at least two, in particular three, pivot stubs ( 18,20,22 ) are mounted to the flange ( 16 ) whose pivot axis ( 61 ) extends substantially parallel to the axis of the air flow through the air nozzle ( 10 ) before reaching the air guiding elements, and the pivot stubs ( 18, 20, 22 ) are movable in a direction parallel to their pivot axis ( 61 ).
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FIELD OF THE INVENTION
The present invention relates to a monitor apparatus and method, and more particularly, to a assistant monitor apparatus and method for vehicle, that is capable of projecting a light beam to illuminate ambient environment of a transportation means for detecting statuses of the transportation mean relating to its ambient environment while displaying the detection on a display device of the transportation means, and further controlling the projection direction of the light beam as well as the reception angle of the reflected light of the light beam so as to reduce blind spots the transportation means while avoiding the whitening effect to be generated.
BACKGROUND OF THE INVENTION
The invention of motor vehicle can be treated as a milestone of our civilization, since not only it has shorten the distance for people traveling between two locations, but the progressing of motor vehicle also promote the development of industry. As the progress of technology, the making of motor vehicle is evolving day by day. However, there are still some parts of a motor vehicle are still not changed with the innovation of technology, one of which is the automobile rear mirror.
Rear mirror is a functional type of mirror found on automobiles and other motor vehicles, designed to allow the driver to see the areas that cannot be seen while looking forward, i.e. those areas behind the vehicle as well as the left- and right-hand sides of the vehicle. However, most convention rear mirrors have shortcomings listed as following:
(1) Fixed visual angle: Typically, a conventional rear mirror is a flat mirror affixed to a specific location of a motor vehicle on a swivel mount allowing it to be freely rotated. However, once a rear mirror is set, it can only provide the driver with a fixed visual angle that can not be changed dynamically as it is needed, such as negotiating a curve or parking. (2) Inferior night vision: A conventional rear mirror can only function well under the condition of good visibility. It is known that conventional rear mirrors can not provide good images at nighttime or while driving in heavy mist. (3) Easy to be damaged: Since most conventional rear mirrors are arranged extruding out the body of the motor vehicle, it is vulnerable to impacts and collisions, even though they are equipped with fold-away feature.
In view of aforesaid shortcomings, there are many attempts trying to improve the operation of rear mirrors for motor vehicles. One of which is an image monitor system for automobiles disclosed in T.W. Pat. No. 564830. The image monitor system uses an image capturing device, either arranged at the interior or exterior of an automobile, to fetch images and generate image signals accordingly, while utilizing an organic light emitting device to display the fetched image signals. Although the aforesaid system can be used to capture images behind the automobile for allowing the driver to see the areas that cannot be seen while looking forward, it is effective only at day time since the image caturing device, being the only means available to the image system for fetching images, can not function well under poor visibility, especially at night time.
Another such attempt is an automobile camera surveillance apparatus disclosed in T.W. Pat. No. 580644, in which a infrared camera is used to cooperate with an infrared emitter for enabling the automobile camera surveillance apparatus to acquire good quality images during day time and night time while utilizing an infrared sensor to avoid the whitening effect. Although the aforesaid apparatus can provide good quality images no matter at day time or night time, there are still blind spots exist since the infrared emitter is fixed to illuminate the surrounding of the automobile with a specific angle that it can only provide the driver with a fixed visual angle and can not be changed as it is needed, such as negotiating a curve while backing. In addition, the aforesaid apparatus uses an image delay method to overcome the whitening effect that it is prone to cause the interrupt of image signals and thus have adverse effect on the judgment of the driver.
One further such attempt is an automobile monitor apparatus with automatic visual angle adjustment ability, disclosed in T.W. Pat. No. 588004, which is an apparatus enabling a rear mirror to be adjusted automatically and dynamically. The aforesaid automobile monitor apparatus uses a sensor to detect the turning of the automobile while enabling the rear mirror to rotate automatically according to the detection. Although he aforesaid apparatus can adjust its visual angle automatically, it is lacking of night vision ability that it can not function well during night time or at poor visibility.
Therefore, it is in need of an assistant monitor method and apparatus capable of overcoming the shortcomings of prior arts.
SUMMARY OF THE INVENTION
The primary object of the present invention is to provide an assistant monitor apparatus for a vehicle, capable of projecting invisible light to illuminate the ambient of the vehicle and thus generating images of its ambient environment for enabling the driver to identify obstacles no matter at day time or night time.
It is another object of the invention to provide an assistant monitor apparatus for a vehicle, which is equipped with a control method capable of detecting the moving direction of the vehicle while controlling the projection angle of an invisible light to change according to the detection, so that the safety of the driver driving the vehicle along with the ambient vehicles and pedestrians are ensured.
Further, another object of the invention to provide an assistant monitor apparatus for a vehicle, which is equipped with a control method capable of detecting the speed of the vehicle while controlling the projection angle of an invisible light and the visual angle of an image sensor according to change according to the detection, i.e. the field of vision is enlarged/shrunk with the speed change of the vehicle.
Yet, another object of the invention to provide an assistant monitor apparatus for a vehicle, which is equipped with a control method capable of detecting the ambient environment of the vehicle using an infrared signal while altering the visual angle of an image sensor according to the detection, or performing a means of signal process upon the result of the detection for adjusting the gain of the image sensor, such that the whitening effect is eliminated.
To achieve the above objects, the present invention provide an assistant monitor method for vehicles, comprising steps of: projecting a light beam to illuminate objects surrounding a transportation means; receiving the reflected light of the light beam so as to generate an image-related signal accordingly; generating a status signal by performing a detection operation to sense the status of the transportation means; processing the status signal so as to correspondingly generate a control signal; and adjusting the projecting angle and intensity of the light beam and the angle of reception for receiving the reflection of the light beam according to the control signal.
Preferably, the detection operation further comprises a step of: detecting a moving condition of the transportation means. Wherein, the moving condition can be a status selected from the group consisting of a turning of the transportation means, moving direction of the transportation means, speed of the transportation means, and the combination thereof.
Preferably, the detection operation further comprises a step of: detecting of the ambient luminance of the transportation means.
Preferably, the assistant monitor method for vehicles further comprises a step of: detecting statuses of invisible light illuminating the ambient of the transportation means while using the result of the detection as a basis for evaluating the influence of whitening effect and thus adjusting the gain of the image signal accordingly.
Preferably, the assistant monitor method for vehicles further comprises steps of: processing the image-related signal to generate an image signal; and enabling a display device to receive the image signal for displaying images thereon accordingly.
Furthermore, to achieve the above objects, the present invention provide an assistant monitor apparatus, adapted for a transportation means, which comprises: at least a light emitter, each for providing a light beam; at least an image sensor, each capable of receiving the reflection of the light beams and thus generating an image-related signal accordingly; at least a sensing controller, each capable of detecting a status of the transportation means and thus generating a status signal accordingly; a servo control unit, coupled to each image sensor and each sensing controller, capable of processing the image-related signal of each image sensor to generate an image signal correspondingly while processing the status signal of each sensing controller to generate a control signal correspondingly; at least a swivel seat, coupled to the servo controller unit, capable of receiving the control signal while controlling the swivel seat to rotate according to the received control signal; and a display device, coupled to the servo controller unit, capable of receiving the image signal while display an image thereon accordingly. It is noted that the light emitter is preferred to be a light source of visible light or a source of infrared light.
Preferably, the light emitter further comprises a parabolic reflector for enabling light of the light emitter to be projected parallelly.
Preferably, the light emitter further comprises a scattering screen for enabling the light of the light emitter to be projected homogeneously.
Preferably, the light emitter is arranged at a location selected form the group consisting of: the front, the left front side, the right front side, the rear and the top of the transportation means.
Preferably, the image sensor can be a visible light sensor, an infrared light sensor, a sensor capable sensing visible light and infrared light, or a device integrating a visible light sensor and an infrared light sensor.
Preferably, the image sensor is arranged at a location selected form the group consisting of: the front, the left front side, the right front side, the rear and the top of the transportation means.
Preferably, the status of the transportation means is a status selected from the group consisting of a turning of the transportation means, moving direction of the transportation means, speed of the transportation means, and the combination thereof.
Preferably, each swivel seat is at least connected to a device selected from the group consisting of the light emitters and the image sensors, while being affixed to the transportation means for enabling the device connected to the swivel seat to rotate to a direction corresponding to the status of the transportation means according to the control signal of the servo control unit.
Preferably, the sensing controller is capable of detecting a variation of the steering mechanism of the transportation means as the transportation means is turning. In a preferred embodiment, the sensing controller is an angular detector capable of detecting the rotating angle of the steering wheel of the transportation means and thus generating an angular signal accordingly while transmitting the angular signal to the servo control unit for enabling the same to generate a corresponding control signal directing the swivel seat to rotate accordingly.
Preferably, the swivel seat is arranged at a location selected form the group consisting of: the front, the left front side, the right front side, the rear and the top of the transportation means.
Preferably, the sensing controller is capable of generating a status signal according to the ambient luminance of the transportation means detected thereby, while transmitting the status signal to the servo control unit for enabling the same to generate a corresponding control signal controlling the intensity of the light projected by the light emitters.
Preferably, the transportation means is an automobile.
Preferably, at least one of the light emitters and at least one of the image sensors can be configured into a module, whereas the module can be arranged at a location selected form the group consisting of: the front, the left front side, the right front side, the rear and the top of the transportation means.
Other aspects and advantages of the present invention will become apparent from the following detailed description, taken in conjunction with the accompanying drawings, illustrating by way of example the principles of the present invention.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1A is a flow chart depicting an assistant monitor method according to the present invention.
FIG. 1B is a flow chart depicting the detection operation of an assistant monitor method according to the present invention.
FIG. 2 is a schematic diagram showing an assistant monitor apparatus according to a preferred embodiment of the invention.
FIG. 3A is a schematic view showing an arrangement of image sensors according to the present invention.
FIG. 3B is a schematic diagram showing the positioning of a display device in an automobile according to the present invention.
FIG. 4A is a schematic diagram showing the arrangement of light emitters and image sensors on a transportation means according to a preferred embodiment of the invention.
FIG. 4B shows the positioning of light emitters and image sensor as the transportation means is moving forward at high speed.
FIG. 4C shows the positioning of light emitters and image sensor as the transportation means is moving backward.
DESCRIPTION OF THE PREFERRED EMBODIMENT
For your esteemed members of reviewing committee to further understand and recognize the fulfilled functions and structural characteristics of the invention, several preferable embodiments cooperating with detailed description are presented as the follows.
Please refer to FIG. 1A , which is a flow chart depicting an assistant monitor method according to the present invention. The assistant monitor method 3 of FIG. 1A starts at step 30 . In step 30 , a light beam is projected to illuminate objects surrounding a transportation means, and then the flow proceeds to step 31 . it is noted that the light beam illuminating objects surrounding the transportation means is a light beam selected form the group consisting of: visible light, infrared light and the combination thereof. In step 31 , the reflected light of the light beam is received so as to generate an image-related signal accordingly while the device used for receiving the reflected light of the light beam is a device selected form the group consisting of: a charge coupled device (CCD), and a complementary metal oxide semiconductor (CMOS), and then the flow proceeds to step 32 .
In step 32 , a detection operation is performed to sense the status of the transportation means and thus generating a status signal accordingly, and then the flow proceeds to step 33 and step 35 simultaneously. The processing of the detection operation is illustrated in FIG. 2B , which is a flow chart depicting the detection operation of an assistant monitor method according to the present invention. The flow of a detection operation starts as soon as the step 31 of FIG. 1A is completed and proceeds to steps 320 , 321 , 322 , 323 , in which the speed, turning and moving direction of the transportation means are detected, as well as the ambient illuminance is detected by a sensor and thus the whitening effect is evaluated, as shown in FIG. 1B , and then the flow proceeds to step 324 . In step 324 , a status signal basing on the preceding detections is generated.
In step 33 , the status signal is processed so as to correspondingly generate a control signal, and then the flow proceeds to step 34 . In step 34 , the projecting angle of the light beam and the angle of reception for receiving the reflection of the light beam are adjusted according to the control signal. In step 35 , the image-related signal is processed so as to correspondingly generate an image signal, while adjusting the gain of the image signal with respect to the whitening effect, and then the flow proceeds to step 36 . In step 36 , a display device is used to receive the image signal for displaying images thereon accordingly and thus enabling the driver of the transportation means to view the ambient of the transportation means.
Moreover, the present invention also provides an assistant monitor apparatus of for vehicle to implement the foregoing method 3 . Please refer to FIG. 2 , which is a schematic diagram showing an assistant monitor apparatus according to a preferred embodiment of the invention. The assistant monitor apparatus 2 is adapted to be arranged on a transportation means, such as a wheeled vehicle, for monitoring the ambient of the transportation means, which is comprised of: a servo control unit 20 , a projection unit 21 , a plurality of swivel seats, numbered as 24 , 25 , a plurality of image sensor 22 , a display device 23 and at least a sensing controller 26 .
The projection unit 21 is electrically coupled to the servo control unit 20 , which is comprised of at least a light emitter 210 . Each light emitter 210 is capable of emitting invisible light, such as infrared light, or visible light, depending on requirement of actual usage. The light emitter 210 can include a parabolic reflector for enabling light of the light emitter 210 to be projected parallelly, or can include a scattering screen for enabling the light of the light emitter 210 to be projected homogeneously. In addition, the light emitter 210 is arranged at a location selected form the group consisting of: the front, the left front side, the right front side, the rear and the top of the transportation means. In this preferred embodiment, the assistant monitor apparatus has a plurality of light emitters 210 , each for projecting a light beam to illuminate objects surrounding the transportation means while being reflected thereby.
Each image sensor 22 is electrically coupled to the servo control unit 20 , and is capable of receiving the reflected light while generating a corresponding image-related signal to be transmitted to the servo control unit 20 . The servo control unit 20 is capable of processing and converting the received image-related signal into an image signal. In a preferred aspect, each image sensor 22 is arranged at a location selected form the group consisting of: the front, the left front side, the right front side, the rear and the top of the transportation means. Moreover, the image sensor 22 can be a visible light sensor, an infrared light sensor, a sensor capable sensing visible light and infrared light, or a device integrating a visible light sensor and an infrared light sensor. In this preferred embodiment, image sensor 22 is a device selected form the group consisting of: a charge coupled device (CCD), and a complementary metal oxide semiconductor (CMOS).
The sensing controller 26 is composed of a first sensor 261 and a second sensor 262 . The first sensor is electrically coupled to the servo control unit 20 , and is used for detecting the speed, turning and moving direction of forwarding/backing of the transportation means while generating a corresponding status signal. In a preferred aspect, the first sensor 261 is capable of detecting a variation of the steering mechanism of the transportation means as the transportation means is turning, e.g. the first sensor 261 can be an angular detector capable of detecting the rotating angle of the steering wheel of the transportation means and thus generating an angular signal accordingly while transmitting the angular signal to the servo control unit 20 for enabling the same to generate a corresponding control signal directing the swivel seat to rotate accordingly. Furthermore, the first sensor 261 can be arranged on the wheel shaft or on the steering wheel for enabling the same to detect the rotation thereof and thus generate a corresponding rotation signal to the servo control unit 20 while enabling the servo control unit 20 to process the received rotation signal and thus direct a corresponding swivel seat to rotate according the result of the signal processing. In addition, the first sensor 261 can be enabled to detect the switching of direction signal lamp while generating a signal corresponding to the switching to be received by the servo control unit 20 . Nevertheless, it is concluded that the first sensor will transmit a signal according to the detection thereof to the servo control unit 20 , where the signal is process and thus converted into a first control signal and a second control signal.
The second sensor 262 is electrically coupled to the servo control unit 20 , which is capable of sensing the ambient illuminance of the transportation means while generating a signal accordingly. The second sensor can be an infrared sensor, an optical sensor, or the combination of the two. In the preferred embodiment of FIG. 2 , the second sensor 262 is composed of an optic sensor 2621 and a plurality of infrared sensors 2622 . Wherein, the optic sensor 2621 is used to detect the ambient illuminance of the transportation means and thus generate a signal to the servo control unit 20 for enabling the same to make an evaluation according to the received signal to determine whether or not to activate a light emitter 210 , or to adjust the intensity of the light emitted 210 ; and each infrared sensor 2622 is capable of sensing infrared light emitted from other infrared emitter, such as an infrared emitter arranged on another vehicle, and thus generating a signal accordingly while transmitting the signal to the servo control unit for enabling the same to generating a second control signal to overcome the whitening effect.
Each of the plural swivel seats 24 , 25 is able to rotate as directed, which is arranged at a location selected form the group consisting of: the front, the left front side, the right front side, the rear and the top of the transportation means. In this preferred embodiment of FIG. 2 , a portion of one of the plural swivel seat 24 is connected to a corresponding light emitter 210 , so that the swivel seat 24 can be directed to rotate according to the first control signal and thus the projection angle of the light emitter 210 connected thereto is adjust correspondingly with respect to the first control signal representing the status of the transportation means; and a portion of t one of the plural swivel seat 25 is connected to a corresponding image sensor 22 , so that the swivel seat 25 can be directed to rotate according to the second control signal and thus the reception angle of the image sensor 22 connected thereto is adjust correspondingly with respect to the second control signal.
It is noted that the positioning of the plural image sensors 22 and the plural light emitters 210 can be arranged at will with respect to actual requirement. As seen in FIG. 4A , three light emitters 210 and three image sensors 22 are arranged on the top of a transportation means according to a preferred embodiment of the invention. Please refer to FIG. 3A , which is a schematic view showing an arrangement of image sensors on an automobile 1 . In FIG. 3A , image sensors are arranged respectively on the back bumper, on the top, and at the locations of conventional side-view mirror the automobile 1 , so that they can replace the functions of conventional real mirrors and thus the shortcomings of conventional rear mirror can be overcame.
The display device 23 is electrically connected to the servo control unit 20 , which is capable of receiving the image signal while displaying images thereon accordingly. It is noted that the display device can be arranged in the transportation means at a position in front of the driver. In the preferred embodiment shown in FIG. 3B , the display device can be a liquid crystal display, or an organic light emitting device, but is not limited thereby.
The present invention is characterized in that: by the using of the plural rotatable light emitters 210 and rotatable image sensors, the viewing angle of a driver of a transportation means can be adjusted while eliminating the whitening effect. As seen in FIG. 2 and FIG. 4A , there are three light emitters 210 and three image sensors 22 being arranged on the top 10 of an automobile. As the automobile is moving forward slowly, those light emitters 210 and image sensors 22 are orientated at a normal position. However, when the automobile is speeding up and the speeding is detected by the first sensor 261 , the first sensor 261 will issue a signal to the servo control unit 20 for enabling the servo control unit to generate a first control signal directing those light emitters 210 to rotate accordingly, such that the field of vision is enlarged, as seen in FIG. 4B .
As seen in FIG. 4B where the automobile is backing, according to the detection of the first sensor 261 , the servo control unit 20 will issue a first control signal and a second control signal for directing the rotation of those light emitters 210 and image sensors 22 , that is, the light emitters 210 are rotate to project light beams toward the back of the automobile and thus the display device will review images of the back of the automobile as signals received by the image sensors 22 are reflected back from the back of the automobile. In addition, when the automobile is turning, the servo control unit 20 can also control those light emitters 210 and image sensors 22 to rotate according to the turn so as to eliminate blind spots. For instance, while parking at curb, the light emitters and image sensors are orientated to observe the two sides, the lower portion and the back of the automobile, so that images displayed on the display device can be used as reference for parking.
As for the whitening effect, it can be reduced through the adjustment of the orientation of image sensors 22 according to the second control signal issued by the servo control unit 20 while the servo control unit is processing the signal detected by the infrared sensor 2622 of the second sensor 2622 , or by employing image signal of another image sensor 22 . In addition, the whitening effect can be eliminated by adjusting the gains of relating image sensors.
It is noted that the arrangement of the light emitters and image sensors is not limited by that shown in FIG. 4A , they can be arranged at any location of the transportation means at will that is helpful to the driver of the transportation means. Furthermore, at least one of the plural light emitters and at least one of the plural image sensors are fitted into a same module, whereas the module can be arranged at a location selected form the group consisting of: the front, the left front side, the right front side, the rear and the top of the transportation means.
While the preferred embodiment of the invention has been set forth for the purpose of disclosure, modifications of the disclosed embodiment of the invention as well as other embodiments thereof may occur to those skilled in the art. Accordingly, the appended claims are intended to cover all embodiments which do not depart from the spirit and scope of the invention.
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The present invention relates to an assistant monitor method for vehicle, comprising steps of: projecting a light beam to illuminate objects surrounding a transportation means; receiving the reflected light of the light beam so as to generate an electric image signal accordingly; generating a status signal by detecting and sensing the status of the transportation means; processing the status signal so as to correspondingly generate a control signal; and adjusting the projecting angle of the light beam and the receiving angle to receive the reflected light beam according to the control signal. Moreover, according to the method, the present invention also provides an assistant monitor apparatus of for vehicle to implement the foregoing method. By means of the aforesaid apparatus provided in the present invention, the projecting direction of the light projector and a sensing angle of the image sensor for receiving the reflected light can be controlled to reduce blind spots of a rear mirror of the transportation means while avoiding the whitening effect to be generated on the rear mirror, such that safety of the driver driving the transportation mean along with the ambient vehicles and pedestrians can be ensured.
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BACKGROUND OF THE INVENTION
This invention relates to joined ceramic and metal having high strength.
A known method for joining ceramic and metal is metallic activation, in which solder is inserted between ceramic and metal, heated, then melted to join ceramic and metal. An alloy containing activated metal, such as silver-copper-titanium alloy (referred to as Ag-Cu-Ti alloy) or silver-copper-nickel-titanium alloy (Ag Cu-Ni-Ti alloy), is widely used as the solder. The solder can easily join ceramic and metal in low temperature range between 800° C. and 900° C. with high joining strength
For another metallic activation, Japan Published Examined Patent Application 35-1216 and Japan Published Unexamined Patent Application 61-127674 disclose ceramic and metal joined through an intermediate solder member which is a combination of titanium (Ti) and an eutectic metal element such as nickel-titanium (Ni-Ti) alloy, nickel copper-titanium (Ni-Cu-Ti) alloy, or copper-titanium (Cu-Ti) alloy.
The intermediate solder member should strengthen the joining of ceramic and metal, but in the Ag-Cu-Ti alloy and the Ag-Cu-Ni-Ti alloy, the eutectic point of Ag-Cu alloy is as low as 780° C., and Cu is selectively oxidized. Accordingly, such an intermediate solder member cannot assure adequate joining strength at high temperature.
The Ni-Ti alloy, the Ni-Cu-Ti alloy, and the Cu-Ti alloy assure almost the same joining strength at high temperature as that at low temperature, but have the joining strength lower than that of Ag-Cu alloy due to their low wettability. Accordingly, the Ni-Ti, Ni-Cu Ti, and Cu-Ti alloys are unreliable, require a long time period for heat treatment, and are expensive to manufacture.
SUMMARY OF THE INVENTION
The object of the present invention is to provide a joined ceramic and metal having high reliability even at high temperature by improving a soldering alloy member used for the easy-to-operate metallic activation method.
This object is realized by joined ceramic and metal. The ceramic and the metal are thermally joined through an intermediate layer. After the ceramic and the metal are joined, the intermediate layer is composed of 20-70% by weight of silver (Ag), 1-20% by weight of palladium (Pd) 10-60% by weight of nickel (Ni), and 1-10% by weight of titanium (Ti).
Ag enhances the fluidity, wettability, and joining strength of the intermediate layer. When the content is lower than 20% by weight, Ag does not sufficiently produce such an effect. When the content exceeds 70% by weight, however, the heat resistance of the intermediate layer deteriorates.
Pd raises the melting point of the intermediate layer and decreases the whole vapor pressure Pd, thus, enhances the heat resistance, reliability, and wettability of the intermediate layer and prevents the metal joined to ceramic from becoming fragile. When the content of Pd is between 2 and 10% by weight, Pd produces this effect, thereby increasing the joining strength. When the content is lower than 1% by weight, Pd produces insufficient effect. When the content exceeds 20% by weight, the fluidity of the intermediate layer is decreased while ceramic and metal are joined through the intermediate layer, thereby adversely affecting the wettability of the intermediate layer.
Ni increases the heat resistance of the intermediate layer. When the content of Ni is between 20 and 50% by weight, Ni maximizes the heat resistance, and the joining strength at high temperature is increased. When the content is below 10% by weight, Ni produces insufficient effect. When the content exceeds 60% by weight, the fluidity of the intermediate layer is decreased while the intermediate layer joins ceramic and metal. The wettability of the intermediate layer is thus adversely affected.
Ti increases the wettability and joining strength of the intermediate layer. When the content of Ti is between 1.5 and 5% by weight, Ti maximizes its effect and strengthens the joining with ceramic. The effect becomes insufficient when the content is below 1% by weight. When the content exceeds 10% by weight, the joining strength is decreased.
When the intermediate layer contains Cu, Cu enhances the fluidity and wettability of the intermediate layer, and increases the joining strength of the intermediate layer on ceramic. The addition of Cu lowers the soldering temperature, decreases residual stress produced in ceramic during cooling, and allows a designer the choice of a variety of metals to join. When the content of Cu exceeds 10% by weight, the resistance to heat and oxidation of the intermediate layer is decreased. The content should be 10% by weight or less.
As shown in FIG. 5, such intermediate layer can be used for a turbo charger rotor. A ceramic shaft 27a of a ceramic turbine wheel 27 engages a metallic journal 29 via the intermediate layer of the present invention comprising two Ni plates 31 and a tungsten (W) plate 33. A metallic sleeve 35 is located around the intermediate layer. The turbo charger rotor can be thus resistive to heat and durable.
This intermediate layer can be manufactured by known methods as follows:
1. insert alloy with a fixed composition between ceramic and metal, heat and melt to join them;
2. place foil of a fixed substance on a joining surface, or galvanize, evaporate, or coat the surface with the fixed substance, subsequently insert alloy containing substances except the fixed substance between ceramic and metal, heat and melt to elute the fixed substance into the alloy;
3. use metal containing the fixed substance and elute the fixed substance into melted alloy in the same way as (2);
4. after joining, thermally diffuse the fixed substance into an alloy of solid phase, instead of elution;
5. mix powdered metals to prepare paste and apply the paste onto the joining end face of ceramic or metal; or
6. combine above methods 1 through 5.
Other methods than the above-specified can be used. However, after the intermediate layer is manufactured, it should have the composition of the present invention.
The composition of the intermediate layer prepared through elution or thermal diffusion can be determined, for example, by using an X-ray microanalyzer (XMA), an electronic probe microanalyzer (EPMA), or an energy-dispersing type X-ray analysis (EDX).
The intermediate layer can join oxide ceramic such as alumina, zirconia, and titania, and it can also join non-oxide ceramic such as silicon nitride, sialon, and silicon carbide.
The intermediate layer can join iron (Fe), carbon steel, nickel, and other metals. However, metal has a different coefficient of thermal expansion from that of ceramic, and a residual thermal stress is produced in ceramic when metal joins ceramic. Accordingly, Ni, iron-nickel (Fe-Ni) alloy, and iron-nickel-cobalt (Fe-Ni-Co) alloy are desirable. Fe-Ni alloy and Fe-Ni-Co alloy include 42-alloy, kovar, invar, superinvar and incoloy.
As shown in FIG. 6, after the intermediate layer joins an Si 3 N 4 sintered body 1 and a Ni plate 3, the intermediate layer comprises layers L1 through L5. The layers L1 through L5 are formed according to the configuration, structure and composition that the intermediate layer had before joining the Si 3 N 4 sintered body 1 and the Ni plate 3, and according to the configuration, structure and composition of the Si 3 N 4 sintered body 1 and the Ni plate 3. The composition for the intermediate layer is specified by averaging the compositions of the layers L1 through L5.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 is a partially sectional view of a first embodiment showing one application of the present invention.
FIGS. 2A through 2F are partially sectional views showing various intermediate layers for the first embodiment.
FIG. 3 is a diagram of a four-point bending test performed on the embodiments for the present invention.
FIG. 4 is a partially sectional view of a second embodiment.
FIG. 5 is a partially sectional view of a turbo charger rotor having the structure of the present invention.
FIG. 6 is a cross sectional view showing an intermediate layer which has joined ceramic and metal.
FIGS. 7 is a secondary electron image photo of the metallic composition of the intermediate layer.
FIG. 8 is an enlarged view of FIG. 7.
FIGS. 9 through 13 are characteristic X-ray image photos showing the distribution of Ag, Ni, Ti, Pd and Cu in the intermediate layer, respectively.
FIGS. 14 is a secondary electron image photo of the metallic composition of the intermediate layer.
FIG. 15 is an enlarged view of FIG. 14.
FIGS. 16 through 20 are characteristic X-ray image photos showing the distribution of Ag, Ni, Ti, Pd and Cu in the intermediate layer, respectively.
DESCRIPTION OF THE PREFERRED EMBODIMENTS
EMBODIMENT 1
As shown in FIG. 1, intermediate members 7 are inserted, respectively, between an Si 3 N 4 body 1 and a Ni plate 3, and between the Ni plate 3 and an Si 3 N 4 body 5. The Si 3 N 4 bodies 1 and 5, which are gas-pressure sintered silicon nitride bodies, are 8 mm in diameter and 20 mm long. The Ni plate 3 is 8 mm in diameter and 0.25 mm thick. The intermediate member 7, the Si 3 N 4 sintered bodies 1 and 5 and the Ni plate 3 are heated to join each other by a vacuum of 10 -4 torr through 10 -5 torr, according to the joining conditions in Table 1.
The intermediate members 7 have the following types of joining structure:
(1) as shown in FIG. 2A, the combination of a metallic foil 9 and a solder 11;
(2) as shown in FIG. 2B, an alloy 13 manufactured by melting with a fixed composition;
(3) a metallic layer 15 comprising fixed substances, being formed on the surface of the Si 3 N 4 sintered body 1 or the Ni plate 3, and being combined with the intermediate member 7 of type (1) or (2), specifically, the metallic layer 15 formed on the Si 3 N 4 sintered body 1 and (1) as the intermediate member 7 as shown in FIG. 2C the metallic layer 15 formed on the Si 3 N 4 sintered body 1 and (2) as the intermediate member 7 as shown in FIG. 2D, the metallic layer 15 formed on the Ni plate 3 and (1) as the intermediate member 7 as shown in FIG. 2E, or the metallic layer 15 formed on the Ni plate 3 and (2) as the intermediate member 7 as shown in FIG. 2F; and
(4) thermal diffusion in vacuum is applied to the intermediate layer having either one of the joining types (1) through (3).
The joining strength of the joined body can be measured as shown in FIG. 3. A 4 mm wide, 3 mm thick, and 40 mm long flexure test piece is cut out from the joined ceramic and metal. The distance between upper supports is 10 mm and the distance between lower supports is 30 mm, centering on a joining intermediate layer 19. A four-point bending test is performed on the test piece with the loading speed of 0.5 mm/min. at both room temperature and 400° C. The breaking strengths of three test pieces are measured and averaged as shown in Table 2.
To ascertain the composition of the joining intermediate layer, after measuring the breaking strengths, the test piece is cut perpendicular to the joining surface. Five points in the intermediate layer are selected at random and analyzed using the XMA. Ni composing the intermediate layer contains eluted substances from the Ni plate 3. The composition of the intermediate layer is shown in Table 1.
TABLE 1__________________________________________________________________________ INTERMEDIATE LAYER COMPO- SITION (% BY WEIGHT) JOINING CONDITIONSSAMPLE HEATING JOINING Notes: Numerals after element symbols refer toNO. Ag Cu Pd Ni Ti CONDITION TYPE % by weight.__________________________________________________________________________EM- 1 64 -- 1 30 5 1080° C. · 15 MIN. (2) Composition before melting: Ag72--Pd2--Ni18--Ti8BODI- 2 45 -- 20 30 5 SAME AS ABOVE (2) Composition before melting: Ag52--Pd24--Ni18--Ti8MENT 3 67 -- 5 23 5 1060° C. · 15 MIN. (1) 5 micron thick Ti foil, 50 micron thick Ag--Pd solder 4 40 -- 20 39 1 1040° C. · 5 MIN. (4) Thermal diffusion at 850° C. for 30 minutes is applied to joined (1) (1.5 micron thick Ti/50 micron thick Ag--Pd solder). 5 68 -- 10 12 10 1060° C. · 5 MIN. (1) 10 micron thick Ti foil, 50 micron thick Ag--Pd solder 6 21 8 8 58 5 1100° C. · 30 MIN. (2) Composition before melting: Ag60--Pd10--Ni15--Ti5--Cu10 7 45 10 10 30 5 1080° C. · 20 MIN. (1) 5 micron thick Ti foil, 50 micron thick Ag--Pd--Cu 8 57 4 6 29.5 3.5 970° C. · 15 MIN. (1) 5 micron thick Ti foil, 100 micron thick Ag--Pd--Cu 9 46 0.5 19 27 7.5 1080° C. · 10 MIN. (3) Electroless Ni plating on ceramic before joining (2) 10 32.5 -- 10 50 7.5 1040° C. · 10 MIN. (1) 5 micron thick Ti foil, 50 micron thick Ag--Pd solder 11 48 -- 6.5 38 7.5 1080° C. · 30 MIN. (2) Compositon before melting: Ag91--Pd5--Ti4 12 50 2 5 40 3 1080° C. · 15 MIN. (4) Thermal diffusion at 850° C. for 30 minutes is applied to joined (2).COM- 1 -- -- -- 70 30 1150° C. · 30 MIN. -- 5 micron thick Ti foilPAR- 2 63 25 -- 10 2 900° C. · 15 MIN. (1) 5 micron thick Ti foil, 50 micron thick Ag--Cu solderISON 3 29 -- 28 42 1 1060° C. · 15 MIN. (4) Thermal diffusion at 850° C. for one hour is appliedDATA to joined (2). 4 75 -- 16 4 5 1020° C. · 5 MIN. (2) Composition before melting: Ag75--Pd20--Ti5 5 60 -- 0.5 28.5 11 1040° C. · 15 MIN. (2) Composition before melting: Ag71--Pd2--Ni12--Ti15 6 50 -- 31 18.5 0.5 1080° C. · 20 MIN. (3) Electroless Pd plating is applied on Ni before joining 1.5 micron thick Ti foil and Ag--Pd solder 7 40 42 9 6 3 1040° C. · 5 MIN. (1) 5 micron thick Ti foil, 20 micron thick Cu, 50 micron thick Ag--Pd--Cu solder 8 17 4 6 63 10 1100° C. · 30 MIN. (1) 20 micron thick Ti foil, 50 micron thick Ag--Pd--Cu solder__________________________________________________________________________
TABLE 2__________________________________________________________________________ ROOM TEMPERATURE 400° C.SAMPLE STRENGTH BROKEN STRENGTH BROKENNO. (kg/mm.sup.2) POSITION (kg/mm.sup.2) POSITION__________________________________________________________________________EMBOD- 1 39 C, C/S 26 C, C/SIMENT 2 38 SAME AS ABOVE 30 SAME AS ABOVE 3 42 SAME AS ABOVE 30 SAME AS ABOVE 4 36 SAME AS ABOVE 29 SAME AS ABOVE 5 37 SAME AS ABOVE 26 SAME AS ABOVE 6 40 SAME AS ABOVE 31 SAME AS ABOVE 7 41 SAME AS ABOVE 30 SAME AS ABOVE 8 44 SAME AS ABOVE 32 SAME AS ABOVE 9 38 SAME AS ABOVE 28 SAME AS ABOVE 10 43 SAME AS ABOVE 35 SAME AS ABOVE 11 42 SAME AS ABOVE 34 SAME AS ABOVE 12 40 SAME AS ABOVE 29 SAME AS ABOVECOM- 1 17 C/S 16 C/SPAR- 2 41 C, C/S 22 SAME AS ABOVEISON 3 21 SAME AS ABOVE 12 SAME AS ABOVEDATA 4 36 SAME AS ABOVE 17 SAME AS ABOVE 5 20 SAME AS ABOVE 10 SAME AS ABOVE 6 22 SAME AS ABOVE 11 SAME AS ABOVE 7 28 SAME AS ABOVE 10 SAME AS ABOVE 8 27 SAME AS ABOVE 14 SAME AS ABOVE__________________________________________________________________________ NOTES C: ceramic C/S: interface of ceramic and intermediate layer
As shown in Table 2, the joined ceramic and metal of the present embodiment has a sufficient joining strength both at room temperature and at high temperature. The interface between the ceramic and the intermediate layer is partly broken at 400° C., but cracks are mostly found inside the ceramic. The joined ceramic and metal of the present embodiment has high reliability. On the other hand, the joined ceramic and metal as the comparison data has insufficient strength at high temperature and has cracks on the interface between the ceramic and the intermediate layer. The joined ceramic and metal of the comparison data has less reliability than that of the present embodiment.
When the Si 3 N 4 sintered body 1 joins the Ni plate 3 through the intermediate member 7 comprising the metallic foil 9 and the solder 11 as shown in FIG. 2A, an intermediate layer 2 has the cross section shown in FIG. 6. The intermediate layer 2 is composed of a rich Ti layer L1, a rich Ag layer L2, a rich Ni-Ti layer L3, a rich Ag layer L4 and a rich Ni layer L5. The layers L2 and L4 include Pd, Ni, and Ti, and sometimes Cu. The layer L3 includes Pd, and sometimes Cu. The layer L5 includes eluted Ni.
EMBODIMENT 2
As shown in FIG. 4, in the same way as the first embodiment, an Si 3 N 4 sintered body 101 joins a Ni plate 103 through an intermediate member 107. At the same time, the Ni plate 103 is joined with a W alloy 121, a Ni plate 123 and a stainless steel 125 in sequence with a silver solder 111. The W alloy 121 contains a small amount of Fe and Ni as assistants to sintering. The W alloy 121 is 8 mm in diameter and 2 mm thick, the Ni plate 123 is 8 mm in diameter and 0.25 mm thick, and the stainless steel 125, with a specification of SUS403 according to Japanese Industrial Standard (JIS), is 8 mm in diameter and 20 mm long. The silver solder 111, which is available on the market, has a specification of BAg8 according to JIS and is 8 mm in diameter and 0.03 mm thick.
The strength test is performed on the second embodiment in the same way as the first embodiment. Test results are shown in Table 3. The sample No 1 as comparison data in Table 3 uses 5 micron thick Ti foil instead of the silver solder.
TABLE 3__________________________________________________________________________ ROOM TEMPERATURE 400° C.SAMPLE STRENGTH BROKEN STRENGTH BROKENNO. (kg/mm.sup.2) POSITION (kg/mm.sup.2) POSITION__________________________________________________________________________EMBOD- 1 38 C 25 C, C/SIMENT 2 38 SAME AS ABOVE 28 SAME AS ABOVE 3 43 SAME AS ABOVE 31 SAME AS ABOVE 4 35 SAME AS ABOVE 26 SAME AS ABOVE 5 41 SAME AS ABOVE 27 SAME AS ABOVE 6 39 SAME AS ABOVE 32 SAME AS ABOVE 7 41 SAME AS ABOVE 30 SAME AS ABOVE 8 44 SAME AS ABOVE 35 SAME AS ABOVE 9 37 SAME AS ABOVE 26 SAME AS ABOVE 10 42 SAME AS ABOVE 35 SAME AS ABOVE 11 40 SAME AS ABOVE 34 SAME AS ABOVE 12 40 SAME AS ABOVE 28 SAME AS ABOVECOM- 1 15 C/S 15 C/SPAR- 2 40 C 21 SAME AS ABOVEISON 3 20 C, C/S 10 SAME AS ABOVEDATA 4 34 SAME AS ABOVE 13 SAME AS ABOVE 5 18 SAME AS ABOVE 8 SAME AS ABOVE 6 20 SAME AS ABOVE 11 SAME AS ABOVE 7 26 SAME AS ABOVE 10 SAME AS ABOVE 8 25 SAME AS ABOVE 13 SAME AS ABOVE__________________________________________________________________________ NOTES C: ceramic C/S: interface of ceramic and intermediate layer
This combination of metals eases thermal stress in ceramic. The second embodiment can also be applied to the joining of ceramic and stainless steel that has a different coefficient of thermal expansion from ceramic.
On the same way as the first embodiment, the composition of the intermediate layer and the distribution of elements in the intermediate layer are analyzed using the XMA. The results of analyzing Sample No. 8 for the second embodiment in Table 3 are shown in Table 4 and FIGS. 7 through 13. The secondary electron image photo of FIG. 7 shows the joined body through the intermediate member 107. Table 4 shows the analysis results of positions 1 through 5 delineated by rectangles in FIG. 7. FIG. 8 is an enlarged view of FIG. 7, and FIGS. 9 through 13 show the distribution of Ag, Ni, Ti, Pd and Cu, respectively.
TABLE 4______________________________________POSITION COMPOSITION (% BY WEIGHT)NO. Ag Cu Pd Ni Ti______________________________________1 58.07 4.54 5.78 28.73 2.872 57.56 4.08 6.10 28.61 3.653 53.58 3.90 6.59 31.57 4.354 58.08 4.52 5.67 28.57 3.165 56.56 3.61 6.33 30.27 3.28Average 56.77 4.13 6.09 29.55 3.46______________________________________
Table 5 and FIGS. 14 through 20 show the analysis results of Sample No. 11 for the second embodiment in Table 3. FIG. 14 shows the intermediate layer, and FIG. 15 shows an enlarged image of FIG. 14. Table 5 shows the composition of positions 1 through 6 in FIG. 15. Since position No. 7 in FIG. 15 is in the Ni plate 103, Table 5 excludes it. FIGS. 16 through 20 show the distribution of Ag, Ni, Ti, Pd and Cu, respectively.
TABLE 5______________________________________POSITION COMPOSITION (% BY WEIGHT)NO. Ag Cu Pd Ni Ti______________________________________1 92.55 0.26 5.85 0.61 0.732 5.73 0.58 10.19 64.73 18.773 92.74 0.05 6.59 0.33 0.604 4.55 0.18 9.92 67.16 18.195 1.29 0.46 3.32 89.95 4.976 91.69 0.03 5.77 1.97 0.53Average 48.09 0.26 6.89 37.46 7.30______________________________________
As shown in Tables 4 and 5, the intermediate layer has nonuniform composition. As shown in FIG. 15, five or more positions in the intermediate layer should be analyzed and averaged to obtain the composition of the intermediate layer. As shown in FIG. 7, it is desirable that beam should be enlarged almost equal to the thickness of the intermediate layer. In this case, five or more parallel positions in the intermediate layer should also be analyzed and averaged to ascertain the composition of the intermediate layer.
EMBODIMENT 3
To test the resistance to oxidation of the intermediate layer of the joined ceramic and metal for the present invention, flexure test pieces are prepared in the same way as the first embodiment. After the test pieces are kept in the atmosphere at 500° C. for one hundred hours, a four-point bending test is conducted at room temperature. Table 6 shows this oxidation test result.
TABLE 6__________________________________________________________________________ INTERMEDIATE LAYER INITIAL STRENGTH AFTERSAMPLE COMPOSITION (% BY WEIGHT) STRENGTH OXIDATION TESTNO. Ag Cu Pd Ni Ti (kg/mm.sup.2) (kg/mm.sup.2)__________________________________________________________________________EMBOD- 1 64 -- 1 30 5 38 28IMENT 2 45 -- 20 30 5 38 32 3 67 -- 5 23 5 43 31 4 40 -- 20 39 1 35 30 5 68 -- 10 12 10 41 35 6 21 8 8 58 5 39 33 7 45 10 10 30 5 41 27 8 57 4 6 29.5 3.5 44 30 9 46 0.5 19 27 7.5 37 29 10 32.5 -- 10 50 7.5 42 36 11 48 -- 6.5 38 7.5 40 31 12 50 2 5 40 3 40 29COM- 1 63 25 -- 10 2 40 12PAR- 2 58 12 5 23 2 40 21ISON 3 40 25 7 25 3 43 14 4 30 40 8 14 8 36 10 5 70 20 1 8 1 38 13 6 45 20 20 5 10 35 17__________________________________________________________________________
As shown in Table 6, samples for the third embodiment show great joining strength even after the oxidation test.
On the other hand, samples as comparison data are remarkably deteriorated after the oxidation test. Broken samples are cut perpendicularly to a joining surface and their composition is observed. As a result, Cu is selectively oxidized, which causes deterioration.
The samples for the third embodiment are hardly oxidized. Since Sample No. 7 contains 10% by weight of Cu, it is slightly oxidized, but it is not deteriorated.
Since sample No 2 of the comparison data which contains 12% by weight of Cu, is deteriorated, the intermediate layer should contain 10% by weight or less of Cu.
Although specific embodiments of the invention have been described for the purpose of illustration, the invention is not limited to the embodiments illustrated and described. This invention includes all embodiments and modifications that come within the scope of the claims.
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Joined ceramic and metal is characterized by ceramic and metal thermally joined through an intermediate layer. The intermediate layer is composed of 20-70% by weight of silver, 1-20% by weight of palladium, 10-60% by weight of nickel and 1-10% by weight of titanium. The joined ceramic and metal has sufficient joining strength both at normal temperature and at high temperature, because the joined ceramic and metal suffers little deterioration even at high temperature. Since the joined ceramic and metal has the characteristics of ceramic such as resistance to heat, corrosion and wear, it can be used for a structure operated at high temperature such as a gas turbine engine, a turbo charger rotor, a piston, a suction valve, and an exhaust valve.
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This is a continuation, of application Ser. No. 639,706, filed Dec. 11, 1975 now U.S. Pat. No. 4,109,570.
BACKGROUND OF THE INVENTION
The present invention relates to a method and apparatus for pitting peaches, especially cling peaches.
Most methods and machines previously known for this purpose generally have utilized blades or cutters to separate the stone from the fruit pulp or flesh. Other known methods and machines do not use blades or cutters and rely on causing relative rotary movement between the stone and the pulp to produce their separation, although the means for securing the pulp and causing its rotation are deffective and inefficient. The efficiency of a peach pitting operation is judged mainly from a time standpoint and amount of fruit recovered. These factors are of paramount importance. The principle objective of the present invention is to provide a unique method and apparatus that will efficiently recover the greatest amount of fruit in the least possible time. The present invention differs from the prior art for many reasons which will become evident as the description of the present invention unfolds and among which are its continuous operation and its use of a novel elastic, fruit-gripping and rotating means.
Some of the most outstanding advantages of the present invention are the following:
A. Better presentation and appearance of the stone-free fruit halves, due to the separation of the stone from the pulp without the intervention of pulp deteriorating elements or tools, whereby it is possible to vary the force with which the fruit is "held" and thus, adapt the invention to different types of peaches, such as those of the clingstone or free-stone types, as well as, to fruit of different degrees of ripeness;
B. Minimum loss of pulp regardless of its shape or size of the stone;
C. Less possibility of obstruction and longer uninterrupted operation; and
D. Lower maintenance costs due to the reduction in the number of moving mechanical parts and to the lack of complex mechanisms.
In accordance with the present invention a peach to be pitted is presented to the apparatus oriented in such manner that its line of separation between its halves is in alignment with two coplanar mounted sharp metallic plates. The plates engage the subject peach and give it a diametrical cut to a depth reaching nearly to the stone and then completely up to the stone whereupon the plates grasp the stone and hold it securely during the ensuing pitting operation. The next step is to simultaneously and uniformly grasp about two-thirds of the external semi-spherical area of each half and then rotate the two halves, for example 180° about their own axis, in opposite directions, maintaining the stone centered and stationary between the metal plates. The grasping of each half of the fruit is achieved by means of the novel elastic gripping means of the present invention and comprises a diaphragm adapted to contact, due to the effect of a fluid acting thereon, a fruit half with a force sufficient to transmit a rotation to the fruit.
As the two halves rotate, and because the stone is firmly held between the two plates, the pulp around it separates from the stone due principally to the different consistency between the wood of the stone and the soft tissues of the pulp, with the separation being effected with minimum tearing of the pulp in its zone of adhesion to the stone. This result is achieved by the combined effect of the rotation and the favorable pressure distribution, generally uniform, applied over the external surface of each half, (regardless of its profile) by the elastic gripping means.
Following this, the two de-stoned or pitted halves are freed, by disengaging the gripping means and the stone is freed by separating the metal plates.
This complete operation as described above is effected by means of a unique combination of mechanical movements operated by a pneumatic or hydraulic system conceived for this machine, and the operation can be continuous, using an automatic feeder or manual feeding.
In the preferred embodiment, the apparatus consists of a rotating plate on which are defined four stations. As each station passes by a feeding station, it receives a peach which is split and de-stoned and afterwards discharged at a discharge station. The inventive combination allows continuous operation, with its consequential advantages. More specifically, the preferred machine consists of a central rotor incorporating a plate with two pairs of diametrically opposed operating stations, determined by eight sectors, four of which are fixed to the plate and four movable with respect thereto with an angular, coplanar movement, thus determining the variation of the aperture of said operating stations. Furthermore, two lateral supports are provided, one on each side of the plate, carrying four pairs of elastic gripping devices, each pair of which is made to move simultaneously and in opposite directions with alternative linear movement oriented perpendicularly to the plate and coinciding with a preselected indexing relative to one of the operating stations. As the elastic gripping devices reaching their closest approach to the plate, a compressed fluid, such as air, simultaneously enters an interior chamber of each gripping device, by means of a charge-discharge valve incorporated into the body of the same, causing the elastic and concave zone of the front wall of the gripping device to deform outwardly, adapting itself with sufficient force to the external surface of the peach half. This deformed condition is maintained during a portion of the rotation of the gripping devices about the common equidistant axis of rotation of the plate and during which both gripping devices rotate approximately 2/3 of a complete turn in opposite directions about their own central axis of rotation. Subsequently, the compressed air is discharged by means of the same valve and the gripping devices are caused to separate, whereby the peaches halves are freed and discharged. The stone or pit is transported to the stone discharge zone where it is freed by the operation station, which is opened, and consequently the stone falls out by gravity or is extracted by a rotary fork synchronized with the plate rotation. This fork sweeps both sides the sectors defining the operating station. Rotation of the plate continues into the loading zone in which a fruit loading device, synchronized with the passage of each operating station, describes an arched to and fro trajectory or path, in such a manner that one of the dead ends of its path coincides with the trajectory or path of said operating stations.
It is obvious that the number of operating stations defined on the plate, as well as the number of sectors and the number of elastic gripping devices, may be varied without departing from the fundamental features of the present invention, such variation principally aimed at changing the operative speed.
BRIEF DESCRIPTION OF THE DRAWINGS
In order to facilitate the best comprehension of the present invention, a specific preferred embodiment will now be described with reference to the accompanying drawings, wherein:
FIG. 1 is a view in perspective of a machine incorporating the novel features of the present invention;
FIG. 2 is a schematic view, partially in vertical plan and partially in vertical section, showing a group of the components of the machine illustrated in FIG. 1;
FIG. 3 is a vertical sectional view across a gripping mechanism of the machine of the present invention;
FIG. 4 is a section along line 4--4 shown in FIG. 3.
DESCRIPTION OF THE PREFERRED EMBODIMENT
The apparatus illustrated in the drawings comprises a main frame 1 having parallel vertical end frames 2 supporting the apparatus components. These frames 2 support a bearing mounted main shaft 3, fitted to which, outside the space defined between supports 2, is a main gear wheel 4 which receives and transmits to the mentioned shaft all driving motions. A plate 5 is mounted on shaft 3. The former is fitted with four gripping and cutting elements, only two of which have been shown and identified with reference 6. These elements 6 are fixed to plate 5 by means, for example, such as bolts. Furthermore, plate 5 serves as support to four shafts (only two have been shown and identified by reference 8) which can rotate with respect to the plate 5 and on which are mounted, without any capacity for rotation or displacement, the four cooperating respective cutting and gripping devices 7 only, two of which are shown and identified.
Obviously, the apparatus will consist of four of these groups composed of the gripping and cutting elements 7 and 6, and their associated components, equidistantly distributed over plate 5. Notwithstanding that from now onwards reference will be made to only one gripping and cutting group 7-6, the description applies to each one of the four groups included in the apparatus. Shaft 8, on which is fixed the gripping and cutting element 7, extends perpendicularly to plate 5 and also has one end of a radial lug 9 fixed on it with the other end of lug 9 connected to a spring 10 whose other end (not visible) is secured to plate 5, in such manner that the mentioned spring 10 causes the angular movement of lug 9 and that of shaft 8 in a clockwise rotation (FIG. 2). Shaft 8 also has fixed on it one end of another radial lug 11 at whose other end is mounted a follower wheel 12 riding on cam 13, integral or fixed to frame 1 in such manner that cam 13 will cause wheel 12, lug 11 and shaft 8 to rotate (counter clockwise) against spring 10 at the opportune movement, during rotation of plate 5 whereupon cutting element 7 will move counter clockwise with respect to cutting element 6, thereby increasing the size of the space defined between toothed surfaces 14 and 15 defined on elements 6 and 7 respectively. It is in this space, as will be explained later, that the peach stone is imprisoned and held by elements 6 and 7. The cutting and gripping elements 6 and 7 besides being provided with toothed portions 14 and 15 whose configuration is similar to that illustrated so as to increase their capacity to retain the peach stone, are provided with cutting edges 16, 17, the purpose of which will be explained later on.
Referring once again to FIG. 1, it will be appreciated that main gear wheel 4 is driven by pinion 18 mounted on shaft 19 to which is fixed a fork 20 (FIG. 2) which for that reason rotates synchronized with plate 5. This fork 20 has each one of its two tines placed, during part of its rotation, at each side of plate 5 and is synchronized in such manner as to sweep past toothed portions 14 and 15 after these have separated, so as to free the stone previously retained by them. Shaft 19 is supported by a bearing 21, in its turn mounted on support 22 integral with or fixed to main frame 1.
Pinion 18 is driven by pinion 23 pinned to a shaft 24, on which in turn is pinned gear 25 driven from an external power source by any known conventional means. Pinion 23 drives pinion 26 pinned to shaft 27 which commands or drives peach feeding mechanism 28.
This feeding mechanism 28 includes a shaft 29 supported by arm 30 and bearing 31. This shaft 29 rotatably supports a first bushing 32 having a salient 33 to which are articulated two arms 34 and 35, whose ends define, in combination, a half cup 36 divided into two spaced parts to enable it to be fitted into the spaces defined in plate 5, by gripping and cutting elements 6 and 7, when cup 36 is taken from its illustrated position in which it receives a peach, to a position in which it delivers the fruit to plate 5 placing the stone of the peach between toothed portions 14 and 15. Through the space defined between the two portions of the half cup 36, there extends a guiding tongue 37 supported by a pivoting arm 38 integral with or fixed to bushing 39 mounted on shaft 29.
Bushings 32 and 39 are integral with or fixed to bracing arms 40 and 41, in whose end portions are mounted the cam followers 42 and 43 in contact with cams 44 and 45 mounted on axle 27.
A spring 46 under tension placed between arm 34 and main frame 1 biases cam follower 42 to follow the profile of cam 44.
Similarly, a spring 47 under tension placed between arm 38 and main frame 1 biases cam follower 43 to follow the profile of cam 45.
In addition, a compensating spring 48, and a guiding and regulating threaded pin 49 with nuts 50 have been provided in order to regulate the angular position of arm 34 in respect to bushing 32. To that effect, this adjusting assembly 48, 49, 50 is mounted between a lug 51 (FIG. 2) fixed to arm 34 and a lug (not shown) integral with or fixed to bushing 32 or with the salient 33.
Referring once again to FIG. 1, it may be appreciated that on shaft 3, are mounted, fixed to it, two rigid structures 60, 61 each one of which is provided with the respective housings for supporting bushings 62. Each supporting bushing 62 supports a gripping assembly 63 which is shown in more detail in FIG. 3.
Each gripping assembly 63 includes a hollow rotary central shaft 64 mounted inside a longitudinally sliding shaft (nonrotary) 65. The sliding shaft 64 is fixed to a pin 67 which rotatably supports a cam follower 66.
As will be described in detail later, rotation of shaft 3 causes the gripping assemblies 63 to rotate round the axis of shaft 3, due to which, the cam followers 66, will come into contact, during part of their run with the respective face 68 of cams 69, each one fixed with its associated end frame 2 on main frame 1. Due to the configuration of the cam face 70 of each cam 69, each cam follower 66 will cause or force its respective gripping assembly 63 to approach plate 5. A return spring 71 is provided in order to bias return of the gripping assembly 63 to its initial position once cam follower 66 ceases to contact the cam face 68. The two cam surfaces of cams 69, 69 face each other and are oriented to cause the approach of two facing gripping assemblies at the proper time.
On each shaft 64 is mounted a gripping head composed of an elastic concave grooved or ridged rubber diaphragm 72, tightened against a cylindrical body 73 by means of a rustless metallic cover 74, held by screws (only their axis 75 being illustrated). The surface of the diaphragm which establishes contact with the fruit, although preferably grooved or ridged, may be ungrooved or unridged if the material of which it is made adheres sufficiently to the fruit. The gripping head is joined to shaft 64 through a metal disc 76 peripherically secured to cylindrical body 73 by means of screws (also only shown by their axis 77) and in its central body by means of screws 80 which run through the body of sensor valve 78.
The body of sensor valve 78 has a recess, dimensioned in a manner such as to receive disc 79, mounted on stem 82 which runs through the body of sensor valve 78 and a complementary body 84 between which a recess 91 has been cut and which defines part of a passage for air, to be described later. Another recess 85 is defined in complementary body 84, in which there is lodged a hermetic seal 86 which embraces stem 82. Disc 79 serves to detect the presence of a peach, illustrated by a dotted line on FIG. 3 and to open the air passage 91 which will now be described.
On the internal end of stem 82 is located a disc valve 87 fixed with the former and against which a spring 88 is supported and located inside a bore 89 defined in axle 64. Normally, disc valve 87 is seated against face 90 of sensor valve body 78 thus obstructing passage 91 which is mentioned above and which is located between complementary body 84 and sensor valve body 78.
Passage 91 is circumferential and surrounds stem 82 so that it is permanently in communication with conduit 92, defined in a radial projecting portion 93 of shaft 64.
Shaft 64 presents on its free end a gear wheel 94 firmly keyed to the same and capable of engaging recess 95, 96 which are crown wheel sectors mounted rigidly on lateral supports 2. Shaft 64 besides being provided with bore 89 presents a central passage 97 which communicates therewith as well as with a rotary air valve 98 communicated with shaft 3 which is hollow in this section by connectors 99 and hose 100.
The hollow portion of shaft 3 is in turn connected to a rotary air valve 101, similar to valve 98. This valve 101 is connected to an air source (not illustrated) by means of tube 102.
Returning now to FIG. 3, passage 92 is in permanent communication with a gripper valve 103 designed to allow the synchronized inlet and outlet of air to chamber 104 defined between diaphragm 72, cylindrical body 73 and metal disc 76.
This gripper valve 103 incorporates a body 105 fixed to disc 76 in a peripherical portion thereof, coinciding with bore or aperture 107 defined in shaft 106. In front of this bore or aperture 107, the wall of cylindrical body 73 has a reduction in thickness, which jointly with the mentioned bore or aperture 107 defines a passage which ends in chamber 104. Body 105 houses shaft 106 free to rotate inside the former and which is provided, as noted, on one end with central axial bore or aperture 107 which in turn connects with two radial diametrically opposed bores 108. These radial bores 108 communicate with passage 109 defined in body 105, which in turn communicates with passage 92.
The axial central bore 107 has on its blind end a communication with two radial bores 110 placed at 90° with respect to radial bore 108. Radial bores 110 communicate, when shaft 106 is in the correctly aligned position, with the atmosphere or ambient. Communication with and closing of passage 109 by means of radial bores 108 and of the two bores 110 with the atmosphere, is obtained by rotating shaft 106. For this purpose, shaft 106 has mounted on its other end a member 111 substantially in the form of a Maltese Cross which defines recesses 112. During a portion of the rotation of gripping assembly 63 around shaft 3, a spigot or rod 113 fixed on arm 114 fixed in turn to transverse bar 115 mounted between lateral end frames 2 will be received in the recesses 112 causing rotation of member 111. The spigot 113 serves to establish a communication between passage 92 and chamber 104. Communication of chamber 104 with the atmosphere is affected by means of pin 116, mounted on support 117 fixed to structure 61. This pin 116 is likewise located in the trajectory which recesses 112 describe round shaft 64.
OPERATION OF THE PREFERRED EMBODIMENT
An automatic feeder or an operator, places a peach in cup 36, oriented with its bisecting line coinciding with guiding tongue 37 and anchored thereto by its peduncle portion. This operation is carried out during the travel of cam followers 42, 43 over the constant diameter portion of cams 44 and 45 while these cams rotate being driven by shaft 27 which in turn is made to rotate by pinion 23, shaft 24 and pinion 25 connected to the driving source (not shown). During this period, cup 36 is stationary, thus facilitating its loading.
When the eccentric surfaces of both cams 44, 45 act on their respective followers, cup 36 will describe an arc accompanied by guiding tongue 37 which reaches the periphery of plate 5, from which point only cup 36 continues in motion, introducing the peach exactly into an aperture defined between plates 6 and 7, whose cutting edges 16 and 17 produce the diametrical cut of the peach pulp, cup 36 reaching its maximum travel the instant in which the center of the fruit reaches toothed zone 14, 15 of the aperture. Thereafter, cap 36 returns towards its position shown in FIG. 1, the peach remaining in position in plate 5, which is rotating, with the peach stone "C" (FIG. 3) lodged between the toothed edges 14, 15 of the aperture. Then follower wheel 12 is drawn or runs over the surface of cam 13 producing counter clock-wise angular displacement of the gripping and cutting element 7, not only to permit the loading of the peach but to allow the discharge of the prior stone as well.
For fruits in which the stone is of a large dimension, arms 34, 35 of cup 36 are articulated on a pin to salient 33 so that the difference in the travel distance of cup 36 is absorbed by compensating spring 48. Furthermore, the tension of this spring and the end point of maximum stroke may be regulated by nut 50 on regulating assembly 49.
When cup 36 and guiding tongue 37 retreat, due to the action of springs 46 and 47, respectively, the peach remains seized between gripping elements 6 and 7. Immediately after follower wheel 12 leaves contact with cam 13 and, as a result of the action of spring 10 on lug 9 of axle 8, plate 7 is forced towards plate 6, firmly gripping the stone between toothed surfaces 14 and 15. This condition then persists during the rotational travel of the plate 5 during which the de-stoning action occurs which will now be described.
Simultaneously with the rotation of plate 5 and once the peach has been fed into it, the two opposite gripping elements 63 will approach each other and engage the peach halves when the cam followers 66, which are mounted on the gripping elements and which ride on cams 68 are moved toward each other by cams 68. At this time each half of the peach will be received inside one of the concave diaphragms 72 located to one side of plate 5.
At that moment, gripper valve 103 is operated by spigot 113, admitting compressed air into chamber 104. It will be noted that chamber 104 will be connected with the central passage 97 of shaft 64 through disc valve 87, 90 (which has already been opened when the half-peach was located in the concave cavity of diaphragm 72 due to the fruit depressing disc 79 and stem 82 against the bias of compressing spring 88) and thus, air under pressure, from its source (not shown) will be in communication directly from the source to chamber 104. The air pressure acts evenly over the internal surface of diaphragm 72, which adapts itself to the shape of the half-peach holding it firmly.
In the case that no peach is fed into the machine, there will be no action on or depression of feeler disc 79 of sensor valve 78, 90 for which reason disc 87 will remain seated against its seat 90 due to the action of spring 88, blocking the passage of air to valve 103 and consequently to chamber 104 of diaphragm 72.
On reaching this condition of the peach halves being firmly gripped by devices 63, facing heads 63 start on inverted rotary motion due to the respective meshing of pinions 94 with the toothed sectors 95, 96 (pinions 94 are fitted with a spot brake illustrated in the detail in FIG. 1. This brake is of a well-known type so that it will not be described in detail although it should be noted that by means of the same, pinions 94 always find themselves in the same position on leaving and coming into contact once again with toothed sectors 95, 96). As the peach has already been diametrically cut, the torsion originated or created by pinion 94 and toothed sectors 95, 96 only acts to unstick the pulp from the stone which is being firmly held between the teeth 14, 15 of plates 6 and 7.
When each one of the mentioned heads 63 has rotated 2/3 of a turn about its own axis, the respective valves 103 actuate on meeting the corresponding pins, stops or plungers 116, communicating chambers 104 of diaphragms 72 with the atmosphere, causing the discharge of air pressure; simultaneously, cam followers 66 run over a depression on the faces of cams 68, and cause a partial separation or withdrawal of the gripping heads, ceasing or eliminating their adhering or gripping action on the peach halves until pinions 94 abandon toothed sectors 95, 96 completing thus one full turn.
At the end of the rotation of heads 63, the final separation commences as a result of cam followers 66 moving over the final run of cams 68 under the biasing influence of return spring 71, leaving at that time the two peach halves free, which then drop due to gravity. At that moment the follower wheel 12 will once again come into contact with cam 13 producing the separation of plates 6 and 7 by action of spring 10, freeing the peach stone which will also drop due to gravity. This condition between the mentioned plates is maintained until feeder assembly 28 has once again placed a peach between them restarting the sequence.
In the event that the stone remains stuck when the plates separate, it will be freed by rotary fork 20, synchronized with plate 5. Fork 20 will sweep over the opposite faces of plate 5 sweep any caught stone peripherally outwardly leaving the resulting aperture between toothed surfaces 14 and 15 free to accept the next peach and to renew operations.
Although in the described embodiment, reference has been made to the use of air as the power supply to cause diaphragm 72 to grip the fruit half, it is possible to use another medium such as another gas or even a liquid whereby the power supply may be either pneumatic or hydraulic.
It will be understood that improvements and modifications may be introduced in the embodiment described by way of example, without departing from the scope of the invention specifically defined in the following claims.
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In a peach bisecting and pitting machine in which the fruit is gripped by a deformable gripper during the pitting operation, apparatus is disclosed for sensing the presence or absence of a fruit within such gripper and for preventing the gripping deformation of the gripper when no fruit is present during the operation of the pitting machine.
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This application is a continuation application of Ser. No. 12/222,669, filed Aug. 13, 2008 now abandoned, and hereby claims the priority thereof to which it is entitled.
FIELD OF THE INVENTION
The present invention generally relates to an insulated die plate assembly for use in underwater pelletizers and other granulation processes that include hot-face or non-fluidic pelletization. More specifically, the present invention relates to an insulated die plate assembly that includes a thin continuous air pocket or chamber formed across the plate assembly such that the upstream portion of the die plate assembly is thermally insulated from the downstream portion of the same assembly, thus allowing the respective portions to co-exist at different temperatures. The plurality of extrusion orifices, individually or in groups, extend through extrusion orifice extensions that project through the insulation air pocket or chamber so that the material to be pelletized or granulated can pass therethrough.
BACKGROUND OF THE INVENTION AND PRIOR ART
Underwater pelletization equipment and its use following extrusion processing have been implemented for many years by Gala Industries, Inc. (“Gala”), the assignee of the present invention. Pelletization dies and die plates, in particular, are demonstrated in prior art disclosures including, for example, U.S. Pat. Nos. 4,123,207, 4,500,271, 4,621,996, 4,728,276, 5,059,103, 5,403,176, 6,824,371, 7,033,152, U.S. Patent Application Publication Nos. 20060165834 and 20070254059, German Patents and Applications including DE 32 43 332, DE 37 02 841, DE 87 01 490, DE 196 51 354, and World Patent Application Publications WO2006/081140 and WO2006/087179. These patents and applications are all owned by Gala and are expressly incorporated herein by reference as if set forth in their entirety.
As well understood by those skilled in the art, die plates used with rotating cutter hubs and blades, such as in underwater pelletizing, have the extrusion orifices or through die holes arranged in a generally circular pattern, or groups of multiple die holes arranged (as in pods or clusters) in a generally circular array. As so arranged, the rotating blades can cut the extrudate as it exits the die holes along a circular cutting face.
It is known in the field of plastic extrusion and cutting to feed plastic into a die plate for extrusion and solidification upon the exit from the die plate, and then to cut the extruded plastic into small pieces externally of the die plate. However, a known problem consists of the plastic freezing up within the die holes and either partially or completely blocking the passage of the plastic therethrough, with the resulting disruption of the entire operation.
To maintain the polymer at a sufficiently high temperature, insulation is desirable to reduce heat transfer from the extrusion die and the molten polymer being extruded through the extrusion orifices to the water circulating through the water box of the underwater pelletizer. Ineffective insulation can result in excessive cooling of the molten polymer as it is being extruded through the extrusion orifices causing freeze off of the molten polymer at the die face.
U.S. Pat. No. 4,378,964 and World Patent Application Publication No. WO1981/001980 disclose a multi-layer die plate assembly for underwater pelletization of polymeric materials in which an insulation layer, preferably zirconium oxide, is fixedly positioned between the body of the die plate and the layers comprising the cutting face of the die. Adjacent or proximal to the insulation layer is a heating chamber through which is circulated a heating fluid for maintenance of the temperature of the die.
U.S. Pat. No. 4,764,100 discloses a die plate construction specifically described for underwater pelletization of plastic extrudate including a closed insulating space formed between the baseplate and the cutting plate through which penetrates the extrusion nozzles, and optional inserts serve to further strengthen and support the structure.
Vacuum heat insulating cavities between extrusion nozzles are disclosed in U.S. Pat. No. 5,714,713 in a multi-step process that includes electron beam welding while the die components are maintained under high vacuum. This disclosure is extended to vacuum heat insulation portions in areas peripherally external to the extrusion nozzles for enhanced insulation performance in U.S. Pat. No. 5,989,009.
Similarly, closed continuous thermal stabilization cavities filled with air or gas are disclosed in U.S. Pat. No. 6,976,834. Additionally, brazing in a furnace at high temperature, 900° C. to 1200° C., under vacuum is disclosed as a manufacturing process with controlled cooling under argon to prevent oxidation thusly presenting an opportunity to introduce vacuum into the thermal stabilization cavities.
German Patent Application No. DE 100 02 408 and German Patent Utility Model No. DE 200 05 026 disclose a hollow space or a multiplicity thereof in the inner region of the nozzle plate and the nosecone extension to enhance temperature control by virtue of the reduction of mass necessitating temperature maintenance and thusly introducing thermal insulation. Use of solid, liquid, or gas as insulating materials is disclosed therein.
World Patent Application Publication No. WO2003/031132 discloses the use of ceramic plates for insulation of the die face from the heated portion of the die body.
Finally, Austrian patent application AT 503 368 A1 discloses a thermally insulated die plate assembly with a detachable face plate that is sealed to the discharge end of the extrusion orifice nozzles by an O-ring or metal seal. This die plate assembly is very fragile and highly susceptible to process melt leakage, thus requiring considerable maintenance.
There is, therefore, a need for a thermally insulated die plate assembly which is robust in construction, retains the air pocket in a sealed condition, requires low maintenance and provides high performance.
SUMMARY OF THE INVENTION
The thermally insulated die plate assembly of the present invention is installed in a conventional manner between the melting and/or mixing devices and the pellet transport components including mechanical, pneumatic, and/or fluid conveyance. The upstream side of the insulated die plate assembly receives molten polymer or other fluidized material from the melting/mixing devices that is subsequently extruded through the multiplicity of orifices extending from the upstream side to the downstream side of the die plate assembly to form extruded strands of material. The extruded strands, with at least marginal cooling, are cut into pellets by rotating cutter blades engaging a cutting surface or cutting die face associated with the downstream side of the die plate in a manner well known in the art of pelletizing.
The thermally insulated die plate assembly of the present invention is retained in position in a conventional manner by fasteners that connect the melting and mixing components, the die plate, and the pellet transport components. The nose cone, optionally a separate component, is retained in position as required by the normally provided nose cone anchor bolt as is understood by those skilled in the art. Similarly, thermal regulation fluid as required enters and exits chambers in the die plate through conventional inlet and outlet orifices, respectively.
The thermally insulated die plate assembly in accordance with the present invention is essentially formed by machining a cutout in the downstream side or die face side of a die plate body, preferably forming a generally circular cavity. The periphery of the cutout cavity should extend beyond the circular pattern or array of extrusion orifices or die holes with a raised circular ridge which matches and encompasses the circular pattern or array of extrusion orifices or die holes. The raised circular ridge thus divides the cutout cavity into, preferably, an annular outer section and a circular inner section. The raised circular ridge is preferably trapezoidal in vertical cross-section with the extrusion orifices extending centrally therethrough. Orifice protrusions project from the upper surface of the raised ridge at the extrusion orifice locations so that the extrusion orifices extend through the orifice protrusions.
Finally, a cover plate with holes matching the orifice protrusions is sized to fit over and into the cutout cavity in the die plate body to complete the downstream side of the die plate assembly and form a generally planar die face. In addition, the upstream side of the cover plate is machined with a counterbore which conforms to the configuration of the orifice protrusions and defines the outside wall of the air cavity around the orifice protrusions and the raised circular ridge. The cover plate is attached around its periphery to the die plate body and attached around its matching holes to the distal end of the orifice protrusions adjacent the die face.
The thickness of the cover plate is less than the depth of the cutout cavity so that when the cover plate is in place a thin, generally flat, continuous air pocket or air chamber is formed around the raised circular ridge and associated orifice protrusions, which air chamber is generally parallel to the die face. The thickness of the air chamber is on the order of about 0.05 millimeters (mm) to about 6.0 mm, and preferably about 0.5 mm to about 1.0 mm. Stated another way, the thickness of the air chamber is preferably about 5% to about 10% of the thickness of the die plate assembly.
The raised circular ridge and associated orifice protrusions which encompass and extend the extrusion orifices from the base of the cutout cavity to the matching holes of the cover plate are together referred to herein as the “extrusion orifice extensions”. The extrusion orifice extensions for each of the extrusion orifices or die holes extend fully through the air chamber so that the orifice extensions are surrounded by the thermally insulating air.
The air chamber is preferably vented to the atmosphere outside the die plate assembly, such as through one or more channels in the die plate body to provide for atmospheric equilibrium of the air chamber. The air chamber thus forms a thermally insulating air pocket or chamber between the typically heated upstream side of the die plate assembly and the downstream side forming the die face, which contacts the cooling water of the waterbox in an underwater pelletizer, or other cooling medium associated with a rotating cutter hub and blade assembly.
The cover plate should be made of a chemical, corrosion, abrasion, and wear-resistant metal. The cover plate can contain at least one circumferential expansion groove on at least one face and preferably contains a multiplicity of circumferential expansion grooves on at least one face. When expansion grooves are formed on both faces, they are preferably arranged in a staggeringly alternating configuration. Preferably, the cover plate is welded in position with nickel steel. More preferably, the cover plate is attached by welding with nickel steel at peripheral grooves circumferentially surrounding the cover plate and at weld locations between the distal end of the orifice protrusions and the inside of the cover plate holes.
The die plate body of the thermally insulated die plate assembly according to the present invention can be thermally regulated by any suitable heating system known to those skilled in the art, such as thermal regulation fluid as required to enter and exit heating chambers in the die plate body to conventional inlet and outlet orifices, respectively. Alternatively, the die plate body can be thermally regulated by at least one of electrical resistance, induction, steam, and thermal transfer fluid. Preferably, the die plate body is heated by electric heaters in techniques known to those skilled in the art.
In a first embodiment of the present invention, the thermally insulated die plate assembly is configured with a one-piece die plate body. In a second embodiment of the present invention, the thermally insulated die plate assembly is configured with a two-piece die plate body having a removable center die insert thermally insulated in accordance with the present invention which is peripherally surrounded by a die plate outer ring thermally regulated by at least one of electrical resistance, induction, steam, and thermal transfer fluid.
As used herein the term “die plate body” is intended to include the body of the die plate when the assembly of the present invention is configured as a one-piece construction and the removable center die insert in combination with the die plate outer ring when the assembly is configured in a two-piece construction.
In addition to having the die face of uniform planarity, the annular cutting face containing the distal ends of the orifice protrusions, and through which penetrate the multiplicity of extrusion orifices, can be raised a certain distance above the remaining portion of the die face, as known to those skilled in the art. The rotating cutting blades thus engage the raised annular cutting face. The raised annular cutting face should be at least 0.025 millimeters higher than the surrounding die face and preferably is at least 0.50 millimeters above the surrounding die face.
Preferably, at least the surface of the annular cutting face engaged by the cutting blades is subjected to an enhancing surface treatment. The enhancing surface treatment includes at least one of nitriding, carbonitriding, electroplating, electroless plating, electroless nickel dispersion treatments, flame spraying including high velocity applications, thermal spraying, plasma treatment, electrolytic plasma treatments, sintering, powder coating, vacuum deposition, chemical vapor deposition, physical vapor deposition, sputtering techniques and spray coating. These surface treatments result in metallizing, attachment of metal nitride, metal carbides, metal carbonitrides, and diamond-like carbon and can be used singly and in any combination. Different surface treatments can be applied to different circumferential planes on the cutting face and should be at least approximately 0.025 millimeters in thickness. Preferably, the treatments are at least approximately 0.50 millimeters in thickness.
The raised circular ridge and associated orifice protrusions are formed in at least one annular ring, and each orifice protrusion can contain at least one to a multiplicity of extrusion orifices arranged in groups, pods, and clusters. The orifice protrusions can be of any geometry including at least one of oval, round, square, triangular, rectangular, polygonal, and in many combinations. Similarly, the orifice protrusions can be arranged concentrically, alternating, in a staggering configuration, and linearly, and can be positioned parallel to the arc of rotation of the cutting blades, perpendicular to the arc and including kidney to comma-like configurations.
In addition, the extrusion orifices can be of any geometry including but not limited to round, oval, square, rectangular, triangular, pentagonal, hexagonal, polygonal, slotted, radially slotted and any combination thereof. A multiplicity of extrusion orifices can be of different geometry in a particular orifice protrusion or die face.
In view of the foregoing, it is an object of the present invention to provide a die plate assembly in which the typically heated upstream portion of the assembly is thermally insulated from the typically cooled downstream portion adjacent the die face by an internal insulation air pocket or air chamber extending substantially parallel to the die face.
A further object of the present invention is to provide a thermally insulated die plate assembly in accordance with the preceding object in which the insulation air pocket or air chamber surrounds extrusion orifice extensions configured as a raised circular ridge and associated orifice protrusions, through which the extrusion orifices extend to the die face.
Another object of the present invention is to provide a thermally insulated die plate assembly in accordance with the preceding object in which the insulation air pocket or air chamber is formed by machining or cutting out a cavity in the downstream side of a die plate body leaving in place the raised circular ridge. The cavity is closed by a cover plate having a counterbore sized to match the extrusion orifice extensions and with holes to match the distal ends of the orifice protrusions.
Still another object of the present invention is to provide a thermally insulated die plate assembly in accordance with the two preceding objects in which the raised ridge has a trapezoidal shape in vertical cross-section to aid in channeling heat to the orifice protrusions and thus maintain the process melt at a desired temperature in the extrusion orifice at the die face.
A still further object of the present invention is to provide a thermally insulated die plate assembly in accordance with the preceding three objects in which the insulation air pocket or air chamber is configured to follow and surround the raised circular ridge and associated orifice protrusions so as to retain the heat in the raised ridge and orifice protrusions in order to maintain the process melt at a desired temperature in the extrusion orifices at the die face.
It is another object of the present invention to provide a thermally insulated die plate assembly in accordance with the preceding objects in which the insulation air pocket or air chamber is vented to the atmosphere outside of the die plate assembly to maintain the temperature and pressure conditions inside the cavity or chamber equilibrated to the atmosphere.
It is a further object of the present invention to provide a thermally insulated die plate assembly in accordance with the preceding objects in which the die plate body is configured in a single-body construction.
Yet another object of the present invention is to provide a thermally insulated die plate assembly in accordance with the preceding objects in which the die plate body is configured in a two-piece construction including a removable center die insert surrounded by a die plate outer ring.
Still yet a further object of the present invention is to provide a thermally insulated die plate assembly in accordance with the preceding object in which the removable insert and the die plate outer ring can be individually and/or separately heated or thermally regulated.
A final object to be set forth herein is to provide a thermally insulated die plate assembly which will conform to conventional forms of manufacture, will have improved strength and robustness, will maintain the insulating air pocket tightly sealed to provide improved thermal insulation in operation, and will be economically feasible, long-lasting and relatively trouble-free in use.
These together with other objects and advantages which will become subsequently apparent reside in the details of construction and operation as more fully hereinafter described and claimed, reference being had to the accompanying drawings forming a part hereof, wherein like numerals refer to like parts throughout.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 is a schematic vertical sectional view of a first embodiment of a thermally insulated die plate assembly in accordance with the present invention in which the assembly is of a single body construction.
FIG. 2 is an enlarged schematic vertical sectional view illustrating further details of the components around an upper extrusion orifice for the embodiment shown in FIG. 1 .
FIG. 3 is a partial cut-away perspective view of the die plate assembly shown in FIG. 1 , illustrating the association of the various components.
FIG. 4 is a schematic vertical sectional view of a second embodiment of a thermally insulated die plate assembly in accordance with the present invention in which the assembly is of a two-piece construction, including a removable center die insert and die plate outer ring.
FIG. 5 is a schematic vertical cut-away side perspective view of one-half of the removable center insert of the die plate assembly shown in FIG. 4 .
FIG. 6 is an enlarged view of the components shown in FIG. 5 , illustrating the detail of the air chamber around the raised circular ridge and the orifice protrusion.
FIG. 7 is a schematic top perspective view of one-half of the removable center insert of the die assembly shown in FIG. 4 , showing the design of the raised circular ridge and the orifice protrusions associated therewith.
FIG. 8 is a schematic bottom perspective view of a cover plate which, when turned over, is assembled onto the top of the removable center insert shown in FIG. 7 to form the air pocket or air chamber of the die plate assembly shown in FIG. 4 .
FIG. 9 is an enlarged schematic vertical section view showing the cover plate of FIG. 8 assembled onto the removable insert shown in FIG. 7 with the welds in place around the periphery of the cover plate and around the extrusion orifices, together with a hard face on the downstream surface of the cover plate.
FIG. 10 is an exploded schematic vertical section view of a thermally insulated die plate assembly similar to FIG. 4 in which the removable center insert includes a separate center heating coil.
FIGS. 11 a - g are a composite perspective view illustrating various configurations for the heat conducting protrusions in accordance with the present invention.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
Although only preferred embodiments of the invention are explained in detail it is to be understood that the invention is not limited in its scope to the details of construction and arrangement of components set forth in the following description or illustrated in the drawings. The invention is capable of other embodiments and of being practiced or carried out in various ways. Also, in describing the preferred embodiments, specific terminology will be resorted to for the sake of clarity. It is to be understood that each specific term includes all technical equivalents which operate in a similar manner to accomplish a similar purpose.
Referring to the drawings, FIGS. 1 , 2 and 3 illustrate one embodiment of the present invention associated with components of a pelletizer, such as an underwater pelletizer. The pelletizer includes an inlet housing 12 from a melting and/or mixing apparatus (not shown). The inlet housing includes a passageway 14 for molten material or other extrudate (hereinafter collectively referred to as “process melt”) that can include organic materials, oligomers, polymers, waxes, and combinations thereof without intending to be limited. Nose cone 16 directs the process melt to the upstream side of the single-body or one-piece die plate assembly constructed in accordance with the present invention and generally designated by reference numeral 10 . The nose cone 16 can be attachedly connected to the die plate assembly by a threaded rod (not shown). The threaded rod is screw threaded at one end into threaded bore 18 of nose cone 16 and at its distal end into threaded bore 20 of die plate 10 . Alternately, the nose cone 16 can be rigidly affixed to or unitary with the die plate 10 and need not be attachedly connected as herein described.
The single-body die plate assembly 10 contains a multiplicity of extrusion orifices 22 concentrically arranged singly or in multiples thereof in at least one annular ring that extends from the upstream face 24 to the downstream face or die face 26 of the die plate assembly 10 . A plurality of cutter blades 28 mounted on a rotatably driven cutter hub 30 in a cutting chamber (not shown) cut the extruded and at least partially solidified process melt extruded through orifices 22 into pellets at the cutting surface of the die face 26 . The pellets thusly formed are transported mechanically, pneumatically, hydraulically, or in combinations thereof to downstream processing, such as a dewatering system, drying equipment and the like.
The die plate assembly 10 is made up with two major components, die plate body 36 and cover plate 38 . A thin, continuous air pocket or air chamber 32 , parallel to die face 26 , is formed between the downstream side of the die plate body 36 and the upstream side of the cover plate 38 . In order for the extrusion orifices 22 to pass through the air chamber 32 , the extrusion orifices 22 extend through a raised circular ridge 34 formed in the downstream face of the die plate body and orifice protrusions 35 positioned on top of the ridge 34 (see FIG. 2 ), which together define the extrusion orifice extensions, generally designated by reference numeral 31 .
The upstream side of the cover plate 38 is provided with a generally circular counterbore 76 which conforms to and receives the circular array of orifice protrusions 35 . The counterbore 76 has outlet holes 39 which match the orifice protrusions 35 and form the distal ends 68 of the extrusion orifices 22 . The distal ends 70 of protrusions 35 then fit into the matching holes 39 in the cover plate 38 . The raised circular ridge 34 and associated heat conducting protrusions 35 , which encompass and provide heat to the distal end 68 of the extrusion orifices 22 , thus extend through and are surrounded by the air chamber 32 .
In order to form the air pocket or air chamber 32 , the central area of the downstream face 26 of die plate body 36 is machined or cut out to provide a circular recess or cavity 33 . The cavity 33 extends beyond the extrusion orifices 22 and is preferably formed with the raised circular ridge 34 in place, although the ridge could be formed as a separate piece and welded or otherwise attached to the bottom of the cavity 33 . The raised ridge thus divides the cavity 33 into an annular outer section 72 and an inner circular section 74 . The orifice protrusions 35 can also be formed during the machining process and thus be integral with the raised ridge 34 . However, preferably, the protrusions 35 are configured as separate collars of the same material as the die plate body 36 (and ridge 34 ) and are adhered to the top of ridge 34 as by welding or the like.
Circular cover plate 38 with holes 39 matching the distal ends 70 of the orifice protrusions 35 overlays the recess cavity 33 and is attachedly connected to die plate body 36 and to orifice protrusions 34 by brazing, welding, or similar technique known to those skilled in the art. Preferably, the cover plate 38 is constructed of an abrasion and corrosion resistant metal and, more preferably, is constructed of nickel steel. Similarly, attachment of the cover plate 38 to the die plate body 36 and to the distal ends 70 of orifice protrusions 35 is preferably achieved by welding and, more preferably, is achieved by nickel steel welding. Weldments 40 and 42 are preferentially made at circumferential grooves 77 peripherally about the cover plate 38 and into the cover plate holes 39 which are sized to expose a portion of the distal end 70 of protrusions 35 for welding or the like. To assist in rigidifying the cover plate 38 to the die plate body 36 , the peripheral edge 80 is designed to rest on ledge 82 cut into the downstream face of the die plate body. The peripheral edge 80 and the die plate body 36 have opposing chamfers which form groove 77 for receiving the peripheral weld 40 and maintain the peripheral edge 80 solidly against the ledge 82 .
The surface of the cover plate 38 and thus the downstream face 26 is preferably coated with a chemical, abrasion, corrosion, and wear resistant coating 60 as described hereinbelow. Once weldment 42 is in place, along with wear resistant coating 60 , if included, the distal end 68 of the extrusion orifices 22 can be completed by machining from the downstream side of the die plate assembly, such as with an EDM machine or otherwise as known by those skilled in the art, thus clearing any weld 42 and coating 60 from the extrusion orifice distal end 68 .
The raised circular ridge 34 is preferably trapezoidal in vertical cross-section to aid in channeling heat to the orifice protrusions 35 , which transfer the heat from the raised ridge to the die face 26 , thus maintaining the process melt at a desired temperature in the extrusion orifice distal end 68 , and to assist in creating a robust thermally insulated die plate assembly. While a trapezoidal cross-section for the raised circular ridge is preferred, other shapes for the ridge cross-section could be designed by those skilled in the art in order to achieve the foregoing goals, as contemplated by the present invention.
The assemblage as heretofore described encloses the circular recess 33 to form the thin, continuous thermal air pocket or air chamber 32 which is preferably connected to the surrounding atmosphere by at least one vent tube 44 . Variation in temperature and/or pressure within the die plate body 10 equilibrates by expansion or contraction of air into and through vent tube 44 thus avoiding vacuum formation and/or pressure build-up which could potentially lead to undesirable deformation of the downstream face 26 . Raised ridge 34 and orifice protrusions 35 through-penetrate the atmospheric air pocket 32 to provide continuous and more uniform heating along the length of the through-penetrating extrusion orifices 22 , and the weldment of their distal ends 70 to the openings 39 in the cover plate 38 serve to strengthen and maintain the planar shape of the cover plate.
As best seen in FIG. 2 the air pocket or chamber 32 is generally parallel to the die face 26 , but extends into the counterbore 76 , as at 78 , in order to surround the outer periphery of each orifice protrusion 35 . The thickness of the air chamber 32 can vary at different locations but should be at least about 0.05 mm to no more than about 6.0 mm deep, and preferably is about 0.5 mm to about 1.0 mm deep. Stated another way, the thickness of the air chamber 32 in the dimension parallel to the die face is preferably about 5% to about 10% of the thickness of the die plate assembly 10 .
Cover plate 38 preferably includes at least one circumferential expansion groove 62 on the portion of the cover plate 38 that extends beyond the circular array of extrusion orifices 22 . More preferably, at least one circumferential expansion groove 62 is on each side of cover plate 38 outside the array of extrusion orifices. Still more preferably, a multiplicity of circumferential expansion grooves 62 are positioned staggeringly on opposite sides of the cover plate 38 . The circumferential expansion grooves 62 can be of any geometry in profile including but not limited to square, angular, rounded, and hemispherical and the multiplicity of grooves on cover plate 38 can be of similar or differing geometries. Preferably, the circumferential grooves are rounded in profile as shown in FIG. 2 .
As described previously, the raised circular ridge 34 of the extrusion orifice extensions 31 is preferably unitary with die plate body 36 and therefore of the same chemical composition. The orifice protrusions 35 , on the other hand, are formed as separate collars and attachedly connected to the top of the raised ridge as by brazing, welding, and any similar mechanism known to those skilled in the art. The protrusions 35 can be of similar or differing composition to the ridge 34 and die plate body 36 of which the composition can include but is not limited to tool steel, hardened tool steel, stainless steel, nickel steel, and the like.
Turning to FIGS. 4 through 9 there is shown a two-piece die plate assembly, generally designated by reference numeral 100 , in accordance with a second embodiment of the present invention. The die plate assembly 100 includes a die plate outer ring 105 and removable center die insert 106 . Since many of the components of the die plate assembly 100 are the same as or very similar to the components of the die plate assembly 10 , the same reference numerals are carried forward from the latter for corresponding components in the former, but preceded by the “1” digit.
Similarly to the FIG. 1 embodiment, the die plate assembly 100 is attachedly connected to an inlet housing 112 from a melting and/or mixing apparatus (not shown). The inlet housing 112 includes a passageway 114 for process melt as heretofore described. Nose cone 116 directs the process melt to the upstream side 124 of the removable insert 106 to which it is attachedly connected by threaded rod (not shown). The threaded rod is screw threaded at one end into threaded bore 118 of nose cone 116 and at its distal end into threaded bore 120 of removable insert 106 .
The removable center die insert 106 includes a multiplicity of extrusion orifices 122 concentrically arranged singly or in multiples thereof in at least one annular ring that extends from the upstream face 124 to the downstream face 126 of removable insert 106 . A plurality of knife blade assemblies 128 mounted on a rotatably driven cutter hub 130 in a cutting chamber (not shown) cut the extruded and at least partially solidified process melt into pellets. The pellets thusly formed are transported mechanically, pneumatically, hydraulically, or in combinations thereof to downstream processing as before.
The central areas of the downstream face 126 of insert 106 are machined or cut out to provide a central circular recess or cavity 133 in the same manner as described above for the first embodiment, including raised circular ridge 134 and orifice protrusions 135 , which together define the extrusion orifice extensions 131 and encase the extrusion orifices 122 through the cavity 133 . A circular cover plate 138 with holes 139 matching the distal ends 170 of the orifice protrusions 135 overlays the recess cavity 133 to form a thin, continuous thermal air pocket or air chamber 132 across the insert 106 generally parallel to the die face 126 . The upstream side of cover plate 138 is also provided with a generally circular counterbore 176 which includes the outlet holes 139 and conforms to and receives the circular array of orifice protrusions 135 . The extrusion orifice extensions 131 made up of the raised circular ridge 134 and orifice protrusions 135 serve to channel and provide heat from the insert body 136 to the distal end 168 of the extrusion orifices 122 , while at the same time the extensions 131 are thermally insulated from cover plate 138 by the air chamber 132 which surrounds the orifice extensions 131 .
The cover plate 138 is attachedly connected to the periphery of the insert body 136 and to orifice protrusion distal ends 170 by brazing, welding, or similar technique known to those skilled in the art. Preferably, the cover plate 138 is constructed of an abrasion and corrosion resistant metal and more preferably is constructed of nickel steel. Similarly, attachment of the cover plate 138 to the insert body 136 and orifice protrusion distal ends 170 is preferably achieved by welding and, more preferably, is achieved by nickel steel welding. Weldments 140 and 142 are preferentially made at circumferential grooves 176 peripherally about the cover plate 138 and onto protrusion distal ends 170 at weldment locus 142 (see FIG. 9 ). The surface of the cover plate 138 and thus the downstream face 126 of die insert 106 is preferably coated with a chemical, abrasion, corrosion, and wear resistant coating as described hereinbelow.
The circular cavity 133 is preferably connected to the surrounding atmosphere by at least one vent tube 144 which passes through both the removable die insert 106 and the die plate outer ring 105 . Variation in temperature and/or pressure within the air chamber 132 equilibrates by expansion or contraction of air into and through vent tube 144 , thus avoiding vacuum formation and/or pressure build-up which could potentially lead to undesirable deformation of the downstream face 126 . Raised ridge 134 and orifice protrusions 135 through-penetrate the atmospheric air pocket 132 to provide continuous and more uniform heating along the length of the extrusion orifices encompassed therewithin. The configuration of the raised circular ridge 134 , preferably trapezoidal in vertical cross-section, serves to channel heat to the orifice protrusions 135 in order to assist in maintaining the process melt in protrusions 135 at the desired temperature prior to exit from the distal end 168 of extrusion orifices 122 . Weldment of the periphery of the cover plate 138 to the insert 106 and of the distal ends 170 of the orifice protrusions 135 in the holes 139 of the cover plate 138 serve to strengthen and rigidify the cover plate in its planar shape, as further described in the next paragraph.
The insert body 136 and cover plate 138 are designed with a multitude of complementary abutting surfaces to improve the effectiveness of the weldments 140 and 142 . This in turn increases the rigidity of the assembled cover plate 138 onto the insert body 136 , improves the sealing of the air chamber 132 and provides an overall robust die plate assembly 110 . First, the machined cutout 133 includes peripheral ledge 182 (see FIGS. 6 and 7 ) which receives a peripheral edge 184 of the cover plate 138 to define the periphery of the air chamber 132 . The complementary abutting surfaces of the insert body peripheral ledge 182 and cover plate peripheral edge 184 are then held together by weldment 140 . Second, holes 139 of cover plate 138 include a countersunk section 186 on their upstream side (see FIG. 8 ) which forms a ledge 188 that engages the outer periphery of the distal ends 170 of the orifice protrusions 135 (see FIG. 9 ). These complementary abutting surfaces 170 and 188 are adhered together by weldments 142 at each extrusion orifice 168 .
The circular counterbore 176 in cover plate 138 differs from the circular counterbore 76 in cover plate 38 in that the former is contoured with tapered side walls 190 to more closely follow the contour of the tapered sides 192 of the raised ridge 134 . By more closely following the contour of raised ridge 134 , the counterbore 176 and resultant air chamber 132 provide additional insulation about the ridge 134 and the associated orifice protrusions 135 . In contrast, the circular counterbore is more rectangular in cross-section and is positioned adjacent the raised ridge 34 without contouring dimensionally with its tapered sides 92 . It is understood that the contours of the circular counterbore 176 adjacent raised circular ridge 134 and of the counterbore 76 adjacent raised ridge 34 are only two non-limiting examples and other designs comparable to and intermediate between these two configurations are encompassed by the present invention. Use of the rectangular counterbore 76 and tapered counterbore 176 can be applied to the solid-body die plate assembly 10 as well as to the two-piece die plate assembly 100 .
If desired, cover plate 138 can be provided with circumferential grooves, such as grooves 62 illustrated and described above for cover plate 38 .
Heating and/or cooling processes can be provided by electrical resistance, induction, steam or heat transfer fluid as has been conventionally disclosed for the single-body die plate 10 as well as the two-piece die plate assembly 100 . As shown in FIGS. 1 and 4 , the die plate body 36 and insert body 136 are each respectively heated by radial electric heaters 46 and 146 positioned in radial slots 47 such as shown in FIG. 3 , as well known in the art. In the two-piece die plate assembly 100 shown in FIG. 4 , the removable insert 106 and the die plate outer ring 105 can each be separately heated by similar or differing mechanisms.
For example, FIG. 10 illustrates a partially exploded view of a die plate assembly, generally designated by reference numeral 200 , which includes a center-heated removable insert 208 . Since many of the components of the die plate assembly 200 are the same as or very similar to the components of the die plate assembly 100 , the same reference numerals are carried forward from the latter for corresponding components in the former, but preceded by the “2” digit instead of the “1” digit.
The die plate assembly 200 thus includes a die plate body, generally designated by reference numeral 212 , comprised of die plate outer ring 205 surrounding center-heated removable insert 208 . The electrical resistance coil 250 is contained in an annular recess or cavity 252 centrally located within the insert 208 adjacent to the upstream face 224 . Nose cone 216 is attachedly connected to removable insert 208 through use of a threaded rod (not shown) that is screw threaded at one end into threaded bore 218 of nose cone 116 and at its distal end into threaded bore 220 of removable insert 208 in a manner similar to that shown in FIGS. 1 and 4 . When attached, nose cone 116 closes off cavity 252 with coil 250 positioned therein. Other methods of fastening are well-known to those skilled in the art. The removable insert 208 can thus be heated separately as by electric radial heaters 146 hereinbefore described in connection with the die plate assembly 100 shown in FIG. 4 .
The downstream face 26 , 126 of die plate assembly 10 , 100 , 200 can be in one plane as shown in FIG. 1 but preferably is of two parallel planes as indicated by the encircled area 66 , 166 in FIGS. 2 and 9 , wherein the area adjacent to the outlets 68 , 168 of extrusion orifices 22 , 122 is raised in a plane parallel to that of the downstream face 26 , 126 . The elevation of the plane above that of the downstream face 26 should be at least approximately 0.025 mm, and preferably is at least approximately 0.50 mm.
Similarly, the recess cavity 33 , 133 is at least approximately 1.05 millimeters in depth, preferably on the order of 5.0 mm to 7.0 mm. The thickness of the cover plate 38 , 138 should be on the order of 1.0 mm to 8.0 mm, preferably about 6.0 mm in order to provide a thickness of the air chamber 32 , 132 on the order of about 0.05 mm to about 6.0 mm, and preferably about 0.5 mm to about 1.0 mm.
The surface of the downstream face 26 , 126 is preferably subjected to a chemical, abrasion, corrosion, and/or wear resistant treatment, i.e., “surface treatment,” in the annular area generally defined by the array of extrusion orifice outlets 68 , 168 and identified by the numeral 60 , 160 in FIGS. 2 and 9 . This annular area includes the cutting face 63 , 163 where the cutting blades engage the die face. The surface treatment should be at least approximately 0.025 mm, and preferably is at least approximately 0.50 mm. The composition of the surface treatment 60 , 160 can be different in the planar area surrounding the extrusion orifice outlets 68 , 168 than that on other parts of the downstream face 26 . Preferably, the surface treatment 60 , 160 is the same on all faces and can involve one, two, or a multiplicity of processes inclusive and exemplary of which are cleaning, degreasing, etching, primer coating, roughening, grit-blasting, sand-blasting, peening, pickling, acid-wash, base-wash, nitriding, carbonitriding, electroplating, electroless plating, electroless nickel dispersion treatments, flame spraying including high velocity applications, thermal spraying, plasma treatment, electrolytic plasma treatments, sintering, powder coating, vacuum deposition, chemical vapor deposition, physical vapor deposition, sputtering techniques, spray coating, and vacuum brazing of carbides.
Surface treatment for all surfaces, other than the cutting face, includes flame spray, thermal spray, plasma treatment, electroless nickel dispersion treatments, high velocity air and fuel modified thermal treatments, and electrolytic plasma treatments, singly and in combinations thereof. These surface treatments metallize the surface, preferably fixedly attach metal nitrides to the surface, more preferably fixedly attach metal carbides and metal carbonitrides to the surface, and even more preferably fixedly attach diamond-like carbon to the surface, still more preferably attach diamond-like carbon in an abrasion-resistant metal matrix to the surface, and most preferably attach diamond-like carbon in a metal carbide matrix to the surface. Other ceramic materials can be used and are included herein by way of reference without intending to be limiting. These preferred surface treatments can be further modified optionally by application of conventional polymeric coating on the downstream face 26 , 126 distal from the extrusion orifice outlet 68 , 168 . The polymeric coatings are themselves non-adhesive and of low coefficient of friction. Preferably the polymeric coatings are silicones, fluoropolymers, and combinations thereof. More preferably the application of the polymeric coatings requires minimal to no heating to effect drying and/or cure.
FIG. 11 illustrates additional configurations of extrusion orifices and orifice protrusions projecting from the raised circular ridge. FIG. 11 a illustrates concentric rings of orifice protrusions 302 projecting from ridge 303 in staggered formation, each protrusion having a single extrusion orifice 304 . The extrusion orifices can be oriented in a multiplicity of groups or pods 306 as illustrated in FIG. 11 b for a grouping of two extrusion orifices 308 , FIG. 11 c for a grouping of three extrusion orifices 310 , FIG. 11 d for a cluster of four extrusion orifices 312 , FIG. 11 e for a pod of sixteen extrusion orifices 314 , FIG. 11 f for a multiplicity of thirty-seven extrusion orifices 316 , and FIG. 11 g for a multiplicity of sixteen extrusion orifices 318 .
Groups, clusters, pods, and a multiplicity thereof can be arranged in any geometric configuration including but not limited to oval, round, square, triangular, rectangular, polygonal, and combinations thereof. The geometries of the orifice protrusions can be further rounded, angled, and chamfered and can contain any number of a multiplicity of orifices. Orientation of the geometries containing the multiplicity of orifices can be circumferentially and parallel to the arc, circumferentially and perpendicular to the arc, staggered and alternatingly circumscribing the arc and any combination thereof. Furthermore, the geometric orientation may conform to the arc as in a kidney shape or comma-shape. A multiplicity of concentric rings, at least one or more, of extrusion orifices can include extrusion orifices, singly or a multiplicity thereof, that can be arranged in a linear array, alternatingly, staggeredly, and any combination thereof relative to the other concentric rings in accordance with the instant invention.
Further, while the outlet of the extrusion orifices 22 , 122 , such as outlet 68 in FIG. 2 and outlet 168 in FIG. 9 , is preferably round, the outlets can be of any geometry including but not limited to round, oval, square, rectangular, triangular, pentagonal, hexagonal, polygonal, slotted, radially slotted and any combination thereof. A multiplicity of extrusion orifice outlets 68 can be of different geometry in a particular protrusion 35 .
Further, the extrusion orifice extensions may include more than one raised circular ridge 34 , 134 , depending upon the arrangement of the extrusion orifices and the width of the cutting blade. In addition, although at least one raised circular ridge 34 , 134 is preferred to form the base of the extrusion orifice extensions 31 , 131 , it may be possible to design the extensions 31 , 131 without any raised ridge. In such circumstances, the orifice protrusions 35 , 135 would extend from the base of cutout 33 , 133 to the respective opening 68 , 168 of the cover plate 38 , 138 .
The foregoing is considered as illustrative only of the principles of the invention. Numerous modifications and changes will readily occur to those skilled in the art. Therefore, it is not desired to limit the invention to the exact construction and operation shown and described, and, accordingly, all suitable modifications and equivalents may be resorted to, falling within the scope of the invention.
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An insulated die plate assembly for use in underwater pelletizing and other granulation processes includes a thin, continuous air chamber formed across the plate assembly generally parallel to the die face such that the heated upstream portion of the die plate assembly is thermally insulated from the downstream portion. The air chamber is atmospherically equilibrated by venting the air chamber to the atmosphere. The plurality of extrusion orifices, either individually or in groups, are formed in extrusion orifice extensions that extend through the insulation chamber so that the process melt to be granulated can pass therethrough. The orifice extensions and the components forming the air chamber around the orifice extensions channel heat along said extensions to maintain the process melt therein at a desired temperature, to help rigidify the die plate assembly and to better seal the air chamber.
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BACKGROUND OF THE INVENTION
The present invention relates to an irrigator for colostomy patients comprised of a bag for receiving flushing liquid and a drainage line.
Such an irrigator is used by colostomy patients in order to perform an intestinal flushing or irrigation. With a careful irrigation a secretion-free period of up to 48 hours may be achieved whereby this secretion-free period depends greatly on the remaining length of the patient's intestine and further patient-specific parameters.
The commonly used irrigators are comprised essentially of a bag which at its upper portion is provided with at least one suspending eye. The bag is further provided with a funnel-shaped means so that filling with tap water is possible without difficulties. A drainage line is connected to the lower portion of the bag which widens into a cone and can be closed off with a clamp, for example, a roller clamp. For performing an intestinal flushing the bag is filled with water and suspended from a wall hook so that due to the elevational difference between the bag and the cone a pressure is generated which is sufficient for the intestinal flushing process.
With this known irrigator it is disadvantageous that a suspension device must be provided at a suitable location. This cannot always be ensured, for example, when the colostomy patient is traveling. Improved irrigators are provided with a check valve at the water inlet, however, when the bag is accidentally dropped from the suspension device and is accidentally impacted at the water inlet a failure of the check valve may not be prevented because, on the one hand, it must be freely movable in order to be opened by the inflowing water and, on the other hand, it is incorporated into the essentially very flexible bag.
For eliminating the disadvantages of the actually very flexible and universally employable irrigators, an electric irrigator has been developed which operates according to a somewhat different principle: instead of a bag a water tank is provided. A stable and stiff housing contains the water tank, a controllable pump unit and electronic controls as well as a voltage supply. The electronic controls regulate the output of the pump. In the known device the voltage supply is in the form of accumulators which must be recharged after each flushing process.
This electric irrigator is essentially independent of any location so that a suspension device is not required. Furthermore, the shut-off clamp for the drainage line is eliminated. However, the device is so heavy that it has not been successful in practice because especially when traveling an additional weight load of, for example, more than 1 kilogram is an unbearable load for a colostomy patient without traveling companion. Furthermore, the accumulators of the device are depleted after a one time use. It is possible to recharge the accumulator with a respective recharging device, however, this is an additional load that must be carried by the colostomy patient. Also, in order to be able to recharge the accumulators, the colostomy patient, when traveling is dependent on a respective electrical outlet, with the recharging process commonly requiring about 10 hours. Furthermore, due to the well-known properties of accumulators the recharging process should be initiated immediately after completion of the irrigation which further impairs the traveling flexibility of the colostomy patient.
The operation of such an electric irrigator solely with batteries, respectively, replacement batteries, is not suitable for a plurality of other reasons.
It is therefore an object of the present invention to provide an irrigator of the aforementioned kind which combines a more flexible handling with a higher safety and reliability without requiring additional costs or substantial weight additions.
BRIEF DESCRIPTION OF THE DRAWINGS
This object, and other objects and advantages of the present invention, will appear more clearly from the following specification in conjunction with the accompanying drawing. It is shown in:
FIG. 1 an inventive irrigator schematically represented in cross-section;
FIG. 2 the irrigator of FIG. 1 with a volume-increasing fold.
SUMMARY OF THE INVENTION
The irrigator of the present invention comprises a bag for receiving a flushing liquid, the bag having a membrane dividing the bag into an air chamber on one side and a closable flushing liquid chamber on the other side; a drainage line connected to the bag; and a pump connected to the air chamber for pressurizing the same. The irrigator further comprises a hose connecting the pump and the sir chamber. Preferably, the pump is a ball-shaped hand pump.
Advantageously, the irrigator further comprises an outlet valve, for reducing the pressure in the air chamber, connected to one of the elementsselected from the group consisting of the sir chamber, the hose, and the pump.
In an advantageous embodiment of the present invention, the drainage line further comprises a valve for the flushing liquid. Preferably, the valve is a pressure reducing valve preset to a maximum release pressure, with the release pressure adjustable between zero and said maximum release pressure.
Preferably, the irrigator further comprises an inlet line or inlet hose connected to the flushing liquid chamber the inlet hose having a shut-off valve. Expediently, the inlet hose and the drainage line are both guided into the flushing liquid chamber and are connected to one another, preferably by a T-connector.
Advantageously, the membrane has a first and a second end position, whereinin the first end position a volume of the flushing liquid chamber is at a minimum and a volume of the air chamber is at a maximum and wherein in thesecond end position the volume of the flushing liquid chamber is at a maximum and the volume of the air chamber is at a minimum. The membrane ismovable between the first and the second end position whereby the maximum volumes of the flushing liquid chamber and the air chamber are essentiallyidentical and especially the minimum volumes of the flushing liquid chamberand the air chamber are essentially identical.
The irrigator is preferably made of a flexible, essentially non-elasticallystretchable material and has at least one volume-increasing fold on either one of the sides. Preferably, the flexible, essentially non-elastically stretchable material is selected from the group consisting of polyethyleneand polyvinyl chloride.
Expediently the bag on the side having the flushing liquid chamber has a filling level indicator and is transparent.
The inventive irrigator has the advantage that it may be used without a suspension device. This means that an intestinal flushing may be performedwithin a restroom that is not provided with such a suspension device. The weight of the inventive irrigator however corresponds practically to the weight of the commonly used manual irrigators because the additional partsare lightweight and the comparatively large check valve as well as the funnel-shaped water inlet of the known devices are no longer needed, respectively, may be replaced by an inlet hose.
It is furthermore expedient that the fact that the known irrigator bags must have a certain pressure resistance or stability in order to prevent breakage when dropped can be employed for the present invention. This pressure stability is now inventively used to generate a pressure via the inventive membrane which divides the bag into two chambers so that the bagis usable independent of its position. An electric system which is especially dangerous in areas with water supplies can be entirely omitted by providing a small hand pump for generating the required pressure. The pressure generated within the air chamber acts via the membrane in the bagonto the flushing liquid chamber. Due to the elasticity of the air volume apressure reserve is furthermore provided so that even at the end of the flushing cycle a sufficient pressure is still present.
Especially advantageous in this context is the use of a pressure reducing valve that in a known manner may be inserted as a small and lightweight component into the drainage line. The pressure reducing valve may be preset to a fixedly determined maximum pressure of, for example, 250 mbar which in practice may be reduced to a value of for example 100 mbar. During the entire flushing cycle the desired flushing pressure is present whereby with the aid of the hand pump a pressure of substantially more than 250 mbar may be generated without difficulties.
Since the flushing liquid chamber is closable, the air chamber may be pressurized without regard to its position. Thus, with respect to the known irrigators, a decisive advantage results based on the closibility ofthe bag, while on the other hand the generation of the required pressure isessentially possible with any desired manual means.
In this context, the use of a manual ball-shaped pump is preferred since onthe one hand it strengthens the hand muscles of the patient and thereby contributes to his physical fitness, and on the other hand for its actuation the use of any abdominal muscles is not required.
The inventive irrigator favorably compares in its functionality to the known electric irrigator. Due to its simple design, its reliability is increased and the accessibility for cleaning is substantially improved.
Furthermore, the inventive irrigator is advantageous with respect to its packing volume because the inventive bag is easily folded, and the manual ball-shaped pump is furthermore elastic. Accordingly, the only hard components of the inventive irrigator are the hoses and the pressure reducing valve which is also made of plastic material and which is furthermore very small. The weight of the inventive irrigator is thus onlya fraction of the weight of an electric irrigator so that considerable handling advantages result.
The material properties of plastic materials such as polyethylene, polypropylene, and polyvinyl chloride may advantageously be used for the function of the device. The wall thickness of the bag to be used corresponds essentially to the wall thickness of the known irrigator whereby the air chamber may be pressurized to its full extent without causing an overextension of the bag. Accordingly, a slight buffering effect of the elastic air volume as well as of the slightly elastic bag material may be utilized. To further simplify the design the manual ball-shaped pump may be constructed such that the pressure that can be generated with it, including a certain safety reserve, does not exceed themaximum pressure of the air chamber.
From German Gebrauchsmuster 83 03 620.2 a device for infusion or transfusion of bodily fluids is known that operates with a membrane and a ball-shaped pump. This device however is provided with a solid tank so that the desired elasticity effect, which may be further increased by the volume-increasing folds of the bag, cannot be utilized. Since furthermore no drainage line as the one used in the present invention is provided, butthe feed as well as the removal of blood takes place via an outlet providedat the cover, there is also no pressure regulating valve provided. Furthermore, this device is designed for transfusion, respectively, reinfusion of blood or plasma replacing substances and is not an irrigator.
Expediently, the inlet line or hose and the drainage line may be connected to the same connector at the flushing fluid chamber whereby it is expedient to provide only one penetration within the wall of the bag and to combine the inlet line and drainage line by a T-connector. This construction has the advantage that only one discontinuity with respect tostiffness exists between the bag and the lines. Thereby, locations of high loads on the materials during folding of the bag are minimized.
According to a further embodiment of the present invention it is suggested to combine the inlet hose and the drainage line. For this purpose, the pressure regulating valve within the drainage line is provided with a bypass which during the drainage cycle is closed and only allows the filling of the bag when the control means is in the filling position. Withthis embodiment the material expenditure and the weight of the device may be further reduced.
It is understood that the inventive membrane is fused in an airtight and watertight manner to the plastic material of the bag. The flushing liquid chamber may have a maximum volume of, for example, two liters so that a sufficient amount of flushing liquid for a one-step flushing is provided. When the aforementioned combination of inlet hose and drainage line is notutilized, the inlet may be closed off by a simple shut-off valve.
It is especially advantageous when the hose connection for the bag is either a threaded or a plug connection. This allows for a relatively simple cleaning when the irrigator becomes soiled.
DESCRIPTION OF PREFERRED EMBODIMENTS
The present invention will now be described in detail with the aid of a specific embodiment utilizing the only drawing.
The inventive irrigator 10 according to the representation in the only drawing has a bag 12 which is comprised of a flushing liquid chamber 14 and an air chamber 16. The flushing liquid chamber 14 and the air chamber 16 are separated by a membrane 18. The membrane 18 is comprised of the same material as the outer walls 20 and 22 of the bag 12 and is fused to the outer walls 20, 22 about the entire circumference of the bag along theseams 24 and 26 schematically represented in FIG. 1. During fusing of the membrane 18 and the outer walls 20, 22, it must be ensured that the membrane 18 is essentially as bulgy as the two outer walls 20, 22. The bulgy design of the membrane as well as of the two outer walls has the advantage that for the folding of the bag these three layers can be placedonto one another in a fitted manner so that the packing volume is extremelysmall.
Laterally staggered, however oppositely arranged relative to one another, aconnector is provided for each of the chambers 14 and 16. A connector 28 ofthe flushing liquid chamber 14 is provided for the connection to the hose-like inlet 30 and the drainage line 32. A connector 34 of the air chamber 16 is provided for connecting the pump 36 thereto. In the shown embodiment the pump is in the form of a manual ball-shaped pump. The pump 36, in a known manner, is provided at both ends with a check valve so thata repeated pressing and releasing of the pump volume of the elastic pump 36results in the desired pumping action. The thus pumped air is introduced via an air hose 38 and connector 34 into the air chamber 16.
In the represented embodiment the pump 36 is connected via a plug connection 40 to the air hose 38. For venting the air chamber 16, for example, when the irrigator 10 must be folded for transporting purposes, or when the flushing fluid chamber 14 must be refilled with water, the plug connection 40 is simply disconnected so that the remaining air withinthe air chamber 16 is released. By manually applying a slight pressure ontothe air chamber 16, the air release may be further facilitated.
According to a further preferred embodiment of the invention it is suggested to provide the pump 36 at its air inlet 42 with a similar plug connection. By simply turning and again inserting the pump 36 into the plug connection 40 of the air hose 38, the remaining air within the air chamber 16 may be pumped out, which is especially expedient for traveling purposes.
As an alternative, a release valve which is not shown in the drawing may beprovided anywhere within the area of the air chamber 16, of the air hose 38and/or the pump 36.
It is furthermore preferable when the connectors 34 and 28 extend essentially within the extension of the membrane 18 close to the seam Thisis advantageous because the connectors 28 and 34 thus extend favorably within the extension of the folded bag 12 so that they do not bulge especially because they do not laterally overlap.
The flushing fluid chamber 14 in the area of the outer wall 22 is provided with a filling level indicator or markings 44 which indicate the filling level of the flushing liquid chamber 14 when the air chamber is completelyempty. It is understood that during the filling of the flushing liquid chamber 14 with water via the inlet hose 30 the plug connection 40 must beseparated so that the remaining air may be released from the air chamber 16unless it has already been pumped out.
The connector 28 is connected via a T-connector 46 to the inlet hose 30 which is provided with a simple shut-off valve 48. For filling the flushing liquid chamber 14 a slightly conical widened portion 50 of the inlet hose 30 is held under a non-represented water faucet. Remaining air within the flushing fluid chamber 14 is of no effect as long as it does not prevent the sufficient filling of the flushing liquid chamber 14. Air may be removed from the chamber 14 by simply turning over the bag 12 so that it can be released via the inlet hose 30.
The drainage line 32 is also connected to the T-connector 46. The drainage line 32 is provided with a pressure reducing valve 52. The pressure reducing valve 52 can be set to positions between zero and a maximum pressure M whereby the maximum pressure M is selected such that it remainsbelow the pressure which would be critical for an intestinal flushing. Between these two end positions the pressure reducing valve 52 is continuously adjustable.
The drainage line 32 is furthermore provided with a known conical portion 54 for connecting the drainage line to the colostomy opening. For filling the flushing liquid chamber 14 the pressure regulating valve 52 is set to zero so that the drainage line 32 is closed. After a sufficient filling level has been reached, the shut-off valve 48 is closed, the pump 36 is inserted with its pressure socket into the plug connection 40, which for example may be in the form of a bayonet plug connection, and the air chamber 16 is pressurized. As soon as the air chamber 16 is completely filled, the cone 54 is applied in the desired manner and the pressure reducing valve 52 is adjusted to the desired pressure with the aid of respective gauge markings. The flushing liquid 14 is then pressed out of the flushing liquid chamber 14 by the pressure that is applied via the membrane 18. After termination of the flushing step the flushing liquid chamber 14 has collapsed to such an extent that the membrane 18 is practically in contact with the outer wall 22 thereby leaving a minimum flushing liquid chamber volume. In contrast, the air chamber 16 still has a high pressure and the air chamber 16 has reached its maximum volume.
For a further filling the plug connection 40 is opened so that the air within the air chamber 16 may be released. For storing the irrigator 10 the remaining air is manually removed from the air chamber 16 so that the outer wall 20 concavely contacts the outer wall 22. This step may be facilitated by removing air via the suction connection of the pump 36. Theirrigator 10 is carefully cleaned and may be folded to a small packing volume.
It is understood that various embodiments of the aforementioned inventive design are possible without leaving the concept of the present invention. For example, the plug connection 40 may be replaced by a release valve which allows the release of the remaining air. Furthermore, it is possibleto connect the inlet hose 30 and the drainage line 32 at opposite ends of the flushing liquid chamber 14. The inlet hose 30 may also be provided with a commonly used funnel in order to facilitate the introduction of water. It is also possible to combine the inlet hose 30 with the drainage line 32 whereby the pressure regulating valve 52 is then bypassed by an integrated check valve in the counter direction which during water introduction opens easily. For this purpose the cone 54 is provided with arespective funnel so that a filling and operation of the irrigator 10 is possible via one single hose. As shown schematically in FIG. 2, the outer walls 20 and 22 of the bag 12 may have volume-increasing folds 20a, 22a.
The present invention is, of course, in no way restricted to the specific disclosure of the specification and drawings, but also encompasses any modifications within the scope of the appended claims.
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An irrigator for colostomy patients consists of a bag for receiving a flushing liquid, the bag having a membrane dividing the bag into an air chamber on one side and a closable flushing liquid chamber on the other side. A drainage line is connected to the bag, and a pump is connected to the air chamber is provided for pressurizing the same.
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This is a division of application Ser. No. 689,293, filed Jan. 7, 1985, now U.S. Pat. No. 4,636,328, which is a division of filed Ser. No. 597,127, filed Apr. 5, 1984, now U.S. Pat. No. 4,563,186.
BACKGROUND OF THE INVENTION
This invention relates generally to products useful for home laundering, and more particularly to a product which incorporates a prespotter with a detergent and having one or more of the following separate functions: detergency, fabric softening, stain removal, bleaching, and bluing; with the advantage being that both the detergent and the prespotter are uniquely packaged together as one product, negating the need to puchase and store separate products for each end use function, and also, unavoidably providing presentation of the prespotter to the detergent user at the time of laundering. Currently, products are available that combine several functions such as detergency/fabric softening, detergency/stain removal, etc. In addition, detergent products often come with use directions suggesting methods for using the product itself as a prespotter for pretreating stains or heavily soiled areas prior to laundering. These products are not nearly as desirable as the product comprising the present invention, which is unique in that it combines a detergent product with an effective self-contained prespotter, all in one package which facilitates storage, handling, use and effectiveness.
SUMMARY OF THE INVENTION
The invention contemplates a prespotter product, either liquid or solid, packaged in a dispensing container. The latter is uniquely combined with the container used to package the laundery detergent in such manner as to facilitate storage, handling and use of both the prespotter and the detergent at the time of laundering. The design is such that the prespotter dispensing container is not only attached to or integral with the detergent container, but can be detached from or otherwise used separately from the detergent product container. Such structural incorporation of the prespotter container into the detergent container is referred to herein as a "fitment", the various unusually advantageous forms of which can best be described by reference to the following drawings and descriptions. Detergent containers useful with the fitment can take the form of bottles or folding cartons as will appear.
The invention also contemplates or enables an improved method for laundering fabric, and which embodies the following steps:
(a) providing a first volume of detergent a portion of which is to be added to fabric laundry wash water,
(b) providing a second and smaller volume of a prespotter composition in close transported association with the first volume of detergent for presentation at the time of laundering,
(c) and separating some of said prespotter composition from such close association with the detergent volume and applying same to a soiled portion or portions of fabric that is thereafter laundered in the wash water containing said added portion of detergent.
As will appear, the step (c) is typically carried out just prior to addition of the fabric to the wash water at the time of laundering, the user being unavoidably alerted to carry out step (c) by virtue of steps (a) and (b). In addition, the method may be further enabled by the following steps:
(i) providing a container containing said first volume of detergent,
(ii) providing a sub-container containing said smaller volume of prespotter composition, and
(iii) mounting said sub-container in close transported association with said container.
The sub-container may take the unusually advantageous form of the "fitment" referred to, and to be described, as well as their methods of mountings on the principle container.
These and other objects and advantages of the invention, as well as the details of an illustrative embodiment, will be more fully understood from the following description and drawings, in which:
DRAWING DESCRIPTION
FIG. 1 is a vertical section showing a fitment adhered to the underside of a bottle overcap;
FIG. 2 is a vertical section showing a fitment cap seated on the bottle finish;
FIG. 3 is a section showing a fitment cap snapped into a friction sleeve in a bottle overcap;
FIG. 4 is a section showing a fitment thread connected to a double threaded bottle overcap;
FIG. 5 is a section showing a fitment flange engaging an indent on a bottle neck;
FIG. 6 is a section showing a tapered fitment wedged into a bottle tapered neck;
FIG. 7 is a section showing a fitment seated on a shelf formed in the bottle, as an indent or part of the bottle handle;
FIG. 8 is a section showing an inner prespotter container seated inside a flanged cup fitment which engages the top of the bottle finish;
FIG. 9 is a section showing a collar under a fitment cap engaging a bottle sealing surface, and the bottle cap sealing on a bottle shoulder;
FIG. 10 is a section showing a collar under a fitment cap engaging an indent on a bottle neck;
FIG. 11 is a section showing a fitment contained in a bottle snap-on overcap;
FIG. 12 is a section showing a fitment molded as an integral part of a bottle overcap;
FIG. 13 is a section showing an inverted fitment thread connected into a double threaded overcap;
FIG. 14 is a section showing a fitment thread connected over the bottle finish, the fitment having a cap attached to a rotary dispensing closure;
FIG. 15 is a section showing a fitment snap connected onto a plug in the bottle overcap;
FIG. 16 is a section showing a fitment received within a recess formed in the bottle as an indent or handle;
FIG. 17 is a vertical elevation showing a fitment molded as an integral part of a bottle, thereby forming a dual chambered container; and
FIG. 18 is a vertical elevation, partly in section, showing a fitment contained in a separate compartment that is an integral part of a folding carton used to hold the detergent.
DETAILED DESCRIPTION
Referring first to the drawings, FIG. 1 illustrates a first container in the form of a bottle 10 having a threaded neck 10a, the bottle containing flowable detergent 100 (as per example liquid detergent or flowable dry granules). The bottle has a removable cap 11 which in turn has a top horizontal wall 12 overlying the neck 10a, and a depending skirt 13 that extends in interfitting section with the neck. As shown, the skirt and neck have interfitting screw threads 14 and 15, other type connections being usable. The bottle, neck and cap may all consists of usable plastic material.
Also provided is a dispensing container as defined by fitment 16 containing a fabric prespotter composition 17. The fitment is indirectly carried by the bottle 10, and directly by the cap 11, to be readily detachable, at least in part, for dispensing the prespotter composition onto fabric as at the time of fabric laundering. Thus, for example, removal of the cap 10 to provide access to the detergent immediately presents the user with the fitment projecting from the removed cap, reminding the user that the fitment is ready to be used for application of prespotting composition to heavily soiled portions of the fabric, as at the precise time of laundering and in conjunction therewith, to obtain a resulting higher quality cleaning of the fabric.
As shown, the fitment has a sub-container 16a and a sub-container cap 16b, the latter being retained by the top wall 12, and specifically to its underside 12a as by means of adhesive, double tape, VELCRO stripping, or other means, each of which is represented by the layer 19. In use, the sub-container 16a may be removed from the cap, as by reverse rotation to unscrew threads 20a and 20b. The prespotter stick carried by sub-container 16a is then exposed for use. Note that the stick may be suitably advanced from the sub-container as by rotation of rotor 22 which serves to advance plunger 23 on a threaded stem 24. Other advancing means may be provided. The prespotter 17 may comprise a stick (as in U.S. Pat. No. 3,953,353) or a liquid, or a composition as defined subsequently herein.
The dispensing device itself can be made from plastic, glass, metal or other suitable material for holding a liquid or a solid. For a liquid prespotter, the product can delivered to the pretreatment area by a number of means including aerosol spray, pump spray, roll-on, squeeze bottle with suitable dispensing cap, etc. A solid prespotter can be packaged as described above in a push-up or screw-up container allowing the user to rub the prespotter solid on the pretreatment area and expose fresh material as needed.
The detergent container can be made from any suitable material including polyethylene, polypropylene, PVC and other plastics, glass, metal, or paperboard. In the case of paperboard, a suitable moisture barrier would be advantageous to maintain the product's effectiveness during storage and use.
In FIG. 2, the elements bearing the same numbers as in FIG. 1 are the same. The fitment cap 16b in addition has a radially projecting flange 23a extending over the rim 10b of the bottle neck 10a and retained on that rim by the underside 12a of the bottle cap 11. Thus, the fitment 16 is completely detachable from the cap 11 when the bottle is removed from the neck 10a.
In FIG. 3, the elements bearing the same numbers as in FIG. 1 are the same. The cap top wall 12 in addition has an integral sleeve 24b depending therefrom, within the bottle neck. The fitment cap 16b may extend telescopically into the sleeve bore 24a, and a flange 25 on the cap may removably snap into an annular recess 26 in the bore wall, as shown.
In FIG. 13, the elements bearing the same numbers as in FIG. 1 are the same. The cap top wall 12 in addition has an integral sleeve 27 depending therefrom, within the bottle neck. The fitment sub-container 16b in this embodiment has threaded connection with the sleeve 27, as afforded by threads 28 and 29. The fitment sub-container cap 16a is thus presented to the user. He may detach the cap 16a and pull the cap and a pre-spotter stick 29a completely free of the sub-container 16b. Both cap and sub-container frictionally interfit at 30, other methods of connection being usable. FIG. 4 is like FIG. 13 except the fitment 116 is in one piece and has an open top at 117, directly below wall 12. Fitment thread 28 engages sleeve thread 29. Prespotter granules in the fitment appear at 118.
In FIG. 15, the elements bearing the same numerals as in FIG. 1 are the same. The fitment cap 16b and the bottle cap top wall 12 include removably interfitting snap connection elements, as for example small flanged boss or plug 31 depending from top wall 12 and received through an opening 32 in the fitment cap top 2all 33. Opening 32 is slightly smaller in diameter than the flange 31a, providing a snap-on interfits Other forms of snap connection are usable.
In FIG. 12, the elements bearing the same numerals as in FIG. 1 are the same. The fitment sub-container 16a has a side wall 35 integrally molded with the bottle cap top wall 12, at 35a, and wall 35 projects and is externally threaded at the upper exterior side of the wall 12. Sub-container cap 16b' is internally threaded at 36 to engage the external thread 37 on wall 35, as shown. Thus, cap 16b' is easily removable, exteriorly, to allow pouring or other dispensing of the prespotter 17' which may be in liquid or flowable granules, or other form.
In FIG. 11, the fitment 16 is primarily (as for example completely) located outside and above the cap top wall 12, and auxiliary means is provided to retain the fitment in position, just above wall 12. In the example, such auxiliary means has the form of a thin-walled plastic overcap 39, having a top wall 40 located to compressively retain the fitment vertically between walls 40 and 12, as shown. The overcap depending skirt 41 is removably mounted on the bottle cap, so that it may be easily detached. As shown, two lips 42 engage the lower rim 43 of the cap 11, and may be pulled free (see arrows 44) to release the overcap, providing access to the fitment 16.
In FIG. 14, the fitment 44 includes a sub-container 45 integral with the bottle cap 11, and extending thereabove. Sub-container cap structure 46 is connected to the sub-container 45, to allow dispensing of the flowable prespotter composition. As shown, the cap structure includes first and second walls 48 and 49, each containing ports 48a and 49a normally out of registration. The walls extend adjacent one another, and are relatively rotatable (i.e. wall 49 may rotate relative to wall 48, for example) to bring ports 48a and 49a into registration, allowing dispensing of prespotter. Wall 49 is shown as having a skirt 50 with annular detent connection at 51 to the sub-container wall 45a, allowing rotation of the skirt and wall 49. Flowable prespotter granules are indicated at 17'.
In FIG. 5, the bottle neck 10a has an internal ledge or ledges 52 seating the fitment sub-container 53. The latter has a flanged undersurface 53a engaging the ledge, which may be annular. In FIG. 6, the modified ledge 52' tapers downwardly, and cooperatively engages or seats the frusto-conical outer surface 53' of the fitment sub-container 53, to position the fitment. Caps for the fitment sub-container appear at 54 in FIGS. 5 and 6, and the fitments are loosely contained within the bottle neck to be completely removable when the bottle cap 11 is removed.
In FIG. 9, the bottleneck 10a has a upper rim 55, and an external flange 56 on the fitment 16 seats on that rim to retain the fitment sub-container 16a within the neck 10a, and the sub-container cap 16b projecting upwardly within the cap upper interior 57. The lower edge or rim 58a of the cap skirt 58 seats and seals against the bottle shoulder 60 between neck 10a and bottle wall taper 10b. In FIG. 10, the bottle neck 10a has an internal integral flange or shoulder 61; and an external flange 62 on the fitment 16 seats on that flange 61. The flange is annular, and the fitment sub-container 16a projects downwardly through the flange into the bottle upper interior 63. Top wall 12 of cap 11 seats and seals on the upper rim 55 of the neck 10a.
In FIG. 8 a receptacle 64 has an external flange 65 seating on the bottle neck rim, and retained in position by the top wall 12 of the cap 11. The upwardly opening receptacle extends downwardly within the bottle neck 10a, and fitment 16 is loosely received in the receptacle, and confined between bottom wall 66 of the receptacle and top wall 12. Receptacle 64 is removable after cap 11 is removed.
In FIG. 7, the bottle 10 has side wall structure that forms a lateral hand reception opening 66 and a manually graspable handle 67 associated with that opening. The wall structure includes vertical walls 68 and 69, and wall upper portion 70 presented internally of the bottle and generally upwardly toward neck 10a and neck opening 71. The fitment 16 is seated at 72 on wall upper portion 70, within upper interior 73 of the bottle, and also extends upwardly into and within the neck opening 71, as shown. The fitment may be sufficiently large in diameter so as to be retained in position by the enck and by the wall portion 70. The opening 66 may be merely an indent, and other than associated with a handle. See also flowable detergent granules at 80, filling the bottle. In FIG. 16, the fitment 16 is received within the opening or indent 66, removably retained as by frictional engagement with the wall structure, as at points 74 and 75.
In FIG. 17, the fitment 85 extends externally of the bottle 10 and is attached thereto, as per example at the vertical location 85a, merging with the bottle side wall. Thus, the vertically elongated fitment may include a portion 85b forming a bottle handle associated with lateral opening 87 through the bottle for finger reception. The fitment is shown to extend upwardly from a location 85c near the bottom of the bottle to a location 85d near the top of the bottle. Fitment cap 88 is exposed externally of the bottle and its cap 11, and is offset laterally from cap 11, so that if cap 88 is removed, the flowable (liquid or dry) prespotter contents of the fitment container can be poured onto fabric to be washed, and if cap 88 is replaced and cap 11 removed, detergent can be poured into the wash water.
In FIG. 18, the carton 89 (as for example cardboard) contains detergent such as dry granules seen at 90. A pour spout appears at 91. The fitment 16 is carried in a separate compartment 92 defined by the carton, as for example by carton walls 93-95 at the top of the carton. A flap 96 is releasable to allow fitment removal.
PRESPOTTER
Prespotters in the form of liquids, powders, aerosols and stocks are known, and are designed to deliver a concentrated amount of effective stain removal ingredient to the stained or heavily soiled area of the garment. Common stain removal ingredients incorporated in laundry prespotter compounds are surfactants, solvents, bleaches, and enzymes. See in this regard U.S. Pat. No. 3,953,353 to Barrett et al, disclosing a stick form prespotter.
A. Surfactants
Surfactants are classed as anionics, nonionics, cationics, amphoterics and zwitterionics. The anionic and nonionic surfactants find the greatest utility in laundry prespotters. Suitable surfactants are described in "McCutcheon's Detergents and Emulsifiers 1982 Annual" and are listed by trade name and chemical type. Without going into great detail, the suitable anionic surfactants include organic sulfonates, sulfates, phosphate and phosphonates which contain hydropilic as well as lipophilic groups. These include, for example, linear higher alkyl benzene sulfonates, higher olefin sulfonates, higher alkyl sulfonates, higher paraffin sulfonates, higher alcohol sulfates, the sulfates of condensations of higher alcohols and lower alkylene oxides, and the fatty acid soaps. The higher alkyl chain lengths will generally be from 12 to 18 carbons. The salt forming cations of these compounds are usually alkali metal cations, ammonium, amines or alkanolamines.
Nonionic surfactants useful in the prespotter product include all surface active agents possessing both lipophilic and hydrophilic groups which do not ionize in water. Suitable nonionic surfactants are the polyoxyalkylene alkylphenols wherein the hydrophobic group contains a phenolic nucleus having a substituent alkyl group of at least 4 but preferably 8-12 carbon atoms and the hydrophilic portion is composed of at least 3 but preferably 6-100 moles of ethylene oxide or propylene oxide per mole of alkylphenol.
Also, suitable nonionic detergents are the polyoxyalkylene alcohols wherein the hydrophobic group is derived from natural or synthetic primary or secondary straight chain fatty alcohols having about 8-22 carbon atoms and the hydrophilic group is composed of at least 3 but preferably 5-100 moles of ethylene oxide or propylene oxide.
Other suitable nonionics are the polyalkylene esters of the higher organic acids usually having 8 or more carbon atoms in the acid hydrophobe and 10 or more moles of ethylene oxide as the hydrophilic group.
Further suitable nonionics are the polyalkylene alkylamides having a hydrophobic group derived from an amide of a fatty acid or ester. Also, suitable are the polyalkylene alkyamines whose hydrophobic group is from a primary, secondary or tertiary amine and whose ethylene oxide content is sufficiently high to impact both water solubility and non-ionic characteristics in neutral or alkaline environments.
A further class of suitable nonionics are the fatty acid esters of various polyols including glycols, glycerols, polyglycerol, hexitols and sugars and their polyoxyethylene condensates.
An additional group of suitable nonionic detergents are the polyalkylene oxide block copolymers made by condensing alkylene oxides with a hydrophobic base itself obtained by condensing alkylene oxides with a reactive organic molecule.
Further suitable types of nonionic detergents include fatty alkanolamides, amine oxides, phosphine oxides, acetylenic glycols, and polyoxyethylene actylenic glycols.
B. Solvents
Numerous organic compounds have found use in prespotter formulations based on their ability to solubilize oily and greasy soils, and hydrocarbon based stains such as ink. These compounds differ from the surfactants in that their mode of action is a solvent effect as opposed to a surface tension reduction effect. These compounds include the lower mono, di and polyhydric alcohols, their alkyl or aryl ethers, their alkyl esters and their alkoxy derivatives. Examples are ethanol, isopropanol, ethylene glycol, glycerol triacetate, the Cellosolves 1/ and the Carbitols. 1/
Other compounds exhibiting desirable solvent properties are the lower hydrocarbons and their halogenated derivatives. Examples are pentane, hexane, decane, trichloroethane, perchloroethylene and carbon tetrachloride. Compounds of this type with sufficiently high vapor pressure often serve a dual function as the propellant in the aerosol products. Examples are propane, butane, and the Freons. 2/
C. Enzymes
Enzymes find use in prespotter products in treating protein or starch based soils which are not readily removed by the other prespotter ingredients. The enzymes catalyze the breakdown of the soil into simpler compounds that can be washed away in the laundering process. Enzymes suitable for use in prespotters are well described in the patent literature and generally are alkaline or neutral pH stable proteinases and/or amylases. Examples are the Esperases and Termamyl enzymes manufactured by Novo Industries A/S of Copenhagen, Denmark and the Maxacal and Maxamyl enzymes manufactured by Gist-Brocades NV. of Delft, Holland.
D. Bleaches
Fabric safe bleaches and in particularly those bleaches that release nascent oxygen as the bleaching agent are suitable for use in a laundry prespotter. These compounds include both inorganic and organic peroxides. Examples of inorganic bleaching agents are sodium perborate, sodium percarbonate, hydrogen peroxide and potassium peroxymonosulfate. Examples of organic oxygen bleaches include monoperoxyphthalates, alkylbutanediperoxoic acids, and diperoxydodecanedioic acids.
E. Other Ingredients
Other compounds find use in laundry prespotters for aesthetic, stability, and physical reasons and not for their stain removal abilities. These could include perfume, fluorescent whitening agents, colorants, diluents, binders and fillers.
Examples of Prespotter Formulas
The following are examples of typical prespotter formulations which are usable:
I. The following is a solid prespotter composition suitable for melting and casting into sticks for use in a push-up or screw-up container, (weight percentages being indicated):
40% Igepal CO-630 (GAF's polyethoxylated nonylphenol)
30% Tergitol 15-S-40 (Union Carbide ethoxylated alcohol)
29% Carbowax 4000 (Union Carbide polyethylene glycol)
1% Esperase 4.0T (Novo Industries enzyme)
II. The following is an example of aerosol prespotter:
10% tetrachloroethylene
15% Neodol 23-6.5 (Shell ethoxylated alcohol)
70% C 10 -C 16 hydrocarbon
5% isobutane (propellant)
III. An example of a suitable liquid prespotter is:
20% Neodol 23-6.5
15% Alfonic 1412-A (Conoco ether sulfate)
2% enzyme
q.s. water, perfume, dye
IV. Detergent
The detergent composition (indicated for example at 10 in FIG. 1) can be any of these types currently well known in the laundry detergent art, including liquids and powders. The main purpose of the detergent is to provide soil removal; however, for this invention a multifunctional detergent product is the preferred embodiment. Additional available functions of the detergent compound are fabric softening, static prevention, bleaching, stain removal and/or whitening, bluing and water softening. Ingredients useful in preparing detergent products include: surfactants, builders, bleaching agents, soil suspending agents, optical brighteners, hydrotopes, dyes and perfumes, borax, enzymes, bluings, and anti soil redeposition agents.
Suitable surfactants for the detergent compound include those listed previously in the prespotter description. The preferred surfactants because of their cost, availability and performance are linear alkylbenzene sufonates, alkylsulfates, alkyl ether sulfates, alpha olefin sulfonates, fatty acid soaps, ethoxylated nonylphenols, the ethoxylated long chain alcohols and polyalkylene oxide block copolymers. The above surfactants can be formulated alone or in combination to achieve the desired soil removal performance.
Alkaline builders are often incorporated, especially in dry detergent formulations. These compounds are well known in the art and serve the purpose of overcoming water hardness and boosting detergency of the product. Suitable inorganic builder salts include pyrophosphates, tripolyphosphates, orthophosphates, carbonates, silicats, sesquicarbonate, bicarbonate, borates, zeolites and the like. Suitable organic builders include citrate, tartrate, gluconate, EDTA and NTA.
Unbuilt detergent compositions are common, especially in liquid forms. Effective performance is achieved by providing generally higher levels of surfactants or recommending higher useage levels.
Other components of detergent composition which may be included are dyes, perfumes, fillers and diluents which tend to improve the aesthetic and processing characteristics of the product.
In order to achieve a multifunctional product, one or more of the following can be added to the detergent composition: enzymes, bleach, fabric softener/antistat. Enzymes have been described elsewhere herein and are available in the form of prills or granules for addition to dry products and as liquids for addition to liquid detergent products. Stable enzyme products, either liquid or powder can be formulated by those skilled in the art.
A preferred embodiment of this invention includes a detergent in combination with a fabric softener/antistat. The combination of fabric softeners with unbuilt liquid detergents and low alkalinity dry detergent is known in the art. The incorporation of fabric softeners, especially the preferred quaternary ammonium compounds with highly alkaline built dry detergents, however, requires a novel approach. We have found that by absorbing the cationic softener onto a highly absorbent water soluble substrate and coating the resulting material with a finely divided solid to act as a barrier between the cationic and the alkaline builder, we can obtain a free flowing bead that when added to a dry detergent imparts effective softening/antistat properties without the stability problems previously associated with fabric softener/alkaline detergent mixtures. The fabric softener bead is composed of the following:
(a) from about 1% to about 90% by weight porous substrate such as puffed borax, dendritic salt, and clay
(b) from about 0.5% to 75% by weight of a fabric softener mixture consisting of one or more of:
(1) from about 1% to 100% by weight of a material or mixture of materials known in the art to provide useful softening and/or antistatic effects on textiles, (usually alkyl quaternary ammonium or imidazolinium compounds);
(2) optionally and preferably from about 1% to 100% by weight of a suitable solubilizing or dispersion aid admixed with (1). Such aids may be selected from groups consisting of nonionic surfactants, amphoteric, zwitterionic surfactants or fatty acid soaps;
(3) optionally and preferably from about 0.1 to about 25% by weight of a hardener such as a wax or high molecular weight polyethylene glycol, admixed with (1);
(c) from about 1% to about 30% by weight of a finely divided solid which provides an external coating on the bead, acts as a barrier, and removes tackiness. Such a solid is selected from the group consisting of amorphous silica, starch, inorganic salts, and other anti-tacky material that dissolve in wash water.
The beads are manufactured in a suitable mixer preferably one which provides gentle agitation. The substrate material is charged into the mixer and the softener mixture applied. Once all of the substrate is coated with the softener mixture, the finely divided solid is charged to the mixer in an amount sufficient to coat the beads and make them free flowing.
The finished fabric softener beads may then be added to any dry detergent. The detergent may be spray dried, dry mixed or agglomerated. It may contain anionic, non-ionic, amphoteric or zwitternionic surfactants or mixtures thereof. It may also include one or more of the auxiliary ingredients previously mentioned.
Suitable fabric softening/antistat compounds are the quaternary ammonium compounds of the following structure, ##STR1## where R 1 represents an aliphatic group of from 1 to 22 carbons, or hydrogen; R 2 represents an aliphatic group of from 12 to 24 carbon atoms, R 3 and R 4 represent alkyl groups of from 1 to 3 carbon atoms; X represents an anion selected from the group consisting of halogen, sulfate, methyl sulfate, phosphate, nitrate and acetate.
Other suitable fabric softening/antistat compounds are the quaternary imidazoline compounds of the following structure, ##STR2## where R 5 represents an aliphatic group of from 1 to 22 carbon atoms or hydrogen; R 6 represents an alkyl group of from 1 to 4 carbon atoms; R 7 represents an alkyl group of from 1 to 4 carbon atoms or hydrogen; and R 8 reprsents an aliphatic group of from 8 to 24 carbon atoms; and X is an anion as mentioned previously.
Other useful quaternary ammonium compounds include dimethyl alkyl benzyl chlorides, complex diquaternary chlorides, diamidoamine based methyl sulfates and other various other quaternary derivatives.
Examples of Detergent Formulas
While many possible detergent formulas are usable for this invention, the following examples are typical detergent formulations are typical of those that can be used with highly advantageous results;
I Liquid Detergent/Fabric Softener
5% sodium linear dodecylbenzene sulfonate
10% nonylphenol ethoxylate
5% sodium xylene sulfonate
3% cationic fabric softener q.s. water, perfume, dye
II Liquid Detergent/Enzyme
20% ethoxylated lauryl alcohol
15% ethoxylated alcohol sulfate
2% protease enzyme q.s. water, perfume, dye
III Dry Detergent/Enzyme
15% sodium linear alkyl benzene sulfonate
10% sodium silicate
25% sodium tripolyphosphate
1% Esperase 4.0T enzyme
0.1% perfume
0.05% fluorescent whitening agent q.s. sodium sulfate
IV Dry Detergent/Bleach/Enzyme/Fabric Softener
15% sodium silicate
22% fabric softener bead*
6% sodium percarbonate
31% sodium carbonate
10% sodium chloride
4% ethoxylated nonylphenol
1% protease enzyme
1% Sipernat 50-S
50% puffed borax
30% ethoxylated nonylphenol
10% ditallow dimethyl quaternary ammonium chloride
10% Sipernat 50-S (amorphous silica)
In the above, the indicated percentages are approximate and by weight.
The subject matter of Deborah Winetzky U.S. patent application Ser. No. 596,037, filing date 4-2-84, entitled "Porous Substrate with Adsorbed Antistat or Softener, Used with Detergent", filed contemporaneously herewith, is incorporated by reference.
From the above, it will be understood that the detergent composition as at 100 is in flowable form, and is characterized as having soil removal properties as well as having one or more of the following properties or capabilities:
fabric softening
antistat
enzymatic dissolution of protein and/or carbohydrate bound soils
bleaching
fabric whitening
water softening
soil suspending or suspension
It will also be understood that the bottle, as at 10 and/or 10a, may have a transparent (glass, plastic, etc.) side wall, and that the fitment dispensing container (as for example at 16) may extend within the bottle to an extent such that the dispensing container can be seen sidewardly through the bottle side wall. In this regard, the dispensing container may also have a transparent side wall (16a for example) whereby the prespotter composition can also be seen through both such transparent side walls.
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The invention relates generally to products useful for home laundering, and more particularly to a product which incorporates a prespotter with a detergent and having one or more of the following separate functions: detergency, fabric softening, stain removal, bleaching, and bluing; with the advantage being that both the detergent and the prespotter are uniquely packaged together as one product, negating the need to purchase and store separate products for each end use function, and also, unavoidably providing presentation of the prespotter to the detergent user at the time of laundering. The invention also concerns methods of use of such products during laundering.
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BACKGROUND OF THE INVENTION
1. Field of the Invention
This invention relates to a method for harvesting fruits, berries and the like, in particular for gathering grapes in whole bunches. The method consists in shaking a plant bearing said fruits, berries and the like by means of shaker members which encompass the plant and are reciprocated between two end positions on each side of a mean position.
2. Description of the Prior Art
Harvesting machines equipped with shaker members driven in transverse reciprocating motion with respect to the direction of forward travel of the machine are now well-known (see for instance U.S. Pat. Nos. 3,667,202, 3,939,629, 4,198,801, 4,236,371, 4,286,426 and 4,391,085 and French Pat. Nos. 2,293,132, 2,509,955 and 2,516,742, although some of the machines disclosed in these patents use beater members instead of shaker members). In known machines of this type, the shaker members usually produce action on the plant within the fruit-bearing zone amidst the vegetation and subject the plant to a sinusoidal or pseudo-sinusoidal movement, the frequency and amplitude of which have the calculated effect of detaching the fruits. As a general rule, the movement is sinusoidal at the level of the drive mechanisms associated with the shaker members and pseudo-sinusoidal at the level of the plant by reason of the flexibility of the latter and also, in certain cases, by reason of the flexibility of the shaker members themselves. In all cases, this movement does not have any discontinuity either during shaking of a plant or during displacement of the machine from one plant to the next. The amplitude of motion (without taking into account the flexibility of the shaker members) is usually of the order of 100 mm (between 75 and 150 mm) and the shaking frequency is usually of the order of 8 cycles per second (between 6 and 10 cycles per second).
Although integral mechanical vintage or grape-harvesting is at present developing throughout the world for obvious economic reasons, a few technical difficulties still remain and tend to check its extension. In particular, the known grape-harvesting machines which are equipped with shaker members displaced in transverse reciprocating motion with respect to the direction of forward travel of the machine are attended by two disadvantages. In the first place, this mechanical action has the effect of bursting-open a relatively large number of individual grapes (called grape berries). In the second place, it has the effect of harvesting grape berries which have been detached from the bunches. These two phenomena give rise to a loss of juice, to difficulties in cleaning of the grapes owing to the number of vine leaves and to wetting of the leaves which are detached at the same time as the grapes. Further consequences include oenological problems which arise from the intimate contact of the released juice with the air and with foreign substances unrelated to the vintage, as well as vinification difficulties in certain particular cases (carbon dioxide maceration, fractional pressing). Furthermore, the shaker members tend to damage the plant itself and this is in turn liable to affect its health. As a mattter of fact, they have a tendency to produce leaf-stripping, breaking of vine-shoots which lead to difficulties in pruning, bud removal which is liable to have an adverse effect on the future yield of the plant, and injuries to the wood through which diseases may thus more readily gain entrance to the plant.
Observations made by the present Applicants by means of time-lapse cameras have in fact shown that detachment of grapes takes place after the plant has been shaked for a certain time, while giving rise to fatigue of the stems or other connecting organs which connect each "mass" (grape berries, bunches, foliage) to the remainder of the plant. Thus any failure of these connecting organs essentially takes place as a result of fatigue. During the period of time required for detachment of grapes, the bunches attached to small branches or flexible vine-shoots rotate in a random movement about their point of atttachment and the different berries of any one bunch or cluster bump against each other. The energy stored by these impacts finally causes detachment of the berries from the bunches. In consequence, when using the known machines equipped with shaker members which are driven in a sinusoidal or pseudo-sinusoidal movement, approximately 80% of the harvest consists of grape berries which have become detached from the bunches and only about 20% of the harvest consists of whole bunches. As they are detached from the bunches, the individual grape berries release juice as a result of opening of their skins. In addition, the powerful action of the shaker members in the fruit-bearing zone of the vine causes impacts between certain bunches and the shaker members. The grape berries thus burst open as a result of crushing and a substantial quantity of juice is released. Furthermore, the same powerful action of the shaker members in a portion of the plant foliage and branches produces a number of injuries including stripped or lacerated leaves, breakage of wood, removal of or injuries to shoots and buds as well as injuries to the wood.
In short, shaking of grapevines by means of shaker members driven in sinusoidal or pseudo-sinusoidal motion essentially results in detachment of grapes in the form of individual berries much more than in the form of whole bunches or clusters, releases large quantities of juice (impact upon grape clusters, detachment of grape berries) and injures the plant as a result of shock impacts on foliage and branches. The foregoing observations are also valid when these machines are employed for harvesting other fruits or berries such as, for example, red currants, black currants, gooseberries and, to some extent, raspberries.
SUMMARY OF THE INVENTION
The main object of the present invention is therefore to provide a method of shaking for harvesting fruits, berries and the like mostly in the form of whole bunches and for releasing a distinctly smaller quantity of juice than was the case with machines of the prior art in which the shaker members were driven in a sinusoidal or pseudo-sinusoidal movement. A subsidiary object of the invention is to provide a method of shaking for harvesting fruits, berries and the like, which causes less damage to harvested fruits as well as to plant foliage and branches.
To this end, the method of the present invention essentially consists in subjecting the shaker members during their displacement at least on one side of their mean position to a succession of motion stages comprising a high-speed motion stage, a practically zero-speed motion stage in one of the two end positions of the shaker members and, between these two stages, an intermediate stage of motion having a high speed gradient, the speed in the high-speed stage being at least equal to 2 meters per second, the time-duration of the practically zero speed stage being at least equal to 30 milliseconds and the speed gradient in the intermediate stage being at least equal to 200 meters per square second.
The intermediate stage having a high speed gradient can be either a deceleration stage which follows the high-speed stage or an acceleration stage which precedes the high-speed stage. Preferably, said succession of motion stages comprises in sequence a high-speed stage, a deceleration stage having a high speed gradient, a practically zero speed stage in said end position, an acceleration stage having a high speed gradient, and a high-speed stage. Furthermore, said succession of stages preferably takes place on both sides of the mean position of the shaker members. In other words, the law of motion of the shaker members is symmetrical with respect to their mean position. Moreover, although it is possible to cause the shaker members to operate on the fruit-bearing zone of the plants, they are preferably designed to produce action solely on the trunks of the plants. The result thereby achieved is that the shaker members are no longer liable to cause bursting-open and loss of juice of certain varieties of fruit or to cause injuries to plant foliage and branches (stripped or lacerated leaves, breakage of wood, breaking-off or injuries to shoots, injuries to the wood of plants) as a result of impacts on part of the fruit as well as on plant foliage and branches.
BRIEF DESCRIPTION OF THE DRAWINGS
Other features of the invention will be more apparent to those skilled in the art upon consideration of the following description and accompanying drawings, wherein:
FIG. 1 shows time-dependency diagrams relating to the motion of the shaker members in the method of the present invention and prior art;
FIG. 2 is a schematic diagram of a grapevine;
FIGS. 3a to 3c are explanatory diagrams relating to the phenomena which, in the method of the present invention, lead to detachment of grapes in whole bunches.
DETAILED DESCRIPTION OF THE INVENTION
In FIG. 1, the solid-line curves A, B and C represent the time-dependent diagrams of movement, speed and acceleration respectively of the shaker members during one reciprocating-motion cycle of the method in accordance with the present invention. By way of comparison, FIG. 1 shows in dashed lines the diagram D of movement, the diagram E of speed and the diagram F of acceleration of the shaker members during one reciprocating-motion cycle in known machines.
In the method according to the invention, it is apparent from FIG. 1 that, starting from the mean position of the shaker members (instant t 0 ), the movement of said members during each reciprocating-motion cycle comprises successively a stage I at a high and substantially constant speed V 1 up to the instant t 1 , then a decleration stage II having a high speed gradient G 1 up to the instant t 2 , then a stage III at zero or practically zero speed up to the instant t 3 , then an acceleration stage IV having a high speed gradient G 2 up to the instant t 4 , then a stage V at a high and substantially constant speed V 2 up to the instant t 5 , then a deceleration stage VI at a high speed gradient G 1 up to the instant t 6 , then a stage VII at zero or practically zero speed up to the instant t 7 , then an acceleration stage VIII at a high speed gradient G 2 up to the instant t 8 , then a stage IX at a high and substantially constant speed V 1 up to the instant t 9 . After the instant t 9 , a new cycle begins and takes place in a manner which is similar to the sequence just described. The speeds V 1 and V 2 can have the same absolute value or different absolute values. Likewise the speed gradients G 1 and G 2 (deceleration or acceleration) can have the same absolute value or different absolute values.
It will be noted that, at equal amplitudes and at equal repetition frequencies of the reciprocating motion, the maximum speeds V 1 and V 2 and the maximum speed gradients G 1 and G 2 are distinctly higher in the method of the present invention than in known machines. As will hereinafter become more clearly apparent, this establishes favorable conditions for detachment of grapes in whole bunches.
Experiments performed by the present Applicants have shown that good results for grape harvesting were obtained by adopting the following values:
(a) total stroke of the shaker members: approximately 100 mm;
(b) frequency of repetition of reciprocating motion: approximately 4 c/s (cycles per second);
(c) duration of each of the two stages III and VII, that is, duration of stopping times of the shaker members at each end of the stroke: approximately 100 milliseconds;
(d) speeds V 1 and V 2 during stages I, V and IX: approximately 5 meters per second;
(e) speed gradients G 1 and G 2 during stages II, IV, VI and VIII: approximately 1000 meters per square second.
With the above-indicated values, approximately 60 to 80% of the grape harvest consisted of whole bunches. It will readily be apparent that the values indicated above may vary according to the type of fruit to be harvested (grapes, black currants, red currants, gooseberries, and so on), according to the variety of fruit (that is to say according to the different species of vine in the case of grapes), according to the method of training of the plant (such as, for example, espalier-training, cordon-training, goblet-training and so on, in the case of grapevines) or according to a number of other factors. Experiments performed by the present Applicants in the case of grapevines have shown that good results could be obtained in regard to detachment of grapes in whole clusters when the following values are adopted :
frequency of repetition of reciprocating motion of shaker members: between 2 and 10 c/s (cycles per second);
amplitude of total stroke in reciprocating motion: between 50 and 150 mm;
stopping time of shaker members at each end of the stroke; between 40 and 250 milliseconds;
speed of displacement of shaker members: between 3 and 8 meters per second;
speed gradient of shaker members: between 250 and 1500 meters per square second.
It will be noted that the diagram of motion A of the shaker members has approximately the shape of a rectangular wave. A number of different actuating devices of the hydraulic, electromagnetic or solely mechanical type already exist for obtaining a movement of this type. However, a convenient solution which has been employed experimentally by the present Applicants consists in making use of double-acting hydraulic jacks for the purpose of actuating the shaker members.
The way in which bunches or so-called grape custers are detached from vine-branches or vine-shoots will now be described. FIG. 2 shows a vine of the vase-formed type comprising a trunk or stock 1 and a certain number of vine-shoots or branches 2, 3, 4 and 5 which carry grape clusters 6, 7, 8, 9, . . . . In order to simplify the following demonstration, it will be assumed that the vine has only one vine-shoot 2 and only one grape cluster 6 (as shown in FIG. 3a). It will further be assumed that the stock or trunk 1, the lower end of which is imbedded in the soil, has a stiffness R 1 in the transverse direction (flexural strength), and that the vine-shoot 2 is embedded at its lower end in the stock or trunk 1, has a stiffness R 2 in the transverse direction which is lower than that of the trunk 1, and is inclined at an angle α 0 with respect to the latter when the vine is in its "rest" position. It will further be assumed that the mass m of the grape cluster 6 is concentrated at a point located at the extremity of a pendulum 10 having a length l and attached to the vine-shoot 2 at a point 11, an angle β 0 being made between the pendulum and the vine-shoot. It will be assumed in addition that the shaker members 12 and 13 are so arranged as to produce action on the trunk 1 of the vine in the upper portion of the trunk, but below the stock crown 14 (FIGS. 2 and 3a) and therefore below the fruit-bearing zone of the vine.
Under the effect of a high-speed horizontal displacement of the shaker members 12 and 13 (stage I of FIG. 1) towards the right, for example, the trunk 1 of the vine undergoes deformation in much the same manner as an elastic beam fixed in the ground, as shown in FIG. 3b. By reason of the low degree of stiffness R 2 of the vine-shoot 2, a movement cannot be instantaneously imparted by the vine-shoot to the mass m of the grape cluster 6. The cluster therefore remains approximately in its previous position of equilibrium. At this moment, the vine-shoot 2 is in position 2a and is inclined with respect to the trunk 1 at an angle α 1 which is smaller than the α 0 and the pendulum 10 which is now in position 10a is inclined to the vine-shoot 2a at an angle β 1 which is smaller than the angle β 0 . Since the pendulum 10 has lost its position of equilibrium as a result of displacement of its point of attachment 11 to 11a, a movement of rotation of the pendulum will accordingly begin in the anticlockwise direction, which will result in an increase in the angle β 1 . During the same period of time, the stiffness R 2 of the vine-shoot 2 will produce a rotation of the latter by bending it towards the right so that the angle α 1 is restored to the value of equilibrium α 1 which will be overstepped during stage III of FIG. 1 and after the abrupt deceleration stage II by reason of the kinetic energy stored in the vine-shoot 2 and in the grape cluster 6. As a result of the two combined movements on the one hand of the vine-shoot 2 and on the other hand of the pendulum 10, the vine-shoot finally occupies a position 2b on the far right is which it is inclined to the trunk 1 at an angle β 2 of higher value than α 0 whilst the pendulum occupies a position 10b in which it is inclined to the vine-shoot 2 at an angle β 2 of higher value than β 0 by virture of the kinetic energy stored in the vine-shoot and in the cluster during their movement from position 2a to position 2b and from position 10a to position 10b, respectively, and by virtue of the abrupt deceleration and the stationary period at the end of the stroke of the shaker members 12 and 13 (stages II and III of FIG. 1). The vine-shoot and the pendulum occupy respectively the positions 2b and 10b at the end of stage III of FIG. 1. In these positions, the general stiffness of the system under the action of a horizontal force is of maximum value since the vine-shoot and the pendulum are practically horizontal. If at this precise moment (instant t 3 ), the shaker members 12 and 13 are subjected to a rapid displacement to the left (stages IV and V of FIG. 1) from the position occupied by said shaker members in FIG. 3b during stage III to the position illustrated in FIG. 3c and corresponding to stage VII in FIG. 1, the accleration of the shaker members 12 and 13 will be instantaneously and practically entirely transmitted to the mass m of the cluster 6 by reason of the horizontal stiffness of the system. The pendulum 10 (that is to say the stem of the grape cluster or bunch 6) will therefore be subjected to a substantial tractive force which will result in rupture of the stem if this force is of greater magnitude than the abscission force of the grape-cluster stem. Should rupture of the cluster stem not take place at this moment, the assembly formed by the trunk 1, the vine-shoot 2 and the pendulum 10 will begin to move towards the left under the action of the rapid displacement of the shaker members 12 and 13. During this displacement, the trunk 1 will undergo a transition from the position shown in FIG. 3b to the position shown in FIG. 3c, and the vine-shoot 2 and the cluster 6 will move towards the left while acquiring high kinetic energy as a result of the high speed of displacement. Under the action of the kinetic energy acquired by the vine-shoot and the cluster, they will reach an end position on the far left as shown at 2c and 6c in FIG. 3c. In this position, the vine-shoot 2 and the pendulum 10 are nearly horizontal and therefore have a satisfactory degree of stiffness in the horizontal direction. At this moment, the shaker members 12 and 13 have already come to a standstill since their speed of travel is higher than that of the foliage and branches. In the extreme left position of the vine-shoot and of the cluster, the deceleration can be of greater magnitude than the acceleration to which they had been subjected during stage IV of FIG. 1 since a slowing-down action is taking place and it is only necessary to absorb the energy of the masses in motion. In consequence, in position 10c, the stem of the grape cluster is subjected to a tractive force of higher value than the force to which it had been subjected in position 10b and rupture of the stem will take place if it had not already occurred in position 10b. If rupture of the grape-cluster stem has still not taken place in position 10c, it will be noted that, immediately after the end of stage VII of FIG. 1, or in other words at the instant t 7 , when the vine-shoot and grape cluster still occupy approximately the extreme left position shown in FIG. 3c, the shaker members 12 and 13 are moved rapidly towards the right (stages VIII and IX of FIG. 1) and the grape-cluster stem will again be subjected to a sharp acceleration, therefore to a tractive force of high value which is capable of producing failure of the stem while it is still in position 10c, then again to a sharp deceleration and therefore to a large tractive force which is capable of causing stem rupture if it has not already occurred, when the vine-shoot and cluster again reach the extreme right-hand position shown in FIG. 3b.
In the event that the stems of the grape clusters are particularly strong, a few back-and-forth movements of the shaker members may prove necessary in order to obtain detachment of the clusters. Nevertheless, experiments performed by the present Applicants have shown that, by means of the method of the present invention, it is possible to detach most of the clusters in one or two back-and-forth displacements of the shaker members.
In short, it will be noted that the movement of the shaker members is a non-continuous reciprocating movement with rapid displacements and stationary periods. The movement of the shaker members after a stationary period must always be initiated when the horizontal stiffness of the vine-shoots and grape-cluster stems is of maximum value. The length of time during which the shaker members remain stationary is of primary importance for allowing sufficient time for the vine-shoots and grape-cluster stems to take up a horizontal position in either or both of the two end positions of the shaker members and for ensuring that the cluster stems are subjected to a sharp horizontal acceleration or deceleration when the cluster stems themselves are in a horizontal position. The value of acceleration or of deceleration when the cluster stems themselves are in a horizontal position. the value of acceleration or of deceleration is also of capital importance for producing a clean break in the stems of grape clusters at either of the two ends of travel of the shaker members. The rate of displacement of said shaker members is also a key factor for imparting a high value of kinetic energy to the system as a whole and thus facilitating rupture of the grape-cluster stems at either of the two ends of travel of the shaker members. It will be noted that the method of the present invention makes is possible to subject the grape clusters to sharp acceleration and/or deceleration at one or both ends of travel of the shaker members and that said acceleration and/or deceleration is capable of producing detachment of whole grape clusters by stem rupture in a very short period of time, thus removing fatigure phenomena which were conducive to detachment of individual grape berries in known machines of the prior art.
It will be understood that the embodiment of the present invention has been described in the foregoing solely by way of example without any limitation being implied. Accordingly, a large number of modifications may readily be made by those versed in the art without thereby departing either from the scope or the spirit of the present invention.
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In a method for harvesting fruits, berries and the like by means of shaker members and in particular for gathering grapes in whole bunches, the shaker members are subjected to a succession of motion stages comprising a high-speed stage, a practically zero speed stage at least at one end of travel of the shaker members and an intermediate stage having a high speed gradient. The speed in the high-speed stage is at least 2 m/s, the time-duration of the practically zero speed stage is at least 30 ms and the speed gradient in the intermediate stage is at least 200 m/s 2 .
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BACKGROUND
1. Field
The present disclosure relates to reclinable seating, and more particularly to self-adjusting reclinable seating.
2. Description of the Related Art
Reclinable seating has been known for many years. Early solutions to devising seating with a reclining backrest used manual recline controls with prefixed reclining positions, for example, employing notches in the hinged connection between the backrest and the seat or by using notches in the armrests of the seating. These early solutions, although still widely used, are deficient because of their very limited range of recline positions and because many do not permit the seat to move in relation to the backrest.
The related art has attempted to solve the deficiencies of manual recline controls with self-adjusting reclinable seating. Self-adjusting reclinable seating does not rely upon prefixed reclining positions. This allows the seating to be positioned anywhere along a range of movement. However, a user may find the positioning of the seat and backrest in the reclining positions in the seating solutions offered by the prior art to be uncomfortable and, consequently, shift his or her position on the seat to accommodate for the backrest's angle of recline. Accordingly, a need remains for seating that improves user comfort and decreases or eliminates the user's need to shift position on the seat when reclined.
SUMMARY
In various embodiments, reclinable seating is disclosed that continuously moves the seat and backrest portions relative to the ground as the user moves. When the user applies a force to the seating by shifting his or her center of gravity, the backrest and seat portions of the seating move in response to the force to recline the seating. The seating is preferably configured to compensate for the tendency of the seat portion to tilt downwards as the backrest portion reclines. Preferably, the front portion of the seat inclines upwards as the backrest reclines. In some embodiments, the position of the seat relative to the ground forms an acute angle, and the angle of the seat relative to the ground is substantially maintained as the seat moves forward and the backrest reclines. Alternatively, the angle of the seat relative to the ground can decrease as the backrest reclines. In certain preferred embodiments, however, the vertical distance of the front of the seat relative to the ground increases. The user can return the seating to an upright position by again shifting his or her center of gravity. Such a configuration eliminates the need for manual recline controls. This seating may improve a user's seating comfort, for example, by decreasing or eliminating the user's need to shift position on the seat when reclined.
The seating can comprise a frame structure to which the backrest portion is pivotably coupled, but the seat portion is not itself pivotally coupled to the frame structure.
The seating can comprise a seat portion that rides on a fixed track that does not move with the seat.
In seating that comprises side or lateral frame structures generally on either side of the seat portion those structures can be formed from at least front and rear upright members, typically joined at their upper portions by a member at least some of which forms an arm rest. Such seating can also comprise at least one cross member joining either or both of the front and rear upright members. Preferably, the track upon which the seat portion rides is not on or part of the upright members or armrest, but is an additional member.
The track can extend generally from the front to the rear portions of the seating between either the front and rear upright members and/or the front and rear cross members. The track can extend generally alongside the seat portion and/or underneath it or in a plane lower than that of the seat portion. Typically, there will be two tracks associated with each seating portion.
The rear portion of the seat in some embodiments is not lifted during the reclining of the seating. Some preferred embodiments of the invention seek to enhance comfort of and convenience of use for the user by configuring the seating such that, in use, the front of the seat portion will rise. The plane or angle of the seat portion, with respect to its front, may decrease with respect to the floor or ground as the seating is reclined, or the plane or angle may remain relatively constant.
In at least one embodiment, seating comprises a backrest configured to recline from an upright position and a seat hingeably connected to the backrest at the rear portion of the seat. The seat is configured to move in relation to the backrest. The seating also includes a track that extends substantially parallel to the sides of the seat. A guide assembly is fixedly attached to the seat and slideably engaged with the track, such that the guide assembly supports the seat on the track. The guide assembly can extend laterally from a side of the seat or extend downwardly from the bottom of the seat. The guide assembly is configured to slide along the track upon application of a force to the backrest and/or seat. Such seating can be incorporated into furniture, such as a chair, couch, or chaise lounge.
Preferably, the guide assembly and track are configured to lift the front portion of the seat as the backrest reclines. For instance, the track can be configured such that at least a portion of the track slopes downward from the direction of the front portion of the seat to the direction of the rear portion of the seat. The guide assembly can be engaged with the track such that the guide assembly is higher on the slope of the track when the backrest is reclined than when the backrest is upright. The guide assembly can include a frictional control, such as a friction member or a knob, for adjusting the amount of friction between the guide assembly and the lower portion of the track. Such frictional control can be used as a tightening mechanism to prevent the guide assembly from sliding on the track, thereby maintaining the seat and backrest in a fixed position.
In certain embodiments, the seating includes a frame. The frame can comprise a front member disposed near the front portion of the seat and/or a rear member disposed near the rear of the seat. The track can extend between the front member and the rear member of the frame. In some embodiments, the track adjoins the front member and the rear member of the frame. Alternatively, the track can be connected to either the front member or the back member. The track need not be connected to either the front or back member.
When present, the front member can be upwardly extending or it can be laterally extending. Like the front member, the rear member can be upwardly or laterally extending. In some embodiments, a second rear member extends perpendicularly from the rear member and provides support for the backrest. The second rear member can be pivotally connected to the backrest. In some embodiments, the second rear member can comprise a pivot, and the backrest is attached to the pivot. The second rear member could also comprise a generally horizontally-extending bar, and the backrest contacts the bar.
The track can optionally comprise at least one stop configured to limit the range of motion of the guide relative to the track. In certain embodiments, the track includes an upper portion and a lower portion separated by one or more generally upward-extending member, such as a bend in the track. The guide assembly can be engaged with the lower portion of the track, which slopes downward from the direction of the front portion of the seat to the direction of the first portion of the seat. The extent of slide of the guide assembly can be limited by the upward-extending member(s) on the track.
In some embodiments the seating comprises a backrest configured to recline from an upright position; a seat comprising a front portion and a rear portion and hingeably connected to the backrest at the rear portion of the seat, the seat being configured to move in relation to the backrest; a frame comprising: an upwardly-extending front member disposed near the front portion of the seat, an upwardly-extending rear member disposed near the rear portion of the seat, a pivot member extending generally horizontally from the rear member and connected to the backrest so that the backrest can pivot about the pivot member, and a track extending between the front member and the rear member. The track has an upper portion, a lower portion, and two generally upward-extending bends connecting the upper portion to the lower portion, at least the lower portion of the track sloping downward from the direction of the front member to the direction of the rear member; and a guide configured to support the seat on the track. The guide is fixedly attached to the seat and slideably engaged with the downward-sloping lower portion of the track, such that the guide is configured to slide along the track upon application of a force to the backrest and/or seat, and the guide being configured to be higher on the slope of the track when the backrest is reclined than when the backrest is upright, the extent of slide being limited by the two generally upward-extending bends on the track.
In some embodiments there is provided reclinable seating comprising: a backrest configured to recline from an upright position; a seat comprising a front portion and a rear portion and hingeably connected to the backrest at the rear portion of the seat, the seat being configured to move in relation to the backrest and a frame. The frame comprises a front member being disposed near the front portion of the seat, a rear member being generally upright and disposed near the rear portion of the seat, a pivot member extending generally horizontally from the rear member and contacting the backrest so that the backrest can pivot about the pivot member. The seating further comprises track extending from the front member toward the rear member, at least a portion of the track sloping downward from the direction of the front member to the direction of the rear member; and a guide configured to support the seat on the track, the guide being fixedly attached to the seat and slideably engaged with the downward-sloping portion of the track, such that the guide is configured to slide along the track upon application of a force to the backrest and/or seat, and the guide being configured to be higher on the slope of the track when the backrest is reclined than when the backrest is upright.
In some embodiments, there is provided reclinable seating comprising: a backrest configured to recline from an upright position; and a seat comprising a front portion and a rear portion and hingeably connected to the backrest at the rear portion of the seat; and a guide fixedly engaged with the seat and slidingly engaged with a track disposed proximate the seat, the guide and track being configured to incline the front portion of the seat as the backrest reclines.
BRIEF DESCRIPTION OF THE DRAWINGS
A general structure that implements the various features of the disclosed apparatuses and methods will now be described with reference to the drawings. The drawings and the associated descriptions are provided to illustrate embodiments and not to limit the scope of the disclosure.
FIG. 1A is a side view of reclinable seating in an upright position.
FIG. 1B is a side view of the reclinable seating in a fully reclined position.
FIG. 2 is a front-perspective view of the reclinable seating comprising supportive straps on the seat and backrest.
FIGS. 3A and 3B are front-perspective views of the inner and outer surfaces of the pivot connection between the backrest and seat in the reclinable seating.
FIG. 4 is a front-perspective view of the reclinable seating in an upright position.
FIG. 5 is a side view of the reclinable seating showing an alternative position for the guide assembly.
FIG. 6 is a bottom-perspective view of a track and guide assembly used in the reclinable seating.
FIG. 7 is a side-perspective view of a track and guide assembly used in the reclinable seating.
FIG. 8 shows a front-perspective view of an example frame for a love seat comprising the reclinable seating.
FIG. 9 shows a rear-perspective view of the connection between the inner tracks and the front member of the frame in the example frame of FIG. 8 .
Throughout the drawings, reference numbers are reused to indicate correspondence between referenced elements. In addition, the first digit of each reference number indicates the figure it which the element first appears.
DETAILED DESCRIPTION
An example embodiment of reclinable seating 100 is shown in FIG. 1A and FIG. 1B . In this example, the seating 100 is a chair. However, the seating 100 can be integrated into a variety of formal and casual, indoor and outdoor seating options, such stationary or swivel rockers or chairs, lounge chairs, action loungers or swivel action loungers, chaise loungers, settees, love seats, couches, and the like.
The seating 100 comprises a backrest 112 portion that is configured to recline from an “upright” position, as shown in FIG. 1A , to a “fully reclined” position, as shown in FIG. 1B . For more formal dining-type seating, the backrest 112 can be in the range of about 102° to 122° (e.g., around 110°) relative to the ground in the upright position and in the range of about 123° to 143° (e.g., around 133°) relative to the ground in the fully reclined position. For lounge-type seating, the backrest 112 can in the range of about 104° to 124° (e.g., around 113°) relative to the ground in the upright position and in the range of 135° to 155° (e.g., around 145°) relative to the ground in the fully reclined position. The seat 114 is generally in the range of 9° to 16° relative to the ground in the upright position for dining- and deep-type seating. The seat angle for the fully reclined position will be discussed in more detail below.
The seating 100 is continuously adjustable, in that a user can position the backrest 112 at any point between upright and fully reclined. The seating 100 also comprises a seat 114 portion. Cushioning can be provided on the seat 114 and/or backrest 112 . However, such cushioning is optional. As shown in FIG. 2 , for instance, the seat 114 and backrest 112 can comprise transverse straps 210 engaged around supportive tubing. As additional examples, the seat and backrest can comprise a fabric or mesh sling, woven straps, or a solid cast material. Sling, strap, and cast seating are known in the art, and the seating disclosed herein can be integrated with each.
With reference to FIG. 1A , the seat 114 can be connected to the backrest 112 at the rear of the seat 114 , for example, using a hinge, pin, rod, or other suitable pivot 116 , so that the seat 114 can move relative to the backrest 112 .
An example pivot 116 is shown in greater detail in FIG. 3A , which shows the pivot 116 from the inside-out, and FIG. 3B , which shows the pivot 116 from the outside-in.
With reference to FIG. 1A , a frame 118 is disposed around the backrest 112 and seat 114 . The example frame 118 includes a front member 120 , rear members 122 , and a track 124 .
The front member 120 is located near the front of the seat 114 . Conventional framing components known in the art can be used for the front member 120 . For instance, a front arm post or other suitable generally upright framing component can be used, as shown in FIG. 1A . As shown in FIG. 4 , two front members 120 can extend upward at a 90° angle relative to the ground. However, any generally upright angle is suitable for use herein. For instance, two front members can be generally trapezoidal relative to each other. Alternatively, a generally horizontal front rail or other non-upright framing component can be used. A front rail 120 ′ is shown in FIG. 8 , which is discussed in more detail below. Materials commonly used for framing are woods, such as teak, cedar, oak, or the like, metals, such as aluminum, steel, iron, or the like, or synthetic polymers, such as heavy-duty plastics and composites. These materials are suitable for use in the embodiments disclosed herein.
Referring again to FIG. 1A , the rear members 122 are located near the rear of the seat 114 . In this example, the rear members 122 include a first rear member 126 and a second rear member 412 , which is omitted from FIG. 1A , but shown in the perspective view of FIG. 4 . Again, conventional framing components can be used for the rear members 122 , and the first rear member can be positioned at any suitable angle. For example, the first rear member 126 can comprise a generally upright member, such as a back upright slat, or a back arm post, as shown in FIG. 1A . A back rail, crest rail, or other generally horizontal framing component, such as the back rail 414 in FIG. 4 , is also suitable. Other irregular angles, such as trapezoidal angles, are also suitable for use.
In the example embodiment of FIG. 4 , a second rear member 412 extends substantially horizontally, e.g., generally perpendicularly, from the first rear member 126 . The second rear member 412 is configured to provide support for the backrest 112 , and to provide a pivot connection to the frame 118 that allows the backrest 112 to move in relation to the seat 114 . The second rear member 412 can comprise a hinge, pin, rod, ball and socket, or other suitable pivot connection adjoined to or passing through the backrest 112 .
As explained above, the second rear member 412 provides a pivotal connection to the backrest 112 . However, the second rear member 412 could be removed, and the back rail 414 or crest rail extending perpendicularly from the first rear member 126 could serve a similar function. In such an embodiment, the backrest 112 does not pivot about a connection to the frame 118 . Rather, the backrest 112 would abut the frame 118 at the back rail 414 , and pivot about the abutment.
Returning again to FIG. 1A , a track 124 extends from the front member 120 toward (that is, in the direction of) the rear members 122 . Preferably, the track 124 adjoins both the front member 120 and the first rear member 126 , but it need not do so. For instance, the track could contact the front member 120 and the ground.
A guide assembly 132 is configured to support the seat 114 on the track 124 . In FIG. 1A , the guide assembly 132 extends laterally from the side of the seat 114 and engages a portion of the track to the side of the seat 114 . An alternative configuration for the guide assembly 132 ′ is shown in FIG. 5 . In that example, the guide assembly 132 ′ extends downwardly from the seat 114 and engages a portion of track 124 ′ underneath the seat 114 . Such a track-and-guide assembly configuration can be advantageously incorporated into seating lacking one or more armrests, as explained in detail below.
An example guide assembly 132 is shown in greater detail in FIG. 6 and FIG. 7 . In this example, the guide assembly 132 comprises a connector portion 610 that is fixedly attached to the seat (not shown). Suitable methods for attaching the connector portion 410 and the seat are known in the art and include screwing, bolting, and so on. The guide assembly 132 also includes a slide portion 612 , comprising a device such as a slide shoe or cylinder, which is slideably engaged with the track 124 . In this example, the slide portion 612 includes a first half slide shoe 614 and a second half slide shoe 614 ′ engaged around the track 124 . At least the inner surfaces of the first half slide shoe 614 and the second half slide shoe 614 ′ are made of a durable material having a low coefficient of friction with the track 124 . The coefficient of friction should be sufficiently low to permit the slide portion 612 to easily slide on the track 124 when the user changes his or her center of gravity on the seating 100 . Furthermore, the material should be sufficiently durable to withstand repeated use under heavy loads. DELRIN®, a polyoxymethylene plastic originally manufactured by DuPont, which is hard, yet has a dynamic coefficient of friction against steel in the range of about 0.19 to 0.41, has been used successfully. However, a variety of durable, low-friction materials, such as compositions of rubbers, resins and plastics (e.g., PTFE, HDPE, TEFLON®), ceramics (e.g., BN), metals (bronze, Mb), and/or graphite are also contemplated for use in the slide portion 612 .
In certain embodiments, the guide assembly 132 also includes a frictional control 616 , such as a knob, that permits a user to increase the amount of friction between the slide portion 412 and the track 124 . In this example, the frictional control 616 is in the form of a wheel. However, alternative knobs, such as a bar, cubical or spherical member, and the like are also suitable for use. In the embodiment of FIG. 6 and FIG. 7 the frictional control 616 increases the tightness of the first half slide shoe 614 and a second half slide shoe 614 ′ around the track 124 . Preferably, the frictional control 616 is adjusted so that the amount of friction between the slide portion 612 and the track 124 is large enough such that a user, sitting relatively still in an equilibrium position, will not cause the slide portion 612 to slide along the track 124 . However, the adjustment will preferably keep the coefficient sufficiently low, such that when the user shifts his or her center of gravity, the slide portion 612 will slide along the track 124 in response to the shift.
As the slide portion 612 slides along the track 124 in response to changes in the user's center of gravity, the seat (not shown) and backrest (not shown) will move accordingly to accommodate the user's position. Thus, once the user adjusts the frictional control 616 to the user's specific body weight, the seating (not shown) will adjust itself to various positions simply by the user shifting his or her weight.
After the initial adjustment, the frictional control 616 no longer needs to be adjusted. However, the frictional control 616 can be adjusted at any time to “lock” the seating 100 into a particular position by increasing the coefficient of friction between the track 124 and the slide portion 612 , such that the slide portion 612 will not move if the user changes his or her center of gravity.
Although the frictional control 616 advantageously permits a high degree of customization to a user's particular weight and center of gravity, it is optional. For example, the materials and configuration of the slide portion 612 can be selected to provide a coefficient of friction that is sufficiently high to permit the slide portion 612 to hold its position when the user stops changing his or her center of gravity for a majority of users, for example, assuming a normal distribution around an average user weight of about 180 lbs (81.6 kg). This configuration would advantageously allow the seating (not shown) to hold an equilibrium position until application of force, as described above, for most users. Materials such as DELRIN® have been found to function without such a frictional control 616 . Such a configuration could be advantageously employed in, for example, the middle section(s) of a couch in which a frictional control is not easily reachable by the occupant; however, it can be employed in any furniture configuration embodying the disclosed seating.
With reference again to FIG. 1A and FIG. 1B , as the seating 100 moves from the upright position ( FIG. 1A ) to the fully reclined position ( FIG. 1B ), the rear portion of the seat 114 begins to lift upward, because the rear portion of the seat 114 is pivotally connected to the backrest 112 , which itself is rotatably connected to the frame 118 . It was discovered, however, that a user's comfort can be improved if the angle of the seat 114 relative to the ground is maintained in the range of 8° to 22° when the backrest 112 is fully reclined. Maintaining such an angle decreases a user's desire to elevate his or her knees when seated in a reclined position if the angle is too steep or, conversely, obviates the user's feeling of sliding off the seat if the angle is too shallow. Thus, certain embodiments include the realization that reclinable seating 100 should increase vertical distance between the front of the seat 114 and the ground as the backrest 112 reclines, to improve user comfort. Accordingly, some preferred embodiments of the invention seek to enhance comfort of and convenience of use for the user by configuring the seating such that, in use, the front of the seat portion will rise. The plane or angle of the seat portion, with respect to its front, may decrease with respect to the floor or ground as the seating is reclined, or the plane or angle may remain relatively constant.
An example method for increasing the vertical distance between the front portion of the seat 114 and the ground as the backrest 112 reclines is explained below. As shown in FIG. 1A , at least a portion of the track 124 slopes downward, with the higher portion of the slope toward the front member 120 and the lower portion of the slope toward the rear members 122 . The guide assembly 132 is engaged with the track 124 within this downward-sloping portion of the track 124 . When the backrest 112 is in the upright position, as in FIG. 1A , the guide assembly 132 is engaged with the track 124 near the bottommost portion of the slope. As the backrest 112 reclines, the guide assembly 132 slides up the slope. When the backrest 112 is fully reclined, as in FIG. 1B , the guide assembly 132 is engaged with the track 124 near the topmost portion of the slope. Such a configuration increases the vertical distance between the front of the seat 114 and the ground as the backrest 112 reclines, permitting the seat 114 to have an angle of 9° to 16° relative to the ground when the backrest 112 is upright, and an angle relative to the ground in the range of 8° to 22° when the backrest 112 is fully reclined. This configuration advantageously improves a user's comfort throughout the range of movement of the seating 100 .
For a user's safety and/or comfort, it can be desirable to limit the seating 100 movement. As explained above, the rear portion of the seat 114 lifts as the backrest 112 reclines. This motion causes the front portion of the seat 114 to move laterally outward (that is, in a direction away from the backrest). It can be desirable to limit this forward lateral travel to between about 3 in. (7.62 cm) and 8 in. (20.32 cm), for example, to about 4¾ in. (12.07 cm) of forward lateral travel for dining-type seating or about 6.375 in. (16.19 cm) of forward lateral travel for deep-type seating. As another example, it can also be desirable to limit the backward lateral travel of the seat 114 (that is, travel toward the direction of the backrest 112 ). As the seat 114 moves backward, toward the backrest 112 , the backrest 112 will move forward toward the seat 114 . If this motion were not limited, the backrest 112 and seat 114 could fold together, which raises a potential safety concern.
Thus, the track 124 can include stops that limit the range of movement of the backrest 112 and/or seat 114 . An example of a stop is an upward-projecting member in the track 124 , such as an upward-projecting bend The example of FIG. 1A includes two upward-projecting bends, a front bend 134 and a back bend 136 . The guide assembly 132 cannot travel up the steep angle between the upward-projecting bends and the lower portion of the track 124 . Thus, the front bend 134 limits the forward lateral travel of the seat 114 . The limitation upon lateral travel of the seat 114 also results in a limitation upon the amount that the backrest 112 reclines. Consequently, the front bend also defines the fully reclined backrest 112 position. The back bend 136 , limits the backward lateral travel of the seat 114 (and, consequently, defines the upright backrest 112 position). One or more of these bends can be eliminated if no limitation on the forward and/or backward lateral movement of the seat 114 is desired, other than the limitations created by the pivot connections described herein. Moreover, alternative stops can be employed, such as solid stoppers placed along the track 124 . The guide assembly 132 and track 124 , including the front bend 134 and back bend 136 is shown in greater detail in FIG. 7 .
Frame components for a couch or loveseat are shown in FIG. 8 . The example loveseat has outer armrests, but lacks inner armrests. The sides of the frame include outer tracks 124 extending between upright front members 120 and upright first rear members 126 . The side tracks 124 include a front bend 134 and a back bend 136 . The center of the frame includes inner tracks 124 ′ extending between a laterally-extending front member 120 ′ and an upright first rear member 126 ′. FIG. 9 shows a detailed rear-perspective view of the connection between the inner tracks and the front member 120 ′ of the frame. A seat and backrest can be engaged with the frame, as described above, between each set of inner and outer tracks. The assembled loveseat would thus comprise a pair of reclining seats and backrests. In the example of FIG. 8 , downwardly-extending guide assemblies (not shown) can be installed on the bottom of the seats (not shown) to engage the inner tracks 124 ′, while laterally-extending guide assemblies (not shown) can be installed on the sides of the seats to engage the outer tracks 124 . When so installed, the front bends 134 of the outer tracks 124 would limit the forward travel of the seats. A three-person couch can be constructed by adding one or more additional seats and backrests between two outer seats and backrests. The additional seats and backrests can be reclinable or stationary.
For purposes of summarizing the inventions and the advantages achieved over the prior art, certain items and advantages of the inventions have been described herein. Of course, it is to be understood that not necessarily all such items or advantages may be achieved in accordance with any particular embodiment of the inventions. Thus, for example, those skilled in the art will recognize that the inventions may be embodied or carried out in a manner that achieves or optimizes one advantage or group of advantages as taught or suggested herein without necessarily achieving other advantages as may be taught or suggested herein. Moreover, various embodiments and features are described herein and it will be understood that the disclosure is intended to include all combinations and selections of those embodiments and features, rather than to be limited to the disclosure to a specific combination or feature that may be disclosed in a particular paragraph hereof.
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In various embodiments, self-adjusting reclinable seating is disclosed. When the user applies a force to the seating by shifting his or her center of gravity, the backrest and seat portions of the seating move in response to the force to recline the seating. The user can return the seating to an upright position by again shifting his or her center of gravity. Such a configuration eliminates the need for manual recline controls. The seating is further configured to continuously vary the angle of the seat and backrest portions relative to the ground as the user moves. In particular, vertical distance between the front of the seat and the ground increases as the backrest reclines. Continuously varying the angle of both the seat and the backrest portions of the seating relative to the ground may improve a user's seating comfort, for example, by decreasing or eliminating the user's need to shift position on the seat when reclined.
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CROSS REFERENCE TO RELATED APPLICATION
[0001] This application claims priority to U.S. Provisional Patent Application Ser. No. 60/672,641, entitled “Modified Air Freshener Device”, filed on Apr. 18, 2005.
FIELD OF THE INVENTION
[0002] This invention relates to vapor-dispensing devices, and more particularly to management of the electrical wiring utilized in the heating unit for promoting vaporization of the volatile materials used in said devices.
BACKGROUND OF THE INVENTION
[0003] Electrical liquid vaporizers (often referred to as “liquid electrics”) are generally well known in the prior art. The primary function of these types of devices has generally been the counteracting of malodors through the delivery of aesthetically pleasing fragrance vapors, or facilitating the delivery of other vapors, such as insecticides or other compositions.
[0004] Typically, such electric liquid vaporizers comprise a housing unit configured to receive a bottle or liquid container portion. The bottle portion contains a wick or wicking system through which the volatile liquids can be migrated to a portion of the wick that is exposed to the air. The exposed portion of the wick is generally heated by a heating element disposed within the housing unit and proximate to the wick in order to suitably facilitate the vaporization of the volatile liquid to be dispensed therefrom. In vaporizers adapted to accommodate refill bottles when the contents of the bottle have been consumed, the bottles may be releasably attached to the housing. For example, the neck of the bottle may be threaded and engaged within the housing unit in a screw-like manner, or the bottle may be interconnected to the housing unit in a “snap-and-fit” manner.
[0005] In devices of this nature, the heating element delivers kinetic energy to molecules of the liquid as contained in the wick, thereby increasing the rate of evaporation to obtain higher fragrance intensity and uniform delivery density over time. Typically, in such units, the back side of the housing is equipped with electrical prongs that may be plugged into a conventional electrical outlet, and lead wires connected to such prongs are run through the body of the unit to the resistance elements in the heater located in the vicinity of the upper end of the wick, thereby causing the heating unit to heat the liquid and vaporized liquid that have been drawn up into the wick. Depending on the configuration and the aesthetic design of the vaporizer unit, the distance traveled by these lead wires may be considerable, and care must be used to keep them separated along the path of their travel.
[0006] In the vaporizer unit utilized in the present invention, an elongated plastic wire guidance frame is used for protecting and guiding these lead wires. Such frame is positioned on the interior of the housing with its bottom end located adjacent the electric prongs, and it extends upwardly, parallel to the longitudinal axis of the wick, to terminate at its upper end in a circular ring structure in which the electrical resistance elements are embedded. The main body of the plastic frame is connected to said circular ring structure by a hinge, and in assembly the ring structure is bent over to a 90° angle to encircle the upper portion of the wick. The lead wires from the electric resistance elements embedded in the circular ring structure are guided through the hinged area downwardly along the body of the plastic frame to the point where they are connected to the electric prongs. A feature of the present invention is the protection of such lead wires in this special environment.
SUMMARY OF THE INVENTION
[0007] The present invention provides a vaporizing device including a system of guidance and protection for the electric warmer lead wires in the course of their run from the electric prongs at one end of the vaporizing device to their connection with the resistance element or elements in the electric warmer that is used to heat and facilitate the liquid and liquid vapor that has been drawn up into the wick. The invention has particular applicability to the protection and guidance of the said lead wires to prevent them from touching as they pass through the hinged area of the wire guidance frame.
[0008] In accordance with one exemplary embodiment of the present invention, the warming device may include a plastic housing having a front side and a back side and an open bottom for receiving a refill bottle; a refill bottle unit containing an active liquid material and including a wick in fluid communication with said active material, said refill bottle being positioned in said housing with said wick extending out the top of said bottle and upwardly in said housing; an elongate longitudinally extending plastic frame, positioned in said housing in proximity to said bottle and wick, with its longitudinal axis parallel to the longitudinal axis of said wick; a circular heating ring hingedly connected to the upper end of said plastic frame and configured to be bent over the top of and to encircle said wick; at least one electric resistance element being positioned on the interior of said circular heating ring; said resistance element being fitted with a pair of resistance wire leads; said longitudinally extending frame having at least one longitudinally extending rib for providing at least a pair of longitudinal channels, and being fitted at its lower end with a pair of electrical prongs in a plug unit for use in an electrical outlet; said electrical prongs in said plug unit extending outwardly through the back side of said housing; said pair of electrical resistance wire leads extending from said resistance element, each wire being positioned in a separate one of said channels and being connected to respective prongs in said plug unit; and at least one projection on the body of said circular heating ring adjacent the said hinge, to guide the respective resistance wire leads through the hinge area and into separate longitudinal channels.
BRIEF DESCRIPTION OF THE FIGURES
[0009] Additional aspects of the present invention will become evident upon reviewing the non-limiting embodiments described in the specification and the claims taken in conjunction with the accompanying figures, wherein like numerals designate like elements:
[0010] FIG. 1 is a perspective overall view showing the front and side of the outside of one embodiment of the heating device of the present invention.
[0011] FIG. 2 is an exploded view of the interior of an embodiment of a heating device, showing the front and back sides of the housing, the elongate wire guidance frame, the interior bottle holding support, and the refill bottle, in accordance with the present invention.
[0012] FIG. 3 is an enlarged front view showing in greater detail the elongate wire guidance frame, including the component circular heating ring hingedly attached thereto.
[0013] FIG. 4 is an enlarged side view showing in greater detail the elongate wire guidance frame, including the component circular heating ring hingedly attached thereto.
DETAILED DESCRIPTION OF EXEMPLARY EMBODIMENTS
[0014] The following description is of exemplary embodiments of the invention only, and is not intended to limit the scope, applicability or configuration of the invention in any way. Rather, the following description is intended to provide a convenient illustration for implementing various embodiments of the invention. As will become apparent, various changes may be made in the function and arrangement of the elements described in these embodiments without departing from the scope of the invention as set forth in the appended claims.
[0015] In one exemplary embodiment of the invention, a vaporizing device, as shown in FIG. 1 , may comprise a housing 10 , a refill bottle or reservoir 12 , and an electric plug 14 at the back side of the housing for plugging into a conventional electrical outlet in order to obtain electrical current for heating the contents of the refill bottle and thus facilitating the dispensing of vapors into the surrounding atmosphere.
[0016] As shown in FIG. 2 , the housing 10 comprises a back cover 15 and a front cover 16 , and two major interior components—namely, a bottle holder 17 and an elongate wire guidance frame 18 . FIG. 2 also shows the refill bottle 12 which may be inserted in the interior of the housing, and subsequently removed for replacement.
[0017] The back cover 15 has a generally flat back side 19 , and side panels 20 and 21 , which curve around to form a top panel 22 , having a vent opening 23 . In the lower part of the back side 19 , an aperture 24 is provided for allowing the electric plug 14 to extend through the back side for plugging into an electrical outlet. The front cover 16 has a generally flat front side 25 , and side panels 26 and 27 , which curve around to form a top panel 28 , having a vent opening 29 . When the bottle holder 17 and the elongate wire guidance frame 18 are assembled (as will be described hereinafter) and positioned on the back cover 15 , the device may be closed by placing the front cover 16 over the back cover 15 so that the edges of side panels 20 and 21 and top panel 22 of the back cover 15 mate with the edges of the side panels 26 and 27 and the top panel 28 of the front cover 16 . The device is secured in this closed position by use of screws applied through the pair of screw posts 30 and 31 in the back cover, which mate with the pair of screw posts 32 and 33 in the front cover 16 . In the closed position, the semicircular vent opening 23 in the back cover mates with the semicircular vent opening 29 in the front cover, to provide a full vent for outward passage of vaporized material. The various parts of the housing may be formed from suitable materials, including plastics such as polypropylene or high density polyethylene.
[0018] The bottle holder 17 is an interior component in the housing and is designed to serve a dual function—namely, a structure for holding the refill bottle 12 and also for anchoring the elongate wire guidance frame 18 . When the bottle holder 17 and the elongate wire guidance frame 18 are assembled (as will be described hereinafter), the assembly may be secured to the back cover 15 by placing the bottom edge 34 of the bottle holder 17 on the bottom shelf 35 of the back cover and is secured in place there by a peg and hole arrangement (not shown). Following this, the two positioning tabs 36 and 37 on the bottle holder 17 are placed on the top surfaces 38 and 39 of screw posts 30 and 31 , respectively, of the back cover 15 , and the device may then be closed by placing the front cover 16 over the back cover 15 so that the edges of side panels 20 and 21 and top panel 22 of the back cover 15 mate with the edges of the side panels 26 and 27 and the top panel 28 of the front cover 16 . As previously mentioned, the device is secured in this closed position by use of screws applied through the pair of screw posts 30 and 31 in the back cover, which mate with the pair of screw posts 32 and 33 in the front cover. In this position, the top portion of the positioning tabs 36 and 37 of the bottle holder 17 are held between the top surfaces 38 and 39 of the screw posts 30 and 31 on back cover 15 and the top surfaces 32 and 33 of screw posts 32 and 33 on front cover 16 . The top areas of positioning tabs 36 and 37 are provided with notches 42 and 43 to enable through passage of the securing screws.
[0019] As will be seen in FIG. 2 , the bottle holder 17 has a central cylindrical body 44 with an open cylindrical top 45 . The bottle holder 17 also has an open bottom 46 , enabling the refill bottle 12 with upwardly extending wick 47 to be inserted upwardly into the interior of the housing and held in place by a “snap-and-fit” arrangement. When the refill bottle 12 is fully inserted up into the bottle holder 17 , the wick 47 extends upwardly through the open top 45 of the central cylindrical body 44 . In FIG. 2 , the wick 47 in this fully extended upward position is shown in phantom dotted lines.
[0020] Preferably, refill bottle 12 is a conventional bottle or similar device configured to receive a volatilizable material and hold the wick 47 firmly in place. The neck 48 of the bottle 12 may be threaded and thus includes a plurality of threads 49 . The threads 49 are suitably configured to receive, for example, a cap securing the refill bottle 12 prior to use. The wick 47 preferably extends to the bottom of the refill bottle 12 .
[0021] In the present embodiment, refill bottle 12 comprises a plastic material that is compatible with the material to be vaporized. For example, refill bottle 12 may be formed of polypropylene, barex and/or PET. However, in certain applications, it may be desirable for bottle 12 to be formed of other materials such as glass or the like. Preferably, bottle 12 is suitably sized for use in connection with household use. In accordance with various aspects of the invention, bottle 12 is preferably configured for receipt of between 25 to about 75 milliliters of liquid material. The weight and moment of the device of the present invention, inclusive of the refill bottle 12 is such that the center of gravity is appropriately positioned and the weight is less than that which would otherwise cause the device to be stable in the electrical outlet.
[0022] Wick 47 may be formed from any conventional wick material. Suitable wick materials include porous/sintered plastics such as high density polyethylene and polypropylene, bonded fibers, glass sintered fibers, ceramic materials, carbon fibers, sintered carbon, wood, compressed wood composites, bundled or woven material fibers, or bundled or manmade fibers. In general, wick 47 may be formed of any suitable material now known or hereafter devised by those skilled in the art.
[0023] In accordance with various embodiments of the invention, the vaporizable material contained in the refill bottle 12 may be any number of conventional materials dispensed from vapor dispensers, including fragrances, disinfectants, sanitizing agents, insect repellants, insecticides, and the like.
[0024] As shown in FIG. 2 , the remaining component on the interior of the housing 10 is the elongate wire guidance frame 18 , which is positioned in the housing 10 in proximity to said refill bottle 12 and said wick 47 , with its longitudinal axis parallel to the longitudinal axis of the wick 47 . In a particular embodiment of the invention, the part 18 is molded from a single piece of plastic and is comprised of two main parts—namely, a lower elongate guidance body 50 and an upper circular heating ring 51 . Electrical prongs 52 and 53 are anchored at the bottom end of the guidance body 50 , and extend outwardly from the back side of the guidance body 50 , for plugging into a conventional electrical outlet. As will be seen in FIG. 2 and in greater detail in FIG. 3 , the heating ring 51 is in the form of a circular trough having concentric outer and inner walls 54 and 55 with an open central passageway 56 .
[0025] Electrical resistance elements 57 and 58 , for producing the heat needed for enhancing the evaporation of vaporizable material from the wick 47 , are positioned in opposing locations on the interior of the heating ring 51 , and a pair of electrical lead wires 59 and 60 are connected to the resistance elements 57 and 58 and are guided down the length of the guidance body 50 for connection at the other end with the electric prongs 52 and 53 . When the prongs 52 and 53 are plugged into an electric wall outlet, the current that runs through the lead wires 59 and 60 causes heating of the resistance elements 57 and 58 . The plastic tabs 61 and 62 are transversely scored (see score marks 63 and 64 ) to enable hinging of the circular heating ring 51 at the score marks, so that, in assembling of the unit, the circular heating ring 51 can be bent to a 90° angle thereby encircling the upper end of the adjacent fragrance-containing wick 47 . This positioning of the circular heating ring 51 in a bent position encircling the wick 47 is shown in FIG. 2 in phantom dotted lines at the top of the bottle holder 17 , with the bottom surface of the circular heating ring 51 resting on the top edge 63 of the central cylindrical body 44 of the bottle holder 17 .
[0026] It is a feature of the invention that special means are utilized to protect the lead wires 59 and 60 and prevent them from breaking or contacting each other as they carry the electrical current from the electric prongs 52 and 53 through the various stages until they reach the resistance elements 57 and 58 . The lower elongate guidance body 50 is provided with a pair of longitudinal ribs 64 and 65 , which produce a pair of channels 66 and 67 with an intermediate buffer space 68 in between. Thus lead wire 59 runs the length of the elongate guidance body 50 while contained in channel 66 , and lead wire 60 runs the length of the body 50 while contained in channel 67 , all with an effective buffer channel 68 between the two. The hinging and bending, which take place in the hinge area where the plastic tabs 61 and 62 are scored, create special opportunities for the lead wires 59 and 60 to be bent, distorted or broken, and it is a feature of the invention that at least one projection or post is mounted in the hinge area to guide the wires through this area. In the embodiment shown in FIGS. 2 and 3 , this feature comprises a pair of cylindrical pegs or posts 69 and 70 . As will be seen, guide post 69 causes the lead wire 59 to be threaded between the post and the outer wall 54 of the circular heating ring 51 , and guide post 70 causes the lead wire 60 to be threaded between the post and the outer wall 54 , thus keeping the two wires thoroughly isolated as they experience the bending and distortion in the hinge area. Further protection of this nature may be gained by use of a plastic rib 73 separating the guide posts 69 and 70 , as shown in FIGS. 2 and 3 .
[0027] In assembling the various component parts of the heating device, the elongate longitudinally extending plastic frame 50 , with its resistance elements 57 and 58 , its electric prongs 52 and 53 , and its electric lead wires 59 and 60 installed, is mounted on the bottle holder 17 by snap fitting locking tabs 7 l and 72 (near the bottom of frame 50 ) over locking ribs 73 and 74 (near the bottom of bottle holder 17 ); pressing frame 50 along its longitudinal length against the longitudinal length of bottle holder 17 ; and then bending the circular heating ring 51 to a 90° angle so that the heating ring can be pressed into position with the bottom surface of the circular heating ring 51 resting on the top edge 63 of the central cylindrical body 44 of the bottle holder 17 , as shown in phantom dotted lines in FIG. 2 . This two-component system is then placed in position on the inside of the back cover 15 of the housing, with the electric prongs 52 and 53 extending through the aperture 24 in the back cover 15 . The device may then be closed by placing the front cover 16 over the back cover 15 so that the edges of side panels 20 and 21 and top panel 22 of the back cover 15 mate with the edges of the side panels 26 and 27 and the top panel 28 of the front cover 16 . As previously mentioned, the device is secured in this closed position by use of screws applied through the pair of screw posts 30 and 31 in the back cover, which mate with the pair of screw posts 32 and 33 in the front cover. As a last step, the refill bottle 12 , with its protective cap removed, may then be inserted up into the bottom of the device and snapped into position so that the top part of the wick 47 extends up into the area where it is encircled by the circular heating ring 51 , which will heat and cause vaporization of the vaporizable liquids when the device is plugged into a conventional electric wall outlet.
[0028] Although the present invention has been disclosed in connection with certain preferred embodiments thereof, variations and modifications may be made by those skilled in the art without departing from the principles of the invention. All of these variations and modifications are considered to be within the true spirit and scope of the present invention as disclosed in the foregoing description and defined by the claims.
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A heating device for the vaporization of active substances, such as air freshener fragrances, disinfectants, sanitizing agents, insecticides and the like, in which a wick is immersed in a fluid active substance and heat is applied to produce vaporization. The heating is produced by one or more electrical resistance elements embedded in a circular heating ring which is hinged to move over the end of the wick and encircle it. The internal wires which carry electrical current from a source of electrical power are led through the hinged area for connection to the electrical resistance elements, and a feature of the invention is the protection of such wires as they pass through the hinged area.
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FIELD OF THE INVENTION
The present invention relates to a method for monitoring the supply of substitution fluid for an apparatus for extracorporeal blood treatment with an extracorporeal blood circuit, which comprises a first chamber of a dialyzer or filter divided by a membrane into the first chamber and a second chamber, and a fluid system which comprises the second chamber of the dialyzer or filter. Moreover, the present invention relates to a device for monitoring the supply of substitution fluid for an apparatus for extracorporeal blood treatment as well as an extracorporeal blood treatment apparatus with a monitoring device for the supply of substitution fluid.
BACKGROUND
Various methods for extracorporeal blood treatment or cleaning are used to remove substances usually eliminated with urine and for fluid withdrawal. In hemodialysis, the patient's blood is cleaned outside the body in a dialyzer. The dialyzer comprises a blood chamber and a dialyzing fluid chamber, which are separated by a semipermeable membrane. During the treatment, the patient's blood flows through the blood chamber. In order to clean the blood effectively from substances usually eliminated with urine, fresh dialyzing fluid flows continuously through the dialyzing fluid chamber.
Whereas the transport of the lower-molecular weight substances through the membrane of the dialyzer is essentially determined by the concentration differences (diffusion) between the dialyzing fluid and the blood in the case of hemodialysis (HD), substances dissolved in the plasma water, in particular higher-molecular weight substances, are effectively removed by a high fluid flow (convection) through the membrane of the dialyzer in the case of hemofiltration (HF). In hemofiltration, the dialyzer functions as a filter. Hemodiafiltration (HDF) is a combination of the two processes.
In hemo(dia)filtration, part of the serum drawn off through the membrane of the dialyzer is replaced by a sterile substitution fluid, which is generally fed to the extracorporeal blood circuit either upstream of the dialyzer or downstream of the dialyzer. The supply of substitution fluid upstream of the dialyzer is also referred to as pre-dilution and the supply downstream of the dialyzer as post-dilution.
Apparatuses for hemo(dia)filtration are known, wherein the dialyzing fluid is prepared online from fresh water and dialyzing fluid concentrate and the substitution fluid is prepared online from the dialyzing fluid.
In the known hemo(dia)filtration apparatuses, the substitution fluid (substituate) is fed to the extracorporeal blood circuit from the fluid system of the machine via a substituate supply line. With pre-dilution, the substituate line leads to a connection point on the arterial blood line upstream of the dialyzer or filter, whereas with post-dilution the substituate line leads to a connection point on the venous blood line downstream of the dialyzer or filter. The substituate line comprises for example a connector with which it may be connected either to the venous or arterial blood line. In order to interrupt the fluid supply, a clamp or suchlike is provided on the substituate line. A hemo(dia)filtration apparatus of this kind is known for example from European Patent Publication No. EP 0 189 561.
The effectiveness of the blood treatment depends on whether the substitution fluid is fed to the extracorporeal blood circuit upstream or downstream of the dialyzer or filter. A knowledge of the mode of treatment, i.e., pre- or post-dilution, is therefore important.
European Patent Publication No. EP 1 348 458 A1 describes a method and a device for monitoring the supply of substitution fluid for an extracorporeal blood treatment apparatus. The propagation time of the pressure waves of a substituate pump disposed in the substituate line is measured in order to detect the supply of substitution fluid upstream or downstream of the dialyzer or filter. The supply of substituate upstream or downstream of the dialyzer or filter is detected on the basis of the propagation measurement. The known method requires the use of a substituate pump generating pressure waves.
There is known from German Patent Publication DE 10 2004 023 080 A1 a device for monitoring the supply of substitution fluid, wherein the supply of substituate upstream or downstream of the dialyzer or filter is detected on the basis of the change in the pressure, for example on the basis of a sudden pressure rise and/or pressure drop after the substituate pump is switched off or switched on. The known method requires the use of a substituate pump generating pressure waves.
A goal of example embodiments of the present invention is to provide a method for monitoring the supply of substitution fluid, which permits the detection of pre- or post-dilution with a high degree of reliability. Moreover, it is a goal of example embodiments of the present invention to provide a device for monitoring the supply of substitution fluid, with which the pre- and post-dilution may be reliably detected. A further goal of example embodiments of the present invention is to create an extracorporeal blood treatment apparatus with such a monitoring device.
SUMMARY
The method according to example embodiments of the present invention and the device according to example embodiments of the present invention for the detection of pre- or post-dilution is based on the measurement and monitoring of the density of the blood or a blood constituent in the extracorporeal circuit. When there is a change in substitution rate Q S at which substitution fluid is fed to the blood in the extracorporeal circuit, and/or blood flow rate Q B at which blood is fed to the first chamber of the dialyzer or filter and/or flow rate Q M at which fluid is withdrawn from the blood via the membrane of the dialyzer or filter, the density of the blood or the blood constituent in the extracorporeal blood circuit changes. It has been shown that the amount and/or the direction of the change, i.e., an increase or reduction in the density by a specific value, depends on whether the substitution fluid is fed to the blood upstream or downstream of the dialyzer or filter. It is then concluded that there is a pre-dilution or post-dilution on the basis of the change in the density of the blood or the blood constituent. Change in density is also understood in this sense to mean the change in concentration of a blood constituent such as for example hemoglobin.
The method according to example embodiments of the present invention and the device according to example embodiments of the present invention in principle require only the single change in substitution rate Q S and/or blood flow rate Q B and/or flow rate Q M at which fluid is withdrawn from the blood via the membrane of the dialyzer or filter. Since the pre- or post-dilution is to be monitored during the blood treatment, which is preferably to be carried out at specific fluid rates Q S , Q B and/or Q M , a preferred embodiment makes provision, after the reduction or increase in at least one of the three fluid rates by a preset amount for a preset time interval, which should be as short as possible, for an increase or reduction again after the lapse of the preset time interval by a preset amount, which in particular corresponds to the amount by which the corresponding fluid rate or the fluid rates has or have been previously reduced or increased, so that the blood treatment may be continued at the same fluid rates. Flow rate Q M withdrawn from the blood is reduced or increased preferably simultaneously in the same time interval preferably by the same amount and, after the lapse of the preset time interval, preferably increased or reduced again by the same amount as substitution rate Q S .
When mention is made below of a change in the flow rate, this may also be understood to mean a reduction in the flow rate by an amount such that the flow rate is zero, i.e., the flow is interrupted.
The amount by which a flow rate is reduced or increased is in principle irrelevant for the detection of pre- or post-dilution. The decisive factor, however, is that a change in the density can be detected selectively for pre- and post-dilution with sufficient reliability.
The method according to example embodiments of the present invention and the device according to example embodiments of the present invention provide different embodiments, which differ from one another by the point of the extracorporeal blood circuit at which the density of the blood or the blood constituent is measured.
A pre- or post-dilution may be detected by a measurement of the density downstream of the point of the extracorporeal blood circuit at which substitution fluid is fed to the blood circuit in the case of a pre-dilution and upstream of the first chamber of the dialyzer or filter. It is also possible to detect a pre- or post-dilution by a measurement of the density downstream of the first chamber of the dialyzer or filter and upstream of the point of the blood circuit at which substitution fluid is fed to the blood circuit in the case of post-dilution. The density may also be detected by a measurement downstream of the point of the blood circuit at which substitution fluid is fed to the blood circuit in the case of post-dilution. It may be decisive that the density is measured immediately after the change in the respective flow rate, since a change in the density may be detected only within a specific time interval, depending on the measurement position. The reason is that, in these cases, the density may reassume its original value after the lapse of this time interval.
It has been shown that the change in substitution rate Q S , with a simultaneous change in flow rate Q M at which fluid is removed from the blood via the membrane of the dialyzer or filter, leads to notably different changes in the density at different points of the extracorporeal circuit. For example, the density may increase or decrease depending on a pre- or post-dilution.
In a first example embodiment, substitution rate Q S is reduced by a preset amount and the density is measured in the blood circuit downstream of the point of the blood circuit at which substitution fluid is fed to the blood circuit in the case of pre-dilution and upstream of the first chamber of the dialyzer or filter. The density of the blood or blood constituent before the reduction in substitution rate Q S and after the reduction in substitution rate Q S are then compared with one another, it being concluded that there is a supply of substitution fluid upstream of the dialyzer or filter if the density after the reduction of the substitution rate has increased by a preset amount. If the density of the blood after the reduction in the substitution rate has not increased by a preset amount, it is concluded on the other hand that there is a supply of substitution fluid downstream of the dialyzer or filter.
The method according to the invention and the device according to the invention do not in principle require the measurement of the density of the blood both before and after the reduction in the substitution rate. It may, in principle, be sufficient to measure the density only after the reduction in the substitution rate, in order to compare the measured value with a characteristic threshold value.
A particularly preferred example embodiment with a particularly significant change in the density of the blood provides for a measurement of the density of the blood or blood constituent in the blood circuit downstream of the point of the blood circuit at which substitution fluid is fed to the blood circuit in the case of post-dilution. After a comparison of the density before and after the reduction in substitution rate Q S and preferably a simultaneous reduction in flow rate Q M , it is concluded that there is a supply of substitution fluid upstream of the dialyzer or filter if the density after the reduction in substitution rate Q S has diminished by a preset amount. It is concluded that there is a supply of substitution fluid downstream of the dialyzer or filter if the density after the reduction in substitution rate Q S has increased by a preset amount.
The increase in the density of the blood or the blood constituent in the case of post-dilution is due to the fact that, immediately after the reduction in substitution rate Q S at which the substitution fluid is fed to the blood and the simultaneous reduction in fluid rate Q M at which fluid is withdrawn from the blood via the membrane of the dialyzer or filter, a corresponding quantity of fluid has also been withdrawn via the membrane from the blood now flowing out of the dialyzer. The blood flowing out of the dialyzer or filter is thus thickened immediately after the reduction in rates Q S and Q M . A reduction in the quantity of the substitution fluid fed to the blood after the passage through the dialyzer (post-dilution) therefore leads directly to an increase in the density of the blood or the blood constituent in the blood circuit downstream of the dialyzer. When, on the other hand, rates Q S and Q M are reduced in the case of pre-dilution, the blood present in the dialyzer or filter has already been diluted by the previous inflow of substitution fluid. Since the filtration in the dialyzer corresponding to the substituate flow is reduced or does not take place, the density of the blood flowing back to the patient diminishes. It is therefore concluded that there is a supply of substitution fluid upstream of the dialyzer or filter (pre-dilution) if the density of the blood or the blood constituent, after the reduction in substitution rate Q S , has diminished by a preset amount or diminished by an amount which is greater than the preset threshold value.
On the basis of the increase or reduction in the density of the blood or blood constituent after the reduction in substitution rate Q S , it is therefore possible to conclude with a high degree of reliability that there is a post- or pre-dilution. The increase or decrease in the density should however exceed a preset threshold value, in order for it to be possible to distinguish reliably between a change in the density of the blood due to a change in the flow rates and general density fluctuations of the blood.
An increase in substitution rate Q S at which fluid is withdrawn from the blood is also possible instead of a reduction in substitution rate Q S . In this example embodiment, the density may be measured downstream of the point of the blood circuit at which substitution fluid is fed to the blood circuit in the case of pre-dilution and upstream of the first chamber of the dialyzer or filter. It is concluded that there is a supply of substitution fluid upstream of the dialyzer (pre-dilution) or filter if the density after the increase in the substitution rate has diminished by a preset amount, and it is concluded that there is a supply of substitution fluid downstream of the dialyzer or filter (post-dilution) if the density after the increase in the substitution rate has not diminished by a preset amount.
In this example embodiment, the density of the blood or the blood constituent in the blood circuit may alternatively also be measured downstream of the point of the blood circuit at which substitution fluid is fed to the blood circuit in the case of post-dilution. It can be concluded that there is a supply of substitution fluid upstream of the dialyzer or filter, preferably with a simultaneous increase in flow rate Q M , if the density after the increase in substitution rate Q S has increased by a preset amount, and it is concluded that there is a supply of substitution fluid downstream of the dialyzer or filter if the density after the reduction in substitution rate Q S has diminished by a preset amount.
As the density of the blood, it is possible to measure both the physical density or mass density, which describes a mass distribution, as well as the optical density of the blood, which is a measure of the attenuation of radiation (for example light) in a medium, i.e., the blood.
For the method according to the invention, consideration may be given in particular to all measurement methods with which a measurement of the physical or optical density of the blood or one of its constituents is possible. For the measurement of the change in the density, a first example embodiment provides for a measurement of the propagation speed of ultrasound in the blood along a measuring distance, while an alternative example embodiment provides for the measurement of the attenuation of light in the blood along a measuring distance. The measurement equipment required for this is generally known to the person skilled in the art. Moreover, optical detectors for the detection of blood and ultrasound measuring distances for the detection of air are in any case generally present in the known dialysis apparatuses.
In a further particularly preferred example embodiment, a signal signaling the operational state of pre-dilution is generated when a pre-dilution is detected, whereas a signal signaling the operational state of post-dilution is generated when a post-dilution is detected. The signal for the pre- or post-dilution may control further devices provided in the blood treatment apparatus. For example, an intervention in the blood treatment may be made.
The device according to the invention for monitoring the supply of substitution fluid may be a component of a blood treatment apparatus or form a separate unit. Since the components required for the monitoring device are generally in any case present in the known blood treatment apparatuses, an integration into the blood treatment apparatuses is appropriate. The corresponding sensors for the density measurement may for example be used. A microprocessor control is also available. The outlay on equipment is therefore small.
The monitoring device according to the present invention comprises a control unit for controlling the substitution apparatus and the ultrafiltration apparatus for withdrawing ultrafiltrate via the dialyzer membrane, in such a way that corresponding flow rates Q S and Q M may be adjusted for the measurement. A measuring unit is used to measure the density of the blood or the blood constituent and an evaluation unit is used to detect the pre- or post-dilution on the basis of the density measurement.
The method according to the present invention and the apparatus according to the present invention may give the user not only an indication of the type of treatment, i.e., pre- or post-dilution, but also deviations between the actual and the desired type of treatment. Moreover, automatic documentation or an automatic limitation of the input parameters is possible. With the method according to the present invention and the apparatus according to the present invention, it is also possible to control other operational parameters of the blood treatment apparatus depending on the respective operational state.
Not only the change in the corresponding flow rates, but also other parameters have an influence on the duration of the change in density. For example, the volume of the blood chamber of the dialyzer and the volume of the hose line sections following the blood chamber have an influence on the duration of the change in density. In this respect, the volume of a partial section of the extracorporeal blood circuit may also be deduced using the density measurement. The level of the change in density depends on the enclosed volume of blood.
Example embodiments of the method according to the invention and of the blood treatment apparatus according to the invention are described in greater detail below by reference to the figures.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 shows an extracorporeal blood treatment apparatus with a device for monitoring the supply of substitution fluid, in particular for detecting pre- and post-dilution, in a very simplified schematic representation.
FIGS. 2A and 2B show the time-related course of the density in the case of pre-dilution and post-dilution with a reduction in substitution rate Q S and flow rate Q M , at which fluid is withdrawn from the blood via the membrane of the dialyzer or filter, by the same amount.
FIG. 3A and 3B show the time-related course of the density in the case of pre-dilution and post-dilution with an increase in substitution rate Q S and flow rate Q M , at which fluid is withdrawn from the blood via the membrane of the dialyzer or filter, by the same amount.
FIG. 4A and 4B show the time-related course of the density in the case of pre-dilution and post-dilution with an increase in the blood flow rate.
DETAILED DESCRIPTION
FIG. 1 shows, in a schematic representation, only the main components of a blood treatment apparatus that are relevant for the monitoring of the pre- or post-dilution. The present blood treatment apparatus is a hemo(dia)filtration apparatus, which comprises a dialyzer 1 , which is divided by a semi-permeable membrane 2 into a first chamber 3 , through which blood flows and which is referred to in the following as the blood chamber, and a second chamber 4 , through which dialyzing fluid flows and which is referred to in the following as the dialyzing fluid chamber. First chamber 3 is incorporated in an extracorporeal blood circuit 5 A, while second chamber 4 is incorporated in dialyzing fluid system 5 B of the hemo(dia)filtration apparatus.
Extracorporeal blood circuit 5 A comprises an arterial blood line 6 , which leads to inlet 3 a of blood chamber 3 , and a venous blood line 7 , which leads away from outlet 3 b of blood chamber 3 of dialyzer 1 . The patient's blood is conveyed through blood chamber 3 of dialyzer 1 by an arterial blood pump 8 , in particular a roller pump, which is disposed on arterial blood line 6 . The blood pump feeds blood to blood chamber 3 of the dialyzer at a specific blood flow rate Q b . Blood lines 6 , 7 and dialyzer 3 form a disposable intended for one-off use, which is inserted into the dialysis apparatus for the dialysis treatment. An air separator (drip chamber) may be incorporated into the arterial and venous blood line in order to eliminate air bubbles.
The fresh dialyzing fluid is made available in a dialyzing fluid source 9 . A dialyzing fluid supply line 10 leads from dialyzing fluid source 9 to an inlet 4 a of dialyzing fluid chamber 4 of dialyzer 1 . A dialyzing fluid discharge line 11 leads from outlet 4 b of dialyzing fluid chamber 4 to a drain 12 . A first dialyzing fluid pump 13 is incorporated in dialyzing fluid supply line 10 and a second dialyzing fluid pump 14 is incorporated in dialyzing fluid discharge line 11 . First dialyzing fluid pump 13 conveys dialyzing fluid from the dialyzing fluid source at a specific dialyzing fluid supply rate Q di to inlet 4 a of dialyzing fluid chamber 4 , while second dialyzing fluid pump 14 conveys dialyzing fluid at a specific dialyzing fluid flow rate Q do from outlet 4 b of dialyzing fluid chamber 4 to drain 12 .
During the dialysis treatment, dialyzing fluid may be fed from dialyzing fluid system 5 B as a substitution fluid to extracorporeal blood circuit 5 A via a substitution fluid line 15 , which branches off from dialyzing fluid supply line 10 upstream of first dialyzing fluid pump 13 .
Substitution fluid line 15 comprises two line sections 15 a and 15 b , one line section 15 a leading to arterial blood line 6 and the other line section 15 b leading to venous blood line 7 .
The substitution fluid is conveyed by means of a substituate pump 16 , in particular a roller pump, into which substitution fluid line 15 is inserted. A sterile filter 17 divided into two chambers 17 a , 17 b is incorporated into substitution fluid line 15 upstream of the substituate pump. The substituate pump together with the respective lines and the sterile filter form the substitution device of the dialysis apparatus. In order to pinch off the two line sections 15 a , 15 b of substitution fluid line 15 , shut-off elements, for example hose clamps, may be provided, which however are not represented for the sake of better clarity.
Blood pump 8 , first and second dialyzing fluid pumps 13 and 14 and substituate pump 16 are connected via control lines 8 ′, 13 ′, 14 ′, 16 ′ to a central control and computing unit 18 , from which the pumps are controlled taking account of the preset treatment parameters.
Blood pump 8 as well as first and second dialyzing fluid pumps 13 and 14 are operated in order to operate the hemo(dia)filtration apparatus as a hemodialysis apparatus, dialyzing fluid flowing through dialyzing fluid chamber 4 of dialyzer 1 . Substituate pump 16 is operated in order to operate the hemo(dia)filtration apparatus as a hemodiafiltration apparatus, so that sterile dialyzing fluid flows as a substitution fluid via sterile filter 17 optionally to arterial admission point 19 downstream of pump 8 and upstream of blood chamber 3 (pre-dilution) or to venous admission point 20 downstream of the blood chamber (post-dilution). Operation of the hemo(dia)filtration apparatus solely as a hemofiltration apparatus is however also possible, if first dialyzing fluid pump 13 is not operated and therefore the inflow of dialyzing fluid into the dialyzing fluid chamber of the dialyzer is interrupted.
The device for monitoring the supply of substitution fluid comprises a control unit which, in the present example of embodiment, is part of central control and computing unit 18 of the blood treatment apparatus. Moreover, the device for detecting pre- and post-dilution comprises a measuring unit 21 A for measuring the density of the blood or a blood constituent, which flows out of blood chamber 3 of dialyzer 2 via a venous blood line 7 back to the patient. Measuring unit 21 A measures the density of the blood in venous blood line 7 downstream of venous admission point 20 , at which substitution fluid flows into venous blood line 7 during the substitution.
Venous measuring unit 21 A comprises an ultrasound transmitter 21 A′ and an ultrasound receiver 21 A″, which are disposed along a measuring distance. The measuring distance may for example run through a venous drip chamber (not shown) or through a section of the venous blood line following the drip chamber. Such ultrasound measuring devices for measuring the density of media are known to the person skilled in the art. The measuring devices are based on the measurement of the propagation speed of ultrasound waves, which are transmitted by transmitter 21 A′ and received by receiver 21 A″. Alternatively, a measuring unit for measuring the attenuation of light may be used to measure the blood instead of an ultrasound measuring device, said measuring unit comprising, instead of the ultrasound transmitter and receiver, a light source disposed on one side of the measuring distance and a light sensor disposed on the other side of the measuring distance.
The device for detecting pre- or post-dilution further comprises an evaluation unit 22 , which is connected via a data line 23 to central control and computing unit 18 . Evaluation unit 22 receives the measured values of measuring unit 21 A via a further data line 24 .
The structure and the mode of functioning of the device for detecting a pre- and post-dilution are explained in detail below.
During the extracorporeal blood treatment, central control and computing unit 18 controls blood pump 8 in such a way that blood flows into blood chamber 3 of the dialyzer at blood flow rate Q b , and controls first and second dialyzing fluid pumps 13 , 14 in such a way that dialyzing fluid flows into dialyzing fluid chamber 4 at dialyzing fluid rate Q di and dialyzing fluid flows out of dialyzing fluid chamber 4 at dialyzing fluid rate Q do . Substituate pump 16 is controlled by control unit 18 in such a way that substitution fluid is fed to the blood optionally upstream and/or downstream of the blood chamber at substitution rate Q S .
For the monitoring of pre- or post-dilution, control unit 18 controls substituate pump 16 in such a way that its delivery rate is preferably reduced by a preset amount only for a preset time interval or substituate pump 16 is stopped. At the same time, control unit 18 controls first and second dialyzing fluid pumps 13 and 14 in such a way that flow rate Q M at which fluid is withdrawn from the blood via membrane 2 of the dialyzer or filter, whereby Q M =Q do −Q di , is simultaneously reduced within the same time interval by the same amount as the substitution rate has been reduced. The effect of this is that less fluid (ultrafiltrate) is removed from the blood via membrane 2 of dialyzer 1 . Before and after the changing of the delivery rates or stopping of the pumps involved, measuring unit 21 A measures the density of the blood or the blood constituent downstream of venous admission point 20 .
It is also possible for substitution rate Q S and flow rate Q M , at which fluid is withdrawn from the blood via the membrane of the dialyzer or filter, to be adjusted to a value of zero. This may be achieved, for example, by the fact that the dialyzer or filter is switched into a bypass operation, so that Q di is then also equal to zero. If there was previously a net ultrafiltration rate which has made a contribution to Q M , flow rates Q S and Q M in this case are not reduced by the same amount, since Q M was greater than the net ultrafiltration amount.
Evaluation unit 22 comprises a comparison device 22 A, which compares the value for the density of the blood or the blood constituent measured before the change in the delivery rates of the pumps with the value for the density measured immediately after the change in the delivery rates. The measurement of the density takes place within a specific time interval after the change in the flow rates, since the original values are re-established after the lapse of the time interval. The time interval should in any event be shorter than the length of the density change (rectangular function), empirical values being usable. It should be noted that the flow rate changes in the mentioned examples—Q S and Q M change by the same amount—lead only to a time-limited change in the density. On the basis of the change in the density, the evaluation unit then detects whether a dilution is taking place and ascertains whether a pre-dilution or post-dilution is present.
The operational states established by evaluation unit 22 are displayed on a display unit 25 , which is connected via a data line 26 to evaluation unit 22 . Furthermore, the evaluation unit generates two control signals, which on the one hand signal the operational state of pre-dilution and on the other hand the operational state of post-dilution. Both control signals are received by control unit 22 via data line 23 , which may undertake an intervention into the machine control depending on the respective operational state of pre- or post-dilution.
In the case of post-dilution, evaluation unit 22 ascertains a short-time increase in the density of the blood at the measurement point. This is due to the fact that the blood has thickened after the passage through blood chamber 3 of dialyzer 1 , since fluid (ultrafiltrate) has been withdrawn from the blood via membrane 2 of dialyzer 1 . Since the already thickened blood in post-dilution is no longer diluted sufficiently with substitution fluid, the density of the blood or the blood constituent increases downstream of the dialyzer for a specific time period. The delivery rates need to be changed only for a short time for the measurement, i.e., the original delivery rates may be re-established after the measurement has taken place, as a result of which an opposite—again time-limited—behaviour of the density change occurs.
In the case of pre-dilution, on the other hand, the blood flowing into blood chamber 3 is diluted by the inflow of substitution fluid upstream of the blood chamber. Immediately after the time at which the delivery rates of the pumps are reduced, still diluted blood first enters into the blood chamber, from which, however, sufficient fluid is no longer withdrawn via the dialyzer membrane after the reduction in the delivery rates. Consequently, the density of the blood emerging from the blood chamber and flowing back to the patient diminishes. The reduction in the density is again measured with measuring unit 21 A, evaluation unit 22 establishing the operational state of pre-dilution.
Comparison device 22 A of evaluation unit 22 calculates the difference between the two measured values of the density before and immediately after the change in the delivery rates. If the amount of the difference is greater than a preset threshold value, i.e., the values measured before and after the change in the substitution rate differ markedly from one another, evaluation unit 22 establishes that a dilution is taking place. Moreover, the evaluation unit ascertains whether an increase or decrease in the density is taking place, i.e., whether the difference between the measured values is positive or negative.
In the case of an increase in the density by an amount which is greater than a preset threshold value, the evaluation unit then ascertains the operational state of post-dilution. If the density has diminished by an amount whose magnitude is greater than a preset threshold value, the evaluation unit then ascertains the operational state of pre-dilution.
FIGS. 2A and 2B show the time-related course of the density of the blood in the case of pre-dilution ( FIG. 2A ) and post-dilution ( FIG. 2B ), substitution rate Q S on the one hand diminishing by a preset amount ΔQ S <0 and flow rate Q M at which fluid is withdrawn from the blood diminishing simultaneously by the same amount.
The graphs of FIGS. 2A and 2B denoted by A show the time-related course of the density in the case of pre- or post-dilution, when the change in density is measured by measuring unit 21 A downstream of venous admission point 20 , as is described by reference to FIG. 1 .
Alternative embodiments, however, also provide for a measurement of the change in density upstream of venous admission point 20 and downstream of blood chamber 3 or downstream of arterial admission point 19 and upstream of blood chamber 3 of dialyzer 1 . Two further alternative measuring units are provided for this purpose, which are denoted in FIG. 1 by 21 B and 21 C. Measuring unit 21 B measures the density upstream of venous admission point 20 and downstream of blood chamber 3 , while measuring unit 21 C measures the density downstream of arterial admission point 19 and upstream of blood chamber 3 .
The graphs of FIGS. 2A and 2B denoted by B show the time-related course of the density in the case of pre- ( FIG. 2A ) or post-dilution ( FIG. 2B ), when the change in density is measured with measuring unit 21 B, while graphs C show the time-related course of the change in density when the density is measured with measuring unit 21 C.
It is shown that a variation in substitution rate Q S , with a simultaneous change in Q M , also leads to a change in the density of the blood upstream of venous admission point 20 and downstream of blood chamber 3 . The density of the blood diminishes both in the case of pre- and post-dilution, the original value for the density being re-established in the case of pre-dilution, in contrast with post-dilution.
It may also be seen that a variation in substitution rate Q S also leads to a change in the density of the blood downstream of arterial admission point 19 and upstream of blood chamber 3 . The density of the blood increases in the case of pre-dilution, whereas with post-dilution it neither increases nor decreases, i.e. it remains the same.
Alternative embodiments of the invention provide for a measurement of the change in density with measuring units 21 B or 21 C, the evaluation unit concluding that there is a pre- or post-dilution on the basis of the nature of the change in density, which is shown in FIGS. 2A and 2B . Suitable devices with which the signals may be evaluated are known to the person skilled in the art. These devices may comprise comparators, timers etc.
It is also possible to combine the aforementioned measuring methods with one another, so that a pre- or post-dilution may be detected on the basis of two or three measurements at different measurement points. For example, it may be concluded that there is a pre- or post-dilution if a change in the signals characteristic of a pre- or post-dilution is detected at least in two measurements at different measurement points.
FIGS. 3A (pre-dilution) and 3 B (post-dilution) show the time-related course of the density of the blood or of a blood constituent, which is measured with measuring units 21 A, 21 B and 21 C, when on the one hand substituate rate Q S is increased by a preset amount and simultaneously the flow rate at which fluid is withdrawn from the blood via membrane 2 is increased by the same amount. The graphs are again denoted, similar to FIGS. 2A and 2B , by A, B and C.
It may be seen that an increase in substitution rate Q S , with a simultaneous change in Q M , leads to a change in the density at all three measurements points in the case of pre-dilution. In contrast to a reduction in the rate, the consequence of an increase in Q S and Q M downstream of venous admission point 20 in the case of a pre-dilution is not to a reduction, but rather to an increase in the density and leads in the case of a post-dilution not to an increase, but rather a reduction in the density (graph A). The density increases upstream of venous admission point 20 and downstream of blood chamber 3 both for the pre- as well as the post-dilution, the original value for the density being re-established (graph B) in the case of pre-dilution, in contrast with post-dilution. The density in the case of pre-dilution diminishes downstream of arterial admission point 19 and upstream of blood chamber 3 , whereas in the case of post-dilution it neither increases nor decreases, i.e. it remains the same (graph C).
In an alternative embodiment, control unit 18 and evaluation unit 22 are designed in such a way that substitution rate Q S and flow rate Q M are reduced and it is concluded that there is a pre- or post-dilution on the basis of the change in the density, as is described by reference to FIGS. 3A and 3B .
In a further example of embodiment, it is not substitution rate Q S or flow rate Q M , but rather blood flow rate Q b that is changed ( FIGS. 4A and 4B ). Control unit 18 controls blood pump 8 in this embodiment in such a way that blood flow rate Q b is increased by a preset amount ΔQ b . Graphs A, B, C again show the time-related course of the density of the blood or the blood constituent, which is measured with the three measuring units 21 A, 21 B, and 21 C. It may be seen that, with measuring units 21 A and 21 B, a pre- or post-dilution may be detected only with a more precise quantitative evaluation of the change in density. The evaluation unit therefore preferably evaluates the measured values of measuring unit 21 C, with which the density downstream of arterial admission point 19 and upstream of blood chamber 3 of the dialyzer is measured. Evaluation unit 22 ascertains a pre-dilution if the density has increased by a preset amount and it ascertains a post-dilution if the density has not increased by a preset amount, i.e. has remained the same. It is of course also conceivable for blood flow rate Q B to be reduced by a preset amount. The measurements then run in each case in the opposite direction.
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An apparatus and a method for monitoring the supply of replacement fluid during an extracorporeal treatment of blood is disclosed. Detection of the supply of replacement fluid upstream or downstream of the dialyser or filter is based on a measurement of the optical or physical density of the blood or of a constituent of blood in the extracorporeal circulation. To detect pre- or post-dilution, the blood flow rate and/or the replacement rate and/or the flow rate of the fluid removed from the blood through the dialyser membrane is altered, and the density of the blood or of the constituent of blood is measured upstream and/or downstream of the dialyser. Additionally, an apparatus for treating blood with an apparatus for monitoring the supply of replacement fluid is disclosed.
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FIELD OF THE INVENTION
Novel indolocarbazole derivatives potentially useful for the treatment of dementias characterized by tau hyperphosphorylation [Alzheimer's disease (AD), frontal lobe degeneration (FLD), argyrophilic grains disease, subacute sclerotising panencephalitis (SSPE) as a late complication of viral infections in the CNS], and cancer.
BACKGROUND OF THE INVENTION
Several dementias, most importantly Alzheimer's disease (AD), are characterized by the formation of intracellular aggregates consisting of the microtubule-associated protein tau, termed neurofibrillary tangles (NFT). The importance of this biochemical abnormality for the clinical syndrome of dementia is illustrated by essentially three facts: (I) there is a close correlation between the state of dementia and the extent and density of NFT in various parts of the cortex [e.g., Bancher C. et al. (1993) Neurosci. Lett. 162, 179-182)]; (ii) individual neurons containing NFT in the cell body and/or the neurites are morphologically degenerating, i.e., lose synaptic connections and eventually die [Braak E. et al. (1994) Acta Neuropathol. 87, 554-567; Callahan L. M. et al., (1995) Neurobiol. Aging 16, 311-314]; (iii) a certain density of NFT in various otherwise unrelated dementias is always associated with dementia, without exception.
The tau protein contained in NFT is severely hyperphosphorylated [Goedert M. et al. (1995) Neurobiol. Aging 16, 325-334; Hasegawa M. et al. (1996) FEBS Lett. 384, 25-30]. This abnormal phosphorylation renders the protein incompetent to retain its original function, i.e., stabilization of the microtubule cytoskeleton, which is of fundamental importance for the integrity of a neuron [Iqbal K. et al. (1994) FEBS Lett. 349, 104-108; Garver T. D. et al. (1996) J. Neurosci. Res. 44, 12-20]. This explains the paucity of intact microtubules in AD brains. Phosphorylation alone is responsible for this effect, as dephosphorylation restores the abilities of tau.
Because of a relationship between tau phosphorylation, cytoskeletal destabilization, synaptic loss and neuronal degeneration, and ultimately dementia, it would be therapeutically desirable to have pharmaceutical means to interfere with the pathological process of tau hyperphosphorylation.
The characteristics of hyperphosphorylated tau in NFT suggest that the protein kinase ERK2 is responsible for the pathological tau modification in AD [Drewes G. et al. (1990) EMBO J. 11, 2131-2138; Roder H. M. et al. (1993) Biochem. Biophys. Res. Commun. 193, 639-647]. ERK2 may exist in an abnormally activated state in AD [Roder H. M. et al. (1995) J. Neurochem. 64, 2203-2212). Inhibition of ERK2 has therefore been suggested as a point of interference to prevent tau hyperphosphorylation, and ultimately to stop NFT formation in neurons.
AD-like tau hyperphosphorylation can be induced in several cellular models (including brain slices), converting tau into a phosphorylation state indistinguishable from tau phosphorylated by ERK2 in vitro. The most convincing cellular models involve PP2A inhibition [Sautier, P. E. et al., Neurodegeneration 3, 53-60 (1994); Harris K. A. et al., Ann. Neurol. 13, 77-87 (1993)].
However, compounds which inhibit ERK2 and thereby prevent AD-like tau hyperphosphorylation in biological model systems, have previously not been disclosed. Such compounds can be expected to affect processes of neurofibrillary degeneration, tied to tau hyperphosphorylation, in a beneficial manner.
The protein kinases of the ERK family, often termed MAP-kinases, have also been implicated in a variety of important cellular regulation events outside the CNS, such as growth, differentiation and inflammation [e.g., Sale E. M. et al., EMBO J. 14, 674-684 (1995); Pages G. et al., Proc. Natl. Acad. Sci. USA 90, 8319-8323 (1993); Cowley S. et al., Cell 77, 841-852 (1994)]. Consequently, aberrant ERK activation has been implicated in several diseases characterized by loss of growth and differentiation control. In some tumors constitutive ERK activation is associated with cellular transformation due to dominant (activating) mutations in signal transduction proteins or viral proteins interfering with ERK inactivators [Sontag E. et al., Cell 75, 887-897 (1993); Leevers S. J. and Marshall C. J., EMBO J. 11, 569-574 (1992); Gallego G. et al., Proc. Natl. Acad. USA 89, 7355-7359 (1992); Gupta S. K. et al., J. Biol. Chem. 267, 7987-7990 (1992)].
The use of the disclosed kinase inhibitors for cancer is also indicated by their ability to inhibit cdc2 kinase. The role of cdc2 and homologous (cdks) kinases in cell cycle control is very well appreciated [Norbury C., and Nurse P., Annu. Rev. Biochem. 61, 441-470 (1992)]. Regulation of these enzymes is essential for both commitment to cell cycle from the resting state (START), and ordered transition through several phases of the cell cycle. The need for regulation is reflected in the existence of numerous positive and negative regulatory features of cdks, such as cyclin subunits, inhibiting (Thr) and activating (Tyr) phosphorylations, and endogenous peptide inhibitors.
Because of this central role of cdks in control of cell cycle and proliferation, they are considered as attractive drug targets for cancer therapies [e.g., Filguera de Azevedo W. et al., Proc. Natl. Acad. Sci. USA 93, 2735-2740 (1996)].
DESCRIPTION OF RELATED ART
Indolocarbazole derivatives structurally related to the invention compounds have been described in the literature. The majority of these compounds are derived from the natural product K252a. The production and isolation of K252a was first published by Kase, et al. [J. of Antibiotics 39, 1059 (1986)]. Subsequent structure elucidation of K252a, b, c and d were reported in the same year by Yasuzawa et al. [J. of Antibiotics 39, 1072 (1986)]. Since the original disclosure and structure elucidation, K252a has been shown to be active in a variety of enzyme and cell-based assays. In particular, these compounds have demonstrated potent protein kinase C (PKC) activity. The most common uses claimed include: cancer, EP 0 323 171 (priority date Dec. 24, 1987), EP 0 643 966 (priority date Mar. 3, 1993), U.S. Pat. No. 4,923,986 (priority date Mar. 9, 1987), U.S. Pat. No. 4,877,776 (priority date Dec. 24, 1987), WO 94 27982 (priority date May 28, 1993); neurodegenerative disorders, WO 95 07911 (priority date Sep. 16, 1993), WO 94 02488 (priority date Jul. 24, 1992), antimicrobial [Prudhomme et al., J. Antibiotics 47, 792 (1994)], and hypertension [Hachisu et al., Life Sciences 44, 1351 (1989)]. ##STR1##
In general, prior art compounds related to the invention are derived from K252a and contain the basic core structure where a tetrahydrofuran moiety is attached to the aglycone forming two glycosidic bonds. Modifications of the K252a core structure include additional substituents on the lactam and indole portions, and modifications of the a-hydroxy ester. The tetrahydrofuran oxygen in the core structure limits the opportunities for further modification.
SUMMARY OF THE INVENTION
Incorporation of a carbon at the tetrahydrofuran oxygen position of the K252a core structure significantly alters the core structure by removing the two glycosidic bonds and replacing the electron rich disubstituted atom with an electronically more neutral tetra-substituted moiety. This change also provides additional opportunities to incorporate functional groups that may enhance properties such as potency, selectivity, stability, toxicity, bioavailability, etc. which can result in an improved biological profile and consequently, a better therapeutic agent.
Compounds containing this important modification are completely inaccessible via synthetic methods used to prepare compounds of the prior art.
According to one aspect of the invention, a composition of matter is provided having the formula of Formula I, as follows: ##STR2## wherein Z is O or 2H (in which case the double bond is two single bonds), R1 is H, OH, CO 2 R9, CONHR9, CH 2 OR9, or CONR 9 R 10 ;
R2 is H or OH; R3 is H or OH; R4 is H or OH;
R5 is H, OH, NR 9 R 10 , NHCOR 9 , OCOR 9 , OCR 9 , halide, COOR 9 , or CONR 9 R 10 ;
R6 is H, OH, NR 9 R 10 , NHCOR 9 , OCOR 9 , OCR 9 , halide, COOR 9 , or CONR 9 R 10 ;
R 7 is H, OH, O or halide;
R8 is H, OH, halide or nothing (when R7 is O);
R9 is an alkyl of 1-6 carbons, a cycloalkyl of 3-6 carbons or H;
R10 is an alkyl of 1-6 carbons, a cycloalkyl of 3-6 carbons or H.
In certain preferred embodiments, Z is O; R1 is OH, CO 2 R9, CHNHR9 or CH 2 OR9; R4 is H; R5 is H; R6 is H; and R8 is H. In other preferred embodiments, Z is O; R1 is CO 2 CH 3 or CONHCH 3 ; R2 is H; R3 is OH; R4 is H; R5 is H; and R6 is H. The most preferred compositions of matter are: ##STR3##
According to another aspect of the invention, pharmaceutical compositions are provided. The pharmaceutical compositions include the compositions of matter described above, together with a pharmaceutically acceptable carrier. The preferred pharmaceutical compositions are as described above. Particularly preferred pharmaceutical compositions are those formulated in an oral dosage form.
In some embodiments, the pharmaceutical composition contains the composition of matter in an amount effective for inhibiting abnormal hyperphosphorylation associated with a dementia. In other embodiments, the pharmaceutical composition contains the composition of matter in an amount effective for inhibiting a cdk kinase, such as cdc2 kinase. In still other embodiments, the pharmaceutical composition contains the composition of matter in an amount effective to inhibit cell proliferation, and in certain embodiments to inhibit cancer cell proliferation by cancer cells expressing abnormal amounts of a cdk kinase.
According to another aspect of the invention, a method is provided for inhibiting in a subject a kinase which binds a compound of Formula I. A compound of Formula I is administered to a subject in need of such treatment in an amount effective to inhibit in the subject the kinase activity. Preferred compounds are as described above. In one embodiment, the subject has a dementia and the compound is administered in an amount effective to inhibit abnormal hyperphosphorylation characteristic of the dementia. The dementia can be, among other things, Alzheimer's disease and the compound can be administered in an amount effective to inhibit phosphorylation activity of ERK2 which is characteristic of abnormal tau hyperphosphorylation in Alzheimer's disease.
According to another aspect of the invention, a method is provided for treating a subject having a cancer which expresses abnormal levels of cdk kinase activity. The method involves administering to a subject in need of such treatment a compound of Formula I in an amount effective to inhibit the cdk kinase activity. In some embodiments, the kinase is cdc2 kinase. The preferred compounds are as described above.
According to another aspect of the invention, intermediates for preparing the compounds of Formula I are provided. The intermediates are described in detail in the text below. Particularly important intermediates are those numbered 13, 19 and 24.
According to still another aspect of the invention, a method is provided which involves the use of a compound of Formula I in the preparation of a medicament. In particular embodiments, the medicament is for treating a dementia (e.g. Alzheimer's disease), a proliferative disorder (e.g. a cancer). These and other aspects of the invention are described in greater detail below.
According to another aspect of the invention, intermediates for manufacturing the above compounds are provided. These are compositions of matter comprising: ##STR4## wherein, Z═O or 2H (in which case the double bond is two single bonds);
R 11 , R 12 ═H, ##STR5## except that when R 11 is not H, then R 12 is H and when R 12 is not H, then R 11 is H;
R 13 , R 13 '═H or OP', and R 14 is H or OP. Preferably, Z is O and R 13 and R 13 ' are H. Most preferable the composition of matter is compound 14. P is a protecting group. Preferred Ps for OP are benzyl- and t-butyl-dimethyl sylyl. Most preferably the composition of matter is compound 12, 13, 18, 19, 23 or 24.
Other compositions of matter are ##STR6## Wherein, Z═O or 2H; R 13 and R 13 '═H or OP; and R14═O, H, OH or OP.
Preferably, Z is O and R 13 and R 13 ' are H. Most preferably the composition of matter is compound 14.
Mixtures of the foregoing compounds including isomeric mixtures also are contemplated.
BRIEF DESCRIPTION OF THE DRAWING
FIG. 1 is a drawing of a blot on okadaic acid stimulated cells showing that compound CIII prevent tau hyperphosphorylation caused by okadaic acid.
FIG. 2. Western-blot comparison of tau from human SY5Y cells and from neonatal rat brain in various states of phosphorylation with PHF-tau from AD-brain. FIG. 2A shows human SY5Y cells. FIG. 2B shows neonatal rat brain. FIG. 2C shows PHF-tau from AD-brain.
FIG. 3 is a drawing of a pair of gels showing neonatal rat tau phosphorylation in vitro by PK40 without and with prior dephosphorylation by PP2B.
FIG. 4 is a drawing of a blot showing that a compound similar to CIII as an inhibitor of ERK2 prevents abnormal AD-like hyperphosphorylation in a SY5Y cell model system.
FIG. 5. Prevention of AD-like tau hyperphosphorylation in adult rat hippocampal brain slices. In an experimental paradigm similar to SY5Y cells tau hyperphosphorylation is prevented by CII at similar doses as in SY5Y cells. Note that the results with AP422, currently the most specific criterion for AD-like tau hyperphosphorylation, are identical to those with the commonly used mAb AT8, indicating that ERK2 alone is responsible for all okadaic acid induced changes in tau phosphorylation because AT8 but not AP422 reactivity can be induced by kinases other than ERK2.
DETAILED DESCRIPTION OF THE INVENTION
The present invention relates to certain novel indolocarbazole derivatives that contain a cyclopentane core structure and may be medicinally useful for the treatment of a variety of disorders, including certain cancers and neurodegenerative disorders. The compounds have ERK2 and/or cdk, and in particular, cdc2, inhibitory activity.
The compounds of the invention, including the preferred compounds have been described above. An aspect of the invention is the replacement of the oxygen molecule of the tetrahydrofuran portion of certain prior art molecules (K252a and analogs) with a carbon atom. Such a class of materials was not available prior to the present invention which also provides a synthetic procedure for preparing this class of materials. The procedure also forms an aspect of the invention. The procedure for making the class of materials is described in detail below in the Examples section.
The most preferred compounds of the invention are indicated and named below:
CI. 9,12-Methano-1H-diindolo[1,2,3-fg:3',2',1'-kl]pyrrolo[3,4-I][1,6]benzodiazocine-1,3(2H)-dione,9,10,11,12-tetrahydro-8,10,11-trihydroxy-(8α,9.alpha.,10α,11α,12α).
CII. 9,12-Methano-1H-diindolo[1,2,3-fg:3',2'0,1'-kl]pyrrolo[3,4-I][1,6]benzodiazocine-10-carboxamide, 2,3,9,10,11,12-hexahydro-10-hydroxy-N-methyl-1,3-dioxo-(9α,10β,12α).
CIII. 9,12-Methano-1H-diindolo[1,2,3-fg:3',2',1'-kl]pyrrolo[3,4-I][1,6]benzodiazocine-10-carboxylic acid, 2,3,9,10,11,12-hexahydro-10-hydroxy-1,3-dioxomethyl ester, (9α,10β,12α).
The invention also involves intermediates for manufacturing the above compounds. The intermediates are described above. Mixtures including isomeric mixtures also may result depending upon the symmetry of the starting molecule. Such mixtures are within the scope of the invention.
To prepare the full range of compounds of the invention, only the chemistry described below, together with chemistry well known to those of ordinary skill in the art is required. In particular, modifications of the core structures can be accomplished using routine chemistry such as that used to make similar modifications to k252a, as detailed in WO94/02488, WO94/27982, WO94/04541 and numerous other U.S. patents and published applications showig derivatives of k252a.
A subject as used herein means humans, primates, horses, cows, pigs, sheep, goats, dogs, cats and rodents.
The pharmaceutical preparations of the invention are administered to subjects in effective amounts. An effective amount means that amount necessary to delay the onset of, inhibit the progression of, halt altogether the onset or progression of or diagnose the particular condition being treated. In general, an effective amount for treating a dementia is that amount necessary to affect favorably abnormal hyperphosphorylation characteristic of the dementia. In one embodiment, the effective amount is that amount necessary to affect favorably abnormal tau hyperphosphorylation associated with Alzheimer's disease. In general, an effective amount for treating cancer will be that amount necessary to favorably affect mammalian cancer cell proliferation in-situ. When administered to a subject, effective amounts will depend, of course, on the particular condition being treated; the severity of the condition; individual patient parameters including age, physical condition, size and weight; concurrent treatment; frequency of treatment; and the mode of administration. These factors are well known to those of ordinary skill in the art and can be addressed with no more than routine experimentation. It is preferred generally that a maximum dose be used, that is, the highest safe dose according to sound medical judgment.
A variety of administration routes are available. The particular mode selected will depend, of course, upon the particular condition being treated, the particular drug selected, the severity of the condition being treated and the dosage required for therapeutic efficacy. The methods of this invention, generally speaking, may be practiced using any mode of administration that is medically acceptable, meaning any mode that produces effective levels of the active compounds without causing clinically unacceptable adverse effects. Such modes of administration include oral, rectal, sublingual, topical, nasal, transdermal, intradermal or parenteral routes. The term "parenteral" includes subcutaneous, intravenous, intramuscular, or infusion. Oral routes are preferred.
Dosage may be adjusted appropriately to achieve desired drug levels, locally or systemically. Generally, daily oral doses of active compounds will be from about 0.01 mg/kg per day to 1000 mg/kg per day. It is expected that IV doses in the range of about 1 to 1000 mg/m 2 per day will be effective. In the event that the response in a subject is insufficient at such doses, even higher doses (or effective higher doses by a different, more localized delivery route) may be employed to the extent that patient tolerance permits.
The compositions may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy. All methods include the step of bringing the conjugates of the invention into association with a carrier which constitutes one or more accessory ingredients. In general, the compositions are prepared by uniformly and intimately bringing the compounds into association with a liquid carrier, a finely divided solid carrier, or both, and then, if necessary, shaping the product.
Compositions suitable for oral administration may be presented as discrete units such as capsules, cachets, tablets, or lozenges, each containing a predetermined amount of the active compound. Other compositions include suspensions in aqueous liquors or non-aqueous liquids such as a syrup, an elixir, or an emulsion.
Other delivery systems can include time-release, delayed release or sustained release delivery systems. Such systems can avoid repeated administrations of the active compounds of the invention, increasing convenience to the subject and the physician. Many types of release delivery systems are available and known to those of ordinary skill in the art. They include polymer based systems such as polylactic and polyglycolic acid, polyanhydrides and polycaprolactone; nonpolymer systems that are lipids including sterols such as cholesterol, cholesterol esters and fatty acids or neutral fats such as mono-, di and triglycerides; hydrogel release systems; silastic systems; peptide based systems; wax coatings, compressed tablets using conventional binders and excipients, partially fused implants and the like. In addition, a pump-based hardware delivery system can be used, some of which are adapted for implantation.
A long-term sustained release implant also may be used. "Long-term" release, as used herein, means that the implant is constructed and arranged to deliver therapeutic levels of the active ingredient for at least 30 days, and preferably 60 days. Long-term sustained release implants are well known to those of ordinary skill in the art and include some of the release systems described above. Such implants can be particularly useful in treating solid tumors by placing the implant near or directly within the tumor, thereby affecting localized, high-doses of the compounds of the invention.
When administered, the formulations of the invention are applied in pharmaceutically acceptable compositions. Such preparations may routinely contain salts, buffering agents, preservatives, compatible carriers, and optionally other therapeutic ingredients. When used in medicine the salts should be pharmaceutically acceptable, but non-pharmaceutically acceptable salts may conveniently be used to prepare pharmaceutically acceptable salts thereof and are not excluded from the scope of the invention. Such salts include, but are not limited to, those prepared from the following acids: hydrochloric, hydrobromic, sulphuric, nitric, phosphoric, maleic, acetic, salicylic, p-toluene sulfonic, tartaric, citric, methane sulfonic, formic, malonic, succinic, naphthalene-2-sulfonic, and benzene sulfonic. Also, pharmaceutically acceptable salts can be prepared as alkaline metal or alkaline earth salts, such as sodium, potassium or calcium salts.
Suitable buffering agents include: acetic acid and a salt (1-2% W/V); citric acid and a salt (1-3% W/V); and phosphoric acid and a salt (0.8-2% W/V).
Suitable preservatives include benzalkonium chloride (0.003-0.03% W/V); chlorobutanol (0.3-0.9% W/V); parabens (0.01-0.25% W/V) and thimerosal (0.004-0.02% W/V).
Suitable carriers are pharmaceutically-acceptable carriers. The term pharmaceutically-acceptable carrier means one or more compatible solid or liquid filler, dilutants or encapsulating substances which are suitable for administration to a human or other animal. The term "carrier" denotes an organic or inorganic ingredient, natural or synthetic, with which the active ingredient is combined to facilitate the application. The components of the pharmaceutical compositions are capable of being commingled with the molecules of the present invention, and with each other, in a manner such that there is no interaction which would substantially impair the desired pharmaceutical efficacy. Carrier formulations suitable for oral, subcutaneous, intravenous, intramuscular, etc. can be found in Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pa. and in the numerous prior art patents relating to K252a and its analogs.
The compounds useful in the invention may be delivered with other therapeutic agents. In the case of cancer, the compounds would be delivered separately or in the form of anti-cancer cocktails. An anti-cancer cocktail is a mixture of any one of the compounds of this invention with another anti-cancer agent such as an anti-cancer drug, a cytokine, and/or supplementary potentiating agent(s). The use of cocktails in the treatment of cancer is routine. In this embodiment, a common administration vehicle (e.g., pill, tablet, implant, injectable solution, etc.) could contain both the compounds useful in this invention (described above) and the anti-cancer drug and/or supplementary potentiating agent.
Thus, cocktails of non-Formula I compounds and Formula I compounds are contemplated. Non-Formula I anti-neoplastic compounds include:
Antineoplastic: Acivicin; Aclarubicin; Acodazole Hydrochloride; Acronine; Adozelesin; Aldesleukin; Altretamine; Ambomycin; Ametantrone Acetate; Aminoglutethimide; Amsacrine; Anastrozole; Anthramycin; Asparaginase; Asperlin ; Azacitidine; Azetepa; Azotomycin; Batimastat; Benzodepa; Bicalutamide; Bisantrene Hydrochloride; Bisnafide Dimesylate; Bizelesin; Bleomycin Sulfate; Brequinar Sodium; Bropirimine; Busulfan; Cactinomycin; Calusterone; Caracemide; Carbetimer; Carboplatin; Carmustine; Carubicin Hydrochloride; Carzelesin; Cedefingol; Chlorambucil; Cirolemycin ; Cisplatin; Cladribine; Crisnatol Mesylate; Cyclophosphamide ; Cytarabine ; Dacarbazine; Dactinomycin; Daunorubicin Hydrochloride; Decitabine; Dexormaplatin; Dezaguanine; Dezaguanine Mesylate; Diaziquone; Docetaxel; Doxorubicin; Doxorubicin Hydrochloride; Droloxifene; Droloxifene Citrate; Dromostanolone Propionate; Duazomycin; Edatrexate; Eflornithine Hydrochloride ; Elsamitrucin; Enloplatin; Enpromate; Epipropidine; Epirubicin Hydrochloride; Erbulozole; Esorubicin Hydrochloride; Estramustine; Estramustine Phosphate Sodium; Etanidazole; Ethiodized Oil I 131; Etoposide; Etoposide Phosphate; Etoprine; Fadrozole Hydrochloride; Fazarabine; Fenretinide; Floxuridine; Fludarabine Phosphate; Fluorouracil; Flurocitabine; Fosquidone; Fostriecin Sodium; Gemcitabine; Gemcitabine Hydrochloride; Gold Au 198 ; Hydroxyurea; Idarubicin Hydrochloride; Ifosfamide; lmofosine; Interferon Alfa-2a; Interferon Alfa-2b ; Interferon Alfa-n1; Interferon Alfa-n3; Interferon Beta- I a; Interferon Gamma- I b; Iproplatin; Irinotecan Hydrochloride ; Lanreotide Acetate; Letrozole; Leuprolide Acetate ; Liarozole Hydrochloride; Lometrexol Sodium; Lomustine; Losoxantrone Hydrochloride; Masoprocol; Maytansine;
Mechlorethamine Hydrochloride; Megestrol Acetate; Melengestrol Acetate; Melphalan; Menogaril; Mercaptopurine; Methotrexate; Methotrexate Sodium; Metoprine; Meturedepa; Mitindomide; Mitocarcin; Mitocromin; Mitogillin; Mitomalcin; Mitomycin; Mitosper; Mitotane; Mitoxantrone Hydrochloride; Mycophenolic Acid; Nocodazole; Nogalamycin; Ormaplatin; Oxisuran; Paclitaxel; Pegaspargase; Peliomycin; Pentamustine; Peplomycin Sulfate; Perfosfamide; Pipobroman; Piposulfan; Piroxantrone Hydrochloride; Plicamycin; Plomestane; Porfimer Sodium; Porfiromycin; Prednimustine; Procarbazine Hydrochloride; Puromycin; Puromycin Hydrochloride; Pyrazofurin; Riboprine; Rogletimide; Safingol; Safingol Hydrochloride; Semustine; Simtrazene; Sparfosate Sodium; Sparsomycinl, Spirogermanium Hydrochloride; Spiromustine; Spiroplatin; Streptonigrin; Streptozocin; Strontium Chloride Sr 89; Sulofenur; Talisomycin; Taxane; Taxoid; Tecogalan Sodium; Tegafur; Teloxantrone Hydrochloride; Temoporfin; Teniposide; Teroxirone; Testolactone; Thiamiprine; Thioguanine; Thiotepa; Tiazofurin; Tirapazamine; Topotecan Hydrochloride; Toremifene Citrate; Trestolone Acetate; Triciribine Phosphate; Trimetrexate; Trimetrexate Glucuronate; Triptorelin; Tubulozole Hydrochloride; Uracil Mustard; Uredepa; Vapreotide; Verteporfin; Vinblastine Sulfate; Vincristine Sulfate; Vindesine; Vindesine Sulfate; Vinepidine Sulfate; Vinglycinate Sulfate; Vinleurosine Sulfate; Vinorelbine Tartrate; Vinrosidine Sulfate; Vinzolidine Sulfate; Vorozole; Zeniplatin; Zinostatin; Zorubicin Hydrochloride. Other anti-neoplastic compounds include: 20-epi-1,25 dihydroxyvitamin D3; 5-ethynyluracil; abiraterone; aclarubicin; acylfulvene; adecypenol; adozelesin; aldesleukin; ALL-TK antagonists; altretamine; ambamustine; amidox; amifostine; aminolevulinic acid; amrubicin; amsacrine; anagrelide; anastrozole; andrographolide; angiogenesis inhibitors; antagonist D; antagonist G; antarelix; anti-dorsalizing morphogenetic protein-1; antiandrogen, prostatic carcinoma; antiestrogen; antineoplaston; antisense oligonucleotides; aphidicolin glycinate; apoptosis gene modulators; apoptosis regulators; apurinic acid; ara-CDP-DL-PTBA; arginine deaminase; asulacrine; atamestane; atrimustine; axinastatin 1; axinastatin 2; axinastatin 3; azasetron; azatoxin; azatyrosine; baccatin III derivatives; balanol; batimastat; BCR/ABL antagonists; benzochlorins; benzoylstaurosporine; beta lactam derivatives; beta-alethine; betaclamycin B; betulinic acid; bFGF inhibitor; bicalutamide; bisantrene; bisaziridinylspermine; bisnafide; bistratene A; bizelesin; breflate; bropirimine; budotitane; buthionine sulfoximine; calcipotriol; calphostin C; camptothecin derivatives; canarypox IL-2; capecitabine; carboxamide-amino-triazole; carboxyamidotriazole; CaRest M3; CARN 700; cartilage derived inhibitor; carzelesin; casein kinase inhibitors (ICOS); castanospermine; cecropin B; cetrorelix; chlorins; chloroquinoxaline sulfonamide; cicaprost; cis-porphyrin; cladribine; clomifene analogues; clotrimazole; collismycin A; collismycin B; combretastatin A4; combretastatin analogue; conagenin; crambescidin 816; crisnatol; cryptophycin 8; cryptophycin A derivatives; curacin A; cyclopentanthraquinones; cycloplatam; cypemycin; cytarabine ocfosfate; cytolytic factor; cytostatin; dacliximab; decitabine; dehydrodidemnin B; deslorelin; dexifosfamide; dexrazoxane; dexverapamil; diaziquone; didemnin B; didox; diethylnorspermine; dihydro-5-azacytidine; dihydrotaxol, 9-; dioxamycin; diphenyl spiromustine; docosanol; dolasetron; doxifluridine; droloxifene; dronabinol; duocarmycin SA; ebselen; ecomustine; edelfosine; edrecolomab; eflornithine; elemene; emitefur; epirubicin; epristeride; estramustine analogue; estrogen agonists; estrogen antagonists; etanidazole; etoposide phosphate; exemestane; fadrozole; fazarabine; fenretinide; filgrastim; finasteride; flavopiridol; flezelastine; fluasterone; fludarabine; fluorodaunorunicin hydrochloride; forfenimex; formestane; fostriecin; fotemustine; gadolinium texaphyrin; gallium nitrate; galocitabine; ganirelix; gelatinase inhibitors; gemcitabine; glutathione inhibitors; hepsulfam; heregulin; hexamethylene bisacetamide; hypericin; ibandronic acid; idarubicin; idoxifene; idramantone; ilmofosine; ilomastat; imidazoacridones; imiquimod; immunostimulant peptides; insulin-like growth factor-1 receptor inhibitor; interferon agonists; interferons; interleukins; iobenguane; iododoxorubicin; ipomeanol, 4-; irinotecan; iroplact; irsogladine; isobengazole; isohomohalicondrin B; itasetron; jasplakinolide; kahalalide F; lamellarin-N triacetate; lanreotide; leinamycin; lenograstim; lentinan sulfate; leptolstatin; letrozole; leukemia inhibiting factor; leukocyte alpha interferon; leuprolide+estrogen+progesterone; leuprorelin; levamisole; liarozole; linear polyamine analogue; lipophilic disaccharide peptide; lipophilic platinum compounds; lissoclinamide 7; lobaplatin; lombricine; lometrexol; lonidamine; losoxantrone; lovastatin; loxoribine; lurtotecan; lutetium texaphyrin; lysofylline; lytic peptides; maitansine; mannostatin A; marimastat; masoprocol; maspin; matrilysin inhibitors; matrix metalloproteinase inhibitors; menogaril; merbarone; meterelin; methioninase; metoclopramide; MIF inhibitor; mifepristone; miltefosine; mirimostim; mismatched double stranded RNA; mitoguazone; mitolactol; mitomycin analogues; mitonafide; mitotoxin fibroblast growth factor-saporin; mitoxantrone; mofarotene; molgramostim; monoclonal antibody, human chorionic gonadotrophin; monophosphoryl lipid A+myobacterium cell wall sk; mopidamol; multiple drug resistance gene inhibitor; multiple tumor suppressor 1-based therapy; mustard anticancer agent; mycaperoxide B; mycobacterial cell wall extract; myriaporone; N-acetyldinaline; N-substituted benzamides; nafarelin; nagrestip; naloxone+pentazocine; napavin; naphterpin; nartograstim; nedaplatin; nemorubicin; neridronic acid; neutral endopeptidase; nilutamide; nisamycin; nitric oxide modulators; nitroxide antioxidant; nitrullyn; 06-benzylguanine; octreotide; okicenone; oligonucleotides; onapristone; ondansetron; ondansetron; oracin; oral cytokine inducer; ormiaplatin; osaterone; oxaliplatin; oxaunomycin; paclitaxel analogues; paclitaxel derivatives; palauamine; palmitoylrhizoxin; pamidronic acid; panaxytriol; panomifene; parabactin; pazelliptine; pegaspargase; peldesine; pentosan polysulfate sodium; pentostatin; pentrozole; perflubron; perfosfamide; perillyl alcohol; phenazinomycin; phenylacetate; phosphatase inhibitors; picibanil; pilocarpine hydrochloride; pirarubicin; piritrexim; placetin A; placetin B; plasminogen activator inhibitor; platinum complex; platinum compounds; platinum-triamine complex; porfimer sodium; porfiromycin; propyl bis-acridone; prostaglandin J2; proteasome inhibitors; protein A-based immune modulator; protein kinase C inhibitor; protein kinase C inhibitors, microalgal; protein tyrosine phosphatase inhibitors; purine nucleoside phosphorylase inhibitors; purpurins; pyrazoloacridine; pyridoxylated hemoglobin polyoxyethylene conjugate; raf antagonists; raltitrexed; ramosetron; ras farnesyl protein transferase inhibitors; ras inhibitors; ras-GAP inhibitor; retelliptine demethylated; rhenium Re 186 etidronate; rhizoxin; ribozymes; RII retinamide; rogletimide; rohitukine; romurtide; roquinimex; rubiginone B 1; ruboxyl; safingol; saintopin; SarCNU; sarcophytol A; sargramostim; Sdi 1 mimetics; semustine; senescence derived inhibitor 1; sense oligonucleotides; signal transduction inhibitors; signal transduction modulators; single chain antigen binding protein; sizofiran; sobuzoxane; sodium borocaptate; sodium phenylacetate; solverol; somatomedin binding protein; sonermin; sparfosic acid; spicamycin D; spiromustine; splenopentin; spongistatin 1; squalamine; stem cell inhibitor; stem-cell division inhibitors; stipiamide; stromelysin inhibitors; sulfinosine; superactive vasoactive intestinal peptide antagonist; suradista; suramin; swainsonine; synthetic glycosaminoglycans; tallimustine; tamoxifen methiodide; tauromustine; tazarotene; tecogalan sodium; tegafur; tellurapyrylium; telomerase inhibitors; temoporfin; temozolomide; teniposide; tetrachlorodecaoxide; tetrazomine; thaliblastine; thalidomide; thiocoraline; thrombopoietin; thrombopoietin mimetic; thymalfasin; thymopoietin receptor agonist; thymotrinan; thyroid stimulating hormone; tin ethyl etiopurpurin; tirapazamine; titanocene dichloride; topotecan; topsentin; toremifene; totipotent stem cell factor; translation inhibitors; tretinoin; triacetyluridine; triciribine; trimetrexate; triptorelin; tropisetron; turosteride; tyrosine kinase inhibitors; tyrphostins; UBC inhibitors; ubenimex; urogenital sinus-derived growth inhibitory factor; urokinase receptor antagonists; vapreotide; variolin B; vector system, erythrocyte gene therapy; velaresol; veramine; verdins; verteporfin; vinorelbine; vinxaltine; vitaxin; vorozole; zanoterone; zeniplatin; zilascorb; zinostatin stimalamer.
Anti-cancer Supplementary Potentiating Agents: Tricyclic anti-depressant drugs (e.g., imipramine, desipramine, amitryptyline, clomipramine, trimipramine, doxepin, nortriptyline, protriptyline, amoxapine and maprotiline); non-tricyclic anti-depressant drugs (e.g., sertraline, trazodone and citalopram); Ca ++ antagonists (e.g., verapamil, nifedipine, nitrendipine and caroverine); Calmodulin inhibitors (e.g., prenylamine, trifluoroperazine and clomipramine); Amphotericin B; Triparanol analogues (e.g., tamoxifen); antiarrhythmic drugs (e.g., quinidine); antihypertensive drugs (e.g., reserpine); Thiol depleters (e.g., buthionine and sulfoximine) and Multiple Drug Resistance reducing agents such as Cremaphor EL. The compounds of the invention also can be administered with cytokines such as granulocyte colony stimulating factor.
The conjugates of the invention also are useful, in general, for treating mammalian cell proliferative disorders other than cancer, including psoriasis, actinic keratosis, etc.
General Preparative Methods
The compounds of the invention may be prepared by use of known chemical reactions and procedures. Nevertheless, the following general preparative methods are presented to aid the reader in synthesizing the inhibitors. More detailed procedures for particular examples are presented below in the experimental section.
In the general methods, the following generic descriptions apply. The group designated P represents a protecting group. It may be appreciated by one skilled in the art that a variety of different protecting groups may be used to protect a potentially reactive functional group (e.g., imide nitrogen, hydroxyl, carboxycylic acid) and that the particular choice will depend upon the reaction conditions required to prepare a given target compound. A description of such protecting groups may be found in: Protective Groups in Organic Synthesis , Second Edition, T. W. Green and P. G. M. Wuts, John Wiley and Sons, New York, 1991.
The group designated X represents a leaving group. It is well-known to those skilled in the art that several different functional groups such as halides, mesylates, tosylates and triflates may serve as leaving groups. It is also known that the choice of a particular leaving group typically depends on such factors as the reactivity of the nucleophile, stability of the compound and ease of synthesis. It is understood that in cases where R represents a potentially reactive functional group such as an alcohol or an amine, appropriate protection and deprotections steps may be required. It is also understood that all variable groups of these methods are as described in the generic description if they are not specifically defined below. When a variable group with a given symbol (i.e., R4) is used more than once, each of these groups may be independently varied within the range of the definition of that symbol.
General Method A The compounds of the invention where the cyclopentane ring is cis-dihydroxylated anti to the indolocarbazole moiety (R 1 ,R 2 , Formula I=--OH) are conveniently prepared by method A. The first key step in the process involves the alkylation of the protected indolo[2,3-a]carbazole moiety with a suitable cyclopentane (ene) electrophile. The protected indolo[2,3-a]carbazole moiety is conveniently prepared using methods described in the literature [Lowinger, T. B. et al., Tetrahedron Lett. 36, 8383 (1995), P=paramethoxy benzyl]. Electrophile 11 where R 14 =--H and X=OMs can be prepared from commercially available 3-acetoxy-cyclopentene-2-ol by treatment with methanesulfony chloride and triethylamine. Derivatives with R 14 ≠H can be prepared using standard methods known to those skilled in the art. Treatment of the protected indolo[2,3-a]carbazole with a base like Cs 2 CO 3 or NaH in a polar parotic solvent like DMF followed by addition of the alkylating agent (11) provides the desired monoalkylated material. Conversion of 12 to alcohol 13 can be accomplished by a variety of methods well-known to those skilled in the art. One method involves a transesterification reaction where the acetate moiety is transferred to an alcoholic solvent by treatment with catalytic NaCN. Cyclization of alcohol 13 to form the 7-membered ring of 14 can be carried out using triphenylshosphine and diethyl azodicarboxylate in a reaction known as the Mitsunobo reaction. An excellent review of this chemistry is described in Organic Reactions 42, 335 (1992). Subsequent oxidation of 14 to diol 15 can be accomplished by an OSO 4 catalyzed cis-hydroxylation. The oxidation reaction is conveniently carried out using a catalytic amount of OSO 4 with a reoxidant such as N-methyl morpholine N-oxide (NMO) in an aqueous tetrahydrofuran (THF) or acetone solution. Similar oxidation using other metal-like Manganese and Ruthenium can also be used. The method used to remove the protecting group P from intermediate 15 will depend on the particular group used.
Deprotection of 15 where P is p-methoxybenzyl can be accomplished by treatment with trifluoroacetic acid (TFA) at elevated temperatures. Addition of a cation scavenger like anisole to the reaction mixture often results in higher yields. Those skilled in the art will appreciate that different protecting groups may be required depending on the reactivity of the various R groups. ##STR7## General Method B
The compounds of the invention where the cyclopentane ring is cis-dihydroxylated anti to the indolocarbazole moiety (R 1 ,R 2 , Formula I=--OH) and R 14 =hydroxyl or a substituent derived from the hydroxyl group are conveniently prepared by method B. The first key step in the process involves the alkylation of the protected indolo[2,3-a]carbazole moiety with a suitable electrophile (17). The protected indolo[2,3-a]carbazole can be prepared using methods described in the literature [Lowinger T. B. et al., Tetrahedron Lett. 36, 8383 (1995), P=paramethoxy benzyl]. Alkylation of the protected indolo[2,3-a]carbazole moiety with mesylate 17 (Johnson et al. . . .) using a base like NaH or Cs 2 CO 3 in a polar parotic solvent like DMF provides the mono-alkylated product 18. Deprotection of the acetonide moiety using standard hydrolysis conditions provide dialcohol 19. Dialcohol 19 can be converted to the cyclized product 20 by hydroxyl directed epoxidation and subsequent intramolecular alkylation, or cyclization using Mitsunobu conditions followed by cis-hydroxylation using O S O 4 . Deprotection of 20 where P is p-methoxybenzyl can be accomplished by treatment with trifluoroacetic acid (TFA) at elevated temperatures. Addition of a cation scavenger like anisole to the reaction mixture often results in higher yields. Those skilled in the art will appreciate that different protecting groups may be required depending on the reactivity of the various R groups. ##STR8## General Method C
The compounds of the invention with an α-hydroxy carboxyl moiety as illustrated in Scheme 3 are conveniently prepared using method C. The first key step in the process involves alkylation of the protected indolo[2,34-a]carbazole moiety with a wuitable cyclopentene electrophile. Protected indolo[2,3-a]carbazole moiety 10 is conveniently prepared using methods described in the literature [Lowinger T. B. et al., Tetrahedron Lett. 36, 8383 (1995) P=paramethoxy benzyl]. Electrophile 22 can be prepared from cyclopentene-3-ol by treatment with methanesulfonyl chloride and triethylamine. Cyclopenpene-3-ol can be prepared according to the procedures described in J. Org. Chem. 32, 4138 (1967). Treatment of the protected indolo[2,3-a]carbazole with a base like Cs 2 CO 3 or NaH in a polar parotic solvent like DMF followed by addition of the alkylating agent (22) provides the desired mono-alkylated material 23. Subsequent activation of the double bond can be accomplished by an OsO 4 with a reoxidant such as N-methyl morpholine N-oxide (NMO) in an aqueous THF or Acetone solution. Cyclization of diol 24 using Mitsunobu conditions provides the bis alkylated adduct 25. A recent review of this Mitsunobu chemistry can be found in Organic Reactions, 42, 335 (1992). Oxidation of alcohol 25 to ketone 26 can be accomplished using a wide variety of reagents and reaction conditions well-known to those skilled in the art. One common method involves the use of chromium based reagents like pyrdinnium chlorochromate (PCC) in an parotic solvent such as methylenechloride. A wide variety of nucleophiles may be added to the ketone moiety in a stereoselective manner. To generate an a-hydroxy carboxyl group it is convient to add carboxylic acid anion equivalent. A general review of this methodology is described in "Unpoled Synthons", Hase T. A., Ed.; John Wiley & Sons, 1987. One example of a carboxylic acid anion equivalent is an ortho thioformyl carbanion [e.g., LiC(SMe) 3 ]. This nucleophile is conveniently prepared by treating tris(methylthio)methane with a strong base like n-BuLi. In general, the addition of the nucleophile to the ketone occurs opposite to the aglycone moiety. The thiocarboxylic acid orthoester is easily hydrolyzed by a lewis acid like boron trifluoride etherate or mercury (II) oxide. Either an ester or a carboxylic acid can be obtained from the orthoester depending on the reagents used in the hydrolysis. The methyl ester (28, Q=OMe) is conveniently obtained by treating the orthoester with mercury (II) chloride and mercury (II) oxide in aqueous methanol. The corresponding carboxylic acid (28, Q=OH) can be obtained by treatment with boron trifluoride etherate in an aqueous THF solution. Once formed, the carboxylic acid can be used as an intermediate to prepare amides (28, Q=NHMe) via a coupling reagent like carbonyldiimidizole (CDI). These procedures are well-known to those skilled in the art. The method used to remove the protecting group P from intermediate 28 will depend on the particular group used. Deprotection of 28 where P is p-methoxybenzyl (PMB) can be accomplished by treatment with trifluoroacetic acid (TFA) at elevated temperatures. Addition of a cation scavenger like anisole to the reaction mixture often results in a higher yielding reaction. Those skilled in the art will appreciate that different protecting groups may be required depending on the reactivity of the various R groups. ##STR9##
EXAMPLES
Example 1
Synthesis of 9,12-Methano-1H-diindolo[1,2,3-fg:3',2',1'-kl]pyrrolo[3,4-I][1,6]benzodiazocine-1,3(2H)-dione,9,10,11,12-tetrahydro-10,11-dihydroxy-(9α,10.alpha.,11α,12α)
In order to develop more compounds having ERK2 inhibiting activity a series of synthetically modified derivatives of K252a were prepared. The preparation of four such compounds in which the preferential inhibition of PK40 over PKC/PKA was maintained by a margin of at least 2-3 orders of magnitude is described in Examples 1-4.
It is believed that these ATP analogs act as inhibitors of PK40(ERK2) by binding to the ATP binding site on PK40. PK40 seems to be particularly susceptible to inhibition by ATP analogs, resulting in similar selectivity to K252a and ATP itself. ##STR10## Step 1. A solution of (1S,4R)-cis-4-acetoxy-2-cyclopentene-1-ol (53 mg, 0.37 mmol) and triethylamine (0.77 mL, 0.55 mmol) in a mixture of benzene (0.8 mL) and pentane (0.8 mL) was cooled to -5° C. -0° C. and treated with methanesulfonyl chloride (0.043 mL, 0.56 mmol) at a rate such that the temperature remained below 0° C. A white precipitate was observed.
In a separate round bottom flask, a solution of aglycone [prepared using the protocols described in Tetrahedron Letters 36, 8383 (1995)] (319 mg, 0.72 mmol) in DMF (6.0 mL) was cooled to -5° C.-0° C. for one hour, the reaction mixture was quenched with brine and extracted with ethyl acetate. The organic phase was dried over Na 2 SO 4 , filtered and concentrated in vacuo. Purification by MPLC (silica, 50-100% CH 2 Cl 2 -hexanes) gave the target compound (55 mg, 22-26%) as a yellow solid. 1 H NMR (DMSO-d 6 ) δ 12.19 (s, 1H), 9.19 (d, J=2.7 Hz, 1H), 9.10 (d, J=2.7 Hz, 1H), 7.78-6.87 (m, 10H), 6.81 (m, 1H), 6.51 (m, 1H), 6.36 (m, 1H), 6.13 (m, 1H), 4.82 (s, 2H), 3.69 (s, 3H), 2.68 (m, 2H), 2.10 (s, 3H); MS (FAB-LSIMS) m/z (relative intensity) 569 (M+, 44), 508 (32), 462 (100), 444 (50), 429 (30); TLC: R f 0.4 (silica, 7% EtOAc-hexanes); MP>200° C. ##STR11## Step 2. A solution of the acetate from step 1 (30 mg, 0.05 mmol) and sodium cyanide (10 mg, 0.2 mmol) in ethanol (2.0 mL) was heated at reflux until no starting material was observed by TLC (2 h). The mixture was concentrated in vacuo, washed in water (20 mL) and extracted with EtOAc (20 mL). The organic extract was dried over Na 2 SO 4 and concentrated to give a yellow oil. Purification by MPLC (silica, 0-15% EtOAc-CH 2 Cl 2 ) afforded the target alcohol (27 mg, 90%) as an orange powder. 1 H NMR (DMSO-d 6 ) δ 12.17 (s, 1H), 9.19 (d, J=2.6Hz, 1H), 9.10 (d, J=2.5 Hz, 1H), 7.78-6.87 (m, 10H), 6.79 (m, 1H), 6.28 (m, 2H), 5.25 (m, 2H), 4.83 (s, 2H), 3.68 (s, 3H), 2.54 (m, 2H); TLC (silica, 10% EtOAc-CH 2 Cl 2 ). ##STR12## Step 3. The alcohol from step 2 was added to a solution of diethyl azodicarboxylate (65.1 mg, 0.46 mmol) and triphenylphosphine (141 mg, 0.54 mmol) in tetrahydrofuran (4.0 mL). After stirring overnight at room temperature, the reaction was quenched with brine and extracted with EtOAc. The organic phase was dried over Na 2 SO 4 , filtered and concentrated in vacuo. The resulting brown oil was purified by MPLC (silica, 20-30% EtOAc-hexanes) to give the cyclized product (60mg, 31%) as a yellow powder. 1 H NMR (DMSO-d 6 ) δ 9.07 (s, 1H), 9.04 (s, 1H), 8.02-6.87 (m, 10H), 6.41 (s 2H), 6.22 (m, 2H), 4.83 (s 2H), 3.68 (s, 3H), 3.15 (m, 1H), 2.71 (m, 1H); TLC: Rf 0.75 (silica, 50% EtOAc-hexanes). ##STR13## Step 4. A solution of the imide from step 3 (49.1 mg, 0.096 mmol) in anisole (0.68 mL) was stirred at room temperature for fifteen minutes and cooled to over 0° C. Over the next twenty minutes, trifluoroacetic acid (6.8 mL) was added to the solution. After allowing the orange mixture to warm to room temperature, the solution was heated to reflux overnight. After removing the solvent in vacuo, the resulting brown oil was washed with saturated. aq. NaHCO 3 (20 mL) and extracted with EtOAc (25 mL). The organic phase was dried over Na 2 SO 4 , filtered and concentrated in vacuo. Purification of the resulting oil via flash chromatography (silica, 0-10% EtOAc-CH 2 Cl 2 ) gave the deprotected imide as an orange powder (34.9 mg, 93%). 1 H NMR (DMSO-d 6 ) δ 11.06 (s, 1H), 9.06 (s, 1H), 6.22 (d, J=2.2 Hz, 2H), 3.12 (m, 1H), 2.70 (m, 1H); MS (FAB-LSIMS) m/z (relative intensity) 390 (M+H, 60), 369 (32), 347 (62), 319 (30), 305 (18) 293 (22), 277 (100), 267 (18), 254 (28), 241 (14), 207 (14); TLC: R f 0.50 (5% EtOAc-CH 2 Cl 2 ). MP>230° C. ##STR14## Step 5--Preparation of Example 2. A solution of the imide from step 4 (14.4 mg, 0.04 mmol) and N-methylmorpholine (0.2 mL) in tetrahydrofuran (0.4 mL) was treated with osmium tetroxide (0.1 mL, 1.0 M in THF) and stirred at room temperature for one hour (until no starting material remained by TLC, EtOAc. The reaction mixture was quenched with NaHSO 3 (1.5 mL, 2 M aqueous solution) and stirred vigorously for 1 hour. The solution was diluted with brine and extracted with EtOAc. The organic phase was dried over Na 2 SO 4 and concentrated in vacuo. The resulting yellow oil was purified by HPLC (0-3% MeOH-chloroform) to afford the target diol as a red-orange powder (9.5 mg, 61%). 1 H NMR (DMSO-d 6 ) δ 11.05 (s, 1H), 9.05 (s, 1H), 9.02 (s, 1H), 7.85 (s, 1H), 7.65 (m, 2H), 7.39 (m, 2H), 5.51 (m, 2H), 5.39 (m, 2H), 4.06 (s, 2H), 3.27 (m, 1H); 2.40 (m 1H). MS (FAB-LSIMS) m/z (relative intensity) 424 (M+H, 34), 381 (24), 362 (12), 310 (16), 185 (42), 121 (72), 93 (100), 55 (50); TLC: R f 0.2 (EtOAc--); MP>230° C.
Example 2
Synthesis of 9,12-Methano-1H-diindolo[1,2,3-fg:3',2',1'-kl] pyrrolo[3,4-I[1,6]benzodiazocine-10-carboxylic acid, 2,3,9,10,11,12-hexahydro-10-hydroxy-1,3-dioxomethyl ester, (9α,10β,12α). ##STR15## Step 1. A solution of cyclopentene-3-ol [prepared using the protocols described in J. Org. Chem. 32, 1967, 4138] (2.1 g, 25.0 mmol) and triethylamine (3.60 mL, 25.8 mmol) in CH 2 Cl 2 (15.0 mL) was cooled to 0° C. and treated with methanesulfonyl chloride (1.9 mL, 24.5 mmol) at a rate such that the temperature remained below 0° C. After warming to room temperature and stirring for two hours, the reaction mixture was quenched with brine (40 mL) and extracted with CH 2 Cl 2 (90 mL). The organic extract was dried over Na 2 SO 4 , filtered and concentrated in vacuo. Purification by MPLC (silica, 15-40% EtOAc-hexanes) gave the desired mesylate as a pale yellow liquid (3.74 g, 92%). 1 H NMR (CDCl 3 ) δ 5.74 (m 2H), 5.38 (m, 1H), 3.02 (s, 3 H, 2.84-2.63 (m, 4H); TLC: R f 0.4 (40% EtOAc-hexanes). ##STR16## Step 2. A solution of the protected aglycone [prepared using the protocols described in Tetrahedron Lett. 36, 1995, 8383] (3.72 g, 8.3 mmol) in dimethylformamide (50 mL) was heated to 60-65° C. and treated with cesium carbonate (10.9 g, 33.3 mmol). The resulting dark red mixture was stirred for 30 min. Over the next four hours, the mesylate from step 1 (4.04 g, 24.9 mmol) was added in 500 mg portions and mixture stirred for two days at 65-70° C. After cooling to room temperature, the reaction mixture was quenched with brine (300 mL) and extracted with EtOAc (300 mL). The organic phase was dried over Na 2 SO 4 , filtered and concentrated in vacuo. Purification by flash chromatography (silica, 25-25% CH 2 Cl 2 -hexanes) gave the desired mono alkylated product as an orange powder (2.0 g, 47%). 1 H NMR (DMSO-d 6 ) δ 12.13 (s, 1H), 9.21 (d, J=2.6 Hz, 1H), 9.09 (d, J=2.7 Hz), 7.77-6.87 (m, 1H), 6.07 (s, 2H), 4.79 (s, 2H), 3.68 (s, 3H), 3.25-3.17 (m, 2H), 3.01-2.93 (m, 2H); MS (FAB-LSIMS) m/z (relative intensity) 511 (M+, 20), 419 (14), 391 (30), 378 (64) 363 (54), 255 (8); TLC: R f 0.5 (60% EtOAc-hexanes). ##STR17## Step 3. A solution of the cyclopentene intermediate from step 2 (1.67 g, 3.26 mmol), and 4-methylmorpholine-N-oxide (60% aqueous solution, 0.55 mL, 5.31 mmol) in tetrahydrofuran (39 mL) was treated with OsO 4 (3.91 mL, 0.1 M in THF, 0.12 eq) and stirred overnight. After quenching mixture with aqueous 2.0 M sodium bisulfite solution and stirring for thirty minutes, the solution was extracted with EtOAc (150 mL) and washed with brine (300 mL). The organic phase was dried over Na 2 SO 4 , filtered and concentrated in vacuo. Purified by flash chromatography (silica 0-10% MeOH-EtOAc) gave the target compound as a orange-yellow solid (1.43 g, 80%). 1 H NMR (DMSO-d 6 ) δ 12.04 (s, 1H), 9.23 (d, J=2.7 Hz, 1H), 9.10 (d, J=2.7 Hz, 1H), 7.80-6.87(m, 10H), 6.11 (m, 1H), 4.81 (m, 4H), 4.74 (m, 2H), 3.68 (s, 3H); MS (FAB-LISMS) m/z (relative intensity) 545 (M+, 18), 438 (40), 338 (10), 255 (8); TLC: R f 0.2 (5% MeOH-chloroform). ##STR18## Step 4. A solution of the diol intermediate from step 3 (277 mg, 0.42 mmol) and triphenylphosphine (383 mg, 1.46 mmol) in tetrahydrofuran (26 mL) was treated with diethyl azodicarboxylate (0.16 mL, 0.98 mmol) at a rate such that the resulting orange-red color of the reaction mixture was allowed to return to its initial yellow color. After the addition was completed, the mixture was stirred for two days and subsequently heated to reflux for one day. The reaction mixture was quenched with brine (100 mL) and extracted with EtOAc (160 mL). The organic phase was dried over Na 2 SO 4 , filtered and concentrated in vacuo. Purification of the resulting oil by MPLC (silica, 0-20% EtOAc-CH 2 Cl 2 ) afforded the cyclized product as an orange powder (165 mg, 75%). 1 H NMR (DMSO-d 6 ) δ 9.13 (d, J=2.7 Hz, 1H), 9.08 (d, J=2.7 Hz, 1H), 8.04-6.96 (m, 10H), 5.98 (m, 1H), 5.70 (m, 1H), 5.41 (m, 1H), 4.89 (s, 2H), 4.29 (m, 1 5H), 3.77 (s, 3H), 3.22 (m, 1H), 2.68 (m, 1H), 2.45 (m, 1H), 2.05 (m, 1H); MS (FAB-LSIMS) m/z (relative intensity) 527 (M+, 32), 420 (62); TLC:R f 0.5(30% EtOAc-CH 2 Cl 2 ). ##STR19## Step 5. A solution of pyridiniumn chlorochromate (89 mg, 0.41 mmol) in CH 2 Cl 2 (2.0 mL) was treated with the alcohol from step 4 (140 mg, 0.27 mmol) as a solution in CH 2 Cl 2 (18 mL). A second portion of pyridinium chlorochromate (40 mg) was added to the brown mixture. After stirring the mixture for 2 hours, the solution was filtered through a short pad of silica gel and concentrated in vacuo. Purification by flash chromatography (silica, 80-100% CH 2 Cl 2 -hexanes) afforded the target ketone as a yellow powder (108 mg, 77%). 1 H NMR (DMSO-d 6 ) δ 9.05 (d, J=2.6 Hz, 1H), 9.03 (d, J=2.4 Hz, 1H), 7.98-6.86 (m, 1H), 6.14 (m, 1H), 5.58 (m, 1H), 4.82 (s, 2H), 3.68 (s, 3H), 3.44 (m, 1H), 3.22 (m, 1H), 3.00 (M, 1H), 2.50 (m, 1H); MS (FAB-LSIMS) m/z (relative intensity) 525 (M+, 14), 418 (30), 2181 (34), 185 (100), 147 (38), 121 (66); TLC: R f 0.6 (20% EtOAc-CH 2 Cl 2 ). ##STR20## Step 6. A solution of tris(methylthio)methane (0.16 mL, 1.15 mmol) in tetrahydrofuran (3.0 mL) was cooled to -78° C. and treated with n-butyl lithium (0.59 mL, 1.6 M, 0.94 mmol). After stirring for twenty minutes, a solution of the ketone from step 5 (199 mg, 0.38 mmol) in tetrahydrofuran (6.0 mL) was added to the reaction mixture and stirred for two hours. After quenching with a saturated ammonium chloride solution (10 mL) and warming to room temperature, the reaction mixture was diluted with water (10 mL) and extracted with EtOAc (90 mL). The organic layer was separated, dried over Na 2 SO 4 and concentrated in vacuo. Purification of the resulting oil by flash chromatography (silica, 20% EtOAc-hexanes) provided the addition product as a yellow solid (67 mg, 26%). 1 H NMR (DMSO-d 6 ) δ 9.06 (m, 2H), 8.17-6.87 (m, 10H), 5.74 (m, 1H), 5.05 (s, 1H), 4.85 (s, 2H), 3.69 (s 3H), 3.01 (m, 2H), 2.17 (s, 9H); MS (FAB-LSIMS) m/z (relative intensity) 679 (M+, 12), 572 (22), 488 (24), 310 (100), 284 (86); TLC: R f 0.8 (50% EtOAc-hexanes). ##STR21## Step 7 A solution of the thiocarboxylic acid orthoester intermediate from step 6 (50 mg, 0.074 mmol) in tetrahydrofuran (5.0 mL) was treated with methanol (12.0 mL), water (1.0 mL), mercury (II) oxide (84 mg, 0.39 mmol) and mercury (II) chloride (236 mg, 0.87 mmol). The reaction mixture was heated to reflux. The solution was diluted with brine (30 mL) and extracted with CH 2 Cl 2 (60 mL). The organic phase was dried over Na 2 SO 4 , filtered and concentrated in vacuo. Purification by flash chromatography (silica, 0-3% EtOAc-CH 2 Cl 2 ) gave the target ester as an orange solid (18 mg, 42%). 1 H NMR (CDCl 3 ) δ 9.25 (m, 2H), 7.60-7.40 (m, 8H), 6.88-6.85) (m, 2H), 5.61 (m, 1H), 5.40 (m, 1H), 4.93 (s, 2H), 4.03 (s, 3H), 3.77 (s, 3H), 3.21 (m, 2H), 2.88 (m, 1H), 2.77 (m, 1H), 1.95 (m, 1H); MS (FAB-LSIMS) m/z (relative intensity) 585 (M+, 8), 478 (8), 277 (11), 185 (100); TLC: R f 0.15 (50% EtOAc-hexanes). ##STR22## Step 8. Preparation of Example 3. A solution of the ester intermediate from step 7 (18 mg, 0.03 mmol) was dissolved in anisole (0.3 mL) over fifteen minutes and subsequently treated with trifluoroacetic acid (2.7 mL). The reaction mixture was heated to reflux for 2 hours (until no starting material remained by TLC, 5% EtOAc-CH 2 Cl 2 ). The solution was concentrated in vacuo. Purification by flash chromatography (silica, 10-20% EtOAc-CH 2 Cl 2 ) afforded the target imide as a yellow solid (11.0 mg, 77%). 1 H NMR (DMSO-d 6 ) δ 11.04 (s, 1H), 9.03 (m, 2H), 7.90-7.33 (m, 6H), 5.81 (m, 1H), 5.71 (m, 1H), 5.54 (s, 1H), 3.83 (s, 3H), 3.08 (m, 2H), 2.76 (m, 1H), 1.71 (m, 1H); 13 CNMR (DMSO-d 6 ) δ 175.3 (C═O), 171 (C═O imide), 170, (C═O imide,), 142.0, 140.0, 129.7, 128.4, 126.8, 126.7, 124.4, 121.3, 121.3, 121.2, 120.4, 120.2, 119.6, 119.5, 119.4, 115.3, 110.4, 109.7, 81.1 (COH), 61.7 (CHN), 55.2 (CHN), 52.07 (OCH3), 45.3, (CH2), 39.0 (CH2); MS (FAB-LSIMS) m/z (relative intensity) 466 (M+H, 14), 423 (6), 185 (28), 93 (100); TLC: R f 0.2 (5% EtOAc-CH 2 Cl 2 ); MP>230° C.
Example 3
Synthesis of 9,12-Methano-1H-diindolol ,2,3-fg:3',2',1'-kl]pyrrolo[3,4-I][1,6]benzodiazocine-1,3,10(2H,9H)-trone, 11,12-dihydro. ##STR23## Step 1. Preparation of Example 4. A solution of the ketone for step 5 of example 2 (15 mg, 0.029 mmol) was dissolved in anisole (0.3 mL) over fifteen minutes and subsequently treated with trifluoroacetic acid (2.7 mL). The mixture was heated to reflux temperatures until no starting material was detected by TLC (10% EtOAc-CH 2 Cl 2 ). The solution was concentrated under reduced pressure and purified by flash chromatography (silica, 0-10% EtOAc-CH 2 Cl 2 ) to afford the target ketone (8.9 mg, 77%) as a yellow solid. 1 H NMR (CDCl 3 ) δ 9.16 (m, 2H), 7.68-7.24 (m, 7H), 5.90 (m, 1H), 5.23 (m, 1H), 3.32 (m, 1H), 3.14-2.93 (m, 2H), 2.52 (m, 1H); MS (FAB-LSIMS) m/z (relative intensity) 405 (M+H, 12), 354 (12), 324 (18), 224 (18), 191 (52); TLC: R f 0.4 (10% EtOAc-CH 2 Cl 2 ); MP>225° C.
Example 4
Synthesis of 9,12-Methano-1H-diindolo[1,2,3-fg:3',2',1'-kl]pyrrolo[3,4-I][1,6]benzodiazocine-10-carboxamide,2,3,9,10,11,12-hexahydro-10-hydroxy-N-methyl-1,3-dioxo-(9α,10β,12α). ##STR24## Step 1. A solution of the thiocarboxylic acid ortho ester intermediate from step 6 of example 2 (28 mg, 0.04 mmol) in 20% H 2 O-tetrahydrofuran (1.3 mL) was treated with mercury (II) oxide (45 mg, 0.21 mmol) and boron trifluoride diethyl etherate (0.073 mL, 0.59 mmol). The reaction mixture was stirred for two hours at room temperature [until only one major spot was seen by TLC (2:3:95 acetic acid-methanol-CH 2 Cl 2 )], diluted with water (10 mL) and extracted with EtOAc (20 mL). The organic phase was dried over Na 2 SO 4 , filtered and concentrated in vacuo. Purification by flash chromatography (silica, 0-10% methanol-CH 2 Cl 2 ) afforded the target acid as an orange solid (76%, 18.0 mg). MS(FAB-LSIMS) m/z (relative intensity) 571(M+, 8), 464 (14), 381 (32), 330 (88), 181 (100); TLC:R f 0.3 (2:3:95 acetic acid-methanol-CH 2 Cl 2 ). ##STR25## Step 2. A solution of carboxylic acid from step 1 (20 mg, 0.034 mmol) in tetrahydrofuran (2.5 mL) was cooled to 0° C. and treated with 1,1'-carbonyldiimidazole (60 mg, 0.37 mmol) and stirred for ten minutes. A solution of approximately 50% methylamine-tetrahydrofuran (2 mL) was quickly added to the reaction. After five minutes, no starting material was observed by TLC (20% EtOAc-CH 2 Cl 2 ) and the reaction mixture was quenched with a saturated citric acid solution (3.0 mL). After warming to room temperature, the solution was diluted with brine (15 mL) and extracted with EtOAc (20 mL). The organic phase was dried over Na 2 SO 4 , filtered and concentrated in vacuo. Purification by flash chromatography (silica, 0-20% EtOAc-CH 2 Cl 2 ) gave the target methyl amide (7.0 mg, 35%). MS (FAB-LSIMS) m/z (relative intensity 584 (M+, 6), 477 (8), 253 (8), 169 (84), 132 (30), 85 (100); TLC:R f 0.3 (20% EtOAc-CH 2 Cl 2 ). ##STR26## Step 3. Preparation of example 5. A solution of the protected methyl amide from step 2 (7.0 mg, 0.01 mmol) was dissolved in anisole (0.5 mL) over ten minutes and subsequently treated with trifluoroacetic acid (4.5 mL). The mixture was heated to reflux for eight hours [no starting material was observed by TLC (50% EtOAc-CH 2 Cl 2 )]. The mixture was concentrated in vacuo and purified by flash chromatography (silica, 10-20% EtOAc-CH 2 Cl 2 ) to afford the methyl amide as a orange powder (3.4 mg, 61%). 1 H NMR (DMSO-d6) δ 11.03 (s, 1HO, 9.04 (m, 2H), 7.94-7.32 (m, 7H), 5.81 (m, 1H), 5.59 (s, 1H), 5.41 (1H) 3.25-3.05 (m, 2H), 2.66 (d, J=1.5 Hz, 3H), 2.64 (m, 1H), 1.74 (m, 1H); MS (FAB-LSIMS) m/z (relative intensity) 465 (M+H, 14), 361 (82), 346 (38), 322 (100), 315 (38); TLC:R f 0.4 (50%EtOAc-CH 2 Cl 2 ); MP>230° C.
Example 5
Preparation and Analysis of Kinases for Inhibitor Assays.
Preparation of Kinases:
Preparation of PKC: PKC was purified from rat brain using the method of Woodgett J. R. and Hunter T., J. Biol. Chem 262, 4836-4843 (1987).
Preparation of cAMP-dependent Kinase: The catalytic subunit of bovine heart PKA was obtained commercially from Sigma.
Preparation of cdc2 Kinase: Human cdc2 kinase was prepared from nocodazole-arrested HeLa cells according to Marshak D. M. er al., J. Cell Biochem., 45, 391-400 (1991).
Preparation of ERK2: Recombinant human ERK2 with a N-terminal histidine (his) tag was prepared as follows: An ERK2 cDNA clone was amplified from a human frontal cortex library by PCR with primers matching the published human sequence [Gonzales F. A. et al, FEBS Lett. 304, 170-178 (1992)]. The histidine tag was introduced by site-directed mutagenesis. The cDNA was cloned into a pET-14b (Novagen) vector and transfected into the E. coli lysogen strain B121pLysS. Single colony transformants were grown in LB medium containing 35 mg/ml chloramphenicol to maintain pLysS and 50 mg/ml kanamycin to an O.D. 600 OF 0.6. The culture was then induced with 0.4 mM IPTG for 4 hours. The expressed ERK2 protein was then analyzed on a 10% SDS PAGE by both coomassie blue staining and anti-ERK Western blotting. Bacterial pellets from 0.5-1 [cultures were freeze-thawed at -78° C. and homogenized by ultra-sonication for 3 min in 15 ml Ni 2+ -column buffer (20 mM Tris HCL pH 7.9, 0.5 M NaCl, 5 mM imidazole, Novagen). After centrifugation at 35,000× g for 30 min supernatants were loaded onto a 1 ml Ni 2+ charged resin (Novagen). After washing with column buffer containing 60 mM imidazole the ERK2 protein was eluted with column buffer containing 1 M imidazole. ERK2 containing fractions were identified by SDS-PAGE and dialyzed into Mono Q A-buffer (25 mM Tris HCL, pH 7.5 25 mM NaCl, 1 mM EDTA). The dialysate was loaded onto a HR5/5 Mono Q FPLC column (Pharmacia) and eluted with a 30 ml gradient from Mono Q A-buffer to the same buffer containing 250 mM NaCl (Mono Q B-buffer) at 1 ml/min collecting 30 fractions. Fractions #19-20 and #27-28 typically contained the peak amounts of two ERK2 conformers, as identified by western blotting. Only the first fraction was applied to HR 5/5 Phenylsuperose FPLC (Pharrnacia) and eluted with a 15 ml gradient from 25 mM Tris, pH 7.5, 150 mM NaCl, 1 mM EDTA, 1 mM DTT to the same buffer containing 25 mM NaCl and 60% ethylene glycol with a flow rate from 0.5 ml/min decreasing to 0.1 ml/min at the end of the gradient. Homogeneous ERK2 typically eluted after 13-14 ml.
For activation of ERK2 to the active PK40 form about 1 mg of purified histidine tagged ERK2 was mixed with 25 ml of CM-Sepharose eluate fraction prepared from bovine brain extracts according to Roder H. M. et al., J. Neurochem. 64, 2203-2212 (1995), adjusted to 2 mM Mg 2 +/0.5 mM ATP and incubated for 2 hrs at 37° C. The mixture was dialyzed twice into 11 each of Ni 2+ column binding buffer (20 mM Tris, pH 2.9, 500 mM NaCl, 5 mM imidazole) to remove traces of DTT and loaded onto 0.3 mL Ni 2+ charged resin (Novagen) at 25 mL/hr. After washing with 10 mL column buffer followed by 4 mL column buffer containing 40 mM imidazole homogeneous activated PK40 erk2 was eluted with 4 mL column buffer containing 1 M imidazole. The product was dialyzed extensively into 10 mM HEPES, pH 7.0, 1 mM EDTA to remove imidazole and traces of Ni 2+ , and finally into 10 mM HEPES, pH 7.0, 1 mM EDTA, 1 mM DTT.
Assays for Kinase Activity:
PK40 erk2 was assayed in 50μ 25 mM HEPES, pH 7.0, 1 mM MgCl 2 , 1 mM DTT, 0.25 mM ATP, 1 mg/mL BSA using 15-30 ng of PK40 erk2 and 0.1 mg/mL myelin basic protein (Sigma) as a substrate.
PKC was assayed in 50 μl 25 mM HEPES, pH 7.0, 10 mM MgCl 2 , 2 mM CaCl 2 , 1 mM EDTA, 1 mM DTT, 0.25 mM ATP, 0.2 mg/mL phosphatidylserine, using 20 ng PKC and 0.08 mg/mL histone III-S as a substrate.
The catalytic subunit of PKA was assayed in 50 μl 25 mM HEPES, pH 7.0, 10 mM MgCl 2 , 1 mM EDTA, 1 mM DTT, using 70 ng PKA and 0.1 mg/mL human recombinant tau protein as a substrate.
cdc2 kinase was assayed in 50 μl 25 mM HEPES, pH 7.0, 1 mM Mg 2+ , 0.25 mM ATP (150-300 cpm/pmole), 1 mM DTT, using 0.5 ng cdc2 kinase, 5 μg human recombinant tau as substrate, and 0.1 mg/mL BSA a as carrier.
Determination of Potency of Kinase Inhibitors
Enzyme, substrate and inhibitor were preincubated for 5-10 min at 4° C. in assay buffers containing a final concentration of 2% DMSO before initiating the reaction with 0.25 mM Υ 2 P-ATP. Samples were incubated for 30 min at 37° C. and reactions were terminated with 10% trichloracetic acid/2% sodium pyrophosphate (TCA/PPA), followed by filtration over a glass fiber filtermat (type A) with a cell harvester (Tomtec). The filtermats were washed twice for several hours with TCA/PPA until all background radioactivity was removed. Precipitable counts were quantitated directly on the filtermat with a microbeta scintillation counter system (Wallac-Pharmacia). Inhibitor data were subjected to curve fitting and IC 50 values were calculated from these curves using the GraphIt program.
Example 6
Determination of Potency of Inhibitors to Prevent AD-like Tau Hyperphosphoalylation in SY5Y Cell Model
In vitro, and presumably also in vivo, tau is a substrate for multiple kinases. The main problem to evaluate inhibitors specifically interfering with the AD-like hyperphosphorylation of tau is to distinguish clearly between normal and abnormal phosphorylation of tau in model systems. In the cell line SY5Y comparisons can be made with tau associated with tangles from human AD brain, because of its human origin. As in fetal brains, SY5Y cells express only one of the 6 splice isoforms of tau, simplifying the survey of tau phosphorylation states.
Methods
SKNSH-SY 5Y cells were plated on fibronectin-coated 6 well (30 mm 2 ) culture dishes (Biocoat®, Collaborative Biomedical Products, Inc.) and grown to confluence in 5 mL of 50% D-MEM/50% F-12 Nutrient Mixture (Ham) supplemented with 15% heat-inactivated bovine serum (JRH Bioscience), 0.1 mM non-essential amino acids solution, 2 mM glutamine and pen/strep/fungizone (GibcoBRL Life Technologies, Inc.). Cell culture medium was changed every 48 hours.
For drug testing, cells were routinely pretreated with inhibitors in 1 mL (30 mm 2 ) for 60 min at concentrations of 30 nM, 100 nM, 300 nM, 1 mM, 3 mM and 10 mM. Compound stocks were all at 10 mM in DMSO and dilutions were made in DMSO. Cells were then treated with 1 μM okadaic acid (ammonium salt; LC Laboratories, dissolved at 1 mM in DMSO) for 90 min. All experiments, including controls, contained a final concentration of between 0.5 and 1% DMSO.
Cells were detached from 30 mm 2 plates and suspended into 1 mL of ice-cold PBS by gentle trituration, transferred into microcentrifuge tubes and sedimented for 12 seconds at 14,000× g. The supernatant was removed and cells were lysed in 250 μl cold homogenization buffer (50 mM MES, pH 5.8, 5 mM sodium pyrophosphate, 50 mM p-nitrophenylphosphate, 1 μM okadaic acid, 2 mM Na-orthovandate, 1 mM EDTA, 1 mM EGTA, 1 mM DTT, 10 glycerol, 10 μleupeptin, 1 μM pepstatin, 1 mg/mL aprotinin, 10 μM chymostatin, 1 mM PMSF, and 1% TRITON®×100) and vortexed briefly to aid in lysis. Cell debris was removed by centrifugation at 14,000× g for 5 minutes at 4° C. and cell supernatants were analyzed by anti-ERK2 and anti-tau Western-blotting as described below.
25 mL of total cell lysate was run on a 10% tris-glycine polyacrylamide gels (Novex, 1.5 mm×10 well) at 100 volts for 2.5 hors and Western-blotted on nitrocellulose (Novex) overnight at 23 volts or 1.5 hrs at 100 V in transfer buffer [Towbin et al. Proc. Natl. Acad. Sci. USA 76, 4350-4354 (1979]) at 4° C. Blots were analyzed for ERK2 and phosphotyrosine immunoreactivity with anti-ERK1+2 (Z033;Zymed Laboratories, Inc.; 1:5,000) and anti-phosphotyrosine (4G10; Upstate Biotechnology Inc.; 1:1,000) mAbs. Blots were also analyzed for phosphorylation-sensitive Tau immuno-reactivity with mAb Tau-1 (Boehringer Mannheim; 1:5,000) and phosphorylation dependent mAb AT8 against FHF-tau (Biosource International; 1:200). Total Tau populations were detected by Tau-1 immunoblotting after treating blots for 16 hrs at 37° C. with 100 units/mL alkaline phosphatase (Gibco BRL) in 5 mL of 50 mM Tris-HCl (pH 8.5), 0.1 mM EDTA. All blots were developed using ECL (enhanced chemiluminescence) Western blotting protocol (Amersham Life Science) with horseradish peroxidase-linked sheep anti-mouse secondary antibody and analyzed on Kodak X-OMAT AR scientific imaging film. Films were scanned into Adobe Photoshop and imported into NIH Image 1.44, where densitometric analysis was performed. Changes in tau phosphorylation were assessed by normalizing densitometrically determined mAb Tau-1 immunoreactivities in cell extracts to Tau-1 reaction after dephosphorylation on the blot. Ratios of Tau-1 reactivity prior to and after dephosphorylation were expressed in % relative to the ratio obtained from control cells not treated with okadaic acid (100%). Proteins isolated form neonatal rat brain were used for comparison in some experiments.
Results
The potency of the compounds of the invention tested, including CII and CIII, in the in vitro kinase assay was well correlated with their inhibitory activity of tau hyperphosphorylation in the cell. Moreover, each of the compounds demonstrated a correlation between inhibition of ERK2 and tau hyperphosphorylation.
Correlation of potencies of inhibition of PK40 activity in vitro, and of OA-induced ERK2 and tau phosphorylation in SY5Y cells. ERK2 phosphorylation was quantified as the ratio of low mobility/total ERK2, densitometrically determined from ERK2 Western-blots (e.g. of FIG. 1). Tau hyperphosphorylation was expressed as densitometrically measured Tau-1 immunoreactivity normalized to total Tau-1 reactivity after unmasking of the epitope by phosphatase treatment of the blots.
In FIG. 2, tau from untreated SY5Y cells is compared to the completely hyper/dephosphorylated state (accomplished by treatment in vitro with PK40(ERK2) and phosphatase 2B, respectively), and to PHF-tau from AD brains with regard to Tau-1 immunoreactivity and electrophoretic mobility. Tau proteins were analyzed as isolated from tissue in comparison to tau exhaustively dephosphorylated with PP2B calcineurin), or hyperphosphorylated in vitro with PK40. Western-blots were stained with mAb Tau-l (FIG. 2A, B, upper panels) or AT8 (FIG. 2C, lanes 4-6). Relative gel mobilities and loading were visualized by Tau-l after complete unmasking of the epitope by phosphatase treatment on the blot (FIGS. 2A, B, lower panels; FIG. 2C, lanes 1-3). The phosphorylation of fetal tau appears to be similar to SY5Y tau. In either case hyperphosphorylation by PK40 completely abolishes residual Tau-1 reactivity and induces a small additional mobility shift. By these criteria SY5Y tau hyperphosphorylated in vitro by PK40 is indistinguishable from tau hyperphosphorylated in situ after okadaic acid induction, and from PHF-tau. Soluble fractions of PHF-tau were extracted from purified PHF by water or SDS.
FIG. 2 shows that in SY5Y cells most of the potential Tau-l reactivity is already masked by phosphorylation, and the electrophoretic mobility of tau is close to maximally retarded. By the criteria of FIG. 2, the phosphorylation state of tau in SY5Y cells does not appear to be substantially different from tau in neonatal rat brains (FIG. 2C). This probably applies to tau from adult brains as well, as newer data avoiding post-mortem artifacts in isolating tau argue against the previously held notion that the fetal phosphorylation state is higher than in the adult state.
Hyperphosphorylation with PK40(ERK2) in vitro does induce a small but detectable change in tau properties as isolated from SY5Y cells. Only in this state the electrophoretic mobility of tau matches exactly the gel mobility of the corresponding pathologically phosphorylated splice isoform extracted from tangles (FIG. 2C). In cells, the same abnormal phosphorylation state can be induced by inhibition of protein phosphatase 2A with okadaic acid.
Example 7
Methods
Neonatal rat tau hyperphosphorylated in vitro by PK40 with or without prior dephosphorylation by PP2B. Equal amounts of purified 32P-hyperphosphorylated tau samples were digested with trypsin, and peptides were analyzed by 2D electrophoresis. The results are shown in FIG. 3. Labeling of peptides was quantified by counting (cpm displayed for each spot). Comparison of total cpm showed that dephosphorylation liberated only about 1/5th of the available ERK2 sites.
Results
In order to demonstrate that the small changes in immunochemical and gel mobility properties observed in the data presented herein is useful and a relevant model for assessing the large AD-like hyperphosphorylation effects which occur the degree of dephosphorylation/hyperphosphorylation of tau in neonatal rat cells was observed. The small change of tau associated with abnormal AD-like phosphorylation in vitro and in cells does not necessarily reflect a small change in the phosphorylation state. As shown in FIG. 3 the degree of hyperphosphorylation of tau from fetal/neonatal rat brains by PK40(ERK2) which were not pre-dephosphorylated is only about 20% lower than the degree of dephosphorylation observed when tau is dephosphorylated completely prior to hyperphosphorylation. In addition, the two-dimensional phosphopeptide maps of tau in this comparative study are qualitatively indistinguishable (FIG. 3).
Example 8
Inhibitors of PK40 Prevent Abnormal AD-like Hyperphosphorylation.
Methods
Compound CIII prevents ERK2 phosphorylation and tau hyperphosphorylation in a correlated fashion (FIG. 4). Compared to control cells (lane C) 1 μM okadaic acid induced ERK2 phosphorylation/activation, as shown by a small gel mobility shift of ERK2 (lane OA) and induction of reactivity with a mAb sensitive to the double phosphorylation of the regulatory Thr-Glu-Tyr motif of ERK2 (anti-active ERK2). Both effects were prevented by ≦1 μM compound CIII (IC50 at about 1 μM, complete at 10 μM). Highly correlated with the effect on ERK2 was the prevention of OA induced tau hyperphosphorylation, as tracked by elimination of Tau-1 reactivity and prevention of a small gel mobility shift typical of AD-like tau. Note that at 10 μM, with ERK2 activation completely arrested, the tau phosphorylation state (including the phosphoisoform pattern) remains unaltered compared to normal phosphorylation in control cells.
Prevention of tau hyperphosphorylation by the preferred compound CIII (FIG. 1). Okadaic acid at 1 μM induced the complete elimination of the Tau-1 epitope (upper panel) as in PHF-tau of AD. The shift in electrophoretic mobility corresponding to human PHF-tau was visualized by phosphatase treatment of duplicate Western-blots (lower panel) to recover the masked Tau-1 epitope. The compound CIII prevents the tau hyperphosphorylation in a dose dependent manner. At fully effective doses (>1 μM) tau remained in a phosphorylation state similar to the normal state in control cells (lane C). Tau in normal cells not treated by okadaic acid is phosphorylated to a substantial degree; this normal phosphorylation was apparently not affected by CIII. The ratio of densitometrically measured Tau-1 signal over the Tau-1 signal after dephosphorylation, a normalizing measure of the total tau population, formed the basis for quantitative analysis to determin IC 50 values.
Results
Inhibitors of PK40(ERK2), exemplified by CIII, indeed prove capable of preventing abnormal AD-like hyperphosphorylation in a SY5Y cell model system. FIG. 1 shows that increasing concentrations of CIII prevent the okadaic acid provoked hyperphosphorylation of tau. This protective effect is highly correlated with the prevention of the activating phosphorylation of ERK2 in the same cells. By binding to ERK2, CIII is able to both inhibit the activity of ERK2 as well as its activation (either via autophosphorylation or via another kinase), with both effects essentially eliminating cellular tau hyperphosphorylating activity. Moreover, the normal cellular phosphorylation state of tau is not affected by CIII in the same concentration range, demonstrating a case of cellular selectivity (not shown).
Example 9
Determination of Potency of Inhibitors to Prevent AD-like Tau Hyperphosphorylation in Rat Hippocampal Brain Slices
Methods
Adult male Long-Evans rats were subjected to CO 2 anesthesia and sacrificed by decapitation. Brains were rapidly removed (<2 min) and whole hippocampus was dissected using a blunt spatula. Hippocampi were cut into 450 mM slices using a McIlwain tissue chopper and placed into ice cold low Ca 2+ Krebs-Bicarbonate buffer (pH 7.) of the following composition in mM: NaCl, 124; KCL, 3.33; CaCl 2 , 0.01; KH 2 PO 4 , 1.25; MgSO 4 1.33; nAhco 3 , 25.7; D-glucose, 10; HEPES, 20. The slices were separated and placed, 5-8 per tube, into 5 mL of low Ca 2+ buffer and incubated for at least 30 min at 33-34° C. with water saturated oxygenation (95% O 2 , 5% CO 2 ). After 30 min the solution was replaced with buffer containing a physiological level of Ca 2+ (1.3 mM) and incubated for an additional 30 min.
After a total equilibration period of at least 1 hr, the slices were pretreated with vehicle or inhibitor at concentrations ranging from 30 nM to 10 μM for 1 hr, and then exposed to either vehicle or okadaic acid fora 90 min. After treatment, the buffer was removed and the slices were sonicated for 10-20 sec in 500 μl of homogenization buffer (100 mM KH 2 PO 4 , pH 6.5, 2 mM EGTA, 2 mM EDTA, 1 μM okadaic acid and the following protease inhibitors: aprotinin (10 μg/ml); leupeptin (10 μM); chymostatin (40 μM); PMSF (100 μM) and pepstatin (6 μg/ml).
Following sonication, the samples were centrifuged 16,000× g for 30 min and the supernatants were removed. After boiling of the supernatants for 5 mn at 100° C. the concentration of protein was determined by the BCA assay (Pierce) using BSA as standard and samples were normalized to equal protein concentration.
Aliquots of the heat stable supernatants were separated on 10% SDS-PAGE and Western-blotted with phosphorylation-sensitive tau mAb Tau-1 and PHF-tau mnAb AT8 as described for SY5Y studies. Blots were developed by an ECL kit (Amersham Life Science). AT8 immunoreactivity was quantitated on Kodak X0OMAT AR film using a Biorad imaging densitometer GS 670, the strongest signals not exceeding an O.D. of 12.
Results
Freshly isolated hippocampal brain slices from adult rats were used for similar experiments under conditions more relevant to the brain (FIG. 5). Again, okadaic acid induced AD-like tau hyperphosphorylation, while CII prevented it with the same IC50 as in SY5Y cells (0.1 μM).
Okadaic acid induced reactivity with the novel phosphorylation dependent mAb AP422. This response was inhibited at the same dose as the response with the more conventional mAb AT8 (FIG. 5), indicating a single tau hyperphosphorylating activity. In vitro reactivity of tau with this mAb can only be induced by ERK2, but not other candidate tau kinases (e.g. cdk, GSK3), providing an independent criterion that ERK2 is the relevant drug target.
The intensity of AP422 reactivity induced by PK40(ERK2) in vitro matches that of isolated PHF-tau from AD-brain (not shown). In contrast, even with the most conservative precautions to avoid post-mortem dephosphorylation in rat brains, AP422 reactivity is completely absent in normal adult tau. This suggests that tau hyperphosphorylation in AD is qualitatively abnormal, and does not involve enhanced activity of normal kinases, but rather the pathological activation of ERK2 as an abnormal tau kinase.
Prevention of AD-like tau hyperphosphorylation in adult rat hippocampal brain slices. In an experimental paradigm similar to SY5Y cells tau hyperphosphorylation is prevented by derivative CII at similar doses as in SY5Y cells.
Note that the results with AP422, currently the most specific criterion for AD-like tau hyperphosphorylation, are identical to those with the commonly used mnAb AT8, indicating that ERK2 alone is responsible for all okadaic acid induced changes in tau phosphorylation.
TABLE 1______________________________________Properties of Preferred Compounds as Inhibitors of ERK2 (PK40),Activation of ERK2, cdc2, and Tau Hyperphosphorylation in BiologicalModels of PHF-tau formation (IC.sub.50 values in μM) CII CIII______________________________________PK40 (ERK2) 0.044 >>30cdc2 0.044 3.3PKA 0.65.sup.a) >100PKC 0.65.sup.a) >100Inhibition in SY5Y 0.57 5.7cells.sup.b) of ERK2activationtau hyperphos. 0.58 3.6Inhibition of tau 0.18 0.9hyperphos. in brainslices.sup.b)______________________________________ .sup.a) = partial inhibition only .sup.b) = means of triplicate determinations .sup.c) = concomitant inhibition of normal tau phosphorylation
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Novel indolocarbazole derivatives potentially useful for the treatment of dementias characterized by tau hyperphosphorylation [Alzheimer's disease (AD), frontal lobe degeneration (FLD), argyrophilic grains disease, subacute sclerotizing panencephalitis (SSPE) as a late complication of viral infections in the CNS], and cancer.
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FIELD OF THE INVENTION
The present invention is concerned with a novel method for the refinement of silver in conventional Moebius cells.
BACKGROUND OF THE INVENTION
One of the major elements present in the slime resulting from copper electrorefining is silver. To recover that silver, the slime is treated by various methods to impure silver anodes. Such anodes are referred to in the art as "Dore" anodes. The composition of a Dore anode greatly varies depending on the source of the slime and of the purity of the original copper anodes, but the silver content is generally from about 80% up to 99%. Dore anodes may also be obtained from lead refining or the treatment of precious metal bearing scrap. Other components or elements of these anodes include copper and precious metals like gold, palladium and platinum.
Dore anodes are refined by electrolysis to produce pure silver metal at the cathode, but this refining also produces anode mud containing gold and other precious metals present in the Dore anode. The silver electrorefining operation is conventionally carried out by using either a Mocbius cell, which is described by Mantell in Electrochemical Engineering, 4 th edition, McGraw Hill Book Company, New York 1960, pp. 166-173; or a Balbach-Thum cell, which is described by de Kay Thompson in Theoretical and Applied Electrochemistry, 3 rd edition, The Macmillan Company, New York, 1939, pp. 257-260. Several considerations will influence the choice of either cell. The Moebius type cell is generally preferred because it requires significantly less floor space, about 1/5 of that of a Balbach-Thum cell, and less energy for a given amount of silver refined. Although the Moebius cell requires more time for removing silver and slime, it needs very little attention during normal operation, as silver crystals building up on the cathodes are scraped mechanically and fall to the bottom of the cell. The Balbach-Thum cell requires frequent manual removal of silver deposited onto the bottom of the cell, which acts as the cathode.
Other significant differences exist between Balbach-Thum cells and Moebius cells, both in the structure and in the physical requirements of the cells, as described in pages 86-87 of Silver: Economics, Metallurgy & Use, (A. Butts & C. D. Coxe), Van Nostrand Company Inc. In a Moebius cell, the anodes and cathodes are suspended in an alternate manner in the cell. The anodes are only partially submerged in the electrolyte which results in a substantial portion of the impure anode being left undissolved ("scrap") at the end of an electrorefining cycle, typically lasting from 24 to 48 hours. The weight of the remaining anode scrap can amount to as high as 30% of the Dore anode originally loaded in the refining cell, and therefore it must be remelted, recast and reelectrolysed, thus increasing the overall costs for obtaining pure silver. On the other hand, in Balbach-Thum cells, the cathode is at the bottom of the cell, and the anodes are deposited at the bottom basket, parallel to the cathode, the bottom of the basket being lined with a cloth to collect the gold mud. Although complete dissolution of the silver anodes appears to occur in Balbach-Thum cells, there are significant manipulations of partially corroded silver anodes for the following reason. As stated above, the anodes are deposited onto the cloth in the basket. Since the anode contains important amounts of impurities, these impurities remain in the basket as anodes dissolve to leave a residue that is referred to in the art as gold mud. After a certain time, the dissolution of silver is impaired by the increasing amount of gold mud in the cloth, and accordingly, gold mud, together with the corroded anodes present therein, must be removed from the basket and the undissolved portion of the anodes must be washed before being returned in the cell.
Both types of cells have in common that the handling of partially corroded anodes and the recovery of gold mud are time-consuming operations, and therefore, any improvement in that respect will result in lower costs for silver refiners.
U.S. Pat. No. 5,100,528 (Claessens et al.) discloses a continuous silver refining cell wherein silver anodes are deposited in a titanium anode basket that is subsequently immersed in a tank containing tile electrolyte. Another silver electrorefining cell has been developed to reduce as much as possible anode scrap, as described by Imazawa et al in "Continuous Silver Electrorefining Operation", Metallurgical Review of the MMIJ, 1984, Vol. 1, No. 1, pp. 150-159. In this cell, tile basket is also made of conductive titanium material to insure contact of the impure silver anode with the positive terminal of the continuous current electrical power source. This cell, as well as the cell described in U.S. Pat. No. 5,100,528, is very complex as it allows for the simultaneous continuous withdrawal of the silver crystals deposited at the cathodes. A further drawback is that they are expensive to build and may be difficult to operate.
The use of conductive baskets is also well known in the plating industry, where replenishment of ions of a metal to be plated is assured by using soluble anodes made of the same metal. In this case, solid anodes may be suspended from the top of the cell, or smaller pieces of the same anode material can be loaded in a partially submerged basket made of inert conductive material. Titanium is conventionally used as material of construction for these baskets. A disadvantage of the use of such conductive baskets in Moebius cells is that some energy is lost at the surface of the basket by the degradation reaction of H 2 O. In addition to the undesirable consumption of energy, this reaction produces O 2 and H + ions, the latter increasing the acidity of the electrolyte and impairing the efficiency of the process, since metals like palladium and platinum will dissolve in an electrolyte having a lower pH, thus significantly contaminating the silver.
U.S. Pat. No. 4,692,222 describes the use of a basket made of electrically conductive material substantially inactive to the electrical process, to contain pieces of copper used as replenishment of copper ions in a plating cell. As an alternative, the electrically conductive material may be replaced with plastic, provided that the plastic baskets contain some means of making electrical contact to the pieces of copper therein, such as by way of a conductive rod extending down into the basket. In this instance, because of the presence of the electrical contact in the electrolyte through the conductive rod, the degradation reaction of water will take place, and the acidity of the electrolyte will increase.
U.S. Pat. No. 4,207,153 is concerned with an electrorefining cell that consists of bipolar electrodes having the anode side made of a basket constructed with an acid resistant metal in which fine cemented copper is added in a slurry form. Again in this case, the material of construction of the anode baskets is a metal, such as stainless steel or titanium.
In view of the above, there is therefore a great need to improve the electroefining of silver, particularly in Moebius cells. For example, it would be desirable to develop a method combining the advantages of both Moebius and Balbach-Thum cells, namely allowing the complete dissolution of silver anodes that would be fed in a continuous manner in the electrolyte while eliminating any silver anode residue from the gold mud produced therefrom, thus preventing the manipulation of partially corroded anodes. With such a method, there would no longer be a need to recycle anode scrap by melting and casting, resulting in significant savings in silver production. Further, as mentioned above, the floor space required for a Moebius cell is significantly smaller than that of a Balbach-Thum cell.
SUMMARY OF THE INVENTION
In accordance with the present invention, there is now provided a method for the continuous electrorefining of silver in a Moebius cell by allowing a complete dissolution of the silver anode without generating acid in the electrolyte. More specifically, the method comprises inserting a silver anode in a basket made of nonconductive material and surrounded by a cloth retaining the gold mud produced during electrolysis. With such a design, the cloth is not in contact with the anode, and therefore, the gold mud may be removed from the cell without the necessity of removing or handling the partially corroded anodes remaining in the basket.
In a preferred embodiment, the basket is made of a thermoplastic material resistant to the highly corrosive environment of a silver electrorefining cell. Thermoplastic materials include high and low density polyethylene, polypropylene, polycarbonate, polyurethane, polyester, TEFLON, polyvinyl chloride (PVC), chlorinated PVC and the like. Any of these materials may also be reinforced with fibers such as fiberglass. The cloth surrounding the basket may be made of material similar to that of the basket, or any other inert material capable of sustaining the corrosive environment of silver electrolyte. To ensure that no acid is generated in the electrolyte, the electrical contact between the power source and the electrode takes place above the surface of the electrolyte.
IN THE DRAWINGS
FIG. 1 illustrates a perspective view of a basket suitable for the present method; and
FIG. 2 illustrates a perspective view of a plurality of baskets of FIG. 1 joined.
FIG. 3 illustrates a perspective view of a basket with a cloth installed therearound.
FIG. 4 is a perspective view illustrating an anode.
DETAILED DESCRIPTION OF THE INVENTION
In the method of the present invention, the conventional Moebius cell has been modified to replace hanging anodes with a basket having its upper edges extending above the electrolyte level in the tank, and wherein the anodes are deposited in a continuous manner. The basket comprises openings on each sidewall to allow the passage of electrolyte and is surrounded by a cloth or bag to collect the gold mud produced from the silver electrolysis. The electrical contact between the anode and the power source is made above the electrolyte level through a portion of undissolved anode or through another anode placed above the first anode. The electrical contact between the cathode and the power source is also made above the electrolyte level. Many advantages results from carrying out the present method in Moebius cells equipped with such baskets. Anodes can be fed in a continuous manner; the production of anode scrap is eliminated, and the gold mud is recovered in the cloth around the basket without the need to remove any partially corroded anode remaining in the basket. The use of a nonconductive material for the basket prevents the generation of oxygen and the production of acid caused by the degradation of H 2 O in the electrolyte. Experience has shown that electrorefining of silver in titanium basket causes the acidity to increase by as much as 1 to 2 g/L. An increase in acidity of the electrolyte near the anodes is detrimental as it promotes an increase in the level of palladium dissolution into the electrolyte, which results in an increase in the contamination of the pure silver metal produced at the cathode.
Sometimes, an increase in the acidity of the electrolyte can be caused by special circumstances resulting in passivation of the anodes, with simultaneous production of oxygen by decomposition of water at the anode/electrolyte interface. However, passivation was definitely not the cause of the acidity increase in the tests carried out by the present inventors with a titanium basket. From a closer examination of the phenomenon, it can be concluded that the increase in acidity observed with the titanium basket is probably caused by a parasitic water decomposition reaction at the surface of the titanium metal, instead of normal silver dissolution of the anode. The liter that some part of the current applied to the basket is diverted to the surface of the basket, instead of to the silver anode, may be explained by the presence of a poorly conductive slime layer building-up at the surface of the anode, thereby decreasing the quality of the electrical contact between the titanium basket and the silver anode.
Referring to FIG. 1, which illustrates a preferred embodiment of the invention, basket 10 made of polycarbonate plastic, for example LEXAN manufactured and sold by General Electric, comprises compartments 12 and 13 adapted to receive an anode 14 therein (FIG. 4). Compartment 12 is made of a pair of walls 16 and 17 provided with a plurality of slots 18 and/or round openings 20, or combinations thereof, and sidewalls 22. It is preferable to avoid orienting slots 18 in a vertical position, as the solid vertical divisions could act as shields against the current, causing vertical sections of the anodes to dissolve at a reduced rate. Horizontal slots are also preferably avoided as they may mechanically prevent anodes from sliding down the basket as they progressively dissolve. In a preferred embodiment, the section of compartment 12 is tapered, that is, sidewalls 22 are wider at the top of compartment 12. The purpose of this taper is to possibly prevent two dissolving anodes to slide one over the other. The bottom of compartment 12 is open, but at least one spacer 24 is provided between walls 16 and 17 to support the anode. The large open surface area of the bottom of compartment 12 serves to eliminate any gold mud freed from the surface of the dissolving anodes.
Compartment 13 is sitting on, moulded with, or secured to the top of compartment 12, and comprises a pair of walls 26 and 27 separated by a pair of sidewalls 28 having a width corresponding to that at the top of sidewalls 22. Walls 26 and 27 also comprise a slot 30 adapted to receive at least one copper lath or strip 32 having one end 34 secured to a piece of a conductive material 36, preferably copper, which is itself secured on the external side of walls 26 and 27, the material 36 being electrically connected to the power source (not shown). The other end 38 of copper lath or strip 32 is inside compartment 13 and in contact with an anode inside compartment 13 (not shown) above the electrolyte surface. Finally, a cloth 40 is installed around the basket to retain any gold mud produced during electrolysis of the anodes (FIG. 3).
In operation, a first anode is slid into compartment 12 through compartment 13, and a second anode is placed on top of the first anode. Compartment 12 is then surrounded with a cloth and placed in an electrolysis bath (not shown) by slowly immersing compartment 12 in the electrolyte solution. Slots 18 and/or openings 20 will allow for the free passage of ions upon application of current in the electrolyte. At no time is the electrolyte solution in contact with copper lath or strip 32, since the latter would dissolve preferentially to the silver anode, thus contaminating the electrolyte solution. Copper lath or strip 32 is then electrically connected to the positive end of a power source via conductive material 36, and a cathode, electrically connected to the negative end of the power source, is inserted in the bath (not shown). The cathode may be any cathode conventionally used in the field of silver refining, or in Moebius cells. As current is applied, the submerged anode inside the basket progressively dissolves and slides downwardly. To maintain electrical contact, a new anode is inserted on top of the one in the basket as the latter progressively falls below the electrolyte surface. The surfaces of the cathodes are scraped from time to time in the conventional manner. Operation of such experimental baskets in a commercial Moebius cell over extended periods of time has shown to be totally problem free. No anode scrap is produced, nor is the acidity of the electrolyte increased inside the cell. Further, the anode is never in contact with the gold mud, thus insuring that substantially all the silver present in the anode is dissolved and deposited at the cathode, thus completely eliminating any undesirable manipulation of partially corroded silver anode while the method is in operation. The method is stopped from time to time to collect the refined silver at the bottom of the cell. The continuity of the process is therefore easily maintained by simply feeding the top of compartment 13 with silver anodes when necessary to preserve the electrical contact. As illustrated in FIG. 2, a plurality of baskets 10 may be joined.
The electrical contact is thus made with the top of the anode and the passage current to the bottom of the anode, which is submerged, is assured without the presence any foreign conductive material. This arrangement significantly differs from that described in U.S. Pat. No. 4,692,222 mentioned above, in that the contact is made from a nonsubmerged or partly submerged anode to the active submerged anode and no conductive material other than the impure silver anode extends down into the basket in the electrolyte solution.
The experimental conditions for carrying the method of the present invention are those used conventionally in any Moebius cells. For example, in the case of silver, the conditions are as follows:
temperature of the electrolyte: 30°-50° C.
voltage: 3-5 volts
current density: 300-900 Amps/m 2
cathode material: titanium, stainless steel or silver
acidity level: 0.1 to 10 g/L of nitric acid
electrolyte: 50-150 g/L Ag + & 10-50 g/L Cu ++ (both as nitrates)
These above parameters are provided to illustrate the preferred experimental conditions, and should not be construed as limiting the scope of the invention.
The appropriate shape and dimensions of a basket are to be adjusted to the size and shape of the anodes to be refined. Any one of ordinary skill in the art can make those adjustments. Similarly, the method of assembly of the various parts of the basket may vary from that used in the experimental basket, wherein the parts have been fastened with screws, the latter being isolated from the electrolyte. Gluing of the various parts or moulding of the basket as one piece can also be envisaged. Finally, the material of construction of the basket, its geometry, and the method of construction and assembly can differ from the example shown, as long as the basket is constructed of nonconductive material presenting an appropriate resistance to the chemical environment prevailing in the silver electrorefining cell. Further, it is imperative that the electrical contact between the anode and the power source be made outside the electrolytic bath and that the cloth surrounding the basket is not in contact with the anode.
While the invention has been described in connection with specific embodiments thereof, it will be understood that it is capable of further modifications and this application is intended to cover may variations, uses or adaptations of the invention following, in general, the principles of the invention and including such departures from the present disclosure as come within known or customary practice within the art to which the invention pertains, and as may be applied to the essential features hereinbefore set forth, and as follows in the scope of the appended claims.
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The present invention is concerned with a method for electrorefining silver in a Moebius cell whereby the anode is completely dissolved and the gold mud is removed without handling of any partially dissolved anodes. The cell is conventional except that the anodes are placed in a basket made of a thermoplastic material and surrounded by a cloth, the electrical contact between the anode and the power source takes place outside the electrolyte. The bottom of the basket is provided with apertures allowing the gold mud produced to tall into the cloth until the anode is completely dissolved.
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This application is a continuation of application Ser. No. 07,603,058, filed Oct. 25, 1990.
BACKGROUND OF THE INVENTION
This invention relates to reciprocating conveyors, and more particularly to the connected assembly of conveyor slats, slat drive beams and reciprocative power drive.
This invention relates to reciprocating conveyors of the type disclosed in my earlier U.S. Pat. Nos. 4,143,760; 4,144,963; and 4,856,645 and provides more simplified and versatile means for detachably connecting together the conveyor slats, slat drive beams and reciprocative power drive on the supporting framework of a reciprocating conveyor.
SUMMARY OF THE INVENTION
This invention provides a reciprocating conveyor with a module which is detachable from the conveyor main frame and which includes the drive cylinders and couplers for releasably attaching the drive cylinders to the slat drive beams, and adjustable clamp mechanism for releasably securing the conveyor slats to the slat drive beams.
It is the principal objective of this invention to provide a reciprocating conveyor with a power drive that is quickly attachable to and detachable from the main frame for facilitating assembly, maintenance and repair.
Another object of this invention is the provision of a reciprocating conveyor with conveyor slats that are quickly attachable to and detachable from the slat drive beams for facilitating assembly, maintenance and repair.
A further objective of this invention is the provision of a reciprocating conveyor of simplified construction for economical manufacture, maintenance and repair.
The foregoing and other objects and advantages of this invention will appear from the following detailed description, taken in connection with the accompanying drawings of a preferred embodiment.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 is a fragmentary plan view of a reciprocating conveyor embodying the features of this invention, a portion being broken away to disclose internal features of construction.
FIG. 2 is a fragmentary sectional view taken on the line 2--2 in FIG. 3.
FIG. 3 is a fragmentary sectional view taken on the line 3--3 in FIG. 1 is a portion being broken away to disclose internal structure.
FIG. 4 is a fragmentary sectional view taken on the line 4--4 in FIG. 1.
FIG. 5 is a fragmentary bottom plan view as viewed in the direction of the arrows 5--5 in FIG. 4.
FIG. 6 is a fragmentary exploded view showing the manner of detachable connection of components of the drive module to the conveyor main frame.
DESCRIPTION OF THE PREFERRED EMBODIMENT
FIG. 1 illustrates the type of reciprocating conveyor disclosed in detail in my U.S. Pat. No. 4,856,645. Its basic components are a plurality of transversely extending frame beams 10 secured in longitudinally spaced apart arrangement to laterally spaced, longitudinally extending frame beams 12.
In the illustrated embodiment, the reciprocating conveyor includes a plurality of elongated fixed slats 14 supported upon and secured to the beams of the conveyor main frame in alternate arrangement with a plurality of elongated reciprocative slats 16. The reciprocative slats are secured releasably to the fixed slats against vertical displacement by elongated flexible clips 18 which also serve as lubricating bearings for enhancing the reciprocative movement of the slats 16 relative to the fixed slats 14. For this purpose the clips are made of synthetic resin or other material having a low co-efficient of friction. The clips are secured to the fixed slats against longitudinal displacement by such means as the rivets 20.
The reciprocative slats 16 are arranged in groups and each group is connected to a different transverse drive beam. In the illustrated embodiment, there are two groups of reciprocative slats and therefore two drive beams 22 and 24.
The foregoing general structural arrangement is described in detail in my earlier U.S. Pat. No. 4,856,645.
In accordance with this invention, the reciprocative slats 16 are releasably attached to their associated transverse drive beams 22, 24 by clamp bolts 26. Each slat is formed with a pair of angle clamp brackets 28 which project downwardly from the underside of the slat and have inturned bottom ends 28' which form a narrow slot between them. The enlarged head 26' of each clamp bolt is received in the slot and bears against the upper surface of the inturned ends 28'.
The undersides of the brackets 28 rest upon a pair of clamp saddles 30, one associated with each bolt 26. Each clamp saddle preferably is made of steel, or other suitably hard material, and is provided with upturned lateral edges. Extending between said lateral edges is a plurality of longitudinally spaced, laterally extending ridges which form upwardly projecting teeth 32. The teeth are disposed to engage the undersurface of the brackets 28 and secure the latter, and hence the slat 16 against displacement relative to the associated drive beam 22, 24.
Each pair of saddles 30 is secured in longitudinally spaced position to a mounting plate 34, as by welding. A hole 36 is provided through each saddle and underlying mounting plate for the passage of the shank of bolt 26. Each bolt shank then passes downwardly through a laterally elongated opening 38 in the upper, intermediate portion of the channel shaped drive beam 22, 24. The enlarged openings 38 accommodate a degree of lateral adjustment of each reciprocative slat 16 relative to its associated drive beam. A washer 40 and nut 42 on each bolt 26 under the drive beam serve to releasably clamp the slat to its associated drive beam between the bolt head 28' and washer 40.
Novel means is provided for connecting each slat drive beam 22, 24 to its associated power drive. Referring primarily to FIGS. 1 and 6 of the drawings, a drive module support frame is formed of a pair of transverse beams 44 spaced apart longitudinally by a pair of laterally spaced, longitudinally extending tubular beams 46. The transverse beams 44 are L-shaped in cross section and each is secured permanently, as by welding, to the confronting, laterally spaced ends of an interrupted transverse main frame beam 10. The tubular beams 46 preferably are secured permanently, as by welded spacer plates 48, to a pair of adjacent longitudinal main frame beams 12.
The above described modular support frame removably mounts a power drive system for reciprocating the transverse drive beams 22, 24 and hence the two groups of load supporting and conveying slats 16. Since the conveyor is illustrated in FIG. 1 to include two drive beams 22 and 24, and hence two groups of slats 16 to be reciprocated in a load-conveying operation, the power drive system includes two fluid pressure piston-cylinder drive units, preferably hydraulic, for operative association with the two drive beams. The cylinders 50 and 52 of the drive units are joined at their head ends by a transverse connector beam 54 and at their rod ends by a transverse connector beam 56. Openings in the beam 56 freely receive therethrough the piston rods 58 and 60 extending from the cylinders 50 and 52, respectively. A similarly apertured transverse plate 62 freely receives the piston rods adjacent their outer ends. Guide sleeves 64 on the plate provide bearings for slidably supporting the piston rods for reciprocation.
The transverse beam 56 and plate 62 also are provided with apertures 66 which are spaced apart for registry with tubular beams 46. Elongated bolts 68 and 70 extend removably through the registering apertures 66 and into internal end threads in tubes 46 to clamp the power drive module removably to the module support frame.
Novel means is provided for detachably connecting the piston rods 58 and 60 to the slat drive beams 22 and 24, respectively. Secured, as by welding, to the underside of the associated channel shaped drive beam (22 in FIGS. 4 and 5) adjacent the downwardly extending side segments of the beam are a pair of anchor blocks 72 and 74 from each of which a pair of spaced clamp bolts 76 project. The bolts are arranged to receive the piston rod 58 between them. A clamp plate 78 is associated with each anchor block and associated pair of clamp bolts, and is provided with spaced openings to receive the clamp bolts therethrough. A nut 80 is fitted onto the threaded end of each clamp bolt for moving the clamp plate toward the piston rod 58 which is interposed between the clamp plate and the associated anchor block.
Each of the downwardly extending side segments of the drive beam 22 is provided with an arcuate groove 82. The grooves are aligned in the transverse direction of the beam and are configured to seat the piston rod 58. By tightening the clamp nuts 80, the clamp plates 78 press the piston rod firmly into the grooves 82 to clamp the piston rod firmly to the drive beam 22.
Positioned between the anchor blocks 72 and 74 is a pair of clamp blocks 84 and 86 provided with confronting half round grooves for receiving the piston rod 58. A pair of clamp bolts 88 extend through unthreaded openings in clamp block 86 and into threaded openings in clamp block 84. The bolts function to clamp the blocks 84 and 86 securely to the piston rod.
To insure against axial displacement of the piston rod 58 relative to the clamp blocks 84 and 86, the openings for at least one of the bolts are disposed to intercept a portion of the circumference of the piston rod (FIG. 5). An arcuate notch 90 is provided in the piston rod to register with the openings for the clamp bolt. The bolt thus effectively secures the piston rod and clamp blocks against axial displacement.
The secured clamp blocks 84, 86 are retained positively between the anchor blocks 72 and 74 by means of a wedge block 92. As best shown in FIG. 5, the anchor block 74 is provided with an inwardly facing surface that is spaced from and forms with the confronting face of the clamp block 84 a relatively small arcuate angle. The wedge block 92 is received slidably within that space and is movable to provide wedging pressure against the clamp block 8 to clamp it frictionally against the opposite anchor block 72. A spiral tension spring 94 is secured at one end to the narrow end of the wedge block and at the other end to an anchor 96 on the drive beam 22. The wedge block thus is urged resiliently in the direction of increasing wedging pressure, to ensure maximum retention of the clamp blocks 84 and 86.
From the foregoing description it will be appreciated that the arrangement of clamp bolts 26 and saddle 30 facilitates assembly and alignment of the slats, as well as disassembly for maintenance and repair. The arrangement of the modular support frame 44 and 46, modular power drive system 50-70 and clamp assembly 72-96 facilitates connection and alignment of the slat drive beams with the piston rods of the power drive and affords rapid installation and removal of the power drive module for efficient maintenance and repair.
It will be apparent to those skilled in the art that various changes and modifications may be made in the size, shape, type, number and arrangement of parts described hereinbefore without departing from the spirit of this invention and the scope of the appended claims.
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A reciprocating conveyor includes a plurality of groups of reciprocating slats supported on a main frame, each group of slats being connected to a separate drive beam by releasable clamp bolts extending through laterally elongated openings in the drive beam for accommodating alignment of the slats with adjacent slats. The drive beams are connected detachably to the piston rods of hydraulic piston-cylinder drive units through quickly attachable and detachable clamps, and the drive units are formed as a drive module that is readily attached to and detached from the main support frame.
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BACKGROUND OF THE INVENTION
This invention relates to packer wheels for use on agricultural equipment.
Many farm implements such as grain drills, row crop planters, air seeders and soil packers for use in diverse applications, use steel packer wheels. Commonly, such wheels are formed from a pair of shallow cup-like half shells joined face to face by welding, the welding bead being on the circumferential wear surface of the hollow wheel. Farm implements using the welded packer wheels are subject to hard wear in normal use and may further be subject to abuse by running the packer wheels on hard pavement or the like which rapidly wears or even destroys the wheels, for example, by wearing down the weld seam and eventially splitting the wheel.
It is an object of the invention to provide a means and method for reinforcing steel packer wheels so as to prolong the life thereof, and which is applicable with equal facility both to new and to used wheels.
A further object of the invention is to provide a means and method as aforesaid which is of simple and economical application, and which can readily be effected in situ.
STATEMENT OF PRIOR ART
Applicant is aware of the following U.S. patents, the relevance of which is that they relate to diverse wheel structures and the like. None of the patents, however, discloses the features of the present invention.
U.S. Pat. No. 36,356--A. W. Brinkerhoff--Sept. 2, 1862
U.S. Pat. No. 313,563--H. Weddle--Mar. 10, 1985
U.S. Pat. No. 463,740--F. P. Circle--Nov. 24, 1891
U.S. Pat. No. 970,476--W. L. Dodd--Sept. 20, 1910
U.S. Pat. No. 1,396,037--S. H. Garst--Nov. 8, 1921
U.S. Pat. No. 2,950,770--R. W. Wilson--Aug. 30, 1960
U.S. Pat. No. 4,020,906L. H. Wells--May 3, 1977
SUMMARY OF THE INVENTION
Broadly stated, the invention consists in reinforcing the periphery of a steel packer wheel of the type described by a surrounding metal band or cap of angle iron rolled into circular form, preferably of a diameter somewhat less than the diameter of the wheel, the band being cut to length, placed around the periphery of the wheel with the ends of the angle iron webs engaging the opposed halves of the wheel and the band being welded in place by spot welding or the like.
For the reinforcement of new or worn packer wheels, for example, pre-rolled reinforcement bands may be provided rolled to the required diameter, but having a length somewhat in excess of that required so that the ends of the band overlap. A band may be resiliently snapped over a wheel to be capped, marked for length, removed and cut to length, replaced around the wheel and welded in place by a weld seam at the ends of the band and spot weld along its length.
The reinforcement bands can be made in different thickness and added strength to resist denting from rocks and splitting open of wheels after the original welding bead has become worn. The cost of fitting the reinforcement band is significantly lower than the replacement cost of a wheel, and the reinforcement band provides a structure which may be stronger than the original wheel. The latter consideration provides a basis for reinforcing new wheels. The invention can be effected speedily and easily without having to remove the packer wheels from the equipment on which they are mounted, and can be applied substantially to any size of packer wheel.
These together with other objects and advantages which will become subsequently apparent reside in the details of construction and operation as more fully hereinafter described and claimed, reference being had to the accompanying drawings forming a part hereof, wherein like numerals refer to like parts throughout.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 is a perspective view of part of a grain drill showing an assembly of packer wheels reinforced in accordance with the invention.
FIG. 2 is an exploded perspective view of a packer wheeler and protective reinforcement band therefor.
FIG. 3 is a perspective view of a reinforced packer wheel.
FIG. 4 is an enlarged sectional view on line 4--4 of FIG. 3.
DESCRIPTION OF THE PREFERRED EMBODIMENT
Referring to FIG. 1, there is illustrated a known form of grain drill 10 having furrowing discs 12 and an assembly of individual packer wheels 16. The packer wheels are reinforced, in accordance with the invention, by peripheral bands or caps 18, as will be described.
As shown more particularly in FIG. 4, each packer wheel 16 comprises left and right shallow cup-like steel half shells 20a, 20b welded together around the peripheries by a circumferential weld seam 22. In conventional packer wheels of this nature, seam 22 is commonly left exposed, so that continuous use of the wheel causes wear on the seam which may eventually lead to splitting of the wheel. Thus, in accordance with the invention, wheel 16 is protected by a band or cap 18 and it is understood that such bands may be attached either when the wheel is new or after it has been in use.
Band or cap 18 is formed from a length of angle iron of suitable dimension such that the edges 18a, 18b of its respective webs will contact the outsides of the respective half shells 20a, 20b (see FIG. 4). The thickness of the band will depend on its wear requirements and may typically be about a 1/4 inch or 5/16 inch. Preferably, the band will initially be supplied as a length 18c (FIG. 2) which has been rolled to a diameter slightly less (e.g. by about 1 inch) than that of wheel 16, but which has a length in excess of that required to cover the circumference of the wheel. This insures, for example, that irregularities in diameters of packet wheels will be accommodated.
The overlength band initially is resiliently snapped over the circumference of the wheel, with its ends overlapping, the correct length of the band is marked thereon, the band is removed, cut to length, and reapplied to the wheel, its reduced diameter insuring that it will properly hug the wheel. Finally, the adjacent ends of the band may be welded together by a weld seam 24, and the band may be spot welded at circumferentially spaced locations 26 to the respective half shell 20a, 20b of the wheel, typically with four or more spot welds per half shell.
While the reinforcing means of the present invention is of generally simple construction and application, it is instrumental in significantly strengthening packer wheels and extending their useful life, inter alia, by protecting weld seam 22.
The foregoing is considered as illustrative only of the principles of the invention. Further, since numerous modifications and changes will readily occur to those skilled in the art, it is not desired to limit the invention to the exact construction and operation shown and described, and accordingly, all suitable modifications and equivalents may be resorted to, falling within the scope of the invention.
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A packer wheel for a farm implement is reinforced by a band of angle-section metal welded around the periphery of the wheel with the edges of respective webs of the band engaging outer surfaces of respective half shells of the wheel.
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CROSS-REFERENCE TO RELATED APPLICATIONS
Not Applicable
FEDERALLY SPONSORED RESEARCH
Not Applicable
SEQUENCE LISTING OR PROGRAM
Not Applicable
FIELD OF THE INVENTION
The present invention relates to an adhesive film in a form of a sheet, strip, tape, label, tag, and the like which is perforated with microscopic holes to provide good air bubble escapability while maintaining good appearance and functionality of the film surface after being adhered to an article.
BACKGROUND OF THE INVENTION
Various types of adhesive films comprising a flexible substrate and an adhesive layer have been heretofore available. Such films are provided in the form of sheets, tapes, strips, labels, tags, and the like. Those films having a pressure sensitive adhesive layer generally are mounted on some type of release liner or other releasable support to protect the pressure sensitive adhesive until the film is ready to be applied to an intended article. The film is then stripped from the release liner and applied.
Typically, the substrate for such a film is a self-supporting web or a sheet of paper, cardboard, plastic, or metal. One major face of the substrate has a pressure sensitive adhesive while the other major face can be further coated and/or printed on. Such coating and/or printing can be accomplished either before or after the application of adhesive to the first major face. Other versions of adhesive film have adhesive coating on both faces of the substrate and are known as “double sided” or “two-sided.”. Adhesive films of this basic construction are manufactured for a variety of commercial and consumer uses including labels, tags, and stickers for industrial and consumer products, decorative films for furniture finish and wall covering, tinting films for building and automotive windows, and antiglare films for computer displays. Such films constructed in accordance with prior art are substantially impervious to air and liquids. This condition is due to a variety of practical considerations including the choice of materials and manufacturing processes used, and requirements for appearance and function.
Problem: When an adhesive film according to the prior art is applied to an article, air tends to become entrapped between the adhesive and the article surface. This condition is shown in FIG. 1 . To prevent such entrapment and the resulting bubble, a considerably high level of skill is necessary during the application step. Consequently, a great amount of labor and time are necessary to perform the bonding application step. Tolerance for errors during the bonding step is very low because the bond strength rises with the passage of time, which makes it more difficult to peel the adhesive sheet from the substrate article and reposition it at later time. When air bubbles are trapped between the adhesive layer and adherent article surface, the appearance of the film is negatively impacted. This condition is highly undesirable especially when the film is used for decorative purposes.
Even when the film is applied to the article surface and trapped air bubbles are avoided, lifting and formation of bubbles can occur at the bond interface when the film is exposed to environment such as heat and light. Exposure to ultraviolet light is considered especially deleterious. This is particularly detrimental to the appearance and functionality of transparent films such as employed for tinting of windows used in buildings and automobiles, and antiglare films used for electronic and computer displays (flat panel, cathode ray tube).
REVIEW OF PRIOR ART
Prior art discloses several approaches to the design of adhesive films that avoid the trapping of air when adhesive film is applied to article. These prior art approaches can be grouped as follows: 1) use of permeable film substrate, 2) use of permeable adhesive structure, and 3) use of permeable surface structure of the adherent article.
1) Use of permeable substrate: Substrate materials for construction of adhesive films having physical characteristics which allow for significant air permeability are well known and are generally referred to as being porous. Porous substrate materials typically have woven, non-woven, knitted, or foamed constructions, or are formed as microporous sheets.
Adhesive films with porous substrate have many applications and are particularly useful as tapes in the medical field. See for example, Lucast et al., in U.S. Pat. No. 5,613,942 and Dunshee et al., in U.S. Pat. No. 5,914,282. When porous substrate is used in construction of adhesive film, one should generally avoid using adhesives which readily migrate into the interstices of the porous substrate, thus filling the pores. Another limitation of films with porous substrate is that when a coating or an ink for decoration is applied to the second, non-adhesive face of the substrate, it tends to close the pores of the porous substrate and initial performance cannot be obtained. This condition is particularly problematic when a coating with sealing properties is highly desirable as the means for protecting the non-adhesive surface of the adhesive film from dust, dirt, moisture, liquids, or human touch, or when such a coating is used to improve the performance, prepare the surface for printing, or protect the print ink. Furthermore, many desirable substrate materials including plastics and metals are not naturally porous and permeable by air. Hence, the usefulness of permeable substrate of prior art for construction of adhesive films is very restricted.
2) Use of permeable adhesive structure: Abe in U.S. Pat. No. 6,015,606 discloses adhesive film having structured adhesive including raised portions. Such raised portions are generated by elastic microspheres included in the adhesive. During the application step, the raised portions on the adhesive layer allow formation of passages which communicate with the atmosphere and through which bubbles trapped between the adherent article and the adhesive layer escape to the atmosphere. This situation is shown in FIG. 2 a . However, as the film is pressed onto the article, the raised portions are gradually flattened thereby closing off the passages. Hence, initial performance is degraded. This situation is shown in FIG. 2 b . Therefore, a precise sequencing is required to assure that all of the trapped air is expelled before the passages are closed off. Such sequencing is, however, difficult to achieve in practice. Furthermore, formation of structured adhesive layer requires special equipment. In addition, once the film is applied to an article, gasses generated at the bond interface when exposed to environment such as heat and light cannot escape and, as a result, cause bubbles and lifting. A more complex adhesive structure disclosed by Abe in U.S. Pat. No. 6,294,250 has the same limitations.
3) Use of permeable adherent surface structure: Kurtz in the U.S. Pat. No. 4,548,846 discloses an adherent article with a specially prepared grooved surface. When adhesive film is applied to such grooved surface, the grooves provide channels for communication with outside atmosphere and allow trapped air to escape. This condition is shown in FIG. 3 . However, this approach is not suitable for general use as it requires special preparation of adherent article surface. Such surface preparation is costly and impractical in most situations, especially when the adherent article is a glass window or computer display. In addition, the need for surface preparation greatly restricts the choice of adherent materials and limits the selection of sites on the surface of substrate article that are suitable for receiving adhesive film.
Permeability of materials by air can be quantified in terms of Gurley value. Gurley value (also known as Gurley seconds) for porosity is measured on a Gurley porosity tester (Gurley Precision Instruments, Troy, N.Y.) and it represents the time (in seconds) for 100 cubic centimeters (about 6.1 cubic inches) of air to flow through 1 square inch area of test material under pressure gradient of 1.2 kilo-Pascals (about 4.9 inches of water). The Gurley value actually represents air resistance, but popularly is referred to as permeability or porosity. A low Gurley value indicates high porosity material, while a high Gurley value indicates a low porosity material. For comparison purpose, 50 pound smooth paper for offset printing has a Gurley value around 20.
SUMMARY OF THE INVENTION
To overcome the limitations of prior art, the present inventors made an extensive study, and as a result, they have discovered a novel construction and a method for manufacture for adhesive film having good air bubble escapability. The invention is based on experimental evidence indicating that very modest air permeability of the film is sufficient to prevent trapping pockets of air between the film and an adherent article when the film is applied to the article surface. The inventors have determined that appropriate air permeability can be achieved by perforating the film with microscopic holes at relatively low areal density. Using this approach, the film is rendered permeable without significantly affecting its appearance or functionality.
The present invention is an adhesive film which is permeable by air. The film comprises a thin flexible substrate such as a sheet, strip, tape, tag, or the like, coated with a layer of adhesive on at least one side. Substrate materials suitable for use with the subject invention include paper, cardboard, plastics, and metal. The substrate may also include a print and/or protective coating on its other surface opposite to the surface coated with adhesive layer. The substrate is perforated by a number of microscopic holes generally perpendicular to its surfaces. Such holes are generally 1 to 300 micrometers in transverse dimension. Size and areal density of the microscopic holes are chosen to provide appropriate permeability by air while avoiding degradation in appearance and functionality of the film. For example, if the subject invention is used as an antireflective film for computer screens such as disclosed by Kishioka et al., in the U.S. Pat. No. 6,599,967, the microscopic holes should be preferably less than about 10 micrometers in size and applied with areal density about 100 to about 1000 per square inch. When used for wall covering, the microscopic holes from about 30 to about 100 micrometers in size and areal density of about 1 to about 100 per square inch can be employed in many cases without adversely affecting the film appearance. For comparison, a typical human hair has a diameter around 70 micrometers. This is also considered the limit of optical resolution of human eye. Objects smaller than 10 micrometers are generally indistinguishable by naked human eye.
In one embodiment of the subject invention, the adhesive is applied over less then 100% of each substrate surface. In particular, adhesive may be applied in regular or irregular patterns that provide predetermined coverage (typically 20 to 90%) of the coated substrate face. The desired level of air permeability is obtained by installing microscopic holes in the substrate so that when averaged over the surface area, a sufficient number of these holes are in locations where the substrate surfaces are not covered by adhesive. The microscopic holes can be installed in the substrate prior to coating with adhesive or after the coating process. Suitable methods for production of microscopic holes include mechanical piercing, perforation by electric discharge (spark), and laser drilling. The microscopic holes can be applied in patterns that are coordinated with the adhesive coating patterns so as to preferentially perforate the substrate in areas not having adhesive coating. Alternately, the holes can be applied in regular, irregular, or even random patterns with sufficient areal density to assure that a sufficient quantity of the holes penetrates the substrate in areas not covered with adhesive coating. If the film substrate also has an ink print and/or decorative/protective coating on the face opposite to that of the adhesive, the holes are installed therethrough so that the desired permeability is achieved.
In another embodiment of the subject invention, the adhesive is applied over generally 100% area of at least one surface. In one variant of this embodiment, the adhesive has microscopic voids forming passages, with some of the passages connecting to the microscopic holes in the substrate. In another variant, the microscopic holes are generated after the adhesive has been applied to the film and penetrate through the adhesive layer with sufficient spatial frequency to achieve the desired level of air permeability.
In each embodiment of the subject invention, the microscopic holes provide a path for air to permeate through the adhesive film of the subject invention. When the film of the subject invention is applied to a substrate, pockets of air trapped between the film and the substrate surface are relieved to outside atmosphere. As a result, formation of bubbles of trapped air is avoided. When adhered film is exposed to environment such as light and heat that cause the materials in the vicinity of adhesive bond interface generate gas, such gas is readily relieved through the microscopic holes to the atmosphere.
In many instances, most notably in consumer articles, it is desirable to remove the product label after the product has been purchased. Yet, very often the adhesive employed (usually pressure sensitive or water soluble type) adheres very well to the article and the label substrate is too weak to carry the force required to peel off the label without breaking. Softening the adhesive with suitable solvent requires great amount of time since the solvent has to penetrate the adhesive layer starting from the edge. In contrast, when the product label is fabricated in accordance with the subject invention, the solvent can readily permeate through the film substrate via microscopic holes and soften the adhesive, thereby making it possible to remove the label shortly after the solvent it applied.
OBJECTS OF THE INVENTION
One object of the invention is to allow removal and venting of air entrapped between adhesive films and surface of adherent article when the film is applied to the article.
Another object of the invention is to allow venting of gases evolved at the bond interface after an adhesive film has been applied to an adherent article.
Yet another object of the invention is to allow for easier removal of adhesive film after it has been adhered to an adherent article.
Yet another object of the invention is to improve appearance of adhesive film adhered to an article.
Yet another object of the invention is to make easier installation of adhesive film onto an article.
Features and advantages of the invention will emerge in the discussion of the embodiments.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 shows a side cross-sectional view of a prior art adhesive film applied to an article wherein a bubble is formed by entrapped air;
FIG. 2 a shows a side cross-sectional view of a prior art adhesive film applied to an article wherein a permeable adhesive structure forming passages is used to relieve trapped air;
FIG. 2 b shows an adhesive film of FIG. 2 a wherein passages used to relieve trapped air have significantly collapsed;
FIG. 3 shows a side cross-sectional view of a prior art adhesive film applied to an adherent surface having relieve passages;
FIG. 4 shows a side cross-sectional view of a first embodiment of the subject invention with adhesive layer applied discontinuously to one face of the substrate;
FIG. 5 shows a side cross-sectional view of a variant of a first embodiment of the invention with adhesive layer applied discontinuously to both faces of the substrate;
FIG. 6 shows a side cross-sectional view of a second embodiment of the subject on using porous adhesive;
FIG. 7 shows a side cross-sectional view of a third embodiment of the subject on with holes installed through the adhesive layer.
DRAWINGS—REFERENCE NUMERALS
10 Adhesive film—First embodiment
10 ′Adhesive film—Variant to a first embodiment
11 Adhesive film—Second embodiment
12 Adhesive film—Third embodiment
21 Substrate
24 Adhesive
27 Microscopic hole
29 Finish layer
32 Surface of substrate
33 Surface of substrate
42 Surface for attaching release liner
43 Surface of adhesive
124 Adhesive
224 Adhesive
DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS
Referring now to FIG. 4 , there is shown a side cross-sectional view of an adhesive film 10 in accordance with a first embodiment of subject invention. The film 10 comprises a flexible substrate 21 having surfaces 32 and 33 . The substrate 21 is a thin flexible member that can be in a form of a sheet, strip, tape, label, or alike. Typical thickness of substrate 21 is 10 to 1500 micrometers. Suitable materials for fabrication of the substrate include paper, cardboard, plastics, and metals. More specifically, suitable plastics include polyethylene, polyvinyl chloride (PVC), polyester, polyurethane, polyacrylate, etc. PVC resin is particularly suitable for the construction of substrate 21 because it can be easily printed onto. In addition, PVC is economical and has good weatherability, which makes it suitable for outdoors use. Furthermore, in the present invention it is possible to use those film substrates to which surface treatment such as printing, embossing, and protective layers is applied. Surface 32 of substrate 21 is coated with a pressure sensitive adhesive 24 , which is applied in a discontinuous manner so that portions 32 a of the surface 32 are generally free of the adhesive material. Preferably, the adhesive 24 covers less than 90% of the surface 32 . The pressure sensitive adhesive 24 may be applied in regular, irregular, or entirely random patterns. Examples of suitable patterns are straight lines, stripes, wavy lines, curves, dots, shapes, checkered, crosshatched, and any combination thereof. A variety of pressure sensitive adhesives can be used with the subject invention including the types that contain elastic microospheres as for example disclosed by Date in U.S. Pat. No. 6,294,250.
The substrate 21 is further perforated by microscopic holes 27 which are installed generally perpendicular to the surface 32 . The pattern for placement of the microscopic holes 27 can be coordinated with the pattern of the adhesive 24 to yield a high percentage of the microscopic holes placed in the portions 32 a of surface 32 . This percentage can be 100% if the adhesive pattern and hole pattern are well coordinated. Holes terminating in surface portion 32 a which is not coated by adhesive are open and available for transport of air through the film 10 . Hole 27 a is an example of an open hole. Unless porous adhesive is used, microscopic holes terminating into the adhesive 24 are deemed substantially blocked by the adhesive and not significantly contributing to air transport through the film. Hole 27 b is an example of a blocked hole. Alternate to coordinated patterns, the pattern for microscopic holes 27 can be uncoordinated with the patterns for adhesive 24 , and can be regular, irregular, or random. Whichever the choice, the areal density and the size of microscopic holes should be chosen so that the permeability of the film 10 rendered by the unblocked holes is in the range of 1 to 1000 Gurley seconds when measured under the already described conditions. Appropriate size and areal density of microscopic holes 27 can be estimated using the theory of air flow through microscopic holes in thin sheets.
EXAMPLE 1
Table 1 shows theoretical predictions of air flow through smooth holes with diameters of 10, 32, and 100 micrometers installed in a 75 micrometer thick sheet impervious to air and operated with a pressure differential of 1.2 kilo Pascals (4.9 inches of water). (Note that this is the same pressure differential normally used in the Gurley tester.) This data is based on theoretical predictions found in “Effect of Pinholes on Sterile Barrier Properties,” by Earl T. Hackett, Jr. presented at the HealthPak Conference, St. Petersburg, Fla., in March 2001.
TABLE 1
Hole Diameter [micrometers]
10 μm
32 μm
100 μm
Flow velocity [cm/sec]
400
3500
5500
Flowrate per hole [cubic
0.000314
0.028
0.039
cm/sec]
Porosity produced by 1 hole
318000
3571
256
per inch square [Gurley
seconds]
Areal density of holes
3,180
36
2.6
necessary to produce poro-
sity of 100 Gurley seconds
[per square inch]
EXAMPLE 2
Table 2 shows several suitable choices of diameter and areal density for microscopic holes suitable to relieve 1 cubic centimeter air bubble to atmosphere in less 5 seconds assuming a constant pressure differential of 1.2 kilo Pascals. Sheet thickness is 75 micrometers. Expectedly, the data shows that smaller holes must be applied with greater areal density to meet the specified venting time during installation of adhesive film to an article. Note that even for a 10 micrometer diameter hole the required areal density of 1,000 to 10,000 holes per square inch is realistic and technically attainable.
TABLE 2
Time (seconds) required to
relieve 1 cubic centimeter air
Areal density of microscopic
bubble for hole diameters
holes [per square inch]
10 μm
32 μm
100 μm
1
2.6
10
3.6
0.26
100
0.36
1,000
3.2
10,000
0.32
As already noted, after the film is applied to the article surface and trapped air bubbles are avoided, gas evolution can still occur at the bond interface when the film is exposed to environment such as heat and light. Such gas is relieved by microscopic holes 27 and lifting and formation of bubbles are avoided. Since the rates at which such gas is evolved are very low, microscopic holes 27 can be very small (typically 1 to 10 micrometers) and installed with low areal density (1 to 1000 per square inch).
Referring further to FIG. 4 , the adhesive film 10 may also include a layer 29 attached to surface 33 of substrate 21 . Layer 29 can be a print ink, protective coating, or decorative coating. Alternately, layer 29 may be a composite layer comprising separate sublayers which may include print ink, protective coating, or decorative coating. Whichever the case, microscopic holes 27 penetrate through the layer of material 29 to provide air permeability for the film 10 .
Microscopic holes 27 may be installed either before or after the adhesive 24 is applied to the substrate 21 . Preferably, the holes are installed after providing the substrate 21 with the finish layer 29 . When the holes are installed after coating the substrate with adhesive 24 , some of the holes 27 may actually penetrate through the adhesive. Depending on the process for production of the holes 27 and the nature of the adhesive 24 , holes 27 penetrating through adhesive 24 may become at least partially closed with passage of time. Holes that remain at least partially open increase the air permeability of the film 10 . Adhesive film 10 may also include a release liner attached to surface 43 the adhesive 24 . Furthermore, the substrate 21 of adhesive film 10 may be also embossed for decorative or other beneficial purposes.
Suitable techniques for installation of the holes 27 include mechanical piercing, electric discharge, and laser drilling. Mechanical piercing method and apparatus suitable for production of holes in the manufacture of the subject adhesive sheet is disclosed by Silverstein in the U.S. Pat. No. 3,789,710. Silverstein's method and apparatus use a heat assisted piercing and are particularly effective for use on substrates made of thermoplastic material. Mechanical piercing can produce holes down to about 0.020 inch diameter.
The use of electric discharge for perforation of dielectric sheet materials has been practiced commercially since the 1940's. Devices and methods for electric discharge perforation have been disclosed by Meaker in the U.S. Pat. No. 2,340,546; Menke in the U.S. Pat. No. 2,528,157; Bancroft et al. in the U.S. Pat. No. 3,385,951; Martin in the U.S. Pat. No. 4,029,938; and Whitman in the U.S. Pat. No. 4,447,709. Electric discharge can produce holes down to about 0.030 inch diameter.
Laser drilling has become a well established commercial practice since its initial introduction in the 1970's. General review of the state of the art in laser drilling is presented by Leo Rakowski in “Non-Traditional Methods for Making Small Holes,” published in Modern Machine Shop, June 2002 issue, pages 76-83. Devices and methods for laser drilling have been disclosed by Lilly et al. in the U.S. Pat. No. 4,410,785; Kimbara et al., in the U.S. Pat. No. 4,568,815; Fukuchi in the U.S. Pat. No. 5,403,990; Steadman in the U.S. Pat. No. 6,344,256; and Hamada in the U.S. Pat. No. 6,720,524. Equipment for laser drilling of the holes suitable for use with the subject invention may also include means for detecting adhesive free portions of surface 33 and preferentially installing the hole (s) at such locations. Laser drilling is particularly suitable for production of precision-located holes smaller than 30 micrometers and as small as about 1 micrometer in diameter.
Referring now to FIG. 5 , there is shown a side cross-sectional view of an adhesive film 10 ′ in accordance with a variant of first embodiment of the subject invention. In this variant, the substrate 21 is coated with pressure sensitive adhesive on both faces: surface 32 is coated with adhesive 24 and surface 33 is coated with adhesive 24 ′. In each case, the adhesive coating is applied discontinuously so that portion 32 a of surface 32 and portion 33 a of surface 33 remain generally free of the adhesive. Preferably, the adhesive covers less than 90% of each the surface 32 and 33 . The adhesive may be applied in regular, irregular, or entirely random patterns. Examples of suitable patterns are straight lines, stripes, wavy lines, curves, dots, shapes, checkered, crosshatched, and any combination thereof. If regular patterns are employed, preferably they should be coordinated and well aligned so that a high percentage of uncoated portions 32 a and 33 a lay directly opposite to each other. A pattern for microscopic holes 27 is preferably chosen so that a large percentage of the holes are at locations where they connect opposing uncoated portions 32 a and 33 a . Adhesives 24 and 24 ′ can be both of the same type or different types. An example of two different types of adhesives that may be simultaneously used with adhesive film 10 ′ are permanent pressure sensitive adhesive and a temporary pressure sensitive adhesive. Adhesive film 10 ′ may also include a release liner attached to surface 42 the adhesive 24 and/or surface 43 of adhesive 24 ′.
Referring now to FIG. 6 , there is shown a side cross-sectional view of an adhesive film 11 in accordance with a second embodiment of subject invention. This embodiment is similar to the first embodiment except that 1) pressure sensitive adhesive 124 is applied substantially continuously over the surface 32 of substrate 21 , and 2) the pressure sensitive adhesive 124 is porous and permeable by air. Suitable porous pressure sensitive adhesive has been disclosed in prior art for example by Copeland in the U.S. Pat. No. 3,121,021. Holes 27 can be installed in any suitable pattern either before or after the adhesive 124 is applied to substrate 21 . Since the adhesive 124 is porous, a large percentage of the holes 27 will connect to one or more pores in adhesive 124 leading up to surface 43 . Air trapped between the adhesive film 11 and adherent article is then relieved by first passing through the adhesive 124 and then through holes 27 into the atmosphere.
Referring now to FIG. 7 , there is shown a side cross-sectional view of an adhesive film 12 in accordance with a third embodiment of subject invention. This embodiment is similar to the first embodiment except that 1) the adhesive 224 is applied substantially continuously over the surface 32 of substrate 21 , 2) the adhesive 224 can be either pressure sensitive or solvent activated, and 3) holes 27 penetrate through the adhesive 224 .
Those skilled in the art can now appreciate from the foregoing description that the broad teachings of the subject invention can be implemented in a variety of forms. Therefore, while this invention has been described in connection with particular examples thereof, the true scope of the invention should not be limited since other modifications will become apparent to the skilled practitioner upon a study of the drawings and the following claims.
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An adhesive sheet is disclosed including a flexible substrate and an adhesive layer formed on at least one of the main surfaces of the flexible substrate. The adhesive sheet further includes a plurality of microscopic holes connecting the opposing surfaces of the sheet and being generally perpendicular to them. Such adhesive sheet is permeable by air and allows good bubble escapability when the sheet is applied to an article. Sufficient permeability of the sheet to air is achieved with microscopic size holes installed in modest areal densities, hence the appearance and functionality of the film surface are not significantly adversely impacted. One intended use of the subject invention is for tinting films used to reduce light transmission in windows for use in buildings and automobiles. In this application visual appearance of the film is paramount. Another intended application of the subject invention is for antireflective film which is applied to electronic computer displays (flat panel, cathode ray tube) to reduce unwanted ambient light reflection and to improve contrast.
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BACKGROUND OF THE INVENTION
1. Field of the Invention
This invention relates to variant aequorin genes and a process for producing variant aequorin proteins. More particularly it relates to variant aequorin genes prepared according to a site-specific mutagenesis method using a synthetic oligonucleotide, and a process for producing the above-mentioned proteins by the use of the above-mentioned genes.
2. Description of the Related Art
Aequorin existent in nature is the so-called photoprotein separated from photogenic Aequorea living in the sea, followed by separation and purification, and has been known as a biologically active substance in living body having a high utility value. Namely, since aequorin emits light by way of metal ions such as Ca 2+ , Sr 2+ , etc., it is utilized as a reagent for detecting trace Ca 2+ (10 -9 M), and in particular, it has been confirmed to be effective for measuring intercellular Ca 2+ . However, its production quantity is extremely small so that it is the present status that the quantity is insufficient even as an agent for research.
Thus, firstly the present inventors separated cDNA gene from photogenic Aequorea, identified it and referred to it as pAQ440 (Japanese patent application laid-open No. Sho 61-135586/1986). Further, we succeeded in producing aequorin protein inside Escherichia coli by means of recombinant DNA technique (Japanese patent application No. Sho 60-280259/1985), and also disclosed that it is possible to detect metal ions such as Ca 2+ by making use of this aequorin protein (Japanese patent application No. Sho 61-103849/1986).
However, as to its photogenic mechanism, many unclarified points are still present. Elucidation of the photogenic mechanism of aequorin protein and its correct understanding will extend a possibility of concrete applications of aequorin protein. More particularly, understanding of aequorin as a functional protein having a utility in the aspect of structure and function of protein will be linked to elucidation of the photogenic mechanism of aequorin and also will have a profound meaning in the aspect of protein engineering and further a commercial utilization value.
In view of the technical situation relative to aequorin protein, the present inventors have prepared variants of natural type aequorin gene (pAQ440) by means of recombinant DNA technique, and have succeeded in producing variant aequorin genes inside Escherichia coli by making use of the above genes. Further, by comparing the structure and function of these variant aequorin genes with those of pAQ440, it has become possible to more profoundly analyze the photogenic mechanism of the latter pAQ440.
As apparent from the foregoing, the object of the present invention is to provide many kinds of specified variant aequorin genes useful for making the above-mentioned analysis possible, and a process for producing variant aequorin proteins by the use of the above variant aequorin genes.
Further, as described above, as to the photogenic mechanism, the present inventors have analyzed the structure and function of the aequorin gene according to the site-specific mutagenesis method (Japanese patent application Nos. Sho 61-245108/1986 and Sho 61-245109/1986).
However, during the regeneration process of aequorin wherein aequorin which is light-emissive due to calcium is reconstructed in the presence of apoaequorin, coelenterazine as a substrate, molecular form oxygen and 2-mercaptoethanol as a reducing agent, it has been known that 2-mercaptoethanol is necessary to be in a high concentration. The reason why 2-mercaptoethanol is required is unclear, but a possibility of converting the --S--S--bond of aequorin protein(apoaequorin) into --SH,HS--is suggested.
Thus, it is very meaningful to produce variant aequorin proteins which do not require the presence of 2-mercaptoethanol as a reducing agent at the time of regeneration of aequorin by means of recombinant DNA technique, and this will be linked to elucidation of the regeneration mechanism of aequorin and further it will have a profound meaning in the aspect of protein engineering and also a utilization value in the scientific and commercial aspect.
In view of the above-mentioned technical situation of aequorin protein, the present inventors have prepared variants of natural type aequorin gene (pAQ440) by means of recombinant DNA technique, and have succeeded in producing variant aequorin genes inside Escherichia coli by making use of these genes.
Further, it has become possible to produce apoaequorin from which regeneration of aequorin is possible without needing the presence of 2-mercaptoethanol, using variant aequorin genes of the present invention as described later. The variant aequorin genes could have been obtained by converting G of TGC as a base arrangement which can form cysteine residual group on the aequorin gene, into C, to thereby exchange the serine residual group into the cysteine residual group in apoaequorin molecule.
SUMMARY OF THE INVENTION
The present invention resides in the following constitutions (1) to (4):
(1) In the following base arrangement of pAQ440 as aequorin gene: ##STR1## variants having converted a base or bases indicated in the following items (i) to (xiii) into other definite base or bases, or having deleted bases indicated therein:
(i) a variant having converted the 220th base G into C;
(ii) a variant having converted the 238th base G into A;
(iii) a variant having converted the 307th base C into T, and also the 308th base A into T;
(iv) a variant having converted the 499th base G into C;
(v) a variant having converted the 568th base T into C;
(vi) a variant having converted the 569th base G into C;
(vii) a variant having converted the 590th base G into C;
(viii) a variant having converted the 607th base G into C;
(ix) a variant having converted the 625th base G into A;
(x) a variant having converted the 616th base G into C, and also the 625th base G into A;
(xi) a variant having converted the 674th base G into C;
(xii) a variant having deleted the 205th to the 207th bases GAT; and
(xiii) a variant having deleted the 592nd to the 594th bases GAT.
(2) In the following base arrangement of pAQ440 as aequorin gene: ##STR2## a process for producing a variant aequorin protein which comprises using variants having converted a base or bases indicated in the following items (i) to (xiii) into other definite base or bases, or having deleted bases indicated therein:
(i) a variant having converted the 220th base G into C;
(ii) a variant having converted the 238th base G into A;
(iii) a variant having converted the 307th base C into T, and also the 308th base A into T;
(iv) a variant having converted the 499th base G into C;
(v) a variant having converted the 568th base T into C;
(vi) a variant having converted the 569th base G into C;
(vii) a variant having converted the 590th base G into C;
(viii) a variant having converted the 607th base G into C;
(ix) a variant having converted the 625th base G into A;
(x) a variant having converted the 616th base G into C, and also the 625th base G into A;
(xi) a variant having converted the 674th base G into C;
(xii) a variant having deleted the 205th to the 207th bases GAT; and
(xiii) a variant having deleted the 592nd to the 594th bases GAT.
(3) In the following base arrangement of pAQ440 as aequorin gene: ##STR3## variants having converted a base or bases indicated in the following items (i) to (iv) into other definite base or bases indicated therein:
(i) a variant having converted the 569th base G into C and the 590th base G into C;
(ii) a variant having converted the 590th G into C and the 674th G into C;
(iii) a variant having converted the 674th G into C and the 569th G into C; and
(iv) a variant having converted the 569th base G into C, the 590th base G into C and the 674th base G into C.
(4) In the following base arrangement of pAQ440 as aequorin gene: ##STR4##
a process for producing a variant aequorin protein which comprising using
variants having converted a base or bases indicated in the following items (i) to (iv) into other definite base or bases indicated therein:
(i) a variant having converted the 569th base G into C and the 590th base G into C;
(ii) a variant having converted the 590th G into C and the 674th G into C;
(iii) a variant having converted the 674th G into C and the 569th G into C; and
(iv) a variant having converted the 569th base G into C, the 590th base G into C and the 674th base G into C.
BRIEF DESCRIPTION OF THE DRAWING
The accompanying drawing shows a chart illustrating the site-specific mutagenesis method of Example 1 of the present invention.
DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS
The variant genes of the present invention may be produced through the process as illustrated in the accompanying drawing. According to the process of the present invention, variations as mentioned later were introduced into the aequorin gene by the use of a synthetic oligonucleotide and according to a site-specific mutagenesis method. The variation process has no particular limitation, but for example, gap-duplex process (Morinaga et al, Bio/Technology, Vol. 2, 636-639 (1984) may be employed. According to the process, for example, a synthetic oligonucletide is used as a variation source as shown later in Table 1. Such a synthetic oligonucleotide may be synthesized employing a commercially available automatic DNA synthesis apparatus and its purification is preferably carried out employing a high performance liquid chromatography. The purified product is subjected to end-phosphorylation in a conventional manner to obtain a primer for preparing a plasmid.
On the other hand, an Eco RI-Hind III fragment and an Aat II fragment of a plasmid pAQ440 shown in the accompanying drawing are used and the Aat II fragment is subjected to dephosphorylation treatment in a conventional manner.
The two fragments based on pAQ440, obtained as above, together with the above-mentioned end-phosphorylated primer are, for example, subjected to three-stage treatment (treatment at definite temperatures and for definite times) to carry out annealing. The three stages refer to a combination consisting of an order of e.g. (100° C., 5 minutes), (30° C., 30 minutes) and (4° C., 30 minutes).
Next, with the resulting variant pAQ gene, transformation into E. coli is carried out as follows:
For example, dXTP (X=G.A.T.C.) obtained as above and Klenow fragment (E. coli polymerase) are reacted in the presence of T 4 -ligase to prepare a duplex chain. The thus formed plasmid duplex chain is transformed into E. coli in a conventional manner. Further, the variant plasmid (variant of pAQ440) is screened using the above-mentioned respective variant source primers as probes, according to colony hybridization. The identification method of the variant has no particular limitation, but the base arrangement is determined e.g. according to dideoxy method (Hattori et al, Anal. Biochem. 152, 232-238, 1986) to detect the variant base.
Next, in the present invention (the invention of production process), production of aequorin protein inside Escherichia coli is carried out using the above-mentioned variant aequorin gene.
Namely, the outline of the production is as follows:
the cDNA fragment of Hind III-Eco RI of the variant pAQ440 gene is subjected to cloning into the Hind III-Eco RI part of the plasmid pUC9-2 having a promoter of lac; the resulting plasmid is transformed into Escherichia coli such as HB101 (D1210i Q ) strain; and using the resulting Escherichia coli and an expression derivative such as IPTG, an aequorin protein is produced inside Escherichia coli.
The production process and the bacterial bodies-collecting process are carried out in a conventional manner. The collected bacterial bodies are dissolved in a suitable known buffer solution, followed by breaking the bacterial bodies in a conventional manner such as ultrasonic wave treatment and obtaining the supernatant by means of centrifugal treatment to use it as an enzymatic solution for measurement.
The method for measuring the luminescence relative to this solution is carried out as follows:
With a definite quantity of the solution are mixed a substrate (coelenterazine) and a reducing agent (2-mercaptoethanol) each in a definite quantity in the case of the above-mentioned inventions (1) and (2), while with the definite quantity of the solution is not mixed 2-mercaptomethanol in the case of the above-mentioned inventions (3) and (4), followed by maturing the resulting respective solutions under ice-cooling for 2 or 3 hours, transferring the resulting solutions into a reaction cell inside a phototube measurement apparatus, further injecting a definite quantity of CaCl 2 solution into the cell and measuring the resulting luminescence.
The synthetic oligonucleotide (primer) of the above inventions (1) and (2) is shown later in Table 1 of Example 1, and the aequorin activity of the primer is shown later in Table 2. The extent to which the aequorin activity varies or is extinct depending on what a site the base arrangement of aequorin gene is varied or base(s) therein are removed at is apparent from Tables 1 and 2.
The synthetic oligonucleotide (primer) to be measured, of the above-inventions (3) and (4) is shown later in Table 3 of Example 2, and the aequorin activity of the primer is shown later in Table 4 of the Example. It is apparent from Tables 3 and 4 that aequorin is reproduced by varying the base arrangement of aequorin gene, even when no 2-mercaptoethanol is added.
In particular, in the case of Cl+2+3S wherein the cysteine residual groups at all of the three parts have been converted into serine residual groups, it is apparent that aequorin is reproduced almost completely.
The present invention will be described in more detail by way of Examples.
EXAMPLE 1
1) Introduction of mutagenesis into aequorin gene (pAQ440) according to a site-specific mutagenesis process using a synthetic oligonucleotide (see the accompanying drawing)
The site-specific mutagenesis process was carried out according to gap-duplex process of Morinaga et al (Bio/Technology, Vol. 2, 630-639 (1984)). Namely, as shown later in Table 1, a synthetic oligonucleotide was used as a variation source. As the synthetic oligonucleotide, there was used a product obtained by preparing a raw product by means of an automatic DNA synthesis apparatus manufactured by ABI Company, followed by purifying it according to high performance liquid chromatography and carrying out end-phosphorylation with T4 kinase. Eco RI-Hind III fragment and Aat II fragment of pAQ440 were used, and Aat II fragment was treated with an alkali phosphatase to carry out dephosphorylation. These two fragments together with the primer were treated at 100° C. for 5 minutes, followed by allowing the resulting material to stand at 30° C. for 3 minutes and further at 4° C. for 30 minutes to carry out annealing and reacting dXTP (X=G, A, T, C) with Klenow fragment (Escherichia coli polymerase) in the presence of T4-ligase to prepare a duplex chain.
The thus formed plasmid duplex chain was transformed into E. coli in a conventional manner, and the variant plasmid (variant of pAQ440) was screened by colony hybridization, using the respective variant source primers as probes. As to the ascertainment of the variant, the base arrangement was determined according to the dideoxy process of Hattori et al (Anal. Biochem. 152, 232-238, 1986) and the variant base was detected.
2) Production of variant aequorin protein inside E. coli by the use of various variant aequorin genes
cDNA fragment of Hind III-Eco RI of variant pAQ440 gene was subjected to cloning into the Hind III-Eco RI part of plasmid pUC9-2 having lac promoter, and transforming into E. coli HB101 (D1210i Q ) strain to produce variant aequorin protein inside E. coli by means of expression inducer IPTG.
Namely, 1 / 100 of the quantity of the bacterial bodies obtained by cultivating pUC9-2 plasmid containing the variant aequorin gene for 12 hours was added to a L-broth medium (10 ml) containing Ampicillin (50 μg/ml), followed by cultivating the mixture at 37° C. for 2 hours, adding IPTG so as to give a final concentration of 1 mM, further cultivating the mixture at 37° C. for 2 hours, collecting the resulting bacterial bodies, washing them with M9 salt solution (5 ml), dissolving the resulting washed material in 20 mM Tris-HCl buffer (pH 7.6) (2.5 ml) containing 10 mM EDTA, breaking the bacterial bodies by supersonic wave treatment (60 seconds), carrying out centrifugal separation at 10,000 rpm for 10 minutes and using the resulting supernatant as an enzyme solution to be measured.
As to the measurement method, coelenterazine as a substrate (6 μg) and 2-mercaptoethanol (10 μl) were added to the enzyme solution (1 ml), followed by allowing the mixture to stand on ice for 2 to 3 hours, transferring it into a reaction cell in a phototube measurement apparatus, further pouring 20 mM CaCl 2 (1.5 ml) therein and measuring the resulting luminescence. The results are shown in Table 2.
TABLE 1______________________________________Synthetic oligonucleotide (primer) used inthe site-specific mutagenesis method and the variation siteVariation Name of Synthetic oligonucleotidessite primer 5' 3'______________________________________220th G1R ##STR5##449th G2R ##STR6##607th G3R ##STR7##569th C1S ##STR8##568th C1R ##STR9##590th C2S ##STR10##674th C3S ##STR11##307 & 308th HF ##STR12##238th E35K ##STR13##625th E164K ##STR14##616 & 625th D161H+K ##STR15##205-207th 24ΔD CAATTTCCTT . . . GTCAACCACA592-515th 153ΔD CAGAGTGTGC . . . ATTGATGAAA______________________________________ =; Variation site .; Deleted site
TABLE 2______________________________________Production of variant aequorininside Escherichia coli Activity ×10.sup.-8 Quanta/sec.______________________________________(Measurement 1)Control (Aequorin) 38.9G1R 0G2R 19.2G3R 37.9HF 0E35K 0E164K 0D161H + K 024ΔD 0153ΔD 0(Measurement 2)Control (Aequorin) 22.9C1S 15.4C1R 11.0C2S 13.6C3S 6.8______________________________________
EXAMPLE 2
Example 1 was repeated except that the synthetic oligonucleotide (primer) used in the site-specific mutagenesis method and the variation site were varied. The variant sources used are shown in Table 3 and the results are shown in Table 4.
TABLE 3______________________________________Synthetic oligonucleotide (primer) used inthe site-specific mutagenesis method and the variation siteVariation Name of Primer base arrangementsite primer 5' 3'______________________________________569th C1S ##STR16##590th C2S ##STR17##674th C3S ##STR18##______________________________________
TABLE 4______________________________________Reproduction of variant aequorinsproduced inside Escherichia coli(addition effect of 2-mercaptoethanol) Relative activity value (%) 2-MercaptoethanolVariant aequorin Non-addition Addition______________________________________Control (Aequorin) 8 100C1S 14 54C2S 21 68C3S 30 18C1 + 2S 0 1C2 + 3S 54 26C3 + 1S 36 8C1 + 2 + 3S 95 21______________________________________ Note: In the above table, 100% refers to 3.0 × 10.sup.-9 light quantum/sec. C1 + 2S: a variant obtained by converting the first and second cysteines into serines; C2 + 3S: a variant obtained by converting the second and third cysteines into serines; C3 + 1S: a variant obtained by converting the third and first cysteines into serines; and C1 + 2 + 3S: a variant obtained by converting the first, second and third cysteines into serines.
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Various variants of photoprotein aequorin (pAQ440), useful for elucidating the mechanism of its luminescence and thereby extending the possibility of concrete applications of aequorin protein, and a process for producing variant aequorin proteins are provided, which variants are obtained by converting base(s) in a specified order of the base arrangement of aequorin gene into other base(s), or by deleting a certain bases in specified continued orders thereof, according to site-specific mutagenesis method.
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RELATED APPLICATIONS
[0001] This application is a continuation of PCT/GB2009/002374 filed on Oct. 5, 2009, which claims priority to GB 0819484.7, filed Oct. 24, 2008 and GB 9818051.5, filed Oct. 3, 2008, all of which is hereby incorporated by reference in their entirety.
SUMMARY OF THE INVENTION
[0002] The present invention relates to the use of AB diblock copolymers and composition thereof as surface treatments. More specifically, the present invention relates to the novel use of AB diblock copolymers and compositions thereof which self assemble into aggregate structures in a suitable medium, and to a method suitable for preparing a surface treatment using same which provides functional benefits associated with easy-clean surface treatments such as dirt-repellency, spot-free finishes and anti-fogging properties. In addition, the treatment of surfaces with the AB diblock copolymers according to the present invention supplementary benefits such as anti-bacterial or anti-fungal properties.
BACKGROUND TO THE INVENTION
[0003] The controlled wetting of surfaces has many potential applications such as the waterproofing of clothes and fabrics, concrete or paints, windows and windshields. In addition, controlled solid-liquid interfacial properties can have benefits in producing low friction surfaces for use in areas such as swimsuits, diving gear, boats and ships, as well as micro-fluidic devices.
[0004] Further applications in the area of “easy-to-clean” surfaces/coatings are also possible (1, 2). Such surfaces are usually designed to facilitate cleaning by minimising the adhesion of dirt and promoting water repellence such that as water “rolls off” the surface it collects the poorly adhered dirt particles (3). Often, “self-cleaning surfaces” such as those described in WO 96/04123 are termed “Lotus-effect” surfaces or coatings, and the technology is termed “Lotus-Effect” technology. Such “self-cleaning surfaces” can be produced by different ways: by creating the surface structures directly from hydrophobic polymers during manufacture or by creating the surface structures after manufacture (specifically by imprinting or etching, or by the adhesion of a polymer made of hydrophobic polymers to the surfaces).
[0005] In the present invention, the terms self-cleaning, easy-to-clean and stay-clean have a specific meaning.
[0006] The term self-cleaning surface treatment or coating, can be used to describe two possible situations.
[0007] The first definition relates to a self-cleaning surface treatment or coating which promotes the removal of dust and or dirt on a surface by means of water droplets rolling off the treated surface.
[0008] The second definition relates to a self-cleaning surface treatment or coating which is able to degrade dust and or dirt present on a surface and the residues thus produced are removed by a rinsing with water.
[0009] In both of the cases above a self-cleaning treatment or coating does not refer to a surface which repels dust/dirt; both of the situations above require water to remove dust and/or dirt from the surface.
[0010] The terms ‘stay-clean’ or ‘easy-clean’ surface treatment or coating both refer to a surface which repels dust and/or dirt. That is, prevents the build up of dust and/or dirt on a treated surface. The term ‘stay-clean’, is also used to refer to a treated surface which remains shiny after contact with water. Therefore, ‘stay-clean’ treatments prevent the formation of water streaks and/or water spots. In addition, a ‘stay-clean’ treatment or coating does not necessary need water for the surface to remain clean and shiny.
[0011] A variety of methods for controlling the wetting of surfaces have been reported, (4,5) based on both the control of the surface chemistry and the surface morphology (6). More recently, combinations of these two approaches have been used (3, 7). It is known for example from basic surface wetting theory that a low energy surface (with a concomitant large contact angle, greater than 100°) will tend to repel water. The result will be the formation of drops that roll off the surface easily.
[0012] U.S. patent application publication number 2002/0048679 (and related European patent application number EP 1018531) describe surfaces from which water runs off easily as having to be either very hydrophilic or hydrophobic. Hydrophilic surfaces have low contact angles with water, and this brings about rapid distribution of the water on the surface and finally rapid run-off of the resultant film of water from the surface. In contrast, hydrophobic surfaces form droplets through large contact angles with water. These droplets can roll off rapidly from inclined surfaces.
[0013] Many materials are known to be capable of producing water repellence. In general the materials possess a very low dielectric constant and are uncharged organics. Amongst these are materials such as halogenated organic polymers, for example polytetrafluoroethylene (PTFE) and derivatives thereof (8). One approach for manufacturing such surfaces is to apply a thin layer of a new material with the appropriate characteristics, for example appearance, durability, adhesion, and application requirements, directly onto the surface of interest. Such surface coatings or surface treatments should be easily and uniformly applied; established within a reasonable amount of time and process constraints; have a minimal environmental impact with respect to their synthesis and application; resist the effects of environmental assault; and provide good economic value.
[0014] The main problems with such materials to date include;
[0015] (a) Determining the best method to deposit the materials onto a surface of interest since the materials are often soluble in a limited number of organic solvents. One possibility is for example a spin-casting method. However, this method usually requires the liberal use of solvents with the associated cost and environmental concerns.
[0016] (b) The durability of the coatings when applied and used in ‘real applications’ is an issue. Damage of the coatings through abrasion and the impact of harsh external conditions can compromise their efficiency. For example, re-coating can not only be difficult but also expensive and is still subject to the same environmental concerns.
[0017] (c) Photodegradation effects caused by sunlight can also compromise the surface integrity and lead to re-application needs.
[0018] Random fluorinated copolymers prepared by radical copolymerisation of monomers in solution in a water-miscible organic solvent using peroxides or azo compounds as initiators have been described (see, for example, EP 542598, U.S. Pat. No. 1,106,630 and US 2004026053), together with their hydrophobic and oleophobic properties on various substrates.
[0019] U.S. Pat. No. 5,324,566 describes the use of hydrophobic fluorinated siloxane polymers for producing water repellent surfaces. It is disclosed in this patent that the water repelling properties of the fluorinated siloxane material can be improved by forming surface irregularities on the surface of such a material. It is for example mentioned that the surface is modified with irregularities of a height from about 0.1 micrometers up to the wavelength of visible light. Likewise, U.S. Pat. No. 5,599,489 and EP 0933388 A2 describe how the structured surface includes fluorine containing polymers or has been treated using alkylfluorosilanes.
[0020] US 2002/0048679 describes surfaces having a smooth, extremely hydrophobic polymer film (for example, polytetrafluoroethylene) and surfaces having a smooth extremely hydrophilic polymer film as examples where water and dirt run off without forming droplets. US 2002/0048679 further describes how a ‘long-term’ hydrophobic coating may be formed by applying certain silane derivatives underneath a hydrophobic coating on a surface. Other self-cleaning surfaces are described in US 2002/0150723, US 2002/0150724, US 2002/0150725, US 2002/0150726, US 2003/0013795 and US 2003/0147932.
[0021] U.S. Pat. No. 3,354,022 discloses water repellent surfaces having a rough micro structure with elevations and depressions and a hydrophobic material based on a fluorine containing polymer. According to one embodiment, a surface with a self-cleaning effect can be applied to ceramic, brick or glass by coating the substrate with a suspension comprising of glass beads (diameter of 3 to 12 micrometres) and a fluorocarbon wax which is a fluoroalkyl ethoxymethacrylate polymer. Unfortunately, such coatings have a disadvantage in that they posses a low abrasion resistance and only a moderate self-cleaning effect.
[0022] Further developments of surface coatings that are designed to produce strongly hydrophobic surfaces include the use of copolymers, polymer blends and mixtures of polymers and nanoparticles (such as titanium dioxide, as described in U.S. Pat. No. 6,800,354, U.S. Pat. No. 7,112,621 B2, U.S. Pat. No. 7,196,043 and DE 10016485.4). For example, coated surfaces have been produced using fluorocarbon polymers that can give contact angles of up to 120°. Titanium dioxide (TiO 2 ) has also been used with such fluorinated surfaces. It is known that under UV irradiation the TiO 2 is photocatalytically active and can produce super-wetting properties as a result of water hydrolysis effects (9). However the addition of TiO 2 present with (fluoroalkyl)silane does not affect the hydrophobicity of the overall material; that is, the modified (fluoroalkyl)silane remains hydrophobic. Consequently, whilst a self-cleaning material has been generated, due to the hydrophobicity of the system, water is able to rinse away any dirt from a treated surface, but, will leave water marks on the surface of the material, thereby failing to produce a system which is both clean and free from water marks.
[0023] The preparation of such surfaces using nanoparticles suffers from several drawbacks including the use of organic solvents (U.S. Pat. No. 3,354,022) and the use of a subsequent heat treatment (U.S. Pat. No. 6,800,354). Thus, there is a need for a simple process including an aqueous system for producing surfaces that are “easy-to-clean” with water and are optically transparent (such surfaces are not necessary hydrophobic, but can also be hydrophilic as illustrated in US 2002/0048679).
[0024] It has also been demonstrated recently that the control over surface wetting can be improved by producing surfaces with a well-controlled micron-sized roughness (10). These rough surface features assist in producing ‘ultrahydrophobic’ substrates by physical methods that include trapping air and reducing contact areas between the water drops and the surface. The basic underlying surface should itself be hydrophobic and when combined with the roughness effects, it results in surfaces with contact angles greater than 150° which are extremely hydrophobic. However, such surfaces are difficult to manufacture, they usually are very fragile and easily damaged and the micron-scale features can cause diffraction effects with light, which can be therefore problematic for use in applications involving glass.
[0025] Despite the above difficulties, products based upon such technology (or derivatives thereof) are beginning to appear in the market place. This is especially true for “self-cleaning” glass surfaces where random roughness is used to overcome diffraction problems. It is still unclear however, how effective these surfaces will be over time.
[0026] In addition to possessing an “easy-to-clean” surface, it is often desirable for the surface to possess an aesthetically pleasing finish, for example spot-free, streak-free or shiny finish that lasts for a reasonable period of time (for example from weeks to months). There are a number of waxes and other products currently in the market which attempt to give a spot-free finish. Typically, these products are designed to hydrophobically modify surfaces so that rainwater and tap water will bead-up' on the treated surface. Nonetheless, it is quite obvious that the beading of water on such surfaces may actually increase the formation of water spots since the beads of water will leave deposits on the surface when they dry. Furthermore, products available on the market often require rinsing with water after use. Typically when the water dries on the surface watermarks, smears, streaks or spots are left behind. These water-marks may be due to the evaporation of water from the surface leaving behind deposits of minerals which were present as dissolved solids in the water (for example calcium, magnesium, sodium ions and salts thereof) or maybe due to deposits of water carried soils, or even remnants from cleaning products (for example soap scum). This problem is often further exacerbated by some cleaning compositions which modify the surface during the cleaning process in such a way that after rinsing, water forms discrete droplets or beads on the surface instead of draining away. These droplets or beads dry to leave noticeable spots or marks referred to as watermarks. A known way of solving this problem is to remove the water drops from the surface using a cloth or chamois before the watermarks form. However this drying process (that is wiping washed and rinsed surfaces) is time consuming and requires considerable physical effort in the overall washing/cleaning process. Furthermore, access to the surface may be a problem so that wiping the surface is not a viable option.
[0027] U.S. Pat. No. 5,759,980 (Blue Coral) describes a composition to eliminate the problem of watermarks on a car. The cleaning composition described therein comprises a surfactant package comprising a fluorosurfactant or a silicone surfactant and mixtures thereof; and a substantive polymer which is capable of bonding to a surface to make it hydrophilic.
[0028] DE-A-2161591 also describes a composition for cleaning cars wherein the surface is made hydrophilic by the application of amino-group containing copolymers such as polymeric ethyleneimines, polymeric dimethylaminoethylacrylate or methacrylate or mixed polymerisates.
[0029] It is believed however, that the polymers described in these documents may be removed from the surface during rinsing of the product from the surface. Hence the surface hydrophilicity that is allegedly provided by the composition described may also be removed from the surface after the first rinse.
[0030] U.S. Pat. No. 6,846,512 B2 (Procter and Gamble) also describes a system and method for cleaning and/or treating a surface and in particular the exterior surface of a vehicle, however the method requires the application of a non-photoactive nanoparticle coating composition to a surface. Such non-photoactive nanoparticles can be inorganic nanoparticles (oxides, silicates, carbonates, hydroxides, layered clay minerals and inorganic metal oxides).
[0031] Therefore, there is a need for a treatment which provides a surface with “easy-to-clean” properties by ensuring that in addition to the repellence of dust and dirt, water-spotting and or streaking is also prevented, even if the surface once rinsed is not physically wiped to remove residual water.
[0032] Whilst many commercial surface coatings based on solutions of polymers in organic solvents are produced by drop-casting or spin coating, alternatives that are based on chemical grafting of polymer films have recently been discussed. Using this approach, coatings that comprise of dense brush-like films of polymers which are chemically attached to a surface are produced. The polymers detailed herein can have controlled chemistry that produces the desired wettability characteristics. Furthermore, the inherent chemical variety available to the synthetic polymer chemist means that such layers can be produced with a wide variety of physical properties, as well as the opportunity for including a stimulus responsive surface.
[0033] Stimuli-responsive polymers (11) are polymers that are able to respond to small changes in their environment with a corresponding large change in a specific physical property. Typical stimuli include: temperature, pH, ionic strength, light-, electric- and magnetic fields. Some polymers respond to a combination of two or more of these stimuli. For coatings or surface treatments, stimulus responsive polymers have the potential to be used in a wide variety of applications where controlled changes in properties such as adhesion, lubrication, and wetting are required.
[0034] GB patent application number PCT/GB2007/004762 describes novel AB block copolymers comprising of a fluorinated and a non-fluorinated portion. However, the use of fluorinated compounds can lead to difficulties in preparing water-based treatments. In addition, there are issues around the environmental impact of using such compounds and their formulation, as detailed below.
[0035] First of all, the use of fluorinated compounds has associated environmental concerns for applications in some commercial products. Public concern over the use of fluorinated compounds is high, and this can have a detrimental impact on the appeal of products that use such materials. Hence, there is a need for an alternative surface treatment composition that is more environmentally friendly to use.
[0036] Secondly, in general, environmental concern means that it is desirable to have a water-based formulation or a formulation having a very low volatile organic component. As it may sometimes be difficult to use fluorinated materials in aqueous formulations due to the low solubility of such compounds in water; using non-fluorinated materials provides more formulation options.
[0037] In addition, and importantly, the wide range of non-fluorinated monomers available means it is possible to fine-tune the “solubility” effectively through the use of different monomers. In comparison, the number of “fluorinated polymers” available are limited to only a few commercially available monomers. Hence, the use of non-fluorinated copolymers can provide improved formulations.
[0038] Easy-clean surface treatments need to be applied on various types of substrates. Therefore the compatibility of the materials with different substrates is also a key parameter. Non-fluorinated and especially alkyl materials provide a wider range of surface energies and therefore an ability to ‘tune’ the longevity of the effect, which is desirable for different applications. For example, building product applications may require up to ten years longevity whereas in homecare applications one to four weeks may be desirable. Thus, there is a need to have improved formulations that provide a better ability to tune these features. This is not available through the fluorinated materials described in the prior art.
[0039] It is therefore an object of the present invention to provide novel compositions that can be deposited onto a substrate surface with or without the need for organic solvents and which overcome the drawbacks of existing compositions in terms of cost of raw materials, production cost, environmental concerns and formulation in water based system.
[0040] It is a further aim of the present invention to provide a novel surface treatment that promotes variable wetting properties on the surface, or in other words provides an “easy-to-clean” surface meaning that an identifiable cleaning benefit (“easier-to-clean”, “cleaner-longer”, “stay-clean” etc.) on a surface will be observed by the end-user.
[0041] It is still a further aim of the present invention to provide novel compositions that are able to demonstrate a variable longevity of effect which is desirable for different application areas.
[0042] It is still a further aim of the present invention to provide novel compositions that are able to demonstrate a durable hydrophilic effect showing improved and homogenous water-sheeting and which are also able to provide a rapid drying surface which dries uniformly.
[0043] The surface treatment of the present invention is both an easy-clean treatment and a stay-clean treatment based on the definitions previously defined with significant advantages when compared to alternative hydrophobic surfaces and to self-cleaning windows, the latter not working for example in dry conditions. In the present invention, the excellent wetting results in a very thin and continuous water film when the surface is wet. When the liquid dries, any minerals in the water (for example lime) are spread uniformly in an extremely thin layer on the surface, which gives a spot free finish appearance. In addition, because the layer of water is so thin, it promotes a fast drying time aiding the formation of a spot-free finish
[0044] Therefore according to a first aspect of the present invention there is provided the use of an AB block copolymer composition as a surface coating wherein the composition comprises (a) an AB block copolymer; and (b) a liquid medium and wherein the AB block copolymer comprises:
(a) a substantially hydrophobic block A, and (b) a substantially hydrophilic block B wherein the hydrophobic block A comprises one or more monomer of formula A
[0000]
wherein R is H or C 1 to C 4 alkyl; Z is O, P or N; and
R′ is selected from the group comprising: C 1 to C 18 linear or non linear alkyl;
C 1 to C 18 alkylamino alkyl; C 1 to C 18 alkoxyalkyl; C 1 to C 18 dihydroxyalkyl; C 1 to C 18 silylalkyl; epoxy alkyl, phosphoryl or phosphoryl alkyl; a styrene based monomer; a vinyl phosphonate or phosphoric acid monomer; and wherein the liquid medium comprises either:
(i) water;
(ii) an organic solvent;
(iii) an organic solvent substantially free from water; or
(iv) an organic solvent and water; and wherein:
the liquid medium further optionally comprises one or more additive, surfactant or wetting agent.
[0056] In the AB block copolymer composition used according to the present the hydrophilic block B comprises one or more monomer of Formula B
[0000]
[0057] wherein R is H or C 1 to C 4 alkyl;
[0058] Z is O, N or P; and
[0059] R′ is selected from the group comprising: H; a C 1 to C 17 alkyl group with a pendent phosphoryl group, hydroxy group, silyl group, epoxy group or amine group.
[0060] When the hydrophobic block A comprises an alkylacrylic or acrylate monomer for Formula A, and R is H or C 1 to C 4 alkyl, and R′ comprises a C 1 to C 18 linear or non linear alkyl group of Formula 1
[0000]
[0061] n is 1 to 11, more preferably 1 to 5.
[0062] When the hydrophobic block A comprises a monomer for Formula A, and R is H or C 1 to C 4 alkyl, and R′ comprises a C 1 to C 18 alkylamino alkyl group as shown in Formula 2
[0000]
[0063] R 1 and R 2 are each independently: H; C 1 to C 6 alkyl group; phenyl; benzyl or cyclohexyl and n is 1 to 17, more preferably, R 1 and R 2 are each independently a C 1 alkyl group and n is 1 to 5.
[0064] When the hydrophobic block A comprises an alkylacrylic or acrylate monomer for Formula A, and R is H or C 1 to C 4 alkyl, and R′ comprises a C 1 to C 18 alkoxyalkyl group as in Formula 3a or 3b, n is 1 to 18, more preferably 1 to 4 and x and y are each independently 0 to 16, more preferably 0 to 6.
[0000]
[0065] When the hydrophobic block A comprises an alkylacrylic or acrylate monomer for Formula A, and R is H or C 1 to C 4 alkyl, and R′ comprises a dihydroxyalkyl group as shown in Formula 4a or 4b, x and y is each independently 0 to 17 or 0 to 16 in Formula 4a and Formula 4b respectively, more preferably x and y is each independently 0 to 7 in Formula 4a or 0 to 6 in Formula 4b.
[0000]
[0066] When the hydrophobic block A comprises an alkylacrylic or acrylate monomer for Formula A, and R is H or C 1 to C 4 alkyl, and R′ comprises a C 1 to C 17 silylalkyl group as shown in Formula 5a or 5b, R 1 is H or C 1 to C 4 alkyl and x and y are each independently 0 to 16, more preferably 1 to 6.
[0000]
[0067] When the hydrophobic block A comprises an alkylacrylic or acrylate monomer for Formula A, and R is H or C 1 to C 4 alkyl, and R′ comprises an epoxy alkyl group as shown in Formula 6a or 6b, x and y are each independently 0 to 16, more preferably 0 to 6.
[0000]
[0068] When the hydrophobic block A comprises a monomer of Formula A, and R is H or C 1 to C 4 alkyl group, and R′ comprises a phosphoryl or phosphoryl alkyl group as shown in Formula 7a and 7b, R 1 is H or C 1 to C 6 alkyl, more preferably H or C 1 alkyl.
[0000]
[0069] When the hydrophilic block B comprises an alkylacrylic acid or acrylic acid, R is H or C 1 to C 4 alkyl as shown in Formula 8
[0000]
[0070] When the hydrophilic block B comprises a monomer of Formula B, R is H or C 1 to C 4 alkyl and R′ comprises C 1 to C 17 alkyl group with a pendent amine or amide group as shown in Formula 9a, 9b, 9c and 9d; n is 0 to 17, and R 1 , R 2 , R 3 and R 4 are each independently H; linear or non-linear C 1 to C 6 alkyl group, phenyl, benzyl or cyclohexyl, most preferably R 1 , R 2 , R 3 and R 4 are each independently C 1 to C 4 alkyl and X − is chosen from the group selected from Cl, Br, I, ½SO 4 , HSO 4 and CH 3 SO 3 , sulfonate, sulphate, carboxylate (acetate, glycolate), hydroxide, or phosphate.
[0000]
[0071] When the hydrophilic block B comprises a monomer of Formula B, R is H or C 1 to C 4 alkyl and R′ comprises C 1 to C 17 alkyl group with a pendent phosphoryl or phosphoryl alkyl as shown in Formula 10a or 10b, R 1 is H or C 1 to C 6 alkyl, most preferably H or C 1 alkyl.
[0000]
[0072] When the hydrophilic block B comprises a monomer of Formula B, R is H or C 1 to C 4 alkyl and R′ comprises C 1 to C 17 alkyl group with a pendent hydroxyl group as shown in Formula 11a, 11b, 11c and 11d n is 1 to 16.
[0000]
[0073] When the hydrophilic block B comprises a monomer of Formula B, R is H or C 1 to C 4 alkyl and R′ comprises C 1 to C 17 alkyl group with a pendent silyl group as shown in Formula 12a, and 12b, x and y are each independently 0 to 16 and n is 1 to 6.
[0000]
[0074] When the hydrophilic block B comprises an alkylacrylate or acrylate of Formula B, R is H or C 1 to C 4 alkyl and R′ comprises C 1 to C 17 alkyl group with a pendent epoxy group as shown in Formula 13a, and 13b, x and y are each independently 0 to 16 and n is 1 to 17.
[0000]
[0075] In accordance with the present invention the polymers comprising the AB block copolymer are comprised of monomers, and the ratio of the monomers comprising each polymer of the block copolymer AB is such that the volume fraction of the hydrophobic block A and the hydrophilic block B leads to the formation of organised aggregates. In addition, the volume fraction of the hydrophobic block A and the hydrophilic block B leads to the formation of micelles.
[0076] The ratio of the monomers comprising the block copolymer AB comprises: 5 to 100 units of A; and 15 to 300 units of B.
[0077] More preferably the ratio of the monomers comprising the block copolymer AB comprises: 15 to 50 units of A; and 80 to 200 units of B.
[0078] Even more preferably the ratio of the monomers comprising the block copolymer AB comprises: 15 to 30 units of A; and 100 to 120 units of B.
[0079] As stated above AB Block copolymers comprise a hydrophobic (“water hating”) block A and a second hydrophilic (“water loving”) block B. Variation in the copolymer properties can be obtained by varying the monomer types (different available chemistries), the molecular weights of the copolymer (at a fixed ratio of the two component block sizes), and the ratio of the molecular weights of the constituent blocks (at a fixed overall molecular weight for the copolymer).
[0080] Importantly, to form micelles (that is aggregates formed by molecules with an amphiphilic character) in aqueous media, the insoluble (or poorly soluble in water) hydrophobic blocks drive the formation of aggregates of the molecules. The structures of the aggregates are dependent on the copolymer concentration and the exact nature of the copolymer molecules. In the present invention copolymers are utilised that form spherical aggregates at the concentrations employed.
[0081] The coronal chemistry for the micellar aggregates should be such that the micelles will adsorb freely onto a wide variety of surfaces.
[0082] The substantially hydrophobic block A preferably comprises one or more monomers selected from the group comprising: alkyl alkylacrylate, alkylaminoalkyl alkylacrylate and a sillylacrylate. More preferably the substantially hydrophobic block A comprises an alkyl alkylacrylate selected from the group comprising a methacrylate; butyl methacrylate (BuMA) and octadecylmethacrylate (ODA). More preferably the hydrophobic block A comprises one or more alkylaminoalkylacrylate alkylacrylate monomer according to Formula A; wherein the alkylaminoalkylacrylate alkylacrylate monomer comprises an alkylaminoalkyl methacrylate or a diethylaminoethylmethacrylate (DEAEMA).
[0083] When block A comprises a silyl (alkyl)acrylate monomer, the silyl (alkyl)acrylate monomer preferably comprises: a trialkoxysilyl group, more preferably, a trimethoxysilyl group, most preferably (trimethoxysilyl) propyl methacrylate (TMSPMA) and (trimethoxysilyl) propyl acrylate (TMSPA).
[0084] When block A comprises a styrenic derivatives, the styrenic derivative preferably comprises styrene, methyl styrene, or styrenic derivatives substituted in ortho, meta, and/or para positions.
[0085] In addition, block A is preferably comprised of:
a homopolymer of an acrylate derivative; a homopolymer of styrenic derivatives; and a random, alternating, gradient or block copolymer based on A1A2, A1A3, A1A4, A2A4 or A3A4 wherein A1 is an alkyl acrylate; A2 an alkylamino acrylate; A3 a siliyl acrylate; and A4 a styrenic derivative.
[0089] A number of chemicals may be employed for the hydrophilic component B, all of which need to be water-soluble. Examples of such chemicals include, but are not limited to one or more polymers selected from the group comprising: hydrophilic organic monomers, oligomers, prepolymers or copolymers derived from vinyl alcohol, N-vinylpyrrolidone, N-vinyl lactam, acrylamide, amide, styrenesulfonic acid, combinations of vinylbutyral and N-vinylpyrrolidone, methacrylic acid, acrylic acid, vinylmethyl ether, vinylpyridylium halide, melamine, maleic anhydride/methyl vinyl ether, vinylpyridine, ethyleneoxide, ethyleneoxide ethylene imine, glycol, vinyl acetate, vinyl acetate/crotonic acid, methyl cellulose, ethyl cellulose, carboxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxymethyl ethyl cellulose, hydroxypropylmethyl cellulose, cellulose acetate, cellulose nitrate, hydroxyalkyl(alkyl)acrylate such as hydroxyethyl(meth)acrylate, hydroxypropyl(meth)acrylate, alkylaminoalkyl(alkyl)acrylate, 2-(dimethyl amino)ethyl methacrylate, 2-(diethyl amino)ethyl methacrylate, 2-(diisopropyl amino)ethyl methacrylate, 2-(N-morpholino)ethyl methacrylate, or a derivative thereof, ethylene glycol(meth)acrylates (for example triethylene glycol(meth)acrylate) and (meth)acrylamide), N-alkyl(meth)acrylamides (for example N-methyl(meth)acrylamide and N-hexyl(meth)acrylamide), N,N-dialkyl(meth)acrylamides (for example N,N-dimethyl(meth)acrylamide and poly-N,N-dipropyl(meth)acrylamide), N-hydroxyalkyl(meth)acrylamide polymers, such as poly-N-methylol(meth)acrylamide and poly-N-hydroxy ethyl(meth)acrylamide, and N,N-dihydroxyalkyl(meth)acrylamide polymers, such as poly-N,N-dihydroxyethyl(meth)acrylamide, ether polyols, polyethylene oxide, polypropylene oxide, and poly(vinyl ether), alkylvinyl sulfones, alkylvinylsulfone-acrylates, (alkyl)acrylate with a pendent phosphorus group such as vinylphosphonate, vinylphosphonic acid, vinylphosphine oxide or any (alkyl)acrylate with a ester function —COOR such as R is C x H 2x PO 3 R 2 wherein x is 2 to 10, most preferably x is 2, and R is a hydrogen or an alkyl group having 1 to 4 carbon atoms, preferably methyl; and related compounds or a combination thereof.
[0090] In addition, the hydrophilic block B is comprised from monomers selected from the group consisting of: hydrophilic organic monomers, oligomers, prepolymers or copolymers derived from vinyl alcohol, N-vinylpyrrolidone, N-vinyl lactam, acrylamide, styrenesulfonic acid, combinations of vinylbutyral and N-vinylpyrrolidone, methacrylic acid, acrylic acid, vinylmethyl ether, vinylpyridylium halide, vinylpyridine, vinyl acetate, vinyl acetate/crotonic acid, hydroxyalkyl(alkyl)acrylate such as hydroxyethyl(meth)acrylate, hydroxypropyl(meth)acrylate, alkylaminoalkyl(alkyl)acrylate, 2-(dimethyl amino)ethyl methacrylate, 2-(diethyl amino)ethyl methacrylate, 2-(diisopropyl amino)ethyl methacrylate, 2-(N-morpholino)ethyl methacrylate, or a derivative thereof, ethylene glycol(meth)acrylates (for example triethylene glycol(meth)acrylate) and (meth)acrylamide), N-alkyl(meth)acrylamides (for example N-methyl(meth)acrylamide and N-hexyl(meth)acrylamide), N,N-dialkyl(meth)acrylamides (for example N,N-dimethyl(meth)acrylamide and poly-N,N-dipropyl(meth)acrylamide), N-hydroxyalkyl(meth)acrylamide polymers, such as poly-N-methylol(meth)acrylamide and poly-N-hydroxy ethyl(meth)acrylamide, and N,N-dihydroxyalkyl(meth)acrylamide polymers, such as poly-N,N-dihydroxyethyl(meth)acrylamide, ether polyols, polyethylene oxide, polypropylene oxide, and poly(vinyl ether), alkylvinyl sulfones, alkylvinylsulfone-acrylates, (alkyl)acrylate with a pendent phosphorus group such as vinylphosphonate, vinylphosphonic acid, vinylphosphine oxide or any (alkyl)acrylate with a ester function —COOR such as R is C x H 2x PO 3 R 2 wherein x is 2 to 10, most preferably x is 2, and R is a hydrogen or an alkyl group having 1 to 4 carbon atoms, preferably methyl.
[0091] Furthermore, the hydrophilic block B is preferably comprised of monomers selected from the group consisting of: hydrophilic organic monomers, oligomers, prepolymers or copolymers derived from acrylamide, methacrylic acid, acrylic acid, hydroxyalkyl(alkyl)acrylate such as hydroxyethyl(meth)acrylate, hydroxypropyl(meth)acrylate, alkylaminoalkyl(alkyl)acrylate, 2-(dimethyl amino)ethyl methacrylate, 2-(diethyl amino)ethyl methacrylate, 2-(diisopropyl amino)ethyl methacrylate, 2-(N-morpholino)ethyl methacrylate, or a derivative thereof, N-alkyl(meth)acrylamides (for example N-methyl(meth)acrylamide and N-hexyl(meth)acrylamide), N,N-dialkyl(meth)acrylamides (for example N,N-dimethyl(meth)acrylamide and poly-N,N-dipropyl(meth)acrylamide), N-hydroxyalkyl(meth)acrylamide polymers, such as poly-N-methylol(meth)acrylamide and poly-N-hydroxy ethyl(meth)acrylamide, alkylvinyl sulfones, alkylvinylsulfone-acrylates and (alkyl)acrylate with a pendent phosphorus group such as vinylphosphonate, vinylphosphonic acid, vinylphosphine oxide or any (alkyl)acrylate with a ester function —COOR such as R is C x H 2x PO 3 R 2 wherein x is 2 to 10, most preferably x is 2, and R is a hydrogen or an alkyl group having 1 to 4 carbon atoms, preferably methyl.
[0092] More preferably the hydrophilic block B is comprised of monomers selected from the group of hydrophilic organic monomers, oligomers, prepolymers or copolymers derived from methacrylic acid, acrylic acid, alkylaminoalkyl(alkyl)acrylate, 2-(dimethyl amino)ethyl methacrylate, 2-(diethyl amino)ethyl methacrylate, 2-(diisopropyl amino)ethyl methacrylate, 2-(N-morpholino)ethyl methacrylate, or a derivative thereof.
[0093] The AB block copolymer may take the form of: linear block copolymer (diblock, triblock or multiblock), miktoarm copolymer (star copolymer), ladder (H-shaped) copolymer, graft and comb (co)polymer; preferably a linear block copolymer.
[0094] Also, the distribution of component monomers within each copolymer block is in the form of homo, random, gradient, alternative, block, graft and comb (co)polymers.
[0095] It is also preferred that the block copolymer is preferably selected from the group comprising: AB blocks, ABA blocks, ABC blocks copolymers.
[0096] In accordance with the present invention the block copolymer comprises at least one block that absorbs to a target surface. The composition may further comprise a primer. Also, the composition may form micelles and the aggregate structures of the composition have a diameter between 3 and 300 nm.
[0097] In a preferred example, the polymers used in the composition are prepared by controlled living radical polymerisation reactions.
[0098] Also in the composition used in accordance with the present invention the liquid medium may comprise water, water and organic solvent, an organic solvent, or an organic solvent free from water, and wherein the block copolymer is preferably completely dissolved in the liquid medium.
[0099] The organic solvent preferably comprises water-miscible organic solvents selected from the group comprising: C 1-6 alcohol, preferably, methanol, ethanol, n-propanol, iso-propanol, n-butanol, and sec-butanol; alkylketones, arylalkylketones, ketoalcohols, cyclic ketones, heterocyclic ketones, ethers, cyclic ethers, esters, and the like and combinations thereof.
[0100] The liquid medium preferably comprises: water or a mixture of water/alcohol or pure alcohol wherein the alcohol is preferably selected from the group comprising: methanol, ethanol, industrial methylated spirit, propanol, isopropanol, tertbutanol, ethylene glycol or glycol ethers.
[0101] The relative proportions of block copolymers AB as components (a) and of liquid medium as component (b) in the composition comprises between 1:100,000 to 1:1, more preferably from 1:10,000 to 1:2, and especially from 1:5,000 to 2:10. Most preferably the relative proportions of component (a) and component (b) in the composition comprises 1:5,000 to :1:10.
[0102] In addition, the composition may further comprise additional components selected from for example dispersants, perfumes surfactants and stabilisers.
[0103] The composition is preferably used to coat a substrate to by means of: dipping, spraying, wiping, spin coating, roller coating, curtain-flowing and brush coating.
[0104] The substrate may be selected from the group comprising: glass, plastics, metals, ceramics, concrete, paper, wood, minerals, painted and/or coated substrates or the substrate may be coated or painted prior to application of the composition with a primer.
[0105] The composition is preferably used to create a coating which has one or more of the following properties, water-sheeting, anti-fog, anti-dust, ant-bacterial and anti-fungal.
[0106] The polymers of the present invention may be in the form of, for example, homo, random, gradient, block (diblock, triblock or multiblock), copolymers, graft and comb (co)polymer. The component monomers within the copolymer may be dispersed randomly, alternately or in blocks. It is preferred however that the copolymer is a block copolymer.
[0107] The block copolymer is preferably selected from the group consisting: of AB blocks, ABA blocks, ABC blocks, comb, ladder, and star copolymers. However, it is most preferred that the block copolymer includes at least one block that is able to be adsorbed to the target surface
[0108] In some circumstances, it can be beneficial to use a pre-treatment such as a primer which can enhance the adhesion of the polymer to the surface. Indeed, a primer is a preparatory coating put on materials before painting or treating. Priming ensures better adhesion of paint or treatment/coating to the surface, increases paint or treatment/coating durability, and provides additional protection for the material being painted or treated/ coated. The primer allows finishing paint or treatment to adhere much better than if it was used alone. For this purpose, primer is designed to adhere to surfaces and to form a binding layer that is better prepared to receive the paint or treatment/coating. Hence, good adhesion of the polymer on a substrate can be achieved through the use of a primer and controlling the primer's physical properties such as porosity, tackiness, and hygroscopy.
[0109] It is also important that the structure of the material should lead to the formation of micelles (that are aggregates formed by molecules with an amphiphilic character; molecules having the tendency to aggregate into larger scale structures (3 to 300 nm) when certain conditions in their environment are changed, for example pH, salt concentration, temperature, solvent etc.) or micellar aggregates (that are micelles that have aggregate into a larger scale structure (3 to 300 nm) in aqueous media
[0110] Preferably, the block copolymers according to the first aspect of the present invention are prepared by means of controlled living radical polymerisation to obtain narrow molecular weight distribution copolymers. Suitable synthetic routes include but are not limited to: Reversible Addition-fragmentation chain transfer (RAFT), Group transfer polymerisation (GTP) and Atomic transfer radical polymerisation (ATRP), Activated regenerated by electron transfer (ARGET), nitroxide-mediated polymerization (NMP).
[0111] The block copolymers of the present invention may be available in solid or substantially solid form, for example a powder, or alternatively may be available as a liquid.
[0112] In the composition according to the present invention the liquid medium preferably comprises of a mixture of water and an organic solvent, or an organic solvent free from water and the block copolymer is preferably completely dissolved in the liquid medium
[0113] Organic solvents suitable for use in the composition of the present invention preferably comprise of water-miscible organic solvents selected from: C 1-6 alcohol, preferably, methanol, ethanol, n-propanol, iso-propanol, n-butanol, and sec-butanol; alkylketones, arylalkylketones, ketoalcohols, cyclic ketones, heterocyclic ketones, ethers, cyclic ethers, esters, and the like and combinations thereof.
[0114] Most preferably the solvent comprises water or a mixture of water/alcohol or pure alcohol where the alcohol is preferably chosen from the group comprising methanol, ethanol, industrial methylated spirit, propanol, isopropanol, tertbutanol, ethylene glycol or glycol ethers.
[0115] Organic solvents substantially free from water: the organic solvents for use in the composition of the present invention preferably include but are not limited to organic solvents selected from the group comprising: tetrahydrofuran, dichloromethane, ethyl acetate, chloroform, lower alcohols, ketones or dimethyl sulphoxide.
[0116] In addition, when the liquid medium comprises an organic solvent substantially free from water the composition preferably further comprises a suitable polar solvent.
[0117] Furthermore, it will be appreciated by one skilled in the art that in the composition of the present invention the organic solvent free from water may comprises a single organic solvent or a mixture of two or more organic solvents.
[0118] The relative proportions of block copolymers AB as components (a) and of liquid medium as component (b) in the composition of the present invention preferably comprises between 1:100,000 to 1:1, more preferably from 1:10,000 to 1:2, and especially from 1:5,000 to 2:10.
[0119] Most preferably the relative proportions of component (a) and component (b) in the composition comprises 1:5,000 to :1:10.
[0120] It will also be appreciated that the composition according to present invention may preferably further comprise additional components or auxiliary agents selected from for example but not limited to dispersants, perfumes, biocides, and stabilisers, surfactants or wetting agents, emulsifiers, colouring agents, dyes, pigments, UV absorbers, radical scavenger, antioxidant, anti-corrosion agent, optical brightener, fluorescers, bleaches, bleach activators, bleach catalysts, non-activated enzymes, enzyme stabilizing systems, chelants, coating aid, metal catalyst, metal oxide catalyst, organometallic catalyst, filmforming promoter, hardener, linking accelerator, flow agent, leveling agent, defoaming agent, lubricant, matte particle, rheological modifier, thickener, conductive or non-conductive metal oxide particle, magnetic particle, anti-static agent, pH control agents, perfumes, preservative, biocide, pesticide, anti-fouling agent, algicide, bactericide, germicides, disinfectant, fungicide, bio-effecting agent, vitamin, drug, therapeutic agent or a combination thereof.
[0121] The copolymers used according to the present invention have been found to form micelles in aqueous solutions. The coronal properties of those micelles can be tuned using triggers such as pH, temperature or salt concentrations; providing variable size of micelles and/or variable adhesion to the surface.
[0122] The compositions used in the present invention have many potential uses. The compositions are trigger-responsive (especially pH and salt concentration) and accordingly have potential for a wide variety of possible uses where controlled changes in surface properties, such as adhesion, lubrication and wetting are required.
[0123] The compositions used according to the present invention are particularly suitable for use as either a surface coating or a surface treatment to form an “easy-to-clean” surface. To this end, the present invention also provides a surface coating or a surface treatment prepared using the composition of block copolymer described according to the first aspect of the present invention.
[0124] There is also provided a method of coating a substrate comprising the steps of preparing a composition according to a first aspect of the present invention and exposing the substrate to the aqueous solution.
[0125] Preferably, the method includes gentle agitation of the copolymer molecules to fully dissolve the molecules in the composition. Preferably, the solution is left to equilibrate for up to 24 hours, prior to application.
[0126] Methods of exposing the substrate to the composition include any known technique for forming a coating from a solution, such as spin coating, dip coating, roller coating, brush coating, gravure coating, wiping, curtain flow or spraying.
[0127] Surfaces that can be treated with the composition of the present invention include, but are not limited to, glass, plastics, metals, ceramics, concrete, paper, wood, minerals, painted and/or coated substrates. Optionally, the substrate may be rinsed with a pure solvent, such as water, to remove any loosely held copolymer molecules.
[0128] The present invention will now be described and illustrated further by reference to the following examples and figures in which:
[0129] Example 1—describes a method for the preparation of block copolymers;
[0130] Example 2—investigates the coating of a substrate with the block copolymer of example 1;
[0131] Example 3—investigates the “easy-to-clean” properties and in particular the “dirt-repellency” properties of a substrate treated with the block copolymer of example 1;
[0132] Example 4—investigates the “water-sheeting” properties of a substrate treated with the block copolymer of example 1;
[0133] Example 5—investigates the “antifog” properties of a substrate treated with the block copolymer of example 1;
[0134] Example 6—describes the “Anti-spotting” properties of surface treatment according to the present invention
[0135] Example 7—investigates the “antibacterial and anti-fungal” properties of a substrate treated with the block copolymer of example 1;
[0136] Example 8—describes the improvement of a concentration of copolymers in water-based formulation using the non-fluorinated block copolymer of example 1 in comparison to a fluorinated copolymer;
[0137] Example 9—Comparison of a NF-AP (15/120)-based surface treatment compared to surface treatments prepared from existing additives which promotes stay-clean properties;
BRIEF DESCRIPTION OF THE DRAWINGS
[0138] FIG. 1 —illustrates the “easy-to-clean” properties of a substrate applied with a surface treatment according to the present invention.
[0139] FIG. 1 a —illustrates the substrate after one dirt cycle.
[0140] FIG. 1 b —illustrates the substrate after three dirt cycle.
[0141] FIG. 1 c —illustrates the substrate after five dirt cycle as described in the present invention.
[0142] FIG. 2 —is a graph showing colour difference ΔE versus the number of dirt cycles obtained by spectrophotometric measurements of the substrates from FIG. 1 .
[0143] FIG. 3 —is a photographic image illustrating the use of the surface treatment according to the present invention on a shower door in a bathroom.
[0144] FIGS. 4 a, 4 b and 4 c —are photographic images illustrating the “water-sheeting” properties of a substrate applied with a surface treatment containing the polymer PBuMa 15 -b-MAA 19 according to the present invention.
[0145] FIGS. 4 a and 4 b illustrate a PVC window frame panel and a black polyester powder coated aluminium panel half treated with a surface treatment from a pure alcoholic solution (ethanol) respectively.
[0146] FIG. 4 c —illustrate a white polyester powder coated aluminium panel half treated with a water-based surface treatment.
[0147] FIGS. 5 a and 5 b —are photographic images illustrating the “water-sheeting” properties of a substrate applied with a surface treatment containing the polymer PBuMa 15 -b-(TMACMA 60 -co-DMAEMA 61 ) according to the present invention.
[0148] FIGS. 5 a and 5 b illustrate a PVC window frame panel and a black polyester powder coated aluminium panel half treated with a surface treatment from a pure alcoholic solution (ethanol) respectively.
[0149] FIGS. 6 a and 6 b —illustrates the “antifog” properties of a substrate applied with a surface treatment containing the polymer PBuMa 15 -b-MAA 119 according to the present invention.
[0150] FIGS. 6 a and 6 b —illustrate a polyester film and a mirror half treated with a water-based surface treatment respectively.
[0151] FIG. 7 —illustrates the “antifog” properties of a substrate applied with a surface treatment according to the present invention.
[0152] FIG. 8 —illustrates the “anti-spotting” properties of a substrate applied with a surface treatment according to the present invention.
[0153] FIGS. 9 , 10 and 11 illustrate the results of tests performed with polymers according to the present invention.
[0154] FIG. 12 illustrates the results of wetting tests performed with polymers according to the present invention in comparison to surface treatments prepared from commercially available existing additives.
ABBREVIATIONS
[0155]
[0000]
AIBN
2,2′-azobis(2-methylpropionitrile)
nBuMA
n-butyl methacrylate
CPDB
4-cyanopentanoic dithiobenzoate
DMAEMA
N,N′-dimethylaminoethyl methacrylate
MAA
Methacrylic acid
PBuMA
Poly(n-butylmethacrylate)
PMAA
Poly(methacrylic acid)
TMACMA
Methacryloyloxyethyl trimethyl ammonium chloride or
N, N′, N″-trimethylammonium chloride methacrylate
DETAILED DESCRIPTION
[0156] The embodiments of the present invention described below are not intended to be exhaustive or to limit the invention to the precise forms disclosed in the following detailed description. Rather, the embodiments are chosen and described so that others skilled in the art may appreciate and understand the principles and practices of the present invention.
EXAMPLE 1
Preparation of Polymers and Block Copolymers According to the Present Invention
[0157] To manufacture the AB diblock copolymers of the present invention a controlled polymer or copolymer synthetic process is required in order to achieve a product with the required properties of, for example, desired molecular weight and narrow weight distribution or polydispersity. Polymers with a narrow molecular weight distribution are able to possess and exhibit substantially different properties to polymers prepared by conventional means.
[0158] Living radical polymerizations (also sometimes referred to as controlled free radical polymerizations) provide a maximum degree of control for the synthesis of polymers with predictable and well-defined structures. Recently, controlled/living radical polymerization (CLRP) has been shown to be a viable technique for the preparation of a large and diverse range of materials with precisely tailored nano- and micro-scale features.
[0159] Group transfer polymerisation (GTP), atom transfer radical polymerization (ATRP), nitroxide-mediated polymerization (NMP), reversible addition fragmentation transfer polymerization (RAFT), and MADIX all form part of these recently developed techniques and even more recently, Activated Regenerated by Electron Transfer (ARGET). These methods allow the synthesis of a large variety of polymeric architectures such as block copolymers, graft copolymers, stars, star-blocks, miktoarm stars or macromolecular brushes.
[0160] Importantly, a controlled polymerisation process is required for controlling the molecular structure of synthetic polymers, and thus for controlling the size of micellar aggregates in solution. Indeed, the aggregate sizes of polymers depend directly on the exact nature of the polymer (that is for example; molecular weight, length of polymer, and ratio between hydrophobic and hydrophilic blocks).
[0161] Whilst the presently described example prepares a block copolymer using the RAFT agent, CPDB (4-cyanopentanoic dithiobenzoate), it will be appreciated that other RAFT agents may be used. Similarly, the block copolymers of the present invention may be prepared by means of other controlled living polymerisation techniques as previously mentioned above.
[0162] For example when using Group transfer polymerisation (GTP), the polymerisation reaction as described in S. P. Rannard, N. C. Billingham, S. P. Armes and J. Mykytiuk, European Polymer Journal, 1993, vol 29 p 407. “Synthesis of monodisperse block copolymers containing methacrylic acid segments by group-transfer polymerization: choice of protecting group and catalyst”; may be followed, the relevant section of which is incorporated herein by reference.
[0163] For example when using atom transfer radical polymerization (ATRP), the polymerisation reaction as described in: Arrainen, Amilcar Pillay; Pascual, Sagrario; Haddleton, David M.; Journal of Polymer Science, Part A: Polymer Chemistry (2002), 40(4), 439-450. “Amphiphilic diblock, triblock, and star block copolymers by living radical polymerization: synthesis and aggregation behaviour” may be followed, the relevant section of which is incorporated herein by reference.
[0164] When using nitroxide-mediated polymerization (NMP), the polymerisation reaction as described in: WO 2007/057620 A1 (Arkema); “Method for preparing a living polymer comprising methacrylic and/or methacrylate units” may be followed, the relevant section of which is incorporated herein by reference.
[0165] However, it will be appreciated by one skilled in the art that modifications may be appropriate to the above methods to prepare a target polymer.
[0000] RAFT Synthesis of PBuMA 15 -b-PMAA 119
[0166] In a first step, the following conditions were used for the synthesis of PBuMA with a targeted polymerization degree of 15. nBuMA (5.01 g, 35.24 mmol), 4-cyanopentanoic dithiobenzoate (CPDB) (0.518 g, 2.34 mmol), AIBN (0.19 g, 1.18 mmol) and propan-2-ol (solvent, 8.45 g, 60% in mass) were introduced in a 250 mL round bottom flask containing a magnetic stirrer. The reaction flask was degassed by nitrogen bubbling for 20 minutes at 0° C. and then heated at 75° C. in a thermostated oil bath under a nitrogen atmosphere. After 5 hours of polymerization, a sample was withdrawn to analyze by 1 H NMR and thus calculate the conversion of BuMA.
[0167] In a second step, a solution containing MAA (24.2 g, 0.28 mmol), AIBN (0.20 g, 1.25 mmol) and propan-2-ol (solvent, 70.2 g, 75% in mass) was prepared in a second round bottom flask. This solution was degassed by nitrogen bubbling for 20 minutes at 0° C. and was then transferred via a cannula to the reaction flask. After stirring for 17 hours at 70° C., the reaction was cooled via an ice bath in order to stop the polymerisation. A total conversion of MAA was determined by 1 H NMR spectroscopy in DMSO at 400 MHz, integrating one vinylic proton (at 5.9 to 6 ppm from MAA) in comparison with the peak at 12.3 ppm corresponding to COOH from both the monomer and the polymer). The polymer was then purified by precipitation in diethyl ether. The recovered polymer PBuMA 15 -b-PMAA 119 was dried in a vacuum oven overnight at 40° C.
[0000] RAFT Synthesis of PBuMA 15 -b-P(TMACMA 60 -co-DMAEMA 61 )
[0168] In a first step, PBuMA 15 was prepared as previously described above from a mixture of nBuMA (2.56 g), CPDB (0.26 g), AIBN (0.09 g) and propan-2-ol (solvent, 4.52 g, 60% in mass). The polymerisation was allowed to proceed for 5 hours at 75° C. and a conversion of 95% obtained by 1 H NMR in CDCl 3 .
[0169] In a second step, a degassed solution containing TMACMA (19.72 g), DMAEMA (11.43 g), AIBN (0.09 g) and propan-2-ol (35.23 g) was transferred via cannula into the reaction flask containing PBuMA 15 . After stirring for 17 hours at 70° C., the reaction was cooled in an ice bath in order to stop the polymerisation. A total conversion of TMACMA and DMAEMA was determined by 1 H NMR spectroscopy in DMSO. The polymer was then purified by precipitation in cold hexane. The recovered polymer PBuMA 15 -b-P(TMACMA 60 -co-DMAEMA 61 )was dried in a vacuum oven overnight at 40° C.
[0170] The same procedure as described above was followed for the synthesis of the copolymer PBuMA 15 -b-PDMAEMA 120 using the appropriate starting materials.
[0000] RAFT Synthesis of P(BuMA 15 -co-DEAEMA 15 )-b-PDMAEMA 120 )
[0171] In a first step, P(BuMA 15 -co-DEAEMA 15 ) was prepared following the same procedure as for the preparation of PBuMA 15 above but using instead a mixture of nBuMA (2.53 g), N,N-diethylaminoethylmethacrylate (DEAEMA, 3.36 g), CPDB (0.26 g), AIBN (0.09 g) and propan-2-ol (solvent, 4.25 g, 60% in mass). The polymerisation was allowed to proceed for 5 hours at 75° C.
[0172] In a second step, a degassed solution containing DMAEMA (22.13 g), AIBN (0.09 g) and propan-2-ol (38.75 g) was transferred via cannula into the reaction flask containing P(BuMA 15 -co-DEAEMA 15 ). After stirring for 24 hours at 70° C., the reaction was cooled in an ice bath in order to stop the polymerisation. The complete conversion of the reactants was determined by 1 H NMR spectroscopy in DMSO. The polymer was then purified by precipitation in cold hexane. The recovered polymer P(BuMA 15 -co-DEAEMA 15 )-b-PDMAEMA 120 ) was dried in a vacuum oven overnight at 40° C.
[0000] NMP Synthesis of PBuMA 15 -b-PMAA 119
[0173] In a first step, the following conditions were used for the synthesis of PBuMA with a targeted polymerization degree of 15. nBuMA (15.01 g, 0.1 mol), styrene (1.12 g, 10.7 mmol), BlocBuilder® (2.68 g, 7.03 mmol), and propan-2-ol (solvent, 8.49 g, 70% in mass) were introduced in a 500 mL round bottom flask equipped with a mechanical stirrer. The reaction flask was degassed by nitrogen bubbling for 20 minutes at 0° C. and then heated at 75° C. in a thermostated oil bath under a nitrogen atmosphere. After 8 hours of polymerization, a sample was withdrawn to analyze by NMR and thus calculate the conversion of BuMA (conversion 73%).
[0174] At the end of this step, the reaction was left to cool down to 50° C. Then, propan-2-ol (solvent, 171.5 g) was added. The mixture was kept under stirring at room temperature overnight.
[0175] In a second step, MAA (73.4 g, 0.85 mol), styrene (7.41 g, 71.2 mmol) and AIBN (0.57 g, 3.48 mmol) were added to the previous mixture. The reaction mixture was degassed by nitrogen bubbling for 20 minutes at 0° C. After stirring for 4 hours at 75° C., a conversion of 92% in MAA was determined by 1 H NMR spectroscopy in DMSO at 400 MHz, integrating one vinylic proton (at 5.9 to 6 ppm from MAA) in comparison with the peak at 12.3 ppm corresponding to COOH from both the monomer and the polymer). IPA was evaporated and the recovered polymer PBuMA 15 -b-PMAA 119 was dried in a vacuum oven overnight at 40° C.
[0000] NMP Synthesis of P(BuMA 15 -co-DEAEMA 15 )-b-PDMAEMA 120 )
[0176] In a first step, PBuMA 15 was prepared following the same procedure as for the preparation of PBuMA 15 above but using instead a mixture of nBuMA (13.6 g), styrene (1.1 g), BlocBuilder® (2.42 g), and propan-2-ol (solvent, 5.8 g, 75% in mass). The polymerisation was allowed to proceed for 8 hours at 75° C.
[0177] In a second step, DMAEMA (59.7 g), TMACMA (105.2 g), styrene (7.3 g), AIBN (0.52 g) and propan-2-ol (solvent, 155.7 g) were added to the reaction flask. The mixture was degassed by nitrogen bubbling for 20 minutes at 0° C. After stirring for 4 hours at 75° C., the polymerization was stopped. IPA was evaporated and the recovered polymer PBuMA 15 -b-PMAA 119 was dried in a vacuum oven overnight at 40° C.
[0178] The same procedure as described above was followed for the synthesis of the copolymer PBuMA 15 -b-PDMAEMA 120 using the appropriate starting materials.
[0000]
TABLE 1
Block A
Block B
Preparation
Batch
BuMa
DEAEMA
Styrene
MAA
DMAEMA
TMACMA
Styrene
Method
1
15
0
0
120
0
0
0
RAFT
2
30
0
0
120
0
0
0
RAFT
3
15
0
1.5
120
0
0
11
NMP
4
15
0
0
0
120
0
0
RAFT
5
15
15
0
0
120
0
0
RAFT
6
15
0
0
0
60
60
0
RAFT
7
15
0
1.5
0
60
60
11
NMP
EXAMPLE 2
Method Describing the Preparation and Application of a Surface Treatment According to the Present Invention
[0179] A polymer or polymeric composition prepared according to the present invention may be coated onto a preferred substrate as described hereafter by any established coating process, for example, but not limited to for example a spray process. Generally, the treatment process involves the following steps:
[0180] Step (1): Dissolution of the copolymer molecules in water or in a mixture of alcohol/water at a desired pH and salt conditions under gentle agitation. Typically the system is left to equilibrate for 24 hours.
[0181] The copolymers chosen are usually not of a high molecular weight (for example the copolymers typically have a range of between 2000 to 100000 g/mol) and such molecules equilibrate rapidly when dissolved in an aqueous solution or in a mixture of alcohol/water.
[0182] Solvents suitable for use in the composition of the present invention are preferably as previously described.
[0183] In the following experimental procedure, the copolymer systems were left for 24 hours simply to be certain that the systems were fully equilibrated. However, the system was also found to equilibrate within much shorter timescales. For example, in pure ethanol the copolymer system was ready to use after just two hours of stirring. In a mixture of water (92% w) and ethanol (8% w), it was necessary to first fully dissolve the polymer in ethanol for two hours and then to add the polymer to water and mix the system again for at least one further hour.
[0184] Agitation of the copolymer systems was required during the process of dissolution and mixing, but it was not found to be critical and simply slowly stirring the copolymer system was found to be sufficient. The length of time for agitation depended on the solvent system.
[0185] Step (2): Exposure of the substrate of interest to the copolymer solution, that is, applying the solution to a desired substrate.
[0186] Whilst not wishing to be bound by any particular theory, evidence from the present invention implies that adsorption is complete after a few minutes. Methods of exposing the substrate to the solution include for example any known technique for forming a coating from a solution such as spin coating, dip coating, roller coating, brush coating, curtain flow or spraying, roller coating, wire-bar coating, extrusion coating, air knife coating, curtain coating, slide coating. More preferably dipping and spraying ensures that every part of the surface has been wetted by the treatment composition.
[0187] The treatment can be applied both interior and exterior surfaces.
[0188] Step (3): Drying the treated surface.
[0189] Preferably the treated surfaces need to be dried after applying the treatment composition. This can be achieved at room temperature or at higher temperatures, but if higher temperatures are used the drying time should be reduced. It should be noted that the drying temperature does not enhance the performance of the coating; rather it shortens the drying time of the treatment. Drying in ambient conditions will only lengthen the drying time.
Substrates
[0190] Various surfaces may be treated including for example metal, metal alloys, glass, plastics, rubber, porcelain, ceramic, tile, enamelled appliances, polyurethane, polyester, polyacrylic, melamine/phenolic resins, polycarbonate, painted surfaces, natural surfaces like wood, cellulose substrates, and the like.
[0191] 1) The metal or metal alloy object or articles may be comprised of a metal or metal alloys selected from the group comprising: aluminium, magnesium, beryllium, iron, zinc, stainless steel, nickel, nickel-cobalt, chromium, titanium, tantalum, rare earth metal, silver, gold, platinum, tungsten, vanadium, copper, brass, bronze and the like or combinations or derivatives thereof or plated articles thereof
[0192] 2) The plastic objects or articles may be comprised of polymers selected from the group comprising: transparent or non-transparent polyurethane, polycarbonate, polyethers, polyesters, polyvinyl chloride, polystyrene, polyethylene, polyvinyl acetate, silicone rubbers, rubber latex, polycarbonate, cellulose esters polycarbonate, polyester-polyether copolymers, ethylene methacrylates, polyolefins, and the like, silicone, natural and synthetic rubbers, nylon, polyamide or combinations thereof
[0193] 3) The glass objects or articles may be comprised at least partially of: glass, such as optical glasses, optical lenses, polarizing glasses, mirrors, optical mirrors, prisms, quartz glass, ceramics and the like or combinations thereof.
[0194] The substrate may include an exterior surface or article member, such as for example: a window sash, structural member or windowpane of a building; an exterior member or coating of a vehicle such as automobile, railway vehicle, aircraft and watercraft; an exterior member, dust cover or coating of a machine, apparatus or article; and an exterior member or coating of a traffic sign, various display devices and advertisement towers, that are made, for example, of metal, plastics, glass, a combination thereof and other materials.
[0195] Examples of substrates, include, but are not limited to: medical devices, protection shields, window sheets, windowpane, greenhouse walls, freezer doors, food packaging foils and printing paper.
[0196] 1) The metal objects can include for example: freezer doors, mirrors, condenser pipes, ship hulls, underwater vehicles, underwater projectiles, airplanes, wind turbine blades and the like.
[0197] 2) The plastic objects can include for example: face shields, helmet shields, swim goggles, surgeon face shields, food packaging, plastic foil, greenhouse walls, greenhouse roofs, mirrors, wind shields, underwater moving objects, airplane windows, shields, and the like.
[0198] 3) The glass objects can include for example: window glasses, greenhouse, glasses, glass sheets, face shields, optical glasses, optical, lenses, polarizing glasses, mirrors, optical mirrors, prisms, quartz glass, parabolic antennas, automobile head beam light glasses, automobile windshields, airplane control light glasses, solar panels, runway lights and the like.
[0199] The coating may also be applied on clear plastic or glass used for example as protective shields, windows, windshields, greenhouse panels, food packaging foils, goggles, optical glasses, contact lenses and the like.
[0200] Likewise the coating may be applied for example: on an exterior surface of a telescope lens, especially a riflescope, a spotting scope, or a binocular to reduce the likelihood of fogging or distortion due to the collection of moisture on the lens without significantly reducing light transmission through the lens in the visible range. That is, scopes used by sportsmen, the military and the like.
[0201] Exterior or interior parts of a building may also benefit form the coating for example: windowpanes, toilets, baths, wash basins, lighting fixtures, kitchenware, tableware, sinks, cooking ranges, kitchen hoods and ventilation fans, which are made from metal, glass, ceramics, plastics, a combination thereof, a laminate thereof or other materials.
EXAMPLE 3
“Easy-to Clean” and Dirt/Dust Repellent” Properties of a Surface Treatment According to the Present Invention
[0202] A surface treatment containing the polymer PBuMA 30 -b-PMAA 119 was applied to one half of one side of a polyester powder coated aluminium panel. The panel was then placed in the bottom of a box containing a soiling material (for example garden soil with a mixture of several components such as clay, sand, formic acid, organic residues from plants). The panel was placed well beneath the soiling material. The box was attached to an electronic orbital shaker and was shaken for 30 seconds at a rate of 640 revolutions/minute. The panel was then removed from the box and tapped twice on a hard surface to remove excess soiling. Photographic images and visual observations were recorded ( FIGS. 1 a, 1 b and 1 c ). The panel was then rinsed by spraying with 20 ml tap-water and allowed to dry. This process was considered as one dirt cycle and was repeated up to 5 times.
[0203] As seen in FIG. 1 , the treated side (bottom of the picture) looks cleaner than the untreated side (top of the picture) of the panel. Indeed, it can be clearly seen that the dirt/dust that has been deposited and stacked on the untreated side remains whereas there is no deposit on the treated part of the panel.
[0204] Besides the visual observation and pictures seen in FIG. 1 , colour measurements were recorded using a spectrophotometer after each dirt cycle to evaluate the colour difference ΔE between the surface prior to exposure to the dirt (that is, a clean surface) and the surface after exposure to dirt (that is the dirty surface).
[0205] The difference between the two surfaces is illustrated in FIG. 2 which shows a comparison of the total colour difference ΔE of the soiled panels. The colour difference is calculated from the CIE 1964 colour system. The system considers the lightness L*, the red-green value a* and the yellow-blue value, b*.
[0000] Δ E =(Δ L 2 +Δa 2 +Δb 2 ) 1/2 Equation 1
[0000] wherein
[0000] Δ L=L 1 −L 2 , Δa=a 1 −a 2 , Δb=b 1 −b 2
And ΔL, Δa, Δb are the colour differences in CIE L*a*b* colour space L 1 , a 1 , b 1 are the L*a*b* values for sample 1 (clean panel before soiling) L 2 , a 2 , b 2 are the L*a*b* values for sample 2 (panel after soiling or rinsing)
[0210] After soiling, the colour difference ΔE is less for the treated panels than for untreated panels. This corresponds to less initial soil adhesion on the treated panels, even after five dirt cycles. This demonstrates clearly that the surface treatment according to the present invention, once coated onto a surface provides “dirt repellent” properties compared with an uncoated surface.
[0211] FIG. 9 illustrates the visual rating of performance or polymer coverage versus the number of water rinses to demonstrate the longevity of the “wetting effect” of the surface treatment applied polyester powder coated aluminium panels. FIG. 9 also illustrates the results for several polymers
[0212] From FIG. 9 it can be seen that the non-fluorinated (either anionic or cationic) (NF-AP or NF-CP) copolymers perform as well as the fluorinated copolymer derivative. That is, there is no loss in terms of performances using a copolymer which is more easily dispersed or solubilised in water (see Example 8 for the solubility comparison of the fluorinated and the non-fluorinated copolymers) and which address environmental/health concerns.
[0213] In addition, it can be seen that it is possible to ‘tune’ the longevity of the effect by ‘tuning’ the composition of the polymer which is utilised depending on the target application.
In FIG. 9 , F CP (30/120) is PTFEMA 30 -b-PDMAEMA 120
NF CP (30/120) is PBuMA 30 -PDMAEMA 120 NF CP (15,15/120) is (P(BuMA 15 -co-DEAEMA 15 )-b-PDMAEMA 120 NF CP (15/60,61) is PBuMA 15 -b-P(TMACMA 60 -co-PDMAEMA 61 ) F AP is PTFEMA 30 -PMAA 120 NF AP is PBuMA 30 -PMAA 120
[0220] FIG. 10 illustrates the wettability performance of selected polymers on two substrates:
i) a polyester powder coated aluminium panel and ii) a glass slide.
[0223] Both substrates were treated with a surface treatment containing the polymer BuMA 30 -MAA 119 . It can be clearly seen in FIG. 10 that depending on the substrate selected, and therefore depending on the target application, the longevity of the effect maybe be tuned.
[0224] FIG. 11 illustrates the performance of a surface treatment according to the present invention in comparison with commercially available products. Listed below are the compositions of known products A and B.
[0225] Product commercially available A has the following ingredients: Aqua, Propylene Glycol Butyl Ether, Alcohol Denat., Ethanolamine, Cocamidopropyl Hydroxysultaine, Parfum, Benzalkonium Chloride, Alkyl Dimethyl Ethylbenzyl, Ammonium Chloride, Tartrate, Sodium Chloride.
[0226] Product commercially available B has the following ingredients: Aqua, C9-11 pareth-3, sodium cumenesulfonate, sodium carbonate, parfum, sodium diethylenetriamine pentamethylene phosphonate, sodium palm kernelate, sodium dodecylbenzenesulfonate, sodium citrate, acrylic acid diquat copolymer, dipropylene glycol, lauramine oxide, benzisothiazolinone, butoxydiglycol, sodium hydroxide, sodium chloride, colorant, geraniol, limonene, linalool.
[0227] Polyester powder coated aluminium panels were then treated with:
1. Known product A only. 2. Known product B only. 3. A mixture of the known product A and the polymer PBuMA 30 -b-PDMAEMA 120 at a concentration of 0.5 g/L 4. A mixture of the known product B and the polymer PBuMA 30 -b-PDMAEMA 120 at a concentration of 0.5 g/L
[0232] All of the panels were then rinsed with sprayed tap water for 30 seconds. A visual rating was allocated. A rating of 5 means very good wettability, a rating of 1 means poor wettability.
[0233] It can be seen from FIG. 11 that the use of a polymer according to the present invention provides improved performance.
[0234] The surface treatment was also tested in a bathroom as seen in FIG. 3 . In FIG. 3 , a shower door has been half treated with a water-based treatment containing the polymer PBuMa 15 -b-(TMACMA 60 -co-DMAEMA 61 ).
[0235] After exposure to a shower in which shampoo and soap had been used, it was clearly observed that the treated side (left side on FIG. 3 ) was much cleaner that the untreated side (right side FIG. 3 ). Indeed, it can be observed that organic residues (from shampoo and soap) and insoluble mineral deposits (from hard water) have adhered and dried on the untreated side of the shower door whereas, no deposits or ‘build-up’ of material are present on the treated surface. Accordingly, this illustrates that the surface treatment reduces the appearance, formation, adhesion and build-up of insoluble mineral deposits, limescale, rust and soap scum when water is allowed to evaporate off most siliceous and non-siliceous surfaces.
[0236] Therefore, it is clear that the surface treatment according to the present invention provides superior “easy-to-clean” results.
EXAMPLE 4
“Water-Sheeting Behaviour” of the Surface Treatment According to the Present Invention
[0237] Panels were first cleaned in soap solution, rinsed with deionised water and then dried with a lint free tissue. The panels were half treated with a surface treatment comprising the polymer PBuMA 15 -PMAA 119 .
[0238] The treated substrates were exposed to continuous water spray for 30 seconds. When observed, the treated side was totally wetted by the water and demonstrated homogeneous coverage of the polymer with no degradation in performance, whatever the substrate, as seen on FIG. 4 a (PVC substrate) and FIG. 4 b (polyester powder coated aluminium panel).
[0239] Similar results were obtained with a treatment containing a cationic polymer PBuMA 15 -b-P(TMACMA 60 -co-PDMAEMA 61 ), as seen in FIG. 5 a (PVC substrate) and FIG. 5 b (painted aluminium panel).
[0240] Accordingly, it is also clear that the surface treatment according to the present invention provides a substrate with a good “water-sheeting” behaviour.
EXAMPLE 5
“Anti-Fog” Properties of Surface Treatment According to the Present Invention
[0241] A surface treatment comprising the polymer BuMA 15 -MAA 119 was applied on a polyester film which was used in food packaging ( FIG. 6 a ) and on a glass mirror ( FIG. 6 b ). The treated substrates were exposed to water vapour rising from a beaker containing tap water heated at 85° C. It was clearly observed that the treated side of the surface was totally fog free (that is, it was completely transparent) whereas on the untreated side of the surface, small droplets formed which produced poor visibility through the film.
[0242] Similar results were obtained with a treatment comprising the cationic polymer PBuMA 15 -b-P(TMACMA 60 -co-DMAEMA 61 ), as seen in FIG. 7 (polyester film).
[0243] Accordingly, it was evident that the surface treatment according to the present invention provides “anti-fog” properties.
EXAMPLE 6
“Anti-Spotting” Properties of Surface Treatment According to the Present Invention
[0244] FIG. 8 illustrates the same panel as in FIG. 4 b but after drying vertically at room temperature. On the untreated side (right), dried watermarks were observed leading to an unpleasant appearance or finish; whereas on the treated side (left) no drying-marks were present. This demonstrates the “spot-free finish effect” provided by using a surface treatment according to the present invention.
EXAMPLE 7
Investigates the “Antibacterial and Anti-Fungal” Properties of a Substrate Treated with the Block Copolymer of Example 1
[0245] A solution of PBuMA 15 -b-P(TMACMA 60 -co-DMAEMA 61 ) (NF CP 15/60,60) in ethanol was evaluated as an anti-bacterial and/or anti-fungal surface treatment in addition to its ability to promote water sheeting ( FIG. 9 ).
[0246] The test was conducted as follows. Ceramic tiles (100×100 mm) were sterilised using alcohol in a Laminar flow cabinet. Two sterile tiles were then coated liberally with 2 ml of a solution of NF CP copolymer and allowed to air dry. The treated tiles and untreated control tiles were then assessed for the protection of the surface to microbial attack as detailed below.
[0247] One treated tile and two untreated tiles were surface inoculated with 1 ml of bacteria as detailed below in a Laminar flow cabinet. The inoculum was spread over the tile surfaces using sterile L shaped spreaders and allowed to air dry. One of the untreated tiles was swabbed to determine the number of colony forming units per tile by serial dilution and plate counting. The treated and untreated tiles were then washed by pouring 100 ml of sterile water over the tile surface and the number of surviving bacteria was determined by serial dilution and plate counting. The washed tile surface was then swabbed, which was serially diluted and plate counted to determine the colonies remaining on the tiles. This procedure was repeated using a fungi system as detailed below in Table 2.
[0000]
TABLE 2
INITIAL INOCULUM LEVEL
TEST SPECIES
Colony forming units per tile
BACTERIA
Pseudomonas
NCIMB 10421
1.6 × 10 7
aeruginosa
Escherichia coli
NCIMB 8879
Staphylococcus
NCIMB 9518
aureus
Enterococcus hirae
NCIMB 8191
FUNGI
Candida albicans
NCPF 3179
4.9 × 10 6
Saccharomyces
CS Lab
cerevisiae
Stock No. 4
Aspsergillus niger
NCPF 2275
Peniciiffium sp
CS Lab
Stock No. 25
[0000]
TABLE 3
Bacteria
COLONY FORMING UNITS REMOVED AFTER:-
SAMPLE
Wash
Swab
TOTAL
NF-CP
7.3 × 10 6
8.7 × 10 3
7.3 × 10 6
CONTROL
2.0 × 10 7
3.3 × 10 5
2.0 × 10 7
[0000]
TABLE 4
Fungi
COLONY FORMING UNITS REMOVED AFTER:-
SAMPLE
Wash
Swab
TOTAL
NF-CP
3.5 × 10 6
2.6 × 10 4
3.5 × 10 6
CONTROL
4.1 × 10 6
3.9 × 10 4
4.1 × 10 6
[0000]
TABLE 5
% REDUCTION AFTER WASH/SWAB : -
SAMPLE
Bacteria
Fungi
NF-CP
54.32
28.05
CONTROL
No reduction
15.53
[0248] The above results indicate:
The sample coated onto the surface of ceramic tiles resulted in lower numbers of colonies being recovered (surviving) after the wash and swab. The total reduction in the number of colonies was 54.32% for bacteria and 28.05% for fungi. On the control ceramic tile showed there was no reduction in bacteria with a lower reduction of 15.53% for fungi.
[0251] Therefore the laboratory tests indicate that when a polymer coating is applied as a surface coating to ceramic tiles according to the present invention there seems to be an effect on the levels of bacteria and fungi inoculated onto the surface.
EXAMPLE 8
Analysis of the Concentration of Copolymers in a Water-Based Formulation Using the Non-Fluorinated Block Copolymer of Example 1 in Comparison to a Fluorinated Copolymer
[0252] The use of non-fluorinated copolymers facilitates the preparation of fully aqueous formulations in comparison to fluorinated copolymers. Indeed, whereas PTFEMA 30 -b-PMAA 120 (F-AP 30/120) is not soluble in water, it has been possible to solubilise PBuMA 15 -b-PMAA 120 (NF-AP 15/120) directly in water without using for example ethanol or surfactants.
[0253] Depending of the use of surface treatments, the concentration of copolymers required may vary. Using non-fluorinated copolymers can lead to a broader range of concentrations available in water based surface treatments.
[0254] The following table gives the maximum concentration (g/L) of copolymers F-AP and NF-AP in denaturated ethanol (IMS) and in water-based formulation. The water-based formulation was prepared by adding 5 mL of the solution of copolymers in ethanol at the maximum concentration into 45 mL water. Therefore, the water-based formulation contained 10 wt % alcohol. The maximum working concentration in a water based formulation can be eight times greater for the non-fluorinated polymer compared to the maximum working concentration for the fluorinated polymer.
[0000]
TABLE 6
Maximum
Maximum concentration
Copolymers
concentration
in aqueous
type
in IMS (g/L)
formulation (g/L)
F-AP (30/120)
75
7.5
F-AP (15/120)
600
60
EXAMPLE 9
Comparison of a NF-AP (15/120)-Based Surface Treatment Compared to Surface Treatments Prepared from Existing Additives which Promotes Stay-Clean Properties
[0255] Water-based surface treatments were prepared using NF-AP (15/20), F-AP (30/120) and as a comparison different commercially available existing additives and using two surfactants, Brij 30 and Glucopone CS 215, to facilitate the spreading of treatments on the tested substrates, in this experiment white-powder coated aluminium Q-panels. The concentration of each surfactant was 0.5 g/L. The existing additives were used at concentrations of 5 g/L, which is the recommended concentration advised by the suppliers. The copolymer of the present invention was used at 10-times lower concentration, 0.5 g/L in a water-based formulation containing 8 wt % ethanol. The table 7 summarises the content of each of the surface treatment formulations used in this comparison.
[0000]
TABLE 7
Additive
concentration
Glucopone
Formulations
(g/L)
Brij 30
CS 215
Water
Ethanol
NF-AP (15/120)
0.5
✓
✓
✓
✓
F-AP (30/120)
0.5
✓
✓
✓
✓
Additive 1
5
✓
✓
✓
—
Additive 2
5
✓
✓
✓
—
Additive 3
5
✓
✓
✓
—
[0256] Each formulation was applied to a Q-panel by the flow-coating method of application and after drying, tap-water was sprayed onto the surfaces following the same procedure as described in example 4. A rating of 5 means very good wettability and water spreads readily over the panel, a rating of 1 means poor wettability and water beads on the panel.
[0257] The results for 12 wetting cycles are shown in FIG. 12 . FIG. 12 shows that the surface treatment comprising NF-AP (15/120) diblock copolymers performs as well as F-AP (30/130) copolymers in terms of water wetting properties and does not have any of the environmental constraints of F-AP (30/130).
[0258] Comparing the formulations prepared using the competitor additives, the surface treatment comprising additive 1 is the only formulation that achieves similar ratings to NF-AP(15/120). This however, is only achieved by using a much higher concentration of additive compared to the concentration of NF-AP (15/120) copolymers.
[0259] Formulations prepared with additives 2 and 3 show a lesser wetting effect than the surface treatments using NF-AP (15/120) and in particular, show a shorter longevity.
[0260] The water sheeting properties of the non-fluorinated product NF-AP performs as well as the fluorinated product F-AP and does not possess any of the environmental constraints associated with using fluorinated products. The only competitor product that displays similar performance to NF-AP is the formulation made with additive 1. The usage rate of this additive is, however, 10 times greater than NF-AP and therefore its use has a larger negative impact on the environment. This comparison demonstrates that there is an opportunity and requirement to improve stay-clean surface treatment products.
[0261] The present invention therefore provides novel uses of AB block copolymers which are able to self assemble into aggregate structures either in water, in a water/alcohol mixture or in a pure alcohol dispersion, for the preparation of a surface treatment which provides a functional coating, that includes the following properties and advantages and provides a surface coating or a surface treatment that imparts one or more functional effects:
[0262] (i) A coating that repels dust and dirt, that is, the coating reduces the adhesion and hence the build-up/depositition of soil/dust and dirt in order to provide a coated surface with a cleaner appearance and also a coating that is easier to clean.
[0263] (ii) A coating that has improved water-sheeting behaviour; meaning that water does not de-wet or experience beading on the surface, rather the water forms a continuous sheet meaning that the surface is wetted by water easily; in other words provides good water wettability.
[0264] (iii) A coating that once applied to a surface prevents the build-up of crystalline scale deposits and the associated surface fouling effects that are visible with the build-up of lime scale.
[0265] The surface treatment is able to reduce the appearance and prevent the build-up and deposition of lime scale. The formation of crystalline deposits due to chemicals present in water which build up over a period of time, particularly in bathrooms, toilets, sinks and particularly in places where there are flows of domestic tap water, are also reduced.
[0266] (iv) A coating that is able to provide ‘anti-fog’ properties. A haze, mist or fog is defined as the formation of small droplets of water on a transparent surface in the presence of water vapour that results in the transparency of the surface being reduced. Consequently, the terms “anti-hazing”, “anti-mist”, “anti-fogging”, “fog resistance” or “fog up free” properties refer to the properties of a transparent surface which has been treated in such a way so that in the presence of water vapour either:
[0267] (1) beads of water are not able to form on the surface and instead water vapour on contact with the surface forms a thin continuous sheet in the form of a film at the surface which is transparent; or
[0268] (2) water is repelled on contact with the surface which results in beads which have the ability to readily roll off the surface. In both cases, the haze which is caused by the formation of small droplets of water on a surface in the presence of water vapour is reduced.
[0269] More specifically, the use of a hydrophilic surface treatment according to the present invention means that when the coating is applied to a surface for example, but not limited to: metal, glass or plastic surfaces, the surface coating or a surface treatment prevents water droplet formation on the selected surfaces when the surfaces are exposed to conditions which can lead to the ‘fogging’ of the surface. Such conditions include for example: the exposure of the surface to air of high humidity, the exposure of the surface to water vapour or the transfer of the surface from a low temperature environment to a higher temperature environment causing the surface to ‘fog up’, that is the surface becomes clouded by condensation formed from the cooling of water alighting on the surface.
[0270] The applied hydrophilic surface treatment of the present invention is useful for preventing water condensation or fogging on metallic, plastic, and glass surfaces and the like. That is, the applied hydrophilic surface treatment of the present invention does not prevent water condensation, but water that has condensed forms a continuous sheet rather then beads. As an aside, when the selected surface coating or surface treatment is clear plastic or glass, the treatment applied to the surface ensures that these particular surfaces maintain a good transparency.
[0271] (v) In addition it has been found that the combination of the durable hydrophilic effect and the fast and uniform drying effect of the polymeric surface coating or surface treatment of the present invention provides treated substrates with ‘anti-spotting’ properties and therefore provides treated surfaces with an aesthetically pleasing finish, that is a treated surface has a ‘spot-free’ finish, more specifically a treated surface which does not display the appearance of water-marks, even after the treated surface has been contacted at a later point in time with water.
[0272] A further feature of the presently claimed surface coating or surface treatment is that the treatment may be applied to a wide range of substrate surfaces, for example but not limited to: plastic, metal or other materials.
[0273] It has been found that the hydrophilic surface treatment of the present invention adheres ‘strongly’ to for example surfaces that include: metals, metal alloys, glass, plastics, rubber, porcelain, ceramic, tile, enamelled appliances, polyurethanes, polyesters, polyacrylics, melamine/phenolic resins, polycarbonates, painted surfaces, and wood.
[0274] Consequently, the hydrophilic surface treatment of the present invention finds particular use in a wide range of application areas such as for example; building and DIY treatments, the car industry for the treatment of interior and exterior metal and glass, bathroom and wet room applications, and general household surface cleaning products.
[0275] The treatment also finds use in other application areas such as for example but not limited to: the food packaging and foils industry, and as protective shields.
[0276] Fogging is a phenomenon observed commonly in applications of plastic films in the food packaging and agricultural sectors. The term ‘Fog’ used herein describes the condensation of water vapour, in the form of small discrete water droplets, creating a translucent appearance, on a plastic film surface when an enclosed mass of air cools to a temperature below its dew point. The extent of the phenomenon depends on the actual temperature and relative humidity of the enclosed air mass, as well as the temperature of the plastic film. Examples of the problems caused by this phenomenon include: fogging of food packaging in chiller cabinets and condensation within greenhouse complexes.
[0277] Food packaging needs to present its contents hygienically and aesthetically. Fogging reduces a consumer's ability to see the product and will give an impression of lower quality. In some applications condensation of water within the packaging may lead to actual reduction in quality.
[0278] In the agricultural sector, the undesirable effects of fogging include for example; reduced total light transmission in greenhouses and water dripping that can lead to plant damage. Further plant damage may be induced by the focussing effect of the water droplets, rather like an array of lenses concentrating solar energy on foliage. The end result of all these effects for food producers is a lower potential yield and reduced product quality.
[0279] Eye protection is also increasingly important in today's industrial environment. Best practices dictate that employees exposed to eye hazards such as airborne debris, fumes, or even excess moisture, must wear goggles, shields or safety glasses. Unfortunately, these eye safety systems are often plagued with fogging. That fogging often causes the frustrated employee to stop wearing their eye protection thus exposing themselves to potential injury and the company to a lawsuit for workers compensation claims. When goggles, shields or safety glasses do not provide adequate fog and condensation protection, employees may spend valuable production time constantly clearing the fog from these lenses. Protective eyewear is often available with glass, plastic and polycarbonate lenses. However none of these provide adequate fog protection. The use of the “anti-fog” surface treatment such as described in the present invention will be suitable on polycarbonate lenses and other plastic lenses like those found in high-end safety eyewear and will aid in keeping protective eyewear fog free and a visibility clear.
[0280] While exemplary embodiments incorporating the principles of the present invention have been disclosed hereinabove, the present invention is not limited to the disclosed embodiments. Instead, this application is intended to cover any variations, uses, or adaptations of the invention using its general principles. Further, this application is intended to cover such departures from the present disclosure as come within known or customary practice in the art to which this invention pertains and which fall within the limits of the appended claims.
REFERENCES
[0000]
1. Emma Dorey, Chemistry & industry, issue 18, 5 (September 2006);
2. Ralf Blossey, Nature Materials, vol 2, 301-306, (2003);
3. Jon Evans, Chemistry & industry, issue 18, 16-17 (September 2006);
4. Mathilde Callies, et al., Soft matter, vol 1, 55-61, (2005);
5. Taolei Sun, et al., Chem. Comm., 1723-1725, (2005);
6. a/ S. Herminghaus, Europhys. Lett., 52, 165, (2000); b/ J. Bico, et al., Colloids Surf., A, 206, 41, (2002); c/ H. Li, et al., Angew. Chem. Int. Ed., 40, 1743, (2001); d/ L. Feng, et al., Angew. Chem. Int. Ed., 41, 1221, (2002); e/ L. Feng, et al., Angew. Chem. Int. Ed., 42, 800, (2003); f/ T. Onda, et al., Langmuir, 12, 2125, (1996);
7. Igor Luzinov, et al., Prog. Polym. Sci., vol 29, 635-698, (2004);
8. a/ Anthony M. Granville, et al., Macromol. Rapid. Comm., vol 25, 1298-1302, (2004); b/ Lei Thai, et al., NanoLetters, vol 4, 7, 1349-1353, (2004); c/ Motoshi Yamanaka, et al., Chem Comm, 2248-2250, (2006);
9. Akira Nakajima, et al., Langmuir, 16 (17), 7044-7047, (2000);
10. a/ Eiji Hosono, et al.; JACS, vol 127, 13458-13459, (2005); b/ Xi Yu, et al., Adv. Mater. Vol 17, 1289-1293, (2005); c/ A. A. Abramzon, Khimia i Zhizu (1982), no. 11, 38 40;
11. J. Rodriguez-Hernandez, et al., Prog. Polym. Sci., 30, 691-724, (2005);
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The present invention relates to the use of AB block copolymer composition as a surface coating wherein the composition comprises (a) an AB block copolymer; and (b) a liquid medium and wherein the AB block copolymer comprises: (a) a substantially hydrophobic block A, and (b) a substantially hydrophilic block B wherein the hydrophobic block A comprises one or more monomer of formula (A) wherein R is H or C 1 to C 4 alkyl; Z is O, P or N; and R′ is selected from the group comprising: C 1 to C 18 linear or non linear alkyl; C 1 to C 18 alkylamino alkyl; C 1 to C 18 dihydroxyalkyl; C 1 to C 18 silylalkyl; epoxy alkyl, phosphoryl or phosphoryl alkyl; a styrene based monomer; a vinyl phosphonate or phosphoric acid monomer; and wherein the liquid medium comprises either: (i) water; (ii) an organic solvent; (iii) an organic solvent substantially free from water; or (iv) an organic solvent and water; and wherein: the liquid medium further optionally comprises one or more additive, surfactant or wetting agent.
| 2 |
BACKGROUND OF THE PRESENT INVENTION
The present invention relates generally to a reverse osmosis purification system for producing drinking water, and more particularly to a monitoring process and device for a reverse osmosis purification system for producing drinking water for monitoring the system to make purified drinking water having a purity quality in conformity with the standards of public health. The present invention provides a function of notifying of the exact timing of replacing of the purifying elements or backwashing reverse osmosis membranes included in the purification system to ensure their effectiveness.
The main culprits of the water pollution today include industrial wastes, household wastes, farm pesticides, and the animal wastes produced by hog and poultry farms. As the pollution problems of sources of our drinking water, such as the rivers, have become increasingly worrisome, people tend to have very little confidence in the quality of their drinking water provided by the water company. Furthermore, people's anxiety over the quality of their drinking water is further aggravated by the fact that the conditions of the water-supplying pipes and reservoirs are often found to be unsatisfactory. As a result, a variety of water-treating devices, such as water-filtering devices, water purifying devices, water softening devices, etc., have become ubiquitous in places like offices, homes, factories, schools, churches, and so forth. In general, such conventional water-treating devices as mentioned above are provided with one or more additional filtration means for enhancing the purity of the drinking water. The conventional reverse osmosis purification systems of drinking water are, in fact, effective in upgrading the quality of the drinking water. Nevertheless, the conventional reverse osmosis purification systems of drinking water are defective in design. The shortcomings inherent in the conventional drinking machines are described explicitly hereinafter.
Reverse osmosis filtration elements are supposed to be replaced or backwashed after a predetermined period of operating time without one knowing the actual conditions of the reverse osmosis filtration elements. In many cases, overused reverse osmosis filtration elements are not replaced or backwashed in time and consumers are unknowingly led to drink the poor quality water from such ineffective water purification systems.
Nowadays, the most popular and effective drinking water purifying element is the reverse osmosis membrane which is so arranged as to form a parallel tangent plane with the flowing direction of the water. The water is forced under pressure against the reverse osmosis filtration element by means of a manually operation switch valve to increase the speed and the flow of the water passing through the reverse osmosis filtration element. Some of the water can be caused to pass through the reverse osmosis filtration element in a vertical angle instead of a parallel manner in order to filter out salts and other micro-impurities.
Referring to FIG. 1, the most common reverse osmosis purification system for producing drinking water is illustrated, which comprises a water pressure pump C1, an impurity filter device C2, a reverse osmosis filtration element C3, and an activated carbon filter C4. The impurity filter device C2 is used to pre-purify the water from tap water or other water sources before feeding it to the reverse osmosis filtration element C3 in order to prolong the service life span of the relatively expensive reverse osmosis filtration element C3. The best number and style of impurity filter devices C2 needed to be installed depends on the water quality and the amount of suspended impurities and organic particles in the source water. The activated carbon filter C4 can be installed before or after the reverse osmosis filtration element C3 for removing any poison contents in water.
Since the mesh of the reverse osmosis membrane of the reverse osmosis filtration element C3 is very tiny, the diameter of each reverse osmosis membrane mesh is very small, ex. 0.00000001 cm. The water pressure pump C1 is used to provide pressurized water with 80 psi to 100 psi in order to penetrate the reverse osmosis membrane. When the pre-purified water from the impurity filter device C2 is pumped through the reverse osmosis filtration element C3, the reverse osmosis membrane can isolate clean water molecules to obtain purified drinking water, wherein the high concentrated waste water is drained off or collected for other cleaning purpose.
However, the reverse osmosis filtration element must be backwashed and cleaned periodically according to the schedule specified by the manufacturer. In order to prolong the service life span of the reverse osmosis filtration element, the impurities deposited in the reverse osmosis filtration element must be removed so as to prevent them from becoming hardened and clogging the reverse osmosis filtration element. It happens from time to time that the cleaning schedule of the reverse osmosis filtration element of the reverse osmosis purification system is unintentionally disregarded or overlooked. Furthermore, the chore of cleaning the reverse osmosis filtration element is not a task that people enjoy to do. It is an irresistible trend of the modem age that the consumers prefer an automated appliance rather than a manually operated appliance.
The reverse osmosis filtration element of the reverse osmosis purification system of drinking water mentioned above is capable of filtering out the impurities, such as unwanted suspended particles, chlorine molecules, pesticides, various organic matters, heavy metals, and organic compounds such as chloroform, which is a carcinogen. In addition, the reverse osmosis filtration element is capable of deodorizing the water. If such impurities as mentioned above are allowed to accumulate in the reverse osmosis filtration element, its filtering effect will be seriously undetermined to an extent that bacteria and fungi can grow and flourish on the accumulated impurities, thereby a potential health hazard is brought about to the users of the reverse osmosis purification system.
Moreover, if the reverse osmosis purification system of drinking water is used less often, the service life span of the reverse osmosis membrane is prolonged accordingly. Therefore, the scheduled maintenance work of the reverse osmosis purification system is likely to be delayed or even skipped. The quality of operating performance of the reverse osmosis purification system is often compromised by the lack of routine maintenance work for the reverse osmosis purification system.
In fact, no matter what kind of the reverse osmosis purification system you have installed, none of the reverse osmosis purification systems are provided with a warning system, which serves to keep the users of the system to be on the alert, for any indication that the reverse osmosis purification system of drinking water is no longer working properly so the drinking water so made is absolutely safe to drink.
SUMMARY OF THE PRESENT INVENTION
The primary object of the present invention is to provide a monitoring process for a reverse osmosis purification system for drinking water for monitoring the effectiveness of the reverse osmosis purification system of drinking water and warning of any ineffective condition, wherein if such ineffective condition persists, it can stop the water from coming out of the reverse osmosis purification system to protect the unaware consumers.
Another object of the present invention is to provide a monitoring process for a reverse osmosis purification system of drinking water which comprises a step of automatically ceasing supply of the drinking water and providing for reverse flowing of water to backwash and clean periodically the impurities deposited in the reverse osmosis filtration element of the reverse osmosis purification system.
It is still another object of the present invention to provide a monitoring device for a reverse osmosis purification system for drinking water, capable of monitoring automatically the quality of the drinking water made by the reverse osmosis purification system, advancing information signals when the output water quality is under a predetermined standard so as to warn of the timing of replacing the disabling filtration element and ceasing the water supply of the reverse osmosis purification system once the discharged drinking water is under a predetermined standard condition to ensure that the drinking water has the highest quality.
It is still another object of the present invention to provide a monitoring device for a reverse osmosis purification system for drinking water having a reverse osmosis filtration element, capable of automatically ceasing the supply of drinking water from the reverse osmosis purification system when the PPM (parts per million) value of the drinking water and the service life of the reverse osmosis membranes are not in conformity with the corresponding specified safety standards, so as to ensure that the reverse osmosis purification system can provide drinking water of highest quality.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 is a block diagram of a reverse osmosis purification system of drinking water having an impurity filter device, a reverse osmosis filtration element and an activated carbon filter according to the present invention.
FIG. 2 is a flow chart of a monitoring device for a reverse osmosis purification system of drinking water of the present invention.
FIG. 3 is a circuit diagram of the monitoring device for a reverse osmosis purification system of drinking water having at least a reverse osmosis filtration element according to the present invention.
FIG. 4 is a circuit diagram of an alternative mode of the monitoring device for a reverse osmosis purification system of drinking water having at least a reverse osmosis filtration according to the present invention.
FIG. 5 is a circuit diagram of another alternative mode of the monitoring device for a reverse osmosis purification system of drinking water having at least a reverse osmosis filtration according to the present invention.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT
The present invention provides a monitoring process and device for a reverse osmosis purification system of drinking water having at least a reverse osmosis filtration element.
As shown in FIG. 1 a most common and effective reverse osmosis purification system of drinking water is illustrated, which comprises a water pressure pump C1, an impurity filter device C2, a reverse osmosis filtration element C3, and an activated carbon filter C4.
The pre-purified water coming out from the impurity filter device C2 is fed to the reverse osmosis filtration element C3. Since the mesh of the reverse osmosis membrane of the reverse osmosis filtration element C3 is very tiny, the diameter of the mesh of the reverse osmosis membrane is very small, ex. 0.00000001 cm. The water pressure pump C1 provides compressed water with 80 psi to 100 psi in order to penetrate through the reverse osmosis membrane. The reverse osmosis membrane can isolate clean water molecules to obtain purified drinking water and highly concentrated waste water which is discharged for disposal or secondary use such as floor washing and toilet flushing.
Referring to FIG. 2, it is a block diagram of the monitoring device of the present invention. The monitoring device of the present invention comprises a microprocessor 31, an LCD indicator circuitry 32 electrically connected to the microprocessor 31, a detecting means 33 electrically connected to the microprocessor 31, a warning means 34 electrically connected to the microprocessor 31, and a power switching means 35 electrically connected to the water pressure pump C1 and the microprocessor 31.
Operational signals are sent from the detecting means 33 regarding the functional integrity of the reverse osmosis filtration element by a sensor detecting the quality of the drinking water so made which are sent to the microprocessor 31. When the microprocessor 31 receives such signals from the detecting means 33, the microprocessor 31 will process a respective response by sending corresponding signals to the warning means 34 and the power switching means 35 for activating them to process predetermined functions, respectively.
The microprocessor 31 provides a central control of the operations of the monitoring device and shares a power source with the reverse osmosis purification system for drinking water. The specific service life data of the reverse osmosis filtration elements of the reverse osmosis purification system are formatted and input into the microprocessor as digital predetermined reference value. A preferred embodiment of the present invention uses a monolithic chip microprocessor 31 such as a model number 8051 or 8052 to provide I/O memory. A plurality of programs stored in the microprocessor 31 control the entire operation of the monitoring device.
The LCD indicator circuitry 32 is electrically connected to the microprocessor 31 for notifying the maintenance personnel of the time of replacing the reverse osmosis filtration element and indicating related information from the microprocessor 31, such as the data of current time, the time when the replacement of each filtration element taken place, the PPM value of the drinking water made, the current value of water making volume, the total value of water making volume, the mechanical breakdown condition, etc. which is all stored in the microprocessor 31.
The detecting means 33 comprises at least a reverse osmosis detecting circuitry electrically connected to the microprocessor 31 for monitoring the functional integrity of each filtration element by detecting the quality of the drinking water made by the reverse osmosis filtration element. The detecting means 33 comprises at least a detector for determining the condition of the reverse osmosis filtration element. The detecting means 33 reads and analyses detected signals from the detector and generates a related condition detecting value. When the condition detecting value reaches a certain predetermined reference value preset in the microprocessor, the detecting means will send a digital signal and transmit such digital signal to the microprocessor.
The warning means 34 is electrically connected to the microprocessor 31 for advancing a warning information sound signal to remind a user of the exact time of replacing a specific filtration element. The warning means 34 is activated by the microprocessor 31 of the monitoring device by sending an activating signal thereto when the condition detecting value approximating the predetermined reference value is detected, in which such predetermined reference value indicates that the service life of the specific filtration element is completed.
The power switching means 35 is electrically connected to the microprocessor 31 and activated by the microprocessor 31 for ceasing the supply of drinking water from the whole reverse osmosis purification system of drinking water when the warning means 34 is activated to generate a warning signal for a predetermined period of time. It means that the specific reverse osmosis filtration element of the reverse osmosis purification system has become ineffective and the drinking water so made is not safe for human consumption.
When the specific worn-out filtration element is replaced by a new one, the maintenance personnel may manually reactivate the monitoring device to produce drinking water again and stop the warning means 32 from providing the warning information signal.
In accordance with the monitoring device for a reverse osmosis purification system of drinking water as disclosed above, as shown in FIGS. 3 to 5, the warning means 34 comprises a sound generating circuitry having a configuration that produces verbal or musical sound for warning consumers about the clogged condition of the water filtration elements. Of course the sound generating circuitry 34 can be replaced by a lighting generating circuitry instead. Moreover, the warning means 34 can comprise a sound generating circuitry and a lighting generating circuitry so as to generating both warning sound and warning lighting.
The warning means comprises a sound generating circuitry 34 which comprises an indicator circuit IC 341, a speaker driving circuit 342 and a speaker 343 electrically connected, in which the indicator circuit 341 stores a verbal or music sound track, and the speaker driving circuit 342 broadcasts the stored verbal sound or music of the indicator circuit IC 341 via the speaker 343.
Various water quality determining methods can be applied to monitor the functional integrity of the reverse osmosis filtration element. Such methods include monitoring of the water pressure difference between an outlet and an inlet of the reverse osmosis filtration element which may increase when the reverse osmosis filtration element C3 is ineffective. The varying PPM of the water discharged from the reverse osmosis filtration element C3 can indicate the drinking water quality and the filtering ability of the reverse osmosis filtration element C3. If the PPM of the water discharged from the reverse osmosis filtration element C3 exceeds 4 PPM, generally, the reverse osmosis membranes of the reverse osmosis filtration element are ineffective. Computing the total volume of the water filtered by the reverse osmosis filtration element C3 can also determine its filtering ability and service life. Detecting of a decrease of water flow out of the reverse osmosis filtration element C3 is an indication of the element being ineffective, because when the reverse osmosis filtration element C3 is clogged, the water flow out of the reverse osmosis filtration element C3 will decrease.
In accordance with the reverse osmosis filtration element C3, as shown in FIG. 3, the reverse osmosis detecting circuitry 33d comprises a plurality of operational amplifiers, OP1, OP2, OP3, and OP4, an analog to digital converter 331 and a PPM detecting sensor 333, such as TDS, electrically connected. The PPM detecting sensor 333 is installed in a water outlet of the reverse osmosis filtration element C3.
When the reverse osmosis filtration element C3 can not normally function and the PPM value detected by the PPM detecting sensor 333 is bigger than 4 PPM, the reverse osmosis filtration element C3 can be judged as ineffective and the drinking water so made is not safe for human consumption. Therefore, a PPM value detected signal detected by the PPM detecting sensor 333 is read by the operational amplifier OP2 which generates a PPM condition detecting value regarding the outlet water PPM. When such PPM condition detecting value rises to a predetermined PPM reference value preset in the operational amplifier OP1, which is the voltage value detected during 4 PPM, a clogged condition of the reverse osmosis filtration element C3 can be judged. In case the PPM condition detecting value generated by the operational amplifier OP2 is bigger than the predetermined PPM reference value of the operational amplifier OP1, a digital signal is sent from the analog to digital converter 331 to the microprocessor 31. The microprocessor 31 will then send an activating signal to activate the warning means 34 to advance the sound generating circuitry 34 to generate verbal or musical warning sound.
The power switching means 35 comprises a power cutoff circuitry 35a which comprises two transistors 351, 353 and two photoelectric driving power transistors 352, 354 electrically connected. The first transistor 351 is continuously activated to conduct electricity according to an activating signal sent from the microprocessor 31. The first photoelectric driving power transistor 352 activates the water pressure pump Cl (as shown in FIG. 1) to pump water flowing through the filtration elements to produce purified drinking water. Periodically, the microprocessor 31 is programmed to send another activating signal to activate the second transistor 353 to conduct electricity that causes the second photoelectric driving power transistor 354 to activate the water pressure pump Cl for automatically backwashing and cleaning the reverse osmosis membrane of the reverse osmosis filtration element C3. Therefore, the water quality is assured and the reverse osmosis membrane of the reverse osmosis filtration element C3 is protected from undesirable water pressure.
The microprocessor 31 is programmed to send a ceasing signal to activate the first transistor 351 when the warning means 34 generates the warning information sound signal for a certain predetermined period of time, in order to stop the water pressure pump C1 for cutting off the drinking water supply of the whole reverse osmosis purification system. At that moment the reverse osmosis filtration element will not produce drinking water any more until the user of the reverse osmosis purification system of drinking water replaces the worn-out filtration element and manually resets and restarts the system. Therefore, the water quality can be assured.
When the reverse osmosis membranes of the reverse osmosis filtration element C3 is clogged, the pressure difference between the inlet water pressure and the outlet water pressure of the reverse osmosis filtration element C3 varies. Therefore, in detecting the inlet water pressure and the outlet water pressure of the reverse osmosis filtration element C3, one can judge whether the reverse osmosis filtration element C3 is clogged and ineffective. Referring to FIG. 4, an alternative mode of the detecting means 33 for the reverse osmosis filtration element is illustrated. The detecting means 33 comprises two identical reverse osmosis detecting circuitries 33e and 33d and two detectors 334, 335.
Each of the reverse osmosis detecting circuitries 33e and 33f comprises a plurality of operational amplifiers, OP1, OP2, OP3, and OP4, and an analog to digital converter. The two detectors are two water pressure detecting sensors 334, 335 electrically connected with the two first operational amplifiers OP2 of two reverse osmosis detecting circuitries 33e, 33f respectively. The water pressure sensor 334 is installed in the water inlet of the reverse osmosis filtration element C3 and connected to the operational amplifier OP2 of the reverse osmosis detecting circuitry 33e. The water pressure sensor 335 is installed in the water outlet of the reverse osmosis filtration element C3 and connected to the operational amplifier OP2 of the reverse osmosis detecting circuitry 33f. In this mode, the clogged condition of the reverse osmosis filtration element C3 can be detected by the differential pressure between the inlet and outlet water pressure.
Referring to FIG. 5, another alternative mode of the reverse osmosis filtration element C3 is illustrated. This alternative mode is different from the previous mode shown in FIG. 3 in that a flow detecting sensor 336 is installed in the water outlet of the reverse osmosis filtration element C3 and connected to the operational amplifier OP2, instead of the PPM detecting sensor 333. In this mode, the clogged condition of the reverse osmosis filtration element C3 is detected by the reduction in outlet flow amount instead of the variation in the PPM value of the drinking water made.
The monitoring process for a reverse osmosis purification system of drinking water is further described hereinafter.
The monitoring process of a reverse osmosis purification system of drinking water having at least a reverse osmosis filtration element and a water pressure pump for pumping pressurized water through the reverse osmosis filtration element comprises the steps of
(1) inputting and formatting specific service life data of the reverse osmosis filtration element into a microprocessor as a predetermined reference value;
(2) monitoring a functional integrity of the reverse osmosis filtration element by detecting the quality of the drinking water so made by at least a detector and transmitting a detected signal to a reverse osmosis detecting circuitry which is electrically connected with the detector and the microprocessor;
(3) generating a condition detecting value regarding the functional condition of the reverse osmosis filtration element by the reverse osmosis detecting circuitry and comparing with the predetermined reference value regarding the service life of the reverse osmosis filtration element;
(4) sending a digital signal, which is readable by the microprocessor, to the microprocessor when the condition detecting value of the reverse osmosis filtration elements approximates the predetermined reference value, indicating that the service life of the reverse osmosis filtration element is completed;
(5) sending an activating signal to a warning means which is electrically connected with the microprocessor and advancing a warning information sound signal to notify of exact time of replacing the reverse osmosis filtration element by the warning means;
(6) cutting off the electric power to the water pressure pump to cease the supply of drinking water from the reverse osmosis purification system by a power switching means which is electrically connected with the microprocessor and activated by the microprocessor when the warning means is activated to generate the warning information sound signal exceeding a predetermined period of time; and
(7) manually stopping the warning information sound signal of the warning means and restarting the reverse osmosis purification system to produce drinking water again once the worn-out reverse osmosis filtration element is replaced by a new one.
In addition, before step (5), the monitoring process further comprises an automatic RO cleaning step of temporarily ceasing the supply of drinking water from the reverse osmosis filtration element by means of the power switching means which is activated by the microprocessor periodically, so as to backwash and clean the impurities clogged on the reverse osmosis filtration element of the reverse osmosis purification system.
In addition, in the monitoring step (2), the detector is a PPM detecting sensor and the monitoring of the reverse osmosis filtration element is operated by detecting a PPM condition value of the outlet water from the reverse osmosis filtration element and transmitting a detected signal to the reverse osmosis detecting circuitry.
In addition, in the monitoring step (2), the monitoring of the reverse osmosis filtration element is operated by two detectors which are two water pressure sensors installed in a water inlet and a water outlet of the reverse osmosis filtration element, respectively, for detecting a water pressure differential variation across the reverse osmosis filtration element.
In addition, in the monitoring step (2), the detector is a flow detecting sensor installed in a water outlet of the reverse osmosis filtration element, and the monitoring of the reverse osmosis filtration element is operated by detecting the reduction in outlet water flow amount from the reverse osmosis filtration element and transmitting the detected signal to the reverse osmosis detecting circuitry.
In addition, after the formatting step (3), the monitoring process further comprises an indicating step of notifing of an exact timing of replacing the reverse osmosis filtration element of the reverse osmosis purification system and indicating related information received from the microprocessor, such as the data of current time, the time when the replacement of each filtration element has taken place, the PPM value of the drinking water made, the current value of water making volume, the total value of water making volume, the mechanical breakdown condition, etc., which are all stored in the microprocessor.
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A monitoring device for a reverse osmosis purification system of drinking water comprising a microprocessor that controls the overall operations of the monitoring system, a LCD indicating circuit that relates information to maintenance personnel, a detecting means that analyses related data for determining the condition and extents of clogging of the reverse osmosis filtration elements, a warning means that produces verbal or musical sound for warning consumers about the clogged condition of the reverse osmosis filtration elements, and a power switching means that cuts off electricity supply to the water pump of the purification system. In operation, the reverse osmosis filtration elements will be clogged by impurities after being used for a period of time. If the reverse osmosis filtration elements are clogged, the monitoring device will make a sound to warn of such condition of the reverse osmosis filtration elements and will eventually cut off the power supply to the pump for stopping water delivery if the clogged reverse osmosis filtration elements are not replaced after a certain period of time.
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FIELD OF THE INVENTION
The present invention relates to concentrated liquid toilet bowl cleaning compositions.
BACKGROUND OF THE INVENTION
Compositions that automatically dispense cleaning agents and adjuvants into toilet bowls have been commercially available for many years. Numerous attempts have been made to add antimicrobial agents to these compositions. However, delivery of efficacious amounts of antimicrobial and other cleaning agents has been difficult.
It would be desirable to provide a liquid toilet bowl cleaning composition that efficiently delivers an efficacious amount of active ingredient to the bowl.
SUMMARY OF THE INVENTION
The present invention is directed to a concentrated liquid toilet bowl cleaning composition comprising an aqueous dispersion of particles of at least one halogen donating compound wherein said particles have a surface modifier adsorbed on the surface thereof in an amount sufficient to achieve a particle size of less than about 400 nanometers (nm). The compositions of the present invention can also contain other conventional ingredients in toilet bowl cleaning compositions such as surfactants, dyes, caustic, antisoiling agents, fragrances and other similar ingredients.
DETAILED DESCRIPTION OF THE INVENTION
The compositions of the present invention comprise halogen donating compounds containing nanoparticles.
A stable suspension of a halogen donating compound in nanoparticle form can deliver a consistent controlled dosage of active ingredients over the life of the product. Conventional suspensions would separate over time and reduce the product efficacy.
In the compositions of the present invention oxidizing species released by the halogen donating compound would not be available to destructively interact with other formulation ingredients. This would allow the incorporation of ingredients which normally are not compatible in liquid halogen bleach systems. For example, incorporation of a dye would be a valuable activity signal for the consumer.
Halogen donating compounds containing nanoparticles delivered to the toilet tank would dissolve more rapidly due to their small size and release sufficient quantities of halogen to sanitize the toilet bowl, with each flush, over approximately a thirty day period. Delivery of efficacious amounts of active to achieve sanitization has typically been an insurmountable hurdle for automatic toilet bowl cleaners due to the large volume of water than must be treated over time.
The quantity of available active halogen donating compound should fall within the range of 35 to 70 weight percent in the toilet bowl cleaner for effective efficacy.
Useful halogen donating compounds include halohydantoins such as 1,3-dichloro-5 5-dimethylhydantoin, 1,3-dichloro-5-ethyl-5-methylhydantoin and 1-bromo-3-3-chloro-5-5-dimethylhydantoin, calcium hypochlorite and similar compounds. Commercially available compositions containing these hydantoins include Dantochlor® RW and 8273 Dantoin® 8-2-5 available from LONZA, Inc., Fair Lawn, N.J.
The particles of this invention contain a discrete phase of a halogen donating compound as described above having a surface modifier adsorbed on the surface thereof. Useful surface modifiers are believed to include those which physically adhere to the surface of the halogen donating compound but do not chemically bond to the halogen donating compound.
Suitable surface modifiers can preferably be selected from known organic and inorganic excipients. Such excipients include various polymers, low molecular weight oligomers, natural products and surfactants. Preferred surface modifiers include nonionic and anionic surfactants. Representative examples of excipients include gelatin, casein, lecithin (phosphatides), gum acacia, cholesterol, tragacanth, stearic acid, benzalkonium chloride, calcium stearate, glyceryl monostearate, cetostearl alcohol, cetomacrogol emulsifying wax, sorbitan esters, polyoxyethylene alkyl ethers, e.g., macrogol ethers such as cetomacrogol 1000, polyoxyethylene castor oil derivatives, polyoxyethylene sorbitan fatty acid esters, e.g., the commercially available Tweens, polyethylene glycols, polyoxyethylene stearates, colloidol silicon dioxide, phosphates, sodium dodecylsulfate, carboxymethylcellulose calcium, carboxymethylcellulose sodium, methylcellulose hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethycellulose phthalate, noncrystalline cellulose, magnesium aluminum silicate, triethanolamine, polyvinyl alcohol, and polyvinylpyrrolidone (PVP). Most of these excipients are described in detail in the Handbook of Pharmaceutical Excipients, published jointly by the American Pharmaceutical Association and The Pharmaceutical Society of Great Britain, the Pharmaceutical Press, 1986, the disclosure of which is hereby incorporated by reference in its entirety. The surface modifiers are commercially available and/or can be prepared by techniques known in the art.
The surface modifier is adsorbed on the surface of the halogen donating compound in an amount sufficient to maintain an effective average particle size of less than about 400 nm. The surface modifier does not chemically react with the halogen donating compound or itself. Furthermore, the individually adsorbed molecules of the surface modifier are essentially free of intermolecular crosslinkages.
As used herein, particle size refers to a number average particle size as measured by conventional particle size measuring techniques well known to those skilled in the art, such as sedimentation field flow fractionation, photon correlation spectroscopy, or disk centrifugation. By "an effective average particle size of less than about 400 nm" it is meant that at least 90% of the particles have a weight average particle size of less than about 400 nm when measured by the above-noted techniques. In preferred embodiments of the invention, the effective average particle size is less than about 250 nm. In some embodiments of the invention, an effective average particle size of less than about 100 nm has been achieved. With reference to the effective average particle size, it is preferred that at least 95% and, more preferably, at least 99% of the particles have a particle size less than the effective average, e.g., 400 nm. In particularly preferred embodiments, essentially all of the particles have a size less than 400 nm. In some embodiments, essentially all of the particles have a size less than 250 nm.
The particles of this invention can be prepared in a method comprising the steps of dispersing a halogen donating compound in a liquid dispersion medium and applying mechanical means in the presence of grinding media to reduce the particle size of the halogen donating compound to an effective average particle size of less than about 400 nm. The particles can be reduced in size in the presence of a surface modifier. Alternatively, the particles can be contacted with a surface modifier after attrition.
These methods are described in detail in U.S. Pat. No. 5,145,684.
The relative amount of halogen donating compound and surface modifier can vary widely and the optimal amount of the surface modifier can depend, for example, upon the particular halogen donating compound and surface modifier selected, the critical micelle concentration of the surface modifier if it forms micelles, etc. The surface modifier preferably is present in an amount of about 0.1-10 mg per square meter surface area of the halogen donating compound. The surface modifier can be present in an amount of 0.1-99.995%, preferably 20-60% by weight based on the total weight of the formulation.
The nanoparticles of the present invention can be incorporated into conventional liquid toilet bowl cleaning compositions, as for example those disclosed in U.S. Pat. Nos. 3,897,357 and 3,970,596, the disclosure of which is incorporated herein. These compositions contain a wide variety of conventionally available anionic, nonionic, cationic and amphoteric surfactants, sulfonate salts, neutralizers, disinfectants, thickeners, antisoiling agents, fluorescent whitening agents, chelating agents and fragrances.
Representative surfactants include alkanolamides, alkylaryl sulfonates, amine oxides, betaines, block copolymers, ethoxylated alcohols, as for example Neodol 23-6.5 available from Shell Chemical Company, alkylphenol ethoxylates, ethoxylated fatty acids, fluorosurfactants, as for example Zonyl FSD available from Dupont, imidazolines and derivatives, quaternary amines, linear alkyl sulfonates, sulfosuccinates and alkyl polyglycosides. Representative disinfectants include alkyl dimethyl benzyl ammonium chloride and orthophenylphenol. Representative thickeners include fumed silica, methyl cellulose derivatives, clays, polyacrylic acid, xanthan gum as for example Kelzan S available from Kelco Division of Merck & Co., Inc., polysaccharides and magnesium aluminum silicate. A representative chelating agent is tetrasodium edta.
The compositions of the present invention can be illustrated by the following representative example.
______________________________________ Preferred Range Wt. % Wt. %______________________________________Example 1Water 31.7 20.0-40 0Surfactant 5.0 0.2-10.0Halohydantoin 60.0 35.0-75.0NanoparticlesAcid Blue #9 3.0 1.0-7.0Sodium Hydroxide 0.2 0-3.0Fragrance 0.1 0.05-0.5Example 2Water Q.S. to 100% 20.0-40.0Zonyl FSD 0.2 0.2-10.0Neodol 23-6.5 5.0 0.2-10.0Halohydantoin 60.0 35.0-75.0NanoparticlesAcid Blue #9 3.0 1.0-7.0Tetrasodium EDTA 3.0 0-6.0Fragrance 0.1 0.05-0.5Example 3Water Q.S. to 100% 20.0-40.0BTC 2125M 0.2 0.2-10.0Neodol 23-6.5 5.0 0.2-10.0Halohydantoin 60.0 35.0-75.0NanoparticlesAcid Blue #9 3.0 1.0-7.0Kelzan S 0.4 0-3.0Fragrance 0.1 0-0.5______________________________________
The foregoing specification, including the specific embodiments and examples is intended to be illustrative of the present invention and is not to be taken as limiting. Numerous other variations and modifications can be effected without departing from the true spirit and scope of the present invention.
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The present invention is directed to a liquid toilet bowl cleaning and sanitizing composition comprising an aqueous dispersion of particles of at least one halogen donating compound wherein said particles have a surface modifier absorbed on the surface thereof in an amount sufficient nanometers (nm). The compositions of the present invention can contain other conventional ingredients in toilet bowl cleaning compositions such as enzymes, surfactants, perfumes, dyes and other similar ingredients. In a preferred embodiment the composition contains:
0.2-10.0 Weight percent surfactant;
35.0-75.0 Weight percent halogen donating nanoparticles;
1.0-7.0 Weight percent dye;
0-3.0 Weight percent alkali;
0.05-0.5 Weight percent fragrance; and
20.0-40.0 Weight percent water.
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This application is a continuation of application Ser. No. 06/411,523, filed 8/25/82, now abandoned.
BACKGROUND OF THE INVENTION
Dessert pies typically have been baked, packaged and sold in frusto-conical pie plates having a side wall extending upwardly and outwardly from a round flat bottom. However, recently a substantial market has developed for dessert pies that are packaged and sold in single serving size wedge shaped slices. Each slice of dessert pie is packaged in a wedge shaped container having substantially the same configuration as the slice of pie packaged therein. Slices of pie packaged in this manner can be purchased by the consumer in any convenient quantity. Thus, the consumer purchases only as many slices of pie as are needed, thereby ensuring that there will be no excess to become stale or spoiled. As an alternative, the individual servings of dessert pies can be frozen either by the baker or by the consumer. The consumer then can purchase a larger number of servings of the dessert pie, which can be thawed out and consumed whenever convenient.
Several wedge shaped containers have been developed for the shipping and storage of individual slices of pie. Paper board containers adapted for this purpose include U.S. Pat. No. 2,220,110 issued to Layton; U.S. Pat. No. 2,701,091 issued to Buttery; U.S. Pat. No. 3,623,650 issued to Watts and U.S. Pat. No. 3,876,131 issued to Tolaas. Wedge shaped plastic containers adapted for the same purposes include U.S. Pat. No. 3,620,403 and U.S. Pat. No. 3,620,411 both of which issued to Rump.
The prior art containers described in the above cited references have been deficient in certain respects. Specifically, each of these prior art containers includes three side walls that are substantially perpendicular to the bottom surface of the container. The slices of pie stored in these prior art containers, however, include a rear edge that slants upwardly and outwardly away from the bottom surface of the pie. Thus, the containers referred to above do not closely conform to the configuration of the slices of pie stored in these prior art containers. As a result, the prior art containers cited above provide poor protection and support for fragile slices of pie.
A second deficiency of the above cited prior art containers is that all include top opening members which require the fragile slices of pie to be loaded and unloaded from the top of the container. This top opening feature has made it difficult for bakers to place the pie into the package and for consumers to remove the pie from the package. More particularly, bakers have found that automatic loading devices cannot reliably place the delicate servings of pie into the packages having top opening members. Attempts to minimize the possibility of damage to the slices of pie during packaging have resulted in low packaging rates. Larger containers facilitate insertion and removal of the pie somewhat, but provide poor support during shipping and storage. Similarly, to remove the slice of pie from one of these prior art containers, the consumer typically will grasp the rear crust of the pie and lift the rear of the pie up. This creates a bending moment on the delicate bottom crust, and thereby makes damage likely.
U.S. Pat. No. 2,583,915 issued to Whitley and U.S. Pat. No. 2,584,379 issued to Chmielewski both are directed to containers for individual wedge shaped slices of pie that conform more closely to the actual configuration of the pie. Specifically, both of these containers include a pair of trapezoidal side walls and a rear wall that slants upwardly and outwardly away from the bottom of the container. The Whitley reference, however, provides a rear wall that offers little support to the structure, and also requires top loading and unloading. The Chimiliski structure provides no top wall and therefore would offer even less structural support for the pie.
U.S. Pat. No. 3,142,430 issued to Meyers is directed to a wedge shaped container with a side opening panel. However, the Meyers container appears to be designed for one or more triangular sandwiches that typically would be formed by slicing a square sandwich along a diagonal. Consequently, all three side walls of the Meyers container are substantially perpendicular to the top and bottom walls. Thus, although the Meyers container avoids top loading, the three upstanding side walls of the Meyers container would provide poor structural support for a fragile slice of pie.
U.S. Pat. No. 4,313,542 which issued to Henry H. Roberts and Raymond A. Cote on Feb. 2, 1982, and which is assigned to the assignee of the subject invention is directed to a single serving pie carton and blank which provides very good structural support for a slice of pie. Specifically, the Roberts et al carton of U.S. Pat. No. 4,313,542 includes a pair of side walls and a rear wall extending between and connecting parallel top and bottom walls. The top wall of the carton of U.S. Pat. No. 4,313,542 is of a larger area than the bottom wall, and the side walls each are trapezoidal. As a result, the rear wall on the erected carton of U.S. Pat. No. 4,313,542 is slanted with respect to the top and bottom walls. Thus, the carton of U.S. Pat. No. 4,313,542 closely conforms to the configuration of the slice of pie stored therein. Additionally, the side and rear walls of the carton of U.S. Pat. No. 4,313,542 provide adequate protection and support for the slice of pie stored in the carton.
Despite the many advantages of the carton of U.S. Pat. No. 4,313,542, it is desired to provide an improved wedge shaped carton that provides the desirable structural support of the carton of U.S. Pat. No. 4,313,542, but that also can be loaded from the rear.
In view of the above, it is an object of the subject invention to provide an improved container and a blank for forming a container for a single slice of pie that enables easy loading and removal of the pie from the rear of the container.
It is another object of the subject invention to provide a container and a blank for forming a container for a single slice of pie that enables loading of the pie into the container at an acceptable rate by known packaging devices.
It is a further object of the subject invention to provide a container and a blank for forming a container for a single slice of pie that has a double side wall and a double slanted rear wall to provide the necessary support for the fragile pie during shipping and storage.
It is an additional object of the subject invention to provide a container for a single slice of pie that can be manufactured easily and inexpensively from a unitary paperboard blank.
SUMMARY OF THE INVENTION
The subject invention provides a rear opening wedge shaped carton for a single slice of pie. The wedge shaped carton includes top and bottom panels, which define a pair of similar isosceles triangles disposed in spaced parallel relationship to one another. The top and bottom panels each include a base edge and a pair of equal side edges which converge toward one another and meet at an apex. Preferably, the top and bottom panels are disposed with respect to one another such that a line extending through the respective apexes would be perpendicular to both the top and bottom panels. Although the angles defining the top and bottom panels are equal, the side and base edges of the top panel are longer respectively than the side and base edges of the bottom panel.
A pair of substantially identical trapezoidal side walls are hingedly attached to and extend between the top and bottom panel side edges. Each trapezoidal side wall is substantially perpendicular to both the top and bottom panels. As explained further below, one trapezoidal side wall is defined by substantially identical inner and outer side wall panels that are adhesively secured into face to face contacting relationship. More particularly, the inner panel is foldably connected to the bottom panel and extends upwardly therefrom, the outer panel is foldably connected to the top panel and extends downwardly therefrom. This double side wall contributes to the strength of the subject container thereby affording adequate protection to the slices of pie stored therein.
The opening members of the subject container include a pair of tabs that are foldably connected respectively to the side walls of the container, and a pair of substantially identical isosceles trapezoidal flaps that are foldably connected respectively to the base edges of the top and bottom panels. More particularly, the base edge of the top panel defines the longer parallel edge of the top flap, and the base edge of the bottom panel defines the shorter parallel edge of the bottom flap. The double rear wall not only enables easy rear loading and unloading of the pie from the subject container, but also contributes to the strength of the container thereby providing the necessary support for the fragile slices of pie stored in the container.
The wedge shaped container described above conforms closely to the size and configuration of the slice of pie stored therein. Specifically, the top wall of the container is larger than the bottom wall to reflect the fact that the top surface of the slice of pie is larger than the bottom surface. Additionally, the rear wall of the container as defined by the rear tabs and the top and bottom flaps is disposed at an angle to the top and bottom panels that corresponds to the angle of the crust of pie between the rear and bottom surfaces of the pie. Thus, the subject container will allow for very little movement of the pie within the container during shipping and storage and will ensure that the pie is uniformly supported on all sides.
The blank for forming the subject container includes a trapezoidal first side panel defined by a pair of parallel but unequal edges and a pair of non-parallel and unequal edges which extend between the parallel edges. The shorter of the top non-parallel edges is perpendicular to the two parallel edges, and will define the front edge of the carton erected from the subject blank.
An isosceles triangular top panel having a pair of equal side edges and a base edge is hingedly connected to the first side panel such that the longer of the two parallel side edges of the first side panel defines a side edge of the isosceles triangular top panel. Similarly, an isosceles triangular bottom panel having a pair of equal side edges and a base edge is hingedly connected to the first side panel such that the shorter of the two parallel edges of the first side panel defines a side edge of the isosceles triangular bottom panel.
A second side panel is foldably connected to the remaining side edge of the top panel. Similarly, a third side panel is foldably connected to the remaining side edge of the bottom panel. The second and third side panels each defines a trapezoid having a size and configuration substantially identical to the first side panel. The second and third side panels are folded into face to face contact to define a side wall of the container. To ensure that the second and third side panels will be in proper register on the erected carton, the second side panel has its longer parallel edge defining the hinged connection to the top panel, whereas the third side panel has its shorter parallel edge defining the hinged connection to the bottom panel.
A front tab is hingedly connected to the shorter of the two non-parallel edges of the first side panel. The fold line between the front tab and the first side panel will define the front edge of the carton erected from the subject blank. On the carton erected from the subject blank, the front tab will be adhesively connected to the third side panel thereby ensuring that the front edge of the subject carton is securely closed.
The subject blank further includes a pair of substantially identical isosceles trapezoidal flaps that are hingedly connected to the base edges of the top and bottom panels respectively. More particularly, the base edge of the top panel defines the longer of the two parallel edges of the trapezoidal flap connected to the top panel. Conversely, the base edge of the bottom panel defines the shorter of the two parallel edges of the trapezoidal flap connected to the bottom panel. A first tab is foldably connected to the longer of the two non-parallel edges of the first side panel, and a second tab is foldably connected to the longer of the two non-parallel edges of the third side panel. The first and second tabs and the pair of isosceles trapezoidal flaps define the rear opening members of the carton erected from the subject blank. The first and second tabs may assume any configuration which assures that the first and second tabs can be properly folded into the erected carton. In an alternate embodiment, however, the first and second tabs assume a locking tab configuration and cooperate with slits provided in one or both trapezoidal flaps.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 is the preferred embodiment of the blank of the subject invention.
FIG. 2 is a perspective view of the partially erected container formed from the blank of FIG. 1.
FIG. 3 is a perspective view of the completely erected container formed from the blank shown in FIG. 1.
FIG. 4 is a portion of an alternate embodiment of the blank of the subject invention.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
The rear opening pie container of the subject invention is erected from a paperboard blank 10 as shown in FIG. 1. Blank 10 includes a trapezoidal first side panel 12 which is defined by a pair of parallel edges 14 and 16 and a pair of non-parallel edges 18 and 20. Edge 18 of first side panel 12 is the shorter of the two non parallel edges, and is perpendicular to the parallel edges 14 and 16 of first side panel 12. Edge 14 is the longer of the two parallel edges of side panel 12, and will define a top side edge of a carton erected from the subject blank.
An isosceles triangular top panel 22 is foldably connected to the first side panel 12 along the longer parallel edge 14 thereof. The top panel 22 is further defined by edge 24, which is equal in length to edge 14, and by base edge 26 which defines the base of the isosceles triangular top panel 22. Edge 24 extends from the intersection of edges 14 and 18 of first side panel 12, such that the intersection of edges 14 and 24 defines the apex of the isosceles triangular top panel 22 from which the equal edges 14 and 24 extend. Top panel 22 will define the top of the container erected from the subject blank 10. Therefore, top panel 22 will substantially conform in size and configuration to the top surface of the slice of pie packaged in the subject container.
Bottom panel 28 is foldably connected to the first side panel 12 along the shorter parallel edge 16 thereof. The bottom panel 28 also is an isosceles triangle, and is further defined by edge 30 which is equal to edge 16. Base edge 32 of bottom panel 28 extends between the non-intersecting ends of the equal edges 16 and 30, and thus defines the base of the isosceles triangular bottom panel 28.
The angle "a" formed by the intersection of the equal edges 14 and 24 of top panel 20 substantially equals the angle "a" formed by the intersection of the equal edges 16 and 30 of the bottom panel 28. It follows that the angles "b" formed by the intersection of the base edge 26 with the equal edges 24 and 14 of top panel 22 will substantially equal the angles "b" formed by the intersection of base edge 32 with equal edges 16 and 30 of bottom panel 28. Thus, top and bottom panels 22 and 28 define similar isosceles triangles. However, top panel 22 is larger than bottom panel 28.
The magnitude of angle "a" will vary according to the relative size of the slice of pie to be packaged in the carton to be erected from blank 10. Since the pie will almost always be cut into four or more pieces, the angle "a" will almost always be less than or equal to 90°. If the pie is cut into six equal slices, the angle "a" will equal 60°, and the top and bottom panels 22 and 28 will define equilateral isosceles triangles.
A second side panel 34 is foldably connected to top panel 22 along edge 24 thereof. Second side panel 34 is identical in size and configuration to first side panel 12. Thus, second side panel 34 includes edge 36 which is parallel to edge 24 and equal in length to edge 16 of first side panel 12. The non-parallel sides of trapezoidal side panel 34 are defined by edges 38 and 40, which correspond in length to edges 18 and 20 respectively of first side panel 12. Additionally, edge 38 of second side panel 34 is substantially perpendicular to both edges 24 and 36 thereof.
A third trapezoidal side panel 42 is foldably connected to bottom panel 28 along edge 30, and is identical in size and configuration to the first and second side panels 12 and 34. The trapezoidal third side panel 42 is further defined by edge 44 which is parallel to edge 30 and by edges 46 and 48. Edge 30 is substantially equal in length to edges 16 and 36 of the first and second side panels 12 and 34. Edge 44 of third side panel 42 is longer than edge 30, and is substantially equal in length to edges 14 and 24 of the first and second side panels 12 and 34. Edges 46 and 48 of third side panel 42 are substantially equal in length to the corresponding edges of the first and second side panels 12 and 34. Also, edge 46 extends from the intersection of edges 16 and 30 substantially perpendicular to edge 30.
Because of the equivalent shapes of first, second and third side panels 12, 34 and 42, the angles "c" shown in FIG. 1 will all be equal. Similarly, the angles "d" will all be equal. The relative magnitudes of angles "c" and "d" will vary according to the relative differences in size between top and bottom panels 22 and 28. The sizes of top and bottom panels 22 and 28, in turn, depends upon the configuration of the slice of pie packaged within the container erected from the blank 10. However, the angle "c" will always be less than 90°, and the angle "d" will always be greater than 90°.
An isosceles trapezoidal top rear flap 50 is foldably connected to top panel 22 along base edge 26 thereof. Base edge 26 is the longer of the two parallel side edges of isosceles trapezoidal top rear flap 50. Edges 52 and 54 converge towards one another from the opposed ends of edge 26. The remaining side of the trapezoidal top rear flap 50 is defined by edge 56 which is parallel to but shorter than edge 26. On the erected carton, as explained further below, top rear flap 50 will be rotated about edge 26 during the opening or closing of the container erected from blank 10.
The bottom rear flap 58 is substantially identical in size and configuration to top rear flap 50, and is foldably connected to the bottom panel 28 along base edge 32 thereof. Edges 60 and 62 of bottom rear flap 58 diverge away from each other as they extend from edge 32. The bottom rear flap 58 is further defined by edge 64 which is parallel to but longer than edge 32. Edge 64 of bottom rear flap 58 is substantially equal in length to edge 26 of top rear flap 50. Similarly, edge 32 of bottom rear flap 58 is substantially equal in length to edge 56 of top rear flap 50. Bottom rear flap 58 can be rotated about edge 32 during the opening and closing of the container erected from the blank 10 shown in FIG. 1.
Rear tabs 66 and 68 also will define a portion of the opening members of the carton erected from the blank in FIG. 1. Specifically, rear tab 66 is foldably connected to the first side panel 12 along edge 20 thereof. Similarly, rear tab 68 is foldably connected to the third side panel 42 along edge 48 thereof. Front tab 70 is foldably connected to edge 18 of first side panel 12, and as explained further herein, front tab 70 functions to securely close the front portion of the container erected from blank 10.
To erect the subject container from the blank 10 shown in FIG. 1, the top and bottom panels 22 and 28 are rotated toward one another about edges 14 and 16 until top and bottom panels 22 and 28 are substantially parallel to one another and perpendicular to the first side panel 12. The first side panel 12 thus defines one of the two identical side walls of the carton erected from blank 10. The second side wall of the subject carton is formed by rotating front tab 70 about edge 18 of first side panel 12 until the angle separating front tab 70 from the first side panel 12 is approximately equal to angle "a". The remainder of the second side wall of the container erected from blank 10 is formed by first rotating the third side panel 42 about edge 30 until it is perpendicular to bottom panel 28, and then rotating the second side panel 34 about edge 24 until it is perpendicular to the top panel 22. In this position, the second and third side panels will be in face to face abutting relationship and the front tab 70 will be in face to face contact with the surface of third side panel 42 opposite second side panel 34. The front tab 70 and the second and third side panels 34 and 42 are adhesively secured in these relative positions to define the second side wall of the container 72 as shown in FIG. 2. The relationship of the second and third side panels 34 and 42 in the second side wall of container 72 helps to ensure that container 72 will have adequate strength to protect the fragile slices of pie stored therein.
As illustrated most clearly in FIG. 2, the subject container 72 has rear opening members defined by top and bottom rear flaps 50 and 58 and rear tabs 66 and 68. This opening in container 72 enables the slidable insertion of the slice of pie the rear of container 72 by mechanized packing equipment without a substantial likelihood of damaging the pie. The pie also may be easily removed from the subject container 72 with considerable ease and with little likelihood of damaging the pie.
The subject container 72 is closed by first rotating the rear tabs 66 and 68 about rear side edges 20 and 48 respectively, until the rear tabs 66 and 68 are substantially in the plane defined by top and bottom base edges 26 and 32. Bottom rear flap 58 then is rotated upwardly about base edge 32 until it lies in face to face contact with the rear tabs 66 and 68. Finally, the top rear flap 50 is rotated downwardly about base edge 26 until it is in abutting face to face relationship with the bottom rear flap 58. The rear tabs 66 and 68 and the bottom and top rear flaps 58 and 50 are secured in this closed position, as shown most clearly in FIG. 3, by any known means, such as adhesive. Once secured in this closed position, as shown in FIG. 3, the rear of the subject container 72 is supported by both top and bottom rear flaps 50 and 58 thereby contributing to the protection of the delicate crust on the pie stored therein.
As is apparent from FIG. 3, the subject container 72 is of virtually the same size and shape as the pie slice inserted therein, thereby prohibiting any significant movement of the pie during shipping and storage. Specifically, the side panels 12, 34, and 42 have a trapezoidal configuration that very closely conforms to the configuration of each side edge of the slice of pie. Additionally, the top and bottom rear flaps 50 and 58, which define the rear edge of the container 72 slope upwardly and away from the bottom panel 20 at an angle that substantially conforms to the angle of the crust extending between the top and bottom surfaces of the slice of pie. These various angular relationships between the panels of the subject container 72, when combined with the side wall constructed from the second and third side panels 34 and 42, and the rear wall formed by the top and bottom rear flaps 50 and 58 provides adequate protection for the delicate slice of pie.
FIG. 4 shows a portion of an alternate embodiment for blank 10 of the subject invention. Briefly, on the alternate embodiment of blank 10, shown in FIG. 4, rear locking tabs 76 and 78 are provided in place of the rear tabs 66 and 68 which were part of the embodiment illustrated in FIG. 1. The rear locking tab 76 is hingedly connected to the first side panel 12 along edge 20 thereof as illustrated in FIG. 4. Similarly, the rear locking tab 78 is hingedly connected to the third side panel 42 along edge 48 thereof. The rear locking tabs 76 and 78 are provided with locking hook members 80 and 82.
The bottom rear flap 84, shown in FIG. 4, is hingedly connected to the bottom panel 28 along the base edge 32. Bottom rear flap 84 differs from the bottom rear flap 58 shown in FIG. 1, in that a pair of locking slots 86 and 88 are provided on bottom rear flap 84. Locking slots 86 and 88 are die-cut into bottom rear flap 84 and are located thereon so as to accept the locking hooks 80 and 82 of the rear locking tabs 76 and 78 respectively.
The alternate blank 10 shown in FIG. 4 is erected into its open position as depicted in FIG. 2 in the same manner as explained above. However, the blank 10 shown in FIG. 4 is closed into the position shown in FIG. 3 by engaging the locking hooks 80 and 82 into the slots 86 and 88 on bottom rear flap 84. More particularly, the container erected from the blank 10 shown in FIG. 4 is closed by first rotating bottom rear flap 84 about base edge 32 until bottom rear flap 84 lies in the plane defined by base edges 26 and 32 of the top and bottom panels 22 and 25 respectively. The rear locking tabs 76 and 78 are folded into face to face relationship with bottom rear flap 84 such that locking hooks 80 and 82 are inserted into and engaged by slots 86 and 88. Top rear flap 50 then is rotated about base edge 26 into face to face relationship with first and second rear locking tabs 76 and 78 and bottom rear flap 84. Top rear flap 50 then is secured in this position by any known means, such as adhesive. As explained above, the container erected in this manner assumes a configuration substantially identical to the size and shape of the slice of pie inserted therein, and thus provides protection during shipping and storage.
In summary, there is provided a paperboard container for individual servings of pie and a blank for forming the same. The subject container is substantially wedge shaped and dimensioned to approximately the same size as the slice of pie therein. The container includes substantially parallel top and bottom panels having an isosceles triangular configuration. The top panel is larger than the bottom panel to reflect the frusto-conical shape of the pie. The side wall panels of the subject container are substantially trapezoidal in configuration with the rear side edges of each side panel extending upwardly and away from the bottom panel toward the top panel. Thus, the subject container provides the necessary support for the fragile piece of pie stored therein. The opening of the subject container is disposed at the rear portion thereof. This rear opening configuration makes the subject container particularly well adapted for automated packaging devices, and substantially minimizes the risk of damage to the pie during packaging. The rear opening configuration also facilitates the removal of a piece of pie from the subject container by the consumer further minimizing any damage to the pie prior to its consumption.
While the preferred embodiments of the subject invention have been described and illustrated, it is obvious that various changes and modifications can be made therein without departing from the spirit of the present invention which should be limited only by the scope of the claims.
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A carton and blank for forming a carton are provided for a single serving of dessert pie. The carton formed from the blank is substantially wedge shaped and includes top and bottom panels disposed in parallel relationship. The top and bottom panels define similar isosceles triangles, but the top panel is larger than the bottom panel thereby reflecting the actual configuration of the pie packaged therein. The subject carton formed from the blank includes a plurality of rear opening flaps providing access to the container from the rear. Additionally, the carton, has a double side wall and a double slanted rear wall to protect the fragile slice of pie.
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SUMMARY OF THE INVENTION
This invention relates to a case for jewellery and/or valuable gemstones.
According to the present invention there is provided a case for jewels and/or gemstones comprising a bottom case portion, an upper case portion, a holder surrounding the peripheries of the case portions for holding the case portions together and locking means for locking the holder in its operative condition, said upper case portion being provided internally with plates for supporting jewels and/or gemstones.
BRIEF DESCRIPTION OF THE DRAWINGS
To the accomplishment of the foregoing and related ends, the invention then comprises the features hereinafter fully described and particularly pointed out in the claims, the following description and annexed drawings setting forth in detail an illustrative embodiment of the invention, this being indicative however of only one in which the principle of the invention may be employed.
In said annexed drawings:
FIG. 1 is a plan view of a case according to the present invention,
FIG. 2 is a side view taken in the direction of arrow 2 of FIG. 1,
FIG. 3 is a bottom view of the case,
FIG. 4 is a side view taken in the direction of arrow 4 of FIG. 1,
FIG. 5 is a section taken along the line 5--5 of FIG. 1,
FIG. 6 is a section taken along the line 6--6 of FIG. 5,
FIG. 7 is a section taken along the line 7--7 of FIG. 5,
FIG. 8 is a section taken along the line 8--8 of FIG. 5,
FIG. 9 is a section taken along the line 9--9 of FIG. 5,
FIG. 10 is a section taken along the line 10--10 of FIG. 5, and
FIG. 11 is a section taken along the line 11--11 of FIG. 5.
DESCRIPTION OF THE PREFERRED EMBODIMENTS
The case comprises a bottom case portion 10 which is circular in plan view, an upper case portion 11 which is also circular in plan view, and a holder 12 in the form of a band which extends around the peripheries of the case portions 10 and 11.
The holder 12 is formed of a non-transparent non-magnetic hard material, such as a metal. It is substantially circular in plan view and has ends 13 which extend radially outwardly forming a pair of flanges 14. In transverse cross-section the body of the holder 12 is part circular. The flanges 14 are each provided with holes 15 and 16. The holes 15 are for the provision of a locking device 17 and the holes 16 enable the case to be linked, or hooked to another object. The external surface of the holder 12 can be engraved with a decorative pattern. When the locking device 17 is unlocked the holder 12 can be expanded by moving the flanges 14 apart so as to allow the case portions 10 and 11 to be removed from or reinserted into the holder 12. In the region of the flanges 14 the holder 12 is provided with a curved recess 18 which receives locating portions 19 provided on case portions 10 and 11.
The upper case portion 11 is formed of a transparent material so that the contents of the case can be viewed. It has a domed portion 20 which forms a magnifying lens to enlarge the main displayed object 21. The periphery of the case portion 11 is part circular in section enabling it to seat in the holder 12. The case portion 11 has an annular downwardly extending flange 22 which is provided on its outer periphery with a portion 23 which engages in a recess 24 provided on the bottom case portion 10 so that the upper case portion 11 cannot be rotated relative to the bottom case portion 10. The upper case portion 11 is stepped internally to provide support for a top transparent support plate 25 and a non-magnetic metal support plate 26 which is retained by a stainless-steel wire spring clip 27 which engages in a groove. The upper case portion 11 also has an annular face 28 against which the bottom case portion 10 seats.
The bottom case portion 10 is formed of transparent material and internally is stepped and provided with a face 29 opposed to the face 28. The face 28 is provided with a groove 30 which receives a seal or sealant material so that an air and moisture and waterproof seal is provided. After the casing portions 10 and 11 have been brought together and sealed a hole or holes 31 are drilled in the peripheral portions at a location or locations where they will be covered by the holder 12 and a magnetic pin 32 is inserted in the or each hole 31. the location angle of inclination and size of the or each hole 31 will be different for each case produced and the location, angle, size and number of holes 31, and thus pins 32, will be recorded for future identification and be given a confidential serial number for security purposes. This will enable each case to be given a security identification. The bottom case portion 11 suppors a bottom transparent plate 33 and a non-magnetic steel bottom plate 34. the bottom transparent plate 33 defines with the bottom case portion 10 a sealed space 35.
The main displayed object 21 is located below the domed portion 20 and is supported by the support plate 26 and located between the support plate 26 and the plate 25. The support plate 26 is held in position by the wire spring clip 27 and provided on the underside of the support plate 26 is a layer of foamed material 36. The support plate 26 is thus upwardly biased by the foam material 36 and urges the object 21 into contact with the plate 25 so that the object 21 is held in a stable position. A description of the object 21 is provided on the underside of the bottom plate 34. Further displayed objects 37 are provided in holders 38 provided on the upper side of plate 25. The holders 38 may be fixed or they may be allowed to move freely on the plate 25. A description of the objects 37 can be provided on the underside of the bottom plate 34.
Provided between the layer of foamed material 36 and the plate 34 is a micro-film 39 of a certificate which the owner will have giving the contents, ownership details etc.
Within the space 35 are objects 40 of any desired shape or form which are movable within the space 35 and which provide a decorative appearance to the case.
The locking device 17 consists of a core or insert 41 formed of a soft metal or other suitable material which can be easily deformed. The core 41 is located within a button member 42 and extends through a stem portion 43 having a flared end 44. Mounted on the stem portion 43 is a stem portion 45 of a second button member 46. Initially the core 41, button member 42 and button member 46 are separate parts. When the flanges 14 have been brought together after the casing portions 10 and 11 have been assembled and inserted into the open holder 12, the stem 45 of button member 46 is inserted into the aligned holes 15 and the core or insert 41 inserted into the stem portion 43 and the stem 43 pushed into the stem 45. Opposed forces are then applied to the button members 42, 46, i.e. by a punch, to change the shape of the button members. Both ends of the core or insert 41 are deformed and prevent separation of the button members.
Removal of the holder 12 can only then be achieved by breaking and destroying the locking device 17, which cannot be re-used.
The plates 26 and 34 each have at their periphery a locating projection 47 which engages in a recess 48 in the respective casing portion.
The plate 33 is sealed to the bottom casing portion 10.
The items 21, 37 may be gemstones or valuable jewellery items.
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A case for jewels and/or gemstones comprises a bottom case portion, an upper case portion and a holder for holding the case portions together, the holder being provided with a locking device. The case portion is provided with support plates for holding the jewels and/or gemstones and one plate is urged towards the other plate by a layer of resilient foam material and held by a wire spring.
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BACKGROUND OF THE INVENTION
The present invention relates to an apparatus for controlling an elevator and, more particularly, to an apparatus having a microcomputer for controlling an elevator.
FIG. 1 is a diagram showing the schematic construction of an apparatus including a microcomputer for controlling the operation of an elevator as it is moved between a plurality of floors. In FIG. 1, reference numeral 1 denotes a cage of an elevator, numeral 2 a balance weight, and numeral 3 a cable engaged on a sheave 4. The cage 1 and the weight 2 are connected to both ends of the cable 3. Reference numeral 5 denotes an electric motor for driving the sheave 4, numeral 6 a pulse generator for generating a pulse proportional to the moving distance of the cage 1 by the rotation of the motor 5, and numeral 7 a counter circuit for counting the number of pulses generated from the pulse generator 6. A microcomputer 8 which includes, as shown in FIG. 3, a CPU 8a, a ROM 8b, a RAM 8c, an input port 8d, and an output port 8e, receives a signal from the counter circuit 7 at the input port 8d and generates an output signal at the output port 8e. Reference numeral 9 denotes a floor, numeral 10 plates provided in a hoistway corresponding to the floors, and numerals 11 and 12 position detectors provided in the cage 1 for producing output signals 11a and 12a when the cage 1 reaches a position about 10 mm lower and about 10 mm higher than the level of each floor, respectively. These output signals 11a and 12a are then sent to the counter circuit 7 and the microcomputer 8.
FIG. 2 shows a diagram iof the detailed arrangement of the counter circuit 7 illustrated in FIG. 1. As shown, the counter circuit 7 includes a pair of 4-bit binary counters CT1 and CT2. An output pulse 6a from the pulse generator 6 is applied directly to a terminal T of the counter CT1 and to a terminal T of the counter CT2 through a NAND gate NAND1 and a NOT gate NOT1 to count running pulses of the cage 1 during the calculating period of the microcomputer 8 and to store the counted pulses to be delivered to the CPU 8a through the input port 8d in the next inputting process. The counter circuit 7 further includes a pair of R-S flip-flops (hereinafter referred to as "flip-flops") FF1 and FF2 having the set terminals S connected to the outputs of NAND gates NAND2 and NAND3, respectively. An up signal UP generated from the microcomputer 8, an output signal 11a from the position detector 11, and a signal produced by passing the output signal 11a through a NOT gate NOT2 and a time constant circuit of a resistor R1 and a capacitor C1 are all applied to the input of the NAND gate NAND 2. A down signal DN generated from the microcomputer 8, an output signal 12a from the position detector 12, and a signal produced by passing the output signal 12a through a NOT gate NOT3 and a time constant circuit of a resistor R2 and a capacitor C2 are applied to the input of the NAND gate NAND3. Further, the outputs Q of the flip-flops FF1 and FF2 are connected to the inputs of an OR gate OR1, and the output signal of the OR gate OR1 is applied to the other input of the NAND gate NAND1. Thus, the counter CT2 stops the counting operation at every rising time of the output signal of the position detector 11 or 12. A reset signal RESET generated from the microcomputer 8 is applied to the counters CT1 and CT2 and the reset terminals R of the flip-flops FF1 and FF2.
FIG. 4 shows the storage memory address of the RAM 8c of the microcomputer 8 which stores the level position data representing the levels of N respective floors in a building wherein FLH(0) denotes the level of the lowermost floor, and FLH(N-1) denotes the level of the uppermost floor.
The operation of the above-described apparatus for controlling the elevator will now be explained.
First, the writing operation of the floor numbers of respective floors in the RAM 8c will be described with reference to the flow chart of FIG. 5.
(a) The microcomputer 8 is first initialized, and the cage 1 is stopped at the lowermost floor. The level corresponding to the lowermost floor is, for example, determined to have a reference value L, and this is written in the address "0" of the RAM 8c as FLH(0). At this time, the present position FSY of the cage has a value L 0 .
(b) Then, the cage 1 is run upward, and the pulse generated from the pulse generator 6 is counter by the counters CT1, CT2 to measure the running distance of the cage. As shown in FIG. 5, upon the start of the writing and calculating program of the microcomputer 8, the counted values DP1 and DP2 of the counters CT1 and CT2 are input to the microcomputer 8 in step 100, and the reset signal RESET is delivered from the microcomputer 8 in the next step 101 to reset the counters CT1 and CT2 and the flip-flops FF1 and FF2. When the resetting operation is finished, the next step 102 determines whether the cage 1 is running upward, and, upon a "NO", the writing and calculating program is terminated. The next step 103 determines whether the output signal 11a of the position detector 11 increases, and, upon a "NO", the program advances directly to step 106 wherein the counted value DP1 of the counter CT1 is accumulated by the microcomputer 8 according to process FSY-FSY+DP1. The FSY is the present position of the cage 1, and the processes in the steps 100 to 103 and 106 are continuously executed during the running of the cage at every calculating period of the microcomputer 8.
(c) When the cage 1 goes up and arrives at the level of the next floor, the output signal 11a of the position detector 11 is detected by the microcomputer 8. This, in turn, provides a "YES" result in step 103. Then, the program advances to step 104, and the process of I+1 is executed so that a new floor number is written in the RAM 8c. The program proceeds to step 105, and the counted value DP2 of the counter CT2 is added to the present position FSY to provide the floor number calculated value FLH(I) to be written in the corresponding address I of the RAM 8c.
Similarly, the writing and calculations from step 100 to step 106 are repeated for subsequent floors up to the uppermost floor, and, in this particularr case, floor numbers FLH(0) to FLH(N-1) corresponding to the levels of N respective floors are written in the RAM 8c, as shown in FIG. 4.
The floor numbers obtained in this manner are utilized for the ordinary operation of the elevator. In other words, the floor numbers stored in the RAM 8c are used for the correction of the present position of the cage, the running distance of the cage from the departing floor to the destination floor, the remaining distance to the destination floor, and the reference speed command corresponding to the remaining distance.
However, the conventional writing and calculation program for the floor numbers as described above produces the following disadvantages.
(a) When a cage is displaced from a level at a floor, the present position of the cage at other floors cannot be corrected.
(b) Even if a certain door zone (the zone for opening or closing the door) is provided to accommodate the displacement of the cage when the elevator is first started, the level of the respective floors cannot be accurately corrected due to the wear of the sheave resulting from its extensive use in a prolonged period of time. In other words, even when a length LDZ of the door zone (stored in advance as a fixed value in the ROM) is taken into account in the determination of the present position of the cage, that is, the present position FSY satisfies the equation
FSY-FLH(I)+LDZ/2,
where I denotes the starting floor, accurate correction cannot be performed since this length is a fixed value and not related to or affected by wear of the sheave.
(c) The level of the floor of the building is not accurately stored in memory. In other words, the position detector does not accurately detect the position of 10 mm above the floor. Thus, there is a difference of 10 mm in the value of floor number FLH(I). Therefore, even if the calculation of FLH(I)-FSY (present position) is, for example, executed so as to obtain the remaining distance, a displacement of 10 mm occurs, thereby lowering the stopping accuracy of the cage.
SUMMARY OF THE INVENTION
An object of the present invention is to eliminate the above-described drawbacks, and its main object is to provide an elevator control apparatus which can accurately store and correct level data of respective floors for producing the present position of an elevator cage, the remaining distance of the cage to a destination floor, and the reference speed command of the cage even if the cage operates from an out-of-level starting position.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 is a diagram showing the entire construction of a conventional apparatus for controlling an elevator;
FIG. 2 is a diagram showing the detail of the counter circuit of the conventional apparatus for controlling the elevator;
FIG. 3 is a schematic diagram showing the construction of a microcomputer in FIG. 1;
FIG. 4 is an explanatory view of a RAM for storing the level position data of the conventional apparatus;
FIG. 5 is a diagram showing a flow chart for writing the level position data in the conventional RAM;
FIG. 6 is a diagram showing the construction of a counter circuit in an apparatus for controlling an elevator according to a first embodiment of the present invention;
FIGS. 7(a) to 7(c) are explanatory views of the RAM in the apparatus of the present invention;
FIG. 8 is a diagram of a flow chart for writing the level position data in the RAM of the apparatus of the invention;
FIG. 9 is a flow chart showing the program used for an apparatus for controlling an elevator according to a second embodiment of the present invention;
FIG. 10 is a flow chart showing the detail of a correcting amount calculating subroutine of FIG. 9; and
FIG. 11 is a flow chart showing the program used for an apparatus for controlling an elevator according to a third embodiment of the present invention.
DESCRIPTION OF THE PREFERRED EMBODIMENT
An embodiment of the invention will be described below in conjunction with the accompanying drawings.
FIG. 6 shows an example of a counter circuit in an apparatus for controlling an elevator according to the present invention wherein the same reference numerals as those in FIG. 2 designate the same or equivalent elements. The description of the same elements will be omitted, and the portion different from that in FIG. 2 will be described in detail.
More particularly, the primary difference from FIG. 2 is that the logic sum of the output signals 11a and 12a of the position detectors 11 and 12 is taken and the counter CT2 stops counting when a signal representing the logic sum changes.
To this end, in this embodiment, a NOR gate NOR1 for producing the logic sum of the output signals 11a and 12a of the positions detectors 11 and 12 in FIG. 1 is provided, the output signal of the NOR gate NOR1 is applied to one input of a NAND gate NAND2 through a NOT gate NOT3, and a signal obtained from the NOT gate NOT3 is passed through a NOT gate NOT2 and a time constant circuit of a resistor R1 and a capacitor C1 is applied to the other input of the NAND gate NAND2. A signal obtained through the NOT gate NOT3 or the NOT gate NOT2 and the time constant circuit is applied to the two inputs of the NAND gate NAND3 through NOT gates NOT4 and NOT5. Thus, when the flip-flops FF1 and FF2 are set by the outputs of the NAND gates NAND2 and NAND3, the counting stop is applied to the counter CT2.
When the counted value obtained from the counter circuit 7 of the arrangement described above is inputted to the microcomputer and calculated as shown in FIG. 8, the level values of the respective floors can be accurately provided.
More specifically, the position detectors 11 and 12 are provided to detect the positions (e.g., 10 mm below the floor) spaced from the level of the floor, but the actual operating point is continued to be changed, from example, from 10 mm below the floor to 300 mm above the floor. Therefore, the present invention is operated to determine the level value FLHD(I) considered at a position 300 mm below the floor and the level value FLHU(I) considered at a position 300 mm above the floor and to write the level values in the RAM 8c of the microcomputer 8 and then calculate (FLHD(I)+FLHU(I))/2 on the basis of these level values, thereby obtaining the actual level values of the respective floors and storing them in the RAM 8c for the correction of the selector and the calculation of the remaining distance.
The writing operation of the level data of the respective floors in the embodiment described above according to the present invention will be described on the basis of the flow chart of FIG. 8.
Before the description of the operation, FIG. 7 will be described. FIG. 7(a) shows the storage memory addresses of the RAM 8c representing the addresses 0 to N-1 as FLHD(0) to FLHD(N-1) of the lowermost to the uppermost floor for positions located a predetermined distance of 300 mm below the corresponding N floor levels, FIG. 7(b) shows the storage memory addresses of the RAM 8c showing the addresses 0 to N-1 as FLHU(0) to FLHU(N-1) of the lowermost to the uppermost floors for positions located a predetermined distance of 300 mm above the corresponding N floor levels, and FIG. 7(c) shows the storage memory addresses of the RAM 8c of the addresses 0 to N-1 as FLHL(0) to FLHL(N-1) of the actual floor level values of the corresponding N floors obtained by taking the average of the values stored in FIGS. 7(a) and 7(b).
When cage 1 is at the lowermost floor, the corresponding actual level value is obtained by (FLHD(0)+FLHU(0))/2, and the result is stored in the address 0 of the RAM 8c as FLHL(0), as shown in FIG. 7(c).
When the cage 1 runs upward, the pulses generated from the pulse generator 6 are counted by the counters CT1 and CT2 to measure the running distance of the cage. As shown in FIG. 8, upon the start of the writing and calculating program of the microcomputer 8, the counted values DP1 and DP2 of the counters CT1 and CT2 are input to the microcomputer 8 in step 200 and the reset signal RESET is fed from the microcomputer 8 in the next step 201 to reset the counters CT1 and CT2 and the flip-flops FF1 and FF2. When the resetting operation is finished, the next step 202 determines whether the cage 1 is running upward. In case of a "NO" result, the writing and calculating program is terminated. In case of a "YES", the program advances to step 203 to determine whether the output signal 12a of the position detector 12 increases. In case of a "YES" in step 203, the program advances to step 204 and provides I+1 as a new floor number to be written in the RAM 8c. This corresponds to a position 300 mm below the floor level and is determined by FLHD(I)←FSY+DP2 in the next step 205.
More particularly, the counted value DP2 of the counter CT2 is added to the present position FSY of the cage, determined by accumulating the counted value DP1 of the counter CT1 input at every calculating period of the microcomputer 8 and the running distance of the cage obtained prior to the counted value DP1 of the counter CT1. The result of the addition (FLHD(I)) is written in the address of the RAM 8c corresponding to the Ith floor. As the cage 1 runs further upward, the present floor position FSY←FSY+DP1 is updated in step 206 with the counted value DP1 of the counter CT1 being accumulated and input to the microcomputer 8 at every calculating period of the microcomputer 8.
On the other hand, in case of a "NO" result in step 203, the program advances to step 207 to determine whether the output signal 11a of the position detector 11 decreases. In case of a "NO", the program advances to step 206 to determine the present position of the cage. Otherwise, the program continues in step 208 to determine the floor position FLHU(I)←FSY+DP2 in relation to a position 300 mm above the floor level of the Ith floor.
More particularly, the counted value DP2 of the counter CT2 is added to the present position value FSY of the cage determined by accumulating the counted value DP1 of the counter CT1 input at every calculating period of the microcomputer 8. The result of the addition (FLHU(I)) is written in the address of the RAM 8c corresponding to the Ith floor.
The program then advances to step 209 to determine the actual level value of the Ith floor according to an average FLHL(I)←(FLHD(I)+FLHU(I))/2. In other words, the average value of the position values for positions 300 mm above and below a floor is obtained and stored in the corresponding address of the RAM 8c as the accurate actual level value for that floor.
Similarly, the writing and calculations from steps 200 and 209 are repeated for subsequent floors up to the uppermost floor so that all actual level values of respective floors of the building are determined and stored in the RAM 8c, as shown in FIG. 7(c).
In the apparatus described above, even if the cage is displaced from the actual floor level position, the position of the cage can be accurately corrected. In other words, the operating point of the position detector is, for example, 300 mm above or below the floor by the plate 10, and is longer than the door zone. Therefore, when the position detector passes the plate 10, such as when the cage, for example, runs upward from the Ith floor, the decrease of the output signal 11a of the position detector 11 is detected by the microcomputer 8 to calculate FSY←FLHU(I)+DP2. When the cage passes the Ith floor, the decrease of the output signal 12a of the position detector 12 is detected to calculate FSY←FSHD(I+1)+DP2, and the decrease of the output signal 11a of the position detector 11 is detected to calculate FSY←FSHU(I+1)+DP2, thereby correcting the position of the cage.
Furthermore, while the apparatus of the present invention detects the running position of the cage along a hoistway path formed of the cage 1, the cable 3, the sheave 4, the motor 5, and the pulse generator 6, the values FLHD(I), FLHU(I), and FLHL(I) stored in the RAM 8c are continuously updated and corrected in relative terms and hence unaffected by changes, such as the length of the cable 3 or the wear of the sheave due to extended use or heavy load. In other words, the distance per one pulse may change as a result of equipment deterioration, but this change only increases or decreases at a constant ratio. Therefore, the levels of the respective floors always exhibit correct values.
According to the present invention as described above, the apparatus obtains the levels of the respective floors by the average value of the detected positions of points above and below each floor by writing the positions of the points (e.g., 300 mm above or below the floor) for the respective floors in the RAM. Therefore, the levels of the respective floors stored in the RAM can be accurately obtained and, even if the cage is displaced from a floor level, the position of the cage can be accurately corrected.
In the apparatus for controlling the elevator according to the embodiment described above, the position detectors 11 and 12 generally have considerable response delay, and, when the response delay is represented by ΔT, an error in the distance of V×ΔT (V represents the velocity of the cage) occurs. As a result, in order to reduce the above-described error, the cage 1 must be operated at a low speed, and, in a building with wide separation in floor levels, the time required to write the floor number values is often long. On the other hand, to write the floor number values while operating the cage at high speed, position detectors with sufficiently fast responding speed must be employed, resulting in high equipment cost.
A second embodiment of the present invention provides an apparatus for controlling an elevator capable of accurately writing the floor number values in the memory while operating the cage at a high speed even when position detectors having considerable response delay are employed.
In order to achieve the above-described object, the present invention compensates for the considerable response delay of the detectors by changing the distance adjustment value in accordance with the moving speed of the cage.
FIG. 9 shows a flow chart of sequence program steps for controlling an elevator according to the second embodiment of the present invention. It is noted that these program steps are stored in a read-only memory 8b of the microcomputer 8.
In FIG. 9, step S 1 decides whether the cage 1 moves upward. In case of a "NO", the controlling program is exited and terminated, while in case of a "YES", the program advances to step S 2 . In step S 2 , the output value DPS of the counter 7 is added to the present position value SYNC of the cage 1, the added result is written as the new SYNC value, and the program then advances to step S 3 . Step S 3 decides whether the output signal 11a of the position detector 11 increases. In case of a "NO", the program is exited and terminated, while in case of a "YES", the program advances to step S 4 . In step S 4 , after a value of 1 is added to the present position FSY of the cage 1, it is stored as a dummy variable I. Then, in step S 5 , a subroutine program for calculating a distance adjustment value CMPS in response to the moving speed of the cage 1 is executed, and, in step S.sub. 6, this adjustment value CMPS is subtracted from the present position value SYNC to obtain FLU(1) and the program is terminated.
FIG. 10 shows the detailed sequence steps of the subroutine program referred to in step S 5 of FIG. 9. First, in step S 6a , the distance adjustment value CMPS is set to zero and the program advances to step S 6b . Here, the output value DPS of the counter 7 represents the moving distance of the cage 1 in a corresponding calculating period of the central processing unit 8a, and, since the period of the unit 8a is always the same, DPS also represents the speed of the cage. Consequently, when the steps S 6b to S 6g shown in FIG. 10 are executed, the distance adjustent value CMPS becomes "0" for DPS<P 1 , "1" for P 1 ≦DPS<P 2 , "2" for P 2 ≦DPS<P 3 , and "3" for P 3 >DPS. In other words, since the response delay time ΔT of the position detector 11 is always constant, accurate correction of the position can be performed by setting the distance adjustment value to 0 to 3 pulses in response to the speed of the cage. Further, in the embodiment described above, the up-running operation of the cage has been described. However, accurate correction of the position can also be performed similarly by the same process for a cage moving in a downward direction.
In the controlling apparatus according to the second embodiment of the invention as described above, the distance adjustment value of the distance is set in response to the moving speed of the cage. Therefore, even if a time response delay occurs in the position detectors, the present position of the cage can be accurately detected. Thus, the apparatus of this embodiment can provide advantages in that, even when inexpensive position detectors of slow responding speed are employed, the floor number values can be accurately written in the memory while operating the cage at a high speed.
In the embodiments of the invention described above, the moving distance of the cage 1 is not directly measured but is indirectly measured from the rotating speed of the motor 5. Therefore, errors are accumulated due to the slip of the cable 3 and the reduction in the diameter of the sheave 4 due to wear and extended use. Thus, in the apparatus for controlling the elevator of the invention, the output signals 11a and 12a of the position detectors 11 and 12 are supplied to the central processing unit 8a, thereby correcting the present position SYNC. For example, when the position detector 11 is advanced to the plate of the Ith floor during an upward run to generate the output signal 11a, SYNC←FLU(I) is executed. Further, when the position detector 12 is advanced to the plate 10 of the Ith floor during a downward run to generate the output signal 12a, SYNC←FLD(I) is executed.
However, in the above correcting method, an error of the distance of V×ΔT occurs because of the response delay of the position detectors 11 and 12, where V represents the speed of the cage and ΔT represents the response delay time of the detectors 11 and 12. Therefore, in the above-described correcting method, drawbacks are raised, for example, that sufficient correction cannot be provided in an elevator at high speed, or an expensive position detector must be employed to reduce the response delay.
A third embodiment of the present invention for solving the above drawbacks will be described.
FIG. 11 shows a flow chart of sequence program steps for controlling an elevator according to this embodiment. It is noted that these steps are stored in a read-only memory 8b of the microcomputer 8.
In FIG. 11, step S 11 advances to step S 12 after the present position FSY is stored in memory as a dummy variable I. Step S 12 decides whether the cage 1 moves in an upward direction. In the case of a "NO", the program is exited and terminated, while in case of a "YES", the program advances to step S 13 . Step S 13 decides whether the present position SYNC of the cage 1 is above (FVL(I)+FVL(I+1))/2, and hence whether the cage 1 passes the intermediate postion between the floor and the next floor. In case of a "YES", the program advances to step S 14 where a value of 1 is added to the dummy variable I to become the present position FSY of the cage 1, and the program advances to step S 15 . In case of a "NO" in step S 13 , the program immediately advances to step S 15 . The step S 15 decides whether the output signal 11a of the position detector 11 increases. In case of a "YES", the program advances to step S 16 . Step S 16 executes a subroutine program for deciding a distance adjustment value CMPS in response to the speed of the cage, and then advances to step S 17 . Step S 17 corrects the present position SYNC of the cage 1 by using the correcting amount CMPS calculated in the step S 16 and the program is terminated. In case of a "NO" in the step S 15 , the counter DPS is added to the present position SYNC of the cage 1 in step S 18 , and the correction of the present position SYNC of the cage is not necessary.
Step S 16 operates the same as that in FIG. 10 and will be omitted in the description.
With this embodiment, the present position of the cage can be accurately corrected by the above-described calculation.
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The actual floor level of each of the floors of a building is determined and stored as a data point in memory by detecting, for each floor, the position of a point located a predetermined distance above the floor level and the position of a point located a predetermined distance below the floor level, storing data representing the above and below points in memory, and calculating a data point for the actual floor level located at the midpoint between the points above and below the actual floor level in the case where the points are the same predetermined distance above and below the actual floor level. The data stored in memory as to the positions of the points is continuously updated each time the elevator cage passes by each floor, and the data point of the actual floor level is recalculated to provide an updated and accurate representation of the actual floor level in memory to account for cable stretch and other mechanical or electronic variations. The positions of the points are determined by counting pulses generated responsive to cage movement.
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TECHNICAL FIELD
[0001] The present invention relates to a radioactive iodine-labeled pyrido[1,2-a]benzimidazole derivative compound or a salt thereof, and a radiopharmaceutical comprising the same.
RELATED ART
[0002] Accumulation of senile plaque (SP) composed mainly of amyloid β protein (Aβ) and neurofibrillary tangle (NFT) composed mainly of tau protein is found in the brain with Alzheimer's disease (AD). Since the accumulation of NFT exhibits high correlation with clinical symptoms, as compared with SP, development of radioactive molecule imaging probes for nuclear medicine diagnosis targeting the tau protein has received attention recently.
[0003] For example, Patent Document 1 describes radioactive iodine-labeled compounds comprising rhodanine and thiohydantoin derivatives having affinity for the tau protein.
[0004] Also, Patent Documents 2 and 3 describe compounds having binding activity against both of the Aβ and the tau protein. Specifically, Patent Document 2 describes a radioactive iodine-labeled compound having styrylbenzimidazole as a nucleus, and Patent Document 3 describes benzimidazolepyrimidines and the like.
RELATED DOCUMENTS
Patent Documents
[0005] Patent Document 1: International Publication No. WO 2011/108236
[0006] Patent Document 2: Japanese Patent Laid-Open (Kokai) No. 2013-237655
[0007] Patent Document 3: Japanese Patent Laid-Open (Kohyo) No. 2013-522365
SUMMARY
[0008] However, the compounds described in Patent Documents 1 to 3 still need to be improved for in vivo imaging agents selective for the tau protein.
[0009] The present invention has been made in light of these circumstances, and aims to provide a novel tau imaging agent capable of selectively imaging a tau protein in living body by a nuclear medicine approach noninvasively.
[0010] The present inventors have completed the present invention by newly finding that a radioactive iodine-labeled pyrido[1,2-a]benzimidazole derivative compound suppresses the nonspecific accumulation to the white matter while maintaining selective binding activity against the tau protein.
[0011] One aspect of the present invention provides a radioactive iodine-labeled compound represented by the following general formula (1) or a salt thereof:
[0000]
[0012] In the general formula (1), when R 1 is a hydrogen atom, R 2 is a radioactive iodine atom or a radioactive iodophenyl group, and when R 1 is a radioactive iodine atom, R 2 is a hydrogen atom or a phenyl group.
[0013] Another aspect of the present invention provides a radiopharmaceutical comprising the aforementioned radioactive iodine-labeled compound or a salt thereof.
[0014] Still another aspect of the present invention provides a diagnostic agent for Alzheimer's disease comprising the aforementioned radioactive iodine-labeled compound or a salt thereof.
[0015] Still another aspect of the present invention provides a compound represented by the following general formula (2) or a salt thereof:
[0000]
[0016] In the general formula (2), when R 3 is a hydrogen atom, R 4 is a trialkylstannyl group, a trialkylsilyl group, a trialkylstannyl phenyl group, or a trialkylsilyl phenyl group, and when R 3 is a trialkylstannyl group or a trialkylsilyl group, R 4 is a hydrogen atom or a phenyl group.
[0017] Still another aspect of the present invention provides a method for producing a radioactive iodine-labeled compound represented by the general formula (1) or a salt thereof from a compound represented by the general formula (2) or a salt thereof by radioactive iodination reaction.
[0018] The present invention can provide a novel tau imaging agent which is capable of selectively imaging a tau protein in living body by a nuclear medicine approach.
[0019] The object mentioned above and other objects, features, and advantages will become further apparent from the following preferred embodiments and the accompanying drawings shown below.
BRIEF DESCRIPTION OF DRAWINGS
[0020] FIG. 1 is a diagram showing a synthesis example of 7-iodo-3-phenylbenzo[4,5]imidazo[1,2-a]pyridine (BIP-1) and a labeling precursor compound for the radioactive iodine-labeled BIP-1.
[0021] FIG. 2 is a diagram showing a synthesis example of 3-(4-iodophenyl)benzo[4,5]imidazo[1,2-a]pyridine (BIP-2) and a labeling precursor compound for the radioactive iodine-labeled BIP-2.
[0022] FIG. 3 is a diagram showing a synthesis example of 7-iodobenzo[4,5]imidazo[1,2-a]pyridine (BIP-3) and a labeling precursor compound for the radioactive iodine-labeled BIP-3.
[0023] FIG. 4 is a diagram showing a synthesis example of 3-iodobenzo[4,5]imidazo[1,2-a]pyridine (BIP-4) and a labeling precursor compound for the radioactive iodine-labeled BIP-4.
[0024] FIGS. 5A-5D are diagrams showing a labeling example of radioactive iodine-labeled pyrido[1,2-a]benzimidazole derivative compounds. FIG. 5A is a diagram showing a synthesis example of 7-[ 125 I]iodo-3-phenylbenzo[4,5]imidazo[1,2-a]pyridine ([ 125 I]BIP-1). FIG. 5B is a diagram showing a synthesis example of 3-(4-[ 125 I]iodophenyl)benzo[4,5]imidazo[1,2-a]pyridine ([ 125 I]BIP-2). FIG. 5C is a diagram showing a synthesis example of 7-[ 125 I]iodobenzo[4,5]imidazo[1,2-a]pyridine ([ 125 I]BIP-3). FIG. 5D is a diagram showing a synthesis example of 3-[ 125 I]iodobenzo[4,5]imidazo[1,2-a]pyridine ([ 125 I]BIP-4).
[0025] FIGS. 6E-6L are diagrams showing results of in vitro autoradiography using an autopsied brain tissue of an Alzheimer's disease patient. FIG. 6E shows results of evaluating the binding affinity of the radioactive iodine-labeled BIP-1 using a brain tissue section of the temporal lobe. FIG. 6F shows results of evaluating the binding affinity of [ 125 I]BIP-1 using a brain tissue section of the frontal lobe. FIG. 6G shows results of evaluating the binding affinity of [ 125 I]BIP-2 using a brain tissue section of the temporal lobe. FIG. 6H shows results of evaluating the binding affinity of [ 125 I]BIP-2 using a brain tissue section of the frontal lobe. FIG. 6I shows results of evaluating the binding affinity of [ 125 I]BIP-3 using a brain tissue section of the temporal lobe. FIG. 6J shows results of evaluating the binding affinity of [ 125 I]BIP-3 using a brain tissue section of the frontal lobe. FIG. 6K shows results of evaluating the binding affinity of [ 125 I]BIP-4 using a brain tissue section of the temporal lobe. FIG. 6L shows results of evaluating the binding affinity of [ 125 I]BIP-4 using a brain tissue section of the frontal lobe.
[0026] FIGS. 7M-7O are diagrams showing results of in vitro autoradiography and immunostaining using an autopsied brain tissue of an Alzheimer's disease patient. FIG. 7M shows results of immunostaining with an antibody against tau. FIG. 7O shows results of immunostaining with an antibody against Aβ. FIG. 7N is an enlarged image of FIG. 6I .
[0027] FIG. 8 is a diagram showing results of evaluating the binding affinity of [ 125 I]BIP-3 using a brain tissue section of the frontal lobe.
[0028] FIG. 9 is a diagram showing results of evaluating the binding affinity of [ 125 I]BIP-3 using a brain tissue section of the temporal lobe.
[0029] FIG. 10 is a diagram showing the proportions of immunopositive sites of tau and Aβ of each brain tissue region and the proportion of a radioactivity accumulation site of [ 125 I]BIP-3 relative to the whole brain tissue section, from region to region of the brain tissue.
[0030] FIG. 11 is a diagram showing results of comparing the intracerebral kinetics of the radioactive iodine-labeled pyrido[1,2-a]benzimidazole derivative compounds according to Examples.
[0031] FIG. 12 is a diagram showing results of evaluating the stability of the radioactive iodine-labeled BIP-3 in plasma.
[0032] FIG. 13 is a diagram showing results of analyzing metabolites of the radioactive iodine-labeled BIP-3 in blood.
[0033] FIG. 14 is a diagram showing results of analyzing metabolites of the radioactive iodine-labeled BIP-3 in brain.
DESCRIPTION OF EMBODIMENTS
[0034] In the present invention, the “radioactive iodine” is not particularly limited as long as it is a radioisotope of iodine, but is preferably a radioactive species used in nuclear medicine diagnostic imaging such as single photon emission computed tomography (SPECT), more preferably, 123 I, 124 I, 125 I, or 131 I. 123 I is furthermore preferred for nuclear medicine diagnostic imaging.
[0035] In the present invention, the “radioactive iodophenyl group” can be any substituent resulting from substitution of at least one hydrogen atom of the phenyl group with a radioactive iodine atom, and is preferably a monoiodophenyl group resulting from substitution of one hydrogen atom of the phenyl group with a radioactive iodine atom, more preferably a iodophenyl group resulting from substitution of a hydrogen atom at position 2, 3, or 4 of the phenyl group with a radioactive iodine atom, and furthermore preferably a substituent resulting from substitution of a hydrogen atom at position 4 of the phenyl group with a radioactive iodine atom (radioactive 4-iodophenyl group).
[0036] The radioactive iodine-labeled compound represented by the general formula (1) may form a salt. Examples of the salt include acid addition salts, for example, inorganic acid salts (e.g., hydrochloride, sulfate, hydrobromide, and phosphate) and organic acid salts (e.g., acetate, trifluoroacetate, succinate, maleate, fumarate, propionate, citrate, tartrate, lactate, oxalate, methanesulfonate, and p-toluenesulfonate). The compound represented by the general formula (1) or the salt thereof may be a hydrate.
[0037] Specific examples of the radioactive iodine-labeled compound according to the present invention include the following compounds:
[0038] radioactive iodine-labeled 7-iodo-3-phenylbenzo[4,5]imidazo[1,2-a]pyridine (a radioactive iodine-labeled compound of the general formula (1) wherein R 1 is a radioactive iodine atom, and R 2 is a phenyl group),
[0039] radioactive iodine-labeled 3-(4-iodophenyl)benzo[4,5]imidazo[1,2-a]pyridine (a radioactive iodine-labeled compound of the general formula (1) wherein R 1 is a hydrogen atom, and R 2 is a radioactive 4-iodophenyl group),
[0040] radioactive iodine-labeled 7-iodobenzo[4,5]imidazo[1,2-a]pyridine (a radioactive iodine-labeled compound of the general formula (1) wherein R 1 is a radioactive iodine atom, and R 2 is a hydrogen atom), and
[0041] radioactive iodine-labeled 3-iodobenzo[4,5]imidazo[1,2-a]pyridine (a radioactive iodine-labeled compound of the general formula (1) wherein R 1 is a hydrogen atom, and R 2 is a radioactive iodine atom).
[0042] Subsequently, a method for producing the radioactive iodine-labeled compound represented by the general formula (1) or the salt thereof will be described. The radioactive iodine-labeled compound represented by the general formula (1) or the salt thereof can be obtained by carrying out a radioactive iodination reaction using a compound represented by the general formula (2) or a salt thereof.
[0043] The trialkylstannyl group in the general formula (2) includes tri(C1-C6 alkyl)stannyl groups, and more preferably a tributylstannyl group. The trialkylsilyl group includes tri(C1-C6 alkyl)silyl groups, and more preferably a trimethylsilyl group.
[0044] In the present invention, the “trialkylstannyl phenyl group” can be any substituent resulting from substitution of at least one hydrogen atom of the phenyl group with a trialkylstannyl group, and is preferably a substituted phenyl group resulting from substitution of one hydrogen atom of the phenyl group with a trialkylstannyl group, more preferably a trialkylstannyl phenyl group resulting from substitution of a hydrogen atom at position 2, 3, or 4 of the phenyl group with a trialkylstannyl group, and furthermore preferably a substituent (4-trialkylstannyl phenyl group) resulting from substitution of a hydrogen atom at position 4 of the phenyl group with a trialkylstannyl group.
[0045] In the present invention, the “trialkylsilyl phenyl group” can be any substituent resulting from substitution of at least one hydrogen atom of the phenyl group with a trialkylsilyl group, and is preferably a substituted phenyl group resulting from substitution of one hydrogen atom of the phenyl group with a trialkylsilyl group, more preferably a trialkylsilyl phenyl group resulting from substitution of a hydrogen atom at position 2, 3, or 4 of the phenyl group with a trialkylsilyl group, and furthermore preferably a substituent (4-trialkylsilyl phenyl group) resulting from substitution of a hydrogen atom at position 4 of the phenyl group with a trialkylsilyl group.
[0046] The compound represented by the general formula (2) may form a salt. The same as the salt that may be formed by the radioactive iodine-labeled compound represented by the general formula (1) can be adopted as the salt.
[0047] The compound represented by the general formula (2) can be prepared according to, for example, the schemes shown in FIGS. 1 to 4 .
[0048] The radioactive iodination reaction can be carried out by allowing a radioactive alkali metal iodide to act on the compound represented by the general formula (2) or the salt thereof. The radioactive alkali metal iodide can be any salt of radioactive iodine and an alkali metal. Examples thereof include radioactive sodium iodide and radioactive potassium iodide.
[0049] The reaction of the compound represented by the general formula (2) with the radioactive alkali metal iodide is performed under an acidic condition and further performed by reaction with an oxidizing agent. Chloramine-T, hydrogen peroxide, peracetic acid, or the like is used as the oxidizing agent.
[0050] In the case of using the obtained radioactive iodine-labeled compound of the general formula (1) as a radiopharmaceutical, it is desirable to remove unreacted radioactive iodide ions and insoluble impurities by purification using a membrane filter, a column packed with various packing materials, HPLC, or the like.
[0051] The radiopharmaceutical according to the present invention can be defined as a formulation comprising the radioactive iodine-labeled compound represented by the general formula (1) or the salt thereof in a form suitable for administration into a living body. This radiopharmaceutical can be prepared as a liquid in which the obtained radioactive iodine-labeled compound of the general formula (1) is mixed with water or saline adjusted, if desired, to appropriate pH, or a Ringer's solution or the like. In this case, it is preferred that the concentration of the present radioactive iodine-labeled compound should be equal to or lower than a concentration at which the stability of the present radioactive iodine-labeled compound mixed therein is obtained. The dosage form of the radiopharmaceutical according to the present invention is preferably an injection. The dose does not have to be particularly limited as long as it is a concentration sufficient for imaging the distribution of the administered compound.
[0052] The distribution of the present radioactive iodine-labeled compound administered into a living body can be imaged by a method known in the art and can be imaged using, for example, single photon emission computed tomography (SPECT) in the case of a [ 123 I]iodine-labeled compound. The tau protein can be imaged on the image thus obtained, and thus, for example, Alzheimer's disease can be noninvasively diagnosed.
EXAMPLES
[0053] Hereinafter, the present invention will be described further specifically with reference to Examples. However, the present invention is not intended to be limited by these contents.
[0054] Abbreviations used in the present Examples are defined as follows:—
BIP-1: 7-iodo-3-phenylbenzo[4,5]imidazo[1,2-a]pyridine BIP-2: 3-(4-iodophenyl)benzo[4,5]imidazo[1,2-a]pyridine BIP-3: 7-iodobenzo[4,5]imidazo[1,2-a]pyridine BIP-4: 3-iodobenzo[4,5]imidazo[1,2-a]pyridine [ 125 I]BIP-1: 7-[ 125 I]iodo-3-phenylbenzo[4,5]imidazo[1,2-a]pyridine [ 125 I]BIP-2: 3-(4-[ 125 I]iodophenyl)benzo[4,5]imidazo[1,2-a]pyridine [ 125 I]BIP-3: 7-[ 125 ]iodobenzo[4,5]imidazo[1,2-a]pyridine [ 125 I]BIP-4: 3-[ 125 I]iodobenzo[4,5]imidazo[1,2-a]pyridine [ 123 I]BIP-1: 7-[ 123 I]iodo-3-phenylbenzo[4,5]imidazo[1,2-a]pyridine [ 123 I]BIP-2: 3-(4-[ 123 ]iodophenyl)benzo[4,5]imidazo[1,2-a]pyridine [ 123 I]BIP-3: 7-[ 123 I]iodobenzo[4,5]imidazo[1,2-a]pyridine [ 123 I]BIP-4: 3-[ 123 I]iodobenzo[4,5]imidazo[1,2-a]pyridine
[0067] In the present Examples, reagents purchased from Nacalai Tesque, Inc., Tokyo Chemical Industry Co., Ltd., Wako Pure Chemical Industries, Ltd., or Sigma-Aldrich Co. LLC were used. However, [ 125 I]sodium iodide was purchased from MP Biomedical, Inc. or PerkinElmer Japan Co., Ltd. and used. An automatically set preparative medium pressure liquid chromatograph system manufactured by Yamazen Corp. (EPCLC-W-Prep 2XY; feeding pump (with a built-in mixer): No. 580D, detector (wavelength-fixed type): prep UV-254W, fraction collector: FR-260) was used as a preparative medium pressure liquid chromatography apparatus, which was equipped with HI-FLASH COLUMN (packing material: silica gel SiOH, pore size: 60 angstroms, particle size: 40 μm, column size: L or 2 L) and INJECT COLUMN (packing material: silica gel SiOH, pore size: 60 angstroms, particle size: 40 μm, column size: M or L). For NMR, measurement was performed with tetramethylsilane as internal standards using an NMR apparatus JNM-AL400 manufactured by JEOL Ltd. All chemical shifts were indicated by ppm on a delta scale (δ), and the fine splitting of signals was indicated using abbreviations (s: singlet, d: doublet, dd: double doublet, ddd: triple doublet, m: multiplet).
[0068] For mass spectrometry, measurement was performed using LCMS-2010EV manufactured by Shimadzu Corp. for atmospheric pressure chemical ionization mass spectrometry (APCI-MS) and using GCmate II manufactured by JEOL Ltd. for electron ionization mass spectrometry (EI-MS).
[0069] In the present Examples, “room temperature” means 25° C.
[0070] In the synthesis example of each compound, each step for the compound synthesis was repeated plural times according to need to secure an amount necessary for use as an intermediate or the like in other syntheses.
[0071] Wallac WIZARD 1470 manufactured by PerkinElmer Japan Co., Ltd. was used for measurement of radioactivity.
(Example 1) Synthesis of 3-phenyl-7-(tributylstannyl)benzo[4,5]imidazo[1,2-a]pyridine (a Labeling Precursor Compound for the Radioactive Iodine-Labeled BIP-1)
[0072] A labeling precursor compound (compound 9) for the radioactive iodine-labeled BIP-1 was obtained according to the scheme shown in FIG. 1 .
Synthesis of 2-bromo-4-phenylpyridine (Compound 7)
[0073] Dimethylaminoethanol (DMAE, 1.50 mL, 15.0 mmol) was dissolved in hexane (20.0 mL), and the solution was stirred under ice cooling. n-Butyllithium (2.5 mol/L solution in hexane, 12.0 mL, 30.0 mmol) was gradually added dropwise thereto under ice cooling, and the mixture was stirred for 30 minutes as it was. A solution of 4-phenylpyridine (776 mg, 5.00 mmol) in hexane (30.0 mL) was gradually added dropwise thereto under ice cooling, and the mixture was stirred for 1 hour as it was. The reaction solution was cooled to −78° C. Then, a solution of carbon tetrabromide (6.30 g, 18.0 mmol) in hexane (15.0 mL) was gradually added dropwise thereto, and the mixture was stirred for 50 minutes as it was. The reaction was terminated by the addition of purified water under ice cooling, followed by extraction with ethyl acetate (100 mL×2). The organic layer was washed with saturated saline and then dehydrated over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography with ethyl acetate/hexane (¼ (volume ratio)) as an elution solvent to obtain compound 7 in an amount of 645 mg (yield: 55.1%).
[0074] 1 H-NMR (400 MHz, deuterated chloroform) δ 8.38 (d, J=5.2 Hz, 1H), 7.66-7.67 (m, 1H), 7.56-7.58 (m, 2H), 7.42-7.49 (m, 4H).
Synthesis of 7-bromo-3-phenylbenzo[4,5]imidazo[1,2-a]pyridine (Compound 8)
[0075] Compound 7 (645 mg, 2.75 mmol) was dissolved in xylene (30.0 mL). To the solution, 2,4-dibromoaniline (690 mg, 2.75 mmol), copper(I) iodide (105 mg, 0.550 mmol), cesium carbonate (2.67 g, 8.26 mmol), and 1,10-phenanthroline (198 mg, 1.10 mmol) were added, and the mixture was then heated to reflux for 24 hours with stirring. The reaction solution was brought back to room temperature, followed by extraction with ethyl acetate (100 mL×2). The organic layer was washed with saturated saline and then dehydrated over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography with ethyl acetate/hexane (¼ (volume ratio)) as an elution solvent to obtain compound 8 in an amount of 78.4 mg (yield: 8.80%).
[0076] 1 H-NMR (400 MHz, deuterated chloroform) δ 8.47 (d, J=7.2 Hz, 1H), 8.08 (s, 1H), 7.88 (s, 1H), 7.77 (d, J=8.7 Hz, 1H), 7.72 (d, J=7.2 Hz, 2H), 7.45-7.55 (m, 4H), 7.19 (d, J=7.0 Hz, 1H).
Synthesis of 3-phenyl-7-(tributylstannyl)benzo[4,5]imidazo[1,2-a]pyridine (Compound 9)
[0077] Compound 8 (95.0 mg, 0.294 mmol) was dissolved in 1,4-dioxane (20.0 mL). To the solution, bis(tributyltin) (295 μL, 0.588 mmol), tetrakistriphenylphosphinepalladium (146 mg, 0.126 mmol), and triethylamine (16.0 mL) were added, and the mixture was heated to reflux for 3 hours with stirring. After the completion of reaction, the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography with ethyl acetate/hexane (½ (volume ratio)) as an elution solvent to obtain compound 9 in an amount of 26.7 mg (yield: 17.0%).
[0078] 1 H-NMR (400 MHz, deuterated chloroform) δ 8.48 (d, J=7.3 Hz, 1H), 8.08 (s, 1H), 7.87-7.89 (m, 2H), 7.72 (d, J=7.5 Hz, 2H), 7.44-7.53 (m, 4H), 7.12 (dd, J=7.2, 1.7 Hz, 1H), 0.87-1.63 (m, 27H).
(Example 2) Synthesis of BIP-1 (Compound 10)
[0079] A non-radioactive compound (compound 10) of BIP-1 was obtained according to the scheme shown in FIG. 1 .
[0080] Compound 9 (24.7 mg, 0.0463 mmol) obtained by the method shown in Example 1 was dissolved in chloroform (15.0 mL). To the solution, 1.00 mL of a solution of iodine in chloroform (50.0 mg/mL) was added, and the mixture was stirred at room temperature for 1.5 hours. The reaction was terminated with a saturated aqueous solution of sodium bisulfite, followed by extraction with chloroform (50.0 mL×2). The organic layer was washed with saturated saline and then dehydrated over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography with ethyl acetate/hexane (½ (volume ratio)) as an elution solvent to obtain compound 10 (BIP-1) in an amount of 10.3 mg (yield: 60.2%). Also, BIP-1 was obtained at a yield of 0.496% by 4-stage reaction from 4-phenylpyridine.
[0081] 1 H-NMR (400 MHz, DMSO-d 6 ) δ 9.18 (d, J=7.3 Hz, 1H), 8.19-8.22 (m, 2H), 7.93-7.99 (m, 3H), 7.66 (dd, J=8.4, 1.4 Hz, 1H), 7.51-7.57 (m, 2H), 7.46-7.51 (m, 2H). HRMS (EI) m/z calcd for C 17 H 11 IN 2 (M + ) 369.9967, found 369.9960.
(Example 3) Synthesis of 3-(4-(tributylstannyl)phenyl)benzo[4,5]imidazo[1,2-a]pyridine (a Labeling Precursor Compound for the Radioactive Iodine-Labeled BIP-2)
[0082] A labeling precursor compound (compound 13) for the radioactive iodine-labeled BIP-2 was obtained according to the scheme shown in FIG. 2 .
Synthesis of 3-bromobenzo[4,5]imidazo[1,2-a]pyridine (Compound 11)
[0083] 2-Bromoaniline (855 mg, 5.00 mmol) was dissolved in xylene (5.00 mL). To the solution, 2,4-dibromopyridine (1.41 g, 6.00 mmol), copper(I) iodide (191 mg, 1.00 mmol), cesium carbonate (4.89 g, 15.0 mmol), and 1,10-phenanthroline (360 mg, 2.00 mmol) were added, and the mixture was then heated to reflux for 9.5 hours with stirring. The reaction solution was brought back to room temperature, followed by extraction with ethyl acetate (100 mL×2). The organic layer was washed with saturated saline and then dehydrated over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography with ethyl acetate/hexane (¼ (volume ratio)) as an elution solvent to obtain compound 11 in an amount of 615 mg (yield: 50.0%).
[0084] 1 H-NMR (400 MHz, deuterated chloroform) δ 8.32 (d, J=7.3 Hz, 1H), 7.94 (d, J=8.2 Hz, 1H), 7.86-7.90 (m, 2H), 7.56 (dd, J=7.3, 7.3 Hz, 1H), 7.41 (dd, J=7.3, 7.3 Hz, 1H), 6.96 (dd, J=7.1, 1.8 Hz, 1H).
Synthesis of 3-(4-bromophenyl)benzo[4,5]imidazo[1,2-a]pyridine (Compound 12)
[0085] Compound 11 (123 mg, 0.500 mmol) was dissolved in toluene (5.00 mL) and ethanol (5.00 mL). To the solution, 4-bromobenzeneboronic acid (100 mg, 0.500 mmol), tetrakistriphenylphosphinepalladium (58.0 mg, 5.00×10 −2 mmol), and potassium carbonate (14.0 mg, 0.100 mmol) were added, and the mixture was then heated to reflux for 11 hours with stirring. The reaction solution was brought back to room temperature, followed by extraction with ethyl acetate (100 mL×2). The organic layer was washed with saturated saline and then dehydrated over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography with ethyl acetate/hexane (¼ (volume ratio)) as an elution solvent to obtain compound 12 in an amount of 90.0 mg (yield: 55.9%).
[0086] 1 H-NMR (400 MHz, DMSO-d 6 ) δ 9.18 (d, J=7.1 Hz, 1H), 8.35 (d, J=8.0 Hz, 1H), 8.02 (s, 1H), 7.91 (d, J=7.6 Hz, 2H), 7.82 (d, J=8.5 Hz, 1H), 7.74 (d, J=7.3 Hz, 2H), 7.52 (dd, J=7.3, 7.3 Hz, 1H), 7.37-7.42 (m, 2H).
Synthesis of 3-(4-(tributylstannyl)phenyl)benzo[4,5]imidazo[1,2-a]pyridine (Compound 13)
[0087] Compound 12 (90.0 mg, 0.280 mmol) was dissolved in 1,4-dioxane (5.00 mL). To the solution, bis(tributyltin) (280 μL, 0.560 mmol), tetrakistriphenylphosphinepalladium (139 mg, 0.120 mmol), and triethylamine (5.00 mL) were added, and the mixture was heated to reflux for 5 hours with stirring. After the completion of reaction, the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography with ethyl acetate/hexane (¼ (volume ratio)) as an elution solvent to obtain compound 13 in an amount of 70.0 mg (yield: 47.0%).
[0088] 1 H-NMR (400 MHz, deuterated chloroform) δ 8.46 (d, J=7.1 Hz, 1H), 7.87-7.95 (m, 3H), 7.50-7.68 (m, 5H), 7.36 (dd, J=8.0, 8.0 Hz, 1H), 7.14 (dd, J=7.1, 1.1 Hz, 1H).
(Example 4) Synthesis of BIP-2 (Compound 14)
[0089] A non-radioactive compound of BIP-2 (compound 14) was obtained according to the scheme shown in FIG. 2 .
[0090] Compound 13 (70.0 mg, 0.130 mmol) obtained by the method shown in Example 3 was dissolved in chloroform (30.0 mL). To the solution, 5.00 mL of a solution of iodine in chloroform (50.0 mg/mL) was added, and the mixture was stirred at room temperature for 1 hour. The reaction was terminated with a saturated aqueous solution of sodium bisulfite, followed by extraction with chloroform (100 mL×2). The organic layer was washed with saturated saline and then dehydrated over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography with ethyl acetate/hexane (¼ (volume ratio)) as an elution solvent to obtain compound 14 (BIP-2) in an amount of 10.0 mg (yield: 20.6%). Also, compound BIP-2 was obtained at a yield of 2.71% by 4-step reaction from 2-bromoaniline.
[0091] 1 H-NMR (400 MHz, DMSO-d 6 ) δ 9.60 (d, J=7.1 Hz, 1H), 8.63 (d, J=8.5 Hz, 1H), 8.33 (s, 1H), 8.00-8.04 (m, 3H), 7.95 (d, J=8.2 Hz, 1H), 7.86 (d, J=8.7 Hz, 2H), 7.80 (dd, J=7.1, 7.1 Hz, 1H), 7.68 (dd, J=7.3, 7.3 Hz, 1H). HRMS (EI) m/z calcd for C 17 H 11 IN 2 (M + ) 369.9967, found 369.9970.
(Example 5) Synthesis of 7-(tributylstannyl)benzo[4,5]imidazo[1,2-a]pyridine (a Labeling Precursor Compound for the Radioactive Iodine-Labeled BIP-3)
[0092] A labeling precursor compound (compound 16) for the radioactive iodine-labeled BIP-3 was obtained according to the scheme shown in FIG. 3 .
Synthesis of 7-bromobenzo[4,5]imidazo[1,2-a]pyridine (Compound 15)
[0093] 2,5-Dibromoaniline (1.24 g, 5.00 mmol) was dissolved in xylene (5.00 mL). To the solution, 2-bromopyridine (585 μL, 6.00 mmol), copper(I) iodide (190 mg, 1.00 mmol), cesium carbonate (4.89 g, 15.0 mmol), and 1,10-phenanthroline (360 mg, 2.00 mmol) were added, and the mixture was then heated to reflux for 22 hours with stirring. The reaction solution was brought back to room temperature, followed by extraction with ethyl acetate (100 mL×2). The organic layer was washed with saturated saline and then dehydrated over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography with ethyl acetate/hexane (1/1 (volume ratio)) as an elution solvent to obtain compound 15 in an amount of 834 mg (yield: 67.8%).
[0094] 1 H-NMR (400 MHz, deuterated chloroform) δ 9.12 (d, J=6.7 Hz, 1H), 8.31 (d, J=8.4 Hz, 1H), 8.01 (d, J=1.5 Hz, 1H), 7.69 (d, J=9.3 Hz, 1H), 7.60-7.64 (m, 1H), 7.52 (dd, J=8.7, 1.7 Hz, 1H), 7.06 (dd, J=6.7, 6.7 Hz, 1H).
Synthesis of 7-(tributylstannyl)benzo[4,5]imidazo[1,2-a]pyridine (Compound 16)
[0095] Compound 15 (834 mg, 3.39 mmol) was dissolved in 1,4-dioxane (10.0 mL). To the solution, bis(tributyltin) (3.40 mL, 6.78 mmol), tetrakistriphenylphosphinepalladium (1.69 g, 1.46 mmol), and triethylamine (10.0 mL) were added, and the mixture was heated to reflux for 6 hours with stirring. After the completion of reaction, the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography with ethyl acetate/hexane (¼ (volume ratio)) as an elution solvent to obtain compound 16 in an amount of 510 mg (yield: 32.8%).
[0096] 1 H-NMR (400 MHz, deuterated chloroform) δ 8.46 (d, J=7.0 Hz, 1H), 8.08 (s, 1H), 7.88 (d, J=8.1 Hz, 1H), 7.69 (d, J=9.3 Hz, 1H), 7.45 (d, J=8.1 Hz, 1H), 7.40-7.42 (m, 1H), 6.84 (dd, J=7.0, 7.0 Hz, 1H), 0.87-1.64 (m, 27H).
(Example 6) Synthesis of BIP-3 (Compound 17)
[0097] A non-radioactive compound (compound 17) of BIP-3 was obtained according to the scheme shown in FIG. 3 .
[0098] Compound 16 (510 mg, 1.11 mmol) obtained by the method shown in Example 5 was dissolved in chloroform (100 mL). To the solution, 10.0 mL of a solution of iodine in chloroform (50.0 mg/mL) was added, and the mixture was stirred at room temperature for 11 hours. The reaction was terminated with a saturated aqueous solution of sodium bisulfite, followed by extraction with chloroform (100 mL×2). The organic layer was washed with saturated saline and then dehydrated over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography with ethyl acetate/hexane (1/1 (volume ratio)) as an elution solvent to obtain compound 17 (BIP-3) in an amount of 210 mg (yield: 64.2%). Also, BIP-3 was obtained at a yield of 14.3% by 3-step reaction from 2,5-dibromoaniline.
[0099] 1 H-NMR (400 MHz, DMSO-d 6 ) δ 9.10 (dd, J=6.7, 0.9 Hz, 1H), 8.17-8.19 (m, 2H), 7.59-7.70 (m, 3H), 7.05 (dd, J=6.7, 6.7 Hz, 1H).
[0100] HRMS (EI) m/z calcd for C 11 H 7 IN 2 (M + ) 293.9654, found 293.9660.
(Example 7) Synthesis of 3-(tributylstannyl)benzo[4,5]imidazo[1,2-a]pyridine (a Labeling Precursor Compound for the Radioactive Iodine-Labeled BIP-4)
[0101] A labeling precursor compound (compound 18) for the radioactive iodine-labeled BIP-4 was obtained according to the scheme shown in FIG. 4 .
[0102] Compound 11 (182 mg, 0.740 mmol) obtained by the method shown in Example 3 was dissolved in 1,4-dioxane (10.0 mL). To the solution, bis(tributyltin) (741 ILL, 1.48 mmol), tetrakistriphenylphosphinepalladium (368 mg, 0.320 mmol), and triethylamine (10.0 mL) were added, and the mixture was heated to reflux for 19.5 hours with stirring. After the completion of reaction, the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography with ethyl acetate/hexane (¼ (volume ratio)) as an elution solvent to obtain compound 18 in an amount of 140 mg (yield: 41.3%).
[0103] 1 H-NMR (400 MHz, deuterated chloroform) δ 8.29 (d, J=6.6 Hz, 1H), 7.76-7.86 m, 3H), 7.44 (dd, J=8.2, 8.2 Hz, 1H), 7.26 (dd, J=8.0, 8.0 Hz, 1H), 6.82 (d, J=6.6 Hz, 1H), 0.79-1.60 (m, 27H).
(Example 8) Synthesis of BIP-4 (Compound 19)
[0104] A non-radioactive compound (compound 19) of BIP-4 was obtained according to the scheme shown in FIG. 4 .
[0105] Compound 18 (140 mg, 0.310 mmol) obtained by the method shown in Example 7 was dissolved in chloroform (30.0 mL). To the solution, 5.00 mL of a solution of iodine in chloroform (50.0 mg/mL) was added, and the mixture was stirred at room temperature for 1.5 hours. The reaction was terminated with a saturated aqueous solution of sodium bisulfite, followed by extraction with chloroform (100-mL×2). The organic layer was washed with saturated saline and then dehydrated over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography with ethyl acetate/hexane (¼ (volume ratio)) as an elution solvent to obtain compound 19 in an amount of 50.0 mg (yield: 55.7%). Also, BIP-4 was obtained at a yield of 11.5% by 3-step reaction from 2-bromoaniline.
[0106] 1 H-NMR (400 MHz, DMSO-d 6 ) δ 8.91 (d, J=7.3 Hz, 1H), 8.31 (d, J=8.2 Hz, 1H), 8.18 (s, 1H), 7.81 (d, J=8.2 Hz, 1H), 7.53 (ddd, J=7.1, 7.1, 0.9 Hz, 1H), 7.39 (ddd, J=8.2, 8.2, 0.9, 1H), 7.28 (dd, J=7.1, 1.6 Hz, 1H). HRMS (EI) m/z calcd for C 11 H 7 IN 2 (M + ) 293.9654, found 293.9652.
(Example 9) Synthesis of [ 125 I]BIP-1 to -4
[0107] [ 125 I]BIP-1 to -4 were obtained according to the scheme shown in FIG. 5 . Specifically, [ 125 I]sodium iodide (3.7 to 7.4 MBq, specific radioactivity: 81.4 TBq/mmol) to which 1 mol/L hydrochloric acid (100 μL) and 3% (v/v) aqueous hydrogen peroxide solution (100 μL) had been added was supplemented with a solution in ethanol of compound 9 obtained by the method shown in Example 1, compound 16 obtained by the method shown in Example 5, or compound 18 obtained by the method shown in Example 7, or a solution of compound 13 obtained by the method shown in Example 3 in methanol containing 0.1% (v/v) acetic acid (1.00 mg/mL, 200 μL). After reaction at room temperature for 40 minutes, the reaction was terminated by addition of a saturated aqueous solution of sodium bisulfite (200 μL) as a reducing agent. The reaction solution was neutralized by addition of a saturated aqueous solution of sodium bicarbonate (200 μL), followed by extraction with ethyl acetate. The extract was dehydrated through a column packed with anhydrous sodium sulfate, and the solvent was then distilled off. The residue was purified using reverse phase high performance liquid chromatography (HPLC) with the corresponding non-radioactive compounds BIP-1 to -4 obtained by the methods shown in Examples 2, 4, 6, and 8 as standards, followed by extraction with ethyl acetate. LC-20AD manufactured by Shimadzu Corp. was used for HPLC, and an ultraviolet spectrum detector SPD-20A and a scintillation survey meter TCS-172 manufactured by Hitachi Aloka Medical, Ltd. were used as detectors. COSMOSIL 5C 18 -AR-II manufactured by Nacalai Tesque, Inc. (4.6 mm I.D.×150 mm) was used as a column for HPLC. A mobile phase and retention time of reverse phase HPLC are shown in Table 1. The purified product was dehydrated through a column packed with anhydrous sodium sulfate, and the solvent was then distilled off. Each compound of [ 125 I]BIP-1 to -4 was obtained at a radiochemical yield of 45 to 85% and a radiochemical purity of 99% or higher.
[0000]
TABLE 1
Retention
time
Compound
Mobile phase (volume ratio)
(min)
[ 125 I] BIP-1
Acetonitrile/water = 6/4
13.5
[ 125 I] BIP-2
Acetonitrile/water = 35/65
6.29
(0.1 v/v % trifluoroacetic acid)
[ 125 I] BIP-3
Acetonitrile/water = 5/5
8.55
[ 125 I] BIP-4
Acetonitrile/water = 5/5
7.12
(Example 10) Synthesis of [ 123 I]BIP-1 to -4
[0108] [ 123 I]BIP-1 to -4 were obtained in the same way as in Example 9 except that 37 to 111 MBq of [ 123 I]sodium iodide (111 MBq/10 μL) was used instead of [ 125 I]sodium iodide.
(Evaluation 1) In Vitro Autoradiography Using Autopsied Brain Tissue of Alzheimer's Disease Patient
(1) In Vitro Autoradiography
[0109] Autopsied brain tissue sections of an Alzheimer's disease (AD) patient (76 years old, male, sections from a frontal lobe site and a temporal lobe site, 6 μm) were used, which were provided from Graduate School of Medicine, Kyoto University. Deparaffinization treatment was performed by washing with xylene (15 min×2), ethanol (1 min×2), a 90 vol % aqueous ethanol solution (1 min×1), an 80 vol % aqueous ethanol solution (1 min×1), a 70 vol % aqueous ethanol solution (1 min×1), and purified water (2.5 min×2). A 10 vol % or 50 vol % aqueous ethanol solution of each of [ 125 I]BIP-1 to -4 (370 kBq/mL) obtained by the method shown in Example 9 was added thereto, and the tissue sections were incubated at room temperature for 2 hours. The tissue sections were washed with a 50 vol % aqueous ethanol solution (2 hr×1), then exposed to an imaging plate (BAS-SR2025 manufactured by Fujifilm Corp.) for 12 hours, and analyzed using a bioimaging analyzer (bioimaging analyzer BAS-5000 manufactured by Fujifilm Corp.). Multi Gauge manufactured by Fujifilm Corp. was used in quantitative analysis.
[0110] The results are shown in FIG. 6 . FIGS. 6E and 6F show the results obtained using [ 125 I]BIP-1. FIGS. 6G and 6H show the results obtained using [ 125 I]BIP-2. FIGS. 6I and 6J show the results obtained using [ 125 I]BIP-3. FIGS. 6K and 6L show the results obtained using [ 125 I]BIP-4. FIGS. 6E, 6G, 6I, and 6K show the results obtained using the brain tissue section of the temporal lobe. FIGS. 6F, 6H, 6J, and 6L show the results obtained using the brain tissue section of the frontal lobe. As shown in FIGS. 6F and 6H , neither [ 125 I]BIP-1 nor [ 125 I]BIP-2 exhibited radioactivity accumulation in the brain tissue section of the frontal lobe, indicating that their binding affinity for the amyloid β protein (Aβ) is low. On the other hand, as shown in FIGS. 6E and 6G , the radioactivity accumulation of [ 125 I]BIP-1 and [ 125 I]BIP-2 in the brain gray matter of the temporal lobe was maintained, indicating that they have binding affinity for tau. These compounds exhibited low nonspecific binding to the brain white matter, and, as a result, provided images with high contrast between the gray matter and the white matter. As shown in FIGS. 6I, 6J, 6K, and 6L , images equivalent to [ 125 I]BIP-1 and [ 125 I]BIP-2 were also obtained for [ 125 I]BIP-3 and [ 125 I]BIP-4.
[0111] From these results, [ 125 I]BIP-1 to -4 had selective binding activity for tau as compared with Aβ and further exhibited low nonspecific accumulation to the white matter, indicating the possibility that they are promising as a skeleton for a tau imaging probe.
(2) Immunostaining Using Autopsied Brain Tissue Section of AD Patient
[0112] Senile plaque (SP) and neurofibrillary tangle (NFT) were stained using sections near the brain sections used in autoradiography. An anti-Aβ 1-42 monoclonal antibody (BC05, manufactured by Wako Pure Chemical Industries, Ltd.) was used as a primary antibody in the immunostaining of SP, and an anti-phosphorylated tau monoclonal antibody (AT8, manufactured by Thermo Fisher Scientific Inc.) was used as an antibody in the immunostaining of NFT. Deparaffinization treatment was performed by washing with xylene (15 min×2), ethanol (1 min×2), a 90 vol % aqueous ethanol solution (1 min×1), an 80 vol % aqueous ethanol solution (1 min×1), a 70 vol % aqueous ethanol solution (1 min×1), and purified water (2.5 min×2). The antigens were retrieved by autoclaving (15 min) in a 0.01 mol/L citrate buffer solution (pH 6.0) and formic acid treatment (5 min). The tissue sections were washed with running water (5 min) and then washed with PBS-Tween 20 (2 min×1). The tissue sections were reacted with primary antibody solutions at room temperature for 1 hour and then washed with PBS-Tween 20 (5 min×3). The tissue sections were reacted with Histofine Simple Stain MAX-PO (MULTI) (manufactured by Nichirei Biosciences Inc.) at room temperature for 30 minutes and then washed with PBS-Tween 20 (3 min×3) and TBS (5 min×1). Finally, the tissue sections were reacted with a DAB solution at room temperature for 1 minute. The tissue sections were washed with distilled water (1 min×1) to terminate the reaction. The brain tissue sections were mounted on slides and then observed under a microscope (BZ-9000 manufactured by Keyence Corporation).
[0113] FIG. 7M shows the results of immunostaining with the antibody against tau. FIG. 7O shows the results of immunostaining with the antibody against Aβ. FIG. 7N is an enlarged image of FIG. 6I . As a result of comparing the enlarged in vitro autoradiography image of the temporal lobe obtained using [ 125 I]BIP-3 with the immunostaining images of tau and Aβ, the radioactivity accumulation of [ 125 I]BIP-3 onto the brain tissue section of the temporal lobe ( FIG. 7N ) was consistent with the accumulation of tau ( FIG. 7M ) as compared with the accumulation of Aβ ( FIG. 7O ), demonstrating that [ 125 I]BIP-3 clearly visualizes tau accumulated in the brain with AD.
[0114] As for [ 125 I]BIP-3, radioactivity accumulated on the brain tissue section was quantitatively analyzed using Multi Gauge to evaluate correlation with immunostaining positive sites of tau and Aβ. As shown in FIG. 8 , the frontal lobe was classified into 4 sites: a. cingulate gyrus, b. straight gyrus, c. inferior frontal gyrus, and d. superior frontal gyrus. As shown in FIG. 9 , the temporal lobe was classified into 6 sites: e. transverse temporal gyrus, f. superior temporal gyrus, g. middle temporal gyrus, h. inferior frontal gyrus, i. parahippocampal gyrus, and j. hippocampus. As a result of calculating the ratios of the immunostaining positive sites of tau and Aβ to the whole area of each site, only Aβ was quantitatively shown to accumulate in the frontal lobe ( FIGS. 10 a to 10 d ). On the other hand, the temporal lobe was shown to have a high ratio of the immunostaining positive site of tau as compared with Aβ ( FIGS. 10 e to 10 j ). As a result of comparing the ratios of the immunostaining positive sites of tau and Aβ with the radioactivity accumulation of [ 125 I]BIP-3, [ 125 I]BIP-3 exhibited low radioactivity accumulation to the frontal lobe ( FIGS. 10 a to 10 d ) and higher radioactivity accumulation to the temporal lobe than the radioactivity accumulation to the frontal lobe ( FIGS. 10 e to 10 j ), indicating that the radioactivity accumulation of [ 125 I]BIP-3 onto brain tissue sections correlates with the rate of accumulation of tau as compared with Aβ.
(Evaluation 2) Comparison of Intracerebral Kinetics
[0115] Each of [ 125 I]BIP-1 to -4 obtained by the method shown in Example 9 was diluted with saline containing 10 vol % ethanol and 0.1 vol % Tween 80. Each of [ 125 I]BIP-1 to -4 was administered to a group of 5-week-old ddY male mice (26 to 28 g; each group involved 5 mice) from the tail veins thereof at 25.0 to 37.5 kBq (100 μL) per mouse. After 2, 10, 30, or 60 minutes, the mice were slaughtered. After blood collection, the brains were taken out, and their weights and radioactivity were measured. As for [ 125 I]BIP-3, the principal organs were also excised, and their weights and radioactivity were measured.
[0116] The results are shown in Table 2 and FIG. 11 . In Table 2, the numerical values shown in the column “Time after administration” are means of % ID/g with standard deviation (SD) shown in parenthesis. [ 125 I]BIP-1 to -4 exhibited high transfer to the brain early after administration and then rapid clearance from the brain. Among others, the radioactivity (Brain 2min ) of [ 125 I]BIP-3 in the brain 2 minutes after administration was 4.74% ID/g. The ratio (Brain 2min/60min ) of radioactivity of [ 125 I]BIP-3 in the brain between 2 minutes and 60 minutes after administration was 79.0, indicating that it exhibits favorable intracerebral kinetics.
[0000]
TABLE 2
Time after administration (min)
Compound
2
10
30
60
Brain 2 min/60 min
[ 125 I] BIP-1
3.51
2.14
0.65
0.23
15.3
(0.20)
(0.21)
(0.06)
(0.03)
[ 125 I] BIP-2
2.73
1.73
0.57
0.26
10.4
(0.37)
(0.39)
(0.07)
(0.05)
[ 125 I] BIP-3
4.74
0.65
0.12
0.06
79.0
(0.57)
(0.07)
(0.01)
(0.01)
[ 125 I] BIP-4
2.37
0.36
0.09
0.06
39.5
(0.18)
(0.05)
(0.01)
(0.01)
[0117] Results of conducting an in vivo radioactivity distribution experiment of [ 125 I]BIP-3 are shown in Table 3. In Table 3, the numerical values shown in the column “Time after administration” are means of % ID for the stomach and the thyroid gland and means of % ID/g for the other tissues with standard deviation (SD) shown in parenthesis. Uptake into the kidney (23.7% ID/g) and uptake into the liver (19.9% ID/g) 2 minutes after administration were at the same level. Also, uptake into the intestine 60 minutes after administration was 29.4% ID/g, indicating a behavior of being gradually excreted from the liver to the intestine. Furthermore, uptake into the thyroid gland was 0.22% ID even 60 minutes after administration, and accumulation to the thyroid gland in conjunction with deiodination was relatively low, suggesting that marked deiodination does not occur in living body.
[0000]
TABLE 3
Time after administration (min)
Tissue
2
10
30
60
Blood
5.20 (0.44)
2.94 (0.41)
1.30 (0.16)
1.11 (0.53)
Liver
19.9 (1.39)
14.4 (2.14)
6.29 (0.45)
5.25 (0.95)
Kidneys
23.7 (2.44)
12.2 (1.55)
10.3 (5.11)
8.99 (4.47)
Intestine
5.41 (0.62)
11.6 (2.43)
21.4 (5.69)
29.4 (7.49)
Spleen
4.76 (0.39)
1.34 (0.28)
0.58 (0.16)
0.71 (0.11)
Pancreas
5.36 (0.91)
1.49 (0.47)
0.78 (0.47)
0.75 (0.30)
Heart
7.66 (1.21)
1.66 (0.75)
0.97 (0.26)
0.83 (0.24)
Lungs
29.7 (4.63)
6.32 (1.16)
1.91 (0.29)
1.45 (0.23)
Stomach
2.70 (0.56)
6.73 (1.64)
5.34 (1.26)
4.42 (2.43)
Brain
4.74 (0.57)
0.65 (0.07)
0.12 (0.01)
0.06 (0.01)
Thyroid gland
0.09 (0.03)
0.06 (0.02)
0.13 (0.03)
0.22 (0.03)
(Evaluation 3) Stability Evaluation of [ 125 I]BIP-3 in Plasma
[0118] Blood was collected from the heart of a ddY mouse (5 weeks old, body weight: 25 to 28 g) under anesthesia with isoflurane. The collected blood was fractionated by centrifugation at 4000×g for 10 minutes to recover a supernatant. [ 125 I]BIP-3 obtained by the method shown in Example 9 (188 kBq, 10.0 μL, ethanol solution) and the mouse plasma sample (200 μL) were mixed. The mixture was incubated at 37° C. for 1 hour, and acetonitrile (400 μL) was added thereto, followed by fractionation by centrifugation at 4000×g for 10 minutes. The supernatant was recovered, treated with Cosmonice Filter (S) (0.45 μm, 4 mm) (Nacalai Tesque, Inc.), and then analyzed by reverse phase HPLC. Analytical conditions for HPLC were the same as the conditions used in Example 9.
[0119] The stability of [ 125 I]BIP-3 in the mouse plasma was evaluated. As a result of analyzing the sample incubated in the mouse plasma for 1 hour by reverse phase HPLC, only the peak of the parent compound was detected ( FIG. 12 ). These results indicated that [ 125 I]BIP-3 is stably present in mouse plasma up to 1 hour.
(Evaluation 4) Log P Value Measurement
[0120] Each of [ 125 I]BIP-1 to -4 (125 kBq) obtained by the method shown in Example 9 was added to a centrifuge tube containing 1-octanol (3.00 mL) and a 0.1 mol/L phosphate buffer solution (pH 7.4, 3.00 mL), vortexed for 2 minutes, and then centrifuged at 4,000×g for 10 minutes. 500 μL of a solution was collected from each layer, and the radioactivity thereof was then measured. A partition coefficient was determined from the 1-octanol/phosphate buffer solution ratio of radioactivity. The results are shown in Table 4.
[0000]
TABLE 4
Compound
Log P
[ 125 I] BIP-1
2.64
[ 125 I] BIP-2
2.61
[ 125 I] BIP-3
3.22
[ 125 I] BIP-4
2.35
(Evaluation 5) Metabolite Analysis of [ 123 I]BIP-3 in Blood.
[0121] A 5-week-old male ddY mouse was used as a normal mouse. [ 123 I]BIP-3 obtained by the method shown in Example 10, which was contained in saline containing 0.1 vol % Tween 80 and 10 vol % ethanol, was administered from the tail vein (3.70 MBq, 100 μL). 2 minutes, 10 minutes, or 30 minutes after administration, the mouse was slaughtered, and blood was collected into a test tube with an inner wall coated with Heparin Sodium Injection (manufactured by Nipro Pharma Corp.). After radioactivity measurement, the blood was centrifuged at 4000×g at 4° C. for 5 minutes and separated into plasma and cell components. To the obtained plasma, a 2-fold volume of methanol was added for protein denaturation, and the mixture was centrifuged at 4000×g at 4° C. for 5 minutes. The obtained supernatant was passed through Cosmonice Filter (S) (0.45 μm, 4 mm) (Nacalai Tesque, Inc.) and analyzed by reverse phase HPLC. Analytical conditions for HPLC were the same as the conditions used in Example 9.
[0122] The results are shown in FIG. 13 and Table 5. In Table 5, the proportion of the parent compound is indicated by mean±standard deviation of n=3. It was suggested that [ 123 I]BIP-3 forms a highly water-soluble metabolite after administration to mice, as compared with the parent compound ( FIG. 13 ). The parent compound was present in blood at a proportion shown in Table 5.
[0000]
TABLE 5
Time after administration
Proportion of
(min)
parent compound
2
83.1 ± 7.7
10
23.6 ± 2.2
30
8.4 ± 1.1
(Evaluation 6) Metabolite Analysis of [ 123 I]BIP-3 in Brain
[0123] A 5-week-old male ddY mouse was used as a normal mouse. [ 123 I]BIP-3 obtained by the method shown in Example 10, which was contained in saline containing 0.1 vol % Tween 80 and 10 vol % ethanol, was administered from the tail vein (3.70 MBq, 100 ILL). After 2 minutes, the mouse was slaughtered, and the brain was excised, homogenized in methanol (2.00 mL) and TBS (2.00 mL), and centrifuged at 4000×g at 4° C. for 10 minutes, followed by the collection of a supernatant. The obtained supernatant was passed through Cosmonice Filter (S) (0.45 μm, 4 mm) (Nacalai Tesque, Inc.) and analyzed by reverse phase HPLC. Analytical conditions for HPLC were the same as the conditions used in Example 9.
[0124] The results are shown in FIG. 14 . As a result of analyzing the brain homogenates by reverse phase HPLC, only the signal peak of the parent compound was detected, indicating that [ 123 I]BIP-3 is stably present in the mouse brain. It was also suggested that the metabolite detected in the blood sample is not transferred to the brain.
[0125] The results shown above indicated that the radioactive iodine-labeled compound according to the present invention can selectively and noninvasively image the tau protein in the brain.
[0126] This application claims the priority based on Japanese Patent Application No. 2015-042748 filed on Mar. 4, 2015, the disclosure of which is incorporated herein in its entirety.
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The present invention relates to a radioactive iodine-labeled pyrido[1,2-a]benzimidazole derivative compound represented by a definite general formula or a salt thereof, or a radiopharmaceutical comprising the same.
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BACKGROUND OF THE INVENTION
This invention relates to a shopping cart attachment and more particularly relates to a shopping cart desk attachment which will provide a substantially flat and stable writing surface.
Most modern supermarkets include shopping carts which a shopper can maneuver over the shopping area to carry goods to be purchased. One of the problems in utilizing a shopping cart relates to the use of a shopping list by the shopper since it is often desirable to mark off listed items as they are located. Without the aid of a desk attachment to the cart providing a substantially flat and stable writing surface, it is inconvenient to mark items off the list. Further, it is usually cumbersome for the shopper to hold a list and a writing instrument while placing items to be purchased in the cart.
Another problem relates to locating items in the shopping area. Many supermarkets include signs located above particular shopping aisles to identify a few of the items located in the respective aisle. However, these shopper guides do not include many of the items located in the shopping area and may be somewhat difficult to read from a distance. Further, it is frequently difficult to see all the signs from any particular point in the store so that it is sometimes necessary to traverse a number of aisles before locating the item desired.
Various desk attachments for shopping carts are known, for example those shown in U.S. Pat. Nos. 4,034,539 and 4,156,318, which are hereby incorporated by reference.
SUMMARY OF THE INVENTION
It is an object of the present invention to provide an improved desk attachment for a shopping cart.
It is another object to provide a collapsible desk attachment for a shopping cart with means for selecting the inclination of the desk attachment when in a use position, especially in conjunction with a shopping cart of the type having a collapsible rear compartment in its basket.
It is another object to provide a collapsible desk attachment particularly adapted for use in conjunction with shopping carts of the type not necessarily having collapsible compartments in their baskets.
Stated in general terms, the present invention is directed to a desk apparatus attachable to a shopper cart for providing a stable surface supported at an angle convenient for viewing or writing by the shopper. The desk apparatus is supported by one or more walls of the shopping cart, especially the back wall, and is readily foldable or, alternatively, removable so as not to interfere with existing cart functions such as nesting or unloading.
Stated somewhat more specifically, in a first mode of the invention, there is provided a desk attachment for a shopping cart having a rear infant carrier compartment collapsible as between its front and rear walls. The attachment includes a planar desk platform of a length sufficient to rest across the top of the compartment when open, and a pivot device at one end of the platform for pivotally engaging the top of one wall of the shopping cart. Stated even more specifically, the device comprises an articulated hanger.
In one preferred embodiment, the hanger has a selected length corresponding to the inclination of the platform with respect to the compartment when open. This embodiment is especially adapted for semipermanent attachment to a shopping cart of the type having a collapsible back wall with an infant carrier in that the desk attachment collapses to a nonuse position which does not hinder collapse of the cart compartment.
Preferably, the desk platform includes a region for receiving and displaying information such as advertising material or the like. This region may comprise a hollow, transparent shell to display advertising material or the like contained therein, and having a removable end cap for access to the material.
In another preferred embodiment, the desk platform further comprises a hinged lid compartment for storing shopper's items such as coupons, lists, or the like. This embodiment is especially useful as a portable desk attachment to be removed from the shopping cart by the user at the conclusion of cart use.
In another mode of the invention, being especially adapted for use with a shopping cart of the type not necessarily having a collapsible rear compartment in its basket, there is provided a cantilevering desk attachment carried on and supported by a single wall of the cart. This desk attachment comprises a desk platform, one or more tracking members for vertically tracking on a basket wall of a shopping cart, a linkage for pivotally linking one end of the platform to the tracking members, and a cantilevering connection for cantilevering the platform from the wall when the tracking members are moved to a terminal position at the top of the wall and the platform is pivoted at the linkage about the top of the wall from a vertical nonuse position to a cantilevered use position.
BRIEF DESCRIPTION OF THE DRAWINGS
Further details are given below with reference to the drawings wherein:
FIG. 1 is a partial perspective view of a shopping cart having a collapsible rear compartment and having attached thereto a preferred embodiment of the desk attachment of the present invention;
FIG. 2 shows the desk attachment of FIG. 1 in a collapsed nonuse configuration when the rear compartment of the cart is collapsed;
FIG. 3 is a fragmented pictorial view of the desk attachment of FIG. 1;
FIG. 4 is a pictorial view of a set of articulated hangers, shown fragmented in relation to one end of the desk attachment of FIG. 1;
FIG. 5 is a partial pictorial view of a shopping cart having a collapsible rear compartment and having attached thereto another preferred embodiment of the invention, being a portable desk attachment with an internal storage compartment;
FIG. 6 is a pictorial view of the desk attachment of FIG. 5 shown removed from the cart and with its storage compartment open;
FIG. 6A is a bottom view of the desk attachment of FIG. 5 having magnetic strips attached thereto;
FIG. 7 is a partial pictorial view of another preferred embodiment which is a desk attachment cantilevered from the top of the rear basket wall of a shopping cart of the type not necessarily having a collapsible rear compartment;
FIG. 8 is a front end view of the desk attachment shown in FIG. 7; and
FIG. 9 is a schematic side view of the desk attachment of FIG. 7 showing the relationship between the cantilevered use configuration and the collapsed nonuse configuration.
DESCRIPTION OF THE PREFERRED EMBODIMENTS
In FIG. 1, there is partially shown a conventional shopping cart 12 with desk attachment 10, in accordance with the invention, affixed thereto. Shopping cart 12 being of conventional design has an open basket of open irregular mesh construction of metal rods, for example as indicated at 14 on a basket side wall. Cart 12 has rear wall 16 which is pivotal about its top rod member 18 so that baskets of a plurality of carts not in use may be serially inserted. Cart 12 has a collapsible rear compartment 20, shown in the open position, which is formed by the front compartment wall 22 being pivotally secured at the base of rear wall 16. Typically, the rear compartment has a collapsible, pivotally mounted seat 23.
Collapsible wall 22 has a top rod member 24 to which are pivotally secured hangers 26a, 26b of desk attachment 10. Desk attachment 10 has a planar desk platform 30 with upper end cap 28 and lower end cap 32. Articulated hangers 26a, 26b are secured to the underside of upper end cap 28 while the lower end cap 32 rests on the top rod member 18 of rear cart wall 16, the overall length of desk attachment 10 being sufficient to span rear compartment 20 when open. End cap 28 has affixed thereto the clamp 34 for holding writing paper on platform 30. Hangers 26a, 26b are selected length such that platform 30 is at a desired inclination when in the use position as shown in FIG. 1. Preferably, the length of hangers 26a, 26b is sufficient such that platform 30 is substantially horizontal.
In FIG. 2, shopping cart 12 is partially shown with its rear compartment 20 collapsed by pivoting collapsible wall 22 against rear wall 16. Upon collapsing rear compartment 20, desk attachment 10 rides over the top 18 of rear wall 16 in a smooth manner since hangers 26a, 26b are articulated, as discussed below. Thus, desk attachment 10 in its collapsed nonuse position hangs vertically behind and adjacent to rear wall 16, without interferring with the conventional collapsing function of the shopping cart 12. Moreover, the articulated connection of the desk attachment 12 permits a number of desk-equipped carts 10 to be telescopically nested in conventional manner, the desk attachment pivoting upwardly and rearwardly as the cart rear wall 16 swings back and up from the FIG. 2 position during nesting.
In FIG. 3, desk attachment 10 is shown in fragmented pictorial view. Platform 30 is preferably a transparent hollow shell having a substantially plane upper surface, and with interior slot 36 for insertion of advertising material 38 which is visible through the upper surface 30' of the platform. After inserting advertising material 38 into slot 36, lower end cap 32 is fitted onto the lower end of platform 30 with hole sets 41a, 41b and 42a, 42b being aligned such that rivets 40a, 40b are secured therethrough to affix lower end cap 32 to platform 30. Assembly of the upper end of desk attachment 10 includes fitting upper end cap 28 onto platform 30, aligning hole sets 45a, 45b and 46a, 46b, then mounting clamp 34 to the top surface 28' of the upper end cap. The mounting clamp 34 includes a clamp base 33 having a hollow interior space 35 with rivet holes (not shown) aligned respectively with holes 45a, 45b. Hangers 26a, 26b then are mounted to the underside of end cap 28 by aligning hole sets 47a, 47b, and finally securing rivets 44a, 44b through the respective aligned hole sets. Cover plate 49 is then fitted over clamp base 33 to conceal its interior 35.
A flap 55 is joined to the clamp base 33 by a resilient connection such as the channel-shaped bridging member 58 integrally molded with the flap and clamp base. A lip 57 protrudes downwardly from the outer edge of the flap 55 and engages the confronting region of the platform upper surface 30'. Shopping lists or the like are held on the platform 30 by the lip 57, and the resilient connection with the clamp base 33 permits removal of the list when desired. The channel 58' formed in the bridging member 58 conveniently holds a pencil while the platform 30 is in the attitude shown in FIG. 1.
In FIG. 4, there is shown a perspective view of the upper end 28 of desk attachment 10 from its underside, illustrating the details of construction of hangers 26a, 26b. Generally, only hanger 26a will be discussed since hanger 26b is substantially identical. Hanger 26a has at its lower end a tab 48a with hole 47a therethrough for alignment with hole 46a in end cap 28. The region on the underside of end cap 28 around hole 46a is channeled as generally indicated at 45a to correspond to the width of tab 48a, to promote rigidity in affixing tab 48a to end cap 28 and to provide an end cap structure flush with the sides of the tab 48a. Hanger 26a at its upper end has metal strap 50 which is deformed at 51 around rod member 24 of cart collapsible wall 22 such that the upper end of hanger 26a is pivotally affixed to rod 24. At the lower end of strap 50 there is a link 52, pivotally linking strap 50 and tab 48a at articulated joints 53a as shown. Thus hanger 26a is said to be an articulated hanger, and in the example shown has two articulations among the three component segments of the hanger such that the hanger is pivotally collapsible at each of the articulations. As discussed above in connection with FIG. 2, the purpose of the articulated hangers is to promote smoothness in collapsing the desk attachment 10 to its nonuse position upon collapsing rear compartment 20 of cart 12; while supporting the desk attachment in a substantially horizontal attitude shown in FIG. 1, conducive for reading a shopping list or the like.
In FIG. 5, another preferred embodiment of the invention is shown by desk attachment 60 which is portable and includes an interior storage compartment. Unlike the other embodiments described herein, the desk attachment 60 is not intended for permanent attachment to the cart 12; instead, the desk attachment preferably is carried by the shopper on his or her rounds and is easily attached to a selected shopping cart in any store. When leaving that store, the shopper removes the desk attachment 60 from the shopping cart.
Desk attachment 60 is shown as mounted on shopping cart 12 of FIG. 1. Thus, compartment 20 is the rear compartment of cart 12 when open, the rear compartment having collapsible wall 22 with top rod member 24 and rear wall 16 with top rod member 18. Desk attachment 60 is supported at its lower end by resting on the top of rear wall 16 at 18, and its upper end is suspended by hanger assembly 70 from top rod member 24 of collapsible wall 22.
Desk attachment 60 has a hinged lid 62 which provides access to the interior desk compartment, as further discussed below, and serves as a desk surface on desk platform 66, with clamp 68 serving to secure writing paper thereto and with holder 69 serving to hold a pencil or the like during shopping. Hinged lid 62 is secured to desk platform 66 at hinges 63a, 63b and by latching member 64. As above, hanger assembly 70 is of selected length corresponding to the desired inclination of the desk attachment 60 in its use position as shown. Preferably hanger assembly 70 will be of a length sufficient to allow desk attachment 60 to rest in substantially horizontal use position. Further, hanger assembly 70 is articulated, as discussed below, to permit a free-hanging configuration of desk attachment 60 in its use position.
In FIG. 6, there is shown a perspective view of the desk attachment 60 as it would appear removed from shopping cart 12 and with its storage compartment exposed. Hinged lid 62 is opened by releasing latching member 64 from latch 65 and then pivoting lid 62 about its hinges 63a, 63b, thereby exposing the interior of platform 66. Preferably, the interior of platform 66 is divided into three subcompartments 67a, 67b, 67c with subcompartment 67a being configured to store note paper and shopping coupons, with subcompartment 67b being configured to store pencils and pens, and with subcompartment 67c being configured to receive hanger assembly 70 upon rotation in the direction indicated by arrow 68 such that hanger assembly 70 lies flat in subcompartment 67c. The subcompartments 67a and 67c also may be used to contain coupons or other articles. A user at the completion of shopping removes desk attachment 60 from the shopping cart by slipping the hooks 72a, 72b off the top rod member 24 of the wall 22, opens hinged lid 62, folds hanger assembly 70 inside and finally closes lid 62. Thus, desk attachment 60 is said to be portable. Hanger assembly 70 is a unitary assembly having straps 71a, 71b laterally joined by cross-member 73 with the upper ends of straps 71a, 71b being deformed so as to form the hooks 72a, 72b which hook over rod element 24 of collapsible wall 22 of cart 12. At the lower end of straps 71a, 71b, assembly 70 has hinges 74a, 74b, and thus is said to be articulated. As discussed above in connection with desk attachment 10, the purpose of the articulated hanger is to permit free suspension of the desk attachment when in use on the shopping cart. Further, the articulations permit in this embodiment a convenient storage configuration after the shopper has removed the attachment from the shopping cart.
In FIG. 6A, there is shown an underside view of the desk attachment 60 removed from the shopping cart. The underside 75 has affixed thereto magnetic strips 76a, 76b toward each end of the desk attachment. Preferably, the magnetic strips are of conventional magnetic adhesive tape. With the magnetic strips, the desk attachment may be temporarily stored in the home by affixing to a metal appliance, e.g. a refrigerator door. Additionally, during use of the desk attachment as shown in FIG. 5, the lower magnetic strip 76a magnetically attaches to rod member 18 of shopping cart 12, thereby promoting writing stability of the desk attachment.
In FIG. 7, there is shown a partial perspective view of another preferred embodiment of the invention which is cantilevered from the top of a shopping basket rear wall, the shopping cart being of the type that does not necessarily have a collapsible rear compartment. FIG. 8 shows a front view of FIG. 7. Cantilevered desk attachment 80 in the use position is cantilevered over top rod member 81 of the rear wall of the shopping cart. The cart basket is of conventional construction being of open rod construction having vertical rod members 82 as part of the rear wall of the cart basket. In such a cart, typically the entire basket is hinged at the extremities of top rod 81 so that the entire basket may be pivoted to a vertical position for serial storage of a plurality of shopping carts when not in use. Desk attachment 80 has desk platform 84 and upper end cap 85 affixed to platform 84 generally as discussed above. End cap 85 has integral thereto cantilever supports 93a, 93b, which act as blocks against rod member 81, thereby establishing a fulcrum support relative to cantilevering rotation. End cap 85 has integral tabs 86a, 86b for pivotal connection to linkage means for securing the desk attachment 80 to the shopping cart. The linkage means comprises tab 86 pivotally formed around link 87 at one side of the link, and at the other side of the link pivotally formed therearound is strap 88 which at its lower end is pivotally formed around connecting rod 90. As shown, the linkage means is preferably a pair of such assemblies. It will be noted that the linkage means is somewhat similar to the articulated hanger of FIG. 4 but being operatively inverted. The linkage is pivotally collapsible at its articulations to promote smoothness during movement between the use and nonuse positions of the desk attachment as discussed below. Connecting rod 90 is insertionally fitted through tracking members 92a, 92b which preferably are sliding members secured in sliding engagement with vertical rod members 82 of the rear wall of the shopping cart. Sliding members 92 are secured to the connecting rod 90 by ring locks 91a, 91b at the respective ends of connecting rod 90. Straps 88 of the linkage means are of selected length such that when sliding members 92 are moved to their upper terminal positions on the rear wall of the cart, desk platform 84 will be at the desired inclination, most preferably a horizontal position, and will be further supported in that position by cantilever supports 93a, 93b on the underside of end cap 85.
In FIG. 9, there is shown a side view of the desk attachment 80 of FIG. 7 illustrating the relationship between the cantilevered use position of the desk and its collapsed nonuse position. Moving the desk attachment 80 from its cantilevered use position to its vertical nonuse position comprises rotating platform 84 over top rod member 81 into the shopping cart basket such that desk attachment 80 hangs from sliding member 82 in a substantially vertical orientation along and in close proximity to the rear wall elements 82 of the shopping cart basket. Under the hanging load that results, sliding members 92 are moved down the rear wall of the cart so that the desk attachment 80 rests at the bottom of the shopping cart basket. Conversely, in returning the desk attachment 80 to its use position sliders 92 are moved up the rear wall of the shopping cart to their terminal positions against rod member 81 and then the desk platform is pivoted about rod member 81 toward the rear of the shopping cart and cantilevers over rod member 81 by virtue of cantilever supports 93, by straps 88 being of appropriate length, and by sliders 92 being terminally moved against rod element 81.
Although the present invention has been described in conjunction with preferred embodiments, it is to be understood that modifications and variations may be utilized without departing from the principles and scope of the invention as defined by the following claims.
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Stated in general terms, the present invention is directed to a desk apparatus attachable to a shopping cart for providing a stable surface supported at an angle convenient for viewing or writing by the shopper. The desk apparatus is supported by one or more walls of the shopping cart, especially the back wall, and is readily foldable or, alternatively, removable so as not to interfere with existing cart functions such as nesting or unloading. The desk platform has a hinged lid compartment for storing shopper's items such as coupons, lists, or the like.
| 1 |
TECHNICAL FIELD
[0001] The present disclosure relates to vehicles, and in particular, to vehicles configured for lawn maintenance including cutting grass.
BACKGROUND
[0002] Grass is commonly maintained with lawn care machinery such as, for example, walk behind lawn mowers, riding lawn mowers, lawn tractors, and/or the like. Riding lawn mowers often provide the convenience of a riding vehicle and a larger cutting deck than typical walk-behind lawn mowers.
[0003] Typically, a riding lawnmower has a large turn radius making it difficult to operate in tight spaces and forcing an operator to make wide turns. This generally increases cut time (e.g. the time it takes to a cut a lawn) and requires additional equipment to cut an entire lawn. Short turn radius steering systems have been developed; however, these systems often employ complex gearing and linkage system. Many of the existing short turn radius steering systems are susceptible to failure related to wear and stress. Moreover, these existing systems are usually expensive and difficult to maintain because they are complex. As such, there is a need for a riding lawnmower with a short turn radius steering system that is easy and inexpensive to maintain and reliable to operate.
SUMMARY
[0004] The present disclosure is directed to a steering system for a riding lawnmower that provides a short turn radius. In one embodiment, the turn radius provided by the steering system is approximately seven inches or less. Moreover, the steering system is not only reliable, but also easy and inexpensive to maintain.
[0005] In one embodiment, a short turn radius steering system comprises a linkage, a pivot bracket, a bracket linkage, and a spindle assembly. The pivot bracket may couple to the linkage. The spindle assembly may couple to the pivot bracket through the bracket linkage. The linkage may be configured to move in a first direction and causing the pivot bracket to translate the motion such that the bracket linkage moves. The steering system may provide a turn radius of approximately five inches or less. The spindle assembly may comprise a spindle arm and a pitman arm, such that the pivot bracket is configured to conduct a force from the linkage to the pitman arm causing the spindle to move. The spindle arm may be coupled to a wheel. The pitman arm may comprise a tab. The tab of the pitman arm may be configured to restrict the wheel from turning more than 90 degrees in one direction. The pivot bracket may be configured to rotatably couple to an axle of a riding vehicle.
[0006] The steering system may also comprise a pivot bolt, which has a rotating surface and an engagement. The rotating surface may be configured to support the pivot bracket and the engagement may couple to the axle. The pivot bolt may have a hollow cavity along its centerline and a cross passage perpendicular to the hollow cavity. The pivot bolt may be configured to receive a lubricant through the hollow cavity and provide the lubricant to the rotating surface through the cross passage.
[0007] In an exemplary embodiment, a riding lawnmower may comprise a steering system with a user input, an axle, and left and right wheels. The steering system may comprise left and right steering linkages, left and right pivot brackets, and left and right spindle assemblies. The left steering linkage may couple to and conduct a force through the left pivot bracket to the left spindle assembly, which causes the left wheel to move. Similarly, the right steering linkage may couple to and conduct a force through the right pivot bracket to the right spindle assembly, which causes the right wheel to move. The left spindle assembly and right spindle assembly may each comprise a spindle arm and a pitman arm. Each of the pitman arms may comprise a tab that is configured to contact the axle to restrict the left or right wheel from turning more than 90 degrees, when the respective wheel is turned toward the centerline of the riding lawnmower. Moreover, in a turn, the geometry of the steering system causes the one wheel (e.g. the inside wheel) to turn sharper than the other wheel (e.g. the outside wheel).
[0008] The axle and the steering system may each comprise a lubricating system that is configured to provide a lubricant to each of the left and right spindle assemblies, and each of the left and right pivot brackets, to reduce wear and/or contamination.
BRIEF DESCRIPTION OF THE DRAWINGS
[0009] A more complete understanding may be derived by referring to the detailed description and claims when considered in connection with the Figures, wherein like reference numbers refer to similar elements throughout the Figures, and:
[0010] FIG. 1A illustrates a top perspective view of an exemplary short turn radius steering system mounted to a riding vehicle chassis, in accordance with an exemplary embodiment;
[0011] FIG. 1B illustrates a bottom perspective view of an exemplary short turn radius steering system mounted to a riding vehicle chassis, in accordance with an exemplary embodiment;
[0012] FIG. 1C illustrates a bottom view of an exemplary short turn radius steering system mounted to a riding vehicle chassis, in accordance with an exemplary embodiment;
[0013] FIG. 2A illustrates a perspective view of exemplary short turn radius steering system components mounted to an axle, in accordance with an exemplary embodiment;
[0014] FIG. 2B illustrates an exploded view of exemplary short turn radius steering system components mounted to an axle, in accordance with an exemplary embodiment;
[0015] FIG. 3A illustrates a perspective view of an exemplary pivot bracket, in accordance with an exemplary embodiment;
[0016] FIG. 3B illustrates a perspective view of an exemplary pivot bracket, in accordance with an exemplary embodiment;
[0017] FIG. 4 illustrates a perspective view of an exemplary pivot bolt, in accordance with an exemplary embodiment;
[0018] FIG. 5 illustrates a perspective view of an exemplary axle, in accordance with an exemplary embodiment; and
[0019] FIG. 6 illustrates an exemplary riding lawn mower, in accordance with an exemplary embodiment.
DETAILED DESCRIPTION
[0020] The following description is of various exemplary embodiments only, and is not intended to limit the scope, applicability or configuration of the present disclosure in any way. Rather, the following description is intended to provide a convenient illustration for implementing various embodiments including the best mode. As will become apparent, various changes may be made in the function and arrangement of the elements described in these embodiments, without departing from the scope of the appended claims. For example, the steps recited in any of the method or process descriptions may be executed in any order and are not necessarily limited to the order presented. Moreover, many of the manufacturing functions or steps may be outsourced to or performed by one or more third parties. Furthermore, any reference to singular includes plural embodiments, and any reference to more than one component or step may include a singular embodiment or step. Also, any reference to attached, fixed, connected or the like may include permanent, removable, temporary, partial, full and/or any other possible attachment option. As used herein, the terms “coupled,” “coupling,” or any other variation thereof, are intended to cover a physical connection, an electrical connection, a magnetic connection, an optical connection, a communicative connection, a functional connection, and/or any other connection.
[0021] For the sake of brevity, conventional techniques for mechanical system construction, management, operation, measurement, optimization, and/or control, as well as conventional techniques for mechanical power transfer, modulation, control, and/or use, may not be described in detail herein. Furthermore, the connecting lines shown in various figures contained herein are intended to represent exemplary functional relationships and/or physical couplings between various elements. It should be noted that many alternative or additional functional relationships or physical connections may be present in a short turn radius steering system.
[0022] Principles of the present disclosure reduce and/or eliminate problems with prior short turn radius steering systems. For example, the present short turn radius steering system eliminates the need for a geared steering mechanism. The reliability of the short turn radius steering system is improved by reducing the wear to (and number of) steering system components. Similarly, the maintenance of the short turn radius steering system is reduced by reducing the number and/or complexity of steering system components.
[0023] In various exemplary embodiments, with reference to FIG. 1A , FIG. 1B , and FIG. 1C , a short turn radius steering system 100 (“STRSS 100 ”) may be any mechanical or electro-mechanical system configured steer a vehicle. STRSS 100 may be configured to provide a short turn radius. For example, the steering system may be configured to provide a turn radius of approximately seven inches or less, when coupled to a vehicle. The vehicle may be a riding vehicle such as, for example, a riding lawnmower (as will be discussed herein as an example). STRSS 100 may comprise a steering assembly 110 , an axle 130 , a user input 140 , and a link 150 . STRSS 100 may be configured to couple to frame 160 . STRSS 100 may also be configured to couple to or otherwise interface with a housing and/or power train.
[0024] STRSS 100 may further comprise an input transfer mechanism 170 . Input transfer mechanism 170 may be any mechanical or electro-mechanical device configured to conduct an input from user input 140 to linkage 150 . For example, input transfer mechanism 170 may be a gear including, for example, a sector gear, a rack, a linkage, or any other device suitable mechanism for transferring an input.
[0025] User input 140 may comprise or otherwise couple to a shaft 142 and an engagement 144 . Shaft 142 may be a mechanical or electro-mechanical device configured to translate an input from user input 140 to transfer mechanism 170 and/or steering assembly 110 . Engagement 144 may be any mechanical or electro-mechanical device configured to interface with transfer mechanism 170 . For example, engagement 144 may be a gear including, for example, a spline gear, a pinion, and/or the like. In one embodiment, shaft 142 and engagement 144 may be coupled together as an assembly or may be formed as a single homogenous structure. Shaft 142 may be made of any suitable material that resists wear including, for example, metal, plastic, a composite material, a polymer material, and the like. Similarly, engagement 144 may be made of any suitable material that resists wear including, for example, metal, plastic, a composite material, a polymer material, and the like.
[0026] Steering assembly 110 may couple to or mount on axle 130 . Steering assembly may also be coupled to link 150 . Steering assembly 110 may be controlled or configured to receive inputs from user input 140 through transfer mechanism 170 . For example, steering assembly 110 is coupled to link 150 . Link 150 is coupled to transfer mechanism 170 . User input 140 is configured to operatively engage transfer mechanism 170 through shaft 142 and engagement 144 . Steering assembly 110 may be configured to receive an input from user input 140 . The input may be translated from user input 140 along shaft 142 through engagement 144 to transfer mechanism 170 . Transfer mechanism 170 may actuate link 150 and provide the input to steering assembly 110 .
[0027] In an exemplary embodiment, with reference to FIG. 2A and FIG. 2B , steering assembly 210 may be any mechanical or electro-mechanical system configured to achieve a short turn radius in response to a user input. In particular, steering assembly 210 may be configured to achieve a turn radius of about 90 degrees. Steering assembly 210 may comprise a pivot bracket 212 , a bracket linkage 214 , and a spindle assembly 216 . Pivot bracket 212 may couple to spindle assembly via bracket linkage 214 .
[0028] Steering assembly 210 may be configured to operatively couple to linkage 250 . Steering assembly 210 may also be rotatably coupled to and retained at axle 230 by bolt 226 . In one embodiment, pivot bracket 212 may be configured to rotate about bolt 226 in response to an actuation of linkage 250 (based on an input from user input 140 as shown in FIG. 1A and FIG. 1B ). The rotation of pivot bracket 212 may be transferred through bracket linkage 214 to spindle assembly 216 , causing spindle assembly 216 to rotate in response to the actuation of linkage 250 . In response to linkage 250 moving in a direction parallel to the centerline of frame 160 (and perpendicular to axle 230 ), pivot bracket 212 transfers motion in a direction perpendicular to frame 160 (and parallel to axle 230 ).
[0029] In an exemplary embodiment, spindle assembly 216 may be any structure suitably configured to retain and steer a wheel. Spindle assembly may comprise a spindle arm 217 , a stop 218 and a pitman arm 220 . Spindle arm 217 may comprise a first end and a second end. At the first end, spindle arm 217 may be configured to rotatably couple to a\the wheel. The wheel may be held in place by stop 218 on one side and by a suitable retainer (e.g. a retainer clip, a fastener, or any other suitable retainer) on the other side. Spindle arm 217 may be coupled to pitman arm 220 . Spindle arm 217 and pitman arm 220 may be coupled to one another. For example, spindle arm 217 may be coupled to pitman arm 220 , such that movement of pitman arm 220 causes rotation of spindle arm 217 .
[0030] At the second end, spindle assembly 216 may be configured to rotatably couple to axle 230 . Spindle assembly 216 may be supported and/or retained within axle 230 by any suitable method. For example, spindle arm 217 may be supported and retained by a washer 222 and retained by a clip 224 . Spindle arm 217 may be configured with a retaining slot, such that when spindle arm 217 is coupled to axle 230 , the slot of spindle arm 217 may be engaged by clip 224 .
[0031] Axle 230 may be configured with a grease fitting 232 (e.g. grease zerk 232 ). Grease fitting 232 may be any suitable structure for receiving and conducting a lubricant (e.g. grease, oil, and the like). When spindle arm 217 is coupled to axle 230 , a lubricant may be supplied through grease fitting 232 to supply a lubricant to spindle arm 217 , such that the amount of heat, wear, and debris is reduced between spindle arm 217 and axle 230 . The addition of the lubricant also provides for smoother rotation at the rotatable joint created when spindle arm 217 is couple to axle 230 .
[0032] Spindle arm 217 may be made of any suitable material to carry a load and inhibit wear. For example, spindle arm 217 may be made of a metal (e.g. steel, titanium, an alloy, and the like), a composite, a polymer or any other suitable material, now known or hereinafter devised. Moreover, spindle arm 217 may be processed in any suitable fashion to inhibit wear and reduce failure. For example, spindle arm 217 may be hardened, stress relieved (e.g. by shot peening), coated (e.g. chromed), or subject to any other suitable processing, now known or hereinafter devised.
[0033] In one embodiment and with continued reference to FIG. 2A and FIG. 2B , pitman arm may be any structure suitable configured to transfer a force and resulting movement. As discussed above, pitman arm 220 may be coupled to spindle arm 217 . Pitman arm 220 may also be coupled to pivot bracket 212 through linkage 214 . Thus, where a force applied to linkage 250 causing linkage 250 to move, the movement (and associated force) are transferred to pivot bracket 212 , which rotates about bolt 226 . The motion and resulting force are applied to bracket linkage 214 , which causes movement of pitman arm 220 and, as such, causes movement of spindle arm 217 . As such, the linear motion of linkage 214 in a first direction is translated through pivot bracket 212 and causes linear motion in a second direction (e.g. perpendicular to the first direction) of bracket linkage 214 . As used herein, “linear” may include fully linear, substantially linear, partially linear, about linear, and/or certain non-linear deviations.
[0034] Pitman arm 220 may be configured with a tab. As discussed above the STRSS 100 is configured to provide a turn radius of substantially 90 degrees. However, in order to insure that STRSS 100 does not allow the wheel of a riding vehicle to turn past 90 degrees, STRSS 100 may be configured with a stop. As such, the tab of pitman arm 220 may be configured and dimensioned such that it contacts and/or engages axle 230 to restrict steering assembly 210 from achieving a turn radius that is greater than 90 degrees when the wheel is turned toward the centerline of a riding vehicle. A turn radius that is greater than 90 degrees may make a riding vehicle difficult to control or may overstress steering components.
[0035] Pitman arm 220 may be made of any suitable material to carry a load to, conduct a force, and inhibit wear. For example, pitman arm 220 may be made of a metal (e.g. steel, titanium, an alloy, and the like), a composite, a polymer or any other suitable material, now known or hereinafter devised. Moreover, pitman arm 220 may be processed in any suitable fashion to inhibit wear and reduce failure. For example, pitman arm 220 may be hardened, stress relieved (e.g. by shot peening), coated (e.g. chromed), or subject to any other suitable processing, now known or hereinafter devised.
[0036] In an exemplary embodiment, with reference to FIG. 3A and FIG. 3B , pivot bracket 312 may be any mechanism configured to translate motion. Pivot bracket may be monolithic or may be an assembly. Each of the top plate and the bottom plate may be configured with one of more coupling points (e.g. holes, threaded studs, and/or the like). Each of the top plate and the bottom plate may also be configured with a hole configured to accept a structure to facilitate rotation. For example, pivot bracket 312 may be configured with a top plate, a bottom plate, and a sleeve. The top plate may comprise a contour, such that, when coupled to the bottom plate there is a gap between the top and bottom plates in the region of the hole configured to accept a structure to facilitate rotation (e.g. pivot hole). The sleeve may be installed at the gap between the top plate and the bottom plate, in each of the top pivot hole and bottom pivot hole. As such, the sleeve acts as a support for a rotating structure such as, for example, a bolt, a spindle, and an axle, or the like. The sleeve may be welded or otherwise fixedly attached to the top plate and the bottom plate to add additional structural support in the region of the pivot holes. Alternatively, a bolt, a spindle, an axle or other suitable rotating structure may be installed directly into the pivot holes of the top plate and the bottom plate.
[0037] Pivot bracket 312 may be configured with appropriate geometric proportions, such that Ackerman steering is achieved in a steering system employing pivot bracket 312 . Ackerman steering describes the situation where the inside wheel of a vehicle is turned sharper than the outside wheel to reduce or prevent scrubbing of the tires. Pivot bracket 312 may be configured to couple to a linkage at a first coupling point, a bracket linkage at a second coupling point and rotate about a structure (e.g. a bolt) at a rotation point. In one embodiment, there may be a linear distance between the first coupling point and the second coupling point of approximately 3.000 inches to 3.700 inches. There may also be a linear distance between the first coupling point and the rotation point of approximately 1.600 inches to 2.250 inches. There may also be a linear distance between the second coupling point and the rotation point of approximately 1.600 inches to 2.250 inches.
[0038] Pivot bracket 312 may be made of any suitable material to carry a load, conduct a force, and inhibit wear. For example, pivot bracket 312 may be made of a metal (e.g. steel, titanium, an alloy, and the like), a composite, a polymer or any other suitable material, now known or hereinafter devised. Pivot bracket 312 may be produced using machined, cast, sintered, stamped (as individual components and assembled) parts, or parts made by any other suitable method. Moreover, pivot bracket 312 may be processed in any suitable fashion to inhibit wear and reduce or prevent failure. For example, pivot bracket 312 may be hardened, stress relieved (e.g. by shot peening), coated (e.g. chromed), or subject to any other suitable processing, now known or hereinafter devised.
[0039] In an embodiment and with reference to FIG. 4 , bolt 426 may be any fastener suitably configured to support a pivot bracket and facilitate rotation. For example, bolt 426 may comprise threads, a rotating structure comprising a surface suitable for rotation, and a head. The threads may be coupled to the rotating structure. The rotating structure may be coupled to the head, such that the head provides a shoulder for a rotating structure (e.g. pivot bracket 312 ). Bolt 426 may be drilled along its centerline to provide a hollow cavity accessible through the head at an opening. The opening may be configured with threads and configured to accept a grease fitting (e.g. a grease zerk). Bolt 426 may also be cross-drilled to provide a passage, which couples the hollow cavity to the rotating surface. The hollow cavity may be used to supply a lubricant to the rotating surface when bolt 426 is installed with a rotating structure such as, for example, a pivot bracket. The lubricant reduces wear, friction, and contamination between the rotating surface and the rotating structure.
[0040] Bolt 426 may be made of any suitable material to carry a load and inhibit wear. For example, bolt 426 may be made of a metal (e.g. steel, titanium, an alloy, and the like), a composite, a polymer or any other suitable material, now known or hereinafter devised. Moreover, bolt 426 may be processed in any suitable fashion to inhibit wear and reduce or prevent failure. For example, bolt 426 may be hardened, stress relieved (e.g. by shot peening), coated (e.g. chromed, Teflon® coated, and the like), or subject to any other suitable processing, now known or hereinafter devised.
[0041] In an exemplary embodiment and with reference to FIG. 5 , axle 530 may be an structure suitable to carry the load of a riding vehicle and couple to a steering assembly. For example, axle 530 may be configured to carry a load of at least 2000 pounds when installed on a lawn tractor. Axle 530 may be configured with one or more spindle holes. The spindle holes may be configured to receive sleeves, bushing, bearings and/or the like. The spindle hole may also be configured to receive a spindle assembly. Axle 530 may also be configured with one or more steering system mounting holes. The steering system mounting holes may be configured with threads or other suitable coupling mechanisms. Axle 530 may be configured to couple to a steering system assembly with a fastener such as, for example, a bolt.
[0042] Axle 530 may be made of any suitable material to carry a load and inhibit wear. Axle 530 may be monolithic. For example, Axle 530 may be made of a metal (e.g. steel, titanium, an alloy, and the like), a composite, a polymer or any other suitable material, now known or hereinafter devised. Axle 530 may comprise multiple components coupled together. Moreover, axle 530 may be cast, pressed, sintered, die-cut, machined, stamped, bonded, laminated, polished, smoothed, bent, rolled, molded, plated, coated, and/or otherwise shaped and/or formed via any suitable method and/or apparatus. Axle 530 may comprise various geometries for reducing weight. Moreover, axle 530 may comprise various geometries for reducing stress or bearing a load.
[0043] In an exemplary embodiment, and with reference to FIG. 6 , the STRSS 100 may be provided as a component of a mowing system. STRSS 100 may be coupled to or installed on a riding lawnmower 680 . Riding lawnmower 680 may be any lawnmower, lawn-tractor, or other suitable riding vehicle configured with a short turn radius. Riding lawnmower 680 may be configured to accept and obtain power from a motor. Moreover, the riding lawnmower may comprise user input 640 , frame 660 , a body 682 , wheels 686 , a cutting deck 688 , and various other components including, for example, gauges, lights, a fuel tank, a starting system, and/or the like.
[0044] Riding lawnmower 680 may be configured with any type of cutting deck 686 including, for example, a center rear discharge cutting deck, a side discharge cutting deck, or any other suitable configuration now known or hereinafter devised. Moreover, riding lawnmower 680 may employ any accessory available or otherwise configured to interface with riding lawnmower 680 including, for example, a vacuum system, a bagging system, a blower system, or any other system now known or hereinafter devised.
[0045] While the principles of this disclosure have been shown in various embodiments, many modifications of structure, arrangements, proportions, elements, materials and components (which are particularly adapted for a specific environment and operating requirements) may be used without departing from the principles and scope of this disclosure. These and other changes or modifications are intended to be included within the scope of the present disclosure and may be expressed in the following claims.
[0046] The present disclosure has been described with reference to various embodiments. However, one of ordinary skill in the art appreciates that various modifications and changes can be made without departing from the scope of the present disclosure. Accordingly, the specification is to be regarded in an illustrative rather than a restrictive sense, and all such modifications are intended to be included within the scope of the present disclosure. Likewise, benefits, other advantages, and solutions to problems have been described above with regard to various embodiments. However, 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 a critical, required, or essential feature or element of any or all the claims. As used herein, the terms “comprises,” “comprising,” or any other variation thereof, are intended to cover a non-exclusive inclusion, such that a process, method, article, or apparatus that comprises 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. When language similar to “at least one of A, B, or C” or “at least one of A, B, and C” is used in the claims or specification, the phrase is intended to mean any of the following: (1) at least one of A; (2) at least one of B; (3) at least one of C; (4) at least one of A and at least one of B; (5) at least one of B and at least one of C; (6) at least one of A and at least one of C; or (7) at least one of A, at least one of B, and at least one of C.
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To reduce the complexity, maintenance, and cost, and to increase the reliability of a riding lawnmower employing a short turn radius steering system, the riding lawn mower may be configured with a linkage and steering assembly that eliminates or reduces complicated gearing. A riding lawn mower may comprise a link system, pivot brackets, and spindle assemblies. The geometry of the steering system may be configured to provide a turn radius of seven inches or less. Moreover, the geometry of the steering system may be configured to provide Ackerman steering, such that, the inside wheel turns sharper than the outside wheel in a turn.
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BACKGROUND OF THE INVENTION
1. Field of the Invention
This invention relates generally to an apparatus for treating work pieces in register with a physical characteristic thereof, and to a synchronizable, overrunning clutch usable therein. More specifically, this invention relates to an apparatus for applying a coating material to work pieces being moved through the apparatus wherein an applicator roll, work moving means, and an overrunning clutch are all pre-set to operate in phase with each other when a first or main drive is operative. When the main drive is inoperative, a second drive through the clutch rotates the applicator roll through a bath of the coating material. Subsequent reactivation of the first drive moves the applicator roll in phase with the work moving means and the second drive stops.
2. Description of the Prior Art
Overrunning or overriding clutches are not new and have long been used in connection with a variety of drive trains. Some examples are shown in U.S. Pat. No. 633,417 relating to a ratchet gear for bicycles, U.S. Pat. No. 3,233,471 relating to a power take off connection, and U.S. Pat. No. 4,049,099 relating to a motorcycle safety hub. It has also been known in the past to print or perform other operations on various materials and work pieces in register with some feature thereof by providing registration marks thereon which are detected by sensors which are operably connected to means for controlling the equipment being used to effect the desired registration of the work piece or material with the operation being performed thereon. One example of this is shown in U.S. Pat. No. 3,915,090 which relates to a printed pattern and embossed pattern registration control system.
The electronically operated registration control systems of the past were very expensive and very complicated, and while overrunning clutches are generally not new, the inventor is not aware of any such clutch capable of operating for a long period of time in a high temperature environment, and which may be mechanically preset and locked in synchronization with other components of the apparatus so that when the apparatus is stopped and then restarted, the registration capabilities are not affected. The inventor is further not aware of any other apparatus for applying a coating material to work pieces wherein, when the main drive system is inoperable the second drive through the clutch rotates the applicator roll in a bath of the material being applied, and wherein subsequent activation of the main drive mechanism causes the first drive to move the applicator roll in phase with the work moving means and the second drive stops.
SUMMARY OF THE INVENTION
This invention relates to an apparatus for treating work pieces in register with a physical characteristic thereof by applying a predetermined amount of coating material to work pieces as they are being conveyed beneath an applicator roll.
The apparatus comprises infeed and outfeed conveyors, an applicator roll and a back-up roll positioned therebetween, a synchronizable, overrunning clutch operably connected to the rolls and conveyors, all mechanically pre-set to operate in phase with each other when the outer housing of the clutch and the inner housing thereof are driven in unison by a main drive system.
The inner housing of the clutch is mounted on the applicator roll drive shaft and is driven by a separate drive system, when the main drive system is disengaged, so that the applicator roll is continuously rotating with its pattern-bearing outer surface passing through a supply of coating material. Means located between the inner and outer clutch housings to connect them when the main drive system is engaged, is overrun when the main drive system is disengaged and the inner housing of the clutch is being driven by its separate drive system. Since the outer housing of the clutch may be pre-set in synchronization with the work feeding means and the applicator roll, and locked in this position, the apparatus may be stopped and started repeatedly with perfect registration being maintained between the applicator roll and the work pieces being moved through the apparatus. Further, the inner housing of the clutch being driven by a separate drive means at a slower rate than that of the main drive system, keeps the applicator roll constantly rotating through the coating material supply. This eliminates the possibility of the coating material charring on the applicator roll and prevents leakage of the coating material at the point where it is supplied to the roll, which would normally occur because of the engraved design on the roll and the fact that the doctor blade of the supply container would not fit into the engraved portion of the pattern on the roll. Still further, means are provided for supplying a cooling lubricant to the clutch, and heat-dissipating means are provided on both the inner and outer housings thereof, thus enabling the clutch to operate for long periods of time in a high temperature environment.
It is an object of this invention to provide an apparatus capable of applying a predetermined amount of coating material, repeatedly, in the same predetermined location on each of a plurality of work pieces being moved through the apparatus;
It is a further object of the invention to provide such an apparatus which can accomplish the above and which may be mechanically pre-set;
It is a still further object of this invention to provide a clutch which can be pre-set and locked in synchronization with the movement of the applicator roll and the work moving means;
Another object of the invention is to provide a clutch through which the applicator roll can be kept turning at all times;
It is a further object of the invention to provide a clutch having heat dissipating features which enable it to be used in a high temperature environment;
It is another object of the invention to provide an apparatus which may be stopped and started without adversely affecting the registration of the pattern on the applicator roll with the location on the work piece where the adhesive is to be applied.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 is a diagrammatic illustration of the apparatus of this invention;
FIG. 2 is a diagrammatically illustrated side view showing the applicator and backup rolls, the adhesive supply means, and a portion of the work moving means of the apparatus of this invention;
FIG. 3 is an end elevational view of the clutch of this invention;
FIG. 4 is a cross-sectional view of the clutch of this invention taken along line 4--4 of FIG. 3; and
FIG. 5 is a cross-sectional view of the clutch of FIG. 3 taken along line 5--5 of FIG. 4.
DESCRIPTION OF THE PREFERRED EMBODIMENT
Referring to the drawings, in FIG. 1 there is shown a diagrammatic illustration of the apparatus of this invention. The apparatus comprises infeed and outfeed conveyors 1 and 2 for moving the work pieces 3 through the apparatus. Vertically aligned work engaging rolls 4 and 5 are positioned between conveyors 1 and 2. The upper roll 4 is an applicator roll which is 23" in circumference and carries an engraved pattern 6 thereon similar in shape to that of a picture frame. The outer engraving 6a is cut to a depth of 14 mils and the 8"×8" inner pattern engraving 6b is cut to a depth of 10 mils. These depths of engraving relate to the fluid carrying capacity of the roll.
The purpose of the picture frame pattern 6 on the applicator roll 4 is to enable it to place adhesive on a work piece such as a tile passing through the apparatus, and to apply a minimum overall amount of adhesive to the tile work piece with the maximum amount of adhesive being applied by the outer quadrangular portion 6a of the engraved pattern 6, and thereby achieve a maximum edge bonding strength with a 25% reduction in the amount of adhesive that would normally be used in such an application.
The processing of the tile work pieces 3 by applying to the face thereof a 2" band of adhesive 7 with a less adhesive 8"×8" center portion 8 requires that the pattern must stay in register with the tile work piece 3. Also, in processing this material there is normally a number of start-ups and shut-downs. However, due to the engraved design 6 on the adhesive applicator roll 4, the roll must constantly turn or leakage will occur between the heated doctor blade 9 (see FIG. 2) and the engraved pattern 6 in the roll 4.
This problem is overcome by the following: The base machine which includes the infeed conveyor 1, the outfeed conveyor 2, the applicator roll 4 and the applicator backup roll 5 are completely timed and driven by a number of gears, timing belts, and the overrunning, set-position clutch 10 mounted on the drive shaft 11 of the applicator roll 4.
The synchronizable overrunning clutch 10 mounted on the drive shaft 11 of the applicator roll as shown in FIGS. 4 and 5 has an outer housing 12 and an inner housing 13. The inner housing 13 of the clutch 10 being keyed to the drive shaft 11 as shown at 14 in FIG. 5 is rotated together with the applicator roll 4. As shown in FIG. 5, the inner housing 13 and the outer housing 12 of the clutch 10 are adapted to be operably connected by means of a latch 49 positioned on the inner housing 13 and a notch 15 on the inner circumference of the outer housing 12 when the outer housing 12 of the clutch 10 is being driven by a first drive means 16 through a belt and pulley arrangement 46 and drive shaft 17 as shown in FIG. 1. Latch 49 is biased toward the outer housing 12 by spring means 42 as shown in FIG. 5. When the first drive means 16 is inoperative, the applicator roll drive shaft 11 is separately driven by a second drive means 18 through a belt and pulley arrangement 45. The inner housing 13 of the clutch 10 rotates therewith and the latch 49 overruns the notch 15 in the outer housing 12 of the clutch 10. When the first drive 16 engages, the second drive 18 shuts off, going into a coast stop.
Referring to FIG. 1, the main body of the apparatus which includes the infeed and outfeed conveyors 1 and 2, the applicator roll 4, and the backup roll 5 therefor are completely timed and speed matched by the gearing drive system and the set-position clutch 10 used on the applicator roll drive shaft.
Still referring to FIG. 1 of the drawings, prior to running any product the apparatus is set up in the following manner: First, one of the conveying lugs 19 is lined up with a set-up mark 20 located on the outfeed conveyor rail 21. Second, the timing belt 22 connecting pulley I on the output shaft 23 of the variable power transmission unit 24 to pulley J is disconnected. The second drive means 18 must be shut off during this setup. Third, the outer housing 12 of the set-position clutch is rotated clockwise until the latch 49 on the inner housing 13 of the clutch 10 engages the notch 15 on the inner circumference of the outer housing 12 and the applicator roll 4 begins turning. Clockwise rotation is continued until the pattern 6 on the applicator roll 4 is phased with a work piece 3. Fourth, the timing belt 22 is then reinstalled, thus locking the entire drive system in phase together. Fifth, the second drive means 18 is turned on and adhesive is placed in the trough 25 through the adhesive fill line 27. It will be noted that once the adhesive is in place in the trough 25, the applicator roll 4 must not stop turning or the adhesive will leak between the pattern 6 of the roll 4 and the heated doctor blade 9.
At this point, the equipment is ready for processing and the following sequence takes place.
When the machine is started, the first drive 16 engages and the second drive 18 shuts off, going into a coast stop. The first drive 16 drives the outfeed conveyor 2 through the belt and pulley arrangement 46, drive shaft 17, right angle drive 47 and belt and pulley arrangement 48. Also driven by the first drive 16 are the infeed section 1 and the applicator backup roll 5, all of which are directly tied together through the following arrangement.
Drive shaft 17 driven by the first drive 16 drives the right angle drive 28 which in turn drives pulley A mounted on shaft 29. Pulley A drives pulley B, which is directly tied to gear C. Gear C drives gear D which turns the applicator backup roll 5 speed matched with the outfeed conveyor 2. Note that gear D is not connected to nor driving the outer portion of set-position clutch gear 30. Gear D also turns gear E. Gear E drives gear F which turns the head shaft 31 of the infeed conveyor 1. The right angle drive 28 also turns pulley G which drives the variable power transmission unit infeed shaft 32 through pulley H.
The unit 24 is required for surface speed matching the applicator roll 4. As the applicator rolls are reconditioned, the diameter of the roll becomes smaller due to regrinding. This changing diameter results in a slight change in surface speed which is compensated for by the variable power transmission unit 24.
The output shaft 23 of the unit 24 turns pulley I. Pulley I drives pulley J which is directly connected to gear K. Gear K drives gear L. Gear L turns the outer housing 12 of clutch 10 through clutch gear 30.
The outer housing 12 of clutch 10 is, at this point, turning at a higher rate of speed than the inner housing 13, and will now engage with the inner housing of clutch 10 by locking with the latch 49. The entire machine at this point is running in phase, and the applicator roll 4 is turning in phase with the base equipment, as determined by initial set-up.
At this point when the first drive 16 is stopped, all gearing, infeed conveyor 1, outfeed conveyor 2, the back-up roll 5 and outer portion 12 of clutch 10 stops. At this same instant, the second drive 18 is started and the applicator roll shaft 11 and the inner housing 13 of the clutch 10 will begin to turn clockwise within the locked outer portion 12.
Now, at the restart of the machinery, the inner housing 13 of the clutch 10 may be at any said location out of normal register with the rest of the machinery. However, when the first drive 16 is energized, the second drive 18 will go into a coast stop, and the notch 15 on the inner circumference of the outer housing 12 of the clutch 10 will engage latch 49 on the inner housing 13, placing the roll 4 instantaneously back in register.
In order to achieve this process of adhesive application, the temperature within the roll 4 which is heated by conventional means, is set at 600° F. As a result of the high temperature environment in which the clutch 10 must function, the clutch is designed with an oil cooling system for the purpose of dissipating heat from the bearings, as well as bearing lubrication.
For this purpose, an oil cooling supply unit 33 is provided which circulates oil through the clutch 10 by way of the oil lines 34 and 35 connected to the lubrication ring 36 (FIG. 4). The ring 36 is held fixed by a torque arm 37 fastened to a supply member 38. The oil is circulated to the bearings 39 through an opening 40 in the lubrication ring 36 and passageways 41 in the outer housing 12 and through the clearance 42 between the inner and outer housings 12 and 13 of the clutch 10. The oil is passed back to the supply unit 33 through line 35. This keeps the bearing below their temperature limit, 300° F., thus eliminating bearing seizure.
In addition to the oil cooling there are two fan means 43 and 44 mounted on the outer ends of the inner and outer housings 12 and 13, respectively. The purpose of these fans is to provide additional heat dissipation.
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Disclosed is an apparatus for applying coating material to work pieces in register with a physical characteristic thereof as they are being moved through the apparatus. The apparatus includes an applicator roll, work moving means, and an overrunning clutch, all pre-set to operate in phase with each other when driven by a first drive through the clutch. When the first drive is inoperative, a second drive through the clutch continues rotation of the applicator roll through a supply of coating material. Subsequent reactivation of the first drive means moves the applicator roll in phase with the work moving means and the second drive stops.
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BACKGROUND OF THE INVENTION
This invention relates to a method of inhibiting parasitic activity by inhibiting the biosynthesis of the glycosyl phosphatidylinositol (GPI) anchor of the parasite. More particularly, the invention relates to the inhibition of parasitic activity by contacting said parasite with selected analogs of myristic acid containing various heteroatoms, substituents and unsaturated bonds.
Glycosyl phosphatidylinositols (GPIs) anchors diverse proteins to the plasma membranes of organisms ranging from the yeasts to mammals. See, e.g., the review article by Low, Biochem. J. 244, 1-13 (1987). One of the most completely characterized GPI anchors is that of the variant surface glycoprotein (VSG) of the parasitic protozoan Trypanosoma brucei. See, e.g., the research article by Ferguson et al. Science 239, 753-759 (1988), for the complete primary structure of the GPI anchors of VSG variant 117, and the review of GPI biosynthesis in T. brucei by Englund, Ann. Rev. Biochem. 62, 121-138 (1993). This parasite, in common with other African trypanosomes, evades the mammalian immune system by antigenic variation in which individual genes encoding immunologically distinct VSGs form a dense surface coat. The VSG coat acts as a macromolecular diffusion barrier which protects the parasite from lytic host-serum components.
Trypanosoma brucei is a protozoan bloodstream parasite responsible for African sleeping sickness which has a devastating effect on human health and on livestock production. Consequently, methods of inhibiting the activity of this and related protozoan parasites would have significant importance to medical science and for the development of therapeutic intervention to parasitic diseases.
Recently, in U.S. Pat. No. 5,151,445, certain myristic acid analogs have been disclosed as useful for inhibiting the growth and viability of bloodstream trypanosome parasites having a GPI membrane anchor. These analogs are oxy-substituted fatty acid analogs of C 13 and C 14 fatty acids or alkyl esters thereof in which a methylene group normally in carbon position from 4 to 13 of said fatty acid is replaced with oxygen. See also Doering et al., Science 252, 1851-1854 (1991).
BRIEF DESCRIPTION OF THE INVENTION
In accordance with the present invention, a method is provided for inhibiting parasitic activity of a bloodstream trypanosome parasite which comprises contacting said parasite with a compound selected from a group of myristic acid analogs containing various. heteroatoms, substituents and unsaturated bonds. For purposes of convenience, these 53 selected analogs are divided into the following sub-groups with their chemical formulas being shown.
Thiatetradecanoic Acids
CH 3 --S--(CH 2 ) 11 --COOH
CH 3 --CH 2 --S--(CH 2 ) 10 --COOH
CH 3 --(CH 2 ) 3 --S--(CH 2 ) 8 --COOH
CH 3 --(CH 2 ) 4 --S--(CH 2 ) 7 --COOH
CH 3 --(CH 2 ) 5 --S--(CH 2 ) 6 --COOH
CH 3 --(CH 2 ) 6 --S--(CH 2 ) 5 --COOH
CH 3 --(CH 2 ) 7 --S--(CH 2 ) 4 --COOH
CH 3 --(CH 2 ) 8 --S--(CH 2 ) 3 --COOH
Oxygen and Sulfur Containing Analogs
CH 3 --CH 2 --S--(CH 2 ) 2 --O--(CH 2 ) 7 --COOH
Oxotetradecanoic Acids
CH 3 --CO--(CH 2 ) 11 --COOH
CH 3 --(CH 2 ) 2 --CO--(CH 2 ) 9 --COOH
CH 3 --(CH 2 ) 3 --CO--(CH 2 ) 8 --COOH
CH 3 --(CH 2 ) 4 --CO--(CH 2 ) 7 --COOH
CH 3 --(CH 2 ) 6 --CO--(CH 2 ) 5 --COOH
CH 3 --(CH 2 ) 8 --CO--(CH 2 ) 3 --COOH
CH 3 --(CH 2 ) 9 --CO--(CH 2 ) 2 --COOH
Ester-containing Analogs
CH 3 --O--CO--(CH 2 ) 10 --COOH
CH 3 --(CH 2 ) 2 --O--CO--(CH 2 ) 8 --COOH
CH 3 --(CH 2 ) 3 --O--CO--(CH 2 ) 7 --COOH
CH 3 --(CH 2 ) 5 --O--CO--(CH 2 ) 5 --COOH
CH 3 --(CH 2 ) 6 --O--CO--(CH 2 ) 4 --COOH
CH 3 --(CH 2 ) 7 --O--CO--(CH 2 ) 3 --COOH
CH 3 --(CH 2 ) 8 --O--CO--(CH 2 ) 2 --COOH
Nitroalkylcarboxylic Acids
O 2 N--(CH 2 ) 12 --COOH
O 2 N--(CH 2 ) 10 --COOH
Halogenated Analogs
Br--(CH 2 ) 12 --COOH
Br--(CH 2 ) 13 --COOH
Tetradecenoic Acids
CH 3 --CH 2 --CH═CH--(CH 2 ) 9 --COOH
CH 3 --(CH 2 ) 5 --CH═CH--(CH 2 ) 5 --COOH
CH 3 --(CH 2 ) 6 --CH═CH--(CH 2 ) 4 --COOH
Tetradecadienoic Acids
CH 3 --(CH 2 ) 4 --CH═CH--CH═CH--(CH 2 ) 4 --COOH
CH 3 --(CH 2 ) 5 --CH═CH--CH═CH--(CH 2 ) 3 --COOH
Tetradecynoic Acids
HC≡C--(CH 2 ) 11 --COOH
CH 3 --(CH 2 ) 2 --C≡C--(CH 2 ) 8 --COOH
CH 3 --(CH 2 ) 3 --C≡C--(CH 2 ) 7 --COOH
CH 3 --(CH 2 ) 4 --C≡C--(CH 2 ) 6 --COOH
CH 3 --(CH 2 ) 5 --C≡C--(CH 2 ) 5 --COOH
CH 3 --(CH 2 ) 6 --C≡C--(CH 2 ) 4 --COOH
CH 3 --(CH 2 ) 7 --C≡C--(CH 2 ) 3 --COOH
CH 3 --(CH 2 ) 5 --C≡C--(CH 2 ) 4 --COOH
Aromatic Moiety-containing Analogs
11 Carbon Equivalent Length
C 6 H 5 --(CH 2 ) 7 --COOH
13 Carbon Equivalent Length
C 6 H 5 --(CH 2 ) 9 --COOH
CH 3 --CH 2 --C 6 H 4 --(CH 2 ) 7 --COOH
CH 3 --(CH 2 ) 3 --O--C 6 H 4 --(CH 2 ) 4 --COOH
14 Carbon Equivalent Length
C 6 H 5 --(CH 2 ) 10 --COOH
CH 3 --(CH 2 ) 4 --O--C 6 H 4 --(CH 2 ) 4 --COOH
CH 3 --(CH 2 ) 3 --O--C 6 H 4 --CH═CH--(CH 2 ) 3 --COOH
CH 3 (CH 2 ) 4 --O--C 6 H 4 --CH═CH--(CH 2 ) 2 --COOH
Hetero-aromatic analogs
CH 3 --(CH 2 ) 6 -furyl-(CH 2 ) 3 --COOH
CH 3 --(CH 2 ) 5 -furyl-(CH 2 ) 4 --COOH
CH 3 --(CH 2 ) 4 -furyl-(CH 2 ) 5 --COOH
2-Furyl-(CH 2 ) 10 --COOH
2-Thienyl-(CH 2 ) 10 --COOH
The chemical structures of the fifteen preferred compounds in the foregoing sub-groups are shown in Table 1 below. These compounds are listed in the approximate order of their toxic effect upon trypanosomes in culture, with the most toxic compounds at the top of the list. For purposes of comparison, the structures of five representative oxy-myristic acid analogs (oxatetradecanoic acids) disclosed in U.S. Pat. No. 5,151,445, are also included in this list. These five oxy-myristic acid analogs are as follows:
11-oxatetradecanoic acid, abbrev. 0-11
10-oxatetradecanoic acid, abbrev. 0-10
8-oxatetradecanoic acid, abbrev. 0-8
7-oxatetradecanoic acid, abbrev. 0-7
5-oxatetradecanoic acid, abbrev. 0-5
TABLE 1__________________________________________________________________________Activityorder Compound Structure and systematic name__________________________________________________________________________ 1 CH.sub.3 (CH.sub.2).sub.3 C.tbd.C(CH.sub.2).sub.7 COOH 9-tetradecynoic acid 2 CH.sub.3 (CH.sub.2).sub.6 --O--(CH.sub.2).sub.5 COOH 7-oxatetradecanoic acid 3 CH.sub.3 (CH.sub.2).sub.6 --CO--(CH.sub.2).sub.5 COOH 7-oxotetradecanoic acid 4 CH.sub.3 (CH.sub.2).sub.6 --S--(CH.sub.2).sub.5 COOH 7-thiatetradecanoic acid 5 CH.sub.3 (CH.sub.2).sub.8 --S--(CH.sub.2).sub.3 COOH 5-thiatetradecanoic acid 6 CH.sub.3 (CH.sub.2).sub.7 --O--CO--(CH.sub.2).sub.3 COOH mono-n-octyl glutarate 7 CH.sub.3 (CH.sub.2).sub.5 --CH═CH--CH═CH--(CH.sub.2).sub.3 COOH 5,7-tetradecadienoic acid 8 CH.sub.3 (CH.sub.2).sub.4 C.tbd.C(CH.sub.2).sub.6 COOH 8-tetradecynoic acid 9 CH.sub.3 (CH.sub.2).sub.3 --O-p-C.sub.6 H.sub.4 --(CH.sub.2).sub.4 COOH 5-(p-butoxyphenyl)pentanoic acid10 CH.sub.3 (CH.sub.2).sub.5 -2,5-C.sub.4 H.sub.2 O--(CH.sub.2).sub.4 COOH 5- 2-(5-n-hexylfuryl)!pentanoic acid11 O.sub.2 N--(CH.sub.2).sub.12 COOH 13-nitrotridecanoic acid12 CH.sub.3 (CH.sub.2).sub.4 --O-p-C.sub.6 H.sub.4 --(CH.sub.2).sub.4 COOH 5-(p-pentoxyphenyl)pentanoic acid13 CH.sub.3 (CH.sub.2).sub.2 --O--(CH.sub.2).sub.9 COOH 11-oxatetradecanoic acid14 CH.sub.3 (CH.sub.2).sub.3 --O--(CH.sub.2).sub.8 COOH 10-oxatetradecanoic acid15 CH.sub.3 (CH.sub.2).sub.8 --O--(CH.sub.2).sub.3 COOH 5-oxatetradecanoic acid16 CH.sub.3 --S--(CH.sub.2).sub.11 COOH 13-thiatetradecanoic acid17 CH.sub.3 (CH.sub.2).sub.5 --O--(CH.sub.2).sub.6 COOH 8-oxatetradecanoic acid18 CH.sub.3 (CH.sub.2).sub.8 --O--CO--(CH.sub.2).sub.2 COOH mono-n-nonyl succinate19 CH.sub.3 (CH.sub.2).sub.6 --CO--(CH.sub.2).sub.3 COOH 5-oxotetradecanoic acid20 CH.sub.3 (CH.sub.2).sub.4 --S--(CH.sub.2).sub.7 COOH 9-thiatetradecanoic acid__________________________________________________________________________
DETAILED DESCRIPTION OF THE INVENTION
While the specification concludes with claims particularly pointing out and distinctly claiming the subject matter regarded as forming the present invention, it is believed that the invention will be better understood from the following detailed description taken in conjunction with the accompanying drawings in which briefly:
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 is a bar graph which shows: Assay of analog toxicity. The toxicity of 16 compounds, identified only by code number was assessed relative to 11-oxatetradecanoic acid (0-11) and ethanol (E) controls. Each bar shows the mean and standard deviation of quadruplicate assays. All compounds were tested at 10 μM. The 0.1% ethanol in control E, corresponding to the final concentration of solvent present in other assays, had no effect on growth. Brackets on the right of the graph indicate the efficacy group designations for this test. As described in Methods herein below, 11-oxatetradecanoic acid and ethanol controls are defined as the middle value of groups 1 and 3, respectively. Compound codes corresponded to the following structures: 21, CH 3 --(CH 2 ) 3 --CO--(CH 2 ) 8 --COOH; 22, CH 3 --(CH 2 ) 7 --NH--CO--(CH 2 ) 3 --COOH; 23, CH 3 --(CH 2 ) 5 --COOH; 24, ethanol; 25, CH 3 --(CH 2 ) 4 --CO--(CH 2 ) 7 --COOH; 26, CH 3 --(CH 2 ) 10 --CO--CH 2 --COOH; 27, CH 3 (CH 2 ) 2 --O--(CH 2 ) 9 COOH (11-oxatetradecanoic acid); 28, CH 3 --(CH 2 ) 8 --CO--(CH 2 ) 3 --COOH; 29, CH 3 --(CH 2 ) 6 --NH--CO--(CH 2 ) 4 --COOH; 30, CH 3 --CH 2 --CO--(CH 2 ) 10 --COOH; 31, CH 3 --(CH 2 ) 5 --CO--(CH 2 ) 6 --COOH; 32, CH 3 --(CH 2 ) 9 --CO--(CH 2 ) 2 --COOH; 33, CH 3 --(CH 2 ) 2 --CO--(CH 2 ) 9 --COOH; 34, CH 3 --(CH 2 ) 8 --NH--CO--(CH 2 ) 2 --COOH; 35, CH 3 --CO--(CH 2 ) 11 --COOH; 36, CH 3 --(CH 2 ) 7 --CO--(CH 2 ) 4 --COOH.
FIGS. 2A and 2B show the chemical structures of the 20 myristate analogs most toxic to trypanosomes arranged into structural groups.
Most of the myristic acid analogs used in the method of the present invention are well-known compounds which have been previously described as useful antiviral agents. See, e.g., Bryant et al., Proc. Natl. Acad. Sci. USA 86, 8655-8659 (1989), and Bryant et al., Ibid. 88, 2055-2059 (1991). In their activity as antiparasitic agents in the present invention, these myristic analogs function in a different manner than as antiviral agents. In their antiviral activity, these compounds serve as substrates of myristoyl CoA:protein N-myristoyltransferase, an enzyme which transfers myristate from myristoyl CoA to the amino terminal glycine residue of eukaryotic cellular and viral protein. In their antiparasitic activity, these compounds are incorporated into the GPI anchor of the parasite. However, the antiparasitic activity may also be mediated, in part, by alteration of N-myristoylated proteins, or by some change in membrane structure caused by incorporation of the myristic acid analog into phospholipids.
The syntheses of the myristic acid analogs used in the method of the present invention also are well-known. Thus, the synthesis of sulfur-containing myristic acid analogs is described, e.g., by Heuckeroth et al., J. Biol. Chem. 263, 2127-2133 (1988), Heuckeroth et al., Proc. Natl. Acad. Sci. USA 85, 8795-8799 (1988), and in U.S. Pat. Nos. 5,073,571 and 5,082,967. Double bond- and triple bond-containing myristic acid analogs are also described in said patents, in Heuckeroth et al., Proc. Natl. Acad. Sci. USA 85, 8795-8799 (1988), and in Rudnick et al., Proc. Natl. Acad. Sci. USA 89, 10507-10511 (1992). Synthesis of azido-substituted myristic acid analogs is described in EP 480,901. The preparation of many of these and other such myristic acid analogs containing oxygen, sulfur, double bond, triple bond and aromatic residues is described in Kishore et al., J. Biol. Chem. 266, 8835-8855 (1991). Synthesis of myristic acid analogs containing carbonyl groups, nitrogen heteroatoms and nitrogen heterocycles is described in Devadas et al., J. Biol. Chem. 267, 7224-7239 (1992). The synthesis of still other such triple bond- and aromatic moiety-containing analogs of myristic acid is described by Gokel et al., Israel J. Chem. 32, 127-133 (1992). Examples 1-43, below, illustrate the synthesis of 40 additional test compounds.
In order to illustrate the invention in greater detail, a total of 247 different myristic acid analogs (listed in Table 2, below) were tested for toxicity to trypanosomes in culture in accordance with a state-of-the-art assay. For comparison the testing included five oxy-myristic acid analogs (oxatetra-decanoic acids) described in U.S. Pat. No. 5,151,445, the disclosure of which is incorporated herein by reference. Based on the test results, these 247 compounds were divided into three efficacy groups in which groups 2 and 3 consisted of the 60 active compounds whereas the 177 compounds of group 1 were inactive. Of the active compounds, the 20 compounds in group 3 were the most active. Although specific examples of the invention are thus illustrated herein, it will be understood that the invention is not limited to these specific examples or the details described therein. References to show the state-of-the-art are indicated in parentheses and appended at the end.
EXAMPLES
Materials and Methods
Materials--Fetal calf serum, hypoxanthine, MEM "alpha" medium (320-2561 AJ), penicillin, pyruvate, streptomycin and thymidine were obtained from Gibco/BRL. Other reagents, where not specified, were from Sigma Chemical Co.
Synthesis of fatty acid analogs. The methods used for synthesizing 203 of the 247 fatty acids shown in Table 1 are described in published reports (Rapaport and Newman, 1947; Kishore et al., 1991; Devadas et al., 1992; Gokel et al., 1992; Rudnick et al., 1992; footnote 3). The methods used to synthesize 40 additional fatty acids included in the panel are described below.
Chemical Analysis. Melting points were measured on a Laboratory Devices MEL-TEMP apparatus in open capillaries and are uncorrected. 1 H-NMR spectra were recorded on a Hitachi Perkin-Elmer R-600 high resolution NMR spectrometer and on a Varian VXR 400 superconducting NMR. Spectra were obtained in CDCl 3 and are reported in ppm (δ) downfield from internal Me 4 Si. IR spectra were recorded on a Perkin-Elmer Model 298 or 599 infrared spectrophotometer. TLC analyses were performed on silica gel 60F-254 plates (thickness=0.20 mm; Merck). Column chromatography was carried out with Merck Kieselgel 60 (70-230 mesh). Combustion analyses were conducted by Atlantic Microlab Inc., Atlanta, Ga. High resolution mass spectrometry was conducted at the Southern California Mass Spectrometer Facility, Department of Chemistry, University of California, Riverside. The CI/NH 3 experiments did not typically show MH+ ions so high resolution mass spectrometry was done on MNH 4 + ions.
General procedure for Wittig reaction. Phosphonium bromide was treated with potassium t-butoxide in tetrahydrofuran (THF) under nitrogen with stirring for 30 min. The solution was cooled with ice. Aldehyde in THF was added dropwise, and the mixture was stirred for 12 h. The mixture was poured into water (150 mL), washed with Et 2 O (50 mL), acidified (pH=1, 2N HCl) and extracted (hexanes, 4×50 mL), dried over MgSO 4 , and the solvent was removed in vacuo. Chromatography (silica gel, 1:1 hexanes-ethyl acetate) and crystallization or Kugelrohr distillation yielded the product.
General procedure for hydrolysis reaction. A nitrile or ester containing compound, sodium hydroxide H 2 O (20 mL), and EtOH (20 mL) were mixed and refluxed for 16 h. The mixture was cooled to room temperature, acidified (pH=1, 2N HCl), and extracted with ethyl acetate (4×50 mL). The organic solution was washed with water (2×50 mL), dried over MgSO 4 and evaporated. The residue was crystallized or distilled to afford the product.
General procedure for hvdrogenation reaction An unsaturated compound, 5% Pd/C or Pd/BaSO 4 and anhydrous EtOH (50 mL) were shaken under 15 psi H 2 for 1.0-4.0 h. The catalyst was filtered and washed with EtOH (2×15 mL). The solvent was evaporated in vacuo. The residue was crystallized or Kugelrohr distilled to afford the product.
TETRADECANDIENOIC ACIDS
Example 1
8,10-Tetradecandienoic acid. This compound was synthesized from 7-carboxyheptyltriphenylphosphonium bromide (9.71 g, 20 mmol) and 2-trans-hexenal (1.96 g, 20 mmol) in 10% hexamethylphosphoric triamide (HMPA)-THF (100 mL) by a Wittig reaction. Kugelrohr distillation yielded the product (1.97 g, 44%) as a yellow oil (bp 123°-126° C./0.01 torr). IR: 3450-2500, 1720 cm -1 ; 1 H-NMR: 0.95 (t, 3H), 1.35 (m, 8H), 1.62 m, 2H), 2.05 (m, 4H), 2.32 (t, 2H), 5.23 (m, 1H), 5.60 (m, 1H), 5.90 (m, 1H), 6.05 (m, 1H), 10.50 (bs, 1H). Anal. Calcd. for C 14 H 24 O 2 : C, 74.95, H, 10.78%; Found: C, 75.01, H, 10.80%.
Example 2
6,8-Tetradecanedienoic acid. This compound was synthesized from 5-carboxypentyltriphenylphosphonium bromide (9.50 g, 20 mmol) and 2-trans-octenal (2.52 g, 20 mmol) in 10% HMPA-THF (100 mL) by Wittig reaction. Kugelrohr distillation yielded the product (1.91 g, 43%) as a pale yellow oil (bp 122°-125° C./0.01 torr). IR: 3500-2500, 1730 cm -1 ; 1 H-NMR: 0.95 (t, 3H), 1.40 (m, 10H), 2.30 (m, 6H), 6.00 (m, 4H), 11.30 (bs, 1H). Anal. Calcd. for C 14 H 24 O 2 : C, 74.95, H, 10.78%; Found: C, 75.04, H, 10.80%.
Example 3
5,7-Tetracanedienoic acid. This compound was synthesized from 4-carboxybutyltriphenylphosphonium bromide (8.87 g, 20 mmol) and 2-trans-nonenal (2.80 g, 20 mmol) in 10% HMPA-THF (100 mL) by a Wittig reaction. Kugelrohr distillation afforded the product (1.96 g, 44%) as a pale yellow oil (bp 116°-119° C./0.01 torr). IR: 3500-2500, 1730 cm -1 ; 1 H-NMR: 0.90 (t, 3H), 1.35 (m, 10H), 2.30 (m, 6H), 5.90 (m, 4H), 10.05 (bs, 1H). Anal. Calcd. for C 14 H 24 O 2 : C, 74.95, H, 10.78%; Found: C, 74.87, H, 10.79%.
AROMATIC ANALOGS
Example 4
8-Phenoxyoctanoic acid. Phenol (1.88 g, 20 mmol) was mixed with NaOH (0.80 g, 20 mmol) in EtOH (50 mL). 8-Bromooctanoic acid (2.23 g, 10 mmol) was then added to the mixture and refluxed for 12 h. After cooling to room temperature, water (100 mL) was added and the mixture was acidified with 2N HCl (pH=2). The solid was filtered and washed with water (2×50 mL), and recrystallized from hexane-ethyl acetate (5:1) to give the product as white brick-like crystals (1.79 g, 76%), mp 67°-68° C.; 1 H-NMR: 1.42 (m, 6H), 1.65 (m, 2H), 1.80 (m, 2H), 2.37 (t, 2H), 3.97 (t, 2H), 6.93 (m, 3H), 7.30 (t, 2H), 10.05 (bs, 1H). Anal. Calcd. for C 14 H 20 O 3 : C, 71.16, H, 8.53%; Found: C, 71.09, H, 8.54%.
Example 5
8-(p-Methoxyphenyl)-7-octennitrile. This compound was synthesized from 6-cyanohexyltriphenylphosphonium bromide (9.05 g, 20 mmol) and p-anisaldehyde (2.72 g, 20 mmol) in THF (100 mL) by a Wittig reaction. Kugelrohr distillation afforded the products (3.26 g, 71%) as a colorless liquid (bp: 143°-146° C./0.05 torr). IR: 2285 cm -1 ; 1 H-NMR: 1.50 (m, 6H), 2.30 (m, 4H), 3.80 (s, 3H), 5.50 (m, 1H), 6.30 (d, 1H), 7.05 (q, 4H).
Example 6
8-(p-Methoxyphenyl)-7-octenoic acid. This compound was synthesized from 8-(p-methoxyphenyl)-7-octennitrile (3.34 g, 15 mmol) by a hydrolysis reaction. Crystallization (hexanes-ethyl acetate) yielded the product (3.29 g, 88%) as white crystals (mp 42°-43° C.). IR: 3400-2500, 1730 cm -1 ; 1 H-NMR: 1.50 (m, 6H), 2.35 (m, 4H), 3.82 (s, 3H), 5.55 (m, 1H), 6.35 (d, 1H), 7.05 (q, 4H), 11.20 (bs, 1H). Anal. Calcd. for C 15 H 20 O 2 : C, 72.55, H, 8,12% Found: C, 72.41, H, 8.07%, Z:E=67:33.
Example 7
8-(p-Methoxyphenyl)octanoic acid. This compound was synthesized from 8-(p-methoxyphenyl)-7-octenoic acid (1.24 g, 5 mmol) and Pd/BaSO 4 (125 mg) by hydrogenation. Crystallization (petroleum ether) afforded the product (1.20 g, 96%) as white crystals (mp 42°-43° C.). IR: 3400-2500, 1705 cm -1 ; 1 H-NMR: 1.40 (m, 10H), 2.40 (m, 4H), 3.80 (s, 3H), 6.95 (q, 4H), 10.10 (bs, 1H). Anal. Calcd. for C 15 H 22 O 2 : C, 71.97, H, 8.86%; Found: C, 72.07, H, 8.88%.
Example 8
7-(p-Ethoxyphenyl)-6-heptenoic acid. This compound was synthesized from 5-carboxypentyltriphenylphosphonium bromide (9.50 g, 20 mmol) and p-ethoxybenzaldehyde (3.00 g, 20 mmol) in THF (100 mL) by a Wittig reaction. Crystallization (hexanes-ethyl acetate) afforded the product (3.18 g, 64%) as white crystals (mp 62°-63° C.), IR: 3450-2500, 1720 cm -1 ; 1 H-NMR: 1.40 (t, 3H), 1.50 (m, 2H), 1.70 (m, 2H), 2.38 (m, 4H), 4.00 (q, 2H), 5.72+6.05 (m, 1H), 6.32 (t, 1H), 7.05 (q, 4H), 10.10 (bs, 1H). Anal. Calcd. for C 15 H 20 O 3 : C, 72.55, H, 8.12% Found: C, 72.53, H, 8.15%. Z:E=45:55.
Example 9
7-(p-Ethoxyphenyl)heptanoic acid. This compound was synthesized from 7-(p-ethoxyphenyl)-6-heptenoic acid (1.24 g, 5 mmol) and Pd/C (125 mg) by a hydrogenation reaction. Crystallization (petroleum ether) afforded the product (1.21 g, 97%) as white crystals (mp 65°-66° C.). IR: 3400-2500, 1715 cm -1 ; 1 H-NMR: 1.32 (m, 7H), 1.55 (m, 5H), 2.30 (t, 2H), 2.50 (t, 2H), 3.95 (q, 2H), 6.90 (q, 2H), 10.20 (bs, 1H). Anal. Calcd. for C 15 H 22 O 3 : C, 71.97, H, 8.86%; Found: C, 71.91, H, 8.87%.
Example 10
6-(p-Propoxyphenyl)-5-hexenoic acid. This compound was synthesized from 4-carboxybutyltriphenylphosphonium bromide (8.87 g, 20 mmol) and p-propoxybenzaldehyde (3.28 g, 20 mmol, synthesized from p-hydroxybenzaldehyde and 1-iodopropane) in THF (100 mL) by a Wittig reaction. Crystallization (petroleum ether) afforded the product (3.75 g, 76%) as white crystals (mp, 49°-50° C.). IR: 3400-2500, 1725 cm -1 ; 1 H-NMR: 1.00 (t, 3H), 1.75 (m, 4H), 2.35 (m, 4H), 3.90 (t, 2H), 5.55 (m, 1H), 6.35 (m, 1H), 7.00 (q, 4H), 11.30 (bs, 1H). Anal. Calcd. for C 15 H 20 O 3 : C, 72.55, H, 8.12%; Found: C, 72.45, H, 8.13%. Z:E=35:65.
Example 11
6-(p-Propoxyphenyl hexanoic acid. This compound was synthesized from 6-(p-propoxyphenyl)-5-hexenoic acid (1.49 g, 6 mmol) and Pd/BaSO 4 (150 mg) by a hydrogenation reaction. Crystallization (petroleum ether) yielded the product (1.38 g, 92%) as white crystals (mp 42°-43° C.), IR: 3400-2500, 1715 cm -1 ; 1 H-NMR: 1.00 (t, 3H), 1.55 (m, 8H), 2.40 (m, 4H), 3.90 (t, 2H), 6.95 (q, 4H), 7.90 (bs, 1H). Anal. Calcd. for C 15 H 22 O 3 : C, 71.97, H, 8.86%; Found: C, 72.04, H, 8.88%.
General Procedure for the Preparation of Aryl-terminal Acids
Example 12
9-Phenoxynonanoic acid
A. 7-Phenoxyheptyl bromide, Phenol (3.10 g, 33 mmol), 1,7-dibromoheptane (7.74 g, 30 mmol) and NaOH (1.34 g, 33 mmol) were refluxed in EtOH (40 mL) for 30 h. After cooling to room temperature, water (150 mL) was added and the mixture was extracted with ethyl acetate (4×50 mL). The organic phase was washed with water (50 mL) and brine (50 mL), and the mixture was dried over Na 2 SO 4 . After evaporation of solvent, the residue was purified by Kugelrohr distillation to give 7-phenoxyheptyl bromide (2.46 g, 30%), bp 126°-130° C./0.10 torr, 1 H-NMR: 1.2-1.9 (m, 10H), 3.36 (t, 2H), 3.91 (t, 2H), 6.7-7.2 (m, 5H).
B. Ethyl 2-ethoxycarbonyl-9-phenoxynonanoate. Sodium (0.22 g, 9.6 mmol) was dissolved in EtOH (20 mL). Diethyl malonate (1.53 g, 9.6 mmol) in EtOH (5 mL) and 7-phenoxyheptyl bromide (2.36 g, 8.7 mmol) in EtOH (5 mL) were subsequently added at room temperature. The reaction mixture was refluxed for 8 h. After evaporation of the solvent, the residue was taken up in ethyl acetate (150 mL). The organic phase was washed with water (2×50 mL), and brine (50 mL), and dried over Na 2 SO 4 . The crude product was purified by Kugelrohr distillation to give ethyl 2-ethoxycarbonyl-9-phenoxynonanoate (1.92 g, 63%), bp 150°-154° C./0.1 torr, 1 H-NMR: 1.24 (t, 6H), 1.1-1.8 (m, 12H), 3.30 (t, 1H), 3.91 (t, 2H), 4.18 (q, 4H), 6.7-7.2 (m, 5H).
C. 9-Phenoxynonanoic acid. A solution of ethyl 2-ethoxycarbonyl-9-phenoxynonanoate (1.84 g, 5.3 mmol) in 20% NaOH (20 mL) was refluxed for 10 h. The solution was acidified with HCl(pH=2) and extracted with ethyl acetate (3×50 mL). The organic phase was washed with water (2×30 mL), and brine (30 mL), and dried over Na 2 SO 4 . After removal of the solvent in vacuo, the residue was heated on an oil bath at 180°-200° C. for 10 min. The crude product was distilled (Kugelrohr) followed by crystallization (hexane) to give the product (1.14 g, 85%), mp 66.5°-67.5° C. (lit. 3 68°-69° C.). IR: 3450-2550, 1720 cm -1 ; 1 H-NMR: 1.26-1.39 (m, 8H), 1.61 (q, 2H), 1.75 (q, 2H), 2.34 (t, 2H), 3.93 (t, 2H), 6.83-6.96 (m, 3H), 7.28 (t, 2H), 10.8 (bs, 1H).
Example 13
9-Phenylthionanoic acid
A. 7-Phenylthioheptyl bromide was prepared from thiophenol (4.40 g, 40 mmol) and 1,7-dibromoheptane (10.32 g, 40 mmol) as described above for 7-phenoxyheptyl bromide. Yield: 46% bp; 132°-136° C./0.05 torr; 1 H-NMR: 1.30-1.85 (m, 10H), 2.90 (t, 2H), 3.35 (t, 2H), 7.25 (s, 5H).
B. Ethyl 2-ethoxycarbonyl-9-phenylthiononanoate was prepared from 7-phenylthioheptyl bromide (4.31 g, 15 mmol) and diethyl malonate (3.20 g, 20 mmol) according to the procedure given above. Yield: 68%, bp: 174°-178° C./0.05 torr; 1 H-NMR: 1.15-1.90 (m, 18H), 2.90 (t, 2H), 3.30 (t, 1H), 4.20 (q, 4H), 7.25 (s, 5H).
C. 9-Phenylthiononanoic acid was obtained from ethyl 2-ethoxycarbonyl-9-phenylthiononanoate (3.66 g, 10 mmol) by basic hydrolysis as described above. Yield: 82%, mp 67°-68° C.; IR: 3450-2550, 1695 cm -1 ; 1 H-NMR: 1.20-1.80 (m, 12H), 2.35 (t, 2H), 2.85 (t, 2H), 7.20 (s, 5H), 10.50 (bs, 1H). Anal. Calcd. for C 15 H 22 O 2 S: C, 67.63; H, 8.32; S, 12.03%. Found: C, 67.54; H, 8.31; S, 12.09%.
Example 14
8-Benzyloxyoctanoic acid
A. 6-Benzyloxyhexyl bromide was prepared from benzyl alcohol (4.75 g, 44 mmol) and 1,6-dibromohexane (9.76 g, 40 mmol) using the general procedure given above. Yield: 36%, bp 100°-105° C./torr: 1 H-NMR: 1.2-1.9 (m, 8H), 3.37 (t, 4H), 4.46 (s, 2H), 7.28 (m, 5H).
B. Ethyl 2-ethoxycarbonyl-8-benzyloxyoctanoate was prepared from 6-benzyloxyhexyl bromide (3.52 g, 13 mmol) and diethyl malonate (2.29 g, 14 mmol) according to the general procedure given above. Yield 60%, bp 152°-158° C./0.15 torr. 1 H-NMR: 1.24 (t, 6H), 1.2-1.9 (m, 1OH), 3.43 (t, 2H), 4.18 (q, 4H), 4.45 (s, 2H), 7.27 (m, 5H).
C. 8-Benzyloxyoctanoic acid was prepared from ethyl 2-ethoxycarbonyl-8-benzyloxyoctanoate (2.6 g, 7.4 mmol) by basic hydrolysis as described above. Yield: 83%, bp 158°-162° C./0.15 torr; IR: 3450-2550, 1710 cm -1 ; 1 H-NMR: 1.24-1.43 (m, 6H), 1.54-1.69 (m, 4H), 2.31 (t, 2H), 3.46 (t, 2H), 4.51 (s, 2H), 7.23-7.38 (m, 5H), 9.55 (bs, 1H). Anal. Calcd. for C 15 H 22 O 3 : C, 71.97; H, 8.86%. Found: C, 71.83; H, 8.90%.
Example 15
8-Benzylthiooctanoic acid
A. Ethyl 8-benzylthiooctanoate. NaH (0.63 g, 16 mmol) was washed with hexane and then suspended in dry THF (60 mL). Benzylmercaptan (1.86 g, 15 mmol) in THF (20 mL) was added and the mixture stirred for 30 min at room temperature. Ethyl 8-iodooctanoate (4.47 g, 15 mmol) in THF (20 mL) was added and the mixture was refluxed for 12 h. After evaporation of the solvent, the residue was dissolved in ethyl acetate (150 mL). The organic phase was washed with water (2×50 mL), and brine (50 mL) and dried over Na 2 SO 4 . The crude product was purified by column chromatography on silica gel with ethyl acetate:hexane (1:5) and subsequent Kugelrohr distillation to give ethyl 8-benzylthiooctanoate (3.7 g, 84%), bp 134°-138° C./0.15 torr. 1 H-NMR: 1.21 (t, 3H), 1.2-1.8 (m, 10H), 2.27 (t, 4H), 3.68 (s, 2H), 4.09 (q, 2H), 7.24 (m, 5H).
B. 8-Benzylthiooctanoic acid. A solution of ethyl 8-benzylthiooctanoate (2.94 g, 10 mmol) and 1M NaOH (60 mL, 60 mmol) in MeOH (30 mL) was heated at 70° C. for 6 h. The reaction mixture was acidified with HCl (pH=1) and extracted with ethyl acetate (150 mL). The organic phase was washed with water (2×50 mL), and brine (50 mL), and dried over Na 2 SO 4 . The crude product was purified by crystallization from hexane to afford the product (2.45 g, 92%), mp 37°-37.5° C.; IR: 3400-2500, 1700 cm -1 ; 1 H-NMR: 1.18-1.43 (m, 6H), 1.52 (q, 2H), 1.61 (q, 2H), 2.33 (t, 2H), 2.39 (t, 2H), 3.69 (s, 2H), 7.12-7.38 (m, 5H), 9.45 (bs, 1H). Anal. Calcd. for C 15 H 22 SO 2 : C, 67.63, H, 8.32%; Found: C, 67.74, H, 8.35%.
Example 16
8-(p-Propylphenyl)-7-octenenitrile. This compound was synthesized from 6-cyanohexyltriphenylphosphonium bromide (9.05 g, 20 mmol) and p-propylbenzaldehyde (2.96 g, 20 mmol) in THF (100 mL) by a Wittig reaction. Kugelrohr distillation afforded the product (3.25 g, 67%) as a colorless liquid (bp 144°-148° C./0.05 torr). IR 2290 cm -1 ; 1 H-NMR: 0.95 (t, 3H), 1.55 (m, 8H), 2.40 (m, 6H), 5.60 (m, 1H), 6.40 (d, 1H), 7.10 (s, 4H).
Example 17
8-(p-Propylphenyl)-7-octenoic acid. This compound was synthesized from 8-(p-propylphenyl)-7-octenenitrile (2.41 g, 10 mmol) by a hydrolysis reaction. Kugelrohr distillation afforded the product (2.36 g, 90%) as a colorless oil (bp 148°-152° C./0.05 torr). IR: 3400-2500, 1720 cm -1 ; 1 H-NMR: 0.95 (t, 3H), 1.45 (m, 8H), 2.45 (m, 6H), 5.65 (m, 1H), 6.40 (d, 1H), 7.15 (s, 4H), 11.30 (bs, 1H). Anal. Calcd. for C 17 H 24 O 2 : C, 78.42, H, 9.29%; Found: C, 78.43, H, 9.30%. Z:E=88:12.
Example 18
8-(p-Propylphenyl)octanoic acid. This compound was synthesized from 8-(p-propylphenyl)-7-octenoic acid (1.30 g, 5 mmol) and Pd/BaSO 4 (130 mg) by a hydrogenation reaction. Crystallization (petroleum ether) afforded the product (1.25 g, 95%) as white crystals (mp 42°-43° C.). IR: 3400-2500, 1705 cm -1 ; 1 H-NMR: 0.95 (t, 3H), 1.45 (m, 12H), 2.50 (m, 6H), 7.05 (s, 4H), 11.40 (bs, 1H). Anal. Calcd. for C 17 H 26 O 2 : C, 77.82, H, 9.99%; Found: C, 77.75, H, 10.04%.
Example 19
7-(p-Butylphenyl)-6-heptenoic acid. This compound was synthesized from 5-carboxypentyltriphenylphosphonium bromide (9.50 g, 20 mmol) and p-butylbenzaldehyde (3.24 g, 20 mmol) in THF (100 mL) by a Wittig reaction. Kugelrohr distillation yielded the product (2.67 g, 51%) as a colorless oil (bp 154°-157° C./0.05 torr). IR: 3400-2500, 1720 cm -1 , 1 H-NMR:0.92 (t, 3H), 1.50 (m, 8H), 2.30 (m, 4H), 2.58 (m, 2H), 5.58+6.15 (m, 1H), 6.38 (t, 1H), 7.18 (m, 4H), 10.30 (bs, 1H). Anal. Calcd. for C 17 H 24 O 2 : C, 78.42, H, 9.29%; Found: C, 78.38, H, 9.29%. Z:E=62:38.
Example 20
7-(p-Butylphenyl)heptanoic acid. This compound was synthesized from 7-(p-butylphenyl)-6-heptenoic acid (1.30 g, 5 mmol) by a hydrogenation reaction using Pd/C (130 mg). Crystallization (petroleum ether) afforded the product (1.19 g, 97%) as white crystals (mp 32°-33° C.). IR: 3400-2500, 1718 cm -1 ; 1 H-NMR: 0.92 (t, 3H), 1.35 (m, 6H), 1.60 (m, 6H), 2.32 (t, 2H), 2.55 (m, 4H), 7.02 (s, 4H), 9.70 (bs, 1H). Anal. Calcd. for C 17 H 26 O 2 : C, 77.82, H, 9.99%; Found: C, 77.73, H, 10.01%.
Example 21
6-(p-Pentylphenyl)-5-hexenoic acid. This compound was synthesized from p-pentylbenzaldehyde (3.52 g, 20 mmol, prepared from p-pentylbenzoyl chloride and lithium tri(t-butoxy)aluminum hydride) and 4-carboxybutyltriphenylphosphonium bromide (8.86 g, 20 mmol) in THF (100 mL) by a Wittig reaction. Kugelrohr distillation (bp 147°-151° C./0.05 torr) afforded the product (2.49 g, 48%). IR: 3400-2500, 1725 cm -1 ; 1 H-NMR: 0.90 (t, 3H), 1.28 (m, 6H), 1.82 (m, 2H), 1.37 (m, 4H), 2.57 (t, 2H), 5.55+6.10 (m, 1H), 6.38 (m, 1H), 7.10 (m, 4H), 10.50 (bs, 1H). Anal. Calcd. for C 17 H 24 O 2 : C, 78.42, H, 9.29%; Found: C, 78.22, H, 9.27%. Z:E=35:65.
Example 22
6-(p-Pentylphenyl)hexanoic acid. This compound was synthesized from 6-(p-pentylphenyl)-5-hexenoic acid (1.30 g, 5 mmol) by hydrogenation reaction using Pd/C (130 mg). Crystallization (petroleum ether) afforded the product (1.13 g, 87%) as white crystals (mp 29°-30° C.), IR: 3400-2500, 1730 cm -1 , 1 H-NMR: 0.89 (t, 3H), 1.32 (m, 6H), 1.60 (m, 6H), 2.35 (t, 2H), 2.58 (m, 4H), 7.07 (s, 1H), 10.30 (bs, 1H). Anal. Calcd. for C 17 H 26 O 2 : C, 77.82, H, 9.99%; Found: C, 77.56, H, 9.90%.
Example 23
7-(p-Propoxyphenyl)-6-heptenoic acid. This compound was synthesized from p-propoxybenzaldehyde (3.26 g, 20 mmol, prepared from 1-bromopropane and 4-hydroxybenzaldehyde) and 5-carboxypentyltriphenylphosphonium bromide (9.50 g, 20 mmol) in THF (100 mL) by a Wittig reaction. Crystallization (petroleum ether) afforded the product (3.15 g, 60%) as white crystals (mp: 52°-53° C.). IR: 3450-2500, 1730 cm -1 ; 1 H-NMR: 1.00 (t, 3H), 1.48 (m, 2H), 1.67 (m, 2H), 1.82 (m, 2H), 2.35 (m, 4H), 3.92 (t, 2H), 5.72+6.05 (m, 1H), 6.35 (d, 1H), 7.05 (q, 4H), 10.40 (bs, 1H). Anal. Calcd. for C 16 H 22 O 3 : C, 73.25, H, 8.45%. Found: C, 73.15, H, 8.45%. Z:E=30:70.
Example 24
7(p-Propoxyphenyl)heptanoic acid. This compound was synthesized from 7-(p-propoxyphenyl)-6-heptenoic acid (1.31 g, 5 mmol) by hydrogenation reaction using Pd/C(130 mg). Crystallization (petroleum ether) afforded the product (1.23 g, 93%) as white crystals (mp: 49°-50° C). IR: 3450-2550, 1725 cm -1 ; 1 H-NMR: 1.00 (t, 3H), 1.37 (m, 4H), 1.60 (m, 4H), 1.79 (m, 2H), 2.36 (t, 2H), 2.53 (t, 2H), 3.87 (t, 2H), 6.95 (q, 4H), 9.80 (bs, 1H). Anal. Calcd. for C 16 H 24 O 3 : C, 72.69, H, 9.15%; Found: C, 72.79, H, 9.16%.
Example 25
6-(p-Butoxyphenyl)-5-hexenoic acid. This compound was synthesized from 4-carboxybutyltriphenylphosphonium bromide (8.86 g, 20 mmol) and p-butoxybenzaldehyde (3.56 g, 20 mmol) in THF (100 mL) by a Wittig reaction. Crystallization (petroleum ether) afforded the product (3.82 g, 73%) as white crystals (mp: 56°-57° C.). IR: 3350-2500, 1700 cm -1 ; 1 H-NMR: 1.00 (t, 3H), 1.50 (m, 2H), 1.80 (m, 4H), 2.40 (m, 4H), 3.90 (t, 2H), 5.50+6.00 (m, 1H), 6.38 (q, 1H), 7.05 (q, 4H), 11.00 (bs, 1H). Anal. Calcd. for C 16 H 22 O 3 : C, 73.25, H, 8.45%; Found: C, 73.32, H, 8.46%. Z:E=37:63.
Example 26
6-(p-Butoxyphenyl)hexanoic acid. This compound was synthesized from 6-(p-butoxyphenyl)-5-hexenoic acid (2.62 g, 10 mmol) by a hydrogenation reaction using Pd/C (260 mg). Crystallization (petroleum ether) afforded the product (2.49 g, 94%) as white crystals (mp 39°-40° C.). IR: 3400=2500, 1705 cm -1 ; 1 H-NMR: 0.96 (t, 3H), 1.35 (m, 2H), 1.50 (m, 2H), 1.62 (m, 4H), 1.75 (m, 2H), 2.35 (t, 2H), 2.52 (t, 2H), 3.92 (t, 2H), 6.95 (q, 4H), 10.30 (bs, 1H). Anal. Calcd. for C 16 H 24 O 3 : C, 72.69, H, 9.15%; Found: C, 72.78, H, 9.18%.
Example 27
Ethyl 8-(4-ethyl)phenoxynonanoate. NaH (0.25 g, 11 mmol) was washed with hexane and then suspended in dry THF (50 mL). 4-Ethylphenol (1.22 g, 10 mmol) in THF (20 mL) was added and stirred for 30 min at room temperature. Ethyl 8-iodooctanoate (2.98 g, 10 mmol) in THF (20 mL) was added and the mixture was refluxed for 12 h. After evaporation of the solvent, the residue was dissolved in ethyl acetate (150 mL), and the organic phase was washed with water (2×50 mL), and brine (50 mL) and dried over Na 2 SO 4 . The crude product was purified by column chromatography on silica gel (ethyl acetate:hexane=1:5) and subsequent Kugelrohr distillation to give the product (0.85 g, 24%), bp 122°-126° C./0.1 torr. IR: 1740 cm -1 ; 1 H-NMR: 1.19 (t, 3H), 1.25 (t, 3H), 1.30-1.80 (m, 10H), 2.28 (t, 2H), 2.57 (q, 2H), 3.90 (t, 2H), 4.12 (q, 2H), 6.86 (d, 2H), 7.08 (d, 2H).
Example 28
8-(4-Ethyl)phenoxyoctanoic acid. This compound was synthesized from ethyl 8-(4-ethyl)phenoxyoctanoate (1.76 g, 5 mmol) by a hydrolysis reaction. Crystallization from hexane gave white crystals (1.40 g, 87%), mp 77°-78° C.; IR: 3450-2950, 1720 cm -1 ; 1 H-NMR: 1.17 (t, 3H), 1.29-1.49 (m, 6H), 1.63 (q, 2H), 1.74 (q, 2H), 2.31 (t, 2H), 2.56 (q, 2H), 3.88 (t, 2H), 6.77 (d, 2H), 7.06 (d, 2H), 10.2 (bs, 1H). Anal. Calcd. for C 16 H 24 O 3 : C, 72.69, H, 9.15%; Found: C, 72.53, H, 9.19%.
Example 29
12-Phenyl-11-dodecenoic acid. This compound was synthesized from 10-carboxydecyltriphenylphosphonium bromide (10.55 g, 20 mmol) and benzaldehyde (2.12 g, 20 mmol) in THF (100 mL) by a Wittig reaction. Kugelrohr distillation (bp 152°-155° C./0.03 torr) and crystallization afforded the product (2.43 g, 44%) as white crystals (mp 27°-27.5° C.). IR: 3400-2500, 1720, 700 cm -1 ; 1 H-NMR: 1.30 (m, 10H), 1.40 (m, 2H), 1.62 (m, 2H), 2.35 (m, 4H), 5.65 (m, 1H), 6.40 (m, 1H), 7.25 (m, 5H), 10.40 (bs, 1H). Anal. Calcd. for C 18 H 26 O 2 : C, 78.79, H, 9.55%; Found: C, 78.66, H, 9.60%. Z:E=93:7.
Example 30
12-Phenyldodecanoic acid. This compound was synthesized from 12-phenyl-10-dodecenoic acid (1.92 g, 7 mmol) by a hydrogenation reaction using Pd/C (190 mg). Crystallization (petroleum ether) afforded the product (1.88 g, 97%) as white crystals (mp 47°-48° C.). IR: 3400-2500, 1700 cm -1 ; 1 H-NMR: 1.30 (m, 14H), 1.60 (m, 4H), 2.32 (t, 2H), 2.57 (t, 2H), 7.20 (m, 5H), 10.20 (bs, 1H). Anal. Calcd. for C 18 H 28 O 2 : C, 78.21, H, 10.21%; Found: C, 78.29, H, 10.25%.
HETEROAROMATIC ANALOGS
Example 31
9-(2-Furyl)-8-nonenoic acid. This compound was synthesized from 7-carboxyheptyltriphenylphosphonium bromide (9.71 g, 20 mmol) and 2-furaldehyde (1.92 g, 20 mmol) in THF (100 mL) by a Wittig reaction. Kugelrohr distillation yielded the product (2.69 g, 61%) as a pale yellow oil (bp 136°-139° C./0.05 torr). IR: 3500-2500, 1730, 710 cm -1 ; 1 H-NMR: 1.40 (m, 8H), 2.35 (m, 4H), 5.55 (m, 1H), 6.30 (m, 3H), 7.35 (s, 1H), 11.40 (bs, 1H). Anal. Calcd. for C 13 H 18 O 3 : C, 70.25, H, 8.16%; Found: C, 69.98, H, 8.26%. Z:E=79:21.
Example 32
9-(2-Furyl)nonanoic acid. This compound was synthesized from 9-(2-furyl)-8-nonenoic acid (0.89 g, 4 mmol) by a hydrogenation reaction using Pd/BaSO 4 (90 mg). Crystallization (petroleum ether) afforded the product (0.84 g, 93%) as white crystals (mp 31°-32° C.); IR: 3450-2500, 1720 cm -1 ; 1 H-NMR: 1.30 (m, 8H), 1.63 (m, 4H), 2.35 (t, 2H), 2.60 (t, 2H), 5.95 (s, 1H), 6.27 (s, 1H), 7.28 (s, 1H), 9.85 (bs, 1H). Anal. Calcd. for C 13 H 20 O 3 : C, 69.61, H, 8.99%; Found: C, 69.42, H, 9.04%.
Example 33
9-(2-(5-Methyl)furyl)-8-nonenoic acid. This compound was synthesized from 5-methylfurfural (2.20 g, 20 mmol) and 7-carboxyheptyltriphenylphosphonium bromide (9.71 g, 20 mmol) in THF (100 mL) by a Wittig reaction. Kugelrohr distillation afforded the product (2.35 g, 50%) as a yellow oil (bp 140°-143° C./0.05 torr). IR: 3400-2500, 1720 cm -1 ; 1 H-NMR: 1.36 (m, 4H), 1.45 (m, 2H), 1.65 (m, 2H), 2.28 (s, 3H), 2.37 (t, 2H), 2.41 (m, 2H), 5.45 (m, 1H), 5.95 (d, 1H), 6.12 (s, 1H), 10.00 (bs, 1H). Anal. Calcd. for C 14 H 20 O 3 : C, 71.16, H, 8.53%; Found: C, 70.85, H, 8.63%. Z:E=9:91.
Example 34
9-(2-(5-Methyl)furyl)nonanoic acid. This compound was synthesized from 9-(2-(5-methyl)furyl)-8-nonenoic acid (0.94 g, 4 mmol) by a hydrogenation reaction using Pd/BaSO 4 (94 mg). Crystallization (petroleum ether) afforded the product (0.87 g, 92%) as white crystals (mp 49°-50° C.); IR: 3400-2500, 1710 cm -1 ; 1 H-NMR: 1.30 (m, 8H), 1.60 (m, 4H), 2.23 (s, 3H), 2.32 (t, 2H), 2.55 (t, 2H), 5.81 (s, 2H), 8.95 (bs, 1H). Anal. Calcd. for C 14 H 22 O 3 : C, 70.56, H, 9.30%; Found: C, 70.39, H, 9.33%.
Example 35
11-(2-furyl)-10-undecenoic acid. This compound was synthesized from 2-furaldehyde (1.92 g, 20 mmol) and 9-carboxynonyltriphenylphosphonium bromide (10.27 g, 20 mmol) in THF (100 mL) by a Wittig reaction. Crystallization (petroleum ether) afforded the product (2.95 g, 59%) as white crystals (mp 45°-46° C.); IR: 3450-2500 cm -1 ; 1 H-NMR: 1.33 (m, 8H), 1.46 (m, 2H), 1.65 (m, 2H), 2.34 (t, 2H), 2.45 (m, 2H), 5.55 (m, 1H), 6.18 (d, 1H), 6.25 (d, 1H), 6.38 (d, 1H), 7.38 (s, 1H), 9.80 (bs, 1H). Anal. Calcd. for C 15 H 22 O 3 :C, 71.97, H, 8.86%; Found: C, 71.93, H, 8.87%. Z:E=43:57.
Example 36
11-(2-Furyl)undecanoic acid. This compound was synthesized from 11-(2-furyl)-10-undecenoic acid (1.25 g, 5 mmol) by a hydrogenation reaction using Pd/BaSO 4 (125 mg). Crystallization (petroleum ether) afforded the product (1.13 g, 90%) as white crystals (mp 40°-41° C.); IR: 3450-2500, 1720 cm -1 ; 1 H-NMR: 1.30 (m, 12H), 1.65 (m, 4H), 2.34 (t, 2H), 2.60 (t, 2H), 5.95 (d, 1H), 6.28 (d, 1H), 7.30 (s, 1H), 10.10 (bs, 1H). Anal. Calcd. for C 15 H 24 O 3 : C, 71.39, H, 9.58%; Found: C, 71.21, H, 9.63%.
Example 37
12-(2-Furyl)-11-dodecenoic acid. This compound was synthesized from 10-carboxydecyltriphenylphosphonium bromide (10.50 g, 20 mmol) and furfural (1.92 g, 20 mmol) in THF (100 mL) by a Wittig reaction. Crystallization afforded the product (2.38 g, 45%) as pale yellow crystals (mp 38°-39° C.); IR: 3450-2500, 1715, 695 cm -1 ; 1 H-NMR: 1.35 (m, 14H), 2.35 (t, 4H), 5.60 (m, 1H), 6.30 (m, 3H), 7.35 (s, 1H), 9.40 (bs, 1H). Anal. Calcd. for C 16 H 24 O 3 : C, 72.69, H, 9.15; Found: C, 72.44, H, 9.06%. Z:E=43:57.
Example 38
9-(2-Thienyl)-8-nonenoic acid. This compound was synthesized from 7-carboxyheptyltriphenylphosphonium bromide (9.71 g, 20 mmol) and 2-thiophenecarboxaldehyde (2.24 g, 20 mmol) in THF (100 mL) by a Wittig reaction. Crystallization afforded the product (2.79 g, 59%) as white crystals (mp 45°-46° C.). IR: 3400-2500, 1720, 710 cm -1 ; 1 H-NMR: 1.45 (m, 8H), 2.35 (m, 4H), 5.55 (m, 1H), 6.50 (d, 1H), 7.00 (m, 3H), 11.00 (bs, 1H). Anal. Calcd. for C 13 H 18 SO 2 : C, 65.51, H, 7.61%; Found: C, 65.58, H, 7.63%. Z:E=75:25.
Example 39
9-(2-Thienyl)-nonanoic acid. This compound was synthesized from 9-(2-thienyl)-8-nonenoic acid (1.19 g, 5 mmol) by a hydrogenation reaction using Pd/C (120 mg). Crystallization afforded the product (1.05 g, 88%) as white crystals (mp 32°-33° C.); IR: 3400-2500, 1715, 705 cm -1 ; 1 H-NMR: 1.35 (m, 12H), 2.35 (t, 2H), 2.85 (t, 2H), 6.95 (m, 3H), 10.35 (bs, 1H). Anal. Calcd. for C 13 H 20 SO 2 : C, 64.96, H, 8.39%; Found: C, 64.81, H, 8.43%.
Example 40
9-(2-(5-Methyl)thienyl)-8-nonenoic acid. This compound was synthesized from 7-carboxyheptylphenylphosphonium bromide (7.28 g, 15 mmol) and 2-(5-methyl)thiophenecarboxaldehyde (1.92 g, 15 mmol) in THF (100 mL) by a Wittig reaction. Kugelrohr distillation (bp 155°-159° C./0.05 torr) and crystallization (petroleum ether) afforded the product (2.43 g, 48%) as pale yellow crystals (mp 38°-39° C.). IR: 3400-2500, 1715 cm -1 ; 1 H-NMR: 1.40 (m, 6H), 1.65 (m, 2H), 2.37 (m, 4H), 2.45 (s, 3H), 5.45+5.90 (m, 1H), 6.41 (t, 1H), 6.65 (m, 1H), 6.75 (d, 1H), 10.05 (bs, 1H). Anal. Calcd. for C 14 H 20 O 2 S: C, 66.63, H, 7.99%; Found: C, 66.54, H, 8.02%. Z:E=72:28.
Example 41
9-(2-(5-Methyl)thienyl)nonanoic acid. This compound was synthesized from 9-(2-(5-methyl)thienyl)-8-nonenoic acid (1.01 g, 4 mmol) by a hydrogenation reaction using Pd/C (200 mg). Crystallization (petroleum ether) afforded the product (0.91 g, 89%) as white crystals (mp 39°-40° C.). IR: 3400-2500, 1720 cm -1 ; 1 H-NMR: 1.32 (m, 8H), 1.63 (m, 4H), 2.32 (t, 2H), 2.45 (s, 3H), 2.71 (t, 2H), 6.54 (s, 2H), 9.50 (bs, 1H). Anal. Calcd. for C 14 H 22 O 2 S: C, 66.10, H, 8.72%; Found: C, 65.97, H, 8.72%.
Example 42
11-(2-Thienyl)-10-undecenoic acid. This compound was synthesized from 2-thiophenecarboxaldehyde (2.24 g, 20 mmol) and 9-carboxynonyltriphenylphosphonium bromide (10.27 g, 20 mmol) in THF (100 mL) by a Wittig reaction. Crystallization (hexanes-ethyl acetate) afforded the product (2.45 g, 46%) as white crystals (mp 61°-62° C.); IR: 3450-2500, 1715 cm -1 ; 1 H-NMR: 1.31 (m, 8H), 1.45 (m, 2H), 1.65 (m, 2H), 2.34 (t, 2H), 2.38 (t, 2H) 5.55 (m, 1H), 6.50 (d, 1H), 6.95 (m, 2H), 7.23 (d, 2H), 10.05 (bs, 1H). Anal. Calcd. for C 15 H 22 O 2 S: C, 67.63, H, 8.32%; Found: C, 67.60, H, 8.34%. Z:E=19:81.
Example 43
11-(2-Thienyl)undecanoic acid. This compound was synthesized from 11-(2-thienyl)-10-undecenoic acid (800 mg, 3 mmol) by a hydrogenation reaction using Pd/C (80 mg). Crystallization (petroleum ether) afforded the product (0.73 g, 91%) as white crystals (mp 41°-42° C.): IR: 3450-2500, 1715 cm -1 ; 1 H-NMR: 1.30 (m, 12H), 1.63 (m, 4H), 2.32 (t, 2H), 2.80 (t, 2H), 6.78 (d, 1H), 6.90 (t, 1H), 7.10 (d, 1H), 9.80 (bs, 1H). Anal. Calcd. for C 15 H 24 O 2 S: C, 67.12, H, 9.01%; Found: C, 67.55, H, 8.89%.
Example 44
The biological activity of a panel of fatty acid analogs that had been tested previously as substrates for purified E. coli-derived S. cerevisiae myristoylCoA:protein N-myristoyltransferase (Nmt) were tested for toxicity against trypanosomes as potential candidates for anti-trypanosomal drugs. For purposes of comparison, several oxatetradecanoic acids described in U.S. Pat. No. 5,151,445 as inhibitors of the growth and viability of bloodstream trypanosome parasites were included in the test panel. For convenience, this panel of fatty acid analogs was subdivided based on chemical differences in their secondary functional group. These functional groups vary with respect to their polarity, steric bulk, conformations, and to a limited degree, overall chain length. The 247 compounds thus tested are organized in Table 2, below, into 20 families. Several of these functional groups should have complex effects on both conformation and stereoelectronic properties (e.g. analogs with ester) whereas others will predominantly affect only one of these properties (e.g. conformation but not polarity in the case of olefins; polarity but not conformation in the case of oxatetradecanoic acids). In many of these families, the effects of the functional group have been assessed at every possible position from C3 through C13 in tetradecanoic acid (e.g. see the thia-and oxotetradecanoic acids listed in Table 2).
To perform the large scale testing, a reproducible and rapid assay was employed. The method exploits the fact that growing trypanosomes secrete large amounts of pyruvic acid, an end product of glucose catabolism (Operdoes, 1987). The pyruvic acid causes a change in color of the phenol red indicator present in the culture medium, providing a quantitative measure of cell growth. A similar assay has been published previously (Zinsstag et al., 1991). The detailed assay procedures used herein are as follows:
Trypanosomes were grown in the presence of analogs or positive and negative controls (11-oxatetradecanoic acid and the ethanol solvent, respectively). To avoid bias in data interpretation analog solutions were identified only by a code number. To evaluate reliability and reproducibility of the assay, several analogs were coded twice. All coded analogs were tested in quadruplicate on at least two separate occasions. After a standard growth period, the absorbance of the culture was determined at 550 nm and 405 nm and an efficacy value calculated from the ratio of these absorbances. Results from a representative test are shown in FIG. 1. This set of coded compounds included samples of ethanol and 11-oxatetradecanoic acid as both coded and uncoded samples (compounds E and 24 and O11 and 27 respectively). The excellent agreement between these samples and the controls attests to the reproducibility of this assay. Quadruplicate samples were generally each within 5% of the mean, and the ratio of the absorbance at 550 nm and 405 nm obtained for 11-oxatetradecanoic acid averaged 1.12 with a standard error of 0.04 for over 100 determinations during a 6 month period.
The analogs were grouped in terms of efficacy, defining 10 μM 11-oxatetradecanoic acid as the center of group 3 and the ethanol controls as the center of group 1 (FIG. 1). The range of values were calculated defining each group independently for each test based on the 11-oxatetradecanoic acid and ethanol values in that trial. This controlled for any differences in medium or cell growth. All compounds classified as group 3 were tested at least twice. After screening and categorizing all analogs in this manner, the code was broken and the structures of the compounds were matched with their efficacy. Note that 11-oxa-, 13-oxa-, and 6-oxatetradecanoic acids fall in groups 3, 2, and 1, respectively. These values correlate well with their effects on trypanosome growth assessed by cell counts using a hemocytometer (Doering et al., 1991).
FIG. 2 shows the structures of the 20 most active compounds which collectively define group 3. They are presented in decreasing order of potency in Table 1, above, and as structural groups in FIG. 2. Nine of the compounds are either thiatetradecanoic or oxatetradecanoic acids. The ether functional group is also present in conjunction with an aromatic residue in three other compounds. An additional four analogs contain oxygen, either in the form of a ketocarbonyl or an ester group. The remaining structures include 13-nitrotridecanoic acid and three unsaturated, fourteen carbon carboxylic acids. 9-Tetradecynoic acid was the most potent anti-trypanosomal agent identified among the 247 compounds screened.
Cells used for Growth Assays
For toxicity assays, cloned T. brucei (strain 427) of variant antigen type 221 (obtained from G. A. M. Cross, Rockefeller University) were harvested from CD-1 mice at a parasitemia of 2-5×10 8 trypanosomes/mL. After centrifugation of the infected blood (430×g; 8 min; 4° C.), the upper portion of the buffy coat was retained, with care taken to avoid contamination with erythrocytes. This material, consisting predominantly of trypanosomes, was then resuspended in BBS containing 1 mg/mL fatty acid free bovine serum albumin. The suspension was centrifuged (3,000×g; 8 min; 4° C.), and the cell pellet resuspended in culture medium to a final density of 1.5×10 7 cells/mL. (The composition of this culture medium was as described above except that 40 μM monothioglycerol was added; Duszenko et al., 1985; Doering et al., 1990; Hamm et al., 1990.) The doubling time of trypanosomes under these culture conditions is approximately 6 h at 37° C.
Growth Assay
This rapid assay, which can accommodate multiple samples, depends on measurement of the color change produced in the medium's phenol red indicator dye due to acidification by growing trypanosomesic. Stocks of analogs (10 mM in absolute ethanol, identified only by a code number) were diluted in culture medium to twice the concentration to be tested. Aliquots of 100 μL were dispensed into 96-well microtiter plates and warmed to 37° C. in a 5% CO 2 incubator before the addition of an equal volume of cell suspension (1.5×10 7 /mL, see above). All assays were performed in quadruplicate in each plate. Control wells included appropriately diluted ethanol (which had no effect on cell growth) and 10 μM 11-oxatetradecanoic acid. The plate was incubated for 36 h at 37° C. and then stored at 4° C. for 12 h to allow equilibration of CO 2 in the medium with that in air. The absorbance of each sample, at 550 nm and 405 nm (values chosen based on the absorption spectra of fresh and acidified media), was then read in a UV max kinetic microplate reader (Molecular Devices). To control for any variation in sample volume, the ratio of absorbance at 550 nm to absorbance at 405 nm for each well was calculated. This ratio was then averaged for each quadruplicate set and normalized to the average obtained in the set of control wells containing 10 μM 11-oxatetradecanoic acid, yielding an "efficacy value".
TABLE 2__________________________________________________________________________Screening fatty acid analogs for toxicity against T. brucei type 221Structure Reference Efficacy Group.sup.1__________________________________________________________________________Saturated Fatty Acids.sup.2CH.sub.3 --(CH.sub.2).sub.6 --COOH 1CH.sub.3 --(CH.sub.2).sub.8 --COOH 1CH.sub.3 --(CH.sub.2).sub.10 --COOH 1CH.sub.3 --(CH.sub.2).sub.11 --COOH 1CH.sub.3 --(CH.sub.2).sub.12 --COOH 1CH.sub.3 --(CH.sub.2).sub.13 --COOH 1CH.sub.3 --(CH.sub.2).sub.14 --COOH 1CH.sub.3 --(CH.sub.2).sub.16 --COOH 1CH.sub.3 --(CH.sub.2).sub.18 --COOH 1Oxatetradecanoic acidsCH.sub.3 --O--(CH.sub.2).sub.11 --COOH Kishore et al., 1991 2CH.sub.3 --CH.sub.2 --O--(CH.sub.2).sub.10 --COOH Kishore et al., 1991 1CH.sub.3 --(CH.sub.2).sub.2 --O--(CH.sub.2).sub.9 --COOH Kishore et al., 1991 3*.sup.3CH.sub.3 --(CH.sub.2).sub.3 --O--(CH.sub.2).sub.8 --COOH Kishore et al., 1991 3*CH.sub.3 --(CH.sub.2).sub.5 --O--(CH.sub.2).sub.6 --COOH Kishore et al., 1991 3bCH.sub.3 --(CH.sub.2).sub.6 --O--(CH.sub.2).sub.5 --COOH Kishore et al., 1991 3**.sup.4CH.sub.3 --(CH.sub.2).sub.7 --O--(CH.sub.2).sub.4 --COOH Kishore et al., 1991 1CH.sub.3 --(CH.sub.2).sub.8 --O--(CH.sub.2).sub.3 --COOH Kishore et al., 1991 3*CH.sub.3 --(CH.sub.2).sub.9 --O--(CH.sub.2).sub.2 --COOH Kishore et al., 1991 2CH.sub.3 --(CH.sub.2).sub.10 --O--CH.sub.2 --COOH Kishore et al., 1991 1Thiatetradecanoic acidsCH.sub.3 --S--(CH.sub.2).sub.11 --COOH Kishore et al., 1991 3*CH.sub.3 --CH.sub.2 --S--(CH.sub.2).sub.10 --COOH Kishore et al., 1991 2CH.sub.3 --(CH.sub.2).sub.3 --S--(CH.sub.2).sub.8 --COOH Kishore et al., 1991 2CH.sub.3 --(CH.sub.2).sub.4 --S--(CH.sub.2).sub.7 --COOH Kishore et al., 1991 3b*CH.sub.3 --(CH.sub.2).sub.5 --S--(CH.sub.2).sub.6 --COOH Kishore et al., 1991 2CH.sub.3 --(CH.sub.2).sub.6 --S--(CH.sub.2).sub.5 --COOH Kishore et al., 1991 3**CH.sub.3 --(CH.sub.2).sub.7 --S--(CH.sub.2).sub.4 --COOH Kishore et al., 1991 2aCH.sub.3 --(CH.sub.2).sub.8 --S--(CH.sub.2).sub.3 --COOH Kishore et al., 1991 3**CH.sub.3 --(CH.sub.2).sub.9 --S--(CH.sub.2).sub.2 --COOH Kishore et al., 1991 1CH.sub.3 --(CH.sub.2).sub.10 --S--CH.sub.2 --COOH Kishore et al., 1991 1Myristic acid analogs containing sulfur and/or oxygen substituentsCH.sub.3 --CH.sub.2 --S--(CH.sub.2).sub.5 --S--(CH.sub.2).sub.4 --COOH Kishore et al., 1991 1CH.sub.3 --CH.sub.2 --S--(CH.sub.2).sub.2 --O--(CH.sub.2).sub.7 --COOH Kishore et al., 1991 2CH.sub.3 --CH.sub.2 --O--(CH.sub.2).sub.2 --S--(CH.sub.2).sub.7 --COOH Kishore et al., 1991 1CH.sub.3 --CH.sub.2 --O--(CH.sub.2).sub.5 --S--(CH.sub.2).sub.4 --COOH Kishore et al., 1991 1CH.sub.3 --O--(CH.sub.2).sub.2 --O--(CH.sub.2).sub.2 --O--(CH.sub.2).sub.5 --COOH Kishore et al., 1991 1Oxotetradecanoic acidsCH.sub.3 --CO--(CH.sub.2).sub.11 --COOH Devadas et al., 1992 2CH.sub.3 --CH.sub.2 --CO--(CH.sub.2).sub.10 --COOH Devadas et al., 1992 1CH.sub.3 --(CH.sub.2).sub.2 --CO--(CH.sub.2).sub.9 --COOH Devadas et al., 1992 2a*CH.sub.3 --(CH.sub.2).sub.3 --CO--(CH.sub.2).sub.8 --COOH Devadas et al., 1992 2bCH.sub.3 --(CH.sub.2).sub.4 --CO--(CH.sub.2).sub.7 --COOH Devadas et al., 1992 2a*CH.sub.3 --(CH.sub.2).sub.5 --CO--(CH.sub.2).sub.6 --COOH Devadas et al., 1992 1CH.sub.3 --(CH.sub.2).sub.6 --CO--(CH.sub.2).sub.5 --COOH Devadas et al., 1992 3**CH.sub.3 --(CH.sub.2).sub.7 --CO--(CH.sub.2).sub.4 --COOH Devadas et al., 1992 1CH.sub.3 --(CH.sub.2).sub.8 --CO--(CH.sub.2).sub.3 --COOH Devadas et al., 1992 3b*CH.sub.3 --(CH.sub.2).sub.9 --CO--(CH.sub.2).sub.2 --COOH Devadas et al., 1992 2CH.sub.3 --(CH.sub.2).sub.10 --CO--CH.sub.2 --COOH Devadas et al., 1992 1Myristic acid analogs containing ester groupsCH.sub.3 --O--CO--(CH.sub.2).sub.10 --COOH Devadas et al., 1992 2CH.sub.3 --CH.sub.2 --O--CO--(CH.sub.2).sub.9 --COOH Devadas et al., 1992 1CH.sub.3 --(CH.sub.2).sub.2 --O--CO--(CH.sub.2).sub.8 --COOH Devadas et al., 1992 2CH.sub.3 --(CH.sub.2).sub.3 --O--CO--(CH.sub.2).sub.7 --COOH Devadas et al., 1992 2aCH.sub.3 --(CH.sub.2).sub.4 --O--CO--(CH.sub.2).sub.6 --COOH Devadas et al., 1992 1aCH.sub.3 --(CH.sub.2).sub.5 --O--CO--(CH.sub.2).sub.5 --COOH Devadas et al., 1992 2bCH.sub.3 --(CH.sub.2).sub.6 --O--CO--(CH.sub.2).sub.4 --COOH Devadas et al., 1992 2CH.sub.3 --(CH.sub.2).sub.7 --O--CO--(CH.sub.2).sub.3 --COOH Devadas et al., 1992 3CH.sub.3 --(CH.sub.2).sub.8 --O--CO--(CH.sub.2).sub.2 --COOH Devadas et al., 1992 3b*CH.sub.3 --(CH.sub.2).sub.9 --O--CO--CH.sub.2 --COOH Devadas et al., 1992 1CH.sub.3 --CH.sub.2 --O--CO--(CH.sub.2).sub.10 --COOH Devadas et al., 1992 1Myristic acid analogs containing amide groupsCH.sub.3 --NH--CO--(CH.sub.2).sub.10 --COOH Devadas et al., 1992 1CH.sub.3 --(CH.sub.2).sub.2 --NH--CO--(CH.sub.2).sub.8 --COOH Devadas et al., 1992 1CH.sub.3 --(CH.sub.2).sub.3 --NH--CO--(CH.sub.2).sub.7 --COOH Devadas et al., 1992 1CH.sub.3 --(CH.sub.2).sub.4 --NH--CO--(CH.sub.2).sub.6 --COOH Devadas et al., 1992 1CH.sub.3 --(CH.sub.2).sub.5 --NH--CO--(CH.sub.2).sub.5 --COOH Devadas et al., 1992 1CH.sub.3 --(CH.sub.2).sub.6 --NH--CO--(CH.sub.2).sub.4 --COOH Devadas et al., 1992 1CH.sub.3 --(CH.sub.2).sub.7 --NH--CO--(CH.sub.2).sub.3 --COOH Devadas et al., 1992 1CH.sub.3 --(CH.sub.2).sub.8 --NH--CO--(CH.sub.2).sub.2 --COOH Devadas et al., 1992 1CH.sub.3 --(CH.sub.2).sub.9 --NH--CO--CH.sub.2 --COOH Devadas et al., 1992 1Myristic acid analogs containing acylamino amide groupsCH.sub.3 --CO--NH--(CH.sub.2).sub.10 --COOH Devadas et al., 1992 1CH.sub.3 (CH.sub.2).sub.3 --CO--NH--(CH.sub.2).sub.7 --COOH Devadas et al., 1992 1CH.sub.3 (CH.sub.2).sub.4 --CO--NH--(CH.sub.2).sub.6 --COOH Devadas et al., 1992 1CH.sub.3 (CH.sub.2).sub.5 --CO--NH--(CH.sub.2).sub.5 --COOH Devadas et al., 1992 1CH.sub.3 (CH.sub.2).sub.6 --CO--NH--(CH.sub.2).sub.4 --COOH Devadas et al., 1992 1CH.sub.3 (CH.sub.2).sub.7 --CO--NH--(CH.sub.2).sub.3 --COOH Devadas et al., 1992 1CH.sub.3 (CH.sub.2).sub.8 --CO--NH--(CH.sub.2).sub.2 --COOH Devadas et al., 1992 1CH.sub.3 (CH.sub.2).sub.9 --CO--NH--CH.sub.2 --COOH Devadas et al., 1992 1aNitroalkylcarboxylic acidsO.sub.2 N--(CH.sub.2).sub.9 --COOH Lu et al., 1994.sup.5 1O.sub.2 N--(CH.sub.2).sub.10 --COOH Lu et al., 1994 2aO.sub.2 N--(CH.sub.2).sub.12 --COOH Lu et al., 1994 3Halogenated analogsBr--(CH.sub.2).sub.12 --COOH Lu et al., 1994 2Br--(CH.sub.2).sub.13 --COOH Lu et al., 1994 2F.sub.3 C--(CH.sub.2).sub.12 --COOH Lu et al., 1994 1F.sub.3 C--CH═CH--(CH.sub.2).sub.10 --COOH Lu et al., 1994 1Tetradecenoic acidsCH.sub.2 ═CH--(CH.sub.2).sub.11 --COOH Kishore et al., 1991 1CH.sub.3 --CH═CH--(CH.sub.2).sub.10 --COOH Kishore et al., 1991 Z12.sup.6 1CH.sub.3 --CH.sub.2 --CH═CH--(CH.sub.2).sub.9 --COOH Kishore et al., 1991 Z11 2bCH.sub.3 --(CH.sub.2).sub.2 --CH═CH--(CH.sub.2).sub.8 --COOH Kishore et al., 1991 Z10 1CH.sub.3 --(CH.sub.2).sub.4 --CH═CH--(CH.sub.2).sub.6 --COOH Kishore et al., 1991 Z8 1aCH.sub.3 --(CH.sub.2).sub.5 --CH═CH--(CH.sub.2).sub.5 --COOH Kishore et al., 1991 Z7 2bCH.sub.3 --(CH.sub.2).sub.5 --CH═CH--(CH.sub.2).sub.5 --COOH Kishore et al., 1991 E7.sup.7 1CH.sub.3 --(CH.sub.2).sub.6 --CH═CH--(CH.sub.2).sub.4 --COOH Kishore et al., 1991 E6 2bCH.sub.3 --(CH.sub.2).sub.6 --CH═CH--(CH.sub.2).sub.4 --COOH Kishore et al., 1991 Z6 1Isomer mixture: 15% E6, 85% Z6 Kishore et al., 1991 E:Z6 1CH.sub.3 --(CH.sub.2).sub.7 --CH═CH--(CH.sub.2).sub.3 --COOH Kishore et al., 1991 E5 1CH.sub.3 --(CH.sub.2).sub.7 --CH═CH--(CH.sub.2).sub.3 --COOH Kishore et al., 1991 Z5 1CH.sub.3 --(CH.sub.2).sub.8 --CH═CH--(CH.sub.2).sub.2 --COOH Kishore et al., 1991 Z4 1CH.sub.3 --(CH.sub.2).sub.8 --CH═CH--(CH.sub.2).sub.2 --COOH Kishore et al., 1991 E4 1CH.sub.3 --(CH.sub.2).sub.9 --CH═CH--CH.sub.2 ----COOH Kishore et al., 1991 Z3 1CH.sub.3 --(CH.sub.2).sub.10 --CH═CH--CH--COOH Kishore et al., 1991 E2 1CH.sub.3 --(CH.sub.2).sub.10 --CH═CH--CH--COOH Kishore et al., 1991 Z2 1CH.sub.3 --CH.sub.2 --CH═CH--(CH.sub.2).sub.3 --COOH Rudnick et al., 1992 C8:Z5 1CH.sub.3 --(CH.sub.2).sub.3 --CH═CH--(CH.sub.2).sub.3 --COOH Rudnick et al., 1992 C10:Z5 1CH.sub.3 --(CH.sub.2).sub.5 --CH═CH--(CH.sub.2).sub.3 --COOH Rudnick et al., 1992 C12:Z5 1CH.sub.3 --(CH.sub.2).sub.10 --CH═CH--(CH.sub.2).sub.2 --COOH Rudnick et al., 1992 C16:Z4 1CH.sub.3 --(CH.sub.2).sub.9 --CH═CH--(CH.sub.2).sub.3 --COOH Rudnick et al., 1992 C16:Z5 1CH.sub.3 --(CH.sub.2).sub.8 --CH═CH--(CH.sub.2).sub.4 --COOH Rudnick et al., 1992 C16:Z6 1CH.sub.3 --(CH.sub.2).sub.10 --CH═CH--(CH.sub.2).sub.3 --COOH Rudnick et al., 1992 C17:Z5 1CH.sub.3 --(CH.sub.2).sub.11 --CH═CH--(CH.sub.2).sub.3 --COOH Rudnick et al., 1992 C18:Z5 1Tetradecadienoic acidsCH.sub.3 --(CH.sub.2).sub.2 --CH═CH--CH═CH--(CH.sub.2).sub.6--COOH See Examples 1CH.sub.3 --(CH.sub.2).sub.4 --CH═CH--CH═CH--(CH.sub.2).sub.4--COOH See Examples 2bCH.sub.3 --(CH.sub.2).sub.5 --CH═CH--CH═CH--(CH.sub.2).sub.3--COOH See Examples 3Tetradecynoic acidsHC.tbd.C--(CH.sub.2).sub.11 --COOH Kishore et al., 1991 2bCH.sub.3 --C.tbd.C--(CH.sub.2).sub.10 --COOH Kishore et al., 1991 1CH.sub.3 CH.sub.2 --C.tbd.C--(CH.sub.2).sub.9 --COOH Kishore et al., 1991 1CH.sub.3 --(CH.sub.2).sub.2 --C.tbd.C--(CH.sub.2).sub.8 --COOH Kishore et al., 1991 2CH.sub.3 --(CH.sub.2).sub.3 --C.tbd.C--(CH.sub.2).sub.7 --COOH Kishore et al., 1991 3aCH.sub.3 --(CH.sub.2).sub.4 --C.tbd.C--(CH.sub.2).sub.6 --COOH Kishore et al., 1991 3CH.sub.3 --(CH.sub.2).sub.5 --C.tbd.C--(CH.sub.2).sub.5 --COOH Kishore et al., 1991 2CH.sub.3 --(CH.sub.2).sub.6 --C.tbd.C--(CH.sub.2).sub.4 --COOH Kishore et al., 1991 2CH.sub.3 --(CH.sub.2).sub.7 --C.tbd.C--(CH.sub.2).sub.3 --COOH Kishore et al., 1991 2CH.sub.3 --(CH.sub.2).sub.8 --C.tbd.C--(CH.sub.2).sub.2 --COOH Kishore et al., 1991 1CH.sub.3 --(CH.sub.2).sub.9 --C.tbd.C--CH.sub.2 --COOH Kishore et al., 1991 1CH.sub.3 --(CH.sub.2).sub.10 --C.tbd.C--COOH Kishore et al., 1991 1CH.sub.3 --(CH.sub.2).sub.7 --C.tbd.C--(CH.sub.2).sub.2 --COOH Rudnick et al., 1992 C13:Y4.sup.8 1CH.sub.3 --(CH.sub.2).sub.6 --C.tbd.C--(CH.sub.2).sub.3 --COOH Rudnick et al., 1992 C13:Y5 1CH.sub.3 --(CH.sub.2).sub.5 --C.tbd.C--(CH.sub.2).sub.4 --COOH Rudnick et al., 1992 C13:Y6 2bCH.sub.3 --(CH.sub.2).sub.9 --C.tbd.C--(CH.sub.2).sub.2 --COOH Rudnick et al., 1992 C15:Y4 1CH.sub.3 --(CH.sub.2).sub.8 --C.tbd.C--(CH.sub.2).sub.3 --COOH Rudnick et al., 1992 C15:Y5 1CH.sub.3 --(CH.sub.2).sub.7 --C.tbd.C--(CH.sub.2).sub.4 --COOH Rudnick et al., 1992 C15:Y6 1CH.sub.3 --(CH.sub.2).sub.10 --C.tbd.C--(CH.sub.2).sub.2 --COOH Rudnick et al., 1992 C16:Y4 1CH.sub.3 --(CH.sub.2).sub.9 --C.tbd.C--(CH.sub.2).sub.3 --COOH Rudnick et al., 1992 C16:Y5 1CH.sub.3 --(CH.sub.2).sub.8 --C.tbd.C--(CH.sub.2).sub.4 --COOH Rudnick et al., 1992 C16:Y6 1Aromatic analogs11 Carbon Equivalent Length.sup.9C.sub.6 H.sub.5 --(CH.sub.2).sub.7 --COOH Kishore et al., 1991 2bC.sub.6 H.sub.5 --(CH.sub.2).sub.2 --CH═CH--(CH.sub.2).sub.3 --COOH Kishore et al., 1991 112 Carbon Equivalent LengthC.sub.6 H.sub.5 --(CH.sub.2).sub.8 --COOH Kishore et al. 1991 1C.sub.6 H.sub.5 --CH═CH--(CH.sub.2).sub.6 --COOH Kishore et al., 1991 1aC.sub.6 H.sub.5 --(CH.sub.2).sub.2 --CH═CH--(CH.sub.2).sub.4 --COOH Kishore et al., 1991 1C.sub.6 H.sub.5 --O--(CH.sub.2).sub.7 --COOH See Examples 113 Carbon Equivalent LengthC.sub.6 H.sub.5 --(CH.sub.2).sub.9 --COOH Kishore et al., 1991 2bCH.sub.3 --C.sub.6 H.sub.4 --(CH.sub.2).sub.8 --COOH Kishore et al., 1991 1CH.sub.3 --CH.sub.2 --C.sub.6 H.sub.4 --(CH.sub.2).sub.7 COOH Kishore et al., 1991 2bCH.sub.3 --(CH.sub.2).sub.2 --C.sub.6 H.sub.4 --(CH.sub.2).sub.6 --COOH Kishore et al., 1991 1CH.sub.3 --(CH.sub.2).sub.3 --C.sub.6 H.sub.4 --(CH.sub.2).sub.5 --COOH Kishore et al., 1991 1CH.sub.3 --(CH.sub.2).sub.4 --C.sub.6 H.sub.4 --(CH.sub.2).sub.4 --COOH Gokel et al., 1992 1CH.sub.3 --(CH.sub.2).sub.5 --C.sub.6 H.sub.4 --(CH.sub.2).sub.3 --COOH Gokel et al., 1992 1aCH.sub.3 --(CH.sub.2).sub.6 --C.sub.6 H.sub.4 --(CH.sub.2).sub.2 --COOH Gokel et al., 1992 1C.sub.6 H.sub.5 --CH.sub.2 --CH═CH--(CH.sub.2).sub.6 --COOH Kishore et al., 1991 1CH.sub.3 C.sub.6 H.sub.4 --CH═CH--(CH.sub.2).sub.6 --COOH Kishore et al., 1991 1CH.sub.3 --CH.sub.2 --C.sub.6 H.sub.4 --CH═CH--(CH.sub.2).sub.5--COOH Kishore et al., 1991 1CH.sub.3 --(CH.sub.2).sub.2 --C.sub.6 H.sub.4 --CH═CH--(CH.sub.2).sub.4 --COOH Kishore et al., 1991 1CH.sub.3 --(CH.sub.2).sub.3 --C.sub.6 H.sub.4 --CH═CH--(CH.sub.2).sub.3 --COOH Kishore et al., 1991 1CH.sub.3 --(CH.sub.2).sub.4 --C.sub.6 H.sub.4 --CH═CH--(CH.sub.2).sub.2 --COOH Gokel et al., 1992 1CH.sub.3 --(CH.sub.2).sub.5 --C.sub.6 H.sub.4 --CH═CH--CH.sub.2--COOH Gokel et al., 1992 1CH.sub.3 --(CH.sub.2).sub.6 --C.sub.6 H.sub.4 --CH═CH--COOH Gokel et al., 1992 1CH.sub.3 --O--C.sub.6 H.sub.4 --(CH.sub.2).sub.7 --COOH See Examples 1CH.sub.3 --CH.sub.2 --O--C.sub.6 H.sub.4 --(CH.sub.2).sub.6 --COOH See Examples 1CH.sub.3 --(CH.sub.2).sub.2 --O--C.sub.6 H.sub.4 --(CH.sub.2).sub.5--COOH See Examples 1CH.sub.3 --(CH.sub.2).sub.3 --O--C.sub.6 H.sub.4 --(CH.sub.2).sub.4--COOH Gokel et al., 1992 1CH.sub.3 --(CH.sub.2).sub.4 --O--C.sub.6 H.sub.4 --(CH.sub.2).sub.3--COOH Gokel et al., 1992 1CH.sub.3 --(CH.sub.2).sub.5 --O--C.sub.6 H.sub.4 --(CH.sub.2).sub.2--COOH Gokel et al., 1992 1CH.sub.3 --O--C.sub.6 H.sub.4 --CH═CH--(CH.sub.2).sub.5 --COOH See Examples 1CH.sub.3 --CH.sub.2 --O--C.sub.6 H.sub.4 --CH═CH--(CH.sub.2).sub.4--COOH See Examples 1CH.sub.3 --(CH.sub.2).sub.2 --O--C.sub.6 H.sub.4 --CH═CH--(CH.sub.2).sub.3 --COOH See Examples 1CH.sub.3 --(CH.sub.2).sub.3 --O--C.sub.6 H.sub.4 --CH═CH--(CH.sub.2).sub.2 --COOH Gokel et al., 1992 1CH.sub.3 --(CH.sub.2).sub.4 --O--C.sub.6 H.sub.4 --CH═CH--CH.sub.2--COOH Goketl et al., 1992 1CH.sub.3 --(CH.sub.2).sub.5 --O--C.sub.6 H.sub.4 --CH═CH--COOH Gokel et al., 1992 1C.sub.6 H.sub.5 --O--(CH.sub.2).sub.8 --COOH See Examples 1C.sub.6 H.sub.5 --S--(CH.sub.2).sub.8 --COOH See Examples 1C.sub.6 H.sub.5 --CH.sub.2 --O--(CH.sub.2).sub.7 --COOH See Examples 1C.sub.6 H.sub.5 --CH.sub.2 --S--(CH.sub.2).sub.7 --COOH See Examples 114 Carbon Equivalent LengthC.sub.6 H.sub.5 --(CH.sub.2).sub.10 --COOH Heuckeroth et al., 1990 2bCH.sub.3 --C.sub.6 H.sub.4 --(CH.sub.2).sub.9 --COOH Kishore et al., 1991 1CH.sub.3 --CH.sub.2 --C.sub.6 H.sub.4 --(CH.sub.2).sub.8 --COOH Kishore et al., 1991 1aCH.sub.3 --(CH.sub.2).sub.2 --C.sub.6 H.sub.4 --(CH.sub.2).sub.7 --COOH See Examples 1CH.sub.3 --(CH.sub.2).sub.3 --C.sub.6 H.sub.4 --(CH.sub.2).sub.6 --COOH See Examples 1CH.sub.3 --(CH.sub.2).sub.4 --C.sub.6 H.sub.4 --(CH.sub.2).sub.5 --COOH See Examples 1CH.sub.3 --(CH.sub.2).sub.5 --C.sub.6 H.sub.4 --(CH.sub.2).sub.4 --COOH Gokel et al., 1992 1CH.sub.3 --(CH.sub.2).sub.6 --C.sub.6 H.sub.4 --(CH.sub.2).sub.3 --COOH Gokel et al., 1992 1C.sub.6 H.sub.5 --(CH.sub.2).sub.2 --CH═CH--(CH.sub.2).sub.6 --COOH Heuckeroth et al., 1990 1CH.sub.3 --C.sub.6 H.sub.4 --CH═CH--(CH.sub.2).sub.7 --COOH Kishore et al., 1991 1CH.sub.3 --CH.sub.2 --C.sub.6 H.sub.4 --CH═CH--(CH.sub.2).sub.6--COOH Kishore et al., 1991 1CH.sub.3 --(CH.sub.2).sub.2 --C.sub.6 H.sub.4 --CH═CH--(CH.sub.2).sub.5 --COOH See Examples 1CH.sub.3 --(CH.sub.2).sub.3 --C.sub.6 H.sub.4 --CH═CH--(CH.sub.2).sub.4 --COOH See Examples 1CH.sub.3 --(CH.sub.2).sub.4 --C.sub.6 H.sub.4 --CH═CH--(CH.sub.2).sub.3 --COOH See Examples 1CH.sub.3 --(CH.sub.2).sub.5 --C.sub.6 H.sub.4 --CH═CH--(CH.sub.2).sub.2 --COOH Gokel et al., 1992 1CH.sub.3 --(CH.sub.2).sub.6 --C.sub.6 H.sub.4 --CH═CH--CH.sub.2--COOH Gokel et al., 1992 1CH.sub.3 --O--C.sub.6 H.sub.4 --(CH.sub.2).sub.8 --COOH Kishore et al., 1991 1aCH.sub.3 --CH.sub.2 --O--C.sub.6 H.sub.4 --(CH.sub.2).sub.7 --COOH Kishore et al., 1991 1aCH.sub.3 --(CH.sub.2).sub.2 --O--C.sub.6 H.sub.4 --(CH.sub.2).sub.6--COOH See Examples 1CH.sub.3 --(CH.sub.2).sub.3 --O--C.sub.6 H.sub.4 --(CH.sub.2).sub.5--COOH See Examples 1CH.sub.3 --(CH.sub.2).sub.4 --O--C.sub.6 H.sub.4 --(CH.sub.2).sub.4--COOH Gokel et al., 1992 3CH.sub.3 --(CH.sub.2).sub.5 --O--C.sub.6 H.sub.4 --(CH.sub.2).sub.3--COOH Gokel et al., 1992 1CH.sub.3 --(CH.sub.2).sub.6 --O--C.sub.6 H.sub.4 --(CH.sub.2).sub.2--COOH Gokel et al., 1992 1CH.sub.3 --O--C.sub.6 H.sub.4 --CH═CH--(CH.sub.2).sub.6 --COOH Kishore et al., 1991 1CH.sub.3 --CH.sub.2 --O--C.sub.6 H.sub.4 --CH═CH--(CH.sub.2).sub.5--COOH Kishore et al., 1991 1aCH.sub.3 --(CH.sub.2).sub.2 --O--C.sub.6 H.sub.4 --CH═CH--(CH.sub.2).sub.4 --COOH See Examples 1CH.sub.3 --(CH.sub.2).sub.3 --O--C.sub.6 H.sub.4 --CH═CH--(CH.sub.2).sub.3 --COOH See Examples 1CH.sub.3 --(CH.sub.2).sub.4 --O--C.sub.6 H.sub.4 --CH═CH--(CH.sub.2).sub.2 --COOH Gokel et al., 1992 2CH.sub.3 --(CH.sub.2).sub.5 --O--C.sub.6 H.sub.4 --CH═CH--CH.sub.2--COOH Gokel et al., 1992 1CH.sub.3 --(CH.sub.2).sub.6 --O--C.sub.6 H.sub.4 --CH═CH--COOH Gokel et al., 1992 1C.sub.6 H.sub.5 --O--(CH.sub.2).sub.9 --COOH Kishore et al., 1991 1C.sub.6 H.sub.5 --S--(CH.sub.2).sub.9 --COOH Kishore et al., 1991 1CH.sub.3 --C.sub.6 H.sub.4 --O--(CH.sub.2).sub.8 --COOH Kishore et al., 1991 1CH.sub.3 --C.sub.6 H.sub.4 --S--(CH.sub.2).sub.8 --COOH Kishore et al., 1991 1CH.sub.3 --S--C.sub.6 H.sub.4 --(CH.sub.2).sub.8 --COOH Kishore et al., 1991 1CH.sub.3 --S--C.sub.6 H.sub.4 --CH═CH--(CH.sub.2).sub.6 --COOH Kishore et al., 1991 1CH.sub.3 --CH.sub.2 --C.sub.6 H.sub.4 --O--(CH.sub.2).sub.7 --COOH See Examples 115 Carbon Equivalent LengthC.sub.6 H.sub.5 --(CH.sub.2).sub.11 --COOH Rapoport and Newman, 1947 1C.sub.6 H.sub.5 --CH═CH--(CH.sub.2).sub.9 --COOH See Examples 1C.sub.6 H.sub.5 --O--(CH.sub.2).sub.10 --COOH See Examples 1Azido-aromatic analogsp-N.sub.3 --C.sub.6 H.sub.4 --(CH.sub.2).sub.6 --COOH Lu et al., 1994.sup.5 1p-N.sub.3 --C.sub.6 H.sub.4 --(CH.sub.2).sub.7 --COOH Lu et al., 1994 1bp-N.sub.3 --C.sub.6 H.sub.4 --(CH.sub.2).sub.8 --COOH Lu et al., 1994 1m-N.sub.3 --C.sub.6 H.sub.4 --(CH.sub.2).sub.8 --COOH Lu et al., 1994 1m-N.sub.3 --C.sub.6 H.sub.4 --(CH.sub.2).sub.10 --COOH Lu et al., 1994 1bp-N.sub.3 --C.sub.6 H.sub.4 --O--(CH.sub.2).sub.5 --COOH Lu et al., 1994 1bm-N.sub.3 --C.sub.6 H.sub.4 --O--(CH.sub.2).sub.5 --COOH Lu et al., 1994 1p-N.sub.3 --C.sub.6 H.sub.4 --O--(CH.sub.2).sub.6 --COOH Lu et al., 1994 1bm-N.sub.3 --C.sub.6 H.sub.4 --O--(CH.sub.2).sub.6 --COOH Lu et al., 1994 1p-N.sub.3 --C.sub.6 H.sub.4 --O--(CH.sub.2).sub.7 --COOH Lu et al., 1994 1m-N.sub.3 --C.sub.6 H.sub.4 --O--(CH.sub.2).sub.7 --COOH Lu et al., 1994 1Nitro-aromatic analogsO.sub.2 N--C.sub.6 H.sub.4 --CH═CH--(CH.sub.2).sub.6 --COOH Lu et al., 1994 1O.sub.2 N--C.sub.6 H.sub.4 --CH═CH--(CH.sub.2).sub.5 --COOH Lu et al., 1994 1aO.sub.2 N--C.sub.6 H.sub.4 --CH═CH--(CH.sub.2).sub.4 --COOH Lu et al., 1994 1H.sub.2 N--C.sub.6 H.sub.4 --(CH.sub.2).sub.6 --COOH Lu et al., 1994 1H.sub.2 N--C.sub.6 H.sub.4 --(CH.sub.2).sub.7 --COOH Lu et al., 1994 1Halo-aromatic analogso-F--C.sub.6 H.sub.4 --(CH.sub.2).sub.8 --COOH Lu et al., 1994 1m-F--C.sub.6 H.sub.4 --(CH.sub.2).sub.8 --COOH Lu et al., 1994 1p-F--C.sub.6 H.sub.4 --(CH.sub.2).sub.8 --COOH Lu et al., 1994 1ap-Cl--C.sub.6 H.sub.4 --(CH.sub.2).sub.8 --COOH Lu et al., 1994 1p-Br--C.sub.6 H.sub.4 --(CH.sub.2).sub.8 --COOH Lu et al., 1994 1ap-CF.sub.3 --C.sub.6 H.sub.4 --(CH.sub.2).sub.8 --COOH Lu et al., 1994 1o-F--C.sub.6 H.sub.4 --CH═C--(CH.sub.2).sub.6 --COOH Lu et al., 1994 1m-F--C.sub.6 H.sub.4 --CH═CH--(CH.sub.2).sub.6 --COOH Lu et al., 1994 1p-F--C.sub.6 H.sub.4 --CH═CH--(CH.sub.2).sub.6 --COOH Lu et al., 1994 1ap-Cl--C.sub.6 H.sub.4 --CH═CH--(CH.sub.2).sub.6 --COOH Lu et al., 1994 1p-Br--C.sub.6 H.sub.4 --CH═CH--(CH.sub.2).sub.6 --COOH Lu et al., 1994 1p-CF.sub.3 --C.sub.6 H.sub.4 --CH═CH--(CH.sub.2).sub.6 --COOH Lu et al., 1994 1Hetero-aromatic analogsCH.sub.3 --(CH.sub.2).sub.7 --furyl--(CH.sub.2).sub.2 --COOH Rudnick et al., 1992 1CH.sub.3 --(CH.sub.2).sub.6 --furyl--(CH.sub.2).sub.3 --COOH Rudnick et al., 1992 2CH.sub.3 --(CH.sub.2).sub.5 --furyl--(CH.sub.2).sub.4 --COOH Rudnick et al., 1992 3CH.sub.3 --(CH.sub.2).sub.4 --furyl--(CH.sub.2).sub.5 --COOH Rudnick et al., 1992 2b2-Furyl-(CH.sub.2).sub.8 --COOH See Examples 1 2-(5-CH.sub.3 --furyl)!-(CH.sub.2).sub.8 --COOH See Examples 12-Furyl-(CH.sub.2).sub.10 --COOH See Examples 2b2-Furyl-CH═CH--(CH.sub.2).sub.6 --COOH See Examples 1 2-(5-CH.sub.3 -furyl)!-CH═CH--(CH.sub.2).sub.6 --COOH See Examples 12-Furyl-CH═CH--(CH.sub.2).sub.8 --COOH See Examples 12-Furyl-CH═CH--(CH.sub.2).sub.9 --COOH See Examples 12-Thienyl-(CH.sub.2).sub.8 --COOH See Examples 1a2-Thienyl-(CH.sub.2).sub.9 --COOH Kishore et al., 1991 1 2-(5-CH.sub.3 -thienyl)!-(CH.sub.2).sub.8 --COOH See Examples 12-Thienyl-(CH.sub.2).sub.10 --COOH See Examples 2b2-Thienyl-CH═CH--(CH.sub.2).sub.6 --COOH See Examples 1 2-(5-CH.sub.3 -thienyl)!-CH═CH--(CH.sub.2).sub.6 --COOH See Examples 12-Thienyl-CH═CH--(CH.sub.2).sub.8 --COOH See Examples 1__________________________________________________________________________ .sup.1 Efficacy groups were assigned as described in Methods and the text Subgroup "a" indicates compounds near the upper boundary of an efficacy group; subgroup "b" indicates compounds at the lower boundary. The 20 mos toxic compounds (Group 3) are highlighted in bold type. .sup.2 Purchased from Nu Chek Prep, Inc. (Elysian, MN) .sup.3 *Indicates compounds that were categorized as group 2 when tested at 2 μM. .sup.4 **Indicates compounds that remained in group 3 when tested at 2 μM. .sup.5 T. Lu, Q. Li, A. Katoh, J. Hernandez, K. Duffin, E. JacksonMachelski, L. J Knoll, G. W. Gokel, and J. I. Gordon, J. Biol. Chem., 269, 5346-5357 (1994) .sup.6 Z, designates cis double bond geometry .sup.7 E, designates trans double bond geometry .sup.8 Y, indicates triple bond .sup.9 Examination of CPK space filling atomic models indicates that the width of an aromatic ring is equivalent to three methylenes.
The antiparasitic agents described herein can be used for administration to mammalian hosts infected with trypanosomes and the like by conventional means, preferably in formulations with pharmaceutically acceptable diluents and carriers. The amount of the active agent to be administered must be an effective amount, that is, an amount which is medically beneficial but does not present toxic effects which overweigh the advantages which accompany its use. It would be expected that the adult human dosage would normally range upward from about one milligram of the active compound. A suitable route of administration is orally in the form of capsules, tablets, syrups, elixirs and the like, although parenteral administration also can be used. Appropriate formulations of the active compound in pharmaceutically acceptable diluents and carriers in therapeutic dosage form can be prepared by reference to general texts in the field such as, for example, Remington's Pharmaceutical Sciences, Ed. Arthur Osol, 16th ed., 1980, Mack Publishing Co., Easton, Pa.
Various other examples will be apparent to the person skilled in the art after reading the present disclosure without departing from the spirit and scope of the invention. All such other examples are intended to be included within the scope of the appended claims.
References
Bryant, M. L., Heuckeroth, R. O., Kimata, J. T., Ratner, L., and Gordon, J. I. (1989) Proc. Natl. Acad. Sci. USA 86, 8655-8659
Bryant, M. L., Ratner, L., Duronio, R. J., Kishore, N. S., Adams, S. P., and Gordon, J. I. (1991) Proc. Natl. Acad. Sci. USA 88, 2055-2059.
Devadas, B., Adams, S. P., and Gordon, J. I. (1991) J. Lab. Comp. Radiopharm. 29, 157-164.
Devadas, B., Lu, T., Katoh, A., Kishore, N. S., Wade, A. C., Mehta, P. P., Rudnick, D. A., Bryant, M. L., Adams, S. P., Li, Q., Gokel, G. W., and Gordon, J. I. (1992) J. Biol. Chem. 267, 7224-7239.
Doering, T. L., Raper, J., Buxbaum, L. U., Hart, G. W., and Englund, P. T. (1990) Methods 1, 288-296.
Doering, T. L., Raper, J., Buxbaum, L. U., Adams, S. P., Gordon, J. I., Hart, G. W., and Englund, P. T. (1991) Science 252, 1851-1854.
Doering, T. L., Pessin, M. S., Hoff, E. F., Hart, G. W., Raben, D. M., and Englund, P. T. (1993) J. Biol. Chem. 268, 9215-9222.
Duszenko, M., Ferguson, M. A. J., Lamont, G. S., Rifkin, M. R., and Cross, G. A. M. (1985) J. Exp. Med. 162, 1256-1263.
Englund, P. T. (1993) Annu. Rev. Biochem. 62, 121-138.
Gokel, G. W., Lu, T., Rudnick, D. A., Jackson-Machelski, E., and Gordon, J. I. (1992) Israel J. Chem. 32, 127-133.
Hamm, B., Schindler, A., Mecke, D., and Duszenko, M. (1990) Mol. Biochem. Parasitol. 40 (1), 13-22.
Heuckeroth, R. O., Glaser, L., and Gordon, J. I. (1988) Proc. Natl. Acad. Sci. USA 85, 8795-8799.
Heuckeroth, R. O., and Gordon, J. I. (1989) Proc. Natl. Acad. Sci. USA 86, 5262-5266.
Heuckeroth, R. O., Jackson-Machelski, E., Adams, S. P., Kishore, N. S., Huhn, M., Katoh, A., Lu, T., Gokel, G. W., and Gordon, J. I. (1990) J. Lipid Res. 31, 1121-1129.
Johnson, D. R., Cox, A. D., Solski, P. A., Devadas, B., Adams, S. P., Leimgruber, R. M., Heuckeroth, R. O., Buss, J. E., and Gordon, J. I. (1990) Proc. Natl. Acad. Sci. USA 87, 8511-8515.
Kishore, N. S., Lu, T., Knoll, L. J., Katoh, A., Rudnick, D. A., Mehta, P. P., Devadas, B., Huhn, M., Atwood, J. L., Adams, S. P., Gokel, G. W., and Gordon, J. I. (1991) J. Biol Chem. 266, 8835-8855.
Kishore, N. S., Wood, D. C., Mehta, P. P., Wade, A. C., Lu, T., Gokel, G. W., and Gordon, J. I. (1993) J. Biol. Chem. 268, 4889-4902.
Opperdoes, F. R. (1987) Annu. Rev. Microbiol. 41, 127-151.
Rapoport, L. and Neuman, M. S. (1947) J. Am. Chem. Soc. 69, 471-472.
Rudnick, D. A., Lu, T., Jackson-Machelski, E., Hernandez, J. C., Li, Q., Gokel, G. W., and Gordon, J. I. (1992) Proc. Natl. Acad. Sci. USA 89, 10507-10511.
Rudnick, D. A. McWherter, C. A., Gokel, G. W., and Gordon, J. I. (1993) Adv. Enzymol. 67, 375-430.
Zinsstag, J., Brun, R., and Gessler, M. (1991) Parasitol. Res. 77, 33-38.
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A method of inhibiting parasitic activity is disclosed in which the biosynthesis, structure and/or function of the glycosyl phosphatidylinositol (GPI) anchor of said parasite may be affected by incorporating into said GPI anchor selected analogs of myristic acid containing various heteroatoms, substituents and unsaturated bonds, including ester-containing analogs, ketocarbonyl-containing analogs, sulfur-containing analogs, double bond- and triple bond-containing analogs, aromatic moiety-containing analogs, nitrated analogs and halogenated analogs.
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CROSS REFERENCE TO RELATED APPLICATIONS
[0001] This application claims priority of German application No. 10 2008 023 053.7 filed May 9, 2008, which is incorporated by reference herein in its entirety.
FIELD OF THE INVENTION
[0002] The present invention relates to an evaluation method for a plurality of two-dimensional fluoroscopy images of an examination object.
BACKGROUND OF THE INVENTION
[0003] The subject matter described above is generally known. It is used in particular to determine and display the blood flow in vascular systems. To this end a contrast agent is injected into the bloodstream and its propagation is captured and displayed. The displayed propagation of the contrast agent enables the user (generally a physician) to make an appropriate diagnosis.
[0004] The evaluation method of the prior art already operates well but is capable of improvement.
SUMMARY OF THE INVENTION
[0005] The object of the present invention is to create possibilities that allow improved and simpler diagnosis by the physician. In particular it should be possible to capture temporal assignment easily and intuitively.
[0006] The object is achieved for the evaluation method, based on an evaluation method of the type described above, in such a manner that the computer outputs each two-dimensional reconstruction display in a coding specific to the respective image group. For the computer program the object is achieved in that it is embodied correspondingly, so that it brings about the execution of such a further developed evaluation method. The same applies to the data medium and the computer.
[0007] Advantageous embodiments of the inventive evaluation method are described in the claims. The preferred embodiments also apply correspondingly to the computer program, the data medium and the computer.
[0008] The object is achieved by the evaluation method for a plurality of two-dimensional fluoroscopy images of an examination object,
in which a computer receives the fluoroscopy images, in which a capture time point at which the respective fluoroscopy image was captured and projection parameters subject to which the respective fluoroscopy image was captured are assigned to each fluoroscopy image, in which the computer combines the fluoroscopy images into image groups in such a manner that
the respective image group contains all the fluoroscopy images, the capture time point of which is between a minimum time point specific to the respective image group and a maximum time point specific to the respective image group and when the image groups are sorted by ascending minimum time points, the corresponding maximum time points form a strictly monotonously ascending order,
in which the respective minimum time point and the respective maximum time point for each image group are defined in such a manner that the fluoroscopy images assigned to the respective image group can be used to determine a three-dimensional object reconstruction of the examination object, in which the computer determines the respective object reconstruction for each image group based on the fluoroscopy images assigned to the respective image group, in which the computer uses the respective three-dimensional object reconstruction to determine a respective two-dimensional reconstruction display, in which the computer outputs the two-dimensional reconstruction displays to a user by way of a display device.
[0018] It is possible for the respective coding to be a color assigned to the respective image group. For example the temporally first reconstruction display can be coded red, the temporally second two-dimensional reconstruction display yellow, the temporally third reconstruction display green etc. Alternatively or additionally the respective coding can be a fill structure assigned to the respective image group. For example the temporally first reconstruction display can be display with a full structure, the temporally second reconstruction display checkered, the temporally third reconstruction display hatched, the temporally fourth reconstruction display dotted, etc.
[0019] It is possible for the computer to output the reconstruction displays simultaneously. Alternatively it is possible for the computer to output the reconstruction displays as a temporal sequence.
[0020] If the reconstruction displays are output as a temporal sequence, it is possible for the computer to display the reconstruction displays in full. In one preferred embodiment of the present invention however the computer only outputs the part of each reconstruction display that corresponds to none of the temporally preceding reconstruction displays. This last procedure can also be realized even if the computer outputs the reconstruction displays simultaneously. In this process, when outputting the respective part of the respective reconstruction display the computer can optionally also output the corresponding parts of the temporally preceding reconstruction displays.
[0021] It is possible for the examination object to be static; in other words it does not move when the fluoroscopy images are being captured. One example of such a static examination object is the human brain and the blood vessel system, which supplies the brain with blood. Alternatively the examination object can be a moving examination object. For example the person can move their head. There can also be respiration-induced or pulse-induced motion when capturing the lungs or abdomen.
[0022] It is possible to capture information about an inherent motion of the examination object while the fluoroscopy images are being captured and to supply this to the computer. In this instance the computer receives this information in addition to the fluoroscopy images. The computer is then able to carry out registration of the fluoroscopy images corresponding to the inherent motion of the examination object before determining the object reconstructions. Alternatively or additionally the computer can also carry out registration of the fluoroscopy images corresponding to the inherent motion of the examination object after determining the object reconstructions.
[0023] Registration methods for registering the two-dimensional fluoroscopy images relative to one another—and also automatic registration methods—are known per se from the prior art. They are as such not the subject matter of the present invention. The same applies to registration methods used to register the three-dimensional object reconstructions relative to one another in some instances.
[0024] It is possible for the computer to determine the minimum time points and maximum time points of the image groups individually. In particular where there is continuous movement of the recording arrangement used to capture the fluoroscopy images it is however possible and also advantageous, if the computer determines the minimum time points and maximum time points of the image groups in such a manner that directly consecutive minimum time points have a uniform temporal setpoint interval for all the image groups and for each image group the difference between the respective maximum time point and the respective minimum time point is equal to a uniform setpoint time period for all the image groups. Continuous movement of the recording arrangement is in particular a continuous rotation of the recording arrangement of a CT system. C-arm systems can also bring this about in some instances.
[0025] The temporal setpoint interval is generally at least as long as half the setpoint time period. It is preferably even as long as the setpoint time period.
[0026] It is possible for the temporal setpoint interval to be permanently predetermined for the computer or to be determined by the computer based on otherwise predetermined variables. Alternatively the computer can receive the temporal setpoint interval from the user.
BRIEF DESCRIPTION OF THE DRAWINGS
[0027] Further advantages and details will emerge from the description which follows of exemplary embodiments in conjunction with the drawings of basic diagrams, in which:
[0028] FIG. 1 shows an x-ray system and an evaluation arrangement,
[0029] FIG. 2 to 4 show flow diagrams,
[0030] FIG. 5 shows an overall display,
[0031] FIG. 6 shows a flow diagram,
[0032] FIG. 7 to 9 show displacement operations of an x-ray source,
[0033] FIGS. 10 and 11 show flow diagrams and
[0034] FIG. 12 shows a displacement operation of an x-ray source.
DETAILED DESCRIPTION OF THE INVENTION
[0035] According to FIG. 1 an x-ray source 1 has a recording arrangement 2 . The recording arrangement 2 comprises an x-ray source 3 and a flat panel detector 4 . The x-ray source 3 and flat panel detector 4 can be moved together. Generally they can be pivoted about a common pivot axis 5 , as shown by corresponding arrows in FIG. 1 . Displacement of the x-ray source 3 and flat panel detector 4 is generally coordinated in this process, so that the pivot axis 5 is disposed between the x-ray source 3 and the flat panel detector 4 at any time point.
[0036] The x-ray system 1 is controlled by a control facility 6 . Further to corresponding activation by the control facility 6 the flat panel detector 4 captures a two-dimensional fluoroscopy image B of an examination object 7 disposed in the region of the pivot axis 5 , for example the brain of a human 7 , from a start time point at capture time points t respectively. The start time point here is selected as required. Generally it is defined in such a manner that it coincides with the start of the introduction of a contrast agent into the part of the blood vessel system of the examination object 7 under consideration.
[0037] The control facility 6 transmits the captured fluoroscopy images B to a computer 8 . Together with the fluoroscopy images B the control facility 6 transmits to the computer 8 the associated capture time point t for every fluoroscopy image B as well as the projection parameters P, subject to which the respective fluoroscopy image B was captured by means of the recording arrangement 2 .
[0038] The computer 8 can be a standard computer. The computer 8 is programmed using a computer program 9 . The computer program 9 can be stored in machine-readable form on a data medium 10 for example and be supplied to the computer 8 by way of the data medium 10 . A CD-ROM is shown as the data medium 10 in FIG. 1 purely by way of example. The data medium 10 could however be configured differently, for example as a USB memory stick or as an SD memory card.
[0039] The computer program 9 has machine code 11 . The machine code 11 can be executed directly by the computer 8 . Execution of the machine code 11 —which naturally takes place during operation of the computer 8 —causes the computer 8 to execute an evaluation method, which is described in more detail below in conjunction with FIG. 2 .
[0040] According to FIG. 2 in a step S 1 the computer 8 receives the fluoroscopy images B. Each fluoroscopy image B is hereby assigned the corresponding capture time point t and the corresponding projection parameters P. The number of received fluoroscopy images B is generally very large. Generally significantly more than 100 fluoroscopy images B are received, for example 200, 300, 450 or yet more fluoroscopy images B. In the context of step S 1 the computer 8 can also preprocess the individual fluoroscopy images B, for example using DSA (=digital subtraction angiography) or contrast amplification.
[0041] In a step S 2 the computer 8 determines a minimum time point t i and a maximum time point t′ i respectively for a number n of image groups G i (i=1 . . . , n). In this process the following equations apply irrespective of the value of the index i
[0000]
t
i+1
>t
i
[0000] t i+1 ′>t i ′ and
[0000] t i ′>t i .
[0042] The difference between directly consecutive minimum time points (i.e. t i+1 −t i ) is referred to below as the group interval. The group interval can be the same for all image groups G i . However this is not necessarily the case.
[0043] Similarly the difference between the maximum time point t′ i and minimum time point t i for each image group G i is referred to below as the group time period. The group time period can—like the group time interval—be the same for all image groups G i . However this is also not necessarily the case.
[0044] In a step S 3 the computer 8 forms the image groups G i . Each image group G i here comprises all the fluoroscopy images B, the capture time point t of which is between the minimum time point t i and the maximum time point t′ i of the respective image group G i .
[0045] The minimum time points t i and the maximum time points t′ i are defined in such a manner for all the image groups G i that a respective three-dimensional object reconstruction R i of the examination object 7 can be determined for each image group G i based on the fluoroscopy images B assigned to the respective image group G i . The computer 8 carries out this determination in a step S 4 . If necessary in step S 4 the computer 8 can carry out a further evaluation of the object reconstructions R i , for example a segmentation of the blood vessel system of the examination object 7 , to the extent that contrast agent flows through it in the context of the object reconstruction R i considered in each instance.
[0046] In a step S 5 the computer 8 determines a type of display in the same manner for all object reconstructions R i . For example the computer 8 can determine whether there should be a parallel projection, a perspective projection or a sectional display. Further display parameters (viewing direction, viewing angle, etc.) can also be determined in some instances.
[0047] Step S 5 is only optional. It is therefore shown with a broken line in FIG. 2 . If it is not present, the type of display can be permanently predetermined for example.
[0048] Step S 5 can—if present—operate fully automatically. Alternatively the cooperation of a user 12 may be required. The cooperation of the user 12 can optionally be of an interactive nature, it then being possible for the input of the user 12 to be changed at any time.
[0049] In a step S 6 the computer 8 uses the respective three-dimensional object reconstruction R i for the respective image group G i to determine a respective two-dimensional reconstruction display D i . The respective reconstruction display D i is determined here taking into account the type of display defined in step S 5 (or the otherwise known type of display).
[0050] In a step S 7 the computer 8 codes each two-dimensional reconstruction display D i in a coding. The coding here is specific to the respective image group G i . The respective coding can be a color assigned to the respective image group G i for example. Alternatively or additionally the respective coding can be a fill structure assigned to the respective image group G i . Both procedures are described in more detail below in conjunction with FIG. 3 to 6 .
[0051] In a step S 8 the computer 8 outputs the coded reconstruction displays D i to the user 12 by way of a display device 13 .
[0052] FIG. 3 shows a possible implementation of steps S 7 and S 8 in FIG. 2 .
[0053] According to FIG. 3 in a step S 11 the computer 8 selects the first reconstruction display D 1 . In a step S 12 the computer 8 assigns the first reconstruction display D 1 its corresponding coding. In a step S 13 the computer 8 outputs the currently selected reconstruction display D i to the user 12 in the coding assigned to it by way of the display device 13 .
[0054] In a step S 14 the computer 8 checks whether it has already executed step S 13 for all the reconstruction displays D i . If not, the computer 8 passes on to a step S 15 . Otherwise the method in FIG. 3 is terminated.
[0055] In step S 15 the computer 8 selects the temporally next reconstruction display D i . The computer 8 then goes back to step S 12 .
[0056] The procedure in FIG. 3 results in the computer 8 outputting the individual reconstruction displays D i one after the other, in other words as a temporal sequence, to the user 12 by way of the display device 13 . Each reconstruction display D i is hereby output in its corresponding coding.
[0057] As described to date, with the procedure in FIG. 3 the respective reconstruction display D i is output in its entirety. Optionally however it is possible to assign a further step S 16 after step S 15 . Step S 16 is only shown with a broken line in FIG. 3 , because it is optional.
[0058] If step S 16 is present, in step S 16 the computer 8 determines the components of the selected reconstruction display D i , which are also present in at least one of the temporally preceding reconstruction displays D j (with j=1, . . . , i−1). As part of step S 16 the computer 8 removes these components from the selected reconstruction display D i . This modification means that for each reconstruction display D i respectively the computer 8 only outputs the part which corresponds to none of the temporally preceding reconstruction displays D j .
[0059] FIG. 4 shows a similar procedure to the procedure described just above in conjunction with FIG. 3 and the optional step S 16 . The procedure in FIG. 4 essentially differs from the last described procedure in FIG. 3 in that step S 13 in FIG. 3 is replaced by steps S 21 and S 22 . In step S 21 the computer 8 adds the part of the currently selected reconstruction display D i , which corresponds to none of the temporally preceding reconstruction displays D j , to an overall display D. The overall display D is displayed in step S 22 .
[0060] The procedure according to FIG. 4 means that during the first iteration the first reconstruction display D 1 is output by way of the display device 13 in the coding assigned to the first reconstruction display D 1 , during the second iteration the part of the second reconstruction display D 2 in the coding assigned to the second reconstruction display D 2 , which was not already displayed in the context of the first reconstruction display D 1 , is also displayed, etc. During the last iteration each part of the reconstruction displays D i is displayed in the coding in which it first comes up. The progression of the propagation of the contrast agent is thus visualized. FIG. 5 shows this procedure.
[0061] As mentioned above, the coding can be a color assigned to the respective image group G i . For example the first reconstruction display D 1 can be displayed in red, the second reconstruction display D 2 in orange, the third reconstruction display D 3 in yellow, etc. It is likewise possible to assign the color red for example to the first reconstruction display D 1 and the color yellow to the last reconstruction display D n . Transition colors from red to yellow are then assigned gradually to the other reconstruction displays D 2 to D n−1 . It is pointed out here for the sake of completeness only that the specified colors are purely exemplary.
[0062] As an alternative or in addition to the assignment of colors, a respective fill structure can be assigned to the respective reconstruction displays D i . For example the first reconstruction display D 1 can be displayed completely filled in, the second reconstruction display D 2 with large checkering, the third reconstruction display D 3 with fine checkering, the fourth reconstruction display D 4 hatched, the hatching running from bottom left to top right, etc. It is likewise possible for example to assign a relatively large number of fill elements to the first reconstruction display D 1 , so that a background is 80% or more covered, and to assign a fill structure, with which only a relatively small proportion of the background is filled, for example 20% or less, to the last reconstruction display D n . In this instance the other reconstruction displays D 2 to D n−1 can show a gradual reduction in the degree of cover from (purely by way of example) 90% to 10%.
[0063] FIG. 6 shows a slight modification of the procedure in FIG. 4 . The difference is that step S 22 is not executed in the context of the loop between steps S 12 and S 16 , but only after leaving the loop, in other words if the check in step S 14 is positive. This modification means that in the context of the overall display D the computer 8 outputs the reconstruction displays D i to the user 12 simultaneously by way of the display device 13 .
[0064] The x-ray system 1 used to capture the fluoroscopy images B can be a CT system for example. In this instance the recording arrangement 2 rotates continuously about the pivot axis 5 . It therefore executes a number of complete circuits continuously about the pivot axis 5 according to the diagrams in FIG. 7 to FIG. 9 . The circuits are shown here as spirals in FIG. 7 to 9 , in order to be able to differentiate the individual circuits in FIG. 7 to 9 from one another. In reality the circuits are of course circular. Also only the path of the x-ray source 3 is shown in FIG. 7 to 9 . At every time point the flat panel detector 4 lies diametrically opposite the x-ray source 3 relative to the pivot axis 5 .
[0065] The group time periods are selected as required in FIG. 7 to 9 . Generally they are selected to be as short as possible, to keep time-related reconstruction artifacts as small as possible. Generally the group time periods are the same for all the image groups G i . They are generally selected so that the recording arrangement 2 (or the x-ray source 3 ) passes through a pivot angle α, which is 180° plus the fan angle β of the recording arrangement 2 , relative to the pivot axis 5 during the group time period Δt i . This procedure allows the so-called Feldkamp algorithm, which is generally known to those skilled in the art, to be used to determine the object reconstructions R i . However it is possible and sometimes also expedient in individual instances to determine the pivot angle α differently. For example it is possible to select the pivot angle α to be smaller and only to carry out a so-called tomosynthesis.
[0066] Generally the user 12 will predetermine the pivot angle α, to be passed through by the recording arrangement 2 during the respective group time period, for the computer 8 . In this instance the computer 8 uses the predetermined pivot angle α and the rotation speed of the recording arrangement 2 known to it to determine the corresponding group time periods automatically. In this instance in particular the group time periods for all the image groups G i are all identical to a setpoint time period Δt.
[0067] As mentioned above, the group intervals can likewise have the same value for all the image groups G i , hereafter referred to as the temporal setpoint interval δt. The temporal setpoint interval δt here—see FIG. 7 —can be longer than the setpoint time period Δt. The temporal setpoint interval δt can however also be identical to the setpoint time period Δt according to FIG. 8 . The temporal setpoint interval δt according to FIG. 9 can (again alternatively) be shorter than the setpoint time period Δt. The temporal setpoint interval δt should however be at least as long as half the setpoint time period Δt.
[0068] It is possible for the temporal setpoint interval δt to be permanently predetermined for the computer 8 . It is likewise possible for the computer 8 to determine the temporal setpoint interval δt automatically based on the setpoint time period Δt. Again alternatively according to FIG. 10 it is possible for the computer 8 to receive the temporal setpoint interval δt from the user 12 . In this instance a step S 31 is inserted between the steps S 1 and S 2 according to FIG. 10 . In step S 31 the computer 8 receives the temporal setpoint interval δt from the user 12 .
[0069] Additionally according to FIG. 10 a step S 32 can also be present. If step S 32 is present, the computer 8 can receive the setpoint time period Δt or the corresponding pivot angle α in step S 32 . As an alternative or in addition to predetermination of the setpoint time period Δt or the corresponding pivot angle α, it is possible for the computer 8 to receive a value for the minimum time point t 1 of the first image group G 1 in the context of step S 32 .
[0070] According to FIG. 10 step S 2 is also modified compared with the procedure in FIG. 2 . In the context of step S 2 in FIG. 10 the computer 8 determines the minimum time points t i and the maximum time points t′ i according to the equations
[0000]
t
i
′=t
i
+Δt
[0000]
t
i+1
=t
i
+δt.
[0071] If the examination object 7 does not move while the fluoroscopy images B are being captured, excellent results can be achieved with the procedures described above. If however the examination object 7 moves while the fluoroscopy images B are being captured, it is possible for motion-induced artifacts to occur to a significant extent. In this instance the procedure in FIG. 2 is preferably modified according to FIG. 11 . The procedure in FIG. 11 is possible here as an alternative or in addition to the procedure in FIG. 10 .
[0072] According to FIG. 11 step S 1 in FIG. 2 is modified in such a manner that in addition to the fluoroscopy images B the computer 8 also receives information I about an inherent motion of the examination object 7 while the fluoroscopy images B are being captured. For example, if the examination object 7 corresponds to the human abdomen or pulmonary chamber, a chest strap may be used to capture a respiratory state of the examination object 7 and transmit it to the computer 8 .
[0073] According to FIG. 11 a step S 41 can be assigned in front of step S 4 in FIG. 2 . In step S 41 the computer 8 carries out registration of the fluoroscopy images B. Registration of the fluoroscopy images B naturally corresponds here to the inherent motion of the examination object 7 . Registration in step S 41 can be rigid or elastic. The corresponding registration methods are known to those skilled in the art. They are as such not the subject matter of the present invention.
[0074] As an alternative or in addition to step S 41 a step S 42 can be assigned after step S 4 . In step S 42 the computer 8 carries out registration of the object reconstructions R i . Registration of the object reconstructions R i naturally also corresponds to the inherent motion of the examination object 7 . Registration in step S 42 can—as with registration in step S 41 —alternatively be rigid or elastic. The corresponding registration methods are also known to those skilled in the art in respect of step S 42 . They are as such not the subject matter of the present invention.
[0075] The present invention has been described above in conjunction with fluoroscopy images B, with the fluoroscopy images B being captured using an x-ray system 1 , which is configured as a CT system. However the present invention can also be used if the fluoroscopy images B are captured by means of a differently configured x-ray system 1 , for example a C-arm x-ray system.
[0076] If the recording arrangement 2 of the differently configured x-ray system 1 is able, in a similar manner to a CT system, to execute a number of complete circuits about the pivot axis 5 , this is immediately evident without further ado. However the present invention can also be applied, if the x-ray source 3 and flat panel detector 3 can only be pivoted over an overall angle γ of maximum 360°, for example 270° or 220° or 200°, according to FIG. 12 . The recording arrangement 2 must then be pivoted back to its original position A after every forward displacement operation V by means of a backward displacement operation V′. The fluoroscopy images B are captured here at least during the forward displacement operations V. Alternatively fluoroscopy images B can be captured or not captured during the backward displacement operations V′. Generally all the fluoroscopy images B captured during a single displacement operation V, V′ form an image group G i . This is shown schematically in FIG. 12 for three displacement operations V, V′. The number (“three”) of displacement operations V, V′ shown here is of course purely exemplary.
[0077] The present invention has many advantages. In particular intuitive assignment of the blood flow to time is possible. A diagnosis based on the assignment of blood flow to time is therefore facilitated for the user (physician) 12 .
[0078] The above description serves exclusively to describe the present invention. The scope of protection of the present invention should however be defined exclusively by the accompanying claims.
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A computer receives a plurality of two-dimensional fluoroscopy images of an examination object, capture time points and projection parameters and combines the images into image groups. Each image group contains all the images, the capture time point of which is between a minimum and a maximum time point specific to the respective image group. When the image groups are sorted by ascending minimum time points, the corresponding maximum time points form a strictly monotonously ascending order. The respective minimum and maximum time points are determined so that the computer reconstructs a three-dimensional object reconstruction of the examination object based on the images assigned to the respective image group. A respective two-dimensional reconstruction display is determined by the respective three-dimensional object reconstruction and outputted to a user in a coding specific to the respective image group by a display device.
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BACKGROUND OF THE INVENTION
The present invention relates to a selector system for a printing head for printing machines and the like comprising code bars, a selector level with an output element connected to the printing head for selection of the character to be printed, an input element adapted to be shifted by a predetermined amount and a group of fulcrum elements selectively arrestable by a group of stops, controlled by the code bars, for shifting the output element by different amounts.
A selector system of this type is known wherein six stops are each adapted to be set by a respective code bar to position a selector lever in six different positions. This system has the disadvantage that as many code bars are necessary as there are settable stops and, therefore, the system proves to be cumbersome, complicated, costly and not very fast.
SUMMARY OF THE INVENTION
The main object of the present invention is to provide a lever selector system with a group of selectively arrestable fulcrum or pivot elements which is simple, fast and of relatively low cost and which utilizes a number of code bars less than the number of stops for the fulcrum elements.
In accordance with these and other objects the present invention provides a selector system for a printing head for use in printing machines and the like for selecting a character to be printed from the printing head. The system comprises at least two actuatable code bars and means for effecting the positioning of the printing head with respect to a first coordinate comprising a selector lever having a set of pivot elements thereon each defining a pivot axis about which the selector lever pivots a preselected amount. Also provided are means responsive to the actuation of the code bars for selecting the pivot element about which the selector lever pivots, comprising a first group of stop members each pivotable in response to the actuation of one of the code bars and each engageable with one of a corresponding number of pivot elements, a second group of stop members each engaged with one of a corresponding number of pivot elements different from those associated with the first group and not pivoting in response to the actuation of any of the code bars and a third group of stop members each engageable with one of a corresponding numbers of pivot elements different from those associated with the first and second groups and pivotable in response to the actuation of either of at least two of the code bars.
BRIEF DESCRIPTION OF THE DRAWINGS
The invention will be described in more detail, by way of example, with reference to the accompanying drawings, wherein:
FIG. 1 is a partial longitudinal view of a selector system according to the present invention;
FIG. 2 is another partial longitudinal view of the system of FIG. 1; and
FIG. 3 is a partial plan view of the selector system according to FIGS. 1 and 2.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
The selector system of the present invention may be used as a decoding device in keyboard-operated typewriters, in teleprinters, in printing apparatus of accounting machines or data processors and in printing machines in general.
Referring to FIG. 1, the selector system is incorporated here, by way of example, in a typewriter provided with a ball-shaped type head having ninety-six characters distributed in six tracks, each of sixteen characters. The selector system comprises character selector mechanism 10 (FIG. 1), for selecting any one of the sixteen characters of a predetermined track, and track selector mechanism 11 (FIG. 2) for selecting the track in which the character to be printed is situated.
The character selector mechanism 10 and the track selector mechanism 11 are actuated by a set of six code bars 12 (FIG. 1) by means of a corresponding set of bars or sliders 13. The code bars 12 are selectively settable in a known manner per se from a keyboard (not shown in the drawings) and are normally held arrested each against a respective fixed stop 14 by means of a slider (not shown in the drawings). Each code bar 12 configured to co-operate with a lug 16 of the respective slider 13.
The sliders 13 comprise a set of three sliders 17, 18 and 19 of the character selector mechanism 10, and a set of three sliders 20, 21 and 22 of the track selector mechanism 11 (FIG. 2). The sliders 13 (FIG. 1) are guided by guide combs 23, only one of which can be seen in the drawings. A corresponding set of springs 26 normally hold the corresponding sliders 13 arrested with the lug 16 against the respective code bar 12.
The slider 17 has a second lug 27 projecting from its edge by a greater length than, and on the opposite side to, the lug 16 and pivoted on pin 28 of stop 29 which is mounted to turn on spindle 30 of frame 31 (FIG. 3) of the typewriter. The slider 17 (FIG. 1) terminates in an L-shaped shoulder 32 configured to cooperate with lug 33 of transmission lever 34.
The slider 18 includes a second lug 36 extending opposite of the lug 16 and pivoted on pin 37 of stop 38 which is mounted to turn on spindle 39 of the frame 31. The slider 18 terminates in an L-shaped shoulder 41 configured to cooperate with the lug 33 of the transmission lever 34.
The transmission lever 34 is mounted to turn on pin 42 of the frame 31 and includes a second lug 43 configured to cooperate with arm 44 of stop 46 which is mounted to turn on pin 47 of the frame 31 (FIG. 3). Spring 48 (FIG. 1) normally holds the transmission lever 34 with the second lug 43 in contact with the arm 44 of the stop 46 and the latter arrested by shoulder 49 against fulcrum element 51 of character selector lever 52.
The slider 19 includes second lug 53 extending opposite of the lug 16 and pivoted on pin 54 of movable support 56 which is mounted to turn on spindle 57 of the frame 31.
The character selector lever 52 is connected at one end by means of pin 61 to an input element including actuating cam frame 62 pivoted on spindle 63 and at the other end by means of pin 64 to an output element constituted by link 65. Fixed to the character selector lever 52, in addition to the fulcrum element 51, are fulcrum elements 66, 67 and 68.
The fulcrum element 51 cooperates not only with the shoulder 49 but also with a second shoulder 69 of the stop 46 in one operative stage of the selector mechanism 10. The fulcrum elements 66 and 67 are configured to cooperate with shoulders 71 and 72, respectively, of the stops 38 and 29 in other operative stages of the selector mechanism 10.
The fulcrum element 68 cooperates with shoulder 75 at one end of slot 76 in lever 74 during a further operative stage. While the lever 74 guides the selector lever 52 by means of the slot 76 during one of the operative stages of the character selector mechanism 10. The lever 74 mounted to turn on pin 77 of the frame 31 and, by means of its slot 76, generally vertically guides the movement of the selector lever 52.
The fulcrum elements 51, 66, 67 and 68 cooperate selectively with the respective shoulders 69, 71, 72 and 73 according to the various code combinations for selecting a series of characters 78 (FIG. 2) disposed on typing or printing head 79.
Actuating means (FIG. 1), which includes a cam 82 and a counter-cam 82', is fixed on a driving shaft 83 which is rotatable in two side plates 84 (FIG. 3). The driving shaft 83 is rotatable cyclically upon every depression of each key in a manner known per se, for example by means of a 360° clutch (not shown in the drawings). The actuating cams 82 and 82' cooperate with two rollers 87, 87' of the input element 62 to shift the right hand end of the character selector lever 52 down by a predetermined amount, and then back to the rest position.
The link 65 (FIG. 1) is connected by means of the pin 64 to the character selector lever 52 and by means of pin 88 to one end of intermediate or actuating lever 89. The actuating lever 89 has, at its other end, change-over element 91 normally accommodated in seat 92 of intermediate element 93 which is movable vertically, guided by means of pin 94 housed in slot 96. Moreover, the intermediate element 93 is controlled and actuated by the actuating means by means of the pin 61 housed in slot 97. The change-over element 91 is configured to cooperate either with shoulder 98 or with shoulder 99 of the movable support 56, so that during one stage of operation the intermediate lever 89 performs two different strokes for each stroke of the link 65, as will be described hereinafter.
The intermediate lever 89 is connected by means of pin 101 to second output element or link 102, which is connected by means of pin 103 to toothed sector 104 of a gearing mechanism indicated generally by 106. The toothed sector 104 is pivoted on pin 107 of movable support 108.
The gearing mechanism 106 includes the toothed sector 104 meshing with pinion 109 rotatable on shaft 110, and four gears 111 (FIG. 2), 112, 113 and 114. The gear 111, which is fixed to the shaft 110, is in mesh wih gear 112 which is rotatable on shaft 116 of frame 117 carrying printing head 79. The gear 113, which is fixed to the shaft 116, is in mesh with the gear 114, which is fixed in turn to shaft 118 to which the printing head 79 is fixed.
The printing head 79 is rotatable with the substantially horizontal shaft 118 to bring the character 78 to be printed in front of platen 121 of conventional carriage 122 movable transversely with respect to the typewriter. The tracks of sixteen characters lie in circles which are centered on the axis of the shaft 118.
The character selector mechanism 10 (FIG. 1) is normally held resiliently at rest by character selection control spring 123 which tends to cause the toothed sector 104 to turn counter-clockwise and urges the intermediate lever 89 downward by means of the link 102. By means of the pin 88, the intermediate lever 89 pushes the link 65 and the character selector lever 52, with the fulcrum element 68 arrested against the shoulder 73 of the lever 74. By means of the change-over element 91, intermediate lever 89 moreover pushes the intermediate element 93, with the end of the slot 97 arrested against the pin 61 of the input element 62, which is controlled in turn by the actuating cams 82, 82'. The actuating cams 82, 82', by means of pin 61, therefore control the selector lever 52 and the change-over element 91 and, consequently, the gearing mechanism 106 with the printing head 79 (FIG. 2).
The slider 20 (FIG. 3) of the track selector mechanism 11 includes a second lug 126 (FIG. 2) projecting from the edge by a greater length than, and extending opposite of the lug 16 (FIG. 1) and pivoted on pin 127 (FIG. 2) of stop 128 which is mounted to turn on spindle 129 of the frame 31. The stop 128 includes shoulder 131 configured to cooperate with fulcrum element 132 of second selector lever 133.
The slider 21 includes second lug 134 extending opposite of the lug 16 and pivoted on pin 136 of stop 137 which is mounted to turn on spindle 138 of the frame 31. The stop 137 includes shoulder 139 configured to cooperate with fulcrum element 141 of the selector lever 133.
The slider 22 includes a second lug 142 extending opposite of the lug 16 and pivoted on pin 143 of second movable support 144 which is mounted to turn on spindle 146 of the frame 31.
The second selector lever 133 is connected at one end by means of the pin 61 to the input element 62 and at the other end by means of pin 147 to first output link 148. Fixed to the second selector lever 133, in addition to the fulcrum elements 132 and 141, is fulcrum element 149 which is housed in slot 151 (FIG. 2) of stop 152 to cooperate with shoulder 153. The stop 152 is mounted to turn on pin 154 of the frame 31. During one operative stage, the fulcrum 149 cooperates with the shoulder 153 to act as a fulcrum and it cooperates in another operative stage with the slot 151 as a guide for the second selector lever 133.
The fulcrum elements 141, 132 and 149 cooperate selectively with the respective shoulders 139, 131 and 153 according to the various code combinations for selecting the track of the character 78 to be printed.
The first output link 148 is connected by means of the pin 147 to the second selector lever 133 and by means of pin 156 to a second intermediate lever 157. The intermediate lever 157 has the pin 156 at one end and, at its other end, it has a second change-over element 158 normally accommodated in seat 161 of second intermediate element 162. The second intermediate element 162 is movable vertically, guided by means of pin 163 of the side plate 84 (FIG. 3) which is housed in slot 164 (FIG. 2). Moreover, the second intermediate element 162 is controlled and actuated by the actuating means utilizing the pin 61 housed in slot 166.
The second change-over element 158 is adapted to cooperate selectively, during one stage of operation of the track selector mechanism 11, either with upper shoulder 171 or with lower shoulder 172 of the movable support 144, so that the second intermediate lever 157 performs two different strokes for each stroke of the link 148, as will be described hereinafter.
The second intermediate lever 157 is connected by means of pin 173 to a second output link 174, which is connected by means of pin 176 to toothed sector 177 of a gearing mechanism indicated generally by the reference 178. The toothed sector 177 is pivoted on pin 179 of support 180 (FIG. 3) fixed to the frame 31.
The gearing mechanism 178 (FIG. 2) includes the toothed sector 177 meshing with pinion 181 rotatable on shaft 182, and a bevel gear 183 fixed to the shaft 182 and meshing with toothed sector 184. The toothed sector 184 is fixed by means of arm 186 and pin 187 to plate 188 which, in turn, is connected by means of pin 189 to the frame 117 carrying the printing head.
The frame 117 is rotatable on sub-vertical shaft 191 on bail 192 to orient the printing head 79 in front of the platen 121 and select the track of the character 78 to be printed. The printing of the selected character 78 takes place by rotation of the bail 192 through the action of a cam (not shown in the drawings), substantially as described in U.S. Pat. No. 3,770,095, until the striking of the printing head 79 against the platen 121 is produced.
The character track selector mechanism 11 is normally held resiliently at rest by track selection control spring 193, which tends to cause the toothed sector 177 to turn counter-clockwise, with the toothed sector pushing the second intermediate lever 157 downwardly by means of the link 174. By means of the pin 156, the second intermediate lever 157 pushes the link 148 and the second selector lever 133, with the fulcrum element 149 arrested against the shoulder 153 by means of the second change-over element 158, the second intermediate lever 157 moreover pushes the intermediate element 162, with the end of the slot 166 arrested against the pin 61 of the input element 62, which is controlled in turn by the actuating cams 82 and 82'. The actuating cams 82, 82', by means of the pin 61, therefore control the second selector lever 133 and the change-over element 158 and, consequently, the gearing mechanism 178 and the frame 117 for the angular positioning of the printing head 79.
By depressing a key of the machine, the counter clockwise rotation of the shaft 83 (FIG. 1) is started in a known manner and, during the first part of the cycle, the bars 12 are positioned according to the code combination corresponding to the depressed key. By means of the rollers 87, the actuating cams 82, 82' cause the input element 62 to turn counter-clockwise and, by means of the pin 61, the input element causes the character selector lever 52 and the track selector lever 133 (FIG. 2) to turn clockwise with the respective fulcrum elements 68 (FIG. 1) and 149 (FIG. 2) on the shoulders 73 and 153, raising the links 65 and 148. At the same time, the intermediate elements 93 and 162 are lowered, following the movement of the pin 61, thus releasing the change-over elements 91 and 158.
As a first example of selection, let it be assumed that the depressed key holds the bars 12 in the position of FIG. 1. The selector lever 52 turns on the fulcrum element 68 until the fulcrum element 51 engages the corresponding shoulder 69. At the same time, the spring 123 causes the change-over element 91 to be arrested against the shoulder 98 of the movable support 56. The selector lever 52, turning clockwise about the fulcrum element 51, raises the actuating lever 89 by the maximum stroke. This is due to the maximum distance of the fulcrum element 51 from the pin 64 and to the minimum distance of the seat 92 from the shoulder 98. The pin 101 of the actuating lever 89 therefore rises by an amount substantially equal to the difference between the stroke of the link 65 and the distance between the seat 92 and the shoulder 98. In the specific case, the pin 101 performs a stroke or travel equal to +3.5 given units and, via the link 102, causes the toothed sector 104 to turn clockwise in opposition to the action of the spring 123. The gearing mechanism 106 transmits the movement to the printing head 79 (FIG. 2), which is rotated counter-clockwise, selecting the fourth row of characters 78 down, starting from the rest position of the head.
Similarly, the second selector lever 133 begins to turn for a brief instant, like the selector lever 52 (FIG. 1), with the fulcrum element 149 (FIG. 2) on the shoulder 153 until it engages the shoulder 139 with the fulcrum element 141, thus raising the link 148. Since the change-over element 158 is free, the spring 193 causes the second intermediate lever 157 to be lowered until it is arrested by the change-over element 158 against the upper shoulder 171 of the movable support 144. In the meantime, the selector lever 133 continues to turn clockwise, raising the intermediate lever 157 and, therefore, the link 174 by means of the link 148 by the maximum stroke equal to +2.5 given units.
The link 174 causes the toothed sector 177 to turn clockwise in opposition to the action of the spring 193. The pinion 181, rotating counter-clockwise with the bevel gear 183, causes a turning movement of the toothed sector 184, the pin 187 and the frame 117 via the pin 189, thus selecting the third track to the right of the character 78 to be printed, starting from the rest position of the head 79. Selection having been completed, the bail 192 causes the frame 117 and the head 79 to strike in a manner against the platen 121 as described in the U.S. Pat. No. 3,770,095.
After rotation through 180°, the actuating cams 82, 82', cause the input element 62 to turn clockwise, raising the intermediate elements 93 (FIG. 3) and 162 by means of the pin 61 and causing the selector levers 52 and 133 to turn counter-clockwise. The springs 123 (FIG. 1) and 193 (FIG. 2) then cause the intermediate levers 89 (FIG. 3) and 157 to be lowered and, by means of the gearing mechanism 106 and 178, bring the head 79 (FIG. 2) back to the original position.
Close to their inoperative positions, the selector levers 53 and 133 cease to engage the shoulders 69 and 139 with the fulcrum elements 51 and 141 and now pivot, by means of the fulcrum elements 68 and 149, on the shoulders 73 and 153. The intermediate elements 93 and 162, by means of their seats 92 and 161, cause the change-over elements 91 and 158 to cease engagement with the shoulders 98 and 171.
As a second example of selection, let it be assumed that the second key depressed positions the code bars 12 (FIG. 1) in such manner as to shift the slider 17 to the left in opposition to the action of the corresponding spring 26. This slider 17 then causes the respective stop 29 to turn clockwise by means of the pin 28, bringing the shoulder 72 out of the path of the fulcrum element 67 and engages the lug 33 with the L-shaped shoulder 32, causing the transmission lever 34 to turn clockwise. By means of the lug 43, this lever 34 causes the stop 46 to turn counter-clockwise, bringing the shoulder 69 out of the path of the fulcrum element 51.
Upon the starting of the actuating cams 82, 82', after the initial rotation of the selector lever 52 with the fulcrum element 68 on the shoulder 73, the fulcrum element 66 engages the shoulder 71 and the lever 52 then turns on the fulcrum element 66, raising the pin 101 by a stroke equal to +2.5 given units, more particularly positioning on the head 79 (FIG. 2) the third row of characters down.
Similarly, if only the slider 18 is shifted, the shoulder 69 out of the path of the fulcrum element 51 by means of the lever 34 and the fulcrum element 67 is arrested by the shoulder 72. The pin 101 shifts by +1.5 given units and the second row of characters down on the hand 79 (FIG. 2) is positioned.
Finally, if both the sliders 17 (FIG. 1) and 18 are shifted, the selector lever 52 will turn with the fulcrum element 68 on the shoulder 73, the pin 101 shifts by +0.5 given units and the first row of characters down on the head 79 (FIG. 2) will be positioned.
It is therefore clear how the system embodying the invention makes it possible to obtain four different positions on the output element 65 (FIG. 1) of the selector lever 52 by shifting in combination only two corresponding code bars 17 and 18, through the use of stop 46 configured to be shifted by each of the two sliders 17 and 18.
Assuming that, together with the sliders 17 and 18, the slider 19 is also shifted, this causes the movable support 56 to turn clockwise, removing the shoulder 98 from the path of the change-over element 91 and positioning the shoulder 99 in place thereof.
The cycle having been started, the spring 123 causes the intermediate lever 89 to be lowered until the change-over element 91 engages the shoulder 99. By means of the link 65, the intermediate lever 89 therefore rises by +0.5 given units and shifts by means of the change-over element 91 by an amount equivalent to the distance between the shoulders 98 and 99 and equal to a positioning by -4 given units. This last amount is greater than the amount of the link 65 and is moreover negative, so that it is the spring 123 that causes the character to be printed to be positioned by means of the gearing mechanism 106 during the lowering of the change-over element 91. The combination of the two movements therefore gives rise to a total shift of -3.5 given units and causes the fourth row of characters from the top to be positioned.
The support 56 (FIG. 1) therefore alters the reference position of the head 79 (FIG. 2) and the selection of the other three rows of characters from the top is effected in dependence upon the combination of positions of the sliders 17 (FIG. 1) and 18 as hereinafter described, as the algebraic sum of the shifts of the elements 88 and 91.
Similarly, for selection of the tracks of characters, by shifting the slider 21 or both the sliders 21 and 20, the corresponding lugs 134 (FIG. 2) and 126 will bring the shoulder 139 of the stop 137 or both the shoulders 139 and 131 of the stops 137 and 128, respectively, out of the paths of the fulcrum elements 141 and 132. By means of the link 148, the intermediate lever 157 will then be shifted by +1.5 or 0.5 given units, respectively, to position the second or first track of characters to the right.
Finally, by shifting the slider 22 (FIG. 3), the movable support 144 is shifted, so that during the lowering of the intermediate element 162 the change-over element 158 is arrested by the shoulder 172 (FIG. 2) and not by the shoulder 171, and the link 174 is shifted by -3 given units which are added algebraically to the shifts defined by the fulcrum elements 149, 132 and 141 to select the three left-hand tracks of the head 79.
During the positioning of the selector mechanisms 10 and 11 (FIG. 3) in the inoperative state, the sliders 13 (FIG. 1) return to the operative state by means of the springs 26 together with the code bars 12 and the spring 48 brings the transmission lever 34 back to the inoperative state together with the stop 46.
The typewriter on which the character selector mechanism 10 and the track selector mechanism 11 (FIG. 3) are mounted is provided with a lower to upper case or shift device known per se and not shown in the drawings, which is connected to control the movable support 108. This device is operated from the keyboard and causes the movable support 108 to be lowered for a specific stroke such that by means of the gearing mechanism 106 it causes the printing head 79 (FIG. 2) to rotate through 180°. Upon altering the reference position of the rows of characters in this way, the operation of the two mechanisms 10 and 11 (FIG. 3) is similar to what has been described in the above-given examples and will select the characters arranged on that part of the head 79 (FIG. 2) which is disposed on the opposite side with respect to the platen 121.
The selector system embodying the invention is particularly simple because of the use of part which in the preferred embodiment are substantially similar to each other. More particularly, the intermediate levers 89 and 157 (FIG. 3), the movable supports 56 and 144, the intermediate elements 93 and 162 and the stops 29, 38, 46, 128 and 137 are alike. Moreover, the character selector mechanism 10 and the track selector mechanism 11 are actuated by actuating means including cams 82, 82', and by a single cam follower.
While preferred embodiments of the invention have been shown by way of example in the drawings, it will be understood that the invention is in no way limited to these embodiments.
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A selector system for a printing head for use in printing machines and the like for selecting a character to be printed from the printing head. The system comprises at least two actuatable code bars. The printing head is positioned with respect to a first coordinate by the use of a selector lever having a set of pivot elements thereon each defining a pivot axis about which the selection lever pivots a preselected amount. In response to the actuation of the code bars, the pivot element about which the selector lever pivots is selected by two stop members each pivotable in response to the actuation of one of the code bars and each engageable with one of two pivot elements, a third stop member engaged with a third pivot element and not pivoting in response to the actuation of any of the code bars and a fourth stop member engaged with a fourth pivot element and pivotable in response to the actuation of either of the two code bars.
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BACKGROUND OF THE INVENTION
The present invention relates in general to an adjustble workpiece securing device and, more particularly, to such a device for positioning and securing in place a workpiece relative to a workpiece support during a machining operation, such as, for instance, a drilling operation, a milling operation, a sawing operation, or the like.
A known difficulty, in addition to safety considerations, which is frequently experienced while performing a machining operation on a workpiece is that of maintaining a specific relationship between the workpiece and the machine cutting element. This is particularly difficult if the workpiece is relatively small or the number of pieces to be fabricated does not justify the construction and utilization of a specially designed holding fixture. A special holding fixture is often constructed for mass production, however, being uneconomical when fabricating only a few pieces, such as models, prototypes and specialty items. To this end, one of the more commonly adopted solutions for holding the workpiece in place and positioning the workpiece relative to the machine cutting element is the utilization of vises, vise grips, adjustable clamps, staples, and the like. While these devices have utility, they do, however, possess a number of disadvantages, such as, they do not permit a workpiece to be locked into position and to be released practically immediately, as and when required.
There is known from U.S. Pat. Nos. 4,477,063, 3,345,889, 2,813,559, 2,486,638 and 552,814, a number of devices suitable for securing a workpiece to a workpiece support so as to enable the performing of a machining operation. Although these devices have utility and have been employed to some degree of success, such devices possess a number of disadvantages which limit their usefulness while forming precision machining operations. For example, these devices are constructed to include a number of interrelated elements which are movable relative to one another in such a manner which permits shifting of the workpiece, to at least a certain degree, during the machining operation. Any such movement, even of the smallest magnitude, will affect the ability to manufacture precision pieces, when taking into consideration the small tolerances which may be specified. Other known workpiece securing devices are disclosed in U.S. Pat. Nos. 3,127,162, 3,697,060, 3,243,055, 2,815,052 and 3,301,548. Similarly, these known devices possess a number of disadvantages which preclude their ability to efficiently and precisely secure a workpiece during a subsequent machining operation.
Accordingly, it can be appreciated that there is an unsolved need for an adjustable workpiece securing device which, in addition to being easily adjustable to workpieces of different sizes and shapes, is constructed to maintain precision alignment of the workpiece during a machining operation in a simple and effective manner.
SUMMARY OF THE INVENTION
It is broadly an object of the present invention to provide an adjustable workpiece securing device which overcomes or avoids one or more of the foregoing disadvantages resulting from the use of the aforementioned devices and which meets the specific requirements of such an adjustable device for use in precision securing of a workpiece relative to a machine cutting element during a machining operation.
Specifically, it is within the contemplation of one aspect of the present invention to provide a device for securing a workpiece to a support having a column member. The device is constructed of a locking assembly securable to a portion of the column member, a first member having a secured end attached to the locking assembly and a displaceable end adapted for engaging the workpiece, a second member having a first end coupled to the first member adjacent the displaceable end and a second end coupled to the locking assembly, and cam means in operative association with the second member for displacing the displaceable end of the first member, whereby the displaceable end of the first member is brought into engagement with the workpiece for securing the workpiece to the support.
In accordance with another embodiment of the present invention, there is provided a device for securing a workpiece to a support having a column member. The device is constructed of a locking assembly securable to a portion of the column member, a first member having a secured end attached to the locking assembly and a displaceable end adapted for engaging the workpiece, a second member having a first end coupled to the first member adjacent the displaceable end and a second end coupled to the locking assembly, and a cam assembly coupling the second end of the second member to the locking assembly about an eccentric path, the cam assembly operative for bringing the displaceable end of the first member into engagement with the workpiece upon movement of the second member by the cam assembly, whereby the workpiece is secured to the support.
In accordance with another embodiment of the present invention, there is provided a device for securing a workpiece to a support having a column member. The device is constructed of a locking assembly releasably securable to a portion of the column member, a longitudinally extending first member having a secured end fixedly attached to the locking assembly and a displaceable end adapted for engaging the workpiece, the first member constructed to be flexible to accommodate displacement of the displaceable end, a first bearing block secured to the first member adjacent the displaceable end, a second bearing block secured to the locking assembly, a longitudinally extending second member having a first end coupled to the first bearing block and a second end coupled to the second bearing block, and a cam assembly coupling the second end of the second member to the second bearing block, the cam assembly comprising a shaft supporting a cam about which the second end of the second member is coupled for movement about an eccentric path in response to the rotation of the shaft, the cam assembly operative to bring the displaceable end of the first member into engagement with the workpiece upon movement of the second member, whereby the workpiece is secured to the support.
BRIEF DESCRIPTION OF THE DRAWINGS
The above description, as well as further objects, features and advantages of the present invention will be more fully understood by reference to the following detailed description of the presently preferred, but nonetheless illustrative, adjustable workpiece securing device in accordance with the present invention, when taken in conjunction with the accompanying drawings, wherein:
FIG. 1 is a front elevational view of the workpiece securing device, constructed in accordance with the present invention, arranged overlying a workpiece support and releasably attached to a column member by means of a locking assembly;
FIG. 2 is a side elevational view, taken from the right in FIG. 1, showing the workpiece securing device in further assembled detail;
FIG. 3 is a top plan view showing an element of the workpiece securing device comprising a flexible, longitudinally extending bar, having a notch at one end thereof;
FIG. 4 is a side elevational view showing an element of the workpiece securing device comprising an elongated shaft supporting an eccentrically mounted cam;
FIG. 5 is a side elevational view, taken from the right in FIG. 4, showing the eccentric arrangement between the shaft and the cam; and
FIG. 6 is a front elevational view showing the locking assembly in an opened arrangement prior to attaching to the column member.
DETAILED DESCRIPTION
Referring now to the drawings, wherein like reference numerals represent like elements, there is shown in FIG. 1 an adjustable workpiece securing device generally designated by reference numeral 100. As shown, the device 100 is operative for securing a workpiece 102 to a workpiece support 104 having a workpiece supporting surface 106. Arranged adjacent the supporting surface 106, and extending transversely upward from the workpiece support 104 is a column member 108. The elements, as thus far described, may comprise a drill press or other such apparatus adapted to perform a machining operation. To this end, the column member 108 may be secured to the workpiece support 104, or in the alternative, may be arranged adjacent thereto and supported by a secondary fixture (not shown). The workpiece 102 may therefore be subjected to a variety of machining operations, for example, a drilling operation, a milling operation, a sawing operation, or the like.
Referring now to FIGS. 1-5, the device 100 is constructed generally of a locking assembly 110, a first longitudinally extending bar 112, a second longitudinally extending bar 114 and a cam assembly 116. The first bar 112 has a secured end designated 118 fixedly secured to a portion of the locking assembly 110, for example, by means of welding or bolting, to prevent relative movement therebetween. The first bar 112 further has a displaceable end designated 120 provided with a U-shaped notch 122, as shown in FIG. 3. The first bar 112 is constructed of suitable material to allow a degree of flexibility along its longitudinal axis during operation of the device 100 for securing a workpiece 102 to the workpiece support 104. Suitable materials may include industrial plastics, mild steel, and other metals which have a degree of resiliency to prevent their cracking or failure resulting from mechanical fatigue or the like during the flexing operation.
A first bearing block 124 is secured to the first bar 112 adjacent its displaceable end 120. A second bearing block 126 is secured to a portion of the locking assembly 110 overlying and spaced from the secured end 118 of the first bar 112. The first and second bearing blocks 124, 126 are each provided with a slot 128 adapted to receive one end of the second bar 114. In this regard, the second bar 114 is provided with a first end designated 130 and a second end designated 132, each having a circular opening 134, 136, respectively. The first end 130 of the second bar 114 is coupled to the first bearing block 124 by a shaft 138 extending through opening 134. The opening 136 and shaft 138 are dimensioned to permit relative pivotal movement between the second bar 114 and the shaft. The second end 132 of the second bar 114 is coupled to the second bearing block 126 by means of the cam assembly 116.
The cam assembly 116 is constructed of a longitudinally extending shaft 140 having a cam 142 eccentrically mounted about a portion thereof and a handle 144 secured to another portion thereof by a collar 146. Specifically, the handle 144 is secured at one end of the shaft 140 designated 148, which is remote from the cam 142, so as to provide effective mechnical advantage. The shaft 140 of the cam assembly 116 extends through the second bearing block 126 such that the cam 142 is positioned within the opening 136 within the second end 132 of the second bar 114. The dimensions and shape of the cam 142 with respect to the opening 136 are such to permit rotational or pivotal movement about an eccentric path upon rotation of the shaft 140 about its longitudinal axis by means of the handle 144. The device 100 is completed by the provision of a resilient pad 150 attached to the bottom surface of the first bar 112 at its displaceable end 120. The resilient pad 150 can be constructed of a variety of materials, for example, polyurethane, synthetic and natural rubbers and the like.
Referring now to FIGS. 1 and 6, the construction of the locking assembly 110 will now be described. The locking assembly 110 is constructed of a first C-shaped half 152 pivotally coupled to a like second C-shaped half 154 by means of a longitudinally extending, transversely inserted pin 156. The first and second C-shaped halves 152, 154 are accordingly adapted to form an enclosed opening for receiving the column member 108. The first C-shaped half 152 is provided with a notched opening 158 arranged centrally and extending inwardly from a peripheral edge 160. A rectangular member 162 having a threaded post 164 extending therefrom is pivotally coupled within the notched opening 158 by means of a transversely inserted pin 166. A handle 168 having a reduced diameter section 170 is threadingly received upon the threaded post 164.
The second C-shaped half 154 is provided with a notched opening 172 extending inwardly from a peripheral edge 174. The notched opening 172 opens into a recess 176 formed within an outer surface portion of the second C-shaped half 154 and forming a shoulder 178, as shown n FIG. 1. The recess 176 is dimensioned so as to receive a portion of the reduced diameter section 170 of the handle 168.
The construction and particular arrangement of the elements of the device 100 having now been described, a description of the operation of the device for securing a workpiece 102 to the supporting surface 106 of a workpiece support 104 will now follow. The locking assembly 110 is enclosed about a portion of the column member 108 and secured thereat to prevent relative movement therebetween. In this regard, the member 162 is pivoted about pin 166 so as to be received within notched opening 172 while the reduced diameter section 170 of the handle 168 is received within the recess 176 of the second C-shaped half 154. Upon rotation of the handle 168 so as to effect increasing threaded engagement with the threaded post 164, the reduced diameter section 170 is brought into engagement with the shoulder 178 so as to pull the first and second C-shaped halves 152, 154 together into secured relationship about the column member 108. The locking assembly 110 is positioned such that the resilient pad 150 attached to the displaceable end 120 of the first bar 112 is arranged overlying and spaced slightly from the exposed surface of the workpiece 102.
After manipulation of the workpiece 102 such that the portion thereof to be machined is exposed within the U-shaped notch 122 within the displaceable end 120 of the first bar 112, the workpiece is secured to the supporting surface 106 of the workpiece support 104 by means of the device 100. This is achieved by rotation of the handle 144 over a limited arc in a clockwise direction, as shown in FIG. 1. Rotation of the handle 144 rotates the shaft 140 and cam 142 which is received within the opening 136 within the second end 132 of the second member 114. The rotation of the cam 142 causes movement of the second end 132 of the second member 114 about an eccentric path resulting in the transmission and application of a mechanical force in a substantially downward direction at its first end 130 which is coupled to the first bearing block 124. In effect, this downward force is transmitted to the displaceable end 120 of the first bar 112 which is displaced downwardly due to its flexible nature, so as to engage the workpiece 102 and secure it to the supporting surface 106 to the workpiece support 104.
To rephrase the foregoing, the distance between shaft 138 and the secured end 118 of the first bar 112 cannot be lengthened due to the aforementioned construction. Therefore, upon the effective lengthening of the second member 114 by rotation of its second end 132 via the eccentric arrangement of the cam 142, such effective lengthening is accommodated by the downward displacement of the displaceable end 120 of the first bar 112. The resulting applied force by the rotation of the handle 144 in a clockwise direction effectively secures the workpiece 102. Release of the workpiece 102 is accomplished by rotation of the handle 144 in a counterclockwise direction.
Since the first bar 112 is fixedly secure at its secured end 118 to the locking assembly 110, there is prevented lateral or transverse movement of its displaceable end during the machining operation which might otherwise result in the inability to produce a precision machined workpiece 102. The device 100, by employing the displaceable end 120 for securing the workpiece 102, as opposed to the pivotally mounted elements of the prior art, further prevents any movement of the workpiece during the machining operation. A machine cutting element (not shown), for example, a drill bit, a cutting tool, etc., can perform machining operations on the workpiece 102 through the U-shaped notch 122 of the displaceable end 120 of the first bar 112. The provision of a resilient pad 150 accommodates irregularities in the surface profile of the workpiece 102, while further insuring the securing of the workpiece by means of the device 100.
Although the invention herein has been described with reference to particular embodiments, it is to be understood that these embodiments are merely illustrative of the principles and applications of the present invention. It is therefore to be understood that numerous modifications may be made in the illustrative embodiments and that other arrangements may be devised without departing from the spirit and scope of the present invention, as defined by the appended claims.
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An adjustable workpiece securing device is disclosed for securing a workpiece to a support while performing one or more machining operations thereon. The device incorporates a cam assembly for application of a force to the displaceable end of a substantially immovable bar to secure the workpiece to its underlying support. The construction of the device to include non-movable elements in those portions which effect the securing of the workpiece, results in the precision alignment of the workpiece with respect to a machine cutting element that can be effectively maintained during the machining operation.
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BACKGROUND OF THE INVENTION
[0001] The present invention relates generally to beverage makers and, more particularly, concerns a beverage maker including a compact integral optical code reader, such as a barcode reader, to be used with ingredient packages containing optical codes, such as for preparation of a beverage.
[0002] FIG. 1 is a schematic representation of a typical beverage preparation machine of the type which prepares and dispenses coffee and tea. The machine M includes a water supply tank T, which is filled with water, and a water pump P pumps water from the tank T into a heater H. The actual beverage is made by pumping the hot water through a cartridge C which contains a powder, or the like, to form the beverage. An optical code, such as a barcode, B is provided on a lower surface of the cartridge C and is read by a barcode reader R when the cartridge is placed into the machine. The barcode may, for example, provide a description of the beverage to be made and instructions for controlling its preparation.
[0003] As is typical, the barcode reader R includes a linear sensor L and a lens N which focuses the barcode on the sensor L. Typically, the lens N has a focal length greater than 25 mm and the sensor L must be placed at a distance of approximately 100 mm from the barcode. Owing to the significant length of the barcode reader R, it is placed in a crosswise orientation general parallel to the barcode B, and a mirror I is provided to bend the light path so that the barcode may be read at the side of the reader R and reflected lengthwise along the reader. If the barcode reader R did not have the mirror I, it would be positioned vertically and would interfere with the placement of a cup to receive the beverage within the apparatus. Nevertheless, even with its illustrated placement, the barcode reader R is large and cumbersome and, because it projects into the open, can possibly be damaged during use of the machine.
[0004] It would therefore be desirable to have a barcode reader which can be kept within the confines of the vicinity of the cartridge, without projecting substantially beyond that vicinity.
SUMMARY OF THE INVENTION
[0005] In accordance with the present invention, a compact barcode reader is provided in which the imaging lens and, preferably, the linear sensor are in a straight line path with the barcode (no bend in path). By using a wide angle lens with a short back focus, it is possible to reduce the distance between the barcode and linear sensor to a fraction of what it was in the prior art. In addition, the maximum image height and the downward projection of the sensor are reduced to a fraction of what they were in the prior art. As a result, despite the straight line optical path, compact barcode reader becomes so small that it does not interfere with the operation of the beverage maker.
BRIEF DESCRIPTION OF THE DRAWINGS
[0006] The foregoing brief description and further objects, features and advantages of the present invention will be understood more completely from the following detailed descriptions of presently preferred, but nonetheless illustrative, embodiments of the invention, which reference being had to the accompanying drawings, in which:
[0007] FIG. 1 is a schematic representation of a typical beverage preparation machine of the type which prepares and dispenses coffee and tea, the machine including a bar code reader;
[0008] FIG. 2 is a schematic representation of the beverage machine of FIG. 1 after a compact barcode reader embodying the present invention has been substituted for the original barcode reader;
[0009] FIG. 3 is an enlarged schematic view of a conventional barcode reader R as seen in FIG. 1 ;
[0010] FIG. 4 is a schematic representation of the optical system of a compact barcode reader 10 embodying the present invention;
[0011] FIGS. 5A and 5B (also referred to herein collectively as FIG. 5 ) are a schematic plan view and side view, respectively, of a first embodiment 10 of a compact barcode scanner embodying the present invention; and
[0012] FIGS. 6A and 6B are a plan view and side view, respectively, of a second embodiment of a compact barcode scanner in with the present invention.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
[0013] FIG. 2 is a schematic representation of the beverage machine of FIG. 1 after a compact barcode reader 10 , embodying the present invention, has been substituted for the barcode reader R. All elements which are identified by the same reference characters as in FIG. 1 are identical. It should be noted that reader 10 is well out of the user's way and is in a protected position, confined within the footprint projected by cartridge C.
[0014] FIG. 3 is an enlarged schematic view of a conventional barcode reader R as seen in FIG. 1 . It will be understood that the barcode is above the mirror I as shown in FIG. 1 . In addition to the elements already discussed, barcode reader R includes an LED D and a projection lens J, which illuminate the barcode. The physical characteristics of a barcode reader in accordance with the prior art and of compact barcode reader embodying the present invention are summarized in Table 1 below.
[0000]
TABLE 1
Prior
Compact
Art
Barcode Reader
X
Y
Focal length (mm)
26.83
6.314
8.34
12.8
Angle of field
30
66
42
66
(degree)
Back focus (mm)
42
7.6
10.8
25.3
Distance between
102
32
50
50
object and image
(mm)
Maximum image
14.3
4.0
4.0
14.3
height (mm)
Width of sensor
28.6
8.0
8
28.6
(mm)
[0015] In one conventional barcode reader, the focal length of the imaging lens N is 26.83 mm and it has an angle of field of 30°, which is typical. The back focus b, the distance between the lens N and the linear sensor L, is 42 mm, and the overall distance a between the barcode and the sensor L (represented in the drawing as only the distance to the mirror) must be maintained at 102 mm. For that reason, it is necessary to provide the mirror I so that the barcode reader R could project laterally (in FIG. 1 ) instead of downward, into the portion of the beverage maker used by the operator. With the optical system of the prior art, the maximum height of the image of the bar code was 14.3 mm and the height dimension c of the sensor L was 28.6 mm.
[0016] Reference is made in Table 1 to the angle of field of a lens. This will be understood to be the angle of view, which is related to a linear dimension of the image on the sensor and the focal length of the lens. In the present context, that would be the angle of view at the image sensor in the direction of image height, which is also referred to herein as the “width” of the sensor. Lenses may be referred to herein as “wide angle” or “normal.” A normal lens will be understood to have an angle of view of approximately 30°. A lens with an angle of view substantially above that will be considered a “wide angle” lens, and a lens with an angle of view substantially below that will be considered a “telephoto.” Referring to Table 1, it will be seen that the prior art barcode readers for beverage makers contained normal lenses.
[0017] FIG. 4 is a schematic representation of the optical system of a compact barcode reader 10 embodying the present invention. Use is made of a wide angle lens 12 which, in the preferred embodiment, has a focal length of 6.31 mm and a field of view of 66°. The back focus b between lens 12 and image sensor 14 is only 7.6 mm, and the wider optical field of the lens 12 permits it to be placed closer to the barcode B, resulting in a total distance a between barcode B and the image sensor 14 of only 32 mm. This permits the maintenance of a straight line path between the barcode B, and the lens 12 , without significant projection of compact barcode reader 10 into the operator's area of the beverage maker (represented by a phantom image of a cup). In addition, the maximum image height produced by the lens 14 is only 4.0 mm, permitting the use of a sensor 14 with a lateral dimension c of only 8 mm.
[0018] To achieve sufficient compactness of the scanner 10 , it is preferred that the total distance a between barcode B and the image sensor 14 in FIG. 4 be no greater than approximately 50 mm. The two right hand columns of Table 1 illustrate the dimensions for two alternate embodiments X and Y which achieve a sufficiently compact construction with a total distance a, which is less than approximately 50 mm. Embodiment X utilizes a lens with an 8.34 mm focal length and a 42° angle of field. It can then make use of the same sensor and maximum image size as the first embodiment. The smaller angle of field makes the lens easier to design and manufacture.
[0019] In alternate embodiment Y, the focal length of the lens is increased to 12.8 and an image and sensor size which are the same as the prior art are used. With the wide angle lens, it is still possible to maintain dimension a no greater than approximately 50 mm.
[0020] FIGS. 5A and 5B (also referred to herein collectively as FIG. 5 ) are a schematic plan view and side view, respectively, of a first embodiment 10 of a compact barcode scanner embodying the present invention. Scanner 10 includes a circuit board 22 and a case 24 which supports the lens 12 and the image sensor 14 . Also, two LEDs 26 , 26 are mounted on the circuit board 22 so as to project light to the left (in FIG. 5 ), to illuminate the barcode.
[0021] Circuit board 22 contains a drive circuit for the sensor 14 , a signal processing circuit, a barcode pattern allows the circuit, an LED drive circuit and a control circuit. For purposes of processing, and it is assumed that the circuit board contains an ASIC with a built-in CPU. The control circuit of the beverage machine may also be built into the ASIC.
[0022] The case 24 is preferably about 13 mm long (left-right dimension in FIG. 5 ), about 20 mm wide (the height dimension in FIG. 5A ) and about 8 mm high (the height dimension in FIG. 5B ). It may be made of any convenient material, such as plastic. It has a provision for retaining the lens 12 and sensor 14 in a required, fixed relationship. Lens 12 is preferably made of plastic, and sensor 14 is preferably a CCD or CMOS image sensor.
[0023] FIGS. 6A and 6B are a plan view and side view, respectively, of a second embodiment 20 ′ of a compact barcode sensor in accordance with the present invention. In FIG. 6 , elements identical to those in FIG. 5 are indicated by the same reference characters. The primary difference is that the sensor 14 is mounted on the circuit board 22 ′, which is otherwise identical to circuit board 22 of FIG. 5 . An angled mirror 28 is provided to produce a bent optical path to image sensor 14 ′. The dimensions of the barcode reader 20 ′ are essentially identical to those of barcode reader 20 .
[0024] Barcode reader 20 is mounted so that the far (right hand) edge of case 24 is about 34 mm from the barcode, and barcode reader 20 ′ is mounted so that the far edge of case 24 is about 33 mm from the barcode.
[0025] Although preferred embodiments of the invention have been disclosed for illustrative purposes, those skilled in the art will appreciate that many additions, modifications, and substitutions are possible without departing from the scope and spirit of the invention as defined by the accompanying claims.
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A compact barcode reader is provided in which the imaging lens and a linear sensor are in a straight line path with the barcode (no bend in path). By using a wide angle lens with a short back focus, it is possible to reduce the distance between the barcode and linear sensor to a fraction of what it was in the prior art. In addition, the maximum image height and the downward projection of the sensor are reduced to a fraction of what they were in the prior art. As a result, despite the straight line optical path, compact barcode reader becomes so small that it does not interfere with the operation of the beverage maker.
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RELATED APPLICATIONS
[0001] The present application is a continuation-in-part of U.S. patent application Ser. No. 13/476,662, entitled “Heavy Duty Matrix Bit,” and filed on May 21, 2012, which claims priority to U.S. Provisional Patent Application No. 61/489,056, entitled “Heavy Matrix Drill Bit” and filed on May 23, 2011, the disclosures of which are incorporated by reference herein.
BACKGROUND OF THE INVENTION
[0002] This invention relates generally to downhole tools and methods for manufacturing such items. More particularly, this invention relates to infiltrated matrix drilling products including, but not limited to, fixed cutter bits, polycrystalline diamond compact (“PDC”) drill bits, natural diamond drill bits, thermally stable polycrystalline (“TSP”) drill bits, bi-center bits, core bits, and matrix bodied reamers and stabilizers, and the methods of manufacturing such items.
[0003] Full hole tungsten carbide matrix drill bits for oilfield applications have been manufactured and used in drilling since at least as early as the 1940's. FIG. 1 shows a cross-sectional view of a downhole tool casting assembly 100 in accordance with the prior art. The downhole tool casting assembly 100 consists of a thick-walled mold 110 , a stalk 120 , one or more nozzle displacements 122 , a blank 124 , a funnel 140 , and a binder pot 150 . The downhole tool casting assembly 100 is used to fabricate a casting (not shown) of a downhole tool.
[0004] According to a typical downhole tool casting assembly 100 , as shown in FIG. 1 , and a method for using the downhole tool casting assembly 100 , the thick-walled mold 110 is fabricated with a precisely machined interior surface 112 , and forms a mold volume 114 located within the interior of the thick-walled mold 110 . The thick-walled mold 110 is made from sand, hard carbon graphite, ceramic, or other known suitable materials. The precisely machined interior surface 112 has a shape that is a negative of what will become the facial features of the eventual bit face. The precisely machined interior surface 112 is milled and dressed to form the proper contours of the finished bit. Various types of cutters (not shown), known to persons having ordinary skill in the art, can be placed along the locations of the cutting edges of the bit and can also be optionally placed along the gage area of the bit. These cutters can be placed during the bit fabrication process or after the bit has been fabricated via brazing or other methods known to persons having ordinary skill in the art.
[0005] Once the thick-walled mold 110 is fabricated, displacements are placed at least partially within the mold volume 114 of the thick-walled mold 110 . The displacements are typically fabricated from clay, sand, graphite, ceramic, or other known suitable materials. These displacements consist of the center stalk 120 and the at least one nozzle displacement 122 . The center stalk 120 is positioned substantially within the center of the thick-walled mold 110 and suspended a desired distance from the bottom of the mold's interior surface 112 . The nozzle displacements 122 are positioned within the thick-walled mold 110 and extend from the center stalk 120 to the bottom of the mold's interior surface 112 . The center stalk 120 and the nozzle displacements 122 are later removed from the eventual drill bit casting so that drilling fluid (not shown) can flow though the center of the finished bit during the drill bit's operation.
[0006] The blank 124 is a cylindrical steel casting mandrel that is centrally suspended at least partially within the thick-walled mold 110 and around the center stalk 120 . The blank 124 is positioned a predetermined distance down in the thick-walled mold 110 . According to the prior art, the distance between the outer surface of the blank 124 and the interior surface 112 of the thick-walled mold 110 is typically twelve millimeters (“mm”) or more so that potential cracking of the thick-walled mold 110 is reduced during the casting process.
[0007] Once the displacements 120 , 122 and the blank 124 have been positioned within the thick-walled mold 110 , tungsten carbide powder 130 , which includes free tungsten, is loaded into the thick-walled mold 110 so that it fills a portion of the mold volume 114 that is around the lower portion of the blank 124 , between the inner surfaces of the blank 124 and the outer surfaces of the center stalk 120 , and between the nozzle displacements 122 . Shoulder powder 134 is loaded on top of the tungsten carbide powder 130 in an area located at both the area outside of the blank 124 and the area between the blank 124 and the center stalk 120 . The shoulder powder 134 is made of tungsten powder. This shoulder powder 134 acts to blend the casting to the steel blank 124 and is machinable. Once the tungsten carbide powder 130 and the shoulder powder 134 are loaded into the thick-walled mold 110 , the thick-walled mold 110 is typically vibrated to improve the compaction of the tungsten carbide powder 130 and the shoulder powder 134 . Although the thick-walled mold 110 is vibrated after the tungsten carbide powder 130 and the shoulder powder 134 are loaded into the thick-walled mold 110 , the vibration of the thick-walled mold 110 can be done as an intermediate step before, during, and/or after the shoulder powder 134 is loaded on top of the tungsten carbide powder 130 .
[0008] The funnel 140 is a graphite cylinder that forms a funnel volume 144 therein. The funnel 140 is coupled to the top portion of the thick-walled mold 110 . A recess 142 is formed at the interior edge of the funnel 140 , which facilitates the funnel 140 coupling to the upper portion of the thick-walled mold 110 . Typically, the inside diameter of the thick-walled mold 110 is similar to the inside diameter of the funnel 140 once the funnel 140 and the thick-walled mold 110 are coupled together.
[0009] The binder pot 150 is a cylinder having a base 156 with an opening 158 located at the base 156 , which extends through the base 156 . The binder pot 150 also forms a binder pot volume 154 therein for holding a binder material 160 . The binder pot 150 is coupled to the top portion of the funnel 140 via a recess 152 that is formed at the exterior edge of the binder pot 150 . This recess 152 facilitates the binder pot 150 coupling to the upper portion of the funnel 140 . Once the downhole tool casting assembly 100 has been assembled, a predetermined amount of binder material 160 is loaded into the binder pot volume 154 . The typical binder material 160 is a copper alloy or other suitable known material. Although one example has been provided for setting up the downhole tool casting assembly 100 , other examples can be used to form the downhole tool casting assembly 100 .
[0010] The downhole tool casting assembly 100 is placed within a furnace (not shown) or other heating structure. The binder material 160 melts and flows into the tungsten carbide powder 130 through the opening 158 of the binder pot 150 . In the furnace, the molten binder material 160 infiltrates the tungsten carbide powder 130 and the shoulder powder 134 to fill the interparticle spaces formed between adjacent particles of tungsten carbide powder 130 and between adjacent particles of shoulder powder 134 . During this process, a substantial amount of binder material 160 is used so that it fills at least a substantial portion of the funnel volume 144 . This excess binder material 160 in the funnel volume 144 supplies a downward force on the tungsten carbide powder 130 and the shoulder powder 134 . Once the binder material 160 completely infiltrates the tungsten carbide powder 130 and the shoulder powder 134 , the downhole tool casting assembly 100 is pulled from the furnace and is controllably cooled. Upon cooling, the binder material 160 solidifies and cements the particles of tungsten carbide powder 130 and the shoulder powder 134 together into a coherent integral mass 310 ( FIG. 3 ). The binder material 160 also bonds this coherent integral mass 310 ( FIG. 3 ) to the steel blank 124 thereby forming a bonding zone 190 , which is formed along at least a chamfered zone area 198 of the steel blank 124 and a central zone area 199 of the steel blank 124 . The coherent integral mass 310 ( FIG. 3 ) and the blank 124 collectively form the matrix body bit 200 ( FIG. 2 ), a portion of which is shown in FIGS. 2 and 3 . Once cooled, the thick-walled mold 110 is broken away from the casting. The casting then undergoes finishing steps which are known to persons having ordinary skill in the art, including the addition of a threaded connection (not shown) coupled to the top portion of the blank 124 . Although the matrix body bit 200 ( FIG. 2 ) has been described to be formed using the process and equipment described above, the process and/or the equipment can be varied to still form the matrix body bit 200 ( FIG. 2 ).
[0011] FIG. 2 shows a magnified cross-sectional view of the bonding zone 190 located at the chamfered zone area 198 ( FIG. 1 ) within the matrix body bit 200 in accordance with the prior art. FIG. 3 shows a magnified cross-sectional view of the bonding zone 190 located at the central zone area 199 ( FIG. 1 ) within the matrix body bit 200 in accordance with the prior art. Referring to FIGS. 2 and 3 , the coherent integral mass 310 is bonded to the steel blank 124 via the bonding zone 190 that is formed along and/or adjacent the surface of the steel blank 124 . The binder material 160 causes a portion of the iron from the steel blank 124 to diffuse into the binder material 160 and react with the free tungsten within the shoulder powder 134 and the tungsten carbide powder 130 , thereby forming this bonding zone 190 . The bonding zone 190 includes intermetallic compounds 290 . These intermetallic compounds 290 have an average hardness level of about 250 HV, which corresponds to about twice the hardness of the binder and steel matrix. According to FIG. 2 , the bonding zone 190 is formed having a thickness 215 ranging from about sixty-five micrometers (μm) to about eighty μm in the chamfered zone area 198 ( FIG. 1 ). According to FIG. 3 , the bonding zone 190 is formed having a thickness 315 ranging from about ten μm to about twenty μm in the central zone area 199 ( FIG. 1 ). The thicknesses 215 , 315 and/or volumes of the bonding zone 190 are dependent upon the exposure time and the exposure temperature. Exposure temperature is related to the type of binder material 160 that is used to cement the tungsten carbide particles to one another. Manufacturers typically use the same binder material 160 over long periods of time, such as ten year or more, because of the knowledge gained with respect to the binder material 160 used. Thus, the exposure temperature is substantially the same from one casting to another. Exposure time is not always the same, but instead, is related to the bit diameter that is to be manufactured. When the bit diameter to be manufactured is relatively large, there is a larger volume of tungsten carbide particles that are to be cemented to one another. Hence, the exposure time also is relatively longer, thereby providing more time for cementing the larger volume of tungsten carbide particles. Thus, since the exposure temperature is the same from one casting to another, and the exposure time is the same for casting similar bit diameters, it follows that the thicknesses 215 , 315 of intermetallic compounds 290 formed within the bit is consistent from one casting to another for a same bit diameter.
[0012] Initially, natural diamond bits were used in oilfield applications. These natural diamond bits performed by grinding the rock within the wellbore, and not by shearing the rock. Thus, these natural diamond bits experienced little to no torque, and hence very little stress was experienced at the bonding zone 190 of the natural diamond bits. With the advent of PDC drill bits, the bits sheared the rock within the wellbore and began experiencing more torque. However, these initial PDC drill bits were fabricated relatively small, about six inch diameters to about 12¼ inch diameters, and the prior art fabrication method described above continued to perform well. Later, PDC drill bits were fabricated having larger diameters and failures began occurring along the bonding zone 190 . Specifically, decohesion began occurring between the blank 124 and the coherent integral mass 310 , or matrix, at the bonding zone 190 . These intermetallic compounds 290 are a source for causing mechanical stresses to occur along the bonding zone 190 during drilling applications because there is a contraction of volume occurring when the intermetallic compounds 290 are formed. These intermetallic compounds are very brittle and some cracks in the intermetallic compounds could occur during the drilling process. These cracks could weaken the bit and lead to catastrophic failure. Now that cutter technology has improved, the demand placed upon the bits have also increased. Bits are being drilled for more hours. Bits also are being used with much more energy, which includes energy produced from increasing the weight on bit and/or from increasing the rotational speed of the bit. This increased demand on the bits is causing the decohesion failure to become a recurring problem in the industry. As the thickness or volume of the intermetallic compounds 290 increases, the risk of decohesion also increases.
BRIEF DESCRIPTION OF THE DRAWINGS
[0013] The foregoing and other features and aspects of the invention will be best understood with reference to the following description of certain exemplary embodiments of the invention, when read in conjunction with the accompanying drawings, wherein:
[0014] FIG. 1 shows a cross-sectional view of a downhole tool casting assembly in accordance with the prior art;
[0015] FIG. 2 shows a magnified cross-sectional view of a bonding zone located at a chamfered zone area within the matrix body bit in accordance with the prior art;
[0016] FIG. 3 shows a magnified cross-sectional view of a bonding zone located at a central zone area within the matrix body bit in accordance with the prior art;
[0017] FIG. 4 shows a cross-sectional view of a blank in accordance with an exemplary embodiment;
[0018] FIG. 5 shows a cross-sectional view of a downhole tool casting assembly using the blank of FIG. 4 in accordance with the exemplary embodiment;
[0019] FIG. 6 shows a magnified cross-sectional view of a bonding zone located at a chamfered zone area within the downhole tool in accordance with the exemplary embodiment;
[0020] FIG. 7 shows a magnified cross-sectional view of a bonding zone located at a central zone area within the downhole tool in accordance with the exemplary embodiment;
[0021] FIG. 8 shows a magnified cross-sectional view of a bonding zone located at a chamfered zone area within the downhole tool in accordance with another exemplary embodiment;
[0022] FIG. 9 shows a magnified cross-sectional view of a bonding zone located at a central zone area within the downhole tool in accordance with another exemplary embodiment;
[0023] FIG. 10 shows a cross-sectional view of a downhole tool casting assembly in accordance with another exemplary embodiment;
[0024] FIG. 11 shows a partial cross-sectional view of a downhole tool casting formed using the downhole tool casting assembly of FIG. 10 in accordance with the exemplary embodiment;
[0025] FIG. 12 shows a cross-sectional view of a downhole tool casting assembly in accordance with yet another exemplary embodiment;
[0026] FIG. 13 shows a partial cross-sectional view of a downhole tool casting formed using the downhole tool casting assembly of FIG. 12 in accordance with the exemplary embodiment;
[0027] FIG. 14 shows a cross-sectional view of a downhole tool casting assembly in accordance with yet another exemplary embodiment; and
[0028] FIG. 15 shows a partial cross-sectional view of a downhole tool casting formed using the downhole tool casting assembly of FIG. 14 in accordance with the exemplary embodiment.
DETAILED DESCRIPTION OF THE INVENTION
[0029] This invention relates generally to downhole tools and methods for manufacturing such items. More particularly, this invention relates to infiltrated matrix drilling products including, but not limited to, fixed cutter bits, polycrystalline diamond compact (“PDC”) drill bits, natural diamond drill bits, thermally stable polycrystalline (“TSP”) drill bits, bi-center bits, core bits, and matrix bodied reamers and stabilizers, and the methods of manufacturing such items. Although the description provided below is related to a drill bit, embodiments of the present invention relate to any infiltrated matrix drilling product.
[0030] FIG. 4 shows a cross-sectional view of a blank 400 in accordance with an exemplary embodiment. The blank 400 includes an internal blank component 410 and a metal coating 420 coupled around at least a portion of the surface of the internal blank component 410 . The internal blank component 410 is similar to the blank 124 ( FIG. 1 ) above. The internal blank component 410 is a cylindrically, hollow-shaped component and includes a cavity 412 extending through the entire length of the internal blank component 410 . According to some exemplary embodiments the internal blank component 410 also includes a top portion 414 and a bottom portion 416 . The top portion 414 has a smaller outer circumference than the bottom portion 416 . According to some exemplary embodiments, the internal blank component 410 is fabricated from steel; however, any other suitable material known to people having ordinary skill in the art is used in other exemplary embodiments.
[0031] The metal coating 420 is applied onto at least a portion of the surface of the internal blank component 410 . In some exemplary embodiments, the metal coating 420 is applied onto the surface of the entire internal blank component 410 . In other exemplary embodiments, the metal coating 420 is applied onto a portion of the surface of the internal blank component 410 . For example, the metal coating 420 is applied onto the surface of the bottom portion 416 , which is the portion that bonds to the matrix material, or a coherent integral mass 710 ( FIG. 7 ), which is described below. The metal coating 420 is applied onto the internal blank component 410 using electroplating techniques. Alternatively, other techniques, such as plasma spray, ion bombardment, electro-chemical depositing, laser cladding, cold spray, or other known coating techniques, are used to apply the metal coating 420 onto the internal blank component 410 in other exemplary embodiments. The metal coating 420 is fabricated using a material that reduces the formation of intermetallic compounds 690 ( FIG. 6 ) along and/or adjacent the surface of the blank 400 ( FIG. 4 ). Specifically, the metal coating 420 reduces the migration of iron from the internal blank component 410 into the binder material 560 ( FIG. 5 ) for reacting with the free tungsten at the temperature and exposure time during the fabrication process. The metal coating 420 is fabricated from nickel according to some exemplary embodiments. Alternatively, the metal coating 420 is fabricated using at least one of brass, bronze, copper, aluminum, zinc, cobalt, titanium, gold, refractory transitional materials such as molybdenum and tantalum, carbide, boride, oxide, metal matrix composites, a metal alloy of any previously mentioned metals, or any other suitable material that is capable of reducing the migration of iron from the internal blank component 410 into the binder material 560 ( FIG. 5 ) for reacting with the free tungsten. Alternatively, a different type of coating, such as a polymer coating, is used in lieu of the metal coating.
[0032] The metal coating 420 is applied onto the internal blank component 410 and has a thickness 422 ranging from about five μm to about 200 μm. In another exemplary embodiment, the metal coating 420 has a thickness 422 ranging from about five μm to about 150 μm. In yet another exemplary embodiment, the metal coating 420 has a thickness 422 ranging from about five μm to about eighty μm. In a further exemplary embodiment, the metal coating 420 has a thickness 422 ranging less than or greater than the previously mentioned ranges. In certain exemplary embodiments, the thickness 422 is substantially uniform, while in other exemplary embodiments, the thickness 422 is non-uniform. For example, the thickness 422 is greater along the surface of the internal blank component 410 that would typically form a greater thickness of the intermetallic compound during the fabrication process, such as the chamfered zone area 598 ( FIG. 5 ).
[0033] FIG. 5 shows a cross-sectional view of a downhole tool casting assembly 500 using the blank 400 in accordance with the exemplary embodiment. Referring to FIG. 5 , the downhole tool casting assembly 500 includes a mold 510 , a stalk 520 , one or more nozzle displacements 522 , the blank 400 , a funnel 540 , and a binder pot 550 . The downhole tool casting assembly 500 is used to fabricate a casting (not shown) of a downhole tool, such as a fixed cutter bit, a PDC drill bit, a natural diamond drill bit, and a TSP drill bit. However, the downhole tool casting assembly 500 is modified in other exemplary embodiments to fabricate other downhole tools, such as a bi-center bit, a core bit, and a matrix bodied reamer and stabilizer.
[0034] The mold 510 is fabricated with a precisely machined interior surface 512 , and forms a mold volume 514 located within the interior of the mold 510 . The mold 510 is made from sand, hard carbon graphite, ceramic, or other known suitable materials. The precisely machined interior surface 512 has a shape that is a negative of what will become the facial features of the eventual bit face. The precisely machined interior surface 512 is milled and dressed to form the proper contours of the finished bit. Various types of cutters (not shown), known to persons having ordinary skill in the art, are placed along the locations of the cutting edges of the bit and are optionally placed along the gage area of the bit. These cutters are placed during the bit fabrication process or after the bit has been fabricated via brazing or other methods known to persons having ordinary skill in the art.
[0035] Once the mold 510 is fabricated, displacements are placed at least partially within the mold volume 514 . The displacements are fabricated from clay, sand, graphite, ceramic, or other known suitable materials. These displacements include the center stalk 520 and the at least one nozzle displacement 522 . The center stalk 520 is positioned substantially within the center of the mold 510 and suspended a desired distance from the bottom of the mold's interior surface 512 . The nozzle displacements 522 are positioned within the mold 110 and extend from the center stalk 520 to the bottom of the mold's interior surface 512 . The center stalk 520 and the nozzle displacements 522 are later removed from the eventual drill bit casting so that drilling fluid (not shown) flows though the center of the finished bit during the drill bit's operation.
[0036] The blank 400 , which has been previously described above, is centrally suspended at least partially within the mold 510 and around the center stalk 520 . The blank 400 is positioned a predetermined distance down in the mold 510 . The distance between the outer surface of the blank 400 and the interior surface 512 of the mold 510 is about twelve millimeters or more so that potential cracking of the mold 510 is reduced during the casting process. However, this distance is varied in other exemplary embodiments depending upon the strength of the mold 510 or the method and/or equipment used in fabricating the casting.
[0037] Once the displacements 520 , 522 and the blank 400 have been positioned within the mold 510 , tungsten carbide powder 530 is loaded into the mold 110 so that it fills a portion of the mold volume 514 that is around the bottom portion 416 of the blank 400 , between the inner surfaces of the blank 400 and the outer surfaces of the center stalk 520 , and between the nozzle displacements 522 . Shoulder powder 534 is loaded on top of the tungsten carbide powder 530 in an area located at both the area outside of the blank 400 and the area between the blank 400 and the center stalk 520 . The shoulder powder 534 is made of tungsten powder or other known suitable material. This shoulder powder 534 acts to blend the casting to the blank 400 and is machinable. Once the tungsten carbide powder 530 and the shoulder powder 534 are loaded into the mold 510 , the mold 510 is vibrated, in some exemplary embodiments, to improve the compaction of the tungsten carbide powder 530 and the shoulder powder 534 . Although the mold 510 is vibrated after the tungsten carbide powder 530 and the shoulder powder 534 are loaded into the mold 510 , the vibration of the mold 510 is done as an intermediate step before, during, and/or after the shoulder powder 534 is loaded on top of the tungsten carbide powder 530 . Although tungsten carbide material 530 is used in certain exemplary embodiments, other suitable materials known to persons having ordinary skill in the art is used in alternative exemplary embodiments.
[0038] The funnel 540 is a graphite cylinder that forms a funnel volume 544 therein. The funnel 540 is coupled to the top portion of the mold 510 . A recess 542 is formed at the interior edge of the funnel 540 , which facilitates the funnel 540 coupling to the upper portion of the mold 510 . In some exemplary embodiments, the inside diameter of the mold 510 is similar to the inside diameter of the funnel 540 once the funnel 540 and the mold 510 are coupled together.
[0039] The binder pot 550 is a cylinder having a base 556 with an opening 558 located at the base 556 , which extends through the base 556 . The binder pot 550 also forms a binder pot volume 554 therein for holding a binder material 560 . The binder pot 550 is coupled to the top portion of the funnel 540 via a recess 152 that is formed at the exterior edge of the binder pot 550 . This recess 552 facilitates the binder pot 550 coupling to the upper portion of the funnel 540 . Once the downhole tool casting assembly 500 has been assembled, a predetermined amount of binder material 560 is loaded into the binder pot volume 554 . The typical binder material 560 is a copper alloy or other suitable known material. Although one example has been provided for setting up the downhole tool casting assembly 500 , other examples having greater, fewer, or different components are used to form the downhole tool casting assembly 500 . For instance, the mold 510 and the funnel 540 are combined into a single component in some exemplary embodiments.
[0040] The downhole tool casting assembly 500 is placed within a furnace (not shown) or other heating structure. The binder material 560 melts and flows into the tungsten carbide powder 530 through the opening 558 of the binder pot 550 . In the furnace, the molten binder material 560 infiltrates the tungsten carbide powder 530 to fill the interparticle space formed between adjacent particles of tungsten carbide powder 530 . During this process, a substantial amount of binder material 560 is used so that it fills at least a substantial portion of the funnel volume 544 . This excess binder material 560 in the funnel volume 544 supplies a downward force on the tungsten carbide powder 530 and the shoulder powder 534 . Once the binder material 560 completely infiltrates the tungsten carbide powder 530 , the downhole tool casting assembly 500 is pulled from the furnace and is controllably cooled. Upon cooling, the binder material 560 solidifies and cements the particles of tungsten carbide powder 530 together into a coherent integral mass 710 ( FIG. 7 ). The binder material 560 also bonds this coherent integral mass 710 ( FIG. 7 ) to the blank 400 thereby forming a bonding zone 590 , which is formed at least at a chamfered zone area 598 of the blank 400 and a central zone area 599 of the blank 400 , according to certain exemplary embodiments. The coherent integral mass 710 ( FIG. 7 ) and the blank 400 collectively form the matrix body bit 600 ( FIG. 6 ), a portion of which is shown in FIGS. 6 and 7 . Once cooled, the mold 510 is broken away from the casting. The casting then undergoes finishing steps which are known to persons of ordinary skill in the art, including the addition of a threaded connection (not shown) coupled to the top portion 414 of the blank 400 . Although the matrix body bit 600 ( FIG. 6 ) has been described to be formed using the process and equipment described above, the process and/or the equipment can be varied to still form the matrix body bit 600 ( FIG. 6 ).
[0041] FIG. 6 shows a magnified cross-sectional view of the bonding zone 590 located at the chamfered zone area 598 ( FIG. 5 ) within the downhole tool in accordance with the exemplary embodiment. FIG. 7 shows a magnified cross-sectional view of the bonding zone 590 located at the central zone area 599 ( FIG. 5 ) within the downhole tool in accordance with the exemplary embodiment. Referring to FIGS. 6 and 7 , the blank 400 includes the internal blank component 410 and the metal coating 420 , which is applied onto the surface of the internal blank component 410 . The coherent integral mass 710 is bonded to the blank 400 via the bonding zone 590 that is formed along and/or adjacent the surface of the blank 400 . According to some exemplary embodiments, the metal coating 420 is thinly applied onto the internal blank component 410 so that a portion of the iron from the blank 400 to diffuses into the binder material 560 and reacts with the free tungsten within the shoulder powder 534 and the tungsten carbide powder 530 , thereby forming this bonding zone 590 . The bonding zone 590 includes intermetallic compounds 690 , which are similar to the intermetallic compounds 290 ( FIG. 2 ). According to FIG. 6 , the bonding zone 590 is formed having a thickness 615 ranging from about five μm to less than sixty-five μm in the chamfered zone area 598 ( FIG. 5 ). In another exemplary embodiment, the bonding zone 590 is formed having a thickness 615 ranging from about five μm to less than fifty μm in the chamfered zone area 598 ( FIG. 5 ). In yet another exemplary embodiment, the bonding zone 590 is formed having a thickness 615 ranging from about five μm to less than thirty μm in the chamfered zone area 598 ( FIG. 5 ). According to FIG. 7 , the bonding zone 590 is formed having a thickness 715 ranging from about two μm to less than about ten μm in the central zone area 599 ( FIG. 5 ). In another exemplary embodiment, the bonding zone 590 is formed having a thickness 715 ranging from about two μm to less than eight μm in the central zone area 599 ( FIG. 5 ). In yet another exemplary embodiment, the bonding zone 590 is formed having a thickness 715 ranging from about two μm to less than six μm in the central zone area 599 ( FIG. 5 ). The thicknesses 615 , 715 and/or volumes of the bonding zone 590 are dependent upon the exposure time, the temperature, and the thickness of the metal coating 420 that is applied onto the internal blank component 410 . As previously mentioned, the metal coating 420 reduces the migration of iron from the blank 400 into the binder material 560 , thereby decreasing the reaction with the free tungsten within the shoulder powder 534 and the tungsten carbide powder 530 during the fabrication process.
[0042] FIG. 8 shows a magnified cross-sectional view of the bonding zone 590 located at the chamfered zone area 598 ( FIG. 5 ) within the downhole tool in accordance with another exemplary embodiment. FIG. 9 shows a magnified cross-sectional view of the bonding zone 590 located at the central zone area 599 ( FIG. 5 ) within the downhole tool in accordance with another exemplary embodiment. Referring to FIGS. 8 and 9 , the blank 400 includes the internal blank component 410 and the metal coating 420 , which is applied onto the surface of the internal blank component 410 . The coherent integral mass 710 is bonded to the blank 400 via the bonding zone 590 that is formed along and/or adjacent the surface of the blank 400 . According to some exemplary embodiments, the metal coating 420 is applied onto the internal blank component 410 such that a smaller portion of the iron from the blank 400 diffuses into the binder material 560 . The diffused iron reacts with the free tungsten within the tungsten carbide powder 530 and the tungsten powder 534 to form this bonding zone 590 . The bonding zone 590 includes intermetallic compounds 690 , which are similar to the intermetallic compounds 290 ( FIG. 2 ). According to FIG. 8 , the bonding zone 590 is formed having a thickness 815 ranging from about five μm to less than sixty-five μm in the chamfered zone area 598 ( FIG. 5 ). In another exemplary embodiment, the bonding zone 590 is formed having a thickness 815 ranging from about five μm to less than fifty μm in the chamfered zone area 598 ( FIG. 5 ). In yet another exemplary embodiment, the bonding zone 590 is formed having a thickness 815 ranging from about five μm to less than thirty μm in the chamfered zone area 598 ( FIG. 5 ). According to FIG. 9 , the bonding zone 590 is formed having a thickness 915 ranging from about two μm to less than about ten μm in the central zone area 599 ( FIG. 5 ). In another exemplary embodiment, the bonding zone 590 is formed having a thickness 915 ranging from about two μm to less than eight μm in the central zone area 599 ( FIG. 5 ). In yet another exemplary embodiment, the bonding zone 590 is formed having a thickness 915 ranging from about two μm to less than six μm in the central zone area 599 ( FIG. 5 ). The thicknesses 815 , 915 and/or volumes of the bonding zone 590 are dependent upon the exposure time, the temperature, and the thickness of the metal coating 420 that is applied onto the internal blank component 410 . As previously mentioned, the metal coating 420 reduces the migration of iron from the blank 400 into the binder material 560 , thereby decreasing the reaction with the free tungsten within the shoulder powder 534 and the tungsten carbide powder 530 during the fabrication process.
[0043] FIG. 10 shows a cross-sectional view of a downhole tool casting assembly 1000 in accordance with another exemplary embodiment. Referring to FIG. 10 , the downhole tool casting assembly 1000 includes a mold 1010 , a stalk 1020 , one or more nozzle displacements 1022 , a blank 1024 , a funnel 1040 , and a binder pot 1050 . The downhole tool casting assembly 1000 is used to fabricate a casting 1100 ( FIG. 11 ) of a downhole tool, such as a fixed cutter bit, a PDC drill bit, a natural diamond drill bit, and a TSP drill bit. However, the downhole tool casting assembly 1000 is modified in other exemplary embodiments to fabricate other downhole tools, such as a bi-center bit, a core bit, and a matrix bodied reamer and stabilizer.
[0044] The mold 1010 is similar to mold 510 and forms a mold volume 1014 , which is similar to mold volume 514 . Since mold 510 has been previously described above, the details of mold 1010 are not repeated again herein for the sake of brevity. The center stalk 1020 and the one or more nozzle displacements 1022 are similar to the center stalk 520 and the nozzle displacements 522 , respectively, and therefore the descriptions of each also are not repeated herein for the sake of brevity. Further, the blank 1024 used within the downhole tool casting assembly 1000 is similar to either the blank 124 ( FIG. 1 ) or the blank 400 ( FIG. 4 ) and therefore also is not repeated herein for the sake of brevity.
[0045] Once the displacements 1020 , 1022 and the blank 1024 have been positioned within the mold 1010 , tungsten carbide powder 1030 , similar to tungsten carbide powder 530 , is loaded into the mold 1010 so that it fills a portion of the mold volume 1014 that is around the bottom portion 1026 of the blank 1024 , between the inner surfaces of the blank 1024 and the outer surfaces of the center stalk 1020 , and between the nozzle displacements 1022 . According to the exemplary embodiment shown in FIG. 10 , this tungsten carbide powder 1030 is the same as tungsten carbide powder 530 described above and includes at least W 2 C and some free tungsten. The process of fabricating W 2 C generally involves the inclusion of free tungsten. However, in other exemplary embodiments as shown in FIG. 12 for instance, this tungsten carbide powder 1030 is absent any free tungsten. Thus, the tungsten carbide powder 1030 , which is absent any free tungsten, includes only WC in some exemplary embodiments. Alternatively, the tungsten carbide powder 1030 , which is absent any free tungsten, includes W 2 C, WC, or a combination of both, while excluding any free tungsten. Thus, any free tungsten is removed either during or after the fabricating process before placing the tungsten carbide powder 1030 within the mold 1010 .
[0046] Shoulder powder 1034 is loaded on top of the tungsten carbide powder 1030 in an area located at both the area outside of the blank 1024 and the area between the blank 1024 and the center stalk 1020 . The shoulder powder 1034 is made of stainless steel powder or other known suitable material that is absent any free tungsten. Some examples of other suitable materials that is usable for the shoulder powder 1034 include other steel powders, nickel powder, cobalt powder, refractory transitional materials such as molybdenum powder and tantalum powder, and/or other metals that have a higher melting temperature than the binder alloy material 1060 but are soft enough to be machined. This shoulder powder 1034 acts to blend the casting to the blank 1024 and is machinable. Once the tungsten carbide powder 1030 and the shoulder powder 1034 are loaded into the mold 1010 , the mold 1010 is vibrated, in some exemplary embodiments, to improve the compaction of the tungsten carbide powder 1030 and the shoulder powder 1034 . Although the mold 1010 is vibrated after the tungsten carbide powder 1030 and the shoulder powder 1034 are loaded into the mold 1010 , the vibration of the mold 1010 is done as an intermediate step before, during, and/or after the shoulder powder 1034 is loaded on top of the tungsten carbide powder 1030 . Although tungsten carbide material 1030 is used in certain exemplary embodiments, other suitable materials known to persons having ordinary skill in the art are used in alternative exemplary embodiments.
[0047] The funnel 1040 is similar to funnel 540 and forms a funnel volume 1044 therein, which is similar to funnel volume 544 . Since funnel 540 has been previously described above, the details of funnel 1040 are not repeated again herein for the sake of brevity. Further, the binder pot 1050 is similar to binder pot 550 and forms a binder pot volume 1054 therein, which is similar to binder pot volume 554 , for holding a binder material 1060 , which is similar to binder material 560 . Since binder pot 550 and binder material 560 have been previously described above, the details of binder pot 1050 and binder material 1060 are not repeated again herein for the sake of brevity. Although one example has been provided for setting up the downhole tool casting assembly 1000 , other examples having greater, fewer, or different components are used to form the downhole tool casting assembly 1000 . For instance, the mold 1010 and the funnel 1040 are combined into a single component in some exemplary embodiments.
[0048] The downhole tool casting assembly 1000 is placed within a furnace (not shown) or other heating structure. The binder material 1060 melts and flows into the shoulder powder 1034 and the tungsten carbide powder 1030 through an opening 1058 of the binder pot 1050 . In the furnace, the molten binder material 1060 infiltrates the shoulder powder 1034 and the tungsten carbide powder 1030 to fill the interparticle space formed between adjacent particles of the shoulder powder 1034 and the tungsten carbide powder 1030 . During this process, a substantial amount of binder material 1060 is used so that it fills at least a substantial portion of the funnel volume 1044 . This excess binder material 1060 in the funnel volume 1044 supplies a downward force on the tungsten carbide powder 1030 and the shoulder powder 1034 . Once the binder material 1060 completely infiltrates the shoulder powder 1034 and the tungsten carbide powder 1030 , the downhole tool casting assembly 1000 is pulled from the furnace and is controllably cooled. Upon cooling, the binder material 1060 solidifies and cements the particles of shoulder powder 1034 and tungsten carbide powder 1030 together into a coherent integral mass 1110 ( FIG. 11 ). The binder material 1060 also bonds this coherent integral mass 1110 ( FIG. 11 ) to the blank 1024 thereby forming a bonding zone 1190 ( FIG. 11 ) therebetween. The coherent integral mass 1110 ( FIG. 11 ) and the blank 1024 collectively form the casting 1100 ( FIG. 11 ) or the matrix body bit 1100 ( FIG. 11 ), a portion of which is shown in FIG. 11 . Once cooled, the mold 1010 is broken away from the casting 1100 ( FIG. 11 ). The casting 1100 ( FIG. 11 ) then undergoes finishing steps which are known to persons of ordinary skill in the art, including the addition of a threaded connection (not shown) to the casting 1100 ( FIG. 11 ). Although the casting 1100 ( FIG. 11 ), or the matrix body bit 1100 ( FIG. 11 ), has been described to be formed using the process and equipment described above, the process and/or the equipment can be varied to still form the matrix body bit 1100 ( FIG. 11 ).
[0049] FIG. 11 shows a partial cross-sectional view of a downhole tool casting 1100 formed using the downhole tool casting assembly 1000 of FIG. 10 in accordance with the exemplary embodiment. Referring to FIG. 11 , the downhole tool casting 1100 includes the coherent integral mass 1110 , the blank 1024 , and the passageways 1120 formed from the removal of the displacements 1020 , 1022 . As mentioned above with respect to FIG. 10 , the coherent integral mass 1110 is formed using the tungsten carbide material 1030 , as described above, and the shoulder powder 1034 , also as described above. According to the exemplary embodiment illustrated in FIGS. 10 and 11 , the shoulder powder 1034 is absent of free tungsten material and the tungsten carbide material 1030 is the same as tungsten carbide powder 530 described above and includes at least W 2 C and some free tungsten. However, in other exemplary embodiments as shown in FIG. 12 for instance, this tungsten carbide powder 1030 is absent any free tungsten. Thus, the tungsten carbide powder 1030 , which is absent any free tungsten, includes only WC in some exemplary embodiments. Alternatively, the tungsten carbide powder 1030 , which is absent any free tungsten, includes W 2 C, WC, or a combination of both, while excluding any free tungsten.
[0050] The intermetallic compounds are formed when iron reacts with free tungsten. According to one of the present exemplary embodiments, the typical shoulder powder 134 having free tungsten is replaced with shoulder powder 1034 , thereby reducing and/or eliminating the formation of these intermetallic compounds, which is very brittle. The shoulder powder 1034 occupies the area adjacent a chamfered portion 1198 of the blank 1024 , similar to chamfered portion 598 ( FIG. 5 ), which experiences high stresses. Thus, by reducing and/or eliminating these intermetallic compounds from that region, the casting or bit 1100 is more durable and has a greater longevity. According to alternative exemplary embodiments, a type of tungsten carbide powder 1030 which also is tungsten free may be used in place of the typical tungsten carbide powder 130 , which includes free tungsten. The tungsten carbide powder 1030 occupies the area adjacent a central zone area 1199 of the blank 1024 , similar to central zone area 599 ( FIG. 5 ), which also experiences high stresses. Thus, by reducing and/or eliminating these intermetallic compounds from that region, the casting or bit 1100 is more durable and has a greater longevity. According to the exemplary embodiments, either or both shoulder powder 1034 and tungsten carbide powder 1030 (which are tungsten free) may be used in lieu of the typical shoulder powder 134 and typical tungsten carbide powder 130 .
[0051] FIG. 12 shows a cross-sectional view of a downhole tool casting assembly 1200 in accordance with yet another exemplary embodiment. Referring to FIG. 12 , the downhole tool casting assembly 1200 includes a mold 1210 , a stalk 1220 , one or more nozzle displacements 1222 , a blank 1224 , a funnel 1240 , and a binder pot 1250 . The downhole tool casting assembly 1200 is used to fabricate a casting 1300 ( FIG. 13 ) of a downhole tool, such as a fixed cutter bit, a PDC drill bit, a natural diamond drill bit, and a TSP drill bit. However, the downhole tool casting assembly 1200 is modified in other exemplary embodiments to fabricate other downhole tools, such as a bi-center bit, a core bit, and a matrix bodied reamer and stabilizer.
[0052] The mold 1210 is similar to mold 510 and forms a mold volume 1214 , which is similar to mold volume 514 . Since mold 510 has been previously described above, the details of mold 1210 are not repeated again herein for the sake of brevity. The center stalk 1220 and the one or more nozzle displacements 1222 are similar to the center stalk 520 and the nozzle displacements 522 , respectively, and therefore the descriptions of each also are not repeated herein for the sake of brevity. Further, the blank 1224 used within the downhole tool casting assembly 1200 is similar to either the blank 124 ( FIG. 1 ) or the blank 400 ( FIG. 4 ) and therefore also is not repeated herein for the sake of brevity.
[0053] Once the displacements 1220 , 1222 and the blank 1224 have been positioned within the mold 1210 , tungsten carbide powder 1230 is loaded into the mold 1210 so that it fills a portion of the mold volume 1214 that is around the bottom portion 1226 of the blank 1224 , between the inner surfaces of the blank 1224 and the outer surfaces of the center stalk 1220 , and between the nozzle displacements 1222 . According to the exemplary embodiment shown in FIG. 12 , this tungsten carbide powder 1230 is absent any free tungsten, and includes W 2 C, WC, or a combination of both, while excluding any free tungsten. In certain exemplary embodiments, the tungsten carbide powder 1230 , which is absent any free tungsten, includes only WC.
[0054] Shoulder powder 1234 is loaded on top of the tungsten carbide powder 1230 in an area located at both the area outside of the blank 1224 and the area between the blank 1224 and the center stalk 1220 . The shoulder powder 1234 is tungsten powder according to some exemplary embodiments; however, in other exemplary embodiments the shoulder powder 1234 is made of stainless steel powder or other known suitable material that is absent any free tungsten. Some examples of other suitable materials that is usable for the shoulder powder 1234 include other steel powders, nickel powder, cobalt powder, and/or other metals that have a higher melting temperature than the binder alloy material 1260 but are soft enough to be machined. This shoulder powder 1234 acts to blend the casting to the blank 1224 and is machinable. Once the tungsten carbide powder 1230 and the shoulder powder 1234 are loaded into the mold 1210 , the mold 1210 is vibrated, in some exemplary embodiments, to improve the compaction of the tungsten carbide powder 1230 and the shoulder powder 1234 . Although the mold 1210 is vibrated after the tungsten carbide powder 1230 and the shoulder powder 1234 are loaded into the mold 1210 , the vibration of the mold 1210 is done as an intermediate step before, during, and/or after the shoulder powder 1234 is loaded on top of the tungsten carbide powder 1230 . Although tungsten carbide material 1230 is used in certain exemplary embodiments, other suitable materials known to persons having ordinary skill in the art are used in alternative exemplary embodiments.
[0055] The funnel 1240 is similar to funnel 540 and forms a funnel volume 1244 therein, which is similar to funnel volume 544 . Since funnel 540 has been previously described above, the details of funnel 1240 are not repeated again herein for the sake of brevity. Further, the binder pot 1250 is similar to binder pot 550 and forms a binder pot volume 1254 therein, which is similar to binder pot volume 554 , for holding a binder material 1260 , which is similar to binder material 560 . Since binder pot 550 and binder material 560 have been previously described above, the details of binder pot 1250 and binder material 1260 are not repeated again herein for the sake of brevity. Although one example has been provided for setting up the downhole tool casting assembly 1200 , other examples having greater, fewer, or different components are used to form the downhole tool casting assembly 1200 . For instance, the mold 1210 and the funnel 1240 are combined into a single component in some exemplary embodiments.
[0056] The downhole tool casting assembly 1200 is placed within a furnace (not shown) or other heating structure. The binder material 1260 melts and flows into the shoulder powder 1234 and the tungsten carbide powder 1230 through an opening 1258 of the binder pot 1250 . In the furnace, the molten binder material 1260 infiltrates the shoulder powder 1234 and the tungsten carbide powder 1230 to fill the interparticle space formed between adjacent particles of the shoulder powder 1234 and the tungsten carbide powder 1230 . During this process, a substantial amount of binder material 1260 is used so that it fills at least a substantial portion of the funnel volume 1244 . This excess binder material 1260 in the funnel volume 1244 supplies a downward force on the tungsten carbide powder 1230 and the shoulder powder 1234 . Once the binder material 1260 completely infiltrates the shoulder powder 1234 and the tungsten carbide powder 1230 , the downhole tool casting assembly 1200 is pulled from the furnace and is controllably cooled. Upon cooling, the binder material 1260 solidifies and cements the particles of shoulder powder 1234 and tungsten carbide powder 1230 together into a coherent integral mass 1310 ( FIG. 13 ). The binder material 1260 also bonds this coherent integral mass 1310 ( FIG. 13 ) to the blank 1224 thereby forming a bonding zone 1390 ( FIG. 13 ) therebetween. The coherent integral mass 1310 ( FIG. 13 ) and the blank 1224 collectively form the casting 1300 ( FIG. 13 ) or the matrix body bit 1300 ( FIG. 13 ), a portion of which is shown in FIG. 13 . Once cooled, the mold 1210 is broken away from the casting 1300 ( FIG. 13 ). The casting 1300 ( FIG. 13 ) then undergoes finishing steps which are known to persons of ordinary skill in the art, including the addition of a threaded connection (not shown) to the casting 1300 ( FIG. 13 ). Although the casting 1300 ( FIG. 13 ), or the matrix body bit 1300 ( FIG. 13 ), has been described to be formed using the process and equipment described above, the process and/or the equipment can be varied to still form the matrix body bit 1300 ( FIG. 13 ).
[0057] FIG. 13 shows a partial cross-sectional view of a downhole tool casting 1300 formed using the downhole tool casting assembly 1200 of FIG. 12 in accordance with the exemplary embodiment. Referring to FIG. 13 , the downhole tool casting 1300 includes the coherent integral mass 1310 , the blank 1224 , and the passageways 1320 formed from the removal of the displacements 1220 , 1222 . As mentioned above with respect to FIG. 12 , the coherent integral mass 1310 is formed using the tungsten carbide material 1230 , as described above, and the shoulder powder 1234 , also as described above. According to the exemplary embodiment illustrated in FIGS. 12 and 13 , the shoulder powder 1234 includes tungsten powder and the tungsten carbide material 1030 is absent free tungsten and includes either WC, W 2 C, or a combination of both. However, in other exemplary embodiments as shown in FIG. 12 for instance, this shoulder powder 1234 is absent any free tungsten. Thus, the shoulder powder 1234 , which is absent any free tungsten, includes stainless steel powder or any other suitable material described above.
[0058] The intermetallic compounds are formed when iron reacts with free tungsten. According to one of the present exemplary embodiments, the typical tungsten carbide powder 130 having free tungsten is replaced with tungsten carbide powder 1230 which is absent of free tungsten, thereby reducing and/or eliminating the formation of these intermetallic compounds, which is very brittle. The tungsten carbide powder 1230 occupies the area adjacent a central zone area 1399 of the blank 1024 , similar to central zone area 599 ( FIG. 5 ), which experiences high stresses. Thus, by reducing and/or eliminating these intermetallic compounds from that region, the casting or bit 1300 is more durable and has a greater longevity. According to alternative exemplary embodiments, the shoulder powder 1234 which is tungsten free, according to some exemplary embodiments, may be used in place of the typical shoulder powder 134 , which includes free tungsten. The shoulder powder 1234 occupies the area adjacent a chamfered portion 1398 of the blank 1224 , similar to chamfered portion 598 ( FIG. 5 ), which also experiences high stresses. Thus, by reducing and/or eliminating these intermetallic compounds from that region, the casting or bit 1300 is more durable and has a greater longevity. According to the exemplary embodiments, either or both shoulder powder 1234 and tungsten carbide powder 1230 (which are tungsten free) may be used in lieu of the typical shoulder powder 134 and typical tungsten carbide powder 130 .
[0059] FIG. 14 shows a cross-sectional view of a downhole tool casting assembly 1400 in accordance with yet another exemplary embodiment. The downhole casting assembly 1400 is similar to downhole casting assembly 1000 ( FIG. 10 ) and/or downhole casting assembly 1200 ( FIG. 12 ) except an intermediate layer 1438 is disposed between the shoulder powder 1434 and the tungsten carbide powder 1430 . The intermediate layer 1438 is meant to minimize stresses caused by thermal expansion according to some exemplary embodiments. The shoulder powder 1434 is similar to shoulder powder 1034 , 1234 ( FIGS. 10 and 12 , respectively) and the tungsten carbide powder 1430 is similar to tungsten carbide powder 1030 , 1230 ( FIGS. 10 and 12 , respectively). At least one of the shoulder powder 1434 and the tungsten carbide powder 1430 is absent of free tungsten. The intermediate layer 1438 is formed by including an amount of tungsten carbide powder 1430 that is used to the shoulder powder 1434 that is used thereby transitioning from the tungsten carbide powder 1430 to the shoulder powder 1434 . The amount of tungsten carbide powder 1430 that is included with the shoulder powder 1434 in the intermediate layer 1438 is about twenty percent to thirty percent by volume with respect to the shoulder powder 1434 . According to some other exemplary embodiments, the amount of tungsten carbide powder 1430 that is included in the intermediate layer 1438 is between ten percent and less than fifty percent by volume. According to certain exemplary embodiments, the composition of the intermediate layer 1438 gradually varies from the bottom of the intermediate layer 1438 to the top of the intermediate layer 1438 , where the composition at the bottom of the intermediate layer 1438 is close to the composition of the tungsten carbide powder 1430 and the composition at the top of the intermediate layer 1438 is close to the composition of the shoulder powder 1434 . This intermediate layer 1438 is harder than the areas where the shoulder powder 1434 is, but is still machinable according to certain exemplary embodiments.
[0060] FIG. 15 shows a partial cross-sectional view of a downhole tool casting 1500 formed using the downhole tool casting assembly 1400 of FIG. 14 in accordance with the exemplary embodiment. The downhole tool casting 1500 is similar to downhole tool casting 1100 ( FIG. 11 ) and/or downhole tool casting 1300 ( FIG. 13 ) except an intermediate layer 1438 is disposed between the shoulder powder 1434 and the tungsten carbide powder 1430 , as described above.
[0061] Although the invention has been described with reference to specific embodiments, these descriptions are not meant to be construed in a limiting sense. Various modifications of the disclosed embodiments, as well as alternative embodiments of the invention will become apparent to persons skilled in the art upon reference to the description of the invention. It should be appreciated by those skilled in the art that the conception and the specific embodiments disclosed may be readily utilized as a basis for modifying or designing other structures for carrying out the same purposes of the invention. It should also be realized by those skilled in the art that such equivalent constructions do not depart from the spirit and scope of the invention as set forth in the appended claims. It is therefore, contemplated that the claims will cover any such modifications or embodiments that fall within the scope of the invention.
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An apparatus and method for manufacturing a downhole tool that reduces failures occurring along a bondline between a cemented matrix coupled around a blank. The cemented matrix material is formed from a tungsten carbide powder, a shoulder powder, and a binder material, wherein at least one of the tungsten carbide powder or the shoulder powder is absent of any free tungsten. The blank, which optionally may be coated, is substantially cylindrically shaped and defines a channel extending from a top portion and through a bottom portion of the blank. The absence of free tungsten from at least one of the tungsten carbide powder or the shoulder powder reduces the reaction with iron from the blank, thereby allowing the control and reduction of intermetallic compounds thickness within the bondline.
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This application is a continuation-in-part of U.S. patent application Ser. No. 09/514,993 filed Feb. 29, 2000 and issued Feb. 13, 2001 as U.S. Pat. No. 6,187,309 which claims benefit of U.S. Provisional Patent Application Ser. No. 60/153,838 filed Sep. 14, 1999 the disclosures of which are hereby incorporated by reference.
BACKGROUND OF THE INVENTION
The therapeutic use of antibodies is generally limited to: (a) imimunotherapy where a specific antibody directed against a discreet antigen is used to counter the effect of that antigen. Examples include using an antitoxin administered to neutralize a toxin, or antibody against an infectious agent to interrupt the pathophysiological process induced by that target organism; (b) the administration, often iv, of high levels of antibody (gamma globulin therapy) to compensate for transient or permanent immune deficiency; and (c) monoclonal antibody therapy to combat cancer, certain autoimmune disorders and metabolic diseases. In all these cases, antibody is provided in relatively high concentrations for the purpose of having that antibody combine directly with its target antigen to render that antigen inoperable, non-infectious or neutralized. For example, Gamnimune™ (Bayer Biological) contains 50 mg protein (immunoglobin) per mL and normal dosing can be up to 1000 mg/kg body weight. Ganunar—P™ I.V. (Aventis Behring) is administered at dosages up to 400 mg/kg body weight. Bayhep B™ (Hepatitis B knunoglobulin) (Bayer Biological) is 15-18% protein [immunoglobulin] is administered at dosages of up to 0.6 ml/kg body weight=0.01 g/kg =100 mg/kg. Further, hnogam Rabies—HT™ (Aventis Pasteur) is 10-18% protein and is administered at a dosage of 0.133 ml/kg (240 mg/kg) body weight.
Of interest to the present application is the disclosure of co-owned, allowed U.S. patent application Ser. No. 09/514,993 which is directed to the administration of anti-ruibeola antibodies for the treatment of symptoms of various central nervous system diseases including autism, multiple sclerosis, attention deficit disorder (ADD) and attention deficit hyperactivity disorder (ADHD). Examples therein emonstrated the efficacy of treating the symptoms of those disease states with dosages of from 0.1 mg to 1 mg of anti-rubeola antibody per dose.
While the administration of larger quantities of immunoglobulins is effective in the treatment of many disease states there remains a dosire in the art for alternative methods for treatment of disease states.
SUMMARY OF THE INVENTION
The present invention is directed to the discovery that the symptoms of disease states associated with the presence of a toxin or infectious agent may be effectively treated by administration of very low levels of antibodies specific for the toxin or infectious agent. The levels of antibodies admninistered are substantially lower than those traditionally administered to directly neutralize target antigens and for example are typically less than 0.1 mg of antibody per day. Specifically, the antibodies may be administered in one or in multiple dosages but the sum of antibodies administered in any 24 hour period is less than 0.1 mg.
While the antibody may be monoclonal or polyclonal, it is preferably monoclonal according to one aspect of the invention. The antibody may be admninistered by a variety of manners but is preferably administered enterically and most preferably orally. Suitable methods of oral administration include oral drench and sublingual administration. According to another preferred aspect of the invention the antibody is administered in an enterically protected form. In addition, the antibodies of the invention may be administered by injection such as by subcutaneous injection.
The symptoms of various disease states can be treated according to the invention including those of various central nervous disorders including autism, multiple sclerosis, attention deficit disorder (ADD), and attention deficit hyperactivity disorder (ADHD), all of which can be treated by administration of very low levels of anti-rubeola antibody. Dosages of antibodies administered according to the invention including anti-rubeola antibodies range from 1×10 −10 to a 1×10 −1 mg/dosage with dosages of from 1×10 −5 to 1×10 −4 mg (e.g. 8×10 −5 mg) and dosages of from 2×10 −5 to 2×10 −3 mg being preferred.
The invention also provides treatment of the symptoms of pulmonary infection by administering an effective amount of anti-Mycoplasma pneumonia antibody with daily dosages of less than 0.1 mg being preferred and daily dosages ranging from 1×10 −5 to 1×10 −3 mg/day being particularly preferred.
The invention also provides treatment of symptoms of Alzheimer's Disease by administering an effective amount of anti-amyloid beta antibodies with daily dosages of less than 0.1 mg being preferred and daily dosages ranging from 1×10 −5 to 1×10 31 3 being particularly preferred.
According to a further aspect of the invention it has been discovered that administration of anti-rubeola antibodies can be effective in the treatment of symptoms of Crohn's Disease. Accordingly, the invention provides a method of treating the symptoms of Crohn's Disease comprising administering an effective amount of anti-rubeola antibody. Preferred dosages are less than 0.1 mg antibody daily with daily dosages ranging from 2×10 −5 to 2×10 −3 mg being particularly preferred.
According to a further aspect of the invention it has been discovered that the administration of anti-Klebsiella pneumnonia antibodies can be useful for the treatment of rheumatoid arthritis and specifically for juvenile rheumatoid arthritis. Preferred dosages are less than 0.1 mg of anti-Klebsiella pneumonia antibody daily with daily dosages ranging from 1×10 −4 to 1×10 −3 mg/day (e.g. 4×10 −4 mg/day) being particularly preferred.
The invention also provides methods for treating the symptoms of diabetes comprising the method of administering an effective amount of antibody directed against glutamnic acid decarboxylase. Preferred dosages are less than 0.1 mg of anti-glutamic acid decarboxylase antibody daily with daily dosages ranging from 1×10 −4 to 1×10 −3 mg/day (e.g. 4×10 −4 mg/day) being particularly preferred.
The invention also provides pharmaceutical compositions for administration to subjects for treatment of the symptoms of disease states comprising antibody specific for a toxin or infectious agent associated with the disease state in a dosage unit of less than 0.1 mg antibody.
DETAILED DESCRIPTION
Without intending to be bound by any particular theory of the invention, it is believed that the invention described herein utilizes antibodies in remarkably low concentrations as molecular signals to induce a response similar or even superior to that seen with the traditional approach of introducing antibody at concentrations several logs greater than that associated with this invention. However, even though the concentrations of antibody are significantly different between traditional use and this invention, the specificity of the reaction remains intact. That is, low level of antibody directed against target A will react with target A but not B, unless B is antigenically closely related to A.
The similarity in responses between traditional gammaglobulin therapy and the invention, and the disparity of concentrations of antibody to induce the desired result, recalls the relationship in concentrations of antigen, or antigenic extract, used by allergists employing the maximum tolerated dose approach to hypersensitivity therapy and those using the neutralization method.
In the case of the present invention results similar to those obtained by traditional gamma globulin therapy are reached by an apparently different pathway. The traditional approach of using specific antibody in high concentration to treat or counter a specific antigen is well understood in that the antibody makes direct contact with its antigen target, combines with it, and alones or in the presence of other factors, such as the complement system, the antigen is destroyed or neutralized. The mechanism of action of the present invention whereby antigens are destroyed or neutralized by a pathway initiated by the presence of low levels of antibodies specific for the antigen is not completely understood but is the focus of ongoing research.
The invention described herein provides methods for treating ADD/ADHD, autism, MS, Crohn's Disease and related disorders. The invention describes the use of specific anti-rubeola antibody used a relatively low dose as a systemic signal to specifically inhibit virus replication or the body's aberrant response to the virus that results in the symptoms characteristic of the diseases.
Anti-rubeola antibody useful in practice of the invention may be obtained from a variety of sources. Suitable antibodies may be polyclonal or monoclonal and can be derived from various animal sources. A preferred anti-rubeola antibody for use in practice of the invention is polyvalent rabbit anti-rubeola antibody available from Cortex Biochemicals, San Leandro, Calif.
Antibodies specific for other antigens such as Klebsiella pneumonia, Mycoplasma pneumonia, chorionic gonadotropins, Amyloid-beta, and glutamic acid decarboxylase may be obtained from various commercial sources. A preferred source of antibody for Klebsiella pneumonia is Bio-Trend Chemikalien, Cologne, Germany and preferred anti-Mycoplasma pneumonia antibodies may be obtained from Cortex Biochemicals, San Leandro, Calif. Preferred sources of anti-amyloid-beta antibodies are Chemicon International Inc., Temecula, Calif. and Boeringer Manneim with preferred antibodies being those directed against human chorionic gonadotropin (hCG) holoprotein. A preferred antibody specific for glutamic acid decarboxylase is available from Chemicon International Inc., Temecula, Calif.
The following examples are illustrative and are not intended to limit either the scope or spirit of the invention.
EXAMPLE
Example I
According to this example, low dosages of anti-rubeola antibody were administered to an eight year old male subject exhibiting the symptoms of attention deficit disorder. Specifically, the subject was treated by sublingual administration once daily of one drop of a composition comprising 8×10 −5 mg of anti-rubeola antibody (Cortex Biochemicals, San Leandro, Calif.). The subject exhibited improvements in concentration and improved grades with some increase in activity in the evenings.
Example II
According to this example, a female subject in her mnid-thirties presented with a 12 year history of multiple sclerosis which primarily affected muscle control of her legs. The subject was treated by sublingual administration twice daily of one drop of a composition comprising 8×10 31 5 mg of anti-rubeola antibody (Cortex Biochemicals, San Leandro, Calif.). After a period of three weeks, the subject exhibited improved motor control and was capable of driving an automobile for the first time in years.
Example III
According to this example, four dogs presenting with progressive central nervous system pathology and exhibiting symptoms similar to those of multiple sclerosis were treated by administration of 8×10 31 5 mg per day dosages of anti-rubeola antibodies by subcutaneous injection. The animals were treated over a period of eight months and were either stable or slowly improving with respect to their condition.
Example IV
According to this example, human patients presenting with cancer of various types (pancreatic, lung and colon) are treated by two to four times daily sublingual administration of 8×10 −5 mg polyclonal anti-hCG antibodies derived from rabbits (Cortex Biochemicals, San Leandro Calif.)
Example V
According to this example, four dogs suffering with osteosarcoma were treated by subcutaneous injection of 3.2×10 −5 mg per day of anti-hCG antibody. Canine osteosarcoma usually metastisizes from the bone to the lungs and animals similarly afflicted typically have a lifespan of six-months. After five months of treatment the dogs do not exhibit signs of metastisis and appear in healthy condition as evidenced by coat condition, appetite, attitude and quality of life.
Example VI
According to this example two patients aged 8 and 9 presented with severe juvenile rheumatoid arthritis and were treated by sublingual administration twice daily of 8×10 −5 mg of antibodies specific for Klebsiella pneumonia obtained from Bio-Trend Chemikalien, Cologne, Germany. Prior to being treated the subjects suffered from pain, restricted range of motion, and joints which were swollen and sore. After one week of treatment according to the methods of the invention, pain and swelling were reduced and the range of movement was increased. Optimnum concentration of antibody per dose has been approximately 4×10 31 4 mg.
Example VII
According to this example, a patient presented with chronic pulmonary infections and fibrosis exhibiting symptoms of shortness or breath, chest pain and decreased stamina. The subject was treated by sublingual administration twice daily of 8×10 −5 mg of antibody to Mycoplasma pneumonia (Biochemicals, San Leandro, Calif.). The subject reported a positive response within 7 days, as evidenced by decreased shortness of breath, decreased chest pain, decreased edema, increased stamina and ability to carry out normal activities of daily living.
Example VIII
According to this example, five patients presented with the symptoms of Alzheimer's disease and were treated by sublingual administration of four drops daily of a composition comprising 5×10 −6 mg of anti-ainyloid beta antibodies (Boeringer Mannheim). At four weeks after treatmnent, three of the patients did not exhibit any effects but one patient reported having an improved pattern of speech as words came easier to her. The fifth subject reported that after two weeks she was no longer “struggling to remember things.”
According to this example five senile dogs were treated by subcutaneous administration with 5×10 −6 mg of anti-amyloid beta antibodies. All the dogs responded positively after two weeks of daily treatment and were more active and interacted more appropriately with their masters.
Numerous modifications and variations in the practice of the invention are expected to occur to those skilled in the art upon consideration of the presently preferred embodiments thereof. Consequently, the only limitations which should be placed upon the scope of the invention are those which appear in the appended claims.
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The invention provides methods and compositions for treating the symptoms of disease states associated with the presence of a toxin or infectious agent having the step of administering an antibody specific for the toxin or infectious agent at a dosage of less than 0.1 mg per day.
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CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This patent application claims the benefit under 35 U.S.C. §119(e) of U.S. Provisional Patent Application No. 61/311,046, filed Mar. 5, 2010, which application is incorporated herein by reference.
FIELD OF THE INVENTION
[0002] The invention broadly relates to recreational go-kart amusements, more specifically for a go-kart and track bumper system.
BACKGROUND OF THE INVENTION
[0003] Recreational go-kart amusements provide a real racing experience on a lower speed track suitable for the general public. Although bumping is not advised, and often prohibited, collisions between other go-karts and the walls that define the track are a frequent occurrence. One commonly known bumper system for go-karts is a continuous steel band, which surrounds the kart. The band may have a width or height of between two to four inches. The band is mechanically mounted to the frame of the go-kart by supports, which may be surrounded by damping sleeves, such as made from rubber or some other resilient material. The sleeves act as dampeners to help absorb any shock or force that the kart may experience during a collision or impact, but there is still a rigid connection between the outer portion of the bumper and the vehicle's body. By providing bumpers that protect the entire go-kart, the occupant of the kart will have some protection in the event of a collision with another go-kart or with a bumper wall that surrounds the track on which the go-kart is used. The bumper walls that define go-kart tracks are also often similar rigid steel frames, including a damping means behind the rigid frame. Often, this dampening means comprises old rubber tires which are laid on their sides, behind the metal bumper for absorbing a portion of the forces that occur in a collision.
[0004] While the metal frame and rubber tire style bumper works sufficiently, it takes up a lot of space, and is therefore not suitable for indoor use. Also, the typical means by which a go-kart is powered is by a gasoline engine, which produces exhaust fumes and also not suitable for indoor use. Thus, the operation of go-carts is limited to locations or seasons that permit outdoor operation. Electric powered vehicles are becoming known which are now powerful enough to provide the necessary speed and torque to provide a fun racing experience. Electric powered go-karts however, must be recharged between each race, which can limit the length of races or time between races. Pit lanes must be adapted to include charging contacts for charging the batteries of the go-karts between races. These charging contacts must be supplied with large currents by high gauge wires. Typically, these contacts are supplied on the underside of the vehicle and the top of a pit lane. However, this requires installation of the high gauge wires underneath the pit lanes, which requires, for example, construction of the pit lanes on a raised platform, or demolition of the concrete or cement flooring in order to cut trenches for the wires.
[0005] For the safety of the drivers and the protection of the vehicles, one rule essentially always implemented at go-kart establishments is the prohibition on intentional bumping of one go-kart into another. This rule is enforced because bumping can lead to dangerous driving and result in high speed crashes. The prior art metal bumper is typically suitable for protecting the driver of the vehicle, but is very stiff and accordingly insufficient to prevent damage to the vehicles during high speed collisions. Consequently, if the go-kart is subjected to a hard impact, as frequently occurs, there is a large potential for structural damage to the go-kart or to the bumper. For example, the go-kart may suffer severe mechanical and structural damage because the impact is received and transferred by a rigid steel bumper directly to the body of the kart. Even if the body of the kart is undamaged, the rigid outer bumper may become bent or mangled. In some cases, the bumper may become so distorted that it disrupts the kart's ability to drive. Although rubber sleeves or other dampening means may be included between the outer frame and the body of the kart, these are usually not sufficient to protect the karts from suffering damage during even relatively mild impacts, as there still must be rigid structural supports supporting the outer bumper on the body of the kart.
BRIEF SUMMARY OF THE INVENTION
[0006] The present invention broadly comprises a bumper assembly including a backing, wherein the backing is substantially rigid, an outer layer, wherein the outer layer semi-flexible, resilient, and non-conductive, a cushion layer sandwiched between the backing and the outer layer, wherein the cushion layer is resiliently compressible. In one embodiment, the outer layer comprises hard plastic and the cushion layer comprises foam rubber. In one embodiment, the bumper assembly is installed as a substantially continuous ring about a go-kart. In one embodiment, the go-kart comprises a chassis, the chassis comprises the backing, wherein the outer layer comprises hard plastic, and wherein the cushion layer comprises foam rubber. In one embodiment, the outer layer comprises an outer lateral surface, and wherein at least one conductive contact is arranged on the outer lateral surface, and wherein the at least one conductive contact is electrically connected to a rechargeable battery of the go-kart.
[0007] In one embodiment, the bumper assembly is arranged on a floor to define a track for vehicles, wherein the outer layer faces the track. In one embodiment, the assembly further comprises a plurality of rods vertically extending from the floor at spaced intervals behind the backing for rigidly supporting the bumper assembly. In one embodiment, each of the rods includes a portion that extends down into the floor. In one embodiment, a brittleness of each of the rods enables the rods to shear or break between the backing and the floor if the rods experience a threshold force exerted by the backing. In one embodiment, the assembly further comprises a plurality of ties, wherein each of the ties corresponds with one of the rods, and each tie is operatively arranged for securing the outer layer, the cushion layer, and the backing to one of the rods. In one embodiment, the ties comprise plastic tie-wraps.
[0008] In one embodiment, the backing comprises first and second backings, the cushion layer comprises first and second cushion layers, and the outer layer comprises first and second outer layers, wherein the first cushion layer is sandwiched between the first outer layer and the first backing for forming a first bumper portion and wherein the second cushion layer is sandwiched between the second outer layer and the second backing for forming a second bumper portion, and wherein the first and second bumper portions are arranged on oppositely disposed sides of the rods. In one embodiment, the assembly further comprises a plurality of ties, wherein each of the ties corresponds to one of the rods, and wherein each of the ties is operatively arranged to secure both of the first and second bumper portions to common ones of the rods.
[0009] The current invention also broadly comprises a system for electric vehicles including a track, a pit area connected to the track and having at least one charging station, the charging station including a battery charger providing a voltage source, at least one first contact electrically connected to the charging station, wherein the at least one first contact is arranged on a vertically oriented surface of the charging station, and an electric vehicle including a rechargeable battery, a bumper having an outer lateral surface, and at least one second contact electrically connected to the rechargeable battery for completing a charging circuit between the battery charger and the battery when the second contact is engaged against and electrically connected to the first contact for recharging the battery.
[0010] In one embodiment, a cushion layer is provided behind the at least one first contact for enabling the at least one first contact to flex away from the bumper in case of interference between the at least one first contact and the at least one second contact for providing mating engagement of the first and second contacts against each other. In one embodiment, the at least one first contact comprises two first contacts, the at least one second contact comprises two second contacts, and wherein a charging circuit for recharging the battery is completed only when each first contact is engaged against and conductively connected with respective ones of the second contacts.
[0011] The current invention also broadly comprises a charging station including a battery charger providing a voltage source, two conductive faceplates, wherein each conductive faceplate is electrically connected to the battery charger, wherein both of the conductive faceplates are arranged on a vertical surface. In one embodiment, a cushion layer is provided behind the conductive faceplates for enabling the faceplates to move forward and back with respect to the vertical surface.
[0012] It is a general object of the present invention to provide a charging system for an electric vehicle where conductive contacts are provided in lateral or vertically orientated surfaces.
[0013] It is another general object of the present invention to provide a space saving bumper design for a vehicle track.
[0014] It is yet another object of the present invention to provide a bumper design for a vehicle, such as a go-kart, that has an outer shell that is not rigidly connected to the body of the go-kart.
[0015] These and other objects and advantages of the present invention will be readily appreciable from the following description of preferred embodiments of the invention and from the accompanying drawings and claims.
BRIEF DESCRIPTION OF THE DRAWINGS
[0016] The nature and mode of operation of the present invention will now be more fully described in the following detailed description of the invention taken with the accompanying drawing figures, in which:
[0017] FIG. 1 is a top view of a go-kart track system;
[0018] FIG. 2A is a perspective view of a track bumper;
[0019] FIG. 2B is a perspective view of a track bumper;
[0020] FIG. 3 is a perspective view of a reverse side of a track bumper;
[0021] FIG. 4A is a perspective view of a track bumper joint;
[0022] FIG. 4B is a perspective view of a track bumper joint with a section of the bumper removed;
[0023] FIG. 5A is a perspective view of a bumper for a hairpin turn;
[0024] FIG. 5B is a perspective view of a bumper for a wider turn;
[0025] FIG. 6A is a side view of a go-kart in a pit area;
[0026] FIG. 6B is a simplified schematic of a charging circuit for recharging a battery of a go-kart;
[0027] FIG. 7A is a perspective view of a contact assembly for a go-kart charging station;
[0028] FIG. 7B is a perspective exploded view of a contact assembly for a go-kart charging station;
[0029] FIG. 8 is a perspective view of charging stations in a pit lane;
[0030] FIG. 9A is a perspective partially exploded view of a wall for a go-kart charging station;
[0031] FIG. 9B is a perspective exploded view of a wall for a go-kart charging station;
[0032] FIG. 10A is a perspective exploded view of a bumper for a go-kart; and,
[0033] FIG. 10B is a perspective view of a bumper for a go-kart.
DETAILED DESCRIPTION OF THE INVENTION
[0034] At the outset, it should be appreciated that like drawing numbers on different drawing views identify identical, or functionally similar, structural elements of the invention. Additionally, it should be appreciated that the use of a trailing letter or prime symbol (′) to append a reference numeral is merely to differentiate between different instances of similar components for ease of discussion or to indicate that two or more elements are similar, related, or alternatives, but that each element having the same base numeral could generally resemble all other elements having that same base numeral, regardless of trailing character, unless otherwise described. While the present invention is described with respect to what is presently considered to be the preferred aspects, it is to be understood that the invention as claimed is not limited to the disclosed aspects.
[0035] Furthermore, it is understood that this invention is not limited to the particular methodology, materials and modifications described and as such may, of course, vary. It is also understood that the terminology used herein is for the purpose of describing particular aspects only, and is not intended to limit the scope of the present invention, which is limited only by the appended claims.
[0036] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood to one of ordinary skill in the art to which this invention belongs. Although any methods, devices or materials similar or equivalent to those described herein can be used in the practice or testing of the invention, the preferred methods, devices, and materials are now described.
[0037] Referring now to the figures, FIG. 1 shows system 10 , which comprises track 50 defined by bumper assembly 12 . The track is arranged as a course or circuit for vehicles, such as go-karts 100 (or simply “karts”) to race about for fun or for competition. As discussed in more detail below, go-karts 100 are electric vehicles having rechargeable batteries. In order to recharge the batteries of the karts, system 10 includes pit area 52 attached to track 50 , the pit area having a plurality of battery chargers 54 , discussed in more detail below. In the embodiment of FIG. 1 , the pit area is divided into four pit lanes 56 , although it should be understood that a different number of lanes could be provided.
[0038] Track bumper assembly 12 generally includes outer shell 14 and backing 15 , between which intermediate cushion 16 is sandwiched. Cushion 16 is secured between outer shell 14 and backing 15 , for example, by use of tie-wraps 18 . The tie-wraps may be, for example, heavy duty plastic tie wraps, or some other strap-like securing device, such as metal or plastic bands, ropes, cables, or the like. The tie-wraps are also be used to secure the outer shell, backing, and cushion layer to support rods 20 . Adhesives or glue may be used in addition to, or in lieu of, the tie-wraps to help bind the outer shell to the inner cushion. Rods 20 provide additional support for the bumper in the event of a collision with the track bumper, such as by a go-kart.
[0039] Various bumper styles are shown throughout the Figures, with FIGS. 2A and 2B illustrating bumpers 12 a, 12 b, and 12 c. It should be understood that any description of bumpers 12 or components of bumpers 12 apply generally to bumpers 12 a, 12 b, and 12 c, unless otherwise noted. In FIG. 2A , two bumpers are arranged on opposite sides of vertical support beam 58 in order to protect karts from being able to hit the support beam. Such a support beam, or some other obstacle or obstruction, may be present, for example, if the track is installed indoors, which is one advantageous use of the current invention. In FIG. 2A cushion 16 of bumper 12 a is formed as a continuous layer between the outer shell and backing, while the cushion in bumper 12 b is formed from discrete or individual bumper sections 16 ′, with gaps 17 located between the bumpers. It should likewise be understood that any description of cushion 16 , or the functions or advantages thereof, applies generally to cushion sections 16 ′ unless otherwise specified. In one embodiment, such as those shown with respect to bumpers 12 b and 12 c, each cushion section could correspond to a separate set of rods.
[0040] Bumper 12 c in FIG. 2B is formed from two bumper sections, namely, sections 12 c ′ and 12 c ″, with both sections having outer shell 14 , backing 15 , and cushion 16 , but with both sections sharing a common set of rods 20 , thereby further reducing the area required to install the bumper where track 50 is located on both sides of the bumper. Like bumper 12 b, bumper 12 c is also shown having discrete bumper sections 16 ′ as opposed to a continuous cushion layer. However, it should be appreciated that any combination of discrete and/or continuous cushions could be used as desired in embodiments of the current invention. Providing discrete cushion sections 16 ′ may increase the ability of the outer shell of the bumper to flex in response to a collision and requires less material, while a continuous cushion may provide more force absorption capabilities, but reduce the amount of flexing by the outer shell of the bumper.
[0041] Thus, it may be desirable to use a relatively thicker outer shell with discrete cushion sections 16 ′ than would be used with continuous cushion 16 , but the particular dimensions should be determined, for example, based on the speed, size, weight, etc., of the karts with respect to the performance and safety requirements for each particular track. In some embodiments, each rod corresponds to one tie-wrap, with the tie-wrap looped about the rod and the outer shell to secure the rod, outer shell, and cushion together. In the dual bumper arrangement of bumper 12 c, the tie-wraps could additionally be secured between both outer shells 14 , both backings 15 , and both cushion sections 16 ′. In this way, according to FIG. 2B , a suitable bumper could be provided for adjacent sections of track 50 in an even further space and material saving manner.
[0042] As one example, cushions 16 are shown in many of the Figures as made from three layers of material. Specifically, in some embodiments, the cushions are made from three layers of 1.25″ thick foam rubber. Layers are used because foam rubber sheets are not generally made having greater thicknesses, but it should be understood that more or less layers of other thickness could be used. For example, in the turn of FIG. 5A , described in more detail below, the cushion layer is shown as a solid continuous block of material. It should thus be appreciated that any cushion could be replaced by cushion formed from a single block of material, instead of three layers, or that a different number of layers could be utilized. It should also be appreciated that other materials could be used in lieu of foam rubber, but that preferred materials would have good compressibility in order to absorb the shock or force from collisions for protecting the driver of a go-kart that collides with the bumper, the go-kart, and the bumper. Furthermore, it may be advantageous to select material for the cushion that is not easily permanently deformed, but that expands back to its original size and shape after the collision such that the bumper is repeatedly ready to absorb the shock of subsequent collisions. The overall thickness of the cushioning of the bumper should be set with respect to the compressibility and/or shock absorbing capabilities of the cushion, the level of performance desired from the cushion, and any other factors important to the owner or operator of the track. The outer shell and backing are provided as much harder and stiffer than the cushion, in the form of hard plastics, or the like, in order to protect the less durable foam layers and to spread the force of a collision out over a wider area of the bumper so that forces can be more easily absorbed by the cushioning layer.
[0043] Outer shell 14 is made, for example, from resilient and durable material, such as a hard plastic of about 0.25″ or 0.5″ inch thickness having a haircell texture on its outer surface. At this thickness, the outer shell is still semi-flexible, but still rigid enough to provide proper support for a bumper. Backing 15 may be, for example, a 1″ thick hard plastic layer. In this described embodiment, the backing is thicker than the outer shell in order to provide rigidity to the bumper, specifically to provide a surface against which the bumper can compress, while the outer shell is thinner because it enables some degree of flexing of the outer shell, which may help disperse forces in a collision. However, it should be understood that other thicknesses, relative sizes of the thicknesses, or materials could be used for creating a bumper according the current invention. Also, different sections or portions of the outer shell or backing for the bumper could vary in thickness, to provide more support and less flexibility to certain sections, such as around corners, or wherever desired. In one embodiment, rods 20 are 1.5″ diameter fiberglass reinforced hard plastic rods. The fiberglass reinforcement is used, for example, to strengthen the rod, although it should again be understood that other materials or dimensions could be used in lieu of those examples explicitly described herein.
[0044] Accordingly, it should be understood that the current invention bumper could be created for a go-kart track that is much thinner than the prior art. For example, a bumper having the dimensions described above could have a total thickness of only about six inches. As discussed above, go-kart tracks were traditionally required to be built outdoors, and therefore, the size of the bumper system did not really matter as a lot of space is available outdoors. However, with the advent of electric go-karts, emissions are no longer an issue and it has become practical to install go-kart tracks indoors. As a result, the size of the track is limited by the size of the building, thus making the task of reducing the size of the bumper absolutely critical. For example, one may wish to convert an old warehouse, or the like, into a go-kart track and thus be limited by the size of the warehouse.
[0045] Rods 20 could have different diameters or cross-sectional shapes as desired, such as polygonal shapes. In one embodiment, the rods are made from plastic and intended to be “sacrificial” in the event of a collision with the wall. By this, it is meant that the rods will break or shear, instead of holding firm and potentially damaging a kart which has contacted the bumper wall, or damaging the floor of the track into which they are mounted, or hurting a driver by abruptly stopping a kart in a severe collision. For example, in one embodiment, the rods are driven, screwed, force fit, or otherwise engaged with the floor forming track 50 . That is, as shown in FIG. 3 , rods 20 may have portion 21 that extends into the floor. With respect to this embodiment, fiberglass reinforced plastic rods may be used to provide sufficient brittleness for the rods to enable rods 20 to sacrificially shear between the backing and the floor when a force is exerted by the backing on the rod, such as when a go-kart collides with a bumper proximate a rod. Thus, for example, in the event of a particularly severe collision between a go-kart and a bumper, the rod will simply shear in half instead of holding firm or bending, thus allowing the bumper to move or flex along with the go-kart to some degree. This is provided as an additional safety feature because if the rod did not break in a severe collision, such as if the go-kart is moving very fast, then the bumper would cause the go-kart to come to a complete stop very abruptly, and abrupt stops tend to transfer a large amount of force to the driver, such as in the form of whiplash. It may also result in the other components of the bumper or the kart to become damaged. By enabling the rods to break, the time period over which bumper 12 stops a colliding go-kart would be increased as the bumper moves, shifts, or flexes with the go-kart, thus decreasing the severity of the crash felt by the driver, the bumper, and the kart. The bumper could then be put back in place, and the broken rod discarded and replaced by a new rod. In this way, the rods can provide a cheap, effective, and quickly repairable safety feature for bumpers 12 of system 10 .
[0046] An example of a bumper wall joint is shown in FIGS. 4A and 4B . That is, joint 22 is created at the boundary between two pieces of outer shell 14 , namely, first shell portion 14 A and second shell portion 14 B. For example, it is not feasible to form the entire outer shell from a single piece of material, and therefore, it will likely be required to secure multiple pieces together. Backing plate 24 is included, with half of the backing plate secured to each of shell portions 14 A and 14 B by fasteners 26 , which are inserted into holes 28 . Cushion 16 , or a layer thereof, may be modified with a section removed, for example, in order to accommodate inclusion of backing plate 24 . The fasteners could be, for example, screws, bolts, ratchet fasteners, rivets, or the like. Alternatively, the fasteners could be replaced by, or supplemented with, glue, epoxy, or other adhesives. Additionally, in the embodiment of FIGS. 4A and 4B , joint 22 is positioned such that a tie-wrap is connected between the two shell portions for more securely securing the two shell portions together (although the tie-wrap is not shown in FIG. 4B for clarity). In FIG. 4B , joint 22 is illustrated with shell portion 14 A removed, providing a better view of joint 22 and plate 24 . A substantially identical system could be used for securing multiple sections of backing 15 together. Since the joints may not be as strong as the remainder of the bumper, it may be advantageous to stagger the backing joints from the outer shell joints so that the joints are not aligned with each other. It may also be advantageous to align each joint, whether for the backing or the outer shell, with rods 20 , as shown, in order to further support the joints.
[0047] In FIG. 5A , bumper 12 is shown doubling back on itself to create hairpin turn 30 . In this embodiment, the bumper splits from resembling a dual-bumper (e.g., resembling bumper 12 c ) to a single bumper, before being recombined after the turn. Additionally, in this embodiment, cushion 16 is included about the entire length of turn 30 for providing sufficient support in the event that a kart collides with the bumper at this location, and also to maintain the shape of the turn. FIG. 5B illustrates wider turn 32 , which would be used for right angle turns, or the like. Since crashes with the wall are most likely to occur at or near the turns, the bumper of system 10 may need to be additionally reinforced at the turns. For example, in turn 32 , auxiliary cushions 34 are included in addition to bumper 12 in order to provide a further layer of cushioning. The auxiliary cushions are shown as discrete portions or sections with gaps 35 between them, but it should be understood that the auxiliary cushion could extend continuously behind bumper 12 , similar to cushions 16 and sections 16 ′ discussed above. Cushion sections 34 are placed behind backing 15 of bumper 12 , with auxiliary backing 36 located behind cushion sections 34 and rods 20 located behind the auxiliary backing
[0048] FIG. 6A shows go-kart 100 in pit area 52 . Each go-kart 100 includes bumper 102 , body/chassis 104 , seat 106 , steering device 108 , and charging contacts 110 and 112 . Bumper 102 is included for protecting body 104 of each kart, and each kart in general, as well as for cushioning a collision between two karts or between a kart and a bumper in order to protect a driver of the kart sitting in seat 106 . Go-karts 100 are preferably electrically powered and steering devices 108 are included as electro-mechanical devices for turning drive wheels 109 of the kart, delivering more or less power to certain wheels (overpowering wheels on one side of the kart will help the kart turn toward the opposite side), etc., in order to turn the go-kart. Contacts 110 and 112 are included for charging a battery or battery pack of the go-kart and are located on lateral surface 114 of bumper 102 , unlike contacts for prior art electric go-karts that have charging contacts located and the underside those karts. Each contact may include conductive bolt 116 , or the like, for electrically or conductively connecting the contacts with the battery of the karts via suitable wiring.
[0049] The pit lanes of the pit area are included both for storage of the karts when not in use, and for recharging of each kart's battery. For example, charging station 60 is formed in vertical surface 62 by contact assemblies 64 and 66 . Framework 68 is shown in FIG. 6A , onto which framework chargers 54 , and any other necessary charging electronics could be secured for connection to contact assemblies 64 and 66 . That is, the contact assemblies are in electrical communication with a power source, e.g., chargers 54 , for forming a charging circuit to charge a go-kart when the contacts of the go-kart come into contact with contacts of the charging station. For example, this is illustrated schematically in the simplified circuit of FIG. 6B . In FIG. 6B , the charging circuit includes voltage source V, switches S 1 and S 2 , and battery B. In one embodiment voltage source V is a 24V battery charger. For example, voltage source V generally represents battery chargers 54 , and battery B represents the battery of any go-kart 100 , while the switches schematically illustrate the coupling/decoupling of go-kart contacts 110 and 112 with charging station contacts 64 and 66 . That is, for example, when contacts 110 and 66 are in contact, switch S 1 would be closed, and when contacts 112 and 64 are in contact, switch S 2 would be closed, with the circuit completed and battery B recharging only if both switches are closed. Rechargeable batteries and their accompanying circuits are well known in the art and could take any form or style, such as lithium ion, lithium iron phosphate, nickel cadmium, lead acid, etc.
[0050] Two possible embodiments for contact assemblies 64 , 66 are shown in FIGS. 7A and 7B . Conductive faceplate 69 of the assemblies may be supported by resilient or spring-like spacers 70 , such as made from metal or plastic, which can partially flex is the contact is pressed inwards. Faceplates 69 substantially resembles contacts 110 and 112 of the go-kart bumper in both structure and function, as conductive plates for enabling completion of the charging circuit. The spacers are affixed, for example, to backing plate 72 . The backing plate is affixable to vertical surface 62 . Cushion layer 74 is included behind the faceplate to enable the contact to partially flex or compress towards the wall when a kart is driven into a pit lane, without causing damage to the kart of charging station. For example, the pit lanes must be narrow enough to ensure an electrical connection is always formed between the faceplates of contact assemblies 64 and 66 and go-kart contacts 110 and 112 when the karts are in the charging stations. A conductive bolt, screw, pin, or the like would be secured in central bore 76 in order to electrically connect the faceplate to the rest of the charging circuit with suitable wiring. In FIG. 7B , the contact assemblies include face plate 69 , but with a cushion layer 80 sandwiched between plates 78 and 82 . Bores 84 a, 84 b, and 84 c are provided in order to enabling wiring to extend to faceplate 69 and/or the bolt, pin, or screw in bore 76 of the faceplate. It should be appreciated that the contact assemblies could take various other forms, and that these embodiments are provided as examples only.
[0051] Pit lanes 56 A and 56 B are shown in FIG. 8 , with go-kart 100 parked in lane 56 B. A bank of battery chargers 54 are shown along the length of pit lanes 56 A, namely designated as chargers 54 A, 54 B, and 54 C. Each charger corresponds to a charging station, namely, stations 60 A, 60 B, and 60 C correspond to chargers 54 A, 54 B, and 54 C, respectively.
[0052] For example, charging station 60 A might include charging contact assemblies 64 A and 66 A and charger 54 A for charging a first kart, while station 60 B might include charging contacts 64 B and 66 B and charger 54 B for charging a second kart, and station 60 C might include charging contacts 64 B and 66 B and charger 54 B for charging a third kart and so on for each charging station. In this way, multiple karts can be simultaneous charged. Thus, the number of charging stations included in the pit area could equal the number of karts which can be simultaneously driven on track 50 . Alternatively, there could be twice the number of charging stations as karts, such that half of the karts could be charging while the other half are driving. It should be appreciated that substantially identical charging stations would be provided for lane 56 B, with the contact assemblies installed in vertical surface 62 B, which vertical surface borders that lane.
[0053] Further examples of side walls 62 are provided in FIGS. 9A and 9B , which illustrate assemblies for side walls 62 ′ and 62 ″. In FIG. 8A , assemblies 64 and 66 are first fully assembled, such as shown in FIG. 7A or 7 B, and installed on framework 68 . Then, front wall 62 ′, having openings 91 A and 91 B, is placed over the contact assemblies, with the openings shaped and sized to accommodate passage of at least a portion of the contact assemblies therethrough. Thus, the faceplates of the assemblies that protrude out from the openings would be able to flex in and out in order to accommodate the bumper of a go-kart and ensure proper electrical connection between go-kart contacts and the charging station contacts. In the embodiment of FIG. 9B , however, only faceplates 69 , namely, faceplates 69 A and 69 B, are included to provide contacts for the charging station. The faceplates are securable to the wall by fasteners such as bolts, screws, pins, rivets, etc. In this embodiment, cushion layer 86 is provided behind the entirety of wall 62 ″, such that the entire wall can flex in and out in response to go-karts entering a pit lane. Since foam rubber and the like looses its compressibility over time and with repeated use, providing a larger cushion layer spreads the absorbed forces and enables the cushion to work properly for a longer period of time. Over time, however, layer 86 may become permanently compressed to some degree, and spacers, such as solid blocks or portions resembling resilient portions 70 in FIG. 7A could be provided between the wall and the faceplates in order to extend the faceplates out from wall 62 ″ and ensure that the faceplates continue to provide proper electrical connection between the go-kart and charging station contacts to complete the charging circuit. Backing plate 88 is provided to add support behind the cushion. An opening for connecting wiring to contact faceplates 69 A and 69 B is formed from holes 92 A, 92 B, and 92 C in wall 62 ″, cushion 86 , and backing plate 88 , respectively.
[0054] It should thus be appreciated that the charging contacts for both the go-karts and the charging stations are positioned in vertically orientated surfaces, such that the contacts are located at in the outer lateral surface of the go-kart bumper and on a wall or wall portion of the pit area. Advantageously, this significantly shortens the path between each battery charger and the charging contacts, which greatly reduces the cost for installing high capacity electrical wiring. Furthermore, it prevents the need to build the pit area on a raised platform, or having to cut trenches in the cement or concrete below the pit area. Furthermore, contacts 110 and 112 might be included on both sides of bumper 102 of each kart 100 , such that the kart can pull into the pit lanes in either direction and get charged.
[0055] Bumper 102 of kart 100 is shown in more detail in FIGS. 10A and 10B . In this embodiment, bumper 102 comprises outer shell 118 . Outer shell 118 may resemble, for example, shell 14 of bumpers 12 in that is a hard, semi-rigid layer, such as formed from hard plastic, for distributing loads throughout the bumper during a collision. Similar to backing 15 , chassis ring 120 is provided to provide support for cushion layer 122 , which is secured between the chassis ring and the outer shell. Cushion 122 is made, for example, from dense foam rubber in order to create sufficient thickness for absorbing, distributing, and dispersing the forces that result from collisions with bumper 102 , such as described above with respect to cushions 16 for bumpers 12 . In one embodiment, the chassis ring is made from aluminum or some other metal in order to provide substantially rigid support for the cushioning layer, although other materials could be used. As with bumpers 12 , the cushion layer of bumper 102 may be formed from three layers of high density foam rubber secured together, such as with glue, epoxy, or other adhesives. Thus, by use of the cushioning layer, forces due to collisions are not transferred directly from bumper to the frame of the kart. Instead, the force is absorbed and distributed and transferred only though cushioning 112 , which effectively dampens any impact before it is felt by the body of the go-karts, unlike prior art bumpers which are at least partially rigidly connected to their corresponding go-kart bodies/chassis.
[0056] In the embodiment of FIGS. 10A and 10B , outer shell 118 includes at least one joint 124 in order to form the bumper as a closed ring about the kart. In a preferred embodiment, there is a complementary joint on the opposite side of bumper 102 for splitting shell 118 into two substantially U-shaped pieces, namely, pieces 118 A and 118 B, for easier construction and maintenance. Joint 124 generally resembles joint 22 of bumpers 12 in that joint 124 also includes backing plate 126 which is securable to both portions of the outer shell via fasteners 128 through bores 130 . Likewise, the fasteners may be screws, bolts, rivets, ratchet fasteners, or any other securing device known in the art. Cushion blocks 132 and/or 134 may be included with at least one of them having a reduced thickness in order to accommodate for the thickness of backing plate 126 . Openings 136 and 138 are also included in lateral surface 114 of the outer shell of the bumper in order to accommodate passage therethrough of wiring in order to connect contacts 110 and 112 to the battery of the kart. Thus, contacts 110 and 112 would be secured over openings 136 and 138 , such as via screws, bolts, or the like. Similar holes may need to be made in cushioning 122 and chassis ring 120 to enable the wiring to travel from the battery in the body of kart 100 to the contacts on the exterior of the bumper.
[0057] Prior art bumper karts could not be charged with wall mounted charging stations, because the bumpers of those karts were made of metal, and therefore conductive. In other words, placing charging contacts on the exterior sides of prior art bumpers would electrify the bumpers and frames of those prior art karts, which could cause damage to the karts and be extremely dangerous for drivers. As a result, prior art charging contacts are located underneath the karts, away from the conductive bumpers. This required corresponding electrical contacts in the floor or road surface of the pit lanes. As discussed above, in order to get the electrical wiring to the pit lane charging contacts, the pit lanes had to be built on an expensive raised platform, which is often impractical or impossible, particularly for indoor tracks. Alternatively, trenches had be dug underneath the track for laying the electrical wiring. Since the track must be paved for the karts to drive on, once the trenches are dug and electrical wiring is laid, the trenches and wiring would be at least partially contained in or covered by concrete or some other road material. As a result, the prior art pit lane charging contacts are expensive and difficult to install, and nearly impossible to perform maintenance on without tearing up the pit lanes and re-laying concrete or another road surface. Furthermore, less wiring is required for the current invention since it is a longer distance to travel under the track to underneath the middle of each pit lane than it is to travel from a position on a wall to another position on a wall. This is important because very thick cables are needed to handle the high currents necessary to charge the batteries of the kart batteries, which cables are extremely expensive. Furthermore, when located on the ground, the contacts must be constantly cleaned of dirt, grime, dust, and the like which accumulates on the contacts over time. Furthermore, it becomes a safety hazard if such contacts are used outdoors in the rain or are otherwise subjected to water. This is not such an issue if the contacts are located in side walls.
[0058] It should again be appreciated in general that other materials or dimensions could be used other than those shown and described herein. However, some guidelines have been provided for selection of dimensions and materials that have been found to work. For example, the dimensions and materials of the outer shell of the bumpers should be chosen such that the bumpers are not too stiff or too flexible. If too stiff, they would not compress, and therefore would result in sudden stops and perhaps even whiplash to the driver and vehicle. If too pliable, then the bumpers would not absorb or disperse the impact outwards away from the karts, for lessening the impact to the karts and driver. Again, the particular materials chosen should reflect the speeds and weights of the karts, age of the drivers, performance desired by the operator of the go-kart track, etc.
[0059] Thus, it is seen that the objects of the present invention are efficiently obtained, although modifications and changes to the invention should be readily apparent to those having ordinary skill in the art, which modifications are intended to be within the spirit and scope of the invention as claimed. It also is understood that the foregoing description is illustrative of the present invention and should not be considered as limiting. Therefore, other embodiments of the present invention are possible without departing from the spirit and scope of the present invention.
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A bumper assembly including a backing, wherein the backing is substantially rigid, an outer layer, wherein the outer layer semi-flexible, resilient, and non-conductive, a cushion layer sandwiched between the backing and the outer layer, wherein the cushion layer is resiliently compressible.
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[0001] The invention relates to plastics articles with inorganic coating, their use and processes for their production.
PRIOR ART
[0002] EP-A 0 193 269 relates to substrates coated with silica particles. The coating has very uniform layer thickness, has exceptionally secure adhesion to the substrate and has good antireflective properties.
[0003] U.S. Pat. No. 4,571,361 describes antistatic plastics films. Here, films composed of, by way of example, cellulose acetate or polyethylene terephthalate are coated with polymerizable lacquer systems which may comprise, by way of example, antimony tin oxide particles. This gives films with abrasion-resistant coatings and with low surface resistances in the range smaller than or equal to 10 7 Ω.
[0004] EP-B 0 447 603 describes antistatic coating compositions comprising a silicate solution and a conductive solution. The two solutions are mixed for hydrolysis and for polycondensation to give the coating composition mentioned, which has a chemical bond between the silicate and the conductive material. The coating composition is suitable for producing antistatic, antiglare visual display screens from panels of glass or of plastic.
OBJECT AND ACHIEVEMENT OF OBJECT
[0005] It is known that substrates, e.g. glass or plastics articles, can be equipped with inorganic layers which, by way of example, may have antistatic properties. These coatings are generally applied to the substrate surface by means of lacquer systems which can be cured via drying or polymerization. This gives coated substrates with fully satisfactory properties in relation to abrasion resistance and, by way of example, electrical conductivity.
[0006] An object was to provide a process which permits plastics articles to be equipped with inorganic coatings, the bonding achieved to the plastics surface being intended to be better than in the prior art.
[0007] This object is achieved by way of a
[0000] process for producing a plastics article from a plastic obtainable via free-radical polymerization with inorganic coating on one or more sides via the following process steps:
[0000]
a) using doctoring, flow coating, or immersion to coat a substrate with a lacquer composition in which a silicon-based adhesion promoter and inorganic particles are present in a ratio of from 1:9 to 9:1 in a solvent which, where appropriate, may also comprise flow control agent,
b) drying the lacquer composition on the substrate, thus obtaining the coated substrate,
c) using one or more substrates thus coated to construct a polymerization cell, where the coated sides are in the interior of the cell,
d) charging a polymerizable liquid composed of monomers capable of free-radical polymerization, where appropriate with polymeric content, to the polymerization cell,
e) free-radical polymerization of the polymerizable liquid in the presence of a polymerization initiator, whereupon the internal inorganic coating transfers from the substrate into or onto the surfaces of the free-radical-polymerized plastic or of the plastics article, and
f) removing the coated plastics article with inorganic coating on one or more sides from the polymerization cell.
[0014] The inventive process can give plastics articles with improved properties in relation to the scrub resistance of the surface. Furthermore, it is possible to achieve very uniform layer thicknesses of the inorganic coatings and high uniformity of the surfaces.
DESCRIPTION OF THE INVENTION
[0015] The invention provides a
[0016] Process for producing a plastics article from a plastic obtainable via free-radical polymerization with inorganic coating on one or more sides.
[0017] A plastics articles means any plastics item which has practically any desired shape and is obtainable through the inventive process. By way of example, preferred plastics articles may have the shape of flat sheets. However, examples of other plastics articles are corrugated sheets, cubes, blocks, round rods, etc. The modulus of elasticity of the plastics article to ISO 527-2 may, by way of example, be at least 1500 MPa, preferably at least 2000 MPa. Examples of the thickness of the sheets range from 1 to 200 mm, in particular from 3 to 30 mm. Examples of usual dimensions for solid sheets are in the range from 3×500-2000×2000-6000 mm (thickness×width×length).
[0018] Depending on the application, the inorganic coating process may take place on one or more sides. In the case of flat sheets, one or both of the large surfaces will preferably be coated. However, it is also possible to coat the smaller edge surfaces or to undertake all-round coating of all of the surfaces.
[0000] The Process Encompasses at Least the Process Steps a) to f)
[0000]
a) using doctoring, flow coating, or immersion to coat a substrate with a lacquer composition in which a silicon-based adhesion promoter and inorganic particles are present in a ratio of from 1:9 to 9:1 in a solvent which, where appropriate, may also comprise flow control agent,
[0020] A substrate means in the first instance an article of practically any desired type in relation to shape and material, as long as it is suitable for the purposes of the invention. In particular, the substrate has to be coatable and suitable for constructing a polymerization cell. Flat sheets composed of a hard, solid material, e.g. ceramic, metal or particularly preferably glass, are particularly suitable for this purpose. Sheets composed of plastic or plastic films can likewise be suitable. In particular, plastics films composed of polyethylene terephthalate can be suitable. In order to be suitable for the construction of a polymerization cell, films may have been applied, adhesive-bonded or absorbed onto a hard substrate, e.g. onto a glass sheet.
[0021] The substrate may be composed of a plastic. Among these are in particular polycarbonates, polystyrenes, polyesters, such as polyethylene terephthalate (PET), where these may also have been modified with glycol, and polybutylene terephthalate (PBT), cyclooefinic copolymers (COCs), acrylnitrile-butadine-styrene co-polymers and/or poly(meth)acylates.
[0022] Preference is given here to polycarbonates, cycloolefinic polymers and poly(meth)acrylates, and particular preference is given here to poly(meth)acrylates.
[0023] Polycarbonates are known to persons skilled in the art. Polycarbonates may be formally regarded as polyesters derived from carbonic acid and from aliphatic or aromatic dihydroxy compounds. They are readily accessible via reaction of diglycols or bisphenols with phosgene or with carbonic diesters via polycondensation or transesterification reactions.
[0024] Preference is given here to polycarbonates which derive from bisphenols. Among these bisphenols are in particular 2,2-bis(4-hydroxyphenyl)propane (bisphenol A), 2,2-bis(4-hydroxyphenyl)butane (bisphenol B), 1,1-bis(4-hydroxyphenyl)cyclohexane (bisphenol C), 2,2′-methylenediphenol (bisphenol F), 2,2-bis(3,5-dibromo-4-hydroxyphenyl)propane (tetrabromobisphenol A) and 2,2-bis(3,5-dimethyl-4-hydroxyphenyl)propane (tetramethylbisphenol A).
[0025] Aromatic polycarbonates of this type are usually prepared via interfacial polycondensation or via transesterification, a detailed description being given in Encycl. Polym. Sci. Engng. 11, 648-718.
[0026] In interfacial polycondensation, the bisphenols are emulsified in the form of an aqueous, alkaline solution in inert organic solvents, such as methylene chloride, chlorobenzene or tetrahydrofuran, and are reacted in stages with phosgene. Catalysts used comprise amines, or in the case of sterically hindered bisphenols also phase-transfer catalysts. The resultant polymers are soluble in the organic solvents used.
[0027] The properties of the polymers can be varied widely via the selection of the bisphenols. If simultaneous use is made of different bisphenols, it is also possible to build up block polymers in multistage polycondensation reactions.
[0028] Cycloolefinic polymers are polymers which are obtainable by using cyclic olefins, in particular polycyclic olefins.
[0029] Cyclic olefins encompass, for example, monocyclic olefins, such as cyclopentene, cyclopentadiene, cyclohexene, cycloheptene, cyclooctene, and also alkyl derivatives of these monocyclic olefins having from 1 to 3 carbon atoms, examples being methyl, ethyl or propyl, e.g. methylcyclohexene or dimethylcyclohexene, and also acrylate and/or methacrylate derivatives of these monocyclic compounds. Furthermore, cycloalkanes having olefinic side chains may also be used as cyclic olefins, an example being cyclopentyl methacrylate.
[0030] Preference is given to bridged polycyclic olefin compounds. These polycyclic olefin compounds may have the double bond either in the ring, in which case they are bridged polycyclic cycloalkenes, or else in side chains. In that case they are vinyl derivatives, allyloxycarboxy derivatives or (meth)acryloxy derivatives of polycyclic cycloalkane compounds. These compounds may also have alkyl, aryl or aralkyl substituents.
[0031] Without any intended resultant restriction, examples of polycyclic compounds are bicyclo[2.2.1]hept-2-ene (norbornene), bicyclo[2.2.1]hept-2,5-diene (2,5-norbornadiene), ethylbicyclo[2.2.1]hept-2-ene (ethyl-norbornene), ethylidenebicyclo[2.2.1]hept-2-ene (ethyl-idene-2-norbornene), phenylbicyclo[2.2.1]hept-2-ene, bicyclo[4.3.0]nona-3,8-diene, tricyclo[4.3.0.1 2,5 ]-3-decene, tricyclo[4.3.0.1 2,5 ]-3,8-decene (3,8-dihydrodicyclopentadiene), tricyclo[4.4.0.1 2,5 ]-3-undecene, tetracyclo[4.4.0.1 2.5 .1 7,10 ]-3-dodecene, ethyl-idenetetracyclo[4.4.0.1 2,5 .1 7,10 ]-3-dodecene, methyl-oxycarbonyltetracyclo[4.4.0.1 2,5 .1 7,10 ]-3-dodecene, ethylidene-9-ethyltetracyclo[4.4.0.1 2,5 .1 7,10 ]-3-dodecene, pentacyclo[4.7.0.1 2,5 ,0,0 3,13 .1 9,12 ]-3-penta-decene, pentacyclo[6.1.1 3,6 .0 2,7 .0 9,3 ]-4-pentadecene, hexacyclo[6.6.1.1 3,6 .1 10,13 .0 2,7 .0 9,14 ]-4-heptadecene, dimethylhexacyclo[6.6.1.1 3,6 .1 10,13 .0 2,7 .0 9,14 ]-4-heptadecene, bis(allyloxycarboxy)tri-cyclo[4.3.0.1 2,5 ]decane, bis(methacryloxy)tri-cyclo[4.3.0.1 2,5 ]decane, bis(acryloxy)tri-cyclo[4.3.0.1 2,5 ]decane.
[0032] The cycloolefinic polymers are prepared using at least one of the cycloolefinic compounds described above, in particular the polycyclic hydrocarbon compounds. The preparation of the cycloolefinic polymers may, furthermore, use other olefins which can be copolymerized with the abovementioned cycloolefinic monomers. Examples of these are ethylene, propylene, isoprene, butadiene, methylpentene, styrene, and vinyltoluene.
[0033] Most of the abovementioned olefins, and in particular the cycloolefins and polycycloolefins, may be obtained commercially. Many cyclic and polycyclic olefins are moreover obtainable by Diels-Alder addition reactions. The cycloolefinic polymers may be prepared in a known manner, as set out inter alia in the Japanese Patent Specifications 11818/1972, 43412/1983, 1442/1986 and 19761/1987 and in the published Japanese Patent Applications Nos. 75700/1975, 129434/1980, 127728/1983, 168708/1985, 271308/1986, 221118/1988 and 180976/1990 and in the European Patent Applications EP-A-0 6 610 851, EP-A-0 6 485 893, EP-A-0 6 407 870 and EP-A-0 6 688 801.
[0034] The cycloolefinic polymers may, for example, be polymerized in a solvent, using aluminium compounds, vanadium compounds, tungsten compounds or boron compounds as catalyst.
[0035] It is assumed that, depending on the conditions, in particular on the catalyst used, the polymerization can proceed with ring-opening or with opening of the double bond.
[0036] It is also possible to obtain cycloolefinic polymers by free-radical polymerization, using light or an initiator as free-radical generator. This applies in particular to the acryloyl derivatives of the cycloolefins and/or cycloalkanes. This type of polymerization may take place either in solution or else in bulk.
[0037] Another preferred plastics substrate encompasses poly(meth)acrylates. These polymers are generally obtained via free-radical polymerization of mixtures which comprise (meth)acrylates. These have been described above and, depending on production requirements, it is possible to use either monofunctional or polyfunctional (meth)acrylates.
[0038] According to one particular aspect of the present invention, these mixtures comprise at least 40% by weight, preferably at least 60% by weight, and particularly preferably at least 80% by weight, based on the weight of the monomers, of methyl methacrylate. Alongside the abovementioned (meth)acrylates, the compositions to be polymerized may also comprise other unsaturated monomers copolymerizable with methyl methacrylate and with the abovementioned (meth)acrylates. Examples of these have in particular been set out under component E).
[0039] The amount generally used of these comonomers is from 0 to 60% by weight, preferably from 0 to 40% by weight and particularly preferably from 0 to 20% by weight, based on the weight of the monomers, and these compounds may be used individually or in the form of a mixture.
[0040] The polymerization is generally initiated using known free-radical initiators, in particular described under component D). The amount often used of these compounds is from 0.01 to 3% by weight, preferably from 0.05 to 1% by weight, based on the weight of the monomers.
[0041] The abovementioned monomers may be used individually or in the form of a mixture. Use may also be made here of various polycarbonates, poly(meth)acrylates or cyclo-olefinic polymers, differing in molecular weight or in monomer composition, for example.
[0042] The plastics substrates may also be produced by cell casting processes. In these, by way of example, suitable (meth)acrylic mixtures are charged to a mould and polymerized. These (meth)acrylic mixtures generally comprise the (meth)acrylates set out above, in particular methyl methacrylate. The (meth)acrylic mixtures may moreover comprise the copolymers set out above, and also, in particular for viscosity adjustment, may comprise polymers, in particular poly(meth)acrylates.
[0043] The weight-average molar mass M w of the polymers prepared by cell casting processes is generally higher than the molar mass of polymers used in moulding compositions. This gives a number of known advantages. With no resultant intended restriction, the weight-average molar mass of polymers prepared by cell casting processes is generally in the range from 500 000 to 10 000 000 g/mol.
[0044] Preferred plastics substrates prepared by the cell casting process may be obtained commercially with the trade name ® Acrylite from Cyro Inc., USA.
[0045] In so far as the substrates are composed of plastic, they may also comprise conventional additives of any type. Examples of these are antioxidants, mould-release agents, flame retardants, lubricants, dyes, flow improvers, fillers, light stabilizers and organophosphorus compounds, such as phosphoric esters, phosphoric diesters and phosphoric monoesters, phosphites, phosphorinanes, phospholanes or phosphonates, pigments, weathering stabilizers and plasticizers. However, the amount of additives is restricted in relation to the application.
[0046] Particularly preferred moulding compositions which encompass poly(meth)acrylates are obtainable with the trade name Acrylite® from the company Cyro Inc., USA. Preferred moulding compositions which encompass cycloolefinic polymers may be purchased with the trade name ®Topas from Ticona and ®Zeonex from Nippon Zeon. Polycarbonate moulding compositions are obtainable, by way of example, with the trade name ®Makrolon from Bayer or ®Lexan from General Electric.
[0047] The plastics substrate particularly preferably encompasses at least 80% by weight, in particular at least 90% by weight, based on the total weight of the substrate, of poly(meth)acrylates, polycarbonates and/or cycloolefinic polymers. The plastics substrates are particularly preferably composed of polymethyl methacrylate, and this polymethyl methacrylate may comprise conventional additives.
[0048] In one preferred embodiment, plastics substrates may have an impact strength to ISO 179/1 of at least 10 kJ/m 2 , preferably at least 15 kJ/m 2 .
[0049] The shape and the size of the plastics substrate are not important for the present invention. Substrates generally used often have the shape of a sheet or a panel, and have a thickness in the range from 1 mm to 200 mm, in particular from 5 to 30 mm.
[0050] The lacquer composition comprises an adhesion promoter and inorganic particles in a ratio of from 1:9 to 9:1 by weight.
[0051] The adhesion promoter may be composed of a colloidal solution of SiO 2 particles or of silane condensates. From 1 to 2% by weight of SiO 2 and from 2.5 to 7.5% by weight of other inorganic particles are preferably present in a solvent or solvent mixture, which, where appropriate, also comprises flow control agent and water. Examples of the concentration at which the flow control agent may be present are from 0.01 to 2% by weight, preferably from 0.1 to 1% by weight.
[0052] The amounts of other binders or polymerizing organic components present are preferably zero or, if non-zero, only very small and non-critical.
[0053] For the purposes of the present invention, the term inorganic means that the carbon content of the inorganic coating is not more than 25% by weight, preferably not more than 17% by weight, and very particularly preferably not more than 10% by weight, based on the weight of the inorganic coating (a). This variable may be determined by means of elementary analysis.
[0054] According to another aspect of the present invention, it is also possible to use silane condensates which comprise a colloidal solution of SiO 2 particles. Solutions of this type may be obtained by the sol-gel process, in particular condensing tetraalkoxysilanes and/or tetrahalosilanes.
[0055] The abovementioned silane compounds are usually used to prepare aqueous coating compositions, by hydrolysing organosilicon compounds with an amount of water sufficient for the hydrolysis reaction, i.e. >0.5 mol of water per mole of the groups intended for hydrolysis, e.g. alkoxy groups, preferably with acid catalysis. Examples of acids which may be added are inorganic acids, such as hydrochloric acid, sulphuric acid, phosphoric acid, nitric acid, etc., or organic acids, such as carboxylic acids, organic sulphuric acids, etc., or acid ion exchangers, the pH for the hydrolysis reaction usually being from 2 to 4.5, preferably 3.
[0056] The coating composition preferably comprises inorganic particles in the form of from 1 to 2% by weight, preferably from 1.2 to 1.8% by weight, SiO 2 and from 2.5 to 7.5% by weight, preferably from 3 to 7% by weight, particularly preferably from 4 to 6% by weight, of antimony tin oxide particles, in water as solvent. The pH set is preferably alkaline, in order that the particles do not agglomerate. The size of these oxide particles is non-critical, but transparency is particle-size-dependent. The size of the particles is preferably not more than 300 nm, and in particular in the range from 1 to 200 nm, preferably from 1 to 50 nm.
[0057] According to one particular aspect of the present invention, the colloidal solution is preferably applied at a pH greater than or equal to 7.5, in particular greater than or equal to 8 and particularly greater than or equal to 9.
[0058] Basic colloidal solutions are less expensive than acidic solutions. Furthermore, basic colloidal solutions of oxide particles can be stored particularly easily and for a long period.
[0059] The abovementioned coating compositions may be obtained commercially with the trade name ®Ludox (Grace, Worms, Germany); ®Levasil (Bayer, Leverkusen, Germany); ®Klebosol (Clariant).
[0060] The flow control agent mentioned is also preferably present, e.g. at a concentration of from 0.1 to 1% by weight, preferably from 0.3 to 0.5% by weight, in order to promote good dispersion of the particles.
[0061] The lacquer composition may be mixed from individual components prior to use.
[0062] For example, use may be made of a commercially available antimony tin oxide solution or suspension in water of strengths from 10 to 15% (solution 1), which may be mixed with a ready-to-use silica sol solution (solution 2) and with a diluent solution (solution 3).
[0063] By way of example, the silica sol solution may initially, in concentrated form, comprise SiO 2 particles in the size range from 10 to 100 nm, preferably from 7 to 50 nm, and may take the form of an aqueous solution or, respectively, suspension which is alkaline and whose strength is from 20 to 30%. The concentrated solution may in turn be adjusted to about 30% strength in H 2 O, to give a ready-to-use solution (solution 2). It is preferable to add a distribution aid or a flow control agent. Examples of suitable materials are surfactants, and addition of [fatty alcohol +3 ethylene oxide, Genapol X 80] is preferred.
[0064] Besides the flow control agent having anionic groups, the coating composition may encompass other flow control agents, e.g. non-ionic flow control agents. Among these, particular preference is given to ethoxylates, and use may in particular be made here of esters or else alcohols or phenols having ethoxy groups. Among these are nonylphenol ethoxylates.
[0065] The ethoxylates in particular encompass from 1 to 20, in particular from 2 to 8, ethoxy groups. The hydrophobic radical of the ethoxylated alcohols and esters preferably encompasses from 1 to 40, preferably from 4 to 22, carbon atoms, and use may be made here of either linear or branched alcohol and/or ester radicals. By way of example, products of this type may be obtained commercially with the trade name®Genapol X80.
[0066] The addition of non-ionic flow control agent is restricted to an amount which has no substantial adverse effect on the antistatic coating. Based on the total weight of the coating composition, from 0.01 to 4% by weight, in particular from 0.1 to 2% by weight, of one or more non-ionic flow control agents is generally added to the coating composition.
[0067] The diluent (solution 3) used may comprise deionized H 2 O which has been adjusted to about pH 9.0 with NaOH. Advantageously, a flow control agent may be present here.
[0068] Flow control agents having at least one anionic group are known to persons skilled in the art, and these flow control agents generally contain carboxy, sulphonate and/or sulphate groups. These flow control agents preferably encompass at least one sulphonate group. Flow control agents having at least one anionic group encompass anionic flow control agents and amphoteric flow control agents which, besides an anionic group, also encompass a catalytic group. Among these, preference is given to anionic flow control agents. In particular, the use of anionic flow control agents permits the production of formable plastics articles.
[0069] The flow control agents having at least one anionic group preferably encompass from 2 to 20, preferably from 2 to 10 carbon atoms, and the organic radical here may contain either aliphatic or aromatic groups. According to one particular aspect of the present invention, use is made of anionic flow control agents which encompass an alkyl or cycloalkyl radical having from 2 to 10 carbon atoms.
[0070] The flow control agents having at least one anionic group may contain other polar groups, such as carboxy, thiocarboxy or imino, carboxylic ester, carbonic ester, thiocarboxylic ester, dithiocarboxylic ester, thio-carbonic ester, dithiocarbonic ester and/or dithio-carbamide groups.
[0071] Particular preference is given to flow control agents of the formula (I)
where X is independently an oxygen or sulphur atom, Y is a group of the formula OR 2 , SR 2 or NR 2 , where R 2 is, independently, an alkyl group having from 1 to 5, preferably from 1 to 3, carbon atoms, and R 3 is an alkylene group having from 1 to 10, preferably from 2 to 4, carbon atoms, and M is a cation, in particular an alkali metal ion, in particular potassium or sodium, or an ammonium ion.
[0072] Based on the total weight of the coating composition, from 0.01 to 1% by weight, in particular from 0.03 to 0.1% by weight, of one or more flow control agents having at least one anionic group is generally added to the coating composition.
[0073] Compounds of this type may in particular be obtained from Raschig AG with the trade name Raschig OPX® or Raschig DPS®, and, by way of example, may be present at a concentration of from 0.1 to 1% by weight, preferably from 0.4 to 0.6% by weight.
[0074] In order to obtain a coating composition ready for use, it is preferable to begin by mixing solutions 2 and 3, for example in a ratio of from 1:1 to 1:2, e.g. 1:1.5, and then to mix the mixture with solution 1 in a ratio of about 1:1.
[0000] a) Drying of the Lacquer Composition on the Substrate to Give the Coated Substrate.
[0075] After doctoring, flow coating or immersion has been used to coat a substrate, e.g. a glass sheet, the lacquer composition is dried. By way of example, this may take place in the temperature range from 50 to 200° C., preferably from 80 to 120° C., and it is necessary to adapt the temperature to the heat resistance of the substrate here. A drying time of from 0.1 to 5 hours, preferably from 2 to 4 hours, is generally sufficient to obtain an almost completely hardened coating. After the drying phase, a further standing phase may follow, e.g. from 12 to 24 hours at room temperature, in order to ensure complete hardening, prior to further use of the coated substrates.
[0076] Since the lacquer layer has been produced from a solution which has solids content of inorganic particles, the layer is composed of a continuous three-dimensional network of sphere-like structures and inevitably having a certain proportion of cavities. EP-A 0 193 269 discloses this structure.
[0000] b) Use of one or More Substrates Coated in this Way to Construct a Polymerization Cell with Coated Sides in the Interior of the Cell.
[0077] One or more of the substrates coated in the above process step may then be used to construct a polymerization cell. A polymerization cell is a sealed-off space into which a liquid polymerizable mixture may be charged and within which this can be polymerized until a polymerized plastics article is obtained, which can be removed in solid form once the cell has been opened. Polymerization cells are well known, e.g. from the production of cast polymethyl methacrylate (see, for example, DE 25 44 245, EP-B 570 782 or EP-A 656 548).
[0078] If, by way of example, a glass sheet has been coated on one side via flow coating in the preceding process step, this may then be used with the coated side inward to construct a polymerization cell composed of two opposite glass sheets forming parallel planes at a distance from one another. The other, second glass sheet may in this case be a normal, uncoated sheet. Separation is ensured via appropriate edgings, or a frame. Particular polymerization cells known from the production of cast polymethyl methacrylate are composed of two glass sheets with a peripheral elastic sealing bead. The elasticity of the bead serves to compensate for shrinkage during the polymerization process. The cell is held together via appropriate clamps. There are apertures for charging and for air removal.
[0000] c) Charging the Polymerization Cell with Polymerizable Liquid Composed of Monomers Capable of Free-Radical Polymerization, where Appropriate with Polymeric Content and, where Appropriate, with Solids Dispersed Therein.
[0079] A polymerizable liquid composed of monomers capable of free-radical polymerization, where appropriate with polymeric content, is then charged to the polymerization cell. In principle, any of the liquids or, respectively, monomers or mixtures of monomers and polymers capable of polymerization in the cell process is suitable. The polymerizable liquid may comprise other soluble or insoluble additives, e.g. pigments, fillers, UV absorbers. Examples of other materials which may be present are impact modifiers or light-scattering particles composed of plastics particles which have a multishell structure and/or have been crosslinked.
[0080] Examples of monomers capable of free-radical polymerization are monomers having one or more vinylic groups, e.g. methyl methacrylate, other esters of methacrylic acid, e.g. ethyl methacrylate, butyl methacrylate, hexyl methacrylate, cyclohexyl methacrylate, esters of acrylic acid (e.g. methyl acrylate, ethyl acrylate, butyl acrylate, hexyl acrylate, cyclohexyl acrylate), or styrene and styrene derivatives, such as α-methylstyrene or p-methylstyrene. Crosslinking monomers, such as triallyl cyanurate, allyl methacrylate or di(meth)acrylates, may likewise be present, but preferably only in relatively small amounts, e.g. from 0.1 to 2% by weight.
[0081] The material may be a homogeneous solution, e.g. composed of 100% of methyl methacrylate, or may be a monomer mixture, e.g. predominantly, from 80 to 99% by weight, methyl methacrylate and from 1 to 20% by weight of other copolymerizable monomers, e.g. methyl acrylate. The solution or the monomer mixture may have polymeric content, and by way of example the mixture charged may be composed of from 70 to 95% by weight of methyl methacrylate and 5 to 30% by weight of polymethyl methacrylate.
[0082] d) Free-Radical Polymerization of the Polymerizable Liquid in the Presence of a Polymerization Initiator, Whereupon the Internal Inorganic Coating Transfers from the Substrate into or onto the Surfaces of the Free-Radical-Polymerized Plastic or of the Plastics Article.
[0083] Prior to charging of the material to the polymerization cell, a polymerization initiator is preferably added, with uniform distribution, to the polymerizable solution or to the mixture composed of monomers capable of free-radical polymerization, where appropriate with polymeric content. The polymerizable liquid may then be polymerized to give the plastic, e.g. at from 40 to 80° C.
[0084] Examples which may be mentioned of polymerization initiators are: azo compounds, 2,2′-azobis(iso-butyronitrile) or 2,2′-azobis(2,4-dimethylvalero-nitrile), redox systems, such as the combination of tertiary amines with peroxides, and preferred examples are peroxides (cf. in this connection, by way of example, H. Rauch-Puntigam, Th. Völker, “Acryl-und Methacrylverbindungen” [Acrylic and methacrylic compounds], Springer, Heidelberg, 1967 or Kirk-Othmer, Encyclopedia of Chemical Technology, Vol. 1, pp. 386 et seq., J. Wiley, New York, 1978). Examples of suitable peroxide polymerization initiators are dilauroyl peroxide, tert-butyl peroctoate, tert-butyl perioso-nonanoate, dicyclohexyl peroxydicarbonate, dibenzoyl peroxide or 2,2-bis(tert-butylperoxy)butane. Another preferred method carries out the polymerization using a mixture of various polymerization initiators of different half-life time, e.g. dilauroyl peroxide and 2,2-bis(tert-butylperoxy)butane, in order that during the course of polymerization, or else at various polymerization temperatures, the flow of free radicals is kept constant. The amounts used of polymerization initiator are generally from 0.01 to 2% by weight, based on the monomer mixture.
[0085] The arrangement usually used for the cells when conducting the polymerization ensures temperature control or heat dissipation, and, by way of example, the cells—which may lie horizontally in racks—may be held under polymerization conditions in hot-air ovens with high air velocity, in autoclaves using water spray, or in water-filled pans. The system is heated to start the polymerization. Controlled cooling is needed in order to dissipate the considerable heat of polymerization, specifically in the gelling region. The polymerization temperatures are usually from 15 to 70° C. at atmospheric pressure. In the autoclave they are advantageously from about 90 to 100° C. The residence time for the polymerization cell in the temperature-controlled medium varies, depending on the nature of the polymerization mixture and on the method, from a few hours to two or more days.
[0086] Examples of other additives which may be added, besides the polymerization initiator, are molecular-weight regulators, e.g. dodecyl mercaptane.
[0087] However, it is preferably to carry out the polymerization without molecular-weight regulators, in order to obtain high molecular weights.
[0088] In order to maximize conversion (>99% of polymer), the temperature should again be raised for a short period towards the end of the polymerization procedure, for example to above 100° C., e.g. to 120° C. It is advantageous to cool the mixture slowly, whereupon the polymer sheets become released from the mould sheets and can be removed.
[0089] When the monomer liquid is charged to the polymerization cell, it penetrates into the cavities of the coating of the substrate. By way of example, SiO 2 and antimony tin oxide may be present in the form of an interpenetrating network. During the polymerization, therefore, there is some degree of penetration of the inorganic layer by the resultant polymer of the plastic article. The result is therefore a coating structure which differs structurally from the subsequently applied coatings known from the prior art.
[0090] “Annealing” may also take place, where appropriate, by permitting the plastics articles to age after the polymerization reaction, preferably while still within the polymerization cell, and heating them again, e.g. for from 2 to 8 hours, to from 40 to 120° C., after the cooling process. This permits escape of residual monomer and reduction of internal stresses within the plastics article.
[0000] e) Removal from the Polymerization Cell of the Coated Plastics Article with Inorganic Coating on One or More Sides.
[0091] Once the polymerization cell has been dismantled or opened, the plastics article with inorganic coating on one or more sides may be removed. It is preferable to produce a polymethyl methacrylate sheet with an electrically conductive coating on one or more sides.
[0000] Plastics Articles
[0092] The plastics article obtainable by the inventive process preferably has an electrically conductive coating whose surface resistance is smaller than or equal to 10 10 Ω, preferably smaller than or equal to 10 7 Ω. No Tyndall effect indicating haze is discernible. Rainbow interference effects, which are evidence of non-uniform layer distribution, are almost or entirely absent on the coated surfaces. By way of example, the surface resistance of the coating may be determined to DIN EN 613402/IEC 61340, using a Wolfgang Warmbier SRM-110 ohmmeter.
[0093] The plastics article is preferably composed of a polymethyl methacrylate, i.e. of a polymer predominantly composed of methyl methacrylate, or of a polystyrene. The plastic may comprise added materials and auxiliaries such as impact modifiers, pigments, fillers, UV absorbers, etc. The plastics article may also be translucent or transparent.
[0094] The layer thickness of the electrically conductive coating is in the range from 200 to 5000 nm, preferably from 250 to 1000 nm, particularly preferably in the range from 300 to 400 nm.
[0095] The inorganically coated surface of the plastics article has a scrub resistance to DIN 53 778 of at least 10 000 cycles, preferably at least 12 000 cycles, in particular at least 15 000 cycles. By way of example, a M 105/A wet-scrub tester from Gardner may be used to determine the adhesion of the coating in the wet-scrub test to DIN 53 778.
[0096] Examples of the use of the plastics article are use for encasing structures, for equipping cleanrooms, for machine covers, for incubators, for displays, for visual display screens and visual-display-screen covers, for rear-projection screens, for medical apparatus and for electrical devices.
[0000] Advantageous Effects of the Invention
[0097] The inventive process permits the production of plastics articles with a coating structure which differs structurally from the subsequently applied coatings known from the prior art. The coating transferred from the coated substrate to the polymeric plastics article during its polymerization is of high quality. No Tyndall effect indicating haze is discernible. Rainbow interference effects, which are evidence of non-uniform layer distribution, are almost or entirely absent on the coated surfaces. Abrasion resistance is higher than that of conventionally coated plastics articles.
EXAMPLES
Inventive Example 1
[0098] Using a ratio of 1:1.5, 25 parts by weight of an anionic silica sol (solids content 30%; ®Levasil obtainable from Bayer AG) were mixed with 0.4 part by weight, made up to 100 parts by weight with deionized water, of an ethoxylated fatty alcohol (®Genapol X80), and with a solution, made up to 100 parts by weight using aqueous NaOH solution at a pH of 9, of 0.5 part by weight of the potassium salt of 3-sulphopropyl O-ethyl dithiocarbonic acid (®Raschig OPX obtainable from Raschig AG).
[0099] 50 parts by weight of this first solution were mixed with 50 parts by weight of an antimony tin oxide solution (12% strength in water; obtainable from Leuchtstoffwerk Breitungen GmbH).
[0100] The resultant coating composition was then applied to a glass pane by the flow-coating process and dried at 100° C. for 3 h. The coated glass panes were used to construct a polymerization cell. During the polymerization of methyl methacrylate, the coating was transferred to the PMMA surface.
[0101] The thickness of the extremely thin layers may be determined by transmission electron microscopy on a thin section. Depending on the direction of flow, the thickness of the layer was in the range from 350 to 400 nm.
[0102] The wet-scrub test to DIN 53778, using a M 105/A wet-scrub tester from Gardner, was used to determine the adhesion of the coating. The value determined was 20 000 cycles at a total layer thickness of 350 nm.
[0103] The surface resistance of the coating was determined to DIN EN 613402/IEC 61340, using a Wolfgang Warmbier SRM-110 ohmmeter. The value determined was 10 6 Ω at a total layer thickness of 350 nm.
[0104] The sheet exhibited good optical properties.
Comparative Example 1
[0105] Inventive Example 1 was in essence repeated, but the coating composition was applied directly to the PMMA sheet by means of flow coating. The resultant coated sheet was then dried at 80° C. for 30 min.
[0106] The adhesion of the coating proved to be non-permanent, and it could be released from the PMMA sheet by repeated rubbing with a conventional wiper cloth.
Comparative Example 2
[0107] Comparative Example 1 was in essence repeated, but the PMMA sheet was first provided with an adhesion-promoting layer (PLEX 9008L, obtainable from Röhm GmbH & Co. KG), and the coating composition was then applied by the flow coating process. The resultant coated sheet was then dried at 80° C. for 30 min.
[0108] The adhesion of the coating proved to be non-permanent, and it could be released from the PMMA sheet by repeated rubbing with a conventional wiper cloth.
Comparative Example 3
[0109] Inventive Example 1 was in essence repeated, but the formulation of the coating composition was changed so that the antimony tin oxide solution (12% strength in water; obtainable from Leuchtstoffwerk Breitungen GmbH) was applied directly to the glass sheet. It was impossible here to obtain uniform flow of the coating.
[0110] The transfer of the coating to the PMMA sheet was non-uniform. Some strong interference effects in the form of rainbow colours appeared, indicating variations in the layer thicknesses of the coating.
Comparative Example 4
[0111] Inventive Example 1 was in essence repeated, but the formulation of the coating composition was changed so that 95 parts by weight of the first solution and 5 parts by weight of the antimony tin oxide solution (12% strength in water; obtainable from Leuchtstoffwerk Breitungen GmbH) are used.
[0112] After transfer of the coating to the PMMA sheets, the coated sheets exhibit haze (Tyndall effect). The surface resistance is >10 9 Ω.
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The invention relates to a method for production of a plastic body, made from a plastic obtained by means of a radical polymerisation with single- or multi-sided, inorganic coating containing silicon. The coating of a substrate is firstly achieved with a paint composition, containing inorganic particles in a solvent which can optionally contain additional flow improvers. One or more of such coated substrates can be used for the construction of a polymerisation chamber, in which the coated sides lie within the chamber. After radical polymerisation of a monomer mixture in the presence of a polymerisation initiator, the internal inorganic coating of the substrate transfers into or onto the surfaces of the radically polymerised plastic or of the plastic body. The invention further relates to the corresponding plastic body and the uses thereof.
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CROSS REFERENCE TO RELATED APPLICATION
[0001] This application is a non-provisional that claims benefit to U.S. Provisional Patent Application No. 62/019,162 filed on Jun. 30, 2014, which is herein incorporated by reference in its entirety.
STATEMENT OF FEDERAL SUPPORT
[0002] The invention was made with government support under contracts R21 HD053608 and R01 HD072080 awarded by the National Institutes of Health. The government has certain rights in the invention.
FIELD
[0003] This patent relates generally to the field of controllable machines, and in particular to systems and methods for controlling a controllable machine through the use of motion available to a user.
BACKGROUND
[0004] Machines can assist people who do not have the ability to walk. Certain machines, like manual wheelchairs, allow a person to move by pushing the wheels of the chair with their arms. Powered wheelchairs allow a person to move using a powered motor. A powered wheelchair may have a joystick, which directs the movement of the wheelchair. This allows the user to move the wheelchair without relying on the user's strength from his or her arms.
[0005] Some people are paralyzed, and have suffered the partial or total loss of use of all their limbs and torso. Some people with tetraplegia retain the limited use of the upper portion of their torso, but may not be able to use their arms to move a joystick of a powered wheelchair.
[0006] People with tetraplegia often retain some level of mobility of the upper body. A person's residual mobility may be used to enable control of computers, wheelchairs and other assistive devices. A control device is needed based on wearable sensors that adapt their functions to the users' abilities.
[0007] In the prior art, one system uses cameras to track infrared light sources to control a machine for a tetraplegic user. However, fluctuations in ambient and natural light compromise the functionality of the system. Another system is known in the prior art that relies on a single sensor placed on the head of the machine user. However, that system is compromised by head movements that affect the direction of gaze, does not rely on the residual mobility in the upper body of the machine user, which is usually more robust than the mobility of the head alone.
SUMMARY
[0008] A method for controlling a powered wheelchair is disclosed. The method may comprise receiving first information from at least one user sensor coupled to a user of the wheelchair, said first information indicating the movement of the user; receiving second information from a reference sensor coupled to the wheelchair, said second information indicating the movement of the wheelchair; using the first information and the second information to prepare at least one instruction to move the wheelchair; and using the at least one instruction to move the wheelchair.
[0009] A tangible storage medium storing a program having instructions for controlling a processor to control a powered wheelchair is also disclosed, the instructions comprising receiving first information from at least one user sensor coupled to a user of the wheelchair, said first information indicating the movement of the user; receiving second information from a reference sensor coupled to the wheelchair, said second information indicating the movement of the wheelchair; using the first information and the second information to prepare at least one instruction to move the wheelchair; and using the instruction to cause the wheelchair to move.
BRIEF DESCRIPTION OF THE DRAWINGS
[0010] FIG. 1 is a block representation of one embodiment of a computing device 10 comprising controller 102 , memory 104 , and I/O interface 106
[0011] FIG. 2 shows one embodiment of a wearable item used to control machine 30 .
[0012] FIG. 3 shows one placement of sensors 52 in relation to user 40 , and also shows one embodiment of monitor 90 .
[0013] FIG. 4 shows a diagram of one aspect of an embodiment of I/O interface 106 .
[0014] FIG. 5 shows a flowchart that reflects steps taken by control module 110 during training phase 500 .
[0015] FIG. 6 shows a flowchart that reflects steps taken by control module 110 during operation of machine 30 .
[0016] FIG. 7 shows one embodiment of the setup of machine 30 in relation to computing device 10 , sensors 50 , and monitor 90 .
[0017] FIG. 8 is an illustration showing how translational and rotational command signals are mapped to visual feedback on monitor 90 .
[0018] FIGS. 9 and 10 relate to exemplary rotation of reference frames of sensors 50 .
DETAILED DESCRIPTION
[0019] This patent discloses a device that facilitates operation of a machine, such as a wheelchair, by a user. The user dons a wearable item. User sensors are attached to the wearable item. One reference sensor is attached to the machine. The user sensors and reference sensor measure motion. The sensors are connected to a computing device. The computing device uses data collected from the sensors to move the machine in a desired direction. Feedback provides the user with the state of each control command, as well as indicating the direction the machine is moving in response to information from the sensors. Examples of feedback include a monitor mounted to the machine, or feedback provided through a vibrating actuator on the user's sleeve. The above description is intended to be an illustrative guide to the reader, and should not be read to limit the scope of the claims.
[0020] FIG. 1 presents a block representation of one embodiment of computing device 10 . Computing device 10 may be a laptop, tablet, smartphone, personal digital assistant (PDA), mobile telephone, personal navigation device, or other similar device. As shown in the FIG. 1 , computing device 10 may comprise a controller 102 . Controller 102 may be composed of distinct, separate or different chips, integrated circuit packages, parts or components. Controller 102 may comprise one or more controllers, and/or other analog and/or digital circuit components configured to or programmed to operate as described herein with respect to the various embodiments. Controller 102 may be responsible for executing various control modules to provide computing and processing operations for control device 10 . In various embodiments, the controller 102 may be implemented as a host central processing unit (CPU) using any suitable controller or an algorithm device, such as a general purpose controller.
[0021] Controller 102 may be configured to provide processing or computing resources to computing device 10 . For example, controller 102 may be responsible for executing control module 110 described herein to cause movement of machine 30 . Controller 102 may also be responsible for executing other control modules or other modules such as application programs.
[0022] Computing device 10 may comprise memory 104 coupled to the controller 102 . In various embodiments, memory 104 may be configured to store one or more modules to be executed by the controller 102 .
[0023] Although memory 104 is shown in FIG. 1 as being separate from the controller 102 for purposes of illustration, in various embodiments some portion or the entire memory 104 may be included on the same integrated circuit as the controller 102 . Alternatively, some portion or the entire memory 104 may be disposed on an integrated circuit or other medium (e.g., hard disk drive) external to the integrated circuit of controller 102 .
[0024] Computing device 10 may comprise an input/output (I/O) interface 106 coupled to the controller 102 . The I/O interface 106 may comprise one or more I/O devices such as a serial connection port, an infrared port, integrated Bluetooth® wireless capability, and/or integrated 802.11x (WiFi) wireless capability, to enable wired (e.g., USB cable) and/or wireless connection between computing device 10 and sensors 50 or between computing device 10 and machine 30 . In the exemplary embodiment, the I/O interface 106 may additionally comprise a PhidgetAnalog 4-Output (Phidgets Inc., Alberta, Canada). I/O interface 106 takes digital information from controller 102 and outputs it in the form of analog voltage signals. Output from I/O interface 106 may be used to control machine 30 .
[0025] The system described herein may further comprise a wearable item that assists the user in controlling the machine 30 . In one embodiment, wearable item may take the form of a vest 60 shown at FIG. 2 . Vest 60 has an opening at the top for the user to slip his or her head through. Velcro strips 602 are attached to vest 60 and may run down the length of each shoulder of the user. Velcro strips 602 are used to couple user sensors 52 to the user. In the embodiment shown at FIG. 2 , vest 60 further comprises Velcro tabs 604 that mesh to securely fit vest 60 around the user, which limits the movements of user sensors 52 due to a poor fit of vest 60 on the user. In this embodiment, the lack of belt buckles or other protruding connectors or items allows the user to rest on the vest 60 for extended periods of time without experiencing discomfort or developing pressure sores.
[0026] In embodiments of the system described herein, control commands 25 used for moving machine 30 are defined by body movements of the user 40 . In one embodiment, user sensors 52 comprise inertial measurement units (IMUs) (sold under the name XTi, from Xsens (Culver City, Calif.)) placed in front and behind each shoulder of user 40 as shown in FIG. 3 . Alternately, a user sensor 52 could be placed adjacent to the upper arm of user 40 . User sensors 52 measure orientation using, for example, tri-axis accelerometers and gyroscopes. In one embodiment, user sensors 52 are used to measure changes in shoulder motion. When user 40 moves his or her shoulders, user sensors 52 move in a corresponding fashion. In one embodiment, each user sensor 52 measures the roll and pitch associated with movement of user 40 's shoulders. Each user sensor 52 may be placed in any orientation except a vertical orientation, to avoid singularity of Euler representation of the orientation of the user sensor 52 . The placement of each user sensor 52 may be adjusted initially by a clinician to optimally measure the roll or pitch or any other representation of the orientation.
[0027] User 40 may be tetraplegic or have a similar condition that prevents him or her from using a standard I/O interface 106 such as a joystick to control machine 30 . In one embodiment, I/O interface 106 is used to convert information from user sensors 52 into control commands 25 sent to computing device 10 causing machine 30 to move, such that a joystick is not needed. FIG. 4 shows a simplified diagram of one embodiment of I/O interface 106 . I/O interface 106 may communicate with computing device 10 via USB, and be wired to an 8-pin header 108 to interface with machine 30 . The description of each of the eight pins in header 108 is provided in the table accompanying FIG. 4 .
[0028] Control module 110 may comprise a set of instructions that may be executed on controller 102 to cause machine 30 to move. In one embodiment, control module 110 makes use of the greatest ranges of motion available to user 40 . For instance, in case of arm paralysis due to a stroke, user 40 is unable to make a particular motion, control module 110 will not use that motion to control machine 30 . In one embodiment, the control module 110 utilizes a control space with eight dimensions, with each dimension representing either roll or pitch changes, from four user sensors 52 , due to user 40 movements over time.
[0029] FIG. 5 is a flowchart reflecting the training steps that may be taken by control module 110 in training phase 500 . The steps identified in FIG. 5 may reflect, for instance, the steps control module 110 takes to train itself to allow a user 40 to control the machine 30 .
[0030] The steps in FIG. 5 reflect a training phase that is used to decrease the dimensionality of the control space. In 502 , user 40 dons the vest 60 having user sensors 52 . In 504 , the computing device 10 is turned on and set to record training information by opening the software application and pressing a record button. In 506 , user 40 performs a sequence of random shoulder motions, known herein as a “training dance.” User 40 is instructed to move their shoulders and/or upper arms in as many varied positions as possible. In 508 , as user 40 performs the training dance, control module 110 records roll and pitch values from the user sensors 52 and reference sensors 54 . User 40 may repeat the training dance as needed to tailor control module 110 to the range of motions available to user 40 .
[0031] In 510 , when the user has completed the training dance, control module 110 prepares a weighing matrix WM that weighs the values of the instantaneous position information (discussed in more detail below). In one embodiment, WM is prepared with a statistical technique known in the art as Principal Component Analysis (PCA), using the information collected during training phase 500 from user sensors 52 . This transformation is defined in such a way that the first principal component accounts for as much of the variability in the information received from each measure (such as roll or pitch) from each user sensor 52 , and each succeeding component in turn has the highest variance possible under the constraint that it be orthogonal to (i.e., uncorrelated with) the preceding principal components. Control module 110 performs orthogonal transformation to convert the set of information collected from user sensors 52 during the training phase 500 into weighing matrix WM. In one embodiment, WM consists of a 2×8 matrix, where each 1×8 vector in WM represents one of two principal components: a first component to control the translational movement of machine 30 and a second component to control the rotational movement of machine 30 . Table A reflects possible WM values for one user 40 of the system. It should be understood that other users 40 will have different ranges of movement, and so their WM values would likely differ from those set forth in Table A.
[0000]
TABLE A
42.8475
1.4445
37.0614
55.5421
−48.6089
53.9579
−6.1819
−88.4512
−56.1509
1.5782
54.3959
−58.7452
40.0270
66.6236
−51.6489
−11.0950
[0032] In other embodiments, WM may be more generally represented as an m×n matrix, where m is the number of desired principal components and n is the number of inputs from user sensors 52 . In other embodiments, WM may be more generally represented as an m×n matrix, where m is number of control signals 25 sent to machine 30 and n is the number of inputs from user sensors 52 . In other embodiments, additional principal components could be used to control machine 30 in supplementary modes, for example, to have machine 30 take a different action (such as a mouse click). In one embodiment, WM may be altered to encourage user 40 to make movements that may have some rehabilitative benefits. For example, if user 40 has a motor disorder that impairs one side of the body more than the other, the specific components of WM can be altered so as to encourage the user 40 to use the weaker side of their body more when controlling machine 30 . This embodiment serves the dual purposes of controlling machine 30 while also providing some rehabilitative benefits for user 40 .
[0033] FIG. 6 is a flowchart that reflects the operation steps in operation phase 600 taken by control module 110 when the user 40 is controlling machine 30 .
[0034] In 602 , control device 10 is turned on and control module 110 is executed. In one embodiment, control module 110 is executed through Matlab. In 604 , user sensors 52 send information regarding roll and pitch measures (or other appropriate measures) to control device 10 for receipt by control module 110 . Also in 604 , reference sensors 54 also send information regarding roll and pitch measures (or other appropriate measures) to control device 10 for receipt by control module 110 . In 606 , control module 110 prepares an unadjusted instantaneous position matrix uIM. In one embodiment, uIM is an 8×1 vector including roll values and pitch values from each of the four user sensors 52 . In other embodiments, uIM may be more generally represented as an m×1 matrix, where m is the number of measures received from user sensors 52 . In 608 , control module 110 prepares a machine position matrix mIM from the values of measures sent by reference sensors 54 . In 610 , having mIM and uIM, control module 110 prepares an instantaneous position matrix IM, which is the user 40 movements, represented in the inertial frame of the machine 30 . In 612 , control module 110 determines position matrix PM by multiplying WM by IM. In one embodiment, PM is a 2×1 matrix.
[0035] Control module 110 uses PM to determine the appropriate control commands 25 to move machine 30 . PM is multiplied by a scalar value to normalize it against the appropriate commands to send to machine 30 .
[0036] In one embodiment, computing device 10 is coupled to a visual display, such as monitor 90 . In one embodiment, monitor 90 is a 7-inch computer monitor mounted to machine 30 . An embodiment of monitor 90 is shown at FIG. 3 . Monitor 90 provides visual feedback to user 40 to indicate how control module 110 is translating the movement of user 40 into movement of machine 30 . Monitor 90 may display a cursor 95 that reflects the current state of control commands 25 . In one embodiment, the position of cursor 95 along the x-coordinate represents the magnitude of the rotational command 25 a being sent to machine 30 , and the position of cursor 95 along the y-coordinate represents the magnitude of the translational command 25 b being sent to machine 30 . To reinforce the learning of the control of the cursor 95 , user 40 has the ability to disconnect the computing device 10 from the machine 30 and play video games using the monitor 90 . In another embodiment, computing device 10 is coupled to a tactile display, such as an array of vibrating actuators 92 . The vibrating actuators 92 give tactile feedback of how the movements of user 40 are translated to the movement of machine 30 by control module 110 . The vibrating actuators 92 may translate either the state of the control commands 25 or the speed and direction of machine 30 through changing amplitudes or frequencies of vibrational stimulation. The vibrating actuators 92 may provide feedback to user 40 that requires less attention than a visual display such as monitor 90 .
[0037] Machine 30 may be operated using control commands 25 . In one embodiment, control commands 25 comprise rotational command 25 a and translational command 25 b . In one embodiment using control module 110 , user 40 can manipulate the orientation of his or her shoulders to adjust rotational command 25 a and translational command 25 b independently. FIG. 7 shows one embodiment of the setup of machine 30 and control module 110 . Information from inertial sensors 50 (comprising user sensor 52 and reference sensors 54 ) are sent to computing device 10 (comprising control module 110 ), which are used to control machine 30 (in this embodiment, a power wheelchair). Computing device 10 further provides visual feedback to monitor 90 .
[0038] In one embodiment, the neutral position of control module 110 represents the position that causes the machine 30 to remain stationary. The neutral position of control module 110 is taken to be the mean posture during the training dance 506 during training phase 500 . At this position, in the current embodiment, the rotational command 25 a and the translational command 25 b are held at 2.5 volts. In other embodiments, the control commands 25 are held at a voltage that for which the machine 30 remains stationary. Shoulder movements away from this mean posture, as measured by user sensors 52 , cause control module 110 to change PM. Changes to PM are translated to changes in the voltages sent by the I/O interface 106 to machine 30 . This causes machine 30 to move in a desired trajectory, defined by the movements of user 40 .
[0039] In another embodiment the neutral position of I/O interface 106 represents the position that causes machine 30 to remain stationary. The neutral position of I/O interface 106 is taken to be the mean posture during the training phase 70 , and is mapped to the center of the monitor 90 . At this position, rotational command 25 a and translational command 25 b are held at 2.5 volts. Shoulder movements away from the mean posture cause machine 30 to move in a direction defined by that movement. In one embodiment, movements that cause the control commands 25 to change from the neutral position cause machine 30 to move forward or turn left. Opposite movements cause machine 30 to move backwards or right. To remove the effect of small involuntary body movements, for example breathing, a dead zone was enforced that spanned roughly 15% of the maximum possible movement along each direction. In other words, for each control command 25 if command signal 25 was within 15% of the maximal movement from the resting posture, command signal 25 would be held at 2.5 volts causing machine 30 to remain stationary. Implementing a dead zone also allows the user 40 to execute translation-only or rotation-only movements. Therefore, the user has the possibility to stop more easily correct erroneous movements while the cursor is still located in the dead zone. The remaining portions of the movements were linearly mapped to the output voltages as can be seen in FIG. 8 .
[0040] Driving Control. In one embodiment, the control commands 25 used for moving machine 30 are defined by body movements. User sensors 52 that measure orientation using tri-axis accelerometers and gyroscopes are placed on the shoulders of user 40 . User sensors 52 are used to measure changes in shoulder motion, for example, changes in the roll and pitch of each of the user sensors 52 . In other embodiments, sensors may be other body parts. For instance, if a user 40 has substantial upper arm mobility, the sensors 52 may be places on the upper arm.
[0041] In one embodiment, machine 30 may be a motorized wheelchair known as the Quantum Q6 Edge (Pride Mobility Products, Exeter, Pa.). However, it should be understood that the use of this particular embodiment was chosen merely for convenience, and a broad range of other machines could be used in its place in accordance with the systems and methods described in our patent. The two control commands 25 needed to move machine 30 are analog voltages, which range from 1.1 to 3.9 volts shown in FIG. 8 . At 1.1 volts, machine 30 drives backwards at the maximum velocity or turns right with the maximum angular velocity (depending on whether the voltage is a translational command 25 b or rotational command 25 a . At 3.9 volts, machine 30 drives forward or turns left at the maximum speed. At 2.5 volts, machine 30 remains stationary. The magnitude of the voltage defines the speed with which machine 30 moves.
[0042] The charts and diagram shown in FIG. 8 reflect how translational and rotational command signals are mapped to visual feedback on monitor 90 . The top right shows monitor 90 where cursor 95 indicates the current state of the two control command signals 25 (reflected by the two plots). The dashed line shown in the diagram titled “Visual Feedback” in FIG. 8 shows a potential path of cursor 95 from the mean posture. The two plots show how the cursor 95 coordinates reflect both the rotational command 25 a (x-axis) and translational command 25 b (y-axis) control commands 25 .
[0043] In one embodiment, after processing by control module 110 , the control commands 25 were generated using I/O interface 106 . This small hardware device allows for output of four independent analog voltages that can range between −10 to 10 Volts. In one embodiment only the first three outputs were used. The first output (output 0) was set to be static at 2.45 Volts. This signal was reqired by machine 30 to ensure that the I/O interface 106 was functioning properly. Analog outputs 1 and 2 were set to rotational command 25 a and translational command 25 b respectively. Communication between I/O interface 106 and computing device 10 were accomplished using the MATLAB libraries provided by Phidget Inc. In one embodiment the pin-out of the analog device was wired to an 8 pin header shown in FIG. 4 . This allowed for easy installation into the armrest where the current joystick is housed in the
[0044] Quantum Q-Logic Controller. In another embodiment, the pin-out of the analog device was wired to a DB9 connector so it could easily interface with the enhanced display of the Quantum power wheelchair.
[0045] Wheelchair Movement Compensation. In one embodiment, machine 30 is able to measure changes in the roll and pitch of user 40 in a moving reference frame without the use of magnetometers, which do not allow the user to appropriately function when the user is in an elevator or in buildings with strong magnetic fields, or when sensors 50 are too close to the magnetic field created by the motors (not shown) of machine 30 .
[0046] For our applications magnetometers, which act as a compass and measure the magnetic field of the Earth, are unreliable in many environments. Specifically, any environment that exhibits a changing magnetic field or large moving metallic objects will render the signals from the magnetometer unreliable. For this reason, the magnetometers were turned off. Because the sensors 50 are unable to detect magnetic north, the sensors 50 instead define an x-axis that is the projection of the sensor's 50 x-axis into the plane perpendicular to the global z-axis (direction of gravity). For this reason, the reference frames for sensors 50 are not perfectly aligned. However, because the vertical axis can be easily found by measuring gravity using the accelerometers, the reference frames of sensors 50 all share the same z-axis with different x- and y-axes. An example of two reference frames for two different sensors 50 is shown in FIGS. 9 and 10 . In both sensors 50 , the z-axis points in the vertical direction while the x- and y-axes of the two reference frames are misaligned by an angle θ.
[0047] FIGS. 9 and 10 show an example rotation of reference frames. All sensors share a common z-axis which points in the opposite direction of gravity. The x- and y-axes of each sensor are the x- and y-axes in the sensor reference frame projected to the plane perpendicular to the common z-axis. The only rotational transformation between any two sensors is reflected by the angle θ. This misalignment means that if user sensors 52 are placed in different orientations on the body, any changes to the roll and pitch of machine 30 will be projected onto different reference frames and each sensor 50 will measure the change differently. For example, a change in the pitch of machine 30 (i.e. driving up a ramp) will likely be reflected as a change in both roll and pitch in sensors 50 , where the general components of roll and pitch will be different for each sensor 50 .
[0048] To account for this misalignment, control module 110 measures the angle θ. To find the θ between any two-sensor reference frames, control module 110 uses Equation (1), where the vectors {right arrow over (a)} and {right arrow over (b)} are vectors whose components are roll and pitch as measured by each of sensors 50 . In one embodiment, vector {right arrow over (a)} is from a user sensor 52 on the user 40 's front left shoulder and vector {right arrow over (b)} is from the reference sensor 54 . The reference sensor 54 could be on machine 30 , for example. (In this embodiment, for every sensor 50 there exists a vector containing the roll and pitch as measured by that sensor 50 .)
[0000]
i
.
θ
=
atan
[
a
⇀
×
b
⇀
a
⇀
·
b
⇀
]
(
1
)
[0049] Using θ, control module 110 constructs a rotation matrix R 12 using Equation (2) that may be used to rotate the angles as measured by a first sensor 50 a into the reference frame of a second sensor 50 b . Control module 110 then projects the measurements from a reference sensor 54 (which may be mounted to machine 30 and only measure angle changes that are a result of machine 30 motion) into the reference frame for each of the sensors 50 . The signals will now be in the same reference frame, so control module 110 subtracts the rotated signal of the reference sensor 54 from the measurements of the other sensors 50 to remove components of machine's 30 motions from sensors 50 .
[0000]
ii
.
R
=
[
cos
(
θ
)
-
sin
(
θ
)
sin
(
θ
)
cos
(
θ
)
]
(
2
)
[0050] Using the rotation matrix with respect to each user sensor 52 , control module 110 projects the measurements from the reference sensor 54 into the frame of each of the user sensors 52 . By subtracting the projected reference sensor 54 measurements from the measurements of the user sensor 52 , control module 110 eliminates the effects of movements from machine 30 alone. Although the systems and methods described in this patent can be used by tetraplegic users to control a motorized wheelchair, it should be understood that other uses are readily available.
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A method for controlling a powered wheelchair is disclosed. The method may comprise receiving first information from at least one user sensor coupled to a user of the wheelchair, said first information indicating the movement of the user; receiving second information from a reference sensor coupled to the wheelchair, said second information indicating the movement of the wheelchair; using the first information and the second information to prepare at least one instruction to move the wheelchair; and using the at least one instruction to move the wheelchair.
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GOVERNMENT INTEREST
The invention described herein may be manufactured, licensed, and used by or for the U.S. Government.
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention includes a chemical weapons (CW) agent decontaminating system comprising absorptive particles and a solution that will effectively degrade chemical warfare agents. The solution can be any decontamination solution that is compatible with the absorptive particles.
The decontamination system described in detail in this invention is an environmentally safe decontamination system for CW agents, such as nerve agents (G and V-type agents) and mustard agent (HD). The decontamination system can be applied to a surface which is contaminated by a CW agent.
2. Brief Description of the Related Art
Chemical weapons are a possible threat if used by terrorists or military organizations against civilian populations or military targets. In the event of such an attack, it will be necessary to have an environmentally safe chemical system to clean up the affected area by decontaminating CW agents into less hazardous chemicals.
Several types of toxic chemical compounds are known. These include mustard (HD) and nerve agents. Mustard agents or gases, also called blister agents, may be nitrogen or chlorinated sulfur compounds. The most common type of mustard agents are the chlorinated sulfur compounds. Long after mustard gas was discovered in 1822, it was used in World War I as a CW agent, causing approximately 400,000 casualties. The sulfur mustard gas is chemical known as bis-(chloroethyl)-sulphide. The nitrogen mustard gas is chemically known as tris(2-chloroethyl)-amine. Mustard gas is a colorless, oily liquid having a garlic or horse-radish odor. It is slightly soluble in water, complicating removal by washing. It primarily attacks humans through inhalation and dermal contact, having an Airborne Exposure Limit (AEL) of 0.003 mg/m 3 . Mustard gas is a vesicant and a alkylating agent which produces a cytotoxic reaction to the hematopoietic tissues. Symptoms usually take effect 4 to 24 hours after initial contact. The rate of detoxification of mustard gas is slow and repeated exposure yields a cumulative effect.
Nerve agents or gases were discovered in 1936, during research on more effective pesticides. Nerve agents inhibit a certain enzyme within the human body from destroying a substance called acetylcholine. This produces a nerve signal within the body forcing the muscles to contract. Nerve agents have an Airborne Exposure Limit (AEL) of 0.00001 mg/m 3 .
Currently, one of the primary chemical warfare agent decontaminating solutions is Decontamination Solution 2. Decontamination Solution 2, or DS2, is a chemical warfare decontaminating solution used by the United States Army. DS2 contains approximately 70% diethylenetriamine (DETA), 28% ethylene glycol monomethyl ether (EGME), and 2% NaOH by weight, and is used for decontaminating a variety of chemical warfare agents. However, DS2 is toxic, corrosive, flammable and hazardous to the environment. EGME is teratogenic, and the secondary amine structure in DETA possesses a possible health hazard from conversion to a potential N-nitrosoamine carcinogen. In addition, DS2 is extremely resistant to biodegradation, particularly with regard to the DETA component of the solution.
Another common chemical decontamination system is STB/HTB slurry. As with DS2 this chemical decontamination system is hazardous to the environment, very corrosive, and can destroy or damage most materials, including plastic and rubber materials, various metals, and delicate electronic equipment. Also, handling these decontamination solutions requires protective gear which results in a cumbersome operation. With STB, the clean up after the application has to be done either by mechanically removing the upper layer of the contaminated surface or by use of concentrated acids to dissolve this layer.
In the last two decades, efforts have been made to formulate new decontamination systems to replace these current decontamination means. To overcome the problems, liquid decontamination systems based on hydrogen peroxide solutions were developed that have the potential to be effective at decontaminating chemical warfare (CW) materials, as well as having a reduced environmental impact compared to previously available systems. The hydrogen peroxide based decontamination solution is described in U.S. Pat. No. 6,245,958, the entire disclosure of which is herein incorporated by reference. The hydrogen peroxide decontamination solution has a broad-spectrum reactivity toward CW agents, while achieving a significant reduction in the toxic, corrosive and environmentally harmful nature of the decontaminant. However, as a liquid the application of the hydrogen peroxide decontamination solution to a surface is problematic because it flows, does not form a surface barrier, and contact time with the contaminated surface is sometimes not sufficient to decontaminate the surface.
Sorbents can be used to absorb CW agent contamination. Examples of these sorbents are described in U.S. Pat. Nos. 5,689,038 and 6,852,903, the entire disclosure of which is herein incorporated by reference.
Usually, the absorption process is fast and the agent is held inside the sorbents, thus reducing its hazard by decreasing its vapor pressure. Use of these sorbents thus makes decontamination methods possible. For example, one method of decontaminating a surface that is believed to include a toxic agent involves coating the contaminated surface with a reactive sorbent, and to decontaminate the absorbed contaminant. The main disadvantage of this approach is that the contaminated sorbent particles have to be decontaminated. The sorbent materials have large surface areas, are very porous, and may be light enough to be airborne, with the result that the hazard can be spread instead of being confined.
Thus, there still exists a need for a decontamination system wherein the decontaminating agent is non-toxic, non-corrosive, non-flammable can be biodegraded or otherwise less hazardous to the environment then current decontamination systems.
SUMMARY OF THE INVENTION
It is therefore an object of the invention to provide a decontamination system and method of use that will effectively degrade chemical warfare agents.
It is a further object of the invention to provide a decontamination solution that is compatible with an absorptive particle which is environmentally safe, is non-corrosive, non-toxic, non-flammable and having a reduced environmental impact compared to previously available systems.
There is a further object of the invention to provide a method for decontaminating surfaces which have been contaminated by CW agents, especially nerve agents and mustard (HD).
It is a further object of the invention to apply a decontamination system to a surface which has been contaminated by a chemical warfare agent by providing a system comprised of sorbents having the ability to decontaminate the absorbed CW agent.
It is a still further object to the invention to provide a system of solid particles mixed with a solution capable of decontaminating the agents, so the solution is absorbed in the particles. The sorbent is dispersed as a suspension or slurry in the liquid, and applied to a contaminated surface.
The invention further includes a process of detoxifying chemical warfare agents by contacting a chemical warfare agent with a sufficient amount of a sorbent for a sufficient time and under conditions which are sufficient to produce a reaction product having less toxicity than the chemical warfare agent. These and other objects of the invention will be more fully understood by reference to the accompanying figures and detailed description of the preferred embodiments.
DETAILED DESCRIPTION OF THE DRAWINGS
FIG. 1 —NMR spectrum at 8 min. after mixing showing VX and EMPA Peaks, using a 4 min. run time (64 scans).
FIG. 2 —NMR at 44 min. after mixing showing predominant EMPA peak.
FIG. 3 —NMR spectrum at 15 min. after mixing showing major HD peaks.
FIG. 4 —NMR spectrum at 66 min. after mixing, showing predominant HD sulfoxide peaks.
FIG. 5 —Kinetic plot of the rate of reaction of HD in a 1:50 ratio of agent to (solid+liquid) decontamination system. The weight ratio of solid to decontamination solution in the decontamination system was 1:8 and 1:12 as plotted on the figure. A comparison was done to the rate for liquid decontaminant alone.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
In one embodiment the invention is directed to a decontamination system comprising absorptive solid material and a decontamination solution. The system comprises an absorptive solid material having a decontamination solution contained therein. More particularly, the system comprises a particulate sorbent having the ability to decontaminate the absorbed agent and is an ideal solution to the problem of decontaminating surfaces contaminated by CW agents.
The system can be most easily achieved by mixing the solid particles with a solution capable of decontaminating the agents, so that the solution is absorbed into the particles. The sorbent is dispersed as a suspension or slurry in the liquid. A commercially effective sorbent and a decontamination solution are chosen such that the liquid will be absorbed by the particles, will be compatible with them, and will not lose its decontamination activity toward the CW agents.
The method achieves the detoxification of chemical warfare agents by contacting a chemical warfare agent with a sufficient amount of a sorbent for a sufficient time and under conditions which are sufficient to produce a reaction product having less toxicity than the chemical warfare agent.
In a most preferred embodiment, once the decontamination system is formulated and applied, this combination should be effective as a physical barrier, in addition to its chemical reactivity. Being a physical barrier is a result of the large absorptive capacity and the physical existence of the particles which block the volatilization of the CW agents from the contaminated surface.
In a particularly preferred embodiment, the solid part of the decontamination system may be any absorbent solid material that is not incompatible with the decontamination solution chosen for use. The following solid material showed high performance, and is given as an example without limiting the potential solid materials that can be used in the invention.
Applicants have found that POLYTRAP® 6603 Adsorber, a lauryl methacrylate/glycol dimethacrylate crosspolymer (CAS# 61181-29-1, herein incorporated by reference) to be an appropriate solid for the specific composition of decontamination solution used in the following example.
This material is a very fine white powder, having particle sizes of less than 1 micron, with agglomerates of 20 to 80 microns. It absorbs up to 12 times its weight of the decontaminating liquid, and still remains highly absorbent when spiked with the chemical warfare material. It shows only slow reactivity with the decontamination solution.
The best results were obtained in the solid-liquid system using the solution composed of potassium carbonate and bicarbonate, hydrogen peroxide and alcohol. Baking soda and hydrogen peroxide, when dilute, possess non-irritating characteristics. When formulated with various human-compatible alcohols, e.g., ethanol (grain alcohol), isopropanol (rubbing alcohol) and polypropylene glycol (food additive), the composition remains non-irritating and non-toxic.
The following description is an example of the decontamination system that was developed utilizing the foregoing approach. It is to be expressly understood that such description is only exemplary and not limiting.
For example, it is possible to have various effective agent-to-decontamination ratios depending on the CW agent to be decontaminated. Examples of these are 1:30 for agent VX, 1:50 for agent HD, and 1:50 for agent GD. When the system includes molybdate, ratios about 1:10 for agent HD are efficient. An additional advantage appears when a color change indicates when the reagent on the particles has been consumed. However, such is not a requirement for the system to be effective in decontaminating CW agents.
VX REACTIONS
Chemical warfare agent VX with the decontamination system showed rapid conversion (less than 1 hour) to much less hazardous material, such as ethyl methylphosphonic acid (EMPA). Commonly observed and highly toxic VX breakdown product EA-2192(S-(2-diisopropylaminoethyl) methylphosphonothioic acid) was not detected. The fate of VX in the decontamination system is shown in FIGS. 1 and 2 with FIG. 1 showing a 4 min. run-time and FIG. 2 showing a 44 min. run-time after mixing with the decontamination system.
MUSTARD (HD) REACTIONS
Reaction of chemical warfare agent HD with the decontamination system (1:50 ratio) showed rapid conversion (8 min.) to a much less hazardous materials such as HD sulfoxide. At a ratio of 1:10, the reaction was complete in about 1 hour. Results from the NMR spectra are shown in FIGS. 3 and 4 with FIG. 3 showing the NMR spectrum at 15 min. and FIG. 4 showing the NMR spectrum at 66 min. after mixing.
FIG. 5 shows kinetic plots comparing the reaction of HD in a liquid solution and with the liquid/solid slurry with ratios of solid:liquid of 1:8 and 1:12, by weight. When molybdate was added, the reaction was too fast to measure. A comparison plot was done to show the rate for a purely liquid decontamination solution.
SOMAN GD REACTIONS
Reactions at 1:50 ratio of chemical warfare agent GD with the decontamination system showed rapid conversion (less than 8 min.) to much less hazardous materials, primarily pinacolyl methylphosphonic acid.
The following Table shows in summary, the CW agent is undetectable by the method (>90% destroyed) after the given times:
Ratio, agent to
CW Agent
decontamination
Time to >90%
VX
1:30
30 min.
GD
1:50
8 min.
HD
1:50
8 min.
1:10
1 hour
BEST MODE KNOWN TO THE INVENTORS
A decontamination solution was prepared by dissolving 5.8 mg of solid, K 2 MoO 4 , in 1.16 ml of the following solution: 1.5 ml of isopropanol, 1.18 ml of 50% H 2 O 2 solution, 0.5 ml of KHCO 3 /K 2 CO 3 solution, 0.2 ml Triton X100, 0.04 ml 5 N NaOH solution and 64.5 mg of solid K 2 CO 3 . KHCO 3 /K 2 CO 3 solution was made from 80.9 mg of K 2 CO 3 and 28.5 mg of KHCO 3 dissolved in 1 ml of distilled water.
0.836 g of the decontamination solution was added to 91.0 mg of the solid. The mixture-slurry was mechanically mixed for homogeneity. 20 μL of VX was added, spiked with a syringe into the mixture. The slurry was packed into a 4 mm glass NMR tube which was flame-sealed, then placed in a 5 mm glass NMR tube, which is also flame-sealed. This was done for operator safety reasons, since some pressure buildup was caused by the reaction of the hydrogen peroxide. When used as a method of decontaminating surfaces contaminated by CW agents the sorbent is dispersed as a slurry or suspension and then is contacted with the CW agent with a sufficient amount of sorbent for sufficient time and are under conditions of which are sufficient to produce a reaction product having less toxicity than the chemical warfare agent.
In a particularly preferred embodiment the system should be effective as a physical barrier, in addition to its chemical reactivity. Being a physical barrier is a result of the large absorption capacity and the physical existence of the particles which block the volatilization of the CW agents from the contaminated surface. The physical barrier may be applied as a layer of solid particles having the liquid decontamination absorbed therein or may be applied as a slurry or suspension.
Thus, we have described a more environmentally safe decontamination system and method than traditional methods based on chlorine bleach or concentrated caustic solutions. This decontamination system also simplifies procedures for storage, handling, and transportation of decontamination material, and also potentially avoiding the bulky protective clothing required to apply and remove previous decontamination materials. Furthermore, the decontamination system does not have the drawbacks of the STB system where clean up after the application has to be done either by mechanically removing the upper layer of the contaminated surface or by use of concentrated acid to dissolve the layer formed by use of the STB decontamination system.
The system according to the present invention can be applied as a solid, suspension or slurry like physical state having an advantage over liquid decontamination solutions and applications where providing a physical barrier over contaminated surfaces is desirable, or in locations where run-off of a liquid from a decontamination operation may present a hazard to people or the environment. As noted above, there is wide range of ratios of the chemical agents to the decontamination system which are still effective to decontaminate surfaces contaminated by CW agents.
It should be understood that the foregoing summary, detailed description, and examples of the invention are not intended to be limiting, but are only exemplary of the inventive features which are defined in the following claims.
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A chemical warfare (CW) agent decontamination system and method for decontaminated surfaces contaminated by CW agents. The system includes both solid particles and liquid solution in admixture such that the solid particles absorb the liquid decontamination material. The method of decontaminating surfaces contaminated with CW agents includes contacting the CW agent with a sufficient amount of a solid-particle sorbent for a sufficient time and under conditions which are sufficient to produce a reaction product having less toxicity than the CW agent. CW agents to be decontaminated include the nerve agents VX and G-type agents, and mustard agent HD. The system is non-toxic and has a reduced environmental impact as compared to the previously available decontamination systems and solutions.
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TECHNICAL FIELD
This invention relates to a helicopter and more particularly a rotor system that exhibits significantly low vibration in the airframe.
BACKGROUND ART
It is becoming increasingly important to minimize vibration in a helicopter. Stringent requirements exist if crew and passenger comfort are to be present. The life of structural components and electronic equipment is greater with minimized vibration provided by special mounting structures. In military aircraft, the presence of armaments and the necessity for accurate fire control make stabilization of the aircraft and minimization of aircraft vibration important.
Heretofore, at least one project was directed at reducing vibration by using modal shaping. Such effort was based on the goal of reducing vibration levels in forward flight by modifying the mass distribution and to a lesser extent the stiffness distribution of the blade by using a modal shaping parameter. In another project, vertical hub shears due to blade flap-wise bending were minimized using mathematical programming techniques. Both programs were said to be based upon simple linear models for blade vibration employing modal analysis and the principles of super-position. Some findings indicate that mere addition of mass to the tip of the blade produces beneficial changes in the modal shaping parameter. The concept of vibration reduction by adding tuning masses has been used in rotor design prior hereto. In a further effort, non-structural tuning masses added to the outboard segments of the blade determined in an automated manner by a structural optimization process.
From the foregoing, it is apparent that there is a demand for further reduction of vibration.
DISCLOSURE OF THE INVENTION
A four-bladed rotor of nodalized rotor construction is provided which minimizes both the 4/Rev vertical hub shear and the 4/Rev pitching and rolling hub moment acting on the airframe. With these oscillatory loads minimized, the airframe does not vibrate at 4/Rev and the ride quality of the aircraft on which the rotor is operative is excellent.
In a more specific aspect, vibratory 4/Rev shears and moments are attenuated by carefully tuning three vibration modes of the rotor which dominate the 4/Rev vibration. Using the proper distribution of stiffness and mass results in optimum tuning of these three modes and hence low vibration.
The three rotor modes and their contribution to cabin vibration are as follows:
1. The third collective beam-wise bending mode which contributes to the majority of the 4/Rev hub vertical shear.
2. The second cyclic beam-wise mode which dominates the 3/Rev blade root beam-wise moments and creates the majority of the 4/Rev hub moments on the airframe.
3. The second cyclic chord-wise bending mode, because of significant beam-chord coupling, produces 5/Rev blade root beam-wise moments which create additional 4/Rev moments on the airframe.
The vibration caused by the foregoing are minimized by:
(a) Employing a stiff, lightweight hub approximately four times as stiff as the blade at 50% radius but of approximately the same running weight as the blade.
(b) Providing a large concentration of mass from approximately 32% to 42% of hub-blade radius. The mass at this location preferably is approximately four times the running weight at 50% radius.
(c) Providing a reduction in mass in the outboard 30% of the hub-blade to approximately 80% of the weight at 50% radius.
(d) Providing an increased beam-wise and chord-wise stiffness for the entire blade.
Thus in accordance with the invention, a nodalized rotor system is provided for a four bladed helicopter. A hub is provided with equally spaced radial arms. A blade is coupled to each of the arms, each of the blades being characterized by:
1. A concentration of mass from about 32% to 42% of the hub-blade radius with the running weight about four times the running weight at 50% of the hub-blade radius.
2. A reduction in the mass of the outboard 30% of the blade to a running weight of about 80% of the running weight at 50% radius.
3. Beam-wise and chord-wise stiffnesses of the hub are approximately four times those at 50% of radius. The blade running weight at the hub is approximately the same as the running weight at 50% radius.
For a more complete understanding of the invention, and for further objects and advantages thereof, reference may now be had to the following description taken in conjunction with the accompanying drawings.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 is an isometric view of a four bladed rotary yoke in a partially exploded view.
FIGS. 2a, 2b are a top view of a blade.
FIG. 3 is a section view taken at lines 3--3 of FIG. 2a.
FIG. 4 is a sectional view taken at lines 4--4 of FIG. 2a; and
FIG. 5 is a sectional view taken along the lines 5--5 of FIG. 2b.
FIG. 6 is a graph showing preferred weight vs. blade radius distribution.
FIG. 7 is a graph showing a preferred beam-wise stiffness vs. blade radius.
FIG. 8 shows a preferred relation between chord-wise stiffness and blade radius.
DETAILED DESCRIPTION
The hub-blade system shown in FIGS. 1-5 is of construction which achieves minimum vibration. Briefly stated, a stiff, lightweight hub region serves to reduce the curvature of the third collective mode at the hub which results in reduction of the 4/Rev vertical shear. A large mass increase extending from 32% to 42% of the radius causes the second cyclic beam-wise mode to attenuate the 3/Rev hub moments and at the same time, reduce 4/Rev vertical shear from the third collective mode. The reduction in mass in the outboard 30% of the blade lowers the 3/Rev root moment. The increased chord-wise stiffness causes the second cyclic chord-wise mode frequency to be very near 5/Rev. This increases the 5/Rev response of this mode and amplifies the 5/Rev beam-wise moment which cancels the 5/Rev moment from the remaining modes. The increase in beam-wise stiffness raises the frequency of the third collective mode well above 4/Rev which reduces the 4/Rev response of the mode and lowers the 4/Rev hub shear. Since the nodalized rotor attenuates the 4/Rev hub vertical shear and the 4/Rev hub moments at the source, a smooth ride is achieved without relying on vibration isolation systems.
Figure 1
FIG. 1 illustrates a four-blade rotor yoke 10 mounted rigidly on the upper end of a mast 11 by means of a hub assembly including a pair of hub clamp plates. Only the upper hub clamp plate 12 is visible.
The hub assembly is characterized by a flat composite fiber-reinforced center yoke section which is secured between the lower face of the upper clamp plate 12 and the upper face of a bottom clamp plate. Four identical arms 20, 22, 24 and 26 extend from the center hub section 13.
Arm 20 comprises a flapping section 30 located immediately adjacent the center hub section 13. A feathering section 32 extends outboard from the flapping section 30 and terminates in a blade bolt attachment structure 34 which is integral with the feathering section 32. The attachment structure 34 has two tangentially-spaced bolt receiving holes 36 and 38.
The feathering section 32 is comprised of four ribs 40, 42, 44 and 46 made up of reinforcing fibers embodied in a solid matrix. The ribs are spaced apart inplane. Fibers in ribs 40 and 42 encircle a fixture defining the bolt hole 36. The fibers in ribs 44 and 46 are formed in a continuous loop that encircles a fixture defining the bolt hole 38 and pass through hub section 13 and then outward in arm 24 to and around a bolt fixture which, as shown, receives bolts 52 and 54.
The inboard end of blade 50 is shown anchored to arm 24 by bolts 52 and 54 to the attachment structure 56. A cuff 58 in the form of an elliptical composite tube is secured integrally with blade 50 by attachment structure 56 and bolts 52 and 54. The cuff 58 extends inwardly and is shown broken away. It would extend to about a midpoint along the length of the flapping section 60 in arm 24. Structure is then provided for resiliently anchoring the inboard end of cuff 58 to the flapping section 60 at about the center of section 60. More particularly, a hole 62 extends vertically through the center of section 60. A shear restraint structure 64 is provided to be mounted in the aperture 62. The shear restraint element includes vertical studs 66 and 68 forming part of a body having an elastomeric center body bonded inside a circular ring integral with studs 66 and 8. A span-wise stub shaft 70 is bonded in the center of the elastomeric center body. The stub shaft 70 has flattened ends which are thinner than the flapping section 30 at the location of hole 62. Shear restraint 64 is secured in hole 62 by a lower clamp plate 72 and an upper clamp plate 74. The upper stud 66 extends into the lower end of a lead-lag damper fixture 76. The lower stud 68 extends downward into a lead-lag damper fixture 78.
Referring now to arm 26, cuff 58 extends inboard from the attachment fixture 34. Cuff 58 is secured to attachment fixture 34 and to blade 50 by blade bolts. The cuff 58 is shown with the upper lead-lag damper 76 mounted in the inboard end of the cuff 58. A pitch horn 82 is secured to the inboard end of the cuff 58.
Thus, it will be understood that the four arms 20, 22, 24 and 26 are identical in construction, each of them being provided with blade bolt attachment fixtures on the outboard end, each of them being attached to the inboard end of a blade and each of them being provided with a cuff which encompasses the feathering section such as section 32 in each arm and extends to the flapping section such as sections 30 and 60 in each arm. Each cuff is connected through lead-lag dampers to a shear restraint member secured in an opening in the flapping section.
By such structure where the center mounting plate, the flapping elements, the feathering elements and the blade attachment structures are integrally formed in a unitary body utilizing fiber-reinforced composite materials, there can be provided a soft inplane bearingless rotor system with lower weight, greater reliability and lower maintenance than conventional soft inplane rotors which employ bearings. It will be seen that the hub assembly consists of a one-piece composite yoke, composite cuffs, elastomeric shear restraints, elastomeric lead-lag dampers and hub clamp plates.
In FIG. 1, the cuff 58 has been shown as a separate element secured to the blade and hub by the blade bolts such as bolts 52 and 54. It is to be understood that the cuff could be made an integral part of a blade. This may be particularly desirable where there is no requirement that the blade be foldable for stowage such as on marine vessels. Where there is no requirement for folding the blades, the blade and cuff made integral would be secured to the end of the yoke by fastening means other than the specific structure shown in FIG. 1. In such case, it is possible to provide a rotor system that is lighter in weight than where the blade bolt coupling arrangement as shown is used.
Where two blade bolts are spaced tangentially as in FIG. 1, blade folding is readily accomplished by removing one of the two pins and then pivoting the blade about the remaining pin as described in U.S. Pat. No. 4,252,504. Thus, the fastening structure has been shown with the understanding that modifications thereof may be employed.
Yoke arm 20 is characterized by an inboard flexural element 30 and outboard feathering element 32. Such flexural elements achieve flapping hinge offset from the center of mast 11. The feathering elements replace highly loaded bearings in which, in the prior art systems, opposed the centrifugal force in conventional soft inplane rotors. The feathering section 32 allows for tailoring flap-wise, inplane, axial and torsional stiffness substantially independently. In addition, the feathering section allows the use of filament-wound unidirectional belts which extend from the leading edge attachment bolt on one arm to and around the trailing edge attachment bolt on the opposite arm. To unify the unidirectional belts, pre-cut ±45° broad goods and unidirectional broad goods are incorporated radially to form web sections and provide the desired stiffness and strength in the yoke for fail-safe operation.
The term "broad goods" as that term is used herein refers to fabrics of fiberglass or graphite in which epoxy coated fibers either unidirectional or with ±45° orientation are utilized to be placed in a mold to cure the epoxy and unify the fibers and epoxy thus producing a composite structure.
Cuff 58 is inboard of blade 50. A metal pitch horn is attached at the inboard end of each cuff. Metal grip plates are bonded to the outboard end of the cuffs for attachment to the blade and yoke. Cuff 58 is elliptical in cross section and is built up with ±45° fabric and unidirectional broad goods to obtain the desired flap-wise, inplane and torsional stiffness. The elastomeric shear restraint is attached to the yoke near the outboard end of the flapping section with upper and lower elastomeric lead-lag dampers attached to the inboard end of the cuffs through the shear restraints. The shear restraints have radial elements for pitch change motion and spherical elements to allow for misalignment due to flapping and lead-lag motion. In order to work the lead-lag dampers and achieve the desired damping, the inplane stiffness of the yoke feathering section is lower than the inplane stiffness of the cuff.
Metal hub clamp plates attached to the central portion of the yoke provide for transmitting loads through the main rotor shaft 11.
The centrifugal load of the blade is transferred directly to the yoke at the blade-cuff-yoke attachment while the flap-wise and inplane loads are distributed between the cuff and yoke based substantially on their relative flap-wise and inplane stiffnesses. The cuffs react to the greatest portion of the flap-wise and inplane loads since it is the stiffest member both flap-wise and inplane. The blade torsion loads are transmitted to the control system through the cuff. Thus, the structure shown in FIG. 1 eliminates the highly loaded lead-lag and/or flapping bearings of conventional soft inplane rotors. It allows for extensive use of fiber and epoxy materials. Because of the presence of multiple independent belts, the blade mounting is rendered substantially fail-safe. It provides a lighter weight rotor due to the use of fiber and epoxy materials and the elimination of highly loaded bearings. It provides for an increase in reliability and decrease in maintenance. Unlike other bearingless rotors, it has elastomeric lead-lag dampers and does not solely rely on aeroelastic and structural damping to avoid ground resonance.
FIG. 2
Connector 110 has an elongated tongue 112 which is integrated into the materials making up the blade 50 for transmission of centrifugal forces on blade 50 to arm 24 and hub 12. Blade 50 is coupled to the end of arm 24 and extends to a blade tip which, by way of example, typically may be about 260 inches from the mast axis. The portion of the hub outboard of the thin flex section 30 is extremely stiff. Connector 110 is provided with a blade attachment fixture having holes 52 and 54 mating with like holes on the end of the arm 24. Blade 50 is constructed such that there is minimum beam deflection beyond the thin flapping section 30.
Blade 50 is a composite blade made up of materials including fiberglass broad goods, graphite and epoxy. A "D" section spar 102 is formed of fiberglass and epoxy and extends the length of blade 50. Honeycomb bodies shaped to define the trailing portion of the blade are secured to the rear of the spar 102. Skins 104 and 105 are made up of fiberglass fabric. The trailing edge of blade 50 includes layers of graphite along the entire length thereof to impart stiffness to blade 50. Spar 102 is made of graphite strands which extend span-wise of blade 50.
A heavy mass 114 extends along the inside of spar 102 from about 32% to 42% of the hub-blade. The 45° hatching in FIG. 2 extending from 32% to 42% points indicate the area actually occupied by the heavy mass 114. As best seen in FIG. 4, mass 114 is adhesively secured to the inside surface of the nose spar 102. Span-wise graphite fibers 107 extend to and beyond the 42% point where they taper off in the zone indicated by the dotted curve 118.
Unidirectional graphite fibers are also added at the blade location centered around the 76% of the hub-blade length.
As shown in FIG. 2, a recess is provided near the trailing edge of the blade for adding weights. Recess 120 has spaced apart cavities capable of receiving one, two or three cylindrical masses as may be necessary to fine tune the balance of blade 50. Similarly, near the tip, a recess 122 is provided for accommodating one or two weights. An end cap 124 is provided at the tip 101 of blade 50.
Referring to FIG. 6, performance characteristics exhibited by a conventional blade structure are illustrated by curve 200. The hub section is indicated as extending from the center of the mast to a point 20% of the radius.
Curve 202 illustrates the same parameters but for data obtained from tests on a system embodying the present invention.
FIG. 6 indicates substantially higher running weight in prior art system from the mast axis intersection 204 through the deep valley 206 and peak 208. Peak 208 is followed by a steep descent 210 followed by a gentler downward slope 212 with a slight increase 214 in the region of 65% to 85% of the hub-blade radius.
In contrast, a blade according to the present invention involves lighter weight in the hub section at the rotor axis 216, followed by a deeper trough leading to a relatively low peak 220 followed by a trough 222 centered at about 30% of the radius. This is followed by a high peak 224 followed by steep descent 226. The dotted curve of FIG. 6 indicates substantial increase in weight in the blade from about 32% to 42% of the hub-blade radius. The descent section 226 is followed by a gradual assymtotic further descent from 42% to the blade tip 228. Thus, FIG. 6 graphically portrays distinctive features of the present invention relative to conventional systems. The peak 224 results from the large mass from approximately 32% to 42% of hub-blade radius. This mass increase to achieve the performance shown in FIG. 6 requires approximately four times the blade running weight as measured at 50% of the radius.
Not only is the weight-radius distribution significant, but also beam-wise stiffness is important. FIG. 7 illustrates variations in beam-wise stiffness as a function of hub-blade radius. In FIG. 7, beam-wise stiffness of a prior art unit is shown by curve 230 whereas beam-wise stiffness of blades made in accordance with the present invention are represented by dotted curve 232. The two curves substantially coincide at the mast axis and both exhibit at deep trough occasioned by the presence of the flex sections 30 and 60. However, the abrupt rise 234 of the dotted curve 232 to a broad peak 236 represents a significant departure from conventional systems. Performance of prior art blades is indicated by the fairly narrow peak 238 which occurs at 20% of the radius.
Peak 238 is followed by a fairly steep descent 240 followed by a gentler slope 242 from about 30% to 90%. In contrast, curve 232 has a more gentle decline section 244 between 30% and 50% followed by a fairly gentle decline portion 246 at about 60% followed by a low peak 248 between 70% and 80%. Beam-wise stiffness is built into a blade to give it the characteristic shown by curve 232 by selection of characteristic of the broad goods employed. Utilization of predominately ±45° broad goods would lend less beam-wise stiffness to the blade section than if unidirectional glass fibers or graphite fibers were employed extending span-wise of the blade.
FIG. 8 illustrates variations in chord-wise stiffness as a function of radius. The variations in chord-wise stiffness is a function of radius for conventional blade is shown by curve 250. Chord-wise stiffness of a blade in accordance with the present invention is illustrated by curve 252. The relationship of curves 250 and 252 are much the same as relationship between curves 230 and 232. Peak 252 is broader and higher than curve 250. The peaks 250 and 252 being centered at about 20% of the radius with the present invention involving greater stiffness over a greater portion of the radius.
Having described the invention in connection with certain specific embodiments thereof, it is to be understood that further modifications may now suggest themselves to those skilled in the art, and it is intended to cover such modifications as fall within the scope of the appended claims.
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A nodalized rotor system is provided for a multi-bladed helicopter. Equally spaced radial arms each have an inboard flapping section to accommodate beam-wise blade flapping and an outboard flex section to accommodate pitch changes. A blade is coupled to the end of each arm with a cuff and pitch horn rigidly connected to the blade and pivotally connected to its arm in the region of the flapping section. The blade has a concentration of weight over the section of blade extending from about 32% to 42% of the hub-blade radius of running weight four times the running weight at 50% of the hub-blade radius. Said blade has a reduced mass at outboard 30% of the hub-blade radius, at a level of 80% of the running weight at 50% of the hub-blade radius.
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TECHNICAL FIELD
The present invention relates generally to a vibratory conveyor apparatus, and more particularly to a conveyor apparatus having an improved differential motion vibratory drive with eccentric weights of the drive mounted in a phase-optimized configuration for increasing the velocity of material conveyed by the apparatus.
BACKGROUND OF THE INVENTION
Vibratory conveyors are widely used for material handling, and typically include a generally elongated conveyor bed, and an associated vibratory drive. Operation of the vibratory drive induces vibratory motion in the conveyor bed, which motion in turn induces movement of articles along the bed. Vibratory drives for such devices typically include one or more pairs of counter-rotating shafts having eccentrically-mounted weights thereon for inducing the desired vibration of the conveyor bed.
One type of vibratory conveyor arrangement, sometimes referred to as a four shaft differential motion conveyor, includes a vibratory drive including first and second pairs of counter-rotating drive shafts, with one pair of drive shafts operated at twice the speed of the second pair. This type of vibratory drive arrangement has been found to induce substantially planar, slow forward and fast rearward motion, which is well suited for gentle handling of delicate materials, such as potato chips, flaked cereals, and the like. In this arrangement, the vibratory drive is configured such that the half-speed and full-speed drive shafts are synchronized, or operated in phase, such that the vibratory forces induced by the eccentrically mounted weights cyclically add in one direction, and cyclically subtract in the other direction. The drive is configured such that the addition of vibratory forces acts in the direction opposite to the material flow, causing a fast pull-back of the conveyor bed. In contrast, the vibratory forces subtract from one another in the direction of material flow, thereby causing the vibratory bed to slowly move forward in the direction of material feed.
The present invention contemplates an arrangement whereby eccentric weights of a differential motion vibratory drive are configured to provide out-of-phase inducement of vibratory motions, thereby substantially increasing the feed rate of material being conveyed, without any change in the rotating and balance of the shafts of the drive.
SUMMARY OF THE INVENTION
A vibratory conveyor apparatus, and vibratory conveyor drive, embodying the principles of the present invention includes first and second pairs of counter-rotating drive shafts upon which first and second eccentric weight sets are respectively mounted. In distinction from previously known vibratory drives, the eccentric weights of the present vibratory drive are arranged such that vibratory forces induced by the first set of weights are out-of-phase with the vibratory motion induced by the second eccentric weight set. The net effect of this phase optimized configuration of the eccentric weights is a substantial increase in the feed rate of the conveyor (on the order of fifty percent) for the same rotating imbalance on the drive shafts when compared to a conventional vibratory drive. Thus, the same material flow rate can be achieved as in a non-optimized system, thereby permitting reduction in drive connection strength, bearing and shaft sizes, etc., thus permitting the present arrangement to be more economically manufactured than previous constructions.
In accordance with the illustrated embodiment, a vibratory conveyor apparatus embodying the principles of the present invention includes an elongated conveyor bed, and a vibratory conveyor drive attached to the conveyor bed for inducing vibratory motion in the bed. The induced vibratory motion of the conveyor bed thereby effects conveyance of articles in a conveying direction along the length of the bed.
The vibratory drive comprises a frame, and first and second parallel pairs of counter-rotating drive shafts rotatably mounted on the frame. A drive arrangement, illustrated as including an electric motor and a system of drive belts, effects conjoint rotation of the first and second counter-rotating drive shafts, with the drive arrangement preferably configured to effect differential motion of the first and second pairs of shafts by rotation of the first pair of shafts at twice the rotational speed as the second pair of counter-rotating shafts.
The present vibratory drive further includes first and second eccentric weight sets respectively mounted on the first and second pairs of counter-rotating shafts. The first weight set includes at least one eccentric weight mounted on each of the first pair of drive shafts for rotation therewith, with the second weight set similarly including at least one eccentric weight mounted on each of the second pair of drive shafts for rotation therewith.
As noted, the first eccentric weight set is eccentrically mounted to induce first reciprocable vibratory forces which are out-of-phase with second reciprocable vibratory forces induced by the second eccentric weight set. It is preferred that the first and second sets of eccentric weights are mounted on the first and second pairs of drive shafts to induce reciprocable vibratory forces along a line substantially parallel to the conveying direction of the conveyor apparatus.
The first vibratory forces induced along this line are out-of-phase with the second vibratory forces in that the maximum values of the first vibratory forces along the line are non-synchronous with the maximum values of the second vibratory forces along the line. In a presently preferred arrangement, the first and second eccentric weight sets are mounted such that the maximum values of the first vibratory forces are induced along the line at 45 degrees of rotation of the first drive shafts after maximum and minimum values of the second vibratory forces are induced along the line. By this arrangement, substantially greater feed rates are achieved for materials being handled by the conveyor apparatus.
Other features and advantages of the present invention will become readily apparent from the following detailed description, the accompanying drawings, and the appended claims.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 is a perspective view of a vibratory conveyor apparatus embodying the principles of the present invention;
FIG. 2 is a perspective view of the vibratory drive of the conveyor apparatus shown in FIG. 1;
FIGS. 3 and 4 are respectively, top and side views of the vibratory drive shown in FIG. 2;
FIGS. 5A-D and 6A-D are diagrammatic views respectively illustrating the motion of eccentric weights of a previously known vibratory drive and of the vibratory drive of the present invention; and
FIGS. 7 and 8 are graphical representations illustrating the theoretical velocities of conveyor beds, and material conveyed thereon, of a previously known vibratory drive, and a vibratory drive embodying the present invention.
DETAILED DESCRIPTION
While the present invention is susceptible of embodiment in various forms, there is shown in the drawings and will hereinafter be described a presently preferred embodiment, with the understanding that the present disclosure is to be considered as an exemplification of the invention, and is not intended to limit the invention to the specific embodiment illustrated.
With reference first to FIG. 1, therein is illustrated a vibratory conveyor apparatus 10 embodying the principles of the present invention. The conveyor apparatus 10 includes a generally elongated conveyor bed 12 along which material to be conveyed is carried, generally in the direction indicated by the arrow C shown in FIG. 1. A vibratory drive 14, embodying the principles of the present invention, is attached to the conveyor bed 12 whereby operation of the vibratory drive induces vibratory motion in the conveyor bed along a line substantially parallel to the conveying direction of material moving along the conveyor bed.
The conveyor bed 12 and the vibratory drive 14 are mounted on a series of isolation supports 16 each including one or more isolation rocker legs 18 which suspend the conveyor bed and drive from isolation A-frames 20. The rocker legs 18 are typically connected with the A-frames, the conveyor bed 12, and the associated drive 14 with suitable bolts or other mechanical fasteners extending through rubber bushings press-fitted into opposite ends of the rocker legs 18. This arrangement allows the conveyor bed and drive to move smoothly forward and backward along a pendular arc. Thus, the isolation mounting arrangement effects mounting of the conveyor bed and vibratory drive for pendular arcuate movement.
With particular reference to FIG. 2, therein is illustrated the vibratory drive 14 of the conveyor apparatus 10. The vibratory drive 14 is sometimes referred to as a four shaft differential motion drive, in that it includes first and second pairs of counter-rotating drive shafts, wherein the first pair of drive shafts are driven at twice the rotational speed of the second pair of drive shafts.
The vibratory drive 14 includes a frame 22 with a first pair of counter-rotating drive shafts 24, and a second pair of counter-rotating drive shafts 26 rotatably mounted in the frame 22. The first and second pairs of shafts are parallel to each other, with the first shafts 24 mounted in vertically aligned relationship, and the second shafts 26 also mounted in vertically aligned relationship, and in laterally spaced relationship to the first shafts 24. Suitable bearings provide the desired rotatable mounting of the drive shafts 24 and 26.
A drive motor 28, preferably comprising an electric motor, operates through the primary drive belt 30 to effect driven rotation of the upper one of drive shafts 24 via a drive input sheave 32. An idler 34, which may be configured as a Lovejoy idler, maintains the desired tension in the drive belt 30.
Conjoint rotation of the drive shafts 24, 26 for counter-rotation is effected via a drive belt 36. The drive belt 36 is trained about a drive pulley 38 mounted on the upper one of first drive shafts 24, with the drive belt 36 in turn effecting driven rotation of the lower one of first drive shafts 24 via a pulley 40, and the desired counter-rotation of second drive shafts 26 by respective pulleys 42, 44. Suitable idlers 45 maintain the desired tension in the drive belt 36. By virtue of the differing diameters of pulleys 38, 40, and pulleys 42, 44, first drive shafts 24 are rotatably driven at twice the rotational speed of second drive shafts 26.
In order to induce vibratory motions in the conveyor bed 12, the vibratory drive 14 includes first and second eccentric weight sets respectively mounted on the first and second pairs of counter-rotating drive shafts. The first weight set includes at least one eccentric weight mounted on each of first drive shafts 24, with the illustrated embodiment including two first eccentric weights 46 mounted on the upper one of drive shafts 24, generally at the center thereof, and two first eccentric weights 48 mounted on the lower one of drive shafts 24, generally at respective opposite ends thereof. Similarly, the second eccentric weight set includes at least one weight mounted on each of the second drive shafts 26. In the illustrated embodiment, a pair of second eccentric weights 50 are mounted on the upper one of second drive shafts 26, generally at respective opposite ends thereof, with a pair of second eccentric weights 52 mounted on the lower one of second drive shafts 26, generally at the center thereof. While the specific weight of each of the first and second weights can be varied while keeping with the principles disclosed herein, in a presently preferred embodiment, the first weight set collectively weighs less than the second weight set. In the illustrated embodiment, each of the four second weights 50, 52 weighs approximately three times each of the four first weights 46, 48.
With reference now to FIGS. 5A-D and 6A-D, the optimized arrangement of the eccentric weights 46, 48, and 50, 52 is diagrammatically illustrated, in comparison to a typical four shaft differential motion vibratory drive (with arrows illustrating the direction of material conveyance on the associated conveyor bed 12). As illustrated in FIG. 5A-D, a conventional drive is configured such that the eccentric weights, designated W 1 and W 2 , of the first and second pairs of counter-rotating shafts (wherein the first shafts rotate at twice the speed of the second shafts) provide a generally additive effect, that is, the maximum values of the vibratory motions induced by the weights are in phase and synchronized with each other. Thus, when the maximum vibrational forces induced by second weights W 2 extend along a line perpendicular to a plane extending through the drive shafts, the vibratory forces induced by the first eccentric weights W 1 are also induced along the line. By virtue of the differential speeds at which the respective drive shafts are rotated, the maximum vibrational forces are added in one direction, and subtracted in an opposite direction.
Reference now to FIG. 6A-D shows the configuration of the eccentric weights of the present vibratory drive, which are mounted in an out-of-phase arrangement so that the maximum values of the vibratory forces of the first eccentric weight set are induced along a line (extending perpendicular to a plane through the first drive shafts) out-of-phase with the maximum values of the vibratory forces created along the line by the second weight set. Thus, as the first and second drive shafts are rotatably driven, maximum values of first vibratory forces are cyclically induced in opposite directions along the aforementioned line attendant to rotation of each of the first shafts, and maximum values of second reciprocable vibratory forces are induced in opposite directions along the line attendant to each rotation of the counter-rotating second drive shafts. The maximum values of the first vibratory forces are induced along the line out-of-phase with the maximum values of the second vibratory forces, with a presently preferred arrangement configured such that the first and second weight sets are mounted so that the maximum values of the first vibratory forces are induced along the line at 45 degrees of rotation of the first drive shafts after maximum and minimum values of the second vibratory forces are induced along the line.
FIGS. 7 and 8 graphically illustrate and compare the theoretical motion of the vibratory conveyor bed 12, and material carried thereon. FIG. 7 illustrates the motion of the bed, and conveyed material, as provided by a conventional four shaft differential motion vibratory drive, as diagrammatically shown in FIG. 5A-D. In contrast, FIG. 8 illustrates graphically the motion of the conveyor bed 12, and material conveyed thereon, as driven by the vibratory drive 14 embodying the principles of the present invention. As will be observed, substantially increased material feed rates are achieved by the vibratory drive configured in accordance with the present invention.
The above-described configuration of the first and second weight sets of the vibratory drive 14 are configured such that the first weight set, including weights 46, 48, induce first reciprocable vibratory forces along the line perpendicular to a plane extending through the first drive shafts 24, 24, with maximum values of the first vibratory forces being cyclically induced in opposite directions along the line attendant to each rotation of the counter-rotating first drive shafts. Similarly, the weights 50, 52 of the second weight set are mounted on the second pair of drive shafts 26, 26 to induce second reciprocable vibratory forces along the aforesaid line, with maximum values of the second vibratory forces being cyclically induced in opposite directions along the line attendant to each rotation of the counter-rotating second drive shafts 26, 26. Maximum values of the first vibratory forces are induced along the line out-of-phase with maximum values of the second vibratory forces to optimize the material handling characteristics of the associated conveyor bed 12. In the illustrated embodiment, the first and second eccentric weight sets are mounted so that maximum values of the first vibratory forces are induced along the aforesaid line at 45 degrees of rotation of the first drive shafts 24 after maximum and minimum values of the second vibratory forces are induced along the line. However, it will be appreciated that the eccentric weight sets can be positioned in an out-of-phase relationship other than at this specific angular orientation.
From the foregoing, it will be observed that numerous modifications and variations can be effected without departing from the true spirit and scope of the novel concept of the present invention. It is to be understood that no limitation with respect to the specific embodiment illustrated herein is intended or should be inferred. The disclosure is intended to cover, by the appended claims, all such modifications as fall within the scope of the claims.
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A vibratory conveyor apparatus includes a vibratory drive having first and second pairs of counter-rotating drive shafts, with first and second eccentric weight sets respectively mounted on the drive shafts. In distinction from previous constructions, the eccentric weights of the vibratory drive are mounted to induce maximum vibratory forces out-of-phase with each other, thereby effecting improved efficiency for material conveyance. The vibratory motion provided by the present conveying system has been found to be particularly suitable for handling of delicate or fragile materials.
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BACKGROUND OF THE INVENTION
[0001] 1. Field of the Invention
[0002] The present invention relates to a medical herb composition, more particularly, to a medical herb composition that can improve the cardiopulmonary function, strength, and the symptoms of breathing difficulties and stagnation of vital energy of a mammal.
[0003] 2. Description of Related Art
[0004] Since many people seek health and nature, the Chinese herb-medicine industry has vigorously developed. Furthermore, owing to toxicity and side effects of “western” medicine, and drug resistance resulting from long-term administration, people have started to develop doubts about chemical drugs and thus constructively seek natural pharmaceuticals and therapy.
[0005] Chinese Herb-Medicine Information published by the Committee on Chinese Medicine and Pharmacy, Department of Health, Executive Yuan indicates: Schisandra is the dried ripe fruit of Schisandra chinensis (Turcz.) Baill. and its closely related plants, and Schisandra can function as kidney tonic and lung astringent, improve work performance, build strength, and help to reduce fatigue; Ginseng is the dried root of Panax ginseng C. A. Meyer, and the function of ginseng is to reinforce the vital energy, to remedy collapse and restore the normal pulse, to generate body fluids, to benefit the lungs, and to calm the nerves; Saliva miltiorrhiza is the dried root of Saliva miltiorrhiza BUNGE, and its function is to activate blood circulation and to transform stasis; and Radix ophiopogonis is the dried root of Ophiopogon japonicus KER-GAWLER and its closely related plants. The function of radix ophiopogonis is to clear away heart-fire, to moisten the lungs, to boost the stomach, and to generate body fluids.
[0006] Conventionally, the composition of Schisandra, Ginseng, and Radix ophiopogonis is used for the treatment of cardiovascular diseases. For example:
[0007] a. Shock: its clinical efficiency for acute obstructive suppurative cholangitis erupt acute DIC severe shock has been proved.
[0008] b. Acute myocardial infarction: it can enhance cardiac output, reduce peripheral vascular resistance, and improve the filling of important tissues and organs.
[0009] c. Heart failure: the composition with the effect similar to Cedi-lanid can improve the left heart function.
[0010] d. Irregular heart rhythms: it can improve sick sinus syndrome, premature beat, ventricular tachycardia, and so on.
[0011] e. Essential hypotension: according to the clinical research, essential hypotension can be improved efficiently by combined administration of Jin Kui Shen Qi Wan and the composition.
[0012] So far, the medical herb composition of Schisandra, Ginseng, and Radix ophiopogonis has often been used for treatment of the above conditions. However, no research indicates the composition can be used for daily heathcare. In addition, the known function of Saliva miltiorrhiza is to activate blood circulation and to transform stasis. However, less research has been performed on whether Saliva miltiorrhiza can raise the vitality of a mammal, such as a human.
SUMMARY OF THE INVENTION
[0013] The present invention provides a medical herb composition of Schisandra, Ginseng, Radix ophiopogonis, and Saliva miltiorrhiza, and proves that the composition of the present invention exhibits the properties of improving the cardiopulmonary function of a mammalian patient without heart disease, raising the patient's strength and vitality. Also, the medical herb composition is capable of efficiently reducing the symptoms of breathing difficulties and stagnation of vital energy.
[0014] The medical herb composition of the present invention comprises Schisandra material, Ginseng material, Radix ophiopogonis material, and Saliva miltiorrhiza material.
[0015] The present invention further provides a medical herb composition, comprising Schisandra extract, Ginseng extract, Radix ophiopogonis extract, and Saliva miltiorrhiza extract.
[0016] The medical herb composition of the present invention can improve the cardiopulmonary function and vitality of a mammal, and reduce the symptoms of breathing difficulties and stagnation of vital energy.
[0017] The method for preparing the medical herb composition of the present invention can be any conventional preparation or extraction. Preferably, the method is concentration, water extraction, or alcohol extraction. More preferably, the method for preparing the medical herb composition of the present invention is a conventional method of preparation for Scientifically Concentrated Traditional Chinese Medicines.
[0018] The term “material” of the medical herb composition disclosed in the present invention refers to Chinese traditional herbs (including herbs of different plant basis but having the same efficacy, or common herbs used as substitutions), the extracts thereof, or the mixtures of the Chinese traditional herbs and the extracts thereof; the extracts can be water-based extracts or alcohol-based extracts.
[0019] Extracts in the medical herb composition of the present invention can be prepared by conventional methods of preparation for scientific herbs, preferably they are prepared by the method disclosed in the present invention. More preferably, the extracts are extracted by water, granulated by spray-drying, and then mixed proportionally with each other.
[0020] Preferably, the medical herb composition of the present invention further comprises a pharmaceutically acceptable carrier. For example, they can be used in orally administered medical herb compositions, the formulations including: capsules, tablets, emulsifiers, liquid suspensions, dispersants, and solvents. Taking tablets as an illustration, the commonly used carriers are galactose or cornstarch; lubricants and magnesium stearate are basic additives. When oral capsules are used, galactose and dried corn starch can act as effective diluting agents. Suitable sweetening agents, seasoning agents or pigments can be added if needed.
[0021] Preferably, the present invention can further comprise an excipient, which can be any kind known in the art, preferably corn starch.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT
[0022] By conventional methods of preparation for Scientifically Concentrated Traditional Chinese Medicines including extraction, separation, concentration, and drying (as disclosed in Sun-Tien Medical Journal 4 and 5, 2005), extract powders of each plant were obtained.
[0023] The medical herb composition A used for the following embodiments comprises 6˜10 grams of Saliva miltiorrhiza extract, 1˜5 grams of Schisandra extract, 5˜9 grams of Ginseng extract, and 5˜9 grams of Radix ophiopogonis extract/per 12 gram of powders.
[0024] The amount of administration depends on the weight of the mammal to be treated. For a dog and a cat, the amount of daily administration is 1˜1.5 g/per 5 Kg. For a human, the amount of daily administration is 1.5˜2 g/per 10 Kg. Since the metabolisms of a dog and a cat are faster than that of a human, the amount of administration for a dog and a cat is about two-fold larger than that for a human.
[0025] The present invention provides the composition A for an older dog or a dog with slight heart disease, and observes the improvement of panting, coughing, and physical activity.
Embodiment 1
[0026] The observed dog of the first embodiment was a male Shetland Sheepdog, 12 years old, intact, and of 8 Kg weight. Its clinical symptoms were poor heart function, slight panting, and heartbeat of 60 times per min.
[0027] After the administration of the composition A for 2 days, activity of the dog obviously improved. After 4 weeks of treatment, the symptom of panting disappeared, and the observed heartbeat rose to 72 times per min. In addition, its heart function of TR:98.6, AS:1.13 improved to TR:78.8, AS:0.88. According to the above results, the medical herb composition A of the present invention can efficiently improve the cardiopulmonary function and activity of an older dog.
Embodiment 2
[0028] The observed dog of the second embodiment was a female Maltese, 12 years old and intact. Its clinical symptoms were poor heart function, panting, weariness, poor vitality and being unwilling to walk during the previous two years. After the administration of the composition A for 5 days, the dog's symptoms of panting and poor vitality improved, and it started to often walk back and forth at home.
[0029] According to the above results, the medical herb composition A of the present invention can improve the cardiopulmonary function an older dog.
Embodiment 3
[0030] The observed dog of the third embodiment was a male Maltese, 12 years old and intact. Its clinical symptoms were poor heart function, panting, weariness, poor vitality and being unwilling to move (heart rate: 120-130 times per min). Ordinarily, the dog had digitalis, hypotensor drugs, and diuretic drugs continuously administered to efficiently control heart disease. However, its vitality and activity remained poor.
[0031] After the assistance of the composition A for two days (administration of digitalis, hypotensor drugs, and diuretic drugs once in the morning and the composition A once in the evening), the dog's symptoms of panting and poor vitality improved, and it started to often walk back and forth at home.
[0032] According to the above results, the medical herb composition A of the present invention can improve the cardiopulmonary function and raise the activity of an older dog.
Embodiment 4
[0033] The observed dog of the fourth embodiment was a female part Dalmatian, 13 years old and intact. Its clinical symptoms were panting, coughing, a slight heart murmur, though not being infected with dirofilariaimmitis, and heart enlargement which was observed by X-ray. It also once fainted. Ordinarily, the dog had enapril, diuretic drugs, and heart assist drugs continuously administered to efficiently control heart disease. However, its vitality and activity remained poor.
[0034] After the assistance of the composition A for one week (administration of enapril, diuretic drugs, and heart assist drugs once in the morning and the composition A once in the evening), the dog's symptoms of panting and appetite improved.
[0035] According to the above results, the medical herb composition of the present invention can obviously improve the symptoms caused by heart disease of an older dog.
[0036] The results of the administration of the composition A for a human are described in the following. An older person or a person with slight heart disease usually exhibits the symptoms of poor strength, breathing difficulties, stagnation of vital energy, and poor vitality. After the administration of the composition A, those symptoms of the observed human were all found to have improved.
Embodiment 5
[0037] The observed human of the fifth embodiment was a male of 170 cm height, 72 Kg weight, and without heart disease. His clinical symptoms were panting when stair climbing from the first to the third floor, breathing difficulties, and stagnation of vital energy.
[0038] After the administration of the composition A for 3 days, his cardiopulmonary function and the symptom of panting caused by stair climbing improved. During the continuous administration of the composition A, the symptoms of panting caused by stair climbing, breathing difficulties, and stagnation of vital energy all disappeared, and the weariness improved.
[0039] According to the above results, the medical herb composition A of the present invention can improve the cardiopulmonary function, strength, and the symptoms of breathing difficulties and stagnation of vital energy, and weariness.
Embodiment 6
[0040] The observed human of the sixth embodiment was a female, 45 years old, 160 cm height, 50 Kg weight, and without heart disease. Her clinical symptoms were panting when stair climbing from the first to the fourth floor (she could not climb stairs to reach the fourth floor without having to rest many times during stair climbing), breathing difficulties and stagnation of vital energy.
[0041] After the administration of the composition A for 3 days, the symptom of panting caused by stair climbing several floors improved and disappeared. During that stair climbing, she no longer needed to take a rest, and her cardiopulmonary function improved. During the continuous administration of the composition A, the symptoms of panting caused by stair climbing, breathing difficulties, stagnation of vital energy, and the weariness all improved.
[0042] According to the above results, the medical herb composition of the present invention can improve the cardiopulmonary function, strength, and the symptoms of breathing difficulties, stagnation of vital energy, and wearness.
Embodiment 7
[0043] The observed human of the present embodiment was a male, 53 years old, 165 cm height, 70 Kg weight, and without heart disease. His clinical symptom was panting when stair climbing from the first to the third floor.
[0044] After the administration of the composition A for 5 days, the symptom of panting caused by stair climbing floors improved. During the continuous administration of the composition A, the symptoms of panting caused by stair climbing, breathing difficulties, and stagnation of vital energy all improved and the weariness significantly decreased.
[0045] According to the above results, the medical herb composition A of the present invention can improve the cardiopulmonary function, and strength, and reduce weariness.
Embodiment 8
[0046] The observed human of the eighth embodiment was a female, 50 years old, 154 cm height, 47 Kg weight, and without heart disease. Her clinical symptoms were weariness, breathing difficulties, and stagnation of vital energy.
[0047] After the administration of the composition A for 5 days, her vitality improved. During the continuous administration of the composition A, the symptoms of breathing difficulties and stagnation of vital energy all disappeared, and the weariness improved.
[0048] According to the above results, the medical herb composition of the present invention can improve strength, reduce weariness, and eradicate the symptoms of breathing difficulties and stagnation of vital energy.
Embodiment 9
[0049] The observed human of the ninth embodiment was a female, 63 years old, 160 cm height, 55 Kg weight, and with low blood pressure. Her clinical symptoms were breathing difficulties, stagnation of vital energy, poor strength, and not being the capable of stair climbing from the first to the third floor without having to rest.
[0050] After the administration of the composition A for one day, the symptoms of breathing difficulties and stagnation of vital energy improved. After the administration of the composition A for 3 days, the symptoms of breathing difficulties and stagnation of vital energy all disappeared. Her strength improved, and she became able to climb stairs from the first to the third floor without having to rest. The weariness clearly had reduced. During the administration of a medicine for clods, her heart became unwell. However, when composition A was administered it was found that, the medicine for colds no longer caused her heart to be unwell. Thus, it is inferred that the composition A may present its efficiency.
[0051] According to the above results, the medical herb composition A of the present invention can improve the cardiopulmonary function and strength, reduce weariness, and the symptoms of breathing difficulties and stagnation of vital energy were eradicated.
Embodiment 10
[0052] The observed human of the tenth embodiment was a female, 88 years old, 161 cm height, 43 Kg weight, heart hypertrophy, and arrhythmia controlled by the administration of western medicine. Her clinical symptoms were poor strength, breathing difficulties, and stagnation of vital energy.
[0053] After the administration of the composition A for 7 days, the symptoms of breathing difficulties and stagnation of vital energy reduced, and her strength improved.
[0054] According to the above results, the medical herb composition A of the present invention can improve the cardiopulmonary function and strength, and the symptoms of breathing difficulties and stagnation of vital energy were eradicated.
Comparative Example 1
[0055] After the administration of the composition A for 2 months, the observed human of the embodiment 5 no longer received the composition A, and her symptoms which were the same as those before the administration of the composition A appeared again.
[0056] Alternatively, the observed human of the embodiment 5 received a composition B as a control group, comprising 5 grams of Schisandra extract, 10 grams of Ginseng extract, and 10 grams of Radix ophiopogonis extract/per 12 gram powders. After the administration of the composition B for 10 days, the cardiopulmonary function of the tested human improved. The symptom of panting when stair climbing improved by the administration of the composition B, but the efficiency of the composition B was less obvious than that of the composition A.
[0057] According to the results, the composition B can improve the cardiopulmonary function and strength, but the efficiency of the composition B is less obvious than that of the composition A. In addition, the composition B cannot obviously improve the symptoms of breathing difficulties and stagnation of vital energy.
Comparative Example 2
[0058] After the administration of the composition A for 2 months, the observed human of the embodiment 6 no longer received the composition A, and her symptoms which were the same as those before the administration of the composition A appeared again.
[0059] Similarly, the observed human of the embodiment 6 then received a composition B as a control group, comprising 5 grams of Schisandra extract, 10 grams of Ginseng extract, and 10 grams of Radix ophiopogonis extract/per 12 gram powders. After the administration of the composition B for 14 days, the cardiopulmonary function of the tested human improved. The symptom of panting when stair climbing improved by the administration of the composition B, but the efficiency of the composition B was less obvious than that of the composition A. In addition, the composition B couldn't obviously improve the symptoms of breathing difficulties and stagnation of vital energy.
[0060] According to the results of the embodiments and comparative examples, the medical herb composition A of the present invention can efficiently improve the cardiopulmonary function, strength, and vitality of a mammal that does not have heart disease.
[0061] The efficiency of the composition A comprising Saliva miltiorrhiza extract is better than that of the composition B non-comprising Saliva miltiorrhiza extract. The composition A can efficiently raise the cardiopulmonary function and strength of a person to improve the symptoms of breathing difficulties and stagnation of vital energy of a mammal.
[0062] Although the present invention has been explained in relation to its preferred embodiment, it is to be understood that many other possible modifications and variations can be made without departing from the spirit and scope of the invention as hereinafter claimed.
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A medical herb composition for the alleviation of cardiopulmonary ailments or the improvement of cardiopulmonary function in a mammal is disclosed. The medical herb composition comprises: Schisandra extract; Ginseng extract; Radix ophiopogonis extract; and Saliva miltiorrhiza extract. The medical herb composition comprising the extracts above is proved to be efficient in enhancing cardiopulmonary function of a mammalian patient without heart disease, enforcing energy and raising strength. The medical herb composition is also capable of reducing the symptoms of breathing difficulties and stagnation of vital energy.
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BACKGROUND OF THE INVENTION
The invention relates generally to aligning elements for applying radiation to a patient and more particularly to systems and methods for properly aligning a source of radiation with an applicator for intra-operative radiation therapy.
DESCRIPTION OF THE RELATED ART
Radiation-emitting devices are generally known and used, for instance, as radiation therapy devices for the treatment of patients. A radiation therapy device typically includes a gantry which can be swiveled about a horizontal axis of rotation in the course of a therapeutic session. A linear accelerator is located in the gantry for generating a high-energy radiation beam. The high-radiation beam can be electron radiation or photon (X-ray) radiation. During treatment, the radiation beam is trained on a treatment site of a patient lying in the isocenter of the gantry rotation. Typically, the patient is supported on a rotatable table. The combination of movements of the gantry and the table permits movement of the patient about mutually perpendicular X, Y and Z axes. These rotations are sometimes referred to by the terms "tilt," "roll" and "yaw," respectively.
Prior to the application of radiation, a treatment setup process is followed. This process includes setting beam parameters such as radiation energy, field size, exposure times, dose and distance. Moreover, the process includes aligning the gantry, a collimator and the patient. The radiation beam is directed at diseased material, but with a goal of minimizing any adverse effect upon adjacent healthy tissue.
For intra-operative treatments, the alignment process also includes aligning an applicator relative to the patient and the source of radiation. Intra-operative treatment typically includes forming an incision through which an electron beam is directed to a treatment site. The applicator is both mechanically and electrically isolated from the source, i.e. the gantry. Mechanical independence is desirable, since the mass of the gantry operates against the ability to manipulate the radiation beam to enter a relatively small operative incision without significant risk to the patient. The applicator is fixed relative to the patient, typically by attachment to the table. The applicator provides beam collimation close to the patient by establishing a radiation field-defining aperture. Thus, the mechanical isolation reliably limits exposure to the desired treatment site.
Electrical isolation is a factor, since any leakage currents from the gantry to the patient place the patient at risk. U.S. Pat. No. 4,638,814 to Spanswick, which is assigned to the assignee of the present invention, asserts that a patient cannot be subjected to ground leakage currents which exceed five micro amperes because blood and body fluids are good electrolytes and because any electrical devices that are in contact with the patient may be disturbed. Spanswick describes a method of aligning an electron applicator with an electron beam source. A number of laser units project beams of light toward a support ring of the electron applicator. The beams are arranged in a mutual orientation, such as four laser units arranged at 90° intervals. Each of the four laser units includes a beam splitter, so that eight beams are formed. The eight beams form four beam pairs, with the two beams of a pair overlapping at a predetermined point from the electron beam source. Consequently, when the support ring is along the plane through the points of intersection, the eight beams form only four areas of illumination. The electron applicator is attached to the operating table, so that the operating table is moved until there are only the four illuminated regions. In addition to aligning the electron applicator and the electron beam source, the use of the intersecting beams determines the spacing between the applicator and the source.
While the system described in Spanswick provided an improvement over the prior art, further improvements are available. Since the positioning of the electron applicator based upon overlapping beams is performed visually, the process is subject to human error. Moreover, the patent points out that the beams must be "exceedingly sharp" in order to achieve precise positioning. As a result, the accuracy of the method depends upon the selection of the sources of the light beams. Another concern relates to the ability to change the spacing between the electron applicator and the electron beam source. This spacing will partially determine the intensity of the electron beam at the treatment site of the patient. If the intersection of beams is to be used to determine the spacing between the electron applicator and the electron beam source, the light beam axes must be adjusted from session to session when the electron beam intensities vary among sessions. This increases the setup time for equipment which is in demand.
What is needed is a system and method for accurately and efficiently positioning a beam applicator without requiring the beam applicator to be connected to a source of the beam.
SUMMARY OF THE INVENTION
A system for applying radiation therapy includes a radiation source that emits a radiation beam into an applicator that is spaced apart from and mechanically independent of the radiation source. An array of targets is affixed to the applicator and at least one imaging device is affixed to the radiation source to form image data representative of the targets. The image data is processed to determine the positions of the targets. In one embodiment, the determination of the target positions is used to automatically adjust either the applicator positioning or the radiation source positioning until the target positions match predefined coordinates. Preferably, the target positioning is determined in three dimensions.
A method of applying the therapeutic radiation includes attaching the applicator so that it has an orientation that is substantially fixed relative to a patient. The applicator is imaged by the imaging devices that are affixed to the radiation source. Based upon the image data, the system determines whether a desired source-to-applicator alignment has been achieved. The relative positioning of the radiation source and the applicator is adjusted until the desired source-to-applicator alignment is achieved. A radiation beam is then directed into the applicator for applying localized radiation to a treatment site. In the preferred embodiment, the method is used for intra-operative radiation therapy.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 is a schematical view of a system for applying localized radiation for intra-operative radiation therapy in accordance with the prior art.
FIG. 2 is a schematical view of a system of applying localized radiation in accordance with the invention.
FIG. 3 is a top view of a radiation applicator having targets in accordance with the invention.
FIG. 4 is a process flow view of a method for utilizing the system of FIG. 2.
FIG. 5 is a front view of a display screen for the applicator of FIG. 3.
DETAILED DESCRIPTION
With reference to FIG. 1, a patient 10 is shown as resting on a table 12 under a gantry 14 of a radiation therapy machine. A radiation beam is directed from a collimator 16 of the gantry toward the patient. The radiation beam is generated by a linear accelerator within the gantry and is emitted from the collimator. The radiation beam may be electron radiation or photon radiation, i.e. X-ray radiation. The gantry is known in the art.
Typically, the collimator 16 determines the final beam geometry. The beam is directed at a treatment site, such as diseased brain tissue of the patient 10. The table 12 and the gantry 14 are maneuvered to provide the desired alignment of the patient 10 to the radiation beam, and the beam is then generated. However, there are circumstances in which it is undesirable to use the collimator 16 as the component for final direction of the radiation beam at the patient. For example, within an intra-operative treatment an incision is formed for passage of an electron beam to a treatment site. An electron beam tends to expand more quickly than an X-ray beam, so that there is greater concern that healthy tissue will be exposed. To reduce the risk, a radiation applicator 18 is utilized. The radiation applicator is spaced apart from the collimator 16 and may have an output end inserted into the incision of the patient 10. The radiation applicator is formed of a material that is opaque to the electron beam, but includes a passageway to the treatment site. The radiation applicator localizes the therapy to the desired treatment site.
Referring now to FIGS. 2 and 3, a radiation applicator 20 in accordance with the preferred embodiment of the invention is shown as including four targets 22, 24, 26 and 28. The targets may be recesses within the surface of the applicator, but preferably are separate members that are formed of a material that facilitates imaging of the targets. As will be explained more fully below, the targets are imaged in order to calculate the spacing and the alignment of the radiation applicator relative to a collimator 30 of the gantry 32 shown in FIG. 2.
While not critical, the targets 22, 24, 26 and 28 are preferably fabricated in the manner described in U.S. Pat. No. 5,446,548 to Gerig et al., which is assigned to the assignee of the present invention. The Gerig et al. patent describes a patient positioning and monitoring system that can be utilized in combination with the invention to be described below.
The targets 22, 24, 26 and 28 preferably include retroreflective material. The arrangement of the targets on the surface of the applicator 20 is not critical. The targets are imaged by a pair of cameras 34 and 36. The cameras may be charge coupled device (CCD) cameras, but other imaging devices may be utilized. The image signals from the cameras 34 and 36 are input to an image processing circuit 38. The image processing circuit cooperates with a position calculation circuit 40 to determine position data for the radiation applicator 20. The image and position processing may include a visual-based coordinate measurement (VCM) system to determine target positioning in three-dimensional space. In the preferred embodiment, the VCM system is a software package which can be integrated with commercially available solid-state cameras, image acquisition and processing boards, and computer hardware. The VCM system combines principles of stereo vision, photogrammetry and knowledge-based techniques to provide precise coordinate and dimension measurement of objects. The two cameras 34 and 36 and the three-dimensional image and position processing of circuits 38 and 40 are calibrated such that the frame of reference is coincident with the system, with an isocenter defined as 0,0,0. The coordinate system is defined such that the X axis lies on a horizontal plane perpendicular to a gantry axis 42 of rotation and passes through the system isocenter, the Y axis is parallel to the gantry axis of rotation and passes through the isocenter, and the Z axis is mutually perpendicular to the other two axes and defines patient height.
Light sources 44 and 46 may be used to enhance performance of the target imaging. In the preferred embodiment, the light sources provide infrared radiation, and each of the cameras 34 and 36 includes an infrared filter. The infrared radiation enables the system to more reliably distinguish light reflected from the targets 22-28, as opposed to background radiation that may be present in the therapy room under ambient light conditions. The light sources may be infrared lasers, with the infrared radiation being spread by lenses, not shown. The use of laser light sources provides the advantage that the spectral bandwidth of the radiation is narrow, providing a further reduction in background interference. Equipping the cameras 34 and 36 with infrared filters reduces the susceptibility of the cameras to background radiation.
The radiation applicator 20 of FIGS. 2 and 3 is shown as being attached to a displaceable table 48 by an L-shaped support device 50. The mechanism for suspending the radiation applicator is not critical. In fact, the applicator may be fixed to the patient, rather than to the table 48. For example, headgear may be fitted to the patient to attach the radiation applicator to the patient.
The radiation applicator 20 is shown as having a truncated cone-shaped beam outlet end 52. The configuration of the inlet and outlet ends of the applicator will depend upon the gantry 32 and the treatment plan of the patient. In the view of FIG. 3, the sloping interior surface 54 is shown as terminating in a circular outlet 56. However, other geometries are contemplated.
The determination of the positions of the targets 22-28 by the image and position processing circuitry 38 and 40 is input to a session manager 58. Based upon inputted data and/or stored data in memory 60, the session manager controls the variable components of the system. In the preferred embodiment, the session managing is completely automated. However, manual adjustments may be required. The session manager 58 may therefore include an operator console and input devices, such as a keyboard.
The session manager 58 compares the positions of the targets 22-28 to preselected coordinates. If the positions of the targets are different than the desired positions, either or both of the gantry 32 and the table 48 are manipulated to reposition the targets. The session manager is housed within a stationary portion 62 of the system that supports the rotatable portion of the gantry 32. The rotatable portion rotates about the gantry axis 42. The table 48 accommodates repositioning along the X axis and the Z axis. Preferably, the circuitry within the stationary portion 62 of the system utilizes a servo approach, so that periodic image captures via the cameras 34 and 36 are utilized to establish the desired target coordinates. Since the table 48 supports the patient, repositioning the radiation applicator 20 relative to the gantry 32 also repositions the patient. As a consequence, manipulation of the gantry 32 or the table 48 does not affect the position of the applicator 20 relative to the patient.
The operation of the system of FIG. 2 is described with reference to FIGS. 2-4. In step 64, the alignment of the applicator 20 to the patient is established. In one embodiment, the applicator-support device 50 is attached to the table 48. While not shown, the device 50 preferably includes an adjustment mechanism. For example, the device may include slide mechanisms that permit vertical and horizontal repositioning of the applicator 20. In another embodiment, the applicator 20 is supported directly by the patient.
The applicator is secured to provide the desired angular alignment relative to a treatment site of the patient. This reduces the risk that healthy tissue will be unnecessarily exposed to radiation. The alignment of the applicator also includes setting the distance between the treatment site and the beam outlet end 52 of the applicator 20.
At step 66, the cameras 34 and 36 of FIG. 2 acquire an image of the targets 22-28. Each camera detects the reflected radiation from the targets. As previously noted, the preferred embodiment includes infrared lasers 44 and 46 and infrared filters in order to reduce the effects of background radiation on the image processing at circuit 38.
At least two cameras 34 and 36 are employed in order to permit position calculation 68 in three dimensions. Stereo vision techniques of a video-based coordinate measurement system are executed within the position calculation circuit 40 to determine coordinates within a coordinate system defined such that the X axis lies in a horizontal plane perpendicular to the gantry axis 42, the Y axis is parallel to the gantry axis, and the Z axis is perpendicular to the other two axes and defines patient height. Each of the three axes of the coordinate system passes through the isocenter of the radiation system.
In step 70, a determination is made as to whether the calculated coordinates of the targets 22-28 match desired coordinates. The position data related to the desired coordinates may be stored in memory 60 of FIG. 2. The determination of whether a correlation exists preferably takes place in software. However, referring briefly to FIG. 5, the determination may be made by an operator using a display 72 that shows both the desired positions 74, 76, 78 and 80 of the targets and the actual positions 82, 84, 86 and 88. If the desired positions and the actual positions are aligned, the applicator 20 is properly aligned with the gantry 32. Consequently, the treatment site of the patient is properly aligned with the radiation beam that will be emitted from the gantry. In such case, the source of radiation can be activated, as shown at step 90 in FIG. 4. If at step 70 no correlation is determined between the coordinates calculated in step 68 and the desired target coordinates, the gantry-to applicator alignment is adjusted at step 92. The realignment may be executed in alternative manners. The stationary portion 62 of the gantry 32 may rotate the displaceable portion about gantry axis 42. Alternatively, the table may be manipulated to correct for tilt and roll. The collimator 30 of the gantry 32 is also adjustable, as is well known in the art. Of course, the gantry-to-applicator alignment may be a combination of these adjustments.
Following the realignment at step 92, the process returns to step 66 in order to acquire an updated image for calculation of updated position data in step 68. Preferably, the steps 66, 68, 70 and 92 utilize servo techniques to automatically and efficiently obtain the desired gantry-to-applicator alignment. When the alignment is achieved, the radiation therapy is initiated at step 90. The arrangement of targets 22-28 is not critical. Preferably, there are three or four targets, but performance may be enhanced in some applications by providing a different number. As previously noted, the targets may be merely recessed or raised areas of the applicator servo, but retroreflective targets enhance the image processing by reducing the effect of background radiation. Fluorescent and phosphorescent materials may also be utilized with the appropriate camera filters to enhance selectivity of reception.
In another embodiment, the targets 22-28 are fixed within the sloping interior surface 54 of the applicator 20 of FIG. 3. This allows the targets to be at different distances from the collimator 30 of FIG. 2, even when the applicator is in the desired position relative to the collimator. The variations in distance facilitate distinguishing actual positions of targets from desired target positions.
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A system and method for applying radiation therapy include utilizing a radiation applicator that is spaced apart from and mechanically independent of a radiation source. An array of targets is affixed to the radiation applicator and cameras image the targets to determine coordinates that are compared to desired target coordinates. If there is a correlation between actual target coordinates and desired coordinates, radiation source-to-applicator alignment is achieved. Consequently, the patient is properly positioned relative to a radiation beam, such as an electron beam. On the other hand, if the actual and desired coordinates are different, the relative position of the radiation source and the gantry is adjusted. Preferably, the adjustment is automated.
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BACKGROUND OF THE INVENTION
This invention relates to closed circuit personal escape breathing apparatus.
In the event of a fire, a factory accident, a coal mine accident or an oxygen deficiency accident, an antitoxic mask is not effective for protecting the user. To provide a personal breathing apparatus effective under such circumstance, various types of breathing apparatus comprising a self-contained oxygen source have been proposed. Most of them utilize an oxygen bottle or a compressed air bottle as an oxygen source. Although oxygen bottles are more often used because they supply high-purity oxygen gas quite handily and compactly, they must be handled and stored with special care. Also, both oxygen and compressed air bottles are heavy, resulting in a heavy and unnecessarily sturdy overall structure for a self-rescue escape breathing apparatus.
On the other hand, it is also known to use a chemical oxygen generator as a source of oxygen for a personal escape breathing apparatus. Although a chemical oxygen generator is light in weight and easy to store compared to oxygen or compressed air bottles, the overall structure of the breathing apparatus including a carbon dioxide canister, breathing bags, a hood, a mouthpiece, etc., is still heavy and bulky. Most such personal breathing apparatus also require special training for safe use.
SUMMARY OF THE INVENTION
Accordingly, an object of the present invention is to provide a safe, light weight and compact personal escape breathing apparatus having a chemical oxygen generator.
Another object of the present invention is to provide a breathing apparatus capable of effectively cooling the high temperature breathing gas to a breathable temperature.
Another object of the present invention is to provide a breathing apparatus comfortably and easily wearable by the user which enables the user to move quickly.
Still another object of the invention is to provide a breathing apparatus having a hood for protecting the user.
A further object of the invention is to provide a breathing apparatus storable in a small package.
A still further object of the invention is to provide a breathing apparatus simple in structure, low in manufacturing cost, and easily used by an untrained person.
With the above objects in view, the personal escape breathing apparatus of the present invention comprises an elongated, flexible, gas-impermeable exhalation bag for receiving exhaled gas from the user. One side of the exhalation bag is directly connected to one of two relatively large opposing open ends of a cylindrical carbon dioxide absorption canister so that it extends substantially perpendicular to the length of the exhalation bag. A chemical oxygen generator is connected to the exhalation bag for supplying oxygen into the exhalation bag. The oxygen generator is thermally insulated and supported from the canister parallel thereto. The cylindrical canister is directly connected at its other large open end to a flexible, gas-impermeable inhalation bag. The inhalation bag is larger in volume than the exhalation bag and, in cooperation with the exhalation bag, supports the canister between the two bags. Part of the side walls of the bags is a common partition wall dividing the two bags. Support means made of a flexible, gas-impermeable sheet material and having a hole through which the user's head can be passed is provided. The support means is integrally attached at its large area portion to the back of the two breathing bags to form integral back walls of them, and its portion with the hole extends from the bags to provide a collar placed around the user's neck. The personal breathing apparatus also comprises a transparent, flexible and gas-impermeable hood for defining a substantially closed space around the user's head. Into the space within the hood extends a mouthpiece connected to the exhalation and the inhalation bags, providing an interface between the user and the apparatus. The hood is provided therein with nose blocking means comprising a frame supported on the inner surface of the hood so that the frame is positioned in front of the user's nostrils, and a soft, flexible and gas-impermeable film such as rubber stretched over the frame to contact the user's nostrils and extend over an area effective for covering the user's nostrils.
BRIEF DESCRIPTION OF THE DRAWING
The present invention will become more readily apparent from the following description of the preferred embodiment of the present invention taken in conjunction with the accompanying drawing, in which:
FIG. 1 is a perspective view of a breathing apparatus constructed in accordance with the present invention in its used position; and
FIG. 2 is a schematic view showing the general arrangement of the breathing apparatus.
DESCRIPTION OF THE PREFERRED EMBODIMENT
Referring to FIGS. 1 and 2, a breathing apparatus 10 of the present invention comprises a mouthpiece 12 serving as an interface between the breathing apparatus 10 and the user 13. The mouthpiece 12 may be of any conventional type comprising a unidirectional switch valve 14 which is connected by a flexible hose 16 to an inlet 15 of an exhalation bag 18. Thus the exhaled gas from the user flows through the mouthpiece 12 and the hose 16 into the exhalation bag 18 wherein the exhaled gas is received and stored.
The exhalation bag 18 is made of a relatively thin, flexible and gas-impermeable material such as plastic film. Preferably, the exhalation bag is of incombustible plastic film such as polyvinyl chloride film, or more preferably, of a fire-resistant material such as poly tetrafluoroethylene. At the lower side of the exhalation bag 18, a relatively large opening is formed, and the opening communicates with an open end of cylindrical carbon dioxide absorption canister 20. The carbon dioxide absorption canister 20 may be any well known type containing a carbon dioxide absorbent and serves to absorb carbon dioxide contained in the exhaled gas stored in the exhalation bag 18. The other open end of the carbon dioxide absorption canister 20 is coupled to a large inhalation bag 22. Similar to the exhalation bag 18, the inhalation bag 22 is made of a relatively thin, flexible and gas-impermeable material such as plastic film preferably of polyvinyl chloride, or more preferably of poly tetrafluoroethylene.
The exhalation bag 18 also has at its lower end an oxygen inlet port 23 connected to a chemical oxygen generator 24. The typical chemical oxygen generator 24 which may be used in the present invention includes the so-called chlorate candle wherein oxygen is generated by pyrolysis of chlorate. This type of oxygen generator also generates small amounts of carbon dioxide, carbon monoxide, chlorine, etc., in addition to oxygen. Most of the commercially available chlorate candles contain therein an absorbent for these undesirable by-product gases. If the chlorate candle used has no absorbent for these gases or has an absorbent of only an insufficient capacity, a by-product gas absorbent may be inserted within the carbon dioxide absorbing canister 20. An oxygen generator which can generate oxygen at a rate of about 2 to 4 liters per minute for about 10 to 60 minutes is suitable.
The oxygen generator 24 generates oxygen by chemical reaction and supplies it to the exhalation bag 18 through an oxygen supply pipe 26 connected to the inlet port 23. The outer casing of the oxygen generator 24 is made of a material having good heat dissipation characteristics such as a metal. The oxygen generator 24 is secured within, and surrounded by, a perforated metal or plastic stand-off cage, 25. This cage prevents user contact with the hot surface of oxygen generator 24 and is secured to the carbon dioxide absorbing canister 20 by any suitable securing means such as support straps 28 wound around the carbon dioxide absorbing canister 20 which is also made of a metal having good heat dissipation characteristics.
Thus, virtually pure oxygen generated from the oxygen generator 24 is supplied through the inlet port 23 into the exhalation bag 18, wherein the oxygen and the exhaled gas are mixed. The mixed gases in the exhalation bag 18 pass through the canister 20 wherein the carbon dioxide gas contained in the mixture is completely absorbed by the absorbent, thereby allowing only a mixture of pure oxygen and nontoxic gases to flow into the inhalation bag 22.
In order to prevent building up of a relatively high pressure in the exhalation bag 18, a relief valve 30 is disposed in the wall of the exhalation bag 18. The relief valve 30 is preferably mounted at a position as remote as possible from the oxygen supply pipe 26 or the inlet port 23 so as to reduce the chances for the high-purity oxygen to escape from the relief valve 30. The relief valve 30 may be set to open with an inner pressure of about 60 mm H 2 O.
The inhalation bag 22 is made of a relatively thin, flexible gas-impermeable material and has a larger volume than that of the exhalation bag 18. The general configuration of the inhalation bag 22 is such that it forms the general contour of the breathing bag system when it is coupled with the exhalation bag 18 as illustrated in the Figures. The outlet end of the canister 20 is coupled to a lower projecting portion of the inhalation bag 22, one side wall of the major portion of the inhalation bag 22 is arranged along the outer surface of the canister 24, and another side wall of the major portion of the bag 22 is directly attached to the corresponding wall of the exhalation bag 18. The wall between the two bags 18 and 22 may be a common single partition wall 32 defining two separate spaces as illustrated in the Figures. The upper portion of the inhalation bag 22 has an outlet 33, and the outlet 33 is communicated to the mouthpiece 12 through an exhalation hose 34.
In order to support the breathing apparatus 10 on the user's chest, a support collar 36 is provided. The support collar 36 is made of a flexible, gas-impermeable sheet material, preferably the same material as that for the exhalation and inhalation bags 18 and 22. The support collar 36 has a round collar portion with a hole through which the head of the user 13 can be passed so that the collar portion is placed on the user's shoulders and around the neck. The support collar 36 also has a large square portion hermetically sealed to the breathing bags 18 and 22 to form their back walls. In other words, two breathing bags 18 and 22 are sealed at their back open sides to the square portion of the support collar 36. Therefore, the breathing bags 18 and 22, the carbon dioxide absorbing canister 20, and the oxygen generator 24 and stand-off cage 25 are directly or indirectly supported from the support collar 36 formed integral with the breathing bags 18 and 22.
A set of pull-cords 38 is attached to the stand-off cage 25 to assist the user 13 to stably fit the breathing apparatus 10 on his chest.
When in use, the user 13 wears a nose block 40 to close his nostrils. The nose block 40 is made of hollow cylindrical or trough-shaped flexible thin film, such as a film of rubber, polyethylene, or polyurethane, supported by a suitable frame or a cylindrical polyurethane foam block. The nose block 40 has a rubber string 42 connected to the frame for supporting the block 40 at the user's nostrils to close them. The support string 42 is attached to the inner rear surface of a transparent plastic hood 44 so that the nose block 40 can be elastically put on to close the nostrils at the same time the user 13 puts the hood 44 on his head. Preferably, the hood is made of a fire resistant material. The hood 44 covers the user's head completely, and has a piece of string 46 for closing the hood 44 around the user's neck to substantially close the space through which the breathable gas can escape and a hostile environmental atmosphere can enter into the hood 44. The transparent hood 44 also has an opening (not shown) at a location corresponding to the user's mouth to which opening the mouthpiece 12 of the breathing apparatus 10 is secured to extend into the interior of the hood 44 and reaches the mouth of the user 13. Thus, the user 13 can safely respire the breathable gas supplied from the breathing apparatus 10 without any danger of inhaling hostile gases.
When the user uses the breathing apparatus of the present invention, he ignites the chemical oxygen generator 24 prior to putting on the transparent hood 44. When the exhalation bag 18 and the inhalation bag 22 are filled with oxygen generated from the oxygen generator 24, the user puts the support collar 36 around his neck, thereby supporting and wearing the breathing apparatus 10 on his chest. Of course, the breathing apparatus can be put on before the oxygen generator 24 is ignited. In order to stably fit the breathing apparatus on the user's chest, the cord 38 is wound around his waist.
When the generation of oxygen is confirmed, the user 13 puts on the transparent hood 44, the mouthpiece 12 and the nose block 40, and then pulls the string 46 to close the hood 44 around his neck as seen in FIG. 1. At this time, the user 13 can safely breathe the breathable gas.
Because of its chemical nature, the chemical oxygen generator 24 generates oxygen gas of as high as 140° C. at the outlet. Further, the reaction of exhaled CO.sub. 2 with absorbent in canister 20 substantially elevates gas temperature. However, with the breathing apparatus as has heretofore been described, the oxygen gas is cooled by heat exchange action with the atmosphere while the gas is flowing through the oxygen supply pipe 26, the exhalation bag 18 and the inhalation bag 22 which have large surface areas. Also, the casings of the oxygen generator 24 and the carbon dioxide canister 20 have good heat dissipating characteristics to cool themselves. Therefore, the mixture of the pure oxygen and air supplied to the user from the mouthpiece 12 will be at a temperature below 50° C. at the normal operating condition, thereby enabling safe respiration.
Even when the amount of oxygen generated from the chemical oxygen generator 24 varies, the flexible, large-volume exhalation bag 18 and the inhalation bag 22 function to absorb or dampen these variations, thereby always maintaining the inner pressure within the bags 18 and 22 at substantially atmospheric pressure, providing no difficulty in breathing by the user. In the event that an excess amount of oxygen is temporarily generated from the oxygen generator 24, or the inner pressure within the system increases because of the accumulated excess amount of oxygen when the oxygen consumption is less than the oxygen generation, the relief valve 30 opens to release the excess amount of gas from the exhalation bag 18 into the atmosphere.
The breathable gas supplied at the mouthpiece 12 is substantially free from carbon dioxide gas because the flow direction of the gas within the apparatus is unidirectional through the carbon dioxide absorption canister 20. Also the breathing resistance is very small because the inner pressure of the system is substantially at the atmospheric pressure and because the system has been sized to eliminate points of flow restriction. For example, the large open ends of canister 20 minimize flow restriction.
The breathing bag and canister systems of the present invention are advantageous in that they are very simple and compact in structure. Also, the apparatus is light in weight and easy to handle and is foldable for convenience in storing.
Since the breathing apparatus 10 is light in weight and flexible and the overall arrangement of the apparatus and the selection of the respective components has been carefully made, the user can very easily, quickly and safely put on the breathing apparatus without any special training and with minimum instructions.
The breathing apparatus of the present invention comprises a transparent, fire-resistant plastic hood 44 for completely covering the head of the user. Therefore the user is protected against toxic gases, smoke, sparks, dust or the like. When necessary, the user can talk to other people while wearing the hood simply by removing the mouthpiece from his mouth. The transparent hood 44 provides an excellent field of view and does not significantly interrupt sound, so that the user can protect himself from any dangerous situation.
The many above mentioned advantages of the emergency breathing apparatus of the present invention over the conventional breathing apparatus of similar type and its low manufacturing cost make the apparatus of the present invention the most suitable for storing in various places such as factories, mines, lower level shopping areas, etc.
In order to assure that the above mentioned effects be fully obtained, the exhalation bag 18 and the inhalation bag 22 shouild both be exposed to the atmosphere without being covered by any thermally nonconductive material such as cloth so as not to degrade the dissipation of heat from the oxygen generation and carbon dioxide absorption. Also, the exhalation bag 18 and the inhalation bag 22 are designed to have a large volume and a large surface area to enhance the heat dissipation. With the inhalation bag 22 larger than the exhalation bag 22, a better result will be obtained. The exhalation bag 18 preferably has dimensions of from 1 to 3 liters for the interior volume and of from 600 to 2,000 square centimeters for the outer surface area, while the inhalation bag 22 preferably has dimensions of from 3 to 5 liters for the interior volume and of from 1,500 to 4,000 square centimeters for the outer surface area.
The inhalation hose 34 and the exhalation hose 16 are preferably independent from each other as illustrated in FIGS. 1 and 2. The plastic hoses 16 and 34 are connected to a unidirectional valve 14 which allows the exhaled gas only to enter into the exhalation hose 16 and which allows the breathable gas only to pass through the inhalation bag 22 to the mouthpiece 12. Since the hoses 16 and 34 are independent, there is substantially no chance for the exhaled gas to be inhaled by the user without being purified unless unlikely unidirectional valve failure occurs.
It is apparent that the general public has been provided with a personal escape breathing apparatus that can be made available in quantity in public dwellings, etc., and that is light in weight, highly compact, simple to use, inexpensive and has a long storage life.
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The personal escape breathing apparatus comprises exhalation and inhalation bags connected by a carbon dioxide absorption canister, a chemical oxygen generator connected to the exhalation bag and a relief valve for releasing built-up gas within the exhalation bag. The two unequal size bags provide a flexible volume sufficient to store the user's vital capacity a surface area sufficient to cool gas heated from the exothermic reaction of O 2 generation and CO 2 absorption, but the bags are readily foldable to minimize the stored size. The two bags are integrally formed on a flexible, gas impermeable sheet which serves both as the back walls of the bags as well and as a support collar which extends from the bags and has a hole for passing the user's head therethrough. The apparatus also comprises a flexible transparent hood and nose block to protect the user from the hostile environment.
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TECHNICAL FIELD
[0001] Embodiments are related to implantable medical leads and systems including implantable medical leads that may carry induced radio frequency energy. More particularly, embodiments are related to implantable medical leads and related systems that include reflection points to control the induced radio frequency energy.
BACKGROUND
[0002] Implantable medical systems include an implantable medical device connected to an implantable medical lead. The implantable medical device is used to produce stimulation signals for delivery to tissue of a patient and/or to sense physiological signals from the tissue of the patient. The implantable medical lead includes electrical contacts on a proximal end that are connected to electrical connectors within the medical device. Electrodes are present on a distal end of the implantable medical lead to contact the tissue at the stimulation site. Filars are present within the lead to carry electrical signals between the contacts at the proximal end and the electrodes at the distal end.
[0003] The implantable medical leads can present an issue for a patient who may need to undergo a magnetic resonance imaging (MRI) scan. An MRI scan exposes the patient to radio frequency (RF) electromagnetic energy. This RF energy may be collected by the filars in the form of induced RF electrical current during the MRI scan. This RF electrical current may be delivered to the tissue of the patient via the electrodes at the distal end.
[0004] The RF electrical current induced onto the filars presents a serious condition. The electrode is a relatively small amount of surface area such that the RF electrical current from a given electrode is dissipated into a relatively small amount of tissue which may heat the tissue by an excessive amount that causes tissue damage. Furthermore, the electrode may be located adjacent to sensitive tissue such as within the brain or spine where tissue damage from the excessive heating by the induced RF current may have severe consequences.
SUMMARY
[0005] Embodiments address issues such as these and others by providing implantable medical leads and implantable medical systems where the implantable medical leads include reflection points that control the radio frequency energy induced onto the filars. The reflection points may be present on the filar(s) or on the insulation layer(s) such as on an inner jacket formed about individual liars or on an outer jacket of the lead. The reflection points may be created in various ways such as changing physical dimensions like the diameter at a given point or by changing the materials that are present at a given point
[0006] Embodiments provide implantable medical systems and leads. The implantable medical lead includes an outer jacket and a filar located within the outer jacket. The filar includes physical changes that establish multiple radio frequency reflection points located along the length of the filar. The implantable medical lead further includes a proximal contact and a distal electrode, with the filar interconnecting the proximal contact to the distal electrode.
[0007] Embodiments provide other implantable medical systems and leads. The implantable medical lead includes an outer jacket and a filar surrounded by an inner jacket. The filar and inner jacket are located within the outer jacket, and the inner jacket includes physical changes that establish multiple radio frequency reflection points located along the length of the filar. The implantable medical lead further includes a proximal contact and a distal electrode, with the filar interconnecting the proximal contact to the distal electrode.
[0008] Embodiments provide additional implantable medical systems and leads. The implantable medical lead includes an outer jacket and a filar being located within the outer jacket such that the outer jacket includes physical changes that establish multiple radio frequency reflection points located along the length of the filar at non-standard intervals of repetition. The implantable medical lead further includes a proximal contact and a distal electrode, with the filar interconnecting the proximal contact to the distal electrode.
[0009] Embodiments provide other implantable medical systems and leads. The implantable medical lead includes an outer jacket and a filar being located within the outer jacket. Discrete circuit elements are electrically coupled to the filar and establish multiple radio frequency reflection points located along the length of the filar at non-standard intervals of repetition. The implantable medical lead includes a proximal contact and a distal electrode, with the filar interconnecting the proximal contact to the distal electrode.
DESCRIPTION OF THE DRAWINGS
[0010] FIG. 1 shows a patient with an implantable medical system in the presence of RF electromagnetic energy.
[0011] FIG. 2 shows an example of a longitudinal cross-section of an implantable medical lead having reflection points provided by changes in filar diameter, filar material, inner jacket diameter, inner jacket material, outer jacket diameter, and outer jacket material.
[0012] FIG. 3 shows a first lateral cross-section of the implantable medical lead of FIG. 2 at a reference point.
[0013] FIG. 4 shows a second lateral cross-section of the implantable medical lead of FIG. 2 at a first reflection point.
[0014] FIG. 5 shows a third lateral cross-section of the implantable medical lead of FIG. 2 at a second reflection point.
[0015] FIG. 6 shows a fourth lateral cross-section of the implantable medical lead of FIG. 2 at a third reflection point.
[0016] FIG. 7 shows a fifth lateral cross-section of the implantable medical lead of FIG. 2 at a fourth reflection point.
[0017] FIG. 8 shows a sixth lateral cross-section of the implantable medical lead of FIG. 2 at a fifth reflection point.
[0018] FIG. 9 shows a seventh lateral cross-section of the implantable medical lead of FIG. 2 at a sixth reflection point.
[0019] FIG. 10 shows an eighth lateral cross-section of the implantable medical lead of FIG. 2 at a seventh reflection point.
[0020] FIG. 11 shows a ninth lateral cross-section of the implantable medical lead of FIG. 2 at an eighth reflection point.
[0021] FIG. 12 shows a tenth lateral cross-section of the implantable medical lead of FIG. 2 at a ninth reflection point.
[0022] FIG. 13 shows an eleventh lateral cross-section of the implantable medical lead of FIG. 2 at a tenth reflection point.
[0023] FIG. 14 shows a longitudinal distribution of reflection points in one example of a lead.
DETAILED DESCRIPTION
[0024] Embodiments provide implantable medical leads and systems that include reflection points along the leads to control RE energy that is induced as RE current onto filars of the leads. The reflection points may be present on the filar or on other elements of the lead such as an inner jacket around the individual filar or an outer jacket that may form the outer body of the lead. The reflection points may be created by physical changes such as a change in diameter of the filar or insulator or a change in the materials that are used for the filar or insulator that produce a change in a characteristic impedance of the lead.
[0025] FIG. 1 shows an environment where an implantable medical system 100 has been implanted within a patient 108 . The implantable medical system 100 includes an implantable medical device (IMD) 102 and an implantable medical lead 104 . The implantable medical lead 104 is connected to the IMD 102 at a proximal end, and the lead 104 extends to a stimulation site where electrodes 106 on the distal end are present to electrically interface with the tissue of the patient 108 .
[0026] The patient 108 is being exposed to RE electromagnetic energy 110 . This RE energy 110 encounters the implantable medical system 100 and may induce RF current onto the lead 106 . However, the lead 106 may include reflection points positioned at various locations to reflect the RF current away from the electrodes and to cause at least some of the RE current to dissipate as heat over the filar(s) present within the lead 104 rather than exiting through the electrodes 106 .
[0027] FIG. 2 shows a longitudinal cross-section of an example of a lead 200 with reflection points. This lead 200 is shown with a single contact 204 , single filar 208 , and single electrode 206 . It will be appreciated that any number of contacts, filars, and electrodes may be present and may benefit from the reflection points. In this particular example, the lead 200 includes a body 202 which may be established by the outer jacket, or the outer jacket may be an outer layer adhered to the body 202 . The body 202 defines a lumen 210 that may be present to receive a stylet that guides the lead 200 during implantation and is removed thereafter.
[0028] The body 202 forming the outer jacket may be made of various materials. Examples include elasthane, silicone, other polymers and the like. Likewise, the filar 208 may be made of various materials such as MP35N® alloy, platinum, silver cored MP35N® alloy, and the like.
[0029] Additionally, the lead 200 may include an inner jacket that is not shown in FIG. 2 but adheres to the outer surface of the filar 204 and isolates the filar 204 from the body 202 . The inner jacket may also be made of various materials. Examples include ethylene tetrafluoroethylene (ETFE), other polymers, and the like.
[0030] The physical parameters including the dimensions and the types of material used for each of the components within the lead 200 such as the outer jacket of the body 202 , the inner jacket, and the filar 206 contribute to the characteristic impedance of the filar 202 . To create a reflection point, the characteristic impedance is altered at a given location where the reflection point is desired. To alter the characteristic impedance and thereby create the reflection point, a physical change is present in either a dimension or a material for the particular component. Examples of such physical changes are present in this example of the lead 200 , where cross-section 3 - 3 shown in FIG. 3 is a reference point showing the normal construction where a reflection point is not present. Cross-sections 4 - 4 through 13 - 13 show examples of some of the other reflection points that are present in this example of the lead 200 .
[0031] FIG. 3 shows a lateral cross-section taken through 3 - 3 of FIG. 2 . Here, the elements of the lead 200 including the body 202 forming the outer jacket, the filar 212 , and the inner jacket 208 on the filar 212 are normal in that this represents the configuration of the areas of the lead where no reflection point is present. In the example of FIG. 2 , this cross-section taken through 3 - 3 is in a normal portion near the proximal end of the lead 200 . It will be appreciated that normal portions such as this that may extend for significant portions of the lead may appear at any point along the lead from proximal tip to distal tip.
[0032] FIG. 4 shows a lateral cross-section taken through 4 - 4 of FIG. 2 where a reflection point is present. Here, the body 202 forming the outer jacket includes additional material 202 ′ creating a larger diameter over a particular length of the lead 200 . The additional material 202 ′ may be the same or different material than the body 202 . The other elements including the filar 212 and inner jacket 214 have not changed. The change in diameter results in a change to the characteristic impedance of the filar 202 thereby producing a reflection point. It will be appreciated that rather than increasing the diameter, the body 202 forming the outer jacket may have a reduced diameter to create a reflection point.
[0033] An alternative to the layer 202 ′ being an additional jacket material, 202 ′ may represent a floating electrode. In this case, the floating electrode may be attached to the body 202 in the same manner as the electrode 206 that is used for stimulation, but the floating electrode is not connected to a filar 212 . The floating electrode presents a physical change to the outer jacket that creates a change in the characteristic impedance of the filar 212 such that the presence of the floating electrode creates a reflection point. In some examples, the floating electrode present at any given reflection point may be capacitively coupled to one or more of the filars within the lead 200 .
[0034] FIG. 5 shows a lateral cross-section taken through 5 - 5 of FIG. 2 where a reflection point is present. Here, the body 202 forming the outer jacket includes one or more types of dopant materials. In this particular example, two dopant materials 216 and 218 are present and create a change in the conductance of the outer jacket over a particular length of the lead 200 . Examples of dopant materials include metals such as titanium, stainless steel, platinum, and the like. The other elements including the filar 212 and inner jacket 214 have not changed. The change in material results in a change to the characteristic impedance of the filar 202 thereby producing a reflection point.
[0035] FIG. 6 shows a lateral cross-section taken through 6 - 6 of FIG. 2 where a reflection point is present. Here, the body 202 forming the outer jacket is normal in size and material. However, the inner jacket 214 includes additional material 214 ′ creating a larger diameter over a particular length of the lead 200 . The additional material 214 ′ may be the same or different material than the material of the inner jacket 214 . The other elements including the filar 212 . and body 202 forming the outer jacket have not changed. The change in diameter results in a change to the characteristic impedance of the filar 202 thereby producing a reflection point. It will be appreciated that rather than increasing the diameter, the inner jacket 214 ′ may have a reduced diameter to create a reflection point.
[0036] FIG. 7 shows a lateral cross-section taken through 7 - 7 of FIG. 2 where a reflection point is present. Here, the body 202 forming the outer jacket is normal in size and material. However, the inner jacket 214 ′ includes at least one type of dopant material. In this particular example, two dopant materials 220 and 222 are present and create a change in the conductance of the outer jacket over a particular length of the lead 200 . Examples of these dopant materials also include titanium, stainless steel, platinum, and the like. The other elements including the filar 212 and body 202 forming the outer jacket have not changed. The change in materials results in a change to the characteristic impedance of the filar 202 thereby producing a reflection point.
[0037] FIG. 8 shows a lateral cross-section taken through 8 - 8 of FIG. 2 where a reflection point is present. Here, both the body 202 forming the outer jacket and the inner jacket 214 are normal in diameter and material. However, the filar 212 ′ has a reduced diameter, such as by creating a crimp and the inner jacket 214 may fill in the area of reduced diameter. The change in diameter of the filar 212 ′ at the area of this cross-section results in a change to the characteristic impedance of the filar 202 thereby producing a reflection point. It will be appreciated that rather than reducing the diameter, the filar 212 ′ may have an increased diameter to create a reflection point such as by welding additional material onto the filar 212 ′.
[0038] FIG. 9 shows a lateral cross-section taken through 9 - 9 of FIG. 2 where a reflection point is present. Here, both the body 202 forming the outer jacket and the inner jacket 214 are normal in diameter and material. However, the filar 212 has a change in material by the addition of a material 212 ″ adjacent to the material 212 , such as by welding a different material 212 ″ onto the existing filar 212 . It should be noted that both materials define the surface, which may provide a more effective reflection point than using an approach with a core considering that the RE induced current is primarily on the surface due to the skin effect. If the filar diameter is to be maintained as shown in FIG. 9 , the existing filar material may have a reduced filar diameter while the new filar material increases the filar diameter back to the normal level. The change in material of the filar 212 ″ at the area of this cross-section results in a change to the characteristic impedance of the filar 202 thereby producing a reflection point.
[0039] FIGS. 4-9 have shown examples where a single parameter such as size or material has changed to produce a reflection point. FIGS. 10-13 show examples where multiple parameters have changed to produce for each of the reflection points.
[0040] FIG. 10 shows a lateral cross-section taken through 10 - 10 of FIG. 2 where a reflection point is present. Here, the inner jacket 214 is normal in diameter and material. However, the filar 212 ″ has a change in material while the diameter may be the same or different, such as by welding a different material onto the existing filar 212 . Additionally, the body 202 forming the outer jacket has additional material 202 ′ that increases the diameter of the body 202 . The combination of the change in material of the filar 212 ″ as well as the diameter of the outer jacket 202 ′ at the area of this cross-section results in a change to the characteristic impedance of the filar 202 thereby producing a reflection point. It will be appreciated that the multiple parameters relating to the filar 212 and the body 202 forming the outer jacket may have additionally or alternatively included other changes such as a reduced diameter of the body 202 ′ forming the outer jacket, a change to the diameter of the filar 212 , and/or a change to the material of the body 202 , 202 ′ forming the outer jacket.
[0041] FIG. 11 shows a lateral cross-section taken through 11 - 11 of FIG. 2 where a reflection point is present. Here, the body 202 forming the outer jacket includes one or more types of dopant materials. In this particular example, one dopant material 216 is present. Additionally, the inner jacket 214 includes additional material 214 ′ increasing the diameter of the inner jacket. The combination of the change in material of the body 202 forming the outer jacket and the change in diameter of the inner jacket 214 results in a change to the characteristic impedance of the filar 202 thereby producing a reflection point. It will be appreciated that the multiple parameters relating to the body 202 forming the outer jacket and the inner jacket may have additionally or alternatively included other changes such as a change in diameter of the body 202 forming the outer jacket, a reduced diameter of the inner jacket 214 , and/or a change in the material of the inner jacket 214 .
[0042] FIG. 12 shows a lateral cross-section taken through 12 - 12 of FIG. 2 where a reflection point is present. Here, the inner jacket 214 ″ includes one or more dopant materials. In this particular example, one dopant material 220 is present. Additionally, the filar 212 ′ has a reduced diameter. The combination of the change in material of the inner jacket 214 ″ and the change in diameter of the filar 212 ′ results in a change to the characteristic impedance of the filar 202 thereby producing a reflection point. It will be appreciated that the multiple parameters relating to the inner jacket and filar may have additionally or alternatively included other changes such as a change in diameter of the inner jacket 214 ″, a change in diameter of the inner jacket 214 ″, and/or a change in the material of the inner jacket 214 .
[0043] FIG. 13 shows a lateral cross-section taken through 13 - 13 of FIG. 2 where a reflection point is present. Here, the inner jacket 214 ″ includes one or more dopant materials. In this particular example, one dopant material 222 is present. The inner jacket 214 ″ also includes additional material 214 ′ increasing the diameter of the inner jacket, Additionally, the filar 212 ′ has a reduced diameter while also including a different material 212 ″ welded onto the existing reduced diameter portion 212 ′. The body 202 forming the outer jacket includes additional material 202 ″ that increases the diameter of the body 202 forming the outer jacket. Furthermore, the additional material 202 ″ is doped with one or more dopants, in this case a single dopant type 218 . The combination of the change in materials and sizes of the inner jacket 214 ′, 214 ″, the filar 212 ′, 212 ″, and the body 202 , 202 ″ forming the outer jacket result in a change to the characteristic impedance of the filar 202 thereby producing a reflection point. it will be appreciated that the multiple parameters relating to the body forming the outer jacket, the inner jacket and the filar may have additionally or alternatively included other changes as well.
[0044] FIG. 14 shows an example of longitudinal distribution 300 of reflection points 302 along the length of a lead. It can be seen that some reflection points are created by a change only to a single element, the outer jacket ( 1 ), the inner jacket ( 2 ), or the filar ( 3 ). It can be seen that some reflection points are created by a change to two elements, the outer jacket ( 1 ) and the inner jacket ( 2 ), the outer jacket ( 1 ) and the filar ( 3 ), or the inner jacket ( 2 ) and the filar ( 3 ). Additionally, it can be seen that some reflection points are created by a change to all three elements, the outer jacket ( 1 ), the inner jacket ( 2 ), and the filar ( 3 ).
[0045] In FIG. 14 it can further be seen that in this example there is a nonstandard interval of repetition. In other words, the spacing from one reflection point to the next reflection point varies. It can also be seen in this example that there is a nonstandard interval of repetition from a reflection point involving a change to a particular element to the next reflection point involving the same element. This nonstandard interval of repetition may assist in reflecting the RF current away from the electrode and in dissipating the RF current as heat in the filar(s).
[0046] While the examples of FIGS. 2-13 show a single filar and a single inner jacket, multiple filars may be present and each filar may have a dedicated inner jacket. The physical change to the filar and/or the inner jacket may vary from filar to filar. For instance, a given reflection point involving the inner jacket ( 2 ) and/or the filar ( 3 ) as shown in FIG. 14 may pertain to one filar, multiple filars, or all filars present within a lead. For instance, some of those reflection points of FIG. 14 may pertain to one filar while others may pertain to multiple filars.
[0047] The reflection points discussed herein may also be created by the presence of discrete circuit elements such as resistors, capacitors, and/or inductors that are electrically coupled to the filar(s). Thus, any or all of the reflection points 302 illustrated in FIG. 14 may be discrete circuit elements with nonstandard intervals of repetition rather than physical changes to the filar, inner jacket, or outer jacket. For instance, there may be series resistors in-line along the filars ( 1 ), series inductors in-line along the filars ( 2 ), and/or capacitors that are parallel from the filar to floating electrodes that may have a large surface area in comparison to the stimulation electrodes and/or may be located in less critical tissue ( 3 ) that are present to vary the characteristic impedance while not adversely affecting the delivery of stimulation signals or sensed signals through the filars.
[0048] While embodiments have been particularly shown and described, it will be understood by those skilled in the art that various other changes in the form and details may be made therein without departing from the spirit and scope of the invention.
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Implantable medical leads and systems utilize reflection points within the lead to control radio frequency current that has been induced onto one or more filars. The radio frequency current may be controlled by the reflection points to block at least some of the radio frequency current from reaching an electrode of the lead and to dissipate at least some of the radio frequency current as heat on the filar. Controlling the radio frequency current thereby reduces the amount that is dissipated into bodily tissue through one or more electrodes of the lead and reduces the likelihood of tissue damage. The reflection points may be created by physical changes such as to material or size in the filar and/or in insulation layers that may be present such as an inner jacket about the filar and an outer jacket formed by the body of the lead.
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BACKGROUND OF THE INVENTION
[0001] The present invention relates to document storage and in particular to a system for converting bulk storage racks into an efficient file storage system.
[0002] It is often desirable, or even legally or contractually required, to store items such as documents, equipment, articles, and the like which may be required in the future. Long term storage facilities are available for storing such items and generally include vast arrays of storage racks, often to great heights. An example of a known document box storage rack 10 is shown in FIG. 1 , with shelves absent to provide a clear view. The rack 10 includes vertical supports 12 , lateral supports 14 , and longitudinal supports 16 . Generally, the shelves in such racking are designed for general storage and are of a size and spaces apart vertically to allow various size boxes to be stacked vertically, laterally, and longitudinally on the shelves. While such shelving provides a versatile storage capacity, it is inefficient for storage of common paper files which fit into a small known number of volumes. Storing paper files in boxes stacked on the shelves also results in difficulty in recovering papers which may be in boxes stacked behind and under other boxes.
BRIEF SUMMARY OF THE INVENTION
[0003] The present invention addresses the above and other needs by providing a rack conversion system which mounts to an existing storage rack and includes lateral tracks for side to side movement of forward bins and longitudinal tracks for front to rear movement of rear bins. The bins are sized to efficiently store a particular item, for example, paper files. The forward bins are movable side to side along the lateral tracks and reside in front of the rear bin. The rear bins are moveable front to rear along the longitudinal tracks and are normally positioned to the rear to allow the side to side movement of the forward bins. The lateral tracks are preferably mounted below the forward bins and do not interfere with the movement of the rear bins, and the longitudinal tracks are preferably mounted above the rear bins and do not interfere with movement of the forward bins. The rack conversion according to the present invention thus allows conversion of known storage racks to efficiently store and retrieve stored material thereby substantially improving known storage systems by as much as 67 percent by allowing easy and direct access to any box in up to three rows of boxes versus a single row of boxes.
[0004] In accordance with one aspect of the invention, there is provided a rack system including a storage rack frame, longitudinal supports, lateral tracks, and three lateral rows of bins. The storage rack frame includes at least four spaced apart uprights, each residing approximately vertically and forming a rectangle, and at least two pairs of lateral beams longitudinally spaced apart and approximately parallel. The pairs of lateral beams are supported by the uprights and reside in an approximately horizontal plane and each lateral beam has a groove in an upper inside edge. Decks normally used for storing material are supported by the shoulders in the lateral beams and four longitudinally spaced apart lateral tracks are mounted above each deck to carry two rows of laterally sliding forward bins. A multiplicity of pairs of longitudinal supports are carried under the lateral beams and each pair of longitudinal supports carries a rear bin. The bins have a bin width W and include two rows of the number N minus one of the forward bins and one row of the number N of the rear bins. The bins preferably have a depth of approximately the height of letter size paper folders. The positions of the lateral tracks are preferably longitudinally adjustable to allow room for letter or legal size folders. The forward bins slidably cooperate above respective lateral tracks to allow lateral movement of the forward bins within each of their respective rows and the row of rear bins normally resides behind the two rows of forward bins. The total width of the rows of forward bins, the number N, and the widths of the individual forward bins are selected to allow access to the rear bins by laterally sliding adjacent forward bins apart. Additionally, the longitudinal supports may be longitudinal tracks allowing the rear bins to move forward and rearward between separated adjacent forward bins.
[0005] In accordance with another embodiment of the invention, there is provided a rack system with the lateral tracks above the respective forward bins and longitudinal tracks below the respective rear bins.
BRIEF DESCRIPTION OF THE SEVERAL VIEWS OF THE DRAWING
[0006] The above and other aspects, features and advantages of the present invention will be more apparent from the following more particular description thereof, presented in conjunction with the following drawings wherein:
[0007] FIG. 1A is a bare prior art storage rack.
[0008] FIG. 1B is the prior art storage rack with decks and boxes stored on the decks.
[0009] FIG. 2 is a storage rack with lateral tracks according to the present invention carried by decks supported by lateral beams.
[0010] FIG. 3 is a perspective view of a forward bin according to the present invention, configured to slidably cooperate with the lateral tracks.
[0011] FIG. 4 is a perspective view of a rear bin according to the present invention, configured to slidably cooperate with longitudinal tracks.
[0012] FIG. 5A is a front view of one of the forward bins.
[0013] FIG. 5B is a side view of one of the forward bins carried on the lateral tracks.
[0014] FIG. 5C is a top view of one of the forward bins.
[0015] FIG. 6 is an end view of one of the lateral tracks having a “C” shaped profile to prevent tipping.
[0016] FIG. 7A is a front view of one of the rear bins carried on the longitudinal tracks.
[0017] FIG. 7B is a side view of one of the rear bins.
[0018] FIG. 7C is a bottom view of one of the rear bins.
[0019] FIG. 8 is an end view of one of the longitudinal tracks.
[0020] FIG. 9 is a top view of the lateral tracks and lateral beams.
[0021] FIG. 10 is an end view of the lateral tracks attached to the deck supported by the lateral beams.
[0022] FIG. 11A is a front view of the longitudinal tracks attached to a longitudinal track assembly.
[0023] FIG. 11B is a top view of the longitudinal tracks attached to the longitudinal track assembly.
[0024] FIG. 11C is an end view of the longitudinal tracks attached to the longitudinal track assembly attached between a pair of lateral beams.
[0025] FIG. 12A is a top view of a possible orientation of the forward and rear bins according to the present invention.
[0026] FIG. 12B shows a top view of the forward and rear bins with forward bins in a first row moved to provide access to a rear bin.
[0027] FIG. 12C shows the rear bin moved forward for better access.
[0028] FIG. 13 is a method for converting know storage racks according to the present invention.
[0029] Corresponding reference characters indicate corresponding components throughout the several views of the drawings.
DETAILED DESCRIPTION OF THE INVENTION
[0030] The following description is of the best mode presently contemplated for carrying out the invention. This description is not to be taken in a limiting sense, but is made merely for the purpose of describing one or more preferred embodiments of the invention. The scope of the invention should be determined with reference to the claims.
[0031] The present invention comprises apparatus for converting existing storage racks into an efficient file storage system. An example of a known storage rack 10 is shown in FIG. 1A , with decks absent to provide a clear view of uprights 12 , lateral beams 14 , longitudinal braces 16 , and diagonal braces 17 . The uprights 12 comprise at least four uprights and are approximately vertical and form a rectangle. A storage rack system 10 may be extended and include a large number of uprights 12 to fill a large warehouse. The lateral beams 14 are longitudinally spaced apart pairs, approximately parallel, and supported by the uprights defining an approximately horizontal plane (i.e., at the same height). The lateral beams 14 are generally the load bearing element of the rack system 10 , and the longitudinal braces 16 and diagonal braces 17 hold the uprights 12 in the vertical position.
[0032] The prior art storage rack 10 with decks 11 , and boxes 13 stored on the decks 11 , is shown in FIG. 1B . The lateral beams 14 include stepped shoulders 40 (see FIG. 10 ) on inside upper edges of the beams 14 to support the decks 11 . Such stepped shoulders 40 are common on known beams 14 used with rack systems and are provided to position and support the decks 11 , perforated decks, and the like, commonly used with rack systems 10 . Unfortunately, the prior art storage rack 10 often results in inefficient use of space and/or difficulty in accessing boxes which have been pushed to the rear.
[0033] A storage rack 10 with lateral tracks 20 according to the present invention, supported by decks 11 (see FIG. 1B ), is shown in FIG. 2 . The present invention advantageously uses the existing decks 11 to avoid major modifications to the storage rack 10 . The lateral tracks 20 preferably comprise two pairs of lateral tracks 20 for carrying two rows of laterally sliding forward bins 18 a (see FIG. 3 ) above the lateral tracks 20 .
[0034] FIG. 3 is a perspective view of the forward bin 18 a according to the present invention configured to slidably cooperate with lateral tracks 20 . The lateral tracks 20 are shown below the bin 18 a , but may also be above the bin 18 a . The bin 18 a may includes the internal struts 19 for additional strength.
[0035] A perspective view of a rear bin 18 b according to the present invention, configured to slidably cooperate with longitudinal tracks 24 (see FIGS. 6 and 7A ), is shown in FIG. 4 . The longitudinal tracks 24 are shown above the bin 18 b , but may also be below the bin 18 b . The bin 18 a may includes internal struts 19 for additional strength.
[0036] A front view of the forward bin 18 a is shown in FIG. 5A , a side view of the forward bin 18 a is shown in FIG. 5B , and a top view of the forward bin 18 a is shown in FIG. 5C . The bin 18 a preferably includes 2 shelves 17 dividing the bin 18 a into three vertical storage spaces. The three storage spaces have heights H 1 , H 2 , and H 3 which are all preferably approximately ten inches. The overall height H 4 of the bin 18 a is preferably approximately 30 inches. The width W 1 of the bin 18 a is preferably approximately 16 inches and the depth D of the bin 18 a is preferably approximately 11 inches. Four rollers (or wheels) 22 are attached to front and rear bottom corners of the bin 18 a to carry the bin 18 a on the lateral tracks 20 . An end view of the lateral track 20 supporting the bins 18 a is seen in FIG. 5B , and a detailed end view of the lateral track 20 alone is shown in FIG. 6 . Bumpers 23 reside on bottom corners of opposing sides 21 of the bins 18 a to prevent direct metal to metal contact of adjacent bins 18 a.
[0037] A front view of the rear bin 18 b is shown in FIG. 7A , a side view of the rear bin 18 b is shown in FIG. 7B , and a top view of the rear bin 18 b is shown in FIG. 7C . The bin 18 b preferably includes 2 shelves 17 dividing the bin 18 b into three vertical storage spaces. The rear bin 18 b has a depth D 2 of preferably 11 inches to accept letter or legal size folders, and a width W 2 which is preferably approximately the same width as the forward bins 18 a . The heights of the rear bin 18 a are preferably the same as the forward bin 18 a . The rear bins 18 b are preferably slidably supported by the longitudinal tracks 24 as shown in FIG. 7A . Rollers (or wheels) 26 are attached to rails 28 mounted to the top 30 of the rear bin 18 b . The rails 28 preferably extend to the fronts 33 of the bin 18 b and bumpers 30 are attached to forward ends of the rails 28 to prevent or reduce damage to the bin 18 b from forward impact, for example, with a lateral beam 14 . Rounded or angled guides 32 are preferably attached to bottom corners of the front 33 of the of the bin 18 b to facilitate the bin 18 b sliding between separated adjacent pairs of the forward bins 18 a . The guides 32 are positioned and shaped to urge the forward bins further apart to allow the rear bin 18 b to slide between the forward bins. A detailed end view of one of the longitudinal tracks 24 is shown in FIG. 8 .
[0038] In another embodiment the rear bins 18 b are stationary and are fixedly attached to the longitudinal supports replacing the longitudinal tracks 24 .
[0039] A top view of the lateral tracks 20 and mounting apparatus comprising mounting plates 34 , adjusting slots 36 , and fasteners 38 according to the present invention, and the lateral beams 14 , are shown in FIG. 9 , and an end view of the lateral tracks 20 are shown in FIG. 10 . The tracks 20 are attached to the mounting plates 34 . Each mounting plate 34 has a pair of adjusting slots 36 . The fasteners 38 pass through the adjusting slots 36 , through the deck 11 , and connect to backing apparatus 42 under the deck 11 to sandwich the deck 11 thereby fixing the position of the lateral tracks 20 . The backing apparatus 42 may be nuts, washers and nuts, plates with threaded holes, plates with nuts attached, or any other apparatus allowing the deck 11 to be sandwiched to fix the position of the lateral tracks 20 . The lateral tracks 20 also include disassembly notches 20 a allowing the front bins 18 a to be removed from the tracks.
[0040] The slots 36 are provided to allow pairs of the lateral tracks 20 to be moved longitudinally to adjust for storage of letter or legal size material. For example, to move a first pair of lateral tracks back approximately three inches and to move a second pair of lateral tracks behind the first pair of lateral tracks back approximately six inches, thereby providing a space for legal size material to extend out the fronts of both rows of the forward bins. Either or both pairs of the lateral tracks may be moved to allow appropriate storage. The default depths and positions of the forward bins 18 a is for letter size material to minimize the reach to the rear bins 18 b.
[0041] The pairs of lateral tracks 20 are advantageously supported by the existing decks 11 residing in the existing stepped shoulders 40 in the lateral beams 14 , and thus may be easily used to modify existing storage racks 10 (see FIGS. 1A and 1B ).
[0042] A front view of the longitudinal tracks 24 attached to a longitudinal track assembly are shown in FIG. 11A , a top view of the longitudinal tracks 24 attached to the longitudinal track assembly are shown in FIG. 11B , and an end view of the longitudinal tracks 24 attached to the longitudinal track assembly attached between a pair of lateral beams 14 are shown in FIG. 11C . The longitudinal tracks 24 are attached between bars 44 and the bars 44 are attached to lower inside edges of the lateral beams 14 . While longitudinally moving rear bins 18 b are preferred, an embodiment with stationary rear bins 18 b provides advantages over known storage racks, and such stationary embodiment may simply include the rear bins 18 b bolted to the decks 11 behind the forward bins 18 a.
[0043] A top view of a possible orientation of the forward bins 18 a and rear bins 18 b according to the present invention is shown in FIG. 12A , a top view of the forward bins 18 a and rear bins 18 b with forward bins 18 a in a first row A moved to provide access to one of the rear bins 18 b is shown in FIG. 12B , and the rear bin 18 b is shown moved forward for better access in FIG. 12C .
[0044] A method for converting know storage racks according to the present invention is described in FIG. 13 . The method includes the steps of attaching two pairs of lateral tracks to top surfaces of decks of storage rack frames, the tracks positioned on an approximately front two-thirds of the decks at step 100 , attaching N pairs of longitudinal tracks under the decks at step 102 , engaging a number N of rear bins to the N pairs longitudinal tracks to allow front to rear motion of the rear bins at step 104 , engaging a number N−1 of forward bins to each of the pairs of lateral tracks to allow side to side of the forward bins at step 106 , and sliding adjacent pairs of the forward bins apart to allow individual ones of the rear bins to slide forward to store and retrieve material in the rear bins at step 108 .
[0045] The bins have been depicted herein as formed of solid sheet metal. In some applications a requirement exists to use a perforated material to allow water to pass through the bins as a fire control requirement. Also, the bins may alternatively be constructed from metal, preferable steel rod. Such steel rod construction meets the fire control requirements and may reduce weights and cost. The steel rod bins may also be constructed to fold into a compact unit for shipping and thereby reduce shipping costs.
[0046] While the invention herein disclosed has been described by means of specific embodiments and applications thereof, numerous modifications and variations could be made thereto by those skilled in the art without departing from the scope of the invention set forth in the claims.
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A rack conversion system mounts to an existing storage rack and includes lateral tracks for side to side movement of forward bins and longitudinal tracks for front to rear movement of rear bins. The bins are sized to efficiently store a particular item, for example, paper files. The forward bins are movable side to side along the lateral tracks and reside in front of the rear bin. The rear bins are moveable front to rear along the longitudinal tracks and are normally positioned to the rear to allow the side to side movement of the forward bins. The lateral tracks are preferably mounted below the forward bins and do not interfere with the movement of the rear bins, and the longitudinal tracks are preferably mounted above the rear bins and do not interfere with movement of the forward bins.
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FIELD OF THE INVENTION
This invention relates to benzobicyclic substituted carboxamide compounds which exhibit 5-HT 3 antagonist properties including CNS, anti-emetic and gastric prokinetic activity and which are void of any significant D 2 receptor binding affinity. This invention also relates to pharmaceutical compositions and methods for the treatment of gastrointestinal and mental disorders using said compounds.
5-Hydroxytryptamine, abbreviated "5-HT", is commonly known as serotonin. Serotonin is found throughout the body including the gastrointestinal tract, platelets, spleen and brain, appears to be involved in a great number of physiological processes such as neurotransmission at certain neurones in the brain, and is implicated in a number of central nervous system (CNS) disorders. Additionally, serotonin appears to act as a local hormone in the periphery; it is released in the gastrointestinal tract, where it increases small intestinal motility, inhibits stomach and colon motility, and stimulates stomach acid production. Serotonin is most likely involved in normal intestinal peristalsis.
The various physiological activities exerted by serotonin are related to the variety of different receptors found on the surface membrane of cells in different body tissue. The first classification of serotonin receptors included two pharmacologically distinct receptors discovered in the guinea pig ileum. The "D" receptor mediates smooth muscle contraction and the "M" receptor involves the depolarization of cholinergic nerves and release of acetylcholine. Three different groups of serotonin receptors have been identified and the following assignment of receptors has been proposed: D-receptors are 5-HT 2 -receptors; M-receptors are termed 5-HT 3 -receptors; and all other receptors, which are clearly not 5-HT 2 or 5-HT 3 , should be referred to as 5-HT 1 -like.
5-HT 3 -receptors have been located in non-neurological tissue, brain tissue, and a number of peripheral tissues related to different responses. It has been reported that 5-HT 3 -receptors are located on peripheral neurones where they are related to serotonin's (excitatory) depolarizing action. The following subtypes f 5-HT 3 receptor activity have been reported: action involving postganglionic sympathetic and parasympathetic neurones, leading to depolarization and release of noradrenaline and acetylcholine, respectively (5-HT 3B subtype); action on enteric neurones, were serotonin may modulate the level of acetylcholine (5-HT 3C subtype); and action on sensory nerves such as those involved in the stimulation of heart nerve endings to produce a reflex bradycardia (5-HT 3A subtype), and also in the perception of pain.
Highly selective 5-HT 3 -antagonists have been shown to be very effective at controlling and preventing emesis (vomiting) induced by chemotherapy and radiotherapy in cancer patients. The anti-emetic effects of 5-HT 3 -antagonists in animals exposed to cancer chemotherapy or radiation are similar to those seen following abdominal vagotomy. The antagonist compounds are believed to act by blocking 5-HT 3 -receptors situated on the cell membranes of the tissue forming the vagal afferent input to the emetic coordinating areas on the brain stem.
Serotonin is also believed to be involved in the disorder known as migraine headache. Serotonin released locally within the blood vessels of the head is believed to interact with elements of the perivascular neural plexus of which the afferent, substance P-containing fibers of the trigeminal system are believed relevant to the condition. By activating specific sites on sensory neuronal terminals, serotonin is believed to generate pain directly and also indirectly by enhancing the nociceptive effects of other inflammatory mediators, for example bradykinin. A further consequence of stimulating the afferent neurones would be the local release of substance P and possibly other sensory mediators, either directly or through an axon reflex mechanism, thus providing a further contribution to the vascular changes and pain of migraine. Serotonin is known to cause pain when applied to the exposed blister base or after an intradermal injection; and it also greatly enhances the pain response to bradykinin. In both cases, the pain message is believed to involve specific 5-HT 3 receptors on the primary afferent neurones.
5-HT 3 -antagonists are also reported to exert potential antipsychotic effects, and are believed to be involved in anxiety. Although not understood well, the effect is believed to be related to the indirect blocking of serotonin 5-HT 3 -mediated modulation of dopamine activity.
Many workers are investigating various compounds having 5-HT 3 -antagonist activity.
REPORTED DEVELOPMENTS
The development of 5-HT 3 agents originated from work carried out with metoclopramide (Beecham's Maxolon, A. H. Robins' Reglan), which is marketed for use in the treatment of nausea and vomiting at high doses. Metoclopramide is a dopamine antagonist with weak 5-HT 3 -antagonist activity, which becomes more prominent at higher doses. It is reported that the 5-HT 3 activity and not the dopamine antagonism is primarily responsible for its anti-emetic properties. Other workers are investigating this compound in connection with the pain and vomiting accompanying migraine.
Merrell Dow's compound MDL-72222 is reported to be effective as an acute therapy for migraine, but toxicity problems have reportedly ended work on this compound. Currently four compounds, A. H. Robin' Zacopride, Beecham's BRL-43694, Glaxo's GR-38032F and Sandoz' ICS-205-930 are in clinical trials for use in chemotherapy-induced nausea and vomiting. GR-38032F is also in clinica trials in anxiety and schizophrenia, and reportedly, Zacopride in anxiety, while ICS-205-930 has been shown to be useful in treating carcinoid syndrome.
Compounds reported as gastroprokinetic agents include Beecham's BRL-24924, which is a serotonin-active agent for use in gut motility disorders such as gastric paresis, audition reflux esophagitis, and is know to have also 5-HT 3 -antagonist activity.
Metoclopramide, Zacopride, Cisapride and BRL-24924 are characterized by a carboxamide moiety situated para to the amino group of 2-chloro-4-methoxy aniline. BRL-43694, ICS-205930, GR-38032F and GR-65630 are characterized by a carbonyl group in the 3-position of indole or N-methyl indole. MDL-72222 is a bridged azabicyclic 3,5-dichlorobenzoate, while Zacopride, BRL-24924, BRL-43694 and ICS-205930 have also bridged azabicyclic groups in the form of a carboxamide or carboxylic ester.
Bicyclic oxygen containing carboxamide compounds wherein the carboxamide is ortho to the cyclic oxygen moiety are reported to have antiemetic and antipsychotic properties in EPO Publ. No. 0234872.
Dibenzofurancarboxamides and 2-carboxamide-substituted benzoxepines are reported to have 5HT 3 -antagonist and gastroprokinetic activity in copending application Ser. Nos. 152,112, 152,192, and 168,824, all of which are assigned to the same assignee as the present application.
SUMMARY OF THE INVENTION
This invention relates to benzobicyclic carboxamide compounds having 5-HT 3 antagonist activity. Preferred compounds of this invention are of the formula ##STR1## wherein: X is hydrogen, alkyl, alkoxy, hydroxy, amino, mono- and di-alkylamino, halo, trifluoromethyl, nitro, sulfamyl, mono- and di-alkylsulfamyl, alkylsulfonyl, carboxy, carbalkoxy, carbamyl or mono- and di-alkylcarbamyl;
Y is hydrogen, alkyl, alkenyl, aralkyl, ##STR2## Z is ##STR3## 3-quinuclidine, 4-quinuclidine, 4-(1-azabicyclo[3.3.1]nonane), 3-(9-methylazabicyclo[3.3.1]-nonane), 7-(3-oxo-9-methylazabicyclo[3.3.1]nonane) or 4-[3-methoxy-1-(3-[4-fluorophenoxy]propyl) piperidine];
R 1 , R 2 , R 3 and R 4 are independently hydrogen or alkyl;
vicinal R 2 groups may together form a carbocyclic ring;
vicinal R 1 rous may form a double bond;
a and b are 1 to 4;
n is 1 to 3;
and pharmaceutically acceptable salts thereof.
This invention related also to pharmaceutical compositions including an effective therapeutic amount of the aforementioned benzobicyclic carboxamide compound and therapeutic methods for the treatment of a patient suffering from gastrointestinal and/or psychochemical imbalances in the brain by administering said pharmaceutical composition.
Another aspect of the present invention relates to a process for the preparation of the above-described compounds.
DETAILED DESCRIPTION
As employed above and throughout the disclosure, the following terms, unless otherwise indicated, shall be understood to have the following meanings:
"Alkyl" means a saturated aliphatic hydrocarbon which may be either straight or branched-chained containing from about 1 to about 6 carbon atoms.
"Lower alkyl" means an alkyl group as above, having 1 to about 4 carbon atoms.
"Aralkyl" means an alkyl group substituted by an aryl radical were aryl means a phenyl or phenyl substituted with one or more substituents which may be alkyl, alkoxy, amino, nitro, carboxy, carboalkoxy, cyano, alkyl amino, halo, hydroxy, hydroxyalkyl, mercaptyl, alkyl mercaptyl, carboalkyl or carbamoyl. The preferred aralkyl groups are benzyl or phenethyl.
"Carbamyl" means a group of the formula ##STR4##
"Alkoxy" means an alkyl-oxy group in which "alkyl" is as previously described. Lower alkoxy groups are preferred. Exemplary groups include methoxy, ethoxy, n-propoxy, i-propoxy and n-butoxy.
"Acyl" means an organic radical derived from an organic acid, a carboxylic acid, by the removal of its acid hydroxyl group. Preferred acyl groups are benzoyl and lower alkyl carboxylic acids groups such as acetyl and propionyl.
The chemical structures for the Z groups defined above are presented below. ##STR5##
Certain of the compounds of the present invention may exist in enolic or tautomeric forms, and all of these forms are considered to be included within the scope of this invention.
The compounds of this invention may be useful in the form of the free base, in the form of salts and as a hydrate. All forms are within the scope of the invention. Acid addition salts may be formed and are simply a more convenient form for use; and in practive, use of the salt form inherently amounts to use of the base form. The acids which can be used to prepare the acid addition salts include preferably those which produce, when combined with the free base, pharmaceutically acceptable salts, that is, salts whose anions are non-toxic to the animal organism in pharmaceutical doses of the salts, so that the beneficial cardiotonic properties inherent in the free base are not vitriated by side effects ascribable to the anions. Although pharmaceutically acceptable salts of said basic compound are preferred, all acid addition salts are useful as sources of the free base form even if the particular salt per se is desired only as an intermediate produce as, for example, when the salt is formed only for purposed of purification, and identification, or when it is used as intermediate in preparing a pharmaceutically acceptable salt by ion exchange procedures. Pharmaceutically acceptable salts within the scope of the invention are those derived from the following acids: mineral acids such as hydrochloric acid, sulfuric acid, phosphoric acid and sulfamic acid; and organic acids such as acetic acid, citric acid, lactic acid, tartaric acid, malonic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, cyclohexylsulfamic acid, quinic acid, and the like. The corresponding acid addition salts comprise the following: hydrochloride, sulfate, phosphate, sulfamate, acetate, citrate, lactate, tartarate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, cyclohexysulfamate and quinate, respectively.
The acid addition salts of the compounds of this invention are prepared either by dissolving the free base in aqueous or aqueous-alcohol solution or other suitable solvents containing the appropriate acid and isolating the salt by evaporating the solution, or by reacting the free base and acid in an organic solvent, in which case the salt separates directly or can be obtained by concentration of the solution.
A preferred class of compounds is described by Formula I: ##STR6## where: X is hydrogen, hydroxy, amino, mono- and di-loweralkylamino, halo, trifluoromethyl, sulfamyl, mono- and di-loweralkylsulfamyl or loweralkylsulfonyl;
Y is loweralkyl, ##STR7## Z is ##STR8## 3-quinuclidine; 4-quinuclidine, 4-(1-azabicyclo[3.3.1]nonane), 3-(9-methylazabicyclo[3.3.1]-nonane), 7-(3-oxo-9-methylazabicyclo[3.3.1]nonane) or 4-[3-methoxy-1-[4-fluorophenoxy]propyl) piperidine];
R 1 , R 2 , R 3 and R 4 are independently hydrogen or loweralkyl;
vicinal R 2 groups may together form a 5- to 7-member carbocyclic ring;
vicinal R 1 groups may form a double bond;
a and b are 1 to 3;
n is 1 to 3;
and pharmaceutically acceptable salts thereof.
More preferred compounds are those of Formula I where:
X is hydrogen or halo;
Y is methyl, ethyl, propyl, i-propyl, butyl, i-butyl, sec-butyl, t-butyl, pentyl, ##STR9## Z is 3-quinuclidine, 4-quinuclidine, 4-(1-azabicyclo[3.3.1]-nonane), 3-(9-methylazabicyclo[3.3.1]-nonane), 7-(3-oxo-9-methylazabicyclo[3.3.1]nonane) or 4-[3-methoxy-1-(3-[4-fluorophenoxy]propyl) piperidine];
R 1 and R 2 are independently hydrogen, methyl or ethyl;
vicinal R 2 groups may together form a 5- and 6-member carbocyclic ring;
vicinal R 1 groups may form a double bond;
a is 1 to 3;
n is 1 or 2;
and pharmaceutically acceptable salts thereof.
The most preferred compounds are those of Formula II: ##STR10## where: X is chloro or bromo;
Z is 3-quinuclidine, 4-quinuclidine or 4-(1-azabicylco[3.3.1]nonane);
R 1 and R 2 are independently hydrogen, methyl or ethyl;
vicinal R 2 groups may together form a 5- or 6-member carbocyclic ring;
vicinal R 1 groups may form a double bond;
and pharmaceutically acceptable salts thereof.
Compounds of this invention may be prepared by the reaction of an amine of the formula H 2 N-Z with a suitably substituted carboxylic acid, acid halide or carboxylic ester of the indene, napthalane, 7(H)-cycloheptabenzene compounds, and dihydro or tetrahydro forms thereof, which correspond to the carboxamide of Formula I.
The carboxylic acid starting compounds and derivatives thereof for the above-mentioned reaction are also novel compounds and comprise part of the present invention. These materials comprise the appropriately substituted indene, indan, napthalene, 1,4-dihydronapthalene, tetralin, 7(H)-cycloheptabenzene, 5,6-dihydro-7(H)-cycloheptabenzene and 5,6,8,9-tetrahydro-7(H)-cycloheptabenzene carboxylic compounds correspondng to the appropriate carboxamide compounds of Formula I.
The carboxylic acid intermediate compounds may be prepared from starting materials such as 4-methoxyindene, 4-methoxyindan, 1-methoxynapthalene, 5-methoxy-1,4-dihydronapthalene, 5-methoxytetralin, 1-methoxy-7(H)-cycloheptabenzene, 1-methoxy-5,6-dihydro-7(H)-cycloheptabenzene or 1-methoxy-5,6,8,9-tetrahydro-7(H)-cycloheptabenzene. These starting materials are commercially available or may be prepared by known methods.
Halogenation of the position para to the ether of the starting material, preferably chlorination with preferred reagents such as N-chloro-succinimide and DMF, affords the methoxy-halo intermediate compound. Further halogenation in the ortho position, preferably bromination with N-bromosuccinimide and DMF, is followed by transformation of the ortho-halo substituent to a carboxy group, preferably by treatment with a strong base such as N-butyllithium and carbon dioxide. The carboxy compound is then reacted with an amine of the formula H 2;l N-Z as defined above to prepare the compounds within the scope of Formula I. The reaction may be conducted at temperatures on the order of 0° C. using a catalytic amount of ethyl chloroformate in chloroform in the presence of triethylamine. The chloroformate adduct is reacted with the amine of the formula H 2 N-Z to obtain the desired carboxamide. The reaction may also be conducted in the presence of a dehydrating catalyst such as a carbodiimide in a solvent at room temperature.
Compounds including various X substituents may be prepared by suitable choice of starting material. Those substituents which require protection may protected and deprotected as necessary or may be converted into the desired substituent from an appropriate precursor group. For example, compounds where X is chloro, bromo or iodo, may be reacted with cuprous cyanide in quinoline at about 150° C. to produce compounds where X is cyano. The cyano group may be converted to the acids, esters or amides.
The halo group may also be converted to the CF 3 group by reaction with trifluoromethyliodide and copper powder at about 150° C. in DMF. The halo group may also be converted to the methylsulfonyl substituent by reaction with cuprous methanesulfinate in quinoline at 150° C.
When X is nitro, selective hydrogenation results in the corresponding amine, which may be mono- or di-alkylated with loweralkyl halides or sulfates. The amino group may also be diazotized to the diazonium fluoride which is then thermally decomposed to the fluorine derivative compound. The amine may also be diazotized and heated in an aqueous medium to form the alcohol or heated in an alcohol to form the alkoxy compound. Chlorosulfonation of the amine group may form the corresponding sulfamyl or mono- and di-alkylsulfamyl groups.
Depending on the chemistry involved in the synthesis, these reactions may be carried out at any appropriate stage of the synthesis. For example, the synthesis of X starting from NO 2 may be done after the closed ring molecule or even after the carboxamide is prepared.
The compounds of this invention may contain at least one asymmetric carbon atom and may have two centers when R 1 =R 2 . As a result, the compounds of Formula I may be obtained either as racemic mixtures or as individual enantiomers. When two asymmetric centers are present the product may exist as a mixture of two diasteromers. The product may be synthesized as a mixture of the isomers and the desired isomer separated by conventional techniques such as chromatography or fractional crystalization from which each diasteromer may be resolved. On the other hand, synthesis may be carried out by known sterospecific processes using the desired form of the inermediate which would result in obtaining the desired specificity.
It is convenient to carry out condensation of the intermediate carboxylic acids mentioned above with the amines of the formula H 2 N-Z using the sterospecific materials. Accordingly, the acid may be resolved into its stereoisomers prior to condensation with resolved amine.
The compounds of this invention may be prepared by the following representative example.
EXAMPLE
The Preparation of (N1-Azabicyclo[2.2.2]oct-3-yl)-8-chloro-5-methoxytetralin-6-carboxamide
Step 1. 5-Methoxytetralin
Tin (II) chloride (0.2 mole) is added to a solution of 5-methoxy-tetralone (0.1 mole) in ethanol-conc. HCl (150 ml, 9:1) at reflux, and the reaction mixture is refluxed for 16 hours, cooled and the alcohol is evaporated. The aqueous residue is diluted with H 2 O, extracted with ether, dried (MgSO 4 ) and evaporated to the desired product.
Step 2. 8-Chloro-5-methoxytetralin
N-Chlorosuccinimide (0.05 mole) is added all at once to the methoxytetralin of step 1 above (0.5 mole) in DMF (150 ml), stirred for 4 hours at 0° C. and poured into ice water. The precipitate is filtered, dried and used as is in the next step.
Step 3. 6-Bromo-8-chloro-5-methoxytetralin
N-Bromosuccinimide (0.028 mole) is added all at once to the chloromethoxytetralin of step 2 above (0.025 mole) in DMF (150 ml) at 0° C., stirred for 4 hours and poured into ice water. The precipitate is filtered, dried and used as is in the next step.
Step 4. 8-Chloro-5-methoxytetralin-6-carboxylic acid N-Butyllithium (0.011 mole, hexane) is added dropwise to the bromochloromethoxytetralin of step 3 above (0.01 mole) in dry THF (100 ml) at -78° C. The reaction mixture is bubbled with CO 2 gas for 5 hours, warmed to 20° C. and poured into 10% aqueous HCl. The precipitate is filtered, dried and used as is in the next step.
Step 5. (N-1-Azabicyclo[2.2.2]oct-3yl)-8-chloro-5-methoxytetralin-6-carboxamide
Ethylchloroformate (4.9 mmoles) is added all at once to the tetralin carboxylic acid of step 4 above (5 mmoles) in chloroform (100 ml) and triethylamine (15 mmoles) at -23° C. and stirred for 1 hour. Aminoquinuclidine dihydrochloride (25 mmoles) and aqueous K 2 CO 3 (25 ml, sat'd) are added to the reaction mixture which is stirred for 1 hour, diluted with H 2 O and separated. The organic layer is washed with H 2 O, dried (MgSO 4 ) and evaporated affording the desired product.
The following compounds are prepared by procedures analogous to those described above.
(N-1-Azabicyclo[2.2.2]oct-3-yl)-7-chloro-4-methoxyindan-5-carboxamide.
(N-1-Azabicyclo[2.2.2]oct-3-yl)-4-chloro-1-methoxy-5,6,8,9-tetrahydro-7(H)-cycloheptabenzene-2-carboxamide.
(1-Azabicyclo[3.3.1]non-3-yl)-8-chloro-5-methoxytetralin-6-carboxamide.
(1-Azabicyclo[3.3.1]non-4-yl)-7-chloro-4-methoxyindan-5-carboxamide.
(1-Azabicyclo[3.3.1]non-4-yl)-4-chloro-1-methoxy-5,6,8,9-tetrahydro-7(H)-cycloheptabenzene-2-carboxamide.
Compounds within the scope of this invention have gastric prokinetic, anti-emetic and lack D 2 receptor binding activity and as such possess therapeutic value in the treatment of upper bowel motility and gastroesophageal reflux disorders. Further, the compounds of this invention may be useful in the treatment of disorders related to impaired gastrointestinal motility such as retarded gastric emptying, dyspepsia, flatulence, oesophageal reflux, peptic ulcer and emesis. Compounds of this invention exhibit 5-HT 3 antagonism and are considered to be useful in the treatment of psychotic disorders such as schizophrenia and anxiety and in the prophylaxis treatment of migraine and cluster headaches. These compounds are selective in that they have little or no dopaminergic antagonist activity.
Various tests in animals can be carried out to show the ability of the compounds of this invention to exhibit pharmacological responses that can be correlated with activity in humans. These tests involve such factors as the effect of the compounds of Formula I on gatric motility, emesis, selective antagonism of 5-HT 3 receptors and their D 2 dopamine receptor binding properties.
One such tst is the "Rat Gastric Emptying: Amberlite Bead Method". This test is carried out as follows:
The study is designed to assess the effects of a test agent on gastric emptying of a solid meal in the rat. The procedure is a modification of those used in L. E. Borella and W. Lippmann (1980) Digestion 20: 26-49.
PROCEDURE
Amberlite beads are placed in a phenol red solution and allowed to soak for several hours. Phenol red serves as an indicator, changing the beads from yellow to purple as their environment becomes more basic. After soaking, the beads are rinsed with 0.1 NaOH to make them purple and then washed with deionized water to wash away the NaOH.
The beads are filtered several times through 1.18 and 1.4 mm sieves to obtain beads with diameters in between these sizes. This is done using large quantities of deionized water. The beads are stored in saline until ready to use.
Male Sprague-Dawley rats are fasted 24 hours prior to the study with water ad libitum. Rats are randomly divided in treatment groups with an N of 6 or 7.
Test agents are prepared in 0.5% methylcellulose and administered to the rats orally in a 10 ml/kg dose volume. Control rats receive 0.5% methylcellulose, 10 ml/kg p.o. One hour after dosing, rats are given 60 Amberlite beads intra-gastrically. The beads are delivered via a 3 inch piece of PE 205 tubing attached to a 16 gauge tubing placed inside the tubing adapter to preent the beads from being pulled back into the syringe. The beads are flushed into each rat's stomach with 1 ml saline.
Rats are sacrificed 30 minutes after receiving the beads and their stomachs are removed. The number of beads remaining in each stomach is counted after rinsing the beads with NaOH.
The number of beads remaining in each stomach is subtracted from 60 to obtain the number of beads emptied. The mean number of beads ± S.E.M. is determined for each treatment group. The percent change from control is calculated as follows: ##EQU1##
Statistical significance may be determined using a t-test for independent samples with a probability of 0.05 or less considered to e significant.
In order to demonstrate the ability of the compounds of this invention as anti-emetic agents the following test for "Cisplatin-Induced Emesis in the Ferret" may be used. This test is a modified version of a paper reported by A. P. Florezyk, J. E. Schurig and W. T. Brodner in Cancer Treatment Reports: Vol. 66, No. 1. January 1982.
Cisplatin had been shown to cause emesis in the dog and cat. Florczyk, et al. have used the ferret to demonstrate the same effects.
PROCEDURE
Male castrated, Fitch ferrets, weighing between 1.0 and 1.5 kg have an in Indwelling catheter placed in the jugular vein. After a 2-3 day recovery period, the experimental procedure is begun.
30 minutes prior to administration of Cisplatin, ferrets are dosed with the compound in 0.9% saine (i.v.) at a dose volume of 2.0 ml/kg.
45 minutes after administration of Cisplatin, ferrets are again dosed with 0.9% saline (i.v.) mixture at a dose volume of 2.0 ml/kg.
Cisplatin is administered (i.v.) 30 minutes after the first dosing with the 0.9% saline. Cisplatin, 10 mg/kg is administered in a dose volume of 2.0 ml/kg.
The time of Cisplatin administration is taken as time zero. Ferrets are observed for the duration of the experiment (4 hours). The elapsed time to the first emetic episode is noted and recorded, as are the total number of periods of emesis.
An emetic (vomiting) episode is characterized by agitated behavior, such as pacing around the cage and rapid to and fro movements. Concurrent with this behavior are several retching movements in a row, followed by a single, large, retch which may or may not expulse gastric contents. Immediately following the single large retch, the ferret relaxes. Single coughs or retches are not counted as vomiting episodes.
D-2 Dopamine Receptor Binding Assay
The D-2 dopamine receptor binding assay has been developed with slight modifications using the method of Ian Cresse, Robert Schneider and Solomon H. Snyder, Europ. J. Pharmacol. 46: 377-381 (1977). Spiroperidol is a butyrophenone neuroleptic whose affinity for dopamine receptors in brain tissue is greater than that of any other known drug. It is a highly specific D-1 dopamine (non-cyclase linked) receptor agent with K 1 values of 0.1-0.5 for D-2 inhibition and 300 nM for D-1 inhibition.
Sodium ions are important regulators of dopamine receptors. The affinity of the D-2 receptor is markedly enhanced by the presence of millimolar concentrations of sodium chloride. The Kd in the absence and presence of 120 mM sodium chloride is 1.2 and o.086 nM respectively. Sodium chloride (120 mM) is included in all assays as a standard condition.
The caudate nucleum (corpous striatum) is used as the receptor source because it contained the highest density of dopamine receptors in the brain and periphery.
PROCEDURE
Male Charles-River rats weighing 250-300 g are decapitated and their brains removed, cooled on ice, and caudate dissected immediately and frozen on dry ice. Tissue can be stored indefinitely at -70° C. For assay caudate is homogenized in 30 ml of tris buffer (pH 7.7 at 25° C.) using the polytron homogenizer. The homogenate is centrifuged at 40,000 g (18,000-19,000 RPM in SS-34 rotor) for 15 minutes. Pellet is resuspended in fresh buffer and centrifuged again. The final pellet is resuspended in 150 volumes of assay buffer.
Specific 3 H-spiroperiodol binding is assayed in a total 2 ml reaction volume consisting of 500 μl of caudate homogenate, 50 mM tris buffer (pH 7.4 at 35° C.), 5 mM MgSO 4 , 2 mM EDTA 2NA, 120 mM NaCl, 0.1% ascorbic acid, 0.4 nM 3 H-spiroperidol and test compound or assay buffer. When catecholamines are included in the assay, 10 μM pargyline should be included in the reaction mixture to inhibit monoamine oxidase. Samples are incubated at 35° C. for 30 minutes followed by addition of 5 ml ice cold 50 mM TRIS (pH 7.7 at 25° C.) and filtration through GF/B glass fiber filters on a Brandel Receptor Binding Filtration apparatus. Filters are washed twice with an additional 5 ml of tris buffer each. Assay groups are performed in triplicate and 1 μM D(+) butaclamol is used to determine nonspecific binding. Filters are placed in vials containing 10 ml of Ecoscint phosphor, shaken for 30 minutes and dpm determined by liquid scintillation spectrophotometry using a quench curve. Proteins are determined by the method of Bradford, M. Anal. Biochem 72, 248(1976) using Bio-Rad's coomassie blue G-250 dye reagent. Bovine gamma Globulin supplied by BIO-RAD is used as the protein standard.
BEZOLD-JARISCH EFFECT IN ANESTHETIZED RATS
Male rats 260-290 g are anesthetized with urethane 1.25 g/kg -1 i.p., and the trachea cannulated. The jugular vein is cannulated for intravenous (i.v.) injection of drugs. Blood pressure is recorded from a cannula in the left carotid artery and connected to a heparin/saline-filled pressure transducer. Continuous heart rate measurements are taken from the blood pressure recordings. The Bezold-Jarisch effect is evoked by rapid, bolus i.v. injections of 5-HT and measurements are made of the fall in heart rate. In each rate, consistent responses are first established with the minimum dose of 5-HT that evokes a clear fall in heart rate. Injections of 5-HT are given every 12 minutes and a dose-response curve for the test compound is established by injecting increasing doses of compound 5 minutes before each injectin of 5-HT. The effect of the compound on the 5-HT-evoked bradycardia is calculated as a percent of the bradycardia evoked by 5-HT before injection of compound.
In separate experiments to measure the duration of 5-HT antagonism caused by the compounds of this invention, a single dose of compound is injected 5 minutes before 5-HT, and the effects of 7 repeated challenges with 5-HT are then monitored. The effects of the compound on the efferent vagal limb of the Bezold-Jarisch reflex are checked by electrically stimulating the peripheral end of a cut vagus nerve. Unipolar electrical stimulation is applied every 5 minutes via a pair of silver electrodes, using 1 ms rectangular pulses in 5 strains with a maximally-effective voltage (20 V at 10 Hz). Pulse frequency may vary from 5-30 Hz and frequency-response curves are constructed before and 10 minutes after i.v. injection of a single dose of compound.
The results of these above tests indicate that the compounds for this invention exhibit a valuable balance between the peripheral and central action of the nervous system and may be useful in the treatment of disorders related to impaired gastro-intestinal motility such as gastric emptying, dyspepsia, flatulence, esophageal reflux and peptic ulcer and in the tretment of disorders of the central nervous system such as psychosis.
The compounds of the present invention can be administered to a mammalian host in a variety of forms adapted to the chosen route of administration, i.e., orally, or parenterally. Parenteral administration in this respect includes administration by the following routes: intravenous, intramuscular, subcutaneous, intraocular, intrasynovial, transepithelially including transdermal, opthalmic, sublingual and buccal; topically including ophthalmic, dermal, ocular, rectal and nasal inhalation via insufflation and aerosol and rectal systemic.
The active compound may be orally administered, for example, with an inert diluent or with an assimilable edible carrier, or it may be enclosed in hard or soft shell gelatin capsules, or it may be compressed into tablets, or it may be incorporated directly with the food of the diet. For oral therapeutic administration, the active compound may be incorporated with excipient and used in the form of ingestible tablets, buccal tablets, troches, capsules, elixirs, suspensions, syrups, wafers, and the like. Such compositions and preparations may, of course, be varied and may conveniently be between about 2 to about 6% of the weight of the unit. The amount of active compound in such therapeutically useful compositions is such that a suitable dosage will be obtained. Preferred compositions or preparations according to the present invention are prepared so that an oral dosage unit form contains between about 50 and 300 mg of active compound.
The tablets, troches, pills, capsules and the like may also contain the following: A binder such as gum tragacanth, acacia, corn starch or gelatin; excipients such as dicalcium phosphate; a disintegrating agent such as corn starch, potato starch, alginic acid and the like; a lubricant such as magnesium stearate; and a sweetening agent such as sucrose, lactose of saccharin may be added or a flavoring agent such as peppermint, oil of wintergreen, or cherry flavoring. When the dosage unit form is a capsule it may contain, in addition to materials of the above type, a liquid carrier. Various other materials may be present as coatings or to otherwise modify thephysical form of the dosage unit. For instance, tablets, pills, or capsules may be coated with shellac, sugar or both. A syrup or elixir may contain the active compound sucrose as a sweetening agent, methyl and propylparabens as preservatives, a dye and flavoring such as cherry or orange flavor. Of course, any material used in preparing any dosage unit form should be pharmaceutically pure and substantially non-toxic in the amounts employed. In addition, the active compound may be incorporated into sustained-release preparations and formulations.
The active compound may also be administered parenterally or intraperiotoneally. Solutions of the active compound as a free base or pharmacologically acceptable salt can be prepared in water suitably mixed with a surfactant such as hydroxypropylcellulose. Dispersion can also be prepared in glycerol, liquid polyethylene glycols, and mixtures thereof and in oils. Under ordinary conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms.
The pharmaceutical forms suitable for injectable use include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. In all cases the form must be sterile and must be fluid to the extent that easy syringability exists. It may be stable under the conditions of manufacture and storge and must be preserved against the contaminating action of microorganisms such as bacteria and fungi. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol, and the like), suitable mixtures thereof, and vegetable oils. The proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants. The prevention of the action of microorganisms can be brought about by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thimersal, and the like. In many cases, it will be preferable to include isotonic agents, for example, sugars or sodium chloride. Prolonged absorption of the injectable compositions involves the incorporation of an agent delaying absorption, for xample, aluminum monostearate and gelatin.
Sterile injectable solutions are prepared by incorporating the active compound in the require amount in the appropriate solvent with various of the other ingredients enumerated above, as required, followed by filtered sterilization. Generally, dispersions are prepared by incorporating the various sterilized active ingredients into a sterile vehicle which contains the basic dispersion medium and the required other ingredients from those enumerated above. In the case of sterile powders for the preparation of sterile injectable solutions, the preferred methods of preparations are vacuum drying and the freeze drying technique which yield a powder of the active ingredient plus any additional desired ingredient from previously sterile-filtered solution thereof.
The therapeutic compounds of this invention may be administered alone to a mammal or in combination with pharmaceutically acceptable carriers, as noted above, the proportion of which is determined by the solutibility and chemical nature of the compound, chosen route of administration and standard pharmaceutical practice.
The physician will determine the dosage of the present therapeutic agents which will be most suitable for prophylaxis or treatment and will vary with the form of administration and the particular compound chosen, and also, it will vary with the particular patient under treatment. He will generally wish to initiate treatment with small dosages by small increments until the optimum effect under the circumstances is reached. The therapeutic dosage will generally be from 0.1 to 20 mg or from about 0.01 mg to about 5 mg/kg of body weight per day and higher although it may be administered in several different dosage units from once to several times a day. Higher dosages are required for oral administration.
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Certain specific substituted benzobicyclic carboxamides and their valuable use as 5-HT3 antagonists having CNS and gastric prokenetic activity void of any significant D 2 receptor binding activity are disclosed.
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BACKGROUND
[0001] Field of the Invention
[0002] The present invention refers to a device which stabilizes the hand and wrist for more effective scrubbing, cleaning, sanding and the like by utilizing an extension which provides resistance from the arm. An extension from the device is joined to the arm such that the working component is stabilized in the hand while working and when not working.
[0003] 2. Description of Concurrent Art
[0004] Present systems scrub, clean, sand and the like various surfaces using devices held only by a hand. Hand scrubbing techniques are common on tile, ceramic, plastic, granite, counter tops, bathroom surfaces, pools, patios, outdoor grills, sanding plaster, removing or roughening surfaces for painting, furniture and wood finishing, garage floors and the like. Often several materials such as sponges, steel wool, brushes, sandpapers, foam, plastic, metal meshes and the like are used individually, in sequence or together.
[0005] There are many automated systems such as motorized machines which roll, vibrate or rotate. These can be hard to control, heavy and expensive limiting them to professional use. Some systems add a handle similar to a broom handle but there is little control during use due to the size and added weight.
[0006] It would be desirable use hand controlled scrubbers and sanders to provide controlled scrubbing. Areas where more force is required can be applied while other areas are cleaned, scrubbed or sanded lightly. It would further be desirable to provide additional support for the hand and the wrist during use to avoid fatigue and permanent damage as occurs with carpal tunnel syndrome and to be able to apply more force for more effective work.
SUMMARY OF THE INVENTION
[0007] The instant apparatus and system, as illustrated herein, is clearly not anticipated, rendered obvious, or even present in any of the prior art mechanisms, either alone or in any combination thereof. The versatile system, method and series of apparatuses for creating and utilizing added support of the hand and wrist by extension onto the arm is described in general and specifics though not every variation is shown. The scrubbing, roughening and sanding device, hereon referred to as the scrubber, secures the device to a person's forearm. The device places and keeps in place, the working end in the hand without the hand physically grabbing and holding it. The hand and forearm simply guide the scrubber or surfaces. In the preferred version, the part of the scrubber in the hand is hinged to the part onto the forearm. The hinge allows for easy movement over surfaces during use as the working end can angle easily. The hinge can be a simple rod and tube or a ball and socket depending on the amount of movement required. Any common type of hinge mechanism can be used though is not required.
[0008] The working portion, that portion in the hand, can be a fixed use such as a sponge or sandpaper. In the preferred embodiment, various attachments are used. A sponge is snapped into position for use and is easily removed and replaced by a sandpaper block or steel wool etc. The scrubber can be designed for several uses by simply changing attachments.
[0009] In an alternative technique, handles are attached or detached to the working component. In some situations, a person may prefer to have a handle on the top or use both a handle on the top and the forearm extension. The forearm extension and other handles are easily attached or detached depending on the use and personal preference during use.
[0010] In the preferred embodiment, the forearm extension is secured to the forearm by materials such as Velcro, snaps, reversible adhesives, interlocking, elastic bands, cloth bands, rope, wire or usual techniques and materials used to join parts together. When the scrubber is secured to the arm, hand muscles are not required to hold the scrubber. The wrist moves in just the direction of the hinge resulting in less adverse forces. The forearm extension can be secured with rubber bands, glove like forms, or the like.
[0011] The scrubber can be constructed of any common material or combination of materials such as wood, metal, ceramic, plastic, reinforce fiber or fabrics, air balloons, sponge, abrasives, steel wool, brushes, and other common materials for cleaning, roughening, sandpapering, removing, or the like.
[0012] The foregoing has outlined the more pertinent and important features of the present invention in order that the detailed description of the invention that follows may be better understood, and the present contributions to the art may be more fully appreciated. It is of course not possible to describe every conceivable combination of components and/or methodologies, but one of ordinary skill in the art may recognize that many further combinations or permutations are possible. Accordingly, the novel architecture described below is intended to embrace all such alterations, modifications, and variations that fall within the spirit and scope of the appended claims.
[0013] There has thus been outlined, rather broadly, the more important features of the versatile arm supported scrubber system and series of accompanying systems and apparatuses and embodiments in order that the detailed description thereof that follows may be better understood, and in order that the present contribution to the art may be better appreciated. There are additional features of the invention that will be described hereinafter and which will form the subject matter of the claims appended hereto.
[0014] In this respect, before explaining at least one embodiment of the invention in detail, it is to be understood that the invention is not limited in its application to the details of construction and to the arrangements of the components set forth in the following description or illustrated in the drawings. The invention is capable of other embodiments and of being practiced and carried out in various ways. Also, it is to be understood that the phraseology and terminology employed herein are for the purpose of description and should not be regarded as limiting.
[0015] These together with other objects of the invention, along with the various features of novelty, which characterize the invention, are pointed out with particularity in the claims annexed to 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 made to the accompanying drawings and descriptive matter in which there are illustrated preferred embodiments of the invention.
[0016] To the accomplishment of the foregoing and related ends, certain illustrative aspects are described herein in connection with the following description and the annexed drawings. These aspects are indicative of the various ways in which the principles disclosed herein can be practice and all aspects and equivalents thereof are intended to be within the scope of the claimed subject matter. Other advantages and novel features will become apparent from the following detailed description when considered in conjunction with the drawings.
BRIEF DESCRIPTION OF THE DRAWINGS
[0017] The advantages of the present apparatus will be apparent from the following detailed description of exemplary embodiments thereof, which description should be considered in conjunction with the accompanying drawings, in which: Having thus described the system in general terms, reference will now be made to the accompanying drawings, which are not necessarily drawn to scale, and wherein:
[0018] FIG. 1 illustrates a plan view of the top and side of the scrubber.
[0019] FIG. 2 illustrates a plan view of various inserts placed into one version of the scrubber.
[0020] FIG. 3 illustrates a plan view from the top, side, bottom and in use of one version of the scrubber.
[0021] FIG. 4 illustrates a plan view of the top and side of a motorized scrubber.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
[0022] Referring to FIG. 1 , scrubber 2 reveals a bottom view of an alternative scrubber. Scrubber 4 is a side view of scrubber 2 . Forearm support 6 has Velcro 8 and Velcro 10 which when wrapped around a forearm, not shown, holds scrubber 2 to the arm. Hinge 12 joins forearm support 6 to plate 14 allowing plate 14 to follow a surface easily during function. For example, when sandpaper is placed on plate 14 and moved up and down a wall, the angle between the arm and the wall changes. The hinge allows for easy angle change of plate 14 to forearm support 6 during this sanding motion. Plate 14 is designed to accept materials, be the material, or accept inserts to provide different functions. A sponge, coarse sponge, steel wool, plastic, abrasive blocks, various sandpapers, brushes, and combinations of these or like materials to clean, remove or roughen surfaces is used.
[0023] Referring to FIG. 2 , an alternative scrubber 20 has plate 30 with attachment forearm support 22 , handle 26 , alternative handle 28 which are attached at hinge 38 , 40 or surface 32 of plate 30 . Each of these components are attached for use or not attached as preferred by the user. Forearm attachment 23 surrounds a forearm by placing the hand through and out hole 24 . In the preferred embodiment, forearm attachment 23 is adjustable to fit securely to a forearm. Alternatively, elastic material, materials that stretch or the like are used. Velcro, interlocking, cinching, or other common methods of tightening a strap or glove can be used. Plate 30 has attachment area 36 to accept attachments. The various attachments are joined by Velcro, snap, friction fit, interlocking, adhesives, or other common methods of joining parts. Attachment 34
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A scrubbing device designed to provide support for the hand and wrist during use by utilizing an extension onto the forearm.
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CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] The present application claims the benefit of the filing date of U.S. Provisional Patent Application No. 61/607,242, filed Mar. 6, 2012 and entitled “Bone Plate and Aiming Block,” the disclosure of which is hereby incorporated by reference herein.
BACKGROUND OF THE INVENTION
[0002] The present invention relates to bone plates, and more particularly, the insertion of screws through plates for the purpose of repairing fractures.
[0003] Bone plates are widely utilized in the repair of certain fractures of bones in both human and animal bodies. Generally, such plates are designed to be fixed on either side of a fracture in order to maintain the portions of the bone created by the fracture in registration with one another in order to promote healing of the bone. Typically, the plates are fixed via screws, pegs, or the like, which may be inserted at different angles in order to secure the best purchase of bone possible.
[0004] It is also widely known to utilize aiming or guiding blocks for guiding a drill and/or a screw during insertion so that the screw ultimately extends along a desired axis. Such guides take many different forms with the general goal being to extend the depth of a bone plate hole and provide stability to the drill and/or screw during the drilling and insertion processes. While generally suited for their intended purpose, these guides have some drawbacks. For instance, many require intricate attachment mechanisms that increase the difficulty of a surgery, while others suffer from misalignment either during attachment or even thereafter. Likewise, many require cumbersome instruments for use in initial placement of the aiming block on the bone plate, as well as overly complicated means for fixing the blocks with respect to the bone plates.
[0005] Therefore, there exists a need for an improved aiming or guide block for use in connection with bone plates.
BRIEF SUMMARY OF THE INVENTION
[0006] A first aspect of the present invention is a bone-fixation system including a bone plate having a recessed section with a plurality of first holes and an aiming block including an extension for reception within the recess and second holes that align with the first holes when the extension is received within the recess. Other embodiments of this first aspect may further include a joystick having a threaded distal end for reception within a first threaded hole of the plate and within a second threaded hole of the aiming block. Still further embodiments may allow the joystick to maintain the aiming block in position when the distal end is threaded into the first threaded hole of the bone plate.
[0007] A second aspect of the present invention is a bone-fixation system, the system comprising a bone plate having a section with a plurality of holes and a recessed area at least partially surrounding one or more of the holes, the recessed area defining a floor surface situated below a top surface of the plate, the floor surface extending at least partially between some or all of the plurality of holes. An aiming device also forms part of the system and has a plurality of holes arranged to align with the plurality of holes in the plate and an extension, the extension being receivable within the recessed area and defining a bottom surface adapted to at least partially rest on the floor surface. In some embodiments of this second aspect, the bone plate includes a head, and the recessed area extends along a major portion of the head.
[0008] A third aspect of the invention comprises a bone-fixation system including a bone plate having a section with a plurality of holes and a recessed area at least partially surrounding one or more of the holes, the recessed area defining a floor surface situated below a top surface of the plate, the floor surface extending at least partially between some or all of the plurality of holes. An aiming device also forms part of the system and has a plurality of holes arranged to align with the plurality of holes in the plate and an extension, the extension being receivable within the recessed area and defining a bottom surface adapted to at least partially rest on the floor surface. Lastly, an insertion tool is included in the system and comprises a handle and a shaft, a distal end of the insertion tool being engageable with the aiming device to manipulate the aiming device into engagement with the plate. In some cases, the insertion tool includes an extension projecting from the shaft and a shoulder, a diameter of the shoulder being greater than a diameter of the extension, the extension being insertable through at least one of the holes of the aiming device and into a hole in the plate so that the shoulder abuts a top surface of the aiming device.
[0009] A fourth aspect of the invention is a method of implanting a bone plate, the method comprising: (1) providing a bone plate having a section with a plurality of holes and a recessed area adjacent one or more of the holes; (2) providing an aiming device having a plurality of holes and an extension, at least some of the plurality of holes being alignable with the plurality of holes in the plate; (3) engaging a distal end of an insertion tool with at least one of the holes in the aiming device; (4) after the engaging step, manipulating the insertion tool to engage the aiming device with the plate, the extension of the aiming device being situated within the recessed area of the plate; and (5) engaging the distal end of the insertion tool with at least one hole in the plate so that a shoulder of the insertion tool engages a top surface of the aiming device to secure the aiming device to the plate. The engaging steps of the method may, in one embodiment, comprise rotating a threaded distal end of the insertion tool, such that the threaded distal end engages a threaded hole formed in the aiming device or the plate.
BRIEF DESCRIPTION OF THE DRAWINGS
[0010] A more complete appreciation of the subject matter of the present invention and the various advantages thereof can be realized by reference to the following detailed description, in which reference is made to the accompanying drawings in which:
[0011] FIG. 1 is a top perspective view of a bone plate according to one embodiment of the present invention.
[0012] FIG. 2A is a top perspective view of a right-oriented aiming block for use with a bone plate according to the present invention.
[0013] FIG. 2B is a top perspective view of a left-oriented aiming block for use in connection with the bone plate shown in FIG. 1 .
[0014] FIG. 3 is a bottom perspective view of the bone plate of FIG. 1 (shown as transparent) with the aiming block of FIG. 2B placed adjacent thereto.
[0015] FIG. 4 is a bottom view of the aiming block of FIG. 2B .
[0016] FIG. 5 is perspective view of a joystick for use in placement of the aiming blocks of the present invention.
[0017] FIG. 6 is a top view of a construct consisting of the bone plate of FIG. 1 , the aiming block of FIG. 2B , and the joystick of FIG. 5 .
[0018] FIG. 7 is a cross-sectional view taken on line A-A of FIG. 6 depicting the cooperation among the bone plate, the aiming block, and the joystick.
[0019] FIG. 8 is a perspective view of the bone plate of FIG. 1 shown placed on a fractured clavicle bone.
[0020] FIG. 9 is a perspective view of the bone plate, aiming block, and joystick construct with cylindrical bodies meant to represent screws, pegs, or other fixation members placed through the holes formed in the aiming block and bone plate.
[0021] FIG. 10 is a perspective view of the bone plate of FIG. 1 shown fully attached to a fractured clavicle.
DETAILED DESCRIPTION
[0022] In describing the preferred embodiments of the invention(s) illustrated and to be described with respect to the drawings, specific terminology will be used for the sake of clarity. However, the invention(s) is not intended to be limited to any specific terms used herein, and it is to be understood that each specific term includes all technical equivalents, which operate in a similar manner to accomplish a similar purpose.
[0023] Referring to the drawings, wherein like reference numerals refer to like elements, FIGS. 1-10 depict components usable in fixation of human clavicle fractures. At the outset, it is to be understood that while the various components discussed herein are directed toward a use in connection with fractured clavicle bones, such components may be modified (if necessary) to have applicability in the repair of fractures in other bones in human or animal bodies. Those of ordinary skill in the art would readily recognize that such components, although discussed in connection with a single purpose, have applicability for other purposes in the orthopedic field.
[0024] Beginning with FIG. 1 , there is shown a bone plate 10 configured for use in fixing a clavicle fracture. Bone plate 10 includes a plurality of bone screw receiving holes 12 that may facilitate the locking or fixation of such screws to plate 10 and the plate to the bone, elongate holes 14 that may facilitate the reduction of the fracture through the use of compression screws, a recessed area 16 including a plurality of bone screw receiving holes 18 similar to bone screw holes 12 , a plurality of K-wire or suture receiving holes 20 , and a threaded hole 22 situated within recessed area 16 . Bone plate 10 is preferably constructed of a metallic material such as titanium or the like, and may be designed to be bendable in order to fit certain profiles of certain clavicle bones. In addition, it is noted that both holes 12 and 18 may be fitted with a rim capable of being deformed by the head of a bone screw, thereby fixing the bone screw to the plate when inserted. Holes 12 , 14 and 18 can also be designed to receive different types of screws, for instance, any number of those holes can receive locking, non-locking or compression screws, as well as pins or other fixation mechanisms.
[0025] FIGS. 2A and 2B depict aiming blocks 30 , which include nearly identical structure, but which are configured for use with two different bone plates 10 . For instance, while block 30 of FIG. 2B is configured to cooperate with recess 16 of plate 10 , as shown in FIG. 1 , block 30 of FIG. 2A exhibits an opposite construction suited for a plate oppositely constructed to the one shown in FIG. 1 . In other words, where plate 10 may be for use with a clavicle on one side of the body, an oppositely configured plate would be utilized on the other side of the body. For the sake of simplicity, only a single aiming block 30 will be referred to herein. Preferably, block 30 is constructed of polymeric or metallic material, such as PEEK, titanium, or stainless steel, but it is to be understood that any suitable type of material may be employed.
[0026] Aiming block 30 includes holes 32 which are designed to align with holes 18 when aiming block 30 is placed within recess 16 of plate 10 . Likewise, a K-wire hole 34 is provided on aiming block 30 to align with K-wire hole 20 of plate 10 . Finally, a threaded hole 36 is provided on aiming block 30 , which is aligned with threaded hole 22 located within recess 16 of plate 10 . As is best shown in FIGS. 3 and 4 , aiming block 30 also includes an extension 38 designed to cooperate and extend into recess 16 of plate 10 . Extension 38 is preferably sized and shaped so as to fit snugly within recess 16 and prevent aiming block 30 from moving when engaged with plate 10 . FIG. 4 best depicts the specific shape of extension 38 , and it is particularly pointed out that the extension is a somewhat discontinuous structure by virtue of the hole structure of block 30 . It is to be understood that extension 38 may be many shapes, as long as such cooperates with recess 16 to keep block 30 aligned with plate 10 . Moreover, extension 38 could be sized so as to form an interference fit or taper lock with recess 16 , or such could include a locking structure designed to cooperate with a locking structure in recess 16 .
[0027] FIG. 5 depicts joystick 40 , which is a tool designed for cooperation with both aiming block 30 and plate 10 . Joystick 40 includes a handle 42 , an elongate shaft 44 , a shoulder section 46 , and a threaded distal tip 48 . In addition, a section 49 extends between shoulder section 46 and distal tip 48 , and includes a diameter that is less than the diameters of both of those flanking sections. As with the other components discussed in the present application, joystick 40 can be constructed of many different materials, including preferably metallic materials such as titanium or stainless steel. It is to be understood that while distal tip 48 is threaded in the preferred embodiment it can include any number of different fixation means, such as taper lock devices, friction fit devices, and ball detent structures.
[0028] In use, as is depicted in FIGS. 6 , 7 , and 9 , joystick 40 is designed to thread into both hole 22 of plate 10 and hole 36 of aiming block 30 . Specifically, during use, a surgeon first threads distal tip 48 into threaded hole 36 of aiming block 30 . In this position, joystick 40 may be utilized to manipulate and move aiming block 30 into a position within the body and on plate 10 , which is in turn placed on a bone. Once extension 38 of aiming block 30 is placed within recess 16 of plate 10 , thereby ensuring proper placement of aiming block 30 on plate 10 , additional threading of joystick 40 , and in particular distal end 48 , can occur. This results in the position best shown in the cross-sectional view of FIG. 7 , where distal tip 48 is threaded into threaded plate hole 22 , and shoulder section 46 abuts a top surface of aiming block 30 around hole 36 . It is to be understood that the smaller diameter of section 49 (as well as its length) allows for joystick 40 to extend through threaded hole 36 of aiming block 30 and ultimately into the plate. In this position, aiming block 30 is pressed against plate 10 by virtue of the abutment of shoulder section 46 against the top surface of the plate, thereby essentially affixing the aiming block in place.
[0029] Remaining FIGS. 8-10 depict proper placement of plate 10 on a fractured clavicle. Specifically, as is shown in FIG. 8 , plate 10 is first placed over a fracture site on the clavicle, so that the fracture line is spanned by at least a portion of the plate. This initial placement may be aided through the use of K-wires or sutures which can be received in holes 20 of plate 10 . With the plate in this position, the above-discussed cooperation among plate 10 , aiming block 30 , and joystick 40 can be established. Any K-wires utilized may also be received within hole 34 of aiming block 30 . Thereafter, fixation elements (represented by cylindrical elements 50 in FIG. 9 ) can be inserted through holes 32 of aiming block 30 and ultimately through holes 18 of plate 10 . As is noted above, the additional structure provided by aiming block 30 , and more particularly the extension provided by holes 32 , allows for a more specific placement of screws at a given angle. In addition, it is noted that aiming block 30 may be utilized to guide a drill, which may be necessary to use prior to inserting screws. Additionally, remaining holes 12 and 14 of plate 10 may accept other screws for fixing plate 10 along the clavicle bone.
[0030] A fully fixed plate 10 with screws placed through certain of its holes is shown in FIG. 10 . Again, although shown and discussed as being for use in connection with repairing a clavicle fracture, plate 10 , aiming block 30 , and joystick 40 may be configured to be utilized in repairing fractures of any bone within the human body. Likewise, it is noted that although specific constructions are shown in the figures, each component of the present invention may vary depending upon intended use or for aesthetic purposes.
[0031] Although the invention(s) herein has been described with reference to particular embodiments, it is to be understood that these embodiments are merely illustrative of the principles and applications of the present invention(s). It is therefore to be understood that numerous modifications may be made to the illustrative embodiments and that other arrangements may be devised without departing from the spirit and scope of the present invention(s) as defined by the appended claims.
[0032] It will also be appreciated that the various dependent claims and the features set forth therein can be combined in different ways than presented in the initial claims. It will also be appreciated that the features described in connection with individual embodiments may be shared with others of the described embodiments.
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A bone-fixation system is disclosed, the system comprising a bone plate having a section with a plurality of holes and a recessed area at least partially surrounding one or more of the holes, the recessed area defining a floor surface situated below a top surface of the plate, the floor surface extending at least partially between some or all of the plurality of holes, and an aiming device having a plurality of holes arranged to align with the plurality of holes in the plate and an extension, the extension being receivable within the recessed area and defining a bottom surface adapted to at least partially rest on the floor surface.
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BACKGROUND OF THE INVENTION
Printing systems for printing articles with identification indicia such as trade names, universal product codes, optical character reading codes, inventory control, product prices, sizes, colors, etc. are well known and may include multi-station arrangements in which the articles to be printed are passed successively to plural printing stations where each article is printed with different information at each station. In situations where different information is desired on opposite sides of the articles they must be turned over and fed through the machine or system again. This, of course, requires changing the indicia on the printing heads. Once these articles are printed they are usually stored until used, at which time they are matched with the product to be associated therewith.
THE PRIOR ART
The following listed patents show plural station printing machines but do not disclose a printing system of the type disclosed and claimed herein which can be a component of a continuous assembly or manufacturing line wherein an article receiving envelope can be formed, e.g. cut out, folded, etc., conveyed to a printing station, then to filling boxing, and cartoning stations, and finally to a storage station while only requiring the printing plates to be changed to conform to the product associated therewith:
1. U.S. Pat. No. 2,205,216, Loughery, 6/18/40
2. U.S. Pat. No. 2,758,538, Crinketal, 8/14/56
3. U.S. Pat. No. 3,180,253, Hildmann 4/27/65
4. U.S. Pat. No. 3,911,813, Scheaffer 10/14/75
The Robertson U.S. Pat. No. 3,732,807, 5/15/73 shows opposite side printing but does not hint at the specific improvement disclosed and claimed herein.
SUMMARY OF THE INVENTION
The present invention relates to a system of printing information indicia on opposite sides of a generally flat product carrying cardboard envelope or the like which is readily adaptable for insertion into an assembly line type operation and which avoids the shortcomings of the prior art mentioned above. As will be discussed specifically later on, the system includes a novel arrangement of printing stations located in the path of a conveyor located in an assembly line between other work stations, including an envelope filling station. Each printing station includes substantially identical printing devices through which the envelopes are conveyed and temporarily stopped to permit information indicia to be printed thereon. The example presented illustrates three identical printers, two of which print on the "top" of the envelope while the other prints on the "bottom" thereof. The "bottom" printer is merely turned upside-down relative to the other two printers. Each printer includes a vertically spaced removable heated printing plate and an anvil or reaction platen. The heated printing plate is mounted to reciprocate towards and away from the anvil or platen. The anvil is adjustable mounted toward and away from the printing plate to compensate for different thicknesses of envelopes.
Further features, advantages and objects of the invention will be best understood from the following detailed description of the specific embodiment when read in connection with the accompanying drawings, in which:
FIG. 1 is a schematic perspective elevational view of the printing system with parts removed for clarity;
FIG. 2 is a schematic top view of a printer;
FIG. 3 is a schematic side view of a printer;
FIG. 4 and 5 show opposite sides of printed envelopes; and
FIG. 6 is simplified block diagram of various components.
DETAILED DESCRIPTION OF THE INVENTION
Referring first to FIG. 1 of the drawings, the system includes a supply magazine M for holding a stack of envelopes E to be conveyed to printing devices 1, 2 and 3. It should be noted here that parts of the printers 1, 2 and 3 have been removed for purposes of clarity. While printers 1 and 2 are disclosed as top printers and printer 3 is a bottom printer this is merely descriptive as any arrangement and any number of printers could be employed and still fall within the intended scope of the invention. Preferably each printer is pivotably supported upon the main frame S to provide easy access to the various printer components. As shown by FIG. 3, each printer includes a support arm or frame 14 supported at one end by a pivot pin means 16 fixed to the frame S and the opposite end of frame 14 is releasably coupled to frame S by a fastener means 18.
Envelopes E are fed from magazine M by feeder arrangement F driven by feeder drive D which could include any conventional motor. At or near the exit side or mouth of the magazine is located a group of endless conveyor belts 4 mounted on and driven by pulleys 5 fixed to shaft 6 mounted at one end in a support and bearing arrangement 7 in the main frame or support S, and at the other end to conveyor drive CD and to frame structure not shown. On the entrance or inboard side of each printer, e.g., the side receiving the incoming envelopes to be printed, are mounted control sensing detectors 8, FIGS. 1 and 3, for detecting incoming envelopes and brush-like means 9 to press the envelopes E against belts 4 to ensure firm contact therebetween. The detectors or sensors may take any well known form and the ones illustrated are vertically spaced electric eyes, the purpose of which will be subsequently disclosed. At the exit or outboard side of each printer are stop pins 10 connected to and selectively actuated by a fluid cylinder 12, FIG. 3. The cylinder 12 moves the pins between a retracted position permitting passage of an envelope and an extended position in the path of an envelope. As pointed out above, printers 1 and 2 are located on one side of the envelope, except the reaction plate and anvil while the third printer is located on the opposite side of the envelope. The third printing arrangement requires a slightly different positioning of the conveyor belts, e.g. the belts 5' are spaced apart further. This is necessary because the moveable heated printing plate must move toward the fixed anvil and thus between the laterally spaced runs of the belts. The belts 5' are supported upon pulleys 5 secured to shaft 6' which, in turn, is driven from belts 4. Note the difference in sizes of the printed matter in FIGS. 4 and 5. In FIG. 4 the area of printed matter is narrow enough to permit the printing plates to pass between the relative close spacing of the belts 5' while the size of the printing plate required for that illustrated in FIG. 5, is much larger. At the exit end of printer 3 is located an extraction device 15 driven by conveyor belts 5, to move the printed envelope to a pushing or transfer device generally indicated by numeral 20 which pushes or transfers the printed envelopes to a work station WS at which station merchandise is placed therein. Pushing or transfer device 20 is comprised of a cylinder 21 having therein a rodless piston attached to an elongated envelope engaging plate 23 by an element 24 adapted to reciprocate back and forth along cylinder 21 through slot 25. Stop means 26 are located on frame S at the exit end of printer 3 to stop and locate the printed envelope on pusher 20. Sensing means 28 is also located at the exit of printer 3 to sense the presence of an envelope E and command pusher or transfer device 20 to move same to the work station WS.
In view of the fact that the printers are generally alike only one is specifically illustrated and described. Attention is directed to FIGS. 2 and 3 which show the details of a printer as employed in this system. The printer generally noted by reference character 30 includes a lower reaction platen member or anvil 31 which is vertically adjustable by screws 32 associated therewith and a support plate 33 connected in any convenient manner to the main support frame S. Adjusting screws 32 provide for a paralleling of anvil 31 and a rough height adjustment or position. An adjusting nut 44 offers final fine adjustment for different thicknesses of the materials or envelopes to be printed. At the entrance end of the anvil 31 is a guide plate having a downwardly tapered end 35 to insure that the envelopes are properly positioned as they approach the printer. Directly above the anvil 31 is a vertically reciprocatable heated printing plate 36 attached to a slideable, generally U-shaped housing 37 having tapered or inclined slots 38 on each leg of the U-shaped housing. This housing 37 can take any number of forms or shapes and the same is not critical to the understanding of the invention. Printing plate 36 is located at the bottom or bite portion of said housing. A second housing 40 is partially embraced by the first named housing 37 and includes horizontally located slots 41 through which follower pins 42 extend as well as through the tapered or inclined slots 38. Bearings 39 are secured to and located at opposite end portions of housing 40 and abutting end portions of the housing 37, as shown by FIG. 3. The bearings 39 confine or restrict movement of housing 37 to displacement in a vertical plane, upon actuation of a fluid cylinder arrangement 43. The follower pins 42 are attached to the rod portion of the piston cylinder arrangement 43 and actuated in a well-known manner.
FIG. 2 is a top view of a printer which shows the printing film arrangement which includes a supply reel 50 having film 51 thereon and a take up reel 52 for the spent film. A guide rod or roller 53 spaced below supply reel 50 directs film 51 from the supply reel through the space between the anvil 31 and printing plate 36. Another guide rod could be located on the opposite side of the plate and anvil to guide the spent film to take-up reel 52. The supply and take-up reels are supported on rods or spindles 54 and 55 respectively that provide lateral adjustment to conform to various positions of the printing head and are adapted to receive rolls of different widths of film.
The individual printers operate in the following manner: When an envelope has been moved and momentarily stopped between printing plate 36 and anvil 31 by the retractable stop pins 10, the rod of the piston cylinder arrangement 43 is caused to move to the right as viewed in FIG. 3, which causes pins 42 to move horizontally in guide slots 41 and ride on tapered or inclined slots 38 forcing slideable support 37 and printing plate 36 down in printing engagement with the film and envelope on fixed anvil 31.
Illustrated in FIGS. 4 and 5 is an example of one type of paper board envelope to be printed. FIG. 4 shows the side of an envelope having information printed thereon at spaced locations M 1 , M 2 and M 3 while FIG. 5 shows the other side of the envelope having information or indicia M 4 applied. The indicia at M 1 and M 2 are printed by the same printing head. These illustrations are mere examples, as different numbers thereof could obviously be applied without departing from the scope of the invention. Arrow B indicates the direction of travel of the envelopes as they move through the system. It is clear from these illustrations that the runs of the conveyor must be spaced differently to compensate for the difference in sizes of the area of printed information or messages illustrated in FIG. 4 and that illustrated in FIG. 5. Printers 1 and 2 are slightly staggered to print on the different areas as illustrated in FIG. 4.
A crank assembly 60 is associated with each of the printers 1, 2, 3 and offers side-to-side adjustment of the print head relative to the machine frame S and the envelope path thus providing proper print registration. A crank mechanism 61 on each print head serves to lock the print head in the adjusted position selected by displacement of the crank assembly 60.
The conventional sensing and control system is located on the support frame to sense various conditions and control various movements to motions of the above described structure. For example, upon starting the system an envelope E is fed from magazine M by feed means F and conveyor 4 to first printer 1, the presence of which is sensed by first sensor 8 which directs pins 10 through air cylinder 12, to move into the path of the envelopes, momentarily, simultaneously stops the feeding function and directs printer 1, via its actuating mechanism 36, 37, 38, 41, 42 and 43 to perform its printing function, e.g. printing plate 36 retracted, pins 10 withdrawn and feeder F and conveyor 4 are again actuated causing the just printed envelope E to move to printer 2 and a fresh envelope moved to printer 1. As previously pointed out printers 1 and 2 are arranged alike and when an envelope E is issued from magazine M to printer 1 and an envelope is issued from printer 1 to printer 2 they operate substantially simultaneously. Printer 3 receives an envelope from printer 2 as printer 2 receives an envelope from printer 1. Note, however, that printer 3 is positioned opposite to printers 1 and 2 and prints on the bottom of the envelope. Envelopes issuing from printer 3 are sensed by sensor 28 which actuates transfer device 20 to transfer the printed envelope to another work station WS.
The specific control systems CS for the various functions are known in the art and form no part of the present invention apart from defining an operative device and presenting a complete disclosure.
It will be manifest from the foregoing description that we have provided an apparatus which may be used to enable the hereinabove set forth and kindered objects of this invention to be realized, and while we have illustrated and described the preferred embodiments of our invention, it is to be understood that these are capable of variation and modification, and we therefore do not wish to be limited to the precise details set forth, but desire to avail ourselves of such changes and alterations as fall within the purview of the following claims.
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A system of printing information on opposite sides of paper board envelopes using heat sensitive films or foils fed between transfer die members and envelopes passing therebetween. The system includes a supply magazine or the like, a conveying system for conveying the envelopes from the supply source to and through the several printers. The printers are longitudinally spaced along the conveyor path and are so located such that information can be printed on both sides of the envelope. At the end or the last printing station a second conveyor or transfer device is provided to transfer the just printed envelopes to a work station wherein delicate articles, such as hosiery, panty hose, etc., are placed therein. The system includes common and well known automatic control means to intermittently feed the envelopes to the several printing stations and subsequently to the envelope filling station.
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CROSS REFERENCE TO RELATED APPLICATIONS
This application claims the benefit under 35 U.S.C. §119(e) of U.S. Provisional Patent Application Ser. No. 61/032,628, filed Feb. 29, 2008.
BACKGROUND
1. Field of the Invention
The present invention relates to water purification systems and, particularly, to water purification systems utilizing oxidation.
2. Description of the Related Art
Water purification systems are commonly used to purify water drawn for consumer use. The water may be obtained directly by the consumer from an individual well or may be provided to the consumer by a municipality or corporation. Irrespective of how the water is provided to the consumer, the water may include impurities that the consumer considers to be undesirable. For example, iron, manganese, hydrogen sulfide, and/or arsenic may be dissolved or otherwise contained within the water. These compounds may negatively effect the clarity, color, odor, and/or taste of the water. Hydrogen sulfide, for example, has an unpleasant odor, is highly corrosive, and is also highly toxic.
A variety of water processing systems are available, either for commercial or consumer use. For example, zeolite based water softener systems are widely used to control water hardness, i.e., remove iron from water, but do not remove other impurities, such as hydrogen sulfide. Additionally, as the impurities contained within an individual consumer's water vary geographically, a conventional system may not successfully remove some of an individual consumer's specific impurities. Moreover, depending on the conditions under which the water was obtained, the concentrations of the impurities may be widely varied, rendering consistent treatment difficult.
SUMMARY
The present invention provides water purification systems and, particularly, water purification systems utilizing oxidation. By passing water through air, the impurities within the water, such as iron, manganese, and/or hydrogen sulfide gas, are oxidized. The oxidized constituents in the water then precipitate out and are removed by filter media. Thus, by utilizing oxidation, the impurities most commonly found in a consumer's water are readily removed. Additionally, the water purification systems of the present invention may also elevate the pH, i.e., decrease the hydronium ion concentration, of the water when the water is acidic. By raising the pH of the water, the oxidation of impurities, such as iron and manganese, is more complete and also occurs at a faster rate. Additionally, the corrosivity of the water is reduced when the pH is elevated.
In one exemplary embodiment, the present invention provides a two-tank water purification system. The two-tank system utilizes a first, oxidation tank that includes a headspace of air. As water passes through the headspace, impurities in the water are oxidized. The water is then transferred to the second, filter tank where impurities precipitated in the water pass through filter media and are removed from the water. In another exemplary embodiment, the present invention provides a three-tank water purification system. The three-tank water purification system is similar to the two-tank system in that it utilizes a first, oxidation tank and a second, filter tank. However, the three-tank system also provides a third, ion resin tank. By passing the water through the ion resin tank, the hardness of the water is reduced. Advantageously, by utilizing an oxidation tank, the present invention coverts arsenic(V) into arsenic(III), which may be removed by filter media contained within the filter tank. Thus, the present systems allow for a substantial reduction in the arsenic level in a consumer's water supply.
In one form thereof, the present invention provides a system for removing impurities from water, the system including: a water inlet; an oxidation tank having a headspace of air contained therein, said oxidation tank in fluid communication with said water inlet through a first pathway; a venturi in fluid communication with said water inlet and said oxidation tank through a second pathway, wherein water received from said water inlet may enter said oxidation tank through both of said first pathway and said second pathway, said venturi having an air inlet in constant fluid communication with the ambient environment, wherein air drawn through said air inlet of said venturi is delivered to said oxidation tank to create said headspace of air; a filter tank in fluid communication with said oxidation tank, said filter tank having filter media contained therein, wherein water travels through said headspace of air in said oxidation tank to oxidize the impurities in the water and then passes through said filter media in said filter tank to remove the impurities from the water; and a water outlet in fluid communication with said filter tank.
In another form thereof, the present invention provides a system for removing impurities from water, the system including: a water inlet; an oxidation tank having a headspace of air contained therein, said oxidation tank in fluid communication with said water inlet through a first pathway; a venturi in fluid communication with said water inlet and said oxidation tank through a second pathway, wherein water received from said water inlet may enter said oxidation tank through both of said first pathway and said second pathway; a filter tank in fluid communication with said oxidation tank, said filter tank having filter media contained therein, wherein water travels through said headspace of air in said oxidation tank to oxidize the impurities in the water and then passes through said filter media in said filter tank to remove the impurities from the water; an ion resin tank in fluid communication with said filter tank, said ion resin tank having a resin media position therein, wherein the water passes through said resin media to lower the hardness of the water; and a water outlet in fluid communication with said ion resin tank.
In yet another form thereof, the present invention provides a method of removing impurities from water, the method including: passing water through a powerhead and into an oxidation tank; passing the water through a headspace of air to oxidize impurities in the water; transferring the water to a filter tank; passing the water through filter media contained within the filter tank to filter oxidized impurities from the water; passing the water through the powerhead; and providing the water to a consumer.
BRIEF DESCRIPTION OF THE DRAWINGS
The above-mentioned and other features and advantages of this invention, and the manner of attaining them, will become more apparent and the invention itself will be better understood by reference to the following descriptions of embodiments of the invention taken in conjunction with the accompanying drawings, wherein:
FIG. 1 is cross-sectional, schematic view of a water purification system of the present invention according to an exemplary embodiment depicting the system in a service cycle;
FIG. 2 is a cross-sectional, schematic view of the system of FIG. 1 depicting the system in a backwash cycle;
FIG. 3 is a cross-sectional, schematic view of the system of FIG. 1 depicting the system in a slow rinse cycle;
FIG. 4 is a cross-sectional, schematic view of the system of FIG. 1 depicting the system in a fast rinse cycle;
FIG. 5 is a cross-sectional, schematic view of a water purification system of the present invention according to another exemplary embodiment depicting the system in a service cycle;
FIG. 6 is a cross-sectional, schematic view of the system of FIG. 5 depicting the system in a backwash cycle;
FIG. 7 is a cross-sectional, schematic view of the system of FIG. 5 depicting the system in a slow rinse cycle;
FIG. 8 is a cross-sectional, schematic view of the system of FIG. 5 depicting the system in a fast rinse cycle; and
FIG. 9 is a cross-sectional, schematic view of the system of FIG. 5 depicting the system in a refill cycle.
Corresponding reference characters indicate corresponding parts throughout the several views. The exemplifications set out herein illustrate preferred embodiments of the invention and such exemplifications are not to be construed as limiting the scope of the invention in any manner.
DETAILED DESCRIPTION
Corresponding reference characters indicate corresponding parts throughout the several views. The exemplifications set out herein illustrate preferred embodiments of the invention and such exemplifications are not to be construed as limiting the scope of the invention in any manner.
Referring to FIG. 1 , a two-tank water purification system manufactured in accordance with the present invention is shown in a service cycle. In this cycle, water enters the purification system through inlet 10 , travels through pipes 11 , 12 , which at least partially define a first pathway, and enters tank 16 . Fluid communication between inlet 10 and pipe 12 , as well as outlet 32 and pipes 30 , 34 described below, may be controlled by a standard water softener powerhead, such as powerhead 13 . In one exemplary embodiment, powerhead 13 is a Fleck®Model 2510 control valve drive assembly commercially available from Pentair, Inc. of Golden Valley, Minnesota. Fleck® is a registered trademark of Fleck Controls, Inc. of Brookfield, Wisconsin.
As water enters the system, if the flow of water through inlet 10 is high enough, a portion of the water traveling through pipe 11 will be diverted through pipe 18 , which at least partially defines a second pathway parallel to the first pathway, and venturi 20 . In one exemplary embodiment, the second pathway is discrete from the first pathway from inlet 10 to oxidation tank 16 , described below. While the flow rate required in any particular system will depend on the size of the purification system, the pressure of the inlet water, and the discharge pressure of the water, a residential system may draw air near its approximate peak flow rate of 10 gallons per minute, for example. As water passes through venturi 20 , air enters the water traveling therethrough via venturi air intake 22 . In order to control the amount of air entering the system, the opening defining air intake 22 may be restricted.
The water traveling through pipes 12 , 18 then enters first, oxidation tank 16 . As the water enters tank 16 it falls through air defining head space 14 in tank 16 , causing impurities in the water to be oxidized. The water then exits tank 16 via pipe 24 and travels to second, filter tank 26 . The water within tank 26 is then filtered through filter media 28 and exits tank 26 via pipe 30 . Filter media 28 may be a calcium carbonate media, filter sand, Birm® filter media, greensand, dolomite, Filter-Age filter media, or an arsenic absorbent media, for example. Birm® and Filter-Age are registered trademarks of Clark Corporation of Windsor, Wisconsin. In one exemplary embodiment, a portion of the filter media will be dissolved in the water if the water is acidic, i.e., has a pH less than 7.0. As a result, the pH of the water will be increased, facilitating greater oxidation of the impurities and lessening the corrosivity of the water. When operating in the service cycle, pipe 30 is in fluid communication with outlet 32 . Outlet 32 then connects to the water service line of a consumer.
Advantageously, by passing the water through a headspace of air, the impurities in the water are oxidized and begin to precipitate out of the water. For example, iron, manganese, and hydrogen sulfide may all be oxidized. Additionally, arsenic(V) may be converted to arsenic(III) as a result of oxidation. While arsenic(V) is able to pass through filter media 28 , arsenic(III) is captured in filter media 28 and removed from the water. As a result, the present purification system provides a substantially higher arsenic removal rate than standard purification systems when an arsenic absorbent media is employed.
Referring to FIG. 2 , in order to flush the purification system and remove any particulate matter from filter media 28 within tank 26 , the system enters a backwash cycle. In the backwash cycle, inlet 10 and pipe 11 are automatically placed in fluid communication with pipe 30 by powerhead 13 , causing intake water traveling through pipes 11 , 30 to enter tank 26 . Specifically, powerhead 13 may place inlet 10 and pipe 11 in fluid communication with pipe 30 after the passage of a predetermined amount of time or after the passage of a predetermined amount of water through powerhead 13 , for example. As the water exits the bottom of pipe 30 , it travels through filter media 28 dislodging various particulate matter and, once tank 26 is filled, the water exits tank 26 via pipe 24 . Water traveling through pipe 24 then enters tank 16 and begins to fill tank 16 . As tank 16 fills, air trapped within head space 14 is forced through pipe 12 , which, as a result of the activation of powerhead 13 described above, is now in fluid communication with drain pipe 34 . Once the water level reaches pipe 12 , the water travels through pipe 12 and exits through drain pipe 34 . After running for a sufficient period of time to remove the particulate matter from the system via drain pipe 34 , the system enters a slow rinse cycle.
Referring to FIG. 3 , the slow rinse cycle is shown. This cycle is utilized to replenish head space 14 with fresh, oxygenated air. Specifically, in this cycle, powerhead 13 is activated to prevent fluid communication between pipe 11 and pipe 12 . As a result, water traveling through pipe 11 is forced through pipe 18 and venturi 20 . As the water travels through venturi 20 , air enters air intake 22 and is combined therewith. The water is then delivered via pipe 18 into tank 16 . Once within tank 16 , the air and water separate and head space 14 begins to form. Water will continue to fill tank 16 and compress the air within head space 14 until head space 14 and the water contained within tank 16 are at substantially equal pressures. At this point, as additional water enters tank 16 , it will begin to travel up pipe 24 and into tank 26 . The water within tank 26 will then travel through filter media 28 and enter pipe 30 . Pipe 30 , as a result of the activation of powerhead 13 described above, is now in fluid communication with drain pipe 34 and water traveling through pipe 30 will exit the system via drain pipe 34 .
Once the slow rinse cycle is complete, the system will enter a fast rinse cycle, shown in FIG. 4 . In this cycle, powerhead 13 is activated to allow water entering inlet 10 to travel through pipes 11 , 12 and enter head space 14 of tank 16 . Additionally, if the volume of water traveling through pipe 11 is sufficiently high, a portion of the water will be diverted through pipe 18 and travel through venturi 20 to draw air into the water, as described above. As the water enters tank 16 via pipes 12 , 18 , the air will separate from the water and rise within tank 16 to maintain head space 14 . The water will then exit tank 16 via pipe 24 and enter tank 26 . After passing through filter media 28 , the water will enter pipe 30 and exit the system via drain pipe 34 . Once the fast rinse is complete, the system will reenter the service cycle. Specifically, powerhead 13 is again actuated and inlet 10 is placed in fluid communication with pipe 11 , as described above. The two-tank system will then, after the passage of a predetermine amount of time or the passage of a predetermined amount of water through powerhead 13 , repeat the process of performing each of the cycles described in detail above.
Referring to FIGS. 5-9 , a three-tank water purification system manufactured in accordance with the present invention is shown. Similar to the two-tank water purification system described in detail above with reference to FIGS. 1-4 , the three-tank system is a water purification system based, in part, on oxidation. However, in addition to the tanks described above with reference to the two-tank system, the three-tank system adds a third, water softener and/or ion resin tank to facilitate additional water treatment. Specifically, the third tank is used to lessen the hardness of the water.
Referring to FIG. 5 , the three-tank water purification system is shown in a service position. Thus, water received through inlet 50 will travel through pipes 52 , 54 , which at least partially define a first pathway, and through pipe 56 , which at least partially defines a second pathway parallel to the first pathway, to enter tank 58 . In one exemplary embodiment, the second pathway is discrete from the first pathway from inlet 50 to oxidation tank 64 , described below. Fluid communication between pipes 52 , 54 , as well as outlet 76 and pipes 74 , 78 described below, may be controlled by a standard water softener powerhead, such as powerhead 53 . In one exemplary embodiment, powerhead 53 is a Fleck® Model 2510 automatic backwash valve drive assembly commercially available from Pentair, Inc. of Golden Valley, Minnesota.
The water entering tank 58 travels through air within head space 60 , oxidizing impurities in the water and causing them to precipitate out of the water. The water then travels through pipe 62 and enters tank 64 where it passes through filter media 66 . Filter media 66 may be a calcium carbonate filter media, filter sand, Birm® filter media, greensand, dolomite, Filter-Ag® filter media, or an arsenic absorbent media, for example. Filter media 66 captures the precipitated impurities while allowing the water to pass therethrough. In one exemplary embodiment, a portion of the filter media will be dissolved in the water if the water passing therethrough is acidic, i.e., has a pH less than 7.0. As a result, the pH of the water will be increased. The water then enters pipe 68 and travels to tank 70 . Within tank 70 , the water travels through resin media 72 and exits via pipe 74 , which is in fluid communication with outlet pipe 76 .
In one exemplary embodiment, resin media 72 may be a high capacity ion exchange softener resin or a fine mesh ion exchange softener resin, for example. By passing the water through resin media 72 , the hardness of the water is substantially reduced. In one exemplary embodiment, the hardness of the water is reduced to less than 5 parts per million of calcium carbonate. Additionally, by passing the water through resin media 72 , arsenic, nitrates, and/or tannic acid may also be substantially removed from the water. In one exemplary embodiment, resin media 72 is selected so that it will remove any substance with a cationic or anionic valence from the water.
In order to backwash resin media 72 and filter media 66 , the three-tank purification system is placed into a backwash cycle, as shown in FIG. 6 . Referring to FIG. 6 , water traveling through inlet 50 passes through pipe 52 , which, as a result of activation of powerhead 53 , is now in fluid communication with pipe 74 . Specifically, powerhead 53 places pipes 52 , 74 in fluid communication with one another after the passage of a predetermined amount of time or after the passage of a predetermined amount of water through powerhead 53 , for example. As a result, the water travels through pipes 52 , 74 and enters tank 70 passing through resin media 72 . The water then travels through pipe 68 into tank 64 and passes through filter media 66 , removing particulate matter therefrom. The water then exits tank 64 via pipe 62 and enters tank 58 .
As water enters tank 58 , the water level within tank 58 rises and forces the air in head space 60 out of tank 58 through pipe 54 , which, as a result of the activation of powerhead 53 described above, is now in fluid communication with drain pipe 78 . Once the water level within tank 58 reaches pipe 54 , the water travels through pipe 54 to drain pipe 78 and exits the system. Additionally, to prevent water exiting tank 58 from entering inlet 50 through pipe 56 , a check valve is provided along the length of pipe 56 . After running for a sufficient period of time to remove the particulate matter from the system and discharge the same through drain pipe 78 , the system enters a slow rinse cycle.
Referring to FIG. 7 , during the slow rinse cycle, the three-tank purification system operates in several ways like a conventional water softener. Specifically, during the slow rinse cycle, valve 80 is opened allowing for brine to be drawn from salt tank 84 through pipe 86 . In one exemplary embodiment, valve 80 is electronically actuated by operation of powerhead 53 . As water enters inlet 50 and travels through pipe 52 , a portion of the water will be diverted through pipe 56 where the water travels through venturi 82 . As the water travels through venturi 82 , it draws brine from salt tank 84 through pipe 86 and into pipe 56 . The brine traveling through pipe 56 then enters tank 58 . The water and brine then travel from tank 58 through pipe 62 and into tank 64 . Once within tank 64 , the water and brine travel through filter media 66 and pipe 68 to enter tank 70 . The water and brine are then drawn through resin media 72 to regenerate resin media 72 . The water and remaining brine then exit tank 70 through pipe 74 , which, due to activation of powerhead 53 , is in fluid communication with drain pipe 78 .
However, unlike a conventional water softener, when salt tank 84 is emptied to a level below the inlet of pipe 86 , a check valve does not stop the flow of fluid into pipe 86 . As a result, air from the ambient environment begins to enter pipe 86 and is pulled into pipe 56 , ultimately entering tank 58 through venturi 82 . In this matter, the air within tank 58 is refilled in a manner similar to that described in detail above with reference to the two-tank purification system. Once a sufficient level of air has accumulated in tank 58 to form head space 60 , valve 80 is closed, such as by activation of powerhead 53 , and water flowing from inlet 50 is allowed to flow through pipes 52 , 56 and into tank 58 . Water will continue to enter tank 58 and will pressurize head space 60 until the pressure of the air within head space 60 is substantially equal to the pressure of the water. Once the pressures are equilibrated, water begins to rise in pipe 62 and travel to tank 64 . The water then travels through filter media 66 and pipe 68 to enter tank 70 . Once within tank 70 , the water will travel through resin media 72 and pipe 74 , which is in fluid communication with drain pipe 78 , allowing the water to exit the system. Once head space 60 is filled and pressurized, the system enters a fast rinse cycle.
Referring to FIG. 8 , once in the fast rinse cycle, valve 80 is closed preventing additional brine and/or air from entering pipe 56 . As water enters inlet 50 and travels through pipes 52 , 56 it enters tank 58 . The water then travels from tank 58 through pipe 62 and into tank 64 . Once within tank 64 , the water travels through filter media 66 and pipe 68 to enter tank 70 . The water then passes through resin media 72 and exits tank 70 through pipe 74 , which, due to activation of powerhead 53 , is in fluid communication with drain pipe 78 . Once the fast rinse cycle is completed, the system enters a refill cycle.
Referring to FIG. 9 , once in the refill cycle, powerhead 53 is activated and valve 80 is again opened. In one exemplary embodiment, valve 80 is electronically actuated by operation of powerhead 53 . Additionally, water is diverted through pipe 56 and pipe 86 to enter salt tank 84 . Once salt tank 84 is sufficiently filled with water, valve 80 is closed and the three-tank purification system reenters the service position. The three-tank system will then repeat the process of performing each of the cycles described in detail above after the passage of a predetermined amount of time or the passage of a predetermined amount of water through powerhead 53 .
While this invention has been described as having preferred designs, the present invention can be further modified within the spirit and scope of this disclosure. This application is therefore intended to cover any variations, uses, or adaptations of the invention using its general principles. Further, this application is intended to cover such departures from the present disclosure as come within known or customary practice in the art to which this invention pertains and which fall within the limits of the appended claims.
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Water purification systems utilizing oxidation. By passing water through a chamber of air, the impurities within the water, such as iron, manganese, and/or hydrogen sulfide gas, may be oxidized. The oxidized constituents in the water may then precipitate out and be removed by filter media. Thus, by utilizing oxidation, the impurities most commonly found in a consumer's water are readily removed. Additionally, the water purification systems of the present invention may also elevate the pH, i.e., reduce the hydronium ion concentration, of the water when the water is acidic. By raising the pH of the water, the oxidation of impurities, such as iron and manganese, is more complete and also occurs at a faster rate. Additionally, the corrosivity of the water is also reduced when the pH is elevated.
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CROSS-REFERENCE TO RELATED APPLICATIONS
This application is a continuation of U.S. application Ser. No. 12/205,737, entitled “INTERCHANGEABLE BAG AND COVER SYSTEM,” filed Sep. 5, 2008, which claims benefit of U.S. Provisional Application No. 60/970,183, entitled “INTERCHANGEABLE BAG AND COVER SYSTEM,” filed Sep. 5, 2007, each of which is hereby incorporated by reference in its entirety.
TECHNICAL FIELD
The present invention is directed to bags and more particularly to bags with removable and interchangeable covers.
OVERVIEW
Bags, such as messenger bags, backpacks, purses, briefcases, etc., are manufactured in very diverse sizes, shapes, colors, designs, and with a variety of materials. However, conventional bags are typically produced as complete units with defined aesthetic appearances and utility features. The interchangeable bag and cover system in accordance with at least one aspect of the present invention provides fellable vessels and multiple removable covers that can be mixed and matched to form a variety of interchangeable bag and cover combinations having varying appearances and utility features.
SUMMARY
An interchangeable bag and cover system in accordance with aspects of the present invention overcome problems experienced in the prior art and provide other benefits. In one embodiment, a convertible bag system is provided that comprises a body having side portions that define an interior area having an opening. The body having a cover-connection portion. A first securing mechanism is coupled to the body. A plurality of covers are interchangeably connectable to the body. Each cover has a body-connection portion releasably attachable to the cover-connection portion of the body, wherein the cover is moveable relative to the body between open position and closed positions. Each cover has a free end portion positionable adjacent to the body when the cover is in the close position. Each cover has a second securing mechanism configured to releasably engage the first securing mechanism to retain the cover in the closed position.
In accordance with another embodiment, an interchangeable bag and cover system is provided that comprises a plurality of bodies, each body having a plurality of panels that define a closed end, an open end, and a cavity configured to contain selected items inserted therein through the opening. Each body has a first connector. A plurality of covers are provide, wherein each cover is interchangeably and releasably connectable to any of the bodies. Each cover, when connected to a selected body, is moveable relative to the selected body between open and closed positions. Each cover extends across the open end of the body when in the closed position, and the cover is positioned to expose the open end when in the open position. Each cover has a second connector releasably engageable with any of the first connectors of any of the bodies, so that any of the covers can be interchangeably used with any of the bodies.
In accordance with another embodiment, a convertible bag and cover assembly is provided that comprises a body having a closed end, an open end, and a cavity configured to contain selected items inserted therein through the opening. The body has a first connector. A cover is releasably connected to the body. The cover, when connected to the body, is moveable relative to the body between open and closed positions. The cover is configured to extend across the open end when in the closed position and to expose the open end when in the open position. The cover has a second connector releasably engageable with the first connector of the body, so that the cover can be removed and replaced by another cover having substantially the same construction as said cover.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 is a front view of a convertible bag system in accordance with an embodiment of the present invention.
FIG. 2 is a back view of the convertible bag system of FIG. 1 .
FIG. 3 is a front perspective view of a body in accordance with an embodiment of the present invention.
FIG. 4 is an isometric view of the body of FIG. 3 illustrating a back panel with cover attachment portions in accordance with an embodiment of the present invention.
FIG. 5 is an enlarged view of a rod mounting system in accordance with an embodiment of the present invention.
FIG. 6 is a top view of a cover of a convertible bag system in accordance with an embodiment of the present invention.
FIG. 7 is a bottom view of the cover of FIG. 6 .
FIG. 8 is an enlarged view of an embodiment of a attachment system illustrating a cover partially attached to a vessel.
FIG. 9 is an enlarged view of the attachment system of FIG. 8 illustrating a plurality of clips positively engaged on a rod.
FIG. 10 is an enlarged view of a single clip engaged on a rod.
FIG. 11 is a side view of the convertible bag system of FIG. 1 .
DETAILED DESCRIPTION
The present disclosure describes bag systems including systems for providing carrying bags having interchangeable vessels and covers in accordance with an embodiment of the present invention. Several specific details of aspects of the invention are set forth in the following description and in FIGS. 1-11 to provide a thorough understanding of certain embodiments of the invention. One skilled in the art, however, will understand that the present invention may have additional embodiments, and that other embodiments of the invention may be practiced without several of the specific features described below.
FIG. 1 is a front view and FIG. 2 is back view of a convertible bag system 10 in accordance with an embodiment of the present invention. The convertible bag system 10 includes an interchangeable bag and cover assembly 12 having a body 14 that defines a vessel, and cover 16 detachably connected to the body. The convertible bag system 10 can also be provided with an integrated strap system 18 (as shown in FIG. 1 ). The integrated strap system 18 can be configured to be removeably attached and/or adjusted, and can include a length adjustment mechanism 19 . Additionally, the interchangeable bag and cover assembly 12 can also include a plurality of mating-type closures 20 for securing the cover 16 in a closed position relative to the body 14 (explained in more detail below). The assembly 12 may also be provided with a carrying handle 22 .
FIG. 3 illustrates a front perspective view of the body 14 in accordance with one embodiment of the invention. The body 14 of the illustrated embodiment includes an open end 24 and a closed end 26 and a plurality of panels 28 . The closed end 26 and panels 28 create a vessel or cavity 30 which may be filled by depositing items through a mouth 31 defined by the open end 24 . In one embodiment, the closed end 26 can be a separate panel that is attached to one or more side panels 28 to form the cavity 30 . In another embodiment, the plurality of panels 28 can be integrally connected or can be stitched, glued, or otherwise secured together at lower edges 32 to form the closed end 26 .
As shown, the body 14 can include strap attachment sites 33 for attaching the integrated strap system 18 . The strap attachment sites 33 can be configured to securely connect to the strap system 18 . In one embodiment, the strap attachment sites 33 can include one or more strap attachment mechanisms (not shown) for releaseably attaching the strap system 18 to the body 14 . In another embodiment, the body 14 can include one or more attachment mechanisms that engage one or more portions of the strap system 18 . In the illustrated embodiment, the body 14 includes first closure attachment sites 34 for integrating a first portion 20 a of the mating-type closure 20 (e.g., the male or female portion of a buckle, a magnet, a snap, a button, a hook or loop strip, etc.). The other portion of the mating-type closure is attached to the strap system.
The body 14 can also be provided with one or more pockets 36 or other compartments. For example, the body 14 can have pockets 36 integrated on an exterior surface 38 and/or integrated on an interior surface 40 of the panels 28 . These pockets 36 can be provided as non-closing pockets or can include a flap or closure mechanism, such as with a zipper, buttons, corresponding hook and loop strips, elastic band, etc., for securing items.
In another embodiment, the cavity 30 of the body 14 may be provided with one or more main internal compartments for storing and transporting items. Internal panels (not shown) may be provided to divide the cavity 30 into a plurality of compartments for separating and/or organizing items within the cavity 30 . Padding 42 may also be provided within the cavity 30 for protecting delicate or fragile items, such as electronic equipment (e.g. laptop computer, camera, music devices, PDA devices, cell phones, etc.), or for additional comfort while transporting the convertible bag system 10 proximal to a user's body. The padding 42 can be integrated within the panels 28 and/or interior panels in some embodiments. Furthermore, the body 14 can be configured to have removable or replaceable interior panels and/or pockets, such that a user can reconfigure, add, or remove these sub-compartment features. Those of ordinary skill in the art will recognize that the size and shape of the pockets and/or panels 28 and the overall size and shape of the body 14 or portions of the body may vary according to preference for the size of the bag, the accommodating capacity, and/or configuration of the cavity 30 .
FIG. 4 is an isometric view of a panel, such as a back panel 44 of the body 14 of FIG. 3 . In accordance with an embodiment of the present invention, the body 14 can include an attachment system 45 having one or more attachment portions 46 integrated on a region, such as the upper region 48 of the back panel 44 . The attachment system 45 allows a variety of interchangeable covers 16 to be independently attached and removed from the body 14 (described in more detail below). As illustrated, the attachment portions 46 can be one or more rods 50 integrated with the back panel 44 of the body 14 . The rod 50 of the illustrated embodiment is a substantially rigid or stiff cylindrical rod. In other embodiments, the rod can be a substantially rigid or stiff bar or other non-cylindrical structure to which the cover 16 is removably attached. In one embodiment, the back panel 44 can include a plurality of access portals 52 through the exterior surface 38 of the back panel to expose the attachment portions 46 . In other embodiments, the attachment system 45 can be integrated with the body 14 in an alternate region or panel 28 .
In some embodiments, a single rod 50 can be integrated with the body 14 , such that the rod spans a length L 1 that encompasses the plurality of access portals 52 . In other embodiments, the attachment portions 46 may comprise a plurality of rods 50 that are independently integrated into the body 14 and exposed to the exterior surface 38 of the back panel 44 by way of the access portals 52 . In this embodiment, the rods 50 can move independently with respect to adjacent rods 50 and provide additional freedom of movement and pliability to the rod integration region (e.g. the upper region 48 of the back panel 44 ). One of ordinary skill in the art will recognize that the rods 50 can be made of metal, plastic, or other sturdy and durable material. Additionally, the rods 50 may have constant or variable diameters or thicknesses appropriate for the selected size and durability requirements of the bag system 10 .
FIG. 5 illustrates one embodiment of a rod mounting system 54 in accordance with the present invention. As shown, the back panel 44 can include supporting loops 56 and/or sleeved receiving caps 58 for receiving the ends 60 of the rod 50 . The supporting loops 56 and receiving caps 58 can be securely fixed (e.g., sewn, glued, or otherwise attached) to the body 14 on the exterior 38 or interior 40 (as shown) of the back panel 44 of the body 14 . As illustrated, supporting loops 56 and receiving caps 58 can be spaced alternately with access portals 52 to provide unobstructed attachment portions 46 from the exterior 38 of the back panel 44 . In another embodiment, the supporting loops 56 and receiving caps 58 can be attached to a panel 28 other than the back panel 44 . In other embodiments, the supporting loops 56 and receiving caps 58 can be attached with an adhesive, tape, corresponding hook and loop strips, zippers, snaps, etc. One of ordinary skill in the art will recognize other mechanisms that can be used to securely mount rods 50 or otherwise integrate rods 50 with the body 14 . Furthermore, one of ordinary skill in the art will appreciate that a plurality of receiving caps 58 and/or supporting loops 56 can be included to securely mount a plurality of rods 50 .
FIG. 6 is a top view and FIG. 7 is a bottom view of the cover 16 in accordance with one embodiment of the present invention. As shown in FIG. 6 , the cover 16 can be configured with decorative or distinctive markings 62 on an outer surface 63 . Distinctive markings 62 can include shapes and colors integrated into a design, indicia, identification information, etc. The outer surface 63 of the cover 16 can also include utility features (not shown) such as handles, pockets, straps, water bottle holders, integrated light systems, speaker systems, etc. In the illustrated embodiment, the cover 16 is in the shape of a flap and made of a flexible material that allows the cover 16 to bend and fold. The cover 16 can also be contoured to correspond to the contours of the body 14 and provide a better fit or seal for the open end 24 when engaged in a closed position (as shown in FIG. 1 ). In another embodiment, the cover 16 can be formed of a substantially rigid or stiff material that has been molded to fit over the open end 24 of the body 14 . In another embodiment, a first portion of the cover can be substantially rigid or stiff, and another portion can be flexible.
As shown in FIG. 7 , an inner surface 64 of the cover 16 has a positive engagement mechanism 65 for releaseably coupling the cover 16 to the body 14 to form the interchangeable bag and cover assembly 12 . As illustrated, the engagement mechanism 65 can be a plurality of clips 66 attached to the inner surface 64 and configured to positively engage the integrated rods 50 on the body 14 . Other positive engagement mechanisms 65 can include snap rings, locking rings, straps, etc. The clips 66 can be attached to the inner surface 64 with a plurality of rivets 68 . In one embodiment, three rivets 68 are used to secure each clip 66 to the cover 16 and prevent rotation or other movement of the clip 66 with respect to the cover 16 . However, one of ordinary skill in the art will recognize that one or more rivets 68 can be used in various configurations. Additionally, the clips 66 can be attached with snaps, screws, thread, adhesive, or other positive attachment mechanisms.
The cover 16 can also include second closure attachment sites 70 for integrating a corresponding half 20 b of the mating closure 20 (e.g. the male or female portion of a buckle, a magnet, a snap, a button, a hook or loop strip, etc.) for mating with the first half 20 a attached to the body 14 .
FIG. 8 is an enlarged view of one embodiment of the attachment system 45 illustrating the cover 16 partially attached to the body 14 . The cover 16 can be removeably attached to the body 14 by positively engaging the clips 66 onto the rod 50 at the attachment portion 46 . As illustrated, the clips 66 can engage the rod 50 through access portals 52 in the exterior surface 38 of the back panel 44 . Each clip 66 can independently engage the rod 50 at the corresponding attachment portion 46 to align and attach the cover 16 to the body 14 . FIG. 9 illustrates a fully-attached cover 16 having the plurality of clips 66 engaging the rod 50 of the corresponding body 14 . FIG. 10 is an enlarged view of a single clip 66 positively engaging the rod 50 at an attachment portion 46 . Independently engaged and separated clips 66 provide flexibility to the attachment system 45 and supports proper alignment of the cover 16 with respect to the open end 24 of the body 14 . The clips 66 can be attached and detached from the rod 50 when the cover 16 is in an open position. Referring back to FIG. 2 , the attachment system 45 can be concealed when the cover 16 overlaps the open end 24 of the body 14 in a closed position.
Following engagement with the rod 50 , the clips 66 can be configured to rotate around the rod 50 while maintaining secure attachment. In this embodiment, the cover 16 can be easily rotated about the rod 50 to provide access to the cavity 30 when in an open position, and rotated about the rod 50 to conform to the contours of the body 14 when in a closed position. FIG. 11 is a side perspective view of the convertible bag system 10 of FIG. 1 following cover 16 attachment and rotation to overlap the open end 24 of the body 14 . The plurality of mating-type closures 20 (e.g. belt buckles, squeeze lock buckles, buttons, snaps, corresponding hook and loop strips, corresponding magnets, etc.) can be engaged for securing the cover 16 in the closed position. Gussets 72 can be incorporated on the sides 74 of the cover 16 to reinforce the cover 16 while in a closed position and to prevent items from falling out of the cavity 30 . Additionally, gussets 72 can prevent moisture, debris, etc. from penetrating the interior cavity 30 . The gussets 72 may be formed from the same material as the cover 16 or from different material. In some embodiments, the gussets 72 may be elastic and allow stretching while manipulating the cover 16 from a closed position to an open position. In other embodiments, the gussets 72 can be removeably attached such that the gussets may be removed from the cover 16 when unnecessary or undesirable.
Referring back to FIG. 1 , and as described above, the integrated strap system 18 can incorporate several features, such as the length adjustment mechanism 19 , shoulder padding 76 , and releasable attachment sites (not shown). The strap system 18 can incorporate one or more straps 78 arranged to be worn on one or more shoulders or other parts of the body. For example, a single strap 78 can be provided to be worn on or over a shoulder of a user. In another embodiment, two independent straps 78 can be provided to be worn over both shoulders such that the convertible bag system 10 operates as a backpack.
The convertible bag system 10 can be configured for use as a messenger bag, backpack, purse, pannier, briefcase, suitcase, saddlebag, etc. Furthermore, the convertible bag system 10 can be configured to have the appearance altered by interchanging or swapping one cover 16 attached to a body 14 for a second cover 16 . Moreover, the function of the convertible bag system 10 can be alterable when the body 14 or strap system 18 is replaced or reconfigured. For example, the integrated strap system 18 can be interchangeable, such that a single messenger bag strap 78 is replaced with two attachable straps 78 configured to be worn in the style of a backpack.
The body 14 and the cover 16 can be formed using a variety of materials, such as leather, fabric, vinyl, mesh, canvas, hard or soft plastic, nylon, or other selected materials or combination of materials, etc. Furthermore, the material may include other beneficial features, such as being waterproof, tear proof, light reflective (e.g. for use at night), washable, breathable, clear, colorful, etc. The material used to form the body 14 can be the same or different from the material used to form the cover 16 . For example, the body 14 can be made of a sturdy, durable fabric while a multiple of different types of covers 16 can be removeably attached in an occasion-dependent manner. For example, a water proof cover can be attached when raining, a leather cover for formal occasions, a cover with multiple pockets for traveling, a hard cover for protecting fragile interior contents, etc.
From the foregoing, it will be appreciated that specific embodiments of the invention have been described herein for purposes of illustration, but that various modifications may be made without deviating from the spirit and scope of the invention. Accordingly, the invention is not limited except as by the appended claims.
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An interchangeable bag and cover system is provided that comprises a body with a first connection portion. A first securing mechanism is coupled to the body. A plurality of covers are interchangeably connectable to the body. Each cover has a second connection portion releasably attachable to the first connection portion of the body, wherein the cover is moveable relative to the body between open position and closed positions. Each cover has a free end portion positionable adjacent to the body when the cover is in the close position. Each cover has a second securing mechanism configured to releasably engage the first securing mechanism to retain the cover in the closed position.
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CROSS REFERENCE TO RELATED APPLICATIONS
[0001] This application is a continuation of co-pending U.S. utility patent application Serial Number (U.S. Ser. No.) 12/102,625 filed April 14, 2008, which is a continuation of co-pending U.S. utility patent application Serial Number (U.S. Ser. No.) 10/655,153 filed Sep. 4, 2003, now U.S. Pat. No. 7,464,706, which is a continuation-in-part of U.S. Ser. No. 09/621,092, filed Jul. 21, 2000, now U.S. Pat. No. 7,305,986, which claims priority from U.S. provisional applications U.S. No. 60/145,464 filed Jul. 23, 1999, and U.S. 60/206,123 filed May 22, 2000, all of which are incorporated herein by reference in their entirety.
FIELD OF THE INVENTION
[0002] The present invention is in the field of drug administration inhalers having improved control over system volumetric air flow rate, medicament particle transport, particle dispersion, particle metered dosimetry and patient compliance.
BACKGROUND OF THE INVENTION
[0003] In the early 1970's it was found that certain medicines could be administered in dry-powder form directly to the lungs by inhalation through the mouth or inspiration through the nose. This process allows the medicine to bypass the digestive system, and may, in certain cases, allow smaller dosages to be used to achieve the same results as orally ingested or injected medicines. In some cases, it provides a delivery technique that reduces side effects for medicines and interactions with other prescribed medicines, as well as providing a more rapid drug medication uptake.
[0004] Inhaler devices typically deliver medicine in a liquid droplet mist or as a dry powder aerosol. Deposition of particulate matter within the human lungs is a very complex and not fully understood phenomenon. People breathe over a relatively broad tidal volume. It is known that lower transport velocities of gas-entrained particles entering the mouth avoid impaction better within the oropharyngeal cavity. This is particularly true of particles greater than one to two microns in diameter.
[0005] In order for particles to remain suspended in a gas stream, their superficial transport velocity must be greater than their gravity settling velocity. For example, a 100 micron particle must have a transport gas velocity of approximately 7 ft/sec or greater for the 100 micron particle to remain in a particle/gas entrainment state. The required transport velocity for smaller particles is much less High speed particles have a greater propensity to impact and deposit on the tissue lining of the oropharyngeal cavity, as noted above. Thus, a significant number of particles are lost and will not enter the lungs, if those particles are not transported at the correct velocity.
[0006] Another common problem with inhalers is that the particles agglomerate, causing clumping of particles that then adhere to the inhaler or the oral cavity, rather than entering the lungs. Most approaches to this problem have been to include a surfactant in, on or with the particles to decrease the adhesion between particles.
[0007] Importantly, it should not be difficult for a patient to load the inhaler with medicine, and to easily and properly use the inhaler so that the correct dosage is actually administered. Many current dry particle inhalers fail in one or more of these important criteria.
[0008] It is therefore an object of the present invention to provide inhalers which are easy to properly use, and which deliver drug powders so that the powder enters the lungs instead of adhering to the back of the throat.
[0009] It is an object of the invention to provide an inhaler which will operate effectively with dry powder medicaments having particles ranging in size from about 0.5 to about 10 microns, and preferably from about 1 to about 5 microns in size.
[0010] It is a further object of the present invention to provide an inhaler that can operate effectively over a broad inhalation tidal volume range of human breath.
[0011] It is a still further object of the present invention to provide an inhaler which controls the volume and velocity of air flow so as to provide effective and desirable colimation, de-agglomeration and entrainment of the inhaled drug.
[0012] A related object is to provide an inhaler which creates a high-shear air flow field and controlled circulating gas action to break up particle agglomeration during proper inhaler usage.
[0013] A more specific object is to provide an inhaler mouthpiece which is sized and shaped to develop an air flow which will air stream entrained medicament particles through the oropharyngeal cavity.
[0014] Another specific object is to provide a medicament-containing inhaler cartridge which will supply medicament for complete air entrainment and proper dispersion into the air stream.
[0015] Yet another object is to provide an inhaler air-flow-controlling check valve which will straighten the air flow and limit the air flow volume and velocity to values between pre-determined maxima and minima so as to properly entrain, de-agglomerate and deliver medicament particles to the inhaler user.
[0016] Other objects and advantages of the invention will become apparent upon reading the following detailed description and upon reference to the drawings. Throughout the drawings, like reference numerals refer to like parts.
SUMMARY OF THE INVENTION
[0017] A dry powder inhaler (DPI) includes an air intake and check valve section; a mixing and cartridge section; and a mouthpiece all designed to control the volume and velocity of the inhaled air and aerosolized drug. This inhaler can be operated over a very broad inhalation tidal volume range of human breath. Several features of the inhaler provide advantageous properties, most significantly with respect to using carefully designated aerodynamic forces to dilute and de-agglomerate the medicament particles, rather than using broad high pressure forces that would contribute to relatively great particle losses in the oropharyngeal region.
[0018] The inhaler intake chamber mounts a check valve bulb having a tapered bulb, bulb travel rod and biasing spring, and one or more perimeter chutes or venturis on the bulb to modulate and control the flow of air through the device. The intake further optionally includes a feedback module (not shown) to generate a tone indicating to the user when the adequate inhalation air-flow rate has been achieved.
[0019] The inhaler mixing section holds a cartridge containing a dry powder medicament. The cartridge has two telescopically assembled halves, and each half has an air inlet hole or orifice-port and an air outlet hole or orifice-port. When the halves are twisted so as to align the air holes, the air stream from the check valve enters the cartridge and then picks up, fluidizes and de-agglomerates the medicament powder in the cartridge. The airflow entraining the particles then exits the cartridge and flows through the mouthpiece to the inhaler user. The cover on the mixing section can open only when the mouthpiece is at an appropriate pre-determined angle to the intake conduit. The mixing section helps to impart a cyclonic flow to air passing through the mixing chamber and cartridge.
[0020] An important feature of the inhaler is the mouthpiece. The mouthpiece is integrated to the swivel joint of the mixing section, and can be rotated back into the inhaler intake section and then enclosed by a cover for storage. A mouthpiece transport conduit has the ability to expand the cross-section of the air flow, which in turn reduces the velocity of approach of the drug powder into the oral cavity. As shown in FIGS. 10 , 18 , 19 , 21 and 23 , the mouthpiece is offset with respect to the centerline of the mixing cavity and mounted cartridge, and the airflow inlet from the check valve mechanism into the mixing chamber and cartridge is also offset. These tangential offsets encourage a helical airflow around the cartridge, as explained in further detail below. Initially, the tangential mouthpiece exit tube increases the velocity of the transport gas, which in turn inducts the discharged particles into the exit tube. The mouthpiece exit tube then expands in one dimension and the transport gas slows while the particle concentration per unit volume becomes more dilute. Flow is expanded to create a secondary shear flow, which helps to further de-agglomerate particles. This also creates a horizontal aspect ratio and therefore aerosol discharge path that is more effective in negotiating and streaming the aerosol through the convoluted pathway of the oral pharynx.
[0021] The mouthpiece expansion wall divergence angle is important for stable particle transport conditions to exist. An optimum divergence angle is between 14 and 16 degrees. However, a slightly larger 17 degree divergence angle can be used to achieve a horizontal aerosol discharge path with a 3:1 aspect ratio closely approximating the aspect ratio at the rear of the human throat. Once the expansion divergence has reached a specified limit, the continuing slot discharge tube maintains the proper collimation of the particles for controlled particle injection speed and direction of the path of the particles into the oral cavity. The mouthpiece includes a tongue depressor, and a tactile protrusion to contact the lips of the user to tell the user that the Dry Powder Inhaler (DPI) is in the correct position.
[0022] The cartridge halves can be twisted into and out of positions in which the air inlet holes and the air outlet holes are respectively aligned. The cartridge can only be inserted into the mixing chamber when a cartridge alignment boss is aligned with a receiving recess at the bottom of the mixing chamber, and a cartridge collar and engages a mating mixing chamber collar ( FIG. 2 ). Each cartridge has a unique key on each half that fits only with a particular part of the inhaler, thereby insuring that the proper cartridge containing the proper medicament is preselected, and further insuring that the cartridge is installed properly in the inhaler.
BRIEF DESCRIPTION OF THE DRAWINGS
[0023] FIG. 1 is an isometric view of the inhaler embodying the invention.
[0024] FIG. 2 is an exploded view of the inhaler shown in FIG. 1 .
[0025] FIG. 3 , including FIGS. 3 a , 3 b and 3 c , is a front isometric view of the medicament containing cartridge used with the inhaler, showing cartridge outlet hole or orifice port alignments.
[0026] FIG. 4 , including FIGS. 4 a , 4 b and 4 c , is a rear isometric view of the medicament-containing cartridge used with the inhaler shown in FIG. 3 , showing inlet hole or orifice port alignments.
[0027] FIG. 5 is a front elevational view of the cartridge shown in FIGS. 3 and 4 .
[0028] FIG. 6 is a rear elevational view of the cartridge shown in FIGS. 3 , 4 and 5 .
[0029] FIG. 7 is a sectional view taken substantially in the plane of line 7 - 7 in FIG. 5 .
[0030] FIG. 8 is a sectional view taken substantially in the plane of line 8 - 8 in FIG. 7 .
[0031] FIG. 9 is a sectional view taken substantially in the plane of line 9 - 9 in FIG. 7 .
[0032] FIG. 10 is a top plan view of the inhaler shown in FIGS. 1 and 2 .
[0033] FIG. 11 is a sectional view taken substantially in the plane of line 11 - 11 in FIG. 10 .
[0034] FIG. 12 is a sectional view taken substantially in the plane of line 12 - 12 in FIG. 10 .
[0035] FIG. 13 is an isometric view of the inhaler shown in FIGS. 1 and 2 but configured for the insertion or removal of a medicament-containing cartridge.
[0036] FIG. 14 is an isometric view similar to FIG. 13 but configured as it appears when a medicament-containing cartridge has been inserted in the inhaler.
[0037] FIG. 15 is a sectional view taken substantially in the plane of line 15 - 15 in FIG. 13 .
[0038] FIG. 16 is a sectional view taken substantially in the plane of line 16 - 16 in FIG. 14 .
[0039] FIGS. 16 a , 16 b and 16 c are fragmentary sectional views taken substantially in the plain of line 16 a - 16 c in FIG. 16 .
[0040] FIG. 17 is an isometric view showing the inhaler of FIGS. 1 and 2 , parts being broken away to permit the diagramming of air flow through the inhaler.
[0041] FIG. 18 is an isometric view similar to FIG. 17 diagramming air flow through and around the inhaler check valve, mixing section, cartridge and mouthpiece.
[0042] FIG. 19 is an isometric view similar to FIG. 18 diagramming air flow through and around the inhaler check valve, inside the cartridge, and through the mouthpiece.
[0043] FIG. 20 is an isometric view similar to FIGS. 1 , 2 , 17 , 18 and 19 showing the inhaler, the inhaler flow-control/check-valve, and the flow-control/check-valve sub-housing.
[0044] FIG. 21 is a top plan view of the inhaler shown in FIG. 20 .
[0045] FIG. 22 is a sectional view taken substantially in the plane of line 22 - 22 in FIG. 21 .
[0046] FIG. 23 is a top plan view substantially similar to FIG. 21 .
[0047] FIG. 24 is a sectional view taken substantially in the plane of line 24 - 24 in FIG. 23 .
[0048] FIG. 25 is an isometric view of the flow-control/check-valve and sub-housing shown on FIGS. 17 , 18 , 19 , 20 , 22 and 24 .
[0049] While the invention will be described in connection with several preferred embodiments and procedures, it will be understood that it is not intended to limit the invention to these embodiments and procedures. On the contrary, it is intended to cover all alternatives, modifications and equivalents as may be included within the spirit and scope of the invention as defined by the appended claims.
DETAILED DESCRIPTION OF THE INVENTION
[0050] An improved inhaler has been developed which has several novel features optimizing performance. Medicament particles can be delivered/administered over a broad range of inhalation velocity and tidal volume of human breath. An inhaler mouthpiece exit tube dilutes, expands, and collimates the particle dispersoid so that the particles do not re-agglomerate during delivery. This inhaler provides the means to effect a process whereby particles are fluidized, suspended, then scavenged from the walls by re-circulating scrubbing air, as well as higher speed-flow-through air, followed by a high-shear flow field discharge into an expanded, slower-moving mass of air that disperses and meters the particle concentration expelled from the unit dose cartridge upper outlet port.
[0051] Inhaler Overview
[0052] FIG. 1 shows an embodiment of a dry powder inhaler 10 described and claimed herein. In broad conceptual terms, an inhaler housing 15 includes an intake section 20 , a mixing section 30 and a mouthpiece 40 . In the preferred embodiment, this inhaler housing 15 is approximately 93 mm long, 38 mm high, and 22 mm thick. The other parts illustrated and described here are of proportionate size. The mouthpiece 40 can be swiveled from a stored position within the housing 15 to a cartridge installation position in which the mouthpiece 40 is oriented at 90 degrees to the long dimension of the housing. When a cap 352 is closed, the mouthpiece can then be further rotated into an operating position in which the mouthpiece is located at a 180 degree position to the long dimension of the housing. When the mouthpiece 40 is stored within the inhaler 15 , a sliding dirt shield cover 16 slidably mounted stored on the housing can be slid upwardly to protect the mouthpiece 40 and the air intake conduit entrance of the inhaler. The housing 15 can be formed of a gamma radiation-proof polycarbonate plastic for the rapid sterilization of the inhaler in mass production, as well as in clinical-hospital use.
[0053] An air passage 50 ( FIG. 17 ) extends through the intake section 20 , the mixing section 30 and the mouthpiece 40 . A swivel joint 80 ( FIGS. 2 and 17 ) connects the mouthpiece 40 to the mixing section 30 . In the preferred embodiment, the mouthpiece and mixing section are one unit, and are connected by a swivel joint to the main housing. The cap 352 is pivotally attached to the mixing section 30 , and an interlock mechanism 355 prevents the mouthpiece 40 from being swung into an operating position unless the cartridge 301 is properly seated and installed. A cartridge 301 shown in FIGS. 3 , 4 and 5 contains a medicament powder, and it can be installed in and removed from the mixing chamber 30 .
[0054] Aerosolized powder is drawn from the cartridge 301 and mixing section 30 through the mouthpiece 40 to the users' oropharangeal cavity via the mouthpiece 40 . As air and powder travel through the mouthpiece, the velocity of the travel slows, thus preparing the powder for effective delivery to the inhaler user's broncheal tract and lungs.
[0055] So that writing or identifying indicia on medicament-containing cartridge 301 can be read easily, the mixing section 30 has a cap 352 which may be configured as a transparent magnifying lens. An arrow 460 ( FIG. 17 ) shows the direction of aerosolized medicament powder discharge from the cartridge and through the mouthpiece.
[0056] Air is caused to enter the inhaler by an inhalation effort which the inhaler user exerts on and in the mouthpiece 40 . As shown particularly in FIG. 17 and as suggested by the air-flow arrows 460 in FIGS. 17 and 18 , ambient air enters the air control system 171 through air intake ports 172 and is directed to an air flow-control/check-valve 180 . As shown in FIGS. 17 , 18 , and 25 , this check valve system 180 includes a conical head 181 mounted upon a bulb rod 182 . A bulb 184 is slidably mounted upon the rod 182 for reciprocation between a stagnant air-flow position and a dynamic air-flow-inhibiting position. The bulb 184 is drawn into a normal relatively downstream air-flow position, by the force of air flow acting to overcome the bulb reactive force of a conical tension spring 185 as suggested particularly in FIG. 19 . This spring is preferably formed of medical grade stainless steel. Chute-like recesses 186 in the surface 187 of the bulb 184 control and direct the flow of air over the bulb 184 . Air-flow straightening vanes 189 mounted on the conical head 181 engage a confronting conical venturi formation or seat 191 ( FIG. 22 ). Air flowing between the head 181 and seat 191 is accelerated and the air-flow straightened, in accordance with known characteristics of gaseous air-flow.
[0057] When the inhaler user draws air through the mouthpiece 40 , air flows to and around the bulb 184 , and the imbalance of air pressure forces acting upon the reciprocating bulb 184 pushes the bulb in a downstream direction along the rod 182 into positions which inhibits air-flow. Because the bulb 184 is mounted to the tension spring 185 , increasing amounts of force are required to draw the bulb 184 into increasingly air-flow-restricting positions. Additional bulb movement control can be provided, if desired, by an opposing second spring (not shown) forming a high-sensitivity push-pull system.
[0058] This bulb and spring mechanism allow the inhaler user to generate a slight partial vacuum in his lungs before the bulb is drawn away from the seating arrangement. Thus, by the time significant vacuum is generated, a slight velocity increase of air-flow through the inhaler assists in drawing the medicament from the cartridge (FIGS. 1 and 17 - 19 ), through the inhaler and into the bronchial region and lungs of the user.
[0059] As suggested particularly in FIG. 20 , the check valve arrangement 180 can be mounted in a sub-housing 200 of intake section 20 , and both components 20 and 180 can be removed from the inhaler housing 50 for cleaning, repair or replacement. A lock device 196 of known design can be used to secure the sub-housing 200 of intake section 20 and contained components within the inhaler housing 15 .
[0060] When air is being drawn through the inhaler 10 and the bulb 184 is drawn along the rod 182 so as to impact the conical head 181 , a clicking sound is produced. In accordance with one aspect of the invention, this clicking sound indicates to the inhaler user that he or she is drawing properly upon the mouthpiece and operating the inhaler correctly. If desired, a vibratory mechanical reed (not shown) can be mounted in the air-flow path to produce an audible signal to the user. Alternatively, an electronic flow or pressure sensor can trigger an audible or visual signal indicator to tell the user that proper air flow has been established.
[0061] This air flow-control/check-valve system 180 serves to deliver air at a predetermined volume and velocity to downstream inhaler parts. The air-flow, at this predetermined volume and velocity, acts to pick-up, fluidize, de-agglomerate and deliver entrained medicament particles to the inhaler user in a dispersed form and at a proper location to enter the user's bronchial system.
[0062] Venturi and Mixing Section
[0063] As suggested particularly in FIGS. 12 , 17 and 18 , the air flow is then drawn through a venturi passage 201 of restricted size, thus increasing the velocity of that air-flow, and into the inhaler mixing section 30 . As shown in FIGS. 10-17 , this mixing section 30 here comprises a fixed support 31 upon which is journaled a cup 32 . It will be noted that the mouthpiece 40 is attached to the swivel cup 32 and can thus act as a handle for pivoting the cup member 32 and mouthpiece to the configurations shown in FIGS. 1 , 14 and elsewhere and as more fully described below.
[0064] In general, the mixing section 30 is provided with shapes on its interior surface to encourage air flow acceleration so as to suspend medicament particles in the air-flow and to de-agglomerate them. Within the cup 32 a medicament-containing cartridge 301 can be mounted. As more fully described below, the cartridge 301 is provided with air inlet and outlet holes ( FIGS. 5-9 ), the cup 32 is sized and shaped so as to direct air into the cartridge through the lower inlet hole. The air then generally flows up through the cartridge in an upward direction while producing a dual counter-rotating helical motion, and out of the cartridge and down the mouthpiece as particularly suggested in FIG. 19 . As suggested in FIG. 18 , excess volume of air can flow around the outside of the cartridge but within the mixing chamber to again mate with the emerging medicament-laden air discharged from the cartridge and flowing into the mouthpiece. Thus, air flowing into the mixing chamber feeds the cartridge inlet holes, helps to extract air flowing out from the cartridge discharge holes, dilutes the medicament-laden air flow, and provides controlled, even concentrations of medicament particles into the mouthpiece air flow. The particle entrainment and dilution in the mouthpiece are provided primarily by the cartridge bypass air.
[0065] As suggested in FIGS. 11 , 12 , 15 and 16 , the mixing chamber inlet port 33 provides vortex shedding which, aided by the top and bottom internal mixing chamber internal swirl toroids 34 and 35 , fluidizes, suspends and scrubs the powder in the cartridge. The upper semi-toroid shape 35 changes air flow direction from dispersion chamber to mouthpiece, thus aiding further de-agglomeration of the medicament particles in the entrained powder stream. To reduce powder cohesion, a modest gas expansion velocity with subsequent air shearing forces (and flow resistance) act to support a fully dispersed flow through the mouthpiece 40 .
[0066] Alternatively, a chamber which includes internal protrusions or spiral shapes can be provided. The interior surfaces of the mixing chamber can be shaped to provide one or more helical flows of air around and within the cartridge, if desired.
[0067] Cartridge
[0068] The cartridge 301 is shown in further detail in FIGS. 3-9 . In the illustrated embodiment, the cartridge 301 comprises an upper half 302 and a lower half 303 , each preferably formed of transparent plastic material. To encourage medicament particle dispersion, the preferable plastic material is provided with ultra smooth surfaces, is capable of being molded into the cartridge components which have and which maintain great dimensional accuracy, does not absorb or otherwise interact with water or moisture, and has electrostatically neutral characteristics such that the medicament powder in the cartridge 301 is not retained by cartridge static charge, and does not adhere to the cartridge halves 302 , 303 . One such material which can be used for the lower half 303 is the Topaz brand of cyclicolephin co-polymer plastic offered by Ticonia Corporation.
[0069] The upper cartridge half 302 defines an air inlet hole 306 and an outlet hole 307 , and the cartridge lower half defines a corresponding air inlet hole 308 and an air outlet hole 309 . This upper half can be made of a clear very low water absorbent nylon. As shown particularly in FIG. 7 , and as suggested in FIG. 3 a , the halves 302 and 303 interengage through a telescopic fit. A circumferential ring and groove arrangement 310 retain the halves 302 and 303 in their assembled configuration.
[0070] As suggested particularly in FIGS. 5 , 6 , 8 , and 9 , the inlet holes 306 and 308 formed at the lower portion of the cartridge are beveled, and the outlet holes 307 , 309 are likewise beveled at an angle of substantially 60 degrees so as to encourage air ingress and egress but to discourage electrostatic adhesion and agglomerate deposition of 10 or larger micron-sized medicament particles on the plastic defining the hole edges. To enable air flow and particle pickup action, the inlet holes 306 and 308 are arranged to overlap or register with one another when the cartridge halves are twisted (as suggested by the arrow A in FIG. 4 c ) into the appropriate cartridge open position, and the holes 306 , 308 are elongated in a vertical direction. Similarly, the outlet holes 307 , 309 are arranged to overlap and provide free air egress when the cartridge halves are appropriately aligned, and the holes are elongated in a horizontal direction so as to orient the air outflow for delivery to the horizontally elongated channel in the mouthpiece 40 .
[0071] This cartridge 301 is approximately one-quarter inch in diameter and its body is approximately 1 inch in axial length, and so to facilitate easy installation and extraction from the inhaler 10 , a handle or manipulator structure 314 is provided atop the cartridge 301 . Here, the handle structure 314 comprises four web extensions 315 which extend from the cartridge body to a finger disk 316 which may have a coined or serrated periphery. A pointer or dial indicator 317 is formed atop the disk 316 and is further discussed below.
[0072] At the bottom of the cartridge 301 , a cartridge installation check boss 319 is formed. In accordance with another aspect of the invention, this check boss can have a unique, non-circular shape of any desired form such as those shown in FIGS. 16 a , 16 b and 16 c . These unique embossments are designed to fit within a closely mating relief 39 formed in the fixed support 31 of the mixing section. These unique embossed shapes will be uniquely associated with particular medicaments, so that a cartridge containing an incorrect medicament cannot be installed in a particular patient's inhaler.
[0073] Cartridge Mounting Mechanism
[0074] To properly mount the cartridge 301 in the inhaler 10 , a mounting mechanism 350 is provided as especially shown in FIGS. 1 , 2 , 13 - 16 and 17 . This mounting mechanism 350 takes the form of a cap 352 formed of clear plastic, pivotally mounted so as to cover the mixing section cup 32 . See especially FIG. 16 . A pivot pin 353 interconnects the cap 352 with an extension 354 of the mount 31 . To facilitate reading indicia marked upon the top of the cartridge pointer 317 , the top of this cap 352 is curved so as to act as a magnifying lens. This dome shape also provides strength to the cover structure.
[0075] The cartridge can be installed and the cap 352 secured in place when the mouthpiece 40 and cartridge are pivoted into their operating positions. To this end, a radially outwardly biased lock pin 356 ( FIG. 2 ) depending from the cap mount 331 pushes the cap 352 upwardly and into an open position when the mouthpiece 40 and cap mount 331 are swiveled into a position so that the mouthpiece is located at approximately 90 degrees to the long or greater dimension of the inhaler body 15 . In this configuration, the lock pin 356 is pushed radially outwardly and the cap 352 is rotated upwardly when the lock pin 356 is pushed into a relief defined in a skirt 360 of the cover 358 ( FIG. 2 ). This arrangement acts as a safety and user prompting feature.
[0076] After the cartridge is inserted into the inhaler and the cap is closed, the mouthpiece 40 can be pivoted out of its cartridge installation and cap release position as shown in FIGS. 13-16 and into the user medication inhalation configuration shown in FIGS. 1 , 17 and 20 - 24 . This mouthpiece pivoting motion can occur only when the cap skirt 360 is pushed down into its closed position and the lock pin 356 is radially depressed so as to permit mouthpiece 40 swiveling action. Thus, when the inhaler user moves the mouthpiece from its stored position within the housing 15 to the cap unlocked position, the cap springs open as shown in FIGS. 13 and 15 , and thereby indicates to the inhaler user that he or she should inspect and, if necessary, replace or insert a new cartridge 301 .
[0077] Mouthpiece
[0078] As suggested above, the mouthpiece 40 discharges particle-laden air to the oropharyngeal cavity of the user. In addition, the mouthpiece diverges the air and particle stream to slow down the particles, and then converges the particle stream to collimate and aim the particles at the rear of the user's mouth. The mouthpiece is long enough so that it extends approximately midway into most users' mouths. To encourage correct inhaler and mouthpiece usage, the inhaler mouthpiece is oriented so as to extend diagonally upwardly at approximately a 3 degree angle X as suggested in FIGS. 22 and 24 . As suggested in FIGS. 21 and 23 , the horizontally spaced walls of the mouthpiece diverge at an angle Y of approximately 5 to 8 degrees. As suggested by a comparison of FIGS. 21 and 22 , the ratio of the height H of the mouthpiece air passage page to the width W of the air passage is approximately 3:1. If desired, a tooth and lip placement embossment 411 can be provided to depend from the distal end 412 of the mouthpiece 40 . The mouthpiece is preferably made of Delrin or Celcon co-polymer acetyl plastic so as to provide proper strength, swivel bearing self-lubricity, and smooth internal and external finish.
[0079] In use, the inhaler employs a regulated flow of air to fluidize and aerosolize medicament particles and transport them to the desired rear region of the orophalangeal cavity. To accomplish this, air is first drawn into the interior of the inhaler housing 15 and through the intake ports 172 as suggested in FIGS. 17 and 18 , to a predetermined volumetric air flow which is controlled by the flow-control/check-valve mechanism 180 . The airstream then enters into the cartridge interior through the vertically elongated and aligned inlet ports 306 . The air entering the cartridge interior immediately impinges upon the opposite cylindrical cartridge wall. The impacted air jet then redistributes itself into several portions. One of the portions flows downwardly into the medicament powder bed, and strips the powder from the cartridge surface and begins to fluidize it into an airborne dust cloud. Another portion of the impingement jet is directed laterally in both directions, which creates dual counter-rotating vertical spinning helical columns. The majority of the fluidized medicament powder is retained in these two columns, where the first deagglomeration action is achieved. Yet another portion of the impingement jet is directed vertically, which creates a vertical high-speed air jet along the cartridge wall into the cartridge discharge port or holes 306 , 309 . Particles in the helical aerosolized columns are scavenged into the jetstream and then discharged from the cartridge. This scavenging effect results in particles being metered out or discharged from the cartridge at a relatively steady particle distribution rate. Particle agglomerations are further broken down by the discharge process. Large agglomerates impinge upon the opposing mixing chamber wall, and are further reduced into smaller agglomerates. Single particles and smaller agglomerates are carried forward through the mixing chamber and into the mouthpiece discharge tube. The remaining agglomerates are pulled apart in the high-shear and shock flow field produced by the mouthpiece tangential entry port. Thus a steady flow of a individual medicament particles emerge from the mouthpiece and into the users oropharyngeal airway. These airstream flows and the sub-stream flows thus result in complete air entrainment of all medicament particles in the cartridge, and delivery of a complete, closely metered medicament dose to the patient.
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A dry powder inhaler having improved aerodynamic properties for diluting, dispersing, and metering drug particles for increasing the efficiency of pulmonary drug delivery to a patient is described. The inhaler comprises, in general, a housing having an air intake, an air flow-control/check-valve, a mixing section and a mouthpiece. A cartridge loaded with a single dose of medicament can be installed in the mixing section.
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This application is a division of application Ser. No. 08/417,640, filed Apr. 6, 1995, now U.S. Pat. No. 5,670,342, which is hereby incorporated by reference.
FIELD OF THE INVENTION
This invention relates to novel peptides derived from polypeptides of the so-called NDF/heregulin family. These peptides exhibit biological properties as a mitogenic and differentiation factor for colon epithelial cells and as a trophic and mitogenic factor for Schwann cells.
BACKGROUND OF THE INVENTION
The protein called neu differentiation factor, or "NDF", is a 44-kilodalton polypeptide originally isolated from rat fibroblasts which has been shown to induce the growth or differentiation of epithelial cells; Peles et al., Cell, Volume 69, pages 205-216 (1992). Both this heat-stable rodent protein and its human homolog, called heregulin, are secreted proteins that were originally purified by heparin-binding chromatography from the media of cultured cancer cells; Peles et al., Cell, above, and Holmes et al., Science, Volume 256, pages 1205-1210 (1992). Several glial cell growth factors (GGF) isolated from bovine brain tissue have been found to be related to these so-called NDF/heregulins; Marchionni et al., Nature, Volume 362, pages 312-318 (1993). Similarly, a group of proteins called ARIA, ranging in molecular weight from 33 to 44 kilodaltons and purified from chicken brain tissue on the basis of their acetylcholine receptor inducing activity, have been shown to be structurally related to the NDF/heregulins; Falls et al., Cell, Volume 72, pages 801-815 (1993). The NDF/heregulin family of proteins is now known to contain at least twelve distinct molecules. It has been reported that the human homolog members of this family are encoded by a single gene, located on human chromosome 8p 12 -p 21 , which contains at least 13 exons whose precise organization has not been determined; Orr-Urtreger et al., Proceedings of the National Academy of Science, USA, Volume 90, pages 1867-1871 (1993).
The cell membrane-bound precursor forms of these proteins (referred to in this description as "proNDF/heregulins") are mosaics of recognizable structural motifs. They include an N-terminal hydrophobic signal peptide, followed by either a so-called "kringle" domain (consisting of about 250 amino acid residues) or an N-terminal non-hydrophobic sequence (consisting of about 40 amino acid residues). Other regions include an immunoglobulin(Ig)-like domain (approximately 70 amino acid residues), a so-called "spacer" domain that contains multiple binding sites for N- and O-linked glycosylation, an epidermal growth factor (EGF)-like domain of about 60-75 amino acid residues that includes 6 cysteine residues, a hydrophobic region of about 25 amino acid residues that functions as a transmembrane domain, and a "cytoplasmic tail" which can vary in length. Some of these transmembranous precursor forms undergo proteolytic cleavage in the cell at both the N-terminus and at the short stretch of sequence (juxtamembrane) that connects the EGF-like domain with the transmembrane domain. Depending on the amino acid sequence in this juxtamembrane region, the NDF/heregulins have been designated subtype 1, subtype 2, subtype 3, etc. Additional variations comprise two forms of the C-terminal loop of the EGF-like domain, which are termed alpha (α) and beta (β), depending on the amino and sequence in this region; Wen et al., Molecular and Cellular Biology, Volume 14, Number 3, pages 1909-1919 (1994).
Originally isolated as a family of molecules that induce phosphorylation of tyrosine residues in the erbB2/Her2 proto-oncogene expression product, the NDF/heregulins were thought at first to be a possible ligand for that receptor; Peles et al., Cell, above; Wen et al., Cell, Volume 69, pages 559-572 (1992); Holmes et al., Science, above, and Bacus et al., Cancer Research, Volume 53, pages 5251-5261 (1993). However, it has more recently been shown that the NDF/heregulins bind to and stimulate the receptor proteins encoded by the genes known as erbB3/Her3 and erbB4/Her4; Plowman et al., Volume 366, pages 473-475 (1993); Kita et al., FEBS Letters, Volume 349, pages 139-143 (1994); Carraway et al., The Journal of Biological Chemistry, Volume 269, Number 19, pages 14303-14306 (1994); and Carraway et al., Cell, Volume 78, pages 5-8 (1994). The EGF-like domains of the various NDF/heregulins appear to be responsible for receptor recognition and act independently of other structural motifs; see Holmes et al., Science, above.
In vitro, NDF/heregulins have been found to be weakly mitogenic for various epithelial cells, including mammary, lung and gastric epithelial cells; Holmes et al., Science, above. However, certain mammary tumor cells apparently undergo growth arrest in response to NDF or its human homolog; Peles et al., Cell, above; and Bacus et al., Cell Growth and Differentiation, Volume 3, pages 401-411 (1992). Treated cells exhibit a mature phenotype which includes a flat morphology, synthesis of the intracellular cell adhesion molecule ICAM-1, and in the case of mammary cells, the secretion of milk components; Bacus et al., Cell Growth and Differentiation, above; and Bacus et al., Cancer Research, above. Recombinantly produced glial growth factors (GGFs) have been observed to be mitogenic for cultured Schwann cells, which otherwise divide very slowly even in the presence of known mitogenic factors; see Marchionni et al., Nature, above. The motor-neuron derived NDF/heregulin family member known as ARIA appears to induce the synthesis of acethylcholine receptors, and possibly other molecules, by post-synaptic muscle cells; see Falls, Cell, above.
SUMMARY OF THE INVENTION
Based on studies conducted with regard to localization of the N- and C-terminal ends of the extracellular ("soluble") portion of membrane-bound NDF/heregulin polypeptides, a putative C-terminal processing site has been assigned to these polypeptides. This C-terminal end has been incorporated into the design of two shorter-length forms of the polypeptides directed specifically to the EGF-like domain. These peptides, which are biologically active and comprise an aspect of the present invention, have the following amino acid sequences, respectively:
SHLVKCAEKEKTFCVNGGECFMVKDLSNPSRYLCKCQPGFTGARCQNYVMAS (SEQ ID NO:1), and
SHLVKCAEKEKTFCVNGGECFMVKDLSNPSRYLCKCPNEFTGDRCQNYVMAS (SEQ ID NO:2).
The present invention additionally comprises DNA molecules encoding these peptides, expression vectors for directing the expression of the encoded peptides in host cells, transformed or transfected eukaryotic and prokaryotic host cells useful in the production of the peptides, a method for the recombinant production of the peptides, methods of use for the peptides in the ex vivo treatment of cells and in human therapy, and compositions containing the peptides as a biologically active component.
This invention is based on the discovery of an important subregion within the known EGF-like domain of extracellular NDF-heregulins, this subregion residing near the C-terminal end and extending from amino acid residue 222 to amino acid residue 228 of extracellular NDF/heregulin (corresponding to the amino acid sequence numbering of published PCT application WO 94/28133, as explained in greater detail further below). More specifically, it has now been recognized that the seven amino acid residue sequence from 222 to 228 in the β form of extracellular NDF/heregulins confers greater biological activity in the assays shown here than the corresponding sequence from the α form of extracellular NDF/heregulins, despite sequence identity in the rest of the molecule. This recognition has enabled the design and construction of biologically active peptides that are capable of duplicating the physiological effects of the longer length NDF/heregulins, while potentially enabling greater ease of delivery in certain therapeutic administrations because of their smaller size.
Moreover, as will be seen from the biological results presented further below, the peptides of this invention are useful in appropriately effective amounts as human colon epithelial and Schwann cell growth factors, possessing the ability to stimulate the proliferation and maturation of such cells. Accordingly, these peptides are utilizable as nutrients for the survival and study of such cells in culture, and potentially as therapeutic agents for the treatment of diseases or conditions resulting from deficiencies, deterioration or abnormalities of such cells in the body.
BRIEF DESCRIPTION OF THE FIGURES
FIG. 1. This figure is a schematic drawing (not in proportional scale) of the extracellular structure of human NDF/heregulin, comprising (distal from the end that binds to the cell membrane): the putative N-terminal "heparin-binding" region, an immunoglobulin (Ig)-like domain, a carbohydrate (or "spacer") domain, and an EGF-like domain proximal to the C-terminal end. The open circles in the spacer domain represent O-linked sugars and the branched closed circles represent N-linked sugars. Four disulfide bonds, one of which is in the Ig-like domain and three of which are in the EGF-like domain, are also shown. Numbers designate amino acid residue positions at selected points along the polypeptide chain, starting sequentially from the N-terminal end and moving towards the C-terminal end. The EGF-like domain begins approximately at amino acid residue position 177 (marked) and ends approximately at amino acid residue position 228 (not marked).
FIG. 2. This figure is a graphical representation of the proliferative effect of the peptides of the invention on human colonic epithelial cells in vitro. These peptides are designated in the figure as EGF-β (SEQ ID NO: 2, above), represented by the closed circles, and as EGF-α/β (SEQ ID NO: 1, above), represented by the open circles. For comparison, two other peptides of equal length are included, designated as EGF-α and EGF-β/α, and represented by the closed squares and open squares, respectively. The latter two are homologs based on the EGF domain of extracellular NDF-heregulins and consist of the amino acid sequences shown further below in this text (SEQ ID NOS: 3 and 4, respectively). Proliferation is measured with a crystal violet dye which stains the cell protein and is indicative of cell number. The results are displayed on the vertical axis in units of fold stimulation, which is the absorbance of peptide-treated cells divided by the absorbance of untreated cells. The picomolar (pM) concentration of peptide used to treat the cells is shown on the horizontal axis. The best results for cell proliferation are seen with EGF-β and EGF-α/β, in accordance with the invention. Some proliferation was obtained with EGF-α, although it is clearly inferior to EGF-β and EGF-α/β. No effect was seen with EGF-β/α.
FIG. 3 (upper and lower panels). This figure comprises microphotographs of fluorescently labeled actin in LIM 1215 human colon epithelial cells, either without treatment (upper panel) or with incubation for three days with 5% fetal bovine serum (FBS, lower panel). In the absence of treatment (upper panel), the cells appeared small and rounded. The cells showed some change with FBS treatment, and they appear slightly larger.
FIG. 4 (upper and lower panels). This figure comprises microphotographs of fluorescently labeled actin in LIM 1215 human colon epithelial cells, following incubation for three days with EGF-α (comparison, upper panel) and EGF-β (this invention, lower panel). Evidence of cellular morphological changes is seen for those cells treated with EGF-β, but not in cells treated with EGF-α. All peptides were added at a 420 picomolar concentration.
FIG. 5 (upper and lower panels). This figure comprises microphotographs of flurosencently labeled actin in LIM 1215 human colon epithelial cells following incubation for three days with EGF-β/α (comparison, upper panel) and EGF-α/β (this invention, lower panel). As with EGF-β (FIG. 4, above), evidence of cell development and maturation is seen for cells treated with EGF-α/β. In contrast, those cells treated with EGF-β/α appear unchanged. All peptides were added at a 420 picomolar concentration.
DETAILED DESCRIPTION OF THE INVENTION
Studies undertaken with respect to cDNAs for α and β forms of extracellular NDF/heregulin, as expressed in Chinese hamster ovary (CHO) cells, have succeeded in localizing the C-terminal end at amino acid residue 228 as the primary site for proteolytic cleavage. Using the particular NDF/heregulins known as α2 and β1, several peptides were designed based on identity with or homology to the EGF-like domains in these proteins. As used here, the proteins referred to as "α2" and "β1" are those which have been disclosed in PCT application WO 94/28133, published Dec. 8, 1994. The sequence of α2 (from amino acid residue 1 to amino acid residue 462) is given in FIG. 32 of the PCT application (see also SEQ ID NO: 8 therein). The sequence of β1 is given partially (from amino acid residue 95 to amino acid residue 645) in FIG. 35 of the published PCT application (see also SEQ ID NO. 14 therein). The first ninety four amino acid residues (N-terminal end) of β1, not depicted in PCT FIG. 35, are identical to the first ninety four amino acid residues of α2 shown in PCT FIG. 32. A depiction of the extracellular ("soluble") portion of the α and β forms of NDF/heregulin is shown in FIG. 1 of the present description.
The initial studies referred to here utilized peptides based solely on sequences of the EGF-like domain of the aforementioned α2 and β1 forms of NDF/heregulin, that is to say, that portion of the extracellular protein from amino acid residue 177 to amino acid residue 228 (see FIG. 1 herein). Studies revealed that the β peptide, referred to herein as EGF-β, was more biologically active than the α peptide (EGF-α) in certain assays. The reason for this difference was not initially apparent. However, during peptide mapping studies of the EGF-like domains of NDF/heregulins, it was discovered that the α and β forms cleaved (degraded) at different rates when subjected to digestion by endoproteinase Lys-C. Specifically, the β form was more resistant to this enzyme and cleaved at a slower rate. Moreover, this phenomenon seemed limited to the lysine residue at position 211. There was no apparent difference in the rate of cleavage between α and β at any other lysine residues in the N-terminal end of the EGF-like domain. This observation suggested that the structural conformation of the region of the molecule containing lysine-211 may differ between α and β, leading to faster enzymatic cleavage for the α form.
Further, it was noted that the amino acid sequence in the EGF-like domain of the α and β forms are identical from amino acid residue position 177 to amino acid residue position 212. It was surmised that the difference in susceptibility to cleavage must be due to conformational differences in the C-terminal end of the EGF-like domain, from amino acid residue 212 to amino acid residue 228. This rationale suggested that the C-terminal end may be critical for biological activity and prompted the synthesis of two chimeras for further testing and confirmation of this hypothesis. Specifically, these two chimeric peptides were based on "switching" the 222-228 amino acid sequence between EGF-α and EGF-β, in order to study the effect on biological activity of this sequence. In all, four peptides were synthesized, including the aforementioned two chimeric peptides. The four peptides had the following sequences:
(1) SHLVK (A) QNYVMAS, or EGF-α/β (SEQ ID NO:1)
(2) SHLVK (B) QNYVMAS, or EGF-β (SEQ ID NO:2)
(3) SHLVK (A) TENVPMK, or EGF-α (SEQ ID NO:3)
(4) SHLVK (B) TENVPMK, or EGF-β/α (SEQ ID NO:4)
in which "(A)" denotes the amino acid sequence CAEKEKTFCVNGGECFMVKDLSNPSRYLCKCQPGFTGARC (SEQ ID NO:5), and
"(B)" denotes the amino acid sequence CAEKEKTFCVNGGECFMVKDLSNPSRYLCKCPNEFTGDRC (SEQ ID NO:6).
The relatively short length of these peptides lended itself to preparation by chemical synthesis, utilizing the following method.
Chemical Synthesis of Peptides
Each peptide was prepared by the Fmoc (fluorenyl-methoxycarbonyl)/t-butyl-based solid phase chemistry method for peptide synthesis. An ABI-431 instrument (Applied Biosystems, Foster City, Calif.), with a single coupling program, was utilized to effect peptide chain assembly starting with a commercially available hydroxymethyl-phenylacetyl (HMP) derivatized polystyrene resin. The dicyclohexyl carbodiimide (DDC) mediated coupling of the C-terminal residue, FmocLys(t-Boc)OH, was catalyzed with 4-dimethylaminopyridine (DMAP). All of the subsequent residues were coupled either as symmetrical anhydrides or hydroxybenztriazole (HOBt) esters. Upon completion of the synthesis, each peptide resin was vacuum dried overnight, then subjected to acidolytic deprotection and cleavage using 20 ml of a mixture comprising trifluoroacetic acid:thioanisole:β-mercaptoethanol:water:phenol in a ratio of 80:5:5:5:5, respectively. After stirring for four hours at room temperature, the suspension was filtered, the filtrate was concentrated (using a rotary evaporator), and the crude peptide was precipitated using cold diethyl ether.
The peptide was immediately suspended in 50 ml of an 8M guanidine buffer containing 100 mM of dithiothreitol (DTT) and 50 mM of TRIS, adjusted to pH 8. After stirring for several hours at room temperature, the solution was applied to a Vydac C 4 preparative reverse phase column and eluted with a 0-60% gradient of 0.1% TFA/acetonitrile over one hour, using a Beckman model 114M solvent delivery system. Fractions with the best analytical profile were pooled and lyophilized.
Optimal conditions for peptide folding to obtain an active product comprised dissolving the linear material (at approximately 1 mg/ml) in a buffer consisting of 25 mM of TRIS, pH 8, 1 mM of EDTA, 1 mM (for α forms) or 0.5 mM (for β forms) of glutathione (oxidized) and 1 mM of glutathione (reduced), and stirring overnight at room temperature. The oxidized, folded material was isolated using a preparative reverse phase column (YMC Co., Ltd., Japan) equipped with a thermostat jacket equilibrated at 40° C. and eluting with a shallow 0.1% TFA/acetonitrile gradient.
The homogeneity of the final products was assessed by analytical HPLC and CZE. Complete characterization was provided by amino acid analysis, electrospray mass spectrometry, partial preview sequencing, and enzymatic fragmentation.
Colon Cell Proliferation
a) Crystal Violet Proliferation Assay. The human colon epithelial cell line, LIM 1215 (Whitehead, R. H. et al., J. Natl. Cancer Inst. 4:759-765, 1985) was grown in RPMI-1640 media supplemented with 5% FBS, 1 μg/ml of hydrocortisone, 1 μg/ml of bovine insulin, 10 μM of alpha thioglycerol, and 1× PSG (0.292 mg/ml of 1-glutamine, 100 units/ml of penicillin G, and 100 μg/ml of streptomycin sulfate). At the start of the assay, the cells were 30% confluent and were proliferating rapidly. Cells were released by trypsin, washed with PBS, and seeded into 96-well plates at 5000 cells/well in low serum (0.05%) media (McCoy's-5A supplemented with 4 μg/ml of transferrin, 10 μg/ml of insulin, 10 mM of selenic acid, 4 nM of triiodothyronine, and 0.03% BSA). Dilutions of test peptide were added immediately on day zero; the total volume was 100 μl. Controls included no treatment and serial dilutions of FBS. The 96-well plates were then incubated for three days at 37° C. in a 5% CO 2 atmosphere. The media were removed by aspiration and 30 μl of 2% crystal violet (Difco) in methanol was added to the cells for fifteen minutes of staining. Excess dye was washed away with distilled water. To each well 100 μl of 0.04N HCL in isopropanol was added and the dye was resolubilized by mixing. Absorbance was determined at 595 nm and the values were plotted as fold-stimulation over background (or no treatment).
b) Stimulation of colon cell proliferation. LIM 1215 cells were treated with the above mentioned peptides, and the results are shown in FIG. 2. As shown in the figure, EGF-β stimulated the proliferation of LIM 1215 cells, while EGF-α was not as potent a mitogen. This strongly suggests that a powerful determinant of mitogenic activity resides in the last sixteen amino acids of the C-terminal portion of EGF-β corresponding to amino acids 213-228 of the full length extracellular NDF/heregulin referred to above. The chimeric peptides helped to pinpoint this determinant of activity to the seven residues corresponding to amino acids 222-228 of full length extracellular NDF/heregulin. Specifically, EGF-α/β consists of the first forty-five amino acid residues from the N-terminal portion of EGF-α and the last seven amino acid residues from the C-terminal portion of EGF-β (or α177-221/β222-228 corresponding to the amino acid numbering of full length extracellular NDF/heregulin). Conversely, EGF-β/α consists of the first forty-five amino acid residues from the N-terminal portion of EGF-β and the last seven amino acid residues from the C-terminal portion of EGF-α (or β177-221/α222-228 corresponding to the amino acid numbering of full length extracellular NDF/heregulin). While EGF-α/β displayed significant mitogenic activity on LIM 1215 colon cells, EGF-β/α did not show any detectable effect under the same conditions (see FIG. 2). These results demonstrate very clearly that the mitogenic activity of the peptides resides in the C-terminal end of the peptide. More specifically, the greatest degree of activity is attributable to the last seven amino acid residues from the EGF-like domain of the β form.
c) Staining of LIM 1215 human colon cells with fluorescent dye. LIM 1215 cells were grown in RPMI-1640 media supplemented with 5% FBS, 1 μg/ml of bovine insulin, 10 μm of alpha thioglycerol, and 1× PSG. At the time of assay, the cells were more than 30% confluent and were proliferating rapidly. The cells were seeded into 24-well plates at 25,000 cells/well in serum-free media (McCoy's-5A, supplemented with 4 μg/ml of transferrin, 10 μg/ml of insulin, 10 mM of selenic acid, 4 mM of triiodothyronine, and 0.03% BSA). Test peptides were added at a concentration of 420 picomolar immediately on day zero; the total volume was 1.0 ml. Controls included no treatment and serial dilutions of FBS. The 24-well plates were then incubated for three days at 37° C. and 5% CO 2 , after which the media were removed by aspiration and the cells were washed in 1.0 ml of PBS with 0.5% BSA. All subsequent washings were performed with this buffer. The cells were then fixed in Orthopermeafix (Ortho Chemicals Co.) for thirty minutes at room temperature, and were washed twice. Then 200 μl of a 10 nM NBD phalloidin fluorescent dye solution in PBS were added and the cells were incubated in the dark (wrapped in aluminum foil) for thirty minutes at room temperature. The cells were washed twice, and inspected using a confocal microscope.
d) Morphogenic activity of peptides on colon epithelial cells. Upon treatment of LIM 1215 cells with the EGF-β peptide, it was evident that the morphology of the cells changed dramatically. FIG. 3 shows the staining of the actin filaments of the cells (see above for procedure) after no treatment (upper panel) and after treatment with 5% FBS (lower panel). In the absence of treatment, the cells appeared small and rounded. In the presence of FBS, the cells changed appearance, becoming only slightly larger but remaining rounded. In contrast, in the presence of EGF-β (FIG. 4, lower panel) the cells underwent a noticeable change in morphology, becoming enlarged and assuming a cobblestone-like appearance. On the other hand, EGF-α (FIG. 4, upper panel) did not produce the same morphogenic changes. Because the cells were proliferating rapidly in 5% FBS serum-containing media (FIG. 3), the unique morphology caused by the EGF-β peptide could not have been due solely to its ability to stimulate proliferation. Moreover, the difference in morphogenic activities between EGF-β and EGF-α must have originated in the last sixteen amino acids of the C-terminus, as this is the only difference in sequence between the two peptides.
Further localization of morphogenic activity was obtained by use of the chimeric peptides, EGF-β/α and EGF-α/β. As seen from FIG. 5, EGF-α/β caused apparent morphogenic changes in LIM 1215 cell (lower panel), while EGF-β/α did not produce any noticeable change (upper panel). Again, the only difference in sequence between these two peptides is the last seven amino acids of the C-terminal portion.
Additional confirmation of the importance of this seven amino-acid sequence was obtained by scoring for various marker proteins on the LIM 1215 cells. An ACAS confocal image cytometer was used to detect a number of markers on the cells without detaching the cells from the culture dish, as is normally done for fluorescence activated cell sorting (FACS) analysis. The data presented in Table 1, below, show that EGF-β caused increased expression (+) of carcino-embryonic antigen (CEA) and integrin β4. Conversely, villin expression was down-regulated (-) by EGF-β. The expression of a number of other markers was unchanged (0) by treatment with EGF-β. Analogous to the previous results characterizing gross, observable morphology changes, neither EGF-α nor EGF-β/α changed the levels of these marker proteins, while EGF-α/β changed the expression of the marker proteins in a manner similar to that seen with EGF-β.
TABLE 1______________________________________Marker Protein ExpressionMarker Protein EGF-α EGF-β EGF-α/β EGF-β/α______________________________________CEA 0 + + 0Integrin 134 0 + + 0Villin 0 - - 0______________________________________
Cancer treatments involving chemo- or radiation-therapy result in severe destruction of the epithelial layer of the colon. The foregoing results indicate that the peptides of the invention can promote re-epithelialization of the colon and alleviate the negative effects caused by damage to the intestinal epithelia.
Schwann Cell Survival and Proliferation
The neurobiological activity of the peptides was also evaluated by studying their effect on Schwann cell survival and growth, as described below.
The sciatic nerve from neonatal rats was used to generate a primary culture of Schwann cells. The cells were plated overnight in 10% serum without exposure to any growth factor. The following day, EGF-β, EGF-α/β and EGF-β/α were added at the concentrations in nanograms per milliliter (ng/ml) shown in Table 2, below. Twenty four hours later, BrdU was added to each test sample for six hours. BrdU is a thymidine analog which is incorporated into the DNA of dividing cells and can be detected by standard immunochemistry procedures. This agent thus provides a means for determining expansion of the total amount of DNA in a test sample and is a measure of whether cell proliferation has occurred. Upon the completion of the test period, Schwann cells were fixed and analyzed immunohistochemically. The cells were first stained for nerve growth factor receptor (NGFR), which is a known marker for Schwann cells in culture, followed by staining for BrdU. Cell counting was carried out as follows: in a given microscope field of view, all recognizable Schwann cells were counted, then the number of cells showing positive for BrdU staining were also counted. For each test sample (or well) two or three fields were counted, amounting to about 200 to 300 Schwann cells in all. The result is expressed in Table 2 as the percent of Schwann cells proliferating.
TABLE 2______________________________________Schwann Cell ProliferationPeptideConcentration,ng/ml EGF-β EGF-α/β EGF-β/α______________________________________0 1 1 10.1 7.5 1 11 13 10 210 14 10 5100 19 17 10______________________________________
As can be seen from these results, both EGF-β and EGF-α/β stimulated the proliferation of Schwann cells to a significantly greater extent than EGF-β/α.
The test results presented above with respect to EGF-β and EGF-α/β indicate the usefulness of these peptides as agents for the survival, growth and proliferation of colon epithelial cells and Schwann cells. As a minimum, these peptides will be utilizable to grow such cells in culture for study in research, and further, for the production of tissue for use in implantation therapy with patients in need thereof. Of particular interest will be patients suffering from conditions or diseases involving deficiencies in, or losses of, such cells. In the case of colon epithelial cells in particular, such conditions include ulcers and colitis, both of which involve deficits in, or deterioration of, colon epithelial cells. The peptides of this invention offer promise as growth factors for the therapeutic treatment of such conditions, whether employed ex vivo to grow replacement tissue or used in vivo for the in situ production of such cells and tissues.
In the peripheral nervous system, Schwann cells, which constitute a class of glial cell, are responsible for the formation of the myelin sheath surrounding and insulating axons in vertebrates. The functional importance of myelin has been underscored by severe impairments in motor function observed in so-called demylelinating diseases, including multiple sclerosis and amyotrophic lateral sclerosis, which are associated with extensive degeneration of the mylein sheath in the central nervous system. Traumatic injury to the peripheral nervous system often involves destruction of myelin which must be repaired for proper healing. As the results shown demonstrate, the peptides of this invention are useful to support the survival, growth and proliferation of Schwann cells in culture, thus enabling a source of such cells for implantation into demyelinated sites of peripheral nerve damage. It is also possible that in vivo administration of these peptides, properly formulated, will result in the regeneration and proliferation of replacement Schwann cells, leading to remyelination and wound healing.
Utilization of the peptides of this invention in accordance with the aforementioned methods of application are well within the ability of the skilled practitioner. The amount of peptide effective for the treatment of a particular disorder or condition in vivo will depend on the specific nature of the disorder or condition, and such amounts can be determined by standard clinical techniques. Where possible, it is desirable to determine the dose-response curve and pharmaceutical compositions of the invention first in vitro, such as in known bioassay systems, and then in useful animal model systems prior to testing humans. Methods of in vivo administration include but are not necessarily limited to intravenous, intramuscular, intraperitoneal, oral or intradermal.
Further, it may be desirable to administer the pharmaceutical compositions of the invention locally to the area in need of treatment. This may be achieved, for example, by local infusion during surgery, injection, catheter, or implant, the implant being of a porous, non-porous, or gelatinous material, including membranes, such as sialastic membranes, or fibers.
The invention also provides for pharmaceutical compositions comprising peptides administered via liposomes, microparticles, or microcapsules. In various embodiments of the invention, it may be useful to use such compositions to achieve sustained release. The peptides of the invention may be administered in any sterile biocompatible carrier, including, but not limited to, saline, buffered saline, dextrose and water, as such, or, if desired, together with any suitable additives.
While the production of the peptides has been specifically illustrated with respect to chemical synthesis, conventional methods of recombinant production provide a suitable alternate means for their preparation. By way of illustration, a nucleotide sequence encoding the peptide can be inserted into an appropriate expression vector, i.e., a vector containing the necessary elements for the transcription and translation of the inserted peptide-coding sequence. A variety of host-vector systems may be utilized to express the peptide-encoding sequence. Such systems include but are not limited to mammalian cell systems infected with virus (e.g., vaccine virus, adenovirus, etc.); insect cell systems infected with virus (e.g., baculovirus); microorganisms such as yeast containing yeast vectors, or bacteria transformed with bacteriophage DNA, plasmid DNA, or cosmid DNA. The expression elements of these vectors vary in their strengths and specificities. Depending on the host-vector system utilized, any one of a number of suitable transcription and translation elements may be used.
Any of the methods previously described for the insertion of DNA fragments into a vector may be used to construct expression vectors containing a chimeric gene consisting of appropriate control signals and peptide coding sequences. These methods may include in vitro recombinant DNA and synthetic techniques and in vivo recombinations (genetic recombination). Expression of nucleic acid sequence encoding the peptide may be regulated by a second nucleic acid sequence so that the peptide is expressed in a host transformed with the recombinant DNA molecule. For example, expression may be controlled by any promoter/enhancer element known in the art.
Once a suitable host system and growth conditions are established, recombinant expression vectors can be propagated and prepared in quantity. As previously explained, the expression vectors which can be used include, but are not limited to, the following vectors or their derivatives: human or animal viruses such as vaccinia virus or adenovirus; insect viruses such as baculovirus; yeast vectors; bacteriophage vectors (e.g., lambda), and plasmid and cosmid DNA vectors, to name but a few.
The resulting expressed peptide may be isolated and purified by standard methods, including chromatography (e.g., ion exchange, affinity, or sizing chromatography), centrifugation, differential solubility, or by any other standard technique for such purification.
The methods of recombinant production described in the previously mentioned PCT application WO 94/28133 are particularly suitable for use herein.
__________________________________________________________________________SEQUENCE LISTING(1) GENERAL INFORMATION:(iii) NUMBER OF SEQUENCES: 6(2) INFORMATION FOR SEQ ID NO:1:(i) SEQUENCE CHARACTERISTICS:(A) LENGTH: 52 amino acids(B) TYPE: amino acid(C) STRANDEDNESS: single(D) TOPOLOGY: linear(ii) MOLECULE TYPE: protein(xi) SEQUENCE DESCRIPTION: SEQ ID NO:1:SerHisLeuValLysCysAlaGluLysGluLysThrPheCysValAsn151015GlyGlyGluCysPheMetValLysAspLeuSerAsnProSerArgTyr202530LeuCysLysCysGlnProGlyPheThrGlyAlaArgCysGlnAsnTyr354045ValMetAlaSer50(2) INFORMATION FOR SEQ ID NO:2:(i) SEQUENCE CHARACTERISTICS:(A) LENGTH: 52 amino acids(B) TYPE: amino acid(C) STRANDEDNESS: single(D) TOPOLOGY: linear(ii) MOLECULE TYPE: protein(xi) SEQUENCE DESCRIPTION: SEQ ID NO:2:SerHisLeuValLysCysAlaGluLysGluLysThrPheCysValAsn151015GlyGlyGluCysPheMetValLysAspLeuSerAsnProSerArgTyr202530LeuCysLysCysProAsnGluPheThrGlyAspArgCysGlnAsnTyr354045ValMetAlaSer50(2) INFORMATION FOR SEQ ID NO:3:(i) SEQUENCE CHARACTERISTICS:(A) LENGTH: 52 amino acids(B) TYPE: amino acid(C) STRANDEDNESS: single(D) TOPOLOGY: linear(ii) MOLECULE TYPE: protein(xi) SEQUENCE DESCRIPTION: SEQ ID NO:3:SerHisLeuValLysCysAlaGluLysGluLysThrPheCysValAsn151015GlyGlyGluCysPheMetValLysAspLeuSerAsnProSerArgTyr202530LeuCysLysCysGlnProGlyPheThrGlyAlaArgCysThrGluAsn354045ValProMetLys50(2) INFORMATION FOR SEQ ID NO:4:(i) SEQUENCE CHARACTERISTICS:(A) LENGTH: 52 amino acids(B) TYPE: amino acid(C) STRANDEDNESS: single(D) TOPOLOGY: linear(ii) MOLECULE TYPE: protein(xi) SEQUENCE DESCRIPTION: SEQ ID NO:4:SerHisLeuValLysCysAlaGluLysGluLysThrPheCysValAsn151015GlyGlyGluCysPheMetValLysAspLeuSerAsnProSerArgTyr202530LeuCysLysCysProAsnGluPheThrGlyAspArgCysThrGluAsn354045ValProMetLys50(2) INFORMATION FOR SEQ ID NO:5:(i) SEQUENCE CHARACTERISTICS:(A) LENGTH: 40 amino acids(B) TYPE: amino acid(C) STRANDEDNESS: single(D) TOPOLOGY: linear(ii) MOLECULE TYPE: protein(xi) SEQUENCE DESCRIPTION: SEQ ID NO:5:CysAlaGluLysGluLysThrPheCysValAsnGlyGlyGluCysPhe151015MetValLysAspLeuSerAsnProSerArgTyrLeuCysLysCysGln202530ProGlyPheThrGlyAlaArgCys3540(2) INFORMATION FOR SEQ ID NO:6:(i) SEQUENCE CHARACTERISTICS:(A) LENGTH: 40 amino acids(B) TYPE: amino acid(C) STRANDEDNESS: single(D) TOPOLOGY: linear(ii) MOLECULE TYPE: protein(xi) SEQUENCE DESCRIPTION: SEQ ID NO:6:CysAlaGluLysGluLysThrPheCysValAsnGlyGlyGluCysPhe151015MetValLysAspLeuSerAsnProSerArgTyrLeuCysLysCysPro202530AsnGluPheThrGlyAspArgCys3540__________________________________________________________________________
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Schwann cells can be treated in vivo to survive longer and to proliferate by contacting them with peptides derived from the EGF-like domain of proteins of the NDF/heregulin family.
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CROSS REFERENCE TO RELATED APPLICATIONS
[0001] This application is based on and claims priority under 35 U.S.C. § 119 with respect to a Japanese Patent Application 2001-160470, filed on May 29, 2001, the entire content of which is incorporated herein by reference.
FIELD OF THE INVENTION
[0002] This invention relates to a vehicle motion control device which is applicable to a brake steering control device, a traction control device and so on.
BACKGROUND OF THE INVENTION
[0003] A Japanese Patent Laid-Open Publication No. 7-304436 discloses a vehicle motion control device of this kind. This known device includes a wheel cylinder equipped on a vehicle wheel, an automatic hydraulic pressure generator generating a brake hydraulic pressure irrespective of the operation of a brake pedal by using an intake vacuum pressure of an engine of a vehicle, a hydraulic pressure control valve disposed between the wheel cylinder and the automatic hydraulic pressure generator, a throttle opening amount automatic adjusting means for adjusting automatically the opening amount of a throttle valve of the engine irrespective of the operation of an accelerator pedal of the vehicle and control means for controlling the automatic hydraulic pressure generator and the hydraulic pressure control valve in accordance with a running condition of the vehicle and for performing an automatic pressure increase control to the wheel cylinder at least when the brake pedal is not operated. Further, the control means controls the throttle opening amount automatic adjusting means in accordance with the running condition of the vehicle and performs an opening amount automatic adjust control to the wheel cylinder.
[0004] In the vehicle motion control device of this kind, when the automatic pressure Increase control is performed intermittently at relative shorter intervals, the vacuum pressure in the automatic hydraulic pressure generator is dissipated excessively and is decreased. As a result, the brake hydraulic pressure which the automatic hydraulic pressure generator can generate is decreased and the performance of the vehicle motion control device decreases. Further, a brake operational force which is required for normal braking is increased.
[0005] A need thus exists for a vehicle motion control device which lessens the decrease of the vacuum pressure in the automatic hydraulic pressure generator when the automatic pressure increase control is performed intermittently at relative shorter intervals.
SUMMARY OF THE INVENTION
[0006] In light of the foregoing, the present invention provides a vehicle motion control device which includes a wheel cylinder equipped on a vehicle wheel; an automatic hydraulic pressure generator generating a brake hydraulic pressure irrespective of the operation of a brake pedal by using an intake vacuum pressure of an engine of a vehicle; a hydraulic pressure control valve disposed between the wheel cylinder and the automatic hydraulic pressure generator; a throttle opening amount automatic adjusting means for adjusting automatically the opening amount of a throttle valve of the engine irrespective of the operation of an accelerator pedal of the vehicle; control means for controlling the automatic hydraulic pressure generator and the hydraulic pressure control valve in accordance with a running condition of the vehicle and for performing an automatic pressure increase control to the wheel cylinder at least non-operating condition of the brake pedal, the control means for controlling the throttle opening amount automatic adjusting means in accordance with the running condition of the vehicle and for performing an opening amount automatic adjust control to the wheel cylinder; intake vacuum pressure decrease condition detecting means for detecting a decrease condition of the intake vacuum pressure; and counter means for counting the number of performance of the automatic pressure increase control performed under the intake vacuum pressure decrease condition detected by the intake vacuum pressure decrease condition detecting means, wherein the control means corrects the throttle opening amount requested to the throttle opening amount automatic adjusting means at the automatic pressure increase control so as to decrease in accordance with the number of performance of the automatic pressure increase control counted by the counter means.
BRIEF DESCRIPTION OF THE DRAWING FIGURES
[0007] A more complete appreciation of the invention and other advantages thereof will be readily obtained as the same becomes better understood by reference to the following detailed description when considered in connection with the accompanying drawings, in which:
[0008] [0008]FIG. 1 is an overview of a vehicle motion control device according to an embodiment of the present invention;
[0009] [0009]FIG. 2 is a schematic illustration of a brake system according to the embodiment of the present invention;
[0010] [0010]FIG. 3 is a partial cross-sectional view of a vacuum booster according to the embodiment of the present invention;
[0011] [0011]FIG. 4 is a flowchart showing a flow of a motion control according to the embodiment of the present invention;
[0012] [0012]FIG. 5 is a flowchart showing a flow of the motion control according to the present invention;
[0013] [0013]FIG. 6 is a flowchart showing details of a step S 113 of FIG. 5;
[0014] [0014]FIG. 7 is a flowchart showing details of a step S 201 of FIG. 6;
[0015] [0015]FIG. 8 is a flowchart showing details of a step S 202 of FIG. 6; and
[0016] [0016]FIG. 9 is a timing chart showing an operation of the embodiment of the present invention.
DETAILED DESCRIPTION OF THE INVENTION
[0017] Having generally described the present invention, a further understanding of the invention can be obtained now according to an embodiment of the present invention with reference to FIGS. 1 to 9 in accompanying drawings.
[0018] Referring to FIG. 1, an engine EG of a vehicle includes a throttle control device TH and a fuel injection device FI. In the throttle control device TH, a main throttle opening amount of a main throttle valve MT is controlled in response to the operation of an accelerator pedal AP. Further, in response to an output of an electronic control unit ECU, a sub throttle valve ST is moved and a sub throttle opening amount is controlled, and further an amount of fuel injection is controlled by the fuel injection device FI. In this embodiment, the engine EG is connected to front wheels FL, FR through a transmission device GS.
[0019] Wheel cylinders Wfl, Wfr, Wrl and Wrr are equipped on wheels FL, FR, RL and RR and are connected to a brake hydraulic pressure control device BC. The wheel FL corresponds to a wheel which is located at front left side of the vehicle. Likewise, the wheel FR corresponds to a wheel on front right side, the wheel RL corresponds to a wheel on rear left side, and the wheel RR corresponds to a wheel on rear right side.
[0020] Wheel speed sensors WS 1 , WS 2 , WS 3 and WS 4 are provided on the wheels FL, FR, RL and RR and are connected to the electronic control unit ECU. Rotational speed of each wheel, that is a pulse signal with pulse number proportional to a wheel speed is inputted into the electronic control unit ECU. Further, sensors such as a brake switch BS for detecting the operation of a brake pedal BP, a front wheel steering sensor SSf for detecting a steering angle δ f of the front wheels FL, FR, a lateral G sensor YG for detecting a lateral acceleration of the vehicle, a yaw rate sensor YS for detecting a yaw rate and a throttle sensor SS for detecting the opening amounts of the main throttle valve MT and the sub throttle valve ST are connected to the electronic control unit ECU. According to the yaw rate sensor YS, a change speed of vehicle yaw angle about the vehicle axis on the vehicle center of gravity, that is yaw angular velocity (i.e., yaw rate) is detected to be outputted as an actual yaw rate γ to the electronic control unit ECU.
[0021] As shown in FIG. 1, the electronic control unit ECU includes a microcomputer CMP which includes a processing unit CPU, memories ROM, RAM, and input ports IPT and output ports OPT all of which are interconnected via a bus. Output signals from the wheel speed sensors WS 1 -WS 4 , the brake switch BS, the front wheel steering angle sensor SSf, the yaw rate sensor YS, the lateral G sensor YG and the throttle sensor SS are inputted from the Input ports IPT to the processing unit CPU via an amplifier circuit AMP. The control signals are outputted from the output ports OPT to the throttle control device TH and the brake hydraulic pressure control device BC.
[0022] In the microcomputer CMP, the memory ROM memorizes programs regading various transactions including flowcharts shown in FIGS. 4 to 8 , the processing unit CPU carries out the program while an ignition switch (not shown) is closed, and the memory RAM tentatively memorizes a parameter data which is required for carrying out the program.
[0023] Next, a brake system including the brake hydraulic pressure control device BC will be explained as follows. As shown in FIG. 2, a master cylinder MC is boosted via a vacuum booster VB in accordance with the operation of the brake pedal BP. A pressure of a brake fluid which is supplied from a master cylinder reservoir LRS into the master cylinder MC is increased to output a master cylinder hydraulic pressure to two brake hydraulic pressure systems of the wheels FR, RL side and the wheels FL, RR side respectively. As it called X type dual circuit is provided in the vehicle motion control device of this embodiment. The master cylinder MC is a tandem type master cylinder having two pressure chambers. A first pressure chamber is in communication with the brake hydraulic pressure system on the wheels FR, RL side, and a second pressure chamber is in communication with the brake hydraulic pressure system on the wheels FL, RR.
[0024] Regarding the brake hydraulic pressure system on the wheels FR, RL side, the first pressure chamber of the master cylinder MC is connected to the wheel cylinders Wfr, Wrl via a main hydraulic pressure conduit MF and branch hydraulic pressure conduits MFr, MFl respectively. The branch hydraulic pressure conduits MFr, MFl are provided with normal-open type two-port two-position solenoid valves PC 1 and PC 2 (hereinafter referred as the solenoid valves PC 1 and PC 2 ) respectively. Check valves CV 1 and CV 2 are provided in parallel with the solenoid valves PC 1 and PC 2 respectively. The check valves CV 1 and CV 2 allow the flow of the brake fluid in the direction only toward the master cylinder MC. The brake fluid in the wheel cylinders Wfr, Wrl is returned to the master cylinder MC and eventually to the master cylinder reservoir LRS via the check valves CV 1 and CV 2 . Accordingly, when the brake pedal BP is released, the hydraulic pressure in the wheel cylinders Wfr, Wrl promptly follows the decrease of the hydraulic pressure of the master cylinder MC side. Normal closed type two-port two-position solenoid valves PC 5 and PC 6 (hereinafter referred as the solenoid valves PC 5 and PC 6 ) are provided on output side branch pressure conduits RFr, RFl which are in communication with the wheel cylinders Wfr, Wrl. An output hydraulic pressure conduit RF confluent with the branch hydraulic pressure conduits RFr, RFl is connected with an auxiliary reservoir RS 1 .
[0025] A hydraulic pressure pump HP 1 is interposed in a hydraulic pressure conduit MFp which is in communication with the branch hydraulic pressure conduits MFr, MFl at upper stream side of the solenoid valves PC 1 and PC 2 . The auxiliary reservoir RS 1 is connected with an inlet side of the hydraulic pressure pump HP 1 via a check valve CV 5 . An outlet side of the hydraulic pressure pump HP 1 is connected to the upper stream side of the solenoid valves PC 1 and PC 2 via a check valve CV 6 . The hydraulic pressure pump HP 1 is actuated by a single electric motor M along with a hydraulic pressure pump HP 2 for sucking the brake fluid from the auxiliary reservoir RS 1 to return to the outlet side. The auxiliary reservoir RS 1 is provided independently from the master cylinder reservoir LRS. The auxiliary reservoir RS 1 may also be called an accumulator which includes a piston and a spring for preserving a predetermined volume of the brake fluid. The check valves CV 5 and CV 6 function as an inlet valve and an outlet valve for restricting the flow of the brake fluid outputted via the hydraulic pressure pump HP 1 in a fixed direction. The check valves CV 5 and CV 6 are unitary structured in the hydraulic pressure pump HP 1 . A damper DP 1 is provided on the outlet side of the hydraulic pressure pump HP 1 . A proportioning valve PV 1 is disposed in a hydraulic pressure conduit which is connected to the wheel cylinder Wrl on the rear wheel side. Likewise, normal open type two-port two-position solenoid valves PC 3 and PC 4 , normal closed type two-port two-position solenoid valves PC 7 and PC 8 , check valves CV 3 , CV 4 , CV 7 and CV 8 , an auxiliary reservoir RS 2 , a damper DP 2 , and a proportioning PV 2 are provided in the brake hydraulic pressure system on the wheels FL, RR side. As mentioned above, the hydraulic pressure pump HP 2 is actuated by the electric motor M along with the hydraulic pressure pump HP 1 . The solenoid valves PC 1 -PC 8 for changing the brake hydraulic pressure of the wheel cylinders of the respective wheels correspond to the hydraulic pressure control valves of the present invention.
[0026] As shown in FIG. 3, the vacuum booster VB includes a booster actuator BD for automatically actuating the vacuum booster VB irrespective of the operation of the brake pedal (i.e., at least when the brake pedal BP is not operated). Known structure of the vacuum booster VB is employed in the vehicle motion control device according to this embodiment. A constant pressure chamber B 2 and a variable pressure chamber B 3 are formed by a movable wall B 1 . The movable wall B 1 is unitary connected to a power piston B 4 . The constant pressure chamber B 2 is always in communication with an intake manifold (not shown) of the engine EG to be introduced with the vacuum pressure. The power piston B 4 is operatively connected to an output rod B 10 for transmitting the power via a fixed core D 2 and a reaction disc B 9 . The output rod B 10 is connected to the master cylinder MC.
[0027] A valve mechanism B 5 including a vacuum valve V 1 for establishing and interrupting the fluid communication between the constant pressure chamber B 2 and the variable pressure chamber B 3 and an air valve V 2 for establishing and interrupting the fluid communication between the variable pressure chamber B 3 and the atmosphere is provided in the power piston B 4 . The vacuum valve V 1 includes an annular valve seat V 11 formed on the power piston B 4 and an elastic valve body V 12 which is detachable to the valve seat V 11 . The air valve V 2 includes an elastic valve seat V 21 equipped to the elastic valve body V 12 and a valve body V 22 which is detachable to the elastic valve seat V 21 . The valve body V 22 is connected to an input rod B 6 which is operatively connected to the brake pedal BP. The valve body V 22 is biased in the direction to be seated on the elastic valve seat 21 by the biasing force of a spring B 7 . The elastic valve body V 12 of the vacuum valve V 1 is biased in the direction to be seated on the annular valve seat V 11 by the biasing force of a spring B 8 . The biasing force of the spring B 8 also biases the elastic valve seat V 21 of the air valve V 2 in the direction to be seated on the Valve body V 22 .
[0028] Accordingly, the vacuum valve V 1 and the air valve V 2 of the valve mechanism B 5 are opened and closed in accordance with the operational force of the brake pedal BP to generate the pressure difference between the constant pressure chamber B 2 and the variable pressure chamber B 3 . Thus, the output force amplified by the operation of the brake pedal BP is transmitted to the master cylinder MC.
[0029] The booster actuator BD includes a linear solenoid D 1 , the fixed core D 2 , and a movable core D 3 . The linear solenoid D 1 which is connected to the electronic control unit ECU attracts the movable core D 3 towards the fixed core D 2 when energized, The attraction force of the linear solenoid D 1 is varied in accordance with the actuating electric current. The fixed core D 2 is disposed between the power piston B 4 and the reaction disc B 9 for transmitting the force from the power piston B 4 to the reaction disc B 9 . The movable core D 3 is positioned opposing to the fixed core D 2 in the linear solenoid D 1 and thus a magnetic gap D 4 is formed between the movable core D 3 and the fixed core D 2 . The movable core D 3 is engaged with the valve body V 22 of the air valve V 2 . By attracting the movable core D 3 relative to the fixed core D 2 in the direction to reduce the magnetic gap D 4 , the valve body V 22 of the air valve V 2 can be unitary moved.
[0030] The input rod B 6 includes a first input rod B 61 and a second input rod B 62 . The first input rod B 61 is unitary connected to the brake pedal BP. The second input rod B 62 is movable relative to the first input rod B 61 for transmitting the force to the output rod B 10 via the key member B 11 by the power piston B 4 . Accordingly, when only the second input rod B 62 is actuated to forward, the first input rod B 61 is left behind. The first and the second input rods B 61 , B 62 structure a mechanism for leaving a pedal behind.
[0031] The master cylinder MC, the vacuum booster VB, and the booster actuator BD correspond to an automatic hydraulic pressure generator of the present invention. The operation of the booster actuator BD and the vacuum booster VB when performing the automatic pressure increase control (e.g., brake steering control and traction control) for automatically pressurizing the wheel cylinders of the wheels to be controlled at least when the brake pedal is not operated will be explained as follows.
[0032] When it is determined that the automatic pressure increase control is required by the electronic control unit ECU, the linear solenoid D 1 is energized, the movable core D 3 is moved towards the magnetic gap D 4 side, and the valve body V 22 of the air valve V 2 is unitary moved with the movable core B 3 against the biasing force of the spring B 7 . Accordingly, the elastic valve body V 12 of the vacuum valve V 1 is seated on the annular valve seat V 11 for interrupting the fluid communication between the variable pressure chamber B 3 and the constant pressure chamber B 1 . then because the valve body V 22 of the air valve V 2 is further moved, the valve body V 22 is separated from the elastic valve seat V 21 and the atmosphere is introduced into the variable pressure chamber B 3 . Accordingly, the pressure difference is generated between the variable pressure chamber B 3 and the constant pressure chamber B 1 to move the power piston B 4 , the fixed core D 1 , the reaction disc B 9 , and the output rod B 10 towards the master cylinder side. Thus, the master cylinder MC automatically generates the hydraulic pressure.
[0033] After the power piston B 4 is engaged with the key member B 11 , the second input rod B 62 engaged with the key member B 11 is unitary moved forwardly with the power piston B 4 . On the other hand, since the forwarding force of the power piston B 4 is not transmitted to the first input rod B 61 , the first input rod B 61 is maintained at an initial position. That is, when the booster actuator BD automatically actuates the vacuum booster VB, the brake pedal BP is maintained at the initial position.
[0034] The booster actuator BD, the solenoid valves PC 1 -PC 8 , and the electric motor M are actuated by the electronic control unit ECU for performing the brake steering control (i.e., over steer control or under steer control). When the ignition switch (not shown) is closed, a program for vehicle motion control according to the flowcharts of FIGS. 4 and 5 is carried out with calculation period of 6 ms.
[0035] In Step S 101 , the microcomputer CMP is initialized to clear various calculated value. In Step S 102 , detection signals of the wheel speed sensors WS 1 -WS 4 , a detection signal (i.e., the steering angle δ f) of the front wheel steering angle sensor SSf, a detection signal (i.e., the actual yaw rate γ a) of the yaw rate sensor YS, a detection signal (i.e., actual lateral acceleration Gya) of the lateral acceleration sensor YG, and a detection signal of the throttle sensor SS are read in.
[0036] Next, in Step S 103 , a wheel speed Vw** of each wheel is calculated and a wheel acceleration DVw** of each wheel is calculated by differentiating wheel speed V** of each wheel. In Step S 104 , a maximum value of wheel speed Vw** of each wheel is calculated as an estimated vehicle body speed Vso at the gravitational center position of the vehicle (Vso=MAX(Vw**)). Then, an estimated vehicle body speed Vso** at each wheel is obtained on the basis of the wheel speed Vw** of each wheel. If necessary, the normalization of each estimated vehicle body speed Vso** is performed in order to reduce the error due to wheel speed difference between inner wheels and outer wheels when the vehicle is turning. Further, the estimated vehicle body speed Vso is differentiated and an estimated vehicle acceleration (including an estimated vehicle body deceleration) Dvso at the gravitational center position of the vehicle is obtained.
[0037] In Step S 105 , an actual slip ratio Sa** of each wheel is calculated as follows based on the wheel speed Vw** and the estimated vehicle body speed Vso** of each wheel obtained in Step S 103 and Step S 104 .
Sa**= ( Vso**−Vw** )/ Vso**
[0038] In Step S 106 , an approximate road surface frictional coefficient μ is estimated based on the estimated vehicle body acceleration Dvso and the detection signal Gya of the lateral acceleration sensor YG as follows.
μ=( Dvso 2 +Gya 2 ) ½
[0039] In Step S 107 , a vehicle body skidding angular velocity D β is obtained based on the actual lateral acceleration Gya, the actual yaw rate γ a, and estimated vehicle body speed Vso as follows.
Dβ=Gy/Vso−γa
[0040] In Step S 108 , a vehicle body skidding angle β is obtained as follows.
β=∫( Gy/Vso−γa ) dt
[0041] In this case, the vehicle body skidding angle β corresponds to a directional angle of the vehicle relative to the running direction of the vehicle. The vehicle body slidding angular velocity D β corresponds to a differentiated value of the vehicle body skidding angle β (i.e., d β/dt).
[0042] In Step S 109 , a brake steering control calculation transaction is carried out to determine a target slip ratio for wheels to be brake steering controlled. In Step S 110 , an anti-skid control is carried out and a front-rear braking force division control is carried out in Step S 111 . In Step S 112 , a traction control is carried out. In each of the Steps S 109 -S 112 , it is judged whether conditions for starting each control are satisfied or whether conditions for ending each control is satisfied. Further, a target slip, ratio for each control is set.
[0043] In Step S 113 , a sub throttle opening amount is determined and an automatic pressure increase is determined in Step S 114 . Namely, in Step S 114 , an operation or non operation of the booster actuator BD is determined. In Step S 115 , a brake hydraulic pressure of the wheel to be controlled is determined. Namely, pressure decrease, pressure increase, or pressure hold is determined. In Step S 116 , an operation or non operation of the electric motor M is determined. After these determinations are outputted in Step S 117 , the Step S 102 is performed.
[0044] [0044]FIG. 6 shows a process of the determination of the sub throttle opening amount in Step S 113 of FIG. 5. In Step S 201 , a correcting amount θ d for moving the sub throttle valve so as to decrease the opening amount is calculated. Next, in Step S 202 , the opening amount θ of the sub throttle valve ST is calculated and the Step S 114 in FIG. 6 is performed.
[0045] [0045]FIG. 7 shows a process of the calculation of the correcting amount θ d in Step S 201 of FIG. 6. In Step S 301 , it is judged whether the condition of vacuum is in decrease condition. Namely, a main throttle opening amount detected by the throttle sensor SS is compared with a first predetermined value and a second predetermined value which is larger than the first predetermined value. When the main throttle valve opening amount is larger than the second predetermined value, it is judged that the vacuum condition is in decrease condition. When the main throttle valve opening amount is smaller than the first predetermined value, it is judged that the vacuum condition is not in decrease condition.
[0046] When the result of the judgment of the Step S 301 is Yes, the Step S 302 is performed and it is judged whether the state of traction control is changed from ending state to starting state. When the state of the traction control is changed, “1” is added to a discrete value of a control counter in Step S 303 . Then, in Step S 306 , the correcting amount θd is calculated and the Step S 202 in FIG. 6 is performed. When the state of the traction control is not changed, it is judged whether the state of the brake steering control is changed from the ending state to starting state. When the state of the brake steering control is changed, “1” is added to a discrete value of the control counter in Step S 303 . When the state of the brake steering control is not changed, the correcting amount θ d is calculated in Step S 306 . When the result of the judgment of the Step S 301 is No, a discrete value of the control counter becomes “0” in Step S 305 and then the correcting amount θ d is calculated in Step S 306 . In Step S 306 , the correcting amount θ d is calculated by multiplying a predetermined value by the discrete value of the control counter.
[0047] [0047]FIG. 8 shows a process the calculation of the opening amount θ of the sub throttle valve ST in FIG. 6. In Step S 401 , it is judged whether the traction control or brake steering control is under control. When the traction control or the brake steering control is not under control, the opening amount of the sub throttle valve θ (n) is set to max value in Step S 402 and the Step S 114 in FIG. 5 is performed. When the traction, control or the brake steering control is under control, it is judged whether the calculation is a first calculation in Step S 403 . When the calculation is a first calculation, an initial opening amount θ l of the sub throttle valve is obtained at a function of the main throttle opening amount θ m and the rotational number of the engine Ne in Step S 404 . Then, in Step S 405 , the opening amount of the sub throttle valve is obtained as follows.
θ( n )=θ i−θd
[0048] Then, the Step S 114 in FIG. 5 is performed, in the above description, (n) means the times of calculation and θ (n) means a present calculated value.
[0049] When the calculation is not a first calculation, in the Step S 406 , the opening amount θ (n) is renewed to a value which is obtained by adding an increase or decrease amount obtained as a function of the actual slip ration Sa** of the wheel to be controlled to the previous calculation valve θ (n−1). Then, the Step S 114 in FIG. 5 is performed.
[0050] [0050]FIG. 9 is a time chart showing the operation of this embodiment. In FIG. 9, dotted line of the opening amount θ shows a case in which the opening amount of the sub throttle valve ST is not corrected with the correcting amount θ d. As shown in FIG. 9, in the condition that the intake vacuum pressure of the engine EG is decreased, the sub throttle opening amount is corrected so as to decrease the opening amount in accordance with the number of performance of the automatic pressure increase control. Therefore, even if the automatic pressure increase control is performed intermittently at relative shorter intervals, the vacuum pressure in the constant pressure chamber B 2 of the vacuum booster VB is prevented from decreasing. Further, it is prevented that the brake hydraulic pressure which the automatic hydraulic pressure generator can generate is decreased and that the performance of the vehicle motion control device decreases. Further, the increase of a brake operational force which is required for normal braking is avoided.
[0051] The principles, preferred embodiment and mode of operation of the present invention have been described in the foregoing specification. However, the invention which is intended to be protected is not to be construed as limited to the particular embodiment disclosed. Further, the embodiment described herein is to be regarded as illustrative rather than restrictive. Variations and changes may be made by others, and equivalents employed, without departing from the spirit of the present invention. Accordingly, it is expressly intended that all such variations, changes and equivalents which fall within the spirit and scope of the present invention as defined in the claims, be embraced thereby.
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A vehicle motion control device which includes a wheel cylinder equipped on a vehicle wheel; an automatic hydraulic pressure generator generating a brake hydraulic pressure irrespective of the operation of a brake pedal by using an intake vacuum pressure of an engine of a vehicle; a hydraulic pressure control valve disposed between the wheel cylinder and the automatic hydraulic pressure generator; a throttle opening amount automatic adjusting device for adjusting automatically the opening amount of a throttle valve of the engine irrespective of the operation of an accelerator pedal of the vehicle; control, device for controlling the automatic hydraulic pressure generator and the hydraulic pressure control valve in accordance with a running condition of the vehicle and for performing an automatic pressure increase control to the wheel cylinder at least non-operating condition of the brake pedal, the control means for controlling the throttle opening amount automatic adjusting device in accordance with the running condition of the vehicle and for performing an opening amount automatic adjust control to the wheel cylinder; intake vacuum pressure decrease condition detecting device for detecting a decrease condition of the intake vacuum pressure; and counter device for counting the number of performance of the automatic pressure increase control performed under the intake vacuum pressure decrease condition detected by the intake vacuum pressure decrease condition detecting device. The control device corrects the throttle opening amount requested to the throttle opening amount automatic adjusting device at the automatic pressure increase control so as to decrease in accordance with the number of performance of the automatic pressure increase control counted by the counter device.
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RELATED U.S. APPLICATIONS
[0001] The present invention is a continuation-in-part of co-pending application, U.S. Ser. No. 09/601,268, filed on Jul. 29, 2000, entitled “FLYING OBJECT WITH A ROTATIONAL EFFECT”.
STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT
[0002] Not applicable.
REFERENCE TO MICROFICHE APPENDIX
[0003] Not applicable.
FIELD OF THE INVENTION
[0004] The invention belongs to the field of flying and to flying objects driven by an engine and used for transport of people and loads and for other purposes. It relates to achievement of effects in tremendously increasing velocity, in minimizing spending of energy, in increasing capability for loading and in enlarging a moved distance without landing.
BACKGROUND OF THE INVENTION
[0005] The invention solves four main problems which are present in functioning the flying objects driven by engine:
[0006] 1) a significant reduction of energy spent in motion,
[0007] 2) an enormous increase of speed,
[0008] 3) considerable enlargement of rate of loading (a weight of embarked objects and part of a weight related to a crew and a passengers),
[0009] 4) an increase of a distance moved with landing-no, which is achieved both on the basis of extension of a capacity for storing fuel, and on the basis of remarkable low quantities of spent energy.
[0010] The advantages of the invention presented above in four points constitute in the same time four main characteristics of efficiency of the invention.
[0011] The construction of the contemporary kinds of aircraft driven by engines is based on effects of a jet engine and on effects of rotating propellers.
[0012] The parts of the body of a contemporary aircraft remain in fixed position during a flying. The body of the aircraft connects all walls of the aircraft and volume closed by them which is suitable for placement of an engine, other technical devices, a load and accommodation of a crew and a passengers. The body does not include propellers and a stream of a jet engine. The body remains in fixed position during flying, i.e. no one part of the body changes position during the flight related to its other parts or related to things located within it while they are not in movement. This fixed position of the body represents an essential constitutive characteristic of the aircraft.
[0013] The rotation of three parts of a flying object creates lessening of the influence of gravity on rotating parts and the loads on the rotating parts. This effect improves the efficiency of flying. The rotation is not a means for lift. Centrifugal force can be directed to counter some gravitational attraction in flight. Increasing any effect of centrifugal force on gravity will lower the energy requirements to carry a cargo load and to fly.
[0014] According to the inventor, two vectors are present in relation between a centrifugal force and a gravitational attraction. The angle between them is 90 degrees during a phase of starting which precedes a phase of taking off. The intensity of centrifugal force increase with enlarging velocity of rotation. The relation between the two vectors disclose an advantage of the invention.
[0015] Furthermore, according to the inventor, the first and second platforms and cover rotate because the relationship improves the properties of the flying object. A crew of the flying object can move from a base to a second platform. This improvement contributes to the appearance of many advantages of the flying object which can be used during a flight, such as appearance of artificial gravitational attraction in the second platform in inter-planetary flight, possibly maintaining engines during a flight, and using cargo stocks during a flight.
[0016] The inventor proposes that the platforms and cover rotate in order that natural laws can be expressed in lessening the influence of gravitational attraction. These rotations provide particular effects in flying. The centrifugal force which is present in rotations ofthe platforms and in rotation of the cover constitutes one vector and gravitational attraction constitutes another vector. With the resultant vector created with them, an effect of lessening of gravitational attraction appears.
BRIEF SUMMARY OF THE INVENTION
[0017] The body of the flying object with a rotational effect consists of a base and three pieces which rotate during a flight, about a particular axis of rotation. The three rotating pieces of the body rotate parallel to the base.
[0018] The inventor believes that the invention is based on natural laws which are incompletely defined in current science. A thorough discussion of the theoretical basis of the present invention can be found in the printed matter “Fundamentals of Physics are Out of Date and Wrong” (2001) by the present inventor.
[0019] The full efficiency in flying is reached when the base and three rotating pieces of the body are in position which makes a right angle with a direction of an influence ofthe attraction of gravity (of earth or other planets). This direction of rotational motion is designed here with the following terms: horizontal motion, horizontal rotation, horizontally, horizontal position, etc.
[0020] The flying object possesses two kinds of motion during flight, i.e. the motion of flying and the rotational motion.
[0021] The flying object flies horizontally or in another direction. Extraordinary special properties arise in the horizontal motion through effects in a field of velocity, capability in loading, in spending of energy and in capability of covering a greater distance without landing in comparison to effects which belong issued on the contemporary aircraft.
[0022] When the position of the flying object is not horizontal it spends a greater quantity of energy for the rotation of the three parts of the body than in case when it flies horizontally. In this occasion of the flying the effects of the significant reduction of spent fuel in motion is less than in case of the horizontal motion.
BRIEF DESCRIPTION OF THE SEVERAL VIEWS OF THE DRAWINGS
[0023] [0023]FIG. 1 is a schematic view of the flying object of the present invention.
[0024] The parts of the flying object which are chosen to be presented in The Figure represent essential components of the flying object which are of importance for demonstrating the efficiency of the applied invention. These fractions of the figure relate to four pieces of the body, three engines for rotation, jet engine, three wheels needed for a starting motion of the flying object and for landing and to an outlet of a jet engine. The three wheels increase the mobility of the flying object when moving on land.
DETAILED DESCRIPTION OF THE INVENTION
[0025] The body of the flying object consists of four pieces, as it is depicted in FIG. 1, i.e. of the base marked in the figure with 1 , the first platform marked with 4 , the second platform marked with 5 and the cover marked with 6 .
[0026] The rotation of the first platform marked with 4 is produced with work of engine marked with the engine 1 . The rotation of the second platform marked with 5 is effected with work of engine marked with the engine 2 . The cover marked with 6 rotates with action of engine marked as the engine 3 . The second platform ( 5 ) and the cover ( 6 ) rotate in the same direction. The first platform ( 4 ) rotates in opposite direction of rotation of the second platform ( 5 ) and the cover ( 6 ). The attributes of such engines are similar to characteristics of those engines which are customarily used for other rotational purposes. They are similar to characteristics of the engines for trucks, for other vehicles or for vessels, i.e. to attributes of other kinds of engines ofthe same category. These engines are designated in the further text as the engines for rotation.
[0027] A power and a force of the engines for rotation are transmitted over an axis to the rotational pieces of the body. The engines for rotation are fixedly connected to their respective platforms or cover so as to rotate around a vertical axis of the flying object. FIG. 1 shows the three separate engines aligned along the vertical axis. A central axis with toothed gears are located in opening in the centers of the platforms and cover.
[0028] The main construction material is metal. The shape of the base and of the platforms is circular. The cover is shaped in the form of a lateral surface of a cone or as halves of a sphere or spherical sector, etc. These three rotating parts of the body rotate regularly with the same speed. The engine 1 is fixed to the base ( 1 ), the engine 2 to the first platform ( 4 ) and the engine 3 to the second platform ( 5 ).
[0029] The rotation of the second platform ( 5 ) has a relative static position in comparison to any chosen point in the base ( 1 ) or to an exterior point out of the flying object when it is at state of rest, i.e. a distance between this exterior fixed point and the chosen point in the second platform ( 5 ) has constant magnitude and it does not change when the flying object is not in motion. Communication between the base and second platform is provided with a tube located in space around the vertical axle of the flying object, having a diameter of 1.5 m and a ladder fixed on a wall of the tube such that only bars of the ladder are visible. The communication provides many advantages which can be used during flight, such as artificial gravitational attraction in the second platform during flight, maintaining engines during flight and using loads and cargo during flight.
[0030] The second platform ( 5 ) provides conditions for loading and accommodation of people. The people, the load, the jet engine, the engine 3 and the fuel are placed in the second platform ( 5 ). The engine 2 is located on the first platform ( 4 ). Alternatively, the people may be accommodated on the base ( 1 ). The first platform, second platform and cover do not rotate in the same direction.
[0031] The achievements of the effects of the flying object, such as they are presented previously, depend on the level of the reached speed of the rotational parts of the body. The representing speed of the rotating pieces is the speed of the middle point placed in the middle of the distance between an axis and a rim of the platforms and of the cover, i.e. the speed ofthe middle point on a radius of the platforms and of the cover. When this speed is beneath 20 m/s the results will be moderate, when it is 30 m/s, they will be successful, when it is close to 50 m/s they will be excellent and when it is 100 m/s they will be more than extraordinary.
[0032] The rotation of rotational elements of the invention do not provide lifting. They contribute the great effectiveness in launching and flying of the flying object in a way that the rotation provides lessening of gravitational attraction on rotational parts of the flying object and on cargo located on the second platform of the flying object.
[0033] The flying object moves by effects produced with the jet engine marked with 8 . The outlet of the jet engine is presented in The Figure with a number 3 . Its location can be alternatively placed in other parts of the flying object. The jet engine does not rotate the platforms. The jet engine provides exclusively a flight power. The jet engine, fixed to the second platform, makes the flying object take off, fly and land and has connections to a plurality of wheels and to the outlet. The function of the jet engine is based on the same principle ofjet engines of the prior art. The jet engine is connected to the outlet by using space located along the vertical axle.
[0034] The wheels are marked in The FIGURE with number 2 .
[0035] The cover ( 6 ) suspended on the vertical axis marked with 7 slides in the groove on the base ( 1 ). It is necessary to provide a separate protection from a difference of pressures, temperatures and quantity of oxygen inside and outside the flying object. In this respect it is convenient to set a cabin for weight and accommodation on the second platform ( 5 ) made from a transparent material and shaped as a lateral surface of a cone covering the whole platform. This cabin will provide this protection. The radius of the platforms, i.e. the radius of the cover is determined with the chosen dimensions of the flying object. The distance between the first platform ( 4 ) and a top point of the cover ( 6 ) is determined with criteria for stability of the flying object and in accordance with determined purpose of use of the flying object. In this respect the flying object for the use as a space ship can have a larger magnitude of the radius than when the flying object is to be used for other purposes.
[0036] The main efficiency of the subjected flying object originates from the rotational motion of three parts of the body. The invention relates to this effectiveness. With improvements and developments of functions of technical components and the operations between them the final effects of this flying object can reach utmost results but the difference in efficiency obtained in this way will be always significantly smaller in comparison of the difference which appears with the application the main attributes of the patent. Therefore, the improvements of this kind could not be constituted with such inventions by which is possible to annul validity of this invention. They will have a meaning of improvement of this invention. In this respect they can relate to all solutions regarding to functioning of the parts of the flying object and to other alternative solutions but not to main characteristics of the flying object. For example they can refer to solutions like: the engine 1 is placed on the first platform ( 4 ), the cover ( 6 ) consists of more than one piece, only one engine rotates three rotating pieces ofthe body, the rotations of three parts of the body is produced with connections between rims and not over an axis, the metal is replaced with an another material, etc. The improvements ofthe patent should be introduced with acquired experiences in its application. For example, if engine 1 is located on the first platform ( 4 ) instead on the base ( 1 ) the effects of flying will be greater. However, a more precise experiences in a field of stability and vibration of object are necessary for application of such solution.
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A flying object with a rotational effect includes a base, a plurality of wheels suitable for starting and landing the flying object, a first platform, a second platform, a cover, a first engine by which rotation of the first platform is provided, a second engine by which the second platform rotates, a third engine by which the cover rotates, a jet engine mechanism for starting, flying and landing the flying object, and an outlet of the jet engine mechanisms. There is also a communicator between the base and second platform and a connector for the first platform, second platform and cover when all rotations are in the same alignment.
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This application is a continuation-in-part application of Ser. No. 687,700 filed on Dec. 31, 1984 now abandoned.
TECHNICAL FIELD
This invention is related to a process for improved incorporation of diallyldimethylammonium chloride into an acrylamide polymer, and to the inverse emulsions produced.
BACKGROUND ART
As illustrated by Example 34 of U.S. Pat. No. 4,077,930 to Lim, et al., a self-inverting emulsion having a viscosity of 2000 cps and containing a polymer derived from acrylamide, diallyldimethylammonium chloride (DADMAC) and 2-methacryloylethyltrimethyl ammonium methosulfate, is known. This emulsion is produced by a polymerization procedure in the presence of a high HLB emulsifier.
One of the major problems in acrylamide, diallyldimethylammonium chloride polymerizations is incomplete incorporation of the latter, i.e. of the DADMAC monomer into the acrylamide polymer. This is due to the fact that acrylamide is considerably more reactive than DADMAC, and therefore tends to self-polymerize rather than react with the cationic monomer. As a result, one or more of the following results: the DADMAC monomer is wasted; it is difficult to predict the composition of the polymer; and/or undesireable charge distributions result. Accordingly, there is an apparent need for a process for effecting an improved incorporation of DADMAC into an acrylamide polymer. An improved process of this kind would be particularly beneficial because it would produce an inverse emulsion polymer of DADMAC of increased viscosity and improved stability. Furthermore, when prepared by the procedure disclosed in the Lim, et al. U.S. Pat. No. 4,077,930, a typical emulsion is relatively unstable, having about 5-6% v/v oil separation and about 5-10% v/v cream after one month at 50° C. Therefore, a process that is capable of yielding an increased DADMAC incorporation would be especially useful if it also produced an inverse emulsion polymer having a very high degree of thermal stability. For example, less than 2% v/v oil separation and less than 2% v/v cream after one month at 50° C. Also it is beneficial to keep the product viscosity below 1000 cps.
SUMMARY OF THE INVENTION
It is accordingly an object of the present invention to provide a process for improved incorporation of diallyldimethylammonium chloride into an acrylamide polymer.
It is a further object of the present invention to provide an inverse emulsion polymer of diallyldimethylammonium chloride with good end use performance and with a viscosity within commercially attractive limits.
It is still a further object of the invention to provide an inverse emulsion polymer of diallyldimethylammonium chloride having a very high degree of thermal stability.
Additional objects, advantages and novel features of the present invention are set forth in the description that follows, and in part will become apparent to those skilled in the art upon examination of the following description or may be learned by practice of the invention.
To achieve the foregoing objects and in accordance with the purpose of the present invention, as embodied and broadly described herein, there is provided a process for improved incorporation of diallyldimethylammonium chloride into an acrylamide polymer. The process includes the step of polymerizing in an aqueous medium the DADMAC and acrylamide in the presence of a copolymerizable monomer having a higher reactivity than DADMAC with acrylamide. The aqueous polymerization medium contemplates emulsion or solution polymerization systems, although an emulsion system is preferred. The copolymerizable monomer selected from the group consisting of a monomer of the general formula: ##STR2## wherein R is --H or CH 3 ;
X is --O--, or --NH--;
n has a value of 2-4; and
A is an ion selected from the group consisting of Cl - , CH 3 SO 4 - , HSO 4 - and NO 3 -
Specific monomers within this formula include, for example, 2-methacryloylethyltrimethylammonium chloride and 2-acryloylethyltrimethylammonium chloride. The monomer of the general formula is present in an amount sufficient to provide improved incorporation of DADMAC into the acrylamide polymer. The polymerizing step is carried out in the presence of emulsifiers that provides a suitable HLB and preferably an HLB of not more than about 8.
The amount of the copolymerizable monomer is sufficient to provide improved incorporation of DADMAC into the acrylamide polymer. Generally, an additional amount of between about 0.1 to about 50 mole percent of the monomer is used based on the total moles of DADDMAC.
DESCRIPTION OF THE PREFERRED EMBODIMENT
By the present invention, the incorporation of diallyldimethylammonium chloride into an acrylamide polymer is substantially improved. The improved incorporation is attained by polymerizing the diallyldimethylammonium chloride monomer with the acrylamide monomer in the presence of a promoter monomer which is more reactive with acrylamide than is the DADMAC monomer. The promoter monomer is selected from the group consisting of those compounds of the general formula: ##STR3## wherein R is --H or CH 3 ;
X is --O--, or --NH--;
n has a value of 2-4; and
A is an ion selected from the group consisting of Cl - , CH 3 SO 4 - HSO 4 - and NO 3 - .
Specific monomers within this formula included, for example, 2-methacryloylethyltrimethylammonium chloride and 2-acryloylethyltrimethylammonium chloride. By "improved incorporation" of the DADMAC, for purposes of the present invention, is meant that the invention results in the incorporation of a percentage of DADMAC into an acrylamide polymer, that is higher than would be obtained in the absence of the promoter monomer.
The invention provides an inverse emulsion copolymer of DADMAC that inverts well and, as a consequence, rapidly releases the polymer into the water to perform its function. The DADMAC copolymer of the invention has a viscosity within commercially acceptable limits and a very high degree of thermal stability.
In the formation of the copolymer of the invention, about 10-99 mole % acrylamide is typically polymerized with about 1-50 mole % DADMAC. In the disclosure of the inventive concept expressed herein, the term "acrylamide" as used herein, include methacrylamide, substituted acrylamides and substituted methacrylamides.
It is an essential feature of the invention that polymerization of acrylamide and DADMAC be in the presence of a copolymerizable promoter monomer whose reactivity with DADMAC is greater than it is with acrylamide and is selected from compounds represented by the above general formula. We have discovered that such promoter comonomers promote a definite improvement in the incorporation of the DADMAC. Various additional monomers which are generally compatible with the copolymer system may be contained with the polymerizable system of the invention of acrylamide, DADMAC and the active promoter comonomers. Illustrative of such additional monomers are: cationic monomers such as quaternary C 1 -C 18 alkyl esters of acrylic acid, or methacrylic acid, quaternary substituted acrylamides and quaternary substituted methacrylamides. Also useful are nonionic and anionic monomers such as styrene, alphamethtyl styrene, acrylonitrile, methacrylonitrile, 2-acrylamidopropane-2-sulfonic acid, acrylic acid, methacrylic acid, maleic and fumaric acids and esters, functional group-containing acrylates and methacrylates such as hydroxyethylacrylate and vinyl acetate.
For use in water treatment, the cationic monomer is highly advantageous, as it contributes to the charge generally desired for this type of end use. The exemplary cationic monomers comprise 2-methacryloylethyltrimethylammonium chloride, and 2-acryloylethyltrimethylammoinum chloride. Referring to Table 1 of U.S. Pat. No. 4,396,752, the reactivity ratios (r 2 :r 1 ) for these two cationic monomers are as follows: acrylamide, r 1 =0.2, and 2-methacryloylethyltrimethylammonium chloride, r 2 =1.75 (r 2 :r 1 =8.75:1); acrylamide, r 1 =0.72, and 2-acryloylethyltrimethylammonium chloride, r 2 =0.66 (r 2 :r 1 =0.92:1). A ratio of 8.75:1 means that 2-methacryloylethyltrimethylammonium chloride is 8.75 times less reactive than acrylamide. Comparison with the reactivity ratio for 2-acryloylethyltrimethylammonium chloride shows that there is a substantial greater reactivity of these monomers with acrylamide.
As illustrated with 2-methacryloylethyltrimethylammonium chloride and 2-acryloylethyltrimethylammonium chloride, copolymerizable monomers having a reactivity ratio in the range of about 8.75-0.92:1 are useful as promoters in the presents invention. However, a copolymerizable monomer not within this range may also be useful, provided that it is more reactive than DADMAC with acrylamide. Essentially, the copolymerizable monomers are sufficiently more reactive than DADMAC with acrylamide such, that they provide improved incorporation of DADMAC into the acrylamide polymer.
The promoter monomer of the general formula will typically be used in an amount that is economical yet effective. Generally, about 0.1 to 40 mole % of the promoter monomer, based upon total moles of the DADMAC monomer, provides improved incorporation of DADMAC into an acrylamide polymer. The proper dosage will depend upon factors including the particular monomer selected for use as the promoter, and the amount of DADMAc. As the amount of DADMAC is increased, it is generally beneficial to increase the amount of promoter monomer. Furthermore, increasing amounts of promoter monomer typically result in increased DADMAC incorporation. While the dosage of promoter monomer required to provide improved incorporation of DADMAC into an acrylamide polymer cannot be predicted with certainty in every instance, a dosage within the above limits can be determined with simple experimentation.
A further essential feature of the present invention is that the polymerization be carried out in an aqueous polymerization medium which is preferably an emulsion polymerization system, but includes, as well, solution polymerization. When emulsion polymerization isused, the one or a combination of surfactants that provide a suitable HLB, preferably an HLB of not more than about 8 are used. Surfactants of this type are well known, and for example, may comprise a mixture of sorbitan monooleate sorbitan trioleate and ethoxylated 12-hydroxystearic acid, such that the mixture has an HLB of 5.5. It will be understood that a single emulsifier could be used, rather than a combination of surfactants, so long as a suitable HLB is obtained.
In the practice of this invention, the procedure used to prepare an inverse emulsion in accordance with the present invention, is for the most part conventional. Therefore, the typical procedure now described is particularly intended to highlight those features that are novel.
A conventional inert hydrophobic liquid such as isoparaffinic oil, is mixed with certain conventional emulsifiers, and the resulting oil phase is homogenized. Afterwards, the emulsified oil phase is mixed with a solution of acrylamide, DADMAC and the promoter monomer, and the mixture is homogenized until about 90% of the droplets are between less than 5 microns in size.
The resulting water-in-oil emulsion is sparged with nitrogen to remove oxygen, and polymerization is inducted, conveniently by the addition of a conventional free radical initiator useful in emulsion polymerization. Exemplary initiators of this type include peroxyester initiators such as t-butylperoxypivalate.
Polymerization is generally carried out at a reaction temperature in the range of about 35°-55° C., advantageously at a temperature in the range of about 40°-45° C. A reaction temperature of about 60° C. will generally be an upper limit for a polymerization that forms an inverse emulsion. Polymerization is continued until less than about 1% acrylamide is present, thereafter a suitable high HLB surfactant, such as ethoxylated octylphenol, ethoxylated oleyl alcohol, preferably an ethoxylated nonylphenol, is slowly added dropwise to complete the preparation. This surfactant is added in an amount sufficient to provide for rapid release of the polymer from the inverse emulsion during intended end use of the emulsion for water treatment.
Once the emulsifier has been added, the inverse emulsion is ready for use, and has a viscosity generally within the range of about 100 to 600 cps, with the viscosity typically being in the range of about 100-300 pcs. Emulsions with appreciably higher viscosities may be undesirable because of pumping and handling problems attendant with excessively viscous liquids.
A complex reaction occurs during polymerization. The complexity of the reaction is evidenced by variability in the percentage of DADMAC incorporation depending upon various factors such as the reaction temperature profile and the concentration of the initiator, for example, applications of the inverse emulsion polymers of the present invention will include utility in coagulation, flocculation and dewatering of municipal sludges and chemical waste sludges.
In the following examples of the present invention and throughout this description and the claims set forth below, all parts and percentages are weight percent and procedures are carried out at ambient temperature and pressure, unless otherwise specified.
EXAMPLE 1
An inverse emulsion terpolymer of diallyldimethylammonium chloride is prepared by mixing an isoparaffinic oil (150 g) available commercially as Chevron Thinner 450 with emulsifiers that provided an HLB of 5.5. The emulsifiers comprised (a) a mixture of sorbitan monooleate and ethoxylated 12-hydroxystearic acid (14.35 g), and (b) a mixture of sorbitan trioleate and ethyoxylated 12-hydroxystearic acid (3.15 g). The resulting oil phase is emulsified using a mixer of the kind conventionally used in preparing emulsion polymers.
The emulsified oil phase is mixed with a solution of 50% commercially available gaseous acrylamide (266.1 g) combined with DADMAC (5.1 g; 62% in water), and with 2-methacryloylethyltrimethyl ammonium chloride (21.8 g; 75% in water). The resulting mixture is emulsified until most of the droplets are between 1 and 3 microns in size.
The resulting water-in-oil emulsion is charged into a 1-liter glass-jacketed resin kettle equipped with a paddle stirrer, nitrogen sparger and thermometer. The emulsion is sparged with nitrogen for 0.5 hours to remove oxygen. Water at 45° C. +/- 1° C. is circulated through the reactor jacket to maintain the reaction temperature. The system is designed to allow circulation of cooling water in the event of an exotherm. 70 Mg of a polymerization initiator, t-butylperoxypivalate is added. The polymerization proceeds for 8 hours at 45° C. Then 2.4 wt. % of an ethoxylated nonylphenol emulsifier containing 9.5 ethoxy units and having an HLB of 13.4, is slowly added dropwise to complete the preparation.
The resulting emulsion has a Brookfield viscosity of 200 cps. The residual DADMAC monomer content is zero, corresponding to a conversion of 100%.
The stability of the product was a trace of oil and no cream after 30 days at 50° C.
EXAMPLE 2
A polymer was prepared in accordance with the procedure used and described in Example 1 except that:
a. 2-acryloylethyltrimethylammonium chloride (DAEM-Q) is substituted for 2-methylacryloylethyltrimethylammonium chloride (DMAEM-Q);
b. the index ratio of DAEM-Q to DADMAC is 1 to 4;
c. the total monomer is 35.8 weight %; and
d. the temperature was varied from 40° C. for 4 hrs., 50° C. for 1 hr, and finally 60° C. for 1 hr.
The viscosity of the emulsion was 200 cps.
The stability of the product was no oil or cream after 33 days at 50° C.
The incorporation of DADMAC was 93% versus an expected incorporation of about 40% if no DMAE-Q was present.
EXAMPLE 3
A series of emulsions were made according to the procedure described in Example 1 with slight modifications in temperature and with compositions as indicated in the following table of data where the effect of adding DMAEM-Q is demonstrated over a range of total cationic monomer.
__________________________________________________________________________EFFECT OF DMAEM-QMOLE % OF MONOMERS % DADMAC ACRYLAMIDE DADMAC.sup.A DMAEM-Q.sup.B INCORPORATED__________________________________________________________________________Low Total 92 8 0 40Cationic 92 7 1 63Monomer 90 5 5 100Medium Total 80 20 0 47Cationic 80 19 1 80Monomer 80 18 2 77High Total 60 40 0 38Cationic 60 39 1 82Monomer__________________________________________________________________________ .sup.A Diallyldimethylammonium chloride .sup.B 2methacryloylethyltrimethylammonium chloride
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The present invention provides a process for improved incorporation of diallyldimethylammonium chloride (DADMAC) into an acrylamide polymer. This invention makes use of a copolymerizable promoter monomer. Also provided by the present invention are inverse emulsion terpolymers of diallyldimethylammonium chloride. The improved incorporation resides in the use of a promoter monomer that is more reactive with acrylamide than is the DADMAC monomer and is selected from ##STR1## wherein R is --H or CH 3 ;
X is --O--, or --NH--;
n has a value of 2-4; and
A is an ion selected from the group consisting of Cl.sup. -, CH 3 SO 4 - , HSO 4 - and NO 3 - .
Specific monomers within this formula included, for example, 2-methacryloylethyltrimethylammonium chloride and 2-acryloylethyltrimethylammonium chloride.
Typical of such promoter monomers are 2-methacryloylethyl trimethyl ammonium chloride and 2-acryloylethyl trimethyl ammonium chloride.
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CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application is a divisional of and claims priority to U.S. patent application Ser. No. 10/925,355, filed Aug. 23, 2004 in the name of Andreas K. Nielsen, which is a divisional of and claims priority to U.S. patent application Ser. No. 10/198,204, filed Jul. 17, 2002 (now U.S. Pat. No. 6,796,622) also in the name of Andreas K. Nielsen, each of which are incorporated herein by reference.
FIELD OF THE INVENTION
[0002] Embodiments of the present invention relate to furniture such as an entertainment center.
BACKGROUND OF THE INVENTION
[0003] Component electronics for audiovisual applications conventionally include multiple, free-standing enclosures that receive power and signals from facility wiring and communicate with other components on wired cables or wireless links. Support for numerous components has conventionally been provided by furniture called an entertainment center. A conventional entertainment center may have open shelving and enclosed shelving for supporting and enclosing not only the components but also media used with the components. Such furniture also conventionally provides holes through the back and through the shelving for accommodating the signal cables and power cables associated with the components.
[0004] A conventional entertainment center is spaced away from a facility wall to allow cabling to be tucked behind the cabinetry of the entertainment center because provisions for cabling inside the cabinetry of the entertainment center are inadequate. The space between the entertainment center and the facility wall also supplies ventilation air for the components.
[0005] The conventional entertainment center provides movable shelving for accommodating consumer electronics assemblies of different vertical height; but, provides fixed horizontal dimensions designed for a maximum component width. Use of a conventional entertainment center is limited by the fixed horizontal width of its design. Users seeking, for example, to accommodate a larger home theater display (e.g., a big screen television set, a rear projection system, or a front illuminated screen) have little recourse but to purchase new furniture in the event the larger width display does not fit the fixed horizontal width provided by an existing entertainment center.
[0006] A large market exists for furniture to support consumer electronics. New products of various sizes are launched into this market annually. Without furniture capable of accommodating different horizontal widths, consumers may be reticent to purchase more expensive entertainment center furniture or may forego the acquisition of newer larger components. Consequently, without the present invention, both the consumer electronics and furniture industries face significant economic impairments to growth in sales.
SUMMARY OF THE INVENTION
[0007] A furniture system according to various aspects of the present invention includes an enclosure of a first space to be occupied by a home theater display wherein the enclosure, when placed against a facility wall provides a second space open to the top of the furniture system for ventilation of the home theater display.
[0008] When the enclosure includes shelving for consumer electronics assemblies, the shelving may be located between a first vertical side and a second vertical side. The first vertical side is adjacent to the display. The second vertical side has a depth greater than the depth of the first vertical side so that a portion of the second space is behind the shelving for ventilation of the consumer electronics assemblies.
[0009] Another furniture system according to various aspects of the present invention includes an enclosure of a space to be occupied by a home theater display and a base for transporting the display into and out from the space. The enclosure includes adjustable members that facilitate extending the enclosure to enclose the display at a width of a set of widths.
[0010] Another furniture system according to various aspects of the present invention includes an enclosure of a space to be occupied by a home theater display and a base for transporting the display into and out from the space. The base includes adjustable members that facilitate extending the base to support the display at a width of a set of widths.
[0011] Another furniture system according to various aspects of the present invention includes a pair of cabinets and a base for supporting a home theater display. The base includes wheels attached to a lower surface of the base to facilitate rolling the base between the cabinets. The base includes at least one section, mechanically coupled to the base that may be placed in one of a set of positions apart from a center of the base to give the base an apparent width that approximates a corresponding width of any of a set of home theater displays of various widths. The section includes a trim surface to block viewing of the wheels from the front of the entertainment furniture system when the section is placed in any position of the set.
[0012] The cabinets may include inner sides shorter in depth than outer sides, thereby forming a passage in the rear of the system for ventilation and cabling.
[0013] By including a multi-section base, the load weight of the display is efficiently coupled to the wheels for a variety of displays. By including trim pieces that overlap, the overall appearance of the base is improved. When the furniture system further includes a bridge, an overlapping aspect of the bridge relative to the cabinets is aesthetically similar to the overlapping appearance of the base for improved appearance of the furniture system as a whole.
[0014] A base, according to various aspects of the present invention, supports a home theater display and includes a stage and at least two sections. The stage and each section provide a respective front surface to block viewing of a space beneath the home theater display and to enhance the appearance of the base. The sections facilitate horizontal positioning relative to each other to establish a width of the base to approximate the width of any one of a set of home theater displays having differing respective widths. The base includes a plurality of wheels in the space that allow movement of the stage and display as a unit on a provided surface.
[0015] The stage and sections may be mechanically coupled by slides. Locks may be added to the slides to maintain the selected positioning.
[0016] According to various aspects of the present invention, a method is performed to mount a home theater display in a furniture system. The method includes, in any order: adjusting a horizontal width of a base for supporting the home theater display; placing a first cabinet against a facility wall; placing a second cabinet against the facility wall and spaced apart from the first cabinet a width sufficient for the base; and rolling the base between the first cabinet and the second cabinet. By supporting the display on a wheeled base and transporting the display on the base as a unit, access is facilitated to cabling for power and signals to the display. Cabling may be fully connected and routed prior to rolling the base between the cabinets.
BRIEF DESCRIPTION OF THE DRAWING
[0017] Embodiments of the present invention will now be further described with reference to the drawing, wherein like designations denote like elements, and:
[0018] FIG. 1 is a perspective view of a furniture system according to various aspects of the present invention wherein the doors of one of the cabinets are omitted for clarity of presentation;
[0019] FIG. 2 is a top view of the furniture system of FIG. 1 wherein the bridge and crown of one of the cabinets are omitted for clarity of presentation;
[0020] FIG. 3 is a perspective view of the underside of a base for use in the furniture system of FIG. 1 ; and
[0021] FIG. 4 is a top view of the bridge and a crown of the furniture system of FIG. 1 .
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
[0022] A furniture system according to various aspects of the present invention supports any of a variety of home theater displays of various widths. The furniture system generally encloses a space for locating the home theater display, the space being enclosed on several sides, for example, the left side, the right side, and the top. The furniture system may further enclose a portion of the rear of the space. Enclosing is typically for establishing, improving, or cooperating with the interior design of a room where the home theater display is to be used. The enclosure provides ventilation for the display according to various aspects of the present invention.
[0023] The display is supported on a base having wheels to transport the base and display as a unit separate from the enclosure portion of the furniture system. The furniture system is typically arranged to abut each vertical side of the home theater display and present to a front view a continuous series of trim surfaces that substantially hide the wheels from view. When the rear of the furniture system is placed against a facility wall, spaces defined by the enclosure accommodate wiring and ventilation and are easily accessible from the front of the furniture system. Conventional materials and techniques of furniture manufacture may be used in the design and construction of furniture systems of the present invention except as described below.
[0024] For example, furniture system 100 of FIGS. 1-4 includes cabinets 102 and 103 , back panel 101 , bridge 104 , and base 105 . Cabinets 102 (and 103 ) support component electronics and media (not shown). Each cabinet 102 ( 103 ) includes inner side 242 ( 244 ), outer side 250 ( 252 ), crown 132 ( 133 ), any number of suitable shelves 121 and 123 , and a cabinet back 246 ( 248 ) having holes 122 and 124 through which power and signal cables may be routed. Because outer side 250 ( 252 ) extends further to the rear than inner side 242 ( 244 ), cabinet 102 ( 103 ) defines a space 216 ( 218 ) for cabling and ventilation.
[0025] A back panel of the furniture system enhances the finished appearance and is retained in a vertical position while cabinets 102 and 103 are moved to establish a suitable width 110 for base 105 . For example, back panel 101 is mounted to allow cabinets 102 and 103 to be repositioned without access to the rear of the furniture system to effect a change in mounting of back panel 101 . Back panel 101 in one implementation rests on a hook 262 ( 264 ) on each cabinet 102 ( 103 ) and slides in groove 414 of bridge 104 . When cabinets 102 and 103 are positioned closer together or farther apart, back panel 101 slides on hooks 262 and 264 and is maintained in a vertical position by groove 414 . Back panel 101 does not obstruct cable passage holes (e.g., 122 and 124 ) or significantly block ventilation holes in cabinet backs 246 and 248 when cabinets 102 and 103 are positioned for a minimum width 110 . Back panel 101 includes stiffeners 210 , 212 , and 214 to reduce warping.
[0026] A bridge provides a visual connection between cabinets, usually at the top of a furniture system, by spanning the width between cabinets. While cabinets are moved to establish a suitable width, the bridge cooperates with the cabinets and the back panel to maintain its position on top of the cabinets. The horizontal position of the bridge can be adjusted (e.g., to center the bridge between the cabinets) without access to the top or rear of the furniture system. A bridge may be supported on the front of crowns of two cabinets and may also be supported via a back panel and hooks on which the back panel is supported. A bridge may have a depth when installed that is substantially equal to the depth of the inner sides of cabinets on which it rests.
[0027] For example, bridge 104 rests on the top of cabinet 102 and rests on the top of cabinet 103 . Bridge 104 nests with back panel 101 in groove 414 to prevent movement of bridge 104 toward the front of furniture system 100 . Preferably, back panel 101 bears no weight of bridge 104 so that back panel 101 slides easily when cabinets are moved. Bridge 104 nests with crowns 132 and 133 via slots 406 and 408 to prevent movement of bridge 104 toward the front or toward the rear of furniture system 100 . A front surface 422 of crown 132 (and a symmetric surface of crown 133 (not shown)) is overlapped by a portion 402 of bridge 104 . When surface 422 includes raised or recessed features, corresponding recesses or raised features may be added to surface 424 to provide an integral appearance when surfaces 422 and 424 are pressed against each other. When supported by cabinets 102 and 103 , bridge 104 covers a space 106 between cabinets 102 and 103 . Bridge 104 may include conventional lighting to illuminate space 106 . In one implementation, bridge 104 is not fastened to either cabinet 102 or 103 but slides on the crown portion 132 and 133 of each cabinet so that bridge 104 is aligned easily over the center of space 106 and flush against crowns 132 and 133 . Bridge 104 may further include U-shaped slots for avoiding interference between body 404 of bridge 104 and lighting in crowns 132 and 133 (e.g., installed in apertures 135 and 137 ).
[0028] A crown provides an aesthetically pleasing top to a cabinet and provides support for lighting and a bridge. A crown cooperates with a bridge according to various aspects of the present invention to support the bridge while the cabinet is being moved toward or away from the other cabinet on which the bridge is supported. For example, crowns 132 and 133 cooperate with bridge 104 as discussed above. Further, crowns cooperate with a bridge of the present invention to provide an aperture 430 for convection cooling of the home theater display and any entertainment equipment components located within cabinets 102 and 103 . Aperture 430 includes a portion 216 rear of cabinet back 246 , a portion 218 rear of cabinet back 248 , and a portion 430 above base 105 . Rear panels, crowns, and/or a bridge of furniture system 100 may include any conventional grills, hole patterns, slots, or voids to facilitate cooling.
[0029] A base, according to various aspects of the present invention provides an adjustable width so as to support one of various width home theater displays and provides a concealed mechanism for moving the base in and out of position between cabinets of the furniture system. Such a base includes sections mechanically coupled to each other and capable of being positioned with respect to each other to provide a base having one of various overall widths. Any mechanical coupling technique may be used to provide discrete or continuously variable positions. Concealment of wheels may be accomplished by expandable trim surfaces, where expansion is accomplished by overlapping, telescoping, deploying, or stretching trim surfaces. A deployed trim surface may be stored as rolled stock in the base. Stretching may include elastic, pleated, or accordioned material. For example, base 105 of FIGS. 1-4 includes stage 113 , section 112 attached to stage 113 by integral slides, and section 114 attached to stage 113 by integral slides. The stage provides wheels for movement of the base; and the sections and the stage provide cooperative overlapping trim surfaces to conceal the wheels. A trim surface of each section overlaps a portion of the nearest cabinet that abuts the base.
[0030] A stage provides support for at least one section and provides transportation for an object placed on the stage or on the section. For example, stage 113 includes platform 111 , casters 302 - 305 , studs 311 - 314 , and trim piece 108 . Section 112 ( 114 ) includes platform 322 ( 323 ), side 306 ( 308 ), and trim piece 107 ( 109 ). Platform 322 ( 323 ) includes a pair of slots 326 ( 327 ) and 328 ( 329 ) for attaching the section to the stage. The underside of section platforms 322 and 323 bears on the an upper side of stage platform 111 . Studs 311 - 314 pass through slots 326 - 329 to accept a stud termination (e.g., a fender washer and nut). Each slot, stud, and termination cooperate to form a slide for mechanically coupling a section to the stage. By loosening stud terminations, each section 112 and 114 may be moved along its respective slides (e.g., along axis 110 ) toward and away from the center of platform 111 . By moving each section a proportional distance from the center of platform 111 , base 113 is extended to any width (W) 110 within the range of the slides. After moving the sections, any suitable lock (e.g., a locking mechanism) may be employed to secure the position, fix the overall width of stage 113 , and more efficiently transfer load borne by base 105 to casters 302 - 305 . For example, stud terminations may be tightened to draw and bind the stage and section together.
[0031] Casters 302 - 305 are fixed to an underside surface of platform 111 and provide load bearing support. Each caster pivots around a vertical axis. Each caster provides a wheel that rotates on a horizontal axis. Any conventional caster may be used. A home theater display placed onto base 113 may rest in part against an upper surface of platform 111 and/or on an upper surface of section platforms 322 and 323 . Weight of the display is communicated via slides to stage 113 and through casters 302 - 305 to the facility surface on which furniture system 100 is placed. In operation, casters 302 - 305 facilitate movement of stage 113 (and a display placed on stage 113 ) along an axis of width 110 so to align stage 113 between cabinets 102 and 103 , and along an axis of depth 120 so to move stage 113 into space 106 . A home theater display atop stage 113 may completely fill the width 110 and depth 120 of space 106 .
[0032] The space directly below stage platform 111 is substantially hidden from view by the cooperation of trim pieces 107 - 109 . Trim piece 107 ( 109 ) extends away from the center of platform 111 and beyond the extremity of platform 322 ( 323 ) to overlap a portion of cabinet 102 ( 103 ) and consequently to cover any portion of space 106 that might remain between base 113 and cabinet 102 ( 103 ). Trim piece 107 ( 109 ) also extends toward the center of platform 111 to overlap a portion of trim piece 108 . When section 112 ( 113 ) is slid toward or away from stage 111 , trim piece 107 ( 109 ) slides in front of trim piece 108 to continue to perform the hiding function.
[0033] Each section 112 and 114 may further include a railing on one or more edges of the section to reduce the risk that an object placed on the base will unexpectedly slide off the base. For example, section 112 ( 114 ) may further include side 306 ( 308 ) that extends above platform 322 ( 323 ) to form a lip 202 ( 206 ). Railings may be added to the upper surfaces of any platform 111 , 322 , and/or 323 . For example, railing 204 ( 208 ) is added on the top rear edge of platform 322 ( 323 ).
[0034] Movement of base 105 is facilitated in any conventional manner. According to various aspects of the present invention, base 105 provides at least one handle or hand-hold to move base 105 . For example, trim piece 108 extends downward yet leaves space for a user to place his or her hand or hands under trim piece 108 and pull on trim piece 108 to move base 105 on depth axis 120 out from between cabinets 102 and 103 . In an alternate implementation, platform 111 is formed with a hand access hole through platform 111 to facilitate pulling base 105 on depth axis 120 out from between cabinets 102 and 103 .
[0035] Assembly of an entertainment system with an entertainment furniture system as discussed above may proceed according to a method performed in any order as follows. Measure the width of the home theater display to be positioned in space 106 . Determine whether it is desired to abut both cabinets 102 and 103 to the sides of the home theater display, and if not add a suitable amount to the width. Assemble sections 112 and 114 to stage 113 . Before tightening stud terminations, extend each section 112 and 114 symmetrically from the center of stage 113 an amount equal to about half the desired width, then lock the sections to the stage (e.g., by tightening the stud terminations). Place back panel 101 against a facility wall. Place cabinet 102 within a few inches of the facility wall as desired, allowing for access to cable TV, power, telephone, Internet, and other facility wiring connections for use by the entertainment system. Place cabinet 103 roughly the desired width from cabinet 102 . Lift back panel 101 onto hooks 162 and 164 . Place bridge 104 on top of the crown portions of cabinets 102 and 103 , centering bridge 104 over space 106 , and fitting bridge 104 onto back panel 101 for maintaining back panel 101 in a vertical position. Move cabinets 102 and/or 103 to obtain the desired width of space 106 . While cabinets 102 and 103 are being moved apart (or together), back panel 101 is confined to slide on axis 120 while being maintained in a vertical position; and, bridge 104 is confined to slide only on axis 120 while being maintained square to the top of cabinets 102 and 103 . If cabinet lighting is provided in bridge 104 or crown portions of cabinets 102 and 103 , connect power wiring. Place a home theater display on base 105 and transport the base and display as a unit to a position in front of space 106 . Place all other entertainment system components (e.g., tuner, amplifier, audio media player, speakers) in cabinets 102 and 103 . Route all cables and wiring from the display to the components. Reach around cabinet inner side 242 ( 244 ) to access cables passing through holes 122 and 124 (and suitable holes in cabinet back 248 (not shown)). Transport the base and display as a unit into space 106 until the trim pieces 107 and 109 meet and overlap a portion of the front trim pieces 142 and 144 of cabinets 102 and 103 .
[0036] Another furniture system according to various aspects of the present invention may include a base as discussed above and an enclosure. The enclosure may include: (a) shelving to one side of a space to be occupied by the base; and (b) a vertical panel on the opposite side of the space. The enclosure may include a bridge and/or a back panel that spans the top and/or rear sides of the space. For example, such a furniture system may include all of the structures discussed above with reference to system 100 , except that: (a) cabinet 102 is replaced by a panel similar to side 250 (e.g., omitting crown, doors, drawer, shelves, as well as front, inside, and rear structures) and supported by being attached to either a back panel similar to 101 and/or to a bridge similar to 104 ; and (b) bridge 104 is replaced with a bridge modified to attach to or cooperate with side 250 (e.g., omitting all of the structure associated with resting on top of and cooperating with a full size cabinet 102 ). The structures and cooperation of the bridge and cabinet 103 would be included in this alternate furniture system. The asymmetric implementation discussed here (cabinet to the right of display) may be implemented as a mirror image (cabinet on left of display) in an alternate implementation.
[0037] In alternative implementations of the furniture systems discussed above, cabinet doors and drawers are partially or entirely omitted. In still further alternate implementations, any arrangement of shelving, doors, and/or drawers may be located between sides 244 and 252 (and/or sides 250 and 242 if implemented).
[0038] Another alternate furniture system according to various aspects of the present invention includes merely a base as discussed above (cabinets 102 and 103 , bridge 104 , and back panel 101 are omitted).
[0039] The foregoing description discusses preferred embodiments of the present invention which may be changed or modified without departing from the scope of the present invention as defined in the claims. While for the sake of clarity of description, several specific embodiments of the invention have been described, the scope of the invention is intended to be measured by the claims as set forth below.
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An entertainment center includes a base that expands horizontally to accommodate different width home theater displays; and, a light bridge that rests on top of one or more cabinets placed on either side of the base. The side cabinets provide a vertical column of open space for accommodating wiring among the entertainment system components and ventilation for heat generated by those components. The base includes casters to facilitate moving the base in and out from between the side cabinets. Sliding portions of the base extend horizontally yet continue to transfer all load weight onto the casters. The front woodwork of the base presents a pleasing seamless appearance as a consequence of overlapping trim pieces.
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BACKGROUND OF THE INVENTION
[0001] 1. Field of the Invention
[0002] The present invention relates to an inkjet printhead. More particularly, the present invention relates to a piezoelectric inkjet printhead capable of reducing a crosstalk and a method of manufacturing the same.
[0003] 2. Description of the Related Art
[0004] An inkjet printhead is a device for ejecting fine ink droplets for use in printing. For example, it is used to print at a desired point on a paper and to print an image of a predetermined color. Inkjet printheads can be generally divided into two types according to the type of ink ejection employed. One type is a thermally-driven inkjet printhead that creates a bubble in ink using a heat source, to thereby eject the ink using the expansion force of the bubble. The other type is a piezoelectric inkjet printhead that uses a piezoelectric element to eject ink using a pressure applied to the ink, which is generated by deformation of the piezoelectric element.
[0005] The construction of a typical piezoelectric inkjet printhead is illustrated in FIG. 1 . Referring to FIG. 1 , a manifold 2 , a restrictor 3 , a pressure chamber 4 and a nozzle 5 , which together constitute an ink channel, are formed in the inside of a channel plate 1 . A piezoelectric actuator 6 is disposed on the channel plate 1 . The manifold 2 is a path through which ink flowing from an ink reservoir (not shown) is supplied to one or more pressure chambers 4 . The restrictor 3 is a path through which the ink flows from the manifold 2 to the pressure chamber 4 . The pressure chamber 4 is a space filled with ink to be ejected. A pressure change, for ejection or refill of ink, is generated in the pressure chamber 4 by changing its volume by driving the piezoelectric actuator 6 . The piezoelectric actuator 6 may deform an upper wall of the pressure chamber 4 , which may serve as a vibration plate 1 a.
[0006] In operation, when the piezoelectric actuator 6 is driven to inwardly deform the vibration plate 1 a , the volume of the pressure chamber 4 is reduced, resulting in a pressure change. Ink in the inside of the pressure chamber 4 is ejected to the outside through the nozzle 5 by the pressure change in the inside of the pressure chamber 4 . Subsequently, when the piezoelectric actuator 6 is driven to outwardly deform and restore the vibration plate 1 a to its original shape, the volume of the pressure chamber 4 increases, resulting in a second pressure change. The second pressure change causes ink to flow into the the pressure chamber 4 from the manifold 2 through the restrictor 3 due to the increased volume.
[0007] A conventional piezoelectric inkjet printhead is illustrated in FIG. 2 . Referring to FIG. 2 , the conventional piezoelectric inkjet printhead is formed by stacking and bonding thin plates 11 through 16 . In particular, a first plate 11 , having nozzles 11 a for ejecting ink, is disposed at the lowermost side of the printhead, a second plate 12 , having a manifold 12 a and ink outlets 12 b , is stacked thereon and a third plate 13 , having ink inlets 13 a and ink outlets 13 b , is stacked on the second plate 12 . The third plate 13 has an ink introducing port 17 for introducing ink to the manifold 12 a from an ink reservoir (not shown). A fourth plate 14 , having ink inlets 14 a and ink outlets 14 b , is stacked on the third plate 13 and a fifth plate 15 having pressure chambers 15 a , the ends of which communicate with the ink inlets 14 a and the ink outlets 14 b , respectively, is stacked on the fourth plate 14 . The ink inlets 13 a and 14 a serve as paths through which ink flows from the manifold 12 a to the pressure chambers 15 a , and the ink outlets 12 b , 13 b , and 14 b serve as paths through which ink is discharged from the pressure chambers 15 a to the nozzles 1 a . A sixth plate 16 closing the upper portion of the pressure chambers 15 a is stacked on the fifth plate 15 , and drive electrodes 20 and piezoelectric films 21 serving as piezoelectric actuators are formed on the sixth plate 16 . Thus, the sixth plate 16 serves as a vibration plate that is vibrated by the piezoelectric actuator and changes the volume of the pressure chamber 15 a disposed beneath it using warp-deformation of the sixth plate 16 .
[0008] FIG. 3 illustrates a view of another example of a piezoelectric inkjet printhead and FIG. 4 illustrates a vertical sectional view of the same. The inkjet printhead illustrated in FIGS. 3 and 4 may have a structure in which three silicon substrates 30 , 40 and 50 are stacked and bonded. Pressure chambers 32 of a predetermined depth may be formed on a backside of the upper substrate 30 . An ink inlet port 31 , connected to an ink reservoir (not shown), may pass through one side of the upper substrate 30 . The pressure chambers 32 may be arranged in two columns, one on each side of the printhead, in a lengthwise direction of a manifold 41 formed on the intermediate substrate 40 . Piezoelectric actuators 60 , for providing driving force fto eject ink to the pressure chambers 32 , may be formed on an upper surface of the upper substrate 30 . The intermediate substrate 40 may have the manifold 41 , which may be connected with the ink inlet port 31 and restrictors 42 . The restrictors 42 may be connected with the respective pressure chambers 32 formed on both sides of the manifold 41 . Also, dampers 43 vertically passing through the intermediate substrate 40 may be formed on the intermediate substrate 40 in positions that correspond to the pressure chambers 32 . Also, nozzles 51 connected with the dampers 43 may be formed in a lower substrate 50 .
[0009] In operation, ink that has flowed into the manifold 41 through the ink inlet port 31 flows into the pressure chambers 32 by way of the restrictors 42 . Subsequently, when the piezoelectric actuators 60 operate to pressurize the pressure chambers 32 , the ink within the pressure chambers 32 passes through the dampers 43 and is ejected to the outside through the nozzles 51 . Here, the restrictors 42 not only serve as paths supplying the ink from the manifold 41 to the pressure chambers 32 but may also prevent the ink from flowing backward to the manifold 41 from the pressure chambers 32 when the ink is ejected.
[0010] However, when the piezoelectric actuators 60 pressurize the pressure chambers 32 , the pressure transferred to the pressure chambers 32 may also be transferred to the restrictors 42 . Such a situation may generate crosstalk between adjacent restrictors 42 . In this regard, crosstalk means mutual interference of pressures between adjacent restrictors 42 , generated when ink is ejected. Crosstalk may affect the size of an ink droplet ejected from the nozzles 51 , causing ink ejection to become non-uniform. That is, when crosstalk is generated, unintended ink may be ejected or an inaccurate amount of ink may be ejected, thus deteriorating print quality.
SUMMARY OF THE INVENTION
[0011] The present invention is therefore directed to a piezoelectric inkjet printhead capable of reducing a crosstalk and a method of manufacturing the same, which substantially overcome one or more of the problems due to the limitations and disadvantages of the related art.
[0012] It is therefore a feature of an embodiment of the present invention to provide an inkjet printhead exhibiting reduced crosstalk between restrictors.
[0013] It is therefore a further feature of an embodiment of the present invention to provide an inkjet printhead formed of three substrates, wherein it is possible to increase the width of a manifold by processing the backside of an intermediate substrate so as to form the manifold and install the manifold in a lower portion of a pressure chamber formed in an upper substrate.
[0014] It is therefore also a feature of an embodiment of the present invention to provide an inkjet printhead having one or more partitions interposed between adjacent restrictors.
[0015] At least one of the above and other features and advantages of the present invention may be realized by providing a piezoelectric type inkjet printhead including an upper substrate, an intermediate substrate, and a lower substrate that are sequentially stacked, wherein the upper substrate may include piezoelectric actuators on an upper surface of the upper substrate and pressure chambers and first restrictors on a lower surface of the upper substrate, the first restrictors extending from the pressure chambers and having a width smaller than a width of the pressure chambers, the intermediate substrate may include dampers passing therethrough, the dampers corresponding to the pressure chambers and second restrictors extending between the first restrictors and a manifold formed from a lower surface of the intermediate substrate, and the lower substrate may include nozzles passing therethrough, the nozzles corresponding to the dampers.
[0016] A part of the intermediate substrate that defines an upper surface of the manifold may also define a lower surface of the pressure chambers. The second restrictors may pass through the part of the intermediate substrate. The upper substrate, the intermediate substrate and the lower substrate may each formed of a single-crystal silicon substrate The upper substrate may be formed from a silicon on isolator wafer that includes a first silicon substrate, an intermediate oxide film, and a second silicon substrate, sequentially stacked, and the pressure chambers and the first restrictors are formed out of the first silicon substrate, and the second silicon substrate serves as a vibration plate for the piezoelectric actuators.
[0017] The intermediate substrate may further include at least one support pillar that contacts the lower substrate, the support pillar extending from a surface of the intermediate substrate that defines an upper surface of the manifold. The intermediate substrate may further include a blocking wall disposed between adjacent restrictors and extending from a surface of the intermediate substrate that defines an upper surface of the manifold. A width of the first restrictors in a width direction of the pressure chambers may be less than, or greater than, a width of the second restrictors in the width direction of the pressure chambers.
[0018] The manifold may have a partition wall formed therein along the length direction of the manifold, the partition wall extending from a surface of the intermediate substrate that defines an upper surface of the manifold and the partition wall may contact the lower substrate.
[0019] At least one of the above and other features and advantages of the present invention may also be realized by providing a method of manufacturing a piezoelectric type inkjet printhead, including, in an upper substrate, forming an ink introducing port, pressure chambers, and first restrictors connected with the pressure chambers, in an intermediate substrate, forming a manifold to a predetermined depth from a lower surface of the intermediate substrate, second restrictors connected to the manifold, and dampers passing through the intermediate substrate, in a lower substrate, forming nozzles passing through the lower substrate, bonding the lower substrate, the intermediate substrate and the upper substrate to each other such that the manifold connects with the ink introducing port, the second restrictors connect with the first restrictors, the dampers connect with the pressure chambers, and the nozzles connect with the dampers, and forming piezoelectric actuators on the upper substrate.
[0020] The method may further include forming a base mask on each of the three substrates, the base mark serving as an alignment reference in the bonding of the substrates. The ink introducing port, the pressure chambers, and the first restrictors may be formed by etching a lower surface of the upper substrate. Each of the upper substrate, intermediate substrate and lower substrate may be formed from a single crystal silicon wafer, the upper substrate is an SOI wafer including a first silicon substrate, an intermediate oxide film, and a second silicon substrate sequentially stacked, and forming the ink introducing port, the pressure chambers, and the first restrictors may include etching using the intermediate oxide film as an etch stop layer. Forming a manifold to a predetermined depth from a lower surface of the intermediate substrate, second restrictors connected to the manifold, and dampers passing through the intermediate substrate may include forming a first etch mask having a predetermined pattern on a lower surface of the intermediate substrate, forming the manifold and a lower portion of the dampers by etching the lower surface of the intermediate substrate to a predetermined depth using the first etch mask, forming a second etch mask having a predetermined pattern on an upper surface of the intermediate substrate, and forming the second restrictors and an upper portion of the dampers that is connected with the lower portion of the dampers by etching the upper surface of the intermediate substrate to a predetermined depth using the second etch mask.
[0021] Forming nozzles passing through the lower substrate may include forming ink guide parts connected with the dampers by etching an upper surface of the lower substrate to a predetermined depth, and forming ink ejection ports connected with the ink guide parts by etching a lower surface of the lower substrate. The lower substrate may be formed from a single crystal silicon wafer having a major surface parallel to a (100) crystal plane, and the ink guide parts may be formed to have inclined side surfaces by using an anisotropic etch process. The bonding of the three substrates may be performed by silicon direct bonding. The method may further include forming a silicon oxide film on the upper substrate before forming the piezoelectric actuators.
BRIEF DESCRIPTION OF THE DRAWINGS
[0022] The above and other features and advantages of the present invention will become more apparent by describing in detail exemplary embodiments thereof with reference to the attached drawings in which:
[0023] FIG. 1 illustrates the construction of a typical piezoelectric inkjet printhead;
[0024] FIG. 2 illustrates a conventional piezoelectric inkjet printhead;
[0025] FIG. 3 illustrates a view of another example of a piezoelectric inkjet printhead;
[0026] FIG. 4 illustrates a vertical sectional view of the piezoelectric inkjet printhead illustrated in FIG. 3 ;
[0027] FIG. 5 illustrates an exploded perspective view of a piezoelectric inkjet printhead according to an embodiment of the present invention;
[0028] FIG. 6 illustrates a partial sectional view of the printhead illustrated in FIG. 5 , taken along the lengthwise direction of the pressure chambers;
[0029] FIG. 7 illustrates a partial perspective view taken along a line A-A of FIG. 6 ;
[0030] FIG. 8 illustrates a plan view of the pressure chamber and the restrictor illustrated in FIG. 7 ;
[0031] FIG. 9 illustrates a plan view of a pressure chamber and a restrictor of a printhead according to a second embodiment of the present invention;
[0032] FIG. 10 illustrates a plan view of a pressure chamber and a restrictor of a printhead according to a third embodiment of the present invention;
[0033] FIG. 11 illustrates a partial sectional view of an inkjet printhead, taken along the lengthwise direction of the pressure chamber, according to a fourth embodiment of the present invention;
[0034] FIG. 12 illustrates a perspective view of the back side of a manifold of the intermediate substrate illustrated in FIG. 11 ;
[0035] FIG. 13 illustrates a plan view of a portion B illustrated in FIG. 12 ;
[0036] FIGS. 14A through 14E illustrate sectional views explaining operations of forming a base mark on an upper substrate in a method of manufacturing a piezoelectric type inject printhead according to the present invention;
[0037] FIGS. 15A through 15G illustrate sectional views explaining operations of forming a pressure chamber and a first restrictor on an upper substrate according to the present invention;
[0038] FIGS. 16A through 16D illustrate sectional views explaining operations of forming an ink introducing port on an upper substrate according to the present invention;
[0039] FIGS. 17A through 17H illustrate sectional views explaining operations of forming the second restrictor on an intermediate substrate according to the present invention;
[0040] FIGS. 18A through 18H illustrate sectional views explaining operations of forming a nozzle on a lower substrate according to the present invention;
[0041] FIG. 19 illustrates a sectional view of an operation of stacking a lower substrate, an intermediate substrate, and an upper substrate to bond the same according to the present invention; and
[0042] FIGS. 20A and 20B illustrate sectional views explaining operations of forming piezoelectric actuators on an upper substrate to complete a piezoelectric inkjet printhead according to the present invention.
DETAILED DESCRIPTION OF THE INVENTION
[0043] Korean Patent Application No. 10-2004-0079959, filed on Oct. 7, 2004, in the Korean Intellectual Property Office, and entitled: “Piezoelectric Type Inkjet Printhead and Method of Manufacturing the Same,” is incorporated by reference herein in its entirety.
[0044] The present invention will now be described more fully hereinafter with reference to the accompanying drawings, in which exemplary embodiments of the invention are shown. The invention may, however, be embodied in different forms and should not be construed as limited to the embodiments set forth herein. Rather, these embodiments are provided so that this disclosure will be thorough and complete, and will fully convey the scope of the invention to those skilled in the art. In the figures, the dimensions of layers and regions are exaggerated for clarity of illustration. It will also be understood that when a layer is referred to as being “on” another layer or substrate, it can be directly on the other layer or substrate, or intervening layers may also be present. Further, it will be understood that when a layer is referred to as being “under” another layer, it can be directly under, and one or more intervening layers may also be present. In addition, it will also be understood that when a layer is referred to as being “between” two layers, it can be the only layer between the two layers, or one or more intervening layers may also be present. Like reference numerals refer to like elements throughout.
[0045] FIG. 5 illustrates an exploded perspective view of a piezoelectric inkjet printhead according to an embodiment of the present invention, FIG. 6 illustrates a partial sectional view of the printhead illustrated in FIG. 5 , taken along the lengthwise direction of the pressure chambers, and FIG. 7 illustrates a partial perspective view taken along a line A-A of FIG. 6 .
[0046] Referring to FIGS. 5 through 7 , the piezoelectric type inkjet printhead may include three substrates 100 , 200 and 300 stacked and bonded together. Each of the three substrates may have elements constituting an ink channel thereon. Particularly, piezoelectric actuators 190 , for generating a driving force for use in ejecting ink, may be formed on the upper substrate 100 . Each of the three substrates 100 , 200 and 300 may be formed of a single-crystal silicon wafer to allow the formation of elements constituting an ink channel more precisely and easily on each of the three substrates 100 , 200 and 300 , e.g., by using micromachining technologies such as photolithography, etching, etc.
[0047] The ink channel may include an ink introducing port 110 , through which ink is introduced from an ink container (not shown), a manifold 210 , in which ink that has flowed through the ink introducing port 110 is stored, first and second restrictors 130 , 220 , for supplying ink from the manifold 210 to a pressure chamber 120 , the pressure chamber 120 filled with ink to be ejected and generating a pressure change to eject the ink, and a nozzle 310 for ejecting the ink. A damper 230 for concentrating energy generated from the pressure chamber 120 by the piezoelectric actuator 190 toward the nozzle 310 and for buffering a drastic pressure change may be formed between the pressure chamber 120 and the nozzle 310 . The elements constituting the ink channel may be distributed on the three substrates 100 , 200 and 300 as described above.
[0048] The pressure chambers 120 , which may have a predetermined depth, and the first restrictors 130 may be formed in the backside of the upper substrate 100 and the ink introducing port 110 may be formed on one side of the upper substrate 100 . The pressure chambers 120 may have a long, rectangular parallelepiped shape along a flow direction of ink and may be arranged in two columns, one on each side of a printhead chip along a lengthwise direction of the manifold 210 . The pressure chambers 120 may also be arranged in one column on one side of the printhead chip along the lengthwise direction of the manifold 210 . The first restrictor 130 provides a flow path that allows the ink from the manifold 210 to flow to the pressure chamber 120 . The first restrictor 130 may have a width smaller than that of the pressure chamber 120 and extends from the pressure chamber 120 to connect with the second restrictor 220 .
[0049] The upper substrate 100 may formed of, e.g., a single-crystal silicon wafer of the type widely used in manufacturing integrated circuits (ICs), and more particularly, may be formed of a silicon on insulator (SOI) wafer. The SOI wafer has a structure in which a first silicon substrate 101 , an intermediate oxide film 102 , and a second silicon substrate 103 are sequentially stacked. The first silicon substrate 101 is made of a single-crystal silicon and has a thickness of about hundreds of μm and the intermediate oxide film 102 may be formed by oxidizing the surface of the first silicon substrate 101 and may have a thickness of about 1-2 μm. The second silicon substrate 103 may also made of a single-crystal silicon and may have a thickness of about tens of μm.
[0050] By using a SOI wafer for the upper substrate 100 , the height of the pressure chamber 120 may be accurately controlled. That is, since the intermediate oxide film 102 , which constitutes an intermediate layer of the SOI wafer, may serve as an etch stop layer, when the thickness of the first silicon substrate 101 is determined, the height of the pressure chamber 120 is determined accordingly. Also, a thickness of the vibration plate may be determined by the thickness of the second silicon substrate 103 . In particular, the second silicon substrate 103 , where it forms the upper wall of the pressure chamber 120 , may be warp-deformed by the piezoelectric actuator 190 during operation, thus serving as a vibration plate that changes the volume of the pressure chamber 120 .
[0051] The piezoelectric actuators 190 may be disposed on the upper substrate 100 . A silicon oxide layer 180 may be formed as an insulation layer between the upper substrate 100 and the piezoelectric actuators 190 . The piezoelectric actuator 190 may have lower electrodes 191 and 192 serving as a common electrode, a piezoelectric thin film 193 that deforms when a voltage is applied, and an upper electrode 194 serving as a drive electrode. The lower electrodes 191 and 192 may be formed on the entire surface of the silicon oxide layer 180 and may be formed of two metal thin film layers including, e.g., a Ti-layer 191 and a Pt-layer 192 . The Ti-layer 191 and the Pt-layer 192 may serve not only as a common electrode but may also serve as a diffusion barrier layer to prevent inter-diffusion between the piezoelectric thin film 193 , on the Ti-layer 191 and the Pt-layer 192 , and the upper substrate 100 , beneath the Ti-layer 191 and the Pt-layer 192 . The upper electrode 194 may be formed on the piezoelectric thin film 193 and serve as a drive electrode for applying a voltage to the piezoelectric thin film 193 .
[0052] The piezoelectric thin film 193 may be formed on the lower electrodes 191 and 192 and may be disposed on the upper portion of the pressure chamber 120 . In operation, the piezoelectric thin film 193 is deformed by application of a voltage. Such deformation of the piezoelectric thin film 193 warp-deforms a portion of the second silicon substrate 103 , i.e., it warp-deforms the vibration plate of the upper substrate 100 that constitutes the upper wall of the pressure chamber 120 .
[0053] The intermediate substrate 200 may include the manifold 210 , which is a common channel connected with the ink introducing port 110 to supply ink, which flows through the ink introducing port 110 , to the pressure chambers 120 . The manifold 210 may be formed to a predetermined depth from the backside of the intermediate substrate 200 , so that a ceiling wall 217 of a predetermined thickness remains on the upper portion of the manifold 210 . That is, the lower end of the manifold 210 may be limited by the lower substrate 300 and the upper end of the manifold 210 may be limited by the ceiling wall 217 , which is the remaining portion of the intermediate substrate 200 .
[0054] As described above, when the pressure chambers 120 are arranged in two columns on both sides of a printhead chip along a lengthwise direction of the manifold 210 , a partition wall 215 may formed in a lengthwise direction inside of the manifold 210 . Thus, the manifold 210 may be divided into two regions, e.g., right and left regions, which is desirable for a smooth flow of the a and for preventing a crosstalk between the divided left and right regions of the manifold 210 when piezoelectric actuators 190 on both sides of the manifold 210 are driven.
[0055] The intermediate substrate 200 may have the second restrictor 220 , which may be a separate channel connecting the manifold 210 with the first restrictor 130 . The second restrictor 220 may be spaced apart from the partition wall 215 , pass through the intermediate substrate 200 , e.g., in a vertical direction, and have an exit communicating with the first restrictor 130 . The second restrictor 220 may not only supply an appropriate amount of ink from the manifold 210 to the pressure chamber 120 in cooperation with the first restrictor 130 , but may also prevent ink from flowing backward to the manifold 210 from the pressure chamber 120 when the ink is ejected.
[0056] A damper 230 may pass through the intermediate substrate 200 and may be formed, e.g., in a vertical direction, in a position that corresponds to one end of the pressure chamber 120 , so as to connect the pressure chamber 120 with the nozzle 310 .
[0057] The first restrictor 130 may extend from the pressure chamber 120 and may be formed in the upper substrate 100 and the second restrictor 220 may be formed in the intermediate substrate 200 such that it corresponds to the first restrictor 130 . With the above-described structure, the first and second restrictors 130 and 220 may be formed in a central portion of the intermediate substrate 200 . This may allow a greater amount of space for formation of the manifold 210 . In other words, one portion of the manifold 210 may have its sides defined by the partition wall 215 and by a wall having a predetermined interval relative to the damper 230 . The thickness of the wall formed by the interval relative to the damper 230 may be reduced in comparison to conventional inkjet printheads. Therefore, the width of the manifold 210 may be increased in comparison to conventional inkjet printheads.
[0058] When the width of the manifold 210 increases as described above, the volume thereof increases and thus crosstalk between the adjacent restrictors 130 and 220 may be reduced. In detail, if a pressure is applied to ink accommodated inside the pressure chamber 120 by the piezoelectric actuator 190 , i.e., when the ink is ejected, the pressure is also transferred to ink inside the restrictors 130 and 220 connected with the pressure chamber 120 . Further, the pressure is transferred to the manifold 210 connected with the restrictors 130 and 220 , so that crosstalk between the adjacent restrictors 130 and 220 may occur. In inkjet printheads according to the present invention, the volume of the manifold 210 may be increased so that the amount of the ink that can be accommodated inside the manifold 210 may be increased. Accordingly, the intensity of the pressure transferred through the restrictors 130 and 220 per unit volume of ink inside the manifold 210 may be reduced, such that the pressure is dispersively absorbed. Since the pressure may be dispersively absorbed, the intensity of the pressure influencing the restrictors 130 and 220 may be reduced, so that crosstalk between the adjacent restrictors 130 and 220 may also be reduced.
[0059] Also, as described above, when the width of the manifold 210 is increased, the cross-sectional area increases, so that the ink ejection may operate stably at a high frequency. In detail, when the piezoelectric thin film 193 is restored after an ink droplet is ejected from the nozzle 310 , the pressure within the pressure chamber 120 is reduced and ink stored in an ink container (not shown) flows into the pressure chamber 120 through the manifold 210 and the restrictor 130 and 220 , to thereby replace the ink that was ejected.
[0060] By increasing the cross-sectional area of the manifold 210 , a flow resistance of ink in the manifold 210 due to wall shear stress may be reduced so that ink inflow supplied through the manifold 210 is increased. Accordingly, the supply of ink under high-frequency ejection may be quickly realized. Thus, even though a large number of ink ejections may be performed in rapid sequence, the ink ejection can be stably performed by increasing the width of the manifold 210 .
[0061] A nozzle 310 may be formed that pierces the lower substrate 300 in a position that corresponds to the damper 230 . In detail, the nozzle 310 may be formed at the lower portion of the lower substrate 300 and may include an ink-ejection port 312 , for ejecting ink, and an ink guide part 311 that is formed at the upper portion of the lower substrate 300 . The ink guide part may serve to connect the damper 230 with the ink-ejection port 312 as well as pressurizing and guiding ink from the damper 230 to the ink-ejection port 312 . The ink-ejection port 312 may have a shape of, e.g., a vertical hole having a predetermined diameter, and the ink guide part 311 may have, e.g., a quadrangular pyramid shape, circular pyramid shape, etc., the cross-section of which tapers toward the ink-ejection port 312 . As described below, accordingl to the present invention, a quadrangular pyramid-shaped ink guide part 311 may be easily formed in a single-crystal silicon wafer-based lower substrate 300 .
[0062] As set forth above, the three substrates 100 , 200 and 300 , formed as described above, may be stacked and bonded to each other to yield a piezoelectric inkjet printhead according to the present invention. Thus, an ink channel including the ink introducing port 110 , the manifold 210 , the restrictors 130 and 220 , the pressure chamber 120 , the damper 230 and the nozzle 310 , sequentially connected, may be formed from the three substrates 100 , 200 and 300 .
[0063] In the operation of an inkjet printhead formed according to the present invention, ink may flow into the manifold 210 through the ink introducing port 110 from the ink container (not shown) and may be supplied to the inside of the pressure chamber 120 through the ink restrictors 130 and 220 . When a voltage is applied to the piezoelectric thin film 193 through the upper electrode 194 of the piezoelectric actuator 190 with the inside of the pressure chamber filled with the ink, the piezoelectric thin film 193 is deformed such that the second silicon substrate 103 , serving as a vibration plate, is warped downward. The volume of the pressure chamber 120 is reduced by the warp-deformation of the second silicon substrate 103 , which increases the pressure in the inside of the pressure chamber 120 , so that the ink in the inside of the pressure chamber 120 is ejected to the outside through the nozzle 310 by way of the damper 230 .
[0064] Subsequently, when the voltage applied to the piezoelectric thin film 193 of the piezoelectric actuator 190 is cut off, the piezoelectric thin film 193 is restored to its original state such that the second silicon substrate 103 serving as the vibration plate is restored to the original state and the volume of the pressure chamber 120 increases. The pressure within the pressure chamber 120 reduces and ink stored in the ink container (not shown) flows into of the pressure chamber 120 through the manifold 210 and the restrictor 130 and 220 to refill the ink in the pressure chamber 120 and thereby replace the ink that was ejected.
[0065] FIG. 8 illustrates a plan view of the pressure chamber and the restrictor illustrated in FIG. 7 , FIG. 9 illustrates a plan view of a pressure chamber and a restrictor of a printhead according to a second embodiment of the present invention, and FIG. 10 illustrates a plan view of a pressure chamber and a restrictor of a printhead according to a third embodiment of the present invention. As described above, for each of FIGS. 8-10 , the upper substrate 100 has the pressure chamber 120 as well as the first restrictor 130 connected to the pressure chamber 120 . The intermediate substrate 200 has the second restrictor 220 , which corresponds to the first restrictor 130 .
[0066] In the embodiment illustrated in FIG. 8 , a width of the second restrictor 220 in the width direction of the pressure chamber 120 is smaller than that of the first restrictor 130 (as illustrated, the width direction of the pressure chamber 120 is defined in a vertical direction in FIG. 8 ). In this embodiment, even when an alignment error is generated between the upper substrate 100 and the intermediated substrate 200 , the exit of the second restrictor 220 can be completely open and unobscured where it interfaces with the first restrictor 130 .
[0067] In the embodiment illustrated in FIG. 9 , the width of the second restrictor 220 in the width direction of the pressure chamber 120 is greater than that of the first restrictor 130 . In this embodiment, even when an alignment error is generated between the upper substrate 100 and the intermediated substrate 200 , the exit of the second restrictor 220 can be unaffected where it interfaces with the first restrictor 130 . That is, an alignment error may have little or no effect on the area of the interface, i.e., the size of the opening, at the interface between the first and second restrictors 120 , 130 .
[0068] In the embodiment illustrated in FIG. 9 , the width of the second restrictor 220 in the width direction of the pressure chamber 120 is smaller than that of the first restrictor 130 , but is increased relative to the embodiment illustratrated in FIG. 8 . Also, the width of the first restrictor 130 is increased so as to remain greater than the increased width of the second restrictor 220 . The width of a portion of the first restrictor 130 where it interfaces with the second restrictor 220 may be less than, equal to, or greater than the width of the pressure chamber 120 . In this embodiment, even when an alignment error is generated between the upper substrate 100 and the intermediate substrate 200 , the exit of the second restrictor 220 can be completely open and unobscured where it interfaces with the first restrictor 130 . In addition to the embodiments just described, a variety of embodiments in which the exit of the second restrictor 220 can be open to the necessary degree in the direction of the first restrictor 130 are envisioned, and the present invention is not limited to the orientations and relative widths described above.
[0069] FIG. 11 illustrates a partial sectional view of an inkjet printhead, taken along the lengthwise direction of the pressure chamber, according to a fourth embodiment of the present invention, FIG. 12 illustrates a perspective view of the back side of a manifold of the intermediate substrate illustrated in FIG. 11 and FIG. 13 illustrates a plan view of a portion B illustrated in FIG. 12 . For the embodiment illustrated in FIGS. 11-13 , the intermediate substrate 200 has both a support pillar 250 and a blocking wall 260 inside the manifold 210 , although these elements need not be used in conjunction. Thus, they are illustrated together merely for ease of description.
[0070] The support pillar 250 may support the ceiling wall 217 of the manifold 210 . That is, the support pillar 250 may extend from a surface of the intermediate substrate that defines an upper surface of the manifold. Detailing the operation of this embodiment, pressure transferred from the pressure chamber 120 may be sufficient to deform the manifold 210 inwardly. That is, the ceiling wall 217 of the manifold 210 may be deformed, resulting in a decrease in volume of the manifold 210 and possible concommitant undesired expulsion of ink. The support pillar 250 may support the ceiling wall 217 of the manifold 210 to prevent this deformation of the ceiling wall 217 . The support pillar 250 may protrude from the ceiling wall 217 of the manifold 210 and may contact a lower substrate 300 to support the ceiling wall 217 of the manifold 210 . A plurality of support pillars 250 may be provided as necessary to efficiently support the ceiling wall of the manifold 210 . Also, the support pillar 250 may have a shape and/or arrangement such that ink flowing in the inside of the manifold 210 is not hindered.
[0071] The blocking wall 260 may serve as a blocking object to reduce crosstalk between the second restrictors 230 . In detail, referring to FIG. 13 , the blocking wall 260 is disposed between adjacent second restrictors 230 to reduce the influence of pressure transferred through the second restrictors 230 . Therefore, the crosstalk occurring between adjacent second restrictors 230 may be reduced. The blocking wall 260 may be formed of sufficient length as compared to the length of the second restrictor 230 so as to effectively reduce crosstalk interference between the second restrictors 230 .
[0072] Hereinafter, a method of manufacturing the a piezoelectric inkjet printhead according to the present invention will be described. As a general matter, the upper substrate, the intermediate substrate, and the lower substrate having the elements constituting the ink channel may be manufactured and subsequently stacked to be bonded to each other and one or more piezoelectric actuators may be formed on the upper substrate. Of course, the operations of manufacturing the upper substrate, the intermediate substrate, and the lower substrate can be performed in any order, such that the lower substrate or the intermediate substrate may be manufactured first, or two or three substrates can be simultaneously manufactured, etc. In the description that follows, the manufacturing method will be described in order of the upper substrate, the intermediate substrate, and the lower substrate, but this order is simply a matter of convenience in description.
[0073] FIGS. 14A through 14E illustrate sectional views explaining operations of forming a base mark on an upper substrate in a method of manufacturing a piezoelectric type inject printhead according to the present invention. Referring to FIG. 14A , the upper substrate 100 may be formed of a single-crystal silicon substrate. By using a single-crystal silicon substrate, widely used manufacturing techniques, e.g., those used to manufacture semiconductor devices, may be employed, thus allowing for efficient mass production. The thickness of the upper substrate 100 may be about 100-200 μm and may be determined to correspond to the height of the pressure chamber 120 that will be formed on the backside of the upper substrate 100 . When an SOI wafer is used for the upper substrate 100 , the height of the pressure chamber 120 may be accurately formed. As described above, the SOI wafer has a stacked structure including the first silicon substrate 101 , the intermediate oxide film 102 stacked or formed on the first silicon substrate 101 , and the second silicon substrate 103 bonded to or formed on the intermediate oxide film 102 . As illustrated in FIG. 14A , silicon oxide films 151 a, b , may be formed on the upper and lower, i.e., backside, surfaces of upper substrate 100 by, e.g., using an oxidization furnace to wet-oxidize or dry-oxidize the upper substrate 100 .
[0074] Referring to FIG. 14B , a photoresist (PR) may be spread on the surfaces of the silicon oxide films 151 a and 151 b . Subsequently, the spread PR may be exposed and developed so as to form an opening 141 to be used in forming a base mark in an edge portion of the upper substrate 100 . Referring to FIG. 14C , the portion of the silicon oxide films 151 a and 151 b exposed by the opening 141 may be removed through, e.g., a wet-etching process, using the PR for an etch-mask, so that the upper substrate 100 is partially exposed. Once completed, the remaining PR may be stripped.
[0075] Referring to FIG. 14D , the exposed portion of upper substrate 100 may be removed by, e.g., a wet etch process, to a predetermined depth, wherein the silicon oxide films 151 a and 151 b serve as an etch-mask, to thereby form a base mark 140 . At this point, a Tetramethyl Ammonium Hydroxide (TMAH) can be used for etchant for silicon in wet-etching the upper substrate 100 . After the base mark 140 is formed, the remaining silicon oxide films 151 a and 151 b may be removed by, e.g., a wet etch process. In this way, any contamination formed during the above processes can be removed as well.
[0076] Referring to FIG. 14E , process described above may be used to form the upper substrate 100 having the base mark 140 formed on the edge portion of the upper surface and the backside of the upper substrate 100 . The base mark 140 may be used in accurately aligning the upper substrate 100 , the intermediate substrate 200 and a lower substrate 300 , when stacking and bonding these substrates. It will be understood that the upper substrate 100 may have the base mark 140 on only the lower, or backside, thereof, or an alignment method or apparatus may be used in which the base mark 140 is not required. Accordingly, the above-described processes may be employed as the situation requires and the present invention is not limited thereby.
[0077] FIGS. 15A through 15G illustrate sectional views explaining operations of forming a pressure chamber and a first restrictor on an upper substrate according to the present invention. Referring to FIG. 15A , the upper substrate 100 , prepared by, e.g., the processes set forth above, may be oxidized to form silicon oxide films 152 a, b , on the upper and lower (backside) surfaces of the upper substrate 100 by, e.g., placing the upper substrate 100 in oxidation furnace, wet-etching, dry-etching, etc. Alternatively, the silicon oxide film 152 b alone may be formed, i.e., the upper substrate 100 may be oxidized only on its backside.
[0078] Referring to FIG. 15B , a second PR may be spread on the surface of the silicon oxide film 152 b . The spread PR may be exposed and developed so as to form an opening 121 for forming a pressure chamber and a first restrictor on the backside of the upper substrate 100 . Referring to FIG. 15C , the backside of the upper substrate 100 may be partially exposed by removing the portion of the silicon oxide film 152 b exposed by the opening 121 through, e.g., a dry etch process such as reactive-ion-etching (RIE), while using the PR for an etch mask.
[0079] Referring to FIG. 15D , the exposed portion of the upper substrate 100 may be etched to a predetermined depth using a PR for an etch-mask to form the pressure chamber 120 and the first restrictor 130 and using the intermediate oxide film 102 as an etch stop layer. Etching of the upper substrate 100 may be performed by, e.g., dry etching using a process such as inductively coupled plasma (ICP). The depth of the features formed at this point may be determined by the thickness of the first silicon substrate 101 , allowing for a precise predetermination of their depth.
[0080] In detail, when an SOI wafer is used for the upper substrate 100 as illustrated, since the intermediate oxide film 102 of the SOI wafer serves as an etch-stop layer, only the first silicon substrate 101 is etched at this stage. Accordingly, when the thickness of the first silicon substrate 101 is controlled, the pressure chamber 120 and the first restrictor 130 may be accurately controlled to a desired height. The thickness of the first silicon substrate 101 may be easily controlled during a wafer polishing process. Further, the second silicon substrate 103 constituting the upper wall of the pressure chamber 120 serves as the vibration plate as described above and the thickness thereof can be also easily controlled during the wafer polishing process.
[0081] FIG. 15E represents the upper substrate 100 after the PR is stripped after the pressure chamber 120 and the first restrictor 130 are formed. Note that, at this stage, contaminants such as a by-product or polymer produced during the above-described wet-etching or dry-etching using RIE, ICP, etc., may attach on the surface of the upper surface 100 . Therefore, the entire surface of the upper substrate 100 may be washed using, e.g., a tetramethyl ammonium hydroxide (TMAH) wash to remove the contaminants. The remaining silicon oxide films 152 a and 152 b may also be removed at this stage by, e.g., a wet etch process.
[0082] Referring to FIG. 15F , the upper substrate 100 having a base mark 140 formed in the edge portions of the upper surface and the backside, the pressure chamber 120 , and the first restrictor 130 formed in the backside, have been prepared. After the pressure chamber 120 and the first restrictor 130 are formed by, e.g., dry etching the upper substrate 100 using the PR for the etch-mask, the PR is stripped. However, unlike the above process, the pressure chamber 120 and the first restrictor 130 may be formed by dry-etching the upper substrate 100 using the silicon oxide film 152 b for the etch-mask after the PR is stripped first. That is, in the case where the silicon oxide film 152 b formed on the backside of the upper substrate 100 is relatively thin, the etching process that forms the pressure chamber 120 and the first restrictor 130 may be performed with the PR in place. Otherwise, in the case where the silicon oxide film 152 b is relatively thick, the etching may be performed using the silicon oxide film 152 b for the etch-mask, after the PR has been stripped.
[0083] Referring to FIG. 15G , silicon oxide films 153 a and 153 b may be further formed on the upper surface and the backside of the upper substrate 100 illustrated in FIG. 15F (note that, if the silicon oxide films 153 a and 153 b are formed, an operation, described below, of forming a silicon oxide layer 180 as an insulation film on the upper substrate 100 can be omitted). When the silicon oxide film 153 b is formed on the inside of the pressure chamber 120 and the first restrictor 130 , the silicon oxide film 153 b does not react to most kinds of ink due to the characteristic of the silicon oxide film 153 b , so that a variety of ink can be used.
[0084] FIGS. 16A through 16D illustrate sectional views explaining operations of forming an ink introducing port on an upper substrate according to the present invention. Referring to FIG. 16A , the ink introducing port 110 may be formed together with the pressure chamber 120 by the operations illustrated in FIGS. 15A through 15G . Next, referring to FIG. 16B , a PR may be spread on the surface of the silicon oxide film 152 a , exposed and developed, so as to form an opening 111 that may be used to piercing the ink introducing port 110 through the upper surface of the upper substrate 100 .
[0085] Referring to FIG. 16C , the upper surface of the upper substrate 100 may be partially exposed by removing the portion of the silicon oxide film 152 a exposed by the opening 111 through, e.g., a dry etching process such as a reactive-ion-etching (RIE), using the PR for an etch mask. Referring to FIG. 16D , the exposed portion of the upper substrate 100 may be etched to a predetermined depth using the PR for an etch mask, after which the PR may be stripped. Etching of the upper substrate 100 may be performed by, e.g., a dry etch process such as ICP. Of course, the upper substrate 100 may be etched using the silicon oxide film 152 a for an etch mask after having first removed the PR.
[0086] The intermediate oxide film 102 of the SOI wafer may serve as an etch-stop layer in the etching of the upper substrate 100 , such that only the second silicon substrate 103 is etched and the intermediate oxide film 102 remains in the ink introducing port 110 . The remaining intermediate oxide film 102 may be removed by processes such as those as described above to pierce the upper substrate and thereby complete the ink introducing port 110 . The upper substrate 100 may be completed by the operations illustrated in FIGS. 15F and 15G , as described above.
[0087] It will be understood that the formation of the ink introducing port on the upper substrate 100 may be performed after forming the piezoelectric actuator. That is, part of the lower portion of the ink introducing port 110 may be formed together with the pressure chamber 120 by the operations illustrated in FIGS. 15A through 15G . In the operation illustrated in FIG. 15E , the pressure chamber 120 of a predetermined depth and part of the ink introducing port 110 of the same depth as the pressure chamber 120 may be formed on the backside of the upper substrate 100 . The ink introducing port 110 formed at a predetermined depth in the backside of the upper substrate 100 may be formed so as to connect with an ink storage (not shown) through a post processing of piercing the upper substrate 100 after processes of bonding the substrates and installing the piezoelectric actuator thereon are completed. That is, the piercing of the ink introducing port 100 may be performed after the operation of forming the piezoelectric actuator is completed.
[0088] FIGS. 17A through 17H illustrate sectional views explaining operations of forming the second restrictor on an intermediate substrate according to the present invention. Referring to FIG. 17A , the intermediate substrate 200 may be formed of a single-crystal silicon substrate and has a thickness of 200-300 μm. The thickness of the intermediate substrate 200 may be determined according to the dimensions of the manifold 210 and the damper 230 .
[0089] A base mark 240 may be formed on the edge portions of the upper and lower, i.e., backside, surfaces of the intermediate substrate 200 . Since operations of forming the base mark 240 on the intermediate substrate 200 may be the same as the operations illustrated in FIGS. 14A through 14E , a detailed description thereof will be omitted. When the intermediate substrate 200 having the base mark 240 formed thereon is put into an oxidation furnace so as to wet-oxidize or dry-oxidize the intermediate substrate 200 , the upper surface and the backside of the intermediate substrate 200 may be oxidized as illustrated in FIG. 17A to form the silicon oxide films 251 a and 251 b . Referring to FIG. 17B , a PR may be spread on the surface of the silicon oxide film 251 b . Subsequently, the PR may be exposed and developed to form an opening 211 for forming the manifold 210 and an opening 231 for forming the damper 230 on the backside of the intermediate substrate 200 .
[0090] Referring to FIG. 17C , the backside of the intermediate substrate 200 may be partially exposed by removing the portion of the silicon oxide film 251 b exposed by the openings 211 and 231 through, e.g., a wet etch process, using a PR for an etch-mask, after which the PR may be stripped. Referring to FIG. 17D , the exposed portion of the intermediate substrate 200 may be removed, e.g., through a wet etch process, to a predetermined depth using the silicon oxide films 251 b for an etch-mask so as to form the lower portions of the manifold 210 and the damper 232 . TMAH may be used as an etchant for silicon in wet-etching the intermediate substrate 200 .
[0091] Referring to FIG. 17E , a PR may be spread on the surface of the silicon oxide film 251 a . Subsequently, the PR may be exposed and developed to form an opening 221 for forming the second restrictor 220 and an opening 233 used in forming the upper portion of the damper 230 on the upper surface of the intermediate substrate 200 . Referring to FIG. 17F , the upper surface of the intermediate substrate 200 may be partially exposed by removing the portion of the silicon oxide film 251 a exposed by the openings 221 and 233 through, e.g., a wet etch process, to a predetermined depth using the PR for an etch-mask, after which the PR may be stripped.
[0092] Referring to FIG. 17G , the exposed portion of the intermediate substrate 200 may be removed through, e.g., a wet etch process, to a predetermined depth using the silicon oxide films 251 a for an etchmask to form the second restrictor 220 and the damper 230 that passes through the lower portion of the damper of FIG. 17D . After removing the remaining silicon oxide films 251 a and 251 b by, e.g., a wet etch process, the intermediate substrate 200 having the base mark 240 , the second restrictor 220 , the manifold 210 , the partition wall 215 , and the damper 230 , may be produced as illustrated in FIG. 17H . Though not shown, a silicon oxide film may again be formed on the entire backside of the upper surface of the intermediate substrate 200 illustrated in FIG. 17H .
[0093] FIGS. 18A through 18H illustrate sectional views explaining operations of forming a nozzle on a lower substrate according to the present invention. Referring to FIG. 18A , the lower substrate 300 may be formed of a single-crystal silicon substrate and may have a thickness of 100-200 μm. A base mark 340 may be formed on the edge portions of the upper surface and the backside of the lower substrate 300 . Since operations of forming the base mark 340 on the lower substrate 300 may be the same as the operations illustrated in FIGS. 14A through 14E , detailed description thereof will be omitted. The lower substrate 200 , having the base mark 340 formed thereon, may be put into an oxidation furnace to wet-oxidize or dry-oxidize the upper surface and the backside of the lower substrate 300 , as illustrated in FIG. 18A , to form silicon oxide films 351 a and 351 b.
[0094] Referring to FIG. 18B , a PR may be spread on the surface of the silicon oxide film 351 a , exposed and developed to form an opening 315 , for an ink guide part 311 of the nozzle 310 , on the upper surface of the lower substrate 300 . The opening 315 may be formed at a position that corresponds the damper 230 formed in the intermediate substrate 200 illustrated in FIG. 17H . Referring to FIG. 18C , the upper surface of the lower substrate 300 may be partially exposed by removing the portion of the silicon oxide film 351 a exposed by the opening 315 through, e.g., a wet etch process, to a predetermined depth using the PR for an etch-mask, after which the PR may be stripped. The silicon oxide film 351 a may be removed by a dry etch process such as RIE.
[0095] Referring to FIG. 18D , the exposed portion of the lower substrate 300 may be removed by, e.g., a wet etch process, to a predetermined depth using the silicon oxide films 351 a for an etch-mask so as to form an ink guide part 311 . TMAH may be used for etchant in wet-etching the lower substrate 300 . When a silicon substrate having a (100) crystal face is used for the lower substrate 300 , the ink guide part 311 having a quadrangular pyramid shape may be formed using an anisotropic wet etch process. In detail, since the etch speed of the crystallize face (111) is considerably slow compared with that of the crystallize face (100), the lower substrate 300 may be effectively wet etched to yield inclined surfaces along the (111) crystal face, thereby formin the ink guide part 311 having the quadrangular pyramid shape. As illustrated, the (100) crystal face becomes the bottom of the ink guide part 311 .
[0096] Referring to FIG. 18E , a PR may be spread on the surface of the silicon oxide film 351 b , exposed and developed to form an opening 316 for an ink ejection port 312 of the nozzle 310 . Referring to FIG. 18F , the backside of the lower substrate 300 may be partially exposed by removing the portion of the silicon oxide film 351 b exposed by the opening 316 through, e.g., a wet etch process, using the PR for an etch mask. The silicon oxide film 351 b may be removed by a dry etch process such as RIE.
[0097] Referring to FIG. 18G , the exposed portion of the lower substrate 300 may be etched to pierce the lower substrate 300 using the PR for an etchmask, so that the ink ejection port 312 connected with the ink guide part 311 may be formed. The etching of the lower substrate 300 may be performed by, e.g., a dry etch process using an ICP. Subsequently, when the PR is stripped, the lower substrate 300 having the base mark 340 on the edge portions of the upper surface and the backside of the lower substrate, and the nozzle 310 consisting of the ink guide part 311 and the ink ejection port 312 formed in the lower substrate 300 is produced as illustrated in FIG. 18H . The nozzle 310 pierces the lower substrate 300 .
[0098] The silicon oxide films 351 a and 351 b formed on the upper surface and the backside of the lower substrate 300 , respectively, may be removed for washing, i.e., to rid the surfaces of contaminants, and, subsequently, a new silicon oxide film can be formed again on the entire surface of the lower substrate 300 .
[0099] FIG. 19 illustrates a sectional view of an operation of stacking a lower substrate, an intermediate substrate, and an upper substrate to bond the same according to the present invention. Referring to FIG. 19 , the lower substrate 300 , the intermediate substrate 200 , and the upper substrate 100 prepared by, e.g., the above-described processes, may be sequentially stacked and bonded to each other. After the intermediate substrate 200 is bonded on the lower substrate 300 , the upper substrate 300 may bonded on the intermediate substrate 200 , although the bonding order can be changed. The three substrates 100 , 200 and 300 may be aligned using a mask aligner. Since the base marks 140 , 240 and 340 for alignment are formed in each of the three substrates 100 , 200 and 300 , a highly accurate alignment may be achieved during the bonding process.
[0100] The bonding of the three substrates 100 , 200 and 300 may be performed by, e.g., silicon direct bonding (SDB). In the SDB process, silicon-silicon oxide bonding is superior to silicon-silicon bonding. Therefore, referring to FIG. 19 , the upper substrate 100 and the lower substrate 300 are used with the silicon oxide films 153 a , 153 b , 351 a and 351 b formed on the surfaces thereof, while the intermediate substrate 200 does not have a silicon oxide film on the surface thereof.
[0101] FIGS. 20A and 20B illustrate sectional views explaining operations of forming piezoelectric actuators on an upper substrate to complete a piezoelectric inkjet printhead according to the present invention. Referring to FIG. 20A , with the lower substrate 100 , the intermediate substrate 200 , and the upper substrate 300 sequentially stacked and bonded, a silicon oxide layer 180 as an insulation film may be formed on the upper surface of the upper substrate 100 , athough this operation may be omitted. That is, in the case where the silicon oxide film 153 a is already formed on the upper surface of the upper surface 100 , as illustrated in FIG. 19 , or in the case where an oxide film of a sufficient thickness is already formed on the upper surface of the upper substrate 100 , e.g., in the operation of annealing during the above-described SDB process, the silicon oxide layer 180 illustrated in FIG. 20A doesn't need to be formed thereon.
[0102] Lower electrodes 191 and 192 of the piezoelectric actuator may be formed on the silicon oxide layer 180 . The lower electrodes may include two metal thin layers, e.g., a titanium (Ti) layer 191 and a platinum (Pt) layer 192 . The Ti-layer 191 and the Pt-layer 192 may be formed on the entire surface of the silicon oxide layer 180 by, e.g., sputtering to a predetermined thickness. The Ti-layer 191 and the Pt-layer 192 may serve not only as a common electrode of the piezoelectric actuator, but also serve as a diffusion barrier layer that prevents inter-diffusion between the piezoelectric thin film 193 on the Ti-layer 191 and the Pt-layer 192 and the upper substrates 100 beneath the Ti-layer 191 and the Pt-layer. Particularly, the Ti-layer 191 at the lower portion increases adhesiveness of the Pt-layer 192 .
[0103] Referring to FIG. 20B , a piezoelectric thin film 193 and an upper electrode 194 may be formed on the lower electrode 191 and 192 . In detail, a piezoelectric material in a paste state may be spread to a predetermined thickness on the upper portion of the pressure chamber 120 using, e.g., screen printing, and then dried for a predetermined period of time. The piezoelectric material can be various materials, e.g., a general lead zirconate titanate (PZT) ceramic material. Subsequently, an electrode material, e.g., a gold-palladium (Ag—Pd) paste may be printed on the dried piezoelectric thin film 193 . The piezoelectric thin film 193 may then be sintered under a predetermined temperature, e.g., a temperature range of 900-1,000° C. The above-described Ti-layer 191 and Pt-layer 192 may act as diffusion barriers to prevent any inter-diffusion between the piezoelectric thin film 193 and the upper substrate 100 that might be generated during a high-temperature sintering process. Thus, the piezoelectric actuator 190 consisting of the lower electrodes 191 and 192 , the piezoelectric thin film 193 and the upper electrode 194 may be formed.
[0104] Since the sintering of the piezoelectric thin film 193 may performed in an open atmosphere, a silicon oxide film may be formed on the inside of the ink channel formed by the three substrates 100 , 200 and 300 during sintering. Since the silicon oxide film formed in this manner does not react to most kinds of ink, a variety of ink may be used. Also, since the silicon oxide film has a hydrophilic property, inflow of air bubbles into the ink flow path when ink is initially filled in the ink channel may be prevented and air bubble generation may be suppressed when the ink is ejected.
[0105] A dicing process, cutting off the three bonded substrates 100 , 200 , and 300 by chip unit, and a polling process of applying an electric field to the piezoelectric thin film 193 to generate a piezoelectric characteristic may be used in completing the piezoelectric inkjet printhead of the present invention. Of course, dicing may be performed before the sintering process of the piezoelectric thin film 193 .
[0106] While described above in detail in order to ensure a thorough understanding of the present invention, the method described herein for forming the respective elements of the printhead is merely exemplary and does not limit the present invention. For example, those skilled in the art will appreciate that various etching methods may be adopted and the order for the respective operations may be changed.
[0107] According to the piezoelectric inkjet printhead and the method of manufacturing the same of the present invention, it is possible to easily increase the width of the manifold by processing the backside of the intermediate substrate so as to form the manifold and install the manifold in the lower portion of the pressure chamber. Therefore, the volume of the manifold may be increase and the amount of ink accommodated therein similarly increased, so that pressure transferred to the inside of the manifold may be dispersively absorbed. Accordingly, when ink droplets are simultaneously ejected from the nozzles, crosstalk between adjacent restrictors may be reduced. Also, by increasing the width of the manifold, the cross-sectional area thereof is similarly increased and, thus, the flow resistance of the manifold is reduced. Accordingly, the amount of ink supply may be increased during the ink refill process that replaces the ejected ink and the printhead can stably operate even when ejecting ink at high-frequencies.
[0108] Further, according to the present invention, since the manifold may be formed below the lower portion of the pressure chamber and the first restrictor, with the manifold ceiling wall interposed therebetween, the substrate may save space to the extent that the width of the manifold in the arrangement of elements constituting an ink channel, and the chip size of printhead may be reduced. Therefore, the number of chips obtained per wafer may be increased, improving productivity.
[0109] Exemplary embodiments of the present invention have been disclosed herein, and although specific terms are employed, they are used and are to be interpreted in a generic and descriptive sense only and not for purpose of limitation. Accordingly, it will be understood by those of ordinary skill in the art that various changes in form and details may be made without departing from the spirit and scope of the present invention as set forth in the following claims.
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A piezoelectric inkjet printhead capable of reducing a crosstalk and a method of manufacturing the same are provided. The inkjet printhead includes an upper substrate, an intermediate substrate, and a lower substrate that are sequentially stacked, wherein the upper substrate includes piezoelectric actuators on an upper surface of the upper substrate and pressure chambers and first restrictors on a lower surface of the upper substrate, the first restrictors extending from the pressure chambers and having a width smaller than a width of the pressure chambers, the intermediate substrate includes dampers passing therethrough, the dampers corresponding to the pressure chambers and second restrictors extending between the first restrictors and a manifold formed from a lower surface of the intermediate substrate and the lower substrate includes nozzles passing therethrough, the nozzles corresponding to the dampers.
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RELATED APPLICATIONS
[0001] This application claims priority to U.S. Provisional Application Ser. No. 62/234,543 filed Sep. 29, 2015, entitled UV and High Energy Visible Absorbing Ophthalmic Lenses, which is hereby incorporated herein by reference in its entirety.
FIELD OF THE INVENTION
[0002] The present invention relates to light absorbing filters, e.g. optical films, laminates, and lenses, and more particularly, to optical filters that absorb harmful ultraviolet and/or high energy visible light.
BACKGROUND OF THE INVENTION
[0003] It is known in the art to use additives to absorb harmful wavelengths of light, including UV light with wavelengths between 280 nm and 380 nm under ANSI standards and 400 nm under other (AUS/NZ) standards. More recently, it has become apparent that HEV (high energy visible) light which is characterized as having wavelengths from 400 nm up to 500 nm, also poses possible damage threats to living tissues or the eyes. This light range has also been attributed to other biological factors such as impacts on circadian rhythms.
[0004] As the absorbed wavelengths of light begin to ingress upon the visible light wavelengths, the result is a visible coloration that under most circumstances is undesirable and due to the blocking of predominantly blue wavelengths, results in a yellow colour or transmission through the absorbing article.
[0005] In general terms, the lower the wavelength of the light, the higher the energy of the photon, and so the greater the possible cellular damage. Light in these wavelengths carries sufficient energy to break chemical bonds, causing damage to the substrates that absorb this light. These substrates can be of biological origin or other so called organic materials, the latter being defined as compounds consisting predominately of carbon based materials such as synthetic polymers used ubiquitously to make articles of commercial value.
[0006] When bonds within inanimate substrates are broken, the primary effect is characterized as a loss of mechanical properties or a change in colour. When bonds within living biological tissue are broken, the tissue damage manifests in a degradation or loss of function that can include lesions and burns, damage to genetic material, degradation of vision, and so forth, effects generally leading to decline of the organism's health and potentially shortening its life.
[0007] The same types of additives that find use in protection of non-living materials can also be effective in protection of living tissue. For example, materials known as sun-screens are widely sold as lotions and creams for topical application to exposed skin tissue, absorbing the harmful rays from the sun and protecting the exposed skin tissue from damage.
[0008] Compounds most useful in protection against harmful UV and HEV radiation strongly absorb light in these damaging wavelengths, and typically contain one or more structural features with extended π-electron clouds, more accurately described as compounds with formal unsaturation or multiple bonds between individual adjacent atoms alternately separated by single bonds between adjacent atoms. Generic structures meeting this broad description generally contain so-called aromatic groups, the parent structure being represented by benzene. Other arrays of atoms can serve as the basis for their structures, including extended linear or cyclic arrays of alternating carbon to carbon double and single bonds, particularly where one or more carbon atoms is replaced by a heteroatom such as nitrogen, oxygen or sulphur. The wavelengths absorbed by these structures can be tuned by the number, type, and arrangement of the constituent atoms, including adjoined (fused) rings and the presence of substituent heteroatoms not involved in the extended system of multiple bonds, which atoms possess unshared (lone or non-bonding) pairs of electrons. Such heteroatoms include but are not limited to nitrogen, oxygen and sulfur, and halogens, particularly chlorine.
[0009] The most useful structures for UV and HEV absorption have a mechanism whereby they can harmlessly “dump” the energy they absorb from the incident light by a reversible transformation of the electronic excited state formed (by light absorption) as heat through atomic motion, more correctly, through transfer of a neutral hydrogen atom (H) or a proton (H + ), from one bonding partner to another, for example between oxygen and nitrogen appropriately arrayed in space, by a process known as tautomerization, a formal rearrangement of atoms and electrons through shifting of single and double bonds. An example of such tautomerization is shown in FIG. 1
[0010] In the above example, the hydrogen atom transfers from the oxygen atom in the ground state to the neighbouring nitrogen atom in the excited state, accompanied by a shift of π-electrons, and back again with liberation of heat and resulting in no net change to the original structure. Such hydrogen atom transfers or migrations are thought to occur because of increased acidity of the group containing the hydrogen atom in the excited state, such that the basicity of the neighboring heteroatom is strong enough to abstract the hydrogen atom or proton to form a new neutral structure, which may also be represented as one in which there are neighbouring opposite charges in the structure, also called a betaine. Other structures can be drawn where the hydrogen atom transfers in the opposite sense from a nitrogen atom in the ground state to an oxygen atom in the excited state and between two appropriately positioned oxygen or nitrogen atoms.
[0011] Other structures are known where the likely energy conversion is accomplished by breaking of a double bond to form two adjacent stabilized radicals, allowing “free” rotation of the newly generated single bond between these two adjacent free radical centers, with ultimate reformation of the double bond and again, with no net change to the molecular structure. An example of such reaction is shown in FIG. 2 .
[0012] Such materials can be used separately or in combination with an array of different substituents around the structure, which substituents are selected on the basis of their ability to modify the wavelengths of light absorbed, the stability of the excited state intermediates, and their effects on the solubility or compatibility of the resultant ground state structures in or with the media in which they are dissolved. There is a wide range of commercially available compounds possessing these key reversible structural characteristics, sold as stabilizing additives.
[0013] However, there is a need in the ophthalmic field for optimization of eye protection against harmful UV and HEV light in eye wear that is cosmetically acceptable or desirable and, hence, commercially successful.
OBJECTS AND SUMMARY OF THE INVENTION
[0014] The present invention provides for the optimization of eye protection against harmful UV and HEV light in eye wear that is cosmetically acceptable or desirable. These objectives are, in part, achieved through providing an ophthalmic article comprising a light absorbing layer having a weight percent of a light absorbing compound in the range of 0.1 to 10 and a transmittance of no more than 50 percent of light having wavelengths of up to 443 nm.
[0015] In certain embodiments of the present invention, the light absorbing layer has a weigh percent of a light absorbing compound of up to 3 or of up to 1. In certain embodiments of the present invention, the light absorbing layer has a thickness of greater than 1 mm or 0.01 to 1 mm. In certain embodiments of the present invention, the light absorbing layer has a transmittance of no more than 50 percent of light having wavelengths of up to 410 nm. In certain embodiments of the present invention, the light absorbing layer is a monolithic film, an adhesive layer of a laminate, a component of a composite ophthalmic lens, a thermoplastic resin, or a curable composition.
[0016] These objectives are, in part, further achieved through providing a method for forming an ophthalmic article comprising: determining a target transmittance of light below a wavelength of 450 nm for the ophthalmic article; determining a target range of thickness of the ophthalmic article; adding a weight percent of a light absorbing compound to a medium based upon the target transmittance, the target range of thickness, and a target CIE color coordinate for the ophthalmic article; and forming the ophthalmic article with medium containing the light absorbing compound.
[0017] In certain embodiments of the present invention, the determining a target transmittance comprises determining a target transmittance of less than 50 percent or determining a transmittance of not more than 50 percent of light having a wavelength of up to 410 nm. In certain embodiments of the present invention, determining a target range of thickness comprises determining a thickness of greater than 1 mm or a thickness in the range of 0.01 to 1 mm. In certain embodiments of the present invention, the adding a weight percent of a light absorbing compound to a medium comprises adding a weigh percent of the light absorbing compound in the range of 1 to 10. In certain embodiments of the present invention, the forming the ophthalmic article comprises forming the ophthalmic article through injection molding of a molten thermoplastic, forming the ophthalmic article through curing of a curable composition, or forming of a composite ophthalmic article having a layer of the medium containing the light absorbing compound.
BRIEF DESCRIPTION OF THE DRAWINGS
[0018] These and other aspects, features and advantages of which embodiments of the invention are capable of will be apparent and elucidated from the following description of embodiments of the present invention, reference being made to the accompanying drawings, in which
[0019] FIG. 1 is a diagram showing a chemical transformation of a light absorbing compound.
[0020] FIG. 2 is a diagram showing a chemical transformation of a light absorbing compound.
[0021] FIG. 3 is a graph showing percent transmittance of different media containing various concentrations of a light absorbing compound according to certain embodiments of the present invention.
[0022] FIG. 4 is a partial cross-sectional view of an optical article according to certain embodiments of the present invention.
[0023] FIG. 5 is a partial cross-sectional view of an optical article according to certain embodiments of the present invention.
[0024] FIG. 6 is a partial cross-sectional view of an optical article according to certain embodiments of the present invention.
[0025] FIG. 7 is a partial cross-sectional view of an optical article according to certain embodiments of the present invention.
[0026] FIG. 8 is a partial cross-sectional view of an optical article according to certain embodiments of the present invention.
[0027] FIG. 9 is a partial cross-sectional view of an optical article according to certain embodiments of the present invention.
[0028] FIG. 10 is a graph showing percent transmittance of laminates containing various concentrations of a light absorbing compound according to certain embodiments of the present invention.
[0029] FIG. 11 is a graph showing percent transmittance of laminates containing various concentrations of light absorbing compounds according to certain embodiments of the present invention.
[0030] FIG. 12 is a graph showing percent transmittance of laminates containing various concentrations of light absorbing compounds according to certain embodiments of the present invention.
[0031] FIG. 13 is a graph showing percent transmittance of light for laminates containing a light absorbing compound and for lenses employing the same according to certain embodiments of the present invention.
[0032] FIG. 14 is a table showing certain optical characteristics of laminates containing a light absorbing compound and for lenses employing the same according to certain embodiments of the present invention.
[0033] FIG. 15 is a partial cross-sectional view of an optical article according to certain embodiments of the present invention.
[0034] FIG. 16 is a partial cross-sectional view of an optical article according to certain embodiments of the present invention.
DESCRIPTION OF EMBODIMENTS
[0035] Specific embodiments of the invention will now be described with reference to the accompanying drawings. This invention may, however, be embodied in many different forms and should not be construed as limited to the embodiments set forth herein; rather, these embodiments are provided so that this disclosure will be thorough and complete, and will fully convey the scope of the invention to those skilled in the art. The terminology used in the detailed description of the embodiments illustrated in the accompanying drawings is not intended to be limiting of the invention. In the drawings, like numbers refer to like elements.
[0036] Generally speaking, the present invention relates to eye health and protection of the human eye through absorbance of harmful ultraviolet (UV) and/or high energy visible (HEV, i.e. blue) light by additives present in the lens materials of construction, including as components within an adhesive layer in a laminate contained within a composite lens, as components within a monolithic sheet used by itself or as part of a laminate or non-laminate structure within a composite lens, added to thermoplastic pellets from which lenses are molded, or added to a curable composition, for example, a thermoset liquid or UV cured monomer compositions or a curable polyurethane based composition, from which lenses are cast. The present invention further relates to light absorbing filters to block damaging photons, while maintaining a good cosmetic appearance with low levels of coloration (or yellowness).
[0037] In certain embodiments, light absorbing filters according to the present invention include an absorbing compound, or compounds employed in combination, of the first class of materials described above, i.e. materials subject to tautomerization in which a hydrogen atom transfers from an oxygen atom in a ground state to a neighbouring nitrogen atom in an excited state. For example, compounds which function by the hydrogen atom transfer mechanism include hydroxyphenyl benzotriazoles, exemplified by 2-(3′-tert-butyl-2′-hydroxy-5′-methylphenyl)-5-chlorobenzotriazole (CAS #: 3896-11-5), available commercially as Tinuvin 326 or Omnistab 326; or pyrrolo[3,4-f]benzotriazole-5,7(2H,6H)-dione, 6-butyl-2-[2-hydroxy-3-(1-methyl-1-phenylethyl)-5-(1,1,3,3-tetramethylbutyl)phenyl]- (CAS#945857-19-2) available commercially as Tinuvin CarboProtect; hydroxyphenyl triazines exemplified by 2-(4,6-diphenyl-1,3,5-triazin-2-yl)-5-[(hexyl)oxy]-phenol, (CAS #147315-50-2) available commercially as Tinuvin 1577; or the mixture of 2-[4-[2-hydroxy-3-tridecyl (and dodecyl) oxypropyl]oxy]-2-hydroxyphenyl]-4,6-bis(2,4-dimethylphenyl)-1,3,5-triazine (CAS #153519-44-9) available commercially as Tinuvin 400; and hydroxybenzophenones exemplified by 2-hydroxy-4-octyloxybenzophenone (CAS#1843-05-6) available commercially as Uvinul 3008; or 2,2′-dihydroxy-4,4′-dimethoxy benzophenone (CAS #131-54-4) available commercially as Uvinul D49 and Cyasorb UV.
[0038] In certain embodiments, light absorbing filters according to the present invention include an absorbing compound, or compounds employed in combination, of the second class of materials described above, i.e. materials subject to the breaking of a double bond to form two adjacent stabilized radicals. Two principle examples of materials of this second class that function by formation of two adjacent stabilized free radical centers from a carbon to carbon double bond allowing the resultant single bond to dissipate energy through rotation, known as diaryl cyanoacrylates include ethyl-2-cyano-3,3-diphenylacrylate (CAS #5232-99-5) commercially available as Uvinul 3035; and 1,3-bis-[(2′-cyano-3′,3′-diphenylacryloyl)oxy]-2,2-bis-{[(2′-cyano-3′,3′-diphenylacryloyl)oxy]methyl}-propane (CAS #178671-58-4) commercially available as Uvinul 3030. This second class of materials tends to absorb shorter wavelength (higher energy) light than the first class of hydrogen atom transfer light absorbers.
[0039] The UV/visible spectrum used to characterize the absorbing properties of molecules is acquired at a fixed path length (1 or 10 mm) and at low molar concentrations (in the range of 10 −4 to 10 −6 moles/liter, depending on the molar extinction coefficient) of the absorber dissolved in a solvent that is transparent in the wavelength region of interest. For organic absorbers of the present invention, the solvent employed is, for example but not limited to, an alcohol (e.g. ethanol), an ether (e.g. tetrahydrofuran), a glycol ether (e.g. propylene glycol monomethyl ether), or a hydrocarbon (e.g. cyclohexane) solvent.
[0040] It has been determined that while the efficacy of light absorbance principally depends on an absorber's molecular structure, the efficacy of light absorbance also strongly relates (1) to the absorber's concentration in the medium in which it is dissolved or dispersed and (2) to the light path length through which it is expected to operate. For example, with respect to a given structure, a longer light path length (at a fixed concentration) results in a lower percentage of transmitted incident light. Analogously, a higher concentration of absorber (at a fixed path length) also results in a lower percentage of transmitted incident light. This behavior falls into two regimes, a linear relationship at low concentrations and/or short path lengths, and a nonlinear relationship at high concentrations and/or long path lengths (Beer-Lambert Law; more absorber or a longer path results in lower light transmittance but additional amounts or increased path lengths absorb less than predicted by the line generated at low concentration or short path lengths).
[0041] Accordingly, in certain embodiments of the present invention, depending on the technical or commercial application and amount of incident light and wavelength region desired to be removed (filtered out), the concentration of the absorber employed is optimized. For example, in a (transparent) coating (generally limited to less than or equal to 10 microns thick), where the path length is very short, a higher concentration of absorber is required to remove the same amount of incident light than is required for a transparent body of macroscopic thickness (millimeters). It has been found that this concentration is difficult to predict because of the nonlinearity of the absorbing behavior.
[0042] This is shown in FIG. 3 which provides a comparison of the behaviour of different concentrations of absorber in GEPM solution, propylene glycol monomethyl ether, having a 1 mm light path to different concentrations of absorber behaviour in a polyurethane laminating adhesive having a 41 μm path. The absorber in GEPM solution results were adjusted to simulate a polycarbonate film in the laminate structure. In other words, the concentration of the absorber in the GEPM solution was adjusted up or down as required by the different absorbers' molar extinction coefficients to absorb the target amount of light below the target cut-off wavelength in the 1 mm path length to observe their spectra and permit estimation of the amount of absorber required in the application.
[0043] The laminate samples shown in FIG. 3 were formed of a standard commercial solvent-borne two-part polyurethane formulation into which absorber was added at levels estimated from their solution behaviour at much longer path lengths prior to casting and lamination. The adhesive layer was approximately 41 micrometres in thickness and was supported by polycarbonate film.
[0044] As shown in FIG. 3 , the absorbance is so strong that as the concentration of the absorber increases, the lower, left shoulder of transmittance shifts farther into the HEV wavelengths, i.e. as concentrations of the absorber increase, so does absorbance of HEV wavelengths. Consequently, in certain embodiments, the effective amounts of the light absorbers employed depends on the manner of application of the absorber within the lens e.g. application as a microns thick laminating adhesive or coating layer, as a fractional millimeter thick monolithic film forming one part of a laminate structure, or as the multi-millimeter thick bulk lens molding material.
[0045] The transmittance shift into the HEV wavelengths is significant because, in certain applications of the present invention, the objective is to achieve a lens with maximum transmission and minimum residual color in transmission while also achieving a degree of UV and HEV light blocking. In certain embodiments, the transmittance should be as close as possible to the resin without the introduction of the absorber, for example, approximately less than 80 percent. However, exact values depend upon the thickness of material and are often approximately less than 90 percent for ophthalmic lenses. A residual color of the ophthalmic article can be expressed by color coordinates (x,y,Y or L*a*b*) but, in view of the above objectives, it can be more meaningful to evaluate the optical articles of the present invention in terms of the transmitted yellow index of the lens (YI [1925 C/2]).
[0046] The effect of the absorber is to selectively remove portions of the UV and blue spectrum. A consequence of doing this is to increase the appearance of yellow in the lens color. Yellow color is often associated with aging or degradation of objects and is therefore found to be aesthetically displeasing. Hence, in certain embodiments, optical articles according to the present invention have yellow indices of preferably less than 3 but no more than 16. At values below 3, the yellow will not be noticed by most observers. In contrast, values above 16 will be found objectionable by most observers. The acceptance between 3 and 16 will depend on the application and viewing conditions.
[0047] The broad range of light absorber structures useful in this invention have different characteristic molar extinction coefficients (a measure of their light absorbing efficiencies). Hence, specification of a generically useful absorber amount by weight percent of composition may seem substantially high in some cases. In certain embodiments, selection of an absorber and the absorber's appropriateness in a given location (related to path length and amount required to absorb the desired amount of light) is optimized. Therefore, the relative phrase “amount sufficient to provide the desired effect” may be more suitable in some cases. For example, the terms λ 50 , λ 10 , λ 5 and λ 1 , defined as the wavelength at which transmittance is 50, 10, 5, and 1 percent, respectively, of the incident light at the stated wavelength, can be more useful. Table 1 below numerically expresses certain of the data employed to generate the graph of FIG. 3 according to this scheme (to the nearest whole nm).
[0000]
TABLE 1
Tinuvin CarboProtect GEPM Solutions;
Tinuvin CarboProtect PU Laminates;
1.0 mm Path Length
41 μm Path Length
λ, (nm)
0.1 wt %
0.2 wt %
0.4 wt %
λ (nm)
1.0 wt %
2.0 wt %
4.0 wt %
λ 50
422
428
433
λ 50
419
425
431
λ 10
408
416
423
λ 10
397
411
419
λ 5
403
413
420
λ 5
385
407
415
λ 1
392
407
416
λ 1
n/a
396
410
[0048] In certain embodiments, as shown in FIG. 4 , a light-absorbing laminate or monolithic film 10 according to the present invention is placed into a mold cavity and a composite lens 12 is formed via injection molding of a molten thermoplastic resin 14 into the mold cavity containing the light-absorbing laminate or monolithic sheet. Detailed descriptions of exemplary injection molding processes are provided in the U.S. Pat. Nos. 5,757,459; 5,856,860; 5,827,614; 6,328,446; 6,814,896; 7,048,997; and 8,029,705, which are hereby incorporated herein by reference in their entireties.
[0049] In another embodiment, as shown in FIG. 5 , a light-absorbing laminate or monolithic film 10 according to the present invention is placed into a mold cavity and a composite lens 18 is formed via casting, wherein the mold cavity containing the laminate or monolithic film is filled with a curable composition 16 , for example a composition employing a liquid monomer mixture or a urethane based prepolymer composition (e.g. Trivex, PPG; CAS #97-23-4), followed by curing of the composition to produce the composite lens 12 . Detailed descriptions of exemplary casting processes are provided in the U.S. Pat. Nos. 7,858,001 and 8,367,211, which are hereby incorporated herein by reference in their entireties.
[0050] In another embodiment of the present invention, a light-absorbing compound(s) is added to, mixed with, or otherwise combined with thermoplastic pellets used for injection molding a lens 20 ( FIG. 6 ) or a portion of a curable composition 22 , for example a composition employing a liquid monomer mixture or a urethane based prepolymer composition (e.g. Trivex, PPG) used for casting a lens ( FIG. 7 ).
[0051] In certain embodiments of the present invention, as shown in FIG. 8 , light absorbing material or materials or compounds are added to, mixed with, or otherwise combined with a liquid applied hard coating 26 that is applied to the molded or cast lens 24 .
[0052] In certain embodiments of the present invention, as shown in FIG. 9 , a light-absorbing compound(s) is added to, mixed with, or otherwise combined with a carrier composition, e.g. a polyurethane adhesive carrier, that is employed to form a light absorbing layer 30 and the light absorbing layer 30 is laminated between to transparent monolithic films 32 , e.g. between two polycarbonate films, to form a light absorbing laminate 34 .
[0053] There are no limitations placed on the number of absorbers that can be used together, nor their locations when used in combination in composite lenses. Thus, different absorbing materials may be added to the adhesive in a laminate and the lens body material, analogous to FIG. 4 for injection molded composite lenses (and correspondingly for cast composite lenses as shown in FIG. 5 ). Likewise, the laminate may contain different absorbing materials in the adhesive and in the films laminated together, as well as in the body of the composite lens formed by injection molding or casting.
[0054] In certain embodiments of the present invention, an UV/HEV activated (photochromic) dye or dyes are employed in a photochromic adhesive layer 40 within a laminate 42 and one or more UV/HEV light absorbers is employed in a monolithic film 44 of the laminate structure on a side 46 opposite from the incident light, adjacent to the body of the lens, closest to the observer's eye behind the lens or ophthalmic article. FIG. 15 shows a composite lens 12 formed of such a photochromic, light-absorbing laminate 42 via injection molding of a molten thermoplastic resin 14 into the mold cavity containing the light-absorbing laminate 42 . FIG. 16 shows a composite lens 18 formed of a photochromic, light-absorbing laminate 42 via casting, wherein the mold cavity containing the laminate 42 is filled with a curable composition 16 , for example a composition employing a liquid monomer mixture or a urethane based prepolymer composition (e.g. Trivex, PPG; CAS #97-23-4), followed by curing of the composition to produce the composite lens 18 .
[0055] In certain embodiments, an ophthalmic lens according to the present invention absorbs up to 99.9% of all light at wavelengths less than 440 nm.
[0056] In certain embodiments, an ophthalmic lens according to the present invention absorbs up to 99.9% of all light at wavelengths less than 420 nm.
[0057] In certain embodiments, an ophthalmic lens according to the present invention absorbs up to 99.9% of all light at wavelengths less than 400 nm.
[0058] In certain embodiments, an ophthalmic lens according to the present invention absorbs up to 99.9% of all light at wavelengths less than 440, 420, or 400 nm. The light is absorbed by additives present in a component of the lens construction, including (1) as a component within an adhesive layer in a laminate contained within a composite lens; (2) as a component within a monolithic sheet or film employed by itself or alone within a composite lens; (3) as a component within a monolithic sheet or film employed as part of a laminate structure contained within a composite lens; (4) as a component added to thermoplastic pellets from which lenses are molded; and/or (5) as a component added to thermoset or curable compositions, for example a composition employing a liquid monomer mixture or a urethane based prepolymer composition (e.g. Trivex, PPG) from which lenses are cast. Detailed descriptions of adhesive layers in laminates are provided in the U.S. Pat. Nos. 8,906,183; 8,298,671; 9,163,108; 9,081,130; and 9,440,019, which are hereby incorporated herein by reference in their entireties.
[0059] In certain embodiments, a laminate or a monolithic film according to the present invention absorbs up to 99.9% of all light at wavelengths less than 440, 420, or 400 nm, and the inventive light-absorbing laminate or monolithic film is placed into a mold cavity and a composite lens is formed through injection molding of a molten thermoplastic resin into the mold cavity containing the light-absorbing laminate or monolithic film.
[0060] In certain embodiments, a laminate or monolithic film according to the present invention absorbs up to 99.9% of all light at wavelengths less than 440, 420, or 400 nm, and the inventive light-absorbing laminate or the monolithic film is placed into a mold cavity and a composite lens is formed through casting wherein the mold cavity containing the laminate or monolithic film is filled with a curable composition, for example a composition employing a liquid monomer mixture or a urethane based prepolymer composition (e.g. Trivex, PPG), followed by curing of the curable composition to produce the composite lens.
[0061] In certain embodiments, an ophthalmic lens according to the present invention absorbs up to 99.9% of all light at wavelengths less than 440, 420, or 400 nm, wherein the thermoplastic pellets used for injection molding or the liquid thermoset or curable composition, for example a composition employing a liquid monomer mixture or a urethane based prepolymer composition (e.g. Trivex, PPG), used for casting the lenses contains the light-absorbing compounds.
[0062] In certain embodiments of the present invention the light absorbing material or materials employed to form any of the above-described light-absorbing laminate, monolithic film, and/or ophthalmic lens are absorbers which reversibly transfer hydrogen atoms or protons in the excited state to a neighboring heteroatom.
[0063] In certain embodiments of the present invention the light absorbing material or materials employed to form any of the above-described light-absorbing laminate, monolithic film, and/or ophthalmic lens are absorbers which reversibly transfer hydrogen atoms or protons in the excited state to a neighboring heteroatom wherein the hydrogen atom or proton is transferred to oxygen or nitrogen.
[0064] In certain embodiments of the present invention the light absorbing material or materials employed to form any of the above-described light-absorbing laminate, monolithic film, and/or ophthalmic lens are absorbers used at a weight percent of up to one in a transparent material having an optical path length greater than 1 mm.
[0065] In certain embodiments of the present invention the light absorbing material or materials employed to form any of the above-described light-absorbing laminate, monolithic film, and/or ophthalmic lens are absorbers used at a weight percent of up to three in a transparent material having an optical path length in the range of 0.1 mm and 1 mm.
[0066] In certain embodiments of the present invention the light absorbing material or materials employed to form any of the above-described light-absorbing laminate, monolithic film, and/or ophthalmic lens are absorbers used at a weight percent of up to ten in a transparent material having an optical path length in the range of 0.01 mm and 0.1 mm.
[0067] In certain embodiments, the light-absorbing laminate, monolithic film, and/or ophthalmic lens of the present invention employ additional functional properties, including but not limited to, coloration, tinting, hard coating, polarization, photochromism, electrochromism, UV absorption, narrow band filtering, easy-cleaning, hydrophobicity, and anti-static. Such functional properties are imparted through a coating or surface treatment of the inventive light absorbing laminate or monolithic film employed alone or as structure contained within a composite lens and/or ophthalmic lens. Alternatively, such functional properties are imparted as a component within an adhesive or protective layer of the laminate; as a component within the monolithic sheet or film; as a component added to thermoplastic pellets from which lenses are molded; and/or as a component added to curable compositions, for example a composition employing a liquid monomer mixture or a urethane based prepolymer composition (e.g. Trivex, PPG), from which lenses are cast.
[0068] As used herein, the term curable composition or compositions includes, but is not limited to, compositions curable through application of thermal energy, UV radiation, electron beam, x-ray, gamma-ray, microwave, and/or radio frequency.
[0069] In certain embodiments of the present invention, a combination of one or more of the above-described embodiments is employed to absorb an amount of light desired in a spectral region required to meet lens performance specifications.
EXAMPLES
[0070] General Procedure: A two-part solvent-borne polyurethane laminating adhesive was prepared from solutions comprising an isocyanate prepolymer, a polyol, a crosslinker and one or more absorbers at various concentrations. The absorbing adhesive solutions were cast onto a release liner at a wet film thickness sufficient to produce a 41 micrometre, plus or minus 2 micrometres, dry adhesive layer and dried for a time and temperature sufficient to remove the volatile solvent (tetrahydrofuran, THF) to less than or equal to 100 mg/m 2 . The dried adhesive layer was transferred to a first polycarbonate optical film and then laminated to a second polycarbonate optical film to make a three-layer laminate structure. The laminates' absorbing characteristics were observed using a UV-vis spectrophotometer (Hunter, Agilent or Perkin-Elmer). Some of the laminates were used to fabricate composite lenses by injection molding using thermoplastic polycarbonate resin pellets.
Example 1
[0071] Tinuvin 326 (BASF) was dissolved in THF and added to the two-part solvent borne polyurethane adhesive solution in amounts sufficient to produce adhesive solutions containing a weight percent of 6, 7, and 8, based on final dried adhesive solids, cast onto release liners, dried, and laminated to produce the experimental laminates. Portions of these laminates were placed into a UV-vis spectrophotometer for spectral characterization, as shown in FIG. 10 and summarized below in Table 2.
[0000]
TABLE 2
Tinuvin 326; 41 μm Laminates
λ (nm)
6%
7%
8%
λ 50
410
411
412
λ 10
401
402
403
λ 5
399
400
401
λ 1
395
397
398
Example 2
[0072] Similar to Example 1, THF solutions containing both Tinuvin 326 and Tinuvin CarboProtect (BASF) were added to the two-part adhesive to provide the absorbers in the amounts indicated based on the dried adhesive solids, which adhesive solutions were cast onto release liners, dried, and laminated to produce experimental laminates with a dried adhesive layer of 41 micrometres. Portions of these laminates were placed into a UV-vis spectrophotometer for spectral characterization, as shown in FIG. 11 and summarized below in Table 3.
[0000]
TABLE 3
5% Tinuvin 326 + CarboProtect; 41 μm Laminates
λ (nm)
0.1 wt %
0.2 wt %
0.3 wt %
0.4 wt %
λ 50
410
412
413
414
λ 10
401
402
402
403
λ 5
399
399
400
400
λ 1
395
395
396
396
Example 3
[0073] Similar to Example 1, THF solutions containing Tinuvin CarboProtect (“TCBP”; BASF), Eusorb 390 (“UV390”; a proprietary heterocyclic styrene derivative, Eutec) or Eusorb 1990 (“UV1990”; a proprietary acrylic ester derivative, Eutec) were added to the two-part adhesive to provide all the absorbers at a weight percent of 2, based on the dried adhesive solids. These adhesive solutions were cast onto release liners, dried, and laminated to produce experimental laminates with a dried adhesive layer of 41 micrometers. Portions of these laminates were placed into a UV-vis spectrophotometer for spectral characterization, as shown in FIG. 12 and summarized below in Table 4.
[0000]
TABLE 4
Different Absorbers, 41 μm Laminates
λ (nm)
UV390
UV1990
TCBP
λ 50
443
434
426
λ 10
434
423
412
λ 5
432
420
408
λ 1
427
415
398
Example 4
[0074] Similar to Example 1, a THF solution containing Tinuvin 326 (BASF) was added to the two-part adhesive to provide the absorber at a weight percent of 6, based on the dried adhesive solids. The adhesive solution was cast onto release liners, dried, and laminated to produce experimental laminates with a dried adhesive layer of 41 micrometers. Wafers were punched from some of the laminates, which were placed into molds and fabricated as composite lenses. Laminates and lenses were characterized by UV-vis spectra, with the results shown in FIGS. 13 and 14 and below in Table 5.
[0000]
TABLE 5
Averages of 14 Pieces
λ (nm)
Laminate
Lens
λ 50
410
410
λ 10
401
402
λ 5
399
400
λ 1
395
397
[0075] Although the invention has been described in terms of particular embodiments and applications, one of ordinary skill in the art, in light of this teaching, can generate additional embodiments and modifications without departing from the spirit of or exceeding the scope of the claimed invention. Accordingly, it is to be understood that the drawings and descriptions herein are proffered by way of example to facilitate comprehension of the invention and should not be construed to limit the scope thereof.
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An ophthalmic lens operable to protect the eye from harmful ultraviolet and high energy visible wavelengths of light and methods for producing the same.
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CROSS-REFERENCE TO RELATED APPLICATION
[0001] This application claims the benefit of U.S. Provisional applications Ser. Nos. 60/221,321 filed Jul. 28, 2000 and No. 60/253,979 filed Nov. 29, 2000.
BACKGROUND OF THE INVENTION
[0002] 1. Field of the Invention
[0003] The present invention relates to insoles for footwear and, more particularly, to means and methods for adjusting and varying the degree and resiliency of support for one or both feet.
[0004] 2. Description of Related Art and Other Considerations
[0005] The narrow part of the sole of a shoe under the instep, called the shank piece, ideally should flex to a certain degree as one walks or runs, to avoid restraining the natural functioning of the foot. Because no one foot is exactly like another, when an adjustment is required, the adjustment must be tailored to the specific foot under consideration. Such tailoring may be obtained by an existing commercially available insole or by a specially constructed insole, such as prescribed or formulated by a podiatrist or other professional. The latter construction may be expensive and, therefore, not a viable option to many. Independent adjustment for differently formed feet or different foot problems between the feet is not easily and possibly inexpensively obtainable. Regardless, any adjustment of the bending movement in one or more zones within a shoe is not easily obtainable.
SUMMARY OF THE INVENTION
[0006] These and other problems and considerations are successfully addressed and overcome by the present invention. An insole comprises one or more internally supported pairs of stacked resilient elements. Each supporting element has at least two axes intersecting one another and is characterized by having a greater resiliency along a first of the axes than along a second of the axes. The elements are relatively movable with respect to one another to enable relative movement of their respective axes to vary the combined resiliency between the elements and, thereby to provide adjustable podiatric support characteristics in the insole.
[0007] Preferably, each element is configured as a spring-like disc, with one being stationary with respect to the remainder of the insole, to thereby act as a stator, and the other being rotatable with the stator. Also preferably, the latter disc, or a rotor, is circular, so that it may be retained within circular confines in the insole and be turned, such as by a screwdriver type tool which may be inserted through an appropriate opening in the bottom of the insole so as to engage a slot formed in the rotor. The use of slots in the rotor forms a visible method of visibly determining the orientation of the rotor with respect to the stator.
[0008] The spring-like disc may take such configurations as a thin spring flat leaf or a spider, and the components of the disc may also be differently formed so as to provide a uniformly or differently programmed resiliency. For example, a circular disc containing parallel strips secured within a peripheral supporting ring, provides different resiliency among the several shorter and longer strips, if the strips have the same widths; however, by tailoring the widths of the several individual strips, their resilient characteristics may be made uniform, or otherwise programmed, as desired.
[0009] Several advantages are afforded by the present invention. The resilient characteristics of an insole are easily and relatively inexpensively obtained. The insole as a whole or in part may be quickly and simply tuned or tailored to the individual foot by the professional or by the individual. Tuning may be effected independently for the two feet, and in as simple a manner as by a screwdriver or like tool. Orientation of the resiliency/stiffness characteristics are made visible. The size of the adjustable elements permits use of the present invention in a wide variety of shoes, whether of a fashionable or work version, or a low or high-heel type.
[0010] Reduction to some extent is possible of tendinitis or related problems due to wearing higher heel shoes by using the invention with such shoes and setting the adjustments on the very low side, as a conceivable method to allow the shanks of the legs to bend more easily, thus resulting in exercising more and reducing the tendon brittleness increase with time in wearing high heels. Due to anatomical differences of feet or legs for many people, individual right and left side shank-piece adjustment will be beneficial.
[0011] A low cost, reliable and functional method is provided for a fit in a thin insole area, where no visibility for styling considerations is important.
[0012] Other aims and advantages, as well as a more complete understanding of the present invention, will appear from the following explanation of exemplary embodiments and the accompanying drawings thereof.
BRIEF DESCRIPTION OF THE DRAWINGS
[0013] [0013]FIG. 1 is a top plan view of a first embodiment of an insole embraced by the present invention, showing interior elements thereof in phantom;
[0014] [0014]FIG. 2 is a bottom plan view of the FIG. 1 embodiment, portraying an entry way to interior elements, which are shown in phantom;
[0015] [0015]FIG. 3 is an enlarged view of a portion of FIG. 2;
[0016] [0016]FIG. 4 is a view, in cross-section, of the first embodiment taken along line 4 - 4 of FIG. 3;
[0017] [0017]FIG. 5 is a view of an interior portion of the first embodiment taken at a first level or layer to depict a stationary resilient member or stator;
[0018] [0018]FIG. 6 is a view of an interior portion of the first embodiment taken at a second level or layer to depict a stationary resilient member or rotor;
[0019] [0019]FIG. 7 is an enlarged view of the central section illustrated in FIG. 6 and showing a first orientation between the rotor and the stator to produce one of the many adjustably resilient stator-to-rotor combinations provided by the present invention;
[0020] [0020]FIG. 8 is a view similar to that depicted in FIG. 7, but showing a second orientation between the rotor and the stator, in which the rotor is turned 90° with respect to that of the stator, to produce another adjustably resilient combination;
[0021] FIGS. 9 - 13 illustrate, in plan and cross-sectional views, different spring configurations of the stator and/or rotor useful in carrying out the concepts of the present invention;
[0022] [0022]FIG. 14 is a second embodiment of the present invention depicting different positionings of three stator-to-rotor combinations for enabling specific adjustably resilient combination to different parts of the foot;
[0023] [0023]FIG. 15 is a view of an assembly of four spring elements oriented along parallel axes to provide a maximum stiffness or resilient characteristic to the insole, as being dependant upon whether all their parallel axes are parallelly or orthogonally disposed with respect to the underlying spring element; and
[0024] [0024]FIG. 16 is a view of the four FIG. 15 spring elements differently rotated to dispose their respective axes in a differently angled orientation thereamongst, so as to illustrate varying degrees of stiffness and resiliency for application to different parts of the foot.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
[0025] As illustrated in FIGS. 1 - 8 , which related to a first embodiment of the present invention, an insole 20 comprises a plurality of layers, as best shown in FIG. 4, such as layers 22 , 24 , 26 and 28 , which are secured together to provide a complete unit for insertion into the shoe of and for support of an individual. Layer 26 , as the bottom layer, may comprise a soft cushion material. Layer 28 , as the top layer, may comprise a finishing layer. Layers 26 and 28 therefore form supporting outer layers for intermediate layers 22 and 24 .
[0026] Intermediate layers 22 and 24 include respective openings 30 and 32 for receipt of a first and second resilient elements 34 and 36 . Together, first and second elements form a pair of stacked first and second resilient elements which are supported by a supporting medium comprising at least layers 22 and 24 . For the embodiment illustrated in FIGS. 1 - 8 , resilient element 36 is fixed with respect to the supporting medium of layers 22 and 24 , and may be referred to as a stator. Stator element 36 is configured to have axes 36 x and 36 y disposed normally with respect to one another. Resilient element 34 , however, is disposed to be moveable, in particular rotatable, within opening 30 and, therefore, with respect to the supporting medium. Accordingly, resilient element 34 may be referred to as a rotor. Rotor element 34 is configured to have axes 34 x and 34 y disposed normally to one another.
[0027] To enable turning of rotor 34 , a slot 38 (see FIGS. 2 - 4 and 6 - 8 ) is formed at its center, and an opening 40 is provided in bottom layer 26 to afford access to slot 38 . As illustrated in FIG. 4, a screwdriver 42 or like tool, having a tip 44 which is shaped similarly to that of the slot, is insertable through opening 40 and, therefore, can engage the slot and turn resilient rotor element 34 . Slot 38 also provides a visible indicator as to the orientation of rotor element 34 with respect to fixed stator 36 . The assembly is so enclosed that it is made water tight, with the only exposed surfaces being the slot and immediately adjacent rotor area; preferably, a rubber washer and/or other protection is placed over and/or around the slot and its area during assembly of the insole. The assembly may also contain suitable thin gasket or washer layers which can flex while providing an effective seal against entry of moisture or other liquid.
[0028] Should it be found that any movement between the elements tend to be too tight, a Teflon, silicone, or similar coating may be inserted or otherwise employed. If. However, there is too mush slippage, a thin rubber washer or suitable material can be used.
[0029] As best depicted in FIGS. 7 and 8, resilient rotor element 34 is shown as comprising a circular thin disc formed, for example, of spring steel, stainless, or any other suitable material. Stator element 36 may take any configuration, and is depicted as a rectangular thin sheet, also formed, for example, of spring steel, stainless, or any other suitable material. The combined rotor and stator elements may have a total thickness of approximately 0.06″ to 0.1″ which will fill within the thickness range of typical suitable shanks of insole 20 of approximately 0.15″ to 0.3″ thick.
[0030] The rotor element includes a closed periphery 46 having open spaces 48 therein which form a link 50 connecting opposed sides of the periphery. As depicted, link 50 lies on axis 34 x and, because of the existence of the link and the absence of any connection dissected by axis 34 y, rotor element 34 is more resilient about axis 34 y than about axis 34 x.
[0031] Stator element 36 comprises a single thin spring flat leaf which cannot move but can spring to some degree, up and down, as one walks or runs due to the change in alternately placing all the body weight on the heel and toes of the foot as they cause the shoe to meet the ground.
[0032] When the rotor and stator elements are aligned so that their respective axes 34 y and 36 x are aligned, as shown in FIG. 7, the combined resiliency due to this orientation, is the greatest. When the rotor and stator elements are aligned so that their respective axes 34 x and 36 x are aligned, as shown in FIG. 8, the combined resiliency due to this orientation, is the least.
[0033] Both the stator and the rotor, in particular the rotor, may be configured as depicted in FIGS. 9 - 13 . Rotor element 60 of FIGS. 9 and 10 is configured as a disc and comprises an annular periphery 62 and a plurality of leaves 64 of uniform widths, formed by slitting the material from which the rotor disc is fabricated. A slot 68 is formed in the center leaf to enable turning of the rotor with respect to the stator. Because the lengths of the leaves are not equal, the resiliency characteristics of this rotor disc vary across its diameter. Should such resiliency characteristics be desired to be uniform or otherwise programmed, a rotor disc 70 , as illustrated in FIGS. 11 and 12 may be employed, having a periphery 72 supporting a plurality of leaves 74 whose widths vary according to the program. Leaves 74 are formed by slits 76 . As in the case of the prior rotor, a slot 78 is placed in the centrally located leaf. Other rotor element configurations may be employed, as desired. An example thereof is depicted in FIG. 13, in which a rotor 80 comprises a periphery 82 and a spider-like plurality of leaves 84 supported on a central hub 86 , in which a turn-effecting slot 88 is located.
[0034] Reference is now made to FIG. 14 which depicts an insole 90 housing three spring elements 92 , 94 and 96 in its insole shank 98 , in which each in combination with its mating portion of the stator, or three individual stators if desired, to provide three pairs of stacked first and second resilient elements supported by insole 90 as the supporting medium. The stacked pairs including spring elements 92 , 94 and 96 are respectively positioned to form adjustments for the respective medial side, center and outside of the shank. Each spring element is provided with its slot, generally identified by indicium 100 , for individual adjustment of the respective paired rotor-stator elements by proper individual orientation thereof. This embodiment is useful, for example, to advantage for a two or three adjustment of the shank is for toeing the shoes in or out and, therefore, it will be possible to adjust and correct for related abnormal foot conditions.
[0035] [0035]FIGS. 15 and 16 illustrate a further embodiment of an insole 110 depicting an assembly of four spring element pairs in which the rotor resilient spring elements of each are shown, comprising an element 112 and its parallelly disposed leaves 114 , an element 116 and its parallelly disposed leaves 118 , an element 120 and its parallelly disposed leaves 122 and an element 124 and its parallelly disposed leaves 126 . Each rotor spring element is paired with its stator element which may be a portion of a leaf spring, such as leaf spring 36 of FIGS. 1 - 8 , or an individual piece. Slots, as generally identified by indicium 128 , are engageable with a tool, such as the tip of a screwdriver, for turning the individual rotor elements into an orientation to provide a desired degree of resiliency or stiffness.
[0036] The orientations of the four elements 112 , 116 , 120 and 124 along their parallel axes provide maximum stiffness or resilient characteristics to the insole, as being dependant upon whether all their parallel axes are parallelly or orthogonally disposed with respect to the underlying spring element. For the toe and heel portions of insole 110 extending in the direction of double-headed arrow line 130 , the orientations of these four elements produce a maximum stiffness in the insole. If they were rotated 90° with respect to that shown in FIG. 15, these orientations would produce maximum resiliency in the insole.
[0037] When the four rotor elements of FIG. 15 are turned to those depicted in FIG. 16, the four spring elements provide different spring characteristics. Specifically, element 112 provides about a 70% stiffness direction to the left, element 116 provides a minimum stiff direction, element 120 provides a maximum stiffness direction, and element 124 provides about a 70% stiffness direction toward the right.
[0038] The embodiment illustrated in FIGS. 15 and 16 can be used to provide the benefits of protection from excessive shock to the heel and forefoot sections of the feet for walking, running and engagement in active sports.
[0039] The quadrature preferred arrangement can be made to be about a 1½″ to 3″ square assembly with a total thickness of approximately 0.063″ to 0.2″ for typical shank embedment. The four adjustment slots can be located on the bottom of the shank or on the bottom inside of the shoe or other footwear. It is evident that the four zones will be able to achieve variations in flexibility. Discrete effects on supination, pronation and other variations in support of arches, and other areas of the feet is made possible with the present invention. By varying the spring temper and material used for the spring plates, additional choices of lighter to heavier duty models can be made.
[0040] The present invention may use a shorter or a full length metal insole, which is shaped flat, thin, or have a spring-back. The insole may rest on the upper inside of the shoe, and be removable and re-insertable for adjustable angle positioning. There can be several areas of location such as one or more discs in the medial arch area and in the metatarsal areas. Various pads, attachments and the like can be placed over this spring-back insole to provide soft adjustable cushioning as well as a flat spring-back, and with adjustable intensity and variable direction of lateral forces. Attachment of pads may be effected by hook and loop attachment systems, and connected to provide lateral stability. The metal flat plates can be made of thicker or thinner sheet materials to provide heavier or lighter zones of plantar support and spring-back action. The areas can have plates of stiffer materials or more dead soft temper materials. The materials can be spring steel, beryllium copper or a host of other materials, such as fiberglass or carbon fibre. The flat discs can be smaller or larger in diameter to suit specific plantar aspect areas. Thus, the present inventive enhanced design affords a totally adjustable spring-back and shock absorber insole which can be used for virtually any type of footwear.
[0041] The spring-back section can be made relatively thin and, together with the cushioning section, can total from 0.1″ for standard use to about 0.25″ for heavy duty work or athletic use. For improved visibility of the round disc with serrated variable and directional areas, the spring-back assembly can have a bottom layer about 0.004″ thick. The discs are about 0.01″ thick and the top layer is a clear sheet of approximately 0.006″ polypropylene or other suitable material, with the bottom layer laminated with about a 0.0005″ layer of polypropylene or other suitable material. The holes in the center sheet can be loaded with the discs and the upper clear plastic sheet can be permanently bonded to the thin 0.0005″ plastic layer on the lower sheet. The result can be a thin, approximately 0.0006″+0.0005″+0.004″ or 0.015″ typical thickness. These dimensions can be reduced to total 0.01″ and provide a thin, rugged, flat, flexible, and adjustable, unique plantar aspect, protective foot exerciser and comfort device.
[0042] The metal plates can provide a cooling effect as they can conduct heat away from the warm heat generating areas.
[0043] Although the invention has been described with respect to particular embodiments thereof, it should be realized that various changes and modifications may be made therein without departing from the spirit and scope of the invention.
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An insole ( 20, 90, 110 ) provides for adjustable pediatric support characteristics for a user's foot. One or more pairs of stacked rotor and stator resilient elements ( 34, 36 ) are supported by the insole. Each pair of resilient elements is characterized by having a greater resiliency when the rotor is oriented along or at 90° with respect to the stator. The rotor is relatively movable with respect to the stator to effect different orientations of the paired rotor and stator and enables the blending of the respective resiliences of the pair and, thereby, for providing the adjustable pediatric support characteristics. A plurality of rotor and stator pairs enables adjustments for different parts of the foot and for differences between an individual's feet.
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CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application is a continuation application of U.S. patent application Ser. No. 13/247,996, filed on Sep. 28, 2011, which is issuing as U.S. Pat. No. 8,303,480 on Nov. 6, 2011, which is a continuation application of U.S. patent application Ser. No. 11/580,272, filed Oct. 12, 2006, which is now U.S. Pat. No. 8,047,979, which is a continuation-in-part of and claims priority to U.S. patent application Ser. No. 11/404,051, filed on Apr. 13, 2006, which is now U.S. Pat. No. 7,282,021, which is a continuation application of U.S. patent application Ser. No. 10/452,947, filed on Jun. 2, 2003, which is now U.S. Pat. No. 7,033,312, which is a continuation application of U.S. patent application Ser. No. 09/839,258, filed Apr. 20, 2001, which is now U.S. Pat. No. 6,572,528. The disclosure of the prior applications are considered part of (and are incorporated by reference in) the disclosure of this application.
TECHNICAL FIELD
[0002] This invention relates to magnetic stimulation techniques, and more particularly to neural stimulation using a magnetic field.
BACKGROUND
[0003] Repetitive transcranial magnetic stimulation (rTMS) has been used with the goal of treating depression, see, e.g., George et al., The Journal of Neuropsychiatry and Clinical Neurosciences, 8:373, 1996; Kolbinger et al., Human Psychopharmacology, 10:305, 1995.
[0004] One example of an rTMS technique uses a figure-8 surface coil with loops that are 4 cm in diameter (Cadwell, Kennewick, Wash.). This coil is placed next to the scalp, and is usually positioned to direct the magnetic field at the prefrontal cortex of the brain, see, e.g., George et al., The Journal of Neuropsychiatry and Clinical Neurosciences, 8:373, 1996. An electric current is run through the magnetic coil to generate a magnetic field, specifically a sequence of single-cycle sinusoidal pulses where each pulse has a frequency of approximately 1800 Hz (or about 560 microseconds per pulse). These pulses are delivered at a repetition rate of 1 to 20 Hz (i.e., one pulse every 0.05 to 1 second), see, e.g., George et al, Biological Psychiatry, 48:962, 2000; Eschweiler et al, Psychiatry Research: Neuroimaging Section, 99:161, 2000.
[0005] Some subjects have declined participation in rTMS studies due to pain induced in the scalp. In addition, seizures have been reported as a result of rTMS treatment, see, George et al, Biological Psychiatry, 48:962, 2000; Wasserman, Electroencephalography and Clinical Neurophysiology 108:1, 1998.
SUMMARY
[0006] The invention concerns treating disorders using novel magnetic field techniques. These techniques have generally been termed low-field magnetic stimulation (LFMS) techniques. These magnetic field techniques generally use low field strengths, high repetition rates, and relatively uniform magnetic field gradients to improve brain function.
[0007] In one aspect of the present invention, a method of treatment involves selecting a person who experiences symptoms of a psychotic disorder, such schizophrenia or a schizoaffective disorder, and subjecting the person's head to a time-varying magnetic field which has been generated to treat the symptoms of the psychotic disorder. The magnetic field that is generated induces an electric field in air comprising a series of electric pulses, where the pulses have a duration less than about 10 milliseconds, and where each pulse has a single polarity and the pulses are separated by periods of substantially no electric field. This aspect of the invention can also be used to treat abuse or dependence on a substance such as alcohol or nicotine. In addition, it can be used to treat other disorders such as attention deficit hyperactivity disorder, post-traumatic stress disorder, obsessive-compulsive disorder, bipolar disorder, panic disorder, and pain and movement disorders.
[0008] Advantages of this aspect of the invention include the following. Subjects with disorders may benefit from the new treatment by the lessening of the severity of the condition. Treatment techniques using this method can be administered inexpensively with relative safety and comfort, and offer a substitute for or complement to treatment by medication. Applications of the new methods include improving the condition of individuals with disorders and studying the effects of brain stimulation using induced electric fields.
[0009] Embodiments of this (and other) aspects of the invention can include the following features. The duration of each pulse in the sequence can be less than or equal to about 1 millisecond. Successive electric pulses can have alternating polarity. The electric field in air can be substantially unidirectional over at least a region of the brain, such as an interior region of the brain, e.g., the prefrontal cortex. The electric field in air can be substantially spatially uniform (e.g., have a change in magnitude within 10% or 20%, or possibly larger) over at least a region of the brain, such as an interior region of the brain, e.g., the prefrontal cortex. The magnetic field that creates this electric field can be a gradient magnetic field (i.e., a magnetic field one or more of whose x, y, or z direction components varies approximately linearly in space). The effectiveness of the method of treatment can be evaluated by evaluating the person for improvement of symptoms after subjecting the person to the magnetic field.
[0010] In another aspect of the present invention, a method of treating a person who experiences symptoms of a psychotic disorder involves generating a time-varying magnetic field, where the magnetic field induces an electric field in air comprising a series of electric pulses. The series of pulses has a frequency of at least about 100 Hz, each pulse has a single polarity, and the pulses are separated by periods of substantially no electric field. Subjecting the person's head to this time-varying magnetic field treats the symptoms of the psychotic disorder, e.g., schizophrenia or a schizoaffective disorder. This aspect of the invention can also be used to treat abuse or dependence on a substance such as alcohol or nicotine. In addition, it can be used to treat other disorders such as attention deficit hyperactivity disorder, post-traumatic stress disorder, obsessive-compulsive disorder, bipolar disorder, panic disorder, and pain and movement disorders. In embodiments of this treatment protocol, the frequency of the series of electric pulses is about 1 kHz.
[0011] In another aspect of the invention, a method of treating a person who experiences symptoms of a psychotic disorder involves generating a time-varying magnetic field with a maximum strength of less than about 500 G (e.g., 50 or 225 G), where the magnetic field induces an electric field in air comprising a series of electric pulses. Each pulse has a single polarity and the pulses are separated by periods of substantially no electric field. The person's head is subjected to the time-varying magnetic field to treat the symptoms of the psychotic disorder, e.g., schizophrenia or a schizoaffective disorder. This aspect of the invention can also be used to treat abuse or dependence on a substance such as alcohol or nicotine. In addition, it can be used to treat other disorders such as attention deficit hyperactivity disorder, post-traumatic stress disorder, obsessive-compulsive disorder, bipolar disorder, panic disorder, and pain and movement disorders. In embodiments of this treatment protocol, the maximum magnetic field strength is less than about 50 G (e.g., 10 G). In other embodiments, the electric pulses have an amplitude less than about 10 V/m (e.g., 5 V/m).
[0012] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, suitable methods and materials are described below. All publications, patent applications, patents, and other references mentioned herein are incorporated by reference in their entirety. In case of conflict, the present specification, including definitions, will control. In addition, the materials, methods, and examples are illustrative only and not intended to be limiting.
[0013] The details of one or more embodiments of the invention are set forth in the accompanying drawings and the description below. Other features, objects, and advantages of the invention will be apparent from the description and drawings, and from the claims.
DESCRIPTION OF DRAWINGS
[0014] FIG. 1 is a diagram of a system and apparatus for administering the present magnetic field treatments.
[0015] FIG. 2 is an example of a magnetic field waveform used in the present magnetic field treatment methods.
[0016] FIG. 3 is an example of an electric field waveform induced using the present magnetic field treatment methods.
[0017] FIG. 4 is a table summarizing the effects of the present treatment.
[0018] FIG. 5 is a table summarizing the statistical significance of the effects of the present treatment.
[0019] FIG. 6 is an example of a magnetic field waveform used in an example of repetitive transcranial magnetic stimulation.
[0020] FIG. 7 is a three-dimensional plot of a magnetic field used in an example of repetitive transcranial magnetic stimulation.
[0021] FIG. 8 is an example of an electric field waveform induced using an example of repetitive transcranial magnetic stimulation.
[0022] FIG. 9 is a contour plot of an electric field used in an example of repetitive transcranial magnetic stimulation.
[0023] FIG. 10 is a three-dimensional plot of an electric field used in an example of repetitive transcranial magnetic stimulation.
[0024] FIG. 11 is a table comparing parameters for an exemplary repetitive transcranial magnetic stimulation protocol to parameters for an exemplary protocol of present magnetic field treatment methods.
DETAILED DESCRIPTION
Apparatuses and Systems
[0025] A device 10 according to the present invention is shown in FIG. 1 . The device 10 has a magnetic coil 12 , an amplifier 14 , and a waveform generator 16 . The waveform generator 16 (e.g., a general-purpose programmable computer or a purpose-built electric circuit) provides an electrical pulse sequence to the amplifier 14 , which amplifies the electrical signals and provides them to the magnetic coil 12 .
[0026] The magnetic coil 12 produces a magnetic field in response to electrical signals received from the amplifier 14 . If the signals vary in time, then it also necessarily produces an electric field, and this electric field is substantially uniform and unidirectional over the region in which the subject's brain is positioned. One way that this can be achieved is if the magnetic field has a spatial gradient that is substantially uniform (i.e. the magnetic field strength of any one vector component of the magnetic field varies substantially linearly with distance). The electric field for any coil configuration can be expressed as the sum of several potential terms; including some related to the magnetic field. If the gradient of the magnetic field is substantially uniform and unidirectional then inhomogeneity in the electric field will be reduced, providing a substantially uniform and unidirectional electric field according to Maxwell's Equations (reference Jackson 1975). (Alternatively, a magnetic coil can be used that generates a substantially uniform and unidirectional gradient magnetic field over only a region of interest of the brain, e.g., the left prefrontal cortex.) Other magnetic configurations can be utilized that are consistent with a substantially uniform electric field as required by Maxwell's Equations. The magnetic coil 12 is large enough to accommodate a subject's head, with a diameter of, e.g., about 35 cm (14 in.).
[0027] When being treated with device 10 , the subject 18 lays down on a standard patient gurney 20 with a head support 22 , with his or her head positioned inside the coil 12 . An alternative would be to use a smaller device where only the top of the patient's head lies within the coil.
[0028] Other devices can also be used for administering the present treatment method. For instance, a conventional magnetic resonance imaging apparatus can be used. Alternatively, instead of using a device such as device 10 that consists of separate components, the device can instead integrate one or more components, e.g., to make the device easily portable. Alternatively or additionally, the magnetic coil can be included in a hat-like structure, and the waveform generator, amplifier, and power source (e.g., a battery) integrated into a control mechanism that the subject carries or wears, i.e., on his or her subject's belt. The subject can self-administer the treatment, and the treatment can be applied while the subject is lying down, standing, sitting, or in motion. Alternatively or additionally, the control device can be pre-set to administer the treatment for specific periods at specific intervals or continuously.
Methods
[0029] Prior to receiving treatment using device 10 , a subject is selected as a candidate for enhancement of brain function. This selection is generally performed by medical professionals, e.g., because the subject has been diagnosed as suffering a psychiatric disorder. Alternatively, a subject could self-select based on a perceived need or desire to enhance brain function. Selection can be based on either subjective or objective criteria, including, e.g., anxiety, moodiness, depression, lethargy, sleepiness, learning difficulties, memory impairments, attention deficit hyperactivity disorder, post-traumatic stress disorder, obsessive-compulsive disorder, bipolar disorder, panic disorder, and pain and movement disorders.
[0030] To administer the treatment, the subject's head is positioned inside coil 12 , and subjected to a time-varying magnetic field. (Alternatively, the subject's entire body could be positioned inside a full-body coil, and subjected to a time-varying magnetic field.)
[0031] The magnetic pulse train used to generate the time-varying magnetic field is shown in FIG. 2 . The pulse train comprises a sequence of pulses delivered at a high rate. As discussed in detail below, the magnetic field induces an electrical field in the subject's brain. This electrical field can interact with neurons to cause cognitive effect. In light of this, the duration of each individual magnetic pulse is selected to be on the order of the refractory period of an axon, i.e., on the order of several milliseconds, see, e.g., E. R Kandel et al., Principles of Neural Science, 1991, which is incorporated by reference herein. Thus, the pulse duration can be from on the order of 0.1 milliseconds to 10 milliseconds (e.g., 0.25 milliseconds).
[0032] For example, each magnetic pulse has a trapezoidal shape, with 128 microsecond ramp times (from zero to plateau) and 768 microsecond plateau times (for a total duration of 1.024 milliseconds). The pulses alternate in polarity, and may be delivered in discrete pulse trains. A single pulse train comprises 512 successive pulses, and so lasts for about a half-second. After a delay of about a second-and-a-half, the pulse train is repeated (giving one pulse train every two seconds), and the treatment concludes after about six hundred repetitions (for a total treatment time of about 20 minutes). Alternatively, the second-and-a-half delay between successive pulse trains can be eliminated.
[0033] At the plateau of each trapezoidal pulse, the maximum magnetic field strength is on the order of 5-10 G, with a magnetic field gradient of, e.g., 0.33 G/cm for some devices, 1.52 G/cm for other devices, and can be substantially greater for still other devices. Pulse sequences yielding maximum magnetic field strengths of up to about 500 G (e.g., 225 G), and maximum magnetic field gradients of up to about 25 G/cm (e.g., 13 G/cm), can alternatively be used.
[0034] These magnetic fields induce electric fields in the subject's brain. The characteristics of these electric fields are defined by the magnetic field parameters according to Maxwell's equation: ∇×E(x, y, z, t)=−∂B(x, y, z, t)/∂t, where ∇×E is the curl of the electric field and
[0000]
∂
B
∂
t
[0000] is the rate of change of the magnetic field over time. In Cartesian coordinates, this equation becomes:
[0000] ∂ E x /∂y−∂E y /∂x=−∂B z /∂t,
[0000] ∂ E y /∂z−∂E z /∂y=−∂B x /∂t,
[0000] ∂ E z /∂x−∂E x /∂z=−∂B y /∂t,
[0000] where the subscripts x, y, and z denote the component of the fields along those respective axes, see, e.g., J. D. Jackson, Classical Electrodynamics, 1975, which is incorporated herein by reference.
[0035] These equations describe fields in free space (i.e., fields produced in the absence of other material). When conductive matter, such as brain tissue, is placed in the changing magnetic field, a charge distribution is also induced, resulting in an electric field. This electric field will affect the overall electric field in the head. This charge distribution can alter the free space electric field by up to about 50%, see Roth et al, Electroencephalography and Clinical Neurophysiology, 81:47, 1991, which is incorporated herein by reference. The pattern of the effect of the charge distribution will depend on the shape and placement of the subject's head.
[0036] Two local field distributions are of particular interest. In the first, the z-component (superior-inferior component) of the magnetic field has a uniform gradient in the y-direction (anterior-posterior direction), and the y-component has a uniform gradient in the z-direction: (B x =0, B y =G(t)z, B z =G(t)y), where G(t) is the value of the gradient. In this case, the electric field can generally be described by the following equation (small additional corrective terms may be involved): (E x =E 0 (t)+1/2(∂G(t)/∂t)·(y 2 −z 2 ), E y =0, E z =0), where E 0 (t) is a spatially constant field term that depends on the size of the coil and, consequently, the extent of the magnetic field. The preceding field description applies equally for the two other orientations, which are obtained by replacement of x with y, y with z, and z with x or by replacement of x with z, y with x and z with y, in both the vector components and coordinates. In addition, a given vector combination of these three field components, which forms an equivalent but rotated field, is also appropriate. Thus, one approach to applying the new treatment techniques involves using a magnetic field that has a vector component with a gradient that is substantially uniform, e.g., to within 10%, in value or direction over a relevant volume of the subject's brain, e.g., a 8 cm 3 volume or the prefrontal cortex.
[0037] In another magnetic field distribution, the magnetic field is uniform over a local volume, which can be expressed as: (B x =0, B y =0, B z =B(t)). The corresponding local electric field can generally be described by the following equation (small additional corrective terms may be involved): (E x =E 0 (t)−a(∂B(t)/∂t)·y, E y =E 0 (t)−(1−a)−(∂B(t)/∂t)·y, E z =0), where a is an arbitrary parameter determined by the details of coil winding.
[0038] In both situations, if E 0 (t) is sufficiently large compared to ∂G(t)/∂t·R 2 or ∂B(t)/∂t·R, where R is an effective radius of the volume of interest, e.g., the radius of a subject's brain, then the local electric field is substantially uniform. The preceding field description applies equally for other orientations and rotations.
[0039] An LFMS magnetic field can have the following spatial dependence: {right arrow over (B)}(x, y, z)=G(y{circumflex over (z)}+zŷ), where G is the gradient magnetic field strength in Gauss/cm (e.g., 0.33 G/cm for certain devices and 1.52 G/cm for other devices, as mentioned above) and “z hat” indicates field in the z direction. This field distribution is accurate over the region of the head but may have a different distribution outside that region.
[0040] The induced electric field accompanying the LFMS magnetic field has the following spatial dependence: {right arrow over (E)}(x,y,z)={dot over (A)} 0 {circumflex over (x)}+1/2G(y 2 +z 2 ){circumflex over (x)}, where “A 0 dot” is time rate of change for the vector potential of the coil at the center of the active region and has the units of electric field (V/m) and “G dot” is time rate of change for the gradient magnetic field. “A 0 ” is a characteristic of the coil and current waveform, and determines the induced electric field strength of the coil. “A 0 dot” can be, e.g., 0.7 V/m for certain devices, 1.5 V/m for other devices, and substantially higher for still other devices. The electric field for the LFMS coil is substantially described by the first term, while the second term produces an inhomogeneity in the volume. The LFMS electric field waveform can be described by 5 parameters: pulse amplitude (V/m), pulse duration (μs), pulse frequency (Hz), repetition time (sec), total treatment time (min) and alternating sign of pulses (yes or no). Additionally, the electric field is characterized by a 6th parameter, the direction of the field. The preceding field description applies equally for the two other orientations, which is obtained by replacement of x with y, y with z, and z with x or by replacement of x with z, y with x and z with y, in both the vector components and coordinates. In addition, a given vector combination of these three field components, which forms an equivalent but rotated field, is also appropriate.
[0041] FIG. 3 shows the electric field waveform induced in the subject's brain when subjected to the magnetic field waveform shown in FIG. 2 . The electric field waveform is a sequence of square pulses of alternating polarity. The pulses are monophasic, here meaning that each pulse has a single polarity. Each pulse is separated from the neighboring pulses by a period of substantially no electric field. The width of each induced electric pulse corresponds to the ramping period for the magnetic field pulses, i.e., 256 microseconds. For the 1.8 G/cm magnetic field pulse amplitude, the electric field amplitude is approximately 1.4 V/m. This electric field strength is approximately an order of magnitude less than the minimum peripheral nerve stimulation threshold of approximately 6-25 V/m, see, e.g., J. P. Reilly, Medical and Biological Engineering and Computing, 27:101, 1989, thus providing an appropriate margin of safety against causing pain or seizures in the patient.
Use of LFMS to Affect Brain Function
[0042] The use of LFMS to date indicates that LFMS affects brain function. LFMS may affect brain function in several ways, with one mechanism being an effect on white matter tracts in the brain. White matter effects could result from an enhancement of electrophysiological function in the neurons making up the white matter tracts. White matter structures such as the corpus callosum may be especially sensitive to the LFMS electric field. This enhancement could produce results directly by increasing white matter function in diseased or compromised neurons through a mechanism similar to long-term potentiation in which neural thresholds are reduced through electrochemical changes; it could also produce results through immediate enhancement of white matter function in cortical circuits that regulate mood and affect; and both of these methods could produce longer lasting effects in post-synaptic gray matter by enhancing cell growth. It is possible that pre-synaptic interaction could provide a basis for immediate mood effects, and post-synaptic effects could provide effects associated with longer times scales such as participation in second messenger systems leading to changes in gene expression, neurotrophic responses and dendritic sprouting in the hippocampus see, E. J. Nestler et al., Neuron 34:13-25, 2002; M. A. Smith M A et al., J Neurosci 15:1768-77, 1995. In particular, post-synaptic changes could affect deficits in Brain Derived Neurotrophic Factor (BDNF) which regulates neural growth and dendtritic sprouting.
[0043] A number of disorders are associated with abnormalities in white matter tracts and BDNF deficits including mood disorders (e.g., bipolar disorder and late-life depression), psychotic disorders (e.g., schizophrenia and other schizoaffective disorders), anxiety disorders (e.g., panic disorder, OCD, and PTSD), ADHD, and substance abuse and dependence. Some of these disorders share activation deficit patterns with depression, as measured by functional magnetic resonance imaging (fMRI) and positron emission tomography (PET). LFMS may treat these disorders and alleviate their symptoms.
[0044] LFMS could affect white matter directly, enhancing white matter function. During white matter enhancement such as occurs in long term potentiation, the electric field induced during the LFMS exposure may cause the observed effects by directly affecting ion concentrations and other electrochemical signaling mechanisms within the neuron. The LFMS electric field is about 1 V/m, of a magnitude that could affect the electrochemical processes supporting neural signaling, see W. Irnich W, MAGMA 2:43-49, 1994; W. Wang et al., In Proceedings of Joint Meeting of the Society of Magnetic Resonance Third Scientific Meeting and Exhibition and the European Society for Magnetic Resonance in Medicine and Biology, 19-25 Aug. 1995 (pp. 73), 1995 [Nice, France: SMR/ESMRMB]. Changes in ion concentration near receptors or ion channels that are caused by the fields from LFMS could provide an effect similar to long term potentiation (LTP). This effect might be strongest in white matter tracts that particularly align with the electromagnetic field. In particular LTP has been studied for involvement in animal models of stress and depression, see M. Popoli et al., Bipolar Disord 4:166-82, 2002; E. Tsvetkov et al., Neuron 41:139-51, 2004, and has been seen in studies in animal models of depression, see Y. Levkovitz et al., Neuropsychopharmacology 24:608-16, 2001; M. Ogiue-Ikeda et al., Brain Res 993:222-6, 2003.
[0045] The direct action of LFMS on white matter could affect the function of networks of neurons in cortical areas. These effects could result from widespread interaction with neurons that participate in a “neural circuit” that controls a high order of brain function. Neural circuits have been implicated in models of depression through patterns of activation using fMRI and PET, see H. S. Mayberg, Br Med Bull 65:193-207, 2003.
[0046] LFMS could also enhance brain function post-synaptically by changing the function of cells located at the synapses at the termination of directly affected neurons. Post-synaptic effects include an increase in brain growth and dendritic sprouting, which reverse the degenerative effects of various diseases. The hippocampus is a brain structure that has been studied as an area that could provide a post-synaptic site for the effects of treatment. Depression, anxiety disorders, schizophrenia and substance abuse disorders are associated with neuronal degeneration in the hippocampus and reductions in dendritic branching, see R. S. Duman et al., Arch Gen Psychiatry 54:597-606, 1997; A. V. Kalueff et al., Science 312:1598-9, 2006; G. Shoval. & A. Weizman, Eur Neuropsychopharmacol. 15(3):319-29, 2005; P. H. Janak, Alcohol Clin Exp Res., 30(2):214-21, 2006. Successful treatment of these disorders increases BDNF expression in the hippocampus, see M. Nibuya et al., J Neurosci 15:7539-47, 1995; B. Chen et al., Biol Psychiatry 50:260-5, 2001; and may increase dendritic sprouting, see S. D. Norrholm & C. C. Ouimet, Synapse 42:151-63, 2001; R. S. Duman et al., Neuropsychopharmacology 25:836-44, 2001. LFMS may additionally strengthen excitatory synaptic strength in the hippocampus through electrophysiological mecahnisms, see M. Korte et al., J Physiol Paris 90:157-64, 1996; H. Kang et al., Neuron 19:653-64, 1997. One explanation of this process suggests that reductions in neurotrophic factors, notably brain derived neurotrophic factor (BDNF), are linked to systems such as cAMP response element binding protein (CREB), through second messenger pathways such as cAMP and Ca++, see M. A. Smith et al., J Neurosci 15:1768-77, 1995; T. E. Meyer & J. F. Habener, Endocr Rev 14:269-90, 1993; A. Ghosh & M. E. Greenberg, Science 268:239-47, 1995. The presence of ions such as Ca in these neural signaling pathways and the electrochemical nature of many of the synaptic receptors and ion channels involved suggest that interaction of these systems with the electromagnetic fields of LFMS is possible. The timing of the LFMS waveform could be an important factor in this successful interaction. The LFMS electric field pulses are 250 microseconds in duration and delivered at 1 kHz with alternating polarity. The timing of the LFMS electric field pulses occurs on a timescale similar to the reaction times of these systems, and this may be a reason for the observation of the observed effects at such low field strengths. LFMS, with its single phase excitation pulses which have sub-millisecond duration, may interact efficiently with these signaling systems in the brain because many components of these systems (such as ion channels) have a response time on the order of 1 ms.
[0047] Antidepressant medications have been hypothesized to increase monoamines at central synapses. This, in turn, influences intracellular second messenger systems, which activates neurogenesis and dendritic sprouting in the hippocampus, and leads to improved neuronal function. It has been proposed that the antidepressant effects of magnetic stimulation of the cortex act through presynaptic inputs to the hippocampus and participate in this process, see M. Popoli M et al., Bipolar Disord 4:166-82, 2002. The time course of patient response to antidepressant treatments is on the order of weeks, and may be indicative of the time required for this neurogenesis, see H. K. Manji HK et al., Biol Psychiatry 53:707-42, 2003. This model of the antidepressant effects of magnetic stimulation of the cortex, suggesting that primary effects occur with stimulation in the cortex but have long term secondary effects in the hippocampus, may apply to LFMS.
[0048] A number of proposed mechanisms for depression have been explored using both cognitive and neurobiological models. Cognitive models have been studied with functional imaging techniques that examine metabolic and hemodynamic changes in resting brain state. These types of studies using PET and MR show a pattern of cortical hypometabolism in dorsal prefrontal cortical regions and of hypermetabolism in paralimbic and ventral cortical regions, see C. E. Bearden et al., Bipolar Disord 3:106-50, 2001 (in particular pages 151-53); H. S. Mayberg, Semin Clin Neuropsychiatry 7:255-68, 2002; R. T. Dunn et al., Biol Psychiatry 51:387-99, 2002; R. M. Post et al., Ann Clin Psychiatry 15:85-94, 2003. These metabolic states are reversed with successful treatment or remission of depression. One study identified pre-treatment perfusion levels in the rostral cingulate as a possible marker of successful treatment, see H. S. Mayberg, Br Med Bull 65:193-207, 2003 in manic depressive disorder, while another implicated cerebellar regions in the neurobiology of bipolar depressive disorder, see T. A. Ketter et al., Biol Psychiatry 49:97-109, 20001. In these models depression is discussed as a dysfunction of balanced neural circuits, with the total interaction between these areas being more important than changed function in any one area. Successful treatment or remission is accompanied by the correction of (or compensation for) this dysfunction. LFMS may interact with these networks because LFMS may induce electric fields in the axons making up these circuits, and may modify electrochemical signaling mechanisms and balance within these neural networks.
[0049] Depression has also been associated with abnormalities in white matter tracts in the brain. Abnormal white matter anisotropy within the frontal and temporal lobes has been observed in patients with late-life depression, see K. Nobuhara et al., J Neurol Neurosurg Psychiatry 77:120-22, 2006. A smaller genu, the region of the corpus callosum where interhemispheric fibers from the frontal regions of the brain cross, has been observed in depressed patients, see I. K. Lyoo et al., Biol Psychiatry 52:1134-43, 2002. In addition to general observations of abnormalities in white matter tracts in persons with depression, such abnormalities have in particular been found in persons with bipolar disorder. Microstructural changes and changes in anisotropy in white matter have been found, see C. M. Adler et al., Bipolar Disorders, 6:197-203, 2004; C. M. Adler et al., Am J Psychiatry, 163:322-24, 2006; J. L. Beyer et al., Neuropsychopharmacology 30:2225-29, 2005. Loss of bundle coherence in prefrontal white matter tracts or other disruption in network connectivity or white matter bundling may be implicated in the symptomatology of bipolar disorder, see Adler et al., Bipolar Disorders, 6:197-203, 2004. LFMS may counteract or mitigate these adverse changes, or enhance function in compromised white matter tracts by enhancing neural signaling through electrophysiological mechanisms similar to potentiation.
[0050] Schizophrenia and schizoaffective disorders have been associated with abnormalities in white matter tracts, cerebral circuit disconnectivity, hippocampal degeneration and with deficits of BDNF. Abnormalities in the amygdale, endtorhinal cortex, middle cerebellar peduncles, the genu and truncus of the corpus callosum, the internal capsule and anterior commissure of the right hemisphere, inferior frontal white matter, anterior cingulate, caudate, insula, inferior parietal lobule, left postcentral gyms, right superior/middle temporal gyms, and bilateral fusiform gyms have been observed in persons with schizophrenia, see M. J. Hoptman et al., Brain Imaging 15(16):2467-70, 2004; H. E. Hulshoff et al., NeruoImage 21:27-35, 2004; G. Okugawa, et al., Neurophychobiology 50:119-23, 2004; P. Kalus et al., Neuroscience Letters 375:151-56, 2005; P. Kalus et al., NeuroImage, 24:1122-29, 2005; A. M. Brickman et al., J Neuropsychiatry Clin Neurosci., 18(3): 364-76, 2006; and N. Rusch & G. Spalletta, Psychiatr Danub. 1:20, 2006. LFMS could provide treatment for the symptoms of schizophrenia and schizoaffective disorders through direct electromagnetic interaction with white matter tracts.
[0051] Schizophrenia has displayed neural circuit changes which could be part of its pathophysiology. Fronto-temporal connectivity changes in white matter tracts, such as the uncinate fasciculus and cingulum bundle, have been observed in persons with schizotypal personality disorder, see M. Nakamura et al., Biol Psychiatry 58:468-78, 2005, and cerebral disconnectivity has been seen in early stages of schizophrenia, see A. Federspiel et al., Neurobiol Dis. 22(3):702-9, 2006. Finally, schizophrenia shares some of the hippocampal volume reduction, see N. Kuroki et al., Biol Psychiatry, 60(1):22-31, 2006, and BDNF dysfunction effects, see G. Shoval & A. Weizman, Eur Neuropsychopharmacol., 15(3):319-29, 2005, that could benefit from any post-synaptic changes affected by LFMS treatment. Treatment of schizophrenia with rTMS has been studied with positive results, particularly in the abatement of auditory hallucinations, see P. B. Fitzgerald et al., World J Biol Psychiatry, 7(2):119-22, 2006; and Y. Jin et al., Schizophr Bull., 32(3):556-61, 2006.
[0052] Anxiety disorders such as PTSD can benefit from post-synaptic changes affected by LFMS because they display BDNF deficits, see A. V. Kalueff et al., Science, 312(5780):1598-9, 2006. PTSD and anxiety disorder have benefited from the electromagnetic rTMS treatment, see H. Cohen et al., Am J Psychiatry, 161(3):515-24, 2004 and may also benefit from LFMS treatment.
[0053] Drug abuse shares many of the cognitive patterns of change in regions regulating mood, cognitive function, memory and reward that are affected in depression, see N. D. Volkow et al., Pharmacol Ther., 108(1):3-17, 2005. It shows changes in the hippocampus similar to those of depression, see L. Pu et al., Nat Neurosci., 9(5):605-7, 2006; and P. H. Janak et al., Alcohol Clin Exp Res. 30(2):214-21, 2006. Treatments for drug abuse reflect this overlap with treatments for depression, and many antidepressant medications are also used in the treatment of drug abuse. LFMS could provide a treatment for drug abuse, providing beneficial effects that parallel these antidepressant based treatments.
[0054] Abnormalities in white matter tracts have also been associated with a number of other disorders, including ADHD, PTSD, and substance abuse, see Teicher et al., Psychiatr Clin N Am 25:397-426, 2002. For example, increased curvature in the genu of the corpus callosum and abnormalities in the posterior midbody and isthmus area of the corpus callosum have been observed in persons who abused methamphetamine, see J. S. Oh et al., Neuroscience Letters, 384:76-81, 2005. Evidence of abnormal white matter microsctructure has also been found in patients with obsessive compulsive disorder, see Arch Gen Psychiatry 62:782-90, 2005. The direct action of LFMS on white matter tracts could provide treatment for these disorders.
EXAMPLES
Experiment
[0055] An experiment demonstrating the LFMS effect in the treatment of depression was performed in 2001 at McLean Hospital, see M. Rohan et al., Am J Psychiatry, 161(1):93-98, 2004. The study population was comprised of participants in three studies of medications for bipolar disorder. These studies were investigating the effects of conventional and non-conventional (omega3 fatty acid supplements) therapies on mood and brain chemistry over a period of time, and involved LFMS MRI scans and clinical interviews on a monthly basis. At the start of these studies the beneficial effects of LFMS were not known, and the LFMS MRI scan was an experimental MRI scan used to measure chemical concentration. Subjects had a diagnosis of Bipolar I or II Disorder and were between the ages of 18 and 65. They were either currently on a course of medication including lithium, Depakote, and other anticonvulsants, or were medication free at the start of the study. Subjects who were given anxiolytic medication during the scan sessions or who were taking medication in addition to those listed above were not considered in this study. Only mood improvement data from first visits was used to prevent confounds due to medication changes.
[0056] The “Brief Affect Scale” (BAS) measures change in immediate mood state on a 7-point scale and was administered to all subjects immediately before and after the MR scanning session. These numerically ranked responses were grouped into the ordinal categories of “improved” (3 to 1), “same” (0) and “worse” (−1 to −3) for statistical treatment.
[0057] Studies were conducted at the McLean Hospital Brain Imaging Center. Scanning was performed on a 1.5T MRI scanner. Subjects with bipolar disorder who received LFMS MRI scans received 20 minutes of LFMS sequences along with 30 minutes of anatomic MR scans at each visit. The LFMS sequence was an Echo-Planar scan that is described below. Some subjects with bipolar disorder were treated with a sham LFMS MRI scan in order to provide an experimental control. The sham MRI scan was identical to original exam, except that the LFMS sequence was replaced with a three-dimensioned spoiled gradient echo scan. Additionally, a group of healthy comparison subjects were given LFMS MRI scans with the same protocol, as a second experimental control group.
[0058] Ordered logistic regression modeling methods were used to examine the differences in BAS scores among the study groups. Data were summarized as means (±SD) or by means with 95% confidence intervals (95% CI). Two sided significance tests, requiring p<0.05 for statistical significance, were employed.
[0059] Twenty-three of 30 subjects with Bipolar Disorder reported improvement in mood of at least 1 point on the BAS scale after LFMS treatment. “No change” was reported by 6 subjects, and a worsening of mood was reported by 1 subject. The mean BAS score for bipolar subjects receiving LFMS was 0.87±0.68. In the subgroup of unmedicated bipolar LFMS subjects, 11 of 11 subjects reported improvement in mood (mean BAS score=1.18±0.41), compared to reports of improvement by 12 of 19 subjects with bipolar disorder in the subgroup taking mood stabilizing medication (mean BAS score=0.68±0.75).
[0060] Three of 10 subjects with Bipolar Disorder who received sham treatment reported improvement in mood after the exam, with 2 reports of worsening in mood. The mean BAS score for bipolar subjects receiving sham treatment was 0.30±1.06.
[0061] Four of 14 healthy subjects reported improvement in mood after an LFMS treatment, with no reports of worsening. The mean BAS score for healthy subjects receiving LFMS treatment was 0.29±0.47. Table A summarizes these BAS improvement scores.
[0062] Ordinal BAS ratings were compared between bipolar subjects who received LFMS treatment (N=30, mean BAS=0.87±0.68) vs. those receiving sham treatment (N=10, mean BAS=0.30±1.06) using ordered logistic regression methods. This difference was statistically significant (z=2.63, p=0.009). The higher BAS scores in the LFMS subjects indicate greater perceived mood improvement in this group compared to the bipolar sham LFMS group.
[0063] Ordinal BAS ratings were compared between unmedicated bipolar LFMS subjects (N=11, mean BAS improvement 1.18±0.41) and medicated bipolar LFMS subjects scans (N=19, mean BAS=0.68±0.75). This difference was statistically significant (z=2.02, p=0.044).
[0064] Ordinal BAS ratings were also compared between bipolar LFMS subjects (N=30, mean BAS=0.87±0.68) and healthy subjects who received LFMS (N=14, mean BAS=0.29±0.47). This difference was also statistically significant (z=2.61, p=0.009). The contrast between bipolar sham LFMS subjects and healthy LFMS subjects was not significant (z=0.29, p=0.77). A summary of these results is listed in FIGS. 4 and 5 . FIG. 4 shows the results of the Brief Affect Scale assessment of mood in all subjects after LFMS or sham treatment. FIG. 5 shows the statistical significance of the contrast between mood improvement in the different groups of subjects.
[0065] We found significant improvement of mood in depressed subjects with bipolar disorder after LFMS treatment. This improvement was absent in bipolar subjects who received sham LFMS treatment, and was also absent in healthy subjects who received LFMS treatment. A greater effect was evident in medication-free subjects.
[0066] The treatments were administered using a General Electric 1.5T Signa MRI scanner. After optional water suppression, slice selective excitation, and a spatial phase encoding pulse, the device applied a train of 512 trapezoidal alternating-polarity magnetic field pulses. These pulses were about one millisecond long, with ramp times of 128 microseconds and 768 microsecond plateau times. During the plateau of each pulse, the gradient was 0.33 G/cm, and the maximum magnetic field in the cortex was about 5 G. The entire train of 512 pulses was repeated every 2 seconds, six hundred times, for a total treatment time of 20 minutes. FIG. 2 is a diagram of the magnetic field pulse train. The ‘X’ gradient coil in the magnetic resonance scanner, having an approximate diameter of about 90 cm (36 in.), was used to apply this sequence, orienting the gradient in the right-left direction for the supine subjects. The gradient of the z-component of the magnetic field from this coil in the x-direction is uniform in both magnitude and direction over a subject's brain to within about 5%.
[0067] The magnetic field induced an electric field in the brains of the subjects. This electric field was oriented from front to back, from the subject's perspective. The induced electric field consisted of 256 microsecond monophasic square pulses, where each pulse has a single polarity and an amplitude of approximately 0.7 V/m. A diagram of this electric field waveform is shown in FIG. 3 .
[0068] To achieve the same electric field with a smaller coil, Maxwell's equations show that a higher magnetic field may be required. Using a coil with a similar shape but smaller diameter, e.g., a “head-sized” 35 cm (14 in.) coil instead of a 36-inch “whole-body” gradient coil that was in the MRI system, to induce a similar same electric field magnitude would employ a magnetic field that reaches approximately 50 G in the head. The magnetic field used to induce such an electric field can have a vector component with a gradient that is slightly less uniform in value and direction, varying by about 10% over the cranial volume. In addition, a higher magnetic field, e.g., 100 G, can be used with a smaller coil that provides a vector component with a substantially uniform gradient over only a region, e.g. 8 cm 3 , of the brain.
Comparative Example
[0069] rTMS employs electric fields on the order of 500 V/m in the cortex, more than sufficient to cause neural depolarization, and fields on the order of 50V/m in subcortical structures, see M. Nadeem et al., IEEE Trans Biomed Eng, 50:900-7, 2003. It uses a bi-phasic waveform that reverses sign during each pulse. The electric field direction for rTMS has a circular pattern similar to a projection of the magnetic loops that are its source. LFMS, however, has electric fields that are relatively weak in comparison to other stimulation techniques (<1 V/m), not enough to depolarize a neuron in general, but that penetrate uniformly through all structures. LFMS uses a monophasic waveform that does not reverse sign during the pulse. Finally, the LFMS field observed to produce this effect has a uniform direction rather than the circular direction of rTMS.
[0070] One example of an rTMS technique uses a figure-8 surface coil with loops that are 4 cm in diameter (Cadwell, Kennewick, Wash.). This coil is placed next to the scalp, and is usually positioned to direct the magnetic field at the prefrontal cortex of the brain, see, e.g., George et al., The Journal of Neuropsychiatry and Clinical Neurosciences, 8:373, 1996. An electric current is run through the magnetic coil to generate a magnetic field, specifically a sequence of single-cycle sinusoidal pulses where each pulse has a frequency of approximately 1800 Hz (or about 560 microseconds per pulse). These pulses are delivered at a repetition rate of 1 Hz (i.e., one single-cycle sinusoidal pulse every 1 second), see, e.g., George et al, Biological Psychiatry, 48:962, 2000; Eschweiler et al, Psychiatry Research: Neuroimaging Section, 99:161, 2000. This waveform is shown in FIG. 6 . As the repetition period is much longer than the time span on the time axis, only one single-cycle sinusoidal pulse appears in FIG. 6 .
[0071] The magnetic field generated by the FIG. 6 waveform is shown in FIG. 7 . The field reaches its maximum strength of approximately 10,000 G at the face of the coil. The strength of this magnetic field decreases rapidly as the distance from the coil increases, to about less than 1 G at about 6 cm to 8 cm, see, e.g., Cohen et al, Electroencephalography and Clinical Neurophysiology, 75:350, 1990.
[0072] FIG. 8 shows the electric field waveform induced in the subject's brain by the magnetic field shown in FIG. 7 . This waveform consists of a series of 560-microsecond single-cycle cosine pulses that repeat every 1 Hz.
[0073] FIG. 9 shows the contour plot and FIG. 10 shows the three-dimensional plot of the electric field induced in free space by the magnetic field shown in FIG. 2 . The electric field is approximately 120 V/m at the face of the coil, and falls to about 0.02 V/m on the side of the head opposite the coil. The contours of this rapidly diminishing electric field reflect the shape of the figure-8 surface coil with 4 cm diameter loops, tilted at 45°, and placed 6.7 cm vertically and horizontally from a position equivalent to the center of the head: the electric field forms roughly circular loops.
[0074] FIG. 11 shows a table comparing parameters for an exemplary rTMS protocol to parameters for an exemplary LFMS protocol. As shown, LFMS uses a lower peak magnetic, a lower peak electric field, a lower electric field pulse duration than rTMS, and a higher field pulse rate. This LFMS technique also uses monophasic pulses of alternating sign compared to the use of biphasic pulses of the same sign in rTMS. The electric field direction in the LFMS technique is unidirectional, while the electric field direction in rTMS is circular.
[0075] A number of embodiments of the invention have been described. Nevertheless, it will be understood that various modifications may be made without departing from the spirit and scope of the invention. Accordingly, other embodiments are within the scope of the following claims.
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The invention involves enhancing brain function by stimulating the brain using magnetic fields. Applications of the new methods include improving the condition of individuals with cognitive disorders, such as depression, and studying the effects of neural stimulation using induced electric fields. These techniques can avoid deleterious effects of psychotropic pharmaceutical treatments, and provide a relatively safe, comfortable, inexpensive means of direct cranial stimulation.
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The invention described herein was made in the course of work under a grant or award from the Department of Health, Education and Welfare.
FIELD OF THE INVENTION
The present invention relates to an apparatus and method for the indirect monitoring of serum metabolites without entering a sensor into the patient's bloodstream or withdrawing blood from the patient. More particularly, the present invention relates to such a method and apparatus wherein the concentrations of metabolites in serum are monitored, analyzed and quantitated in real time by analyzing the dialysate solutions which are being equilibrated with the blood via a hemodialyzer.
BACKGROUND OF THE INVENTION
Significant use of dialysis therapy for patients suffering from renal disease has only been realized in recent years and the use of clinical chemistries to measure the progress of dialysis therapy is infrequent with end stage renal patients since the loss of blood for analysis must be held to a minimum in these patients because of chronically low hemocrits and because the cost of serum screens is high due to the operation of automated clinical analyzers for multiple factor analyses. As a consequence, the progress of most end stage renal patients on dialysis is followed only by a monthly assay for serum levels and by body mass measurement at each treatment session. However, it is generally recognized that a simple assay such as blood urea nitrogen (B.U.N.) would provide invaluable information on the progress of the therapy thereby enabling monitoring of the therapy and providing the opportunity for improved control of therapy. With prior art apparatus and methods such monitoring and control is accomplished by sampling the blood of the patient, and as noted previously, such techniques are not satisfactory.
SUMMARY OF THE INVENTION
An object of the invention is therefore to provide for improved blood monitoring; another object is to provide for improved dialysis; and a further object is to provide an improved apparatus and method for monitoring the progress of dialysis therapy.
Another object of the invention is to provide an apparatus by which the concentrations of metabolites in serum can be monitored, analyzed and quantitated by analyzing the dialysate solutions which are being equilibrated with the blood.
A further object of the invention is to provide an apparatus and method which provides biochemical data for monitoring of therapy and which utilizes the data for improved control of dialysis therapy.
A still further object of the invention is to provide an apparatus and method which utilizes dialysate fluid to monitor the progress of dialysis therapy.
An even further object of the invention is to provide an apparatus and method for providing one or several assays of serum metabolites during the course of dialysis therapy.
The present invention accomplishes the above objects by utilizing at least one ion-specific electrode which is contacted with a diverted portion of the dialysate effluent stream. The electrode EMF is converted to dialysate concentrations on the basis of pre-trial calibrations, and the dialysate concentrations, in turn, are related to serum levels by factors governing mass transfer through the dialyzer.
A knowledge of urea levels during dialysis can provide precise estimates to pre- and post-dialysis body levels of urea. From these, protein catabolism rates can be projected, from which metabolic acid and phosphate burdens and energy requirements for maintaining stable metabolism can be estimated. The present invention thus provides a simple means for automatic sensing and computation of metabolic balances and the procedures of the invention do not require blood access and are equally applicable to hemofiltration procedures or to hemo- and peritoneal dialysis.
In a specific example of the present invention, an aliquot of waste dialysate is sampled by a small peristaltic pump and metered with an equal volume of buffer solution into an immobilized urease column. During the passage of the solution through the column, the urea is hydrolized to ammonia and in the presence of the buffer the ratio of ammonium-ion to ammonia plus ammonium-ion is constant. This solution then passes through an ammonium-ion sensitive elctrode compartment and an EMF signal is provided via a pH meter to a strip-chart recorder or other data accumulating device. Prior to the beginning of dialysis, and at selected intervals during the treatment, calibrating solutions may be diverted from their respective reservoirs to the sensor. These calibrating solutions serve to detect any drifts in the electronics or other aberrations and in addition, they provide a check on the stability and response of the enzyme and electrode with time.
The above and other objects, advantages and the nature of the invention will be more readily apparent from the following detailed description of preferred embodiments taken in conjunction with the drawings, wherein:
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 is a somewhat diagrammatic view of an apparatus in accordance with the invention.
FIG. 2 is a graph of the potentiometric response curves of a phosphorous ion-selective electrode as a function of phosphate, sulfate, chloride and nitrate ion concentration.
FIG. 3 is a graph showing the concentration of urea nitrogen in dialysate outflow plotted semi-logarithmically versus time.
FIG. 4 is a graph showing the potentiometric response curve of the phosphorous ion-selective electrode as a function of Monitrol II serum control concentration.
FIG. 5 is a graph of the computed, on-line dialysate urea nitrogen.
FIG. 6 is a graph of the computed, on-line blood urea nitrogen.
FIG. 7 is a graph of the computed, on-line blood phosphorus.
FIG. 8 is a graph of the dialysate outlet on-line phosphorus.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
In the drawings, wherein like reference numerals indicate like parts throughout the several views, an apparatus for monitoring urea during dialysis therapy is indicated generally at 10 in FIG. 1. The apparatus includes a conduit 11 for conveying patient dialysate effluent to waste and a ball rotameter 12 is connected in the conduit 11 for measuring the dialysate flow rates. A branch conduit 13 is connected with the dialysate effluent conduit 11 for diverting a portion of the dialysate effluent to a three-way valve 14 connected in a calibration conduit 15 which is joined, in turn, with a plurality of three-way valves 16 provided at the base of a plurality of reservoirs 17 containing urea calibrating solutions. Downstream of the valve 14, the conduits 13 and 15 are combined into a single dialysate conduit 18 which leads to a peristaltic pump 19. A buffer conduit 20 extends from a container 21 of buffer concentrate to the peristaltic pump 19 for conveying buffer to the pump. The container 21 and reservoirs 17 may be supported in a suitable housing 22, if desired. Conduits 18 and 20 are combined downstream of the pump 19 into a single conduit 23 which leads to a three-way valve 24, connected in one position with an immobilized urease column 25 and in another position with a urease by-pass conduit 26, which extends between valve 24 and a second valve 27 downstream of the column 25. A discharge conduit 28 leads from the valve 27 downstream of the column 25 to an ammonium ion-sensitive electrode 29** with an internal reference probe. The electrode is extended into a receptacle or container 30 which has a waste or discharge connection 31 leading to a drain. Suitable wiring 32 leads from the electrode to a pH meter 33 which in turn is connected by coupling 34 with a suitable chart recorder or the like 35 for recording the output of the electrode 29 based upon the sensed concentration of the ammonium ion in the discharge from the column 25 through conduit 28.
EXAMPLE I:
According to one example of the invention, an experiment was carried out at the New Orleans Veteran's Administration Hospital on a male patient with two ml/day of residual clearance, and who had been on dialysis for two years and was considered stable. The patient was monitored during the second and third treatment of a thrice weekly schedule. Blood access was through a bovine graft, and an Extracorporeal EX-04 hollow fiber--dialyzer (not shown) was used, and dialysate was provided by a Milton Roy central proportioning system (MED 1390) through a bedside station. Normal hemodialysis procedures were not altered except to route the waste dialysate solution to drain via a small container from which the analytical system sampled.
The analytical procedure was essentially as described in the International Journal of Artificial Organs, Volume 1, No. 3, pages 116 through 122 (1978), Klein, E., Montalvo, JG, Wawro, R., Holland, FF, and Lebeouf, A., except that the immobilized urease column 25 replaced the soluble enzyme preparation used previously. The apparatus illustrated in FIG. 1 was used for sensing the urea and an aliquot of the waste dialysate was sampled by the peristaltic pump and metered with an equal volume of buffer solution into the immobilized ureas column 25. During the passage of the solution through the column, the urea was hydrolized to ammonia (in the presence of the buffer the ratio of NH 4 + /(NH 3 +NH 4 + ) is constant). The solution then passed through the ammonium ion-sensitive electrode compartment 30 and an EMF signal was conducted through line 32 to the pH meter 33, which in turn, supplied a signal to a strip-chart recorder 35 or other data accumulating device. Prior to the beginning of dialysis, and at selected intervals during the treatment, calibrating solutions were diverted from the reservoirs 17 to the conduit 15 and thence into conduit 18 and the electrode compartment. These calibrations serve to detect any drifts in the electronics or other aberrations. In addition, they provide a check on the stability and response of the enzyme and electrode with time. However, the results of the experiment indicated that such frequent calibration is not required and indications are that the urea electrode system can be operated with only a pre- and a post-dialysis calibration. The small drift observed during a six hour treatment period (2.5 mV) was linear in time and would thus not lead to serious errors.
A phosphate (P i ) electrode was operated in a similar manner except that no enzyme was used. Instead, a reservoir was used to maintain a constant partial pressure of oxygen since the response curve of this electrode is affected by the disolved pO 2 concentration. The sensitivity of the phosphate electrode is illustrated in FIG. 4, and its selectivity over other ions in FIG. 2. Because of the very dilute phosphate concentrations required to bring the levels to the linear response portion of the curve, the dialysate was diluted 50:1 with buffer. This dilution can also be performed with fresh dialysate containing additional buffer. However, it was more convenient to provide a separate diluent.
In order to provide a comparison of the results obtained by the indirect assay achieved with the apparatus of the invention, clinical procedures were followed utilizing blood samples taken at the beginning of dialysis, midway through dialysis treatment and at the termination of the dialysis treatment procedure. The blood samples were centrifuged after being allowed to settle for ten minutes and the plasma was analyzed by an Autoanalyzer. The accuracy of the procedures of the invention was found to be ±0.2 mg% for P i and ±0.2 mg% for serum urea nitrogen (SUN).
The dialysate flow rates were measured with the ball rotameter 12, calibrated prior to the experiment, and the blood flow was set by a calibrated blood pump (D-W No. 7404) (not shown) at 200 ml/min.
From the data obtained with the apparatus of FIG. 1, the arterial metabolite concentration (C B ) for a single pass dialysate system is related to the dialysate outflow concentration (C Do ) by
C.sub.B =C.sub.Do (K/Q) (1)
where Q is the dialysate flow rate in ml/min and K is the dialyzer clearance in ml/min. However, this relationship is valid only if the dialysate inlet solution is free of the metabolite. For assays of dialysate solution components which do have finite concentrations entering the dialyzer, such as K + , Na + and acetate or bicarbonate ions, the procedure must be altered since the value of C Di is not zero. In these instances a difference analysis (C Do -C Di ) is required. If there is a significant inlet concentration, as with Ca 2+ , K + , etc., the relationship becomes
C.sub.B =(C.sub.Do -C.sub.Di) (K/Q) (2)
where C Di and C Do are the inlet and outlet concentrations of the species in the dialysate fluid and C B is the arterial concentration. With the data obtained by analyzing the dialysate outlet fluid the serum arterial concentration can be determined via equations (1) and (2). Only the flow rate and the dialyzer clearance need be known. Moreover, the serum concentration itself is not the parameter needed for evaluation of the therapy. Rather, the total mass of such species transferred is desired and this can be achieved by summing the cross-product of the instantaneous concentration and the flow rate, i.e.,
M.sub.i =ΣQ.sub.D (C.sub.Do -C.sub.Di)
For the computation of body K + burden, it is possible to measure the differential concentration (C Do -C Di ) by use of differential electrodes. The product of this difference times the flow rate summed (or integrated, if a function is found) provides a measure of the mass of K + removed during dialysis. Since the K + burden is a important factor in the control of cardiac rate, and reflects intracellular protein neutralization, the control of this ion is important. In other words, in addition to providing needed biochemical data for the monitoring of therapy the procedure of the invention provides the opportunity for improved control of therapy. The analysis can be used as input data to a microprocessor which can then use the information to exercise control of the dialysis procedure. For example, if independent K + and urea assays are conducted and the target K + level is achieved before the urea level, the processor can initiate an infusion of K + to counteract the dialysis.
The assays described herein are based on well established mass transfer equations for the removal of metabolite by dialysis, i.e., ##EQU1## where Q d is the dialysate flow rate in ml/min., and K is the dialyzer clearance in ml/min.
Moreover, by either continuous or intermittent measurement of the dialysate outflow it is possible to determine not only the instantaneous serum levels but also the pre- and post-dialysis levels by extrapolation to zero time and to the end of dialysis.
For a metabolite which is distributed throughout the entire body water and whose intercompartmental transfer rates are high compared to the dialyzer clearance, the serum concentration during dialysis is given by
Ln C.sub.B =Ln C.sub.B.sup.o -(K/V)t (3)
where C B o is the pre-dialysis serum level, K is the dialyzer clearance and V is the body water volume. For urea, the assumptions necessary for this relationship have been established previously (M=V o C o -V t C t , where subscript o refers to pre-dialysis and subscript t refers to post-dialysis); however, for phosphate ions, the distribution and the intercompartmental transfer rates are not known and this relationship may be valid.
FIG. 5 shows the dialysate concentration versus time for urea during a six hour dialysis. The plot is linear on a semi-log scale as would be expected by substituting equation (1) into equation (3). The slope of the plot is given by K/V. Using a forty liter body water volume for the patient, the dialyzed clearance is calculated directly from the raw data. When these dialysate concentrations are converted to serum concentrations by equation (1) the results shown in FIG. 6 are obtained. The Autoanalyzer results reported by the clinical laboratory are also shown in this figure.
Five trials were carried out in a similar fashion. The pre-dialysis BUN calculated from regression plots of data illustrated by FIG. 6 are given in Table 1 together with the clinical measurements obtained by Autoanalyzer. The slope of log C Do versus time was also used to obtain the dialyzer clearance and these data are tabulated together with the correlation coefficient of the regression analysis.
TABLE I______________________________________REGRESSION ANALYSES OF lnC.sub.sun vs. t FROMDIALYSATE ANALYSESExperi-ment C.sup.o K RatioNo. (mg/dl) (ml/min) r.sup.2 C.sup.o (Blood)* C.sup.o /C.sup.o (Blood)______________________________________104 59.5 140 .9965 60 0.99105 61.5 151 .9917 69 0.89106 45.3 145 .9963 52 0.87107 53.9 143 .9982 56 0.96108 49.1 127 .9948 55 0.89Mean 53.9 141 58.4 0.92St.Dev. 6.8 8.9 6.6 0.05______________________________________ *By Autoanalyzer
Finally, it is possible to calculate the urea nitrogen removed from the patient by the relationship
M=V.sub.o C.sub.o -V.sub.t C.sub.t
The patient on average lost 2.4 liters of isotonic water by ultrafiltration; the equation for this patient can thus be written to yield
M=400 C.sub.o -376 C.sub.t
with concentrations in mg/dl nitrogen. These results are shown in Table 2.
TABLE II______________________________________UREA NITROGEN MASS REMOVED DURING DIALYSISTrial C.sub.o C.sub.t Mass Removed G.sub.BUNNo. (mg/dl) (mg/dl) (gm) (mg/min)______________________________________104 59.46 16.85 17.45105 61.54 15.81 18.67106 45.25 12.20 13.51 4.4107 53.92 14.84 15.99108 49.07 15.70 13.72 5.6______________________________________
It is possible to compute urea generation rates using data from consecutive treatment periods. Using the relationships described by Gotch (Gotch, G. A., Sargent, J. A., Keen, M., Lamb, M., Prowitt, M. and Grady, M.: Clinical Results of Intermittent Dialysis Therapy Guided By Ongoing Kenetic Analysis of Urea Metabolism, Trans. Amer. Soc. Artif. Int. Organs, 22, 175 (1976)), it should also be possible to estimate the protein catabolism rates, phosphate burden and a metabolic acid generation for patients whose urea concentrations are known during each treatment. In the experiments conducted with the apparatus of the invention and set forth in Tables I and II, trials 105-106 and 107-108 were paired for the second and third dialyses of a thrice weekly schedule. Using the end values for trial 105 and the pre-dialysis value for trial 106, the generation rate (G) of serum urea nitrogen was calculated to be 4.4 mg/min. Similarly, for the 107-108 trial pair, the G SUN was found to be 5.6 mg/min. Two phosphate monitoring experiments were carried out. The first used intermittent aliquots of dialysate effluent from the patient's bedside calibration. The continuous monitoring trail is shown in FIG. 7, where the calculated blood inorganic phosphorous concentration is plotted as a function of tie together with the clinical lab results in plasma. Unlike the urea nitrogen results, this plot is not log-linear. The data indicates that transfer from a secondary pool of phosphate begins to dominate the serum concentrations during the latter half of the dialysis. These data are insufficient to determine whether this originates from tissue burdens or bone phosphate. The non-linearity of the Ln P i vs. time plot indicates that the serum values are not representative of total body levels over the time span of the dialysis. Therefore, it is not possible to use equation (3) to estimate total removal of inorganic phosphorus. However, integration of the area under the C Do vs. time curve provides an estimate of the P i removed, since the dialysate flow rate was constant. The data shown in FIG. 8 were used with manual integration and led to an estimate of 1200 mg P i removed during a six hour dialysis.
Thus, with the present invention, the blood levels of specific metabolites for various patients can be determined during the dialysis treatment without invasion of the circulation. The use of ion-selective electrodes coupled, when necessary, with enzyme provides a convenient method for continuous measurements. The data can be important in the control of therapy of end stage renal disease patients. The procedures are simple and are thus useful not only in a hospital situation, but also in limited care facilities or even with home patients. The invention thus makes the development of safer and more individually designed treatment protocols possible.
The foregoing description of the specific embodiments will so fully reveal the general nature of the invention that others can, by applying current knowledge, readily modify and/or adapt for various application such specific embodiments without departing from the generic concept, and, therefore, such adaptations and modifications should and are intended to be compehended within the meaning and range of equivalents of the disclosed embodiments. It is to be understood that the phraseology or terminology employed herein is for the purpose of description and not of limitation.
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An apparatus and method are disclosed for monitoring, analyzing and quantitating in real time the concentrations of metabolites in serum by analyzing the dialysate solutions which are being equilibrated with the blood via a hemodialyzer. Thus, access to certain metabolically important species is provided without the necessity of blood sampling. The apparatus includes at least one ion-selective electrode coupled with the dialysate effluent stream, and the electrode EMF is converted to dialysate concentrations based on precalibration. The dialysate concentrations, in turn, are related to serum levels by factors governing mass transfer through the dialyzer.
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CROSS-REFERENCE TO RELATED APPLICATIONS
This is a continuation-in-part of application Ser. No. 11/054,185 filed Feb. 9, 2005 entitled BRA PAD CONSTRUCTION and now U.S. Pat. No. 6,997,775, which was a continuation-in-part of application Ser. No. 10/804,403 filed Mar. 19, 2004 entitled A BRASSIERE AND RELATED BREAST CUP CONSTRUCTION and now U.S. Pat. No. 7,052,360, and application Ser. No. 10/911,269 filed Aug. 4, 2004 entitled PADS HAVING A CENTRAL SUMMIT FOR BRAS AND THE LIKE and now U.S. Pat. No. 6,986,696, all of which are incorporated here by reference.
FIELD AND BACKGROUND OF THE INVENTION
The present invention relates generally to the field of bras and related garments, and in particular to a new and useful method and pad product having a thicker central summit area for use in bras, camisoles, slips, swimsuits or any other breast covering garment where padding is desired.
It is known to provide resilient pads in bras to accentuate the figure. Padded bras are not always desirable, however. Bras without pads are also known but these have limited ability to enhance the figure.
Recently, materials for the manufacture of brassieres have been developed that allow for more convenient manufacture of a brassiere. Traditionally the cup forms of a brassiere have, in order to introduce a three dimensional cup shape therein, consisted of several panels which have been sewn or otherwise affixed together. With the advent of moldable synthetic materials such as foam and synthetic fabric materials, cup forms are now moldable into a single panel of material or assembly of panels of materials to define the three dimensional cup form. The ability to mold material to define a cup form of a desirable shape has allowed the manufacturing process to be simplified or accelerated. As well as providing support to a breast of a wearer, the cup forms are often also required for additional benefits to the wearer.
Some women prefer that a brassiere conceals some if not all of the regions of the breasts. For modesty, it is desirable that the nipples of a wearer at all times remain unnoticeable from the exterior of the brassiere and any over garment that may be worn by the wearer. Molded cup forms of brassieres that are currently available generally do not provide for any enhancement to the cup form for such purpose. Molded cup forms are normally of a substantially even thickness across the body of the cup and while it may be possible to increase the thickness of the cup in order to thereby reduce the visibility of the nipples of a wearer to the exterior of the brassiere, such increasing thickness may add to the cost of manufacture of the brassiere. Furthermore it is undesirable for increased thickness of the brassiere to exist at its perimeter if the presence of the brassier entirely, is to be as unobtrusive as possible. It is desirable for the perimeter of the bra to be relatively thin so that it has the appearance of feathering in with the skin of the wearer.
The patent prior art contains various relevant examples.
U.S. Pat. No. 4,013,750 discloses a method for making brasserie pad pre-forms which can produce a bra pad having a thicker central region than its outer regions. A mold apparatus is utilized which produces a substantially conical pad of polyester fibers with a summit which is thicker than the periphery of the conical pad. Also see U.S. Pat. No. 3,947,207.
Other patents of interest to the present invention are:
U.S. Pat. No.
Inventor(s)
2,507,543
Prager
2,565,400
Skeoch
2,616,093
Talalay
2,627,368
Jantzen
2,702,769
Alderfer
2,845,974
Ashton et al.
3,164,655
Howard et al.
3,186,271
Kaiser
3,311,007
McGee
3,417,755
Howard et al.
3,464,418
Silverman
3,502,083
Howard et al.
3,800,650
Schroder
4,351,211
Azzolini
5,017,174
Gowrylow
5,299,483
Ber-Fong.
U.S. Pat. No. 2,627,368 to Jantzen discloses a method of making curved pad filler in which a mold is provided with a concave part for receiving a part of a blank of material. A means are provided for pushing or pressing the blank into the concave part of the mold. A sharp moving knife is passed between the mold and the pressing element, resulting in a curved shoulder pad filler and uniformly tapered portions extending from the thick end to a feathered edge.
U.S. Pat. No. 3,186,271 to Kaiser discloses an apparatus and method for producing shaped articles consisting of foam such as sponges and cushions.
Neither the Jantzen nor the Kaiser patents teach or suggest a sheet of material having a pair of thicker areas positioned so that they correspond to the location where the central summit of the bra pad will be when it is completed.
U.S. Pat. Nos. 3,164,655, 3,417,755 and 3,502,083 to Howard et al. disclose molding of a blank to give it a desired shape and contour but fail to teach or suggest forming a foam sheet of material having a pair of thicker areas positioned so that their position corresponds to the location where the central summit of the bra pad will be when it is completed after thermoforming.
U.S. Pat. No. 2,616,093 to Talalay discloses an apparel pad such as a shoulder or breast pad, which as a concavo-complex shape with a thickness graduated from a relatively thick portion to a relatively thin portion using different pieces of material to build up the pad.
U.S. Pat. No. 3,311,007 to McGee discloses an apparatus for producing at least one contoured surface upon a foamed material pad but is very different from the present invention because it teaches the effects of cutting a foam member which is compressed by a male mold portion against an opposite flat mold portion, and thus, the contour of the shaved material is based on the shape of the male mold portion. McGee fails to teach contouring of an article based on a foam material being pressed to cover and penetrate a recess before the foam material is shaved.
U.S. Pat. No. 2,727,278 to Thompson discloses a method of making a molded composite bra, in which the thickness of filler material in each bra pad has a summit thickness greater than the thickness surrounding the summit. The process for making the molded bra is however very different from the present invention and does not teach shaving a material compressed into a recess.
The remaining patents disclose other pad-related technology which are distinguishable from the invention, and they are enclosed for general reference.
A need remains for an improved pad, as well as a method for producing such a bra pad, which adds some padding effect to the bra but in a very subtle manner so that the padding is barely perceptible.
SUMMARY OF THE INVENTION
It is an object of the present invention to provide a method of manufacturing a bra pad having a thicker central summit area, as well as the pad itself and the apparatus for manufacturing the pad, comprising holding a sheet of uniform thickness, resilient and formable material, such as thermoplastic foam, and forming the sheet to have one or two thicker summit areas corresponding to the summits of the bra or bra-like garment (here called a bra for any garment in which the pads are ultimately used). Each pad thus has a thicker summit area for extending over the summits of the breasts of a wearer of the bra.
A further object of the invention is to provide the bra pad made in accordance with the method of the invention.
A further object of the present invention is to provide a bra or brassiere which includes molded cup forms which address the abovementioned limitations of the prior art or which will at least provide the public with a useful choice.
It is a further object of the present invention to provide a molded cup form for a brassiere including a laminated structure of a first panel of a flexible foam material and a second panel material, the first and second panels being substantially coextensive to each other and define a breast cup perimeter shape, wherein the first panel of flexible foam material is of varying thickness, providing a zone of greater thickness at a region or regions away from the perimeter as compared to regions of lesser thickness more proximate to the perimeter. Preferably the zone of greater thickness is located where, in use, a nipple of the wearer of the bra incorporating the breast cup is normally located.
Preferably the first panel is of a uniform thickness save for the zone of greater thickness, the zone of greater thickness having a maximum thickness at the center of the zone and being of a gradually reducing thickness toward the perimeter of the zone.
The second panel is disposed to the first major side of the first panel, to form a coextensive planar assembly which is molded to define a cup shape into the planar assembly and then any excess non-cup shape defined regions are removed from the assembly.
This invention may also be said broadly to comprise in the parts, elements and features referred to or indicated in this specification, individually or collectively, and any or all combinations of any two or more of said parts, elements or features, and where specific integers are mentioned herein which have known equivalents in the art to which this invention relates, such known equivalents are incorporated herein as if individually set forth. For the purposes of illustrating the invention, there is shown in the drawings a form which is presently preferred, it being understood, however, that this invention is not limited to the precise arrangements shown.
The various features of novelty which characterize the invention are pointed out with particularity in the claims annexed to and forming a part of this disclosure. For a better understanding of the invention, its operating advantages and specific objects attained by its uses, reference is made to the accompanying drawings and descriptive matter in which a preferred embodiment of the invention is illustrated.
BRIEF DESCRIPTION OF THE DRAWINGS
In the drawings:
FIG. 1 is a side elevation view of an open shaving mold used to make the pads and to practice the method of the present invention with a sheet of polyurethane foam material therebetween;
FIG. 2 is a view similar to FIG. 1 of the shaving mold in its closed position and with a shaving device in an initial position of use;
FIG. 3 is a view similar to FIG. 2 with the shaving apparatus in a final position;
FIG. 4 is a side elevational view of a shaved or graduated sheet component of the bra pad in accordance with the present invention;
FIG. 5 is a view similar to FIG. 4 of an assembled pre-form of the bra pad according to the present invention;
FIG. 6 is an exploded view of a forming mold with the pre-form bra pad between the mold halves thereof;
FIG. 7 is a sectional view of a formed component for creating two foam pads of the present invention;
FIG. 8 is a top plan view of the formed component of FIG. 7 ;
FIG. 9 is a view of a pair of bra pads constructed in accordance with the present invention;
FIG. 10 is an exploded sectional view through an assembly of panels prior to being formed and laminated together for the purposes of providing the bra cup, according to another embodiment of the present invention;
FIG. 11 is a sectional view through an assembly of panels of FIG. 10 , prior to being molded;
FIG. 12 illustrates two panel assemblies of the invention, prior to being laminated together and prior to being formed into a three dimensional cup form by molding elements;
FIG. 13 is a plan view of a cup form having been molded and trimmed to define a perimeter suitable for incorporation as part of a brassiere;
FIG. 14 is a sectional view through an alternative configuration of an assembly of panels to that of FIG. 11 ;
FIG. 15 is an alternative to FIG. 14 ;
FIG. 16 is a perspective view of a brassiere incorporating the cup forms of the invention;
FIG. 17 is a sectional view through section 17 - 17 of FIG. 13 wherein the assembly of panels according to that shown in FIG. 12 is provided; and
FIG. 18 is a sectional view through section 17 - 17 of FIG. 13 wherein an assembly of panels as shown in FIG. 14 is provided.
DESCRIPTION OF THE PREFERRED EMBODIMENTS
Referring now to the drawings, in which like reference numerals are used to refer to the same or functionally similar elements, FIG. 1 shows a shaving mold generally designated 10 comprising a lower shaving mold portion 12 and an upper shaving mold portion 14 with a thickness of e.g. 7 mm polyurethane foam 16 therebetween. Although polyurethane foam is illustrated, any thermo plastic foam material can be used according to the present invention and in fact any formable material can be used which is resilient and is capable of being formed into a permanent yet resilient three-dimensional shape. The shaving mold halves or portions 12 and 14 can be made of wood, plastic, metal or other suitable rigid material. Lower mold half 12 contains a pair of recesses 18 in its upper surface which are positioned so that they are near the central summit of each bra pad to eventually be made in accordance with the present invention.
FIG. 2 illustrates the shaving mold in its closed position with the resilient formable sheet of material 16 pressed down onto the lower mold half so that some of the material of sheet 16 is pressed into each recess 18 but also a thickness of material, for example at 20 , remains along the shaving mold halves.
A shaving apparatus generally designated 22 is also illustrated in FIG. 2 which comprises a movable carriage 24 , which carries a blade, knife or shaving member 26 that extends transversely the full width of material sheet 16 (perpendicular to the plane of FIG. 2 ). Blade 26 is also positioned intermediate to the upper and lower shaving mold halves 14 , 12 respectively so that a portion of the layer 20 can be neatly shaved from the sheet 16 . For this purpose, member 26 may be heated (e.g., a cutting wire), may be mounted for movement like a band saw, may be reciprocally vibrated back and forth like an electric knife or oscillated in any other appropriate way for cutting the foam material of sheet 16 .
With the shaving apparatus 22 activated to vibrate, heat or otherwise activate member 26 , the carriage 24 is moved in the direction of arrow A and across the sheet 16 until it reaches its final position shown in FIG. 3 . In this position a slice 30 has been made in sheet 16 thus achieving the shaving effect. FIG. 4 shows the shaved component or graduated sheet 16 a which is removed from the shaving mold after it is opened and which contains a pair of thicker material areas 17 at a summit e.g. of 5.5 mm thickness, surrounded by thinner material areas 19 , e.g. 1 mm thick. FIG. 8 illustrates in dotted line the two summit areas 17 on the rectangular and graduated sheet 16 a which, in FIG. 8 , has already been attached to as second outer cup sheet 32 , e.g. 2 mm thick, shown in FIG. 5 which is also made of polyurethane foam material. Shaved or graduated sheet 16 a forms an inner cup sheet.
As shown in FIG. 5 , each of the cup sheets 16 a and 32 may also include a laminate or fabric covering 33 and 34 , respectively, made, for example, of nylon or nylon with spandex. This is a conventional covering for foam pads used in bras. It is important that in accordance with the present invention, the laminate 33 be on the outer inner surface of the inner cup sheet 16 a so that it is not shaved away by the shaving apparatus 22 and that the outer cup sheet 32 have its laminate 34 on its outer surface. This leaves the inner surfaces of panels 16 a and 32 free to receive sprayed on glue. After the glue is sprayed on the two surfaces are pressed against each other to produce the single composite pre-form illustrated in FIG. 5 .
In FIG. 6 a thermo-forming mold 40 is generally designated 40 and, as illustrated, includes a lower female mold portion or half 42 and an upper mold half or portion 44 . The pre-form 16 a, 32 is positioned between the mold halves 42 , 44 with the summits 17 centered on a pair of recesses 46 formed in the lower female mold half 42 which also correspond with a pair of male projections 48 formed in the male mold half 44 . Each projection 48 may also include a slight recessed or flattened area 49 or an area which is shaped to keep from completely crushing the summit areas 17 of the inner cup sheet 16 a.
The mold halves are heated to the appropriate level for molding the pre-form into a finished molding illustrated in FIGS. 7 and 8 . The finished molding has thicker summit areas 17 , e.g. 5-6 mm thick, surrounded by the thinner surrounding areas 19 , e.g. 1 mm thick, which completely encircle each summit area 17 and have an inner area of e.g. 2 mm thick, so that a bra manufactured with or containing the bra pads of the present invention will have a slightly thicker area 17 , for example 3 mm, over the summit of each breast summit, and thinner material, e.g. tapering down to 1 mm, in thinner areas 19 .
FIG. 9 illustrates the pair of pads 52 , 54 which are cut from the molding of FIGS. 7 and 8 and are ready for use in a bra, in a conventional manner. The pads 52 , 54 may also be used in other garments for covering the torso of a woman and which contain bra or bra-like structures such as bathing suits, camisoles, and the like.
With reference to FIG. 16 there is shown a bra or brassiere 101 including two breast cup constructions 102 which have been engaged to various other components of the brassiere 101 such as for example body straps 103 and over the shoulder straps 104 .
The breast cups 102 are engaged together at an intermediate connection 105 . The breast cups have a perimeter 106 and a body portion 107 inward of the perimeter 106 . The breast cup is of a form having been molded and to a large extent is of a single structure comprising or consisting of a plurality of overlying and preferably substantially coextensive panels defining the assembly of the cup form. It is however envisaged that the breast cup of the present invention may have disposed therefrom or engaged thereto by means of sewing or otherwise affixing additional panels which may extend from the perimeter 106 of the cup form or may be associated with the cup form 102 intermediate of the perimeter 106 and define part of the body portion 107 of the cup form.
The two breast cups 102 of the brassiere are substantial mirror image about the intermediate connection 105 . Reference has been and will now be made to a single breast cup formed or to be formed from precursor materials, however, it will be appreciated that such reference is also reflective of the provision of the same form of breast cup for the other cup to be incorporated into a brassiere.
With reference to FIG. 13 , there is shown a breast cup 102 . The breast cup is molded to a three dimensional form, such as a cup form appropriate for the purpose of supporting and covering at least part of the breast of the wearer. The breast cup 102 has been molded from materials which, with reference to FIG. 10 , may include a first panel of flexible foam material 108 , preferably a second panel of flexible foam material 109 , a covering panel of flexible fabric material 110 and a second panel of covering flexible fabric material 111 . In an alternative form however as for example shown in FIG. 14 , the breast cup may be defined by a first panel of flexible foam material 108 , the covering flexible fabric material 110 and the second panel of covering flexible material without there being a provision of a second panel of flexible foam material 109 .
While reference herein is made to such panels being directly affixed to each other preferably by laminating such as by heat and/or adhesive laminating, it will be appreciated that panels or panel assemblies consisting of plies of sheet material may be provided intermediate of those panels.
With reference to FIG. 10 , there is shown a sectional view of the panels of the breast cup of the present invention consisting of a first panel of a flexible foam material 108 and a second panel of a flexible foam material 109 . Disposed and preferably substantially coextensive with the first panel of foam material 108 there is provided a panel of flexible fabric material 110 . The laminated assembly of the panel 108 and 110 may be provided from roll stock material to be used in the method of the present invention. The fabric material 110 may for example be nylon and the foam material may for example be polyurethane. The foam panel 109 includes a first major surface 113 which is exposed and a second major surface 114 against which the fabric panel 110 is laminated. In this precursor form of the assembly of panel 108 and 110 , such an assembly is in an unmolded condition and in a natural state assumes a flat or planar condition.
A second panel of flexible foam material 109 in assembly for example with a second panel of flexible fabric material 111 is also provided. The second panel of foam material 109 includes an exposed major surface 115 and a covered major surface 116 against which the second flexible fabric panel is laminated. Like the assembly of panels 108 and 110 , the panels 109 and 111 may be provided in a precursor form from a feed of roll stock and in a natural state assume a substantially planar or flat condition.
The size of the resulting rectangular cut precursor panel assemblies is such that when subjected to molding in a molding machine to define the three dimensional cup form thereof, it is of a sufficiently large size to define the entire desired cup form. The first panel of foam material 108 is preferably of a greater thickness X than the thickness Y of the second panel of foam material 109 .
With reference to FIG. 11 , the first panel of foam material 108 is formed to define a zone of increased thickness 116 . This zone of increased thickness 116 is provided intermediate of the perimeter 117 of the assembly of panels 108 , 110 . The zone of increased thickness 116 is also provided inward (inward of the perimeter) of that region of the panel assembly 108 , 110 into which a molded cup form to ultimately define a breast cup of the present invention will be defined.
Accordingly when formed to a cup form with the other panels to define the breast cup of the present invention as shown in FIG. 13 , the zone of increased thickness 116 is provided inward from the perimeter 106 of the breast cup. In the preferred form the first panel of flexible foam material prior to being molded is formed to be of a substantially constant thickness Z save for the zone of increased thickness 116 . In the most preferred form such contouring is by the shaving of the panel to define the contoured shape on the first major side 113 of the precursor panel of flexible foam material 108 as disclosed in greater detail above.
After having been formed/shaped the then contoured first major surface 113 A of the first panel of flexible foam material 108 will include the zone of increased thickness 116 extending from regions of reduced thickness at or towards the perimeter of the panel assembly 108 , 110 . The zone of increased thickness may for example be a dome shape as for example shown in FIG. 11 and of a constant diameter D.
Alternatively the shape may be of a gradually undulation as for example shown in FIG. 14 . So that the existence of this zone of increased thickness in the final version of the brassiere is to a large extent disguised, it is preferred that the zone of increased thickness 116 has a maximum thickness or summit substantially centrally within the zone and provides a reduction in thickness towards the perimeter 119 of the zone. Such reduction in thickness may be by a linear tapering, for example, shown in FIG. 14 . In the most preferred form the second panel of flexible foam material 109 is not subjected to any contouring. The first panel of flexible foam material 108 is subjected to contouring but only on the non-fabric side of the first panel, opposite to panel 110 .
The assembly of panels 108 , 110 is then laminated with the assembly of panels 109 , 111 in a molding device as for example shown in FIG. 12 . The molding device consists of two mold portions 120 and 121 each having formed therein a profile or contour of a kind to introduce into the precursor assemblies of panels the three dimensional or cup form of the breast cup. The upper mold portion 120 for example includes a concave relief and the lower portion 121 provides a convex upstand of a substantially complimentary shape to the concave recess of the upper mold portion 120 .
The assemblies of panels 108 , 110 and 109 , 111 are positioned intermediate of the mold portions in a manner so that they overly each other in an appropriate condition (preferably coextensively) whereupon the two mold portions are then brought together. The two mold portions are preferably heated. Additional adhesive may be placed intermediate of the assemblies so that both pressure adhesive and heat will ensure that a good laminated bond can be established between the two subassemblies. Upon the formation of the cup form into the precursor panel or panel assemblies, the cup form can be trimmed from the molded precursor panels to define a perimeter shape such as for example shown in FIG. 13 . Part of the perimeter of the cup form 106 may include an additional compression zone 123 where the overlying panels of material have been subjected to more enhanced compression than that of the main body portion 107 . Such additional compression zones may serve the purpose of allowing for the cup to define a flange useful for the purposes of securing the cup to other components of the brassiere.
With reference to FIG. 13 , it can be seen that upon the forming of a three dimensional form or cup form in the precursor materials as well as laminating the precursor materials together, will locate the zone of increased thickness 116 inward from the perimeter 106 of the breast cup 102 . The zone of increased thickness 116 is provided within the body portion 107 of the breast cup 102 . This zone of increased thickness is positioned to correspond with the usual location of the nipple of the breast of a wearer of a brassiere incorporating the breast cup 102 .
With reference to FIG. 17 there is shown a cross sectional view through section 17 - 17 of FIG. 13 wherein the zone of increased thickness 116 is shown to be provided to enhance the overall thickness of the breast cup in such zone. Thickness B is greater than thickness C. While the thickness is perhaps only marginally greater at B than at C, a further enhancement to reduce the visibility of a nipple of a wearer through the breast cup is as a consequence of the higher density of material at the zone of increased thickness 116 . Once the breast cup has been formed, the zone of increased thickness 116 will compress slightly such compression enhancing the material density at this zone thereby reducing the likelihood of observing the presence of the nipple through the breast cup. In the preferred form the thickness E is substantially the same as the thickness X and accordingly at the region of maximum thickness of the zone of increased thickness 116 , little or no shaving or removal of the foam from the precursor precontoured panel of flexible foam material 8 has occurred.
With reference to FIG. 15 , there is shown an alternative to the formation of the zone of increased thickness 116 wherein a first ply of foam material has engaged to its exposed major surface 113 a second ply of material 124 such as a like foam material which has been contoured to provide the same desired profile to the assembly of the first ply and the second ply 124 as that shown for example in FIG. 11 or 14 .
While in the most preferred form, the second assembly consisting of the second panel of flexible foam material 109 and panel of fabric material 111 laminated by adhesion to the first panel of foam material, with reference to FIG. 18 there is an alternative where the first panel 108 receive the flexible panel of fabric material 111 , directly engage without the presence of a second panel of foam material 109 being present. An assembly of such a configuration formed to a cup form is shown in FIG. 18 .
While a specific embodiment of the invention has been shown and described in detail to illustrate the application of the principles of the invention, it will be understood that the invention may be embodied otherwise without departing from such principles.
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A method of manufacturing a breast-covering garment pad having a thicker summit area, as well as the pad itself, includes holding a sheet of resilient and formable material of uniform thickness, such as thermoplastic foam, and forming the sheet to have a graduated thicker summit area corresponding to each breast summit of the pad or a garment including the pad, and a surrounding thinner area. Each pad thus has a thicker summit area for extending over the nipples the breasts.
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FIELD OF THE INVENTION
The present invention relates generally to ink jet printing, and more specifically, to aligning and installing components of a continuous ink jet printhead.
BACKGROUND OF THE INVENTION
Ink jet printing systems are known in which a printhead includes a jetting module that defines one or more rows of nozzles in a nozzle plate which receive a recording fluid, such as a water-based ink, from a pressurized fluid supply manifold and eject the ink in rows of parallel streams. Such printing systems achieve image production by allowing drops which are to be printed to contact the recording medium and deflecting drops that are not to be printed to a drop catcher device.
Conventional methods for assembling the components of a printhead include locating the jetting module or drop generator with the aid of an assembly fixture, then using an adhesive such as epoxy to fasten it in place. A charge plate/catcher assembly is then aligned to the drop generator using external adjustment fixtures. Once a proper alignment is achieved, the charge plate/catcher assembly is fastened with screws or adhesive to the common frame holding the drop generator.
Traditional systems allow replacement of a printhead by creating field replaceable units which includes a jetting module, a charge plate, and a catcher. Some field replaceable units also include fluid system components such as valves and pressure and temperature sensors, and support electronics for the inkjet module. As the number of jets to be controlled increased, it became impractical to connect each charge electrode in the field replaceable printhead to the controlling charge driver electronics that were not part of the field replaceable printhead. In such printheads, it became preferable to include charge driver electronics in the field replaceable unit. As the charge plate was also subject to failure, such field replaceable units were preferable because, in addition to the jetting module, the charge plate was also field replaceable.
Unfortunately, existing assembly and alignment methods have several drawbacks. For example, using an adhesive increases assembly time because it takes several hours for the adhesive to cure and using epoxy is problematic because epoxy is sensitive to heat and humidity. Additionally, the final fastening of the charge plate/catcher assembly alters the alignment, usually requiring realignment.
High costs of shipping make it advantageous to replace only the jetting module rather then the entire printhead. Additionally, jetting modules providing higher resolution require high precision alignment. Accordingly, there is a need for a jetting module to be a field replaceable unit that an be properly aligned during installation.
SUMMARY OF THE INVENTION
According to a feature of the present invention, an apparatus for installing a jetting module in a printhead includes a drop deflection mechanism, a catcher, a printhead frame including a first set of mounting features, a jetting module including a second set of mounting features that correspond to the first set of mounting features of the printhead frame, and a coupling frame including a second set of fluid and electrical connections that correspond to a first set of fluid and electrical connections of the jetting module. The coupling frame provides a force to maintain contact between the first and second sets of mounting features after the first and second sets of mounting contact each other. The coupling frame also provides the force to maintain contact between the first and second sets of fluid and electrical connections after the first and second sets of fluid and electrical connections contact each other.
According to another feature of the present invention, a method for mounting a jetting module in a printhead including a drop deflection mechanism and a catcher includes providing a printhead frame including a first set of mounting features, providing a jetting module including a second set of mounting features that correspond to the first set of mounting features of the printhead frame, providing a coupling frame including a second set of fluid and electrical connections that correspond to a first set of fluid and electrical connections of the jetting module, causing the first and second sets of mounting features to contact each other, causing the first and second sets of fluid and electrical connections to contact each other, and providing a force to maintain contact between the first and second sets of mounting features, and between the first and second sets of fluid and electrical connections.
BRIEF DESCRIPTION OF THE DRAWINGS
In the detailed description of the preferred embodiments of the invention presented below, reference is made to the accompanying drawings, in which:
FIGS. 1A and 1B are schematic side views of a printhead including a jetting module, drop deflection mechanism and catcher in a printhead frame;
FIG. 2 is an inverted isometric view of a jetting module and first and second mounting features;
FIG. 3 is an isometric view of the printhead showing the carriages and actuators for installing the jetting module and making fluid and electrical connections to it;
FIG. 4 is a side view of the printhead with the jetting module lowered into an aligned position without fluid and electrical connections having been made;
FIG. 5 is an exploded view of portions of the printhead showing fluid and electrical connections; and
FIG. 6 is a front view of a coupling frame showing electrical connections.
DETAILED DESCRIPTION OF THE INVENTION
The present description will be directed in particular to elements forming part of, or cooperating more directly with, apparatus in accordance with the present invention. It is to be understood that elements not specifically shown or described may take various forms well known to those skilled in the art.
Referring to FIG. 1A , a printhead 10 according to the present invention includes a jetting module 18 , a drop deflection mechanism 12 , a catcher 14 , and a frame 20 . The drop deflection mechanism can be a gas flow deflection mechanism, such as is described in U.S. Pat. No. 6,588,888, an electrostatic deflection mechanism, such as is described in U.S. Pat. No. 4,636,808, or other drop deflection mechanisms known in the art. In FIG. 1 , the invention the drop deflection mechanism is a gas flow deflection mechanism, including of a positive gas flow duct 15 and a negative gas flow duct 17 . Positive gas flow duct 15 is connected to a fan or blower that produces a positive pressure in the gas flow duct from which a flow of gas is directed across the trajectories of drops 19 formed by the jetting module. Negative gas flow duct 17 is connected of a vacuum source, producing a vacuum or negative pressure in the gas flow duct. The suction of gas into duct 17 produces a flow of gas across the drop trajectories 19 . Typically, the placement of the blower, vacuum source, and the gas flow duct extensions that connect the positive and negative gas flow ducts to the blower and vacuum source relative to the jetting module is controlled by the amount of available space around printhead 10 . Catcher 14 is positioned under the negative gas flow duct 17 , but can alternatively be located under the positive gas flow duct.
Operation of the printhead 10 depends critically on the alignment of catcher 14 and drop deflection mechanism 12 relative to jetting module 18 . The printhead frame 20 includes a first set of mounting features 22 , and at least one of the drop deflection mechanism 12 and the catcher 14 is affixed to the printhead frame 20 . In a preferred embodiment, the catcher 14 and at least a portion of the drop deflection mechanism 12 are assembled together, and this catcher-drop deflector assembly is affixed to the printhead frame 20 . The jetting module 18 includes a second set of mounting features 30 that correspond to the first set of mounting features 22 of the printhead frame 20 . The second set of mounting features 30 can be integrally formed in the jetting module 18 . The jetting module 18 also includes a first set of fluid and electrical connections 50 .
Referring to FIG. 1B , the printhead frame 20 includes a first set of mounting features 22 , a carriage 24 for installing a jetting module 18 , and a coupling frame 26 supported by a second carriage 28 to enable making fluid and electrical connections to the jetting module 18 . The mounting features 22 are preferably kinematic alignment features. These kinematic alignment features allow the jetting module 18 to be precisely positioned in the printhead 10 .
One type of kinematic alignment feature, known as a “2-2-2 mount” or a “three-groove mount” is shown in FIG. 2 . FIG. 2 shows a jetting module, in an inverted position, to show the three V-groove alignment features 30 . Spherical mounting features 22 are shown in each of the V-grooves. When the spacing of the three spherical mounting features 22 is fixed by some structure (which has been hidden in FIG. 2 to better show the engagement of the mounting features), the three V-groove mounting features 30 in the jetting module 18 can engage the three spherical mounting features (each groove contacting a sphere at two points) in only one position. When the jetting module 18 is separated from the spherical mounting features 22 , the jetting module can be returned to the original position to high precision by again having the mounting features 30 engage the mounting features 22 .
While the 2-2-2 mount is shown in the illustrated embodiments, other kinematic mount configurations, such as a “3-2-1 mount” can be employed. In a 3-2-1 mount, also known as a “cone, groove, and flat” mount, one set of alignment features is a system which includes three balls, and the second set of alignment features includes a cone shape, which constrains 3 degrees of freedom, a v-groove, which constrains 2 degrees of freedom, and a flat, which constrains one degree of freedom. In this way all six degrees of freedom can be defined.
The use of kinematic mount features can provide not only reproducible alignment of printhead components, such as the alignment of the jetting module 18 to the drop deflection mechanism 12 , but they can be employed to enable interchangeability of parts. In the jetting module production process, fixtures that engage the mounting features 30 of the jetting module can be used to align the nozzle array 32 of nozzle plate 34 with high precision to the alignment features 30 of the jetting module 18 . The nozzle plate 34 can then be secured in that aligned position using an epoxy or other adhesive bonding process. Similarly, fixtures that engage the mounting features 22 of the printhead frame 20 can be used to align the catcher-drop deflector assembly of the printhead 10 with high precision relative to the first set of mounting features 22 . In this manner, the nozzle array 32 of the nozzle plate 34 attached to the jetting module 18 and the catcher-drop deflector assembly are each precisely aligned relative to the respective kinematic mounting features, so engagement of the kinematic features of the jetting modules 18 with the kinematic features of the printhead frame 20 produces consistent alignment of the nozzle array 32 to the gas flow ducts 15 , 17 and the catcher 14 .
The consistency of alignment of the critical printhead components, for example, nozzle array 32 , drop deflection mechanism 12 , and catcher 14 , depend on the consistency of the mounting features 22 , 30 . The spherical mounting features 22 are therefore preferably fabricated from a material, for example, a ceramic or hardened metallic material, that won't be elastically deformed by the contact forces. It is also desirable to harden the contact surfaces of V-groove mounting features 30 that are machined into the jetting module. Alternatively, the contact surfaces of the grooves can comprise inserts of a material, such as a hardened metal or ceramic, that won't be elastically deformed by the contact forces.
In some embodiments, the mounting features 22 are located in three holes of printhead frame 20 that are machined precisely by jig grinding. Three spheres are then press fit into these holes. Alternatively, the mounting features 22 can be truncated spheres or hemispheres rather than complete spheres that are secured in the three holes of the printhead frame 20 . As the mounting features 22 that are used to align the jetting module 18 are also used to align deflection mechanism 12 and catcher 14 to the printhead frame 22 , small variations in the placement of the mounting features 22 from one printhead frame 20 to another don't produce alignment errors between the nozzle array 32 of the jetting module 18 and the deflection mechanism 12 and catcher 14 secured to the printhead frame 20 . Similarly, small variations in the mounting features 30 of the jetting module 18 don't produce alignment errors of the between the nozzle array 32 of the jetting module 18 and the catcher-drop deflector assembly as the same mounting features 30 are used both for the locating the nozzle array 32 on the jetting module 18 and locating the jetting module 18 in the printhead frame 20 .
Referring back to FIG. 1B , in some embodiments, the printhead frame 20 includes a third set of mounting features 35 that are precisely aligned to the mounting features 22 . This third set of mounting features 35 enables the printhead 10 , and more significantly the nozzle array 32 , to be aligned with precision to other printer components, such as paper guides or other printheads.
While the mounting features 22 , 30 of the jetting module 18 and the printhead frame 20 enable the jetting module 18 to be aligned with precision to the deflection mechanism 12 and catcher 14 , alignment integrity can be compromised if the jetting module 18 isn't allowed to settle into proper engagement with the alignment features 22 of the printhead frame 20 . The printhead 20 therefore includes an carriage 24 to enable the jetting module 18 to properly engage the alignment features 22 of the printhead frame 20 .
Referring back to FIG. 1B , carriage 24 of the printhead frame 20 is located on guide posts 36 that allow the carriage 24 to move vertically, substantially perpendicular to the plane defined by the mounting features 22 . The carriage includes a pocket 38 into which the jetting module 18 can be inserted when the carriage is in the up position as shown in FIG. 1B . The pocket 38 is shaped to receive the jetting module 18 , and supports the jetting module 18 before lowering the jetting module 18 into position to engage the first set of mounting features 22 of the printhead frame 20 . The pocket 38 serves to establish the location of the jetting module 18 sufficiently to enable the second set of mounting features 30 to contact the first set of mounting features 22 , while providing sufficient clearance to allow the jetting module 18 to shift laterally as needed to properly engage the first set of mounting features 22 of printhead frame 20 .
Referring to FIGS. 1B , 3 and 4 , the carriage 24 is moved up and down on the guide posts 36 by an actuator 40 . Actuator 40 may be a stepper motor, a solenoid, or any other actuator known to those in the art, so long as it operates to cause relative movement of the jetting module 18 to bring the first set of mounting features 22 of the printhead frame 20 and second set of mounting features 30 of the jetting module 18 into contact with each other. Actuator 40 causes the carriage 24 to be lowered and the second set of mounting features 30 of jetting module 18 are brought into contact the first set of mounting features 22 of the printhead frame 20 (shown in FIG. 4 ). The actuator 40 continues to lower the carriage 24 , and the jetting module 18 lifts off from the pocket 38 allowing the jetting module 18 to shift laterally so that first set of mounting features 22 fully engages the second set of mounting features 30 . As the carriage 24 continues to be lowered, load management features 42 begin to apply a load to the jetting module 18 to maintain secure alignment of the jetting module 18 with the printhead frame 20 . In some embodiments, load management features 42 include spring plungers, though other load management features can be used, provided they do not produce an over-constraint to the system. The forces applied by each of the load management features 42 to the jetting module 18 are substantially perpendicular to the plane defined by the mounting features 22 to maintain the integrity of the alignment. The forces applied by the load management features 42 are applied at locations between the locations of the three mounting features 22 or 30 so as not to produce a torque on the jetting module 18 that could cause one of the three mounting features 22 or 30 to fail to fully engage the mating features 30 or 22 and thereby compromise the integrity of the alignment.
A second carriage 28 is also located on the guide posts 36 . This second carriage 28 is moved up and down on the guide posts 36 by second actuator 44 . A coupling frame 26 is attached to the second carriage 28 through a biasing mechanism 46 .
FIG. 5 provides an exploded view of portions of the printhead 10 . The carriage 24 for locating the jetting module 18 has been omitted to enable the jetting module 18 and the fluid and electrical connects 50 to be seen more clearly. As shown in FIG. 5 , the coupling frame 26 includes a second set of fluid and electrical connections 48 that are designed to mate with a first set of fluid and electrical connections 50 that are a part of the jetting module 18 . After the carriage 24 has lowered the jetting module 18 into place so that the first and second set of mounting features 22 , 30 are fully engaged, second actuator 44 is employed to lower the second carriage 28 and the attached coupling frame 26 . Alignment pins 52 on the coupling frame 26 engage alignment holes 52 in the jetting module 18 to guide the coupling frame so that the appropriate fluid and electrical connections are made between the first and second sets of fluid and electrical connections 48 and 32 .
As a result of the force on the coupling frame 26 provided by the biasing mechanism 46 , the coupling frame 26 provides a force to maintain contact between the second set of mounting features 30 of the jetting module and the first set of mounting features 22 of the printhead frame after the second set of mounting features 30 of the jetting module 18 and the first set of mounting features 22 of the printhead frame 20 contact each other. The force provided by the coupling frame 26 also serves to maintain contact between the second set of fluid and electrical connections 48 of the coupling frame 26 and the first set of fluid and electrical connections 50 of the jetting module 18 after the second set of fluid and electrical connections 48 of the coupling frame 26 and the first set of fluid and electrical connections 50 of the jetting module 18 contact each other.
The first set of fluid and electrical connections 50 on the jetting module 18 can include one or more fluid ports 56 and an electrical contact board 58 . The second set of fluid and electrical connectors 30 on the coupling frame 26 can include corresponding fluid ports 60 and an electrical contact board 62 having electrical contacts 64 . Preferably, the fluid ports 55 , 60 of the jetting module 18 and the coupling frame 26 are of a drip resistant type, preventing any fluid from dripping from the fluid ports 56 , 60 while a jetting module 18 is being replaced. To prevent the fluid port connection from applying any lateral loads to the jetting module 18 , o-ring face seals are used on at the fluid port 56 on the jetting module 18 as well as on the fluid port 56 mating port in the second set of fluid and electrical connections 48 on the coupling frame 26 . Additionally, the mating fluid port in the second set of fluid and electrical connections 48 can be float mounted to the coupling frame 26 to ensure that proper sealing is achieved without providing any lateral forces. Likewise, the electrical contact board 58 in the first set of fluid and electrical connections 50 can be float mounted to the jetting module 18 .
Referring to FIG. 6 and back to FIG. 5 , in some embodiments, electrical contacts 64 can be spring pin contacts that are attached to electrical contact board 62 . This type of electrical contact 64 is commercially available from Interconnect Devices, Inc., Kansas City, Kans. Such electrical contacts 64 can vary in length as shown so electrical contacts 64 can make and break electrical contact with the corresponding contacts on the electrical contact board in a prescribed order so that the contacts to first make contact while establishing electrical connection are the last ones to break contact when such a connection is to be broken. Through the use of such first make-last break electrical connections, the printhead 10 can be made to safely replace a jetting module while electrical power is still supplied to the electrical contact board 62 . Other types of first make-last break connections can be used, as can other types of electrical contacts in general, provided that they do not over constrain the system and therefore compromise the integrity of the jetting module alignment.
Coupling frame 26 is attached to the second carriage 44 by a biasing mechanism 46 . Biasing mechanism 46 can be a spring, though other types of biasing mechanisms can be used, provided they are capable of providing a force to the jetting module 18 after the second set of mounting features 30 of the jetting module 18 and the first set of mounting features 22 of the printhead frame 20 . The force provided by the biasing mechanism 46 through the coupling frame 26 is substantially perpendicular to the plane defined by the first set of mounting features 22 . The biasing mechanism 46 provides sufficient compliance to the enable the coupling frame to rotate and shift laterally to enable all the fluid and electrical connections to be made without producing significant torques or lateral forces that would compromise the integrity of the alignment. To reduce the risk of the jetting module 18 shifting as the fluid and electrical connections are made it is preferable that load managing features 36 provide a force to the jetting module 18 before the coupling frame 26 begins to contact the jetting module 18 . The second carriage 28 with the attached coupling frame 26 are lowered into position by an second actuator 44 . This actuator can be a stepper motor, a solenoid, or any other actuator known to those in the art. Additionally, this actuator can be the same actuator as actuator 40 , or it can be a second actuator as is shown in FIG. 3 . Other embodiments can include limit switches and stall-sensing circuitry to enable the actuator to be stopped when the jetting module 18 is bearing the entire load, though other methods of controlling change in position can be used. The use of limit switches and stall-sensing circuitry allows the mechanism to recalibrate itself in the event of an unforeseen power failure during printhead installation.
The invention has been described in detail with particular reference to certain preferred embodiments thereof, but it will be understood that variations and modifications can be effected within the scope of the invention.
PARTS LIST
10 Printhead
12 Drop deflection mechanism
14 Catcher
15 Positive gas flow duct
17 Negative gas flow duct
19 Drop trajectories
18 Jetting module
20 Printhead frame
22 First set of mounting features
24 Carriage
26 Coupling frame
28 Second carriage
30 Second set of mounting features
32 Nozzle array
34 Nozzle plate
35 Third set of mounting features
36 Guide posts
38 Pocket
40 Actuator
42 Load management features
44 Second actuator
46 Biasing mechanism
48 Second set of fluid and electrical connections
50 First set of fluid and electrical connections
52 Alignment pin
54 Alignment hole
56 Fluid ports
58 Electrical contact board
60 Fluid ports
62 Electrical contact board
64 Electrical contacts
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A mechanism for aligning the jetting module in a continuous inkjet printhead and for making fluid and electrical connections to the jetting module without compromising the alignment is disclosed. A mechanism to aid in installing the jetting module is also disclosed.
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TECHNICAL FIELD
This invention relates to a method and device for everting flexible tubular members, such as tubular food casings and the like, by means which frictionally engage the interior surface of the flexible tubular member in such manner as to effect everting by the combined force of pushing the casing to the point of everting and pulling the casing from the point of everting in such a manner as to reduce the longitudinal tensile forces on the casing at the point of everting.
BACKGROUND ART
In the production of flexible tubular members, such as food casings and the like, it is frequently desirable to coat and/or layer the interior surface of the tubular member with one or more of various compositions to achieve various effects. For example, when the tubular member is a cellulosic food casing, it may be desirable to coat the interior surface thereof with a moisture proof barrier coating containing compounds such as polyvinylidene chloride, polyolefins, vinyls, polyesters, nylons or other suitable copolymers and polymers; to coat the interior of the casing with compositions containing food release additives, or lubricants; to coat the interior of the casing with compositions containing a colorant or flavorant composition; or, any of multiple other compositions.
U.S. Pat. No. 3,378,379, describes one method of internally coating flexible tubular members wherein the coating composition is applied in a "slugg" to the interior of the tube during processing. Disadvantages of such process are the difficulty of controlling quality, quantity and drying the coating applied. One solution to the problems associated with slugg coating methods has been to coat the external surfaces of the tubular member, under regulated conditions to obtain the desired quantity and quality of coating being applied, then turning the tubing inside out so as to position the controlled coated surface on the interior of the tubing, a process called "everting".
U.S. Pat. No. 3,242,524 describes a method of everting wherein a substantially air impermeable tubular material having a closed end is everted by utilizing a pressure differential to pull the closed end portion through the noneverted casing. Such everting method requires a great deal of space and energy to achieve its goal and is only operable with substantially air impermeable tubular material having sufficient circumferential or hoop strength to resist the imposed air pressure.
U.S. Pat. No. 4,073,737 describes a device for everting tubular casing wherein the casing is passed through a ring member, folded back over the exterior surface of the casing and the ring member is displaced relative to the fixed casing end thereby everting the casing. The ring member is electromagnetically coupled to the displacing apparatus to obtain displacement. Such process requires substantial tensile strength of the casing in that it must be strong enough to sustain the forces necessary to "pull" itself through the point of everting plus withstand the weight of its unsupported length. There is also an incremental increase of abrasion at the point of everting which results from the electromagnetic attachment of the displacing apparatus and the ring member.
U.S. Pat. No. 4,162,557 describes a method and device of everting wherein tubular casing is shirred on a "stick", the end of the casing is closed and the tubing everted during deshirring by pulling one end of the shirred tubing through the bore of the shirred stick and out through the opposite end.
U.S. Pat. No. 4,292,711 describes a similar process and device for everting a shirred stick wherein the everting process is achieved during deshirring and stuffing of the casing with emulsified food products, thus pulling the casing through the opposite end utilizing the stuffing pressure differential. It should be readily apparent that coupling the everting process with shirring and/or stuffing significantly limits the commercial use of the process.
It is, therefore, a primary object of the present invention to provide a device for everting flexible tubular members which overcome the shortcomings of the prior art.
It is a further object to provide an everting method which permits space and energy efficient everting of unshirred flexible tubular members.
It is a still further object of the present invention to provide an everting method and device which acts to reduce the pulling forces at the point of everting.
These and other objects of the invention will become apparent from the specification, claims and the accompanying drawings.
SUMMARY OF THE INVENTION
The invention relates to a process and apparatus for turning an elongated flexible tubing inside out which comprises frictionally engaging the interior surface of the tubular member, axially dispacing said tubular member by means of such frictional engagement to a point of everting and drawing everted tubular member from the point of everting over the exterior surface of the tubular member.
By the process of the invention, means are provided to frictionally engage the interior surface of the flexible tubing to be everted thus continuously drawing the tubing axially to the point of everting. Any means can be utilized for frictional engagement though it is preferred to use opposing belt means frictionally engaging interior surfaces of the tubular member. When two opposing belt means are engaging the interior surface, engagement is preferably at opposite interior surfaces. It is also within the contemplation of the invention, however, to utilize more than two belt means displaced about the interior surface of the tubing.
The drawing of everted tubular member from the point of everting over the exterior surface of the tubular member can be achieved by multiple means. Preferably, such means comprise a gripping means which grips the distal everted end of the casing and means for varying the distance between the gripping means and the point of everting. Preferably, the gripping means is maintained stationary while the point of everting is moved progressively away therefrom, but the instant invention contemplates movements of either or both in the process of the invention.
As will be apparent from the aforesaid description, the instant invention contemplates a significant reduction of linear tensile force being applied axially to the flexible tubing during everting. As distinct from prior art processes which pull tubing through the point of everting, the instant invention pushes the tubing to the point of everting and thereafter pulls the everted casing away from the point of everting. The result is a significant decrease in tensile forces at the point of everting where the casing is also being subjected to shearing forces occasioned by its deformation from being turned inside out. This reduction in tensile force decreases the tendency of the tubing to rupture and/or abrade at the point of everting.
The tubing suitable for use in the present invention can be flexible, seamed or seamless tubing made from multiple materials. Preferred tubing is that used as casings for food products such as seamed or seamless tubing formed of regenerated cellulose, cellulose ether such as the ethyl, propyl, hydroxy, alkyl and the like ethers, proteins, carbohydrates, collagens, alginates, starches as well as other synthetic or artificial materials. The tubing can also be reinforced with fibers such as, for example, those employed in the production of paper, rice paper, and the like, hemp, rayon, flax, nylon, polyethylene terephthalate and the like. The tubing can be substantially air impermeable or it can be porous such as net-line sheathing and the like.
The tubular casings can be made by any known process such as, for example, by the cuprammonium, decetylation of cellulose acetate, viscose, denitration of cellulose nitrate processes or extrusion or appropriate compositions. Tubular casings reinforced with fibers can be made by the method and apparatus described, for example, in U.S. Pat. Nos. 2,105,273; 2,144,889; 2,910,380; 3,135,613 and 3,433,663.
Coating materials suitable for use as coatings with tubular food casings are well known and may be prepared, for example, from polyvinylidene chloride resin copolymers, polyethylene and other polyolefin resins, polyester resins, nylon, polyurethane resins and suitable combinations thereof. The coating is applied to the exterior surface of the casing whereupon the casing is then turned inside out using the process of this invention.
The use and type of a primer on the surface of casing employed prior to application of the coating or applying the coating directly to the surface of the casing will depend on the type of coating to be employed, the degree of adhesion required and the service requirements for the casing. It is known, for example, that various cationic thermosetting resins are advantageously employed as primers for enhancing adhesion of certain polyvinylidene chloride copolymer coatings to cellulosic casing surfaces. Exemplary of polyvinylidene chloride copolymer resins coatings advantageously employed with tubular food casings and the method of application, may be found, for example, in the disclosures of U.S. Pat. Nos. 2,961,323, 3,328,330 and 3,369,911.
In certain instances, it may be desirable to coat the interior surface of the non-everted casing with a friction increasing or decreasing agent, additive or similar material to aid in the frictional engagement of the interior surface. Such agent, additive etc., may be applied by known methods such as "slugging" techniques or may be applied by means in conjunction with the frictional engagement means.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 is a schematic view of the device of the present invention, illustrating one stage of the eversion process.
FIG. 2 is a schematic view of the device of the present invention, illustrating a second stage of the eversion process.
FIG. 3 is a partial cross section top view of the opposing belt apparatus.
FIG. 4 is a vertical cross section of the belt bar apparatus of an embodiment of the invention.
FIG. 5 is a bottom view of the opposing belt apparatus.
FIG. 6 is a partial cross section side view of the opposing belt apparatus.
FIG. 7 is a top view, horizontal cross section of the belt bar apparatus of an embodiment of the invention.
DESCRIPTION OF THE PREFERRED EMBODIMENT
In a preferred embodiment of the invention as shown in the drawings and referring particularly to FIGS. 1 and 2, the invention comprises a frame 1 for supporting the apparatus, a clamp 2 for gripping an everted distal end portion 3 of flexible tubular member 4, supplied from supply reel 5 which is everted at everting point 6 by means of opposing belt apparatus 7. Take up reel 8 receives the everted tubular member.
The frame 1 comprises spaced vertical members 1a and 1b and a horizontal connecting track member 1c. Supply and takeup reels 5 and 8 respectively, are located near the frame 1. A pair of guide rollers 9 are positioned near the supply reels 8 and 5 and the clamp 2 is attached to the frame member 1a. The opposing belt apparatus 7 is displaced along track member 1c of frame 1 by being mounted to carriage 10 which is driven by suitable drive means (not shown).
The opposing belt apparatus is more particularly shown in FIGS. 3-7. In FIGS. 3, 5 and 6, representing top, bottom and side views respectively of the apparatus, wherein frame 20, supports everting drive means 21 which is cooperatively engaged through shaft 22, pulley 23, belt 24, pulley 25 and shaft 26, to cause gear 27 and equal sized intermeshed gear 28 and shaft 29 to rotate in opposing directions at the same speed. Each of shafts 26 and 29 extend through frame 20 and engage one of equal size drive pulleys 30 and 31 which each drive a belt 32 and 33 around adjacent guide rollers 34 and 35 onto belt bars 36 and 37. The belt bars are pivotably attached by shafts 38 and 39 and comprise multiple rollers 40 to allow relatively free rotation of belts 32 and 33 about belt bars 36 and 37. Pivotal attachment of the belt bars at 38 and 39 allow coordinated adjustment of the belt bar with the interior width of the flexible tubing being everted, through adjustable spring tension means 41. Air cylinder 42 extends and contacts piston 43 which acts through pivot coupling 44 and arms 45 and 46 to variably engage adjacent rollers 34 and 35 on belts 32 and 33, thereby allowing variable adjustment of the angle of the belts contacting the interior surface of the tubing. Edge detector 47, adjustably mounted on frame member 48 detects the position of the point of everting along the belt bars and is interconnected, by conventional control means, with air cylinder 42, everting drive means 21 and carrier drive means (not shown) to allow coordinated adjustment of the aforesaid elements. The edge detector can be any suitable conveniently available means such as laser detecting means, optical, mechanical, electrical or combination thereof edge detecting means. Electric eye edge detecting means are preferred.
Thus, in operation, the edge detector 47 senses the location of the point of everting on the belt bars, and detects changes therein. Conventional control means interconnect the edge detector with the carrier drive means and/or everting drive means 21 to adjust either or both the speed of carrier displacement along horizontal track member 1c or the speed of everting. Preferably, both the carrier drive means and everting drive means are separate variable speed drive means. Air cylinder 42 actuates adjustment of guide rollers 34 and 35 before, during or after the everting cycle as needed. Typically there is little need for vascillating adjustment of the guide rollers during an everting cycle except when utilizing irregular diameter and/or thickness tubing. Generally, however, as the distance of the carrier from the gripping means increases, the force of frictional engagement of the opposing belt means to the interior surface of the tubing is advantageously increased by adjustment of the belts through air cylinder 42.
FIG. 4 depicts a cross section view at 4--4 of belt bars 36 and 37, showing the relative operating position of belts 32 and 33 rollers 40, noneverted flexible tubular member 4 and everted flexible tubular member 3.
FIG. 7 depicts a top view, horizontal cross section at 7--7 of belt bar 36 and 37, showing the relative operating position of belts 32 and 33, rollers 40, guide rollers 34 and 35 and drive pulleys 30 and 31.
FIG. 1 depicts operation with, for example, the flexible tubular member being thin walled flexible tubular food casing, wherein a free end of the casing 4 is drawn from the supply reel 5, passed between guide rollers 9, onto belt bars 36 and 37, doubled back over and the so everted distal end portion 3 being fastened into clamp 2. The exact position of the everting point 6 along belt bar 36 and 37 is not critical and as will be seen in the discussion hereafter can be adjusted if desired. The spread of the belt bars is pivotably adjusted about shaft means 38 and 39 such that the outside surface of belts 32 and 33 frictionally engage opposing interior surfaces of the flexible casing so that noneverted casing will be drawn from supply reel 5. It should be understood that the instant invention contemplates combinations of adjustment means including springload adjustment means 41, pneumatic adjustment means 42, etc., which may be sensor or otherwise controlled to provide indexed frictional engagement force on the interior surface of the flexible tubular member.
Referring back to FIG. 1, as the opposing belt apparatus engages and draws the noneverted tubular member from the supply reel, the carriage is caused to move along track 1c at a displacement rate approximately equal to the rate at which casing is drawn from the supply reel. Movement of the carriage can be by suitable separate drive means or can be by cooperative engagement with the everting drive means of the opposing belt apparatus. Thus it can be seen that as the casing is drawn from the supply reel and the apparatus is displaced at an equal rate along track 1c, the point of everting 6 should remain constant in relation to the belt bars. The drive means of the apparatus are interconnected with sensing device 47 proximate the belt bars which acts in adjustment of drive speed to adjust the position of everting point 6 as may be desired.
Referring now to FIG. 2 when the carriage 10 has reached the limit of its traverse on track 1c, proximate verticle support member 1b, the noneverted portion 4 of the casing is severed adjacent to clamp 2. The free end of the everted casing 3 is then removed from the clamp, attached to take-up reel 8, and wound thereon. Typically, the free end of the everted casing is spliced to previously everted casing already on take-up reel 8 and take-up reel 8 is automatically driven by separate drive means (not shown) thus winding up the everted casings. The direction of the carriage can be reversed with the opposing belt apparatus drawing the noneverted casing at a rate equal to the rate of its displacement along 1c back to its starting position adjacent verticle support 1a and at a rate equal to the take-up of take-up reel 8. Alternatively, the carriage and opposed belt apparatus can be maintained at the end of its traverse or at some point therebetween, with the opposing belt apparatus continuing to draw the remaining noneverted tubing at a rate equal or proximate to the rate of wind up on take-up reel 8. When the cut end of uneverted casing 4 is drawn up the belt bars and everted, the casing will no longer be supported at the end of the frame near 1b and drops to the supporting structure. A trough 49 is provided to prevent the everted casing from becoming soiled or damaged as it is being wound on take-up reel 8, typically such trough will include roller conveyor means to avoid damage to the casing.
It is important to note that the amount of casing which can be everted in the course of a single operation is at least equal to twice the distance between the two verticle frame members 1a and 1b, and that the forces imposed on the casing during the everting process are minimal, thus representing a significant efficiency in space and energy. Of particular interest, the forces at the point of everting are a combination of push from the opposed belt apparatus and pull from the weight of unsupported casing resulting in a reduction in tensile forces at the point of everting over prior art apparatus.
The invention being aforesaid described, it will be obvious that the same can be varied in many ways. Such variations are not to be regarded as a departure from the spirt and scope of the invention, but all such modifications are intended to be included within the scope of the following claims.
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A method and device for everting flexible tubular members, such as food casings and the like, is disclosed wherein a tubular member is axially displaced by a frictional engagement means, which means is deposed in a distal end portion of the member, and which frictionally engages the interior surface of said member and displaces said member to a point where the member is folded back over itself (everted) and then displaces said everted member, from the point of everting over the exterior surface of the noneverted tubular member.
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FEDERALLY SPONSORED RESEARCH
Not Applicable
SEQUENCE LISTING OR PROGRAM
Not Applicable
BACKGROUND
1. Field of Invention
This is a motor vehicle safety device that warns of vehicles in the driver's blind-spot.
2. Prior Art
Drivers of motor vehicles should be aware of other nearby vehicles, particularly when they are changing lanes on a multilane highway. Rearview mirrors, required safety equipment for automobiles, address the need drivers have to monitor the traffic situation behind them. Some drivers have difficulty making adequate use of their rearview mirrors. One problem arises when another vehicles is close to them in an adjacent lane, slightly behind the driver's vehicle, so the nearby vehicle is not visible in the inside rearview mirror and is not visible in the driver's peripheral vision when the driver is looking straight ahead. This is the so-called blind-spot problem. Another related problem is that some drivers do not check their rearview mirror every few seconds to continually update their knowledge about the traffic situation behind them. These problems become worse when distractions, such as cell phone conversations or disruptive children, compete for the driver's attention. These problems also worsen when long trips fatigue drivers.
Traffic safety experts and people working in the automobile industry recognize the blind-spot problem. Systems have been developed, in addition to rearview mirrors, to address this problem. Typical prior-art systems, represented by U.S. Pat. No. 6,388,565, have sensors, signal processing, and a driver interface. These three elements in the prior art systems have problems what retard widespread use. The sensors are typically technically advanced and sophisticated devices such as radar or ultrasound. These technically sophisticated sensors are generally expensive, which is a problem for widespread deployment. Another disadvantage of technically sophisticated sensors is that they generally require technically sophisticated signal processing. For a system that uses, for example, radar, the signal processing must either determine when a vehicle is in the blind-spot, or it must present data that will allow the driver to determine a blind-spot presence. Making a safety system responsible for interpreting the sensor data for the driver is risky. False warning mistakes annoy the driver, and mistakes of missed vehicles are dangerous. Different cases that need to be considered make interpretation difficult. For example, the system will detect cars in the blind spot when stuck in traffic jams or when in a city; but warnings sent to the driver in these situations might be unwelcome. The interface to the driver is typically a warning such as a flashing light, a sound, or a vibration that the driver feels. The interface must provide a positive warning to the driver without annoying the driver. An interface that is helpful without being annoying is difficult.
The present invention uses tire noise of nearby vehicles to give blind-spot warnings. U.S. Pat. No. 3,158,835 has many elements of the present invention. However, anyone implementing the system taught by U.S. Pat. No. 3,158,835 would find that the sounds presented by the system that originate from the host vehicle would limit usefulness of the system. U.S. Pat. No. 3,158,835 does not adequately teach how to discriminate between the sounds from the host vehicle and the useful sounds of nearby vehicles. Perhaps because sources of constant noise are annoying, there are no known direct descendants of U.S. Pat. No. 3,158,835, and it has not been developed into an available product. The philosophy of quieting host noise to enhance the usefulness of environmental noise for safety is shown in U.S. Pat. No. 6,325,173 that shows the use of wind screens in front of bicyclists' ears so they can better hear overtaking cars. The car safety invention described here differs from the bicycle windscreen patent because it teaches how to make useful sounds available to someone operating a vehicle inside a sound-blocking enclosure.
Another prior art, U.S. Pat. No. 4,943,798 and similar patents, uses many of the same elements of this invention but for the purpose of monitoring the mechanical health of remote tires and wheels on tractor trailer trucks.
Another prior art, U.S. Pat. No. 5,278,553, uses microphones outside a car. This patent teaches how to warn a deaf driver, or a driver listening to a loud sound system, when an emergency vehicle's siren is sounding nearby. The purpose of this patent, the nature of the signal processing, and the interface to the driver are all different from the present invention.
The near absence of prior art blind-spot warning systems that use tire noise is striking. This absence is due in part to basic goals and assumptions that guide the automotive industry. Modern automobiles are quiet inside. They are designed to block road or tire noise, and wind noise. Most people judge quiet cars to be good, and quieter cars to be better. The ability to keep passenger compartments quiet has been aided by the widespread use of automobile air conditioners so windows often remain closed in all types of weather, particularly at highway speeds. The automobile industry considers road noise, in particular, to be a nuisance with no redeeming value. The use of road noise as a useful and interesting sensual input is a paradigm shift for the automotive industry. This helps explain why the use of tire noise to alert drivers to vehicles in their blind-spot has not been pursued by the automotive industry, but instead was demonstrated by a bicycle rider who was able to build a demonstration in his basement from inexpensive components.
Objects and Advantages
This invention alerts a driver to vehicles in his blind spots by allowing the driver to hear nearby vehicles. Another object of this invention is to help drivers to be more alert by making driving a more sensually rich experience. Another object of this invention is to not annoy drivers with useless noise. A further object of this invention is to make driving more interesting.
This invention can be implemented with inexpensive hardware. The sensors are electret microphones in one demonstration implementation. The signal processing is relatively simple because this system does not make any decisions concerning the need to warn the driver about blind-spot intrusions. The data is presented to the driver without interpretation. The driver provides the interpretation function. Also, the signal processing need use only audio frequency signals, which are easy to manipulate.
The interface is straightforward. The driver hears sounds that seem to come from nearby vehicles. The sounds actually come from inexpensive loudspeakers. These sounds resemble the sounds that would be heard from nearby vehicles if the noise-blocking passenger compartment were not in the way. A driver using this system does not perceive any increase in wind noise or tire noise coming from his vehicle. The sounds from this safety system are of much higher quality, that is, free from extraneous noise, than what a driver would hear if she opened her windows at highway speeds. Drivers find the sounds made by this system, which seem to come from the highway environment, easy to interpret, useful, and interesting.
This system does not noticeably add objectionable noise to the passenger compartment. By using directionally selective microphones and electronic signal processing that exploits the directional properties of the microphones, the system essentially rejects noise coming from the host vehicle. The only sounds that the driver notices coming from the safety system are useful sounds from nearby vehicles.
The data interpretation function is done by the driver. This is an important point that makes this system superior to the prior art represented by U.S. Pat. No. 6,388,565. People are extremely good at interpreting sounds from activities happening close to them, when the sounds are not blocked by an enclosure. This ability to interpret sounds is built into people's neurological system. It operates naturally and it operates unconsciously, that is, without conscious effort. New sounds coming from behind have a high priority ability to focus attention. To say this another way, new sounds coming from behind are automatically considered to be very important by primitive parts of the human brain. This ability does not need to be learned. The ability to accurately and automatically interpret sounds that correspond to environmental situations is shared by many animals. This remarkable ability is the result of millions of years of evolution. The vehicle safety system described here makes use of this ability.
Another advantage of this invention is that drivers find that using this device is interesting. Drivers appreciate the additional sensual inputs provided, not only for the safety benefit, but because the sounds make driving more fun. Being able to hear clearly what is happening nearby is a welcome, natural ability enjoyed by people who have normal hearing, and sadly missed by people who are hearing impaired. No one, for example, would consider wearing ear plugs while making love, except perhaps if they had been married for thirty years. People enjoy the sounds from this system because they mitigate the aural sensory deprivation caused by modern, sound-insulated cars.
One benefit of the sounds provided by this system being interesting is that drivers do not need to be encouraged or coerced to use the system. They enjoy using the system.
Another benefit of this invention is that because driving is more interesting when drivers can hear what is happening around them, drivers stay more alert and better focused on their driving tasks on long trips.
The sounds produced by this safety system need not interfere with traditional in-car activities. The driver has no difficulty conversing with passengers or listening to the car radio while using this system. Passengers are barely aware of the system's presence.
Microphones have advantages as sensors. They are inexpensive, the required signal processing for use in blind-spot warnings is simple, and microphones are adequate to do an excellent job for automobiles. However, there are applications for which passive microphones have limitations and for which cost is not a major concern. One example is a system to warn a pilot of nearby aircraft. The advantages of an interface that mimics natural sound could be combined with radar sensors, or any sensors that can detect objects and estimate their location.
DRAWING FIGURES
FIG. 1 shows an automobile with this sound-based safety system.
FIG. 2 shows two loudspeakers mounted on the driver's seat.
FIG. 3 shows directional microphones incorporated into an automobile's taillight assemblies.
FIG. 4 shows another embodiment of directional microphones suitable for mounting on the rear of an automobile.
FIG. 5 is a block diagram of the preferred embodiment of this sound-based safety system.
FIG. 6 shows a sound-based safety system joined with other automobile components to address the problem of children being injured by vehicles backing out of parking spots.
FIG. 7 is a block diagram of a level-dependent filter.
FIG. 8 is a block diagram of the controls for the level-dependent filter.
FIG. 9 is a block diagram of a compressor.
FIG. 10 is a block diagram of method to compensate for varying pavement surfaces.
FIG. 11 is a block diagram of a safety system that has a human interface that is based on sound.
FIG. 12 is a block diagram of a sound-based safety system adapted for people with asymmetric hearing
FIG. 13 is a circuit diagram of the level-dependent filter shown in FIG. 7 .
FIG. 14 is a circuit diagram of controls that mate with the circuit diagram of FIG. 13 .
FIG. 15 is a circuit diagram of the compressor shown in FIG. 9 .
DETAILED DESCRIPTION
FIGS. 1 and 2 —Preferred Embodiment
FIG. 1 shows the rear of an automobile, the host vehicle for a sound-based safety system, with two directionally discriminating microphones 20 mounted on the back, electronic signal processing 22 inside the car, two loudspeakers 24 mounted on the driver's seat beside the headrest, interconnecting wiring 26 between the microphones 20 and signal processing 22 , and interconnection wiring 28 between the signal processing 22 and loudspeakers 24 . The microphones 20 on the back of the host vehicle are directional so that they respond strongly to sounds coming from vehicles near the host vehicle while responding only weakly to sounds coming from the host vehicle. The primary source of sound that this system uses is tire noise. The host vehicle produces tire noise and this is usually not a useful sound. By using directional microphones, the system provides a much clearer aural picture of the driving environment.
FIG. 2 shows the loudspeakers 24 mounted on the driver's seat so they are close to the driver's ears. This loudspeaker placement allows the system to easily and clearly convey location information to the driver. This loudspeaker placement has the further advantage that passengers in the vehicle are not generally aware of the sounds from the safety system. FIG. 2 also shows controls 30 mounted on the driver's seat headrest. This placement avoids changing the design of the dashboard or other control-intensive location in the vehicle. Further, this location of controls 30 near the safety system loudspeakers 24 is logical in that it is close to the mechanical embodiment of the system's interface to the driver. The controls 30 will be simple, perhaps a volume control and a single switch that will select either a normal mode of operation or a mode for people with asymmetrical left-right hearing. Once these two controls have been set, they will rarely need to be changed.
Directionally Discriminating Microphones
The objective of this sound-based safety system is to enable the driver to hear vehicles in his blind spots while not annoying the driver with sounds that originate from his own vehicle. Directionally discriminating microphones play an important role. Directionally discriminating microphones are preferentially sensitive to sounds that come from certain orientations and discriminate against other sounds. The directionally discriminating microphones of this system are aimed at vehicles behind and beside the host vehicle and discriminate against sounds that come from the host vehicle.
The directionally discriminating microphones for this safety system can be implemented in several ways. For demonstrating the principles of this invention without making irreversible modifications to an existing automobile, the microphones have been parabolic reflectors that mount on the car with magnets so the microphones can be placed, repositioned, and removed without modifying the car. These microphones are shown in FIG. 1 . The microphones for the demonstration system were molded on a parabolic surface 15 centimeters in diameter at the outer edge of the mold, and the focal point of the parabola is 3.3 centimeters from the inside-most point of the parabola surface. In each reflector an electret microphones about 10 millimeters in diameter and 7 millimeters in length is mounted with its acoustic openings facing the innermost point of the parabola and about 3.2 cm from the innermost point of the reflector surface. The parabolic reflector and electret microphone are covered with a windscreen made from a fabric that is acoustically nearly transparent but which inhibits wind from blowing directly on the electret microphone. The windscreens reduces noise caused from air passing by the microphones due to the forward motion of the vehicle or due to wind. The fabric wind screens were treated to make them water-repellent, so the microphones operate properly in wet weather. The microphones are aimed so that the axes of the parabolic reflectors, that is the axis of maximum sensitivity to sound, point down about 5 degrees. The axes of the parabolic reflectors point slightly to the sides. The microphone on the right side points to the right by about ten degrees. The microphone on the left points to the left by about ten degrees. The microphones are positioned approximately as shown in FIG. 1 .
The parabolic reflector microphones described above have advantages for developing and demonstrating the system on an existing vehicle, but a better choice is available for a mass-produced product. FIGS. 3 and 4 each show two directional microphones. In FIG. 3 the microphones are incorporated into the taillight assemblies of an automobile. These microphones each have a tapered acoustic waveguide 32 with external opening 34 . The waveguides curve upward inside the vehicle and end at electret microphones 38 . The external openings 34 of the waveguides 32 are covered with screens 36 . These screens prevent insects and other objects from entering the waveguides and they serve as windscreens that reduces noise from air moving past the vehicle as a result of vehicle motion and natural air currents from wind. Tapered acoustic waveguides are well known for their ability to make efficient loudspeakers by improving the acoustic impedance match between the loudspeaker driver and the air in the listening room. This safety invention exploits the directional properties of tapered acoustic waveguides. The external openings 34 of the waveguides 32 have dimensions that are large compared to the wavelengths of some portion of the spectrum of sounds of interest. For sounds that have wavelengths smaller than the dimensions of the openings, the microphones are directional. The same general relationship between size of the microphone, wavelengths of sound, and directionality apply to microphones with parabolic reflectors. By making the openings 34 of the waveguides 32 non-circular, the pattern of the directionality can be made non-circular. The waveguides 32 shown in FIG. 3 are curved so that the electret microphones 38 inside the automobile are protected from environmental hazards such as rain and car washes. That is, the electret microphone elements 38 that may be water-sensitive are protected from water because water will drain downhill, away from the water-sensitive elements. This arrangement mimics the way that the most sensitive parts of the human ear are protected.
FIG. 4 shows that the opening of the acoustic waveguides 32 can be substantially non-symmetric from left to right so that although the axes of the waveguides point nearly straight back, the response of the left microphone to a vehicle close to the host vehicle and on the left side of the host vehicle will be much stronger than the response of the right microphone. In FIG. 4 the two waveguides are mounted side-by-side near the center of the automobile, and their axes of maximum sensitivity both point straight back from the vehicle. Opening region 40 extends further toward the back of the vehicle than opening areas 42 . Because of these asymmetrical openings, the two microphones respond differently to vehicles in the left and right blind spots, thus allowing the position of vehicles in the left and right blind spots to be accurately distinguished by ear.
Block Diagram of the Preferred Embodiment— FIG. 5
FIG. 5 shows a block diagram of one channel of the safety system. The blocks starting with microphone amplifier 44 , including level-dependent filter 46 , level-dependent filter controller 48 , level-dependent filter controls 50 , compressor 52 , volume control 54 , and power amplifier 56 are the signal processing portion of the system. The directional microphone 20 , the level-dependent filter 46 and the level-dependent filter controller 48 are elements that work together to make the system relatively insensitive to noise originating from the host vehicle while making it sensitive to sounds coming from nearby vehicles.
FIG. 5 shows several less-common signal processing functions, which are represented in FIG. 5 by the level-dependent filter 46 and its controller 48 , and the compressor 52 . The level-dependent filter 46 complements the directional microphones 20 that are directional only for the higher portion of the frequency spectrum that represents sounds of interest. If the microphones were directionally selective for the entire spectrum of sounds for which the system responds, they would be quite large compared with the taillights of automobiles. By employing a level-dependent filter, larger microphones are unnecessary.
FIG. 6 , a System Addressing Backing Accidents in Driveways
FIG. 6 shows a system, which includes the sound-based safety system, that reduces the danger of backing over children in driveways. The problem of injuries to children from people backing automobiles out of driveways may be addressed by the following combination of measures: (a) Limit reverse speed initially to a slow speed, perhaps walking speed of 3 miles per hour, by a governor, or to a low acceleration, (b) Automatically mute the car radio/sound system when the vehicle is backing, (c) Automatically increase the gain of the sound-based safety system when the vehicle is backing. These three measures are shown as a system, in block-diagram form, in FIG. 6 . When the vehicle transmission 58 is in reverse, the sound-based safety system 60 has its gain increased, the radio sound system 62 is muted, and the vehicle speed or acceleration is limited by engine control 64 . This allows a child playing behind the vehicle to scream and alert the driver before being overrun.
Level Dependent Filter and Controller
The level-dependent filter 46 has two basic specifications. First, when there are no loud sounds nearby, such as sounds produced by high-speed vehicles near the host vehicle, the level-dependent filter should have no noticeable effect on the signals passing through it. Second, when the host vehicle is traveling at speed and there is another vehicle nearby, the level-dependent filter should make the sounds from the nearby vehicle seem natural. The level-dependent filter in this case counteracts the frequency dependence of the directional microphones without losing the directional advantages of the microphones. One consequence of the first specification is that if the host vehicle is at rest and a person outside the vehicle and not on the axes of the microphones speaks, the driver will hear the person speaking and the sound will seem natural. This ability will help drivers from backing over children in driveways as noted in the system of FIG. 6 .
Having described the objectives of the level-dependent filter, the structure of one embodiment can now be understood.
FIG. 7 shows a block diagram of a level-dependent filter. The notation of this block diagram is familiar to engineers who work with dynamic system designs. The blocks 72 and 74 with “1/s” inside are integrators. The “s” variable is the Laplace transform variable which, roughly speaking, represents frequency. The blocks 76 and 78 with “2*zeta*omega o ” and “omega o 2 ” are gains. The circles 66 , 68 , and 70 are summing junctions. The four blocks 72 , 74 , 76 , and 78 , and two summing junctions 66 and 68 comprise a second order “state-space” filter with a high-pass output from summing junction 66 , a bandpass output from gain block 76 , and a low-pass output from gain block 78 . The “resonant frequency” of the filter is omega o and the damping ratio is zeta. When the variable gain blocks 80 and 82 have gain of 1, the signal output, formed by summing three signals at summing junction 70 , is the same as the input signal on the left of FIG. 7 . When a vehicle is nearby and at speed, the control signals 50 , from the level-dependent filter controller 48 , change the gains of blocks 80 and 82 to make the sounds heard by the driver seem more natural. Without the level-dependent feature of this filter, vehicles would sound unnaturally high in frequency as the directional microphones responded preferentially to the higher frequencies of the vehicles that are near their axis of symmetry.
FIG. 8 shows the level-dependent filter controls in block diagram form. FIG. 8 shows two independent controls 50 provided to the level-dependent filter, called “bandpass filter control” and “high-pass filter control.”. The bandpass filters 84 and 90 respond to signals in some selected band of frequencies. If there is adequate signal in the frequency region accepted by bandpass filter 84 or bandpass filter 90 , the rectifier and low-pass filter 86 or 92 produces a change in a slowly varying, nearly direct-current signal. These near-direct-current signals are further provided with gain, zero, and possibly dead-zone adjustments, by blocks 88 and 94 , to interface appropriately with the level-dependent filter. Because the control signals 50 , provided to the level-dependent filter 46 to change gains, have slowly changing levels, there is no noticeable distortion caused by the level-dependent filters.
FIG. 7 shows the mathematical concept of the level-dependent filter without showing a practical implementation. FIG. 13 is a circuit diagram of an implementation of a level-dependent filter using analog circuits. While the implementation shown here is well suited to testing and demonstrating the concepts of this invention, a shipped product would likely be implemented with digital signal processing.
Circuit Diagrams of Level Dependent Filter and Controller
The circuit diagrams of FIGS. 13 , 14 , and 15 are designed to operate with four AA size alkaline batteries as the power supply. The power supply voltage is designated as “Vc.” The voltage designated as “Vc/2” is half the battery voltage. In FIG. 13 , op amps 134 and 136 form the two integrators of the state space filter. Pot 138 adjusts the resonant frequency of the filter, and it also affects the damping ratio of the filter. Pot 138 adjusts the gain shown in FIG. 7 as “omega o 2 .” This one pot adjusts the resonant frequency of all three paths of the filter, the low-pass, bandpass and high-pass paths. Pot 140 adjusts the damping ratio. Pot 140 with op amp 142 adjusts the gain shown in FIG. 7 as “2*zeta*omega o .” This adjustment changes the damping ratio for all three paths. These adjustments are useful for experimenting, but could be fixed for a shipped product. JFET 144 changes the gain of the bandpass path. JFET 146 changes the gain of the high frequency path. These two JFETs are used as voltage controlled resistors. The use of JFETs for this purpose is well-known and is described in application notes from JFET manufacturers. In order to obtain proper operation of the JFETs, the JFETs must be selected for proper on resistance and gate-source cutoff voltage, and the individual devices must have control voltages that come from circuits that have gain and offset adjustments, and these adjustments must be adjusted for the particular individual JFET that they control. This need for adjustments is of little concern for a demonstration implementation, but for a mass-produced product this would be a serious disadvantage. For this and other reasons, using digital signal processing to implement is attractive. Op amp 148 sums the low-pass, bandpass and high-pass paths. Op amp 150 performs the summing function that in FIG. 7 is done by summing junctions 66 and 68 .
FIG. 14 shows a circuit diagram of an implementation of the level-dependent filter controller that works with the circuit of FIG. 13 . Op amps 154 and 156 with JFET 158 and associated resistors provides a reference voltage that is used repeatedly to adjust the offset of the controls for the JFETs that are used as voltage controlled resistors. This reference voltage is independent of supply voltage and it has a temperature dependence that derives from JFET 158 in such a way that the properties of the system do not change noticeably with temperature. Op amps 160 , 162 , and 164 form the bandpass filter for the filter controller for the level-dependent filter's bandpass gain. The configuration shown allows a relatively high resonant frequency and a very low damping ratio to be implemented with op amps that have a modest gain-bandwidth. While this configuration was useful for experimental purposes, it is not necessary, and a simpler bandpass filter would be adequate. FIGS. 7 and 8 show two independent controls 50 . The control for the level-dependent band pass filter path is the more important in the sense that it uses high frequency signals to control much lower frequency signal gains in the level-dependent filter, and thus implements the objective of obtaining natural-sounding output from directional microphones that have limited directional bandwidth. The control for the gain of the high-pass path of the level-dependent filter makes the sound output of the system more interesting by giving the sounds produced an additional sense of depth. This high-pass section of the level-dependent filter changes the color of the sound of a nearby vehicle as it comes closer to the host car. The control for the high-pass path uses the bandpass filter of the level-dependent filter as the filter that selects the spectral region whose signal energy changes the gain of the level-dependent filter's high pass path. That is, signal 152 of FIG. 13 is also signal 152 of FIG. 14 . For the bandpass controller, potentiometer 166 adjusts the resonant frequency of the bandpass filter, potentiometer 168 adjusts the gain of the bandpass controller, potentiometer 170 adjusts the dead zone, potentiometer 172 adjusts the control offset, and potentiometer 174 adjusts the high limit. For the high-pass controller, potentiometer 176 adjusts the gain, and potentiometer 178 adjusts the control offset.
Compressor
FIG. 9 is a block diagram of a compressor. The purpose of the compressor is to keep loud sounds from being uncomfortably loud. The problem addressed by the compressor is that occasionally there are unusually loud sounds from traffic, such as sounds made by a truck or a horn. The compressor turns down the volume on sounds that would otherwise be unpleasantly loud. The signal strength of the output of the compressor gets monitored by a rectifier and low-pass filter, 98 . Based on the output signal strength, the gain at the input to the compressor gets adjusted by a variable gain element 96 , with louder signals causing the gain to be reduced.
FIG. 15 is a circuit diagram of a compressor. This circuit shows two channels corresponding to the preferred embodiment of a left and a right channel. The JFETs 180 and 182 are used as voltage controlled resistors as is done in the level-dependent filter. The rectifier for the right channel, formed by op amp 184 and associated components, gets inputs from both the left and right channels through resistors 186 and 188 . Using inputs from both channels as inputs to the gain control for each channel keeps the level of attenuation from the compressors in the left and right channel approximately balanced. For the left channel, potentiometer 190 adjusts offset and potentiometer 192 adjusts gain.
Signal Levels
Returning to FIG. 5 , the microphone amplifier 44 , volume control 54 , and power amplifier 56 use routine technology. Amplifying microphone signals to drive a loudspeaker is well-known art. However, parts of this safety system, the level-dependent filter 46 and the level-dependent filter controller 48 , are nonlinear and so signal levels are important. The gain of the microphone amplifier 44 for the demonstration system described here has a voltage gain of about 6 for use with an electret microphone with gain of −42 dB where 0 dB is 1 volt per pascal, mounted in a 15 centimeter diameter parabolic reflector. This gain is appropriate for dry pavement. For wet pavement, a gain of about 3 is appropriate because tires make more noise on wet pavement. These gains work well with the circuits shown in FIGS. 13 and 14 .
FIG. 10 , Automatically Monitoring Highway Acoustic Properties
FIG. 10 is a block diagram of a sound-based safety system such as is shown in FIG. 5 but with the addition of a microphone 100 whose purpose is to monitor the condition of the pavement and the speed of the host vehicle that together determine the tire noise characteristic of that combination of pavement and speed. The signal of the pavement-monitoring microphone 100 is used to change the signal processing properties of the sound-based safety system. The signal processing block 102 monitors the signal from the pavement monitoring microphone 100 to produce a nearly-dc control signal indicative of signal strength from the pavement monitoring microphone 100 . This control signal from signal processing block 102 changes the characteristics of signal processing block 104 . One use of the pavement-monitoring microphone is to change the gain of the microphone amplifiers 44 that are part of signal processing block 104 . This gain, as has been noted, is profitably changed based on pavement conditions. Wet pavement makes more noise than dry pavement, and some pavements are noticeably more quiet than others. Making automatic gain adjustments would make this sound-based safety system sound more natural and more useful to the user. Also, the pavement-monitoring microphone would automatically increase gains at low speed to improve safety when backing up.
Additional Embodiment—A System with Generalized Sensors
FIG. 11 shows another embodiment of this invention. This embodiment makes use of the previously described sound-based interface to the user, but with sensors 106 of any sort. In this embodiment, the user hears sounds that seem natural and that represent important nearby objects. However, the sensors are not necessarily microphones, and the sounds are synthesized, If radar sensors were used, for example, the signals sent to the loudspeakers 24 would be generated based not on directly sensed sounds from outside the system, but would be based on estimated locations of nearby items of interest. The sensors 106 , orientation estimator 108 and distance estimator 110 would detect and estimate the location of items of interest. Then the system would generate signals that when played by the loudspeakers would represent the sensed objects in the object's estimated position. The objects could be assigned a base sound that could resemble tire noise, aircraft noise, ship propeller noise, or other sounds. A base sound generator 112 creates a signal representing this base sound. The volume of the sound is used to represent estimated distance. The volume is adjusted by the volume control 114 based on the estimated distance from the distance estimator 110 . The estimated direction of the object would be indicated by processing the object's assigned sound signal through an appropriate “head-related transfer functions,” 116 . Such “head-related transfer functions” can be used, for example, to make sound convincingly seem to originate from behind the listener when the loudspeakers are in fact in front of the listener. These “head-related transfer functions” represent the effect of a listener's head on the sounds that reach the insides of his ears. These head-related effects of course are strongly dependent on where sounds originate relative to the orientation of the listener. Thus seemingly natural sounds can be generated from position information of any sort. Alternately an array of loudspeakers could be used in place of head related transfer functions 116 and two loudspeakers 24 . These synthesized sounds can be used as an output of a warning system to alert someone that an object has come close enough to deserve their attention.
Additional Embodiment—A System for People with Asymmetrical Hearing
The systems described so far require that the person using them have balanced hearing in their left and right ears. Some people have a hearing problem that makes them less able to localize the source of a sound. This limitation is addressed by the concept shown in FIG. 12 . This system is a user-selectable configuration of the system of which one channel is shown in FIG. 5 . The microphones 118 and 120 are the same directional microphones used for the previous configurations. The left filter 122 and right filter 124 represent almost all of the signal processing functions. For this configuration the left and right filters are deliberately different so as to give the tire noise from a vehicle in the left blind spot a different tonal color than the tire noise from a vehicle in the right blind spot. This is easy to do because tire noise has a broad frequency spectrum, so different parts of the spectrum can be emphasized by the left and right filters. The level-dependent filters can be used for this left-right difference so that low-level signals are not given unbalanced tonal color. The outputs from the left and right filters are summed together by summer 126 . The output of the summer is a single common signal 128 that goes to both the left power amplifier and loudspeaker 130 , and the right power amplifier and loudspeaker 132 . Thus a person with hearing in only one ear can benefit from the system is several ways. She will be aware of nearby vehicles from sound coming from the system, and she will be able to differentiate by ear vehicles in the left and right blind spots because they sound different.
Conclusion, Ramifications, and Scope
The invention described here makes driving safer and more interesting by providing useful, natural-sounding aural information to the driver. Sounds that originate from nearby vehicles are useful. Sound that originate from the host vehicle is noise that provides no useful information about the traffic environment. The safety system must be able to discriminate against host vehicle noise, and this ability is a central technical challenge for this sound-based safety system.
The description above describes how a demonstration of this safety system has been implemented and suggests how a practical, mass-produced sound-based safety system can be realized. Extensions and useful implementation details will occur to those skilled in electronic, acoustic, and automotive arts. The directional microphones, for example, could be realized by using arrays of small individual transducers. Digital signal processing can be used in the signal processing.
The description above provides concrete examples of this invention and thus serves to aid understanding of the following claims. The claims alone describe the full scope and coverage of this invention.
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A motor vehicle safety device allows the driver to hear nearby vehicles, so the driver can tell by ear when vehicles are in his blind spots, without significantly increasing the sound level inside the vehicle when there are no vehicles close to the host vehicle's blind spot. One benefit of this invention is the blind spot alert, or blind spot warning. Another benefit is that, because this invention communicates aural information from the host vehicle's environment to the driver, the driving experience is sensually richer and more interesting. The driver remains more alert and focused on the driving task. Elements of this invention, all of which are inexpensive, include directionally selective microphones ( 20 ) mounted on the vehicle, electronic signal processing ( 22 ), and loudspeakers ( 24 ) that are mounted close to the ears of the driver.
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This application claims the benefit of provisional applications No. 60/037,995, filed on Feb. 13, 1997 and 60/037,148, filed on Feb. 14, 1997.
FIELD OF THE INVENTION
This invention relates to novel derivatives of camptothecin, and will have special application to derivatives having substitutions at the C-7 position, and also at one of the C-9, C-10, C-11 or C-12 positions.
BACKGROUND OF THE INVENTION
Camptothecin (CPT) and certain of its derivatives are potent anti-cancer agents and have been the subject of intensive research since the discovery and isolation of camptothecin more than 30 years ago.
CPT was isolated in 1966 by Wall and Wani from Camptotheca accuminata , a Chinese yew. CPT was subsequently observed to have potent anti-cancer activity and was introduced into human clinical trials in the late 1970's. CPT lactone was noted to be very poorly water soluble (about 1 μg/mL), and in order for CPT to be administered in human clinical trials it was originally formulated with sodium hydroxide which increased the solubility of the drug. Sodium hydroxide formulation of camptothecin resulted in hydrolysis of the lactone E-ring of the camptothecin molecule, and formed the water soluble CPT carboxylate species. The sodium hydroxide formulation of CPT created a water soluble CPT species that permitted clinicians to administer larger doses of the drug to cancer patients undergoing Phase I and Phase II clinical trials.
Years later that it was learned that the carboxylate species of parenterally administered CPT had approximately one-tenth or less of the antitumor potency of the lactone form. Clinical trials with sodium hydroxide formulated CPT were disappointing due to significant systemic toxicity and the lack of substantive anti-tumor activity, and clinical studies of CPT were temporarily abandoned in the early 1980's.
Further clinical development of camptothecin derivatives was not pursued until the mid-1980's. At that time it was reported that CPT had a unique mechanism of action which involved the inhibition of DNA synthesis and DNA replication by interactions with the ubiquitous cellular enzyme Topoisomerase I (Topo I). This new information about the mechanism of action of camptothecin derivatives rekindled the interest in developing new Topo I inhibitors as anti-cancer drugs. Subsequently, several research groups began attempting to develop new camptothecin derivatives for cancer therapy. In general, it was observed that camptothecin and many of its derivatives exhibited very poor water solubility. This poor water solubility limited the clinical utility of the drug because prohibitively large volumes (e.g., 5 or more liters) of water had to be delivered to the patient in order to administer an effective dose of the drug. Because of the poor water solubility, a great deal of research effort was directed at generating water soluble CPT derivatives.
Some of the more well-known water soluble camptothecin derivatives include: 9-dimethylaminomethyl-10-hydroxy camptothecin (Topotecan), 7-[(4-methylpiperazino)methyl]-10,11-ethylenedioxy camptothecin, 7-[(4-methylpiperazino) methyl]-10,11-methylenedioxy camptothecin, and 7-ethyl-10-[4-(1-piperidino)-1-piperidino]carbonyloxy camptothecin (CPT-11).
Other substituted camptothecin derivatives with different solubility and pharmacologic properties have been synthesized as well; examples of these camptothecin derivatives include 9-amino camptothecin and 9-nitro camptothecin which are both are poorly soluble in aqueous and nonaqueous media and have been tested in humans.
Of this diverse group of substituted camptothecin derivatives undergoing human clinical development, CPT-11 is one of the most extensively studied in clinical trials in human patients with cancer. CPT-11 (Irinotecan/Camptosar®) was approved for human use by the FDA in June, 1996. It is noteworthy that CPT-11 is biologically inactive and requires activation by a putative carboxylesterase enzyme. The active species of CPT-11 is the depiperidenylated 10-hydroxy 7-ethyl camptothecin (claimed in Miyasaka et al. U.S. Pat. No. 4,473,692 (1984)), also known as SN38. SN38 is a toxic lipophilic metabolite which results from in vivo bioactivation of CPT-11 by a carboxylesterase enzyme. SN38 is very poorly soluble in water and has not been directly administered to human patients with cancer. Recently it has been reported in human patients that SN38 undergoes further metabolism to form an inactive glucuronide species. The glucuronide species also appears to be involved in producing human toxicity (diarrhea and leukopenia are the major dose-limiting toxicities) and substantial interpatient variability in drug levels of the free metabolite and its glucuronide. CPT-11 has been studied in human clinical trials in the United States, Europe and Japan and several patient deaths due to drug toxicity have been reported in association with the use of CPT-11.
In view of the very limited number of potentially active camptothecin derivatives in the poorly water soluble/highly lipid soluble category, there clearly remains a large unmet need to develop potent, poorly water soluble, highly lipophilic camptothecins which do not require metabolism to an active species and are less susceptible to metabolic inactivation and clinically important types of drug resistance in tumors.
SUMMARY OF THE INVENTION
The new compositions of matter disclosed and claimed in the present invention address these unmet needs and can, in addition to topical and parenteral routes of administration, be administered orally which is more convenient for many patients undergoing treatment for cancer.
The present invention overcomes the prior art limitations and has significant utility in patient safety, because these new compositions do not undergo A-ring or B-ring glucuronidation (and implicitly deglucuronidation) and they are not prodrugs which require metabolic activation. Also, because the compounds are lipophilic and can be directly administered in their active lactone form, it is submitted that they will have superior bioavailability relative to CPT-11, Topotecan, 9-amino camptothecin, 9-nitro camptothecin, 7-[(4-methylpiperazino)methyl]-10,11-ethylenedioxy camptothecin, 7-[(4-methylpiperazino)methyl]-10,11-methylenedioxy camptothecin, and other forms of the drug.
The instant invention is also aimed at overcoming other important limitations in bioavailability/pharmacokinetics and common tumor mediated drug resistance mechanisms (e.g., MDR, MRP, LRP) observed with the use of water soluble camptothecins or 9-amino or 9-nitro substituted camptothecins as anticancer agents.
The novel camptothecin derivatives claimed in the present invention represent a new class of antitumor compounds that do not require metabolic activation and exhibit potent antitumor activity against common types of human cancer including but not limited to cancers of the lung, breast, prostate, pancreas, head and neck, ovary and colon. The compounds described by the instant invention have also been shown effective against malignant melanoma neoplasms.
The compounds of this invention all possess Topoisomerase I inhibitory activity similar to that of other camptothecin derivatives but have significant structural modifications rationally designed for superior active site binding capability and tissue penetration. The compounds are designed to avoid untoward metabolism and drug resistance mechanisms which are common in mammalian tumors. Until now, lipophilic camptothecin derivatives with poor water solubility have not been pursued because of limitations in pharmaceutical formulations and methods of use. These novel camptothecin derivatives can be readily formulated in a pharmaceutically acceptable manner by dissolving the drug composition in an organic solvent, or in a mixture of organic solvents which have a high degree of physiologic safety. This allows for the direct administration of these new and non-obvious compounds to cancer patients.
The inventors have discovered several new derivatives of CPT, essentially an entirely new class of molecules which include substitutions at one or more of the a) C-7; and/or b) one of the C-9, C-10, C-11 or C-12 positions in the 20(S)-camptothecin molecule or 20(RS)-camptothecin mixture. These new compounds all possess the following characteristics:
1. Potent antitumor activity (nanomolar or subnanomolar activity in inhibiting the growth of human tumor cells in vitro);
2. Potent inhibition of human Topoisomerase I;
3. Lack of susceptibility to MDR/MRP/LRP drug resistance;
4. Lack the requirement for metabolic drug activation;
5. Do not undergo A-ring or B-ring glucuronidation;
6. Can be administered in the lactone species directly to patients for the purpose of treating a variety of cancers;
7. Low molecular weight (e.g., MW <600);
8. Highly soluble in organic pharmaceutical solvents or co-solvents (e.g., propylene glycol, PEG 300-400, dimethyl acetamide (DMA), dimethyl isosorbide (DMI), N-methyl pyrrolidinone (NMP)); and
9. Can be administered orally, in addition to parenterally and topically, to subjects with cancer.
This invention has, as its primary objective, the creation of new and useful lipophilic, poorly water soluble, substituted camptothecin derivatives suitable for nonaqueous oral and parenteral formulations, to be administered to patients with cancer. This invention also teaches new convergent and efficient chemical syntheses of these novel substituted camptothecin derivatives using commercially available and relatively inexpensive natural isolates of camptothecins. Accordingly, a number of new A-ring and B-ring modifications are taught in this invention.
The present invention teaches a novel process of homolytic acylation of camptothecin and camptothecin derivatives regiospecifically at the C-7 position based on a Minisci type reaction. A slight variation to the earlier stated methodology for C-7 alkylation permits the stabilization of the transient acyl radical that enables acylation of the parent scaffold in high yield. The present invention also describes novel processes to make certain key versatile synthons for extensive chemical transformations at the C-7 position, and/or at one of the C-9, C-10, C-11 or C-12 positions.
The novel compounds of this invention are of the following formula:
wherein R 1 is hydrogen; acyl, C 2 -C 8 alkenyl, or C 2 -C 8 alkynyl optionally substituted by one or more halogen atoms or OR 4 or lower alkyl for a corresponding hydrogen atom therein; oxo; aryl; arylalkyl; arylalkenyl; arylalkynyl; heterocycle; SR 5 ; —S(O)-lower alkyl; -lower alkyl-P(O)R 6 R 7 , or X—(C 0 -C 6 alkyl, C 0 -C 8 alkenyl, or C 0 -C 8 alkynyl)—SiR 8 R 9 R 10 ;
R 2 is hydrogen, halo, lower alkyl, amino or nitro, provided that R 1 and R 2 are not both hydrogen;
R 4 is hydrogen or lower alkyl;
R 5 is hydrogen or lower alkyl;
R 6 and R 7 are each individually hydrogen or lower alkyl;
R 8 , R 9 and R 10 are each individually hydrogen or lower alkyl;
R 11 is hydrogen, hydroxy or acetoxy; and
X is sulfur or X is absent; or
a pharmaceutically acceptable salt thereof.
It is therefore a principal object of this invention to provide for new, useful and non-obvious lipophilic and poorly water soluble derivatives of camptothecin, in particular, substituted analogs having either a substitution at the C-7 position, or a substitution at one of the C-9, C-10, C-11 or C-12 positions of the molecule, or a disubstituted camptothecin having a first substitution at C-7, and a second substitution at one of C-9, C-10, C-11 or C-12. Most preferably, the compounds of this invention will be substituted at the C-9 or C-10, or disubstituted at C-9 or C-10, and C-7.
It is another object of the present invention to provide a fascile and efficient synthetic methodology for the preparation of a new class of substituted camptothecins.
Another object of the present invention includes the manufacture and utilization of the versatile 7-triflyloxy camptothecin as a key intermediate for the preparation of widely varied multi-substituted camptothecins.
Another object of this invention is to provide a method of treating mammalian cancers and leukemias by administering an antineoplastic or antileukemic dose of the novel CPT derivatives to a patient diagnosed with cancer or leukemia.
Another object of this invention is to provide for pharmaceutical formulations of the novel CPT derivatives, which may be administered to patients parenterally, orally or topically.
Other objects of this invention will become apparent upon a reading of the following specification.
DESCRIPTION OF THE PREFERRED EMBODIMENTS
Definitions
“Scaffold” means the fixed part of the molecule of the general formula given.
“Fragments” are the variable moieties of the molecule, designated in the formula by variable symbols, such as R x or the like. Fragments may include one or more of the following moieties:
“C x -C y ” alkyl means a straight-chain or branched-chain hydrocarbon containing as few as x and as many as y carbon atoms. Examples include “C 1 -C 6 alkyl” (also referred to as “lower alkyl”), which includes a straight or branched chain hydrocarbon with no more than 6 total carbon atoms.
“C x -C y alkenyl” or “C x -C y alkynyl” means a straight or branched chain hydrocarbon with at least one double bond (alkenyl) or triple bond (alkynyl) between two of the carbon atoms.
“Halogen” or “Halo” means chloro, fluoro, bromo or iodo.
“Acyl” means —C(O)—X, where X is hydrogen, lower alkyl, aryl, lower alkenyl or lower alkynyl.
“Aryl” means an aromatic ring compound of one or more rings comprised entirely of carbon atoms.
“Arylalkyl” means an aromatic ring as defined above, bonded to the scaffold through an alkyl moiety (the attachment chain).
“Arylalkenyl” and “Arylalkynyl” both mean the same as “Arylalkyl”, but including one or more double or triple bonds in the attachment chain.
“Heterocycle” means a cyclic moiety of one or more rings, fused or unfused, wherein at least one atom of one of the rings is a non-carbon atom. Preferred heteroatoms include oxygen, nitrogen, sulfur and phosphorous, or any combination of two or more of those atoms.
“Alkoxycarbonyl” means an alkoxy moiety bonded to the scaffold through a carbonyl.
“Acyloxy” means an acyl moiety bonded to the scaffold through an oxygen atom.
Examples of the above moieties are as follows:
C 1 -C 6 alkyl includes methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, amyl and the like;
C 2 -C 8 alkenyl or alkynyl includes vinyl, propenyl, butenyl, acetylenyl, propynyl, and other like moieties with double and triple bonds;
Acyl includes formyl, acetyl, propionyl and others;
Aryl includes phenyl and naphthyl, as well as substituted variants wherein one of the hydrogen atoms bonded to the ring atom is substituted by a halogen atom, an alkyl group, or another of the above-listed moieties;
Arylalkyl includes benzyl, phenethyl, and the like;
Arylalkenyl and arylalkynyl includes phenyl vinyl, phenylpropenyl, phenylacetylenyl, phenylpropynyl and the like; and
Heterocycle includes furanyl, pyranyl, thionyl, pyrrolyl, pyrrolidinyl, prolinyl, pyridinyl, pyrazolyl; imidazolyl, triazolyl, tetrazolyl, oxathiazolyl, dithiolyl, oxazolyl, isoxazolyl, oxadiazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, piperazinyl, oxazinyl, thiazolyl, and the like, as well as fused ring heterocycles such as benzopyranyl, benzofuranyl, indolyl, phthalyl, quinolinyl, pteridinyl, and the like.
Alkoxycarbonyl includes methoxycarbonyl, ethoxycarbonyl, isopropoxycarbonyl, and the like.
Acyloxy includes formyloxy, acetoxy, propionyloxy, and the like.
The camptothecin derivatives of the present invention have the following general formula:
wherein R 1 is hydrogen; acyl, C 2 -C 8 alkenyl, or C 2 -C 8
alkynyl optionally substituted by one or more halogen atoms or OR 4 or lower alkyl for a corresponding hydrogen atom therein; oxo; aryl; arylalkyl; arylalkenyl; arylalkynyl; heterocycle; SR 5 ; —S(O)-lower alkyl; -lower alkyl-P(O)R 6 R 7 , or X—(C 0 -C 6 alkyl, C 0 -C 8 alkenyl, or C 0 -C 8 alkynyl)-SiR 8 R 9 R 10 ;
R 2 is hydrogen, halo, lower alkyl, amino or nitro, provided that R 1 and R 2 are not both hydrogen;.
R 4 is hydrogen or lower alkyl;
R 5 is hydrogen or lower alkyl;
R 6 and R 7 are each individually hydrogen or lower alkyl;
R 6 , R 9 and R 10 are each individually hydrogen or lower alkyl;
R 11 is hydrogen, hydroxy or acetoxy; and
X is sulfur or X is absent; or
a pharmaceutically acceptable salt thereof.
The compounds of Formula I are synthesized preferably according to the following procedures.
Alkylation of protonated camptothecin
The homolytic alkylation of camptothecin is generalized for a variety of alkyl substitutions at the C-7 position. While designing these processes for scale-up synthesis, factors such as simplicity, economy and availability of certain reagents, overall yield and selectivity have been carefully considered. The Minisci type alkylation (Minisci, F., 1973) is also optimized for various phenolic camptothecins without prior protection to the phenolic moiety. Minisci type alkylations of heteroaromatic bases have several advantages. Polar effects related to the nucleophilic character of the carbon-centered radicals and the electron deficiency of the protonated heterocyclic bases play a significant role in the synthetic yield of these reactions. Reactivity and positional and substrate selectivity are two of the major merits (Vorbruggen, H., 1988). The rearomatization of the radical adduct is very selective and quick rapid due to strongly nucleophilic radicals of the pyridinyl type. Reactions of this category are an Iron (II) salt mediated exothermic process that affords selective substitutions at α or γ positions of the heterocyclic ring. In the present invention, we have taken advantage of these factors to selectively introduce alkyl substitutions at the C-7 position of camptothecin skeleton such as certain novel lower alkyl groups, trifluoroethyl, polyfluoroethyl and monofluoro ethyl groups.
C-7 Acylation of protonated camptothecin:
Acylation of the heteroaromatic bases such as camptothecins are of great interest due to the fact that electrophilic aromatic substitutions are generally ineffective with these types of heterocyclic systems. Further, the high reactivity and selectivity of the C-7 position of camptothecin due to increased nucleophilicity under acidic conditions would provide the desired products with minimal unwanted by-products. The respective acyl radicals can easily be obtained from the corresponding aldehydes in the presence of excess trifluoro acetic acid at low temperature. Minisci type alkylation procedures were found extremely effective with various camptothecin derivatives. However, Minisci-type acylations of CPT have not to date been reported. These types of homolytic substitutions are of significant value as an alternate tool for heterocyclic systems where classical Friedel-Crafts reactions can not be effectively performed. The present invention teaches such novel acylation reactions on the quinoline bearing CPT skeleton.
In principle, the more stable the carbonium ion is the more nucleophilic will be the corresponding radical. Therefore, almost all the electrophilic species that are useful in the Friedel-Craft reaction can be utilized, as the corresponding radicals, for the selective substitution of the heteroaromatic bases. This opens a wide variety of organic compounds as radical sources for C-7 substitution of camptothecin. Those types of compounds include: alkanes, alkenes, alkylbenzenes, alkyl halides, alcohols, ethers, aldehydes, ketones, carboxylic acids, amines, amides, oxaziridines, N-chloramines etc. The inventors submit that the major determinants of the reaction conditions that lead to either the desired alkylated product or acylated product are largely controlled by the type of acid present in excess and the free radical initiator.
C-7 Halogenation:
Chlorination and bromination at the C-7 position of camptothecin are best done on an electron deficient nitrogen bearing camptothecin skeleton. It is very evident from the literature that the oxide function at N 1 position of a quinoline moiety could generate substantial nucleophilicity to α and γ positions of the heterocylic base. Such effects would be enhanced further upon a protonation event on the N-oxide. In the case of camptothecin skeleton, an absolute γ selectivity is envisioned as the a positions are already blocked. The inventors' observed that such nucleophilic halogenation proceeds smoothly and selectively on 20-acetoxy- camptothecin 1- oxide in presence of excess trihalophosphine oxide at 40° C. The camptothecin derivatives thus prepared are subsequently utilized as synthons for cross-coupling reactions as stated below.
Stille type coupling at the C-7 position:
Stille's procedure (J, K. Stille, 1986; J, K. Stille 1987) provides one of the most useful methods to construct carbon-carbon single bonds. The reaction is catalyzed by organometallic reagents derived from group IA metals via coupling of organic electrophiles and organostannanes in presence of lithium halide. Similar cross coupling where boronic acids or esters are employed in place of organostannanes are called Suzuki cross-coupling Reaction (George B. S., 1994). Excess stoichiometric amounts of lithium chloride are essential for the completion of the reaction as lithium chloride is consumed for the formation of tributyltin chloride and lithium triflate. A variety of organic electrophiles are used in the cross-coupling reaction of which bromides, iodides and triflates are extensively studied (Kurt Ritter, 1993). The rate of the reaction can be modulated readily based on the composition and concentration of the organic electrophile. A better understanding of the mechanistic aspects of the rate limiting transmetallation process led to the recent developments involve the use of cocatalytic Cu(I) and Pd(0) species in this coupling reaction. The role of the Cu(I) species has been envisioned (Liebeskind, 1990) in Sn/Cu transmetallation. The resulting organocopper species would then transmetallate onto Pd(II) at a higher rate than the stannane itself. This is currently known as the “copper effect.” The scope of the reaction is extremely wider than this application. A large number of structurally varied organic groups including vinyl, alkyl, allyl, aryl, acetylenic, amino, amido and [(trimethylsilyl)methyl] moieties on tin could easily be transferred onto aryl and heteroaryl skeletons displacing the vinyl triflate or unsaturated halides in high yields. However, the conventional Stille reaction conditions are unacceptable for some of our novel entities. Further, modifications were sought out in this direction that resulted in making the palladium catalyzed cross-coupling highly conceivable to incorporate such functionalities in extremely mild conditions as well as in high yields. In all these coupling reactions, tris(dibenzylideneacetonyl)bis palladium(0) served as the catalyst while tri(2-furyl)phosphine exhibited its noticeable role in enhancing the rate of activation of the ligand properties even at room temperature.
Suzuki Cross-Coupling Reaction:
The Stille coupling and the Suzuki coupling are very similar in many respects at a fundamental level, however, in terms of scalability for large scale production of the new compositions the Suzuki coupling has certain advantages. The necessary use of tin in stoichiometric amounts in the Stille reaction makes the Suzuki coupling more attractive. However, no generally applicable set of reaction conditions has yet been found to affect this reaction. At the same time, Suzuki coupling is an extremely convergent approach for the incorporation of cyclopropyl, phenyl and certain other polyfluoroalkyl functionalities into a camptothecin scaffold. Recent reports by Wright and co-workers (Wright, S. W., 1994) simplified the reaction conditions by employing fluoride ion instead of incompatible bases to generate boronate anion. However, boronate anion may be crucial in the reaction medium to effect boron to palladium transmetallation. The recent report unambiguously suggested the capability of fluoride ions to exhibit significant affinity for boron and considerable stability of fluoborate ions. Additionally, the report also has addressed the favoring weak basicity and poor nucleophilicity of fluoride ions and the weakness of the palladium-fluorine bond in Suzuki coupling reactions.
The following Schemes illustrate the general processes used to produce novel camptothecin derivatives of this invention, and in no way are to be considered limiting of the invention.
Scheme I illustr the preparation of the C-7 acyl derivatives of this invention, and also the preparation of the 20-dehydroxy derivative of CPT.
The selective acylation at the C-7 position on the B-ring is achieved by the procedures outlined above. In the above scheme, “A” represents an alkyl chain of 1-6 Carbon atoms, most preferably 1-2 Carbon atoms, to form 7-Acetyl CPT or 7-Propionyl CPT, and R 11 is hydroxy.
Conversion of the 20-hydroxy moiety to a hydrogen atom is achieved by a selective 20-position deoxygenation. Typical reagents are bases, such as Lawsson's Reagent, or similar compounds.
Scheme II illustrates the preparation of 7-halo CPT derivatives, and also the preparation of the key intermediate 7-keto CPT. The first step in the synthesis of either of these compounds is the conversion of CPT to camptothecin-1-oxide. In Scheme II, R 11 is typically a protected hydroxy moiety, most preferably an acetoxy moiety, which is deprotected back to a hydroxy moiety after the 7-position moieties have been added. Typical deprotection of the 20-acetoxy moiety and conversion to 20-hydroxy is accomplished by use of alkali metal salts and aqueous alcohols, most preferably potassium carbonate and methanol.
The halogenation at C-7 is also achieved by the general procedures described above. Conversion and regioselectivity of CPT-1-oxide to 7-keto CPT is also described above, with the most preferred procedures outlined in Example 3 below. 7-Keto CPT is used extensively as a key intermediate in many of the selective schemes for producing the 7-substituted CPT derivatives of this invention.
Schemes III and IV detail the synthetic procedures for making the novel CPT derivatives which form the subject matter of this invention.
Scheme III illustrates the synthesis of the 7-trifluoromethanesulfonyloxy (triflyloxy) intermediate which is key to the substitution of various 7-position moieties which form the subject matter of this invention.
As shown, 7-keto CPT is converted into the triflate intermediate by reacting with a sulfonate ester and an alkali metal salt, or with triflic anhydride. The resulting 7-triflate intermediate possesses excellent properties for substitution reactions to be performed on the molecule, allowing for diverse moieties to be attached to the CPT scaffold.
Scheme IV illustrates the synthesis of the novel C7-substituted CPT derivatives of this invention. The key intermediate, 7-trifluoromethanesulfonyl CPT, is converted into one of the novel compound of this invention by following the general methods outlined in the specification, supra.
The two general moieties which are incorporated directly by displacing the triflyloxy moiety are the silyl moieties and the thioether moieties shown in scheme IV. As stated above, the silyl moieties are formed through a modified Stille coupling, through the use of a palladium mediated tributyltin-alkylsilane substitution. The ( ) n− , refers to an alkyl (or alkenyl or alkynyl) group, where n stands for the number of carbon atoms, preferably 0 to 6, most preferably 0 to 3. When n is 0, the preferred synthesis utilizes an organolithium mediated displacement using hexamethyl disilane as the preferred reagent.
The silyl moieties may be converted into 7-alkenyl or 7-alkynyl moieties (designated by the letter “Z”), by reacting with an alkali metal salt, which both removes the silyl moiety and also serves to convert the 20-acetoxy moiety to the hydroxy moiety. 7-alkenyl and 7-alkynyl substituted CPT derivatives may also be prepared directly from the 7-triflate by the modified Stille coupling as described above.
7-thioethers are prepared by reacting the 7-triflate with the appropriate alkyl sulfide under basic conditions. In the scheme shown ( ) m− stands for an alkyl (or alkenyl or alkynyl) group and m is 0 to 6, preferably 1 to 3. Y indicates that a silyl moiety may be appended to the terminal end of the reagent, and will be transferred to the resulting compound. An example of such a thioether reagent is 2-trimethylsilyl ethyl-1-mercaptan, which would form 7-(β-trimethylsilyl) ethylthio CPT.
7-thioethers may be converted into the 7-sulfoxy derivatives by reacting with a per-acid, such as perbenzoic acid, most preferably m-chloroperbenzoic acid. Other derivatives may be prepared by utilizing the syntheses described above, in conjunction with the specific examples listed below.
Scheme V illustrates the synthetic process for producing 10-substituted compounds of this invention, and also the general process for producing 7, 10 di-substituted derivatives of CPT. As shown, CPT is modified from its natural form to produce the 10-fluoro CPT derivative, and by extension, 7,10 di-substituted derivatives, as described and claimed in this invention.
In the preferred process, CPT is first hydrogenated to allow acylation of the N-1 nitrogen by reaction with an acylating agent, preferably an acid chloride, and most preferably, acetyl chloride to form the intermediate N-acetyl CPT. This intermediate is then subjected to a nitration reaction. The protected nitrogen acts as an amino moiety and selective addition of the nitro- group at the C-10 position (para) occurs. Manipulation of the reaction conditions and the base structure of the CPT intermediate determines where the nitro- group will attach to the scaffold. The positioning will be addressed in future applications by these applicants.
After nitration, the 10-nitro hydrogenated CPT is subjected to hydrogenolysis to convert the 10-nitro moiety to the more reactive 10-amino species. This conversion is preferably accomplished by bubbling hydrogen gas through a solution of the 10-nitro CPT in the presence of a catalyst. In the most preferred embodiment shown, hydrogen gas is bubbled through a polar solution of methanol and the 10-nitro intermediate in the presence of platinum oxide.
The 10-amino hydrogenated CPT is then halogenated (the 10-fluoro species is shown as the preferred species, but these procedures may also be used to synthesize other 10-halo CPT compounds). A halogenating agent, such as a boron trifluoride derived fluorinating reagent, is employed to effect halogenation. The most preferred agent is boron trifluoride diethyl etherate in an organic solvent, such as chloroform. To complete the reaction, the solution is refluxed in a nonpolar solvent, such as toluene.
As shown, the 10-halo hydrogenated CPT is then converted back to its dehydrogenated form by first deprotecting the N-1 moiety to remove the acetyl group, and then dehydrogenating the B-ring in a common manner. Preferably, a strong acid is employed to effect deprotection, and then a proton acceptor is employed to remove the extra hydrogens and restore the B-ring to its naturally unsaturated form. Most preferably, deprotection is effected with a mineral acid, such as sulfuric acid, and dehydrogenation is effected by an organic base, such as 2,3-dichloro-5,6-dihydro-1,4-benzoquinone (DDQ).
The 10-fluoro CPT may be converted to the 7,10 disubstituted species as shown. The 10-fluoro CPT is treated with an aldehyde to effect selective addition at the C-7 position according to the Minisci conditions described above. As shown in the most preferred scheme above, a trimethylsilyl alkyl moiety is added by reacting the 10-fluoro CPT intermediate with a trimethylsilyl (TMS) aldehyde to form a one carbon less TMS alkyl chain. In the most preferred compound described in the specific examples below, 3-trimethylsilyl propanal is the reagent used to produce the most preferred final compound, 10-fluoro-7-(β-trimethylsilyl) ethyl camptothecin.
Scheme VI illustrates one general process for preparing 9-halo and 9,7-disubstituted derivatives of CPT. As shown, natural CPT is subjected to nitration, as by reaction with concentrated nitric acid. The addition of the nitro moiety to natural CPT selectively takes place at the 9-position, as shown.
Protection of the 20-hydroxy moiety, hydrogenation of the 9-nitro, conversion to 9-halo, deprotection, and the addition at the 7-position is effected similarly to the scheme shown above as Scheme V, with the exception that no operations are performed to selectively hydrogenate the B-ring, which is necessary in Scheme V to effect addition at the 10-position. Exact conditions of the most preferred synthesis are outlined in the specific examples below.
The schemes above have been set forth as general examples to assist those skilled in the art in the understanding of the present invention and in the synthesis of these novel and non-obvious compounds. The schemes are in no way intended as limiting of the invention, nor should they be construed as such.
The following specific examples illustrate selected modes for carrying out the invention and, like the schemes, are not to be construed as limiting the specification or the claims in any way.
EXAMPLE 1
7-Acetyl Camptothecin
Camptothecin (5 g, 14.36 mmol) was dissolved in trifluoroacetic acid/acetic acetic acid (60 mL; ratio, 1:1) and deionized water added (15 mL) along with freshly distilled acetaldehyde (20 mL; excess) followed by dropwise addition of concentrated sulfuric acid (5 mL) at 0° C. using an ice bath over a period of 15 minutes. To the above stirred reaction medium is then introduced a 70% aqueous solution of t-butylhydroperoxide (3 ml) followed by iron sulfate heptahydrate (7.8 g, 28 mmol) in 1 mL water. The reaction mixture was then stirred at 0° C. to 25° C. for an additional 24 hours. The reaction mixture was then diluted with water and extracted with diethyl ether (500 mL×1), chloroform (250 mL×1) and then n-butanol (250 mL ×4). The organic portions were extracted out using diethyl ether and chloroform and discarded as fractions lacking desired product, while the n-butanol portion was concentrated to dryness at 40° C. and the crude product was recrystallized from a 90% chloroform/methanol mixture to furnish 4.2 g of the title compound (75% yield).
1 H NMR (300 MHz; d6-DMSO): 0.87 δ (3 H, t, J=7 Hz); 1.86 δ (2 H, q, J=5 Hz); 2.78 δ (3 H, s); 5.29 δ (2 H, m); 5.38 δ (2 H, m); 6.51 δ (1 H, bs, OH); 7.35 δ(2 H, s); 7.78 δ (1 H, t, J=13.5 Hz); 7.92 δ (1 H, t, J=7.64 Hz); 8.13 δ (1 H, d, J=8.35 Hz); 8.23 d (1 H,d, J=8.38 Hz)
13 C NMR: δ 7.84, 30.41, 31.7, 50.27, 65.35, 73.21, 97.42, 119.78, 123.26, 124.86, 126.12, 131.4, 138.5, 143.87, 143.25, 145.31, 149.34, 150.05, 156.63, 157.68, 172.46, 205.05
FAB-MS: 391 (M+1)
EXAMPLE 2
7-Propionyl Camptothecin
Camptothecin (1 g, 2.8 mmol) was dissolved in trifluoroacetic acid/acetic acetic acid (6 mL; ratio, 1:1) and deionized water (3 mL) and freshly distilled propionaldehyde (3.0 mL; excess) were added, followed by dropwise addition of concentrated sulfuric acid (1 mL) at 0° C. using an ice bath over a 15 minute period. To the above stirred reaction medium was then introduced a 70% aqueous solution of t-butylhydroperoxide (3 mL) followed by iron sulfate heptahydrate (1.56 g, 5.6 mmol) in 1 ml water. The reaction mixture was then stirred at 0° C. to 25° C. for an additional 24 hours. The reaction mixture was then diluted with water and extracted with diethyl ether (100 mL×1), chloroform (50 mL×1) and then n-butanol (100 mL×4). The organic portions were extracted out using diethyl ether and chloroform, and were discarded as fractions lacking desired product, while the n-butanol portion was concentrated to dryness at 40° C. The crude product was recrystallized from a 90% chloroform/methanol mixture to furnish 0.86 g of the title compound (74% yield).
3 H NMR (300 MHz; d6-DMSO): 0.87 d (3 H, t, J=7 Hz); 1.26 δ (3 H, t, J=6.8 Hz); 1.84 d (2 H, q, J=5 Hz); 3.15 d (2 H, q, J=5.1 Hz); 5.29 δ (2 H, m); 5.38 δ(2 H, m); 6.51 δ (1 H, bs); 7.35 δ (2 H, s); 7.72 δ (1 H, t, J=13.5 Hz); 7.90 δ(1 H, t, J=7.64 Hz); 7.98 δ (1 H, d, J=8.35 Hz); 8.20 δ (1 H,d, J=8.38 Hz)
13 C NMR: δ 7.54, 7.74, 30.31, 36.7, 49.81, 65.21, 72.33, 96.88, 119.48, 123.12, 125.69, 130.63, 131.72, 140.97, 143.14, 143.25, 145.31, 149.97, 156.55, 157.68, 172.36, 204.91
FAB-MS: 405 (M+1)
EXAMPLE 3
7-Keto camptothecin (Camptothecinone)
Camptothecin 1-oxide (1 g, 2.7 mmol) was dissolved in trifluoroacetic acid (2 mL), anhydrous methylene chloride (15 ml) and added trifluoroacetic anhydride (16 mL). The reaction mixture was then refluxed under a positive pressure of argon for 48 hours. The reaction mixture was then cooled to room temperature and diluted with water (15 mL) and stirred for 6 hours. The product was then precipitated out by pouring the reaction mixture into crushed ice. The precipitated product was then filtered, washed with excess water, once with diethyl ether and dried under vacuum to obtain 687 mg of the desired product (66% yield).
1 H NMR (300 MHz; d6-DMSO): 0.87 δ (3 H, t, J=7 Hz); 1.96 δ (2 H, q, J=5 Hz); 2.78 δ (3 H, s); 5.86 δ (2 H, m); 5.40 δ (2 H, m); 6.81 δ (1 H, bs); 7.38 δ (1 H, t, J=13.5 Hz); 7.47 δ (2 H, s); 7.71 δ (1 H, t, J=7.64 Hz); 7.73 δ (1 H, d, J=8.35 Hz); 8.14 δ (1 H,d, J=8.38 Hz)
13 C NMR: δ 6.89, 29.55, 49.6, 66.123, 79.90, 94.78, 105.12, 118.48, 123.31, 124.26, 124.95, 132.06, 141.69, 143.55, 155.35, 164.88, 200.432
FAB-MS: 461 (M+1 for the triflic acid salt)
EXAMPLE 4
20-acetoxy-7-Trifluoromethanesulfonyloxy-camptothecin
20-Acetoxy camptothecinone (220 mg, 0.54 mmol) was dissolved in anhydrous pyridine (4 mL) and anhydrous methylene chloride (10 mL). The above solution was stirred well while lowering the temperature to −10° C. using an ice bath. To it was then slowly introduced triflic anhydride (0.5 ml, 1.05 mol) and the reaction continued to completion. The reaction mixture was then diluted with methylene chloride (20 mL), washed with water and the organic portion was concentrated to dryness. The product thus obtained upon analysis was found substantially pure for the subsequent step.
1 H NMR (300 MHz; CDCl 3 ): 0.87 δ (3 H, t, J=5.4 Hz); 2.12 δ (2 H, q, J=7.2 Hz); 2.21 δ (3 H, s); 5.42 δ(2 H, ABq, J 1 =17.5 Hz; J 2 =6.1 Hz); 5.49 δ (2 H, q, J=2.5 Hz); 7.14 δ (1 H, s); 7.97 δ (1 H, t, J=7.2 Hz); 8.05 δ (1 H, t, J=7.9 Hz); 8.12 δ (1 H, d, J=8.4 Hz); 8.35 δ (1 H, d, J=6.2 Hz)
FAB-MS: 540 (M+1)
EXAMPLE 5
20-Acetoxy-7-chloro camptothecin
20-Acetoxy camptothecin-1-oxide (800 mg, 1.96 mmol) was taken up as a suspension in phosphorus oxychloride (10 mL) and stirred at 40° C. for 48 hours under a positive blanket of inert gas. The reaction mixture was then diluted with methylene chloride (25 mL) and cooled to 0° C. using an ice bath. The reaction mixture was then diluted with water (50 mL) and stirred for 3 hours. The organic portion was then extracted out using methylene chloride (50 mL×5), concentrated and flashed through a bed of silica gel using chloroform to obtain the desired product (642 mg; 77.1% yield).
1 H NMR (300 MHz; CDCl 3 ): 0.90 δ (3 H, t, J=5.4 Hz); 2.12 δ (2 H, q, J=7.2 Hz); 2.21 δ (3 H, s); 5.42 δ (2 H, ABq, J 1 =17.5 Hz; J 2 =6.1 Hz); 5.49 δ (2 H, q, J=2.5 Hz); 7.07 δ (1 H, s); 7.87 δ (1 H, t, J=7.2 Hz); 7.95 δ (1 H, t, J=7.9 Hz); 8.21 δ (1 H, d, J=8.4 Hz); 8.27 δ (1 H, d, J=6.2 Hz)
FAB-MS: 425.1 (M+1 )
EXAMPLE 6
7-Chloro camptothecin
20-Acetoxy-7-chloro camptothecin (100 mg, 0.23 mmol) was dissolved in reagent grade methanol (20 mL) and added aqueous potassium carbonate (20 mg in 5 mL water) and stirred for 1 hour at room temperature. The resulting reaction mixture was concentrated to 5 mL under vacuum and diluted with water (20 mL). The precipitated product was then filtered, dried and analyzed to the desired product (60 mg; 67%).
1 H NMR (300 MHz; CDCl 3 ): 0.87 δ (3 H, t, J=5.4 Hz); 1.85 δ (2H, q, J=7.2 Hz); 3.6 δ (1 H, s); 5.31 δ (2 H, s); 5.43 δ (2 H, s); 7.07 δ (1 H, s); 7.87 δ (1 H, t, J=7.2 Hz); 7.95 δ (1 H, t, J=7.9 Hz); 8.21 δ (1 H, d, J=8.4 Hz); 8.27 δ (1 H, d, J=6.2 Hz)
13 C NMR: δ 7.54, 30.31, 49.81, 65.21, 72.33, 96.88, 119.48, 123.12, 125.69, 126.96, 130.63, 131.72, 140.97, 143.14, 143.25, 145.31, 149.97, 156.55, 157.68, 172.36
FAB-MS: 383.1 (M+1)
EXAMPLE 7
20 Acetoxy-7-vinyl-camptothecin
The 20-acetoxy-7-triflate (100 mg, 0.1855 mmol) was dissolved anhydrous and degassed anhydrous dimethylformamide (5 mL) and added zinc chloride (50.5 mg, 0.371 mmol). To it was then added tris(dibenzylideneacetonyl)bis palladium(0) (17 mg, 0.371 mmol) followed by tri(2-furyl) phosphine (20 mg, 0.074 mmol). The resulting solution was stirred for approximately 30 minutes at room temperature. To it was added vinyl tributyltin (60 mL, 0.223 mmol). The reaction mixture was then stirred at room temperature for 48 hours. The resulting dark brown colored reaction mixture was then diluted with methylene chloride (25 mL), filtered, and washed with water (15 mL). The crude product obtained after concentration was then flashed through a columnar bed of florisil, the fractions pooled, concentrated, dried under vacuum and analyzed.
1 H NMR (300 MHz; CDCl 3 ): 0.87 δ (3 H, t, J=5.4 Hz); 1.85 δ (2 H, q, J=7.2 Hz); 2.31 δ (3 H, s); 3.6 δ (1 H, s); 5.42 δ (2 H, ABq, J 1 =17.5 Hz; J 2 =6.1 Hz); 5.61 δ (2 H, s); 6.15 δ (2 H, dd, J=12.8 Hz); 6.4 δ (1 H, d, J=2.5 Hz); 7.07 δ (1 H, s); 7.87 δ (1 H, t, J=7.2 Hz); 7.95 δ (1 H, t, J=7.9 Hz); 8.21 δ (1 H, d, J=8.4 Hz); 8.27 δ (1 H, d, J=6.2 Hz)
EXAMPLE 8
7-Vinyl camptothecin
20-Acetoxy-7-vinyl camptothecin (100 mg, 0.23 mmol) was dissolved in reagent grade methanol (20 mL) and added aqueous potassium carbonate (20 mg in 5 mL water) and stirred for 2 hours at low temperature. The resulting reaction mixture was acidified to pH 4 using 1 N HCl and the precipitated product was filtered, dried and analyzed to the desired product (30 mg; 47% yield).
1 H NMR (300 MHz; CDCl 3 ): 0.87 δ (3 H, t, J=5.4 Hz); 1.85 δ (2 H, q, J=7.2 Hz); 3.6 δ (1 H, s); 3.6 δ (1 H, s); 5.42 δ (2 H, ABq, J 1 =17.5 Hz; J 2 =6.1 Hz); 5.61 δ (2 H, m); 6.15 δ (2 H, dd, J=12.8 Hz); 6.4 δ (1 H, d, J=2.5 Hz); 7.07 δ (1 H, s); 7.87 δ (1 H, t, J=7.2 Hz); 7.95 δ (1 H, t, J=7.9 Hz; 8.21 δ (1 H, d, J=8.4 Hz); 8.27 δ (1 H, d, J=6.2 Hz)
13 C NMR: δ 7.54, 30.31, 49.81, 65.21, 72.33, 96.88, 99.6, 119.48, 123.12, 125.69, 126.96, 130.63, 131.72, 137.2, 140.97, 143.14, 143.25, 145.31, 149.97, 156.55, 157.68, 172.36
FAB-MS: 373(M+1)
EXAMPLE 9
20-Acetoxy-7-(β-trimethylsilyl)ethynyl camptothecin
The 20-acetoxy-7-triflate (100 mg, 0.1855 mmol) was dissolved anhydrous and degassed anhydrous dimethylformamide (5 mL) and added zinc chloride (50.5 mg, 0.371 mmol). To it was then added tris(dibenzylideneacetonyl)bis palladium(0) (17 mg, 0.371 mmol), diisopropyl ethylamine (50 μL) followed by tri(2-furyl)phosphine (20 mg, 0.074 mmol). The resulting solution was stirred for approximately 30 minutes at room temperature. Then added propargylic trimethyl silane (0.1 mL). The reaction mixture was then stirred at room temperature for 48 hours. The resulting dark brown colored reaction mixture was then diluted with methylene chloride (25 mL), filtered, washed with water (15 mL). The crude product obtained after concentration is then flashed through a columnar bed of florisil, the fractions pooled, concentrated, dried under vacuum and analyzed.
1 H NMR (300 MHz; CDCl 3 ) 0.3 δ (9 H,s); 0.87 δ (3 H, t, J=5.4 Hz); 2.3 δ (2 H, q, J=7.2 Hz); 2.31 δ (3 H, s); 5.42 δ (2 H, ABq, J 1 =17.5 Hz; J 2 =6.1 Hz); 5.61 δ (2 H, m); 7.07 δ (1 H, s); 7.87 δ (1 H, t, J=7.2 Hz); 7.95 δ (1 H, t, J=7.9 Hz); 8.21 δ (1 H, d, J=8.4 Hz); 8.27 δ (1 H, d, J=6.2 Hz)
EXAMPLE 10
20-Acetoxy-7-methylthio camptothecin
The intermediate triflate (100 mg, 0.186 mmol) was dissolved in anhydrous 1,4-dioxane and cooled to 0° C. under a stream of argon. To it was then added diisopropyl ethylamine (0.1 mL; 0.557 mole) and slowly bubbled methanethiol for 5 minutes. The reaction mixture was then stirred under a balloon pressure for 15 hours. After 15 hours, the reaction mixture was diluted with methylene chloride (25 mL) and washed with water (20 mL×4), dried over anhydrous sodium sulfate, filtered and concentrated to obtain the crude product of the title compound in approximately 80.5% yield.
1 H NMR (300 MHz; CDCl 3 ): 0.87 δ (3 H, t, J=5.4 Hz); 2.31 δ (2 H, q, J=7.2 Hz); 2.28 δ (3 H, s); 2.31 δ (3 H, s); 5.42 δ (2 H, ABq, J 1 =17.5 Hz; J 2 =6.1 Hz); 5.61 δ (2 H, m); 7.07 δ (1 H, s); 7.65 δ (1 H, t, J=7.2 Hz); 7.75 δ (1 H, t, J=7.9 Hz); 8.1 δ (1 H, d, J=8.4 Hz); 8.61 d (1 H, d, J=6.2 Hz)
FAB-MS: 438 (M+1)
EXAMPLE 11
7-Methylthio camptothecin
20-Acetoxy-7-methylthio camptothecin (100 mg, 0.23 mmols) was dissolved in reagent grade methanol (20 mL) and added aqueous potassium carbonate (25 mg in 0.1 mL water) and stirred for about 3 hours at low temperature. The resulting reaction mixture was acidified with 1 N HCl to precipitate the lactone form of the compound. The precipitated product was then filtered, washed with water (10 mL×4) and with ether (10 mL), dried under vacuum. The pale yellow powder was then analyzed to the desired product (65 mg; 77% yield).
1 H NMR (300 MHz; CDCl 3 ): 0.87 δ (3 H, t, J=5.4 Hz); 2.28 δ (2 H, q, J=7.2 Hz); 2.31 δ (3 H, s); 3.6 δ (1 H, s); 5.42 δ (2 H, ABq, J 1 =17.5 Hz; J 2 6.1 Hz); 5.61 δ (2 H, s); 7.07 δ (1 H, s); 7.65 δ (1 H, t, J=7.2 Hz); 7.75 δ (1 H, t, J=7.9 Hz); 8.1 δ (1 H, d, J=8.4 Hz); 8.61 δ (1 H, d, J=6.2 Hz)
FAB-MS: 394 (M+1)
EXAMPLE 12
20-Acetoxy-7-methylsulfoxo camptothecin
20-Acetoxy-7-methylthio camptothecin (25 mg, 0.057 mmol) was dissolved in anhydrous methylene chloride (10 mL) and cooled to 0° C. using an ice bath under a stream of argon. Freshly purified m-chloroperbenzoic acid (10.3 mg, 1 equivalent) Was added, and the reaction mixture was stirred for 2 hours at low temperature. The reaction mixture was then diluted with methylene chloride (20 mL) and washed with water (10 mL×4), dried and concentrated to obtain the title compound in the crude form. The product was then flash chromatographed over a bed of florisil using 10% methanol in chloroform to furnish the desired sulfoxide as a diastereomeric mixture in 60% yield.
1 H NMR (300 MHz; CDCl 3 ): 0.87 δ (3 H, t, J=5.4 Hz); 2.29 δ (2 H, q, J=7.2 Hz); 2.31 δ (3 H, s); 3.32 δ (3 H, s); 5.42 δ (2 H, ABq, J 1 =17.5 Hz; J 2 =6.1 Hz); 5.61 δ (2 H, m); 7.07 δ (1 H, s); 7.65 δ (1 H, t, J=7.2 Hz); 7.75 δ (1 H, t, J=7.9 Hz); 8.1 δ (1 H, d, J=8.4 Hz); 8.61 δ (1 H, d, J=6.2 Hz)
FAB-MS: 454 (M+1)
EXAMPLE 13
7-Methylsulfoxol camptothecin
20-Acetoxy-7-methylsulfoxo camptothecin (100 mg, 0.18 mmols) was dissolved in reagent grade methanol (20 mL) and added aqueous potassium carbonate (25 mg in 0.1 mL water) and stirred for about 3 hours at low temperature. The resulting reaction mixture was acidified with 1 N HCl to precipitate the lactone form of the compound. The precipitated product was then filtered, washed with water (10 mL×4) and with ether (10 mL), dried under vacuum: The pale yellow powder was then analyzed to the desired product (65 mg; 61% yield).
1 H NMR (300 MHz; CDCl 3 ) 0.87 δ (3 H, t, J=5.4 Hz); 2.21 δ (2 H, q, J=7.2 Hz); 3.6 δ (1 H, s); 5.42 δ (2 H, ABq, J 1 =17.5 Hz; J 2 =6.1 Hz); 5.61 δ (2 H, m); 7.07 δ (1 H, s); 7.65 δ (1 H, t, J=7.2 Hz); 7.75 δ (1 H, t, J=7.9 Hz); 8.1 δ (1 H, d, J=8.4 Hz); 8.61 δ (1 H, d, J=6.2 Hz)
FAB-MS: 411 (M+1 )
EXAMPLE 14
20-Acetoxy-7-ethylthio camptothecin
The intermediate triflate (100 mg, 0.186 mmol) was dissolved in anhydrous 1,4-dioxane and cooled to 0° C. under a stream of argon. To it was then added diisopropyl ethylamine (0.1 mL; 0.557 mole) and slowly added ethanethiol (0.4 mL) and then stirred the reaction mixture under a balloon pressure for 15 hours in a well ventilated hood. After 15 hours, the reaction mixture was diluted with methylene chloride (25 mL) and washed with water (20 mL×4), dried over anhydrous sodium sulfate, filtered and concentrated to obtain the crude product of the title compound in approximately 80.5% yield.
1 H NMR (300 MHz; CDCl 3 ): 0.87 δ (3 H, t, J=5.4 Hz) ; 1.26 δ (3 H, t, J=5.8 Hz); 2.21 δ (2 H, q, J=7.2 Hz); 2.31 δ (3 H, s); 2.28 δ (3 H, s); 3.19 δ (2 H, q, J=7.2 Hz); 3.6 δ (1 H, s); 5.42 δ (2 H, ABq, J 1 =17.5 Hz; J 2 =6.1 Hz); 5.61 δ (2 H, m); 7.07d (1 H, s); 7.65 δ (1 H, t, J=7.2 Hz); 7.75 δ (1 H, t, J=7.9 Hz); 8.1 δ (1 H, d, J=8.4 Hz); 8.58 δ (1 H, d, J=6.2 Hz)
FAB-MS: 468 (M+1)
EXAMPLE 15
7-Ethylthio camptothecin
20-Acetoxy-7-ethylthio camptothecin (100 mg, 0.21 mmol) was dissolved in reagent grade methanol (20 mL) and added aqueous potassium carbonate (25 mg in 0.1 mL water) and stirred for about 3 hours at low temperature. The resulting reaction mixture was acidified with 1 N HCl to precipitate the lactone form of the compound. The precipitated product was then filtered, washed with water (10 mL×4) and with ether (10 mL), dried under vacuum. The pale yellow powder was then analyzed to the desired product (69 mg; 76% yield).
1 H NMR (300 MHz; CDCl 3 ): 0.87 δ (3 H, t, J=5.4 Hz); 1.26 δ (3 H, t, J=5.8 Hz); 2.21 δ (2 H, q, J=7.2 Hz); 2.28 δ (3 H, s); 3.19 d (2 H, q, J=7.2 Hz); 3.6 d (1 H, s); 5.42 δ (2 H, ABq, J 1 =17.5 Hz; J 2 =6.1 Hz); 5.61 δ (2 H, m); 7.07 δ (1 H, s); 7.65 δ (1 H, t, J=7.2 Hz); 7.75 δ (1 H, t, J=7.9 Hz); 8.1 δ (1 H, d, J=8.4 Hz); 8.58 δ (1 H, d, J=6.2 Hz)
FAB-MS: 425 (M+1)
EXAMPLE 16
20-Acetoxy-7-isopropylthio camptothecin
The intermediate triflate (100 mg, 0.186 mmol) was dissolved in anhydrous 1,4-dioxane and cooled to 0° C. under a stream of argon. To it was then added diisopropyl ethylamine (0.1 mL; 0.557 mole) and slowly added isopropylthiol (1 mL). The reaction mixture was then stirred under a balloon pressure for 15 hours in a well ventilated hood. After 48 hours, the reaction mixture was diluted with methylene chloride (25 mL) and washed with water (20 mL×4), dried over anhydrous sodium sulfate, filtered and concentrated to obtain the crude product of the title compound in approximately 60.5% yield.
1 H NMR (300 MHz; CDCl 3 ): 0.87 δ (3 H, t, J=5.4 Hz); 1.26 δ (6 H, d, J=5.8 Hz); 2.19 δ (2 H, q, J=7.2 Hz); 2.31 δ (3 H, s); 2.28 δ (3 H, s); 3.59 δ (2 H, q, J=7.2 Hz); 5.42 δ (2 H, ABq, J 1 =17.5 Hz; J 2 =6.1 Hz); 5.61 δ (2 H, m); 7.07 δ (1 H, s); 7.65 δ (1 H, t, J=7.2 Hz); 7.75 δ (1 H, t, J=7.9 Hz); 8.1 δ (1 H, d, J=8.4 Hz); 8.58 (1H, d, J=6.2 Hz)
FAB-MS: 482 (M+1)
EXAMPLE 17
20-Acetoxy-7-phenylthio camptothecin
The intermediate triflate (100 mg, 0.186 mmol) was dissolved in anhydrous 1,4-dioxane and cooled to 0° C. under a stream of argon. To it was then added diisopropyl ethylamine (0.1 mL; 0.557 mole) and slowly added phenyl mercaptan (0.2 mL). The reaction mixture was then stirred under a balloon pressure for 15 hours in a well ventilated hood. After 48 hours, the reaction mixture was diluted with methylene chloride (25 mL) and washed with water (20 mL×4), dried over anhydrous sodium sulfate, filtered and concentrated to obtain the crude product of the title compound in approximately 80.5% yield.
1 H NMR (300 MHz; CDCl 3 ) : 0.87 δ (3 H, t, J=5.4 Hz); 2.19 δ (2 H, q, J=7.2 Hz) ; 2.28 δ (3 H, s); 4.82 δ (2 H, ABq, J 1 =17.5 Hz; J 2 =6.1 Hz); 5.61 δ (2 H, s); 6.93−7.61 δ (5 H, m); 7.07 δ (1 H, s); 7.65 δ (1 H, t, J=7.2 Hz); 7.75 δ (1 H, t, J=7.9 Hz); 8.1 δ (1 H, d, J=8.4 Hz); 8.61 δ (1 H, d, J=6.2 Hz)
13 C NMR: δ 7.32, 20.56, 31.63, 50.08, 66.91, 66.98, 75.43, 95.97, 120.47, 125.46, 127.14, 127.49, 128.5, 128.55, 128.72, 129.07, 129.92, 130.15, 130.99, 131.12, 131.56, 140.19, 145.76, 146.11, 149.23, 152.03, 157.07, 167.59, and 169.94
FAB-MS (M+1): 500
EXAMPLE 18
7-Phenylthio camptothecin
20-Acetoxy-7-phenylthio camptothecin (100 mg, 0.21 mmol) was dissolved in reagent grade methanol (20 mL), aqueous potassium carbonate (25 mg in 0.1 mL water) was added, and the solution stirred for about 3 hours at low temperature. The resulting reaction mixture was acidified with 1 N HCl to precipitate the lactone form of, the compound. The precipitated product was then filtered, washed with water (10 mL×4) and with ether (10 mL), and then dried under vacuum. The pale yellow powder was then analyzed to the desired product (79 mg; 80% yield).
1 H NMR (300 MHz; CDCl 3 ): 0.87 δ (3 H, t, J=5.4 Hz); 1.89 δ (2 H, q, J=7.2 Hz); 3.6 δ (1 H, s); 4.82 δ (2 H, ABq, J 1 =17.5 Hz; J 2 =6.1 Hz); 5.61 δ (2 H, s); 6.93−7.61 δ (5 H, m); 7.07 δ (1 H, s); 7.65 δ (1 H, t, J=7.2 Hz); 7.75 δ (1 H, t, J=7.9 Hz); 8.1 δ (1 H, d, J=8.4 Hz); 8.61 δ (1 H, d, J=6.2 Hz)
13 C NMR: δ 7.32, 20.56, 31.63, 50.08, 66.91, 66.98, 75.43, 95.97, 120.47, 125.46, 127.14, 127.49, 128.5, 128.55, 128.72, 129.07, 129.92, 130.15, 130.99, 131.12, 131.56, 140.19, 145.76, 146.11, 149.23, 152.03, 157.07, 167.59, and 169.94
FAB-MS (M+1): 457
EXAMPLE 19
20-Acetoxy-7-(4-fluorophenyl)thio camptothecin
The intermediate triflate (100 mg, 0.186 mmol) was dissolved in anhydrous 1,4-dioxane and cooled to 0° C. under a stream of argon. To it was then added diisopropyl ethylamine (0.1 mL; 0.557 mole) and slowly added 4-fluorophenyl mercaptan (0.2 mL). The reaction mixture was then stirred under a balloon pressure for 15 hours in a well ventilated hood. After 48 hours, the reaction mixture was diluted with methylene chloride (25 mL) and washed with water (20 mL×4), dried over anhydrous sodium sulfate, filtered and concentrated to obtain the crude product of the title compound in approximately 80.5% yield.
1 H NMR (300 MHz; CDCl 3 ) : 0.87 δ (3 H, t, J=5.4 Hz) ; 2.19 δ (2 H, q, J=7.2 Hz); 2.28 δ (3 H, s); 4.82 δ (2 H, ABq, J 1 =17.5 Hz; J 2 =6.1 Hz); 5.61 δ (2 H, m); 6.93−7.61 δ (4 H, m); 7.07 (1 H, s); 7.65 δ (1 H, t, J=7.2 Hz); 7.75 δ (1 H, t, J=7.9 Hz); 8.1 δ (1 H, d, J=8.4 Hz); 8.61 δ (1 H, d, J=6.2 Hz)
13 C NMR: δ 7.42, 31.63, 50.08, 66.01, 66.98, 72.49, 98.01, 116.92, 117.21, 118.84, 125.12, 128.38, 128.52, 130.43, 130.84, 131.48, 133.19, 133.3, 139.69, 146.17, 149.36, 149.36, 149.98, 152.07, 160.99 and 173.82
FAB-MS (M+1): 518
EXAMPLE 20
7-(4-fluorophenyl)thio camptothecin
20-Acetoxy-7- (4-fluorophenyl) thio camptothecin (100 mg, 0.21 mmol) was dissolved in reagent grade methanol (20 mL) and added aqueous potassium carbonate (25 mg in 0.1 mL water), and stirred for about 3 hours at low temperature. The resulting reaction mixture was acidified with 1 N HCl to precipitate the lactone form of the compound. The precipitated product was then filtered, washed with water (10 mL×4) and with ether (10 mL), and dried under vacuum. The pale yellow powder was then analyzed to confirm the desired product (79 mg; 80% yield).
1 H NMR (300 MHz; CDCl 3 ): 0.87 δ (3 H, t, J=5.4 Hz); 2.23 δ (2 H, q, J=7.2 Hz); 3.6 δ (1 H, s); 4.82 δ (2 H, ABq, J 1 =17.5 Hz; J 2 =6.1 Hz); 5.61 δ (2 H, s); 6.93−7.61 δ (4 H, m); 7.07 δ (1 H, s); 7.65 δ (1 H, t, J=7.2 Hz); 7.75 δ (1 H, t, J=7.9 Hz); 8.1 δ (1 H, d, J=8.4 Hz); 8.61 δ (1 H, d, J=6.2 Hz)
13 C NMR: δ 7.42, 31.63, 50.08, 66.01, 66.98, 72.49, 98.01, 116.92, 117.21, 118.84, 125.12, 128.38, 128.52, 130.43, 130.84, 131.48, 133.19, 133.3, 139.69, 146.17, 149.36, 149.36, 149.98, 152.07, 160.99 and 173.82
FAB-MS (M+1): 475
EXAMPLE 21
20-Acetoxy-7-trimethylsilyl camptothecin
Hexamethyl disilane (62 μL, 0.3 mmol) was taken up in a flame dried round bottom flask under argon. To it was added anhydrous hexamethyl phosphoramide (0.5 mL) and anhydrous tetrahydrofuran at room temperature. The reaction medium was then cooled to 0° C. using an ice bath and methyllithium was introduced (220 μL, estimated as 30.8 mg per mL). The dark colored solution was then stirred at low temperature for 20 to 30 minutes. Copper(I) iodide 42 mg, 0.22 mmol) was taken up in a separate predried round bottom flask and added anhydrous tetrahydrofuran (4 mL) to form a suspension of the copper iodide. To this suspension was then added tri-n-butyl phosphine (117 μL, 0.47 mmol) and the mixture stirred at room temperature for one hour. The resulting homogenous colorless solution was then cooled to 0° C. and transferred to the above organolithium reagent prepared using a cannula at −78° C. The reaction medium was then stirred for the next 15 to 20 minutes. The ongoing intermediate triflate synthon (114 mg, 0.213 mmol) was taken up in anhydrous tetrahydrofuran under a blanket of purified argon and then transferred to the above cuprate reagent at −78° C. The dark reaction solution was then stirred for 15 hours and then quenched with saturated ammonium chloride solution. The organic soluble portion was then taken up in chloroform (25 mL). The aqueous portion was then repeatedly extracted with chloroform (25 mL×3). The combined organic portion was then dried over with anhydrous sodium sulfate, filtered and concentrated to yield the desired product in the crude form. The crude form was then flash chromatographed over a bed of silica gel using 10% methanol in chloroform to obtain the title compound in 75% yield.
1 H NMR (300 MHz; CDCl 3 ): 0.645 δ (9 H, s); 0.90 δ (3 H, t, J=5.4 Hz); 2.12 δ (2 H, q, J=7.2 Hz); 2.21 δ (3 H, s); 2.23 δ (3 H, s); 5.42 δ (2 H, ABq, J 1 =17.5 Hz; J 2 =6.1 Hz); 5.49 δ (2 H, q, J=2.5 Hz); 7.12 δ (1 H, s); 7.87 δ (1 H, t, J=7.2 Hz); 7.95 δ (1 H, t, J=7.9 Hz); 8.21 δ (1 H, d, J=5.4 Hz); 8.27 δ (1 H, d, J=5.2 Hz)
13 C NMR: δ 1.03, 7.58, 30.23, 51.7, 65.23, 72.36, 96.43, 96.43, 118.88, 127.51, 128.31, 128.70, 129.69, 130.48, 131.44, 135.95, 143.46, 145.42, 147.20, 150.15, 156.74; 172.58
FAB-MS: 464 (M+1)
EXAMPLE 22
7-Trimethylsilyl camptothecin
20-Acetoxy-7-trimethylsilyl camptothecin (100 mg, 0.21 mmol) was dissolved in reagent grade methanol (20 mL) and added aqueous potassium carbonate (25 mg in 0.1 mL water), and stirred for about 3 hours at room temperature. The resulting reaction mixture is then cooled to 5° C. and acidified with 1 N HCl to precipitate the lactone form of the compound. The precipitated product was then filtered, washed with water (10 mL×4) and with ether (10 mL), and dried under vacuum. The pale yellow powder was then analyzed to confirm the desired product (60 mg; 63% yield).
1 H NMR (300 MHz; CDCl 3 ): 0.645 δ (9 H, s) ; 0.90 δ (3 H, t; J=5.4 Hz); 2.12 δ (2 H, q, J=7.2 Hz); 2.23 δ ( 3 H, s); 3.6 δ (1 H, s); 5.42 δ (2 H, ABq, J 1 =17.5 Hz; J 2 =6.1 Hz); 5.49 δ (2 H, q, J=2.5 Hz); 7.12 δ (1 H, s); 7.87 δ (1 H, t, J=7.2 Hz); 7.95 δ (1 H, t, J=7.9 Hz); 8.21 δ (1 H, d, J=5.4 Hz); 8.27 δ (1 H, d, J=5.2 Hz)
13 C NMR: δ 1.03, 7.58, 30.23, 51.7, 65.23, 72.36, 96.43, 96.43, 118.88, 127.51, 128.31, 128.70, 129.69, 130.48, 131.44, 135.95, 143.46, 145.42, 147.20, 150.15, 156.74, 172.58
FAB-MS: 421 (M+1)
EXAMPLE 23
20-Acetoxy-7-(β-trimethylsilyl)ethynyl camptothecin
The 20-acetoxy-7-triflate (100 mg, 0.1855 mmol) was dissolved anhydrous and degassed anhydrous dimethylformamide (5 mL) and added zinc chloride (50.5 mg, 0.371 mmol). To it was then added tris(dibenzylideneacetonyl)bis palladium(0) (17 mg, 0.371 mmol) followed by tri(2-furyl)phosphine (20 mg, 0.074 mmol). The resulting solution was stirred for approximately 30 minutes at room temperature, then acetylenic trimethylsilane (0.1 mL) was added. The reaction mixture was then stirred at room temperature for 48 hours. The resulting dark brown colored reaction mixture was then diluted with methylene chloride (25 mL), filtered, and washed with water (15 mL). The crude product obtained after concentration is then flashed through a columnar bed of florisil, the fractions pooled, concentrated, dried under vacuum and analyzed.
1 H NMR (300 MHz; CDCl 3 ): 0.45 δ (9 H, s); 0.87 δ (3 H, t, J=5.4 Hz); 1.85 δ (2 H, q, J=7.2 Hz); 2.31 δ (3 H, s); 5.42 δ (2 H, ABq, J 1 =17.5 Hz; J 2 =6.1 Hz); 5.61 δ (2 H, m); 7.07 δ (1 H, s); 7.87 δ (1 H, t, J=7.2 Hz); 7.95 δ (1 H, t, J=7.9 Hz); 8.21 δ (1 H, d, J=8.4 Hz); 8.27 δ (1 H, d, J=6.2 Hz)
FAB-MS (M+1): 501
EXAMPLE 24
20-Acetoxy-7-ethynyl camptothecin
20-Acetoxy-7-trimethylsilylethynyl camptothecin (100 mg, 0.21 mmol) was dissolved in reagent grade methanol (20 mL) and added aqueous potassium carbonate (25 mg in 0.1 mL water) and stirred for about 15 minutes at low temperature. The resulting reaction mixture was then cooled to 5° C. and acidified with 1 N HCl to precipitate the lactone form of the compound. The precipitated product was then filtered, washed with water (10 mL×4) and with ether (10 mL), and dried under vacuum. The pale yellow powder was then analyzed to confirm the desired product (40 mg; 53% yield).
1 H NMR (300 MHz; CDCl 3 ): 0.90 δ (3 H, t, J=5.4 Hz); 2.12 δ (2 H, q, J=7.2 Hz); 2.23 δ ( 3 H, s); 3.6 δ (1 H, s); 4.06 δ (1 H, s); 5.42 d (2 H, ABq, J 1 =17.5 Hz; J 2 =6.1 Hz); 5.49 δ (2 H, q, J=2.5 Hz); 7.12 δ (1 H, s); 7.87 δ (1 H, t, J=7.2 Hz); 7.95 δ (1 H, t, J=7.9 Hz); 8.21 δ (1 H, d, J=5.4 Hz); 8.47 δ (1 H, d, J=5.2 Hz)
EXAMPLE 25
7-Ethynyl camptothecin
20-Acetoxy-7-ethynyl camptothecin (50 mg, 0.11 mmol) was dissolved in reagent grade methanol (5 mL) and added aqueous potassium carbonate (25 mg in 0.1 mL water), and then stirred for about 2 hours at low temperature. The resulting reaction mixture was then cooled to 5° C. and acidified with 1 N HCl to precipitate the lactone form of the compound. The precipitated product was then filtered, washed with water (10 mL×4) and with ether (10 mL), and dried under vacuum. The pale yellow powder was then analyzed to confirm the desired product (60 mg; 63% yield).
1 H NMR (300 MHz; CDCl 3 ):0.90 δ (3 H, t, J=5.4 Hz) ; 2.12 δ (2 H, q, J=7.2 Hz); 3.6 δ (1 H, s); 4.06 δ (1 H, s); 5.42 δ (2 H, ABq, J 1 =17.5 Hz; J 2 =6.1 Hz); 5.49 δ (2 H, q, J=2.5 Hz); 7.12 δ (1 H, s); 7.87 δ (1 H, t, J=7.2 Hz); 7.95 δ (1 H, t, J=7.9 Hz); 8.21 δ (1 H, d, J=5.4 Hz); 8.47 δ (1 H, d, J=5.2 Hz)
EXAMPLE 26
7-(β-trimethylsilyl)ethyl camptothecin
Camptothecin (500 mg, 1.44 mmol) was suspended in deionized water (10 mL) and freshly distilled 3-trimethylsilyl-1 propanal (3.0 mL; excess) followed by dropwise addition of concentrated sulfuric acid (5.5 mL) at 0° C. using an ice bath over a period of 15 min. To the above stirred reaction medium was then introduced a 30% aqueous solution of hydrogen peroxide (2 mL) followed by iron sulfate heptahydrate (156 mg) in 1 mL water. The reaction mixture was then stirred at 25° C. for an additional 24 hours. The reaction mixture was then diluted with ice-cold water and extracted with chloroform (50 mL×3). The combined organic portion was then dried over anhydrous sodium sulfate, filtered and concentrated to obtain the crude product in 65% yield. The crude product was then purified over a silica gel column using 90% chloroform/methanol mixture to furnish 0.46 g of the title compound (54% yield).
1 H NMR (300 MHz; CDCl 3 ): 0.01 δ (9 H, s) ; 0.48 δ (2 H, q, J=4.8 Hz); 0.90 δ (3 H, t, J=5.4 Hz); 1.53 δ (2 H, q, J=6.6 Hz); 2.12 δ (2 H, q, J=7.2 Hz); 2.23 δ (3 H, s); 3.6 d (1 H, s); 5.42 δ (2 H, ABq, J 1 =17.5 Hz; J 2 =6.1 Hz); 5.49 δ (2 H, q, J=2.5 Hz); 7.12 δ (1 H, s); 7.87 δ (1 H, t, J=7.2 Hz); 7.95 δ (1 H, t, J=7.9 Hz); 8.21 δ (1 H, d, J=5.4 Hz); 8.27 (1 H, d, J=5.2 Hz)
13 C NMR: δ 1.03, 7.58, 9.62, 23.48, 30.23, 51.7, 65.23, 72.36, 96.43, 96.43, 118.88, 127.51, 128.31, 128.70, 129.69, 130.48, 131.44, 135.95, 143.46, 145.42, 147.20, 150.15, 156.74, 172.58
FAB-MS: 492 (M+1)
EXAMPLE 27
20-Acetoxy-7-(β-trimethylsilyl)ethylthio camptothecin
The intermediate triflate (100 mg, 0.186 mmol) was dissolved in anhydrous 1,4-dioxane and cooled to 0° C. under a stream of argon. To it was then added diisopropyl ethylamine (0.1 mL; 0.557 mole), and slowly added trimethylsilyl ethanethiol (0.25 mL). The reaction mixture was then stirred under a balloon pressure of argon for 15 hours in a well ventilated hood. After 15 hours, the reaction mixture was diluted with methylene chloride (25 mL) and washed with water (20 mL×4), dried over anhydrous sodium sulfate, filtered and concentrated to obtain the crude product of the title compound in approximately 80% yield.
1 H NMR (300 MHz; CDCl 3 ) : 0.01 δ (9 H, s); 0.87 δ (3 H, t, J=5.4 Hz); 0.98 δ (2 H, q, J=4.8 Hz); 1.26 δ (3 H, t, J=5.8 Hz); 1.89 δ (2 H, q, J=7.2 Hz); 2.31 δ (3 H, s); 2.28 d (3 H, s); 3.05 δ (2 H, q, J=5 Hz); 3.19 δ (2 H, q, J=7.2 Hz); 5.42 δ (2 H, ABq, J 1 =17.5 Hz; J 2 =6.1 Hz); 5.61 δ (2 H, s); 7.07 δ (1 H, s); 7.65 δ (1 H, t, J=7.2 Hz); 7.75 δ (1 H, t, J=7.9 Hz); 8.1 δ (1 H, d, J=8.4 Hz); 8.58 δ (1 H, d, J=6.2 Hz)
FAB-MS: 523(M+1 )
EXAMPLE 28
7-(β-trimethylsilyl)ethylthio camptothecin
20-Acetoxy-7-ethylthio camptothecin (100 mg, 0.21 mmol) was dissolved in reagent grade methanol (20 mL) and added aqueous potassium carbonate (25 mg in 0.1 mL water) and stirred for about 3 hours at low temperature. The resulting reaction mixture was acidified with 1 N HCl to precipitate the lactone form of the compound. The precipitated product was then filtered, washed with water (10 mL×4) and with ether (10 mL), and then dried under vacuum. The pale yellow powder was then analyzed to confirm the desired product (69 mg; 76% yield).
1 H NMR (300 MHz; CDCl 3 ): 0.01 δ (9 H, s); 0.87 δ (3 H, t, J=5.4 Hz); 0.98 δ (2 H, q, J=4.8 Hz); 1.26 δ (3 H, t, J=5.8 Hz); 1.89 δ (2 H, q, J=7.2 Hz); 2.31 δ (3 H, s); 2.28 δ (3 H, s); 3.05 δ (2 H, q, J=5 Hz); 3.19 δ (2 H, q, J=7.2 Hz); 3.6 δ (1 H, s); 5.42 δ (2 H, ABq, J 1 =17.5 Hz; J 2 =6.1 Hz); 5.61 δ (2 H, s); 7.07 δ (1 H, s); 7.65 δ (1 H, t, J=7.2 Hz); 7.75 δ (1 H, t, J=7.9 Hz); 8.1 δ (1 H, d, J=8.4 Hz); 8.58 δ (1 H, d, J=6.2 Hz)
FAB-MS: 481 (M+1)
EXAMPLE 29
20-Acetoxy-7-(α-trimethylsilyl)methylthio camptothecin
The intermediate triflate (100 mg, 0.186 mmol) was dissolved in anhydrous 1,4-dioxane (2 mL) and cooled to 0° C. under a stream of argon. To it was then added diisopropyl ethylamine (0.1 mL; 0.557 mole) and slowly added trimethylsilyl methanethiol (0.2 mL). The reaction mixture was then stirred under a balloon pressure of argon for 15 hours in a well ventilated hood. After 48 hours, the reaction mixture was diluted with methylene chloride (25 mL) and washed with water (20 mL×4), dried over anhydrous sodium sulfate, filtered and concentrated to obtain the crude product of the title compound in approximately 70% yield.
1 H NMR (300 MHz; CDCl 3 ): 0.15 δ (9 H, s); 0.87 δ (3 H, t, J=5.4 Hz); 1.26 δ (3 H, t, J=5.8 Hz); 2.21 δ (3 H, s); 2.19 δ (2 H, q, J=7.2 Hz); 2.31 δ (2 H, s); 2.38 δ (2 H, s); 5.42 δ (2 H, ABq, J 1 =17.5 Hz; J 2 =6.1 Hz); 5.61 δ (2 H, s); 7.07 δ (1 H, s); 7.65 d (1 H, t, J=7.2 Hz); 7.75 d (1 H, t, J=7.9 Hz); 8.22 δ (1 H, d, J=8.4 Hz); 8.55 δ (1 H, d, J=6.2 Hz)
FAB-MS: 509(M+1)
EXAMPLE 30
7-(α-trimethylsilyl)methylthio camptothecin
20-Acetoxy-7-methylthio camptothecin (100 mg, 0.21 mmol) is dissolved in reagent grade methanol (20 mL) and added aqueous potassium carbonate (25 mg in 0.1 mL water), and stirred for about 3 hours at low temperature. The resulting reaction mixture was acidified with 1 N HCl to precipitate the lactone form of the compound. The precipitated product was then filtered, washed with water (10 mL×4) and with ether (10 mL), and dried under vacuum. The pale yellow powder was then analyzed to confirm the desired product (59 mg; 67% yield).
1 H NMR (300 MHz; CDCl 3 ): 0.15 δ (9 H, s); 0.87 δ (3 H, t, J=5.4 Hz); 1.26 δ (3 H, t, J=5.8 Hz); 2.19 δ (2 H, q, J=7.2 Hz); 2.28 δ (2 H, s); 2.38 δ (2 H, s); 3.6 δ (1 H, s); 5.42 δ (2 H, ABq, J 1 =17.5 Hz; J 2 =6.1 Hz); 5.61 δ (2 H, s); 7.07 δ (1 H, s); 7.65 δ (1 H, t, J=7.2 Hz); 7.75 δ (1 H, t, J=7.9 Hz); 8.1 δ (1 H, d, J=8.4 Hz); 8.58 δ (1 H, d, J=6.2 Hz)
FAB-MS: 467 (M+1)
EXAMPLE 31
20-Dehydroxy camptothecin
Camptothecin (500 mg, 1.44 mmol) was suspended in 1,4-dioxane (10 mL) and added Lawsson's reagent (290.5 mg, 0.72 mmol). The reaction mixture was then heated to 90° C. for 10 hours under an inert atmosphere. The resultant homogeneous reaction mixture was then concentrated, organic portion was taken up in chloroform (25 mL) and the aqueous fraction was repeatedly extracted with chloroform (25 mL×3). The combined organic portion was then concentrated to get the title compound in the crude form. The crude product was then flash chromatographed over a bed of florisil using 10% chloroform in methanol to furnish the desired product in 40% yield in diastereomeric mixture.
1 H NMR (300 MHz; CDCl 3 ): 1.07 δ (3 H, t, J=5.4 Hz); 2.12 δ (2 H, q, J=7.2 Hz); 3.69 δ (1 H, t, J=6.6 Hz); 5.42 δ (2 H, ABq, J 1 =17.5 Hz; J 2 =6.1 Hz); 5.59 δ (2 H, q, J=2.5 Hz); 7.62 δ (1 H, s); 7.71 δ (1 H, t, J=7.2 Hz); 7.85 δ (1 H, t, J=7.9 Hz); 8.01 δ (1 H, d, J=5.4 Hz); 8.23 δ (1 H, d, J=5.2 Hz); 8.47 δ (1 H, s)
13 C NMR: δ 11.1, 25.25, 29.6, 45.81, 49.93, 66.04, 99.76, 120.79, 128.10, 128.24, 128.72, 129.8, 130.73, 131.2, 146.12, 147.27, 149.06, 158.01 and 171.01
FAB (M+l): 361.2
EXAMPLE 32
20-Acetoxy-7-(γ-trimethylsilyl)-propen-α-yl camptothecin
The 20-acetoxy-7-triflate (100 mg, 0.1855 mmol) was dissolved anhydrous and degassed anhydrous dimethylformamide (5 mL) and added zinc chloride (50.5 mg, 0.371 mmol). To it was then added tris(dibenzylideneacetonyl)bis palladium(0) (17 mg, 0.371 mmol) followed by tri(2-furyl)phosphine (20 mg, 0.074 mmol). The resulting solution was stirred for approximately 30 minutes at room temperature, then propargylic trimethylsilane (0.1 mL) was added. The reaction mixture was then stirred at room temperature for 48 hours. The resulting dark brown colored reaction mixture was then diluted with methylene chloride (25 mL), filtered, washed with water (15 mL). The crude product obtained after concentration was then flashed through a columnar bed of florisil, the fractions pooled, concentrated, dried under vacuum and analyzed.
1 H NMR (300 MHz; CDCl 3 ): 0.26 δ (9 H, s) ; 0.97 δ (3 H, t, J=5.4 Hz); 2.02 δ (2 H, s); 2.24 δ (2 H, q, J=7.2 Hz); 2.21 δ (3 H, s); 5.42 δ (2 H, ABq, J 1 =17.5 Hz; J 2 =6.1 Hz); 5.61 δ (2 H, m); 7.2 δ (1 H, s); 7.77 δ (1 H, t, J=7.2 Hz); 7.85 δ (1 H, t, J=7.9 Hz); 8.21 δ (1 H, d, J=8.4 Hz); 8.32 δ (1 H, d, J=6.2 Hz)
FAB-MS (M+1): 501
EXAMPLE 33
20-Acetoxy-7-(propen-α-yl) camptothecin
20-Acetoxy-7-[(γ-trimethylsilyl) -propen-α-yl] camptothecin (100 mg, 0.21 mmol) was dissolved in reagent grade methanol (20 mL) and added aqueous potassium carbonate (25 mg in 0.1 mL water), and then stirred for about 15 minutes at low temperature. The resulting reaction mixture was then cooled to 5° C. and acidified with 1 N HCl to precipitate the lactone form of the compound. The precipitated product was then filtered, washed with water (10 mL×4) and with ether (10 mL), dried under vacuum. The pale yellow powder was then analyzed to the desired product (40 mg; 53% yield).
1 H NMR (300 MHz; CDCl 3 ): 0.97 δ (3 H, t, J=5.4 Hz); 2.02 δ (2 H, s); 2.24 δ (2 H, q, J=7.2 Hz); 2.21 δ (3 H, s); 5.42 δ (2 H, ABq, J 1 =17.5 Hz; J 2 =6.1 Hz); 5.61 δ (2 H, m); 7.2 δ (1 H, s); 7.77 δ (1 H, t, J=7.2 Hz); 7.85 δ (1 H, t, J=7.9 Hz); 8.21 δ (1 H, d, J=8.4 Hz); 8.32 δ (1 H, d, J=6.2 Hz)
EXAMPLE 34
7-(γ-trimethylsilyl)propen-α-yl camptothecin
20-Acetoxy-7-(γ-trimethylsilyl)propen-α-yl camptothecin (50 mg, 0.11 mmol) was dissolved in reagent grade methanol (5 mL) and added aqueous potassium carbonate (25 mg in 0.1 mL water) and stirred for about 2 hours at low temperature. The resulting reaction mixture was then cooled to 5° C. and acidified with 1 N HCl to precipitate the lactone form of the compound. The precipitated product was then filtered, washed with water (10 mL×4) and with ether (10 mL), dried under vacuum. The pale yellow powder was then analyzed as the desired product (60 mg; 63% yield) and 10% of the isomerized congener the corresponding 7-allenic derivative.
1 H NMR (300 MHz; CDCl 3 ): 0.26 δ (9 H, s); 0.97 δ (3 H, t, J=5.4 Hz); 2.02 δ (2 H, s, corresponds to the acetylenic counterpart); 2.24 δ (2 H, q, J=7.2 Hz); 5.42 δ (2 H, ABq, J 1 =17.5 Hz; J 2 =6.1 Hz); 5.6 δ (2 H, m); 7.2 δ (1 H, s); 7.77 δ (1 H, t, J=7.2 Hz); 7.85 δ (1 H, t, J=7.9 Hz); 8.21 δ (1 H, d, J=8.4 Hz); 8.32 δ (1 H, d, J=6.2 Hz)
EXAMPLE 35
20-Dehydroxy-7-Ethyl-camptothecin
7-Ethyl camptothecin (456 mg, 1.213 mmol) was suspended in 1,4-dioxane (10 mL) and added Lawsson's reagent (5 mg, 0.665 mmol). The reaction mixture was then heated to 90° C. for 10 hours under an inert atmosphere. The resultant homogeneous reaction mixture was then concentrated, the organic portion was taken up in chloroform (25 mL) and the aqueous fraction was repeatedly extracted with chloroform (25 mL×3). The combined organic portion was then concentrated to get the title compound in the crude form. The crude product was then flash chromatographed over a bed of florisil using 10% chloroform in methanol to furnish the desired product in 40% yield in diastereomric mixture.
1 H NMR (300 MHz; CDCl 3 ): 1.08 δ (3 H, t, J=5.4 Hz) ; 2.38 δ (3 H, t, J=5.4 Hz; 2.1 δ (2 H, q, J=7.2 Hz); 3.19 δ (2 H, q, J=7.8 Hz); 3.69 δ (1 H, t, J=6.6 Hz); 5.42 δ (2 H, ABq, J 1 =17.5 Hz; J 2 =6.1 Hz); 5.59 δ (2 H, q, J=2.5 Hz); 7.62 δ (1 H, s); 7.71 δ (1 H, t, J=7.2 Hz); 7.85 δ (1 H, t, J=7.9 Hz); 8.12 δ (1 H, d, J=5.4 Hz); 8.20 δ (1 H, d, J=5.2 Hz)
13 C NMR: δ 11.13, 13.87, 22.91, 25.25, 45.75, 49.20, 65.97, 99.56, 120.45, 123.52, 126.85, 127.02, 130.12, 130.6, 145.79, 146.76, 147.25, 149.97, 151.95, 157.97, 171.01
FAB (M+1): 389.1
EXAMPLE 36
N-Acetyl-1,2,3,4-tetrahydrocamptothecin
Camptothecin purchased from China was further purified by recrystallization, using reagent grade dimethylformamide as solvent preferably at a concentration at about 1 g of camptothecin in 10 to 15 mL of dimethylformamide and warming to approximately 130° C. Platinum catalyst was generated in situ. Platinum oxide (2.0 g) in glacial acetic acid (200 mL) was stirred under a blanket of hydrogen (1 atm) at room temperature for about an hour. Camptothecin (10.0 g, 0.023 mole) and additional acetic acid (300 mL) were added to the above suspension. The mixture was then agitated vigorously under hydrogen for another 3.5 hours (consumption of about 1.0 L of hydrogen was measured). The solution was transferred into another flask under nitrogen. Solvent was removed under high vacuum at room temperature to give 12.7 g of crude tetrahydrocamptothecin intermediate.
To the above tetrahydrocamptothecin (12.1 g) without any further purification or isolation was then slowly added excess acetyl chloride (50 mL). The suspension generated was then stirred under an inert atmosphere at ambient temperature overnight. Excess acetyl chloride was evaporated in vacuo. The residue was dissolved in chloroform, washed with brine and dried over anhydrous sodium sulfate. Solvent was removed to give 10.3 g of crude 1-acetyl-20-acetoxy tetrahydrocamptothecin. A portion of the crude product (4.8 g) was subsequently purified over silica bed by flash column using ethyl acetate-methanol mixture. The isomeric mixture of crude 1-acetyl-20-acetoxy tetrahydrocamptothecin was isolated (3.05 g, 53.5% yield from camptothecin) as off-white crystals.
1 H NMR (250 MHz Varian; CDCl 3 ) : 0.89 δ (3 H, t, J=6.25 Hz); 1.91-2.21 δ (2 H, m); 2.09 δ (3 H, s); 2.69-2.91 δ (2 H, ABq, J 1 =1.75 Hz; J2=4.25 Hz); 3.41 δ (1 H, dd, J=5.75 Hz); 3.58 δ (1 H, m); 2.55 δ (1 H, dd, J=7.75 Hz); 5.24 δ (1 H; ABq, J 1,2 =14.25 Hz); 6.3 δ (1 H, s); 6.49 δ (1 H, d, J=8.5 Hz); 6.81 δ (1 H, m); 7.18-7.25 δ (3 H, m)
EXAMPLE 37
1-acetyl-10-Nitro-tetrahydrocamptothecin
1-acetyl-20-acetoxy tetrahydrocamptothecin (1.786 g, 4.1 mmol) in 25 mL concentrated sulfuric acid was cooled in an acetone-ice bath. 3.0 mL of fuming nitric acid was added dropwise to the above thick solution while maintaining vigorous stirring. After 60 minutes in the ice, the reaction product was extracted out using chloroform. The organic portion was washed with sodium bicarbonate aqueous solution, brine and dried over sodium sulfate. Solvent was removed to give 1.11 g of 10-nitro-1-acetyl tetrahydrocamptothecin (61% yield).
1 H NMR (250 MHz Varian; CDCl 3 ): 0.89 δ (3 H, t, J=6.25 Hz); 1.91-2.21 δ (2 H, m); 2.09 δ (3 H, s); 2.69-2.91 δ (2 H, ABq, J 1 =1.75 Hz; J2=4.25 Hz); 3.41 δ (1 H, dd, J=5.75 Hz); 3.58 δ (1 H, m); 2.55 δ (1 H, dd, J=7.75 Hz); 5.24 δ (1 H; ABq, J 1,2 =14.25 Hz); 6.49 δ (1 H, d, J=8.5 Hz); 6.66 δ (1 H, s); 7.12 δ (1 H, d, J=7 Hz); 7.18-7.25 δ (3 H, m)
EXAMPLE 38
1-Acetyl-10-Amino-tetrahydrocamptothecin
To the ongoing nitro intermediate (3.43 g, 7.7 mmol) and platinum oxide (0.5 g) in methanol (400 mL), hydrogen was then bubbled for approximately 3 hours. The catalyst was then filtered while keeping the magma wet and the solvent was removed over aspirator vacuum to deliver the 10-amino title compound in quantitative yield.
1 H NMR (250 MHz Varian; CDCl 3 ): 0.89 δ (3 H, t, J=6.25 Hz) 1.91-2.21 δ (2 H, m); 2.09 δ (3 H, s); 2.69-2.91 δ (2 H, ABq, J 1 =1.75 Hz; J2=4.25 Hz); 3.41 δ (1 H, dd, J=5.75 Hz); 3.58 δ (1 H, m); 2.55 δ (1 H, dd, J=7.75 Hz); 5.24 δ (1 H; ABq, J 1,2 =14.25 Hz); 6.59-6.72 δ (5 H, d, J=8.5 Hz)
EXAMPLE 39
1-Acetyl-10-Fluoro-tetrahydrocamptothecin
A solution of 10-amino-1-acetyl tetrahydrocamptothecin (1.28 g, 3.1 mmol) in 300 mL chloroform was cooled down in acetone-ice bath (−15° C.). Boron trifluoride diethyl etherate (1.5 mL, 1.5 equiv.) in 7 mL was then slowly added. After the addition, the mixture was allowed to warm to room temperature. After stirring about 15 minutes the mixture was cooled back in acetone-ice bath. t-Butyl nitrite (0.54 mL, 1.5 equiv.) in 30 mL chloroform was added dropwise. The mixture was stirred in ice bath for 30 minutes and then warmed to room temperature for 60 minutes. Solvent was removed in vacuo. To the residue was added 20 mL toluene and heated to 100-110° C. for 1 hour. Toluene was removed under vacuum. The desired product was then extracted out using chloroform, washed with brine to obtain 0.48 g of the title compound. The product was further purified by flash column chromatography using ethyl acetate:methanol (10:1) as eluent.
1 H NMR (250 MHz Varian; CDCl 3 ): 0.89 δ (3 H, t, J=6.25 Hz); 1.91-2.21 δ (2 H, m); 2.09 δ (3 H, s); 2.69-2.91 δ (2 H, ABq, J 1 =1.75 Hz; J2=4.25 Hz); 3.41 δ (1 H, dd, J=5.75 Hz); 3.58 δ (1 H, m); 2.55 δ (1 H, dd, J=7.75 Hz); 5.24 δ (1 H; ABq, J 1,2 =14.25 Hz); 6.59-6.72 δ (5 H, d, J=8.5 Hz)
EXAMPLE 40
10-Fluorocamptothecin
10-Fluoro-1-acetyl tetrahydrocamptothecin (0.45 g, 1.1 mmol) in 20 mL 20% sulfuric acid was refluxed for 2 hours. After cooling to room temperature, the reaction mixture was extracted with chloroform, washed with brine and then with a saturated solution of sodium bicarbonate. The product was then dried over anhydrous sodium sulfate. Solvent was removed to deliver 0.26 g 10-fluoro-tetrahydrocamptothecin (64% yield).
To the above 10-fluoro-tetrahydrocamptothecin (0.26 g, 0.7 mmol) in 20 mL of peroxide free 1,4-dioxane and to it was added 0.35 g of DDQ. The mixture was refluxed for 1 hour, then cooled to room temperature. Precipitate was washed with chloroform. The obtained organic portion was combined with mother liquid and washed with a saturated solution of sodium bicarbonate, 2% aqueous HCl, brine, and then dried over anhydrous sodium sulfate. Solvent was evaporated to obtain 0.26 g of 10-fluorocamptothecin in quantitative yield.
1 H NMR (250 MHz Varian; CDCl 3 ): 0.89 d (3 H, t, J=6.25 Hz); 1.91-2.21 d (2 H, m); 3.59 d (1 H, s); 5.22 d (2 H, s); 5.24 d (1 H; ABq, J 1,2 =14.25 Hz); 7.53-7.67 d (3 H, m); 8.24 d (1 H, dd, J=4.25 Hz), 8.34 d (1 H,s)
EXAMPLE 41
10-Fluoro-7-(β-trimethylsilyl)ethyl Camptothecin
The 10-fluoro camptothecin intermediate (60 mg) was suspended in water (10 mL) and iron (II) sulfate heptahydrate (100 mg) was added and stirred for approximately 15 minutes. To the above suspension was then added 3-trimethylsilyl propanal (0.5 mL), followed by glacial acetic acid (5 mL) as co-solvent. The colloidal reaction mixture was then stirred and concentrated sulfuric acid (4 mL) added while cooling. Once addition of acid was complete, the pot temperature was raised to room temperature and 30% hydrogen peroxide in water (0.5 mL) added. The reaction mixture was then stirred for 6 hours during which time the reaction was completed. The reaction mixture was then poured into crushed ice and allowed to stand for 2 hours. The precipitated product was then filtered and washed with water followed by hexanes, and dried to deliver the title compound as a pale yellow powder. The crude product was then flash chromatographed over silica gel (mesh 100-230) using chloroform to 5% chloroform-methanol as a gradient. The desired fractions were pooled together, the solvent evaporated, and dried to produce the target compound in 45% yield.
1 H NMR (250 MHz Varian; CDCl 3 ): 0.139 d (9 H,s); 0.88 d (2 H, m); 1.02 d (3 H, t, J=6.25 Hz); 1.91-2.21 d (2 H, m); 3.59 d (1 H, s); 5.22 d (2 H, s); 5.24 d (2 H; ABq, J 1,2 =14.25 Hz); 7.57-7.61 d (3 H, m); 8.24 d (1 H, dd, J=4.25 Hz)
13 C NMR (300 MHz, Varian, CDCl 3 ) δ −2.03, 7.69, 17.43, 24.22, 31.49, 49.17, 66.33, 72.71, 98.19, 107.07, 107.38, 118.71, 120.37, 120.71, 126.87, 133.18, 146.45, 146.78, 150.31, 157.76, 163.10, 174.09.
EXAMPLE 42
9-Nitrocamptothecin
Camptothecin (25 g) in concentrated sulfuric acid (500 mL) was cooled in an ice-bath. To it was then added 70% nitric acid (30 mL), drop-wise to control the reaction temperature. The reaction mixture was then stirred for 36 hours, poured into excess crushed ice and the organic portion was extracted out using chloroform. The combined organic fraction was washed with freshly prepared 10% sodium bicarbonate solution and brine, and then dried over anhydrous sodium sulfate. Solvent was removed and the residue was purified by flash silica gel column using hexane/ethyl acetate (1:1) as eluent to furnish 2.7 g of 9-nitrocamptothecin.
EXAMPLE 43
20-Acetoxy-9-nitro camptothecin
To 9-nitrocamptothecin (1.12g) in glacial acetic acid (10 mL) was added excess acetyl chloride at room temperature. After the mixture was stirred at room temperature for 24 hours, it was poured into ice, extracted with methylene chloride. The methylene chloride solution was washed with brine and dried over sodium sulfate. The solvent was evaporated. The crude product was subsequently purified by flash column chromatography to get 0.88 g of 9-nitro-20-acetoxycamptothecin.
EXAMPLE 44
20-Acetoxy-9-amino camptothecin
9-nitro-20-acetoxycamptothecin (1.5 g) was dissolved in 150 ml reagent grade ethyl acetate. Platinum dioxide (276 mg) was then added to the above solution at room temperature. The mixture was bubbled with hydrogen for approximately 30 minutes and stirred for about an hour. Methanol was then added to dissolve the precipitate. The catalyst was filtered and solvent was removed. The crude product was recrystallized from a mixture of methylene chloride and diethyl ether to give 1.14 g of 9-animo-20-acetoxycamptothecin.
EXAMPLE 45
9-Fluorocamptothecin
Boron trifluoride etheral solution (0.54 mL) in 10 mL anhydrous methylene chloride was taken in a three-neck round bottom flask fitted with an additional funnel and a thermometer. The reaction mixture was then cooled down using ice-acetone bath. To the above solution was then added dropwise at −15° C. 9-amino-20-acetoxy camptothecin (1.14 g, 2.8 mmol) in 100 mL methylene chloride. After an hour, t-butyl nitrite (0.39 mL) in 20 mL methylene chloride was introduced dropwise. The reaction mixture was then stirred in the ice-acetone bath for about 40 minutes. Solvent was removed and to the residue 200 mL of reagent grade toluene was added. The mixture was refluxed under nitrogen for approximately 3 hours. Organic portion was decanted from the residue and concentrated under vacuum. The crude product was purified by flash column chromatography using hexane and ethyl acetate (1:2) as eluent to deliver 380 mg of 9-fluoro-20-acetoxycamptothecin.
To 9-fluoro-20-acetoxycamptothecin (380 mg) in 30 mL methanol was added 107 mg potassium carbonate and two drops of water. After stirring the reaction mixture for about 3 hours, 37% hydrochloric acid was used to adjust pH acidic. The product was precipitated out upon dilution with crushed ice. Mother liquid was concentrated to one-third volume and precipitated the product as mentioned above. The precipitated product was then washed with diethyl ether. The pale yellow product thus obtained is then dried (260 mg) and characterized to 9-fluorocamptothecin.
1 H NMR (300 MHz, DMSO- d6): 0.86 δ (t, J=7.2 Hz, 3 H), 1.85 δ (m, 2 H), 5.28 δ (s, 2 H), 5.42 δ (s, 2 H), 6.53 δ (broad, 1 H), 7.35 δ (s, 1 H), 7.54 δ (t, J=8.8 Hz, 1 H), 7.86 δ (q, J=8.5 Hz, 1 H), 8.01 δ (d, J=8.4 Hz, 1 H), 8.82 δ (s, 1 H)
EXAMPLE 46
9-Fluoro-7-(β-trimethylsilyl)ethyl camptothecin
The 9-fluoro camptothecin intermediate (75 mg) was suspended in water (10 mL), added iron (II) sulfate heptahydrate (150 mg) and stirred well for approximately 15 minutes. To the above suspension was then added 3-trimethylsilyl propanal (0.5 mL) followed by glacial acetic acid (5 mL) as co-solvent. The colloidal reaction mixture was then stirred and added concentrated sulfuric acid (4 mL) while cooling. Once addition of acid was over, the pot temperature was raised to room temperature and 30% hydrogen peroxide in water (0.5 ml) added. The reaction mixture was then allowed to stir for 6 hours at which time the reaction was over. The reaction mixture was then poured into crushed ice and allowed to stand for 2 hours. The precipitated product was then filtered and washed with water followed by hexanes, and dried to get the title compound in pale yellow powder. The crude product was then flash chromatographed over silica gel (mesh 100-230) using chloroform to 5% chloroform/methanol as a gradient. The desired fractions were pooled together, the solvent evaporated and dried to get the title compound in 45% yield.
1 H NMR (250 MHz Varian; CDCl 3 ): 0.154 δ (9 H,s); 0.94 δ (2 H, m); 1.04 δ (3 H, t, J=6.25 Hz); 1.91-2.21 δ (2 H, m) ; 3.19 δ (2 H, m) 3.59 δ (1 H, s); 5.22 δ (2 H, s) ; 5.24 δ (2 H; ABq, J 1,2 =14.25 Hz); 7.57-7.71 δ (3 H, m); 8.08 δ (1 H, dd, J=4.25 Hz)
13 C NMR: δ −2.08, 7.68, 13.99, 18.25, 22.54, 27.28, 27.43, 31.5, 49.28, 66.31, 72.7, 98.4, 112.72, 113.03, 117.62, 118.99, 126.89, 127.47, 129.54, 129.67, 146.73, 147.14, 150.23, 151.41, 152.67, 157.72, 161.1, 174.03
The foregoing description has been directed to particular embodiments of the invention in accordance with requirements of the Patent Statutes for the purposes of illustration and explanation. It will be apparent, however, to those skilled in this art, that many modifications, changes and variations in the claimed antitumor compositions, solutions, methods of administration of the antitumor compositions set forth will be possible without departing from the scope and spirit of the claimed invention. It is intended that the following claims be interpreted to embrace all such modifications and changes.
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This invention relates to novel derivatives of camptothecin, and will, particularly to derivatives having a substitution at the C-7 position, or at one of the C-9, C-10, C-11 or C-12 positions, or to disubstituted derivatives having a first substitution at C-7 and a second at one of C-9, C-10, C-11 or C-12. The invention also includes methods of using the compounds as Topoisomerase I inhibitors to treat patients with cancer. The invention also includes pharmaceutical formulations which consist of the novel compounds in solution or suspension with one or more pharmaceutical excipients or dilutes.
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[0001] The present application is a continuation-in-part of U.S. application Ser. No. 09/280,329 filed Mar. 29, 1999, which claims priority under 35 U.S.C. §119(e) to GB9806649.1 entitled Material and Methods Relating to a New Retrovirus” filed Mar. 27, 1998 and U.S. Provisional Application, No. 60/115,268 of the same title, filed Jan. 8, 1999. The disclosures of all of the above-identified applications are hereby incorporated by reference as though set forth in full herein.
FIELD OF THE INVENTION
[0002] The present invention concerns materials and methods relating to a novel retrovirus associated with autoimmune disease, as well as diagnostic techniques and kits, to antibodies which bind said retrovirus and their use in diagnosis. Also included are methods of treatment of autoimmune disease and compositions for use in those methods.
DESCRIPTION OF RELATED ART
[0003] A substantial body of indirect data supports the hypothesis that a retrovirus may be the etiological agent in a range of autoimmune diseases such as rheumatoid arthritis (RA), Sjogren's syndrome (SS) and systemic lupus erythematosus (SLE), but convincing direct evidence is still lacking.
[0004] The hypothesis that retroviral infection has a role to play in the pathogenesis of RA is given support by research demonstrating that human T-cell lymphotropic virus type I (HTLV-I) (the etiologic agent of adult T-cell leukemia (ATL) and tropical spastic paraparesis (TSP)) is associated with an arthropathy (usually chronic and oligoarticular) that has many features in common with RA (Nishioka. K. et al. The Lancet 1989; I: 441). Mice transgenic for the HTLV-I tax gene also develop a polyarthritis resembling RA (Iwakura. Y. et al. Science 1991; 253: 1026-1028). These mice express high levels of the viral transactivator protein Tax in the joints along with high levels of interleukin-1α messenger RNA. Other reports have demonstrated that human synovial cells which are transgenic for the Tax protein show enhanced proliferative capacity and GM-CSF production (Sakai. M. et al. J. Clin. Invest.; 1993; 92: 1957-1966; and Nakajima. T. et al. J. Clin. Invest.; 1993; 92: 186-193) and also increased expression of IL-6 (Mori. N. et al. J. Rheumatol.; 1995; 22: 2049-2054). An animal model of spontaneous inflammatory arthritis induced by a retrovirus is the caprine arthritis encephalitis virus-infected goat. This disease shares some features in common with RA in that CAEV-induced lesions contain large numbers of inflammatory cells including activated macrophages, macrophage-like type A synovial cells and type B synovial fibroblasts in addition to T cells (Wilkerson. M. et al. J. Rheumatol.; 1995; 22: 8-15). CAEV infects monocytes and macrophages and proviral DNA has been detected at multiple sites (Zink. M. et al. Am.
[0005] J. Pathol.; 1990; 136: 843-854) suggesting that viral expression is dependent on the maturation state of monocytes, with macrophages in lesions showing high levels of viral gene expression. The present inventors have recently described the cloning and sequencing of a 930 bp fragment (JC96) of a new human retroviral genome from particles purified from tissues and cultured cells or tissues (Griffiths. D. et al. J. Virol. 1997; 71: 2866-2872). This sequence corresponded to part of a novel pol gene containing overlapping reading frames encoding part of the protease (PR) and reverse transcriptase (RT) enzymes. This information forms part of previously filed European application 96912159.9 in the name of Griffiths et al.
[0006] The similarity of JC96 to rodent IAP genes suggested that the novel retrovirus may encode the human IAPs reported by Garry et al (Garry. R. F.; et al 1990. Science 250: 1127-1129). However, rodent IAPs are thought to be encoded by endogenous retroviruses with defective envelope genes (Kuff, E. L.; et al 1988 Adv. Cancer Res. 51: 183-276). In addition, extracellular virions were not detected in the cultures studied by Garry et al (Garry. R. F.; et al 1990. Science 250: 1127-1129).
[0007] The low abundance of JC96 in tissues, the high level of sequence similarity between different isolates, and the maintenance of open reading frames for two of its enzymes support the hypothesis that the new retrovirus is part of an exogenous retrovirus.
[0008] Further studies on the retrovirus have been prevented by the inability to amplify similar sequences from human cell lines and tissues, due to its extremely low abundance. RT-PCR and standard PCR with degenerate primers based on other conserved regions of retrovirus genomes has proved unsuccessful in allowing the present inventors to extend the sequence into gag or env.
SUMMARY OF THE INVENTION
[0009] The present invention relates to the further characterization of the novel retrovirus previously reported in European patent application number 96912159.9., U.S. Provisional Application 60/115,268 and U.S. application Ser. No. 09/280,329.
[0010] Unlike the large numbers of endogenous retroviral sequences which have already been described (Nakagawa. K. et al. Arthritis and Rheumatism 1997; 40: 627-638; and Patience. C. et al. Trends in Genetics 1997; 13: 116-120), this new retroviral agent has all the characteristics of an exogenous (i.e., infectious) agent. To date there are only four known infectious human retroviruses, HIV 1 and 2, and HTLV-I and II (the “human” foamy virus has recently been found to be a zoonosis) (Weiss R. A.; Nature 1996; 380: 201). The novel retrovirus has therefore been designated human retrovirus-5 (HRV-5) to which the present invention relates.
[0011] In the initial studies of the present inventors, HRV-5 RNA was detected in 6/18 cell or tissue homogenates layered on sucrose density gradients both from patients with SS and patients with normal salivary glands. This method however, although extremely sensitive, is not suitable for epidemiological studies. The present inventors realized that it was desirable to detect proviral DNA which is a much more robust assay, albeit less sensitive. As the original sequence was cloned from a patient with SS, the present inventors tested 97 salivary gland biopsies from patients and controls. Surprisingly, they found only two positives; one being from a patient with RA who also has secondary SS (Rigby et al.; Arthritis and Rheumatism 1997: 40:2016). The present inventors therefore concluded that HRV-5 was unlikely to replicate in salivary glands and so other autoimmune and inflammatory diseases were screened for the presence of HRV-5 proviral DNA sequences. In the course of these new studies, other primer sets were evaluated and from these HRV-5 was found to selectively concentrate in synovial tissues, particularly in inflamed joints.
[0012] However, even with this knowledge, the further characterisation of HRV-5 has only been possible since the design of a particular set of primers (“best” primers) which were more sensitive for detecting HRV-5DNA in clinical tissues than other primers used. It has only been through the use of these primers that further nucleotide sequence has been obtained from positive DNA samples.
[0013] The inventors have now detected HRV-5 proviral DNA in inflamed joints (RA, osteoarthritis (OA), reactive arthritis and psoriatic arthritis) but not normal synovium. Further, HRV-5 proviral DNA has been detected in blood from patients with RA, systemic lupus erythematosus (SLE) and inflammatory bowel diseases. This may be because the virus is tropic for cell types abundant in these tissues such as macrophages or fibroblasts. It is possible that some types of arthritis may be an unusual reaction to a common infection. Table I shows further disease states in which the present inventors has detected HRV-5.
[0014] Therefore, at its most general, the present invention provides materials and methods relating to HRV-5 for use in treatment, diagnosis or therapy of autoimmune diseases and other inflammatory diseases such as arthritis, and SLE.
[0015] In a first aspect the present invention provides a double-stranded nucleic acid molecule (SEQ ID NOS: 1 and 4, 127) which comprises a novel nucleotide sequence which encodes a peptide as shown in FIG. 1 (SEQ ID NOS: 1,2,3,4), FIG. 3 (SEQ ID NO: 5), FIG. 6 (SEQ ID NOS: 8,9,10,11) FIG. 10 (SEQ ID NOS: 12, 13, 14), FIG. 12 (SEQ ID NOS: 13, 15, 16, 17, 18), FIG. 13 (SEQ ID NOS: 19, 20) or FIG. 21, (SEQ ID NO: 103) or variants, mutants or fragments thereof.
[0016] [0016]FIG. 1 shows gag and protease (pro) genes (encoding nucleocapsid, dUTPase and the N-terminal part of protease). FIG. 3 shows the pol gene (encoding RT/RNaseH and integrase). FIG. 6 shows the combined gag and pro sequences as shown in FIGS. 1 and 3. The nucleotide sequence according to the present invention is shown in upper case. FIG. 10 shows additional gag sequence with the nucleocapsid region in lower case.
[0017] [0017]FIG. 21 shows the full determined HRV-5 sequence.
[0018] [0018]FIG. 22 shows the sequence of HRV-5 Gag-PR in an EcoRI digested pBlueScript KS+ vector.
[0019] Further, the present invention provides a nucleic acid molecule which has a nucleotide sequence encoding a polypeptide which includes the amino acid sequence shown in FIGS. 1, 2, 3 , 6 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 18 , 19 , 20 , or 21 , or part thereof. FIG. 2 shows a comparison between the amino acid sequence shown in FIG. 1 (HRV-5) and that obtained from samples from seven individuals (SEQ ID NOS: 21, 22, 23, 24, 25, 26, 27, 28). As can be seen from the figure, natural variation in the HRV-5 amino acid sequence occurs between individuals.
[0020] The coding sequence may be that shown in FIGS. 1, 3, 6 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 18 , 19 , 20 or 21 or it may be a mutant, variant derivative or allele of these sequences. The sequence may differ from that shown by a change which is one or more of addition, insertion, deletion and substitution of one or more nucleotides of the sequence shown. Changes to a nucleotide sequence may result in an amino acid change at the protein level, or not, as determined by the genetic code as shown, for example, in FIG. 2.
[0021] As used herein the term “variant” applies to retroviral sequences which are homologous in the gag, pol, protease, nucleocapsid, RT/RNaseH, integrase or dUTPase genes to the sequence shown in FIG. 1, FIG. 3, FIG. 6, FIG. 10, FIG. 12, FIG. 13, FIG. 14, FIG. 15, FIG. 16, FIG. 18, FIG. 19 or FIG. 21 for example having at least 80%, or at least 85% or at least 90%, preferably 95%, or even more preferably 98% homology to the sequence. The term “fragment” refers to fragments which are large enough to hybridise under stringent conditions to said sequence. Suitably such fragments will be from 20 bases to 1 kilobase in length, and preferably from 400-500 bases in length.
[0022] Generally, nucleic acid according to the present invention is provided as an isolate, in isolated and/or purified form, or free or substantially free of material with which it is naturally associated, such as free or substantially free of nucleic acid flanking the gene in the human genome. Nucleic acid may be wholly or partially synthetic and may include genomic DNA, cDNA or RNA. Where nucleic acid according to the invention includes RNA, reference to the sequence shown should be construed as reference to the RNA equivalent, with U substituted for T.
[0023] Nucleic acid sequences encoding all or part of the protease, gag, pol, integrase, RT/RNaseH, nucleocapsid or dUTPase genes and/or its regulatory elements, such as the LTR, can be readily prepared by the skilled person using the information and references contained herein and techniques known in the art (for example, see Sambrook, Fritsch and Maniatis, “Molecular Cloning, A Laboratory Manual, Cold Spring Harbor Laboratory Press, 1989, and Ausubel et al, Short Protocols in Molecular Biology, John Wiley and Sons, 1992). These techniques include the use of the polymerase chain reaction (PCR) to amplify samples of such nucleic acid, e.g. from genomic sources or chemical synthesis. Modifications to the HRV-5 sequences can be made, e.g. using site directed mutagenesis, to lead to the expression of modified HRV-5 polypeptides or to take account of codon preference in the host cells used to express the nucleic acid.
[0024] In order to obtain expression of the HRV-5 nucleic acid sequences, the sequences can be incorporated in a vector having control sequences operably linked to the HRV-5 nucleic acid to control its expression. Such sequences may optionally include the HRV5 LTR sequences disclosed herein. The vectors may include other sequences such as promoters or enhancers to drive the expression of the inserted nucleic acid, nucleic acid sequences so that the HRV-5 polypeptides are produced as a fusion and/or nucleic acid encoding secretion signals so that the polypeptides produced in the host cell are secreted from the cell. The particular polypeptides can then be obtained by transforming the vectors into host cells in which the vector is functional, culturing the host cells so that the polypeptides are produced and recovering the polypeptides from the host cells or the surrounding medium. Prokaryotic and eukaryotic cells are used for this purpose in the art, including strains of E. coli, yeast, and eukaryotic cells such as COS or CHO cells. The choice of host cell can be used to control the properties of the polypeptides expressed in those cells, e.g. controlling where the polypeptides are deposited in the host cells or affecting properties such as there glycosylation. The vectors and host cells described above each form separate aspects of the present invention.
[0025] PCR techniques for the amplification of nucleic acid are described in U.S. Pat. No. 4,683,195. In general, such techniques require that sequence information from the ends of the target sequence is known to allow suitable forward and reverse oligonucleotide primers to be designed to be identical or similar to the polynucleotide sequence that is the target for the amplification. PCR comprises steps of denaturation of template nucleic acid (if double-stranded), annealing of primer to target, and polymerization. The nucleic acid probed or used as template in the amplification reaction may be genomic DNA, cDNA or RNA. PCR can be used to amplify specific sequences from genomic DNA, specific RNA sequences and cDNA transcribed from mRNA, bacteriophage or plasmid sequences. The HRV-5 nucleic acid sequences provided herein readily allow the skilled person to design PCR primers. References for the general use of PCR techniques include Mullis et al, Cold Spring Harbor Symp. Quant. Biol., 51:263, (1987), Ehrlich (ed), PCR technology, Stockton Press, NY, 1989, Ehrlich et al, Science, 252:1643-1650, (1991), “PCR protocols; A Guide to Methods and Applications”, Eds. Innis et al, Academic Press, New York, (1990).
[0026] Also included within the scope of the invention are antisense oligonucleotide sequences based on the HRV-5 nucleic acid sequences described herein. Antisense oligonucleotides may be designed to hybridize to the complementary sequence of nucleic acid, interfering with the production of polypeptide encoded by a given DNA sequence, or simply the replicative and invasive processes of the retrovirus. The construction of antisense sequences and their use is described in Peyman and Ulman, Chemical Reviews, 90:543-584, (1990), Crooke, Ann. Rev. Pharmacol. Toxicol., 32:329-376, (1992), and Zamecnik and Stephenson, P.N.A.S, 75:280-284, (1974).
[0027] Oligonucleotide probes or primers, as well as the full-length sequence (and mutants, alleles, variants and derivatives) are also useful in screening a test sample containing nucleic acid for the presence of HRV-5, the probes hybridising with a target sequence from a sample obtained from the individual being tested. The conditions of the hybridisation can be controlled to minimise non-specific binding, and preferably stringent to moderately stringent hybridisation conditions are preferred. The skilled person is readily able to design such probes, label them and devise suitable conditions for the hybridisation reactions, assisted by textbooks such as Sambrook et al (1989) and Ausubel et al (1992).
[0028] Binding of a probe to target nucleic acid (e.g. DNA) may be measured using any of a variety of techniques at the disposal of those skilled in the art. For instance, probes may be radioactively, fluorescently or enzymatically labelled. Other methods not employing labelling of probe include examination of restriction fragment length polymorphisms, amplification using PCR, RNAase cleavage and allele specific oligonucleotide probing.
[0029] Probing may employ the standard Southern blotting technique. For instance DNA may be extracted from cells and digested with different restriction enzymes.
[0030] Restriction fragments may then be separated by electrophoresis on an agarose gel, before denaturation and transfer to a nitrocellulose filter. Labelled probe may be hybridised to the DNA fragments on the filter and binding determined. DNA for probing may be prepared from RNA preparations from cells.
[0031] Preliminary experiments may be performed by hybridizing under low stringency conditions various probes to Southern blots of DNA digested with restriction enzymes. Suitable conditions would be achieved when a large number of hybridizing fragments were obtained while the background hybridization was low. Using these conditions nucleic acid libraries, e.g. cDNA libraries representative of expressed sequences, may be searched.
[0032] Those skilled in the art are well able to employ suitable conditions of the desired stringency for selective hybridization, taking into account factors such as oligonucleotide length and base composition, temperature and so on. Generally, specific primers are upwards of 14 nucleotides in length, but not more than 18 to 24. Those skilled in the art are well versed in the design of primers for use processes such as PCR.
[0033] In accordance with the present invention, nucleic acids, e.g. probes or primers, having the appropriate level of sequence homology with the protein coding region of any of the nucleic acid sequences mentioned herein may be identified by using hybridization and washing conditions of appropriate stringency. For example, hybridizations may be performed, according to the method of Sambrook et al., (22) using a hybridization solution comprising: 5× SSC, 5× Denhardt's reagent, 0.5-1.0% SDS, 100 μg/ml denatured, fragmented salmon sperm DNA, 0.05% sodium pyrophosphate and up to 50% formamide. Hybridization is carried out at 37-42° C. for at least six hours. Following hybridization, filters are washed as follows: (1) 5 minutes at room temperature in 2× SSC and 1% SDS; (2) 15 minutes at room temperature in 2× SSC and 0.1% SDS; (3) 30 minutes-1 hour at 37° C. in 1× SSC and 1% SDS; (4) 2 hours at 42-65° C. in 1× SSC and 1% SDS, changing the solution every 30 minutes.
[0034] One common formula for calculating the stringency conditions required to achieve hybridization between nucleic acid molecules of a specified sequence homology is (Sambrook et al., 1989):
T m =81.5° C.+16.6 Log [ Na+]+ 0.41(% G+C )−0.63(% formamide )−600/ #bp in duplex
[0035] As an illustration of the above formula, using [Na+]=[0.368] and 50% formamide, with GC content of 42% and an average probe size of 200 bases, the T m is 57° C. The T m of a DNA duplex decreases by 1-1.5° C. with every 1% decrease in homology. Thus, targets with greater than about 75% sequence identity would be observed using a hybridization temperature of 42° C. Such a sequence would be considered substantially homologous to the nucleic acid sequence of the present invention.
[0036] A further aspect of the present invention provides an oligonucleotide or polynucleotide fragment of the nucleotide sequence shown in FIGS. 1, 3, 6 , 10 , 11 or 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 or 22 or a complementary sequence, in particular for use in a method of obtaining and/or screening nucleic acid. The sequences referred to above may be modified by addition, substitution, insertion or deletion of one or more nucleotides, but preferably without abolition of ability to hybridise selectively with nucleic acid of HRV-5, that is wherein the degree of homology of the oligonucleotide or polynucleotide with one of the sequences given is sufficiently high.
[0037] In some preferred embodiments, oligonucleotides according to the present invention that are fragments of any of the sequences shown in FIGS. 1, 3 6 , 10 , 12 or 13 - 22 are at least about 10 nucleotides in length, more preferably at least about 15 nucleotides in length, more preferably at least about 20 nucleotides in length. Such fragments themselves individually represent aspects of the present invention. Fragments and other oligonucleotides may be used as primers or probes as discussed but may also be generated (e.g. by PCR) in methods concerned with determining the presence in a test sample of HRV-5.
[0038] Methods involving use of nucleic acid in diagnostic and/or prognostic contexts, for instance in determining the presence of HRV-5 are discussed below.
[0039] The present invention also provides polypeptides encoded by the nucleic acid sequences provided in FIGS. 1, 3, 6 , 10 , 12 or 13 - 16 , 18 - 22 .
[0040] The skilled person can use the techniques described herein and others well known in the art to produce large amounts of the nucleocapsid, dUTPase, protease, RT/RNase H and integrase polypeptides, or fragments or active portions thereof, for use as pharmaceuticals, in the developments of drugs and for further study into its properties and role in vivo. Further, also within the scope of the present invention are viral proteins such as superantigens or regulatory proteins which may be produced by HRV-5. Such proteins are usually found close to the 3′ end of the virus. All HRV-5 proteins and polypeptides or fragments thereof will have commercial value apparent to the skilled person, for example as antigens for vaccines, for raising virus-specific antibodies and also for serological assays such as ELISAs and western blots.
[0041] Thus, a further aspect of the present invention provides a polypeptide which has the amino acid sequence shown in FIGS. 1, 2, 3 , 6 , 10 , 11 or 12 , 14 - 16 , 18 - 22 which may be in isolated and/or purified form, free or substantially free of material with which it is naturally associated, such as other polypeptides or such as human endogenous polypeptides other than HRV-5 polypeptide or (for example if produced by expression in a prokaryotic cell) lacking in native glycosylation, e.g. unglycosylated.
[0042] Polypeptides which are amino acid sequence variants, alleles, derivatives or mutants are also provided by the present invention. A polypeptide which is a variant, allele, derivative or mutant may have an amino acid sequence which differs from that given in FIGS. 1, 2, 3 , 6 , 10 , 11 , 12 , 13 - 16 , 18 - 22 by one or more of addition, substitution, deletion and insertion of one or more amino acids as shown in FIG. 2. Each variant shown in FIG. 2 and FIG. 20 forms a separate aspect of the invention. Preferred such polypeptides have HRV-5 function, that is to say have one or more of the following properties: immunological cross-reactivity with an antibody reactive with the polypeptide for which the sequence is given in FIGS. 1, 2, 3 , 6 or 21 ; sharing an epitope with the polypeptide for which the amino acid sequence is shown in FIGS. 1, 2, 3 , 6 , 10 , 11 , 12 , 13 or 21 (as determined for example by immunological cross-reactivity between the two polypeptides).
[0043] A polypeptide which is an amino acid sequence variant, allele, derivative or mutant of the amino acid sequence shown in FIGS. 1, 2, 3 , 6 , 10 , 11 , 12 , 13 or 21 may comprise an amino acid sequence which shares greater than about 50% sequence identity with the sequence shown in FIGS. 1, 2, 3 , 6 , 10 , 11 , 12 , 13 or 21 greater than about 60%, greater than about 70%, greater than about 75%, greater than about 80%, greater than about 85%, greater than about 90% or greater than about 95%. Particular amino acid sequence variants may differ from those shown in FIGS. 1, 2, 3 , 6 , 10 , 11 , 12 or 21 by insertion, addition, substitution or deletion of 1 amino acid, 2, 3, 4, 5-10, 10-20 20-30, 30-50, 50-100, 100-150, or more than 150 amino acids. Examples of variants are shown in FIGS. 2 and 20 each form a separate aspect of the invention.
[0044] Screening for the presence of one or more of these in a test sample has a diagnostic and/or prognostic use, for instance in determining the presence of HRV-5, as discussed below. The present invention also includes active portions, fragments, derivatives of the HRV-5 polypeptides of the invention.
[0045] A “fragment” of an HRV-5 polypeptide means a stretch of amino acid residues of at least about five to seven contiguous amino acids, often at least about seven to nine contiguous amino acids, typically at least about nine to 13 contiguous amino acids and, most preferably, at least about 15, 20 to 30 or more contiguous amino acids. Fragments of an HRV-5 polypeptide sequence may comprise antigenic determinants or epitopes useful for raising antibodies to a portion of the amino acid sequences.
[0046] A polypeptide according to the present invention may be isolated and/or purified (e.g. using an antibody) for instance after production by expression from encoding nucleic acid. Polypeptides according to the present invention may also be generated wholly or partly by chemical synthesis. The isolated and/or purified polypeptide may be used in formulation of a composition, which may include at least one additional component, for example a pharmaceutical composition including a pharmaceutically acceptable excipient, vehicle or carrier. A composition including a polypeptide according to the invention may be used in prophylactic and/or therapeutic treatment as discussed below.
[0047] A polypeptide, peptide fragment, allele, mutant or variant according to the present invention may be used as an immunogen or otherwise in obtaining specific antibodies. Antibodies are useful in purification and other manipulation of polypeptides and peptides, diagnostic screening and therapeutic contexts. This is discussed further below.
[0048] A polypeptide according to the present invention may be used in screening for molecules which affect or modulate its activity or function. Such molecules may be useful in a therapeutic (possibly including prophylactic) context.
[0049] A further important use of the HRV-5 polypeptides is in raising antibodies, or at least antibody binding domains, that have the property of specifically binding to the HRV-5 polypeptides, or fragments or active portions thereof.
[0050] The production of monoclonal antibodies is well established in the art. Monoclonal antibodies can be subjected to the techniques of recombinant DNA technology to produce other antibodies or chimeric molecules which retain the specificity of the original antibody. Such techniques may involve introducing DNA encoding the immunoglobulin variable region, or the complementarity determining regions (CDRs), of an antibody to the constant regions, or constant regions plus framework regions, of a different immunoglobulin. See, for instance, EP-A-184187, GB-A-2188638 or EP-A-239400. A hybridoma producing a monoclonal antibody may be subject to genetic mutation or other changes, which may or may not alter the binding specificity of antibodies produced.
[0051] The provision of the novel HRV-5 polypeptides enables for the first time the production of antibodies able to bind it specifically. Accordingly, a further aspect of the present invention provides an antibody able to bind specifically to the polypeptide whose sequence is given in FIGS. 1, 2, 3 , 6 , 10 , 11 , 12 , 13 or 21 . Such an antibody may be specific in the sense of being able to distinguish between the polypeptide it is able to bind and other human endogenous polypeptides for which it has no or substantially no binding affinity (e.g. a binding affinity of about lOOOx worse). Specific antibodies bind an epitope on the molecule which is either not present or is not accessible on other molecules. Antibodies according to the present invention may be specific for the wild-type polypeptide. Antibodies according to the invention may be specific for a particular mutant, variant, allele or derivative polypeptide as between that molecule and the wild-type HRV-5 polypeptides, so as to be useful in diagnostic and prognostic methods as discussed below. Antibodies are also useful in purifying the polypeptide or polypeptides to which they bind, e.g. following production by recombinant expression from encoding nucleic acid.
[0052] Preferred antibodies according to the invention are isolated, in the sense of being free from contaminants such as antibodies able to bind other polypeptides and/or free of serum components. Monoclonal antibodies are preferred for some purposes, though polyclonal antibodies are within the scope of the present invention.
[0053] Antibodies may be obtained using techniques which are standard in the art. Methods of producing antibodies include immunizing a mammal (e.g. mouse, rat, rabbit, horse, goat, sheep or monkey) with the protein or a fragment thereof. Antibodies may be obtained from immunized animals using any of a variety of techniques known in the art, and screened, preferably using binding of antibody to antigen of interest. For instance, Western blotting techniques or immunoprecipitation may be used (Armitage et al, Nature, 357:80-82, 1992). Isolation of antibodies and/or antibody-producing cells from an animal may be accompanied by a step of sacrificing the animal.
[0054] As an alternative or supplement to immunizing a mammal with a peptide, an antibody specific for a protein may be obtained from a recombinantly produced library of expressed immunoglobulin variable domains, e.g. using lambda bacteriophage or filamentous bacteriophage which display functional immunoglobulin binding domains on their surfaces; for instance see WO92/01047. The library may be naive, that is constructed from sequences obtained from an organism which has not been immunized with any of the proteins (or fragments), or may be one constructed using sequences obtained from an organism which has been exposed to the antigen of interest.
[0055] Antibodies according to the present invention may be modified in a number of ways. Indeed the term “antibody” should be construed as covering any binding substance having a binding domain with the required specificity. Thus the invention covers antibody fragments, derivatives, functional equivalents and homologues of antibodies, including synthetic molecules and molecules whose shape mimics that of an antibody enabling it to bind an antigen or epitope.
[0056] Exemplary antibody fragments, capable of binding an antigen or other binding partner are the Fab fragment consisting of the VL, VH, C1 and CH1 domains; the Fd fragment consisting of the VH and CH1 domains; the Fv fragment consisting of the VL and VH domains of a single arm of an antibody; the dAb fragment which consists of a VH domain; isolated CDR regions and F(ab′)2 fragments, a bivalent fragment including two Fab fragments linked by a disulphide bridge at the hinge region. Single chain Fv fragments are also included.
[0057] Humanized antibodies in which CDRs from a non-human source are grafted onto human framework regions, typically with the alteration of some of the framework amino acid residues, to provide antibodies which are less immunogenic than the parent non-human antibodies, are also included within the present invention
[0058] A hybridoma producing a monoclonal antibody according to the present invention may be subject to genetic mutation or other changes. It will further be understood by those skilled in the art that a monoclonal antibody can be subjected to the techniques of recombinant DNA technology to produce other antibodies or chimeric molecules which retain the specificity of the original antibody. Such techniques may involve introducing DNA encoding the immunoglobulin variable region, or the CDRs, of an antibody to the constant regions, or constant regions plus framework regions, of a different immunoglobulin. See, for instance, EP-A-184187, GB-A-2188638 or EP-A-0239400. Cloning and expression of chimeric antibodies are described in EP-A-0120694 and EP-A-0125023.
[0059] Hybridomas capable of producing antibody with desired binding characteristics are within the scope of the present invention, as are host cells, eukaryotic or prokaryotic, containing nucleic acid encoding antibodies (including antibody fragments) and capable of their expression. The invention also provides methods of production of the antibodies including growing a cell capable of producing the antibody under conditions in which the antibody is produced, and preferably secreted.
[0060] The present invention also provides protein antigens obtained from the sequences provided herein. The protein antigens may be used in the preparation of vaccines. If the purified protein is not antigenic per se, it can be bound to a carrier to make the protein immunogenic. Carriers include bovine serum albumin, keyhole limpet hemocyanin and the like. Vaccination can be conducted in conventional fashion. For example, the antigen, whether a viral particle or a protein, can be used in a suitable diluent such as water, saline, buffered salines, complete or incomplete adjuvants. The immunogen may be administered using standard techniques for antibody induction, such as by subcutaneous administration of a physiologically compatible, sterile solutions containing inactivated or attenuated virus particles or antigens.
[0061] As a further aspect, the present invention provides agents for use in treatment, diagnosis and therapy of autoimmune and other inflammatory diseases such as arthritis and SLE associated with HRV-5.
[0062] The HRV-5 polypeptides, antibodies, peptides and nucleic acid of the invention described above as well as those derived from the nucleic acid and amino acid sequences shown in FIGS. 1, 2, 3 , 6 , 10 , 11 , 12 , 13 or 21 can be formulated in pharmaceutical compositions. These compositions may comprise, in addition to one of the above substances, a pharmaceutically acceptable excipient, carrier, buffer, stabilizer or other materials well known to those skilled in the art. Such materials should be non-toxic and should not interfere with the efficacy of the active ingredient. The precise nature of the carrier or other material may depend on the route of administration, e.g. oral, intravenous, cutaneous or subcutaneous, nasal, intramuscular, intraperitoneal routes. The invention provides methods of treatment of autoimmune or other inflammatory diseases involving, for example, the application of inhibitors of retroviral replication such as inhibitors of reverse transcription (such chain terminators, for example zidovudine) and protease inhibitors or other anti-viral drugs. Further examples include inhibitors of integrase or dUTPase activity or inhibitors of accessory proteins such as regulatory proteins which may be produced by the virus.
[0063] For use in these methods, the above-mentioned agents may be suitably administered in the form of a pharmaceutical composition in which they are combined with a pharmaceutically acceptable carrier or diluent. Such compositions form a further aspect of the invention.
[0064] Suitable pharmaceutically acceptable carriers include solid and liquid carriers such as water, aqueous ethanol or the like, as are conventional in the art. The form of the composition may be suitable for oral, topical or parenteral use. Suitable forms of the composition include tablets, capsules, syringes, creams, suspensium, solutions, reconstitutable powders and sterile forms for injection or infusions. Other conventional pharmaceutical acceptable materials such as diluents, binders, preservative etc may be included.
[0065] The agent is administered in a therapeutically effective amount. The precise dosage will depend upon the particular agent being employed. The nature of the disease being located as well as the patient and can be determined by a clinician in the usual manner.
[0066] The agents may be capable of protecting a patient immunized therewith against infection or the consequence of infection by the corresponding wild-type virus.
[0067] With regard to diagnosis, wild-type virus may be detected in tissue samples using an assay system developed from knowledge of HRV-5. For example, the present invention provides the diagnosis of autoimmune and other inflammatory diseases, particularly arthritis, by use of a specific binding member such as (a) nucleic acid hybridizable with a nucleic acid associated with wild-type HRV-5; (b) a substance comprising an antibody binding domain with specificity for one or more epitopes or sequences characteristic of polypeptide expressed by the wild-type HRV-5.
[0068] Where the specific binding member comprises nucleic acid, the member may simply be used as a specific probe in accordance with standard techniques and procedures. Alternatively, the specific binding member may comprise a pair of oligo- or polynucleotide sequences for use in an amplification technique such as PCR.
[0069] In particular, the present invention provides oligonucleotide primer pairs for amplification of polynucleotide sequences (be they in the form of DNA, RNA, single-stranded or double-stranded) which comprises, or is derived from, the nucleotide sequence of HRV-5 as shown in FIGS. 1 to 6 , 10 to 13 and 14 - 22 .
[0070] The primer pairs may be designed by use of the sequence information provided herein. Having increased the copy number of polynucleotide sequence associated with HRV-5, the amplified sequences may be detected by standard methods such as the provision of radioactive nucleotides for inclusion in the sequences being copied, ethidium bromide staining, sequencing and hybridization probing.
[0071] The present invention therefore provides a method for diagnosing autoimmune diseases, particularly arthritis, by taking a suitable sample from a patient, for example, the synovial membrane, and detecting the presence or absence of HRV-5 by adding to the sample suitable specific binding members as described above. If the specific binding member was a pair of oligonucleotide primers, the method may also include the steps of adding other standard ingredients for carrying out a polynucleotide sequence amplification (an amplification based on a DNA template or an RNA template), and applying standard hybridization, elongation and denaturation or strand separation conditions to amplify any new polynucleotide sequence positioned between the two primers and looking for the presence or absence of an amplified product the determine the presence or absence of HRV-5.
[0072] Generally, as mentioned earlier, specific primers are upwards of 14 nucleotides in length, but not more than 18-24.
[0073] A further aspect of the present invention provides an oligonucleotide or polynucleotide fragment of the nucleotide sequences disclosed herein, or a complementary sequence, in particular for use in a method of obtaining and/or screening nucleic acid. The sequences referred to above may be modified by addition, substitution, insertion or deletion of one or more nucleotides, but preferably without abolition of ability to hybridize selectively with nucleic acid characteristic of HRV-5, that is wherein the degree of homology of the oligonucleotide or polynucleotide with one of the sequences given is sufficiently high.
[0074] Oligonucleotides according to the present invention that are fragments of any of the sequences disclosed herein are at least about 10 nucleotides in length, more preferably at least about 15 nucleotides in length, more preferably at least about 20 nucleotides in length. Such fragments themselves individually represent aspects of the present invention.
[0075] Preferably oligonucleotide primers according to the present invention comprise the nucleic acid sequence:
A 5′ - TCAGAAGGTGATTGGCCGAAGTCA - 3′; (SEQ ID NO: 29) 5′ - GGTCCTCATTTGTTAATGTCAGTC - 3′; (SEQ ID NO: 30) or B 5′ - CCCTTCAGCCAGGAGATAATACT - 3′; (SEQ ID NO: 31) 5′ - ATGTCTCTTCCCCATAATGTGATG - 3′; (SEQ ID NO: 32)
[0076] Preferably the above two sets of primers are used in nested PCR assay with set A being first stage primers and set B being second set primers.
[0077] The present invention provides further primer sets for use in assays described above, comprising the nucleic acid sequence:
C 5′ - CCATCACATTATGGGGAAGAGACA - 3′; (SEQ ID NO: 33) 5′ - GAATGTCTTGTTCATGTAGAGGTAT - 3′; (SEQ ID NO: 34) D 5′ - GCCATTGTCATGGCTGGACAACAA - 3′; (SEQ ID NO: 35) 5′ - CCTTCAGATCGAGTACTATTAATGG - 3′; (SEQ ID NO: 36)
[0078] wherein set C may be used as first stage primers and set D may be used as second set primers.
E 5′ - GCCATGACACCATCAAGAAGTGCT - 3′; (SEQ ID NO: 37) 5′ - TGCTTTGGGATCATAGTAGGAAC - 3′; (SEQ ID NO: 38) F 5′ - ATTAGGCTCCAGAGAAGGCAGAAG - 3′; (SEQ ID NO: 39) 5′ - CCGGGAGTCCAGGTTGTAATG - 3′; (SEQ ID NO: 40)
[0079] wherein set E may be used as first stage primers and set F may be used as second set primers.
[0080] Using a nested PCR technique, the applicants have found that samples containing as little as 1-10 molecules of viral DNA per sample can be detected. When using this technique, care should be taken with controls in order to avoid false positives.
[0081] The above sequences may also be used to design longer nucleotide probes useful in detecting HRV-5 sequences. Additional nucleotide bases (e.g. N=0 to 200 where N may be any nucleotide) may be added to either end of these primers. Preferably, these additional nucleotide bases are derived from the sequence shown in FIG. 12 or 21 (SEQ ID NOS: 15, 18 and 127).
[0082] Diagnostic tests of infection by the virus based on immunological methods, such as peptide and protein enzyme linked immunosorbent assay (ELISAs), and western blots, as well as on PCR and other DNA or RNA detection methods, form a further aspect of the invention.
[0083] As described above, viral antigens form a further aspect of the invention. For instance, the retrovirus or viral antigens can be used to raise antibodies which may be monoclonal or polyclonal in a conventional manner.
[0084] These antibodies can be used to screen samples such as synovial membrane samples and other tissues or cell cultures (e.g. peripheral blood cells) taken from patients suspected of suffering from, for example, arthritis and other diseases, by for example immunohistochemistry, for the presence of virus. Therefore the invention also provides an antibody which binds an antigen of the above described as well as diagnostic kits which contain said antibody.
[0085] Further suitable antigens which can be used to raise antibodies are those containing epitopes from the matrix (MA) and capsid (CA) and other gag proteins as well as env, pro, pol, dUTPase, RT/RNase H, integrase, viral regulatory proteins or superantigens.
[0086] Viral antigens according to the present invention may be used to raise an immune response in a mammalian subject, preferably a human subject and as such be used in the production of vaccines. Conventional vaccines comprise either infectious (“live”) or non-infectious (“killed”) virus particles. Upon administration, all vaccines should have the following properties: a) cause less severe disease than the natural infection; b) stimulate effective and long-lasting immunity, and c) be genetically stable. The production of vaccines is now well developed in the art. With killed virus vaccines, it can be a problem to produce sufficient material cheaply and ensure that no infectious virus survives the inactivation procedure. Therefore, DNA technology may be used to identify parts of the viral genome that encodes particular viral proteins against which protective immunity may be directed. This may be achieved by a)expression of the entire protein, e.g. GAG, CA, or ENV, or any other viral proteins, particularly regulatory proteins; expression of a fragment of the protein containing the antigenic site; or c) chemical synthesis of a peptide which contains the antigenic site. For a) and b) viral nucleic acid (e.g. FIGS. 1, 3, 6 , 10 , 12 , 13 or 21 variants or fragments thereof) may be excised and inserted into an appropriate expression vector, together with control (promoter, stop and polyadenylation) signals. In this way there is a small part of the viral genome, by definition non-infectious, which by insertion into a host cell growing on an industrial scale will produce very large amounts of protein very cheaply. Bacterial expression systems may be used. However, in order to accomplish eukaryotic-type cotranslational and post-translational modifications, such as glycosylation and proteolytic cleavage, eukaryotic cells may be used.
[0087] Live vaccines evoke the most effective immunity and therefore a nucleotide sequence encoding the antigenic site of interest may be inserted into a pre-existing live virus, so that it is expressed naturally as the virus multiplies. This has previously been achieved for viruses including influenza, rabies, herpes simplex type I and hepatitis B viruses, using vaccinia virus as the live vaccine.
[0088] The present invention provides vaccines comprising nucleotide sequences or polypeptide sequences as disclosed above. Further, the present invention provides methods of treating a mammalian subject using such vaccines so as to raise an immune response.
[0089] In addition, the invention provides methods of detecting antibodies to viral proteins. These methods are useful in disease diagnosis, including RA, systemic lupus erythematosus and other autoimmune diseases, for example, see Table I.
[0090] Particularly preferred is an ELISA for detection of antibodies to the virus peptides or proteins. Specific assay devices of the invention comprise a viral antigen of the retrovirus of the invention immobilized on a support. Suitably purified recombinant viral antigens are used. These antigens may be expressed in eukaryotic or prokaryotic cells such as bacterial, yeast or mammalian cells, preferably bacterial cells. Affinity purified anti-viral antigen sera such as rabbit sera can be used to capture antigen for immobilization.
[0091] In addition cultured virus could form the basis of a virus isolation assay as is known in the art. Methods which may be useful in the culture of the virus include direct culture methods (such as those described by Weiss R. A., Chpt 3 in Weiss et al (eds), 1982 RNA Tumor Viruses (Cold Spring Harbor Laboratory press) and Brookes et al., Brit. J. Rheum. 1995 34: 226-231), co-cultivation methods, for example by culturing tissue samples with a target cell line. In such a method, the tissue samples is either digested with trypsin or homogenized with a mortar and pestle. This is then placed into a flask with typically 105-106 tissue culture cells.
[0092] Suitable tissue cells which are permissive for viral growth may include T and B lymphocytes, monocytes, macrophages, fibroblasts and epithelial cells.
[0093] Alternatively, virus may be cultured by xenografting virus into suitably nude or severe combined immunodeficient (SCID) mice. Using this method, tissue samples such as synovial membrane, may be implanted subcutaneously for example into the mid-flank of an anaesthetized mouse. After this, evidence of virus growth may be assessed using PCR for RNA and/or DNA or by the sensitive RT assay described by Silver et al., Nucleic Acids Res. 1993, 21: 3593-3594, and the virus isolated.
[0094] The association of HRV-5 with autoimmune diseases and inflammatory bowel diseases as discussed above, allows for screening methods to determine agents such as chemical compounds which are effective in the treatment of these diseases. Such screening methods, together with agents discovered as a result of them, form a further aspect of the invention.
[0095] The present invention further provides a vector for use in gene therapy comprising disabled HRV-5. Vectors such as viral vectors have been used in the prior art to introduce gene into a wide variety of different target cells. Typically the cells are exposed to the target cells so that transfection can take place in a sufficient proportion of the cells to provide a useful therapeutic or prophylatic effect from expression of the desired polypeptide. The transfected nucleic acid may be permanently incorporated into the genome of each of the targeted cells, providing long lasting effect, or alternatively, the treatment may have to be repeated periodically. Disabled HRV-5 virus vectors may be prepared by deletion or inactivation of one or more specific viral proteins, by standard methods apparent to the skilled person (Naldini zufferey R. et al Nature Biotechnol. 1997 15:871-875).
[0096] Such vectors may be utilized to deliver nucleic acids encoding therapeutic molecules to tissues which are selectively infected by HRV-5. In this embodiment, the LTR of the virus is ligated upstream of a therapeutic gene of interest. A helper virus is co-administered with this construct to a target cell in vitro. Such helper viruses enable replication of defective viruses by providing structural proteins and enzymes in trans during the mixed infection and thereby generate viral particles capable of a single round of infection. A suitable helper virus allows LTR-gene constructs that lack almost all the viral genome (which has been replaced with the therapeutic gene of interest) to infect target cells when subsequently administered in vivo.
[0097] Specific transgenes or therapeutic genes for use in the vectors of the invention can fall into several categories. The identity of such genes and their GenBank Accession numbers are provided below. These include, without limitation, cytokines (e.g., interleukin-2 (GenBank Accession code U25676), and IL-7 (XM — 005266)), tumor suppressor genes (e.g., p53 (P04637) and suicide′genes such as herpes simplex virus type 1 thymidine kinase (V00470). Other transgenes may be functional copies of a single gene where the disease is due to a defective or mutated copy of this gene. Example of such diseases (and the therapeutic gene) are adenosine deaminase deficiency (adenosine deaminase, NM — 000022), mucopolysaccharidosis type II (iduronate-2-sulfatase, XM — 018134), and familial hypercholesterolemia (low density lipoprotein receptor, NM — 000527) and cystic fibrosis (cystic fibrosis transmembrane conductance regulator, M28668).
[0098] The ability of HRV-5 to infect synovial membrane may confer unique properties on HRV-5 derived vectors as gene vectors for treatment of rheumatoid arthritis. Suitable transgenes in this case may be cytokines or related immunomodulatory molecules such as the interleukin-1 receptor antagonist protein (IRAP, GenBank code NM — 000577).
[0099] The vectors described above will also be useful for the generation of cell lines and/or transgenic animals expressing heterologous genes of interest.
BRIEF DESCRIPTION OF THE DRAWINGS
[0100] Aspects and embodiments of the invention will now be described, by way of example, with reference to the accompanying figures. Further aspects and embodiments will be apparent to those skilled in the art. All documents mentioned in this text are incorporated herein by reference.
[0101] [0101]FIG. 1 shows the nucleotide sequence (SEQ ID NOS: 1 and 4) and derived amino acid sequence of HRV-5 nucleocapsid and dUTPase coding regions (SEQ ID NOS: 2 and 3). Both strands of the nucleotide sequence of the new sequence are shown with the deduced amino acid sequences of the gag and pro genes. The previously published region is shown in lower case. Nucleotides 1-26 are derived from the degenerate primer (8532) and so may not represent the genuine sequence of HRV-5 at these positions. Nucleotides 884-907 represent specific primer 4146 which was also used to amplify this region.
[0102] [0102]FIG. 2 shows an alignment of the deduced nucleocapsid amino acid sequences of HRV-5 from seven individuals (SEQ ID NOS: 22-29). The sequences are shown aligned with the prototype HRV-5 clone. A dash (-) indicates identity with HRV-5 and a dot (.) indicates a gap introduced into the alignment to allow for insertions and deletions. The sequence marked NC20 was amplified from DNA from the blood of a patient with rheumatoid arthritis. The other sequences (NC2-NC11) were amplified from DNA from the blood of patients with SLE.
[0103] [0103]FIG. 3 shows the sequence of the HRV-5 pol gene.
[0104] Both strands of DNA are shown (SEQ ID NOS: 5 and 7). The region of HRV-5 pol downstream of the previously published sequence is shown. The previously published sequence is shown in lower case. Note that nucleotides 1877-1896 are derived from the degenerate integrase primer used to clone this fragment and so may not represent the genuine sequence of the virus in this region.
[0105] [0105]FIG. 4 shows the deduced amino acid sequence of a DNA sequence used as a sequence tag and designated Sjo-1 and its alignment with other, known retroviral sequences (SEQ ID NOS: 41 and 48).
[0106] [0106]FIG. 5 is a nucleotide sequence and translation of JC96 showing two open reading frames (SEQ ID NOS: 49-52). The protease (PR) open reading frame is frame a and the reverse transcriptase (RT) open reading frame is frame c.
[0107] [0107]FIG. 6 shows the sequence data of FIGS. 1, 2 and 3 combined (SEQ ID NOS: 8, 9, 10 and 11). The novel sequence shown in upper case.
[0108] [0108]FIG. 7 shows alignments of deduced PR and RT amino-acid sequences of clones of JC96 from five individuals (SEQ ID NOS: 53-57). Note that the JC96 sequence extends further 5′ than the other clones. This is because JC96 was obtained using degenerate primers whereas the other clones were generated using internal specific primers based on the JC96 sequence.
[0109] [0109]FIG. 8 shows a diagram of Indirect ELISA using His-myc tagged proteins.
[0110] [0110]FIG. 9 shows a diagram of Capture ELISA using His-myc tagged proteins.
[0111] [0111]FIG. 10 shows sequence of a fragment of the HRV-5 Gag gene (SEQ ID NOS: 12 and 14). The nucleocapsid region (described in Example 3 and FIG. 1) is shown in lower case. The remaining sequence was cloned in 5 stages. The region between the Eco RI site (at nucleotide 1205, marked in bold) and the nucleocapsid was cloned by Vectorette PCR. The region between the Cla I site (nucleotide 262, marked in bold) and the Eco RI site was cloned by a separate Vectorette PCR. Nucleotides 1 to 461 were cloned in 3 stages using the rapid amplification of cDNA ends (RACE) method adapted for use on double stranded genomic DNA.
[0112] [0112]FIG. 11 shows CLUSTALW multiple sequence alignment of HRV-5 CA protein with CA proteins of other B and D-type retroviruses (SEQ ID NOS: 58, 59, 60 and 61). It should be noted that there is generally very little primary sequence similarity in this protein between different retroviruses. The most conserved region is known as the major homology region (MHR, Craven et al, 1995, J. Virology, 69: 4213-4227) and is indicated in bold typeface. Conserved residues and conservative substitutions are indicated by * and : respectively.
[0113] [0113]FIG. 12 shows the full HRV-5 sequence (gag-pro-pol; SEQ ID NOS: 13, 15, 16, 17, and 18).
[0114] [0114]FIG. 13 shows the sequence of the deposited HRV5gagpol 17.1 clone aligned with the consensus HRV-5 sequence from FIG. 12 (SEQ ID NOS: 19 and 20). Matches between the 2 sequences are marked with (|), gaps are indicated by a dash (-).
[0115] [0115]FIG. 14 shows a nucleic acid sequence of the Gag3fragment (SEQ ID NO: 92) with the deduced amino acid sequence (SEQ ID NO: 93). Only the coding (+) strand is shown. Nucleotides in lower case were also present in a previously cloned fragment.
[0116] [0116]FIG. 15 shows a nucleic sequence of the Gag4 fragment (SEQ ID NO: 94) with deduced amino acid sequence (SEQ ID NO: 95). Only the coding (+) strand is shown. Nucleotides in lower case were also present in the Gag3 fragment.
[0117] [0117]FIG. 16 shows a nucleic acid sequence of the Gag5fragment (SEQ ID NO: 96) with deduced amino acid sequence (SEQ ID NO: 97). Only the coding (+) strand is shown. Nucleotides in lower case were also present in the Gag4 fragment.
[0118] [0118]FIG. 17 shows a nucleic acid sequence of the Gag6 fragment (SEQ ID NO: 98). Only the forward (+) strand is shown. Nucleotides in lower case were also present in the Gag5 fragment.
[0119] [0119]FIG. 18 shows a nucleic acid sequence of the IN2 fragment (SEQ ID NO: 99) with deduced amino acid sequence (SEQ ID NO: 100). Only the coding (+) strand is shown. Nucleotides in lower case were also present in a previously cloned fragment.
[0120] [0120]FIG. 19 shows a nucleic acid sequence of the IN3 fragment (SEQ ID NO: 101) with deduced amino acid sequence (SEQ ID NO: 102). Only the coding (+) strand is shown. Nucleotides in lower case were also present in the IN2 fragment. Nucleotides in lower case and italics are not HRV-5 but are human DNA present downstream of the integration site.
[0121] [0121]FIG. 20 shows an alignment of the Gag-PR region of the reference strain with another clone obtained from the same patient.
[0122] [0122]FIG. 21 shows the nucleotide sequence of a representative clone of HRV-5 is shown (GenBank Accession AF******; SEQ ID NO: 127). This clone was assembled from several PCR fragments. Open reading frames for gag, pro and pol are shown (SEQ ID NO: 103) and potential heptanucleotide frameshifting sites between the ORFs are boxed. The putative PBSHIS and polypurine tract are marked in bold as are specific amino acid motifs discussed in the text (PPXY in gag, DTG in PR and YMDD in RT).
[0123] [0123]FIG. 22 shows the sequence of an HRV-5 Gag-PR product in a EcoRI digested pBlueScript KS+ vector (SEQ ID NO: 104).
[0124] [0124]FIGS. 23A and 23B are a series of micrographs and Western blots. Retroviral Gag proteins were tagged with green fluorescent protein (GFP) and expressed in 293T cells. FIG. 23A: Gag-GFP produced in 293T cells gives a cytoplasmic speckled pattern with HRV5 which is similar to that obtained for MPMV and unlike the cell surface staining seen with MLV Gag. FIG. 23B: Extracts from the cells shown in FIG. 23A were fractionated by sucrose density gradient centrifugation. As with MLV and MPMV, HRV-5 appears to form core particles with a density around 1.22 g/ml, the typical density of retroviral cores. Therefore, HRV-5 behaves as expected for a B/D type retrovirus in this system. Arrows indicate expected size of Gag-GFP fusion proteins (approx. 90 kDa).
DETAILED DESCRIPTION OF THE INVENTION
EXAMPLE 1
[0125] Development of Specific PCR Assays for HRV-5.
[0126] Three nested PCR assays specific for HRV-5 were developed. These assays each used primer sets derived from different regions of JC96 (Griffiths et al., 1997 J. Virol. vol. 71 pp. 2866-2872). Optimal PCR conditions and the sensitivity of each primer set were determined using a plasmid which contained the cloned sequence serially diluted in the presence of 500 ng of human genomic DNA. Under optimal conditions, all primer sets were found to have a sensitivity of nominally 1 molecule of viral DNA. Since 500 ng of human DNA represents the DNA content of approximately 75,000 cells, these primer sets should each be sufficiently sensitive to detect 1provirus in 75,000 cells.
[0127] The primer sets were:
[0128] Assay 1
[0129] First stage primers:
[0130] 4143 5′- TCAGAAGGTGATTGGCCGAAGTCA-3′; (SEQ ID NO: 29)
[0131] 4144 5′-GGTCCTCATTTGTTAATGTCAGTC-3′; (SEQ ID NO: 30)
[0132] Conditions: initial denaturation at 94° C., 4 mins followed by 40 cycles of 94° C., 45 secs; 52° C., 45 secs; 72° C., 45secs. One microlitre transferred to second stage.
[0133] Second stage primers:
[0134] 4145 5′-CCCTTCAGCCAGGAGATAATACT-3′; (SEQ ID NO: 31)
[0135] 4146 5′-ATGTCTCTTCCCCATAATGTGATG-3′; (SEQ ID NO: 32)
[0136] Conditions as first stage but for only 30 cycles.
[0137] Assay 2
[0138] First stage primers:
[0139] 3493 5′-CCATCACATTATGGGGAAGAGACA; (SEQ ID NO: 33)
[0140] 3496 5′-GAATGTCTTGTTCATGTAGAGGTAT; (SEQ ID NO: 34)
[0141] Conditions: initial denaturation at 94° C., 3 mins followed by 40 cycles of 94° C., 45 secs; 52° C., 45 seas; 72° C., 30 seas. One microliter transferred to second stage.
[0142] Second stage primers:
[0143] 3494 5′- GCCATTGTCATGGCTGGACAACAA; (SEQ ID NO: 35)
[0144] 3495 5′- CCTTCAGATCGAGTACTATTAATGG; (SEQ ID NO: 36)
[0145] Conditions as first stage but for only 30 cycles.
[0146] Assay 3
[0147] First stage primers:
[0148] 0831 5′-GCCATGACACCATCAAGAAGTGCT; (SEQ ID NO: 37)
[0149] 2061 5′-TGCTTTGGGATCATAGTAGGAAC; (SEQ ID NO: 38)
[0150] Conditions: initial denaturation at 94° C., 3 mins followed by 25 cycles of 94° C., 30 seas; 60° C., 60 seas; 72° C., 30seas. One microlitre transferred to second stage.
[0151] Second stage primers:
[0152] 2062 5′-ATTAGGCTCCAGAGAAGGCAGAAG; (SEQ ID NO: 39)
[0153] 2063 5′-CCGGGAGTCCAGGTTGTAATG; (SEQ ID NO: 40)
[0154] Conditions: initial denaturation at 94° C., 3 mins followed by 25 cycles of 94° C., 45 seas; 58° C., 60 seas; 72° C., 30 secs.
[0155] For each PCR one fifth of the reaction products were analysed by agarose gel electrophoresis.
EXAMPLE 2
[0156] Detection of HRV-5 in Inflamed Joints
[0157] In preliminary experiments, each PCR assay was used to test a number of human DNA samples. Although the different PCR assays had similar sensitivities, surprisingly, primer set 1 (SEQ ID NOS: 29, 30) was found to detect HRV-5 sequences in more human DNA samples than did the other primer sets, i.e. many DNA samples found to be positive by assay 1 were negative using assays 2 and 3. This indicated that assay 1 is more sensitive for detecting HRV-5 DNA in clinical tissue samples than the other assays. This primer set (SEQ ID NOS: 29 and 30) was therefore used to screen a larger number of human DNA samples from a variety of tissues and diseases (Table 1).
TABLE 1 Frequency of detection of HRV-5 proviral DNA in different tissue samples. Samples Samples Tissue Disease tested positive Synovium Rheumatoid arthritis 25 12 reactive arthritis 5 3 Osteoarthritis 5 3 Psoriatic arthritis 2 2 Ankylosing spondylitis 1 0 Normal 7 0 Salivary Sjögren's syndrome 26 0 gland Normal 4 0 Lymph node 27 0 Non-malignant Bone marrow Miscellaneous 31 0 Blood Rheumatoid arthritis 26 3 SLE 56 11 Osteoarthritis 3 1 Normal 67 1 Bowel Crohn's disease 10 1 Ulcerative colitis 9 8
[0158] Of 38 synovial membranes studied from patients with various arthropathies, 20 were positive for HRV-5 proviral DNA (53%). Positive samples were identified from patients with rheumatoid arthritis, osteoarthritis and psoriatic arthritis. Seven normal synovial membranes were negative. In addition, DNA from 27 benign lymph nodes, 26 salivary gland biopsies from patients with primary Sjogren's syndrome, 4 normal salivary glands and 31 bone marrow biopsies were negative. Of 152 peripheral blood DNA samples tested, 16 (8%) were positive (3/26 rheumatoid arthritis, 11/56 systemic lupus erythematosus (SLE), 1/3 osteoarthritis and 1/67 normal blood).
[0159] The results of this PCR screen therefore indicate that HRV-5 can rarely be detected in most human DNAs, reaching a level of 1-2% in normal blood. Exceptions are in inflamed synovia where the rate of detection is >50% and in blood of patients with joint diseases and SLE.
EXAMPLE 3
[0160] Cloning of the Nucleocapsid Region of HRV-5.
[0161] DNA samples found to be positive for HRV-5 sequences were used to amplify a region upstream of the known sequence of the virus. This PCR utilised a degenerate primer based on the zinc finger sequence motif conserved among retroviral nucleocapsid proteins. This degenerate primer was used in a hemi-nested PCR with reverse primers (from Assay 1) specific for the protease region of HRV-5. Due to the limited amounts of DNA in the samples available for study and the low abundance of HRV-5 in these DNA samples, DNA from different sources was pooled in order to increase the amount of target HRV-5 DNA in the PCR and thereby increase the chances of a successful amplification. The sources of the DNA were normal blood from an apparently normal subject and salivary gland DNA from a patient with rheumatoid arthritis.
[0162] The primers used were:
8532 5′- TGYTTYAARTGYGGIMRIMMIGGICA; (SEQ ID NO: 62) 4144 5′- GGTCCTCATTTGTTAATGTCAGTC; (SEQ ID NO: 30) 4146 5′- ATGTCTCTTCCCCATAATGTGATG; (SEQ ID NO: 32)
[0163] (where Y=C or T, R=A or G, M=A or C and I=inosine)
[0164] Approximately 1 μg of genomic DNA from each source were added to a 50 μl PCR reaction containing 10 mM Tris-Cl pH 8.3, 50 mM KCl, 2 mM MgCl2, 200 μM each dNTP, 2.5 units Taq polymerase (Qiagen) and 20 pmol of primers 8532 and 4144. The reactions were amplified on a Stratagene Robocycler Thermal cycler for 40 cycles of 94° C. 1 min, 42° C. 1 min 30 secs, 72° C. 3 mins with an initial denaturation at 94° C. for 3 mins. Three microliters of the products of this PCR were then reamplified using primers 8532 and 4146 for 40 cycles of 94° C. 1 min 10 secs, 42° C. 1 min 10 secs, 72° C. 3 mins with an initial denaturation at 94° C. for 3 mins. The products of this PCR were cloned into pBluescript using standard methods. Several plasmid clones were sequenced and a consensus found (FIG. 1).
EXAMPLE 4
[0165] Amplification of HRV-5 Nucleocapsid Sequences from Patients with RA and SLE
[0166] DNA from patients with RA and SLE was tested for the presence of HRV-5 nucleocapsid sequences using nested PCR with primers specific for this region of HRV-5.
[0167] In the first stage, PCR, DNA was amplified with primers:
[0168] NCF3 5′-GCAGGGGCATCTAATGAGGGAAT-3′; (SEQ ID NO: 63)
[0169] NCR1 5′-CTGAAATTGTTTCYGCCCTCACCT-3′; (SEQ ID NO: 64)
[0170] wherein Y is a C or a T.
[0171] Conditions: initial denaturation at 94° C., 4 mins followed by 40 cycles of 94° C., 45 secs, 60° C., 45 secs; 72° C., 45 secs. One microliter of the products transferred to second stage.
[0172] Second stage primers:
NCF4 5′ - AGATTTCCAGCCCGAGATCGGCAG -3′; (SEQ ID NO: 65) NCR2 5′ - TGTGGCCCCATTTGAGGTGTTAG -3′; (SEQ ID NO: 66)
[0173] Conditions at first stage but for only 30 cycles.
[0174] Following agarose gel electrophoresis, PCR products were purified, subcloned into pBluescript and several clones from each patient were sequenced. The variation in amino acid sequence is shown in FIG. 2.
EXAMPLE 5
[0175] Cloning a Region of HRV-5 Integrase.
[0176] Following the successful amplification of a region upstream of HRV-5 protease, attempts were made to clone a region downstream of the previously known sequence. The DNA used in this experiment was from the blood of an apparently normal subject (same sample as above).
[0177] The primers used were:
4143 5′-TCAGAAGGTGATTGGCCGAAGTCA (SEQ ID NO: 29) 3494 5′-GCCATTGTCATGGCTGGACAACAA (SEQ ID NO: 35) 3382 5′-CCAGGICCRTTRTCTGTTTT (SEQ ID NO: 67) 3383 5′-TGIGTRACATCCATTTGCCA (SEQ ID NO: 68)
[0178] Approximately 3 μg of DNA were added to a 50 μl PCR reaction containing 20 pmol each of primers 4143 and 3382. The reactions were amplified on a Stratagene Robocycler Thermal cycler for 40 cycles of 94° C. 1 min 20 sec, 50° C. 1 min 30 secs, 72° C. 3 mins with an initial denaturation at 94° C. for 4 mins. One microliter of the products of this PCR was then reamplified using primers 3494 and 3383 for 40 cycles of 94° C. 1 min 20 secs, 44° C. lmin 30 secs, 72° C. 3 mins with an initial denaturation at 94° C. for 4 mins. The products of this PCR were cloned into pBluescript using standard methods. Several plasmid clones were sequenced and a consensus found (FIG. 3).
EXAMPLE 6
[0179] Comparison of HRV-5 with other Described Retroviruses.
[0180] The conclusion from this comparison is that DNA from cells expressing HIAP-I and HIAP-II particles do not contain HRV-5 DNA.
[0181] In order to test whether the HIAP-I and HIAP-II cell lines described by Garry et al (Garry. R. F.; et al 1990Science 250:1127-1129; and Garry R. F.; et al Aids Res. Hum. Retroviruses 1996; 12: 931-940 repectively) contain HRV-5 sequences the two cell lines were obtained from the American Type Culture Collection. These cell lines have Accession Codes CRL-11213 (HIAP-I) and CRL-11622(HIAP-II). A vial of purified HIAP-II virus (VR-2503) was also obtained. The HIAP-I (VR-2394) virus preparation has not been released for study.
[0182] The cells were supplied as frozen ampules (on dry ice) and on receipt were immediately transferred to liquid nitrogen for storage. Subsequently, each vial was thawed at 37° C. and half of each cell stock was diluted in 10 ml RPMI-1640 culture medium supplemented with 10% foetal calf serum. The cells were then centrifuged at 1200 g for 5 mins at room temperature (22° C.) and the cell pellet suspended in 5 ml RPMI-1640 medium with 20% serum.
[0183] Cells were then cultured at 37° C. in a humidified atmosphere containing 5% CO 2 .
[0184] The remaining half of each cell stock was then used to prepare DNA (using standard procedures) directly, without culture. This DNA was then tested for HRV-5 sequences using PCR Assay 1 and both cell lines were negative although PCR for control genomic sequnces were positive. This result demonstrates that the cell lines described by Garry et al. do not contain HRV-5 and therefore proves that HRV-5 is not the same virus as either HIAP-I or HIAP-II.
EXAMPLE 7
[0185] Detection of HRV-5 DNA in Ulcerative Colitis.
[0186] HRV-5 specific PCR assay 1 (Example 1) was used to examine DNA from bowel biopsies from patients with Crohn's disease and ulcerative colitis. Of 10 bowel biopsies from Crohn's disease, HRV-5 DNA was detected in only 1 sample. In contrast, HRV-5 DNA was found in gut tissue from 8 of 9 patients with ulcerative colitis. Furthermore, the load of HRV-5 DNA in these samples was very high compared to that observed in other positive samples. One sample in particular had a sufficiently high load of HRV-5 DNA to permit the cloning of a further 1200 bp of the viral Gag gene (see Example 8).
EXAMPLE 8
[0187] Cloning of a Region of the Gag Gene of HRV-5
[0188] Following the cloning of the nucleocapsid and integrase genes of HRV-5, attempts were made to clone additional regions of the Gag gene. Initial experiments which adopted the degenerate primer PCR approach were unsuccessful. Therefore, more general PCR strategies for cloning flanking DNA, or “chromosome walking”, were utilised. Specifically, the Vectorette PCR system [Arnold and Hodgson, 1991, PCR Methods Appl. 1: 39-42] was used successfully to clone 1.2 kbp of the HRV-5 Gag gene.
[0189] The Vectorette PCR system involves restriction enzyme digestion of the target DNA and subsequent ligation of double stranded oligonucleotide linkers (‘Vectorettes’) to the cut DNA ends. In practice, the target DNA is digested (separately) with a number of different enzymes in order to maximize the probability that one of these restriction sites is within a suitable range for PCR amplification. In addition, the oligonucleotide linker is designed in such a way that non-specific amplifications are minimized [Arnold and Hodgson, 1991, PCR Methods Appl. 1: 39-42].
[0190] For cloning the HRV-5 Gag gene, Vectorette PCR was performed using a kit obtained from Genosys Biotechnologies (UK). Five microgram aliquots of DNA from colon tissue of a patient with ulcerative colitis which was known to be positive for HRV-5 (using specific assay 1) were digested (separately) with the restriction enzymes Cla I, Eco RI, Bam HI and Hind III and the appropriate Vectorette linkers were ligated on to the cut DNA. Three rounds of digestion and ligation were performed to minimise concatamer formation as recommended in the manufacturer's protocol. Nested PCR was then performed on aliquots of the ligation products using HRV-5 specific primers in conjunction with primers derived from the linker sequence. This experiment resulted in the amplification of sequences upstream of the nucleocapsid. The primers used are shown below. Vectorette primer sequences are proprietary and not known. These PCR amplifications were performed on a Stratagene Robocycler PCR machine and used Pfu Turbo DNA polymerase (Stratagene) to minimize nucleotide misincorporation.
[0191] First stage PCR:
[0192] Vectorette primer I (supplied in Genosys kit)
[0193] HRV-5 Nucleocapsid primer
[0194] 5′- CTGAAATTGTTTCYGCCCTCACCT (SEQ ID NO: 64) (where Y is a C or a T)
[0195] Conditions: Initial denaturation at 95° C., 4 mins followed by 40 cycles of 95° C., 1 min 10 seas; 62° C., 1 min; 72° C., 6 mins.
[0196] One microliter of the first round products were transferred to the second stage.
[0197] Second stage PCR:
[0198] Vectorette nested primer II (supplied in Genosys kit) HRV-5 Nucleocapsid primer
[0199] 5′-TGTGGCCCCATTTGAGGTGTTAG (SEQ ID NO: 66)
[0200] Conditions: Initial denaturation at 95° C. for 4 mins followed by 40 cycles of 95° C., 1 min 10 seas; 62° C., 1 min; 72° C., 6 mins.
[0201] When the second stage PCR products were analysed by agarose gel electrophoresis, a smear ranging from approximately 300 bp to 1500 bp was observed. These products were analyzed by Southern blotting and hybridized with a digoxygenin-labelled oligonucleotide probe specific for the HRV-5 nucleocapsid region (5′-GCTGTTGTCCATATACACCTGATC; (SEQ ID NO: 69) in order to identify any HRV-5 fragments present within this smear.
[0202] Hybridized probe was detected using reagents from Boehringer Mannheim (DIG detection kit). A band of approximately 800 bp was observed and the remainder of the PCR products were electrophoresed on an agarose gel and the appropriate region of the gel excised. DNA purified from this gel slice was subcloned into pBluescript (Stratagene) and plasmids containing HRV-5 sequences were identified and sequenced. The sequence obtained overlapped with the known nucleocapsid region of HRV-5 and extended to an EcoR I site 480 bp upstream of NC. This new fragment of the HRV-5 genome was designated Gagl. As expected, the region of HRV-5 nucleocapsid represented by the degenerate primer 8532 (nucleotides 1-26 in FIG. 1) was found to have a number of mismatches when compared to the genuine sequence of Gag1.
[0203] Subsequently, a primer based on the Gag1 sequence was used to clone a further region of the HRV-5 Gag gene using 1 μl of the second stage PCR products of the Cla I Vectorette-adapted DNA as template.
[0204] Primers used:
[0205] Vectorette sequencing primer (supplied in Genosys kit)
[0206] HRV-5 Gag primer (CA2R) 5′ CTGTACTATCTTAGTTAGGCTGTG
[0207] (SEQ ID NO: 70)
[0208] Conditions: Initial denaturation at 95° C. for 4 mins followed by 40 cycles of 94° C., 1 min 10 secs; 51° C., 1 min 10 secs; 72° C. 3 mins.
[0209] This PCR produced a clear band of approximately 1000 bp after analysis by agarose gel electrophoresis.
[0210] Following cloning and sequencing this product was found to extend the known HRV-5 gag sequence to a Cla I restriction site 1250 bp upstream of the original NC fragment. This second region (between the Cla I and Eco RI sites) was denoted Gag2. The composite sequence of HRV-5 Gag is shown in FIG. 10.
EXAMPLE 9
[0211] Bacterial Expression of Recombinant HRV-5 Gag Protein
[0212] The major capsid protein of retroviruses (CA) is commonly used as a target antigen in immunological detection assays. In order to develop such an assay for HRV-5, a region of the gag protein of HRV-5 likely to represent CA was expressed in a bacterial expression system. The region of HRV-5 most likely to represent CA was identified by comparison with published sequences of other B and D-type retroviruses (FIG. 11). The appropriate DNA sequence was re-amplified from the cloned PCR fragments obtained previously, gel purified and blunt-end cloned into pBluescript using standard methods.
[0213] Primers used:
[0214] Forward (containing an Nco I site)
[0215] 5′-AGAGACCATGGAACCAGGCCAGGTGTTTCCTG; (SEQ ID NO: 71)
[0216] Reverse (containing Xba I site)
[0217] 5′- GAGATTCTAGAAATTGTCGGGTTACAGCTACTGC (SEQ ID NO: 72)
[0218] Conditions were 94° C. for 4 mins followed by 30 cycles of 94° C., 1 min 10 secs; 55° C., 1 min 10 secs; 72° C., 1 min 30 secs.
[0219] The resulting plasmids were sequenced to check that the PCR had not introduced errors into the Gag sequence and selected plasmids were then digested to completion with Xba I and partially digested with Nco I before subcloning the 700 bp HRV-5 CA fragment into the bacterial expression vector pTrcHis2B (Invitrogen) which had previously been digested with Nco I and Xba I. The resulting plasmid was designated pTrc-CA.
[0220] The pTrcHis2B expression vector was used because it allows the production of the desired protein fused to two epitope tags, namely a polyhistidine tag and a “myc” tag. The poly histidine (HIS-6) tag allows the purification of the desired protein using affinity chromatography on Nickel-agarose beads [Schmitt et al 1993, Mol. Biol. Rep., 18: 223-230]. The c-myc epitope tag allows the detection of the expressed protein in immunoblots using a monoclonal antibody specific for this epitope [Evan et al, 1985, Mol. Cell Biol. 5: 3610-3616].
[0221] A 2 ml culture of transformed bacteria containing plasmid pTrc-CA was grown overnight in Luria Bertani broth supplemented with 100 μg/ml ampicillin. This culture was then diluted 1 in 10 with fresh medium and grown for 1 hour at 37° C. with shaking. IPTG was then added to a final concentration of 1 mM in order to induce expression of the tagged HRV-5 CA protein and the culture grown for a further 90 mins. Extracts of the bacteria were then analysed by SDS-PAGE and production of the desired CA protein was confirmed by the presence of a 30 kDa protein following immunoblotting with the anti-myc monoclonal antibody, 9E10 [Evan et al, 1985, Mol. Cell Biol. 5: 3610-3616].
[0222] This protein was subsequently purified by metal chelate chromatography using a commercial kit (Xpress System, from Invitrogen) and was obtained substantially free of contaminating bacterial proteins. The recombinant HRV-5 CA protein is now ready for use as a target antigen in immunoblots, ELISAs and other serological assays for the detection of anti-HRV-5 antibodies in human sera. In addition the protein will be used to generate specific rabbit polyclonal and rat monoclonal antibodies as has already been achieved for the protease and reverse transcriptase proteins of HRV-5.
[0223] Cloning of HRV-5 Gag for Bacterial Expression
[0224] The HRV-5 Gag protein was PCR amplified and subcloned into the bacterial expression vector pTrcHIS2B (Invitrogen). This vector provides C-terminal c-myc and polyhistidine tags to facilitate detection and purification of the expressed protein.
[0225] Primers used:
Forward; SEQ ID NO: 105: ATGGAACGA CCATGG AGTTCTTTGGCTACTCTTTG; Reverse: SEQ ID NO:106 GAGA TCTAGA TTAGTACCGAATATTCGGTGACTCGTA
[0226] HRV-5 Gag was amplified from HRV-5 plasmid DNA in a 50 microliter reaction volume containing 10 pmol of each primer, using pfuTurbo DNA polymerase (Stratagene) as recommended. Conditions were 30 cycles of 94° C., 45 secs; 55° C., 45 secs; 72° C., 2 mins, with an initial denaturation at 94° C. for 4 minutes. The PCR product was gel-purified, digested with NcoI and XbaI (sites contained in the primers) and ligated into digested pTrcHis2B to generate plasmid pTrcGag. The plasmid was sequenced to confirm the construct was as desired.
[0227] For Gag expression in E. coli , BL21 CodonPlus cells (Stratagene) were transformed with pTrcGag using standard methods. Protein expression was induced in selected transformants by inoculating a 2 ml of LB-broth containing 100 μg/ml ampicillin and 150 μg/ml chloramphenicol with a single colony and culturing overnight at 37° C. with shaking at 300 rpm. The culture was diluted 1 in 10 with fresh medium/antibiotics and grown for 1 hour at 37° C. with shaking. Protein expression was induced by addition of IPTG to a final concentration of lmM and growing for a further 3 hours. Protein was detected by western blotting using an anti-myc monoclonal antibody.
[0228] The HRV-5 Gag protein was purified by metal chelate affinity chromatography from 100 ml cultures (grown and induced under similar conditions as aboveand scaled up) using procedures recommended by the manufacturer. Bacterial pellets were resuspended in 5 ml/g wet weight of extraction buffer (6 M guanidine hydrochloride, 100 mM NaH 2 PO 4 , 10 mM Tris-HCl pH 8.0) and lysed by incubation on ice for 15 mins followed by brief sonication on ice (2×30 second bursts with a 30 second gap; MSE soniprobe). The lysate was then centrifuged at 10,000 rpm (in Beckman JA-20) for 10 minutes at 4° C. and the supernatant removed. Triton X-100 (final concentration 1%), β-mercaptoethanol (10 mM) and imidazole (10 mM) were then added followed by 750 μl of a 50% slurry of nitrolotriacetic acid-Ni 2+ -Sepharose (NTA-Ni 2+ ) beads (Qiagen; prewashed three times in extraction buffer). The samples were mixed for 1 hour at room temperature.
[0229] After binding of proteins, the NTA-Ni 2+ beads were washed with 50 bed volumes of extraction buffer pH 8.0, 50 bed volumes of wash buffer (6 M urea, 100 mM NaH 2 PO 4 , 10 mM Tris-HCl pH 6.3) and 50 bed volumes of wash buffer containing 25 mM imidazole (pH 6.3). Proteins were then eluted from the NTA-Ni 2+ beads with 2 bed volumes of extraction buffer containing 100 mM imidazole pH 6.3 and 2 bed volumes of extraction buffer with 250 mM imidazole pH 6.3. Fractions were taken at various stages of washing for analysis by SDS-PAGE, Coomassie staining and immunoblotting.
EXAMPLE 10
[0230] Cloning of an Additional Fragment of HRV-5 Gag
[0231] In addition to Vectorette PCR, other DNA-walking methods were used to extend the HRV-5 sequence. A further 260 bp was cloned using a procedure based on 5′ RACE (5′ amplification of cDNA ends, Frohman et al., 1988, Proc Nat Acad Sci USA. 85: 8998-9002) which was adapted for use on genomic DNA. The adaptations were designed to enrich the target DNA with HRV-5 sequences and to prepare single stranded DNA which may serve as a template for the tailing step of the RACE reaction.
[0232] Three micrograms of DNA from normal blood were added to a PCR reaction containing a single primer specific for HRV-5.
[0233] Primer:
[0234] HRV-5 Gag primer (CA2R1)
[0235] 5′-(biotin)-GCTTCCTGGCTCTCTAAATCCTTC (SEQ ID NO: 73)
[0236] Conditions were an initial denaturation at 94° C. for 4 mins followed by 40 cycles of 94° C., 1 min; 62° C., 1 min 10 secs; 72° C., 3 mins.
[0237] The HRV-5 specific primer used in this reaction was modified in that it was synthesised with a biotin molecule at its 5′ terminus. The purpose of this single primer PCR was to generate single stranded DNA molecules extending from the known region of HRV-5 Gag into the upstream flanking sequence. These single stranded DNA molecules were purified using streptavidin coated magnetic beads by utilising the 5′ biotin modification of the primer used in the PCR. This purification was performed using the KilobaseBINDER kit (Dynal, Sweden) as recommended.
[0238] The selected DNA fragments were then further modified by the addition of a “tail” of deoxyadenosine nucleotides to the 3′ end of the purified DNA. This was achieved using terminal transferase and DATP and utilised reagents in the 3′ and 5′ RACE kit (Boehringer) essentially as recommended.
[0239] The selected, tailed single stranded DNA molecules were then subjected to PCR amplification using HRV-5 specific primers (from the known Gag2 region) and primers designed to the synthetic oligo dA tail (provided in the RACE kit).
[0240] First stage primers:
[0241] HRV-5 Gag primer (CA2R2) 5′-CTCACCGGTTCATTACAATAGCTGC (SEQ ID NO: 74)
[0242] Anchor tailed primer:
[0243] 5′-GACCACGCGTATCGATGTCGACTTTTTTTTTTTTTTTTV (Where V is a C a G or an A; SEQ ID NO: 75).
[0244] Conditions were an initial denaturation at 94° C. for 4 mins followed by 40 cycles of 94° C., 1 min 10 secs; 55° C., 1 min 10 secs; 72° C., 3 mins 30 secs. One microliter of first round products were transferred to the second stage.
[0245] Second stage primers:
[0246] HRV-5 Gag primer (CA2R3) 5′-GCTGCCCTGCCATAATTCTTCCTG (SEQ ID NO: 76)
[0247] Anchor primer: 5′-GACCACGCGTATCGATGTCGAC (SEQ ID NO: 77)
[0248] Conditions were an initial denaturation at 94° C. for 4 mins followed by 40 cycles of 94° C., 1 min 10 seas; 55° C., 1 min 10 seas; 72° C., 3 mins 30 secs.
[0249] Cloning and sequencing of the second stage PCR products established the sequence of a further region of HRV-5 upstream of Gag2. This region was denoted Gag3.
[0250] This modified RACE procedure was subsequently used to clone 2 additional fragments of the HRV-5 gag gene, denoted Gag4 and Gag5. The Gag4 fragment was amplified from 1 mg of DNA from the colon tissue of a patient with ulcerative colitis.
[0251] Single primer PCR:
[0252] HRV-5 Gag Primer (CA3R1) 5′-(biotin)-TCCCACCTGCCTCCACTGCTGTAG (SEQ ID NO: 78)
[0253] Conditions were an initial denaturation at 94° C. for 4 mins followed by 40 cycles of 94° C., 1 min; 62° C., 1 min 10 seas; 72° C., 3 mins. Single stranded extension products were purified using streptavidin coated magnetic beads as for the Gag3 fragment. A polynucleotide tail was then added as for the Gag3 fragment except that in this case a deoxygaunosine tail was added instead of polyadenosine. The selected, tailed single stranded DNA molecules were then subjected to PCR amplification using HRV-5 specific primers (from the known Gag3 region) and primers designed to the synthetic oligo dG tail.
[0254] First stage primers:
[0255] HRV5 Gag primer (CA3R2) 5′-ACCAGGGGGACGTCTCTATGACTG (SEQ ID NO: 79)
[0256] Anchor tailed primer:
[0257] 5′- GACCACGCGTATCGATGTCGACCCCCCCCCCCCCCCCD
[0258] (where D is an A, a G or a T; (SEQ ID NO: 80).
[0259] Conditions were an initial denaturation at 94° C. for 4 mins followed by 40 cycles of 94° C., 1 min 10 secs; 55° C., 1 min 10 secs; 72° C., 3 mins 30 secs. One microliter of first round products were transferred to the second stage.
[0260] Second stage primers:
[0261] HRV-5 Gag primer (CA3R3) 5′-CTTAGGAATGCGTGAAATTTCCTC (SEQ ID NO: 81)
[0262] Anchor primer: 5′-GACCACGCGTATCGATGTCGAC (SEQ ID NO: 77)
[0263] Conditions were an initial denaturation at 94° C. for 4 mins followed by 40 cycles of 94° C., 1 min 10 secs; 55° C., 1 min 10 secs; 72° C., 3 mins 30 secs.
[0264] Cloning and sequencing of the second stage PCR products established the sequence of a further 45 bp of HRV-5 upstream of Gag3. This region was denoted Gag4. This procedure was then repeated to clone the Gag5 fragment.
[0265] Single primer for extension reaction (from HRV5 Gag):
[0266] 5′-(biotin)-GCATTCAGCCCATAACGGATGATC (SEQ ID NO: 82)
[0267] Conditions were an initial denaturation at 94° C. for 4 mins followed by 40 cycles of 94° C., 1 min; 61° C., 1 min; 72° C., 2 mins. Single stranded extension products were purified using streptavidin coated magnetic beads as for the Gag3 fragment. A polydeoxygaunosine tail was then added as for the Gag4 fragment. The selected, tailed single stranded DNA molecules were then subjected to PCR amplification using HRV-5 specific primers (from the known Gag3 region) and primers designed to the synthetic oligo dG tail.
[0268] First stage primers:
[0269] HRV5 Gag primer (CA4R2) 5′-AAGATGTAGCCAGTGGGCAAGGAG (SEQ ID NO: 83)
[0270] Anchor tailed primer:
[0271] 5′-GACCACGCGTATCGATGTCGACCCCCCCCCCCCCCCCD
[0272] (where D is an A, a G or a T; SEQ ID NO: 80). Conditions were an initial denaturation at 95° C. for 4z mins followed by 40 cycles of 94° C., 1 min 10 secs; 55° C., 1 min 10 secs; 72° C., 2 mins 30 secs. One microliter of first round products were transferred to the second stage.
[0273] Second stage primers:
[0274] HRV-5 Gag primer (CA4R3) 5′-GTAGCCAAAGAACTCCATTGTCTG (SEQ ID NO:84)
[0275] Anchor primer: 5′-GACCACGCGTATCGATGTCGAC (SEQ ID NO: 77)
[0276] Conditions were an initial denaturation at 95° C. for 4 mins followed by 40 cycles of 94° C., 1 min 10 secs; 55° C., 1 min 10 secs; 72° C., 2 mins 30 secs.
[0277] Cloning and sequencing of the second stage PCR products established the sequence of a further 160 bp of HRV-5 upstream of Gag4. This region was denoted Gag5. In total the 3 extension products obtained using the modified RACE procedure yielded 458 bp of sequence information upstream of the ClaI site of the Vectorette PCR products. The composite sequence of HRV-5 Gag is shown in FIG. 10.
[0278] The composite sequence of HRV-5 Gag is shown in FIG. 10.
[0279] Extended Gag3 sequences are shown in FIG. 14; nucleic acid sequence, SEQ ID NO: 92, amino acid sequence, SEQ ID NO: 93. Extended Gag4 sequences are shown in FIG. 15; nucleic acid sequence, SEQ ID NO: 94; amino acid sequence, SEQ ID NO: 95. Gag5 sequences are shown in FIG. 16, SEQ ID NO:SEQ ID NO: 96, amino acid sequence, SEQ ID NO: 97.
[0280] In total, using the RACE PCR we successfully cloned 458 bp of the HRV-5 genome comprising the 5′ terminus of the gag gene and a large region of the 5′ untranslated leader sequence. The final fragment of HRV-5 leader sequence and a part of the 5′ long terminal repeat was cloned using Vectorette PCR.
[0281] The Vectorette PCR system involves restriction enzyme digestion of the target DNA and subsequent ligation of double stranded oligonucleotide linkers (‘Vectorettes’) to the cut DNA ends. In practice, the target DNA is digested (separately) with a number of different enzymes in order to maximize the probability that one of these restriction sites is within a suitable range for PCR amplification. In addition, the oligonucleotide linker is designed in such a way that non-specific amplifications are minimized (Arnold and Hodgson, 1991, PCR Methods Appl. 1: 39-42).
[0282] For cloning the final fragment of the HRV-5 leader region, Vectorette PCR was performed using a kit obtained from Genosys Biotechnologies (UK). Five micrograms of DNA from the blood of an apparently normal individual was digested with the restriction enzyme Nsp I and blunt-ended Vectorette linkers were ligated on to the cut DNA.
[0283] Three rounds of digestion and ligation were performed to minimize concatamer formation as recommended in the manufacturer's protocol. Nested PCR was then performed on aliquots of the ligation products using HRV-5 specific primers in conjunction with primers derived from the linker sequence. This experiment resulted in the amplification of sequences upstream of the Gag5 region The primers used are shown below. Vectorette primer sequences are proprietary and not known. These PCR amplifications were performed on a Stratagene Robocycler PCR machine and used Pfu Turbo DNA polymerase (Stratagene) to minimize nucleotide misincorporation.
[0284] First stage primers:
[0285] HRV-5 specific primer (CA4R3)
[0286] 5′- GTAGCCAAAGAACTCCATTGTCTG; SEQ ID NO: 84)
[0287] Vectorette primer (Genosys)
[0288] Amplification conditions were 40 cycles of 95° C., 1 minute 10 seconds; 55° C., 1 minute 10 seconds; 72° C., 3 minutes with an initial denaturation at 95° C. for 4 minutes. 1 μl of the first stage products were transferred to the second stage PCR.
[0289] Second stage primers:
[0290] HRV-5 specific primer (GAG6R2)
[0291] 5′-TTGGAGCGGTGGGCGTARTGGAAGG; SEQ ID NO: 107Vectorette nested primer (Genosys)
[0292] Where R is an A or a G.
[0293] Conditions were 40 cycles of 95° C., 1 minute 10 seconds; 60° C., 1 minute 10 seconds; 72° C., 3 minutes with an initial denaturation at 95° C. for 4 minutes). Analysis of the products of this PCR identified an 85 bp region upstream of Gag5 which extended the known sequence of HRV-5 into the 5′ long terminal repeat. This fragment was designated Gag6. See FIG. 17; (SEQ ID NO: 98).
EXAMPLE 11
[0294] Cloning an additional fragment of HRV-5 Integrase
[0295] The degenerate primer and RACE PCR cloning methods were combined to clone an additional 260 bp fragment of the HRV-5 integrase gene. 1 μg of DNA from colon tissue of a patient with ulcerative colitis was added to a RACE primer extension reaction as described in Example 10 for the Gag3 fragment.
[0296] Primer for single primer PCR (from HRV-5 pol gene):
[0297] Primer (INF6bio) 5′-(biotin)-GTTGCCATAGTTCCAAAGATTCCTG; (SEQ ID NO: 85)
[0298] Conditions were an initial denaturation at 95° C. for 4 mins followed by 40 cycles of 94° C., 1 min; 61° C., 1 min; 72° C., 2 mins. Single stranded extension products were purified using streptavidin coated magnetic beads as for the Gag3 fragment. A polydeoxyadenosine tail was then added as for the Gag3 fragment. The selected, tailed single stranded DNA molecules were then subjected to PCR amplification using HRV-5 specific primers (from the known Gag3 region) and primers designed to the synthetic oligo dA tail.
[0299] First stage PCR
[0300] HRV5 Pol primer (INF6) 5′-GTTGCCATAGTTCCAAAGATTCCTG (SEQ ID NO: 85)
[0301] Anchor tailed primer:
[0302] 5′- GACCACGCGTATCGATGTCGACTTTTTTTTTTTTTTTTV (SEQ ID NO: 75)
[0303] (Where V is a C a G or an A).
[0304] Conditions were an initial denaturation at 95° C. for 4 mins followed by 40 cycles of 94° C., 1 min 10 secs; 55° C., 1 min 10 secs; 72° C., 2 mins. One microliter of first round products were transferred to the second stage.
[0305] Second stage primers:
[0306] HRV-5 Pol primer (INF7) 5′-GAGCCAATCCCCGTGGCCTTAAAC (SEQ ID NO: 86)
[0307] Degenerate retrovirus integrase primer (IN-GIPl): 5′-YTGKCCYTGKGGATTRTARGG (SEQ ID NO: 86)
[0308] (Where Y is a C or a T; K is a G or a T and R is an A or a G).
[0309] Conditions were an initial denaturation at 94° C. for 4 mins followed by 35 cycles of 94° C., 1 min 10 secs; 50° C., 1 min 30 secs; 72° C., 1 min 20 secs.
[0310] Cloning and sequencing of the second stage PCR products established the sequence of a further 260 bp of the HRV-5 pol gene. This region was denoted IN2. This region represents nucleotides 4648 to 4693 of the sequence presented in FIG. 12. Note that nt 4941 to 4961 are derived from the degenerate primer IN-GIP1 and so may not represent the genuine sequence of HRV5 in this region.
EXAMPLE 12
[0311] Accession Number
[0312] A plasmid (pHRV5gagpol 17.1) containing HRV-5 gag, pro and pol genes was deposited with the European Collection of Cell Cultures (ECACC) on 19 March 1999 under the Accession number 99031901. This plasmid was constructed from the various PCR amplified fragments of HRV-5. Since the sequences shown in FIG. 12 represents the consensus sequence of the various PCR fragments, the plasmid pHRV5gagpol 17.1 has a number of nucleotide differences from this consensus sequence. These differences are shown in FIG. 13. The applicants give their unreserved and irrevocable consent to the materials being made available to the public in accordacne with appropriate national laws governing the deposit of these materials, such as Rules 28 and 28a EPC. The expert solution under Rule 28(4) EPC is also hereby requested.
Example 13
[0313] Bacterial Expression and Antibody Production.
[0314] In order to develop antisera and monoclonal antibodies (Mabs) for the detection of viral proteins in primary tissue and in culture, fragments of the potential gag, pro and pol proteins of HRV-5 have been expressed using the bacterial expression vector pTrc99A (Pharmacia) in the M15 [pREP4] (Qiagen) bacterial host strain. This has been accomplished using PCR amplified regions of the appropriate HRV-5 genes. In addition to gene-specific nucleotides the 5′ PCR primers also contained nucleotides encoding 6 consecutive histidine residues (His 6 -tag) to facilitate purification of the proteins by means of a Ni 2+ -containing resin marketed by Qiagen (Ni 2+ -NTA resin). The 3′ primers also included nucleotides encoding a 10 amino-acid epitope from the human c-myc gene to enable detection of the proteins by western blotting with a monoclonal anti-c-myc antibody (9E10) specific to this epitope (Evan et al. 1985 , Mol. Cell Biol. 5: 3610-3616). In addition to the His 6 and c-myc sequence tags, the PCR primers also contained restriction sites to enable cloning into the pTrc99A vector.
[0315] Proteins were purified using Ni 2+ -NTA resin (Qiagen). Overnight cultures of bacteria carrying the subcloned fragments of HRV-5 were grown in Luria-Bertani broth supplemented with ampicillin (100 μg/ml) and kanamycin (25 μg/ml). The next day these were diluted 1:10 into fresh antibiotic-containing broth and grown at 30° C. for one hour (optical density at 600 nm approximately 0.6). Expression of the proteins was then induced by addition of iso-propyl-thio-galactoside (IPTG; 1 mM) and culture continued for a further 90 minutes (OD 600 =0.9). Cells were pelleted by centrifugation and resuspended in NTA-purification buffer pH 8.0 (8M urea, 100 mM NaH 2 PO 3 , 10 mM TRIS-Cl). Cells are then lysed by three cycles of freeze-thawing followed by brief sonication. Clarified lysates are then incubated with Ni 2+ -NTA resin for four hours at 4° C. and then poured into a chromatography column support (Bio-Rad). Contaminating proteins are washed off with NTA-purification buffer pH 6.3 containing 25 mM imidazole. Finally the purified proteins are eluted from the resin with NTA purification buffer pH 6.3 containing 250 mM imidazole.
[0316] Fragments of HRV-5 proteins have also been expressed in E.Coli and purified using the glutathione-S-transferase (GST) system (Pharmacia). These proteins were used to raise polyclonal antisera in rabbits. These antisera are used as control antibodies for the ELISAs (discussed below).
[0317] The identity of the purified proteins can be confirmed by western blotting using the 9E10 Mab specific for the c-myc epitope tag. The proteins can then be used to raise rabbit polyclonal antisera in a known manner, preferably with the use of affinity purification to improve the specificity of the sera.
[0318] Antibody Production
[0319] Rat monoclonal antibodies specific for the HRV-5 proteins may be produced. CBH/Cbi rats may be immunized 4 times at 21 day intervals with 100 μg of either the PR or RT protein. The third immunization is preferably given via the intra-peritoneum, the other three immunizations via Peyer's patches. The immunogens may be emulsified in complete Freunds adjuvant (Difco Labs) prior to the first inoculations and in incomplete Freunds for subsequent immunizations.
[0320] Three days after the last immunization, mesenteric lymph node cells may be fused with rat myeloma Y3-Ag 1,2,3, [Dean et al., 1986, Methods in Enzymology, Vol 121, pp 52-59]. Supernatants from the resulting hybridomas are then screened for antibodies to the immunizing antigen by ELISA and by immunoblot.
[0321] ELISA plates are prepared by coating them with immunizing antigen at a concentration of lug/ml in PBS and incubating overnight at 4° C. Hybridoma supernatants can then be screened for binding to the immunizing antigen. After incubation for about 1 hour at room temperature, the plates are washed 3 times in wash buffer (PBS, 0.1% BSA, 0.05% Tween-20). Bound rat antibody may be detected using goat anti-rat immunoglobulin conjugated to horseradish peroxidase (Seralab) and incubated at room temperature for about 1 hour. Plates may be washed 3times in wash buffer and bound antibody detected by TMB (Sigma) to produce a soluble blue end product developed over 20 minutes. Acidification with 0.5 M H 2 SO 4 stopping solution produces a yellow colour which may be read using a microplate autoreader at 450 nm.
[0322] Candidate hybridoma supernatants identified by ELISA may be used to probe immunoblots of the immunizing proteins. The supernatants can be used at dilutions of 1:200-1:25 and detected with goat anti-rat immunoglobulin-horseradish peroxidase conjugate (Harlin SeraLab, diluted 1:2000) and enhanced chemiluminescence (ECL, with reagents supplied by Amersham).
[0323] Mouse Mabs may also be prepared by methods which are conventional in the art.
[0324] ELISAs and Immunofluorescence
[0325] ELISAs for the detection of antibodies to HRV-5 proteins may be developed. An indirect ELISA and a capture ELISA system can be produced.
[0326] Indirect ELISA (FIG. 8)
[0327] ELISA plates are coated with recombinant HRV-5 proteins or synthetic peptides derived from HRV-5 proteins (50 μl; 5 μg/ml) and incubated at 4° C. overnight. The plates are then washed 3 times with PBS (100 μl per well), blocked with PBS/2% casein (100 ml/well) for 1hour at 37° C. and washed again 3 times with PBS. Test sera and standard control sera (50 μl; prepared in PBS/0.5% casein) are incubated on the plates at various dilutions for 1 hour at 37° C. and the plates washed 3 times in PBS. An anti-human alkaline phosphatase conjugate (Sigma 1:1000 dilution) is then incubated on the plates for 1 hour, 37° C. and washed 4 times in PBS, once in PBS/0.1% Tween 20 and then once in PBS (100 μl per well for each wash). Conjugates to human IgG and IgM can be used which may allow the distinction between early HRV-5 infection (IgM antibodies) and established HRV-5 infection (IgG). For control wells using polyclonal rabbit antisera or rat monoclonal antibodies, goat anti-rabbit IgG or goat anti-rat IgG conjugates are used respectively. Alkaline phosphatase substrate (Sigma-104; 50 μl/well) is then added to yield a yellow end product read at 405 nm with a microplate autoreader (BioTek Instruments).
[0328] Capture ELISA (FIG. 9)
[0329] ELISA plates are coated with an anti-c-myc monoclonal antibody (9E10, Evan et al, 1985, Mol. Cell. Biol. 5: 3610-3616) (5 μg/ml; 50 μl/well) overnight at 4° C. Plates are then washed 3 times in PBS, blocked with PBS/2% casein (100 μl/well) for 1 hour at 37° C. and washed with PBS as before. Recombinant HRV-5 protein is then bound to the plates (as above for indirect ELISA) and the plates are washed 3 times with PBS (100 μl/well). Test sera are then incubated on the plates and detected using the alkaline phosphatase conjugate as described above for the indirect ELISA. The use of a capture ELISA may increase specificity of the ELISA since minor bacterial contaminants in the recombinant protein preparations will not bind to the 9E10-coated plates.
[0330] All ELISA results may be confirmed by immunoblotting.
[0331] Immunofluorescence
[0332] The anti-HRV-5 monoclonal antibodies may be used to examine human tissue sections by indirect immunofluorescence. Tissue sections (6 μm thick) were cut in OCT compound (Miles Diagnostics), fixed in 1:1 acetone/methanol at −20° C. and air-dried. The sections are then incubated with 50 μl of diluted test antibody for 30 mins at room temperature and washed twice in PBS (5 mins) and once in water. Bound antibodies are then detected using an anti-rat IgG fluorescein isothiocyanate conjugated antibody (Sigma F1763; 50 μl) for 30 mins at room temperature. The slides are then washed twice with PBS (5 mins) and once in water before mounting in glycerol with 2.5% (w/v) 1,4 diazobicyclo-2.2.2. octane and viewing under ultraviolet light.
[0333] As mentioned above the HRV-5 Gag polyprotein has been expressed and purified as a polyhistidine tagged protein in E. coli . This protein was then used as the target antigen in western blots with human sera. In these experiments we have identified 2 sera from patients with systemic lupus erythematosus which reacted with the HRV-5 Gag protein.
[0334] Epitone Mapping
[0335] In order to identify specific epitopes of HRV-5 Gag that are reactive with lupus sera, we generated a series of overlapping peptides (15 mers) derived from the N-terminus of Gag. This region corresponds to the matrix (MA) domain of retroviral Gag polyproteins. These peptides were synthesised on a cellulose membrane using the SPOTS kit (Sigma-Genosys) as recommended and exposed to the positive sera identified by western blot. 2peptides showed strong reactivity with these sera. We then prepared large quantities of these peptides for use in ELISAs. The peptide sequences were SFSSKRGKRGGRKIHC; SEQ ID NO: 108 and PWFLQQWRQVGRKLRC; SEQ ID NO: 109. (The C-terminal cysteine residues are not part of the Gag sequence but are added to increase sensitivity in the ELISA.
[0336] For the ELISA, these 2 peptides were mixed together in PBS to a final concentration of 10 μg/ml each. This solution was used to coat ELISA plates. 50 μl was added to each well and left overnight (16 hours) at room temperature. The solution was then discarded and the plates were washed 3 times with PBS containing 0.05% Tween 20 (PBS/Twn). Plates were then blocked for 2 and a half hours with blocking buffer (5% low fat milk powder in PBS/Twn) at room temperature before washing again 3 times with PBS/Twn. Patient sera were added (50 μl, diluted 1 in 50 in blocking buffer) and the plate incubated for 2 hours at room temperature with occasional gentle mixing. The plates were then washed 3 times with PBS/Twn and incubated again with blocking buffer for 30 minutes before washing agin 3 times with PBS/Twn and addition of the secondary antibody, goat anti-human IgG conjugated to horse radish peroxidase (1:3000 dilution, Bio-Rad) for 1 hour at room temperature. The plates were then washed 7 times before developing.
[0337] We have also tested a CA peptide in an ELISA assay, WKVIPRKGERIRHSLTC; SEQ ID NO: 110.
EXAMPLE 14
[0338] Detection of HRV5 in Patient Samples
[0339] Materials and Methods
[0340] Patients.
[0341] The study was approved by the Riverside Research Ethics Committee (RREC 0102) and all participating patients gave written consent. Synovial biopsy samples and peripheral blood samples were obtained from patients attending the Rheumatology clinic at Charing Cross Hospital, London, UK. Lymph node DNA samples were a kind gift from Dr Ruth Jarrett (LRF Glasgow). Blood DNA was examined from 37 individuals (17 with RA,3 OA, 17 normal).
[0342] DNA Extraction from Tissue Samples
[0343] Synovial biopsy tissue or labial salivary glands were processed immediately or stored at −20° C. Each sample was cut into 0.5-1 mm 3 fragments with a sterile scalpel and incubated in 200μl of UV-irradiated lysis buffer (10 mM Tris-HCl (pH 8.3), 50 mM KCl, 2.5 mM MgCl 2 , 0.5% v/v NP40, 0.5% v/v Tween) and Proteinase K added to a final concentration of 2 mg/ml for 48 hours at 56° C. The Proteinase K was then inactivated by heating to 95° C. for 15 minutes followed by centrifugation at 10,000× g for 10 minutes. The supernatant was stored in aliquots at −20° C. Suitability of the DNA for PCR was verified using primers for the single copy gene ERV-3 as described previously (Griffiths et al, J. Virol. 1997: 71: 2866-2872) DNA was extracted from peripheral blood lymphocytes using the DTAB/CTAB method (Gustincich et al Biotechniques. 1991; 11: 298-300) and analysed as described above.
[0344] Cloning a Sequence Tar for Sio-1
[0345] Approximately 10 mg of homogenized SS salivary gland lip biopsy were co-cultured with 10 5 H9 cells in RPMI 1640 medium supplemented with 10% fetal calf serum (Biological Industries). The cultures were passaged twice weekly at a ratio of 1:8. After 14 days, the cells were homogenized using an ultra-Turrax T25 tissue grinder (IKA Labortechnik) at maximum speed and on ice. Cellular debris was removed by centrifugation at 4,000× g for 10 minutes at 4° C. The supernatant was then re-centrifuged at 20,000× g for 20 minutes at 4° C. to remove mitochondria and other sub-cellular organelles. The resultant supernatant was layered over a linear 20-65% (w/v) sucrose gradient. Sucrose gradients were prepared and run in a Beckman SW28 as described by Boyd et al., Lancet , (1989), ii:814-817. They were then centrifuged at 100,000 g for 16 hours. 1 ml fractions were collected and a 20 μl solution of RNA was prepared from these as follows: to 250 μl sucrose, 750 μl of RNAzol B (Biotecx Laboratories, Inc. Texas) is added followed by 125 μl chloroform. This mixture is then vortexed briefly, incubated on ice for 5 minutes and centrifuged at 13000× g, 4° C. for 15 minutes. Nucleic acids are then precipitated from the aqueous phase by addition of an equal volume of isopropanol and incubation on ice for 15 minutes. Precipitated RNA is pelleted by centrifugation (13000 g, 4° C. for 15 minutes) and the pellets washed in ice-cold 75% ethanol. Finally the RNA is resuspended in 20 μl water.
[0346] These solutions were subjected to reverse transcriptase-polymerase chain reaction (RT-PCR) using the degenerate pol primers described by Shih et al., J. Virol . (1989) 63: 64-75 which are capable of amplifying a wide variety of retroviral sequences. The products were then cloned into the pBluescript (KS-) plasmid (Stratagene) using standard methods (Sambrook et al 1989, Molecular Cloning 2nd ed. (Cold Spring Harbor Laboratory press)) and sequenced using an Applied Biosystems model 373A automated DNA sequence. A 126 bp clone was obtained and designated Sjo-1. Part of the deduced amino acid sequence of Sjo-1 is shown in FIG. 4 aligned with several other retroviral sequences (identified in a FASTA search of the entire Genbank and EMBL databases). The abbreviations and GenEMBL accession codes used in FIG. 4 are as follows.
[0347] SRV-2 Simian type D retrovirus serotype 2 (gb_vi:M16605)
[0348] MMTV Mouse mammary tumor virus (gb_vi:M15122)
[0349] Jaag Jaagsiekte sheep retrovirus (gb_vi:M80216)
[0350] RSV Rous sarcoma virus (gb_vi:Dl0652)
[0351] HTLV-1 Human T-cell leukemia virus type I (gb_vi:L10341)
[0352] HIV-1 Human immunodeficiency virus type 1 (gb_vi:D21166)
[0353] MOMLV Moloney murine leukemia virus (gb_vi:J02255)
[0354] The Sjo-1 sequence was detected in co-cultures after 14 days of co-cultivation and was obtained from fractions with a buoyant density of 1.15-1.16 g ml −1 (the typical density of mature retroviral particles). This sequence was not detected in co-cultures which were passaged for longer than a month. It appears that no transfer of the virus occurred in these experiments. Moreover, it is believed that the co-cultivation, if indeed it plays a role, leads to stimulation of the cells which produce the virus.
[0355] The closest homologues of this short region as illustrated in FIG. 4 are the D and B-type retroviral sequences; SRV-2 (simian retrovirus serotype 2) and MMTV (mouse mammary tumor virus). Whilst the aligned region is too short for this comparison to be very meaningful, it did provide information which was useful in the design of subsequent primers for flanking regions such that these were biased towards B and D-type retroviral families. Sjo-1 could not be detected in H9 cells which had not been co-cultivated with SS salivary gland biopsy. Co-cultures from three individuals, two with primary SS and one with sicca syndrome were examined. Both the SS co-cultures were positive for Sjo-1 RNA whilst the sicca sample was negative.
[0356] Cloning a Larger Fragment of the Viral DNA
[0357] Degenerate primers for the active site of the protease (PR) gene of B and D-type retroviruses were designed. The PR gene, encoding as it does an enzyme, contains the second most highly conserved region of the retroviral genome. At the active site there is conservation of an aspartic acid-threonine-glycine (DTG) motif and this information was used in primer design. When these degenerate primers were used in conjunction with specific 3′ primers anchored within the Sjo-1 sequence, a further 806 bp of sequence was amplified from sucrose gradient purified viral RNA. The primers used were:
1992 (5′ GAGGTCATCCATGTAGTGTAAAATTTG 3′; SEQ ID NO: 88) 1784 (5′ TAAAATTTGTACTTTTGGGCACTGCTG 3′; SEQ ID NO: 89) 3095 (5′ TAGAYACKGGAGCWGATGT 3′; SEQ ID NO: 90) 3096 (5′ IIIITAGAYACWGGRGCMGA 3′; SEQ ID NO: 91)
[0358] Where: K=G or T, M=A or C, R=A or G, W=A or T, Y=C or T and I=inosine.
[0359] Synthesis of the cDNA was primed with 100 ng 1992, followed by PCR with 200 ng each of 1992 and 3096. Cycles were 94° C. 1 min, [94° C. 1 min; 50° C. 1 min; 72° C. 1 min 30 secs] for 25 cycles and a final extension at 72° C. for 7 mins. 1 μl of the 1st round product was transferred to a second PCR reaction using 200 ng each of primers 3095 and 1784. Cycles were [94° C. 1 min; 52° C. 1 min; 72° C. 1 min 30 secs] for 25 cycles followed by a final extension at 72° C. for 7 mins. The nucleotide sequence and the deduced amino acid sequence of this clone, designated JC96, are shown in FIG. 5. The two NcoI restriction sites are marked in bold. This fragment was removed to generate the positive control plasmid for PCR (pJC96ΔNco). Note that nucleotides 1-14 and 918-932 are derived from the degenerate primers used to clone Sjo-1 and JC96 and so may not represent the genuine sequence of this element in those regions.
[0360] In FIG. 7, the following annotations have been used:
[0361] CH is from DNA of the submandibular gland of a patient with rheumatoid arthritis and secondary SS.
[0362] JC is the original clone from gradient fractionated RNA from a lip biopsy of a primary SS patient.
[0363] RB was cloned by RT-PCR from gradient fractionated RNA from the spleen of a primary SS patient with a B-cell lymphoma.
[0364] FD was cloned by RT-PCR from gradient fractionated RNA from the parotid gland of a non-SS subject.
[0365] MB was cloned by RT-PCR from gradient fractionated RNA from the submandibular gland of a non-SS subject.
[0366] The differences are mostly single base changes but there are also apparent insertions and deletions of bases that do not disrupt the ORF. One interesting observation is that the majority of differences between the five sequences occur in the CH sequence which unlike the other four sequences was amplified from DNA. A further observation from this data is that the PR ORF of one of the clones, MB, is truncated by 39 amino acids. This would render the virus non-viable if it were not compensated for by the RT ORF opening 39 amino acids earlier in this clone. The lengths of the overlap of the two ORFs are identical. The significance of these observations is at present unclear.
[0367] When considering these data attention should be drawn to the fact that PCR is notorious for giving false positive results due to cross-contamination of samples with the products of previous PCR experiments. This problem is greatly exacerbated when performing nested PCR experiments as here. Therefore in the abovementioned experiments, care was taken with controls to avoid false positives and to monitor the occurrence of cross-contamination. Specifically the measures taken were:
[0368] i) Separation of all experimental samples by including water controls which are taken through both stages of the nested reaction.
[0369] ii) UV cross-linking reaction mixes prior to the addition of template DNA.
[0370] iii) The use of a positive control which is a different size from the viral sequence. This was made by removing an internal NcoI fragment from the JC96 clone (indicated in FIG. 5).
[0371] Further Cloning of the Viral Genome.
[0372] From the above data provided by the present invention, it is clear that a “good” biopsy (i.e. one with a sufficiently high viral load) is required in order for HRV-5 to be cloned. Having established this, the present inventors have further provided sequence data and nested PCR primers which have been shown to detect proviral DNA in sample tissues. Therefore, even in the light of the fact that this element is present at very low levels in the specimens so far examined, and the fact that conventional methods (such as screening of a cDNA library prepared from infected tissue) cannot be used to clone the remainder of the virus the present invention provides materials and methods which would enable those skilled in the art to obtain further sequence data of HRV-5. Firstly inverse PCR methods as by Silver et al. (supra), Ochman et al, (supra) and Triglia et al, (supra) may be applied to genomic DNA obtained from an infected biopsy sample using primers disclosed herein or from the sequence data given in the figures. Secondly, viral sequences flanking the sequence data provided herein for HRV-5 may be amplified using degenerate PCR primers derived from other conserved regions of retroviral genomes in conjunction with primers specific for the HRV-5. Suitable primers are degenerate primers which work on a variety of retroviral sequences although they should be biased towards A, B and D-type sequences.
[0373] By coupling these primers with the specific primers described above, the cloned region of the genome could be expanded to include all but the long terminal repeat (LTR) and 3′ part of env. 5′ and 3′ rapid amplification of cDNA ends (RACE) (Frohman et al. 1988 , Proc. Nat. Acad Sci. USA 85: 8998-9002) respectively can be used to clone these regions. The target material for these primers will be genomic DNA or RNA containing HRV-5 sequences, eg from inflamed synovia or blood from patients with SLE or RA. Indeed these the aforementioned regions have been cloned using the methods described in following examples.
EXAMPLE 15
[0374] Cloning the 3′ Terminus of the HRV-5 Genome.
[0375] The final fragment of the HRV-5 genome was cloned using vectorette PCR on a Vectorette library constructed from Cla I digested DNA from bowel tissue from a patient with ulcerative colitis.
[0376] First stage primers:
[0377] HRV-5 pol primer (IN2F1)
[0378] 5′-CACGTCACTGTAGATACATATTCAG-3′; SEQ ID NO: 111
[0379] Vectorette primer (Genosys)
[0380] Conditions were 40 cycles of 94° C., 1 minute 10 seconds; 60° C., 1 minute 10 seconds; 72° C., 3 minutes with initial denaturation at 94° C. for 4 minutes. 1 μl of the first stage products were transferred to the second round reaction.
[0381] Primers:
[0382] HRV-5 pol primer (IN2F2)
[0383] 5′-GGTGTAGTTATGGCCACAGCCATG; SEQ ID NO: 112.
[0384] Vectorette nested primer (Genosys)
[0385] Conditions for this PCR were as for the first stage. In this experiment a third round of PCR was required to obtain a clean product and 1 pl of the second stage products was transferred to a third stage reaction containing primers IN2F3 and a vectorette primer.
[0386] Primers
[0387] HRV-5 pol primer (IN2F3)
[0388] 5′-AACACTGCTTGCAGGCTTTTGCAG-3′ SEQ ID NO: 113.
[0389] Vectorette sequencing primer (used as a third stage primer)
[0390] Conditions for this stage were 35 cycles of 94° C., 1 minute 10 seconds; 52° C., 1 minute 10 seconds; 72° C., 2 minutes with an initial denaturation at 94° C. for 4 minutes. Analysis of the products by agarose gel electrophoresis revealed a single product of 1455 bp. Sequencing revealed this to contain 997 bp of HRV-5 sequence comprising the remainder of the pol gene and the 3′ LTR. The fragment also included 458 bp of flanking genomic (i.e., non-HRV-5) DNA. Thus in this reaction the vectorette PCR allowed the amplification of the 3′ virus integration site. See FIGS. 18 and 19.
EXAMPLE 16
[0391] Amplification of the 5′ Long Terminal Repeat
[0392] Confirmation that the 3′ terminal region of HRV-5 was also present 5′ to gag was provided by PCR with specific primers in a hemi-nested PCR.
[0393] Primers:
U3F1 5′-CTGTGGGGAGCAACTCGGACTATAC; SEQ ID NO: 114 G2R1 5′-GCTTCCTGGCTCTCTAAATCCTTC; SEQ ID NO: 115 G2R2 5′-CTCACCGGTTCATTACAATAGCTGC; SEQ ID NO: 116.
[0394] PCR was performed on DNA extracted from a blood sample from a normal individual and colon tissue from a patient with ulcerative colitis. PCRs were performed using the Expand High Fidelity PCR System for Roche Molecular as recommended. First stage PCR was with primers U3F1 and G2R1. The conditions were 40 cycles of 94° C., 1 minute 20 seconds; 52° C., 1 minute 20 seconds; 68° C., 2 minutes with an initial denaturation at 94° C. for 4 minutes. One microlitre of the first round products were transferred to a second round hemi-nested PCR with primers U3F1 and G2R2. Conditions were as for the first round. A 1100 bp product was amplified from both samples. Sequencing confirmed that the expected LTR region (initially cloned as part of IN3) was present upstream of the gag sequence. In addition, the products of this PCR included fragment Gag7, Gag6, Gag5, Gag4 and part of Gag2, confirming that these regions are contiguous in the HRV-5 genome.
[0395] A full length HRV-5 clone was then constructed from the various PCR amplified fragments with the structure LTR-gag-pro-pol-LTR. See FIG. 21.
[0396] The cloning of the HRV5 LTR will facilitate methods for assessing expression and tropism of HRV5 in different cell types.
[0397] Reporter plasmids were constructed by amplifying the LTR of HRV-5 using the PCR and cloning into the luciferase reporter vector pGL-3 (Promega). LTR fragments were amplified in 50 μl reaction volumes using the Expand high fidelity PCR system (Roche Molecular) as recommended with primers LTR-F (5′-CTGTGGGGAG CAACTCGGACTATAC; SEQ ID NO: 114) and LTR-R (5′-CTTGCTGCTCCTCCGCACGCGG; SEQ ID NO: 117) using the plasmid pHRV56 as a template. PCR fragments were gel purified and blunt-end cloned into Sma I digested pGL-3 using standard procedures. Candidate clones were sequenced to confirm the identity and orientation of the LTR insert.
[0398] The ability of the HRV-5 LTR to drive expression of the luciferase reporter gene was then tested using the Dual-Luciferase Reporter Assay System (Promega) as recommended. This assay system measures the HRV-5 LTR activity relative to the activity of the SV40 early promoter (which is active in most cell types) in the same cell type. For example, in the 293-T cell line (a human embryonic kidney epithelial line) HRV-5 LTR had 39% of the activity of the SV40 early promoter under the assay conditions used.
EXAMPLE 17
[0399] A. Expression of HRV-5 Gag in Mammalian Cells
[0400] A diagnostic assay for HRV-5 infection can be based on indirect immunofluorescence assays (IFA) to detect anti-HRV5 antibodies present in patient serum samples. As we have not yet established a culture system for HRV-5, we have expressed the HRV-5 Gag polyprotein as a recombinant antigen in the human embryonic kidney epithelial cell line 293-T.
[0401] The HRV-5 gag gene was PCR amplified from human genomic DNA as follows:
[0402] Primers were:
F1 5′-TAGGAAAGAGGTATTTACTGG; SEQ ID NO: 118 R1 5′-ATCACGAATATTGGCGTATTCCATGG; SEQ ID NO: 119 F2 5′-GGGAGACTGTCTTCCACTACG; SEQ ID NO: 120 R2 5′-TGATGGTTGCAAATGGCCTGCCTC; SEQ ID NO: 121.
[0403] First round PCR reaction mixtures contained 10 pmol of F1 and R1 primer, 25 mM of each dNTP (Pharmacia), 2.5 mM MgCl 2 , 2.5 U of Taq polymerase in PCR buffer number 3 (Expand Long Template System, Roche Molecular), and 100 ng of DNA from bowel tissue of a patient with ulcerative colitis in a final volume of 50 μl. PCR cycling conditions were as follows: 3 min at 94° C.; 30 cycles, each consisting of 1 min at 94° C., 1 min at 51°, and 3min at 72° C. 1 μl of the first round products were transferred to a second stage PCR containing 10 pmol of F2 and R2 primer, 25 mM of each dNTP (Pharmacia), 2.5 mM MgCl 2 , 2.5 U of Taq polymerase in PCR buffer number 3 (Expand Long Template System, Roche Molecular), in a final volume of 50 μl. PCR cycling conditions were as for the first round of PCR. All the PCR amplifications were performed on a MJ research PTC200 apparatus, Peltier Thermal cycler. Analysis of second round PCR products on 1% TAE agarose gel revealed 3 kb and 0.9 kb bands.
[0404] Gag-PR PCR products were separated on an agarose gel, and the 3 kb PCR products were purified using the QIAquick Gel Extraction kit (Qiagen). Purified PCR products were blunt-end cloned into EcoR V-digested pBlueScript KS+ vector. This plasmid is named pBlue-gag124.
[0405] The HRV-5 Gag gene was then subcloned from pBlue-gag124 into pcDNA3.1+ (Invitrogen) using Nhe I and BamH I restriction sites contained in the PCR primers to generate plasmid pcDNA3.1+/HRV-5 Gag. Then, the GFP coding region was inserted into this plasmid as a C-terminal tag downstream of gag, using BamH I and Xba I restriction sites to create plasmid pcDNA3.1+/HRV-5 Gag-GFP.
[0406] Cloned PCR products were sequenced using an Applied Biosystems 373A automated DNA sequencer. Computer-aided analysis of protein and nucleotide sequences was performed with Sequencher program (FIG. 22).
[0407] Transfections were performed in six-well plates (Greiner). Cells were passaged the day before preparation of the six-well plates. On the day of the transfection, the cells were ˜70% confluent. Transfections were carried out with Lipofectamine (Gibco BRL) in accordance with the user's manual. The total amount of plasmid DNA used in transfections was 1.6 ug for each well, in a final volume of 1 ml of OPTIMEM 1 (Gibco BRL, ref 31985-047) for 5 to 6 hours at 37° C., after which the transfected cells were washed twice with DMEM, and the medium was changed to DMEM containing fetal calf serum. The cells were processed for further studies 24 to 48 hours after transfection.
[0408] HRV-5 Gag proteins can be expressed using any standard mammalian expression vector (e.g, pcDNA3.1, Invitrogen) using methods well known in the art.
[0409] However, in preliminary experiments using pcDNA3.1+/HRV-5Gag-GFP, only a very low level of Gag-GFP protein expression was observed. To obtain a higher expression level, we used an inducible mammalian expression system to express HRV-5 Gag-GFP fusion proteins. This system (Geneswitch) contains an intron between the promoter and the HRV-5 Gag coding sequence.
[0410] The “Geneswitch” System (Invitrogen) is an inducible expression system with a transcription control mechanism that offers minimal levels of basal expression in mammalian cells. The “Geneswitch” expression vector pGene/V5-His provides a hybrid promoter sequence, GAL4 UAS/E1b consisting of a 10-base pair TATA box sequence from the Adenovirus E1b gene and six binding sites for the yeast GAL4 protein. Without additional factors, the GAL4 UAS/E1b sequence is transcriptionally silent, yielding the lowest possible level of basal expression.
[0411] For inducible expression, the addition of mifepristone activates transcription from the GAL4 UAS/Elb promoter and expression of the desired protein, in this case the HRV-5 Gag-GFP fusion protein.
[0412] Plasmid constructs
[0413] Primers used:
F7-SEQ ID NO: 122 ATAAGAAT GCGGCCGC TAAACTATGCCATGGAGTTCTTTGGCTACTCTTTG R7-SEQ ID NO: 123 ATAGTTTA GCGGCCGC ATTCTTATGGTACCGAATATTCGGTGTCTCGTAAC F9-SEQ ID NO: 124 ATAAGAAT GCGGCCGC TAAACTATGCCATGGTGAGCAAGGGCGAGGAGCTG TTCACCTTCACC R9- SEQ ID NO: 125 ATAGTTTA GCGGCCGC ATTCTTATGCTTGTACAGCTCGTCCATGCCGAG R1O- SEQ ID NO: 126 ATAGTTTA GCGGCCGC ATTCTTATTTACTTGTACAGCTCGTCCATGCCGAG
[0414] The HRV-5 Gag gene was amplified from gagl24-pBlue plasmid, using F7 and R7 primers. The GFP gene was amplified from pCDNA3.1-emerald plasmid using F9 and R9 primers. The HRV-5 Gag-GFP fusion fragment was amplified from pcDNA3.1+/HRV-5 Gag-GFP using F7 and R10 primers. PCR reactions were performed as described above.
[0415] GFP, HRV-5 Gag and HRV-5 Gag-GFP PCR products were cloned into pGene/V5-His using a Not I restriction site engineered into the primer. HRV-5 Gag and GFP genes were cloned in frame with V5-His Tag in their C-terminus. The constructs are called pGene/HRV-5-Gag-GFP, pGene/GFP, pGene/HRV-5 Gag.
[0416] Transfections were performed in 293T cells plated in six-well plates (Greiner) as described above. 293-T cells were co- transfected with pSwitch and pGene/HRV-5 Gag-GFP, pGene/GFP. The day after transfection, mifepristone was added to the culture medium to a final concentration of 20 nm. The total amount of DNA used in transfections was 1.6 μg of pGene constructs and 0.4 μg of pSwitch plasmid. The cells were processed for further studies 24 hours after transfection.
[0417] Eight hours after induction, green cells were already visible. Twenty-four hours after transfection, about 20% of transfected cells are green indicating expression of HRV-5-Gag-GFP proteins.
[0418] HRV-5 Gag-GFP proteins are localized in the cytoplasm of transfected cells with a fairly homogeneous distribution (FIG. 23A). Immunoblot analysis of cell lysates prepared from 293T cells transfected with pGene/HRV-5 Gag-GFP showed a strong 25 kDa protein using monoclonal anti-GFP antibodies (JL8) (FIG. 23B).
[0419] While certain of the preferred embodiments of the present invention have been described and specifically exemplified above, it is not intended that the invention be limited to such embodiments. Various modifications may be made thereto without departing from the scope and spirit of the present invention, as set forth in the following claims.
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The present invention relates to a novel retrovirus associated with autoimmune disease. The present invention provides nucleotide and amino acid sequences relating to GAG, PRO and POL proteins of the retrovirus as well as diagnostic techniques and antibodies for use in diagnosis. The retrovirus (HRV-5) according to the present invention has been detected in inflamed joints (RA, osteoarthritis (OA), reactive arthritis and psoriatic arthritis) but not normal synovium. Further, HRV-5 proviral DNA has been detected in blood from patients with RA and systemic lupus erythematosus (SLE).
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CROSS REFERENCE TO RELATED APPLICATIONS
This is a continuation-in-part application of U.S. patent application Ser. No. 08/621,781, filed Mar. 22, 1996, which is incorporated by reference herein.
BACKGROUND OF THE INVENTION
Colorectal cancer is the most common visceral cancer in the United States. Each year, more than 160,000 new cases of colorectal cancer are detected which account for more than 60,000 deaths. The national incidence of colorectal cancer appears to be on the rise, as it increased by 9.4% from 1973 to 1986 based on a sample of 10% of the U.S. population. Unfortunately, the five-year survival rate has not improved significantly over the past four decades. As prognosis worsens with more advanced cancers, many physicians and several national medical societies advocate routine screening to increase early stage detection. However, while the rationale for screening is sound, such efforts at secondary prevention require an enormous use of medical resources and have not been shown to be effective in a general population.
Colorectal cancer provides unique opportunities for primary intervention among human malignancies because it progresses through clinically recognizable stages from normal mucosa through enlarging and increasingly dysplastic polyps which eventuate in carcinoma. Support for the adenoma to carcinoma sequence is provided by epidemiological studies, shared genetic properties of both adenomas and carcinomas, and the natural history of adenomas as observed in patients with familial adenomatous polyposis. Nicholson ML, et al., "Increased Cell Membrane Arachidonic Acid in Experimental Colorectal Tumors," Gut 32:413-8 (1991); Fearon E R, et al., "Colonal Analysis of Human Colorectal Tumors," 238 Science 193 (1987); and Bussey H J R, "Familial Polyposis Coli," Family Studies, Histopathology, Differential Diagnosis, and Results of Treatment (Johns Hopkins University Press, Baltimore 1975). Genetic factors appear to mediate the development of colonic adenomas in familial adenomatous polyposis (FAP), for example, and may also play a role in the development of sporadic adenomas and carcinomas. In addition, there is evidence for an accumulating series of genetic deletions and mutations including known oncogenes and tumor suppressors, that accompany the transition from normal mucosa to adenoma to carcinoma.
The precursor relationship of colorectal adenoma to carcinoma and the high prevalence of adenomas makes them an attractive target in chemoprevention trials. The prevalence increases with age in moderate and high risk populations, reaching 20-40% at the age of 50-60 years, and 50% or more for individuals older than 70 years. The steepest increase in adenoma prevalence occurs between the ages of 50-59. However, removal of polyps does not change the pathogenetic milieu responsible for their growth and development. The recurrence rate for colorectal adenomas has been variably reported, but most studies document an adenoma recurrence rate of 20-60% by two years. Nava H, et al., "Follow-up Colonoscopy in Patients With Colorectal Adenomatous Polyps," 30 Dis. Colon Rectum 465 (1987); Olsen H W, et al., "Review of Recurrent Polyps in Cancer in 500 Patients With Initial Colonoscopy for Polyps," 31 Dis. Colon Rectum 222 (1988); Williams C. B. and Macrae F. A., "The St. Mark's Neoplastic Polyp Follow-up Study," 10 Front Gastrointest. Res. 1226 (1986). Winawer recently reported that 28% of patients who had newly diagnosed adenomas removed by colonoscopy had additional polyps detected at a one-year follow-up examination, and of those patients, 22% had new adenomatous polyps again detected on examination two years later. Winawer S. J., et al., "Randomized Comparison of Surveillance Intervals After Colonoscopic Removal of Newly Diagnosed Adenomatous Polyps," 328 New Engl. J. Med. 901 (1993). Patients who have undergone surgical resection of a primary colorectal cancer have also been shown to be at high risk of developing metachronous adenomas. Olsen H. W., et al., "Review of Recurrent Polyps in Cancer in 500 Patients With Initial Colonoscopy for Polyps," 31 Dis. Colon Rectum 222 (1988).
Several studies have focused attention on bile acids as a potential mediator of the dietary influence on colorectal cancer risk. Hofmann A. F., "Chemistry and Enterohepatic Circulation of Bile Acids," Hepatology 4S-14S (1984). Bile acids are important detergents for fat solubilization and digestion in the proximal intestine. Specific transport processes in the apical domain of the terminal ileal enterocyte and basolateral domain of the hepatocyte account for the efficient conservation in the enterohepatic circulation. Only a small fraction of bile acids enter the colon; however, perturbations of the cycling rate of bile acids by diet (e.g., fat) or surgery (e.g., cholecystectomy) may increase the fecal bile acid load and perhaps account for the associated increased risk of colon cancer. Hill M. J., "Bile Flow and Colon Cancer," 238 Mutation Review 313 (1990). Studies linking perturbations in fecal bile acids with human colon cancer, however, have been inconsistent and controversial. The inconsistencies could stem from differences in the populations studied, patient selection, or methodologic artifacts in measuring fecal bile acid excretion.
Thus, chemoprevention of colorectal cancer, by dietary or pharmacologic intervention, remains to be established. There is a continuing need, therefore, to develop new chemopreventative treatments for colorectal adenomas.
SUMMARY OF THE INVENTION
The present invention provides a method for preventing a recurrence of colorectal adenomas in a human patient afflicted with such adenomas comprising administering ursodeoxycholic acid (URSO), or an amino acid conjugate of ursodeoxycholic acid or a pharmaceutically-acceptable salt thereof, in an amount effective to prevent the recurrence of colorectal adenomas following removal thereof. A dose of about 50 to 7500 mg per day of ursodeoxycholic acid, its amide-conjugate or a pharmaceutically-acceptable salt thereof is preferably administered to the patient. More preferably, the dose is about 200 mg to 5000 mg. For example, in the working examples presented herein below, the dose is at about 750 mg to 1500 mg per day. The ursodeoxycholic acid, its amide-conjugate or a pharmaceutically-acceptable salt thereof is preferably administered orally. If an amino acid conjugate of ursodeoxycholic acid is to be administered, it is preferred that the URSO be conjugated to taurine or glycine. More preferably, the URSO will be conjugated via an amido group to taurine.
Ursodeoxycholic acid is also referred to herein as "URSO" or "ursodiol" or "ursodeoxycholate." The taurine-conjugate of ursodeoxycholic acid is also referred to herein as "tauroursodeoxycholic acid" or "TURSO" or "tauroursodiol" or "taurodeoxycholate."
The present method optionally further comprises administering a nonsteroidal anti-inflammatory agent (NSAID), or a pharmaceutically-acceptable salt thereof, in combination with the administration of ursodeoxycholic acid, its amino acid conjugate or a pharmaceutically-acceptable salt thereof to prevent the recurrence of colorectal adenomas. Preferably, the nonsteroidal anti-inflammatory agent is sulindac, a phenolic NSAID or a pharmaceutically acceptable salt thereof.
For example, if sulindac is selected as the NSAID, it can be administered orally at a dose of about 10 mg to 1500 mg per day. Preferably, sulindac is administered at a dose of about 50 mg to 500 mg per day. More preferably the sulindac is orally administered at a dose of about 150 mg to 300 mg per day.
Phenolic NSAIDs useful in the present method include 5-aminosalicylic acid, acetylsalicylic acid, acetaminophen, sulfasalazine, benzalazine, olsalazine, N-acetyl-5-aminosalicylic acid, 4-amino-2-hydroxy benzoic acid, or biologically equivalent metabolites thereof. Most preferably, the aminosalicylic acid is 5-aminosalicylic acid. 5-aminosalicylic acid is also referred to herein as 5-amino-2-hydroxy benzoic acid or mesalamine.
If mesalamine is selected for use in the present method, it can be administered orally at a dose of about 10 mg to 10000 mg per day. Preferably, mesalamine is administered at a dose of about 500 mg to 8000 mg per day. More preferably the mesalamine is orally administered at a dose of about 1000 mg to 5000 mg per day.
As used herein with respect to the present method, the term "afflicted with" encompasses a patient at risk of recurrence or development of colorectal adenomas, as well as a patient who has developed said adenomas, and who is at risk for recurrence or progression of the condition.
DETAILED DESCRIPTION OF THE INVENTION
Ursodeoxycholate (URSO), which is the hydrophilic 7-beta epimer of chenodeoxycholate, is notable for its lack of cytotoxicity in a variety of model cell systems including colonic epithelia. As a drug, it is rapidly absorbed from the proximal small intestine, extracted by the liver, conjugated and secreted, whereupon it enters the enterohepatic circulation. These properties have led to its clinical use in gallstone dissolution and as proposed treatment in the chronic cholestatic cholangiopathies, primary biliary cirrhosis and sclerosing cholangitis.
URSO has the advantage of being virtually free of side effects. Doses of ursodeoxycholate at 15 mg/kg/day used in primary biliary cirrhosis trials were extremely well tolerated and without toxicity. Poupon R E, et al., "A Multicenter, Controlled Trial of Ursodiol for the Treatment of Primary Biliary Cirrhosis," 324 New Engl. J. Med. 1548 (1991). An extensive review of the use of URSO in clinical trials revealed that treatment with URSO resulted in 1) an infrequent, transient elevation of hepatic transaminases, 2) a frequent reduction in serum triglycerides, and 3) a transient, mild diarrhea in 3% of patients (range=0-9% of patients) that resolved spontaneously without dose reduction. Bachrach W H and Hofmann A F, "Ursodeoxycholic Acid in the Treatment of Cholesterol Cholelithiasis," 27 Dig. Dis. Sci. 833 (1982). Doses of up to 22-25 mg/kg/day can be well-tolerated. Further, the drug can be administered in a single daily dose, which can lead to improved compliance over multiple divided doses.
While the precise mechanism of action is unknown, the beneficial effect of URSO therapy is closely linked to the enrichment of the hepatic bile acid pool with this hydrophilic bile acid. It has thus been hypothesized that bile acids more hydrophilic that URSO will have even greater beneficial effects that URSO. For example, tauroursodeoxycholate (TURSO) the taurine conjugate of ursodeoxycholate.
In this respect, amino acid conjugates of URSO are significantly more polar that URSO. It has been shown that orally administered unconjugated URSO undergoes rapid biotransformation to conjugated species during first pass clearance. Furthermore, it has been reported that negligible proportions of unconjugated URSO are present in the bile of humans. Therefore, the therapeutic effectiveness of URSO can be enhanced via conjugation. Crosignani et al., "Tauroursodeoxycholic acid for the treatment of primary biliary cirrhosis: a dose-response study (abstract)", 18 Hepatology 606 (1993).
TURSO retains the positive characteristics of URSO administration including tolerance and low toxicity. In addition, compared with URSO, TURSO causes a greater increase in the hydrophilic/hydrophobic bile acid pool, limits lithocholate formation and increases the hepatic URSO concentration. Rodrigues, C. et. al., "Tauroursodeoxycholate Increases Rat Liver Ursodeoxycholate Levels and Limits Lithocholate Formation Better Than Ursodeoxycholate," 109 Gastroenterology 564 (1995). Clinical trials using TURSO suggest that, like URSO, TURSO is valuable as a drug to treat primary biliary cirrhosis. Ferri F. et al., "Taurodeoxycholic acid in the treatment of primary biliary cirrhosis. A controlled study in comparison to ursodeoxycholic acid," 143 Clinica Terapeutica 321 (1993).
Nonsteroidal anti-inflammatory drugs (NSAIDs), such as sulindac or phenolic NSAIDs can inhibit the neoplastic transformation of colorectal epithelium. Several mechanisms may explain the NSAID chemopreventative effect; including inhibition of prostaglandin synthesis, growth factors, or genetic mutations that ultimately lead to colorectal cancer. As of yet, however, the exact mechanism(s) remains to be established.
All NSAIDs inhibit cyclooxygenase, the enzyme that converts arachidonic acid to prostaglandins and thromboxanes. Patients receiving relatively low doses of NSAIDs (e.g., piroxicam, 7.5 mg/day) have shown a sustained, significant reduction (>20%) in colorectal mucosal PGE 2 concentrations. Earnest DL, et al., "NSAIDs for Prevention of Colon Cancer; Early Studies with Piroxicam in Humans," Presented at Fourth International Conference on Prevention of Human Cancer: Nutrition in Chemoprevention Controversies (Jun. 3-6, 1992). Immune surveillance is also enhanced by drugs such as NSAIDs that reduce PGE 2 synthesis. Id. Thus, prostaglandin inhibition can potentially suppress abnormal proliferation of colorectal epithelium and progression toward dysplastic lesions.
Indomethacin, piroxicam, and sulindac have all been shown to inhibit carcinogen-induced colonic tumors in rodents. Narisewa T, et al., "Inhibition of Development of Methylnitrosourea-Induced Rat Colon Tumors by Indomethacin Treatment," 41 Cancer Research 1954 (1981); Pollard M, et al., "The Suppressive Effect of Paroxican on Autochthonous Intestinal Tumors in the Rat," 21 Cancer Letters 57 (1983); Moorghen M, et al. "The Protective Effect of Sulindac Against Chemically-Induced Primary Colonic Tumors in Mice," 156 J. Pathol. 341 (1988). In humans, however, indomethacin achieves relatively low colonic concentrations, and has not been shown to inhibit or induce regression of colonic polyps. Hucher H. B., et al., "Studies on the Absorption, Distribution, and Excretion of Indomethacin in Various Species," 153 J. Pharmacol. Exp. Ther. 237 (1966).
The most dramatic example of abnormal colonic proliferation occurs in familial adenomatous polyposis (FAP), a relatively rare genetic disorder that manifests an extraordinary number of adenomatous colonic polyps and resulting cancers in affected individuals. Since 1983, numerous published reports have described moderate to marked polyp regression in FAP patients treated with sulindac for up to six months. Waddell W. R. and Longhry R. W., "Sulindac for Polyposis of the Colon," 24 J. Surg. Onc. 83 (1983); Labayle D, et al., "Sulindac Causes Regression of Rectal Polyps in Familial Adenomatous Polyposis," 101 Gastroenterology 635 (1991); Rigau J, et al., "Effects of Long-Term Sulindac Therapy on Colonic Polyposis" 115 Annals of Internal Medicine 952 (1991); Waddell W. R., et al., "Sulindac for Polyposis of the Colon," 157 Am. J. Surg. 175 (1989). This effect occurred both in patients with only residual rectal mucosa (following total colectomy) and in patients with diffuse colonic polyposis. Polyp regression was typically rapid. Polyps, however, recurred relatively quickly after stopping sulindac.
On the other hand, although the mode of action is unclear, the ability of phenolic NSAIDs to scavenge radicals is thought to be a major factor responsible for the observed therapeutic efficacy. Fischer C., et. al., "Radical-derived Oxidation Products of 5-aminosalicylic acid and N-acetyl-5-aminosalicylic Acid", 661 J. Chromatography, 57 (1994). It has further been hypothesized that production of reactive oxygen metabolites contribute significantly to the tissue injury that occurs during active inflammatory bowel disease. Ahnfelt-Rhonne I., et al., 38 Dan. Med. Bulletin, 291 (1991). Therefore, agents that decrease the amounts of reactive oxygen metabolites by inhibiting the production or scavenging may reduce the inflammatory reaction. Ahnfelt-Rhonne I., supra.
Mesalamine, which is the active metabolite of sulfasalazine, is a radical scavenger and its therapeutic action may be explained in-part through this effect. Ahnfelt-Rhonne I., et al., "Clinical Evidence Supporting the Radical Scavenger Mechanism of 5-aminosalicylic acid", 98 Gastroenterology 1162 (1990). In fact, it has been suggested that mesalamine may be useful as an anticarcinogenic compound. Mestecky J, "Antioxidant Properties of 5-aminosalicylic Acid: Potential Mechanism for its Protective Effect in Ulcerative Colitis," Advances in Mucosal Immunology, 1317-21 (Plenum Press, New York and London) (1995).
The potential chemopreventative benefits of sulindac, mesalamine or any other NSAID used as a single agent is tempered by their well-known toxicities and moderately high risk of intolerance. Abdominal pain, dyspepsia, nausea, diarrhea, constipation, rash, dizziness, or headache have been reported in 3-9% of patients. Physician's Desk Reference, 1433-1435 (Medical Economics Company, 1993). Toxicities reported in 1-3% of patients include flatulence, anorexia, gastrointestinal cramps, pruritus, nervousness, tinnitus, and edema. A large number of other toxicities have been reported associated with sulindac in less than 1% of cases, including renal and hepatic toxicity, and gastrointestinal bleeding. NSAIDs have been increasingly recognized as an important cause of peptic ulceration. The elderly appear to be especially vulnerable, as the incidence of NSAID-induced gastroduodenal ulcer disease, including gastrointestinal bleeding, is higher in those over age 60; this is also the age group most likely to develop colorectal cancer, and therefore, most likely to benefit from chemoprevention.
The amount of URSO, TURSO, sulindac, or mesalamine required for use in treatment varies not only with the particular form of each agent but also with the severity of the symptoms being treated and the age and condition of the patient.
For human dosage, effective amounts of URSO or amino acid conjugated URSO would fall generally in the range of 50 to 7500 mg per day of ursodeoxycholic acid for adult patients. Preferably, the dose is about 200 mg to 5000 mg of URSO or amide-conjugated URSO per day. More preferably, the dose is about 750 mg to 1500 mg URSO or amide-conjugated URSO per day.
Effective amounts of sulindac can be administered at a dose of about 10 mg to 1500 mg per day. Preferably, sulindac is administered at a dose of about 50 mg to 500 mg per day. More preferably the sulindac is administered at a dose of about 150 mg to 300 mg per day. Compositions of this invention may be administered one or more times daily.
Effective amounts of mesalamine can be administered at a dose of about 10 mg to 10000 mg per day. Preferably, mesalamine is administered at a dose of about 500 mg to 8000 mg per day. More preferably the mesalamine is administered at a dose of about 1000 mg to 5000 mg per day.
The pharmaceutically acceptable salts of the biologically active compounds may include carboxylic acid salts, such as alkali metal carboxylates and quaternatery ammonium salts. These physiologically acceptable salts are prepared by methods known in the art, e.g., by dissolving the free amine bases with an excess of the acid in aqueous alcohol, or neutralizing a free carboxylic acid with an alkali metal base such as a hydroxide, or with an amine.
Although the compounds of the present invention and/or its salts may be administered as the pure chemicals, it is preferable to present the active ingredient as a pharmaceutical composition. Pharmaceutical compositions comprising unit dosage forms of URSO, TURSO, sulindac, mesalamine or salts thereof in combination with a pharmaceutically acceptable carrier are commercially available or may be prepared from standard ingredients using standard techniques. The invention thus further provides a pharmaceutical composition comprising one or more of the claimed compounds and/or a pharmaceutically acceptable salt thereof, together with one or more pharmaceutically acceptable carriers therefor and, optionally, other therapeutic and/or prophylactic ingredients. The carrier(s) must be "acceptable" in the sense of being compatible with the other ingredients of the composition and not deleterious to the recipient thereof.
Pharmaceutical compositions include those suitable for oral or parenteral (including intramuscular, subcutaneous and intravenous) administration. The compositions may, where appropriate, be conveniently presented in discrete unit dosage forms and may be prepared by any of the methods well known in the art of pharmacy. Such methods include the step of bringing into association the active compound with liquid carriers, solid matrices, semi-solid carriers, finely divided solid carriers or combination thereof, and then, if necessary, shaping the product into the desired delivery system.
Pharmaceutical compositions suitable for oral administration may be presented as discrete unit dosage forms such as hard or soft gelatin capsules, cachets or tablets each containing a predetermined amount of the active ingredient; as a powder or as granules; as a solution, a suspension or as an emulsion. The active ingredient may also be presented as a bolus, electuary or paste. Tablets and capsules for oral administration may contain conventional excipients such as binding agents, fillers, lubricants, disintegrants, or wetting agents. The tablets may be coated according to methods well known in the art, i.e., with enteric coatings.
Oral liquid preparations may be in the form of, for example, aqueous or oily suspension, solutions, emulsions, syrups or elixirs, or may be presented as a dry product for constitution with water or other suitable vehicle before use. Such liquid preparations may contain conventional additives such as suspending agents, emulsifying agents, non-aqueous vehicles (which may include edible oils), or preservative.
The typical acceptable pharmaceutical carriers for use in oral formulations are exemplified by sugars as lactose, sucrose, mannitol, and sorbitol; starches such as corn starch, tapioca starch, and potato starch; cellulose and derivatives such as sodium carboxymethyl cellulose, ethyl cellulose, and methyl cellulose; calcium phosphates such as dicalcium phosphate and tricalcium phosphate; sodium sulfate, calcium sulfate; polyvinyl pyrrolidone, polyvinyl alcohol, stearic acid, alkaline earth metal stearates such as magnesium stearate and calcium stearate; vegetable oils such as peanut oil, cottonseed oil, sesame oil, olive oil, and corn oil; nonionic, cationic and anionic surfactants; ethylene glycol polymers; beta-cyclodextrin; fatty alcohols and hydrolyzed cereal solids; as well as other non-toxic compatible fillers, binders, disintegrants, buffers, antioxidants, lubricants, flavoring agents, and the like commonly used in pharmaceutical formulations.
The compounds according to the invention may also be formulated for parenteral administration (e.g., by injection, for example, bolus injection or continuous infusion) and may be presented in unit dose form in ampules, pre-filled syringes, small bolus infusion containers or in multi-doses containers with an added preservative. The compositions may take such forms as suspensions, solutions, or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing and/or dispersing agents. Injectable formulations use aqueous physiologically acceptable carriers, e.g., distilled water, and preferably contain a compatible buffer system selected to maintain the pH in the desired range of 6.5 to 8, preferably about 7.0 to 7.4. A typical buffer system is a combination of sodium dibasic phosphate and sodium monobasic phosphate. Alternatively, the active ingredient may be in powder form, obtained by aseptic isolation of sterile solid or by lyophilization from solution, for constitution with a suitable vehicle, e.g., sterile, pyrogen-free water, before use.
For topical administration to the epidermis, the compounds of the present invention may be formulated as ointments, creams or lotions, or as the active ingredient of a transdermal patch. Suitable transdermal delivery systems are disclosed, for example, in Fisher et al. (U.S. Pat. Nos. 4,788,603) or Bawas et al. (U.S. Pat. Nos. 4,931,279, 4,668,504 and 4,713,224) or Chien et al. (U.S. Pat. Nos. 4,818,540, 5,296,230, and 5,045,319). When desired, the above-described compositions can be adapted to provide sustained or prolonged release of the active ingredient employed, e.g., by combination thereof with certain hydrophilic polymer matrices, e.g., comprising natural gels, synthetic polymer gels or mixtures thereof.
Ointments and creams may, for example, be formulated with an aqueous or oily base with the addition of suitable thickening and/or gelling agents, such as gelatin, vegetable oils, polyalkylene glycol, or alcohol. Lotions may be formulated with an aqueous or oily base and will in general also contain one or more emulsifying agents, stabilizing agents, dispersing agents, suspending agents, thickening agents, or coloring agents. The active ingredient can also be delivered via iontophoresis, e.g., as disclosed in U.S. Pat. Nos. 4,140,122, 4383,529, or 4,051,842. Topical compositions may also include standard liquid formulations, e.g., distilled water or physiological saline solutions, in combination with nontoxic thickeners and preservatives.
Compositions suitable for topical administration in the mouth include unit dosage forms such as lozenges comprising active ingredient in a flavored base, usually sucrose and acacia or tragacanth; pastilles comprising the active ingredient in an inert base such as gelatin and glycerin or sucrose and acacia; mucoadherent gels, and mouthwashes comprising the active ingredient in a suitable liquid carrier.
The pharmaceutical compositions according to the invention may also contain other adjuvants such as flavorings, coloring, antimicrobial agents, or preservatives.
It will be further appreciated that the amount of the compound, or an active salt or derivative thereof, required for use in treatment will vary not only with the particular salt selected but also with the route of administration, the nature of the condition being treated and the age and condition of the patient and will be ultimately at the discretion of the attendant physician or clinician.
The desired dose may conveniently be presented in a single dose or as divided doses administered at appropriate intervals, for example, as two, three, four or more sub-doses per day. The sub-dose itself may be further divided, e.g., into a number of discrete loosely spaced administrations; such as multiple inhalations from an insufflator.
All publications, patents and patent documents are incorporated by reference herein, as though individually incorporated by reference. The invention has been described with reference to various specific and preferred embodiments and techniques. However, it should be understood that many variations and modifications may be made while remaining within the spirit and scope of the invention.
The following examples are intended to illustrate but not limit the invention.
EXAMPLE 1
A total of 900 patients are recruited to study the chemopreventative effects of ursodeoxycholic acid (URSO) to prevent the recurrence of metachronous adenomatous colorectal polyps. The study patients are male and female, age 50 and older who have had complete endoscopic or surgical resection of a histologically verified colorectal adenoma (at least 5 mm in size) or early-stage carcinoma (Duke's A or B1) resulting in a neoplasm-free colorectum, within three months prior to entering the study. The study patients must have an intact rectum and more than half of the colorectum remaining.
The patients are divided into three treatment groups. The treatment groups, defined by the dosages of sulindac and URSO, are shown below:
______________________________________Placebo 750 mg q/d URSO 750 mg b.i.d. URSO______________________________________n = 300 n = 300 n = 300______________________________________
To ensure that both the patient and the medical professionals who care for the patient are blind to the identity of the treatment assignment, only the study coordinator and the study group statisticians have access to the uncoded list of patients' identification numbers and their treatment assignments. In addition, all patients take the same number of pills each day (active drug, placebo or both). Patients take the URSO tablets (250 mg) or its placebo orally twice a day with meals for about one year. URSO and placebo are available from Axcan Pharma (Interfalk, Canada Inc., Quebec, Canada).
One year after initiating the study, each patient receives a follow-up coloscopic examination. Following sedation with intravenous midazolam and/or a narcotic at doses deemed appropriate by the colonoscopist, the rectum is intubated and the colonoscope advanced to the cecum in the usual fashion. Upon withdrawal of the colonoscope, all neoplastic lesions are identified, and their location and size recorded. All neoplastic lesions visualized are removed in the usual fashion, using the electrocautery snare or hot biopsy-forceps technique. The colonoscopist documents (1) whether a complete or a limited examination was performed, (2) the quality of the preparation, and (3) whether or not all visualized polypoid tissue was removed.
The primary endpoint of the study is the recurrence of polyps considered as a dichotomous outcome. A logistic regression for polyp recurrence (yes/no) at one year is used to assess treatment effects. Distributions of polyp size and number is determined for and compared among randomized groups. Although the randomization procedure should result in balanced treatment groups, the stratification factors and a few other variables (e.g., size, number of index polyps) thought to be associated with recurrence of polyps are included as covariates in the logistic regression model. Patients who "drop out" during the follow-up period (either due to toxicity or non-compliance) are considered as treatment failures (recurrent polyps), based on an "intent to treat" philosophy. The incidence of toxicity and compliance rates for each treatment arm is estimated, and the rates are compared among the treatment groups using a logistic regression analysis.
Summaries of the distribution of primary and secondary outcomes done by each stratification factor separately, is tabulated using means and standard errors, medians, and inter-quartile range, or percentages, as appropriate for continuous or discrete data. Distributions of primary and secondary endpoints is also tabulated separately by sex and by ethnic/racial minority status.
EXAMPLE 2
A total of 1200 patients are recruited to study the chemopreventative effects of ursodeoxycholic acid (URSO), the nonsteroidal anti-inflammatory drug (NSAID) sulindac, or URSO in combination with sulindac, to prevent the recurrence of metachronous adenomatous colorectal polyps. The study patients are male and female, age 50 and older who have had complete endoscopic or surgical resection of a histologically verified colorectal adenoma (at least 5 mm in size) or early-stage carcinoma (Duke's A or B1) resulting in a neoplasm-free colorectum, within three months prior to entering the study. The study patients must have an intact rectum and more than half of the colorectum remaining.
The patients are divided into nine treatment groups. The treatment groups, defined by the dosages of sulindac and URSO, are shown below:
______________________________________ 750 mg qd 750 mg BID Placebo BID URSO URSO TOTAL______________________________________Placebo BID n = 150 n = 100 n = 150 400150 mg qd n = 100 n = 200 n = 100 400Sulindac150 mg BID n = 150 n = 100 n = 150 400SulindacTOTAL 400 400 400 1200______________________________________
The factorial design recruits 1200 total patients randomized as shown per cell, yielding 400 patients per dosage group for each study drug.
To ensure that both the patient and the medical professionals who care for the patient are blind to the identity of the treatment assignment, only the study coordinator and the study group statisticians have access to the uncoded list of patients' identification numbers and their treatment assignments. In addition, all patients take the same number of pills each day (active drug(s), placebo, or both). Patients take the sulindac tablets (150 mg) or its placebo orally twice a day with meals for about one year. The URSO tablets (250 mg) or its placebo are also taken orally twice a day with meals for about one year. Sulindac and its matching placebo are available from Merck Sharp and Dohme (West Point, Pa.). URSO and placebo are available from Interfalk (Quebec, Canada).
One year after initiating the study, each patient receives a follow-up coloscopic examination. Following sedation with intravenous midazolam and/or a narcotic at doses deemed appropriate by the colonoscopist, the rectum is intubated and the colonoscope advanced to the cecum in the usual fashion. Upon withdrawal of the colonoscope, all neoplastic lesions are identified, and their location and size recorded. All neoplastic lesions visualized are removed in the usual fashion, using the electrocautery snare or hot biopsy-forceps technique. The coloscopist documents (1) whether a complete or a limited examination was performed, (2) the quality of the preparation, and (3) whether or not all visualized polypoid tissue was removed.
The primary endpoint of the study is the recurrence of polyps considered as a dichotomous outcome. A logistic regression for polyp recurrence (yes/no) at one year is used to assess treatment effects. Distributions of polyp size and number is determined for and compared among randomized groups. Although the randomization procedure should result in balanced treatment groups, the stratification factors and a few other variables (e.g., size, number of index polyps) thought to be associated with recurrence of polyps are included as covariates in the logistic regression model. Patients who "drop out" during the follow-up period (either due to toxicity or non-compliance) are considered as treatment failures (recurrent polyps), based on an "intent to treat" philosophy. The incidence of toxicity and compliance rates for each treatment arm is estimated, and the rates are compared among the treatment groups using a logistic regression analysis.
Summaries of the distribution of primary and secondary outcomes done by each stratification factor separately, is tabulated using means and standard errors, medians, and inter-quartile range, or percentages, as appropriate for continuous or discrete data. Distributions of primary and secondary endpoints is also tabulated separately by sex and by ethnic/racial minority status.
NSAIDs are ubiquitous, are available in over-the-counter preparations as well as prescription varieties, and are often used to treat a wide spectrum of symptoms and diseases. In order to prevent contamination of groups by the inadvertent use of an NSAID, patients are given a list of NSAIDs, as well as a list of over-the-counter medications that contain an NSAID (e.g., Darvon contains aspirin). Patients are instructed to avoid these agents (Tylenol may be used). If the prolonged use of an NSAID is medically necessary, the patient is disqualified from the study.
EXAMPLE 3
A total of 1200 patients will be recruited to study the chemopreventative effects of tauroursodeoxycholic acid (TURSO), the phenolic NSAID mesalamine, or TURSO in combination with mesalamine, to prevent the recurrence of metachronous adenomatous colorectal polyps. The study patients will be male and female, age 50 and older who have had complete endoscopic or surgical resection of a histologically verified colorectal adenoma (at least 5 mm in size) or early-stage carcinoma (Duke's A or B1) resulting in a neoplasm-free colorectum, within three months prior to entering the study. The study patients must have an intact rectum and more than half of the colorectum remaining.
The patients will be divided into nine treatment groups. The treatment groups, defined by the dosages of mesalamine and TURSO, are shown below:
______________________________________ 750 mg qd 750 mg BID Placebo BID URSO URSO TOTAL______________________________________Placebo BID n = 150 n = 100 n = 150 400400 mg qd n = 100 n = 200 n = 100 400Mesalamine400 mg BID n = 150 n = 100 n = 150 400MesalamineTOTAL 400 400 400 1200______________________________________
The factorial design recruits 1200 total patients randomized as shown per cell, yielding 400 patients per dosage group for each study drug.
To ensure that both the patient and the medical professionals who care for the patient are blind to the identity of the treatment assignment, only the study coordinator and the study group statisticians will have access to the uncoded list of patients' identification numbers and their treatment assignments. In addition, all patients will take the same number of pills each day (active drug(s), placebo, or both). Patients will take the mesalamine tablets (400 mg) or its placebo orally twice a day with meals for about one year. The TURSO tablets (750 mg) or its placebo will also be taken orally twice a day with meals for about one year. Mesalamine and its matching placebo are available from Procter and Gamble Pharmaceuticals (Norwich, N.Y.). TURSO and placebo are available from Interfalk (Quebec, Canada).
One year after initiating the study, each patient will receive a follow-up coloscopic examination. Following sedation with intravenous midazolam and/or a narcotic at doses deemed appropriate by the colonoscopist, the rectum will be intubated and the colonoscope advanced to the cecum in the usual fashion. Upon withdrawal of the colonoscope, all neoplastic lesions will be identified, and their location and size recorded. All neoplastic lesions visualized will be removed in the usual fashion, using the electrocautery snare or hot biopsy-forceps technique. The coloscopist will document (1) whether a complete or a limited examination was performed, (2) the quality of the preparation, and (3) whether or not all visualized polypoid tissue was removed.
The primary endpoint of the study will be the recurrence of polyps considered as a dichotomous outcome. A logistic regression for polyp recurrence (yes/no) at one year will be used to assess treatment effects. Distributions of polyp size and number will be determined for and compared among randomized groups. Although the randomization procedure should result in balanced treatment groups, the stratification factors and a few other variables (e.g., size, number of index polyps) thought to be associated with recurrence of polyps will be included as covariates in the logistic regression model. Patients who "drop out" during the follow-up period (either due to toxicity or non-compliance) will be considered as treatment failures (recurrent polyps), based on an "intent to treat" philosophy. The incidence of toxicity and compliance rates for each treatment arm will be estimated, and the rates are compared among the treatment groups using a logistic regression analysis.
Summaries of the distribution of primary and secondary outcomes done by each stratification factor separately, will be tabulated using means and standard errors, medians, and inter-quartile range, or percentages, as appropriate for continuous or discrete data. Distributions of primary and secondary endpoints will also be tabulated separately by sex and by ethnic/racial minority status.
NSAIDs are ubiquitous, are available in over-the-counter preparations as well as prescription varieties, and are often used to treat a wide spectrum of symptoms and diseases. In order to prevent contamination of groups by the inadvertent use of an NSAID, patients will given a list of NSAIDs, as well as a list of over-the-counter medications that contain an NSAID (e.g., Darvon contains aspirin). Patients will be instructed to avoid these agents. If the prolonged use of an NSAID becomes medically necessary, the patient will be disqualified from the study.
All publications are incorporated by reference herein, as though individually incorporated by reference. The invention has been described with reference to various specific and preferred embodiments and techniques. However, it should be understood that many variations and modifications may be made while remaining within the scope of the invention.
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A method for protecting a colorectum against a recurrence of adenomas is provided, wherein ursodeoxycholic acid or an amide-conjugate thereof, or ursodeoxycholic acid or an amide-conjugate thereof in combination with sulindac or a phenolic NSAID is administered to a patient afflicted with colorectal adenomas in an amount effective to prevent the recurrence of colorectal adenomas following the removal thereof.
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CROSS-REFERENCE TO RELATED APPLICATIONS
This patent application is a continuation of my earlier application, Ser. No. 353,250, filed on Mar. 1, 1982, for Drivable, Steerable Platform for Lawnmower and the Like, now U.S. Pat. No. 4,463,821.
BACKGROUND OF THE INVENTION
This invention relates generally to steerable vehicles, and more particularly to a drivable, steerable platform.
Drivable, steerable platforms have been used in industrial and agricultural equipment. Known prior art devices utilize complex mechanical linkages to effectuate steering. The mechanical steering linkages are actuated by hydraulic cylinders driven by a selectively actuated hydraulic pump. The wheels can typically be steered through angles greater than 180°. Due to mechanical limitations of the linkage system, however, the wheels cannot be steered through an angle of 360°.
Typically, such platforms receive their driving power from an internal combustion engine or an electric motor driven by a battery. The engine or motor drives a hydraulic pump which delivers fluid under pressure to hydraulic motors attached to each wheel of the platform. The hydraulic motors that drive the wheels must be carefully regulated for the wheels to each turn at the same speed.
Other known prior art devices include cable steering systems. Such devices include a plurality of spools on which cable is wound and unwound to effectuate steering. In such systems, the wheels of the vehicle cannot be steered through an angle of 360°.
Yet other known prior art devices include wheels powered by an engine through a transmission, pulleys, belts, shafting and gearing assemblies. Sprockets and gear chains may be included to effectuate steering. Hydrauic pumping devices may be used, and the wheels are typically permitted to turn through about 180°.
The control apparatus of known prior art devices permits only limited control of vehicle steering and driving. One known prior art remote control lawnmower can be steered only through relatively large angular turns. Another known prior art lawnmower operates only on the principle of random motion within a boundary.
The known prior art devices offer complex mechanical and/or hydraulic construction and relatively poor control over device steering and driving.
SUMMARY OF THE INVENTION
According to the present invention, a drivable, steerable platform is provided which can be accurately controlled. The platform may be guided in any direction by manual control, remote control, and cassette and computer program control, without a steering wheel. Control structure is provided to permit angular movement in any direction as fine as 0.1°, and straight line movement as fine as a fraction of an inch. The platform has a minimum turning radius of zero.
In one embodiment, a drivable, steerable platform includes a frame member, and 3+N wheel assemblies, N=0, 1, 2, . . . . The frame member is generally disposed in a frame member plane oriented substantially parallel to the surface upon which the platform is to move.
Each wheel assembly includes support structure rotatably connected to the frame member. The support structure is permitted to rotate about an axis substantially perpendicular to the frame member plane.
A wheel member is rotatably mounted on the support structure. The wheel member is permitted to rotate in a wheel rotation plane about an axis substantially parallel to the frame member plane. The wheel rotation planes of the 3+N wheel members are substantially parallel to each other and are all substantially perpendicular to the frame member plane.
Each wheel assembly further includes a first drive structure to drive the wheel member about its axis of rotation. A first steering structure is also provided to rotate the support structure about its axis of rotation. The steering structure permits rotation of the support structure and hence the wheel member through 360°.
A first endless device is provided and connected to each of the first drive structures to rotate each of the 3+N wheel members substantially in synchronism. A second endless device is also provided and connected to each of the first steering structure to rotate each of the 3+N support structures substantially in sychronism.
Structure is provided for selectively driving the first and second endless devices. The drive structure includes a driving device, and first and second clutch structures to selectively connect the driving device to the first and second endless devices, respectively.
According to another aspect of the invention, means are included for activating the drive structure. Relay structures are provided to selectively actuate the first and second clutch structures. A control circuit is provided for selectively operating each of the relay structures.
In accordance with another aspect of the present invention, a receiver is included. The receiver receives broadcasted signals from a remote control point. The received signals are processed to provide control signals for the control circuit. A transmitter may be included for broadcasting signals back to the remote control point.
According to another aspect of the invention, the platform is fixedly connected to a housing structure which accommodates a lawnmower blade. The blade is disposed substantially parallel to the frame member plane, and is driven by the driving device.
BRIEF DESCRIPTION OF THE DRAWINGS
The invention will further be described by reference to the accompanying drawings which illustrate the particular embodiments of a drivable, steerable platform in accordance with the present invention, wherein like members bear like reference numerals and wherein:
FIG. 1 is a perspective view of one embodiment of a drivable, steerable platform according to the present invention;
FIG. 2 is a perspective view of the wheel assembly employed in the platform of FIG. 1, and FIG. 2A is a perspective view of an alternate wheel assembly;
FIG. 3 is a perspective view of another embodiment of a drivable, steerable platform according to the present invention, having a lawnmower housing accommodating a lawnmower blade;
FIG. 4 is a planar view of sensor apparatus used in the platform of FIG. 3;
FIG. 5 is a schematic block diagram of control circuitry included on the platform according to the present invention; and
FIG. 6 is a schematic block diagram of control circuitry provided at the remote control point according to the present invention.
DESCRIPTION OF THE PREFERRED EMBODIMENTS
Referring now to the drawings, and in particular to FIG. 1, there is shown in perspective view a drivable, steerable platform 10 having a frame member 12 generally disposed in a frame member plane. The platform 10 includes four identical wheel assemblies 14, each of which are illustrated in greater detail in FIG. 2. Each wheel assembly includes a first support structure 16 rotatably connected to the frame member 12. The structure 16 includes a fork 18 fixedly connected to a gear 20. The gear 20 is free to rotate on a shaft 22 which is rotatably mounted on the fram member 12 by a bearing assembly 24. Angular movement of the gear 20 about the axis of shaft 22 produces a similar angular rotation of the fork 18 about the same axis.
Support structure 16 further includes an axle 26 mounted in the fork 18. The axis of axle 26 is disposed substantially parallel to the frame member plane. Wheel member 28 is mounted on the axle 26. The wheel member 28 rotates about the axis of axle 26 in a wheel rotation plane substantially perpendicular to the frame member plane.
A pulley 30 is mounted on the shaft 22, as is a gear member 32. The gear member 32 meshes with a gear portion 34 of the wheel member 28. Rotation of the pulley 30 causes rotation of the gear 32, which in turn drives the gear portion 34, rotating the wheel member 28 about the axis of the axle 26.
In the embodiment illustrated in FIGS. 1, 2 and 3, the pulley 30 is driven by a first endless drive belt 36 disposed on one side of the frame member 12. The gear 20 is driven by a second endless drive belt 38 disposed on the other side of the frame member 12. Alternately, the drive belts 36 and 38 may both be disposed on the same side of the frame member 12.
Preferably, the drive belts 36 and 38 are each geartype endless belts which suitably mate with gear portions included on the pulley 30 and the gear 20. The drive belts 36 and 38, however, may be of any suitable construction, such as "V" belts, chains, and so forth, and the structure of the pulley 30 and the gear 20 altered accordingly.
In the embodiment illustrated in FIG. 3, the endless drive belts 36 and 38 are disposed on opposite sides of the frame member (not illustrated). Six identical wheel assemblies are provided in this embodiment, each wheel assembly being disposed at one of the vertices of a regular hexagon.
A housing 40 is movingly connected to the frame member (not illustrated). A lawnmower blade (not illustrated) is accommodated in the housing 40 and mounted on a shaft 42. A motor or engine (not illustrated) is suitably mounted on the housing 40 and directly connected to end 44 of the shaft 42. The motor causes the shaft 42 to rotate in only one direction as indicated by the arrow in FIG. 3.
A pulley 46 is rotatably mounted on the housing 40 and connected by a belt 50 to the shaft 42. The pulley 46 slidingly accommodates a square shaft 48. The shaft 48 is journalled at one end to the frame member (not illustrated), and is free at the other end to move through the pulley 46.
The pulley 46 and the housing 40 may be moved up and down along the shaft 48 to adjust the height of the lawnmower blade 49. The motor moves up and down with the housing 40 and the pulley 46. The square shaft 48 accommodated by the pulley 46 effectively couples the motor to the platform structure which is to be driven at each lawnmower height setting.
Driving and steering power is provided to the wheel assemblies 14 from the motor through the shaft 48. A belt 52 connects a pulley 54 mounted on the shaft 48 to a driving clutch 56. The clutch is operated by a relay structure (not illustrated). When the relay is operated to actuate the driving clutch, the belt 36 is made to move thereby driving each wheel member 28 substantially in synchronism.
Any slack which may exist in the belt 36 is taken up by belt tension structure 58. The structure includes a spring-loaded tension roller which applies tension to the belt. Impulses tending to be imparted to the belt 36, such as by actuating the driving clutch 56, are absorbed by the spring member of the belt tension structure 58.
A pulley 60, mounted on the shaft 48, is coupled to a steering clutch and brake 62 by a belt 64. The steering clutch and brake 62 is actuated by a second relay structure (not illustrated). When actuated, the clutch mechanism of steering clutch and brake 62 imparts rotative motion from the motor to a shaft 66. The shaft 66 in turn drives the belt 38. When the brake mechanism of the steering clutch and brake 62 is actuated, the shaft 66 is locked in position, thereby locking the belt 36 and gears 20 and forks 18 in position. Belt tension structure 68 is included to take up any slack of belt 38. Belt tension structures 58 and 68 function identically.
In the embodiment illustrated in FIG. 1, the driving clutch 56 and the steering clutch and brake 62 are both mounted on the shaft 42 driven by the motor. In an alternate embodiment (not illustrated), either one or both of the driving clutch 56 and the steering clutch and brake 62 are replaced by d.c. motors. The unnecessary belts, pulleys, and so forth are eliminated.
In other alternate embodiments, the steering clutch and brake 62 is replaced by a suitable electric braking device 63 which operates either on the shaft 66, or the shaft 22 (see FIG. 24) of one or more of the wheel assemblies 14. In operation, when the driving clutch 56 is actuated and the braking device 63 is not, the first support structures 16 of the wheel assemblies 14 rotate about the axis of the shaft 22, thereby effectuating steering. The driving clutch is actuated for a predetermined period of time to steer the first support structures 16 through a predetermined angle. When the braking device 63 is actuated, the first support structures 16 cannot rotate; the wheel members 28 rotate about the axles 26, thereby effectuating driving.
With continued reference to FIG. 3, steering sensor structure and driving sensor structure are included to sense the orientation of the first support structures 16, and the distance travelled by the wheel members 28, respectively. The steering sensor structure includes a steering sensor wheel 70 mounted on the shaft 66, and a steering sensor pickup device 72 mounted in proximity to the steering sensor wheel 70. The sensor wheel 70 and the pickup device 72 are best illustrated in FIG. 4.
The driving sensor structure includes a driving sensor wheel 74 mounted on an axle 76, and a driving sensor pickup device 78 in proximity to the sensor wheel 74. The sensor wheel 74 and the pickup device 78 are similar to those illustrated in FIG. 4.
A steering tension device 80 and a driving tension device 82 are included to adjust the tension of the belts 64 and 52, respectively. The tension devices 80 and 82 are each spring loaded and are similar in construction to belt tension structures 58 and 68, but they provide different functions. They prevent stalling of the motor due to loading of the lawnmower blade and of the wheel members 28.
The driving tension device 82 varies the speed of rotation of the wheel members 28 by permitting slippage of the belt 52 as a function of lawnmower blade loading caused by the grass being cut. Similarly, steering tension device 80 permits slippage of the belt 64 as a function of resistance to steering imparted to the wheel assemblies 14 by the grass. In the illustrated embodiment, the tension devices 80 and 82 are adjusted so that the engine speed, which is normally approximately 3600 rpm, never falls below 2200 rpm. Tension devices 80 and 82 are especially adapted for use with spring clutches which typically actuate in approximately 20 milliseconds.
Structure is also included to readily indicate the direction in which the platform is heading. A belt 84 couples a gear 86 mounted on the shaft 66 with a gear 88 mounted on a shaft 90. So coupled, the shaft 90 rotates in synchronism with the forks 18 of the first support structures 16.
The shaft 90, which is suitably supported in the frame member 12, contains structure for supporting a direction indicating member such as an arrow, a video camera, a seat, and so forth. The direction indicating member is initially oriented to point in the same direction as the first support structures 16. Thereafter, the direction indicating member turns in synchronism with the first support structures 16.
In applications of the present platform to areas other than lawnmowing, for example robot vacuum cleaning devices that are to be oriented in the direction of platform movement, such as a vacuum cleaning tool head or a seat, may be coupled to the shaft 90. So coupled, the device will be seated in synchronism with the first support structures 16 of the platform 10.
Referring now to FIG. 5, control circuitry 100 of the platform 10 is illustrated in block diagram form. A receiver 110 receives a signal broadcasted from a remote control point. The output of the receiver 110 is coupled to a frequency to voltage converter 112 which produces an appropriate electrical signal to drive a line selector 114.
The line selector 114 selectively activates steering command lines A, B, C, D and driving command lines A', B', C', D'. Lines A, B, C, D are conductively connected to a manual angle selector 116 which generates an appropriate steering angle signal. The steering angle signal is coupled to an angle comparator 118 which also receives a steering angle error signal from an electronic compass 120. The steering angle error signal represents the difference between the compass heading the platform 10 should be following, and the one it actually is. Such errors can be brought about by terrain features. Correction for such deviations, however, is effectuated in the illustrated embodiment only when a steering angle signal is produced. The steering angle error signal is added to the steering angle signal in the angle comparator 118 and an appropriate signal fed to a steering counter 122.
The steering counter 122 produces an appropriate signal which is fed to a digital-to-analog converter 124. The converter 124 produces an appropriate signal to actuate the steering clutch and brake 62 previously described.
The steering counter 122 receives an input signal from a steering sensor 126 which includes the steering sensor wheel 70 and the steering sensor pickup device 72 previously described.
Lines A', B', C', D' of the line selector 114 are conductively connected to a manual moving selector 128 which produces an appropriate drive signal. The manual moving selector 128 also receives an input signal from the steering counter 122 which is used to coordinate driving and steering of the platform 10. In the present embodiment, the wheel members 28 are not driven when the forks 18 are being steered to a new orientation. Thus, when the signal received by the moving selector 128 from the steering counter 122 indicates that steering is being effectuated, the drive signal produced by moving selector 128 is not coupled to driving comparator 130. The drive signal is coupled to the driving comparator 130, however, when the signal received by the moving selector 128 from the steering counter 122 indicates that a steering operation is not in progress. It will be apparent to those skilled in the art that if it is desired, the wheel members 28 may be driven when the forks 18 are being steered to a new orientation.
The driving comparator 130 further receives an input signal from a driving counter 132 which in turn receives an input signal from a driving sensor 134. The driving sensor 134 includes the driving sensor wheel 74 and the driving sensor pickup device 78 previously described. The driving counter 132 keeps track of the distance travelled by the wheel members 28.
An output signal from the driving comparator 130 is coupled to a digital-to-analog converter 136. An output of the line selector 114 is coupled to a digital-to-analog converter 138. Output signals from the digital-to-analog converters 136 and 138 are used to selectively operate the driving clutch 56 as previously described.
In the embodiment illustrated in FIG. 5, the direction indicating device includes a video camera 140 which is conductively coupled to a transmitter 142. So coupled, data indicative of the scene viewed by the camera 140 is received by the transmitter 142 for broadcasting to a remote control point. Also received by the transmitter 142 are signals from the steering sensor 126 and the driving sensor 134 containing information regarding the orientation of the platform 10 and the distance travelled by the platform 10, respectively. This information is also transmitted to the remote control point.
Referring now to FIG. 6, control circuitry 150 at the remote control point is illustrated in block diagram form. A receiver 160 receives signals broadcasted by the transmitter 142 of the control circuitry 100. The received signals are processed and fed, in part, to a video display device 162 and, in part, to a computer 164. The data displayed on the video device 162 includes the orientation of the platform 10, the elasped distance travelled by the platform 10, and the present steering angular position or bearing of the platform 10.
The computer 164 further receives input signals from a steering selector 166 and a driving selector 168. The steering and driving selectors 166 and 168 are manually adjustable devices which permit the operator to readily select pre-programmed steering angle commands A, B, C, and pre-programmed driving distance commands A', B', C'. Additionally, the selectors 166 and 168 permit numeric selection of values using the digits 0 through 9. Such selection is represented by steering selector command line D and driving selector command line D'.
The computer 164 receives information from the receiver 160, the steering selector 166, and the driving selector 168. It processes this information in accordance with its programmed instructions and provides control signal information to a transmitter 170 for broadcast to the receiver 110 of control circuitry 100.
As will be apparent to those skilled in the art, the control circuitry 150 at the remote control point can readily be incorporated in the control circuitry 100 on the platform 10. In such an embodiment, the camera 140, the video display device 162, the receivers 110 and 160, the frequency to voltage converter 112, and the transmitters 142 and 170 are not needed. Similarly, numerous features of the embodiment described in FIGS. 5 and 6 can be eliminated without detracting from the present invention. For example, the camera 140 and the video display device 162 can readily be eliminated from the drivable, steerable lawnmower of the present invention.
The principals, preferred embodiments and modes of operation of the present invention have been described in the foregoing specification. The invention is not to be construed as limited to the particular forms disclosed, since these are regarded as illustrative rather than restrictive. Moreover, variations and changes may be made by those skilled in the art without departing from the spirit of the invention.
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Control apparatus for an omnidirectional, polar coordinated platform for a lawnmower and the like is disclosed in which a line selector has at least one steering command line coupled to an angle selector, and at least one driving command line coupled to a moving selector. The angle selector produces a steering angle signal which is combined with a compass signal in an angle comparator to produce a steering signal, which is received by a steering counter that selectively activates a steering device. The moving selector produces a drive signal which is received by a driving comparator that selectively activates a driving device.
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CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] I hereby claim the benefit under Title 35, United States Code Section 119(e) of any United States Provisional Application(s) listed below:
[0002] Application Ser. No.: 61/849,728
[0003] Filing Date: Feb. 1, 2013
STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH AND DEVELOPMENT
[0004] Non-applicable
THE NAMES OF PARTIES TO A JOINT RESEARCH AGREEMENT
[0005] Non-applicable
INCORPORATION-BY-REFERENCE OF MATERIAL SUBMITTED ON A COMPACT DISC
[0006] Non-applicable
BACKGROUND OF THE INVENTION
[0007] 1. Field of the Invention
[0008] The present invention generally relates to insulating, grasping and labeling devices, and more particularly to a beverage container sleeve and label.
[0009] 2. Description of the Related Art Including Information Disclosed Under 37 CFR 1.97 and 37 CFR 1.98
[0010] The following description of the art related to the present invention refers to a number of publications and references. Discussion of such publications herein is given to provide a more complete background of the principles related to the present invention and is not to be construed as an admission that such publications are necessarily prior art for patentability determination purposes.
[0011] Coffee, Tea and other hot beverage container sleeves, also known as coffee sleeves, coffee clutches, hot cup jackets, paper zarfs, card-zarfs and cup holders, are roughly cylindrical sleeves that fit tightly over handle-less disposable beverage cups.
[0012] Beverage container sleeves' main purpose is to insulate the drinker's hands from the heat emanated by hot beverages through the container's wall. Secondary purposes include, but are not limited to: (1) facilitate grasping of the beverage container; and (2) provide the means to design and make, and/or space, for a label. Such a label comprises logos, messages, drawings and distinctive colors.
[0013] Beverage container sleeves are typically made of textured paperboard, but can be made using other disposable or non-disposable materials. Disposable beverage container sleeves allow coffee houses, fast food restaurants, and other hot beverage sellers to avoid double-cupping, the practice of using two or more nested paper cups to insulate a single hot beverage. Non-disposable beverage container sleeves can be made of more durable materials and are generally purchased by consumers for their hot beverages.
[0014] Coffee is one of the most cherished and widely consumed beverages in the world. Coffee's stimulating caffeine effect and unique taste makes it a preferred drink for people to start their day. According to Live Science, over 54% of Americans over the age of 18 drink coffee every day, which shows just how popular this beverage is. Coffee sleeves have become a dire necessity for the consumers who are regularly on the move and who purchase their coffee “to-go.” Most coffee houses offer coffee sleeves in order to ameliorate the burning effect of grasping an unprotected cup containing a very hot beverage. An alternative is to offer coffee in doubled cups if too hot. By using coffee sleeves you not only remove the burning factor but also keep retail costs low by avoiding double cupping. The same can be held true for other hot beverages, i.e. hot cocoa, tea, apple cider, etc.
[0015] Disposable and compostable hot beverage container sleeves provide the added advantage of protecting the environment. Many sleeves currently on the market are recyclable, thus minimizing the environmental effect of disposing of non-recylcable materials. An even more desirable environmental effect could be achieved if the amount of material used to make an effective sleeve can be significantly reduced.
[0016] Insulating beverage container sleeves have traditionally been constructed to wrap around the object using the complete circumference of the object plus an additional length to paste or join the cylinder/cone label together. Solutions to reduce material have focused on using thinner materials, and reducing the surface area of current insulating sleeves, beverage container holders and labels. Unfortunately, there has not been a solution to radically reduce the amount of materials used.
[0017] At a minimum, there is a need for insulating beverage container sleeves and holders that comprise the characteristics listed below: (1) adequate insulation, (2) comfortable handling, (3) environmental friendliness, (4) relatively low manufacturing cost, (5) low material requirement (in some cases less than 40% of the material when compared with current solutions), and (6) rapid preparation for use on a cup.
BRIEF SUMMARY OF THE INVENTION
[0018] Objects, advantages and novel features, and further scope of applicability of the present invention will be set forth in part in the detailed description to follow, taken in conjunction with the accompanying drawings. The objects, advantages and novel features, and further scope of applicability of the present invention will become apparent to those skilled in the art upon examination of the following, or may be learned by practice of the invention. The objects and advantages of the invention may be realized and attained by means of the instrumentalities and combinations particularly pointed out in the appended claims.
[0019] The present application discloses and claims a unique sleeve adapted to slidably receive and engage the outer sidewall of a beverage container such as a cup, a conical object or a cylinder. The sleeve comprises approximately 40% less material currently used in the industry, by creating a cylinder from a cut, or several cuts in a flat material. The rationale behind the present invention is that the length of material required to manufacture prior art objects is the complete circumference of a cup, conical object or a sleeve in order to engage the outer sidewall. One of the principal inventive aspects of the present invention is that it uses approximately one half of the amount of material required to manufacture most of the sleeves of the prior art, plus 5% to 10% depending on the surface and material used, while still producing the same insulating, grasping and labeling result. The present invention is produced using substantially less material than the prior art sleeves through a simple process of cutting, folding and pasting.
BRIEF DESCRIPTION OF THE SEVERAL VIEWS OF THE DRAWINGS
[0020] The accompanying drawings, which are incorporated into and form a part of the specification, illustrate an embodiment of the present invention and, together with the description, serve to explain the principles of the invention. The drawings are only for the purpose of illustrating a preferred embodiment of the invention and are not to be construed as limiting the invention.
[0021] FIG. 1 : is a frontal perspective view of the sleeve of the present invention.
[0022] FIG. 2 : is a top view of the sleeve of the present invention.
[0023] FIG. 3 : is an inverted top view of the sleeve of the present invention.
[0024] FIG. 4 : is a side view of the sleeve of the present invention.
[0025] FIG. 5 : is a frontal view of various designs of the sleeve preform of the present invention.
[0026] FIG. 6 : is a frontal view of various designs of the sleeve preform of the present invention.
DETAILED DESCRIPTION OF THE INVENTION
[0027] The present invention is manufactured from a single, planate piece of malleable material, such as cardboard, corrugated cardboard, paperboard, plastic mesh, solid plastic, neoprene, cotton and other thick fabrics and materials commonly found in the art. The material used may be capable of receiving printing, an adhesive label and/or embossing on one or both sides. In the preferred embodiment, the material is printed on one or both sides with a logo, a motto, a pattern, a color or similar decoration or designation of origin.
[0028] In manufacturing the invention, the material is trimmed to size and two or more slits ( 8 ) are cut across the material. This can be achieved by cutting or stamping the material. In the preferred method of manufacture, the cutting and trimming is performed by a single pass of a slitter-scorer. The resultant body ( 1 ) of the sleeve comprises a top length ( 2 ), a bottom length ( 3 ), a left edge ( 4 ), a right edge ( 5 ), a front or outside surface ( 6 ) and a back or inside surface ( 7 ). After the slits ( 8 ) have been made, the body ( 1 ) of the sleeve comprises three or more horizontal strips ( 9 ) above and below the slits ( 8 ) that are capable of moving independently from one another. The slits ( 8 ) extend all the way through the material, from the outside surface ( 6 ) to the inside surface ( 7 ). However, the slits ( 8 ) do not extend all the way to the two edges ( 4 , 5 ). The slits terminate before reaching the edges, and the resulting areas between the termination of the slits and the right and left edges form the right flap ( 10 ) and the left flap ( 11 ). These flaps are glued down during manufacture to stabilize the sleeve and hold its shape. Multiple embodiments of the preform ( 12 ) after cutting and trimming are shown in FIGS. 5 and 6 .
[0029] In the preferred embodiment, as depicted in FIGS. 5 and 6 , the top length ( 2 ) is longer than the bottom length ( 3 ). If both lengths are equal, the preform is rectangular and the result of gluing the flaps ( 10 , 11 ) down is a cylinder. A cylindrical embodiment may have some usefulness, but standard beverage cups are tapered. In order to be useful for the most commonly used hot beverage cups, the lengths of the top and bottom are different, resulting in a conical frustum when the sleeve is assembled. In the conical frustum embodiments, the slits ( 8 ) and the corresponding strips ( 9 ) are different lengths. The top slit ( 13 ) is the longest because the resultant strips encircle a tapered cup in an area where it has a larger diameter. Each slit below the top slit is progressively shorter. The bottom slit ( 14 ) is the shortest, since it wraps around a narrower area of the cup. The difference in slit length is clearly depicted in FIGS. 5 and 6 .
[0030] The length of each slit ( 8 ) is determined by the type of beverage container the sleeve is made to envelop. The amount that the beverage container tapers and the ideal height of the sleeve on the beverage container will be the key factors in determining length of the slits ( 8 ), as well as the top length ( 2 ) and bottom length ( 3 ) of the sleeve body ( 1 ). In the preferred embodiment, the length of each slit ( 8 ) is equal to one half the circumference of the cross-section of the cup at the position where the slit will sit on the cup when the sleeve is placed on the cup.
[0031] To facilitate the truncated conical formation, the top ( 2 ) and bottom lengths ( 3 ) of the sleeve body are slightly arched in the preferred embodiment. The horizontal slits ( 8 ) are also arched in the preferred embodiment, as pictured at the top of FIG. 5 . All of the curves of the two lengths ( 2 , 3 ) and the slits ( 8 ) are identical in the preferred embodiment. There are alternate embodiments wherein the slits ( 8 ), the lengths ( 2 , 3 ) and/or the edges ( 4 , 5 ) are not a simple rounded shape. They can be wavy, zigzaged, have protrusions or recesses to cause variations in the aesthetic look of the finished sleeve. Some examples of these alternative embodiment preforms are shown in FIGS. 5 and 6 .
[0032] In the preferred embodiment a series of lines ( 15 ) are scored into the surface of the preform ( 12 ). The scoring can also all be done on the front ( 6 ) and back ( 7 ) or on one surface only. The scoring ( 15 ) is depicted as dotted lines in FIGS. 5 and 6 . In the preferred embodiment, four areas are scored. The first scored area ( 15 a ) is at the interface between the slits ( 8 ) and the left flap ( 11 ). The second scored area ( 15 d ) is at the interface between the slits ( 8 ) and the right flap ( 10 ). The third scored area ( 15 b ) is on every other strip ( 16 ) starting with the topmost strip (odd numbered strips). The scoring ( 15 b ) is in the identical location on every odd numbered strip ( 16 ). The fourth scored area ( 15 c ) is on every other strip ( 17 ) starting with the second strip from the top (even numbered strips). The scoring ( 15 c ) is in the identical location on every even numbered strip ( 17 ). In the preferred embodiment, the third ( 15 b ) and fourth ( 15 c ) scored areas do not line up with one another. They are offset, as depicted in FIGS. 4 , 5 and 6 .
[0033] In order to begin assembly of the sleeve preform ( 12 ) into a finished sleeve, the even ( 17 ) and odd numbered strips ( 16 ) are separated in opposite directions from one another. Then the strips are folded along the third ( 15 b ) and fourth scored areas ( 15 c ). This results in the configuration depicted in FIG. 4 . FIG. 4 also clearly demonstrates the fact that the sleeve of the present invention can be manufactured using a fraction of the material required to produce traditional beverage sleeves. In the preferred embodiments, paste is applied to the back surface ( 7 ) of one flap and the front surface of the other flap prior to folding. The flaps are then folded downward along the first ( 15 a ) and second ( 15 d ) scored areas, with the pasted side facing the strips ( 9 ). This adheres each flap to the even or odd numbered half of the strips ( 16 or 17 ), so that the flaps do not stick up in the finished product.
[0034] The finished sleeve is shaped like a truncated cone, as depicted in FIG. 1 . The sleeve is ready to receive the base of a beverage cup and to be slid upward on the cup until it is firmly engaged to the cup. The top view of the final shape of the sleeve is shown in FIGS. 2 and 3 . The difference between FIGS. 2 and 3 is which side of each flap receives the paste. In one embodiment, the right flap ( 10 ) is glued on the front ( 6 ) and the left flap ( 11 ) is glued on the back ( 7 ). In the other embodiment, the strips are folded in the opposite direction; the right flap ( 10 ) is glued on the back ( 7 ), and the left flap ( 11 ) is glued on the front ( 6 ).
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The invention relates to a sleeve adapted to slidably receive and engage the outer sidewall of a container such as a cup, a conic object or a cylinder. The sleeve is comprised of a minimum of 40% less material currently used in the industry, by creating a cylinder from a cut, or several cuts of a flat material. The basis of the invention is that current similar objects engage in covering the complete diameter of a cup, conic object or a sleeve in order to engage the outer sidewall. The innovation comprises of using half the circumference plus 5% to 10% depending on the surface and material used—still producing the same result, while saving material.
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This application is the U.S. National Phase of International Application PCT/IT03/00257, filed on Apr. 24, 2003 and claims priority to European Patent Office Foreign Patent Application Nos. 02425274.4, filed Apr. 30, 2002.
FIELD OF THE INVENTION
The present invention relates to re-epithelializing pharmaceutical compositions especially for ophthalmic use.
BACKGROUND ART
It is well known that epithelial cells, for example in the cornea, may suffer injuries caused by foreign bodies, such as abrasions, cuts and wounds (accidental, surgical, immunological etc), and postinfective ulcers. Injuries of this sort generally require long wound healing periods; cause much discomfort and often an imperfect wound closure.
SUMMARY OF THE INVENTION
The object of the present invention is a pharmaceutical composition that can accelerate re-epithelialization, especially of the corneal tissue, and is also well tolerated.
This goal is achieved using xanthan gum for the preparation of a medication for the treatment of epithelial wounds, as well as of pharmaceutical compositions containing xanthan gum, as detailed in the claims herewith annexed.
Other characteristics, and the advantages of the pharmaceutical topical composition, as described in the present invention, will become apparent from the following description of some preferred embodiments of formulations of the pharmaceutical composition, which are presented for purposes of illustration and are not intended to be construed as limiting.
DETAILED DESCRIPTION OF THE INVENTION
A surprising experimental finding was the observation that xanthan gum shows a high re-epithelializing function, that is to say, it is able to accelerate the formation of new epithelial cells at the level of the damaged epithelial zone, as shown also in an in vivo experiment reported later in the present description.
Xanthan gum is a heteropolysaccharide with a molecular weight between 3-7,5×10 6 Da, produced through a process of fermentation by the bacterium Xanthomonas campestris.
The primary structure of xanthan is a branched chain, with a main chain of β(1→4)-D-glucose identical to cellulose wherein, a trisaccharide chain with a glucosidic link β(1→3), composed of acetylated mannose, glucuronic acid, and mannose is linked to every other second residue; finally, to each carbon C4 and C6 of the terminal unit of mannose a molecule of pyruvic acid is linked in a variable proportion of 25-50%, that completes the structure of the lateral chain of the polymer.
The available data suggests a single helix conformation (but a double or triple helical structure cannot be ruled out) where the lateral chains of the polymer tend to align with the main chain (with non covalent type of interactions) protecting the glucosidic links present there. The result is a stiff rod-like structure that confers great stability to the molecule with an excellent protection from strong acids and bases, high temperatures, freezing and thawing cycles, enzymatic attack, prolonged mixing, shear degradation, variations of ionic force and pH.
Consequently, on account of the structural properties just described, xanthan gum, in preformed gel form, makes it possible to carry out adequately the important function of mechanical protection.
Furthermore, following lot of experiments, it has been surprisingly observed that the admixture of xanthan gum with hyaluronic acid, as an active principle of a re-epithelializing composition in a preparation as a preformed gel, causes an increase in the rate of re-epithelializing of the damaged epithelium and, in addition, promotes the reorganization of the newly formed epithelium that results in the formation of cellular layer of superior quality.
In particular, wound-healing studies carried out under a scanning electron microscope, revealed a surprising degree of epithelial organization following a treatment with the pharmaceutical re-epithelializing composition according to the invention, as will be explained in detail.
It is well known that hyaluronic acid not only favors cellular proliferation but also stabilizes the basal layer of the epithelium stimulating the production of lamina and fibronectin.
In any event, when xanthan gum and hyaluronic acid are used as a mix in their capacity as re-epithelializing agents, they have a surprising synergic effect.
Hyaluronic acid is an high molecular weight polysaccharide with polyanionic features, high capacity to retain water, viscous, bioadhesive and pseudoplastic properties with no evidence of tixotropy. Its primary structure consists of β(1→4) disaccharide blocks each constituted of D-glucuronic acid and N-acetyl-D-glucosamine linked together through a β(1→3) bond.
In view of the observations previously described, a further embodiment of the present invention is to provide topical re-epithelializing pharmaceutical compositions in preformed gel consisting essentially of xanthan gum as active principle, eventually mixed with hyaluronic acid, and pharmacologically accepted additives.
The percentage of xanthan gum relative to the total volume of the preformed gel is preferably between 0.7% to 5%, more preferably between 0.8% and 3%, and more highly preferably between 0.9% and 1.5%.
The excipients are chosen among isotonic agents, buffers, solvents or vehicles, antioxidants, pH adjusting and similar.
In particular, the possible isotonic agents of the composition of the invention may be ionic, such as NaCl, KCl or non-ionic, for example glycerol, mannitol or a mix thereof.
Possible buffers may be those commonly used for instance in ophthalmic formulations such as phosphate or borate, acetate, a mix of these buffers such as citrate/phosphate, or even buffers not frequently used in the ophthalmic field, such as Tris.HCl, or based on histidine or arginine.
Therefore, the composition of a preformed gel with xanthan may be a balanced saline solution, or otherwise, o saline composition not necessarily balanced because of the presence of ions of Ca +2 e Mg +2 .
Possible antioxidants include sodium citrate, ascorbate or sulfate.
Possible pH adjusting are organic or inorganic acids or bases with their respective acid and basic salts.
Possible solvents or vehicles are water or a mixture of water/oil.
It has been observed that when salts are added to a composition containing >0.25% xanthan, there is an increase of viscosity proportional to the concentration of xanthan and of the added salts, although a viscosity plateau is reached, for example, with as little as 0.1% of NaCl. Therefore, xanthan behaves differently toward the variations of ionic force than other polyelectrolytes, toward which the presence of salts (that decreases the degree of hydration and repulsion between chains) promotes intermolecular interaction and a molecular collapse from a random coil (with a higher viscosity) to a compact coil structure (with a lower viscosity). In xanthan solutions the addition of salts decreases the degree of hydration and the charge repulsion between the carboxylate anions of the lateral chains of the molecule, which consequently stabilizes the stiff rod-like conformation and promotes a stronger and more rigid three-dimensional network that increases viscosity (about twofold at 0.1% of NaCl for 1% xanthan) and significant yield-value, that in general render the solutions of the polymer more protected against factors such as thermal treatment, attacks from acids and bases, prolonged mixing, etc.
In solution, the single helixes tend to associate forming a complex ordered meshwork of rigid molecules held together mainly by weak Van der Waals forces. The effect of the distinctive and unique structure of xanthan in solution is, already for moderate concentrations (1-2.5%), a gel-like consistency with significant yield stress values (hence, excellent ability to favor the formation of suspensions and emulsions) and good viscosity.
Taken together, the properties thus far examined, along with the low toxicity, bioadhesiveness, and compatibility with the most common excipients and available commercial packaging render xanthan gum advantageously suitable also as delivery system as well as a protective agent on purely mechanical grounds.
As mentioned before, an additional embodiment of the present invention may include hyaluronic acid.
Specifically, the quantity of hyaluronic acid present in said composition ranges from 0.01% to 1% of the total volume of the preformed gel, preferably from 0.05% to 0.5%, better still from 0.1% to 0.4%. Hyaluronic acid is present as a salt. Possible counter ions may be, for example, sodium, potassium, calcium or magnesium.
In yet another embodiment of the present invention the re-epithelializing pharmaceutical composition may include, aside from the admixture of xanthan gum and hyaluronic acid as re-epithelializing agents, one or several pharmacological agents chosen among antiinfective, antiinflamatory, anesthetizing and mydriatic agents.
The invention is further disclosed by means of the following non limiting examples of same formulations.
FORMULATION 1
Components
Quantity
Function
Xanthan gum
1.0000 g
Active principle, re-epithelializing
Sodium chloride
0.3500 g
Isotonic agent
Sodium phosphate,
0.3638 g
Buffer
dibasic•12H 2 O
Sodium phosphate
0.0354 g
Buffer
monobasic•H 2 O
Glycerol
1.0000 g
Isotonic agent
Purified water q.s. to
100.0 ml
Solvent
FORMULATION 2
Components
Quantity
Function
Xanthan gum
1.0000 g
Active principle,
re-epithelializing
Sodium chloride
0.3500 g
Isotonic agent
Potassium chloride
0.1500 g
Isotonic agent
Magnesium•chloride 6H 2 O
0.0120 g
Isotonic agent
Calcium chloride•2H 2 O
0.0084 g
Isotonic agent
Sodium phosphate
0.0890 g
Buffer
dibasic•12H 2 O
Sodium phosphate
0.0069 g
Buffer
monobasic•H 2 O
Sodium citrate•2H 2 O
0.0590 g
Buffer/antioxidant
Glycerol
1.0000 g
Isotonic agent
Purified water q.s. to
100.0 ml
Solvent
FORMULATION 3
Components
Quantity
Function
Hyaluronic acid sodium salt
0.1500 g
Active principle,
re-epithelializing
Xanthan gum
1.0000 g
Active principle,
re-epithelializing
Sodium chloride
0.3500 g
Isotonic agent
Potassium chloride
0.1500 g
Isotonic agent
Magnesium chloride•6H 2 O
0.0120 g
Isotonic agent
Calcium chloride•2H 2 O
0.0084 g
Isotonic agent
Sodium phosphate
0.0890 g
Buffer
dibasic•12H 2 O
Sodium phosphate
0.0069 g
Buffer
monobasic•H 2 O
Sodium citrate•2H 2 O
0.0590 g
Buffer/antioxidant
Glycerol
1.0000 g
Isotonic agent
Purified water q.s. to
100.0 ml
Solvent
FORMULATION 4
Components
Quantity
Function
Hyaluronic acid sodium salt
0.1500 g
Active principle,
re-epithelializing
Xanthan gum
1.0000 g
Active principle,
re-epithelializing
Sodium chloride
0.3500 g
Isotonic agent
Potassium chloride
0.1500 g
Isotonic agent
Magnesium chloride•6H 2 O
0.0120 g
Isotonic agent
Calcium chloride•2H 2 O
0.0084 g
Isotonic agent
Tris base
0.2425 g
Buffer
HCl 1N q.s. to
pH 7.4-7.6
Buffer
Sodium citrate•2H 2 O
0.0590 g
Buffer/antioxidant
Glycerol
0.5000 g
Isotonic agent
Purified water q.s. to
100.0 ml
Solvent
FORMULATION 5
Components
Quantity
Function
Netilmicin sulfate
0.4550 g
Active principle
equivalent to
Netilmicin base
0.3000 g
Sodium hyaluronate
0.1500 g
Active principle,
re-epithelializing
Xanthan gum
1.0000 g
Active principle,
re-epithelializing
Sodium chloride
0.8700 g
Isotonic agent
Sodium hydroxide 1M q.s. to
pH = 7.00-7.6
pH adjusting
Purified water q.s. to
100.0 ml
Solvent
FORMULATION 6
Components
Quantity
Function
Netilmicin sulfate
0.4550 g
Active principle
equivalent to
Netilmicin base
0.3000 g
Sodium hyaluronate
0.1500 g
Active principle, re-epithelializing
Xanthan gum
1.0000 g
Active principle, re-epithelializing
Sodium phosphate
0.5000 g
Buffer
dibasic dodecahydrate.
Sodium phosphate
0.1465 g
Buffer
monobasic monohydrate
Sodium citrate dihydrate
2.1000 g
Buffer/antioxidant
Purified water q.s. to
100.0 ml
Solvent
FORMULATION 7
Components
Quantity
Function
Netilmicin sulfate
0.4550 g
Active principle
equivalent to
Netilmicin base
0.3000 g
Sodium hyaluronate
0.1500 g
Active principle, re-epithelializing
Xanthan gum
1.0000 g
Active principle, re-epithelializing
Tris base
0.2425 g
Buffer
HCl 1M q.s. to
pH 7.4-7.6
Buffer
Sodium citrate
2.1000
Buffer/antioxidant
dihydrate
Purified water q.s. to
100.0 ml
Solvent
FORMULATION 8
Components
Quantity
Function
Netilmicin sulfate
0.4550 g
Active principle
equivalent to
Netilmicin base
0.3000 g
Sodium hyaluronate
0.1500 g
Active principle, re-epithelializing
Xanthan gum
1.0000 g
Active principle, re-epithelializing
Tris base
0.2423 g
Buffer
HCl 1M q.s. to
pH 7.4-7.6
Buffer
Sodium chloride
0.7000 g
Isotonic agent
Purified water q.s. to
100.0 ml
Solvent
FORMULATION 9
Components
Quantity
Function
Dexamethasone disodium
0.1500 g
Active principle
phosphate
Xanthan gum
1.0000 g
Active principle, re-epithelializing
Sodium phosphate
0.5000 g
Buffer
dibasic•12H 2 O
Sodium phosphate
0.1465 g
Buffer
monobasic•H 2 O
Sodium citrate•2H 2 O
2.1000 g
Antioxidant
Purified water q.s. to
100.0 ml
Solvent
FORMULATION 10
Components
Quantity
Function
Dexamethasone disodium
0.1500 g
Active principle
phosphate
Netilmicin sulfate
0.4550 g
Active principle
equivalent to
Netilmicin base
0.3000 g
Xanthan gum
1.0000 g
Active principle, re-epithelializing
Sodium phosphate
0.5000 g
Buffer
dibasic•12H 2 O
Sodium phosphate
0.1465 g
Buffer
monobasic•H 2 O
Sodium citrate•2H 2 O
2.1000 g
Antioxidant
Purified water q.s. to
100.0 ml
Solvent
In general, in the compositions of the invention, glycerol displays a dispersing action towards xanthan gum, preventing the formation of clumps and lumps during the dispersal phase of the polymer in H 2 O.
A general description of a procedure for the preparation of a pharmaceutical composition in accordance with the present invention will now follow. By way of illustration, the formulation prepared is for 100 ml/g of product.
Procedure for the Preparation of a Preformed Re-Epithelializing Gel
In a volume of purified water of about 50 ml all the additives of the formulation are added and dissolved, adding each component after the preceding one has been completely dissolved.
If the composition requires it, a predetermined quantity of one or more of the pharmacological agents listed above is added to the solution until said pharmacological agent(s) is/are completely dissolved or mixed.
Separately, one gram of xanthan gum is added to 50 ml of water and is dispersed on the surface of the liquid, without stirring, to avoid the formation of lumps. Alternatively, the dispersion may be homogenized with a paddle stirrer or a homogenizer so as to accelerate the process while avoiding the formation of lumps. If the composition requires it, hyaluronic acid is also dispersed in this phase.
The homogeneous dispersion is then autoclaved until a minimum F0=15 valid for the sterility is obtained (lethality, expressed in terms of equivalent of time in minutes at a 121° C. temperature with reference to the killing of microorganisms during the process of steam sterilization).
A this point, the solution of the additives sterilized thorough filtration (if a suspension sterilize in suitable manner) is aseptically added to the xanthan gum dispersion and stirred for about 1 hr. at a speed that will allow for smooth mixing without excessive turbulence, until a homogeneous gel is obtained.
Finally, the gel may be aseptically distributed in the appropriate containers.
To illustrate the efficacy of the main compositions of the invention, two experiments will be describe that were carried out to verify, in an in vivo re-epithelializing model, the effect of 2 preformed gels according to the aforesaid formulations—one (Formulation 2) containing only xanthan gum (XNT) and another (Formulation 3) containing both xanthan gum and hyaluronic acid (EPG)—in comparison to a solution containing only 0.15% sodium hyaluronate and salts (EYP) and a saline solution with no polymers (SOL).
Re-Epithelialization Efficacy
The difference between the two experiments lies in the fact that the first is designed to asses the dynamic and quantitative aspects of re-epithelialization and the second to asses the morphological and qualitative aspects of re-epithelialization following treatment with the various formulations. In the first experiment a confocal ophthalmoscope (CSLO) was used to follow the re-epithelialization rate and in the latter a scanning electron microscope (SEM) was used for the ultrastructural analysis.
For each experiment New Zealand albino rabbits, subdivided in 6 treatment groups according to what is described in the next two paragraphs, were used
Animals
Male New Zealand albino rabbits (Charles River Italia), medium weight 2.400 Kg, were used.
The animals were allocated in animal rooms maintained in standard conditions of humidity (50%±10% RH) and temperature (19±2° C.) with alternating cycles of artificial light (12 hours darkness/light). The animals were fed and allowed water ad libitum.
Treatment Scheme and Regimen
After checking the eyes of the animals to exclude eventual ophthalmological pathologies, the animals were assigned to six different treatment groups according to the following scheme:
Animals used during the different observation and treatment times
T 0
T 24h
T 48h
T 72h
T 96h
Control
4
—
—
—
Untreated wound
4
4
4
4
4
EPG
4
4
4
4
4
XNT
4
4
4
4
4
EYP
4
4
4
4
4
SOL
4
4
4
4
4
Legend
Control: animals with intact cornea not pharmacologically treated.
Untreated wound: animals with corneal wound not pharmacologically treated
EPG, XNT, EYP, SOL: animals with corneal wound treated with the different formulations
All the tested substances were administered 5 times a day until the end of the experiment.
Experimental Model
The animals were anesthetized by an i.m. injection of ketamine (37.5 mg/kg b.w.) and xylazine (10 mg/kg b.w.), and with oxybuprocaine (1 drop/eye).
The corneal wound was executed using an Algerbrush with a 1 mm tip. With the aid of a sterile parafilm mask, with a 6 mm hole at the center, a circular area was de-epithelialized. The eye was immediately washed with sterile BBS to remove cell debris and the treatment was performed.
In time course the rabbits were evaluated at 0, 24, 48, 72 and 96 hours with a CLSO coupled to an image-processing system, or they were sacrificed for SEM analysis (0, 24, 48, and 72 hours).
The research method and results of each experiment are described hereafter.
CLSO Experiment
The eyes of the rabbits of each treatment group were treated with a 25 μl solution of 0.5% sodium fluorescein. After 2 minutes the excess of fluorescein was washed away with a physiological solution. The sedated rabbits were then examined through CLSO. This system detects the fluorescent signal that originates from the epithelium lacking damaged zone and measures quantitatively the damaged area through an image-processing system.
Results
The CLSO analysis revealed that the wound heals spontaneously after 72 hours in all the treated groups.
The group treated with the formulation containing only xanthan gum as active principle (XNT) showed an accelerated re-epithelialization process already 24 hours after the treatment. The wound's closure was at least 30% more advanced than in the groups “Untreated wound”, EYP and SOL. A higher re-epithelialization rate (50% higher than the other groups) was observed 48 hours after the treatment in both the group treated with xanthan gum only (XNT) and the group treated with xanthan gum mixed with hyaluronic acid (EPG). There were no observed differences between the group treated with only sodium hyaluronate (EYP) and the groups SOL and “untreated wound”.
SEM Experiment
At predetermined times (0, 24, 48, 72 hours from the beginning of treatment) the animals of the different treatment groups were sacrificed (Tanax i.v.). Rapidly following the sacrifice the bulb was enucleated and the corneas excised and immediately fixed with 2% glutaraldehyde during 24 hours. Following fixation the corneas were processed for SEM analysis.
Results
All the corneas processed for observation immediately after corneal de-epithelialization (T 0 ) exhibit wounds with sharp raised margins and naked stroma. The controls (intact corneas) exhibit an homogeneous epithelium with a good degree of cellular differentiation, and a normal presence of “holes” (circumscribed areas lacking microvilli that are present on the surface of the epithelial cells with probable communication functions), serrated cellular contacts and numerous microvilli, presence of superficial epithelium with the typical mosaic aspect that reflects the different maturation stages (dark, medium light and light cells).
T24 Ore
Twenty four hours after the beginning of the experiment, the corneas of the group “Untreated wound” exhibit a de-epithelialized area with an entirely naked stroma, with the margin of the epithelium lacking zone sharp but hardly raised. All the newly formed cells present at the margins of the “wound” or slightly outside show few microvilli, and are not clearly differentiated into dark, medium and light.
The margins of the wounds of the corneas of the SOL group are similar to those of the preceding group, but the newly formed cells are more differentiated, with the presence of the three differentiation stages, and more profuse microvilli. Moreover, the cells are centripetally elongated, in contrast to the samples taken from the “Untreated wound” group, where the oblong shape is less evident.
In the corneas of the EYP group the margin of the epithelium-deprived zone is flattened and circumscribed by a ring of differentiated newly formed cells with a centripetally elongated aspect.
The corneas of the XNT group have an aspect to a large extent similar to those of the EYP group.
The corneas in the EPG group exhibit a flattened wound margin with cells with microvilli more numerous than in the other treatment groups. The newly formed cells exhibit a fair number of “holes”.
T 48 Ore
The corneas of the “Untreated wound” group observed after 48 hours at the lowest magnification, exhibit a quite disorganized de-epithelialized zone, with marked and indented margins, and newly formed cells with partially enlarged junctions. A small number of cells are elongated and the small number of microvilli is short and distributed uniformly with no differentiation between light, medium and dark cells.
The samples of the SOL group also exhibit a de-epithelialized zone with quite irregular contours with marked margins, although the newly formed cells appear more differentiated, and the microvilli more numerous with virtually normal shape. The edges of the cells bordering the margins of the re-epithelialized zone are enlarged and in some cases raised.
The corneas of the EYP group re-epithelialized similarly to the corneas of the other groups. However, the contours of the de-epithelialized zone remain irregular, even if the degree of differentiation, the distribution and the quality of the microvilli of the newly formed cells is good.
The samples from the XNT treatment group exhibit irregular wound contours, but the state of the newly formed epithelium is notably better than that of the other groups. The new epithelium zone at the proximities of the wound margins presents a ring of centripetally elongated cells. Moreover, the degree of cellular differentiation, as well as the cellular contours are good, although zones where the cells appear raised in part persist. The microvilli are normal and numerous.
The organization of the samples of the EPG treatment group is similar to that of groups EYP and XNT. However, the edge of the wound, as in the previous observation time, is still flat. Consequently, the newly formed zone with centripetally oriented cells is larger, and in general, even at the lowest magnification, the aspect of the de-epithelialized zone is more uniform.
T 72 Ore
After 72 hours of treatment all the groups exhibit a healed wound, although small, spottily-distributed areas barren of cells and with enlarged junctions persist. This phenomenon is part of the normal re-epithelialization process and is caused by the continuous rearrangement of the newly formed epithelium.
The differences between the groups lie in the organization of the newly formed epithelium. In fact, in the “Untreated wound” group the epithelium appears uniform because of the presence of short and scant microvilli that give the epithelium a “pasty” appearance. Thus, the typical dark, medium and light cell differentiation is not present, except in the zones of newly formed epithelium more distant from the center, probably because in those zones the cellular turnover has returned to normal, while at the center cellular multiplication is still chaotic.
A certain degree of epithelial organization is exhibited by the SOL samples. In fact, even at the central zone, re-epithelialized later, a hint of differentiation is present, and in comparison to the corneas of the “Untreated wound” group, the microvilli are more numerous and “not-pasty”.
The differences between the groups treated with the products containing biopolymers persist even at 72 hours, although the corneas treated with EPG are better that those treated with XNT, and the latter are better than those of the EYP group. In general the aspect of the corneas treated with EPG is similar to that of the controls (intact corneas), with numerous and long microvilli, a fair number of holes uniformly distributed in the cellular layer, and a good representation of cells at the diverse differentiation stages.
According to what has been described so far, the re-epithelializing pharmaceutical composition in preformed gel form accelerates the reconstruction of the damaged epithelium.
Moreover, said composition advantageously favors the reorganization of the epithelium and consequently increases the adhesion and stability of the new epithelium in the underlying connective tissue.
A further advantage of the composition, according to the present invention, is its formulation as a preformed gel as a consequence of which the re-epithelializing pharmaceutical composition also performs a mechanically protective function.
Preferably, when the composition of the invention includes the sodium salt of hyaluronic acid, its formulation exhibits extremely favorable characteristics for a product of topical use.
In particular, the consistency is that of an almost transparent, light cream colored, pleasant to the touch, non-sticky, easily spreadable and absorbed soft gel. The sensations upon instillation are similar: the preparation does not burn, the “blurry vision” sensation is very limited o non-existent while that of freshness and lubrication of the eye persists. Additionally, the product is easily administered both in terms of release from the container (ease of drop formation and delivery) and distribution of the drops on the ocular surface.
Furthermore, it was surprisingly observed that hyaluronic acid, although present in water at concentrations almost seven times lower than that of xanthan gum, has notable stabilization ability with respect to the conformation of the latter.
In fact, the viscosity of xanthan gum solutions without salts decrease in about 30% following thermal treatment.
On the contrary, the viscosity of xanthan gum solutions and hyaluronic acid sodium salt decreases only in 10-15% after thermal treatment.
In particular, the study of the rheological characteristics of the product has given the following results.
As an illustration, the viscosity/shear rate (η/γ) diagram of a composition consisting of 1% xanthan gum+hyaluronic acid was studied and compared to a composition of 1% xanthan+saline solution (BSS) and 1% xanthan+H 2 O.
The rheological profile of the complete product presents very high η (viscosity) and well-defined shear stress at low γ, and therefore, good strength, reticule consistency, and retention at the site of application. Viscosity (η) decreases rapidly as shear rate increases with a high degree of pseudoplasticity that confers good spreadability and distribution to the system at the application site, and gives the user a comfortable sensation. The η/γ curve obtained by gradually increasing the shear rate coincides with that of the reverse path, obtained by gradually diminishing it; therefore, the system presents no tissuetropy and reacquires its structure instantaneously upon cessation of the shear stress.
In particular for ocular applications, this translates itself advantageously in the recovery of the structure and viscosity of the product between blinks consequently increasing the time of corneal contact.
As may be assessed from what has been described herewith, a re-epithelializing pharmaceutical composition according to the present invention answers to the needs mentioned in the introductory section and overcomes the shortcomings of the current state of the arts.
Obviously an expert in the field, in order to satisfy contingent and specific requirements may introduce numerous modifications and variations to the above-described composition, without departing from the scope of the invention as defined by the following claims.
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The present invention relates to a pharmaceutical formulation comprising xanthan gum as a re-epithelializing active principle optionally mixed with hyaluronic acid. The composition speeds up and improves advantageously the formation of newly grown epithelium.
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TECHNICAL FIELD OF THE INVENTION
This invention relates to a structural member formed of a metal and reinforced by a blow-molded member. More specifically, this invention relates to a structural member made of extruded metal with a blow-molded hollow plastic reinforcement located in the interior of the extruded metal.
BACKGROUND OF THE INVENTION
Today's automotive design seeks new methods of manufacturing lighter components having increased structural rigidity. Such lightweight components find use in vehicle seats, cross car beams, support brackets, etc. It is also desirable to reduce the number of components in vehicles such that one component performs more than one function. With regard to vehicle cross car beams, much effort has previously focused on utilizing the structural integrity of the outboard register ducts to support the substrate. These previous designs typically required significant reinforcement with an additional steering column support bracket.
SUMMARY OF THE INVENTION
In accordance with the preferred embodiment of the present invention, a structural member is formed of an extruded substrate reinforced by a blow molded member. In order to retain the blow molded member to the substrate, the substrate is provided with an inwardly extending channel formed therein. A portion of the blow-molded member engages the portions of the substrate that define the inwardly extending channel to secure the blow molded member to the substrate, such that the substrate is mechanically bonded to the blow-molded member.
In another aspect of the present invention, the inwardly extending channel has a neck portion defining a first dimension and a body portion defining a second dimension, wherein, the first dimension of the neck portion is smaller than the second dimension of the body portion.
In yet another aspect of the present invention, the inwardly extending channel is adapted to support a plurality of communication members therein.
In still another aspect of the present invention, the inwardly extending channel is adapted to support a mounting device for attaching the structural member to another object.
Further features and advantages of the invention will become apparent to one ordinary skilled in the art from the following discussion and the accompanying drawings.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 is a perspective view of a structural member illustrated as a cross car beam in accordance with the teachings of the present invention and showing in phantom an instrument panel as installed in a motor vehicle;
FIG. 2 is a perspective view of the structural member in FIG. 1 shown alone;
FIG. 3 is a cross sectional view of one embodiment of a structural member incorporating the principles of the present invention; and
FIG. 4 is a cross sectional view of another embodiment of a structural member incorporating the principles of the present invention.
DETAILED DESCRIPTION
Referring to FIGS. 1 and 2 , an instrument panel and dashboard 10 (shown in phantom) having a structural member 12 embodying the principles of the present invention is shown therein. The instrument panel 10 and structural member 12 are installed in the interior of a motor vehicle. The structural member 12 is illustrated as a cross bar 14 . The cross bar 14 extends horizontally across the motor vehicle generally from the left A pillar 18 to the right A pillar 18 . Additionally, the cross bar 14 has an aperture 20 to accommodate a steering wheel and may have additional features to attach different components, such as a glove compartment, an audio system, a display for the climate control, a passenger airbag, etc.
A support bracket 16 serves as an upright support for the cross bar 14 . The support bracket 16 is positioned substantially perpendicular to the cross bar 14 and is attached to the cross bar 14 at one end and attached to the floor (not shown) of the motor vehicle at the other end. The structural member 12 forms the backbone of the instrument panel and dashboard 10 .
Although in the drawings the structural member 12 is shown and described as a cross beam 14 , it must be understood that the structural member 12 is not limited to use exclusively in this arrangement. The structural member 12 can be used in a variety of components in a motor vehicle. For example, it may be used as a duct for the air conditioning unit in a car, or fluid in the radiator support. Alternatively, the structural member 12 may be used in other application not relating to motor vehicles such as routing for electrical lines in a building walls etc.
Referring to FIG. 3 , the structural member 12 comprises an extruded substrate 22 and a blow molded member 24 located within and reinforcing the substrate 12 . Preferably, the substrate 22 is formed from a suitable metal such as aluminum, iron, copper or alloys thereof. The blow molded member 24 is preferably formed from materials such as plastic, plastic composite or thermoplastic resin such as PET or nylon.
The substrate 22 is formed by extrusion, and an inwardly extending channel 26 in a wall portion 27 of the substrate 22 is part of the extrusion profile. Any appropriate number of inwardly extending channels 26 may be defined in the substrate, and three such channels 26 are shown herein as an example.
The inwardly extending channel 26 is formed such that it is defined by a neck portion 28 and a body portion 30 . The neck portion 28 is adjacent to the wall portion 27 of the substrate 22 and defines a first outer dimension 32 . The body portion 30 extends from the neck portion 28 toward an interior of the substrate 22 and defines a second dimension 34 . This second dimension 34 is greater than the first dimension 32 , and the neck portion 28 forms an undercut relative to the body portion 30 .
The body portion 30 such that portions 36 of the blow molded member 24 engage the inwardly extending channel 26 and wrap around the inwardly extending channel 26 adjacent the neck portion 28 . The portions 36 of the blow molded member 24 adjacent the neck portion 28 are secured in place by the larger body portion 30 , as shown in FIG. 3 .
The engagement of the blow molded member 24 and the inwardly extending channel 26 provides the necessary mechanical bond to hold the blow molded member 24 to the substrate 22 .
The substrate 22 of the structural member 12 can have an open profile, such as that shown in FIG. 3 , wherein the substrate 22 provides a substantially C-shaped profile. If the substrate 22 has an open profile, preferably the blow molded member 24 is further secured to the substrate 22 by using a portion of the blow molded member 24 to encapsulate an edge 42 of the substrate 22 , as shown by the circle designated by reference letter A of FIG. 3 .
Alternatively, the blow molded member 24 can be further secured to the substrate 22 by folding a flange portion 44 of the substrate 22 over onto the blow molded member 24 , as shown by the circle designated by reference letter B of FIG. 3 . The substrate 22 can also have a closed profile, as shown in FIG. 4 , wherein the substrate 22 has a substantially circular, or square, or rectangular shape, such that the substrate 22 presents a hollow tubular profile.
The inwardly extending channel 26 can serve various other purposes within the vehicle and elsewhere. Referring to FIG. 3 , the inwardly extending channel 26 can be adapted to support communication members 38 , such as electrical wiring, or fiber optic cable or other devices adapted to transport electrical current or signals, fluids, air, between various components within the motor vehicle. Further, the inwardly extending channel 26 can also be used to support a mounting device 40 that could be used to attach objects to the structural member 12 , or to mount the structural member 12 to another object.
As a person skilled in the art will recognize from the previous description and from the figures and claims, modifications and changes can be made to the preferred embodiment of the invention without departing from the scope of the invention as defined in the following claims.
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A structural member of the present invention includes a substrate having portions defining an inwardly extending channel and a blow molded member in contact with the substrate. The blow molded member has portions that engage the portions of the substrate that define the inwardly extending channel such that the blow molded member is secured to the substrate.
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This application is based on Application No. 2001-148843, filed in Japan on May 18, 2001, the contents of which are hereby incorporated by reference.
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to a power steering system which computes an error in the reading of a detected torque value of an interface circuit of a torque detecting portion by means of a controller for controlling an electric power steering control unit and which makes it possible to effect correction for restraining error on a software basis.
2. Description of the Related Art
A conventional power steering system will be described with reference to the drawings. FIG. 5 is a diagram showing the system configuration of a conventional power steering system.
In FIG. 5, numeral 1 indicates an external device, and numeral 2 indicates an electric power steering control device. Numeral 3 indicates a controller, numeral 4 indicates a torque sensor, and numeral 5 indicates a motor.
Further, in the drawing, numeral 11 indicates a condition setting portion, numeral 21 indicates a detecting portion, numeral 91 indicates a torque sensor adjusting circuit portion, and numeral 24 indicates a control portion.
Next, the operation of the conventional power steering system will be described with reference to the drawings.
In a conventional method for restraining torque value reading error, the precision of the parts used in the detecting portion 21 of the controller 3 is controlled to thereby control the controller 3 so as to involve as few errors as possible.
Further, to achieve an improvement in accuracy, an arbitrary torque signal is input from the external device 1 , and a detection torque signal of the controller 3 is measured. To eliminate the error involved, correction is performed on a hardware basis by soldering an adjusting resistor, etc. to the torque sensor adjusting circuit portion 91 .
That is, conventionally, the correction of the detection value of the torque sensor 4 is performed as follows. The external device 1 and the controller 3 are connected to each other. An arbitrary torque signal is input from the external device 1 , and the torque signal used by the controller 3 is measured. To cancel the differential therebetween, correction for eliminating reading errors is performed on a hardware basis by an adjusting resistor, etc. of the torque sensor adjusting circuit portion 91 .
By thus performing correction on the controller 3 on a hardware basis, the torque signal detected by the controller 3 is taken in by the control portion 24 as a normal value, making it possible to perform control.
The conventional power steering system described above has a problem in that when correcting a reading error of the torque sensor 4 , which cannot be corrected even by part precision control, it is necessary to perform the correction from outside or provide a reference value for the torque sensor 4 , so that dedicated equipment is required, resulting in rather high cost. Further, in effecting correction, it is necessary to perform a hardware operation such as the mounting of an adjusting resistor, etc.
SUMMARY OF THE INVENTION
This invention has been made with a view toward solving the above problem in the prior art. It is accordingly an object of this invention to provide a power steering system in which the correction of the detection torque value is effected not from outside by means of an adjusting resistor or the like but on a software basis, whereby it is possible to cancel the torque-detection interface reading error of the controller itself.
In accordance with the present invention, there is provided a power steering system comprising an external device for outputting an arbitrary torque signal in an error measurement mode, and an electric power steering control device which detects the torque signal, computes the differential between the detected torque value and a reference torque value, stores the differential as a torque correction value, and uses the detected torque value after correcting it by the torque correction value in the actual control mode.
Further, in accordance with the present invention, the external device includes a storage instruction portion for giving instructions to operate in the measurement mode and a condition setting portion for outputting the arbitrary torque signal, and the electric power steering control device includes a torque sensor for detecting a steering torque applied to the steering system of the vehicle, a motor for generating a steering assistance torque in accordance with a control current, and a controller having a detecting portion for detecting the torque signal through the torque sensor, a computing portion for computing the differential between the detected torque value and a reference torque value, a storage portion for storing the differential as a torque correction value, and a control portion which, in the actual control mode, corrects the torque value detected by the torque sensor by the torque correction value and outputs a control current for the motor in accordance with the corrected torque value.
In accordance with this invention, there are provided a power steering system comprising an external device which, in an error measurement mode, outputs an arbitrary torque signal, computes the differential between the transmitted detection torque value and a reference torque value, and sends out the differential as a torque correction value, and an electric power steering control device which detects the torque signal, transmits the detected torque value to the external device, stores the torque correction value transmitted from the external device, and, in the actual control mode, uses the detected torque value after correcting it by the torque correction value.
Further, in accordance with this invention, the external device includes a first communicating portion which gives instructions to operate in the measurement mode, receives the detected torque value, and sends out the torque correction value, and a condition setting portion for outputting the arbitrary torque signal, and the electric power steering control device includes a torque sensor for detecting a steering torque applied to the steering system of the vehicle, a motor for generating a steering assistance torque in accordance with a control current, and a controller having a detecting portion for detecting the torque signal through the torque sensor, a second communicating portion for transmitting the detected torque value to the external device and receiving the torque correction value, a storage portion for storing the received torque correction value, and a control portion which, in the actual control mode, corrects the torque value detected by the torque sensor by the torque correction value and outputs a control current for the motor on the basis of the corrected torque value.
Further, in this invention, the first communicating portion of the external device and the second communicating portion of the controller are connected to each other in a wireless fashion.
Furthermore, in this invention, the torque correction value is a gain correction value of the torque signal.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 is a block diagram showing a power steering system according to Embodiment 1 of this invention;
FIG. 2 is a flowchart showing the operation of a power steering system according to Embodiment 1 of this invention;
FIG. 3 is a block diagram showing a power steering system according to Embodiment 2 of this invention;
FIG. 4 is a flowchart showing the operation of a power steering system according to Embodiment 2 of this invention; and
FIG. 5 is a block diagram showing a conventional power steering system.
DESCRIPTION OF THE PREFERRED EMBODIMENTS
Embodiment 1
A power steering system according to Embodiment 1 of this invention will be described with reference to the drawings. FIG. 1 is a block diagram showing a power steering system according to Embodiment 1 of this invention. It is to be noted that in the drawings, the same or equivalent components are indicated by the same reference numerals.
In FIG. 1, numeral 1 indicates an external device constituting a part of an inspection apparatus of a production line and formed by a personal computer or the like, and numeral 2 indicates an electric power steering control device. Numeral 3 indicates a controller, numeral 4 indicates a torque sensor for detecting a steering torque applied to the steering system of the vehicle, and numeral 5 indicates a motor for generating a steering assistance torque for the steering system of the vehicle in accordance with an electric current from the controller 3 .
Further, in the drawing, numeral 11 indicates a condition setting portion for determining a torque value (reference torque value) to be supplied to the controller 3 , numeral 12 indicates a storage instruction portion for placing the controller 3 in a mode in which storage is possible (error measurement mode), numeral 21 indicates a detecting portion, numeral 22 indicates a computing portion, numeral 23 indicates a storage portion, and numeral 24 indicates a control portion. The condition setting portion 11 and the storage instruction portion 12 are provided in the external device 1 , and the detecting portion 21 , the computing portion 22 , the storage portion 23 , and the control portion 24 are provided in the controller 3 .
Next, the operation of the power steering system of Embodiment 1 will be described with reference to the drawings.
FIG. 2 is a flowchart illustrating the operation of the power steering system of Embodiment 1 of this invention.
In step 101 , the external device 1 places the controller 3 of the steering control device 2 in the error measurement mode by means of the storage instruction portion 12 . That is, by connecting the external device 1 , the controller 3 realizes that it is in a state in which a torque correction value (offset) is stored (error measurement mode). At this time, the controller 3 resets the torque correction value of the storage portion 23 to place the system in a non-correction state.
Next, in steps 102 and 103 , the external device 1 applies an arbitrary torque signal by means of the condition setting portion 11 . On the other hand, the controller 3 detects a torque value of the torque signal at that time obtained through the torque sensor 4 by means of the detecting portion 21 .
Next, in steps 104 and 105 , the controller 3 obtains, through computation by the computing portion 22 , the differential between a reference torque value provided internally beforehand and the torque value of the detected arbitrary reference torque signal. And, it stores the differential in the storage portion 23 as a torque correction value.
And, when controlling the motor 5 by the control portion 24 (actual control mode), the controller 3 can cancel the reading error of the torque reading interface of the controller 3 by performing correction on the torque value detected by the detecting portion 21 on the basis of the torque correction value (differential) stored in the storage portion 23 .
That is, the power steering system of Embodiment 1 comprises the electric power steering control device 2 equipped with the torque sensor 4 for detecting a steering torque applied to the steering system of the vehicle, the controller 3 for supplying an electric current in accordance with the magnitude and direction of the steering torque to the motor 5 , and the motor 5 for generating a steering assistance torque in accordance with the electric current, and the external device 1 capable of generating torque signal, wherein when the torque signal is supplied from the external device 1 to the controller 3 , the differential between the torque value of the torque signal detected by the controller 3 and the reference torque value provided inside the controller 3 beforehand is computed by the computing portion 22 , and the value thus obtained can be stored in the storage portion 23 inside the controller 3 , thereby providing a function by which reading error in the interface portion of the controller 3 itself is restrained.
As described above, in Embodiment 1, the reading error correction of the torque signal detecting circuit of the controller 3 can be realized not on a hardware basis but on a software basis, and software correction is possible independently of the accuracy of the torque signal detecting circuit. Further, the correction can be expedited and automated.
Embodiment 2
A power steering system according to Embodiment 2 of this invention will be described with reference to the drawings. FIG. 3 is a block diagram showing a power steering system according to Embodiment 2 of this invention.
In FIG. 3, the components which are the same as or equivalent to those of FIG. 1 are indicated by the same reference numerals. Numeral 31 indicates a communicating portion for the external device, and numeral 32 indicates a communicating portion for the electric power steering control device connected to the communicating portion 31 through a cable.
In Embodiment 2, the computing portion 22 described with reference to Embodiment 1 is provided in the external device 1 .
Next, the operation of the power steering system of Embodiment 2 will be described with reference to the drawings.
FIG. 4 is a flowchart showing the operation of the power steering system of Embodiment 2 of this invention.
In step 201 , the external device 1 places the controller 3 of the electric power steering control device 2 in an error measurement mode by means of the communicating portion 31 . That is, by connecting the communicating portion 31 to the communicating portion 32 , the controller 3 realizes that it is in a state in which the torque correction value (offset) is stored (error measurement mode). At this time, the controller 3 resets the torque correction value of the storage portion 23 to place the system in a non-correction state.
Next, in step 202 , the external device 1 supplies an arbitrary torque signal to the controller 3 by way of the torque sensor 4 of the electric power steering control device 2 by means of the condition setting portion 11 .
Next, in steps 203 and 204 , the controller 3 detects a torque value of the torque signal at that time by means of the detecting portion 21 , and transmits the detected torque value to the external device 1 by means of the communicating portions 32 and 31 .
Next, in steps 205 and 206 , the external device 1 computes, by means of the computing portion 22 , the differential (offset) between a reference torque value it has provided and the detected torque value transmitted to thereby obtain the torque correction value. The external device 1 transmits the torque correction value to the controller 3 by means of the communicating portions 31 and 32 .
Next, in step 207 , the controller 3 stores the torque correction value transmitted from the external device 1 in the storage portion 23 .
And, when controlling the motor 5 by the control portion 24 (actual control mode), the controller 3 performs correction on the torque value detected by the detecting portion 21 on the basis of the torque correction value stored in the storage portion 23 , whereby it is possible to cancel the reading error of the controller 3 .
That is, as in Embodiment 1 described above, in the power steering system of Embodiment 2, when an arbitrary torque signal is supplied from the external device 1 , the detected torque value of the torque signal detected by the controller 3 is transmitted from the controller 3 to the external device 1 by using the communicating function provided in the external device 1 and the controller 3 ; in the external device 1 , the differential between the detected torque value received and the reference torque value it has provided is computed to obtain the value of the reading error in the torque signal interface portion of the controller 3 , and the torque correction value is transmitted from the external device 1 to the controller 3 by using the above-described communicating function, and stored in the storage portion 23 in the controller 3 .
As described above, in accordance with Embodiment 2, the computing portion 22 is provided in the external device 1 , and a communicating function is provided therein, whereby the electric power steering control device 2 can be adjusted through ordinary torque detection, without having to perform any special computation, and the torque signal correction procedure can be changed solely by changing the external device 1 . Further, through communication, the electric power steering control device 2 is caused to realize that it is in the state in which storage is effected (error measurement mode), so that it is possible to effect switching to the error measurement mode from the external device 1 with an arbitrary timing, making it possible to perform correcting operation through control by the external device 1 .
Embodiment 3
While in Embodiment 2 described above the communicating portions 31 and 32 are connected to each other through a cable, it is also possible to establish a wireless connection between these communicating portions to realize a protocol allowing communication with a plurality of electric power steering control devices 2 , whereby it is possible to effect communication between a single external device 1 and a plurality of electric power steering control devices 2 in a production line, thereby simplifying the equipment of the production line.
Further, since a wireless connection is adopted, it is possible to freely select a production line layout.
That is, in the power steering system of Embodiment 3, the communicating function of Embodiment 2 is made wireless instead of a cable connection, and the external device 1 is provided with a communication system which allows communication with a plurality of electric power steering control devices 2 .
As described above, in Embodiment 3, the communication is executed on a wireless basis, and a protocol is established which allows communication with a plurality of electric power steering control devices 2 , whereby it is possible to effect communication between a single external device 1 and a plurality of electric power steering control devices 2 , thereby simplifying the equipment.
Embodiment 4
While in the above-described embodiments a value (torque correction value) for restraining the reading error of the torque signal used is stored, a gain correction value can be stored in Embodiment 4. The construction of the power steering system of Embodiment 4 is the same as that of one of the above-described embodiments.
In order that an ideal torque signal may be obtained independently of the level of the torque signal used or the circuit accuracy of the controller 3 , the torque signal used is corrected by a gain correction value, making it possible to cancel the above-mentioned influence.
That is, in the power steering system of this Embodiment 4, it is possible to store a gain correction value in the storage portion 23 in the electric power steering control system 2 so that an ideal torque may be obtained for the torque signal used in the electric power steering control device 2 .
As described above, in this Embodiment 4, signal level can be corrected by multiplying the torque signal used by the controller 3 by an arbitrary gain correction value, making it possible to store the gain correction value. In order that an ideal torque signal may be obtained independently of the level of the torque signal used or the circuit accuracy of the controller, the torque signal used is corrected by the gain correction value, making it possible to cancel the above-mentioned influence.
Further, in accordance with this invention, the above-mentioned torque correction value is a gain correction value of a torque signal, thereby making it possible to cancel the influence of a reading error.
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Disclosed is a power steering system which involves no dedicated equipment, no increase in cost, and no such hardware operation for correction as the mounting of an adjusting resistor. The power steering system includes an external device which outputs an arbitrary torque signal in an error measurement mode, and an electric power steering control device which detects the torque signal, computes the differential between the detected torque value and a reference torque value, stores the differential as a torque correction value, and, in the actual control mode, uses the detected torque value after correcting it by the torque correction value, whereby it is possible to perform reading error correction on a software basis and to expedite and automate the correction.
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CROSS REFERENCE TO RELATED APPLICATION
The present invention is based on provisional patent application Ser. No. 60/243,987 filed Oct. 30, 2000.
BACKGROUND OF THE INVENTION
This invention relates to an automatic roach trap of the type wherein a roach entering the trap interrupts the beam of radiation to trigger coercive means which urges the roach into a disposable container. In particular, the invention is directed to a roach trap wherein the opening to the removable container is maintained in a closed position during periods of inactivity.
The interest in controlling the roach population in areas inhabited by man has been present as long as history has been recorded. The roach population has survived and, in fact, flourished despite repeated attempts to control it both through chemical and mechanical methods. Today, there is greater public recognition of the dangers inherent in the use of chemical insect control agents and increased attention is being directed to the use of mechanical trapping arrangements for insect control.
The durable roach exists in several varieties and different sizes. This insect continues to thrive despite the many attempts to provide a non-chemical approach to reducing its population. Not only do roaches belong to a variety of different species having a wide range in size, the roach is a remarkably adaptable insect capable of finding its way out of various trapping mechanisms. It is important that any trapping device maintain control over the trapped roaches since they have demonstrated an ability to exit through extremely small crevices and irregular openings.
One approach to trapping roaches is disclosed in my U.S. Pat. No. 5,815,982 wherein the trapping device compensates for the wide variation in size and weight of the roach by utilizing a beam of radiation to trigger the coercive mechanical sweep. The device described therein utilizes a movable barrier that is opened by the mechanical sweep. The bounded passageway along which the roach is urged has an opening that communicates with the opening in an underlying storage container. Thus, access between the storage container and the end of the bounded passageway is interdicted by a pivotal top mounted barrier door which rotates, when struck by the sweep, within a connecting chamber or vestibule. The captured roach is then free to drop down into the box area or remain within the vestibule. Upon rare occasions, a roach remaining in the vestibule could facilitate a rechallenge of the sweep mechanism if it evades the swinging barrier door. Even more of an annoyance was that the trap left the vestibule space available for any roach unwilling to move to the removable box.
Accordingly, the present invention is directed to the provision of an automatic roach trap provided with means to continually close off the underlying storage container so that roaches can not reenter the passageway thereto. In addition, the present container is provided with a cover that is movable in relation to the underlying roach receiver so that the container is automatically closed as the user withdraws the container from the trapping device. Also, the invention provides a mechanical test for the user to readily verify battery and trap functionality.
SUMMARY OF THE INVENTION
The present invention is directed to an automatic roach trap having a removable container to receive and retain trapped roaches within the bounded enclosure forming the roach trap. The enclosure has two levels with an intermediate floor between its top member and base member. The removable container is located in an access port in one of the enclosure walls and located beneath an opening in the floor.
A tilt platform is located in the enclosure adjacent the entryway for the roaches. A first opening is located in the floor adjacent the platform and a movable barrier is pivotally mounted between the opposing sidewalls. The barrier is located between the platform and the first opening. The free end of the barrier adjacent the floor has a closure member affixed thereto. This member overlays the first opening so that the opening is closed when the barrier is in the inactive position. Thus, roaches are unable to leave the removable container once deposited therein. In addition, the barrier is releasably coupled to the enclosure when the platform is not active. As the platform is driven into a tilt position, the barrier is then released for movement.
The bounded enclosure includes means for detecting the presence of a roach on the platform and provides an actuating signal to drive means that is operatively connected to the barrier. When the presence of a roach is detected, the drive means causes the platform to tilt, the barrier to move and the closure member to permit the addition of a roach to the container. The tilt platform prevents roaches from exiting through the entryway during actuation. In addition, the floor of the enclosure has an arcuate curved region which conforms to the arcuate path of the closure member to prevent roaches from exiting the container and seeking to leave the enclosure by a circuitous route.
The removable container includes a receiver dimensioned for placement in the access port with a movable cover supported thereon by guides located on opposing sides of the receiver. The receiver contains a first stop which limits the movement of the cover in one direction due to a projection mounted on the cover. A hand-grippable tab is provided on the cover so that the cover is moved from open to close position prior to withdrawal from the access port. During withdrawal, the projection mounted on the cover contacts the edge of the opening in the receiver thereby providing a second stop when the cover is in the closed position.
The removable container further includes engaging means mounted on the cover for contacting and maintaining the cover in the closed position so that it is not inadvertently opened by the user. The engaging means includes a pair of L-shaped prongs located on a opposing edges of the covers with the prongs being urged inwardly by the guides when the cover moves between open and closed positions. The prongs each include a cam mounted thereon for contact with the guides during movement. The bounded enclosure is provided with a releaseable detent on its base member. This detent engages a mating recess in the bottom of the removable container to both insure registration of the container opening with the opening in the floor of the bounded enclosure and also to enable the force supplied to the tab by the user to move the cover to its closed position before overcoming the restraining force applied by the detent. When the movement of the tab causes the prongs to travel along the guides and the cover contacts the stop, the withdrawal of the closed container from the access port takes place. Thus, the present invention essentially eliminates the opportunity for trapped roaches to exit the storage container during operation of the roach trap and further insures that the removable container is in its closed position when withdrawn for disposal.
Further features and advantages of the invention will become more readily apparent from the following detailed description of a preferred embodiment when viewed in conjunction with the accompanying drawings.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 is a view in perspective of a preferred embodiment of the present invention showing roaches in the entryway thereof.
FIG. 2 is a exploded view of the embodiment of FIG. 1 .
FIG. 3 is a view of the front of the embodiment shown in FIG. 2 .
FIG. 4 is a top cross sectional view taken along line 4 — 4 of FIG. 3 .
FIG. 5 is a front cross sectional view taken along line 5 — 5 of FIG. 4 .
FIG. 6 is a side cross sectional view taken along line 6 — 6 of FIG. 3 .
FIG. 7 is partial side view showing the movement of the tilt platform and moveable barrier of FIG. 6 .
FIG. 8 is a partial view in perspective of the drive and latching means of the tilt platform of FIG. 7 .
FIG. 9 is an expanded view in perspective of the pivot of the latching means shown in FIG. 8 .
FIG. 10 is a partial side view showing the drive means of the present embodiment.
FIG. 11 is a detail view in perspective showing the beam interrupter shown in FIG. 10 .
FIG. 12 is a view in perspective showing the removable container with the cover separated therefrom.
FIG. 13 is a view in perspective showing the removable container in the closed position.
FIG. 14 is a view in perspective showing the removable container in an open position.
FIG. 15 is a cross sectional view of the guide taken along line 15 — 15 of FIG. 13 .
FIG. 16 is a partial cross sectional view taken along line 16 — 16 of FIG. 13 .
FIG. 17 is an expanded view of the prong shown in FIG. 13 .
FIG. 18 is an expanded view of the prong shown in FIG. 14 .
FIG. 19 is an expanded view showing the prong urged inwardly by the guide in the removable container.
FIG. 20 is a partial view in perspective showing the removable container in the access port.
FIG. 21 is similar to FIG. 20 with the container partially removed.
FIG. 22 is a partial top view in section taken along line 22 — 22 of FIG. 21 .
DESCRIPTION OF THE PREFERRED EMBODIMENT
Referring now to the embodiment shown in FIG. 1, the roach trap includes a bounded enclosure 14 having a curved top member 17 , a base member 18 and walls extending therearound. The entryway 15 is shown with a partition 16 dividing the entryway into two discrete areas. The roaches are shown entering the bounded enclosure 14 . One of the side walls is provided with a transparent viewing window 12 which enables the user to view the removable container contained in the device. For ease of assembly, the parts are made of molded plastic with the constructional features shown more clearly in FIG. 2 which is an exploded view showing the curved top member overhanging the entryway 15 .
In FIG. 2, the entryway 15 is an inclined plane to the intermediate floor 19 which receives tilt platform 21 thereon as shown by the dotted outline. The bounded enclosure for trapping is formed by sidewalls 26 and 27 and a portion of the curved top member 17 . The partition 16 extends up the entryway 15 and terminates on floor 19 before reaching the tilt platform. A driven arm 32 extends through sidewall 27 and engages a shaft 37 mounted in the end of the tilt platform. The driven arm 32 is positioned in a keyway 33 formed in the end of drive arm 31 . The drive arm is coupled to drive motor 34 . The embodiment is powered by six batteries 35 which are contained in the side of the roach trap and held in position by conventional contacts and the access cover 36 . The batteries also operate the emitter-detector pair 42 which establishes the beam of radiation across the tilt platform.
A beam actuated by plunger 49 is positioned just above the emitter-detector 42 and is manually operable to enable the user to determine if the batteries are sufficiently charged to operate the device. In normal operation, the device as seen in FIG. 11 is continually operational so that the manual interrupter triggers the tilt platform to indicate that sufficient power remains. Activation followed by no movement of the tilt platform 21 in indicates that batteries need to be replaced.
The movable barrier 23 is pivotally mounted in notches in the side walls 26 and 27 . At the lower or free end of the movable barrier is a closure member 24 which serves to provide a barrier to any roaches previously trapped. As shown in FIG. 2, the movable barrier has lateral extensions 13 which serve to support the barrier in the notches. The movable barrier is positioned adjacent to contact disk 22 which is affixed to the tilt platform. The curve on contact disk 22 causes the disk to rotate and urge the movable barrier away from the vertical position. A reinforcing ridge 25 is provided on the movable barrier for engagement with the disk and to provide clearance between the two moving parts.
Turning now to FIG. 3, the entryway 15 is shown divided by partition 16 . The cover 17 is shown with the actuating plunger 49 for the beam interruption operation extending upwardly therefrom. The sidewalls 26 and 27 are shown in dashed outline. The view taken along line 4 — 4 of FIG. 3 shows the general layout of the trapping mechanism. The entryway 15 terminates at the horizontal floor 19 . The opposing sidewalls have lateral extensions so the entering roaches are directed to encounter the tilt platform 21 . The heavy-outline 50 crossing the tilt platform is the path of the beam of radiation from the emitter detector pair 42 located on the outside of the sidewalls and transmitting the beam through openings therein. The movable barrier 23 with the closure member extending therefrom is adjacent the tilt platform. As shown, a contact lip 28 is provided on the barrier member to contact the tilt platform and maintain the barrier in a vertical position. The circuit board 51 containing the electrical components for signal processing is shown in the light-dashed lines and is mounted beneath the floor 19 . The wiring connections to drive motor 34 are not shown and reside in the space between the battery assembly and the side wall as seen in FIG. 5 . As shown therein, the curved top member is provided with a limit stop 29 centrally located. This stop limits the angle of tilt of the tilt platform 21 when actuated. The contact disk is provided at the edge of tilt platform 21 so that a tilting of the platform causes the contact disk to urge the vertically positioned movable barrier to its open position. The removable container 41 is shown in its underlying position beneath the floor.
In FIG. 6, the floor 19 is shown with a contour or recess that permits the tilt platform to rest thereagainst in the same plane as floor 19 so that the roach does not encounter any discontinuity. The termination of the intermediate barrier provided by the floor 19 is a curved section 44 which extends upwardly and is in conformance with the arcuate path of the closure member 24 . Upon interruption of the beam, the tilt platform 21 rotates about shaft 37 and contact disk 22 causes the movable barrier 23 to rotate on its pivot. The closure member moves along the arcuate section of 44 of floor 19 . This prevents previously trapped roaches residing in the underlying container from exiting the device. The stop 29 located on the top member 17 serves to limit the angle of tilt platform 21 and provides a jarring force to any roach residing thereon. As a result, a roach is dislodged from the tilt platform and drops through the opening in the floor into the container. It is to be noted in FIG. 6 that the beam interrupting plate 57 is shown in dashed outline connected to the plunger 49 .
The movement of the tilt platform and movable barrier is shown more clearly in FIG. 7 wherein the tilt platform 21 is rotated to the limit stop 29 with the contact disk urging the movable barrier out of its vertical position. As a result, the roach is deposited in the underlying container through opening 55 in the cover 46 and into receiver 47 . It is to be noted that the contact disk has an opening therein 56 which allows the beam 50 to extend across the tilt platform.
The ability of roaches to escape from mechanical traps has created problems in the past when the trapping mechanism is to be operating without attention over a long period of time. Heretofore, entrapped roaches have managed to find a path to escape when the device is accepting or trapping another roach. The present invention utilizes the combination of the curved floor 44 and the closure member 24 to maintain control during trapping of roaches that have been previously trapped. The return movement of the movable barrier 23 and the corresponding movement of the closure member 24 causes roaches to return to the container. When the tilt platform returns to its rest position on floor member 19 , a latching mechanism is used to maintain the movable barrier in a vertical position. In FIG. 8, the barrier 23 is shown vertical with the tilt platform return to its rest position. A tab 61 extends upwardly from the floor 19 through a mating notch in platform 21 to engage the free end of locking arm 38 . As shown, the arm is pivotally coupled to the movable barrier. FIG. 9 shows barrier 23 to have a reinforcing tab 64 which receives pivot pin 63 in a mating hole. The sealing tab 66 is located on the end of locking arm 38 to seal the clearance opening formed in the barrier. The movable arm contains a beveled notch 62 which releaseably engages tab 61 . As platform 21 is driven to a tilt position, the locking arm moves along with the tilt platform and frees itself from the tab 61 thereby permitting the barrier 23 to be driven by contact disk 22 . The tilt platform rotates about shaft 37 which is coupled to the driven arm 32 . In FIG. 10, the drive mechanism for the tilt platform about shaft 37 is shown. The shaft is coupled to the driven arm 32 which has a lateral extension that resides in keyway 33 of drive arm 31 . The drive arm is affixed to the drive motor 34 . When a roach interrupts the beam of radiation across the tilt platform, the drive motor is actuated and the drive arm is rotated to the dashed position in FIG. 10 . As a result, the keyway forces the driven arm 32 downwardly causing rotation of the platform about the access of shaft 37 . As mentioned previously, the angle of tilt of the platform 21 is limited by the limit stop 29 located on the underside of the cover. Also shown in FIG. 10 is the beam interruption plunger 49 with its transverse support 52 having tabs which are received in the notches 53 of the side wall. As seen in FIG. 11, the transverse support with the ends thereof in the notch is a flexible member so that pressure exerted on the plunger causes the blocking member 57 to move vertically within guides 59 . A limit tab 58 is provided as a safety measure to prevent overstressing of the flexible transverse support 52 . In the at rest or normal position, the transverse support is horizontal and the blocking member 57 does not interrupt the beam 50 . The interruption of the beam results in actuation of the tilt platform if the batteries have sufficient stored charge. If the batteries need replacement, no reaction takes place and the user knows that it is time to replace batteries.
The electrical schematic for the circuitry used in the above-described embodiment is shown in FIG. 14 of my prior U.S. Pat. No. 5,815,982. The operation of the circuitry is the same with the interruption of the beam providing a signal to a logic circuit which causes the drive motor to be actuated. In the embodiment shown, the return of the tilt platform to its original position is effected by the movement of the keyway. The movable barrier utilizes a gravity return and the locking arm reengages the tab 61 as seen in FIG. 8 .
The removable container 41 shown in FIG. 1 is described in greater detail in FIG. 12 wherein cover 46 is shown removed from receiver 47 . The receiver is a container having a large area opening 76 in the top surface with a channel 73 centrally positioned therein and extending to the opening. As will later become more apparent, the channel serves to establish a first stop for the cover when it is inserted into guides 82 . The guides are provided on opposing edges of the receiver 47 and extend substantially the entire length thereof. In the embodiment shown, the guides terminate short of the ends of the receiver. In addition, a cutout section 83 is provided in each guide near the front of the container. The overlying cover 46 includes a centrally located projection 72 which extends downwardly and is matingly received in the channel 73 of the receiver. An opening 71 is provided in the cover adjacent to the end of the projection. Next to the opening is the releaseable engaging means for the cover which includes a pair of L-shaped prongs 84 separated from the adjacent material by slots 85 . Intermediate the prongs 84 is an elongated tab 74 which serves as a guide during insertion and removal. A hand-grippable tab 75 completes the cover. In operation, the cover is inserted into the guides 82 and urged into its open position wherein the openings 71 and 76 are in alignment.
The insertion of the cover 46 into the receiver 47 is shown in FIGS. 13, 14 and 15 . In FIG. 13, the edge sections 81 of the cover have been inserted into the mating guides 82 and the tab is used to urge the cover into position. No resistance is met to achieve the position shown in FIG. 13 . However, at that point, the L-shaped prongs on either side of the cover enter into contact with the adjacent detents 86 . By urging the prongs 84 inwardly by means of the triangular projections 90 formed thereon, the projections pass the detents and the cover can be moved to the open position shown in FIG. 14 . The term open position is used to describe the condition where the two openings are in alignment so that access to the interior of the container is available. When the cover and receiver are in the open position, the projection on cover 46 is received in the channel 73 to both maintain alignment during relative movement and to provide a stop for the cover so that in the open position, the openings are in alignment. Also, the projection travels along the channel when the cover is moved to the position shown in FIG. 13 with the projection contacting the edge of the opening in the receiver 47 thereby forming a second stop as seen in FIG. 16 .
The positions of the prongs 84 and the projections located on the outer ends thereof are seen in FIGS. 17, 18 and 19 . When the cover is closed as shown in FIG. 13 with the tab having been used to withdraw the cover to cause misalignment of the openings, the end of prong 84 rests at detent 86 . To reopen the container requires the application of force to the prongs so as to overcome the effect of the detent. When the cover is in the open position, each prong and its triangular projection reside within a cutout section 83 of a guide 82 . A camming surface 91 is provided to contact the triangular projection on the prong and urge it inwardly in the manner shown in FIG. 19 . This enables the cover to be moved from the open to closed position. As shown, the prongs are bounded by slots 85 which enable inward movement into the bounding slots. In summary, the cover is initially in the open position and the user inserts it into the roach trap enclosure. When trapping has occurred and the user wishes to withdraw the removable container from the device, the tab 75 is pulled so that the camming action causes the prongs to move inwardly and the cover is partially withdrawn and the openings are non-aligned. As mentioned, the closed position for the removable container is shown in FIG. 13 . The user is prevented from inadvertently returning the cover to the open position by the detents 86 located at the ends of the receiver guides 82 .
Referring now to FIGS. 20, 21 and 22 , the interaction of the device enclosure with the removable container is shown in further detail. The cover contains an elongated tab 74 intermediate the prongs 84 . An alignment notch 93 is provided in the central portion of the exterior wall to maintain the alignment of the cover, receiver and enclosure wall during insertion and removal of the container. The relative movement between cover and receiver takes place while the container is within the device enclosure. The container is also provided with a centrally located elongated channel on its bottom surface which engages a biased detent 95 formed on the bottom of the device enclosure. The biased detent 95 is shown in FIGS. 5 and 6. The molded plastic enclosure enables an inwardly displaced protrusion to be formed on the bottom for use in guiding the container by riding in the channel. The receiver is provided with a mating recess at a particular location in the channel to appropriately position the receiver within the device enclosure. Continued application of force to the tab 75 causes the closed container to overcome the force of the protrusion 95 and permit withdrawal of the container. Thus, the container is prevented from inadvertent displacement during operation. In addition, internal guides can be used within the device enclosure to further maintain the cover in alignment and to maintain the prongs in position during continued use. For example, the access port for the removable container is provided with recesses 98 to allow passage of the projections 90 therethrough. Further, the entry at the access port is facilitated by the use of radius corners 99 as shown in FIG. 22 . The radius corners together with recesses 98 inwardly urge the L-shaped prongs 84 to facilitate insertion of a closed container.
While the above-description has referred to a specific embodiment of the invention, it is recognized that many modifications and variations may be made therein without departing from the scope of the invention as claimed.
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An automatic roach trap having a receiving container removably located in the trap enclosure. The trap utilizes a beam to detect roaches on a platform therein and actuates a mechanism to open an internal closure and coerce the roach into the underlying container. Access to the container is restricted during operation to prevent the escape of trapped roaches. The container is automatically closed upon withdrawal and designed to prevent inadvertent reopening during disposal.
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FIELD AND BACKGROUND OF THE INVENTION
[0001] The invention relates to a device for providing a breathing gas, in particular to a device for conditioning a breathing gas, for managing the weight of a breathing creature, in particular for stimulating weight reduction. The invention further relates to a method and to a use of a device for conditioning a breathing gas and for providing said breathing gas to a breathing creature, for managing the weight of a breathing creature, in particular for stimulating weight reduction of the breathing creature.
[0002] In developed countries around the world, there is a tremendous interest in personal fitness, wellness and para medication. At the same time there is a disturbing trend that people, including adults and children are becoming overweight. By overweight, it is meant that the subject has exceeded the acceptable weight range and percent body fat generally considered as healthy determined by factors including, but not necessarily limited to age, height, sex, and body type.
[0003] Overweight produces a wide range of health concerns including sleep apnoea, orthopaedic complications, arterial sclerosis, diabetes, heart disease and also social and psychological problems etc. All these undesirable conditions contribute in development of an unsatisfactory quality of life and in some cases premature death.
[0004] Therefore, many people want to maintain a specific weight or even lose weight to maintain or enhance their physical condition. To lose weight the body needs to burn more energy than is provided by the food intake. Known diet methods include restriction of amounts and kinds of food, exercises and use of diet drugs to reduce or maintain body weight.
[0005] However, managing weight via known diet methods takes a long period of time, even when combined with exercises or diet drugs. Many people are not capable of maintaining a reduced food intake and/or an increased exercise level over a long period of time and therefore do not achieve the amount of weight loss aimed for or even gain weight in spite of there efforts. Also, even when the diet results in a loss of weight, for a variety of reasons, most people find it very difficult to maintain significant weight reduction over time.
[0006] Therefore only a few people are able to achieve a significant reduction of weight, and even less are able to maintain this condition.
SUMMARY OF THE INVENTION
[0007] It is an object of the invention to obviate the problems described hereinabove and in particular to enable weight reduction of a breathing creature.
[0008] According to the present invention, this object has been achieved by providing a device according to claim 1 , a method according to claim 26 and a use of a device according to claim 28 .
[0009] The invention provides a device for providing a breathing gas, the device comprising gas supply means and gas conditioning means. Thus a device according to the invention can provide a breathing creature with a breathing gas. The breathing gas is conditioned by forming particles comprising a frozen fluid in the breathing gas. When the breathing creature inhales the breathing gas, his body comes into contact with the gas and the particles comprising the frozen fluid. The breathing gas and the particles will be warmed by the body of the creature, preferably to a temperature at which the frozen fluid melts.
[0010] The warming of the breathing gas and the particles by the body of the breathing creature requires energy. The energy used by the body in the process of warming up the breathing gas and particles is provided for by burning extra energy c.q. calories. Thus, a device according to the invention will increase the burning of energy by the body of the breathing creature and thus stimulate the metabolism of the breathing creature. This will help the breathing creature manage his weight, in particular to maintain a specific weight, or induce weight reduction of the breathing creature in a controlled manner.
[0011] Furthermore, by forming the particles in the breathing gas the capacity of the breathing gas to comprise energy is increased, because more energy is needed to warm or cool a breathing gas comprising such particles than for warming or cooling an unconditioned breathing gas. Thus, by conditioning the breathing gas, the potential of energy exchange between the body of the breathing creature and the breathing gas is increased. Therefore, the body of a breathing creature will, while breathing a breathing gas provided by a device according to the invention, use more energy than while breathing an unconditioned breathing gas of the same temperature.
[0012] The invention thus provides a device for conditioning a breathing gas to increase the energy consumption of a person inhaling the gas and thus increasing the metabolism of the person. A device according to the invention may therefore assist in managing the weight of a breathing creature, more in particular in managing the weight reduction of the breathing creature, and/or in maintaining the breathing creature at a specific weight.
[0013] It is noted that the particles may be formed in different ways. For example, a substance may be added in the form of a fluid, vapour or droplets, to a cooled breathing gas, the temperature of the breathing gas cooling the substance into a frozen fluid. Preferably, the fluid is added in the form of small droplets, which need less cooling than a gaseous fluid to obtain particles comprising frozen fluid. In a further preferred embodiment the droplets are cooled to a temperature slightly above to their freezing temperature prior to being added to the breathing gas. Alternatively, the particles can also be added to the breathing gas in frozen i.e. solid form, for example in the form of ice particles or ice crystals. Thus the gas can be conditioned in a limited amount of time.
[0014] The temperature of the conditioned breathing gas and/or the particles is lower than the body temperature of the breathing creature breathing the gas. In a preferred embodiment, the particles are frozen particles of a substance having a phase change, changing from solid to liquid and/or gas, below the body temperature of the breathing creature. Preferably the temperature of the conditioned breathing gas is such that the particles melt within the breathing ducts of the breathing creature, in particular in the back of the nose or throat such that remaining liquid can be swallowed by the user and does not run out of the nose of the creature. Thus, the frozen fluid is no longer part of the exhaled breathing gas and remains in the users' body where it is further warmed, retracting extra energy from the body.
[0015] A device according to the invention can be used for increasing the energy consumption of a passive breathing creature. For example a person may use the device while sleeping, watching television, driving a car, sunbathing at the beach or sitting behind a pc, thus stimulating his metabolism to reduce weight or to prevent weight gain.
[0016] Also, a device according to the invention may be used for increasing the metabolism of an active person. For example a breathing creature may use the device while running to further increase the energy consumption of his body. Furthermore, when used during exercising, the cooling effect of the breathing gas may prevent overheating of the body and allow the person to exercise for a prolonged period of time.
[0017] Also, by cooling the body of the user during exercising, less natural body fluid is lost via transpiration. In addition, fluid from molten particles may remain in the body of the user. Thus, the intake of fluid by the person during exercise is less critical and the risk of dehydration is reduced. Furthermore, after exercising the device may be used to reduce the temperature of the body to a normal level more quickly, thus enhancing the recuperation of the body.
[0018] Also, by nature the mucous membrane comprised in the breathing ducts, lungs and nasal cavity is humid. During intense exercise, especially when breathing dry air, a lot of the fluid of the mucous membrane is absorbed by the breathing gas, and thus removed from the body. A device according to the invention may reduce the loss of fluid from the mucous membrane, and thus prevent damage to the membrane, by adding fluid to the breathing gas. It can be used to provide a conditioned breathing gas to the user prior to, during, or after exercising.
[0019] Thus the invention provides a device for enhancing the physical condition, and hence the performance of a breathing creature such as a human being.
[0020] The invention furthermore relates to a method for managing the weight reduction of a breathing creature, for example a human, by supplying a breathing gas to the nose of the creature with the device according to the invention.
[0021] The invention also relates to the use of a device according to the invention for conditioning a breathing gas by lowering the temperature of the breathing gas to induce weight reduction and/or prevent weight gain of a person breathing the conditioned breathing gas.
[0022] Further objects, embodiments and elaborations of the device and the method according to the invention will be apparent from the following description, in which the invention is further illustrated and elucidated on the basis of a number of exemplary embodiments, with reference to the drawings.
BRIEF DESCRIPTION OF THE DRAWINGS
[0023] FIG. 1 is a schematic view in section of a device according to the invention;
[0024] FIG. 2 schematically shows a user using an embodiment of an alternative device according the invention; and
[0025] FIG. 3 is a schematic view partially in section of the alternative device of FIG. 2 .
DETAILED DESCRIPTION
[0026] First, the invention will be further elucidated on the basis of the schematic exemplary embodiment of a device according to the invention as shown in FIG. 1 . Thereafter, some particular alternative embodiments will be described.
[0027] FIG. 1 shows a device 1 for providing a breathing gas according to the invention. The device 1 comprises gas conditioning means 6 for conditioning the breathing gas, and gas supply means 3 for supplying the breathing gas to the nose of a breathing creature, more specifically a human, using the device. The device is preferably of such size and weight that it can be worn on the body of the user without limiting his freedom of movement. The gas conditioning means 6 comprise a housing 2 provided with a gas inlet 11 and a gas outlet in the form of a connection valve 8 for connecting the gas supply means to the gas conditioning means. The gas conditioning means 6 further comprise a gas transport duct 10 for transporting a breathing gas from the gas inlet 11 to the valve 8 . In the preferred embodiment shown, the gas conditioning means 6 are provided with a helical gas transport duct 10 which provides a long track for conditioning the gas while being compact in over all size.
[0028] As a drive means for transporting the breathing gas a fan 4 is provided near the air inlet 11 . The fan is driven by a drive (not shown) to draw in air from the surroundings for use as a breathing gas. The pressure generated by the fan drives the air via the transport duct 10 . The flow of the air drawn into the inlet 11 is indicated with arrows 5 .
[0029] The gas conditioning means 6 are configured to form particles comprising a frozen fluid in the breathing gas. More in particular, the gas conditioning means are configured to cool the breathing gas and to condition the level of humidity of the breathing gas. For conditioning the breathing gas, the gas conditioning means 6 comprise cooling means 15 and humidifying means 14 .
[0030] The cooling means 15 , comprise a cooling duct 12 , which spirals within the transport duct 10 . The cooling means 15 further comprise means for transporting a cooling fluid via the cooling duct 12 for cooling a breathing gas transported via the transport duct 10 .
[0031] The humidifying means 14 comprise a water reservoir 16 and means for humidifying the breathing gas by adding water from the reservoir in the form of small droplets to the breathing gas. Water from the reservoir may for example by injected under pressure via nozzles into the gas transport duct, causing the water to form a mist of small droplets in the breathing gas. These droplets, due to their small size, are picked up and carried along by the flow of breathing gas. Alternatively, water may also be added to the breathing gas by an ultrasonic humidifier, which may be used to vaporize the water using an ultrasonic wave produced by means of a piezoelectric transducer.
[0032] The gas supply means 3 for supplying the breathing gas to a user's nose comprise a gas duct 13 and a gas outlet 7 . The gas duct 13 is a hose made out of a flexible material such as plastic or rubber. At one end the gas duct 13 is provided with means for connecting the duct to the valve 8 of the gas conditioning means 6 . At an opposite end, the gas duct 13 is provided with the gas outlet 7 which is configured to in use be located near an opening of the users' nose for providing a user with the conditioned breathing gas.
[0033] In the embodiment shown, the gas outlet 7 is provided in the form of a mask 9 comprising the actual gas outlet. The mask 9 is configured to in use be placed over the nose of a person, such that the actual outlet of the gas duct is positioned adjacent the opening of the user's nose. The mask 9 , more in particular the actual gas outlet, is positioned near the opening of the nose by positioning means 9 in the form of an adjustable band. Alternatively, the gas supply means may for example be provided with a gas outlet and positioning means for positioning the outlet in the opening of the user's nose.
[0034] In addition, or as an alternative, to the drive means provided in the gas conditioning means 6 , the gas supply means 3 may also be provided with drive means for transporting the breathing gas.
[0035] For providing a breathing gas with the device 1 according to the invention, air is drawn in via the inlet 11 into the gas duct 10 and is transported via this gas duct to the valve 8 . While the breathing gas is transported via the duct 10 it is cooled by the cooling duct 12 to a temperature below the freezing point of water. Preferably, the gas conditioning means are configured to condition the breathing gas such that the temperature of the breathing gas is between −30 and −1° C. and preferably between −15 and −1° C. When the breathing gas is cooled sufficiently the small water droplets added to the breathing gas will freeze to form frozen particles. Due to their small size, the droplets freeze quickly. The breathing gas is thus conditioned by adding particles to the gas, which particles comprise a frozen fluid.
[0036] To facilitate the absorption of the droplets by the breathing gas, the droplets are preferably added to the breathing gas in little concentrations and in intermediate steps. Thus the breathing gas, while transported via the transport duct 10 , is subsequently subjected to stages of cooling the flow of breathing gas, droplets and/or particles, and to stages of adding more droplets to the flow of breathing gas. The breathing gas is preferably also cooled during and after the adding of the droplets to prevent the temperature of the breathing gas to rise above the freezing point of the added fluid. In a preferred embodiment the water, or alternative fluid, is cooled before it is added to the breathing gas, preferably to just above its freezing point. Thus the droplets do not need extensive cooling by the breathing gas to freeze into frozen particles. By providing the fluid via anti-drip nozzles, fluid freezing to the nozzle outlets may be prevented.
[0037] The embodiment shown is provided with a gas supply means for inhaling the conditioned breathing gas via the nose. The breathing gas comprising the frozen particles is transported via the flexible duct 13 and the gas outlet 7 of the supply means 3 to the nose of the user of the device 1 . When the user inhales, the breathing gas enters the body of the user via the nose ducts. The biological function of the nose is to warm air on inhalation and remove moisture on exhalation. Thus, a breathing gas inhaled and/or exhaled via the nose will be more warmed than a breathing gas inhaled and/or exhaled via the mouth. Thus, providing the breathing gas via the nose will draw more energy from the body from the breathing creature and is thus beneficial for managing the weight of the breathing creature according to the invention.
[0038] In a preferred embodiment, the particles are frozen particles of a substance, such as water, having a phase change, changing from solid to liquid and/or gas, below the body temperature of the breathing creature. Preferably the temperature of the conditioned breathing gas, and or the temperature and/or size of the particles is such that the particles melt within the breathing ducts of the breathing creature, in particular in the back of the nose or throat such that remaining liquid can be swallowed by the user and does not run out of the nose of the creature. Thus the frozen fluid is no longer part of the exhaled breathing gas and remains in the users' body where it is further warmed, retracting extra energy from the body.
[0039] Preferably, the temperature of the breathing gas and the particles is about −3° C. when entering the nose of the breathing creature, such that at least a substantial part of the particles melts before the breathing gas is exhaled again. For example, a sensor may be provided near the gas outlet to monitor the diameter of the particles in the breathing gas and/or the temperature of the breathing gas, which information can be used to adjust the gas conditioning means. To prevent the breathing gas and the particles from warming up in the flexible duct 13 of the gas supply means, the duct can for example be isolated and/or provided with cooling means.
[0040] A device according to the invention thus provides a breathing gas which is conditioned by reducing its temperature, to increase the metabolism of a breathing creature breathing the gas. Because of this additional use of energy, the weight loss of the user increases. With a device according to the invention the weight loss of the user may be managed such that the weight loss is increased.
[0041] The exemplary device shown may be used by a breathing creature to breathe air from the surroundings while the gas conditioning means condition said air. The gas conditioning means are configured to condition the breathing gas such that the temperature of the breathing gas is lower than the surrounding temperature, which is in normal circumstances between 5° C. on a cool day outside to 25° C. on a warm day or inside. Preferably, the gas conditioning means are configured to condition the breathing gas such that the temperature of the breathing gas is between −30 and −1° C. lower than the surrounding temperature. Thus, the temperature of the conditioned breathing gas is lower than the temperature of surroundings. Breathing the conditioned breathing gas takes more energy from the user's body than breathing the air of the surroundings, because the relatively cool conditioned breathing gas takes more energy warming up while inside the body of the user.
[0042] In the embodiment shown the breathing gas is cooled by a cooling duct running within the breathing gas transport duct, thus cooling the gas and small droplets added to the breathing gas. In an alternative, the gas conditioning means may be configured to subject the breathing gas and the added particles or droplets to frost, or to an alternative phase change material for a cooling medium.
[0043] In the embodiment shown, droplets of water are added to the breathing gas. Alternatively, the gas conditioning means may be configured to add a fluid, such as water, in the form of a vapour or gas, or in the form of frozen particles. The gas conditioning means may for example also be configured to generate particles of ice and to add these particles to the breathing gas. For example, the device may comprise cooling elements to freeze water into bodies of ice, or the device may comprise a space for storing bodies of ice formed outside the device, for example in a separate fridge. The device may further comprise automatic means for crunching the bodies of ice into small particles or for example a rasp for grating the body of ice to generate small particles, which particles are then added to the flow of breathing gas.
[0044] In a preferred embodiment the gas conditioning means comprise at least one cooling element for forming a body of ice thereupon, preferably by way of guiding moist air along its cooled surface. The cooling element is movably supported relative to a scraper body for moving the body of ice along the scraper body to generate small ice particles. In a further alternative the rasp or grater is also formed by a body of ice.
[0045] By guiding the breathing gas along the ice being crunched or gartered, the particles of ice may be introduced onto the stream of breathing gas.
[0046] In an alternative embodiment, a device according to the invention comprises gas conditioning means configured to expand a pressurised breathing gas to lower the temperature of the breathing gas. Preferably, the gas conditioning means are furthermore conditioned to add a fluid in the form of vapour or gas to the breathing gas prior to expanding, for forming particles comprising frozen fluid within said breathing gas upon expansion of the breathing gas. The vapour or gas may also be added during the expansion of the breathing gas.
[0047] In a further preferred embodiment the breathing device and in particular the gas conditioning means are configured to add an additive to the breathing gas. For example, cartridges comprising an additive in gaseous or liquid form may be provided for inserting in a cradle in the gas conditioning means for adding the additive to the breathing gas. Control means may be provided for controlling the amount of additive added, the moment at which it is added, for example at the end of a time interval, etc.
[0048] For example, the gas conditioning means may be configured to add oxygen to the breathing gas, thus providing a user with extra energy during exercising. Also, an aromatic substance may be added to the breathing gas. For example by adding menthol aroma the gas user may experience a sense of freshness which motivates him during excercising. For example by adding lavender aroma the breathing gas may relax the user which may be beneficial when the device is used during sleep. Furthermore, a medicine may be added to the breathing gas, for example insulin for use by diabetics or bronchodilators for the treatment of asthma.
[0049] A device according to the invention may also be provided with means for treating air, such as a filter for removing pollutants such as dust particles from the air to be used as a breathing gas to provide the breathing creature with clean air.
[0050] The embodiment shown uses the air out of the surrounding environment for conditioning. In an alternative embodiment, the breathing gas may for example also be provided from a pressurised reservoir. Such a reservoir may for example be a refillable reservoir comprised within the device or for example be a separate canister connectable to the air inlet of the device. For example, when the air in the environment is relatively warm it may be profitable to provide the gas conditioning means with a breathing gas which is cooler than the air of the environment, thus limiting the work of the conditioning means to be done to condition the breathing gas by cooling. By providing the device with a pressurised breathing gas the gas conditioning means may be limited in size and energy consumption. Thus the device can be small and easy to handle.
[0051] Furthermore, when the breathing gas is provided under pressure, it may not be necessary to use a fan, or similar means such as a bellow, to drive the breathing gas via the transport ducts. The supply of flow of gas may be simply be regulated via an adjustable valve.
[0052] The gas conditioning means, in particular the gas inlet may for example also be connectable to a gas pre-conditioning means, for conditioning the breathing gas, such as the air from the surroundings, prior to entering the device. Thus the gas conditioning means of the device only have to cool the air a little or not at all. By providing the device with a pre conditioned breathing gas the gas conditioning means may be limited in size and energy consumption. Thus the device can be small and easy to handle which may enhance its fitness to for example be worn on the body while the user is exercising.
[0053] Furthermore, the device may be provided with gas supply means which can be disconnected from the conditioning means for enabling use of the device with different gas supply means. Thus a user can replace the gas supply means, or part thereof such as the gas outlet or mask. For example in a gym or fitness centre or medical centre, gas conditioning means may be provided which are mounted to sports equipment such as an exercise machine or ergo meter, for example a stationary bicycle, treadmill or rowing machine. A user of the exercise machine can use his personal gas supply means to provide himself with conditioned breathing gas from the fixed gas conditioning means. Because each user can connect his gas supply means to the device, multiple users can subsequently use the device, without the need of the gas outlet to be cleaned.
[0054] In a further preferred embodiment, the device is provided with means for connecting multiple gas supply means to the gas conditioning means, thus enabling multiple users to use the same device at the same time. In a preferred embodiment the device comprises detection means for detecting how many users are connected and to adjust the provision of conditioned breathing gas in relation to the number of detected users.
[0055] A device according to the invention may be designed as a portable device for example for use during walking or cycling, or as a more robust design for example for use while sleeping, doing a work out on a home trainer, etc. A device can for example be worn via a belt, in a back pack, etc.
[0056] Furthermore, a device according to the invention may also be used in combination with a gas duct comprising a mouthpiece, or a gas duct comprising a combination of a nosepiece and a mouthpiece. The positioning means connected to the air duct configured to fix the actual gas outlets in the nose openings of a user may be provided with extra securing means for securing it near or in the nose of the user and or his mouth, such that the mouthpiece may be used while sleeping.
[0057] In an embodiment according the invention the device comprises control means for controlling the gas conditioning means, in particular the cooling means and the humidifying means. The device may further comprise control means for controlling the gas supply means, for example by way of a valve or fan to control the gas flow.
[0058] Preferably a user, or for example a fitness instructor, can control the process parameters such as the speed of the flow of breathing gas, the amount and size of particles added to the breathing gas, the amount of additive added to the breathing gas and/or the temperature of the breathing gas. A user may for example switch off the adding of particles to inhale cooled breathing gas only.
[0059] In addition the control means may be provided with a control system and sensors for partially or fully automated control of the gas conditioning means. For example a temperature sensor may be provided near the gas outlet to detect the temperature of the conditioned breathing gas. The detected temperature can be provided to the control system and/or display to enable adjustment of the gas conditioning means, in particular the cooling means, by the control system or a user of the device. Similarly, a sensor may be provided to monitor the diameter of the particles in the breathing gas, for example near the gas outlet, which information can be used to adjust the gas conditioning means.
[0060] In a further preferred embodiment, a control system controls the parameters relative to each other such that the user may enter for example only one parameter or a user profile such as “low intensity” for use of the device while sleeping or “high intensity” for use of the device during exercising.
[0061] A device according to the invention may be provided with an active or a passive system, or both. With an active system the flow of breathing gas is synchronized with the breathing pattern of the breathing creature using the device. A control system detects the breathing pattern of the breathing creature and on basis of that information regulates the speed and pressure of the flow of breathing gas to match the breathing pattern. An active system is especially suitable for providing a breathing gas to a sleeping user.
[0062] With a passive system the breathing gas is provided at a constant speed and pressure, which makes it easier to manage the flow and cooling of the breathing gas by a control system.
[0063] A device according to the invention may be provided with a power source such as a battery for running the conditioning means and/or the control means etc. In addition, or as an alternative, the device may be adapted to be connected to the electricity grid.
[0064] The invention furthermore provides a method for managing the weight of a breathing creature, for example a human being. The method comprises conditioning a breathing gas and supplying the breathing gas to the nose of the creature with a device as disclosed. The breathing gas may be conditioned by adding particles comprising frozen fluid to the breathing gas. Furthermore, the temperature of the breathing gas may be lowered to form particles comprising frozen fluid within the breathing gas.
[0065] Thus, a device according to the invention can be used in a method for conditioning a breathing gas by lowering the temperature of the breathing gas to increase the metabolism of a breathing creature, such as a human being, breathing the conditioned breathing gas to manage the weight, and in particular to induce weight reduction, of the human being.
[0066] Preferably, a substance is added to the breathing gas in liquid or gaseous form to form the particles in the breathing gas. The substance may also be added in the form of solid i.e. frozen particles. Preferably the temperature of the breathing gas is lowered, for example by use of a compressor and expansion valve, to form particles comprising frozen fluid within the breathing gas. Alternatively, particles comprising frozen fluid may be added to the breathing gas. Preferably, the frozen particles are ice crystals created from water droplets of water vapour.
[0067] In a further embodiment according to the invention, the device may be adjustable to provide only a cooled breathing gas to the users' nose, the gas not comprising frozen fluid particles, to limit the intake of liquid by the user of the device.
[0068] According to a further aspect of the invention the invention provides a further device for providing a breathing gas. Said device comprises gas supply means for supplying a breathing gas to a user's nose and gas conditioning means for conditioning the breathing gas. The gas conditioning means may be connected to the gas supply means and condition the breathing gas before said breathing gas reaches the nose of the user. The device is used for controlling the weight loss of the user.
[0069] The gas supply means may comprise at least one gas outlet which is configured to in use be located near and/or in an opening of the users nose. The gas supply means may comprise positioning means for positioning the at least one gas outlet near and/or in the opening of the users nose. The gas supply means may comprise positioning means for positioning the at least one gas outlet adjacent and/or in to the opening of the users nose.
[0070] The breathing gas may be air. The gas supply means may be configured to supply air to the user's nose and the gas conditioning means may be configured to condition the air. The gas supply means may comprise an air inlet for letting in air.
[0071] The gas conditioning means may be configured to condition the temperature of the breathing gas. The gas conditioning means may be configured to condition the temperature of the breathing gas such that the temperature of the breathing gas is between −30 and 60° C. and preferably −15 and 45° C.
[0072] An embodiment of the device according the invention comprises one or any combination of two or more of the following features; the gas conditioning means may be configured to humidify the breathing gas, the gas conditioning means may be configured to increase the level of humidity of the breathing gas, the gas conditioning means may be configured to add vapour to the breathing gas, the gas conditioning means may be configured to add an additional substance having a vapour form to the breathing gas, the gas conditioning means are configured to add vapour particles to the breathing gas, the gas conditioning means are configured to add steam to the breathing gas and the gas conditioning means are configured to moisten the breathing gas. These features facilitate the conditioning of the breathing gas.
[0073] In an embodiment of the device according to the invention, the gas conditioning means are configured to lower the temperature of the breathing gas. In this embodiment the weight loss of the user is controlled such that the weight loss is increased. Because of the low temperature of the breathing gas, the user will, due to the natural reaction of the body, use energy to make the breathing gas warmer. Because of this additional use of energy, the weight loss of the user increases. The gas conditioning means may be configured to cool the breathing gas. The gas conditioning means may be configured to condition the breathing gas such that the temperature of the breathing gas is between −30 and −1° C. and preferably between −15 and −1° C. The gas conditioning means may be configured to condition the breathing gas such that the temperature of the breathing gas is lower than the surrounding temperature. The gas conditioning means may be configured to condition the breathing gas such that the temperature of the breathing gas is between −30 and −1° C. and preferably between −15 and −1° C. lower than the surrounding temperature. The gas conditioning means may be configured to subject the breathing gas to frost. The gas conditioning means may be configured to form particles comprising ice in the breathing gas. The gas conditioning means may be configured to form ice particles in the breathing gas. The gas conditioning means may be configured to form ice crystals in the breathing air. The gas conditioning means may be configured to subject the vapour to frost. The gas conditioning means may be configured to subject the vapour particles to frost. The gas conditioning means may be configured to subject the steam to frost. The gas conditioning means may be configured to lower the temperature such that vapour particles present in the breathing gas freeze and form ice particles.
[0074] In an embodiment of the device according the invention, the gas conditioning means are configured to increase the temperature of the breathing gas. In this embodiment the weight loss of the user is controlled such that the weight loss is reduced. Because of the high temperature of the breathing gas, the user will, due to the natural reaction of the body, use less energy because the breathing gas (almost) does not need to be made warmer by the user. Because of this reduction in use of energy, the weight loss of the user reduces.
[0075] In an embodiment of the device according the invention, the gas conditioning means may be configured to add an additive to the breathing gas. The gas conditioning means may be configured to add oxygen to the breathing gas. The gas conditioning means may be configured to add an aromatic substance to the breathing gas. The gas conditioning means are configured to add a medicine to the breathing gas.
[0076] In an embodiment according the invention the device comprises control means for controlling the gas conditioning means. The device may comprise further control means for controlling the gas supply means. The gas supply means may comprise drive means for transporting the breathing gas. The gas supply means may comprise a gas duct. The gas conditioning means may comprise humidifying means for increasing the level of humidity of the breathing gas. The gas conditioning means may comprise cooling means for cooling the breathing gas. The gas conditioning means may comprise warming means for warming the breathing gas.
[0077] The device according to the invention may be used for breathing air from the surroundings, while the gas conditioning means conditions said air. The gas conditioning means may condition said air such that the temperature of said air is lower than the temperature of the surroundings. The conditioning means may condition said air such that the temperature of said air is higher than the temperature of the surroundings.
[0078] The invention further relates to the use of a device according the invention. The invention also relates to a method for controlling the weight loss of a breathing creature, for example a human, by supplying a conditioned breathing gas to the nose of the creature with a device according to the invention. The breathing gas may be conditioned such that the temperature of the breathing gas is lowered and/or increased.
[0079] The invention is in the enclosed figures explained in more detail, wherein FIG. 2 shows an user using an embodiment of the device according the invention and FIG. 3 shows the device of FIG. 2 in an enlarged view.
[0080] FIG. 2 shows a user 102 using an embodiment of the device 101 according the invention. The user is a breathing creature, more specifically a human. The device 101 comprises gas supply means 103 for supplying a breathing gas to the nose 105 of the user 102 . The gas supply means 103 comprise positioning means ( 109 of FIG. 3 ) to position the gas outlets ( 107 of FIG. 3 ) in the openings 108 of the nose 105 . In use, the user 102 breaths the breathing gas in via his nose 102 . The device 101 comprises gas conditioning means 106 for conditioning the breathing gas.
[0081] The device 101 uses air as breathing gas. The gas supply means 103 comprise an air inlet 111 for letting in air from the surroundings. The gas conditioning means 106 are configured to condition said air. The gas conditioning means 106 are configured to lower the temperature of the air and/or to condition the level of humidity of the air.
[0082] The device 101 is in FIG. 3 shown in an enlarged view. Some elements located inside the device 101 are shown for clarity reasons. The device 101 comprises an air inlet 111 and two gas outlets 109 . A gas duct 110 extends between said inlet 111 and outlets 107 . The gas duct 110 connects the air inlet 111 with drive means 104 which are configured to suck air via the air inlet 111 in the air duct 110 . Control means 112 are via a communication line 118 connected to the drive means 104 . The air supply of the gas supply means 103 is adjustable via said control means 112 . The drive means 104 are controllable by rotating the control means 112 in the direction shown by arrow 113 . The gas duct 110 extends further from the drive means 104 and through humidifying means 114 . The drive means 104 are configured to blow the air through said part of the air duct 110 . The humidifying means 114 are configured to increase the level of humidity in the air by adding steam to the air. The gas duct 110 extends further from the humidifying means 114 through cooling means 115 . The cooling means 115 are configured to cool the air. The gas conditioning means 106 are with a second communication line 121 connected to second control means 119 . The gas conditioning means 106 are controllable by rotating the second control means 119 in the direction of arrow 120 . The degree in which the air is conditioned is adjustable by the second control means 119 . The gas conditioning means 106 are controllable such that the humidifying means 114 , the cooling means 115 may be used separately or in combination with each other. This means that in use the humidifying means 114 and/or the cooling means 115 may be used. The gas duct 110 extends from the gas conditioning means 106 to the outlets 107 . Positioning means 109 are connected to the air duct 110 adjacent to the outlets 107 . The positioning means 109 are configured to fix the outlets 107 in the nose openings of a user.
[0083] This means that the device 101 may be used for breathing air from the surroundings, while the gas conditioning means 106 conditions said air. The gas conditioning means 106 may condition said air such that the temperature of said air is lower than the temperature of the surroundings. The conditioning means 106 may condition said air such that the temperature of said air is higher than the temperature of the surroundings.
[0084] The invention also relates to a device 101 comprising one or any combination of two or more of the following features: gas supply means 103 , drive means 104 , gas conditioning means 106 , gas outlet 107 , opening nose 108 , positioning means 109 , gas duct 110 , air inlet 111 , first control means 112 , humidifying means 114 , cooling means 115 , warming means 116 , communication line 118 , second control means 119 , second communication line 121 .
[0085] It is noted that under mammals, humans as well as other mammalians are understood herein, such as for example pets like dogs or cats, as also other mammalians such as horses or cattle. The method is suitably used in humans, preferably in moderate overweight humans (BMI 25-30), more preferably in obese people (adipose, BMI>30).
[0086] From the foregoing, it will be clear to the skilled person, that within the framework of invention as set forth in the claims also many variations other than the examples described above are conceivable.
[0087] For example the gas conditioning means may in addition be configured to increase the temperature of the breathing gas, for example, such that the temperature of the breathing gas is higher than the surrounding temperature. The gas conditioning means may be configured to condition the breathing gas such that the temperature of the breathing gas is between 16 and 40° C. and preferably between 16 and 25° C. higher than the surrounding temperature, preferably such that the temperature of the breathing gas is between 36 and 60° C. and preferably between 36 and 45° C.
[0088] In such an embodiment the weight loss of the user may be controlled such that the weight loss is reduced. Because of the high temperature of the breathing gas, the user will, due to the natural reaction of the body, use less energy because the breathing gas (almost) does not need to be made warmer by the user. Because of this reduction in use of energy, the weight loss of the user reduces. Thus the weight loss of a breathing creature can be managed in a controlled manner.
[0089] For example, the gas duct may extend through warming means configured to warm the air. The degree in which the air is conditioned preferably is adjustable by the control means. The gas conditioning means may be controllable such that the humidifying means, the cooling means and the warming means may be used separately or in combination with each other. This means that in use the humidifying means and/or the cooling means and/or the warming means may be used.
[0090] Thus the breathing gas can be conditioned in a controlled manner when the device collects relatively cold air from its surroundings, for example when the user is exercising at sub zero temperatures, it can warm the air to limit de energy that will be spend by the body of the breathing creature to warm the conditioned air. This may be beneficial when the user only wants to loose a limited amount of weight, or wants to maintain a specific body weight. Also, such a device may be used to provide fluid to the nose and lungs of the breathing creature to humidify the mucous membrane, without stimulating the metabolism of the creature.
[0091] Furthermore, a device according to the invention may be provided with detection means to detect the body temperature of the breathing creature using the device. For example, the temperature may be detected via a detector placed on the skin of the breathing creature, or may be derived from monitoring the temperature difference between breathing gas inhaled and breathing gas exhaled by the breathing creature. A control system may control the gas conditioning means on the basis of the registered body temperature of the breathing creature to control the energy used by the breathing creature in warming the breathing gas.
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The invention relates to a device for providing a breathing gas, in particular to a device for conditioning a breathing gas for stimulating weight reduction of a breathing creature. The invention provides a device for providing a breathing gas, comprising gas supply means and gas conditioning means. The device provides a breathing creature with a breathing gas which is conditioned by adding particles comprising a frozen fluid to the breathing gas. When the breathing creature inhales the breathing gas, his body comes into contact with the gas and the particles comprising the frozen fluid. The breathing gas and the particles will be warmed by the body of the creature, preferably to a temperature at which the frozen fluid starts to melt. The warming of the particles and the breathing gas by the body of the breathing creature requires energy, and therefore stimulates the metabolism of a breathing creature, promoting fat burning and inducing weight reduction.
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RELATED APPLICATIONS
This application is a continuation-in-part claiming priority to PCT/GB2009/002286 filed Sep. 25, 2009, which claims priority to GB 0818483.0 filed Oct. 8, 2008. This application also claims priority to U.S. Provisional Patent Application Ser. No. 61/390,051, filed Oct. 5, 2010. The disclosure of each is incorporated herein by reference.
BACKGROUND
The current invention relates to leisure and amusement slide elements and systems.
GB 2224948 discloses a leisure slide comprising a circular bowl having an exit aperture formed in its base. A rider travels down a tubular slide and circuits at least partway around the bowl before exiting the bowl through the exit aperture. The rider may slide with the aid of flowing water or a waxed plastic bag. In those arrangements in which the slide is a waterslide, the rider drops into a splash pool provided below the bowl.
U.S. Pat. Nos. 6,354,955 and 6,485,372 disclose a waterslide bowl element having a bottom wall configured to form a throat around a rider exit opening in the bottom of the bowl. The bowl holds an annular ring of water around the throat that slows down and conducts the rider to the exit opening. The waterslide bowl may be used by riders on inner tubes.
The known leisure rides of this type have a limited throughput, as there must be sufficient interval between riders to ensure that consecutive riders do not collide with each other. Typically, a rider should have exited the bowl before the next rider begins their ride. This is undesirable for individuals wanting to ride the slides, as they may have to queue to ride the slide. Equally, it is undesirable for the operator, as they may need to provide additional waterslides to cope with demand.
At least some of the problems associated with known prior art leisure rides may be overcome by the disclosed elements and systems.
SUMMARY
Leisure and amusement slide elements and systems are disclosed. In one embodiment, a waterslide apparatus includes a bowl having a curved sidewall, two or more rider entrances for enabling riders to slide into the bowl and to circuit at least a portion of the bowl, and a receptacle for forming a pool of water to receive a rider exiting the bowl. A nozzle is provided for directing a jet of water to bias a rider towards an edge of the pool.
In another embodiment, a waterslide apparatus includes a bowl, at least one chute for introducing a rider into the bowl, and a receptacle for forming a pool of water to receive a rider exiting the bowl. A nozzle is provided for providing a jet of water to bias a rider towards an edge of the pool.
In still another embodiment, a slide apparatus includes a bowl having upper and lower ends and first and second entrances. The first and second entrances are distinct from one another and are spaced apart from the bowl lower end. The first and second entrances are configured to bias all users of the first and second entrances to travel about at least a portion of the bowl in a common direction, whether clockwise or counter-clockwise.
In yet another embodiment, an exit system is provided for use with a leisure slide having a bowl. The exit system includes first and second exit slides and a housing configured to be positioned at a lower end of the bowl. The housing has a first exit port leading to the first exit slide and a second exit port leading to the second exit slide. The first and second exit ports are spaced apart from one another such that one user may pass through the first exit port generally simultaneously with another user passing through the second exit port.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 shows a plan view of a waterslide in accordance with one embodiment of the present invention.
FIG. 2 shows a first side elevation of the waterslide of FIG. 1 .
FIG. 3 shows a second side elevation of the waterslide of FIG. 1 .
FIG. 4 shows a schematic representation of a launch mechanism for the waterslide of FIG. 1 .
FIG. 5 shows a plan view of a waterslide in accordance with another embodiment of the present invention.
FIG. 6 shows a side elevation of the waterslide of FIG. 5 .
FIG. 7 shows a plan view of a waterslide in accordance with yet another embodiment of the present invention.
FIG. 8 shows a side elevation of the waterslide of FIG. 7 .
FIG. 9 shows an enlarged view of the launch station of the waterslide of FIG. 7 .
FIG. 10 shows a partial cutaway side elevation of the waterslide of FIG. 7 .
FIG. 11 shows an exit system according to an embodiment of the present invention.
FIG. 12 shows a top view of the exit system of FIG. 11 .
FIG. 13 shows a partial view taken from line A-A of FIG. 12 .
DETAILED DESCRIPTION
A plan view of a waterslide 1 in accordance with a first embodiment of the present invention is shown in FIG. 1 . The waterslide 1 comprises a bowl 3 , first and second chutes 5 , 7 and a spiral staircase 9 . The waterslide 1 may be used, for example, in a leisure or amusement park.
The bowl 3 has a generally oval plan form and is approximately 13.5 meters long and approximately 9.5 meters wide. While various dimensions are described herein, those skilled in the art will appreciate that other dimensions may also be appropriate. The bowl 3 has a sidewall 11 formed from a series of moldings supported on a metal framework 13 . A rim 15 is provided around an upper edge of the bowl 3 , and an aperture 17 is formed in the center of the bottom of the bowl 3 . The rim 15 curves inwardly, and a middle region of the sidewall 11 below the rim 15 is substantially vertical. The lower region of the sidewall 11 slopes downwardly towards the aperture 17 .
A first rider entrance 19 is provided at a first end of the bowl 3 , and a second rider entrance 21 is provided at a second end thereof. The first and second rider entrances 19 , 21 are provided proximal the upper edge of the bowl 3 and are arranged generally tangential to its circumference. The first and second chutes 5 , 7 are connected to the first and second rider entrances 19 , 21 such that riders R, R′ may slide down the chutes 5 , 7 and enter the bowl 3 . The momentum of the riders R, R′ allows them to travel at least partway around the bowl 3 before exiting through the aperture 17 .
It may be desirable for the first and second chutes 5 , 7 to be substantially the same as each other. As shown in FIGS. 2 and 3 , the first and second chutes 5 , 7 comprise upper sections 23 , 23 ′, mid-sections 25 , 25 ′ and lower sections 27 , 27 ′. The upper sections 23 , 23 ′ are positioned above the center of the bowl 3 and are inclined at approximately 15° to the vertical. The mid-sections 25 , 25 ′ and the lower sections 27 , 27 ′ in plan form curve through approximately 270° to guide the riders R, R′ to the rider entrances 19 , 21 . The lower sections 27 , 27 ′ are arranged substantially horizontally such that the riders R, R′ enter the bowl 3 travelling substantially parallel to the rim 15 . The term chute is used herein to refer to slides, flumes, and the like.
The staircase 9 leads to a gantry 29 where a launch station 31 is located. As shown in FIG. 4 , the launch station 31 comprises first and second pivotally mounted platforms 33 , 35 . A pair of riders R, R′ enters the launch station 31 from the side and each stand on their respective platforms 33 , 35 . A launch mechanism 37 is provided for pivoting the platforms 33 , 35 between an extended position and a retracted position (shown in dashed lines in FIG. 4 ). The launch mechanism 37 is configured to ensure that the platforms 33 , 35 pivot to their retract positions generally simultaneously, thereby ensuring that the riders R, R′ are launched together.
The launch mechanism in the embodiment of FIG. 4 comprises a lever 39 to be actuated manually, for example by an operator; but the mechanism 37 could be automated. The launch station 31 may be provided with means to allow the riders R, R′ to confirm that they are ready to be released. For example, the riders R, R′ may be required to each press a respective button 41 , and once both buttons 41 have been pressed, the message “READY” may be displayed on screens 43 , and countdown timers 45 may activate.
The framework 13 supports the bowl 3 and the staircase 9 and may, for example, be of conventional construction. The gantry 29 is mounted on a pair of vertical columns. To provide additional support for the gantry 29 , a first set of tethered cables 49 may be provided. A second set of cables 51 may additionally (or alternately) extend from the gantry 29 to support the upper sections 23 , 23 ′ and the mid-sections 25 , 25 ′ of the chutes 5 , 7 .
A splash pool 53 ( FIG. 2 ) may be provided below the bowl 3 so that the riders R, R′ exit the bowl 3 through the aperture 17 and fall into the pool 53 . A filtration system 55 may be provided to treat the water in the pool 53 and may be provided with a pump (not shown) to pump the water to the top of the chutes 5 , 7 via a pipe 57 . In use, water may be continuously introduced into the top of the chutes 5 , 7 so that there is a steady stream of water down the chutes 5 , 6 . Water may also be pumped to a perforated conduit extending around the rim 15 to wet the interior surface of the bowl 3 to reduce friction. Or, rather than provide a stream of water over the chutes 5 , 7 and/or the interior of the bowl 3 , a water spray may be provided to provide lubrication. A heater may be provided in the filtration system 55 to heat the water.
The operation of the waterslide 1 will now be described with reference to FIGS. 1 to 4 . The riders R, R′ climb the staircase 9 to the gantry 29 and enter the launch station 31 in pairs. A rider R, R′ stands on each of platform 33 , 35 in the launch station 31 and respectively press the buttons 41 to confirm that they are ready to be launched. Once both riders R, R′ have confirmed that they are ready, the countdown timer 45 begins. When the countdown timer 45 reaches zero, the operator pulls the lever 39 to operate the launch mechanism 37 , and the platforms 33 , 35 pivot to their retracted positions. The riders R, R′ then drop at generally the same time into the upper sections 23 , 23 ′ of the respective first and second chutes 5 , 7 and accelerate as they slide towards the bowl 3 .
The riders R, R′ travel down the chutes 5 , 7 and both enter the bowl 3 at substantially the same time. The riders R, R′ are travelling substantially horizontally when they exit the lower sections 27 , 27 ′ of the chutes 5 , 7 and enter the bowl 3 through the first and second rider entrances 19 , 21 respectively. The rider entrances 19 , 21 are located near the rim 15 of the bowl 3 and the momentum of the riders R, R′ allows them to travel at least partway around the bowl 3 .
The riders R, R′ are unlikely to collide with each other as they travel around the bowl 3 . If a first rider R is travelling quicker than a second rider R′, then the quicker first rider R will be higher up the sidewall of the bowl 3 than the slower second rider T. Thus, if the first rider R is travelling sufficiently quickly to catch up with the second rider R′, the riders R, R′ will be at different heights.
The riders R, R′ slow down due to frictional forces, and the reduced centripetal forces cause them to travel towards the bottom of the bowl 3 . The riders R, R′ may come to rest at the bottom of the bowl 3 , or they may slide directly through the aperture 17 and enter the pool 53 . The riders R, R′ may then exit the waterslide 1 at the side of the pool 53 . To reduce the likelihood of the riders R, R′ colliding with each other as they enter the pool 53 , a divider or partition (not shown) may be provided in the middle of the aperture 17 . The likelihood of the riders R, R′ colliding with each other is reduced since the divider or partition keeps them apart if they enter the pool 53 from opposite sides of the aperture 17 . Instead of (or in addition to) the divider or partition, a jet of water may be provided in the pool 53 to move the riders R, R′ away from the area below the aperture 17 once they are in the water. It may be desirable for the jet of water to be provided in the middle of the pool 53 and directed upwardly, thereby causing the water at the top of the pool 53 to move out towards the edges of the pool 53 . The jet of water will thereby move the riders R, R′ towards the sides of the pool 53 .
A waterslide 101 according to another embodiment of the present invention is shown in FIGS. 5 and 6 . The waterslide 101 corresponds in many ways to the waterslide 1 shown in FIG. 14 , and like reference numerals have been used for like components, albeit incremented by 100 for clarity.
The waterslide 101 comprises a bowl 103 into which riders are introduced. The bowl 103 is shown to be circular rather than oval, and the waterslide 101 comprises three chutes 105 , 106 , 107 down which three riders travel simultaneously. The riders enter the bowl 3 through three rider entrances 119 , 120 , 121 equally spaced around the circumference of the bowl 103 (i.e. spaced apart from each other by approximately) 120°). The launch station (not shown) may be modified from the launch station 31 to launch the three riders into the respective chutes 105 , 106 , 107 at substantially the same time.
A further distinction between embodiments 1 , 101 is that the bowl 103 is not provided with an aperture 17 in its base. Rather, a shallow pool 153 is formed in the base of the bowl 3 and the riders drop directly into the pool 153 . This arrangement may be desirable since the pool 153 does not have to be as deep as the pool 53 . Thus, an individual who is not a confident swimmer can ride the waterslide 101 and then stand up in the pool 153 . A second spiral staircase 159 is provided in the middle of the pool 153 leading to a platform 161 to allow a rider to exit the waterslide 101 .
A waterslide 201 according to yet another embodiment of the present invention is shown in FIGS. 7 to 10 . The waterslide 201 corresponds in many ways to the waterslide 1 shown in FIGS. 1 to 4 , and like reference numerals have been used for like components, albeit incremented by 200 for clarity.
The waterslide 201 comprises a bowl 203 into which riders R, R′ are introduced. As shown most clearly in FIG. 7 , the bowl 203 is circular and the two rider entrances 219 , 221 are opposed from each other. The launch station 231 is provided on a gantry 229 accessed via a staircase 209 , as shown in FIG. 8 . The launch station 231 is adapted to launch two riders R, R′ into the respective chutes 205 , 207 at substantially the same time. An enlarged side view of the launch station 231 is shown in FIG. 9 . Although the launch station 231 is shown with the riders R, R′ standing back-to-back, it will be appreciated that they may face each other prior to launch.
As shown in the cutaway section of FIG. 10 , the bowl 203 has a shallow pool 253 formed in the base thereof, similar to the arrangement in the waterslide 101 . The riders R, R′ may walk through the pool 253 to the centrally located spiral staircase 259 .
As shown in FIG. 10 , the chutes 205 , 207 have a substantially circular cross-section, but it will be appreciated that different cross-sections, for example oval cross-sections, may also be appropriate. Moreover, the chutes 205 , 207 may be open in sections or along a portion of their length. The bowl 203 has an inwardly directed rim 215 , as shown in FIG. 10 .
As will be appreciated by those skilled in the art, the waterslides and bowls described herein may be adapted to be ridden by a rider travelling on a craft, such as an inflatable inner ring or the like. Further, while embodiments have been described with particular reference to waterslides, it will be appreciated that the elements and features described herein may be applied to other leisure rides. For example, a rider may travel on a waxed fabric bag or a waxed fabric mat without the aid of flowing water. In addition, the bowl described herein may form only part of a larger system. For example, a rider may exit the bowl and enter another chute or slide.
FIGS. 11 through 13 show an exit system 500 that may be incorporated into a leisure slide, including those shown in FIGS. 1 through 10 . For example, the system 500 may replace the aperture 17 and the pool 53 in the embodiment of FIGS. 1 through 4 . The exit system 500 has a pool 502 at a base 504 of the bowl and a housing 510 with two exit ports 512 , 512 ′ at offset (e.g., generally opposed) angles. The pool 502 surrounds the housing 510 and is created by a shallow ridge 503 at the entrance to the ports 512 , 512 ′ that is higher than the base 504 of the bowl. The housing 510 is shown to be generally semi-spherical, though other shapes may alternately be used. It may be desirable for the angle between the exit ports 512 , 512 ′ to be generally equivalent to an angle between entrances (e.g., entrances 19 , 21 ). The exit ports 512 , 512 ′ are sized to allow the riders R, R′ to pass through, and lead to exit slides (or “chutes”) 514 , 514 ′ designed to take the riders R, R′ clear of the bowl or on to another part of the ride, aided by the flow of water from the pool 502 . As the chutes 514 , 514 ′ may pass closely to one another, it may be desirable for the chutes 514 , 514 ′ to have side walls that prevent undesirable contact between the riders R, R′.
In use, the two exit ports 512 , 512 ′ may allow two riders R, R′ to generally simultaneously exit the bowl while travelling in different (e.g., generally opposite) directions. As such, multiple riders may generally simultaneously enter the bowl while travelling in different directions, and may generally simultaneously exit the bowl while travelling in different directions. While at any given time the riders may travel in different directions, it should be appreciated that the riders may travel in a common overall direction (i.e., all of the riders may travel clockwise, or all of the riders may travel counter-clockwise). The ride may accordingly be safe for multiple users at one time, and may be cleared much quicker for use by subsequent users compared to rides with a single exit. While an arrangement for two riders R, R′ is shown in FIGS. 11 through 13 , those skilled in the art will appreciate that alterations may be made to accommodate additional riders in light of the teachings herein (e.g., an additional exit port and chute may be added for each additional rider). In addition, the exit system 500 may be constructed without the pool 502 for slides that do not include water.
Many different arrangements of the various components depicted, as well as components not shown, are possible without departing from the spirit and scope of the present invention. Embodiments of the present invention have been described with the intent to be illustrative rather than restrictive. Alternative embodiments will become apparent to those skilled in the art that do not depart from its scope. A skilled artisan may develop alternative means of implementing the aforementioned improvements without departing from the scope of the present invention. It will be understood that certain features and subcombinations are of utility and may be employed without reference to other features and subcombinations and are contemplated within the scope of the claims.
For the avoidance of any doubt, the contents of UK patent applications GB 0809011.0 (filed May 19, 2008) and GB 0815789.3 (filed Aug. 29, 2008)—both of which are incorporated by reference into PCT/GB2009/002286—are incorporated herein by reference.
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Leisure and amusement slide elements and systems are disclosed. In one embodiment, a waterslide includes a bowl having a curved sidewall, two or more rider entrances for enabling riders to slide into the bowl and to circuit at least a portion of the bowl, and a receptacle for forming a pool of water to receive a rider exiting the bowl. A nozzle is provided for directing a jet of water to bias a rider towards an edge of the pool. Another slide apparatus includes a bowl having upper and lower ends and first and second entrances distinct from one another and spaced apart from the bowl lower end. The first and second entrances are configured to bias all users of the first and second entrances to travel about at least a portion of the bowl in a common direction, whether clockwise or counter-clockwise.
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CROSS REFERENCE TO RELATED APPLICATION
This application is a continuation-in-part of application Ser. No. 07/715,374, filed Jun. 14, 1991, John R. Axe, et al. now U.S. Pat. No. 5,203,343.
BACKGROUND OF THE INVENTION
1. Field of the Invention
This invention relates in general to a method and apparatus for controlling sleep disorder breathing, particularly one utilizing positive air pressure supplied to a person's breathing passages.
2. Description of the Prior Art
The majority of patients diagnosed with sleep disorders in the United States suffer from excessive daytime sleepiness. The leading cause of this symptom is sleep apnea.
Sleep disorder breathing, such as hypopnea, apnea, or other partial pharyngeal closure, is often combined with pharyngeal wall vibration, which may or may not be audible. Sleep apnea is a potentially lethal condition characterized by multiple obstructive, central or mixed apneas occurring during sleep. A characteristic symptom of sleep apnea includes repetitive episodes of pharyngeal wall vibration, often referred to as snoring when audible. The vibration noted with this syndrome is one in which inspiratory vibrations gradually increase when pharyngeal closure or obstruction of the upper airway develops. A loud, choking inspiratory gasp then occurs as a person's respiratory efforts succeed in overcoming the occlusion. The person frequently wakes. In the morning, the aroused person is usually aware of neither the breathing difficulty nor of the numerous accompanying body movements that at times violently disturb his sleep. A diagnostic study is necessary for an adequate description of the person's sleep breathing pattern.
Apneic episodes during sleep are defined as cessations of air flow at nose and mouth lasting 10 seconds or longer and can be readily documented by polysomnographic recordings. Variations in night-to-night frequency of apneic pauses exist in many patients, with increased frequency appearing to follow upper respiratory infections or use of sedating drugs or alcohol.
In obstructive sleep apnea (OSA), breathing passageways are blocked. In central sleep apnea (CSA), the brain has ceased signaling the body to breathe. Obstructive hypopnea is a milder form of obstructive apnea, usually referring to episodes of partial obstruction of the upper airway passages. Central hypopnea is a milder form of central apnea. Excessive pharyngeal wall vibration, without hypopnea or apnea occurrences, can also be a serious problem. Obstructive and central apnea, obstructive and central hypopnea, and pharyngeal wall vibration will be referred to herein as sleep disorder breathing. In the case of central apnea, the passageways are still open. The lungs of the person form a reservoir for air flow even though the person is not breathing.
Treatments available for sleep apnea vary from weight loss to surgical intervention to prosthetic devices. Although weight loss is the most desirable approach, few patients are able to comply with their diets, and very few can afford to continue the exposure to the symptoms of sleep apnea for six months to a year while losing sufficient weight to reduce or cure the condition. Surgical approaches are only effective in about 50% of the cases, are invasive, expensive and may produce undesirable side effects.
The most successful treatment device has been the nasal continuous positive airway ventilator ("CCPAP"). CPAP initially used an adapted vacuum sweeper motor to supply air under pressure to a hose. The hose fed a nasal mask attached it to the patient's face. The advantages of the nasal CPAP system are that it produces immediate relief, is non-invasive and can be used while achieving weight loss and thus avoids the need for surgery. The primary problem with nasal CPAP has been compliance. While nearly all of patients are fitted with nasal-CPAP as an initial treatment modality, many cease using the system after about six months.
Investigation of the causes for poor compliance among patients has identified three primary factors all relating to patient comfort. The first factor is the lack of perfect fit and discomfort of wearing the nasal mask. The positive pressure of the ventilator flow is often mentioned as the second factor. Some patients experience an uncomfortable and annoying sensation from the forced air stream in their nose and mount. Third, dry mouth and throat are often cited as the source of dissatisfaction with the sleep apnea ventilators.
SUMMARY OF THE INVENTION
The method and apparatus of the invention provide for the detection and control of sleep disorder breathing in a person. Control of sleep disorder breathing with reduced discomfort due to flow of forced air, is accomplished by selection of pressure for the air flow. Increased pressure is selected upon detection of sleep disorder breathing. Absent occurrence of sleep disorder breathing, the forced air flow is reduced in pressure.
For sleep, a patient is fitted with a nasal mask adapted to deliver air from a source of compressed air to the patient's nasal passages. A hose connects the compressed air source and nasal mask. Detection of sleep disorder breathing involves monitoring of face mask pressure and pressure difference (ΔP) between two spaced points along the hose. Specific conditions, including occurrence of apnea, hypopnea and pharyngeal wall vibration are identified. Also detectable are nasal mask problems such as dislodgement of the mask or leakage from the mask. Inhalation and exhalation by the patient are also detected. Diagnosis of apnea, hypopnea, pharyngeal wall vibration and complete or partial closure of the breathing path is based on measurements of breathing by the patient.
Pressure selection is microprocessor controlled and is responsive to detection of specific conditions. Pressure may be adjusted to multiple levels during and following occurrences of sleep disorder breathing. Increased pressure for inhalation, exhalation, or both may be used to suppress sleep disorder breathing, with the pressure level adjusted to achieve suppression of the condition. Mask dislodgement results in reduction of pressure to a minimum level.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 is a block diagram illustrating the method and apparatus of this invention;
FIG. 2 is a pair of graphs, one illustrating the difference in pressure that exists between the mask and the compressor output and the other illustrating the mask pressure during an occurrence of obstructive sleep apnea;
FIG. 3 is a pair of graphs, one illustrating the difference in pressure that exists between the mask and the compressor output and the other illustrating the mask pressure during an occurrence of central sleep apnea;
FIG. 4 is a pair of graphs, one illustrating the difference in pressure that exists between the mask and the compressor output and the other illustrating the mask pressure during an occurrence of obstructive sleep hypopnea;
FIG. 5 is a pair of graphs, one illustrating the difference in pressure that exists between the mask and the compressor output and the other illustrating the mask pressure during an occurrence of central sleep hypopnea;
FIG. 6 is a pair of graphs, one illustrating the difference in pressure that exists between the mask and the compressor output and the other illustrating command pressure to the compressor for periods of normal breathing as well as episodes of pharyngeal wall vibration and obstructive hypopnea;
FIG. 7 is a pair of graphs, one illustrating the difference in pressure that exists between the mask and the compressor output and the other illustrating command pressure to the compressor for normal breathing as well as episodes of pharyngeal wall vibration, obstructive hypopnea, and obstructive apnea;
FIG. 8 is a pair of graphs, one illustrating the difference in pressure that exists between the mask and the compressor output and the other illustrating command pressure to the compressor for normal breathing as well as episodes of central hypopnea, and central apnea; and
FIGS. 9-29 are logical flow charts of a computer process executed on a microprocessor detecting episodes of control and obstructive hypopnea and adjusting mask pressure for the control thereof.
DETAILED DESCRIPTION OF THE INVENTION
Referring to FIG. 1, the apparatus will include any type of mask or nostril adapter 39. Mask 39 may be a commercially available product that has two nozzles, each of which fits within a nostril (not shown) of a user. Mask 39 connects to a flexible hose 41 that leads to a low pressure air source such as compressor 43. Mask 39 and hose 41 make up an interface for supplying air under pressure to the user. Compressor 43 draws in ambient air and compresses it to a pressure which can be selected as described below. Increasing the pressure will increase the flow rate of the air through the hose 41 if mask 39 is open to atmosphere.
The differential pressure transducer 45 senses the dynamic pressure difference between the output of the compressor 43 and the mask 39. Differential pressure transducer 45 has one sensing tube 46 connected to the interior of mask 39. Another sensing tube 47 connects to the output of compressor 43. Mask sensing tube 46 is downstream from output pressure sensing tube 47. The pressure difference between sensing tubes 46 and 47 corresponds to the quantity of air flow through the hose 41. Normal breathing causes the difference in pressure sensed by the pressure transducer 45 to fluctuate.
Pressure transducer 48 measures only the dynamic pressure in the mask 39. Pressure transducer 48 is connected to sensing tube 46. Mask pressure transducer 48 and differential pressure transducer 45 apply analog signals to amplifier/filter circuitry 49. The amplifier/filter circuitry 49 amplify the signal and may optionally filter out signals clearly not associated with sleep disorder breathing. Electrically actuated valves 51, 53 connected into sensing tubes 47, 46, respectively, are normally closed. These valves are used for periodic calibration of pressure transducers 45 and 48. When actuated, each valve 51, 53 opens the sensing tubes 46, 47 to the atmosphere. The amplifier 49 applies the sensed pressure waveforms to an analog to digital converter 55, which in turn is applied to a microprocessor 57. Microprocessor 57 will control the output pressure of the pressure source 43 of the pressure transducers 45 and 48 respectively. Microprocessor 57 performs the calibration, also on a timed basis.
The microprocessor 57 is programmed to sample the incoming signals from converter 55 at a rate of 4000 times per second and process the sampled signals at the rate of 10 times per second. For every 400 pressure difference values collected, a mean pressure difference value and a pressure difference standard deviation value are calculated and stored. The mean pressure difference value calculation is, in effect, a low pass filter, whereas the standard deviation calculation is, in effect, a high pass filter. The mean pressure difference values are used to calculate a mean pressure difference base line, which is arbitrarily defined as the signal level dividing inspiration and expiration.
If the mean value is larger than the pressure difference base line value by a threshold for more than 15 seconds, the algorithm responds with a "mask off" signal. Experience has shown that if the mask 39 is removed, the pressure difference becomes very large and will exceed an pressure difference base line value established before the mask was dislodged.
The microprocessor 57 algorithm uses the pressure difference standard deviation values to calculate the energy of disturbances in the pressure difference signal greater than an arbitrarily defined threshold. The threshold level is determined according to the following formula:
standard deviation threshold=(command pressure-A)* B+C
where A, B and C are fixed empirical values that set the threshold above the level of disturbances caused by ordinary turbulence in the hose 41. Alternately, the standard deviation threshold values could be adaptive and changed based on past standard deviation values calculated for the person utilizing the mask 39. If the standard deviation value is equal to zero for 10 seconds then the system responds with a "power off" signal.
Detection of pharyngeal wall vibration is based on the energy and duration of the pressure waveforms associated with the sleep disorder breathing. The energy is calculated as the sum of pressure difference standard deviation values in excess of the standard deviation threshold divided by the pharyngeal wall vibration duration. The algorithm responds with a "pharyngeal wall vibration" signal when the energy of the standard deviation values is greater than an energy threshold, and when the duration of pharyngeal wall vibration exceeds a duration threshold. The command pressure is raised after a selected number of pharyngeal wall vibration signals, such as three, where the time between successive sleep disorder breathing signals does not exceed a selected duration, such as 20 seconds. The amount by which pressure from compressor 43 is raised is adjustable. The command pressure is reduced after any selected period, such as five minutes, in which no sleep disorder breathings occur. The amount by which pressure is reduced is adjustable.
The command pressure from microprocessor 57 is output as a digital signal, which passes through digital to analog converter 58 where it is converted to an analog signal for varying the speed, and thus the output pressure, of compressor 43. The microprocessor 57 can vary the output of compressor 43 with each inspiration and expiration cycle, increasing pressure during inspiration and decreasing pressure to a lower base level during expiration. Either level may be adjusted independently if sleep disorder breathing is detected. Also, the output of compressor 43 is modulated by a small amplitude 5 Hz signal, which is used to detect the difference between central and obstructive apnea and central and obstructive hypopnea.
FIGS. 2-5 illustrate graphical traces of episodes of obstructive sleep apnea (OSA), central sleep apnea (CSA), obstructive sleep hypopnea (OSH) and central sleep hypopnea (CSH), obtained from a normal subject simulating the conditions. Referring to FIG. 2, the curve 59 represents the delta P measurement measured by pressure transducer 45. Curve 61 represents the mask pressure sensed by transducer 48. The magnitudes of the pressures of curves 59 and 61, as illustrated by the graph of FIG. 2, are shown against the same time coordinate for convenience. Period 63 indicates normal breathing. During period 63, the delta P measurement 59 increases and decreases normally. The mask pressure 61 also increases and decreases normally, about 180° degrees out of phase with the delta P measurement 59, during normal breathing. Delta P 59 will be relatively high during inspiration, while the mask pressure 61 will be reduced.
Period 65 corresponds to the occurrence of OSA. During OSA, the upper airway is blocked completely. Consequently, little flow will occur and the pressure difference measurement will be insignificant. The mask pressure 61 will fluctuate as indicated by the numeral 67 proportional to the five hertz modulation applied to compressor 43 (FIG. 1).
Curve 59 is graph of a delta P measurement, or the changes in difference in pressure between sensing tubes 46, 47 over time. Under normal circumstances, delta P curve 59 is always positive with a greater pressure at compressor output sensing tube 47 than at interface sensing tube 46. The difference in pressure increases when the person inhales and decreases when the person exhales. The curve 61 represents the mask pressure during normal breathing.
In FIG. 3, numeral 69 indicates an occurrence of CSA. In CSA, the brain has signaled the body to stop breathing. Because the upper airway is open, the lungs function as a reservoir. Consequently, the pressure difference measurement of the 5 hertz modulation during CSA is larger than that observed during OSA. Conversely, the mask pressure measurement of the 5 hertz modulation during CSA is less than that observed during OSA.
Delta P curve 59 has a normal breathing section 63 just as in FIG. 2. However, section 69 indicates that breathing has stopped. The delta P curve 59 becomes almost constant. This indicates that there is no dynamic pressure changing due to a person's breathing, and thus the difference between the pressure sensing tubes 46 and 47 will be almost constant, except for the pressure variations due to 5 Hz modulation.
If that condition occurs, there will be essentially no cycles above a noise threshold level to compute areas upon and compare to the average area of the past 50 breath cycles. The microprocessor 57 in this instance will initiate a delay, preferably ten seconds. If at the end of the delay breathing has not resumed, the microprocessor 57 increases pressure in attempt to alleviate the condition in the same manner as described previously. Also, the microprocessor 57 will attempt to determine whether the condition of lack of breathing is due to central sleep apnea (CSA) or obstructive sleep apnea (OSA). In obstructive apnea, breathing passageways are blocked. In central apnea, the brain has ceased signaling the body to breathe. In the case of central apnea, the passageways are still open.
The curves shown in FIGS. 2 and 3, illustrate the difference in both the patient mask pressure and the delta P pressure signals for OSA and CSA. Specifically, the 5 Hz modulation frequency present in the mask pressure is accentuated and delta P diminished when OSA occurs. This is due to the fact that during OSA the airway is obstructed reducing the overall airway volume and increasing its resistance. Conversely, during CSA changes in delta P and mask pressure due to the 5 Hz modulation pressure resemble normal breathing. Detection of CSA is accomplished by noting that flow through hose 41 has stopped.
Referring to FIG. 4, a milder form of OSA called obstructive sleep hypopnea, or OSH, is illustrated. OSH is a partial obstruction of the upper airway, which allows some air to pass. In the episode 71 of OSH, there is some pressure difference in hose 41 varying at a low frequency due to breathing. However, the amplitude of the pressure difference 59 is much less in OSH 71 than in normal breathing 63. Mask pressure 67 reflects the 5 hertz modulation.
In FIG. 4, section 63 represents normal breathing, while section 71 represents partially obstructed breathing or obstructive hypopnea. The amplitude of delta P curve 59 in region 71 is much less than before. The reason is that due to the partial obstruction, there will be less flow of air into and out of the person. The difference in pressure between sensing tubes 46, 47 is considerably less in section 71 than in section 63.
When hypopnea is detected Microprocessor 57 will ordinarily signal compressor 43 to increase the output upper pressure first in an attempt to alleviate that condition. If the hypopnea is not eliminated then the upper pressure will be increased further until the maximum allowed pressure is reached. Furthermore, the output pressure will be reduced if the condition ceases to exist after a selected time period. Hypopnea can occur and be detected with the delta P measurements even though no other sleep disorder breathing signals are occurring.
FIG. 5 depicts Central Sleep Hypopnea (CSH), which is a milder form of CSA. CSH is characterized by shallow breathing, although there is no blockage of the upper airway. Pressure differences occurring in hose 41 are reduced substantially relative to those occurring during normal breathing in 63. Mask pressure fluctuates, but because the upper airway is open, the 5 hertz modulation of pressure will be the same as the case of breathing with no obstruction 63.
Tables 1-2 provides command pressure components and indicates the combinations of events indicating a condition to be treated.
The processes described with reference to the flow charts of FIG. 9-29 include various diagnostic determinations. The basic determinations are set out in Table 1. The letters relate into graphic depictions of the conditions shown in FIGS. 6-8.
TABLE 1______________________________________A - No pharyngeal wall vibration and power onB - Pharyngeal wall vibration occurringC - Central or obstructed sleep hypopneaD - Central or obstructed sleep apneaE - Normal breath volumeF - Complete pharyngeal closureG - Partial pharyngeal closureH - Upper airway openI - Mask offJ - Mask leakO - Power onP - Power off______________________________________
Complete diagnosis for purposes of treatment or response requires combining of several basic indications as set out in Table 2.
TABLE 2______________________________________CONDITIONS DIAGNOSIS______________________________________A + E + H Normal breathingB + E + H Pharyngeal wall vibration (PV) onlyA + C + H Central hypopneaA + C + G Obstructive hypopneaA + D + H Central apneaA + D + F Obstructive apnea______________________________________
FIG. 6 illustrates various abnormal breathing conditions and the modification of command pressure to treat the conditions as they occur. The upper curve 601 is a pressure difference measurement showing breathing over a period of time including sessions of normal breathing, indicated by conclusions A, E and H, pharyngeal wall vibration (B+E+H) and obstructive hypopnea (A+C+G). During the first period of normal breathing, the command pressure to the compressor 43 (FIG. 1) is at a minimum level indicated by curve 603 and is not varied with inspiration and expiration cycles. Pharyngeal wall vibration, indicated by "PV", is shown occurring during the inspiration and expiration cycles of breathing. This higher frequency wave form is detected through standard deviation calculations. After detection of pharyngeal wall vibration, command pressure 603 begins to follow inspiration and expiration cycles of the patient, with inspiration command pressure being substantially boosted over expiration command pressure. The command pressure 603 is raised after detection pharyngeal wall vibration signals 93, where the time between pharyngeal wall vibration signals does not exceed 20 seconds. The command pressure includes an inspiration level, set at a first increment of pressure component level P3 (Press 3), and an expiration level which here returns to base pressure. Expiration command pressure can be boosted over minimum levels under certain circumstances, however. After normal breathing returns or is restored, overall command pressure 603 is reduced, first by cutting inspiration cycle pressure, followed by elimination of the inspiration cycle boost and concluded with gradual reduction in base pressure to minimum levels.
Referring to FIG. 7, occurrences of OSH and OSA are illustrated. After the onset of OSH, command pressure 703 is increased for inspiration levels by adjustment of a pressure component level P2 (or Press 2). However, the difference between the inspiration level and base pressure is not allowed to exceed a maximum differential.
During OSA, the base level of command pressure 703 is ramped up in steps as long as it does not exceed a maximum permitted base pressure level. Obviously, inspiration is not occurring during apnea, so no variation in command pressure due to inspiration and expiration occur. FIG. 7 also shows episodes of normal breathing, and pharyngeal wall vibration and obstructive hypopnea.
FIG. 8 shows episodes of central hypopnea and apnea in pressure waveform 801. In the case of central hypopnea, the base pressure level of command pressure 803 remains constant. If breathing remains shallow for ten seconds, an inspiration cycle appears and its level gradually increases until normal breathing reappears. During the occurrence of central apnea, the command pressure 803 remains constant.
FIG. 9 is a logical flow chart illustrating a main program for microprocessor 57. The main program is used to control flow of the process among a plurality of subroutines relating to the acquisition of data from mask 39 and hose 41, the processing of that data, the use of the processed data for diagnostic purposes and the control of air pressure applied to the mask. The main program is entered at step 1000 with a call to initialize various variables, arrays and flags used by the subsequent data acquisition, data processing, diagnostic and pressure adjustment subroutines. Then step 1002 is executed to call a Getdata subroutine in which data is retrieved from an analog to digital converter 55 and organized for use by the data processing and diagnostic subroutines. Step 1004 is a call to the data processing subroutine. Step 1006 is then executed to call the diagnostic subroutine. Finally a test is done to determine if power to the compressor for the mask is still on at step 1008. If power is on, step 1010 is executed to call a pressure adjustment subroutine. Processing is then returned to step 1002. If compressor power was off at step 1008, the NO branch is followed to discontinue execution of the program.
FIG. 10 is a logical flow chart illustrating a subroutine for initialization of assorted variables and flags used by subsequent subroutines described herein. The subroutine is entered at step 1100 with initialization of an analog to digital converter sampling rate and the setting of the number of channels and sample size used. In the preferred embodiment, analog to digital converter 55 samples the pressure difference along hose 39 and the mask pressure 4000 times a second. There are two channels, corresponding to the pressure difference and mask pressure signals respectively. The data is stored to two arrays each sized for 400 such sample points corresponding to a sampling interval. Step 1102 is executed to initialize indices for a pressure difference array and mask pressure array to which the values from the channel arrays will be transferred. In step 1104 an index is initialized to an array used for storing measurements of the area between the delta P curve and the base line. The size of this array is 50. In step 1106 a number of sample and calculated variable values are initialized. The specific variables used will be introduced in the discussion of the appropriate subroutines. Similarly at step 1108 initial values for a number of flags are set. Again specific flags will be described at the time of the discussion of the appropriate subroutine. After step 1108 processing is returned to the main program.
FIG. 11 is a logical flow chart illustrating acquisition of data by microprocessor 57 from A/D converter 55. Step 1200 is an input/output step corresponding to the transfer of data to buffer arrays from the analog to digital converter for an interval of 400 samples. Step 1202 controls looping through step 1200 until a full interval has been loaded into the buffer arrays. Once a full interval of samples has been transferred to a buffer array, step 1204 is executed to initialize an index. Until a full interval of samples has been accumulated the process loops from step 1202 back to step 1200. Next, step 1206 is executed to transfer data from one buffer array into a pressure difference array. This array is sometimes also referred to as a delta P array. In step 1208 mask pressure readings are loaded into a pressure reading array from the transfer buffers. Step 1210 provides for incrementation of the index in use. Step 1212 controls looping of the transfer process back through step 1206. Once the index exceeds in size a buffer array the YES branch is followed to the return the processing to the main program of FIG. 9.
FIG. 12 is a logical flow chart illustrating a data processing subroutine. The data process subroutine consists essentially of a series of calls to five calculation functions. These functions include a subroutine for calculation of a mean value and a standard deviation value for the samples in the pressure difference array (step 1300). Step 1302 is a call to a function for the calculation of a baseline and the area of the mean value of the pressure difference array. Step 1304 is a call to a subroutine for calculation of a hypopnea threshold using the previously calculated mean. Step 1306 is a call to a calculation of the area and duration of the standard deviation of the delta P signal. Step 1308 is a call to a subroutine for calculation of the energy and phase of the pressure difference and mask pressure at a frequency of 5 hertz. The subroutine is then exited back to the main program.
FIG. 13 is a logical flow chart illustrating the subroutine used for the calculation of the mean and standard deviation of a set of samples from a pressure difference array. The process is entered with step 1400 with determination of the average value of the entries in the pressure difference array. In step 1404, the standard deviation is calculated using the mean and mean square values previously determined. Next, step 1406 is executed to store the mean value into a storage array of pressure difference mean values having a size of 400. This group of values is used for calculating an initial baseline. Incrementation of an appropriate index for this array is also done at this time. The subroutine is then exited back to the parent subroutine.
FIG. 14 illustrates a logical flow chart of a subroutine used for calculation of the mean pressure difference baseline and area. Area is a proxy for the energy content of the delta P signal. The process is entered at step 1500 where it is determined if a baseline has already been obtained. If YES, the YES branch is followed to step 1502 where the last calculated baseline is stored as the old baseline. Next, step 1504 is executed to generate a current baseline as a function of the old baseline and the current mean. Next, step 1506 is executed to determine if the current pressure difference mean exceeds the new baseline. If not, a new area of expiration is set equal to the old area plus the new baseline less the current pressure difference mean (step 1508). Next, step 1510 is executed to set the expiration flag to negative and processing is returned to the parent subroutine.
If at step 1506 it is determined that the current pressure difference mean exceeds the new baseline, the YES branch is followed to step 1512 to determine if the inspiration flag is positive. If YES, step 1514 is executed to calculate a new inspiration area equalling the old area plus the mean less the current baseline. Processing is then returned to the parent subroutine. If however the inspiration flag is negative, the NO branch is followed from step 1512 to step 1516. There the area of respiration is set equal to the area of inspiration and expiration. In step 1518 the area of inspiration is reset to equal the pressure difference mean less the baseline. The inspiration flag is set to positive and the expiration area is set to zero. This is done preparatory to the next respiratory cycle.
If at step 1500 it is determined that a current baseline has not yet been obtained, the NO branch is taken to step 1520. At step 1520 it is determined if a completed interval has been acquired. If NO, processing is returned to the main program for acquisition of another interval of sample points. If the array of 100 mean values is completed in step 1520, the YES branch is taken to step 1522 where the current baseline is set to equal zero and an appropriate flag is set to mark a baseline as available. In step 1524 the array of mean values are summed. In step 1526 this sum is divided by the array size to generate a baseline. Processing is then returned to the parent subroutine.
FIG. 15 is a logical flow chart of a subroutine for the calculation of a hypopnea threshold for use in the diagnostic subroutines. The process is entered at step 1600 where it is determined if a minimum required number of measurements for the area between delta P and the base line (referred to as "Area" for brevity) from step 1518 have previously been obtained. If YES, step 1602 is executed to add the latest Area measurement to a First-In, First-Out (FIFO) array of such measurements and to drop the oldest Area measurement from the array. Next, step 1604 is executed to sum and average a set of the measurements. The subset includes the middle 30 by magnitude of the 50 measurements in the FIFO buffer. In step 1606 an hypopnea threshold is established to be equal to 30% of the average of the subset. After step 1606, processing is returned to the parent subroutine. Returning to step 1600, if a minimum number of Area calculations have not been performed, the NO branch is taken to step 1608 where the current measurement is simply added to the array of Area measurements. At step 1610 it is determined if the Area measurement array was filled by the last added entry. Step 1612 is executed to set a flag indicating that the mean pressure difference array is filled. Processing then continues with execution of 1604 as set forth above. Along the NO branch from step 1610 processing is returned to the main program.
FIG. 16 is a logical flow chart of a subroutine used for the calculation of the area of the standard deviation of delta P which exceeds a threshold. The results are used for detection of pharyngeal wall vibration. The process is entered with execution of step 1700. There a variable called standard deviation threshold is set equal to a function of the current command pressure and old standard deviation values. The calculation of command pressure is described below. Next, in step 1702, it is determined if the current standard deviation exceeds the standard deviation threshold just calculated. If YES, step 1704 is executed to set a flag so indicating and step 1706 is executed to generate a measure of the area of the standard deviation. The measure is equated to an area found by summing the values by which the standard deviations exceed the threshold. If at step 1702 a negative determination has been made, step 1708 is executed to determine if the standard deviation over threshold flag has previously been set. If YES, step 1710 is executed to reset the flag. Step 1712 is then executed to store the area of standard deviation over threshold and duration. If at step 1708 the flag has not been set processing is simply returned to the parent subroutine. After completion of step 1706 or 1712 processing is returned to the parent subroutine.
FIG. 17 illustrates a logical flow chart for the subroutine for use in calculation of energy of the 5 Hz signal and phase difference between the pressure and pressure difference signals. The process is entered at step 1800 to determine if one second has elapsed since the last such calculation. If not, the calculation is not done and processing is returned immediately to the parent subroutine. If one second has passed since the last energy and phase measurement, the energy and phase difference calculations are done at step 1802 before return to the parent subroutine.
FIG. 18 is a logical flow chart of a diagnostic subroutine. The diagnostic subroutine includes a plurality of calls used for the detection of various types of obstructed breathing and for detection of leak from or loss of the face mask. Step 1900 reflects a call to a subroutine used for the detection of pharyngeal wall vibration. Step 1902 is a call to a subroutine for the detection of apnea. Step 1904 is a call to a subroutine for the detection of hypopnea. Step 1906 is a call to a subroutine for the detection of a mask off condition or a mask leak condition. Step 1908 is a call to a subroutine for the detection of pharyngeal closure. Step 1910 is a call to a subroutine for the detection of whether compressor power is off.
FIG. 19 illustrates a logical flow chart for the subroutine used for detection of pharyngeal wall vibration. Step 2000 is used to determine if the area and duration of the standard deviation of delta P as calculated in step 1700 exceeds a threshold. If not, step 2002 is executed to set a flag indicating no pharyngeal wall vibration is occurring. If YES, a flag is set indicating such vibration at step 2004. After either step 2002 or 2004 processing is returned to the parent subroutine.
FIG. 20 illustrates a logical flow chart for the subroutine used for detection of apnea. The subroutine is entered at step 2100 with a comparison of the absolute value of the ΔP mean less the current base line with the apnea threshold. If the former is less than the latter, step 2102 is executed to determine if the condition detected at step 2100 has persisted for more than 10 seconds. If the condition has persisted for more than 10 seconds an apnea flag is set to ON at step 2104 and processing is returned to the parent subroutine. If either step 2100 or 2102 is not true, step 2106 is executed to set the apnea flag to OFF and processing is returned to the parent subroutine.
FIG. 21 illustrates a logical flow chart for a subroutine used for the detection of hypopnea. The process is entered at step 2200 where it is determined if the Mean is less than the hypopnea threshold. If YES, step 2202 is executed to determine if the condition has persisted for more than 15 seconds. If the condition has persisted more than 15 seconds, the YES branch is followed to step 2204 to set the hypopnea flag to ON. If either the step 2200 or 2202 conditions are not met, the hypopnea flag is set to OFF by execution of step 2206. After step 2206, the process is returned to the parent subroutine.
FIG. 22 is a logical flow chart for a subroutine used for detection of a mask off condition or a mask leaking condition. The process is entered with execution of step 2300 where it is determined if the mean pressure difference between sensing tubes 46 and 47 exceeds a mask off threshold. If YES, step 2302 is executed to determine if the condition has lasted more than 5 seconds. If the condition has lasted more than 5 seconds, a mask off flag is set to high at step 2304 and processing is returned to the parent subroutine. If the condition has not lasted over 5 seconds at step 2302, the NO branch is followed to step 2305 where the mask off flag is set to low before returning processing to the parent subroutine. The NO branch from step 2300 directs processing to step 2306 where it is determined if the baseline exceeds the mask leak threshold. If YES, a mask leak flag is set to high at step 2308. If NO a mask leak flag is set low by execution of step 2310. After either step 2308 and 2310, step 2305 is executed.
FIG. 23 illustrates the logical flow chart for a process subroutine used for the detection of closure of the breathing path. The process is entered with execution of step 2400 where the energy of the pressure difference array is compared to the threshold level for closure. If the energy of the pressure difference array less than the threshold level, the YES branch is followed to step 2402 where it is determined if the energy of entries in the mask pressure array are greater than a threshold. If YES step 2404 is executed to determine if the phase difference is greater than a phase difference threshold. If YES, step 2406 is executed to determine if the conditions of step 2400, 2402 and 2404 have exceeded 5 seconds. If YES, step 2408 is executed to set the closure flag to high. If the conditions have not yet lasted 5 seconds the NO branch is followed to step 2410 to set the closure flag as low. After completion of step 2408 and 2410 processing is returned to the parent subroutine.
If any of the conditions tested at steps 2400, 2402 or 2404 fail, step 2412 is executed. At step 2412 it is determined if the energy of the pressure difference array is less than the threshold level for partial closure. If it does, step 2414 is executed to determine if the energy of entries in the mask pressure array is greater than a threshold. If YES, step 2416 is executed to determine if the phase difference exceeds a partial closure phase difference threshold. If YES, step 2418 is executed to determine if the conditions of 2412, 2414 and 2416 have persisted beyond 5 seconds. If YES, step 2420 is executed to set a partial closure flag to high. If any of the conditions of 2412 through step 2418 fail, step 2422 is executed to set the partial closure flag low. After either step 2420 or 2422, the processing is returned to the parent subroutine.
FIG. 24 illustrates a logical flow chart for a subroutine used for the detection of a power off condition of the compressor used to pressurize face mask 39. Entered at step 2500, it is determined if the standard deviation of delta P and the baseline fall below their respective power off threshold levels. If YES, step 2502 is executed to determine if the conditions have lasted more than 5 seconds. If YES, step 2504 is executed to set the power flag to off. Processing is then returned to the parent subroutine. If the result of the tests of step 2500 or 2502 are negative, step 2506 is executed to set the power flag to ON. Processing is then returned to the parent subroutine.
FIG. 25 is a logical flow chart of a subroutine called for adjustment of command pressure. Command pressure is the output requested of compressor 43. The command pressure adjustment subroutine comprises four calls to subroutines. Steps 2600, 2602 and 2604 are calls to subroutines for adjustment of components contributing to the command pressure. Call 2606 provides for combinations of the components to provide command pressure.
FIG. 26 is a logical flow chart of a process for a subroutine for adjustment of a base pressure level, Press 1. Entered at step 2700 it is determined if the compressor is on and if processing is in the first sample interval. If YES, step 2702 is executed to set a flag indicating the first sample interval is completed. Step 2704 is then executed to set Press 1 and preliminary adjustment components Press 2P and Press 3P to their respective minimum permitted values. Processing is then returned to the parent subroutine. If the result at step 2700 is negative, step 2706 is executed to determine if a mask leak or mask off flag has been set high. If YES, step 2704 is executed as set forth above. If NO, step 2708 is executed to determine if the apnea and complete closure flags are both set high. If YES, step 2710 is executed to determine if more than 10 seconds have passed since the last boost in base pressure and to determine if base pressure is less than the maximum allowed. If both conditions are satisfied, step 2712 is executed to boost base pressure and reset the appropriate timer. Processing is then returned to the parent subroutine. If at step 2710 either condition failed then no further action is taken and processing is returned to the parent subroutine.
If at step 2708 a negative result is obtained, step 2714 is executed to determine if more than 300 seconds have passed since the last change in base pressure. If NO, processing is returned immediately to the parent subroutine. If YES, step 2716 is executed to determine if base pressure is greater than the minimum. If base pressure is equal to minimum, the NO branch is followed to return processing to the parent subroutine. If at step 2716 base pressure exceeded minimum, step 2718 is executed to cut base pressure and to reset the timer used at step 2714. Processing is then returned to the parent subroutine.
FIG. 27 illustrates a logical flow chart for a subroutine used for the adjustment of preliminary pressure component Press 2P. At step 2800 it is determined if the hypopnea; or partial closure flags are set. If neither flag is set, processing is advanced to step 2802 where it is determined if more than 10 seconds have passed since the last change in Press 2P. If YES step 2804 is executed to determine if Press 2P exceeds its minimum allowed value. If either of the conditions of 2802 or 2804 are not met, processing is immediately advanced to step 2816. Following the YES branch from step 2804, step 2806 is executed to reduce Press 2P and reset of the appropriate timer. Processing then advances to step 2816.
Returning to step 2800 and following the YES branch, step 2807 is executed to reset timers running on Press I and Press 2P. The timers track time elapsed since the last change in value of Press 1 and Press 2P. Step 2808 is then executed to determine if the time elapsed since the last boost of Press 2P exceeds 5 seconds. If YES, step 2810 is executed to boost Press 2P by a unit and the boost timer is reset to zero. Next, step 2812 is executed to determine if Press 2P exceeds its maximum allowed level. If YES, step 2813 is executed to boost base pressure Press I by one unit and to reduce Press 2P to its maximum pertained level. Next, step 2814 is then executed to determine if Press 1 now exceeds maximum permitted command pressure level. If NO, processing advances to step 2816. If YES, step 2815 is executed to reset Press 1 to the maximum permitted value for command pressure. Following the NO branch from step 2812, or after execution of step 2814, the processing is advanced to step 2816. Step 2816 is also executed along the NO branch from step 2808.
At step 2816, the sum of Press 1 and Press 2P are compared to the maximum permitted value for command pressure. Where the sum exceeds the maximum permitted value, the YES branch is taken to step 2818 to set command pressure component Press 2 to the maximum permitted value of command pressure less Press 1. At step 2820, it is determined if the inspiration flag is set. If YES, step 2822 is executed to set Press 2 to Press 2P. If NO, step 2824 is executed to set Press 2 to zero because expiration is occurring. Processing is returned to the appropriate parent subroutine after any of steps 2818, 2822 and 2824.
FIG. 28 illustrates a logical flow chart for a subroutine used for the adjustment of preliminary pressure component Press 3P. At step 2900 it is determined if the pharyngeal wall vibration flag is set. If the pharyngeal wall vibration flag is not set, processing is advanced to step 2902 where it is determined if more than 10 seconds have passed since the last change in I Press 3P. If YES, step 2904 is executed to determine if Press 3P exceeds its minimum allowed value. If either of the conditions tested in steps 2902 or 2904 are not met, the NO branches are taken to step 2916. Following the YES branch from step 2904, step 2906 is executed to reduce Press 3P and reset of the appropriate timer. Processing then advances to step 2916.
Following the YES branch from step 2900, step 2907 is executed to reset timers running on Press 1, Press 2P and Press 3P. The timers track time elapsed since the last changes in value of Press 1, Press 2P and Press 3P. Step 2908 is then executed to determine if the time elapsed since the last boost of upper base pressure exceeds 5 seconds. If YES, step 2910 is executed to boost Press 3P by a unit and to reset the boost timer for Press 3P. Next, step 2912 is executed to determine if the new Press 3P exceeds its maximum allowed level. If YES, step 2913 is executed to boost base pressure Press I and to reduce Press 3P to its maximum permitted level. Next, step 2914 is executed to determine if Press I now exceeds the maximum permitted level for command pressure. If NO, processing advances to step 2916. If YES, step 2915 is interposed and executed to reset Press I to the maximum permitted value for command pressure. Following the NO branch from step 2908, step 2912 or from step 2914 advances processing to step 2916.
At step 2916, the sum of Press 1 and Press 3P are compared to the maximum permitted value for command pressure. Where the sum exceeds the maximum permitted value, the YES branch is taken to step 2918 to set Press 3 to the maximum permitted command pressure level less Press 1. Along the NO branch from step 2916 step 2920 determines if the inspiration flag is set. If YES, step 2922 is executed to set Press 3 to Press 3P. If NO, step 2924 is executed to set Press 3 to zero because expiration is occurring.
Following steps 2918, 2922, or 2924, processing advances to step 2926 where it is determined if Press 3 exceeds a minimum level. If Press 3 is greater than the minimum limit, pressure level Press 2 is reset to 0 and the subprocess exited. If Press 3 does not exceed the minimum level, the pressure components are left unchanged and the subprocess exited.
FIG. 29 is a logical flow chart illustrating adjustment of command pressure. The process is entered in step 3000 where command pressure is set equal to the sum of components Press 1, Press 2P and Press 3P. In step 3002 the phase of an oscillating pressure value is reversed, i.e. the negative of the old value is used. Next, step 3004 is executed to set output pressure to command pressure plus oscillating pressure. In step 3006 output pressure value is output to the digital to analog converter. Processing is then returned to the appropriate parent subroutine.
The invention provides air or a mixture of breathable gases at low pressure to a sleeper when sleep disorder breathing is not occurring. This is more comfortable to the user than the higher pressures used to control sleep disorder breathing. If the system fails to stop the sleep disorder breathing an alarm can be sounded to wake other people or the person to avoid a potentially dangerous situation. The system automatically adapts to the level of air pressure required by the user during the night.
While the invention has been shown in only one of its forms, it should be apparent to those skilled in the art that it is not so limited but is susceptible to various changes without departing from the scope of the invention.
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A method and device for controlling sleep disorder breathing utilizes variable multiple level pressures. A pressure source supplies compressed breathable gas at a relatively low pressure to the user's airway. Pressure transducers monitor pressures and convert them into electrical signals. The electrical signals are filtered and processed to extract specific features such as duration and energy levels. If these features exceed selected threshold values for duration and energy level over a minimum period of time, then the microprocessor declares the presence of sleep disorder breathing. If a selected number of these events occur within a selected time period, then the microprocessor adjusts the pressure delivered by the pressure source. If sleep disorder breathing is not detected within a certain time period, then the microprocessor lowers the pressure level gradually. The device and method disclosed in this patent is capable of detecting apnea, hypopnea, and pharyngeal wall vibration. Further, it is able to distinguish between obstructive, central and mixed apnea and hypopnea.
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[0001] This application is a continuation application under 35 U.S.C. 120 of commonly assigned U.S. patent application Ser. No. 14/607,923, entitled Systems and Methods for Percutaneous Intravascular Access and Guidewire Placement, filed on Jan. 28, 2015, and now allowed, which in turn is a continuation application under 35 U.S.C. 120 of commonly assigned U.S. patent application Ser. No. 13/668,190, entitled Systems and Methods for Percutaneous Intravascular Access and Guidewire Placement, filed on Nov. 2, 2012, and now U.S. Pat. No. 8,951,276, which in turn claims the benefit under 35 U.S.C. 119(e) of the filing date of Provisional U.S. Application Ser. No. 61/556,128, entitled Systems and Methods for Percutaneous Intravascular Access and Guidewire Placement, filed on Nov. 4, 2011. All of the foregoing applications are expressly incorporated herein by reference, in their entirety.
BACKGROUND OF THE INVENTION
[0002] In the body, various fluids are transported through conduits throughout the organism to perform various essential functions. Blood vessels, arteries, veins, and capillaries carry blood throughout the body, carrying nutrients and waste products to different organs and tissues for processing. Bile ducts carry bile from the liver to the duodenum. Ureters carry urine from the kidneys to the bladder. The intestines carry nutrients and waste products from the mouth to the anus.
[0003] In medical practice, there is often a need to connect conduits to one another or to a replacement conduit to treat disease or dysfunction of the existing conduits. The connection created between conduits is called an anastomosis.
[0004] In blood vessels, anastomoses are made between veins and arteries, arteries and arteries, or veins and veins. The purpose of these connections is to create either a high flow connection, or fistula, between an artery and a vein, or to carry blood around an obstruction in a replacement conduit, or bypass. The conduit for a bypass is a vein, artery, or prosthetic graft.
[0005] An anastomosis is created during surgery by bringing two vessels or a conduit into direct contact. The vessels are joined together with suture or clips. The anastomosis can be end-to-end, end-to-side, or side-to-side. In blood vessels, the anastomosis is elliptical in shape and is most commonly sewn by hand with a continuous suture. Other methods for anastomosis creation have been used including carbon dioxide laser, and a number of methods using various connecting prosthesis, clips, and stents.
[0006] An arterio-venous fistula (AVF) is created by connecting an artery to a vein. This type of connection is used for hemodialysis, to increase exercise tolerance, to keep an artery or vein open, or to provide reliable access for chemotherapy.
[0007] An alternative is to connect a prosthetic graft from an artery to a vein for the same purpose of creating a high flow connection between artery and vein. This is called an arterio-venous graft, and requires two anastomoses. One is between artery and graft, and the second is between graft and vein.
[0008] A bypass is similar to an arteriovenous graft. To bypass an obstruction, two anastomoses and a conduit are required. A proximal anastomosis is created from a blood vessel to a conduit. The conduit extends around the obstruction, and a second distal anastomosis is created between the conduit and vessel beyond the obstruction.
[0009] As noted above, in current medical practice, it is desirable to connect arteries to veins to create a fistula for the purpose of hemodialysis. The process of hemodialysis requires the removal of blood from the body at a rapid rate, passing the blood through a dialysis machine, and returning the blood to the body. The access to the blood circulation is achieved with (1) catheters placed in large veins, (2) prosthetic grafts attached to an artery and a vein, or (3) a fistula where an artery is attached directly to the vein.
[0010] Hemodialysis is required by patients with kidney failure. A fistula using native blood vessels is one way to create high blood flow. The fistula provides a high flow of blood that can be withdrawn from the body into a dialysis machine to remove waste products and then returned to the body. The blood is withdrawn through a large access needle near the artery and returned to the fistula through a second large return needle. These fistulas are typically created in the forearm, upper arm, less frequently in the thigh, and in rare cases, elsewhere in the body. It is important that the fistula be able to achieve a flow rate of 500 ml per minute or greater, in order for the vein to mature or grow. The vein is considered mature once it reaches >4 mm and can be accessed with a large needle. The segment of vein in which the fistula is created needs to be long enough (>6 cm) to allow adequate separation of the access and return needle to prevent recirculation of dialysed and non-dialysed blood between the needles inserted in the fistula.
[0011] Fistulas are created in anesthetized patients by carefully dissecting an artery and vein from their surrounding tissue, and sewing the vessels together with fine suture or clips. The connection thus created is an anastomosis. It is highly desirable to be able to make the anastomosis quickly, reliably, with less dissection, and with less pain. It is important that the anastomosis is the correct size, is smooth, and that the artery and vein are not twisted.
SUMMARY OF THE INVENTION
[0012] The present disclosed invention eliminates the above described open procedures, reduces operating time, and allows for a consistent and repeatable fistula creation.
[0013] The present invention comprises a device to allow passage of a guidewire from a primary blood vessel to an adjacent secondary blood vessel, which comprises a main body having a primary lumen and a secondary lumen and a piercing member disposed in the secondary lumen, and configured to be moved distally out of the secondary lumen, and to pierce through tissue while being distally moved. A third lumen located within the piercing member is configured to allow placement of a guidewire from the primary blood vessel to the adjacent secondary blood vessel.
[0014] In one embodiment, the secondary lumen is constructed out of superelastic material, such as Nitinol, that is shaped such that the distal tip is oriented toward the adjacent secondary blood vessel. The secondary lumen may have a “J” shape heat set into the secondary lumen; however, different shapes may be used depending upon the type of anatomy that is being accessed. The primary lumen is configured with a stiffness such that it has the ability to straighten the shape of the secondary lumen. Either advancing or retracting the primary lumen relative to the secondary lumen can adjust the rise, or shape, of the secondary lumen. Shaping the primary lumen can further modify the angle at which the piercing member exits the secondary lumen. In an alternative embodiment, the shape of the secondary lumen may be modified using a tendon wire. In still another embodiment, the piercing member is designed to remain in a substantially straight configuration.
[0015] In another aspect of the invention, the distal tip of the secondary lumen has a feature to make it such that it will not perforate the primary lumen as it is being placed into a desired position within the body. In the first embodiment noted above, the tip has a large diameter polymer tip that has a rounded distal edge and is atraumatic. This distal tip also has features that make it visible under different imaging techniques, such as ultrasound, fluoroscopy, CT, or MRI. There is a coil constructed of a radiopaque material, embedded in the polymer tip. Small particles of air or other radiopaque materials known to those skilled in the art can also be used to increase the radiopacity of the tip.
[0016] The hollow piercing member has a sharp point on the distal tip that exits from the primary vessel by puncturing its wall and enters into the secondary vessel in the same manner. In one embodiment, the sharp distal point is constructed using a lancet point. The primary bevel is ground at an angle between 12 and 20 degrees with a secondary angle between 5-20 degrees, with a rotation angle between 25-45 degrees. The needle grind is designed such that it pierces through the vessel wall and does not core, or cut a plug, through the vessel wall, to minimize bleeding between vessels when removed after the guidewire is placed into the secondary vessel. The outer diameter of the piercing member is also minimized to further reduce bleeding. The piercing member is oriented within the secondary lumen such that the tip of the lancet point is directed toward the adjacent secondary vessel. Other piercing mechanisms, or needle point grind configurations, known to those skilled in the art may be provided.
[0017] More particularly, there is provided a device for creating intravascular access and guidewire placement, which comprises a main body having a first lumen, a piercing member disposed in that lumen, and configured to be moved distally out of said lumen and to pierce through tissue while being distally moved, and a handle attached to the main body and having an actuator for moving the piercing member. A second lumen is disposed within the piercing member. A guidewire is disposed in the second lumen for delivery into a desired site from a distal end of the second lumen. The piercing member has a sharp point on one end thereof.
[0018] In one disclosed embodiment, a third lumen is disposed within the main body, outwardly of the first lumen. The piercing member is retractable into the first lumen. The third lumen is defined by a needle guide having shape memory properties, the needle guide being actuatable to a curved orientation by adjustment of a position of the main body to create an incrementally adjustable radius of curvature on the needle guide. The piercing member has shape memory properties, and is actuatable to create an incrementally adjustable radius of curvature.
[0019] The actuator for moving the piercing needle linearly comprises a slide. In the curved embodiment, a second actuator is disposed on the handle for actuating the needle guide to a curved orientation. This actuator comprises a rotatable knob. In both embodiments, the first lumen is defined by a needle guide having an atraumatic distal tip having a relatively large diameter. The atraumatic distal tip is comprised of a polymer material and further comprises radiopaque materials. Preferably, the radiopaque materials comprise a plurality of coils constructed of a radiopaque material.
[0020] The sharp point preferably comprises a lancet point and primary bevels.
[0021] In another aspect of the invention, there is disclosed a method of creating intravascular access and guidewire delivery, which comprises steps of positioning the main body of a device within a primary vessel and manipulating a distal end of the device to engage an inner wall of the primary vessel and to push the primary vessel into close engagement with an adjacent secondary vessel. Yet another step comprises extending the piercing member distally from the main body, through the wall of the primary vessel, and through an adjacent wall of the secondary vessel, so that the end of the piercing member is disposed within the secondary vessel for creating a communicating aperture on the opposing walls of the primary and secondary vessel.
[0022] In one embodiment, the method comprises a further step of incrementally adjusting a radius of curvature of the piercing member. In both embodiments, the positioning step is performed percutaneously.
[0023] The method further comprises a step of advancing a guidewire distally through a lumen in the piercing member from the primary vessel into the secondary vessel, and a step of withdrawing the device from the vessel, thus leaving the guidewire in place and crossing from the primary vessel to the secondary vessel through said communicating aperture.
[0024] In still another aspect of the invention, a method of creating a passage between adjacent primary and secondary blood vessels is disclosed, comprising a step of positioning a main body of the device within the primary vessel and extending a piercing member distally from the main body, through the wall of the primary vessel, and through an adjacent wall of the secondary vessel, so that the piercing member is disposed within the secondary vessel. The secondary lumen is linearly actuated to move relative to a distal end of the piercing member for articulating the distal end of the piercing member for cutting a small communicating aperture from the primary blood vessel to the adjacent secondary blood vessel.
[0025] The method further comprises the step of advancing a guidewire distally within the piercing element to pass from the primary blood vessel, while maintaining position substantially within the primary blood vessel, to the adjacent secondary blood vessel.
[0026] The invention, together with additional features and advantages thereof, may best be understood by reference to the following description taken in conjunction with the accompanying illustrative drawings.
BRIEF DESCRIPTION OF THE DRAWINGS
[0027] FIG. 1 a is a view of one embodiment of the device of the present invention, wherein the device has been percutaneously or surgically positioned at a desired location in a blood vessel;
[0028] FIG. 1 b is a view, similar to FIG. 1 a , of another embodiment of the device of the present invention, wherein the device has been percutaneously or surgically positioned at a desired location in a blood vessel;
[0029] FIG. 2 a is a view of the FIG. 1 a embodiment of the present invention, illustrating the distal piercing element in isolation;
[0030] FIG. 2 b is a view, similar to FIG. 2 a , of the embodiment of FIG. 1 b , illustrating the distal piercing element in isolation;
[0031] FIG. 3 a is a view similar to FIG. 2 a , wherein the distal piercing element of FIG. 2 a has been advanced distally to push the blood vessel in which it is disposed into contact with the adjacent blood vessel;
[0032] FIG. 3 b is a view similar to FIG. 2 b , wherein the distal piercing element of FIG. 2 b has been advanced distally to push the blood vessel in which it is disposed into contact with the adjacent blood vessel;
[0033] FIG. 4 a is a view similar to FIG. 3 a , wherein the piercing element is advanced from the primary blood vessel into the adjacent secondary blood vessel;
[0034] FIG. 4 b is a view similar to FIG. 3 b , wherein the piercing element is advanced from the primary blood vessel into the adjacent secondary blood vessel;
[0035] FIG. 5 a is a view similar to FIG. 4 a , wherein a guidewire is extended from the primary blood vessel and into the adjacent secondary blood vessel;
[0036] FIG. 5 b is a view similar to FIG. 4 b , wherein a guidewire is extended from the primary blood vessel and into the adjacent secondary blood vessel;
[0037] FIG. 6 illustrates the small communicating aperture and the guidewire placement created by the device and methods of the present invention after either embodiment of the inventive device of FIGS. 1 a -5 b has been withdrawn from the procedural site; and
[0038] FIG. 7 illustrates an isolated detail view of the distal tip of the piercing element for the illustrated embodiments.
DESCRIPTION OF THE PREFERRED EMBODIMENT
[0039] Referring now more particularly to the drawings shown in FIGS. 1 a - 7 , there are illustrated several embodiments of a device and system constructed in accordance with the principles of the present invention. As illustrated in FIG. 1 a , one embodiment of the device 10 comprises a handle or handpiece 2 and a main body shaft 12 having a primary lumen 18 and a secondary lumen 14 ( FIG. 2 a ). To begin the inventive method of intravascular access and communication, the practitioner selects an appropriate procedural site having each of a primary blood vessel 24 and a secondary blood vessel 26 ( FIG. 1 ) in close proximity to one another. In currently preferred approaches, the primary blood vessel 24 comprises a vein, and the secondary blood vessel 26 comprises an artery, but the invention is not limited to this arrangement. The main body 12 is inserted into primary vessel 24 so that the distal end 32 thereof ( FIG. 2 a ) lies within the blood flow passage of the primary vessel. Preferably, this insertion step is performed using percutaneous technique, but open surgery may also be employed.
[0040] With reference now to FIG. 2 a , a piercing element 20 comprises a needle guide 34 , lumen 22 , and a distal tip 36 , and can be adjustably oriented axially within the secondary lumen 14 of a needle guide 16 . These elements are further adjustably oriented axially within lumen 18 of the needle guide 16 , and lumen 22 provides an externally communicating passage. A distal end 40 of the needle guide 16 comprises a blunt large diameter atraumatic tip, comprised of a polymer material, having a rounded distal edge. This distal tip 40 also has features that make it visible under different imaging techniques, such as ultrasound, fluoroscopy, CT, or MRI. There is a coil 42 constructed of a radiopaque material, embedded in the polymer tip 40 . Small particles of air or other radiopaque materials known to those skilled in the art may also be used to increase the radiopacity of the tip.
[0041] Referring to FIGS. 2 a and 3 a , the blunt tip 40 is manipulated to contact an inner wall of the primary vessel and to push it into desired engagement with the adjacent wall of the secondary vessel, as shown in FIG. 3 a . The position of desired engagement is arranged to optimize the piercing step to be next described. The distal tip 36 of the piercing element 20 may be longitudinally extended with respect to the needle guide 34 , between a range of the radius of curvature along axis 35 of needle guide 34 , using a slide 8 on the handle 2 . A first, or retracted, position is illustrated in FIG. 2 a , where the distal tip 36 is within the secondary lumen 14 of needle guide 16 . As will be described more fully below, the retracted orientation is utilized during the initial device insertion steps, as well as the device withdrawal steps, while variable extended orientations are the operative orientation for creating the communication passageway and guidewire placement. Needle guide 34 of piercing element 20 is fabricated of a material that has shape memory properties that allow it to be held in an essentially axial position indefinitely by needle guide 16 , while in the orientation shown in FIG. 2 a , and can achieve an incremental increase in the radius of curvature as distal tip 36 is extended beyond the end of needle guide 16 as shown in FIG. 3 a . This variable orientation of the radius of curvature may be desirable by the practitioner to more effectively aim the distal tip 36 of the piercing element 20 in order to achieve a more desirable orientation for access from primary vessel 24 to secondary vessel 26 . In one version of this embodiment, the needle guide 34 is fabricated of a superelastic material, such as Nitinol, to achieve this curvature effect. However, it should be noted that the needle guide 34 need not necessarily be made of a superelastic material for this embodiment to function. Since the shape of the needle guide comes from the secondary lumen 14 , its shape is determined by moving the primary lumen 18 axially.
[0042] Referring again to FIG. 3 a , once the main body 12 is inserted into primary vessel 24 and advanced to the desired site determined by the practitioner using ultrasound or fluoroscopic imaging, as previously described, it may be desired to adjust the radius of curvature of needle guide 34 to increase the angle of the axis of distal tip 36 by rotating knob 4 of handle 2 . Since piercing distal tip 36 is configured to have echogenic and radiopaque properties to allow the practitioner to visualize the orientation of piercing tip 36 under real time imaging guidance, and the main body 12 of device 10 is incrementally rotatable about its axis, this will allow the practitioner to more effectively aim piercing tip 36 through direct visualization as secondary blood vessel 26 is “nudged” by the atraumatic tip of the needle guide 16 of the device 10 as the main body is incrementally rotated and the radius of curvature as desired, to allow more accurate penetration from primary blood vessel 24 to secondary blood vessel 26 .
[0043] With reference now to FIG. 4 a , once the practitioner has oriented piercing tip 36 as desired for optimal penetration, knob 4 of handle 2 is advanced to penetrate from primary blood vessel 24 through the primary vessel wall 44 to secondary blood vessel 26 through the secondary vessel wall 46 . This may be done under direct imaging guidance to verify complete penetration without extending beyond the flow passage of blood vessel 26 . The practitioner may also verify acceptable penetration through direct visualization of blood that flows through lumen 22 and exits aperture 4 of handle 2 as shown in FIG. 1 .
[0044] With reference now to FIG. 5 a , once penetration from primary blood vessel 24 to secondary blood vessel 26 has been achieved, a guidewire 28 , preferably having a diameter of 0.014″ or less, is advanced through an aperture 6 of the handle 2 until the guidewire is positioned in the blood flow path of blood vessel 26 sufficiently to allow device 10 to be removed while retaining its position in blood vessel 26 .
[0045] With reference now to FIG. 6 , once guidewire 28 is sufficiently in position as previously described, the practitioner withdraws the device 10 completely from the body, thus leaving the guidewire in the desired position and crossing from primary vessel 24 to secondary vessel 26 .
[0046] FIG. 7 illustrates a detail view of the configuration of the piercing tip 36 utilized in both of the illustrated embodiments. The tip is configured to have a lancet point 48 to enhance the penetration from primary blood vessel 24 to secondary blood vessel 26 . A primary bevel 50 is ground at an angle between 12 and 20 degrees with a secondary angle between 5-20 degrees, with a rotation angle between 25-45 degrees. The needle grind is designed such that it pierces through the vessel wall and does not core, or cut a plug, through the vessel wall, to minimize bleeding between vessels when removed after the guidewire is placed into the secondary vessel. The outer diameter of the piercing member is also minimized to further reduce bleeding. The piercing member is oriented within the secondary lumen such that the tip of the lancet point is directed toward the adjacent secondary vessel. Other piercing mechanisms, or needle point grind configurations, known to those skilled in the art may be provided.
[0047] The embodiment of FIGS. 1 b , 2 b , 3 b , 4 b , and 5 b (the “B” embodiment) is similar in most respects to that of FIGS. 1 a , 2 a , 3 a , 4 a , and 5 a (the “A” embodiment), differing only in the details to be explained below. All common elements to those in the A embodiment are identified by common reference numerals in the figures illustrating the B embodiment, and the method sequencing shown in FIGS. 2 b , 3 b , 4 b , and 5 b is similar to that shown in FIGS. 2 a , 3 a , 4 a , and 5 a . FIGS. 6 and 7 are common to both embodiments.
[0048] The major difference between the A and B embodiments is that in the B embodiment the primary lumen 14 has been eliminated. This is because, in this embodiment, the shape of the needle guide 34 is not adjustable. Thus, it remains straight, and need not be fabricated of superelastic material. This arrangement is possible because the blunt tip 40 may be manipulated by the practitioner to ensure that the adjacent vessel walls of the primary and secondary vessel may be pierced by an axial advancement of the piercing member, as shown in FIG. 3 b . As a result of this change, the knob 4 has also been eliminated, since control of the curvature of needle guide 34 is not required.
[0049] Accordingly, although an exemplary embodiment and method according to the invention have been shown and described, it is to be understood that all the terms used herein are descriptive rather than limiting, and that many changes, modifications, and substitutions may be made by one having ordinary skill in the art without departing from the spirit and scope of the invention.
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A device for allowing passage of a guidewire from a primary blood vessel to an adjacent secondary blood vessel includes a main body having a primary lumen and a secondary lumen, and a piercing member disposed in the secondary lumen, and configured to be moved distally out of the secondary lumen, and to pierce through tissue while being distally moved. A third lumen located within the piercing member is configured to allow placement of a guidewire from the primary blood vessel to the adjacent secondary blood vessel. In one embodiment, the secondary lumen is configured to allow articulation of the distal end of the piercing element. The piercing member has a sharp point on one end to facilitate cutting a small communicating aperture from the primary blood vessel to the secondary blood vessel.
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BACKGROUND OF THE INVENTION AND RELATED ART STATEMENT
The present invention relates to a stored gas inflator which has a pressure vessel filled with high-pressure gas to eject the gas through a gas port, and more particularly, to a stored gas inflator comprising a burst shim for closing the gas port, and an initiator for applying burst pressure to the burst shim, wherein the burst shim is ruptured by the burst pressure from the initiator to open the gas port.
One known form of a gas supply unit for inflation of an airbag is a stored gas inflator which releases pressurized gas stored in a pressure vessel through a gas port. It should be noted that such an airbag is a safety device mounted in a vehicle such as an automobile and designed to be inflated to protect an occupant in the event of an emergency.
FIG. 4 is a sectional view showing a conventional example of such a stored gas inflator. The stored gas inflator 100 shown in FIG. 4 comprises a pressure vessel 102 which is filled with high-pressure gas. The pressure vessel 102 is provided with gas ports 104 for allowing the high-pressure gas filled therein to be released. Normally, the gas ports 104 are air-tightly closed by a thin-plate-like burst shim 106 which is disposed to overlay an inner surface of the pressure vessel 102 . The burst shim 106 is ruptured to open the gas ports 104 when a predetermined pressure (burst pressure) is applied from the outside of the pressure vessel 102 .
Near the gas ports 104 of the pressure vessel 102 , an initiator (detonator) 108 for applying burst pressure to the burst shim 106 is disposed. The initiator 108 has a base portion 108 a fixed to the outer surface of the pressure vessel 102 , and a detonating portion 108 b extending from the tip of the base portion 108 a . The detonating portion 108 b explodes in response to a detonation signal from a controller (not shown).
The pressure vessel 102 is provided, near the gas ports 104 thereof, with a burst pressure inlet 110 into which the detonating portion 108 b is inserted. The aforementioned burst shim 106 also air-tightly closes the burst pressure inlet 110 .
As the initiator 108 receives a detonation signal from the controller (not shown), the detonating portion 108 b explodes in the burst pressure inlet 110 so as to apply burst pressure to the burst shim 106 facing the burst pressure inlet 110 . As a result, the burst shim 106 is ruptured so as to open the gas ports 104 , whereby the gas is released through the gas ports 104 .
In the stored gas inflator 100 having the aforementioned structure, the burst shim 106 closing the gas ports 104 is always subjected to the stored gas pressure from the inside of the pressure vessel 102 . On the other hand, the initiator 108 applies the burst pressure to the burst shim 106 from the outside of the pressure vessel 102 under a condition at a pressure (atmospheric pressure) significantly lower than the aforementioned stored gas pressure.
Therefore, to rupture the burst shim 106 against the stored gas pressure from the inside of the pressure vessel 102 , the initiator 108 must apply burst pressure which is higher twice or more than the stored gas pressure of the pressure vessel 102 , so that the required power (explosion power) of the initiator 108 should be extremely high.
It is an object of the present invention to provide a stored gas inflator which is triggered for gas releasing operation even with a relatively low power initiator.
Further objects and advantages of the invention will be apparent from the following description of the invention.
SUMMARY OF THE INVENTION
A stored gas inflator of the present invention comprises: a pressure vessel filled with high-pressure gas and having a gas port, a burst shim for closing the gas port; and a gas blasting initiator for applying burst pressure to the burst shim. The pressure vessel is divided into a small chamber facing the gas port and a main chamber having a capacity larger than that of the small chamber. The burst shim is composed of a first burst shim, and a second burst shim, wherein the small chamber and the gas port are partitioned from each other by the first burst shim, and the small chamber and the main chamber are partitioned from each other by the second burst shim. The small chamber and the main chamber are filled with high pressure gas, respectively, and the initiator is mounted to the small chamber. The burst pressure of the second burst shim is set to be lower than the stored gas pressure of the main chamber.
According to the stored gas inflator as mentioned above, the initiator explodes inside the small chamber filled with the high-pressure gas. The first burst shim closing the gas port is always subjected to the stored gas pressure from the inside of the small chamber. As the initiator explodes inside the small chamber, gas blasted by the initiator rapidly increases the inner pressure of the small chamber. When the inner pressure of the small chamber reaches the burst pressure of the first burst shim, the first burst shim is ruptured.
In the stored gas inflator of the present invention, the initiator increases the stored gas pressure in the small chamber, and the increased pressure ruptures the first burst shim. Therefore, the initiator may have such power capable of increasing the stored gas pressure in the small chamber to the burst pressure of the first burst shim. That is, even a relatively low power initiator can easily rupture the first burst shim.
In the stored gas inflator of the present invention, it is preferable that, in the pressure vessel, the small chamber and the main chamber communicate with each other through a small hole.
According to this structure as mentioned above, the small chamber and the main chamber are always at the same pressure in the normal state before the actuation of the initiator. The second burst shim is subjected to the same pressure from the both sides. Therefore, a member which can be ruptured when subjected to a relatively low gas pressure can be employed as the second burst shim. This can eliminate the need of another process of filling gas into the small chamber besides the process for the main chamber. Filling of gas into both of the small chamber and the main chamber can be achieved by only one filling process, thereby facilitating the assembly of the stored gas inflator.
In one embodiment of the present invention, the gas pressure in the small chamber is increased according to the detonation of the initiator, thereby rupturing both the first burst shim and the second burst shim and thus releasing the gas.
In another embodiment of the present invention, the gas pressure in the small chamber is increased according to the detonation of the initiator, thereby first rupturing the first burst shim and thus releasing gas from the small chamber. Then, the second burst shim is ruptured when the difference between the gas pressure in the small chamber and the gas pressure in the main chamber exceeds the burst pressure of the second burst shim, thereby releasing the gas filled in the main chamber.
BRIEF DESCRIPTION OF THE DRAWINGS
FIGS. 1 ( a ) and 1 ( b ) are explanatory views showing the structure of a stored gas inflator according to an embodiment of the present invention;
FIG. 2 is an enlarged sectional view of a portion 2 in FIG. 1 ( b );
FIG. 3 is a sectional view of a main part of a stored gas inflator according to another embodiment of the present invention; and
FIG. 4 is a sectional view of a stored gas inflator according to prior art.
DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS
Hereinafter, embodiments of the present invention will be described with reference to the attached drawings. FIGS. 1 ( a ) and 1 ( b ) show the structure of a stored gas inflator according to an embodiment of the present invention, wherein FIG. 1 ( a ) is a perspective view of the stored gas inflator, and FIG. 1 ( b ) is a perspective sectional view taken along line 1 ( b )— 1 ( b ) of FIG. 1 ( a ). FIG. 2 is an enlarged sectional view of a portion 2 of FIG. 1 ( b ).
The stored gas inflator 10 comprises a pressure vessel 12 which has an elongated cylindrical profile, and is filled with high-pressure gas. The gas in the stored gas inflator 10 is pressurized at a predetermined inner pressure Pm. The pressure vessel 12 is provided, at one end in the longitudinal direction, with a gas port 14 .
The gas port 14 is closed by a first burst shim 16 . The first burst shim 16 is designed to be ruptured to open the gas port 14 when subjected to a pressure equal to or higher than a predetermined pressure value P 1 from the inside of the pressure vessel 12 . The pressure value P 1 is higher than the pressure Pm of the stored gas. Hereinafter, this pressure value P 1 is called as “burst pressure P 1 ” of the first burst shim 16 .
The inside of the pressure vessel 12 filled with high-pressure gas is divided, by a second burst shim 22 and a partition 24 , into a small chamber 18 facing the gas port 14 and a main chamber 20 having a capacity larger than that of the small chamber 18 . At the boundary between the small chamber 18 and the main chamber 20 of the pressure vessel 12 , the partition 24 is formed to stand in the centripetal direction from an inner surface of the pressure vessel 12 . The partition 24 is provided at its center with a gas introduction opening 26 . The second burst shim 22 is disposed to close the gas introduction opening 26 and to divide the small chamber 18 and the main chamber 20 , and is connected to the partition 24 around the peripheral edge thereof.
The partition 24 is provided with a small hole 28 for allowing fluid communication between the small chamber 18 and the main chamber 20 . The small hole 28 always allows the fluid communication between the small chamber 18 and the main chamber 20 , whereby the gas stored in the small chamber 18 and the gas stored in the main chamber 20 are pressurized always at the same pressure (the aforementioned predetermined pressure Pm). In this state, the second burst shim 22 is subjected to the same gas pressure Pm at the both sides, i.e. from the small chamber 18 and the main chamber 20 .
The second burst shim 22 is designed to be ruptured to open the introduction opening 26 when subjected to a pressure equal to or higher than a predetermined pressure value P 2 . Hereinafter, this pressure value P 2 is called as “burst pressure P 2 ” of the second burst shim 22 . The burst pressure P 2 of the second burst shim 22 is lower than the pressure Pm of gas stored in the small chamber 18 and the main chamber 20 .
As will be described later, in a first embodiment of the present invention, the burst pressure P 2 is substantially equal to or slightly lower than (P 1 −Pm).
The small chamber 18 is provided with an initiator mounting portion 32 . Mounted to the mounting portion 32 is an initiator 30 for applying burst pressure to the first and second burst shims 16 and 22 .
The initiator 30 has a large-diameter base portion 30 a and a detonating portion 30 b extending from the tip of the base portion 30 a. The initiator 30 has a connector 30 c at the bottom of the base portion 30 a, and is connected to an initiator controller (not shown) via the connector 30 c. The detonating portion 30 b explodes in response to a detonation signal from the initiator controller.
The initiator mounting portion 32 has a mounting hole 34 for the insertion of the detonating portion 30 b into the small chamber 18 . To mount the initiator 30 to the mounting portion 32 , the detonating portion 30 b is inserted into the small chamber 18 through the mounting hole 34 while the base portion 30 a is air-tightly fitted in and strongly fixed to the mounting portion 32 .
In this embodiment, the stored gas inflator 10 is provided with a tubular male threaded joint portion 40 continuously formed from the gas port 14 . The male threaded joint portion 40 has external thread 40 a formed on the outer surface thereof. Though there is no illustration, the male threaded joint portion 40 is screwed into a female threaded joint portion of a gas supply pipe for a passenger protection airbag mounted on a vehicle, such as an automobile, whereby the stored gas inflator 10 is air-tightly connected to the supply pipe for supplying gas to the airbag.
The small chamber 18 of the pressure vessel 12 is substantially rectangular in section taken along a direction perpendicular to the longitudinal direction. That is, in the small chamber 18 , each pair of the opposite faces is flat and parallel to each other. By clamping such a pair of opposite faces with a tool, such as a wrench, the pressure vessel 12 can be rotated with a large torque, thereby securely screwing the male threaded joint portion 40 into the female threaded joint portion.
Inside the male threaded joint portion 40 , a filter 42 is arranged for preventing fragments of the ruptured burst shims 16 , 22 from entering together with gas stream into the aforementioned gas supply pipe during the gas releasing operation of the stored gas inflator 10 .
Hereinafter, the operation of the stored gas inflator 10 having the aforementioned structure will be described.
The pressure vessel 12 which is divided into the small chamber 18 and the main chamber 20 is filled with high-pressure gas having inner pressure Pm. Because the small chamber 18 and the main chamber 20 communicate with each other through the small hole 28 , the inside of the small chamber 18 and the inside of the main chamber 20 are both at the inner pressure Pm.
The first burst shim 16 closing the gas port 14 for providing communication between the small chamber 18 and the outside of the stored gas inflator is subjected to the stored gas pressure Pm from the inside of the small chamber 18 . The second burst shim 22 dividing the vessel into the small chamber 18 and the main chamber 20 is subjected to the gas pressure Pm from the both sides, i.e. from the small chamber 18 and the main chamber 20 .
In the event of an emergency, such as a vehicle collision, the initiator 30 receives a detonation signal from the initiator controller (not shown), whereby the detonating portion 30 b exposed to the inside of the small chamber 18 explodes. This explosion rapidly increases the inner pressure of the small chamber 18 .
In the first embodiment, by this rapid increase in the inner pressure of the small chamber 18 , the first and second burst shims 16 , 18 are ruptured substantially simultaneously or with some time difference so as to open the gas port 14 and the gas introduction opening 26 . Therefore, the communication between the main chamber 20 and the gas port 14 is ensured, thereby releasing a large amount of gas from the gas port 14 into the airbag through the gas supply pipe.
In the stored gas inflator 10 , the initiator 30 is mounted to the small chamber 18 which is filled with high-pressure gas, and is designed to increase the inner pressure of the small chamber 18 to the burst pressure of the first burst shim 16 , thereby rupturing the first burst shim 16 . Therefore, the initiator 30 is enough to have such power (explosion power) capable of increasing the stored gas pressure Pm in the small chamber 18 to the burst pressure P 1 of the first burst shim 16 . That is, a low power initiator may be employed as the initiator 30 .
In this first embodiment, the first burst shim 16 is ruptured when the gas pressure in the small chamber 18 is increased from Pm by (P 1 −Pm). The second burst shim 22 is ruptured when the gas pressure in the small chamber 18 is increased from Pm by P 2 . P 2 may be substantially equal to (P 1 −Pm) or slightly smaller than (P 1 −Pm). In either case, the gas pressure in the small chamber 18 is increased by (P 1 −Pm) and by P 2 so as to rupture the burst shims 16 , 22 . In this first embodiment, it is preferable that the burst pressure P 2 for the second burst shim 22 is set as lower as possible within a range where the first burst shim 16 can be ruptured.
In a second embodiment of the present invention, first, the first burst shim 16 is ruptured without rupturing the second burst shim 22 when the gas pressure in the small chamber 18 is increased by detonation of the initiator 30 , whereby gas inside the small chamber 18 is released through the gas port 14 . This gas release results in reduction in gas pressure in the small chamber 18 . At a point when the gas is released from the small chamber 18 until the difference (Pm−P′) between the gas pressure Pm exerted by the inner pressure of the main chamber 20 and the pressure P′ exerted by the inner pressure of the small chamber 18 exceeds P 2 , the second burst shim 22 is ruptured, whereby the gas stored in the main chamber 20 is released through the gas port 14 .
In this second embodiment, the burst timing of the second burst shim 22 can be adjusted by selecting the burst pressure P 2 of the second burst shim 22 within a range lower than Pm. In this manner, the stored gas inflator 10 is operable as a dual stage stored gas inflator.
In the aforementioned embodiments, the stored gas inflator 10 has the pressure vessel 12 in which the small chamber 18 and the main chamber 20 communicate with each other through the small hole 28 , whereby the high-pressure gas is filled in the small chamber 18 and the main chamber 20 simultaneously. In addition, the stored gas inflator 10 can be quite simply assembled. According to the design specification of the pressure vessel and/or the initiator, the small hole 26 may be eliminated and the small chamber 18 and the main chamber 20 may be air-tightly separated from each other. In this case, the small chamber 18 and the main chamber 20 are filled with high-pressure gas, respectively.
In the aforementioned embodiments, the burst shims 16 , 22 may be separate thin disc members to close the gas port 14 and introduction opening 26 , respectively. Alternatively, the burst shims 16 , 22 may be fragile areas of extensions integrally formed with and extending from the peripheries of the gas port 14 and the introduction opening 26 to close the gas port 14 and introduction opening 26 , respectively. The fragile areas are ruptured when subjected to the predetermined pressures.
The stored gas inflator of the present invention may have an initiator 300 which is mounted to the small chamber 18 in such a manner that the gas blasting direction of the initiator 300 is directed toward the first burst shim 16 as shown in FIG. 3 . FIG. 3 is a sectional view similar to FIG. 2 but showing an example of the initiator according to another embodiment.
The initiator 300 has the same structure as in the initiator 30 mentioned above, that is, having a large-diameter base portion 300 a and a detonating portion 300 b extending from the tip of the base portion 300 a. The initiator 300 has a connector 300 c at the bottom of the base portion 300 a, and is connected to an initiator controller (not shown) via the connector 300 c. The detonating portion 300 b explodes in response to a detonation signal from the initiator controller to blast high-pressure gas along the central axial line L of the initiator 300 extending through the base 300 a and the detonating portion 300 b.
An initiator mounting portion 320 to which the initiator 300 is mounted is formed in such a manner that the central axial line L of the initiator 300 is inclined toward the first burst shim 16 , and, thereby, holds the base portion 300 a such that the gas blasting direction of the detonating portion 300 b which is exposed to the inside of the small chamber 18 through the mounting hole 340 is oriented toward the first burst shim 16 .
According to this structure as mentioned above, as the detonating portion 300 b of the initiator 300 explodes inside the small chamber 18 , gas is blasted toward the first burst shim 16 so that the blast pressure directly acts as power for rupturing the burst shim 16 , thus promoting the rupture of the burst shim 16 . As a result, an initiator having further lower power can be employed as the initiator 300 . Further, according to the second embodiment of the present invention, the initiator is arranged such that its axis is inclined toward the first burst shim as mentioned above, thereby ensuring the rupture of the first burst shim prior to the rupture of the second burst shim.
As described above in detail, a stored gas inflator of the present invention ensures its gas releasing operation even with a low power initiator.
While the invention has been explained with reference to the specific embodiments of the invention, the explanation is illustrative and the invention is limited only by the appended claims.
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A stored gas inflator is formed by a pressure vessel including a gas port, a small chamber facing the gas port, and a main chamber situated adjacent to the small chamber and having a capacity larger than that of the small chamber. A high pressure gas is filled in the small chamber and the main chamber. A first partition closes the gas port, and a second partition separates the small chamber and the main chamber so that a burst pressure of the second partition is set to be lower than a stored gas pressure in the main chamber. A gas blasting initiator is mounted to the small chamber for applying burst pressure to at least one of the first and second partitions to allow the main chamber to eject the gas.
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RELATED APPLICATION
This application is a continuation of co-pending application Ser. No. 11/412,671 filed on Apr. 27, 2006 and herein incorporated by reference in its entirety.
BACKGROUND
The present application is directed to devices and methods for stabilizing vertebral members, and more particularly, to intervertebral implants and methods of use for replacing an intervertebral disc, vertebral member, or combination of both to distract and/or stabilize the spine.
The spine is divided into four regions comprising the cervical, thoracic, lumbar, and sacrococcygeal regions. The cervical region includes the top seven vertebral members identified as C1-C7. The thoracic region includes the next twelve vertebral members identified as T1-T12. The lumbar region includes five vertebral members L1-L5. The sacrococcygeal region includes nine fused vertebral members that form the sacrum and the coccyx. The vertebral members of the spine are aligned in a curved configuration that includes a cervical curve, thoracic curve, and lumbosacral curve. Intervertebral discs are positioned between the vertebral members and permit flexion, extension, lateral bending, and rotation.
Various conditions may lead to damage of the intervertebral discs and/or the vertebral members. The damage may result from a variety of causes including a specific event such as trauma, a degenerative condition, a tumor, or infection. Damage to the intervertebral discs and vertebral members can lead to pain, neurological deficit, and/or loss of motion.
Various procedures include replacing the entirety or a section of a vertebral member, the entirety or a section of an intervertebral disc, or both. One or more replacement implants may be inserted to replace the damaged vertebral members and/or discs. The implants reduce or eliminate the pain and neurological deficit, and increase the range of motion.
SUMMARY
The present application is directed to intervertebral spacers for positioning between first and second vertebral members. The spacer may include a first contact surface to contact the first vertebral member and a second contact surface to contact the second vertebral member. The spacer may include a fluid chamber positioned between the contact surfaces and have telescoping inner and outer members with the outer member having a first sidewall and being sized to receive the second member. A slot may extend through the first sidewall and into communication with the fluid chamber. The slot may include first and second sides and an intermediate gap. An elongated clamping member with a first end and a second end may extend into the outer member and across the slot with the first end on a first side of the slot and the second end on a second side of the slot. The elongated clamping member may be movable to adjust the gap between a first size for the inner member to be movable relative to the outer member to adjust a distance between the first and second contact surfaces, and a second size for the inner member to be fixed relative to the outer member.
The spacer may also include an outer member. The outer member may have a first cavity with an open first end and a cavity wall, a slot that extends through the cavity wall and intersects with the first cavity, a receptacle that extends across the slot with a first section on a first side of the slot and a second section on a second side of the slot, and a first contact surface configured to contact against the first vertebral member. The spacer may also include an inner member. The inner member may have a second contact surface configured to contact against the second vertebral member, and a column having a second cavity. The column may extend through the open first end and into the first cavity, and may have solid walls to contain a fluid. The spacer may include a retaining mechanism that extends into the first and second sections of the receptacle and across the slot to adjust a size of the first cavity. The retaining mechanism may be adjustable between a first position with the first cavity larger than the column for the inner member to be movable relative to the outer member, and a second position to prevent the relative movement between the outer member and the inner member.
The spacer may also include a first contact surface and a second contact surface. A fluid cylinder may be positioned between the first and second contact surfaces and configured to contain a fluid. The fluid cylinder may include an outer cylinder with an open first end that telescopingly receives an inner cylinder. A slot may extend through the outer cylinder at the open first end and intersect with the fluid cylinder. A seal may be positioned in the slot to prevent the fluid from leaking from the fluid cylinder.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 is a perspective view of an exemplary intervertebral spacer in a retracted position disposed between two vertebral members.
FIG. 2 is a perspective view of an exemplary intervertebral spacer in an extended position disposed between two vertebral members.
FIG. 3 is an exploded perspective view of an exemplary intervertebral spacer.
FIG. 4 is a perspective view of an inferior member for an exemplary intervertebral spacer.
FIG. 5 is a perspective view of a superior member for an exemplary intervertebral spacer.
FIG. 6 is a detail view of one exemplary intervertebral spacer.
FIGS. 7 and 8 illustrate an exemplary method of inserting the intervertebral spacer.
DETAILED DESCRIPTION
The present application relates to implants for replacing an intervertebral disc, vertebral member, or combination of both, and to methods of inserting the same. The implant comprises an intervertebral spacer 10 that can be inserted between vertebral bodies in a compact configuration as shown in FIG. 1 and subsequently expanded to contact the adjacent vertebral bodies as shown in FIG. 2 .
FIGS. 3-5 illustrate one exemplary embodiment of the intervertebral spacer 10 . The intervertebral spacer 10 comprises an inferior member 12 and a superior member 60 movable with respect to the inferior member 12 from a retracted position to an extended position. As will be described in more detail below, the inferior member 12 includes a first cylinder 22 , and the superior member 60 includes a second cylinder 72 that is insertable into the first cylinder 22 . The cylinders 22 and 72 together define a expansion chamber. When fluid is introduced into the expansion chamber, the superior member 60 is urged away from the inferior member 12 . While cylinders 22 and 72 are shown having a circular cross-section, those skilled in the art will appreciate that the cylinders 22 and 72 can have other shapes, such as square, rectangular, oval, kidney-shape, etc.
FIG. 4 illustrates details of one embodiment of the inferior member 12 . The inferior member 12 comprises a body 14 including a bottom surface 15 that contacts an adjacent vertebral body. The bottom surface 15 can be textured to grip the vertebral body. For example, teeth, ridges, or grooves can be formed in the bottom surface 15 to improve gripping capability. The body 14 has an oblong configuration including a central section 16 and wing sections 18 and 20 . Cylinder 22 is formed in the central section 16 . A fluid port 24 is formed in the central section 16 for introducing fluid into the expansion chamber formed by cylinders 22 and 72 . A one-way valve 26 ( FIG. 3 ) is disposed in the fluid port 24 that allows introduction of fluid, such as a saline solution, into the expansion chamber, and prevents fluid from exiting the expansion chamber. One or more cavities 30 may be formed in the wing sections 18 and 20 to reduce weight and material requirements.
A slot 32 is formed in the wing section 18 . Slot 32 divides the wing section 18 into first and second clamping portions 34 and 36 , respectively, and intersects both the wall and bottom of the cylinder 22 . A compressible seal 50 is disposed within the slot 32 to prevent fluid from leaking from the expansion chamber. Clamping portion 34 includes a recessed surface 38 . A pair of spaced-apart ears 40 project outward from the recessed surface 38 for mounting a pin 42 . The ends of the pin 42 are firmly secured in openings formed in the ears 40 . Any suitable techniques for securing the pin 42 can be used. A screw hole 44 extends inward from the recessed surface 38 to receive a locking screw 46 . The screw hole 44 crosses the slot 32 such that the screw hole 44 is divided into two portions 44 a , 44 b . Portion 44 b of the screw hole 44 is threaded. When the locking screw 46 is tightened, the clamping portions 34 and 36 are pulled together, causing a slight contraction of the cylinder 22 . As will be hereinafter described, this clamping arrangement functions as a locking mechanism to lock the superior member 60 firmly in place once proper height adjustment has been made.
The superior member 60 , shown in FIG. 5 , comprises a plate 62 having a top surface 64 that engages an adjacent vertebral body. The top surface 64 can be textured to grip the vertebral body. For example, small teeth, ridges, or grooves can be formed in the top surface 64 to improve gripping capability. The top plate 62 is shaped to generally correspond to the shape of the inferior member 12 . The top plate 62 includes a central section 66 and wing sections 68 and 70 . A cylinder 72 extends from the bottom surface of the top plate 62 . Cylinder 72 is sized to fit within the cylinder 22 in the inferior member 12 . In one embodiment, the interior dimension of the cylinder 22 and exterior diameter of the cylinder 22 are sized to close tolerances such that a seal is formed between the interior wall of cylinder 22 and outer surface of cylinder 72 . However, those skilled in the art will appreciate that a ring seal 52 may be used to form a fluid tight seal between cylinders 22 and 72 . An annular groove 54 may also be formed in the outer surface of the cylinder 72 to position the seal 52 .
A mechanism can be provided to prevent the inferior member 12 and superior member 60 from separating. In one embodiment, a pair of resilient fingers 74 extends downward from the bottom surface of the top plate 62 of superior member 60 . The enlarged ends 76 of the resilient fingers 74 are configured to engage the locking tabs 28 on the inferior member 12 . When the superior member 60 is assembled with the inferior member 12 , the ends of the locking fingers 74 contact the locking tabs 28 . Camming surfaces 78 on the enlarged ends 76 of the locking fingers 74 cause the resilient fingers 74 to flex outward and pass over the locking tabs 28 . Once the enlarged ends 76 have passed over the locking tabs 28 , the resilient fingers 74 return to their original position, thereby preventing separation of the superior member 60 . Thus, the resilient fingers 74 and locking tabs 28 cooperate to retain the superior member 60 in place.
FIG. 6 illustrates an alternate method of preventing separation of the inferior member 12 and superior member 60 . In this embodiment, an inwardly projecting lip 80 is formed at the top end of cylinder 22 and an outwardly projecting lip 82 is formed at the bottom end of cylinder 72 . In this embodiment, the superior member 60 can be assembled with the inferior member 12 by dipping the superior member 60 in a cold liquid, such as liquid nitrogen, to shrink the superior member 60 . When the superior member 60 shrinks, the lip 82 on cylinder 72 will pass through the lip 80 on cylinder 22 . The superior member 60 will then expand to its original size as it returns to ambient temperatures.
The inferior member 12 and superior member 60 can be made of any suitable material, such as PEEK. The bottom of the inferior member 12 and/or top plate 62 of the superior member 60 could be porous to allow the in-growth of bone. An embedded biologic coating, such as hydroxia appetite (HA), BMP, or calcium phosphate could be used to promote bone in-growth. The contact surfaces of the inferior and superior members 12 and 72 could also be textured to grip the adjacent vertebral bodies.
In use, the superior member 60 is assembled to the inferior member 12 and placed in a compact configuration with the superior member 60 in a retracted position relative to the inferior member 12 as shown in FIG. 1 . The intervertebral spacer 10 , in a compact configuration, is inserted through a cannula 150 into an intervertebral space between two vertebral bodies ( FIG. 1 ). Those skilled in the art will appreciate that the intervertebral spacer 10 can replace one or more disks and/or vertebral bodies. After the insertion of the intervertebral spacer 10 , fluid or compressed air is introduced into the expansion chamber to cause the superior member 60 to extend away from the inferior member 12 as shown in FIG. 2 . The superior member 60 is raised until the contact surfaces of the inferior and superior members 12 and 60 are engaged with the adjacent vertebral bodies. Once the height of the intervertebral spacer 10 is properly adjusted, the locking screw 24 is tightened to lock the superior member 60 in a fixed position relative to the inferior member 12 . Tightening the locking screw 46 causes the cylinder 22 of the inferior member 12 to contract and clamp against the exterior surface of cylinder 22 . Thus, the cylinder 22 itself functions as a clamp that will lock the inferior and superior members 12 , 60 in position, even in the event that fluid leaks from the expansion chamber.
FIGS. 7 and 8 illustrate an exemplary insertion tool 100 to insert the intervertebral spacer 10 . The insertion tool 100 includes an elongate housing 102 having three lumens 106 , 108 , and 110 formed therein. Access to the intervertebral space is gained through a cannula 150 inserted into the body. FIGS. 7 and 8 illustrate the distal end of the cannula 150 and insertion tool 100 . The insertion tool 100 includes a hook member 102 that engages pin 42 on the intervertebral spacer 10 . As the intervertebral spacer 10 is advanced through the cannula 150 , the intervertebral spacer 10 initially assumes the position shown in FIG. 7 . When the intervertebral spacer 10 exits from the end of the cannula 150 , a push rod 104 is used to rotate the intervertebral spacer 10 into the proper angular position.
The hook member 102 and push rod 104 pass through the first lumen 106 . The second lumen 108 aligns with the locking screw 46 . The third lumen 110 aligns with the fluid valve 26 . After the intervertebral spacer 10 is properly positioned, a fluid delivery line can be inserted through lumen 110 and engaged with the fluid valve 26 to deliver fluid into the expansion chamber to expand the intervertebral spacer 10 . A tool can then be inserted through the middle lumen 108 to tighten the locking screw 42 .
The embodiments described above include member 60 being a superior member and member 12 being inferior. In another embodiment, the orientation of these members 60 , 12 may be interchanged with member 60 functioning as an inferior member and member 12 functioning as a superior member.
One embodiment includes accessing the spine from a postero-lateral approach. Other applications contemplate other approaches, including posterior, anterior, antero-lateral and lateral approaches to the spine, and accessing other regions of the spine, including the cervical, thoracic, lumbar and/or sacral portions of the spine.
The term “distal” is generally defined as in the direction of the patient, or away from a user of a device. Conversely, “proximal” generally means away from the patient, or toward the user. Spatially relative terms such as “under”, “below”, “lower”, “over”, “upper”, and the like, are used for ease of description to explain the positioning of one element relative to a second element. These terms are intended to encompass different orientations of the device in addition to different orientations than those depicted in the figures. Further, terms such as “first”, “second”, and the like, are also used to describe various elements, regions, sections, etc and are also not intended to be limiting. Like terms refer to like elements throughout the description.
As used herein, the terms “having”, “containing”, “including”, “comprising” and the like are open ended terms that indicate the presence of stated elements or features, but do not preclude additional elements or features. The articles “a”, “an” and “the” are intended to include the plural as well as the singular, unless the context clearly indicates otherwise.
The present invention may be carried out in other specific ways than those herein set forth without departing from the scope and essential characteristics of the invention. The present embodiments are, therefore, to be considered in all respects as illustrative and not restrictive, and all changes coming within the meaning and equivalency range of the appended claims are intended to be embraced therein.
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An intervertebral spacer for positioning between vertebral members. The spacer may include contact surfaces that are configured to contact against the vertebral members. A fluid cylinder may be positioned between the first and second contact surfaces and configured to contain a fluid. The fluid cylinder may include an outer cylinder with an open first end that telescopingly receives an inner cylinder. The spacer is configured to maintain the distance between the contact surfaces at a desired amount.
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BACKGROUND OF THE INVENTION
The instant invention relates to inkjet printheads and more particularly to a maintenance system for an ink jet printhead.
Printheads are used in many applications today, and a preferred printhead is an inkjet printer. Such printers spray small dots of ink on paper and typically move along an axis of transport. When inkjet printers are not in use they are moved to a maintenance station where a cleaning and maintenance procedure is effected which includes wiping, priming, spitting and capping. In some applications of the inkjet printer, such as in a postage meter, there is not enough room along the axis of transport to dock the printhead, and moving the printhead in a two-directional horizontal plane is excessively complex. Thus, use of an inkjet printhead in a postage meter would be difficult to effect.
Accordingly, the instant invention provides a maintenance system which does not require the inkjet printhead to move to the maintenance station and thus permits use of the inkjet printer in applications such as postage meters where it would otherwise not be feasible.
SUMMARY OF THE INVENTION
Thus, the instant invention provides apparatus and a method for cleaning and maintaining an inkjet printhead with a maintenance head. The apparatus includes: an inkjet printhead translatable in a first plane; a device for translating the printhead to a cleaning station; an inkjet maintenance head translatable in a second plane, wherein the first plane is not parallel to the second plane; and a device for translating the maintenance head in at least two directions in the second plane to engage the printhead at the cleaning station.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 a schematic, perspective view of a postage meter having an inkjet printer showing the printhead and maintenance head in accordance with the instant invention;
FIG. 2 is a schematic, side, elevational view of the maintenance head in its home position;
FIG. 3 is similar to FIG. 2 but shows the maintenance head in the capping position adjacent the printhead.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT
In describing the preferred embodiment of the instant invention, reference is made to the drawings, wherein there is seen in FIG. 1 a postage meter 8 having an inkjet printing system generally designated 10 which includes an inkjet printhead 12 and an inkjet maintenance head 14 for servicing and cleaning the printhead 12. The printhead 12 is used for printing postage indicia on an envelope 16 and also on tape 18 passing therebelow as explained in further detail hereinbelow. The printhead 12 includes a pair of rollers 20 and 22 which ride on a pair of rails 24 and 26 respectively. A lead screw 28 is driven by a drive motor 30 and threadingly engages the top of the printhead 12 in order to translate the printhead 12 back and forth along the rails 24 and 26. The printhead 12 can be stopped in one of three positions. FIG. 1 shows the printhead 12 stopped at station 1 indicated by arrow 32, at which station 1 the printhead 12 can print on the tape 18 in conventional manner. The printhead 12 can also be stopped at station 2 indicated by the arrow 34 at which station 2 the printhead 12 can print on the envelope 16 in conventional manner. The home or resting position of the printhead 12 is at station 3 indicated by the arrow 36.
The maintenance head has a camming surface 19 and 14 sits on a track 38 and is translatable along the track 38 by means of a pin 40 which engages an aperture (not shown) in the maintenance head 14 The track 38 is vertically aligned with the printhead station 3. The pin 40 is seated in a block 42 which threadingly engages a lead screw 44 which in turn is driven by a drive motor 46. The track 38 includes a slot 48 in which the pin 40 is translated. As best seen in FIGS. 2 and 3, the track 38 includes a horizontal path or section 50, an angled, cam section 52, and a second, horizontal section 54 at the end thereof. The cam section 52 is shown angled at a diagonal, but other angles could be employed. In FIGS. 1 and 2, the maintenance head 14 is shown at its home or resting position which is station 4 indicated by the arrow 56. The maintenance head 14 is situated at station 4 whenever the printhead 12 is being used to print the envelopes 16 or the tape 18.
Whenever the printhead 12 is not being used to print envelopes 16 or tape 18, the printhead 12 is translated by the lead screw 28 to the position of station 3 and remains stationary at station 3. Whenever the printhead 12 is stationary at station 3, the inkjet printing system 10 is programmed to move the maintenance head 14 to station 5 indicated by the arrow 57 into a cleaning position which is a docking relationship with the printhead 12, as shown in FIG. 3, i.e. the maintenance head 14 is moved below the printhead 12.
The movement of the maintenance head 14 along the track 38 to the station 5 will now be described. The maintenance head 14 moves in a single, vertical plane which is aligned with the printhead home station 3. The initial movement of the maintenance head 14 along the track 38 is from left to right on the first horizontal path 50. Continued translation of the pin 40 by the drive motor 46 causes the maintenance head 14 to approach the cam section 52, at which point the camming surface 19 of the maintenance head 14 engages the cam section 52 to thereby lift the maintenance head 14 as it is being translated from left to right. When the camming surface 19 has finished traversing the cam section 52, the maintenance head 14 is elevated and moves again from left to right along the second horizontal track section 54 to the cleaning position seen in FIG. 3. Thus, the maintenance head 14 experiences lateral and vertical movement in being moved from its home position at station 4 to its cleaning position at station 5 where the top surface of the maintenance head 14 engages the bottom surface of the printhead 12. The lateral movement takes place along the horizontal track sections 50 and 54, and both lateral and vertical movement takes place along the cam section 52. The movement along the horizontal track sections 50 and 54 comprises movement in one direction and the movement along the cam section 52 comprises movement in a second direction. Thus, there is movement by the maintenance head 14 in two directions. Clearly, the two directions of movement will comprise elements of both lateral and vertical movement. Since both lateral and vertical movement of the maintenance head 14 is required to move it into its cleaning position at station 5, movements other than what is shown in FIGS. 1-3 could be employed, e.g. one direction of movement could be purely horizontal and another direction of movement could be purely vertical.
When the maintenance head 14 moves past the printhead 12 located thereabove, the wiper (not shown) of the maintenance head 14 wipes the nozzles (not shown) on the bottom of the printhead 12 in conventional manner. The capping device (not shown) of the maintenance head 14 hermetically seals the nozzles of the printhead 12 when the maintenance head 14 is stopped from further translation along the track 38, and a vacuum can be applied from the maintenance head 14 to remove ink from the nozzles. Additionally, the nozzles of the printhead 12 can be fired into the spittoon of the maintenance head.
The inkjet printing system 10 described hereinabove is arranged in such a way that it occupies a minimum of space and thus can be used in many applications which otherwise lack sufficient space for an inkjet printer. A postage meter is just one example of the many applications for which the foregoing inkjet printing system 10 is suitable.
While the present invention has been disclosed and described with reference to a single embodiment thereof, it will be apparent, as noted above that variations and modifications may be made therein. It is, thus, intended in the following claims to cover each variation and modification that falls within the true spirit and scope of the present invention.
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Apparatus and a method for cleaning and maintaining an inkjet printhead with a maintenance head. The apparatus includes: an inkjet printhead translatable in a first plane; a device for translating the printhead to a cleaning station; an inkjet maintenance head translatable in a second plane, wherein the first plane is not parallel to the second plane; and a device for translating the maintenance head in at least two directions in the second plane to engage the printhead at the cleaning station.
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CROSS REFERENCE TO RELATED APPLICATIONS
[0001] The present application is a continuation in part of U.S. Ser. No. 11/140,272, which in a continuation-in-part of U.S. Ser. No. 11/076,169, which is a continuation-in-part of U.S. Ser. No. 10/926,209, which claimed priority to provisional application Ser. No. 60/503,678.
FIELD OF THE INVENTION
[0002] The present invention relates to an improved light therapy delivery apparatus.
BACKGROUND OF THE PRIOR ART
[0003] Ultraviolet (UV) light can be used to treat a multitude of medical problems, including for example bacterial, viral and fungal infections, poisoning, fatigue, Alzheimer's disease, allergies and asthma, rheumatic diseases and arthritis, diabetes, hepatitis, and cancer, because UV light sterilizes the blood and acts as an antibiotic. The UV light is applied either to the patient's skin or directly to the blood. If the UV light is applied to the skin it is typically provided to the patient's skin either with a wrap or lamp.
[0004] Applying the UV light directly to a patient's blood supply is known as photoluminescence or UV blood illumination (UBI). UV blood illumination increases oxygen, destroys toxins and boosts the immune system. In prior art UBI, a small amount of blood is drawn from the patient, up to about 250 cc. The blood that is drawn travels through a cuvette or glass chamber. The blood is repeatedly illuminated with UV light and then returned to the body. The process is repeated, typically a day or several days later. These treatments are time consuming, and require regular trips to a medical facility. In addition, trained personal must be available to provide the treatments.
[0005] Because of the problems associated with UBI, a need developed for providing UV light to a patient's blood without having to draw blood. Meeting this need numerous prior art references disclosed the application the light sublingual with the use of mouth guards, toothbrushes, and elongated light tubes. However, these have proven to be not very effective because of specific problems associated with the materials used and the applications themselves.
[0006] It is well known that certain UV light cannot penetrate certain plastics and resins. In addition, trying to force the UV light down a tube towards an eyelet or window was also shown to diminish the UV light. Specific light guides can be employed to communicate the UV light down a tube without diminishing the UV light characteristics. But rather then employ additional material or costs, it has also been suggested to place the source of the UV light at the end of the applicator. The type of UV light source can effect the applicator greatly. For example, the use of a cold cathode tube to supply the UV light source can radiate a lot of heat, having a working temperature of about 101° F. This temperature range is dangerous and harmful to the user, especially when the applicator end is placed sublingually or rectally.
[0007] There one embodiment of the present invention address the need for an apparatus that includes a UV light source which when in use keeps the apparatus within a temperature range that would not be harmful to the user.
SUMMARY OF THE INVENTION
[0008] In an embodiment of the invention there is provided a light therapy apparatus. The apparatus includes a main casing having front and rear ends; a light source inserted through the front end of the main casing; a front cap having a central bore for receiving the light source and having a treaded internal structure for securing the front cap to corresponding threaded external structure on the front end of the main casing; a secondary casing having a base end positioned within the front cap and over the front end of the main casing, the secondary casing further including a shoulder section extending outwardly from the base end out of the front cap to partially cover a section of the light source; a shroud placed over the exposed portion of the light source and having at least a flexible bottom end for tightly fitting over an end of the shoulder section, the shroud being made of a light-resistance material to prevent light from the light source from penetrating the shroud; a lens positioned through the shroud to direct light from the light source out of the shroud; and a fan positioned within the casing and directed to transmit air flow to the shroud.
[0009] In other embodiments the shroud may include a rigid portion covering the light source; may be further defined as having a base portion extending upwardly to form a tubular shaped covering that terminates into a top portion, the tubular shaped covering includes a front portion, a back portion, and a pair of side portions, the front portion extends inwardly from the base to a concave section, and the back portion extends inwardly from the base to a concave section, the tubular shaped covering is bent away from the base portion at an angle of about 25-35°; or may include an internally defined annular flange extending radially inward that would come into contact with the shoulder section when the shroud is placed thereover.
[0010] In yet other embodiments, the casing includes an air intake aperture and/or the shroud could include an air exhaust aperture. Other embodiment may use cooling tubes to help direct the air flow from the fan.
[0011] Numerous advantages and features of the invention will become readily apparent from the following detailed description of the invention and the embodiments thereof, and from the accompanying drawings.
BRIEF DESCRIPTION OF THE DRAWINGS
[0012] A fuller understanding of the foregoing may be had by reference to the accompanying drawings, wherein:
[0013] FIG. 1 a is an illustration of an apparatus for light therapy in accordance with a first embodiment;
[0014] FIG. 1 b is a partially exploded view of FIG. 1 a;
[0015] FIG. 2 a is a perspective view of a shroud used to cover a light source for a light therapy apparatus;
[0016] FIG. 2 b is a sectional view of the apparatus in FIG. 2 a;
[0017] FIG. 2 c is a side view of the apparatus in FIG. 2 a;
[0018] FIG. 2 d is a side perspective view of another embodiment of a shroud;
[0019] FIG. 3 is an illustration of an apparatus for light therapy in accordance with another embodiment; and
[0020] FIG. 4 is an illustration of an apparatus for light therapy in accordance with another embodiment.
DETAILED DESCRIPTION OF THE INVENTION
[0021] While the invention is susceptible to embodiments in many different forms, there are shown in the drawings and will be described herein, in detail, the preferred embodiments of the present invention. It should be understood, however, that the present disclosure is to be considered an exemplification of the principles of the invention and is not intended to limit the spirit or scope of the claims by the embodiments illustrated.
[0022] Referring to FIGS. 1 a and 1 b, there is shown an apparatus 100 for the delivery of UV light to a patient. Ultraviolet light can be used to treat many diseases including infections, poisoning, fatigue, allergies, hepatitis, cancer and HIV. UV light increases the oxygen combining power of the blood, destroys toxins, viruses, fungi, bacteria, and boosts the immune system. UV light also sterilizes the blood and acts as an antibiotic. Preferably, UV light at one or more therapeutic wavelength is utilized in the present invention. More preferably the light is either UV-A or UV-C light is utilized in the present invention. For some conditions and/or diseases UV-A light is more effective than UV-C and for other conditions and/or diseases UV-C light is more effective than UV-A light. The wavelengths or wavelengths of light to be used to treat the patient are selected based on the wavelength or wavelength that will best treat the condition or disease of the patient.
[0023] The apparatus 100 is preferably designed to allow a patient to administer the UV light sublingual, under the tongue. The capillaries under the tongue are close to the surface. These capillaries are very sensitive. Capillary exposure of the mucous membrane is significantly greater than other exposed body surfaces. The greater capillary exposure allows for greater penetration of the ultraviolet spectrum. It is also believed that similar exposure can happen rectally.
[0024] The apparatus 100 is attached to a power supply (not shown) by power cord 105 . The power supply may simply plug directly into an AC outlet and/or utilize a DC converter. This is not an important aspect of the embodiments. The apparatus 100 includes a UV light source 110 , which for this embodiment includes a cold cathode UV bulb. The light source 110 is connected to a circuit board 120 by a connector 125 , which is preferably a polarized connector. The circuit board 120 would typically include a controller/software and timing mechanism with commands to turn the light source on/off, control the length of treatment time in a given time period, etc.
[0025] The apparatus 100 includes a main casing 130 to house the components. The main casing 130 includes a rear cap 140 that may be treaded onto the rear end 132 of the main casing 130 . A rear set screw 142 is used to secure the rear cap 140 onto the rear end 132 .
[0026] The light source is inserted through the front end 134 of the main casing 130 and is secured in place by a front cap 145 that may be threaded onto the front end 134 . Similarly, a front set screw 147 is used to secure the front cap 145 onto the front end 134 .
[0027] The front cap 145 includes a central bore 149 such that it can slide over the UV light source 110 and slide over a secondary casing 150 . The secondary casing 150 is captured and secured to the main casing 130 because the secondary casing 150 includes a base end 152 that has a larger diameter then the diameter of the central bore 149 . Extending from the base end 152 of the secondary casing 150 is a shoulder section 155 that covers a portion of the UV light source 110 . The base end 152 also has a larger diameter than the shoulder section 155 .
[0028] A shroud 160 (illustrated in FIGS. 2A-2D ) is placed over the exposed portion of the UV light source 110 and secured or attached around the perimeter of the shoulder section 155 . The shroud 160 is rigid such that the shroud can maintain its shape and such that it does not come into contact with the UV light source 110 . As mentioned the UV light source can generate a significant amount of heat. To help protect the user the shroud 160 includes an internal cavity that positions the interior material a distance away from the UV light source. The shroud 160 may be disposable such that a replacement shroud 160 can be used for the next treatment. Alternatively, the shroud 160 may be easily removable and washable. Further details of the shroud are discussed below.
[0029] In one embodiment the shroud 160 further includes a lens 165 to allow the UV light source 110 to exit. When the shroud 160 incorporates the lens 165 , the rest of the shroud 160 would preferably be made of a photo-resistant or other like material. This helps ensure that the UV light is properly directed out of the shroud at a pre-determined section.
[0030] To cool down the area of contact between the apparatus and the user, a fan 170 is inserted near the rear end 132 of the casing 130 . The fan 170 is controlled by the circuit board 120 . The fan 170 directs air through the casing 130 into the front cap 145 and down the shroud 160 and acts to cool the UV light source 110 . An air intake aperture 175 is positioned on the casing 130 near the front end 134 .
[0031] Referring now to FIG. 3 , in another embodiment the apparatus 200 includes similarly marked components but also includes a cooling tube 210 to help direct the air flow from the main casing 130 through the secondary casing 155 and into the shroud 160 —towards the end of the UV light source 110 . The cooling tube 210 includes a first opened end 212 positioned within the main casing 130 and includes a second opened end 214 positioned within the shroud 160 .
[0032] It was further determined that even with the fan and a cooling tube, that the end of the shroud 160 may still be too hot for insertion into and/or to make contact with a portion of a user's body 101° F. However, by placing an outlet opening 162 on the shroud 165 in a position opposite the second opened end 214 of the cooling tube 210 , that the temperature of the shroud 165 was reduced to a temperature of about 88° F., a working temperature that permits the surface of the shroud to come into contact with the user's body without harming or burning the user.
[0033] Referring now to FIG. 4 , in another embodiment the apparatus 300 includes similarly marked components but includes a pair of cooling tubes 310 and 310 . The first cooling tube is referred to as a cooling input tube 310 and it includes a first end 312 that is positioned near the fan 170 and includes a second end 314 that is positioned within the shroud 350 . The second cooling tube is referred to as a heat output tube 320 . The heat output tube 320 includes a first end 322 that is positioned within the shroud 350 and includes a second end 324 that exhausts out of the casing 130 . The second end 314 of the cooling input tube 310 and the first end 322 of the heat output tube 320 are positioned at diametrical opposite positions in the shroud, such as, but not limited, the bottom and the top portions of the shroud 160 . In addition the shroud 160 could further include an outlet opening 162 to help vent air that has become heated from contact with the UV light source.
[0034] Referring back to FIGS. 2A-2D , the shroud 160 as mentioned can include a lens 165 that permits the UV light to penetrate therethrough for the treatment of the blood. The lens is preferably made of a fused quartz material, such as but not limited to GE Type 124 Fused Quartz.
[0035] The shroud 160 may also include an outlet opening 162 to help vent the heated air circulating around the UV light source. The shroud 160 may be further defined as having a base portion 400 that extends upwardly to form a tubular shaped covering 410 that further terminates into a top portion 420 . The tubular shaped covering 410 includes a front portion 430 , a back portion 440 , and a pair of side portions 450 . The front portion 430 extends inwardly from the base 400 to a concave section 432 . The back portion 440 also extends inwardly from the base 400 to a concave section 440 . The termination from the tubular shaped covering 410 to the top portion 420 is slightly bent from the axis of the tubular shaped covering. The angle defined by the bending is α and is preferably about 25°-35°. Internally the shroud 160 may include an annular flange 460 approximately near the base portion 400 termination to the tubular shaped covering. The flange 460 extend radially inward and act as a stop when the shroud 160 is inserted over the shoulder section 155 of the secondary casing 150 . Lastly, the shroud 160 may include a ribbed or flexible end 470 below the base 400 such that it may be secured to the secondary casing by tightly fitting the flexible end over the end of the secondary casing.
[0036] From the foregoing and as mentioned above, it will be observed that numerous variations and modifications may be effected without departing from the spirit and scope of the novel concept of the invention. It is to be understood that no limitation with respect to the specific methods and apparatus illustrated herein is intended or should be inferred.
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An light therapy apparatus is defined to include a UV light source secured to a casing. A shroud is placed over an exposed portion of the UV light source and is secured or attached around the perimeter of the casing end. Since the UV light source can generate a significant amount of heat, the casing includes an internal fan. Various tubing configurations may be used to help direct the air flow from the fan around the UV light source. In addition, a vent opening in the shroud was found to reduce the temperature of the shroud to prevent damage to a person's user the apparatus.
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BACKGROUND OF THE INVENTION
This invention relates generally to improved high precision lens molds for use in the manufacture of very thin contact lenses and to the method and apparatus for making the improved lens mold. Lens molds are usually produced in matched pairs from thermoplastics and the combination of matched pairs forms the mold cavity to define the optical contact lens. More particularly, the invention relates to precision lens molds made by filling a mold cavity through a center gate on the central axis of the mold cavity rather than through a side gate on the edge of the mold cavity.
As is known in the art, optical contact lenses are typically manufactured by dosing a UV curable polymer into a concave front, or optical, curve lens mold and mating a convex back or base curve lens mold onto the front lens mold to create a filled mold cavity. The front lens mold and base lens mold are injection molded from a thermoplastic polymer, such as polystyrene. Standard practice is to form the front and back lens molds by injecting the liquid polymer into a closed mold through a side gate along the edge of the closed mold cavity, with a corresponding outlet gate positioned on the opposite side of the closed mold cavity. The liquid polymer enters the edge of the cavity and flows across the cavity to completely fill it. This side gate method for formation of a circular spherical part leads to a lack of precision from non-uniform, asymmetric flow and non-uniform plastic shrinkage in different directions with respect to radius, dimensional instability, surface radius irregularity, flatness, roundness and especially knife edge radius uniformity. The lack of knife edge uniformity subsequently leads to misalignment, known as decentration or tilt, when the base lens mold is joined to the front lens mold in the manufacture of the actual contact lens. Tilt adversely affects the lens center thickness and the resulting contact lens is not within acceptable tolerance values and must be rejected.
While this is a problem in current manufacture, the percentage loss of contact lenses can be maintained within acceptable levels since the tolerances are relatively large for lenses with thicknesses of 70 to 230 microns or more. However, it is desirable to improve manufacturing yield of typical contact lenses as well as to manufacture very thin contact lenses with thicknesses on the order of 50 microns to improve oxygen transmission, user comfort and optical properties. Such lenses require a lens center thickness tolerance in the range of only +/-5 microns. Such a precise thin lens cannot be consistently manufactured using lens molds produced from present side gate methodology, the irregularities resulting in the lens molds from asymmetrical polymer flow across the curved mold cavity being well outside the small tolerance ranges for various measurement parameters.
It is the universally held position by those knowledgeable in the art that gates should be located only in non-critical areas of plastic parts, and therefore center gating has not been considered possible for production of mold curves used to make precision optical lenses because of the inherent flow disturbances and sink mark aberrations occurring near the gate location, which in the case of the lens mold is an extremely critical area. Additionally, since the center gate must by necessity be on the non-critical side of the lens mold, the injection molding processing would be more difficult due to the reduced amount of polymer subjected to proper melt pressure. It has been found however that such problems can be overcome and that a lens mold within precise tolerances can be manufactured using center gate methodology. The use of center gating for delivering liquid polymer into a circular spherical mold cavity as herein described better ensures uniform filling of the cavity because of axisymmetric flow, which results in more uniform shrinkage and therefore improved physical properties of the resulting lens mold.
It is an object of this invention to provide a method and apparatus for the manufacture of precision lens molds suitable for use in the manufacture of contact lenses, the lens mold being manufactured by center gate processing methodology. It is a further object to provide such a method and apparatus for the manufacture of precision lens molds suitable for the manufacture of very thin contact lenses on the order of 50 microns in lens center thickness. It is a further object to provide a particularly defined mold core in combination with a particularly defined liquid polymer injection probe means to practice the method of the invention. It is a further object to provide such method and apparatus whereby both the front lens molds and back lens molds may be produced using center gated technology.
SUMMARY OF THE INVENTION
The invention is an apparatus and method of manufacturing lens molds for the production of optical contact lenses, the lens mold being center gated at the central axis, as well as the resulting lens molds formed by this process. The lens molds are manufactured of a thermoplastic material, which may be either crystalline or non-crystalline due to the axisymmetrical nature of the lens mold configuration. The lens mold has a circular perimeter formed by a flat annular flange which surrounds and extends from a spherical central portion having a convex side and a concave side. One side of each lens mold, the concave side for a front lens mold and the convex side for a back or base lens mold, is defined as the critical side and must pass extremely tight tolerance parameters. The lens molds are typically between approximately 0.8 to 1.0 mm thick, the molding cavity being formed by a mated core member and an insert member, the insert member forming the critical side of the part and being manufactured to extremely high tolerances of less than 1 micron. A center gate is located in the core member at the central axis of the mold cavity, the gate comprising a tubular conduit between approximately 0.8 to 1.2 mm in length and from approximately 0.5 to 1.2 mm in diameter, with a slight flaring of approximately 2 degrees, the diameter of the gate being slightly larger at the exit end adjacent the mold cavity than at the gate entrance. The edge at the juncture of the gate and the mold cavity is chamfered or radiused. The core member expands and enlarges backward in a conical, bell-shaped or flared manner beginning at the entrance of the gate to form a reserve area to receive any excess liquid polymer after the mold cavity has been filled and to provide space to receive the liquid polymer delivery means. The polymer delivery means is comprised of a polymer delivery probe or nozzle configured with a tapering nose, having a delivery conduit of between approximately 0.5 to 1.2 mm in diameter, and is positioned with its tip between approximately 0.5 to 1.3 mm from the entrance of the gate. The probe and insert member are composed of a material having high heat conductivity and the polymer dosing is performed using high precision injection molding equipment. The lens mold produced by the apparatus is extremely precise due to axisymmetrical flow and shrinkage, having measurable critical values with much smaller deviation than the deviation of similar values in lens molds produced with side gated technology.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 is a cross-sectional detail view of the critical area of the injection molding apparatus for production of a front lens mold.
FIG. 2 is a cross-sectional detail view of the critical area of the injection molding apparatus for production of a back lens mold.
FIG. 3 is a perspective view of a front lens mold.
FIG. 4 is a perspective view of a base lens mold.
FIG. 5 is a cross-sectional view of a contact lens as formed within the mold cavity created by combining a front lens mold and a base lens mold produced according to the invention.
DETAILED DESCRIPTION OF THE INVENTION
With reference now to the drawings, the invention will be described in detail with regard to the best mode and preferred embodiment. FIGS. 1 and 2 are details illustrating the critical portion of a melt delivery apparatus in the vicinity of the mold cavity, the melt delivery apparatus being a precision injection molding apparatus for delivering molten polymer into a mold cavity under heat and pressure for formation of a plastic part, in this case a lens mold for subsequent use in the manufacture of a contact lens.
FIG. 1 illustrates the apparatus for production of a front lens mold 30, shown in FIG. 3, under the methodology of the invention. The front lens mold 30 is configured as a partially spherical object with a concave side 31 and a convex side 32, defined in general as a portion of a sphere sliced by an imaginary plane to provide a generally circular perimeter. An annular, generally planar flange 33 surrounds and extends from the partial spherical portion around the circular perimeter. A mold cavity 11 is created by mating a front curve insert 12 and a core member 13 within separable mold block halves 98 and 99. The mold cavity 11 is configured as a portion of a sphere having a convex side 14 and a concave side 15, with a peripheral portion to form the annular flange 33 of the front lens mold 30 centered on the central axis. The front curve insert 12 is a precisely machined member fixed within the mold block back half 99 of the injection molding apparatus, the convex surface 14 of the front curve insert 12 forming the curved mold wall for the critical concave side 31 of the front lens mold 30 to be produced. The front curve insert 12 may be of the standard multi-part stacked assembly requiring one or more shims or bushings for proper alignment, but is preferably constructed as a unitary member precisely machined to provide correct alignment and positioning relative to the core member 13.
The core member 13 is a member fixedly inserted within the mold block front half 98 of the injection molding apparatus. The forward concave surface 15 of the core member 13 forms the curved mold wall for the non-critical side 32 of the mold cavity 11. Coaxially positioned on the central axis of the spherical concave surface 15 is center gate 16, generally circular in cross-section, which comprises a gate exit 51 having a radiused or chamfered edge 52 along the juncture between the gate 16 and the concave surface 15 of the mold cavity 15, a slightly tapered channel 53 and a gate entrance 54 for receiving the liquid polymer, the channel 53 increasing in diameter at the rate of approximately 2 degrees from the gate entrance 54 to the gate exit 5 . Preceding the entrance 54 of the center gate 16 is a polymer receiving reservoir 17 formed by a conical wall 18 which adjoins the entrance 54. Conical wall 18 is preferably formed at an angle of approximately 45 degrees to the central axis. The polymer receiving reservoir 17 is constructed to receive excess liquid polymer when the center gate 16 and the mold cavity 11 are completely filled during the injection step, and also provides the access means for positioning of the polymer injection probe or nozzle 20 which delivers the liquid polymer under heat and pressure to the center gate 16 and the mold cavity 11. The injection probe 20 has a tapered nose 21 having a conical wall 22 and ending in a probe tip 23 containing a cylindrical delivery conduit 24. The probe wall 22 and the polymer reservoir wall 18 are substantially parallel or increasingly separated in the direction away from the center gate 16 in order to create a nonrestricting flow channel for the excess polymer. Preferably, for a polymer reservoir wall 18 at 45 degrees to the central axis, the probe wall 22 is configured at a 30 degree angle off the central axis. The probe 20 is connected to the general liquid polymer delivery means of the injection molding apparatus. The probe 20 and front curve insert 12 are composed of high strength, high heat conductivity materials, such as nickel coated brass or stainless steel.
The dimensions of the various components are critical, as is the relationship between the dimensions of the components for a given choice of variables related to the choice of polymer material, polymer processing and flow characteristics, and lens mold size and thickness, to insure production of precision lens molds meeting desired tolerances. For the formation of a front lens mold approximately 1.0 mm in thickness, the internal diameter of the center gate 16 should be between approximately 0.6 to 1.2 mm, with a preferred diameter of approximately 0.75 mm, and the axial length of the channel 53 should be between approximately 0.8 to 1.2 mm, with a preferred length of approximately 1.0 mm. Increasing the center gate 16 diameter to greater than 1.2 mm results in unacceptable enlargement of the sink mark depression on the critical side 31 of the front lens mold 30. Decreasing the diameter of the center gate 16 reduces the sink mark depression, but the diameter must be kept greater than approximately 0.6 mm to insure sufficient flow volume to completely fill the mold cavity 15. The internal diameter of the delivery conduit 24 of the probe 20 should be generally equal to or greater than the diameter of the entrance 54 of the center gate 16. For a center gate 16 diameter of 0.75 mm, the internal diameter of the delivery conduit 24 is preferably 1.0 mm. The distance between the probe tip 23 and the entrance 54 of the center gate 16 is very critical to insure proper flow into the mold cavity 16, the precise distance being dictated by the dimensions of the center gate and the polymer flow characteristics. The distance from probe tip 23 to center gate entrance 54 is between approximately 0.8 to 1.3 mm, and is preferably approximately 1.06 mm in the heated state for the front lens mold.
For production of the base lens mold 40 as shown in FIG. 4, the overall apparatus is very similar to that described above, with the required change in the configuration of the mold cavity 15 as shown in FIG. 2, such that the polymer flow direction is reversed within the mold cavity 15 instead of being a continually forward flow as in the mold cavity 15 for the front lens mold 30. Like the front lens mold 30, the back lens mold 40 has a convex side 41, a concave side 42 and an annular flange 43. Here the back curve insert 19 member has a concave surface 25 which becomes the mold wall for the critical convex side 41 of the base curve mold 40. The core member 13 is now configured such that the cavity end has a convex surface 26 to form the non-critical concave side 42 of the base lens mold 40. The mold cavity 15 for a base lens mold 40 is typically approximately 0.8 mm in thickness. The dimensions and spatial relationship for the center gate 16 and probe 20 are adjusted due to the reverse flow required to fill the mold cavity 15 of the base lens mold 40. The center gate 16 diameter is smaller, being between approximately 0.5 to 1.0 mm, and preferably approximately 0.6 mm. Preferably, the internal wall 18 of the polymer receiving reservoir 17 is radiused rather than planar, and the conical wall 22 of the injection probe 20 is narrower, angled at approximately 22.5 degrees off the central axis. The delivery conduit 24 is also smaller, being sized at approximately 0.8 mm for a 0.6 mm center gate 16. The distance between the probe tip 23 and the center gate entrance 54 is between approximately 0.5 to 1.0 mm, and preferably approximately 0.72 mm in the heated state.
To fabricate the center gated lens molds 30 or 40, the injection molding apparatus is assembled with the components set forth above. Processing parameters are determined by the particular characteristics of the polymer being utilized. For polystyrene, a polymer commonly used in the formation of lens molds, the probe 20 is heated to approximately 570 degrees F and the core member 13 and curve insert 12 or 19 is heated to approximately 150 degrees F. For injection and fill of the liquid polymer, peak pressure is preferably approximately 18,000 psi and hold pressure is maintained at approximately 6,000 psi. Cure time is between approximately 6 and 10 seconds. Because of the axisymmetrical flow from the center gate 16 into the mold cavity 11, it is now possible to use crystalline polymers, such as polypropylene, for production of the lens molds. Polypropylene is not suitable for use with side gated technology because its highly directional shrinkage results in unacceptable variations in the finished product. For polypropylene, the temperatures are slightly lower--the probe 20 being maintained at approximately 420 degrees F and the core member 13 and curve insert 12 or 19 being maintained at approximately 130 degrees F. The polymer is dosed in a predetermined volume to insure complete fill of the mold cavity 15, with excess polymer flowing into the receiving recess 17.
The resulting front lens mold 30 and base lens mold 40 produced by this methodology are shown in FIGS. 3, 4 and 5. The lens molds 30 and 40 separate from the waste material adjacent the entrance 54 of the center gate 16, such that a sprue 61 of cured polymer extends from the non-critical sides 32 and 42 of each of the front lens mold 30 and base lens mold 40. Because the molding of the contact lens 90 occurs between the critical sides 31 and 41, the sprues 61 do not interfere. Since production of contact lenses with center of lens thicknesses in the range of 50 microns requires tolerances at most of +/-5 microns, there are a number of critical areas on the lens molds 30 and 40 which must be maintained within precise parameters. Of particular importance are the surface and edge characteristics of the critical sides 31 and 41. Application of the methodology set forth above produces lens molds 30 and 40 with thickness variations less than 1 micron in magnitude at the centrally located sink mark site, and the use of the center gate 16 produces uniform axisymmetrical fill in all radial directions, resulting in an improved knife edge 62 at the junction between the front lens mold 30 and the base lens mold 40. Variation in knife edge measurements for side gated front lens molds typically range up to 25 microns, whereas variations in knife edge measurements for center gated front lens molds are less than 2 microns. Mean peak to valley measurements, performed on a Zygo interferometer, can typically range up to 3 wave for side gated lens molds, while mean peak to valley values for center gated lens molds are less than 1 wave. The center Bated methodology produces front lens molds having variation in sagittal depth of only plus or minus 3 microns.
To manufacture a contact lens 90 with a center of lens thickness on the order of 50 microns, a front lens mold 30 and a base lens mold 40 are produced according to the process set out above. Preferably, the apparatus is constructed such that multiple lens molds are produced simultaneously. The front lens mold 30 is then placed in a holding fixture and dosed with a UV-polymerizable polymer of a type well-known in the art. The base lens mold 40 is then combined with the front lens mold 30 as shown in FIG. 5 to create the mold cavity of correct shape. Pressure is applied to the base lens mold 40 to properly seat and maintain it in correct alignment with front lens mold 30, and the liquid polymer is exposed to UV energy to cure the polymer. After curing, the mold cavity is opened and the cured polymer contact lens 90 is removed for subsequent processing.
It is contemplated that substitutions and equivalents for components or steps set forth above may be apparent to those skilled in the art, and therefore the true scope and definition of the invention is to be as set forth in the following claims.
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A method and apparatus for the manufacture of lens molds used in the formation of optical contact lenses, the apparatus including a center gate aligned on the central axis of the lens mold cavity for delivery of the melt polymer in an axisymmetrical manner. The methodology produces lens molds of extremely precise dimensions as measured against lens molds produced with side gated technology.
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BACKGROUND OF THE INVENTION
1. Field of the Invention
This invention relates to a method of reducing gastric secretion or ulcer formation and more particularly, to reducing such secretion or formation in mammals, including humans, with a substituted N-aminoalkylpyrrole.
2. Discussion of the Prior Art
It is known in the art that 2-substituted-indole-lower alkanecarboxamides have anti-secretory or anti-ulcer activity, as reported in U.S. Pat. Nos. 4,021,448 and 4,069,337. U.S. Pat. No. 3,997,557 reveals substituted N-aminoalkylpyrroles, of the subject invention, which are disclosed as having antiarrhythmic, central nervous system depressant, antiinflammatory and antihypertensive activity. No literature has been found that discloses or suggests the use of such substituted N-aminoalkylpyrroles as anti-secretory or anti-ulcer agents.
SUMMARY OF THE INVENTION
This invention relates to a method of reducing gastric secretion or ulcer formation and more particularly, to reducing such secretion or formation in mammals with a substituted N-aminoalkylpyrrole.
The method comprises administering to a mammal an effective anti-secretory amount or an effective anti-ulcer amount of a substituted N-aminoalkylpyrrole having the formula ##STR1## wherein Z is a straight or branched saturated or olefinically unsaturated hydrocarbon chain of from 2 to 5 carbon atoms; R 1 is hydrogen or alkyl of from 1 to 3 carbon atoms; R 2 is alkyl of from 1 to 3 carbon atoms or phenyl; or R 1 and R 2 together with the nitrogen atom to which they are attached form a heterocyclic selected from the group consisting of pyrrolidinyl, piperidino, piperazinyl, imidazolidonyl and morpholino; R 3 is hydrogen or phenyl or substituted phenyl; R 4 is alkyl of from 1 to 6 carbon atoms, alkoxy of from 1 to 4 carbon atoms, halogen, trifluoromethyl, hydroxy, nitro, cyano, amino, acetamido, phenyl or substituted phenyl; n is an integer from 0 to 3, inclusive; X is alkylene of from 3 to 7 carbon atoms; and R 5 is hydrogen, alkyl of from 1 to 5 carbon atoms, alkoxy of from 1 to 2 carbon atoms or halogen; or a physiological tolerable acid addition salt thereof.
DETAILED DESCRIPTION
This invention relates to a method of treatment with substituted N-aminoalkylpyrroles having useful anti-secretory and anti-ulcer activities and having the formula ##STR2## wherein Z represents a straight or branched, saturated or olefinically unsaturated hydrocarbon chain of 2-5 carbon atoms; R 1 represents a hydrogen atom or loweralkyl of from 1-3 carbon atoms; R 2 represents loweralkyl of from 1-3 carbon atoms or phenyl; or R 1 and R 2 together with the nitrogen atom to which they are attached form a heterocycle selected from the group consisting of pyrrolidinyl, piperidino, piperazinyl, imidazolidonyl and morpholino; R 3 represents a hydrogen atom, phenyl or substituted phenyl; R 4 can be situated meta, ortho or para and represents alkyl of from 1-6 carbon atoms, alkoxy of from 1-4 carbon atoms, halogen, trifluoromethyl, hydroxy, nitro, amino, cyano, acetamido, unsubstituted or substituted phenyl; n is the integer 0, 1, 2 or 3; and X is alkylene of from 3-7 carbon atoms, ##STR3## and R 5 is hydrogen, alkyl of from 1-5 carbon atoms, alkoxy of from 1-2 carbon atoms, or halogen; and their physiologically tolerable acid addition salts. The above compounds and their preparation are fully described in U.S. Pat. No. 3,997,557 which is incorporated by reference hereinto. Some typical compounds include:
1-(2-dimethylaminoethyl)-2-phenyl-4,5,6,7-tetrahydroindole;
1-[2-(1-imidazolidonylethyl)]-2-phenyl-4,5,6,7-tetrahydroindole;
1-(2-dimethylaminoethyl)-2-(p-methoxyphenyl)-4,5,6,7-tetrahydroindole;
1-(3-dimethylaminopropyl)-2-(p-methoxyphenyl)-4,5,6,7-tetrahydroindole;
2-(p-bromophenyl)-1-(3-dimethylaminopropyl)-4,5,6,7-tetrahydroindole;
2-(p-bromophenyl)-1-[2-(1-morpholinoethyl)]-4,5,6,7-tetrahydroindole;
1-(2-methylaminoethyl)-2-(m-trifluoroethylphenyl)-4,5,6,7-tetrahydroindole;
1-(3-dimethylaminopropyl)-2-(p-chlorophenyl)-4,5,6,7-tetrahydroindole;
1-(2-isopropylaminopropyl)-2-(p-chlorophenyl)-4,5,6,7-tetrahydroindole;
2-(p-hydroxyphenyl-1-(2-isopropylaminoethyl)-4,5,6,7-tetrahydroindole;
1-(2-diisopropylaminoethyl)-2-(p-hydroxyphenyl)-4,5,6,7-tetrahydroindole;
1-(2-diethylaminoethyl)-2-phenyl-5-methyl-4,5,6,7-tetrahydroindole;
1-(2-diethylaminoethyl)-2-phenyl-5-(t-butyl)-4,5,6,7-tetrahydroindole;
1-(2-diethylaminoethyl)-2-phenyl-5-methoxy-4,5,6,7-tetrahydroindole;
1-(2-isopropylaminoethyl)-2-(3,4-dichlorophenyl)-4,5,6,7-tetrahydroindole;
1-(3-dimethylaminopropyl)-2,3-diphenyl-4,5,6,7-tetrahydroindole;
1-[3-(1-pyrrolidinopropyl)]-2-(p-fluorophenyl)-4,5,6,7-tetrahydroindole;
1-(3-dimethylaminopropyl)-2-phenyl-4,5-dihydrobenz[g]indole;
1-(3-dimethylaminopropyl)-2-phenyl-4,5-dihydrobenz[e]indole;
1-(3-diethylaminopropyl)-4,5-dihydro-2-phenylbenz[e]indole;
1-(3-methylaminopropyl)-2-phenyl-7-chloro-4,5-dihydrobenz[e]indole;
1-(3-methylaminopropyl)-2-phenyl-1,4,5,6-tetrahydrocyclopenta[b]pyrrole;
1-(2-methylaminoethyl)-2-(m-trifluoromethylphenyl)-1,4,5,6,7,8-hexahydrocyclohepta[b]pyrrole;
1-(3-dimethylaminopropyl)-2-(p-methoxyphenyl)-1,4,5,6,7,8-hexahydrocyclohepta[be]pyrrole;
1-(3-methylaminopropyl)-2-(p-methoxyphenyl)-1,4,5,6,7,8-hexahydrocyclohepta[be]pyrrole;
1-(3-dimethylaminopropyl)-2-(p-bromophenyl)-1,4,5,6,7,8-hexahydrocyclohepta[b]pyrrole;
1-(3-dimethylaminopropyl)-2-(p-cyanophenyl)-1,4,5,6,7,8-hexahydrocyclohepta[b]pyrrole;
1-(3-dimethylaminopropyl)-2-(p-nitrophenyl)-1,4,5,6,7,8-hexahydrocyclohepta[b]pyrrole;
1-(3-dimethylaminopropyl)-2-(p-aminophenyl)-1,4,5,6,7,8-hexahydrocyclohepta[b]pyrrole;
1-(3-dimethylaminopropyl)-2-(3,4,5-trimethoxyphenyl)-1,4,5,6,7,8-hexahydrocyclohepta[b]pyrrole;
1-(3-dimethylaminopropyl)-2-(p-fluorophenyl)-1,4,5,6,7,8-hexahydrocyclohepta[b]pyrrole;
1-(3-dimethylaminopropyl)-2-phenyl-4,5,6,7,8,9-hexahydrocycloocta[b]pyrrole;
1-(2-ethylaminoethyl)-2-phenyl-4,5,6,7,8,9-hexahydrocycloocta[b]pyrrole;
1-(3-dimethylaminopropyl)-2-(p-nitrophenyl)-4,5,6,7,8,9-hexahydrocycloocta[b]pyrrole;
1-(3-dimethylaminopropyl)-2-(p-aminophenyl)-4,5,6,7,8,9-hexahydrocycloocta[b]pyrrole;
1-(3-dimethylaminopropyl)-2-(p-fluorophenyl)-4,5,6,7,8,9-hexahydrocycloocta[b]pyrrole;
1-(3-dimethylaminopropyl)-2-(p-methoxyphenyl)-4,5,6,7,8,9-hexahydroocta[b]pyrrole;
1-(3-methylaminopropyl)-2-phenyl-4,5,6,7-tetrahydrodinole;
2-(p-bromophenyl)-1-(3-dimethylaminopropyl)-1,4,5,6,7,8-hexahydrocyclohepta[b]pyrrole;
2-(p-cyanophenyl)-1-(3-dimethylaminopropyl)-1,4,5,6,7,8-hexahydrocyclohepta[b]pyrrole;
1-(3-methylaminopropyl)-2-phenyl-7-chloro-4,5-dihydrobenz-[e]indole;
1-(3-diethylaminopropyl)-2-(p-methoxyphenyl)-4,5,6,7,8,9-hexahydrocycloocta[b]pyrrole;
1-(4-diethylamino-2-butenyl)-2-phenyl-4,5,6,7-tetrahydroindole hydrochloride;
1-(3-dimethylaminopropyl)-2-phenyl-1,4,5,6-tetrahydrocyclopenta[b]pyrrole;
1-(2-methylaminoethyl)-2-phenyl-1,4,5,6,7,8-hexahydrocyclohepta[b]pyrrole;
1-(3-diethylaminopropyl)-2-phenyl-1,4,5,6,7,8-hexahydrocyclohepta[b]pyrrole;
1-(3-diethylaminopropyl)-2-phenyl-1,4,5,6,7,8-hexahydrocyclohepta[b]pyrrole; and
1-(1-methyl-2-dimethylaminoethyl)-2-phenyl-1,4,5,6,7,8-hexahydrocyclohepta[b]pyrrole; and the physiologically acceptable salts of the above compounds.
These compounds are prepared as described in U.S. Pat. No. 3,997,557. Most advantageously, the compounds of the present invention are prepared by condensation of an appropriate γ-diketone with an appropriate aminoalkylamine or aminoalkyleneamine as illustrated in the following equation: ##STR4## wherein X, Z, n, R 1 , R 2 and R 4 are as defined earlier. In one procedure, the γ-diketone and the aminoalkylamine are allowed to react, with or without a solvent such as acetic acid or ethanol, at a temperature between 50°-120° C., for a period of time from several minutes to 24 hours in the presence or absence of an acidic catalyst such as hydrochloric acid.
When R 4 represents NO 2 , the nitro can be reduced by methods known to the art such as by shaking a solution of the corresponding compound of the invention in glacial acetic acid on the Parr Hydrogenator with a Pd on carbon catalyst. Also, when R 4 represents Br, the bromo can be displaced with a cyano group by methods known to the art such as by reacting with cuprous cyanide.
The anti-secretory activity and the anti-ulcer activity of the substituted N-alkylaminopyrroles of this invention can be demonstrated using conventional, standard biological test procedures, such as those described in U.S. Pat. No. 4,021,448 and 4,069,337. In particular, the procedure of Shay et al. Gastroenterology 5, 43 (1945) may be employed to determine anti-secretory activity. The anti-ulcer activity of the substituted N-alkylaminopyrroles can be determined using the method described by Selmici et al. Acta. Physiol. Acad. Sci. Hung. 25(1), 101-104 (1964).
It is of course understood that the actual determination of the biological data definitive for any particular compound of the invention is readily determined by standard test procedures by technicians versed in pharmacological test procedures without an undue amount of experimentation.
The substituted N-alkylaminopyrroles are administered in an effective amount sufficient to inhibit in mammals, secretion of gastric fluids and/or to inhibit stomach ulceration, typically in an amount of from 10 mg/kg of body weight per day to 200 mg/kg of body weight per day. The compounds are preferably administered orally.
The substituted N-alkylaminopyrrole compounds can be prepared for use by incorporation in unit dosage form as tablets or capsules for oral administration to patients or animals either alone or in combination with suitable adjuvants such as calcium carbonate, starch, lactose, sodium bicarbonate, sodum lauryl sulfate, sugar, dextrose, mannitol, cellulose, gum acacia and the like. Alternatively, they can be formulated for oral administration in aqueous alcohol, glycol or oil solutions or oil-water emulsions in the same manner as conventional medicinal substances are prepared. They can also be formulated for oral use with foodstuffs or admixed with foodstuffs for veterinary use.
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This invention relates to a method of reducing gastric secretion or ulcer formation and more particularly, to reducing such secretion or formation in mammals with a substituted N-aminoalkylpyrrole.
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This application is a continuation of International Application No. PCT/EP00/10643, filed on Oct. 28, 2000.
BACKGROUND OF THE INVENTION
1. Field of the Invention
The invention relates to an adjusting armature for the back rest of vehicle seats, in particular, of motor vehicles seats, wherein the back rest, which is optionally adjustable about a first axis of rotation in an inclined position and lockable in the adjusted inclined position by means of an adjusting device, can be folded forwardly and backwardly about a second external axis of rotation, positioned at a distance from the first axis of rotation, and is secured in its folded-back position on a locking bolt receptacle, stationarily arranged on the seat, by means of a locking bolt, engaging releasably the locking bolt receptacle and axially moveably arranged on a rotary bracket pivoting with the back rest and spring-loaded in the locking direction, and is supported by means of a stop receptacle on a stop bolt stationarily arranged on the seat.
2. Description of the Related Art
A similar device is disclosed in European patent application 0 937 603 A1. In this document an adjusting armature for the back rests of motor vehicle seats is described in which, on the one hand, the back rest is adjustable with regard to its incline about an axis and, on the other hand, is foldable about another axis. Locking is possible in the upright position of the back rest by means of a pin that is spring-loaded or receives a conical end which engages in a springy fashion a corresponding receptacle. A play-free arrangement is not ensured in all directions.
In an adjusting armature of the aforementioned kind of the present assignee, described in the German patent application 199 18 737.1-16, the armature component, which effects the adjustment and locking of the inclined back rest position and has a first axis of rotation, is arranged adjacent to a further armature component having a second axis of rotation. In order to transfer the back rest into a forwardly folded position which provides a table function, the second axis of rotation is arranged at a spacing above the first axis of rotation. For this purpose, generally on the frame of the seat part or on a locking plate fixedly connected thereto, an armature part of the armature component, which enables the inclination of the back rest in a position of use for the user of the seat, is secured detachably by means of a stop bolt and a locking bolt that is axially moveable in the locking direction and loaded by a force storing device.
Moreover, a bearing bracket of the second armature component is fixedly connected with the frame of the seat part or the locking plate and extends upwardly and past the first axis of rotation. This bearing bracket at its upper area is connected by means of an axle bolt with a rotary bracket to form a joint which provides the second axis of rotation of the adjusting armature. The rotary bracket is connected to the armature part that is detachably secured with the stop bolt and the locking bolt on the seat part and is pivotable therewith. As a result of the second axis of rotation being positioned higher, the back rest can be placed above the upholstery of the seat part in a table function position such that the backside of the back rest forms a horizontal plane without the upholstery of the back rest and of the seat part counteracting this. For securing this table function position, a pneumatic spring is arranged between the axis of rotation and the bearing bracket.
In this known solution, the axially movable locking bolt has a circular cross-section and engages in the locking situation a matching bore which, however must be slightly greater than the diameter of the locking bolt because of unavoidable tolerances. As a result of this unavoidable play, rattling cannot be prevented when the vehicle drives on bumpy roads.
SUMMARY OF THE INVENTION
It is an object of the invention to improve an adjusting armature of the aforementioned kind such that a securing or bracing is possible that eliminates play of the rotary bracket relative to the locking plate.
In accordance with the present invention, this is achieved in that the axially movable locking bolt has a guide section and a locking section and is subjected on its guide section, in addition to its axial guiding, also to a controlled rotational movement, based on which a radially changing support curve provided on the locking section can be supported on a planar support surface of the locking bolt receptacle so as to eliminate play.
By superimposing on the axially movable locking bolt a rotary movement such that its locking section with the adjustable radially changing support curve automatically readjust on a planar support surface of the locking bolt receptacle as a result of the spring loading action, a bracing that eliminates play is obtained in the locking situations so that the adjusting armature is free of rattling noises independent of its unavoidable tolerances.
For forming the radially changing support curve in connection with a support surface contacting it, the locking section of the annular pin has a periphery as follows: a first partial peripheral area extends about approximately 180° with a constant radius and is adjoined by a peripheral area of approximately 90° in which the support curve extends which, starting with the constant radius of the first partial peripheral area, has a continuously decreasing radial spacing from the center of the locking bolt, and then has a transition into at least one planar area which then adjoins finally the aforementioned first partial peripheral area with the constant radius. The locking bolt receptacle has, in addition to a circular circumferential area, a support surface which can be brought into contact with the support curve.
The support curve which has a continuously decreasing radial spacing from the center of the locking bolt can be designed as a logarithmic spiral with which the manufacturing tolerances and play can be compensated which do not reach the adjusting range resulting from the support curve and which are within the tolerances.
According to one embodiment of the invention, for axially guiding the locking bolt and providing a superimposed rotary movement derived from this axial movement, the guide section of the locking bolt is arranged axially slidably in a bushing secured on the rotary bracket and engages with at least one sliding block at least one sliding gate extending spirally in the bushing like a thread. In this connection, the bushing is advantageously surrounded by a trigger sleeve which has at least one guide groove ascending in the axial direction and whose slant or gradient is greater than the slant of the thread-like sliding gate of the bushing. The sliding gate is engaged by the sliding block which penetrates it and engages the guide groove of the trigger sleeve.
In order to prevent a malfunction which could possibly occur as a result of canting, according to a further embodiment of the invention the sliding gate as well as the guide groove are positioned on two locations of the bushing and the trigger sleeve which are diametrically opposite one another, wherein the sliding block is comprised of two guide pins which are arranged on the guide section of the locking bolt, penetrate through the sliding gate, and project into the guide groove. Moreover, an actuation device which is located remote from the locking mechanism for releasing the locking bolt can be realized in that the trigger sleeve has a connecting finger provided for attaching a pulling means thereto, such as a Bowden cable, for introducing a rotary movement into the trigger sleeve.
Since in the inactive position of the trigger sleeve the locking bolt projects from the bushing as a result of spring loading of the locking bolt in the locking direction, it is advantageous for the return movement of the back rest from its forwardly folded position when a guide rail is provided on the seat which projects into the pivot path of the locking bolt and has a slanted surface. This ensures that in the inactive state of the trigger sleeve the return pivot movement can be performed to such an extent until the locking bolt is able to drop into the locking bolt receptacle provided on the seat part.
Even though it is conceivable to arrange the guide rail and the locking bolt receptacle directly on the frame of the seat part, it may be advantageous for manufacturing-technological reasons when the bearing bracket together with the locking plate that is provided with the locking bolt receptacle as well as the guide rail is fixedly connected with the seat part.
In order for a safe correlation of the locking bolt to the locking bolt receptacle to be possible at the end of the return folding movement, on the one hand, and to provide a 3-point bracing of the rotary bracket relative to the seat part, on the other hand, the locking plate advantageously has underneath its locking bolt receptacle a stop for the rotary bracket and an armature part that is connected to the rotary bracket and comprises the first axis of rotation.
BRIEF DESCRIPTION OF THE DRAWING
In the drawing:
FIG. 1A shows a seat in a schematic side view, comprising an adjusting armature according to the invention arranged between the seat part and the back rest, wherein the back rest is in a position of use for the user of the seat;
FIG. 1B shows the seat illustrated in FIG. 1A in a schematic side view wherein the back rest has been pivoted forwardly into a table position;
FIG. 2 shows the adjusting armature according to the invention in a perspective view at an angle from behind;
FIG. 3 shows the adjusting armature, also in a perspective view analog to FIG. 2, in which however the bearing bracket and the trigger sleeve have been removed;
FIG. 4 shows the adjusting armature of FIG. 2 in a side view onto its exterior side;
FIG. 5 shows the adjusting armature shown in FIG. 4 in an end view;
FIG. 6 shows the adjusting armature of FIG. 4 in a section according to section line VI—VI of FIG. 4;
FIG. 7 shows the adjusting armature according to FIG. 4 in a side view onto its inner side;
FIG. 8A shows in section the area of the adjusting armature receiving a locking bolt, the adjusting armature in the position illustrated in FIG. 1A wherein, however, the locking bolt is illustrated in its release position;
FIG. 8B shows the locking area of the adjusting armature illustrated in FIG. 8A in a broken-away view onto the inner side;
FIG. 9A shows the sectional view illustrated in FIG. 8A of the locking area in which the locking bolt is shown in a position in which it has dropped into the locking bolt receptacle;
FIG. 9B shows the locking area illustrated in FIG. 9A in a broken-away view onto the inner side of the adjusting armature;
FIG. 10A shows the locking area of the adjusting armature illustrated in FIG. 8A in section, wherein the locking bolt has been positioned so far into the locking bolt receptacle that play in the system is eliminated;
FIG. 10B shows the locking bolt illustrated in FIG. 10A in the locking bolt receptacle in a broken-away side view of the adjusting armature;
FIG. 11A shows the locking area illustrated in section in analogy to FIG. 10A, wherein the locking bolt is in a rotary position which compensates tolerances and is play-free;
FIG. 11 b shows the locking bolt illustrated in FIG. 11A in a broken-away side view onto the inner side of the adjusting armature;
FIG. 12 shows the locking bolt of FIG. 10B in an enlarged representation relative to FIG. 10B, wherein the locking bolt is arranged in the locking bolt receptacle in a play-eliminating position.
DESCRIPTION OF THE PREFERRED EMBODIMENTS
FIG. 1A shows a vehicle seat with a seat part 10 and a back rest 11 wherein the back rest 11 , fastened on the seat part 10 by means of the adjusting armature 12 , is positioned at such an incline that a user can be seated in the seat. In this connection, on the seat frame of the seat part 10 the adjusting armature 12 comprised of two armature components 13 and 14 is fastened on each longitudinal side of the seat. With the adjusting armature component 13 the incline of the back rest 11 relative to the seat part can be adjusted and secured, for which purpose, for example, a so-called planetary armature can be used which comprises a simple planetary gear and whose armature part connected with the back rest 11 is pivoted about a first axis of rotation 15 in a self-locking way.
This first armature component 13 arranged on both longitudinal sides of the seat has arranged adjacent thereto a second armature component 14 which has a bearing bracket 16 secured on the frame of the seat part 10 and a rotary bracket 17 pivotably connected thereto by a joint 18 . The lower part of the rotary bracket 17 is bent and fixedly connected to the armature part 19 , correlated with the seat part 10 , of the armature component 13 of the seat part 10 .
In the position of use of the seat by a user, the armature part 19 and the rotary bracket 17 are connected by means of a stop receptacle 20 in connection with a stop bolt of a locking plate 22 and a locking bolt 21 releasably engaging it. The locking plate 22 , in turn, is fixedly connected together with the recessed fastening area 23 of the bearing bracket 16 with, for example, the frame of the seat part 10 . The joint 18 which connects the bearing bracket 16 and the rotary bracket 17 with one another has an external second axis of rotation 24 of the armature component 14 about which the rotary bracket 17 , together with the first armature component 13 remaining in its adjusted position, is pivoted together with the back rest 11 such that it can be transferred into a table function position as illustrated in FIG. 1 B.
In the adjusting armature illustrated in FIGS. 1 through 5, the second external rotary axis 24 in the position of use of the seat illustrated in FIG. 1A is located at a spacing above the first axis of rotation 15 of the armature component 13 , wherein this spacing is selected such that, upon movement of the back rest 11 into the table position illustrated in FIG. 1B, the upholstery of the seat part 10 and the back rest 11 will not have a negative effect on the table function position.
For arresting the back rest in a position of use in which a user can sit in the seat, the rotary bracket 17 fixedly connected to the armature part 19 and the armature part 19 have a stop receptacle 20 on one side with which a stop bolt 25 secured on the locking plate 22 can be partially engaged. On the side opposite the stop receptacle, a bushing 26 is fixedly connected on the rotary bracket 17 and the armature part 19 connected thereto. The guide section 28 of the locking bolt 21 is axially moveably supported within the bushing 26 . A locking section 29 of the locking bolt 21 adjoins the guide section 28 and can engage a locking bolt receptacle 30 of the locking plate 22 . The guide section 28 of the locking bolt 21 has a hollow cylindrical recess 31 which is provided for receiving a pressure spring 32 . This pressure spring 32 is supported with one end on the bottom of the bushing 26 and loads the locking bolt 21 in the locking direction.
As illustrated in FIGS. 7, 8 B- 11 B and most clearly in FIG. 12, the periphery of the locking section 29 on the locking bolt 21 has a constant radius about a partial area 33 of approximately 180° which is adjoined by a circumferential area 34 of approximately 90° in which a support curve 35 extends which, starting with the constant radius, has a continuously decreasing radial spacing from the center 36 of the locking bolt 21 and has a transition into at least one planar area 37 .
The support curve 35 is advantageously formed as a logarithmic spiral while the planar area 37 is comprised of two planar roof-shaped partial planes 38 and 39 abutting one another. The locking section 29 of the locking bolt 21 in the locking situation is surrounded by a locking bolt receptacle 30 which about a further circumferential area has a greater diameter than the diameter of the locking bolt 21 . This wide circular circumferential area of the locking bolt receptacle 30 is interrupted by a support surface 40 which extends as slanted plane whose normal extends at an angle of 90° at a slant to the front side of the seat part 10 and in a downward direction.
In order to enable a play-free bracing of the armature component 14 relative to the seat part 10 , a readjustment of the support curve as a result of the rotation of the locking section 29 of the locking bolt 21 relative to the support surface 40 on the locking plate 22 is required. For this reason, the bushing 26 in the illustrated embodiment has two diametrically oppositely extending thread-like (spiral) sliding gates 41 , which can be seen most clearly in FIGS. 3, 10 A and 11 A. The sliding gate 41 is formed by thread-like slots in the cylinder mantle area of the bushing 26 . Guide pins 43 functioning as a sliding block 42 engage this sliding gate 41 and project past it outwardly, as is clearly illustrated in FIG. 3 and FIG. 9 A.
The bushing 26 is engaged by a trigger sleeve 44 which also has guide grooves 45 ascending also in the axial direction. The guide pins 43 projecting from the sleeve 26 engage the guide grooves 45 . In order to ensure that, during a rotational movement of the trigger sleeve 44 , it rests always against the rotary bracket 17 as a result of the action of the pressure spring 32 , the guide grooves 45 also have an ascending course whose slant is however substantially greater than the slant of the slots of the bushing 26 forming the sliding gate 41 . The trigger sleeve 44 has at its circumference a connecting finger 47 which can be the point of contact for a pulling member, for example, in the form of a Bowden cable.
In order to automatically push back the locking section 29 of the locking bolt 21 projecting from the bushing 26 and the armature part 19 upon return movement of the back rest 11 without actuating the trigger sleeve 44 , the locking plate 22 has a guide rail 48 which projects into the pivot path of the locking bolt 21 and has at its side facing the armature part 19 a slanted surface 49 by which the locking bolt 21 in the last phase of the return movement is forced into the bushing 26 against the force of the pressure spring 32 . When the armature component 14 is returned in the locked position, a stop 50 is provided below the locking bolt 21 on the locking plate 22 against which stop the underside of the rotary bracket 17 and the armature part 19 rest. This stop 50 as well as the stop bolt 25 in the locking situation receive counter forces of the locking force exerted by the locking section 29 of the locking bolt 21 ; this is illustrated in FIG. 7 by the arrows. This results in a safe play-free 3-point support in the locking situation.
For explaining the locking function, FIGS. 8A and 8B will be used as a starting point. Here it is shown that the locking bolt 21 is retracted completely into the bushing 26 against the force of the pressure spring 32 loading it so that its end face does not project past the outer side of the armature part 19 . The locking bolt 21 is transferred by the trigger sleeve 44 into this position. This unlocking or release position can be seen in FIGS. 8A and 8B.
When the trigger sleeve 44 is now released, by means of the pressure spring 32 the locking bolt 21 is moved into the position illustrated in FIGS. 9A and 9B where it has dropped into the locking bolt receptacle 30 of the locking plate 22 . In this connection, the locking bolt 21 has been rotated by means of its guide pins 43 with the sliding gate 41 into the position illustrated in FIG. 9B; however, in this position there is still play all-around between the locking section 29 of the locking bolt 21 and the locking bolt receptacle 30 as can be seen, in particular, in FIG. 9 B. Since however the pressure spring 32 still exerts its pressure force and moves the locking bolt 21 farther axially, it rotates accordingly in a clockwise direction because of the sliding gate 41 and the guide pins 43 engaging therein so that finally the support curve 35 will rest against the support surface 40 of the locking bolt receptacle 30 , as illustrated in FIG. 10 B. In this position a tensioned locking action of the armature component 14 on the locking plate 22 connected to the seat frame results.
The tensioned position (bracing position) shown in the preceding FIGS. 10A and 10B is also present in FIGS. 11A and 11B in which, however, as a result of a different tolerance position of the locking bolt receptacle 30 relative to the position shown in FIG. 10B, locking bolt 21 has been moved farther.
As mentioned above, the illustrated and described configuration of the present invention is to be viewed only as an exemplary embodiment.
While specific embodiments of the invention have been shown and described in detail to illustrate the inventive principles, it will be understood that the invention may be embodied otherwise without departing from such principles.
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An adjusting armature for a back rest of a vehicle seat, wherein the back rest is incline-adjustable about a first axis and can fold relative to the seat part about a second axis, has a rotary bracket connected to the back rest for pivoting with the back rest. A locking bolt receptacle is stationarily arranged on the seat part and has a planar support surface. A locking bolt is axially moveably arranged on the rotary bracket and spring-loaded in a locking direction for engaging releasably the locking bolt receptacle. A stop bolt is stationarily arranged on the seat part and cooperates with a stop receptacle on the rotary bracket. The locking bolt has a guide section and a locking section having a radially changing support curve. The guide section can rotate causing the radially changing support curve to be supported on the planar support surface for eliminating play.
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U.S. PATENT DOCUMENTS
[0001]
2,761,338
September 1956
Hardy
81/3.38 R
3,722,327
March 1973
Strassel
81/3.36 R
3,800,345
April 1974
Feliz
7/14.6
4,018,110
April 1977
Spriggs
81/3.08
4,387,609
June 1983
Poisfuss
81/3.36
4,422,355
December 1983
Burns
81/3.46
4,606,245
August 1986
Veverka
81/3.36
4,875,394
October 1989
Crudgington
81/3.08
4,947,711
August 1990
Glebeler
81/3.37
5,275,070
January 1994
St. Denis
81/3.29
5,347,889
September 1994
St. Denis
81/3.29
5,868,044
February 1999
Sonderman
81/3.29
FOREIGN PATENT DOCUMENTS
[0002]
53681
September 1937
Denmark
81/417
25798
February 1953
Finland
81/3.09
BACKGROUND OF THE INVENTION
[0003] 1. Field of the Invention
[0004] The present invention applies to specific improvements to bottle stopper removers for removing mushroom-shaped stoppers, those commonly made from either cork or plastic, from champagne and other sparkling beverage bottles, and more specifically applies to extractors that incorporate opposing bifurcated jaws and a pair of handles about a common pivot; jaws that provide a leveraged lifting action for removing the stopper by squeezing said handles.
[0005] 2. Description of Related Art
[0006] Invention and use of bottle stopper removers for sparkling beverages sealed with mushroom-shaped stoppers are known to the public. The concept of using bifurcated jaws for such devices was first introduced by Spriggs, U.S. Pat. No. 4,018,110. While the concepts disclosed by Spriggs are valid, significant refinements brought forth in Crudgington U.S. Pat. No. 4,875,394 were necessary to produce a viable product of this type.
[0007] This type of bottle stopper remover in its basic form is comprised of upper and lower bifurcated jaws that engage about the neck or top of the bottle. Each jaw forms a pair of prongs with essentially a U-shaped blade incorporated therein. Depending on its application the blade associated with the lower jaw rests directly on either the flared section directly below the bottle's lip or on the top of the bottle's lip, while the blade belonging to the upper jaw is positioned under the head of either a cork or plastic stopper. A squeeze of a pair of handles about a common pivot results in the spreading of the jaws which in turn serves to exert an upwardly-directed leveraged force on the stopper, thus eliminating the need to manually “wrestle” the stopper out of the bottle.
[0008] 3. Object of the Invention
[0009] It is the object of the present invention to provide significant improvements to inventions previously disclosed by Spriggs and Crudgington that enhance the function of hand manipulable devices of this type for removing mushroom shaped stoppers from sparkling beverage bottles.
SUMMARY OF THE INVENTION
[0010] The present invention focuses particularly on certain improvements in such pullers hereafter referred as the champagne bottle opener, or simply the opener, puller or extractor. Prior art neglects to address problems arising from the wide dimensional variances found in sparkling beverage bottles and stoppers contained therein. Of greatest concern is the variation in diameter of the lip at the top of the bottle and the diameter of the stopper, particularly those made of natural cork The lip of sparkling wine bottles will vary in diameter from about 1.04″ to 1.15″ and the size of cork stoppers varies even more; in some cases the cork's head is only slightly larger than the bottle's lip. If the problems associated with these dimensional variances is not adequately addressed, the opener of the bifurcated jaw type may fail to function properly: if too large the upper jaw may inadvertently slip over a small cork stopper without lifting it; or if too small, the opener may break or worse yet, chip shards of glass from the bottle's lip while attempting to slide over the lip. For an opener to be reliable over the broadest range of bottle and cork configurations, the problems arising from dimensional variances are examined and improvements are set forth. The full implication of these size variations will be detailed along with advancements in the current invention that address the corresponding issues.
[0011] Introduced in my invention are significant refinements in the upper and lower bifurcated jaws that improve stopper retaining means, stopper gripping means and bottle anchoring means, along with identifying the importance of the material used to obtain desired mechanical characteristics. Prior art neglects to introduce the advantages of an opener that provides the means to inform the user that the tool has been fully and properly positioned for extracting a stopper, this being another object of my invention. Additionally, inherent problems, with spring clip mechanisms introduced in prior art for retaining or holding a stopper during extraction, are detailed herein. An improvement set forth eliminates the need for using spring clip(s) or other means to grab or clamp the stopper, yet prevents the released stopper from inadvertently ricocheting out of the puller's stopper-retaining device during extraction.
[0012] The wish-bone shaped handle configuration depicted in prior art for bifurcated stopper extractors is replaced with an improved design that is fully set forth. The problems inherent in this configuration are addressed, with embodiments that enhance the manipulation of the opener without sacrificing leverage capability or vertical lift.
BRIEF DESCRIPTION OF THE DRAWINGS
[0013] FIG. 1 is a perspective view of the assembled Champagne Opener consisting of an upper lever, lower lever, a pair of hinge pins that snap together and an internal hinge spring not shown. Also illustrated are the two types of mushroom-shaped stoppers, a typical one made of cork and the other a typical one made of plastic.
[0014] FIGS. 2 & 2 a are perspective views of the opener assembly and the lower lever positioned for extraction of all mushroom-shaped plastic stoppers from a typical sparkling beverage bottle.
[0015] FIGS. 3 & 3 a are perspective views of the opener assembly and the lower lever positioned for removal of a cork stopper sealing an unusually large-lipped sparkling beverage bottle.
[0016] FIGS. 4 & 4 a are perspective views of the opener assembly and the lower lever positioned for removal of cork stoppers sealing all normal sized sparkling beverage bottles.
[0017] FIG. 5 is a perspective view of the upper lever showing preferred embodiments of the upper jaw and associated elements.
[0018] FIG. 6 is a top perspective view of the upper jaw detailing preferred embodiments of the blade configuration.
[0019] FIG. 7 is a bottom orthographic view of the upper jaw detailing preferred embodiments of the blade configuration and the stopper retaining means.
[0020] FIG. 8 is a front orthographic view of the upper jaw positioned for extraction of all plastic stoppers.
[0021] FIG. 8 a is a side orthographic section view of FIG. 8 primarily illustrating the relationship between plastic stopper and stopper retaining means.
[0022] FIG. 9 is a front orthographic view of the upper jaw positioned for extraction of a cork stopper sealing an unusually large-lipped sparkling beverage bottle.
[0023] FIG. 9 a is a side orthographic section view of FIG. 9 primarily illustrating the relationship between cork stopper and stopper retaining means.
[0024] FIG. 10 is a perspective view of the lower lever showing preferred embodiments of the lower jaw and associated elements.
[0025] FIG. 11 is a bottom orthographic view of the lower jaw showing preferred embodiments of the lower jaw.
[0026] FIG. 12 is a front orthographic section view of FIG. 4 detailing embodiments of the upper and lower blade configuration when applied to a mushroom-shaped cork stopper sealed to a normal sized sparkling beverage bottle.
[0027] FIG. 13 is a side view of the opener assembly with the upper and lower levers in the “relaxed” position illustrating preferred embodiments to the handle configuration and the stopper retaining means.
[0028] FIG. 14 is a side view of the opener assembly with the upper and lower levers in the fully squeezed position illustrating preferred embodiments to the handle configuration and the stopper retaining means.
DESCRIPTION OF PREFERRED EMBODIMENTS
[0029] The basic elements comprising a bifurcated stopper puller are not new to the art as they were introduced and described in prior art. The present invention introduces numerous and significant improvements to all such pullers. Whereas the preferred configuration of the improvements relating to the invention has been illustrated and described herein, it should be realized that the embodiments are to be considered in all respects illustrative and not restrictive.
[0030] The bifurcated stopper puller illustrated in FIG. 1 is comprised of a pair of levers, upper 1 and lower 1 a , which at one end form a pair of handles, upper 2 and lower 2 a , and at the opposite end a pair of bifurcated jaws, upper 3 and lower 3 a . The levers 1 and 1 a are joined by a pivot pin assembly 4 , so that the squeezing together of the handles 2 and 2 a causes the opening of upper 3 and lower 3 a jaws. Typically, a spring (not shown) is placed between the handles 2 and 2 a for returning the levers 1 and 1 a to their original rest position, making the puller easier to hold during placement. Additionally, stopper gripping means 5 is positioned between the handles 2 and 2 a for conventional cork removal by gripping and rotating the stopper. A stopper retaining member 6 is affixed to the upperjaw 3 . Bifurcated jaws, upper 3 and lower 3 a each have a pair of ridges 14 and 14 a formed around their perimeters for reinforcement. The interior of upper 3 and lower 3 a jaws contain upper blade 11 and lower blade 11 a respectively, each of which forms a generally “U” shaped upper recess 10 and lower recess 10 a . Upper recess 10 provides the means for addressing either a mushroom-shaped plastic stopper 7 a below its base 15 , or mushroom-shaped cork stopper 7 b at it's downwardly presented shoulder 15 a ; and the lower recess 10 a provides the means for anchoring to either the lip 17 or shoulder 19 of a sparkling wine or similar beverage bottle 18 sealed with either plastic stopper 7 a or cork stopper 7 b . Henceforth, any reference that refers to both plastic stopper 7 a and cork stopper 7 b , will be referred to simply as stopper 7 . To accommodate the wide variety of bottle-stopper configurations three positions for placing the opener around the bottle 18 are available as illustrated in FIGS. 2, 3 & 4 , wherein each position addresses different stopper 7 and bottle 18 configurations. As shown in FIGS. 2 & 2 a , the opener rests on shoulder 19 of bottle 18 , that being the proper anchoring position for removing all plastic stoppers 7 a . As seen in FIGS. 3 & 3 a , the opener rests on top of the bottle's lip 17 a having unusually large internal and external diameters as is the case with certain European brands. FIGS. 4 & 4 a illustrate the third manner of inserting the opener for most cork stopper 7 b and bottle 18 configurations, where the opener is sized to rest on top of the typical bottle's lip 17 and to slip around the base of a typical cork stopper's head 15 a.
[0031] FIGS. 5, 6 , 7 , 8 , 8 a , 9 & 9 a show the upper jaw 3 configuration in various views, with FIGS. 8 & 8 a illustrating the application with a typical plastic stopper 7 a and sparkling beverage bottle 18 ; and FIGS. 9 & 9 a showing one of two possible positions to engage a cork stopper 7 b , in this case one sealing a sparkling beverage bottle 18 with an unusually large lip 17 a . In order to prevent any stopper 7 from inadvertently ricocheting out from under the stopper retaining member 6 , prior art introduced the use of a spring loaded stopper retaining member or a stopper retaining member with one or more spring loaded clips. Experience has shown that the use of a spring loaded mechanism to grip the stopper 7 has several inherent problems: springs tend to weaken over time, making them less reliable; the force that springs apply for gripping purposes tends to work against the insertion of the opener; and the wide size range of cork stoppers 7 b results in the spring clip mechanism becoming ineffective for unusually large or small stoppers 7 b . Spring clip(s) are found to be either too loose for small-headed corks or too tight for large-headed corks. Even in those cases where properly sized, spring clip(s) tend to impede the insertion of the opener around the stopper because the clip(s) exert a counter force while engaging about the stopper's head. The result is an increased difficulty in positioning the tool for insertion about the stopper 7 , or increased difficulty in inserting the opener into the proper position for extraction. In the present invention, the stopper retaining member 6 , either attached to or made part of the upper jaw 3 , includes a refinement that eliminates the need to grip the stopper 7 in order to prevent its accidental ejection from the opener. Rather than proving means to grip the stopper 7 , a stopper deflecting means 8 is centered within the stopper retaining member 6 , and is positioned and beveled in such a manner as to deflect the released stopper 7 towards the rear of the upper jaw 3 where it is safely contained within the retaining member 6 . This deflecting means 8 can best be understood in FIGS. 8 a & 9 a . Since the deflecting means 8 is not required to make contact with the pre-extracted stopper 7 in order to be effective, the stopper retaining member 6 along with deflecting means 8 can be sized to accommodate even the larger cork stoppers 7 b without sacrificing its effectiveness with smaller stoppers 7 .
[0032] Another significant improvement set forth is the addition of a pair of rails 9 on both sides and within the interior of stopper retaining member 6 , most clearly visible in FIG. 5 . As can be visualized from viewing FIGS. 8 & 9 , the pair of rails 9 helps guide the insertion of the opener around any stopper 7 . FIGS. 8 a & 9 a show how the rails 9 are positioned above and primarily parallel to upper blade 11 . The pair of rails 9 can be effectively spaced apart so that they make contact with most plastic stoppers since the dimensional variance of plastic stoppers 7 a is nominal. Furthermore, a common element of all plastic stoppers 7 a is that the widest portion is at the base of the head 15 , thereby permitting the base of the head 15 to rest underneath rails 9 as illustrated in FIG. 8 . Thus, pair of rails 9 provides the means to impede the upward motion of a released plastic stopper 7 a and assist in discarding it from the opener by preventing the dislodged plastic stopper 7 a from lifting up and catching on the beveled protrusion 8 as it is being pushed out of the opener.
[0033] As evident in FIGS. 5, 6 & 7 , the stopper gripping means of blade 11 within upper jaw 3 has been enhanced by introducing a pair of opposing curvatures 13 within the generally “U” shaped recess 10 described in prior art. When these curvatures 13 are viewed together as illustrated in FIG. 6 , the pair of curvatures 13 form a primarily circular slot 16 , thereby increasing the possible surface contact between blade 11 and any stopper 7 when the opener is positioned as shown in FIG. 2 or 3 . In both positions, the pair of curvatures 13 are aligned with and conform to the circular shape of all type stoppers 7 so that with plastic stoppers 7 a as shown in FIG. 2 , increased surface contact is made between blade 11 and the base of the plastic stopper head 15 ; or with cork stoppers 7 b as shown in FIG. 3 , increased surface contact is made between blade 11 and the downwardly presenting portion of a cork stopper's head 15 a . Also included within the upper jaw 3 as seen in FIG. 6 is a secondary generally circular recess 12 positioned at the base of primary recess 10 for positioning the opener as seen in FIG. 4 . And while recess 12 was disclosed in prior art, it is made significantly more effective by introducing an upwardly facing chamfer 22 seen most clearly in FIG. 6 so that recess 12 is wider at the top of blade 11 than at the bottom and having a cross-sectional width sufficient to permit the opener to pass under and around the base of a cork stopper 7 b . By introducing chamfer 22 to recess 12 , engagement between blade 11 and downwardly facing shoulder 15 a is improved thereby eliminating the requirement to engage about a partially lifted the stopper 7 b as defined in prior art. Recess 12 is further enhanced by increasing its curvature past 180° as shown in FIG. 7 so that blade 11 slightly encircles the cork stopper 7 b , thus providing the means to generate a slight locking action when the opener is positioned for extraction.
[0034] As viewed in FIG. 7 a further innovation within the upper jaw 3 is the slight tapering of blade 11 at the entrance of upper recess 10 where the width of the upper recess 10 narrows from the entrance with the narrowest point 21 being at the front of opposing curvatures 13 . By making the upper jaw 3 and/or blade 11 from a rigid material with some degree of flexibility, as with certain plastics, the narrowest point of blade separation 21 can be made to spread apart slightly during insertion. The primary recess 10 in upper blade 11 at its narrowest point 21 can thereby be appreciably less than the diameter of bottle 18 where applied, that being directly under the head of plastic cork 7 a as seen in FIG. 2 , or appreciably less than the diameter at the base 15 a of cork stopper 7 b as seen in FIG. 3 . This embodiment enhances the gripping means of blade 11 by further encompassing either type stopper 7 thereby increasing contact through the extended arc length of curvatures 13 . Furthermore, the momentary splaying action of blade 11 during insertion of the opener creates a spring-loaded force that assists the user in properly positioning the opener by centering either bottle 18 as shown in FIG. 8 , or cork stopper 7 b as shown in FIG. 9 , within the circular slot 16 as blade 11 returns from its flexed to normal shape. In addition, the momentary splaying of blade 11 generates a slight snapping action that can be felt, thereby informing the user that the puller has been fully and properly inserted.
[0035] FIGS. 8 & 8 a illustrate a typical sparkling beverage bottle 18 sealed with a plastic stopper 7 a . When the opener is positioned for extraction, the circular slot 16 within upper blade 11 shown in FIGS. 6 & 7 is centered about the bottle 18 . Normally, all plastic stoppers 7 a cover the bottle's lip as shown in FIGS. 2 & 2 a necessitating that upper blade 11 pass over lip 17 during removal of a plastic stopper 7 a . For most domestic sparkling beverage bottles, the diameter of circular slot 16 is sized to be larger than lip 17 thereby providing adequate clearance for upper blade 11 to pass over bottle lip 17 during extraction. As seen in FIG. 7 , to remove a plastic stopper 7 a sealing a sparkling beverage bottle with the largest diameter lip 17 , curvatures 13 have been modified to accommodate a larger diameter lip 17 . On each side of blade 11 curvature 13 has been elongated by splitting each curve into two nearly identical curvatures 13 whose radii are bisected by a slight separation 33 thereby forming two pair of adjacent curvatures 13 as seen in FIG. 7 . The separation 33 between curvatures 13 enables upper blade 11 to slide over a bottle lip 17 having a diameter greater than that of curvatures 13 , without necessitating the increase of the cross-sectional width of circular slot 16 . By manufacturing the upper jaw 3 and/or upper blade 11 from a rigid material with some degree of flexibility, as with certain plastics, blade 11 can be made to spread apart sufficiently during the extraction of any plastic stopper 7 a . By this means circular slot 16 remains sufficiently small for blade 11 to make the best possible contact with the underside 15 of a plastic stopper 7 a or the downwardly presenting shoulder 15 a of a cork stopper 7 b.
[0036] FIGS. 10 & 11 illustrate several improvements to the lower jaw 3 a . The jaw's ridges 14 a are significantly strengthened by incorporating a taper 20 from tip to base as viewed most clearly in FIG. 11 . Tapered ridges 20 also assist in guiding the insertion of the opener around the bottle's shoulder 19 or bottle's lip 17 . The anchoring means of blade 11 a has been enhanced by introducing a pair of opposing curvatures 13 a within the primary generally “U” shaped recess 10 a brought forth in prior art. When the pair of curvatures 13 a are viewed together as seen in FIG. 11 , they form a primarily circular slot 16 a , thereby encouraging the opener to become properly positioned about a bottle's shoulder 19 as illustrated in FIGS. 2 & 2 a . Again referring to both FIGS. 10 & 11 , by adding downwardly facing chamfers 24 to blade 11 a at curvatures 13 a , the positioning of the opener for removal of a plastic stopper 7 a is enhanced. By contouring chamfers 24 to that of the typical bottle's shoulder 19 , a tighter fit under plastic stopper 7 a is made possible when the opener is positioned as shown in FIG. 2 . Furthermore, anchoring of the lower jaw 3 a has been improved when blade 11 a is positioned about the bottle 18 as shown in FIGS. 3 & 3 a because of the increased contact with bottle lip 17 made possible by the conforming shape of the pair of curvatures 13 a . As seen in FIGS. 10 & 11 a secondary generally circular recess 12 a is shown at the base of primary recess 10 a , and while recess 12 a was disclose in prior art, it has been made significantly more effective by introducing a downwardly facing chamfer 23 that generally conforms to the bottle's lip 18 when positioned as shown in FIGS. 4 & 4 a . By adding chamfer 22 to secondary slot 12 in upper jaw 3 shown in FIG. 6 , and by adding a reversed corresponding chamfer 23 to secondary slot 12 a in the lower jaw 3 a shown in FIGS. 10 & 11 , the opener can be inserted between cork stopper 7 b and bottle lip 17 without first having to partially dislodge the stopper from the bottle as required in the configuration claimed in prior art. The means to accomplish the placement of the opener shown in FIG. 4 as previously described can best be visualized by referring to FIG. 12 that illustrates the manner in which the upper and lower blades 11 & 11 a form a tapered edge that is defined by opposing chamfers 22 and 23 within slots 12 and 12 a.
[0037] FIGS. 13 and 14 illustrate several improvements in the pair of handles 2 and 2 a over prior art. Experience reveals that with the wishbone handle configuration previously disclosed, the handles have an undesirable tendency to cross at their ends 21 & 21 a when fully squeezed if made from a material having even a slight degree of flexibility as with most plastics. By reshaping the lower handle 2 a so that its end 21 a is primarily parallel to upper handle's end 21 , the tendency for them to cross is greatly minimized. Furthermore, by including a stop means 25 between handles 2 & 2 a , their ends 21 & 21 a are prevented from making contact with one another when fully squeezed. This improvement not only prevents the squeezed handles 2 & 2 a from crossing but eliminates the possibility of the user's palm from being pinched from handles that touch. By incorporating the stop means 25 as part of the stopper gripping means 5 , the stop means 25 which would otherwise be an unattractive element becomes essentially hidden. Additionally, the lower handle 2 a incorporates an upward curvature 26 thereby approximating a shallow “S” shape. This embodiment effectively reduces the maximum handle separation 27 in the relaxed position at the location where the opener is gripped, as seen in FIG. 13 ; at also improves the grasping of the handles for users with smaller hands without sacrificing the maximum possible angular separation 28 of jaws 3 and 3 a available with the prior configuration, as seen in FIG. 14 . Additional benefits are gained by reshaping the stopper retaining member 6 . As can be seen in both orthographic FIGS. 13 & 14 , the stopper retaining member 6 is in the form of a hood, and while the configuration was previously disclosed, the hood has been improved by the inclusion of front and rear tapers 31 & 32 making the hood 6 wider at its base 29 than at its apex 30 . The front taper 31 increases the user's view of stopper 7 while positioning the opener. The rear taper 32 expands the effective space 33 for the user's thumb to be inserted under the stopper retaining member 6 for pushing the extracted stopper 7 out of the opener. Additionally, the rear taper 32 provides reinforcement to the upper jaw 3 by permitting the extension of the base 29 further towards the rear of the upper ridge 14 than would otherwise be possible.
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The Champagne Bottle Opener, a hand manipulable device is described for removing mushroom-shaped stoppers from sparkling beverage bottles. It includes a pair of bifurcated jaws and opposing handles about a common pivot wherein each jaw contains improvements over prior art, improvements that enable the device to function more effectively for the wide dimensional variances in bottle and cork diameters commonly found in the marketplace. The opposing handles contain improvements as well permitting the device to be operated more easily and safely. Also included in the present invention are features that generate a tactile “snap” when the device is properly inserted about the bottle, and provide improved means for anchoring the tool when engaging in the extraction of any mushroom-shaped stopper.
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BACKGROUND OF THE INVENTION
The invention concerns a method for partially regenerating the catalytic properties of an aged maleic anhydride catalyst. In particular, it has been found that the catalytic properties of a vanadium-phosphorus-oxygen oxidation catalyst used in the conversion of hydrocarbons to maleic anhydride can be partially regenerated by contacting the aged catalyst with sulfur trioxide.
Maleic anhydride is a commercially valuable chemical. It can be used alone or with other acids in the manufacture of alkyd and polyester resins. It is a versatile chemical intermediate also useful as a monomer to produce various copolymers, such as the copolymer of maleic anhydride and vinyl acetate. Significant quantities of maleic anhydride are produced each year to satisfy these needs.
The prior art teaches that maleic anhydride can be produced by oxidizing hydrocarbons, such as butane, butene, butadiene and benzene. The oxidation is carried out in the presence of an oxidation catalyst. The prior art further teaches that vanadium-phosphorus-oxygen catalysts are especially active to catalyze the vapor-phase oxidation of hydrocarbons to maleic anhydride. For instance, the high-surface-area catalyst described in U.S. Pat. No. 3,864,280, granted to Schneider on Feb. 4, 1975, provides high yields of maleic anhydride from butane. These catalysts comprise a vanadium-phosphorus-oxygen complex having an intrinsic surface area in the range from about 7 to 50 square meters per gram, a phosphorus to vanadium atomic ratio in the range of 0.9-1.8:1, and an average vanadium valence in the range 3.9 to 4.6.
During the oxidation process, the catalyst is contacted with hydrocarbon under reducing conditions. Typically the oxidation is carried out at from about 300° C. to about 500° C. In practice, an oxidation feed gas is fed to a tube reactor containing the catalyst material. Shortly into the reactor the hydrocarbon begins to oxidize rapidly thus creating a hot-spot. It has been observed that as the time of reaction on the catalyst increases, the activity and selectivity of the catalyst decreases. This is called "catalyst aging."
Accordingly, it is desirable to find a process for regenerating catalytic properties of aged catalyst to regain the initial high catalyst activity and selectivity. The selection of a suitable regenerating agent and the regeneration conditions which are used are critical, since over-regeneration of the catalyst has been found to result in a very non-selective catalyst. U.S. Pat. No. 4,020,174, issued to Partenheimer on Apr. 26, 1977, describes the use of regenerating agents to reactivate the catalytic properties of vanadium-phosphorus-oxygen catalysts. The agents are selected from the halide-containing compounds.
SUMMARY OF THE INVENTION
This invention provides a method for regenerating a vanadium-containing oxidation catalyst used in the production of maleic anhydride by contacting aged catalyst with a sufficient amount of sulfur trioxide to regenerate the vanadium-containing catalyst by raising the average vanadium valence to a value below 5.0, preferably from about 3.9 to about 4.6.
BRIEF DESCRIPTION OF THE FIGURE
The following detailed description refers to the accompanying FIGURE, which graphically illustrates one example of the relationship between the relative productivity change for a preferred high surface area catalyst and the amount of sulfur trioxide used to regenerate the catalytic properties.
DETAILED DESCRIPTION OF THE INVENTION
This invention provides a process for partially regenerating a vanadium-containing catalyst used in the oxidation of hydrocarbons to maleic anhydride by contacting aged catalyst with sulfur trioxide. Catalyst regeneration using sulfur trioxide is visualized as an equilibrium between a reduced catalyst site in contact with sulfur trioxide and an oxidized catalyst site in the presence of sulfur dioxide. The forward step of the equilibrium, that is the reaction of sulfur trioxide (SO 3 ) with a reduced catalyst site is extremely fast and can occur even at very low SO 3 concentrations. It has been found that catalyst selectivity for maleic anhydride improves almost linearly with the amount of SO 3 contacted with the aged catalyst. However, it has been unexpectedly found that this improvement does not continue with increasing amounts of SO 3 . In other words, for any given catalyst there is an optimum SO 3 level. If the amount of SO 3 contacted per gram of catalyst is above the optimum level then the selectivity of the catalyst begins to decrease until for many catalysts it may drop below the aged level.
The regeneration process can be carried out in situ or by external methods. In-situ regeneration offers the advantage of a continuous operation which can be carried out in the reactor vessel under normal operating conditions, but also necessitates the use of corrosion-resistant equipment.
The in-situ regeneration can be carried out by injecting a known amount of liquid SO 3 into the feed stream to the reactor. The reactor can be maintained at normal operating conditions during the SO 3 injection. Accordingly, suitable conditions for in-situ regeneration include a temperature from about 20° C., preferably about 200° C. to about 600° C., most preferably from about 300° C. to about 450° C.; and a pressure from about atmospheric up to about 100 psig, preferably from about 4 to about 50 psig, and most preferably about 4 to 10 psig.
External regeneration can be carried out by removing the aged catalyst from the reactor and charging it to a stainless-steel vessel, drying the catalyst, and then injecting SO 3 into the vessel while heating to temperatures in the range as specified for the in-situ regeneration.
Using either an in-situ or an external regeneration method, catalyst productivity can be increased as much as about 25%. Accordingly, a significant improvement in catalyst life can be obtained by periodically treating the catalyst with SO 3 , or by continuously feeding low concentrations of SO 3 in the feed stream.
It has been found that initially catalyst selectivity improves almost linearly with the amount of SO 3 contacted with aged catalyst. However, it has been unexpectedly found this improvement does not continue with increasing amounts of SO 3 . For any given vanadium-containing catalyst, there is an optimum amount of SO 3 which can be used in the regeneration process. If the amount of SO 3 contacted with aged catalyst exceeds the optimum level, the selectivity of the catalyst begins to decrease until for many catalysts it may actually drop below the selectivity of the untreated aged catalyst. The relationship between selectivity and the amount of SO 3 used in the regeneration process often varies for differing catalysts, such that the optimum amount of SO 3 will not be the same for all vanadium-containing catalysts. However, as a general rule, the optimum amount of SO 3 per gram of aged catalyst can be determined by considering the effect of SO 3 on the average vanadium valence of the catalyst. It has been found that about 13.5 microliters of SO 3 will raise the average vanadium valence of one gram of aged catalyst by a valence value of 0.1. Since vanadium-containing catalysts are known to have a preferred average vanadium valence, the optimum amount of SO 3 per gram of aged catalyst can be closely approximated by substracting the average vanadium valence of the aged catalyst (V aged ) from the preferred average vanadium valence of that catalyst (V desired ) and multiplying the remainder of 135 microliters. This calculation can be represented by the equation:
(SO.sub.3) optimum per gram of aged catalyst = 135 (V.sub.desired -V.sub.aged)μl
Accordingly, in a preferred embodiment of this invention aged vanadium-containing catalyst is regenerated by contacting each gram of aged catalyst with an amount of SO 3 determined by multiplying the desired change in average vanadium valence of the aged catalyst by 135 microliters. In any event, care should be exercised when using amounts of SO 3 above the optimum, since for many catalysts such amounts may either give very little benefit or actually further degenerate the already aged catalyst.
The following example illustrates practice of this invention. Other embodiments consistent with the invention will be apparent from the example. Accordingly, the example is not intended to limit the scope of the claims which follow.
EXAMPLE
Using a catalyst prepared according to U.S. Pat. No. 3,864,280, herein incorporated by reference, butane was oxidized to maleic anhydride.
This oxidation was carried out continuously for one year to obtain an aged catalyst. Aliquots of the aged catalyst were tested for selectivity and then regenerated by both in-situ and external treatment methods. In-situ regeneration was carried out by injecting SO 3 (Allied Chemicals, Sulfan) into the test reactor feed stream while maintaining the vessel at the normal operating conditions as listed in Table I. About 1 hour after in-situ treatment, a test run was started to evaluate catalyst performance. External regeneration was carried out by placing the aged catalyst in a 1/2-inch stainless-steel tube and drying the catalyst at 300° C. in flowing inert gas for approximately 8 hours. After drying, SO 3 was injected into the tube and the catalyst was heated to 300° C. for 2 to 3 hours. Following the SO 3 treatment, the catalyst was replaced in the test reactor vessel and reevaluated for performance. The test conditions are summarized in Table I and the results of the tests are summarized in Table II.
TABLE I______________________________________RUN CONDITIONS______________________________________Temperature 705° F (375° C)Pressure 4.5 psigFeed butane concentration 2.55 % by vol.Feed oxygen concentration 10% by vol.Amount of catalyst 11 gramsButane feed rate 12 cc/hourTotal gas flow rate 1.72 liters/minute______________________________________
TABLE II______________________________________EFFECTS OF REGENERATIONSO.sub.3 Level Catalyst RelativeRun microliters/ Productivity ChangeNo. gram Catalyst Method P.sub.R.sup.* lb/hr-ft.sup.3 P.sub.R /P.sub.R.sbsb.O______________________________________1 -- -- 1.67 1.00 (P.sub.R.sbsb.O)2 1.40 In-situ 1.69 1.023 3.33 In-situ 1.87 1.124 4.54 External 1.91 1.145 6.56 External 2.10 1.266 18.18 External 1.51 0.907 18.18 External 1.57 0.948 90.9 External 1.41 0.84______________________________________ *Under standard run conditions given in Table I
In Table II, productivity is defined as the pounds of maleic anhydride produced per hour per cubic foot of reactor volume.
The Figure accompanying this description was obtained by plotting the SO 3 level against the relative change in productivity. As can be seen, with up to the optimum of about about 8 microliters of SO 3 per gram of catalyst the productivity increased almost linearly with SO 3 level. At SO 3 levels between about 8 microliters/g and about 15 microliters/g, productivity was improved, but unexpectedly decreased with increasing SO 3 level. At SO 3 levels above about 15 microliters/g, catalyst productivity was actually degraded below the productivity of the untreated aged catalyst.
In this case, the 26% improvement for example Run No. 5 returns the catalyst to a performance level it had at about half of its total life, before regeneration. Thus, catalyst life can be significantly extended with SO 3 regeneration.
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The catalytic properties of a complex catalyst comprising vanadium, phosphorus and oxygen which is used for the oxidation of hydrocarbons to maleic anhydride can be partially regenerated by contacting the catalyst with sulfur trioxide.
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CROSS REFERENCE TO RELATED APPLICATIONS
This application is a continuation-in-part (CIP) of Ser. No. 09/093,111, filed Jun. 8, 1998 now U.S. Pat. No. 5,953,796, the disclosure of which is incorporated herein by reference.
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to reclosable plastic bags having slide zippers. More particularly, the present invention relates to a method and apparatus for making slide-zippered reclosable bags on form-fill-seal (FFS) machines.
2. Description of the Prior Art
Methods and apparatus for manufacturing reclosable plastic bags on FFS machines using reclosable zippers are well-known in the art. These prior art methods and apparatus, however, are limited to interlocking zippers which are directly opened and closed by the hands of the bag user and are not designed for the utilization of a slider for opening and closing the zipper.
The method and apparatus of the present invention, on the other hand, relate specifically to reclosable bags having a slide zipper. Reclosable bags having slide zippers are generally more desirable to consumers than bags which have traditional interlocking zippers since it is much easier for the user to open and close bags having a slide zipper. It is thus commercially highly desirable and advantageous to provide a method of and apparatus for manufacturing slide-zippered reclosable plastic bags in a continuous, automated process.
Slide zippers for use with plastic bags are well known in the reclosable fastener art. Examples of conventional slide zippers can be found in U.S. Pat. Nos. 5,007,143, 5,008,971, 5,131,121 and 5,664,299. Typical slide zippers comprise a plastic zipper having two interlocking profiles and a slider for opening and closing the zipper. The slider straddles the zipper and has a separator at one end which is inserted between the profiles in order to force them apart, that is, the separator plows between the profiles forcing them to disengage. The other end of the slider is sufficiently narrow to be able to close the zipper.
Recently, a new type of slider zipper has been developed which, as discussed fully below, improves on prior art slide zippers and includes features which facilitate the manufacture of bags in automated form fill processes.
It is therefore the object of the present invention to provide a unique and novel method and apparatus for making slide-zippered bags on an FFS machine.
SUMMARY OF THE INVENTION
The present invention is, in two aspects, a method of making slide-zippered plastic bags on an FFS machine and an apparatus for making slide-zippered plastic bags on an FFS machine.
In a first embodiment of the present invention, the slider is preapplied to the zipper at the zipper manufacturing site. Then, at the FFS site the plastic bags are made on the FFS machine utilizing conventional and well-known FFS technology, such as disclosed in U.S. Pat. No. 4,894,975. To facilitate guiding and alignment of the zipper, the zipper is provided with guiding flanges.
In a second embodiment of the present invention, the plastic bags are made on the FFS machine and the zipper is attached to the bags in the conventional manner. A coil of sliders, each slider being connected to its two adjacent sliders, is used to feed the sliders into the FFS machine, which sliders are then applied by a slider insertor mechanism to the zipper. In a slight variation of this embodiment, the slider insertor mechanism can be positioned to apply the sliders to the zipper before the zipper is fed into the FFS machine for sealing to the plastic bags.
In a third embodiment of the present invention, the plastic bags are made on the FFS machine and the zipper is attached to the bags in the conventional manner. A magazine of individual or interconnected sliders is used to feed a slider insertor mechanism which applies the sliders to the zipper. In a slight variation of this embodiment, the slider insertor mechanism can be positioned to apply the sliders to the zipper before the zipper is fed into the FFS machine for sealing to the plastic bags.
In a fourth embodiment of the present invention, the plastic bags are made on the FFS machine and the zipper is attached to the bags in the conventional manner. Bulk sliders are introduced into a vibratory feeding bowl which orients and feeds the sliders to the slider insertor mechanism which applies the sliders to the zipper. In a slight variation of this embodiment, the slider insertor mechanism can be positioned to apply the sliders to the zipper before the zipper is fed into the FFS machine for sealing to the plastic bags.
The present invention will now be described in more complete detail with reference being made to the figures identified below wherein the same numerals represent identical elements.
BRIEF DESCRIPTION OF THE DRAWINGS
In the accompanying drawings:
FIG. 1 is a cross sectional view of an interlockable zipper in accordance with the present invention;
FIG. 2 is a perspective view of a slide zipper in accordance with the present invention attached to a plastic bag;
FIG. 3 is a cross sectional view of the closing end of the slider and zipper;
FIG. 4 is a cross sectional view of the opening end of the slider and zipper;
FIG. 5 shows an FFS machine adapted to make slide zippered bags according to a first embodiment of the present invention;
FIG. 6 shows a side view of the vertical seal bars of the FFS machine of FIG. 5 disposed to seal the zipper to the thermoplastic film;
FIG. 7 shows a cross sectional view of the zipper guide and the vertical seal bars of the FFS machine of FIG. 5;
FIG. 8 shows an FFS machine adapted to make slide zippered bags according to a second embodiment of the present invention;
FIG. 9 shows an FFS machine adapted to make slide zippered bags according to a third embodiment of the present invention; and
FIG. 10 shows an FFS machine adapted to make slide zippered bags according to a fourth embodiment of the present invention.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT
FIG. 1 shows a cross sectional view of interlockable zipper 10 which may be used to practice the present invention. The zipper 10 is formed of a resilient plastic material such as polyethylene and comprises a first profile 12 and a second profile 14 . The zipper 10 is disposable across the mouth 11 of a plastic bag 13 , as shown in FIG. 2 . For purposes of this description the bag 13 will be assumed to be oriented with its mouth 11 on top as depicted in FIG. 2 .
The first profile 12 has a base 15 having an inner side 16 and outer side 18 , a top portion 20 , a bottom surface 22 , a flange 24 , a top hooked arm 26 and a bottom hooked arm 28 .
The top hooked arm 26 and the bottom hooked arm 28 of the first profile 12 have hooked ends 30 and 32 which are directed away from each other. Thus, the hooked end 30 of top hooked arm 26 is oriented upwardly while the hooked end 32 of the bottom hooked arm 28 is oriented downwardly. As is clear from FIG. 1, the top hooked arm 26 is longer and thinner than the bottom hooked arm 28 . The top hooked arm 26 is thus more flexible than the bottom hooked arm 28 , thereby providing for ease of opening of the zipper 10 from the outside of a bag employing the zipper 10 . Conversely, because bottom hooked arm 28 is shorter and thicker than top hooked arm 26 , and thus less flexible, the internal opening force will be greater.
The second profile 14 likewise has a base 33 having an inner side 34 and an outer side 36 , a top portion 38 , a bottom surface 40 , a flange 42 , a top hooked arm 44 and a bottom hooked arm 46 . The top hooked arm 44 and bottom hooked arm 46 of the second profile 14 have hooked ends 48 and 50 which are directed towards each other and positioned and sized to engage the hooked ends 30 , 32 of the first profile hooked arms. Thus, the top hooked arm 44 has a downwardly oriented hooked end 48 which is engageable with the hooked end 30 of the top hooked arm 26 of the first profile 12 and the bottom hooked arm 46 has an upwardly oriented hooked end 50 which is engageable with the hooked end 32 of the bottom hooked arm 28 of the first profile 12 . This two-arm configuration of the zipper 10 provides a relatively leak proof seal. The second profile 14 may also have an inwardly directed wedge or bump 52 which is located between the top hooked arm 44 and the bottom hooked arm 46 and aids in guiding the profiles into and out of engagement. The profile flanges 24 , 42 provide a means by which the zipper may be guided in an automated bag making process, such as on a form-fill-seal machine, and also provide a means by which the zipper may be sealed to the bag 13 .
The slide zipper assembly is further provided with a slider 54 which slides along the mouth 11 of the bag 13 as shown in FIG. 2 . FIGS. 3 and 4 show how the zipper 10 cooperates with the slider 54 . Thus, the slider 54 has a closing end 56 and an opening end 58 . As shown in FIG. 2, the slider 54 is slidable in an opening direction “O” in which the zipper profiles 12 , 14 are disengaged by the slider, and a closing direction “C” in which the zipper profiles 12 , 14 are engaged by the slider.
FIG. 3 shows the details of the closing end of the slider and FIG. 4 shows the details of the opening end of the slider. It should be understood that for purposes of clarity the zipper 10 and slider 54 in FIGS. 3 and 4 are shown with the same orientation. However, when one actually looks at the zipper from the closing end and the opening end the orientations of the zipper and slider will be reversed.
The slider 54 straddles the zipper 10 and is slidable along the zipper 10 in the closing and opening directions. The profiles are closed and sealed to each other at both ends to ensure that the zipper 10 does not become separated at its ends during use. In addition, the zipper 10 may be provided with a stopper at both ends which serves to prevent the slider from becoming disengaged from the zipper.
The slider 54 has a top portion 60 , a first arm 62 and a second arm 64 . The first arm 62 has an inner side 66 , an outer side 68 , and an inwardly directed bottom tab 70 . Likewise, second arm 64 has an inner side 72 , an outer side 74 , and an inwardly directed bottom tab 76 . The inner sides 66 , 72 of the slider arms are tapered towards the closing end 56 so that at the closing end the arms are sufficiently close to press the profiles into engagement with each other.
The tab 70 of the first arm 62 has a tapered top surface 78 , a side surface 80 , and a tapered bottom surface 81 . The tapered top surface 78 of the tab 70 mates with the bottom surface 22 of the first profile 12 , imparting a generally upward force thereto. This force, as discussed below, plays a role in the opening and closing action of the slider 54 .
The tab 76 of the second arm 64 likewise has a tapered top surface 82 , a side surface 84 , and a tapered bottom surface 85 . The tapered top surface 82 mates with the bottom surface 40 of the second slider arm 64 .
The mating of the profile bottom surfaces 22 , 40 and the slider tab tapered top surfaces 78 , 82 ensures that the slider 54 is securely positioned over the zipper 10 and reduces the possibility that the slider 54 will be pulled off the zipper 10 . The slider tab tapered bottom surfaces 81 , 85 facilitate insertion of the slider 54 over the zipper 10 .
As is clear from FIG. 3, the zipper 10 is captured between the inner sides 66 , 72 of the slider arms 62 , 64 and between the two tabs 70 , 76 . The tabs 70 , 76 cooperate with the slider top 60 to hold the slider 54 in place. The inner sides 66 , 72 of the slider arms 62 , 64 are sufficiently close at the closing end so that when the slider 54 is moved in the closing direction “C”, the inner sides 66 , 72 of the slider arms 62 , 64 press against the outer sides 18 , 36 of the first and second profiles 12 , 14 , thereby effecting engagement of the profiles 12 , 14 .
FIG. 4 shows the opening end 58 of the slider 54 . At the opening end 58 the inner sides 66 , 72 of the slider arms 62 , 64 are sufficiently far apart so as to not impart a closing force to the profiles 12 , 14 . To this end, at the opening end 58 a separator blade 86 extends downwardly from the slider top as shown. In addition, the inner side 66 of first slider arm 62 is contoured to define a cavity 88 which extends upwardly into the top 60 . The separator blade 86 is positioned so that when the slider 54 is moved in the opening direction, the separator blade 86 will deflect the top hooked arm 26 of the first profile 12 downwardly and out of engagement with the top hooked arm 30 of the second profile 14 . A component of the force on the top hooked arm 26 of the first profile 12 will also direct the now disengaged profile 12 sideways and into cavity 88 .
As the slider 54 is moved in the opening direction “O”, the separator blade 86 deflects the top hooked arm 26 of the first profile 12 downwardly and out of engagement with the top hooked arm 30 of the second profile 14 until the top hooked arm 26 engages bump 52 . The bump 52 provides a camming surface for the top hooked arm 26 as a component of the force exerted by the separator blade acts on the top hooked arm 26 to urge the first profile 12 away from the second profile 14 . Simultaneously, the top surface 78 of the tab 70 pushes the bottom portion 22 of the first profile 12 upwardly. This upward deflection in combination with the outward deflection of the first profile 12 by the separator blade 86 disengages the bottom hooked arm 28 of the first profile 12 from the bottom hooked arm 46 of the second profile 14 and moves the first profile 12 up and into the cavity 88 . Alternatively, means could be provided to force the second profile downwardly out of engagement with the first profile, as opposed to forcing the first profile upwardly or both upwardly and downwardly together.
Thus, the combined action of the separator blade 86 and first slider arm tab 70 on the first profile 12 serves to open the zipper as the slider is moved in the opening direction. Movement of the slider in the closing direction causes the slider arms to force the profiles into engagement.
Because of the attractiveness of slide zippers to consumers, it is commercially highly desirable to manufacture slider-zippered bags in a continuous automated process, such as on an FFS machine.
FIG. 5 shows a bag being manufactured on an FFS machine 100 in accordance with a first embodiment of the present invention. Thermoplastic film 102 is fed from a continuous supply thereof into the FFS machine 100 and wrapped around a forming collar 104 and around a filling tube 106 to bring the longitudinal edges 108 , 110 of the film 102 together to form a tube. The interlocked zipper 10 having sliders 54 preapplied thereto is fed from a continuous coil thereof 112 between the longitudinal edges 108 , 110 of the film 102 as shown, after which vertical seal bars 114 seal the zipper flanges 24 , 42 to the longitudinal film edges 108 , 110 to form what will be the top of the bag. The sliders 54 must be clear of the vertical seal bars 114 such that the sliders 54 do not interfere in the sealing of the zipper 10 and are not crushed by the vertical seal bars 114 , as shown in FIG. 6 . It is thus critical that the zipper flanges 24 , 42 be long enough to eliminate any interference between the sliders 54 and the vertical seal bars 114 .
The zipper flanges 24 , 42 also serve to allow the zipper 10 to be guided into the FFS machine 100 by zipper guide member 116 , and thereby keep the zipper aligned with the edges of the film, as shown in FIG. 7, which shows a cross section of the zipper 10 , the slider 54 , the film 102 , the vertical seal bars 114 , and the zipper guide member 116 .
Then, further downstream in the FFS machine 100 cross seal bars 118 form the sides of the bags by transversely sealing the tube of film. The cross seal bars 118 simultaneously seal the first side 120 of the bag 122 presently being made and seal the second side 124 of the preceding bag 126 (the first side seal of the preceding bag had previously been made), capturing a single slider between the two sides of the preceding bag 126 , and cut the 126 preceding bag from the film 102 . After the first side 120 is completed, the bag may be filled, if desired. Cross seal bars 118 may also seal the ends of the zipper 10 together to prevent the slider 54 from becoming detached therefrom. When the film 102 advances once again, the cross seal bars 118 complete the second side of the present bag, capturing a single slider between the two sides, and cut the present bag from the film and also complete the first side of the succeeding bag. In this manner slide-zippered bags are continuously made.
A second embodiment of the present is shown in FIG. 8 . In this embodiment, as in the first embodiment as well as all other embodiments, the FFS machine 100 functions in the same manner. The difference with this embodiment from the first embodiment, however, is that the zipper 10 does not have the sliders 54 preapplied thereto. Rather, the sliders 54 are applied to the zipper after the zipper is sealed to the longitudinal edges 108 , 110 of the film 102 .
As shown in FIG. 8, the sliders are supplied from a continuous coil 128 to a slider insertor mechanism 130 . Each slider 54 is connected to its adjacent slider via a connector 132 . This connection may be achieved in any number of ways. For example, the sliders may be mechanically connected. Alternatively, the sliders may be connected by a carrier adhesive tape. Still alternatively, the sliders may be connected by a metal or plastic wire or molded together by a plastic “runner”.
The connected sliders are fed into the slider insertor 130 . As the film advances through the FFS machine and as bags are made, a slider 54 is removed from the connector 132 and applied to the zipper 10 of the bag 122 presently being made. The use of tapered bottom surfaces 81 , 85 on the slider 54 facilitate this application. After the slider 54 is applied to the zipper 10 , the connector scrap 132 exits the slider insertor 130 and the first side seal of the bag is made by the cross seal jaws 118 . The bag is then completed as discussed above.
In a slight variation of this second embodiment, the slider insertor mechanism 130 can be positioned to apply the sliders 54 to the zipper 10 between the zipper roll 112 and the FFS machine 100 .
A third embodiment of the present invention is shown in FIG. 9 . In this embodiment once again the zipper 10 is sliderless as it is sealed to the longitudinal edges 108 , 110 of the film 102 . A box magazine 134 of individual stacked sliders 54 is connected to the slider insertion mechanism 130 . As the film 102 advances through the machine and as the zipper 10 is attached to the film, the sliders are automatically applied to the zippers of the individual bags by the insertor 130 . The magazine is interchangeable with other magazines and may be replaced by another magazine when it becomes empty. Other types of commonly used magazines may also be employed, such as a coil type magazine wherein the sliders are attached to each other.
In a slight variation of this third embodiment, the slider insertor mechanism 130 can be positioned to apply the sliders 54 to the zipper 10 between the zipper roll 112 and the FFS machine 100 .
In a fourth embodiment of the present invention, the zipper 10 is similarly sealed to the longitudinal edges 108 , 110 of the film 102 without the sliders 54 being preapplied. Instead, a vibratory feeder bowl 136 is used to orient and deliver sliders 54 to the slider insertor 130 . Bulk sliders 54 are loaded by the bag maker into the vibratory feeder bowl 136 . The vibratory feeder bowl 136 then orients the sliders 54 and feeds them to the slider insertor 130 , which then applies the sliders to the zippers. The vibratory feeder bowl 136 may vibrate in either a translational manner (back and forth) or in a rotational manner. Generally, when the FFS machine is running at a slow speed, such as less than 60 bags per minute, a translational device may be used. When faster speeds are desired, however, the rotational type of feeder bowl should be used to adequately provide for high speeds.
In a slight variation of this fourth embodiment, the slider insertor mechanism 130 can be positioned to apply the sliders 54 to the zipper 10 between the zipper roll 112 and the FFS machine 100 .
Any of the foregoing embodiments may be used to make slide-zippered plastic bags on an FFS machine in a continuous, rapid manner. Modifications to the above would be obvious to those of ordinary skill in the art, but would not bring the invention so modified beyond the scope of the appended claims.
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A method and apparatus for manufacturing reclosable bags having slide zippers on a form-fill-seal machine is provided. In a first embodiment the sliders are preapplied to the zipper and the bags are made using conventional form-fill-seal techniques. In a second embodiment a coil of sliders is fed into the form-fill-seal machine where the sliders are applied to the zippers by an insertor mechanism. In a third embodiment a magazine of individual or connected sliders is used to feed a slider insertor mechanism which then applies the sliders to the interlocked zippers. In a fourth embodiment bulk sliders are introduced into a vibratory feeding bowl which then orients and feeds the sliders to the slider insertor mechanism.
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BACKGROUND AND SUMMARY OF THE INVENTION
This invention relates to a new and improved apparatus for dispensing a predetermined amount of fluid sealant into a can end recess for subsequent air tight attachment to a metallic can body in the manufacture of beverage containers and the like.
The current state of the art for applying a uniform bead of sealant to a can end member on a high speed production line for can ends, has progressed to the point of utilizing available electro pneumatic nozzles attached to mechanical support devices which are mounted in relatively fixed positions. The actuation of the dispensing of fluid sealant has generally been accomplished by means of an assembly which senses the proximity of the can end to the dispensing nozzle, when the can end is being rotated. Fluid sealant is then dispensed as the can end groove for receiving the sealant is rotated underneath the dispensing nozzle.
Adjustment of the proximity sensing device and the positioning of the arm is critical to the high speed operation of such a device. In the past, the proximity of the can end to the dispensing nozzle was sensed by the movement of a rocker arm assembly, which physically engaged the top of a can lid hold down pad shaft. As is customary with such devices, a considerable amount of play could develop requiring constant adjustment and attention thus decreasing the overall output of can ends from a production line incorporating such a device. The result of improper adjustment would be the dispensing of too much sealant or not enough sealant to accomplish the purpose for which the sealant is used. The subsequent container assembled from the can end might then not be properly sealed which could cause premature spoilage of the contents where perishable. In the same manner, the improper location of the nozzle over the can end being spun may cause the sealant to be placed in the wrong location of the can member, i.e., on portions of the can end other than the intended groove or recess, thus defeating the proper sealing function when the groove is subsequently attached to the open end of a can body.
It can be seen, therefore, that it is of critical importance that the positioning of a dispenser for fluid sealant over the groove in a can end be accurately and repeatedly accomplished. Likewise, the apparatus for providing the precise location should be capable of being serviced easily and returned to its operative position with a minimum of time spent for adjustment of the apparatus.
It is also highly desirable that a preferred apparatus for dispensing fluid sealant include as an integral portion thereof further apparatus for sensing can end proximity, which eliminates the drawback of complicated mechanical linkage which, as previously discussed, is prone to certain deficiencies in use.
Further, it is desirable to reduce the number of external pipes and lines servicing the dispenser gun and the controls for actuation of the flow of fluid sealant from the dispenser gun. External lines only tend to make repair and adjustment cumbersome by their presence and are prone to abuse and frequent repair or replacement during the operation of a high speed can end fabricating operation.
The present invention aims to eliminate most of the aforementioned problems by providing an apparatus which is capable of firmly supporting a fluid dispensing gun which is actuatable by improved can end sensing means, both of which are mounted on a support arm which is firmly located as to lateral position, but supported at its extremity by both horizontal and vertical pivoting means to enable the arm when serviced to be removed from its operative position over the can end to a position sufficiently removed from the work station to facilitate adjustment, cleaning or the like when required, and then simply and easily returned to a precise location for subsequent use.
These advantages are accomplished by providing a base plate positioned on a work table adjacent the can end feed transport means which will generally be bringing can ends from a stamping press. The base plate has mounted thereon pivoting means for supporting a dispenser arm that permits arcuate movement of the dispenser arm in both the horizontal and vertical planes, and clamping means for positioning the dispenser arm in a predetermined location generally transverse to the can end feed direction. The dispenser arm of the present invention contains at the end opposite the pivot means, a can end hold down pad assembly comprising, proximity sensing means responsive to actuation by the upward vertical engagement of a can end by reciprocal means located in the can end feed path, which reciprocal means moves the can end upward against the hold down pad of the assembly of the present invention while the can end is being rotated, electro-pneumatic means also mounted on the dispenser arm and responsive to the signal generated by the proximity sensing means for providing pneumatic pressure to preferrably lift a needle valve within a sealant dispenser gun to permit the discharge of fluid sealant from a supply under pressure, out through the nozzle of the dispenser gun and into the groove of the rotating can end. The speed of rotation and time of sealant discharge are adjustable to coincide with exactly one revolution of the can end under the dispensing gun while sealant is being discharged.
Accordingly, by use of the apparatus of the present invention, sealant can be properly applied to can ends on a can end feed transport means at each station equipped with the apparatus herein described at rates in excess of 400 can ends per minute.
BRIEF DESCRIPTION OF THE DRAWING
FIG. 1 is a side elevational view in line drawing and partly in cross-section, of an illustrative embodiment of the apparatus of the present invention.
FIG. 2 is a partial plan view of the apparatus of FIG. 1.
FIG. 3 is an enlarged partial cross-sectional view of a portion of the apparatus of FIG. 1.
FIG. 4 is a partial end view, partly in cross-section, of the apparatus of the present invention.
FIG. 5 is a schematic view of the controls and sequence of operation of the apparatus of the present invention.
DETAILED DESCRIPTION
Referring now to FIG. 1, in general, the apparatus of the present invention comprises a base plate 1 to which is mounted a pivot block 2 having located thereon a vertical pivot enabling the pivot block 2 to rotate about the vertical axis of the pivot. The dispenser arm 6 is received in a recess 5 in pivot block 2, shown in FIG. 3 and in the location where horizontal pivot 4 communicates through dispenser arm 6 in a manner to permit dispenser arm 6 to be rotated about horizontal pivot 4 in an upward arc.
Clamp 7 located on base plate 1 centrally of dispenser arm 6 is attached to base plate 1 via machine screws 15, and is shown in greater detail in FIG. 2. Referring to FIG. 3, the clamp 7 for holding support arm 6 is composed of a support block 8 containing a recess for receiving, in close tolerance and in a generally horizontal position, the dispenser arm 6. Dispenser arm 6 is held in this position by the action of hinge block 9 and swing bolt 13. Hinge block 9, an inverted L shaped member, has the lower leg disposed in a recess (not shown) in support block 8. Hinge pin 11 is disposed horizontally through support block 8, the recess, and perpendicular to and communicates through the downward pointing arm of hinge block 9. Hinge pin 11 provides an axis about which the hinge block 9 can be rotated upward sufficiently to permit dispenser arm 6 to be received in recess 5 of support block 8. Likewise, hinge block 9 in its operative clamping position will be rotated so that the horizontal arm of the inverted L will engage the top most portion of dispenser arm 6 holding it firmly into recess 5 of support block 8. The clamping action of hinge block 9 is provided by the swing bolt 13, bushing 10 and internally threaded knob 12. Hinge block 9 is constructed with a U-shape recess in the upper arm of the inverted L so as to receive a swing bolt 13 which is pivoted via swing bolt pivot 14 to provide freedom of movement from the vertical position shown in FIG. 3 to a horizontal position away from engagement with hinge block 9 (not shown) allowing hinge block 9 to be rotated about hinge pin 11 for either receiving dispenser arm 6 or lifting dispenser arm 6 out of the recess 5 in support block 8. The clamping action of swing bolt 13 is provided by bushing 10, acting as a spacer, and the action of threaded knob 12. When threaded knob 12 is tightened against bushing 10, bushing 10 is forced against hinge block 9, as shown in FIG. 3, and vertical movement of dispenser arm 6 is prevented. With dispenser arm 6 in its horizontal position as shown in FIGS. 1 and 2, the distal end of dispenser arm 6, ie. the end opposite the pivot block 2, contains mounted thereon a hold down pad bracket 20, a solenoid 22 and a fluid sealant dispenser gun 40.
The hold down pad bracket 20 will preferably be comprised of a vertical base and a shelf 32 which is threaded to receive a plunger assembly 31 comprising a threaded plunger guide 35 and a plunger guide nut 36, and having received in the plunger guide 35 a plunger 33 which is spring biased vertically downward by spring 34 acting against plunger guide 35 and plunger seat 37. Plunger seat 37 has disposed on the face thereof a downwardly protruding dowel 38 which is engaged by a recess in the end of hold down pad shaft 21 which extends upwardly from the hold down pad 24. The hold down pad shaft 21 is threaded at its top most extremity to engage lock nuts 39 which prevent unrestricted downward movement of hold down pad 24 and its accompanying shaft but is unrestricted as to upward movement until engaging dowel 38.
Hold down pad bracket 20 also contains at its uppermost extremity a proximity sensor 30 which responds to the upward movement of plunger 33 by producing an electrical signal.
Dispenser arm 6 is also provided with internal conduits or channels, communicating there through (as shown in the cross-sectional view of dispenser arm 6, FIG. 3) which communicate with an air line 18 and a fluid sealant supply line 19. Air line 18 communicates through a channel provided in dispenser arm 6 with solenoid 22. Likewise, fluid sealant line 19 communicated through another channel in dispenser arm 6 with a dispenser gun 40. The supply of fluid sealant is under pressure from a pressure source and reservoir (not shown) and is dispensed through the nozzle 41 of dispenser gun 40 by the application of air pressure to solenoid 22 which when actuated by the control circuitry 60 (FIG. 5) in response to a signal from proximity sensor 30, allows the air under pressure from the air line 18 to be applied to a chamber inside of dispenser gun 40 whereby a piston is raised inside dispenser gun 4 (not shown) to which is attached a needle valve (not shown), causing it to rise, opening an outlet in the lower tip of nozzle 41 to permit the fluid sealant under pressure in line 19 to be dispensed in a predetermined manner from the discharge nozzle 41.
Operation
Referring now to FIG. 5 the sequence of operation of the apparatus according to this invention will be more fully understood. Generally, the apparatus of the present invention will be located so that the hold down pad 24 is positioned in vertical alignment with a can end pathway which normally utilizes means for engaging the sides of the can ends and moving them along the pathway from a source of stacked ends to a stationary position on a reciprocally moving rotating work station 50 as shown in FIG. 5a. The can end is presented to the work station 50 by linear movement along the pathway. When the can end 55 is positioned by the pathway transport means (not shown) onto work station 50 then work station 50 is rotated and cam actuated upwardly to engage the can end 55 with the hold down pad 24. As the combination of work station 50, can end 55, and hold down pad 24 are vertically displaced upwardly the recess in the upper end of shaft 21 engages the dowel 38 of plunger assembly 31 displacing the plunger 33 upwardly into the proximity of the sensor 30. Sensors suitable for use include Sensor No. 4943D 0379 by Electro Products of Sarasota, Florida. If the proper adjustments as to height and length of travel have been made to the plunger guide nut 36 and the position of the threaded portion of plunger assembly 31 on hold down pad bracket shelf 32 (shown in FIG. 1), the proximity sensor 30 will generate a signal which will be amplified by a proximity amplifier and fed electrically to a control box 60 (such as Nordson Corp. Timer Model No. CT6) containing adjustments as to delay in the onset of solenoid actuation and the duration of actuation and the output of the control box 60 will be the input to the solenoid valve for it to allow a supply of air at preferrably about 45-50 p.s.i. to be applied to a piston within dispenser gun 40 raising a needle type valve within nozzle 41 permitting the flow of fluid sealant from the nozzle 41 into the annular groove of the can end illustrated while the work station 50 is rotating and approaching and departing its uppermost position. Solenoid valves such as No. 255B-610E by Mac Valves, Inc. of Wixom, Michigan have been found to be suitable for this application. The time delay for the onset of application of air pressure to the dispenser gun 40 and the duration of air supply responsive to a signal from sensor 30 is adjusted to correspond to one full revolution of the work station 50 as it nears its uppermost position and begins its travel back into registry with the pathway for the can ends. At C in FIG. 5 the can end with sealant will be displaced by transport means (not shown), placing another can end without sealant onto work station 50 while it is in registry with the pathway. The same sequence of operation previously described is then repeated. In addition, hold down pad 24 and hold down pad shaft 21 can be provided with a collar 42 for limiting the upward travel of the hold down pad to prevent damage to the apparatus in the event of a failure of the plunger assembly to hold position due to the backing off of plunger guide nut 36 or failure of the spring or breakage of dowel pin 38 or the like. This collar 42 will also prevent accidental engagement of the can end with the dispenser air nozzle 41 which could damage the nozzle and require service of the apparatus.
In the practice of the present invention, it is contemplated that the fluid sealant used can be the conventional latex and clay composition used normally for beverage applications, however, any other suitable sealant can be used which will flow under pressure and provide the necessary sealing function particularly for food grade containers. It is also contemplated that conventional electro-pneumatic dispensing guns can be used, such as those provided by the Nordson corporation of Amherst, Ohio, (for example, Compound Gun No. A11A 709570) which typically are connected to a sealant supply under a pressure of from between sixty and ninety pounds per square inch pressure with the composition temperature maintained in the range of from about 90° F. to about 110° F.
It has been found by the use of the apparatus of the present invention that a more uniform application of sealant to can end recesses is accomplished with a minimum of so-called pigtail curl, which is excess sealant and, therefore, waste. This means there is a reduction in cost from excess sealant application and from scrap created by improper sealing. In addition, the apparatus of the present invention can, when properly adjusted, maintain a rate of operation in an excess of four hundred can ends per minute, with a minimum of down time for readjustment of the apparatus, thereby producing further economies in the operation of applying sealant to can ends.
It can be seen from the foregoing that the apparatus of the present invention can be utilized in a wide variety of applications not limited to application of sealant to beverage can ends. It is intended that the claims be construed to include alternative embodiments of the inventive concepts disclosed herein except insofar as limited by the prior art.
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An apparatus for accurately dispensing predetermined amounts of fluid sealant onto can ends which comprises a dispenser arm mounted at one end for horizontal and vertical arcuate movement, a clamp for releasably holding the arm in one operative position, a can end hold down located on said dispenser arm and capable of reciprocal and rotational movement, and a proximity sensor responsive to the reciprocal movement of said can end hold down to generate a control signal when the can end hold down is approaching the apex of its reciprocal movement and dispenser mounted on said dispenser arm proximate to said can end hold down and capable of dispensing a predetermined amount of fluid sealant onto a can end in a predetermined location in timed response to the signal from said proximity sensor.
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FIELD OF THE INVENTION
This invention relates to metal cutting tool assemblies of the kind wherein an exchangeable cutting insert is releasably retained in an insert retaining slot formed in a holder blade. The invention relates particularly to such a cutting tool assembly wherein the insert is retainably clamped within the retaining slot between a resiliently displaceable clamping jaw and a rigid base jaw without the use of additional mechanical clamping means such as clamping screws or the like.
BACKGROUND OF THE INVENTION
One known form of cutting tool assembly of the kind to which the invention relates involves the so-called “wedge clamping” of the insert in the insert retaining slot. Here, the insert, having a single cutting edge, is provided with a wedge-shaped body which forcibly inserted and is retained within a correspondingly wedge-shaped retaining slot, the actual clamping of the insert within the slot being effected by the resilient outward displacement of the clamping jaw as a result of the forced insertion of the insert into the slot. With this type of cutting tool assembly, the resilient displacement of the jaw is effected by the insertion of the insert into the slot, but when it is desired to remove the insert, special means have to be provided for mechanically ejecting the insert from the slot, these means involving the direct exertion of an ejection pressure on the insert. It will be understood that both the insertion and removal of the insert is accompanied by significant friction with consequent wear on the blade jaws which are, in general, of a much softer material than that of the insert.
Alternatively, it is known (GB 1379637) to introduce into and clamp an insert within an insert retaining slot by first of all mechanically displacing outwardly a resiliently clamping jaw, introducing the insert into the slot and then allowing the jaw to spring back on to the insert in a clamping position. When it is desired to remove the insert from the slot, the clamping jaw is again displaced outwardly, allowing for the removal of the insert. The outward displacement of the jaw is effected using a mechanical key which is displaced in frictional contact with the inside of the clamping jaw, thereby leading to frictional wear of the jaw and/or the key.
BRIEF SUMMARY OF THE INVENTION
It is an object of the present invention to provide a new and improved metal cutting tool assembly in which the above-referred-to disadvantages are substantially reduced or overcome.
According to the present invention, there is provided a metal cutting tool assembly comprising a rigid holder blade; an insert receiving slot formed in a leading end of the holder blade and defined between a resiliently displaceable clamping jaw formed integrally with said holder blade and rigid base jaw forming part of the holder blade; spaced apart displacement and supporting surfaces respectively formed in or on said clamping jaw and said holder; and a slot opening key, a pair of spaced apart projecting prongs of said key adapted to engage said surfaces, at least one of said prongs being displaceable with respect to said holder blade so as resiliently to displace said clamping jaw outwardly with respect to said base jaw into an opening position for insertion or removal of an insert.
Preferably, there is formed in the holder blade an extension slot communicating with said insert receiving slot and extending rearwardly thereof. There can be formed in the clamping jaw forwardly of said extension slot a clamping jaw aperture, said displacement surface being constituted by a rim of said clamping jaw aperture.
In accordance with one preferred embodiment of the present invention, the supporting surface is formed on an upper surface of said clamping jaw adjacent said extension slot, one of said prongs being adapted to project into said clamping jaw aperture whilst the other of said prongs bears on said supporting surface, whereby a levering displacement of said one prong with respect to the other prong results in the outward displacement of said clamping jaw.
Alternatively, and in accordance with another preferred embodiment of the present invention, the supporting surface is formed in said base jaw, said supporting surface being constituted by a rim of said base jaw aperture and wherein said opening key is provided with means for displacing said prongs apart whereby, with said prongs projecting respectively into said clamping jaw and base jaw apertures, displacement apart of said prongs results in said outward displacement of said clamping jaw.
Thus, with a cutting tool assembly in accordance with the present invention, displacement of the clamping jaw, whether effected by a levering action or by way of a direct, linearly directed displacement, is not accompanied by any direct contact, either with the insert or with the inner surface of the clamping jaw, and in this way damage thereto is avoided or minimized. Furthermore, introduction into and removal of the insert from the slot is not accompanied by any frictional resistance by the opposite jaw surfaces and there is therefore avoided frictional wear of these surfaces leading to an extended life of the holder blade as a whole.
BRIEF DESCRIPTION OF THE DRAWINGS
For a better understanding of the present invention and to show how the same may be put into practice by way of example, reference will now be made to the accompanying drawings, in which:
FIG. 1 is a side elevation of a holder blade of a cutting tool assembly in accordance with the present invention;
FIG. 2 is a side elevation showing the retention of a cutting insert in the holder blade shown in FIG. 1 ;
FIG. 3 is a perspective view of the cutting tool assembly shown in FIG. 2 , together with an associated retaining slot opening key;
FIG. 4 is a similar view to that shown in FIG. 3 , with a modified form of retaining slot opening key;
FIG. 5 is a side elevation of a further form of holder blade for a cutting tool in accordance with the present invention;
FIG. 6 is a perspective view of the holder blade shown in FIG. 5 and a cutting insert clampingly retained therein, together with an appropriately mounted retaining slot opening key;
FIG. 7 is a perspective view of a further form of cutting tool assembly in accordance with the present invention, with an associated retaining slot opening key; and
FIG. 8 is a perspective view of a still further form of cutting tool assembly in accordance with the present invention, with an associated retaining slot opening key.
DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS
As seen in FIG. 1 of the drawings, a holder blade 1 for a metal cutting tool assembly in accordance with the present invention comprises a rigid body portion 2 with which are formed integrally a clamping jaw 3 and a base jaw 4 . The clamping jaw 3 is coupled to the body portion 2 via a relatively narrow neck portion 5 , thereby allowing for a limited degree of flexible resilience of the clamping jaw 3 with respect to the body portion 2 and with respect to the base jaw 4 , the latter forming a rigid whole with the body portion 2 .
As can be seen in dotted lines in FIG. 1 of the drawings, the clamping jaw 3 , in its unstressed position, has its forward tip 6 directed downwardly towards the base jaw 4 and is spaced therefrom by a distance h 1 .
In order to allow for the introduction of an insert 7 (shown in FIG. 2 of the drawings) having a height h 2 , the clamping jaw 3 must be displaced upwardly in the direction of the arrow 8 ( FIG. 1 ) so that its forward tip 6 is spaced from the base jaw 4 by a distance h 3 where h 3> h 2 . As seen in FIG. 1 of the drawings, there is formed in a leading end of the holder blade 1 , and defined between opposite surfaces of the damping jaw 3 and base jaw 4 , an insert retaining slot 9 , a rear end of which communicates with a rearwardly extending extension 10 of the slot 9 and a lower, curved aperture 11 . As can be seen in FIG. 2 of the drawings, the location of the extension 10 is such as to be bordered by the narrow neck portion 5 of the clamping jaw. The lower, curved aperture 11 is provided so as to ensure that the lower, innermost edge of the insert is properly located within the aperture 11 without encountering the slot wall. The retained insert 7 is abutted by an abutment 12 of the body portion 2 , and the upper, innermost edge of the insert is located within the extension 10 . In this way there is prevented possibly damaging abutment of the inner edges of the insert with the body portion.
As can furthermore be seen in FIG. 2 of the drawings, with the insert 7 clampingly retained within the insert retaining slot 9 , the clamping jaw 3 bears clampingly downwardly on the upper surface of the insert 7 in the direction of the arrow 13 .
There is formed in the clamping jaw 3 , forwardly of the neck portion 5 , a throughgoing aperture 14 , whilst there is formed in the base jaw 4 , adjacent a front edge thereof, a throughgoing aperture 15 .
Reference will now be made to FIG. 3 of the drawings, for a detailed description of an insert retaining slot opening key 21 and the manner in which it is used in order to open the insert retaining slot so as to allow for the introduction of the insert. As seen in FIG. 3 of the drawings, the retaining slot opening key 21 comprises a body 22 having a pair of integrally formed legs 23 a, 23 b from which respectively project a pair of spaced-apart prongs 24 a, 24 b.
Located between the legs 23 a, 23 b and bearing against them is a wedge-like spacer 25 having a throughgoing threaded bare 26 through which extends a screw 27 , an upper end of which remote from the spacer 25 is coupled to a turning handle 28 .
Rotation of the turning handle 28 in the direction of the arrow 29 results in an inwardly-directed displacement of the spacer 25 , thereby giving rise to an outwardly-directed displacement of the legs 23 a, 23 b and a consequent outwardly-directed displacement of the prongs 24 a, 24 b in the direction of the arrows 30 a, 30 b.
If now, and prior to the rotation of the handle 28 so as to cause the outward displacement of the prongs 24 a, 24 b, the latter are inserted in the apertures 15 , 14 and rotation of the handle 28 takes place in the direction of the arrow 29 , it will be readily seen that there occurs an outwardly-directed displacement of the clamping jaw 3 . As a consequence, the clamping jaw 3 effectively pivots about its narrow neck portion 5 , thereby increasing the spacing between the clamping jaw 3 and the base jaw 4 and allowing for the introduction or removal of the insert 7 . Rotation of the handle 28 in the opposite direction allows for the clamping jaw 3 to return into a clamped position, thereby clampingly retaining the insert in position.
FIG. 4 shows a modified form of turning key 33 having a fixed projecting prong 34 a and an eccentrically rotatable projecting prong 34 b which is coupled to a turning handle 35 , rotation of which in one sense gives rise to widening the spacing between the prongs 34 a, 34 b and rotation in the other sense from this widened spacing results in a return to the original spacing.
If now, as before, the prongs 34 a, 34 b are positioned within the apertures 15 , 14 , rotation of the handle in one sense gives rise to an outwardly-directed displacement of the clamping jaw, allowing for the insertion or removal of the insert.
It will be appreciated that, in the embodiments shown in FIGS. 3 and 4 of the drawings, a rim of the aperture 14 in the clamping jaw 3 constitutes a clamping jaw displacement surface, whilst a rim of the aperture 15 in the base jaw 4 constitutes a support surface.
Reference will now be made to FIGS. 5 and 6 of the drawings where, as can be seen, the clamping and base jaws define between them, as before, an insert retaining slot which communicates with a rearwardly-directed extension 10 and a lower, curved aperture 11 .
As before, there is formed in the clamping jaw 3 a throughgoing aperture 14 , but in this embodiment there is not formed any through-going aperture in the base jaw 4 . As seen in FIG. 6 of the drawings, a turning key 41 is formed with a pair of spaced-apart, fixed cylindrical prongs 42 , 42 b with the prong 42 a extending through the aperture 14 whilst the prong 42 b rests on an upper fulcrum surface of the Bolder blade 1 . If now the key is rotated in the direction of the arrow 43 , it can be seen that there will be a levering displacement outwardly of the clamping jaw 3 with respect to the prong 42 b. In this embodiment, the rim of the aperture 14 serves as a displacement surface whilst the holder blade 1 , upon which rests the prong 42 , serves as a supporting fulcrum surface.
In a modified embodiment shown in FIG. 7 of the drawings, a rearwardly-directed extension 10 ′ of the insert retaining slot 9 is shaped to receive the prong 42 b of the key 41 , with the other prong 43 a extends through the aperture 14 . Here again, upon rotation of the key 41 in the direction of the arrow, a levering outward displacement of the clamping jaw is effected with respect to the prong 42 b. In the case of this embodiment, the rim of the aperture 14 again constitutes a displacing surface whilst the rim of the extension 10 ′ constitutes a supporting fulcrum surface.
In a still further modification shown in FIG. 8 of the drawings, an additional aperture is formed in an upper portion of the body portion 2 of the holder, adjacent to and spaced from the aperture 14 and displaced inwardly with respect to the slot extension. If now the prongs 42 a, 42 b are inserted in the apertures 14 , 45 and the key is rotated in the direction of the arrow, levering outward displacement of the clamping jaw is effected about the fulcrum constituted by the prong 42 b, with the rim of the aperture 14 constituting a displacement surface and the rim of the aperture 45 constituting a supporting fulcrum surface.
Whilst in the embodiments specifically described above clamping retention of a cutting insert having substantially parallel upper and lower surfaces has been described, it will be readily appreciated that the present invention can be extended to the so-called “wedge clamping” of inserts having a wedge-shaped body portion arranged to be retained within a corresponding wedge-shaped slot formed in the holder blade.
It will be furthermore understood that the present invention is not restricted to any particular kind of cutting insert such as, for example, the cutting insert specifically illustrated, but is readily applicable to other forms of cutting inserts.
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A metal cutting tool assembly comprising a rigid holder blade, an insert receiving slot formed in a leading end of the holder blade and defined between a resiliently displaceable clamping jaw formed integrally with the holder blade and rigid base jaw forming part of the holder blade, spaced apart displacement and supporting surfaces respectively formed in or on the clamping jaw and the holder, and a slot opening key, with a pair of spaced apart projecting prongs of the key adapted to engage the surfaces. At least one of the prongs is displaceable with respect to the holder blade so as resiliently to displace the clamping jaw outwardly with respect to the base jaw into an opening position for insertion or removal of an insert.
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BACKGROUND OF THE INVENTION
[0001] 1. Field of the Invention
[0002] This invention relates to a method for correcting the optical system of an eye using an intraocular lens system. Particularly, this invention relates to a method of correcting focusing abnormalities and optical aberrations measured by wave front or similar technology to quantify optical aberrations in the optical system of the eye, using a laser, or other apparatus and/or methods of fabricating or modifying a lens, for the optical system of an eye having a foldable, interchangeable intraocular lens system provided therein.
[0003] 2. Description of Related Art
[0004] The field of refractive surgery has evolved rapidly during the past few decades. Current procedures and methods used by refractive surgeons may not satisfy the total refractive needs of the patient. Particularly, the most commonly performed refractive surgical procedures, such as, for example, cataract extraction with intraocular lens implantation, in addition to the most recently popularized corneal refractive surgical procedures, such as eximer laser photoblation, exhibit limitations. One reason for the limitations is the lack of post-operative refractive accuracy. The lack of post-operative refractive accuracy renders the commonly known refractive surgical procedures uncompetitive with currently available non-surgical alternatives for patients, for example, glasses and contact lenses. Further, because refractive surgery requires local or general anesthesia and incisions into the eye, a need exists for decreasing the trauma resultant from the surgery.
[0005] Recently, a need has arisen for efficient treatment of presbyopia, or the diminished power of accommodation of the eye. Presbyopia is a condition which typically affects a large number of people as they age, with the severity of the condition varying depending on the person. Difficulties arise in treating presbyopia because typically once a person manifests symptoms of presbyopia, the symptoms worsen as the person ages. As a person's condition worsens, a different, usually more powerful, lens is required to correct the condition. Conventional techniques for replacing an intraocular lens each time the patient's vision deteriorated do not always present a practical or cost-effective approach. Recent developments in the field, of refractive surgery have made intraocular treatment of presbyopia a feasible course of treatment for those patients that desire or need improved vision, however a need exists for more precise techniques and devices for use in refractive intraocular surgery.
[0006] Patients suffering from eye trauma or other eye afflictions may have the iris or other portions of the eye distorted, destroyed, or discolored. Currently, such patients are typically prescribed cosmetic contact lenses. Cosmetic intraocular lens replacement is emerging as a viable alternative, however a need exists for more efficient intraocular lens replacement in order to minimize eye trauma and establish cosmetic intraocular lens replacement as a safe and effective alternative to cosmetic contact lenses and other nonsurgical treatments. As surgical techniques become more effective, safer, and less painful, patients may choose to have elective lens replacement surgery to change the color, structure, or shape of their eyes. By providing a minimally invasive method for lens replacement as described in an embodiment herein, the surgeon is able to limit the drawbacks of the procedure.
[0007] Current procedures and methods for refractive surgery require the performing surgeon to execute the procedure with a high level of skill and experience. Currently, methods and procedures for carrying out refractive surgery involving intraocular lenses generally require direct visualization of the intraocular lens assembly within the eye. Such visualization, although not outside the scope of a surgeon skilled in the art, increases the degree of difficulty of the procedure, thus increasing the chance that a surgical error or other problem will arise in the surgical procedure, leading to unwanted complications. Thus, a need exists for intraocular lens assemblies and systems whose structures provide less complex methods of insertion into and extraction from the eye.
[0008] Currently, refractive cataract surgeons performing the most common refractive surgical procedure, i.e., routine cataract surgery, obtain refractive accuracies in a ±0.75 to ±1.00 diopter (D) range. However, the industry has established goals of obtaining refractive accuracies in the ±0.25 D range. Therefore, there is a need in the industry to provide a more accurate alternative to the current procedure. Furthermore, analyses of current corneal refractive technologies indicate the presence of a significant amount of preexisting or naturally occurring post-operative, as well as preoperative, image distortion (optical aberration) or degradation, particularly under low light conditions, such as when driving at night.
[0009] Due to the practical limits of performing intraocular surgery, as well as the biological and physical behavior of the human eye during and after various types of intraocular surgery, predictability at the ±0.25 D accuracy level with-a single surgical procedure is difficult to achieve as a practical matter. Furthermore, factors such as biometry errors, variable wound healing, and capsular contraction around the intraocular lenses contribute to decreasing the likelihood of achieving the desired refractive accuracy. Accordingly, practitioners in the industry have found that an adjustable intraocular lens (IOL), hereinafter referred to as the MC-IOL (multi-component) or C-IOL (compound), following lens extraction surgery provides a plurality of desirable options for refractive surgeons and patients.
[0010] An adjustable IOL allows fine tuning of the initial refractive result by exchanging at least one of the optical elements of the lens implant. As a result, accuracies in the ±0.25 D range are readily attainable. Furthermore, patients are provided with an opportunity to exchange the “old” lens components with new and hopefully more accurate components. Such an objective is obtainable if the surgeon has an effective, efficient, and safe method of performing lens element exchanges. Additionally, months and/or years after the refractive surgical procedure, if the optical properties of the inserted IOL, for example, the multifocality, become problematic, the surgeon should have the ability to safely exchange the undesirable optical elements of the IOL to correct any optical aberrations that the patient will not or cannot tolerate.
[0011] In 1990, the inventor of this application developed a multi-component intraocular lens, hereinafter referred to as the MC-IOL ( FIG. 1 ), for use following clear lens or refractive cataract surgery, wherein the optical properties of the MC-IOL can be modified at any post-operative time. The base intraocular lens component of the MC-IOL is shown in FIG. 1 . The mid lens attaches to the top of the base lens and holds the third component of the MC-IOL, the top lens, in place.
[0012] The base intraocular lens 10 and the mid lens 20 each have securing flanges 16 , 18 and 20 , 24 , respectively, extending therefrom. The MC-IOL also comprises at least one top lens 30 , as illustrated in FIG. 1 . The top lens 30 is positioned on top of the mid lens 20 . See FIGS. 1-2 .
[0013] The MC-IOL also includes projections (or haptics) 11 and 13 which securely hold the MC-IOL in the tissue of the human eye. The above-described
[0014] structure permits the base intraocular lens 10 to form a platform upon which the mid lens 20 is placed, and to hold the top lens 30 . During routine cataract surgery, the MC-IOL replaces the crystalline lens of the human eye. Once a patient's eye has healed after such a surgery, the surgeon reenters the eye and replaces, if necessary, and more than once, the top lens 30 and the mid lens 20 to modify the optical characteristics of the eye until the desired levels for each optical characteristic are attained.
[0015] FIGS. 3A-3B illustrate an assembled compound intraocular lens, hereinafter C-IOL, used with a preexisting lens within the human eye. The C-IOL has two components similar to the mid lens ( FIGS. 4A-4B ) and the top lens ( FIGS. 5A-5B ) components of the MC-IOL. FIG. 5 also illustrates the axis orientation mark 85 used in some embodiments of MC-IOL lenses, to aid in positioning and orienting the lens. The preexisting lens can be the crystalline lens of the eye with the C-IOL placed in the sulcus ( FIG. 6 ) or in the anterior chamber angle ( FIG. 7 ) of the eye's optical system. However, the C-IOL can also be used with a conventional IOL, as well as with an accommodating IOL, and mounted in the sulcus ( FIG. 8 ), in the anterior chamber angle ( FIG. 9 ), in the anterior chamber with posterior chamber fixation ( FIG. 10 ) or in the anterior chamber with iris fixation ( FIG. 11 ). Thus, a surgeon modifies the optical characteristics of the optical system of the eye by using the mid and top lenses in tandem with the preexisting conventional IOL implant or crystalline lens of the eye.
[0016] The C-IOL and MC-IOL provide numerous enhanced features. For example, the C-IOL and MC-IOL can each be structured as a monofocal or multifocal optical system, correct astigmatism, as well as comprise ultraviolet light-absorbing, tinted, or other such chemically treated materials.
[0017] It should be understood that there are various reasons why an adjustable MC-IOL or C-IOL is more desirable than a single component implant. In order to achieve all the permutations and combinations of the astigmatism, multifocality, and spherical correction needed to achieve emmetropia would take an inventory of over ten thousand lenses, whereas with the MC-IOL (multiple components) concept, an inventory of about one hundred components would be necessary. With anterior chamber lenses, progressive encapsulation or engulfment of the lens haptics by uveal tissue in the angle often occurs 1-2 years post-operatively. The engulfment typically makes the removal of the lenses and their haptics more difficult. Exchange of iris fixated anterior chamber lenses does not typically guarantee precise position or orientation. Posterior chamber lenses similarly cannot be removed because of posterior capsule fibrosis. Easy removal and exchangeability is critical for any customized emmetropic system, which can be provided by a specially designed multicomponent lens system.
[0018] Therefore, based on the above, a MC-IOL having three elements rather than one permits refractive customization and adjustability for all refractive errors, as well as for all patients, while using a minimal number of lens elements or parts and requiring little customization on the part of the manufacturer. Thus, it has become very important in the refractive surgery art to be able to individualize and/or customize surgery such that the surgeon can easily and safely, as well as accurately, modify the refractive power of an intraocular lens implant.
[0019] For example, U.S. Pat. No. 5,288,293 to O'Donnell, Jr. discloses a method of modifying a single IOL. O'Donnell suggests that the refractive power of a single IOL may be varied before implantation so that the changes can be made in situ by the ophthalmologist after determining the extent of correction required to improve the vision of the patient before the lens is made. However, the surgical implantation procedure itself may create additional optical aberrations which cannot be anticipated preoperatively and thus the primary lens implant cannot account for these optical aberrations.
[0020] As such, it may be argued that if a lens can be modified before being implanted, as suggested by O'Donnell, Jr., it should be possible to modify the implanted lens by removing the implanted lens, modifying the lens, and then reimplanting the modified lens into the optical system of the eye. However, the design of current intraocular lenses typically makes such a procedure difficult and impractical. Furthermore, after a period of time with normal healing, it becomes physically dangerous and/or nearly impossible to the patient to have the implanted lens removed once the eye tissue takes hold on the capsular fixation holes of the lens. Therefore, such an argument is not realistic, practical, or safe. A single component intraocular lens, which in general is not designed to be removed and with only two optical surfaces, cannot accurately allow for compensation of sphere, cylinder, cylindrical axis, and all forms of optical aberrations that may be discovered after the initial implantation. However, the MC-IOL typically will have four removable optical surfaces which can compensate for these optical properties.
[0021] The inventor of this application invented the previously discussed MC-IOL and C-IOL that are designed specifically to permit the easy exchange of optical elements at a post-operative period without risk to the human eye or to the patient, beyond the risk of ordinary intraocular surgery. The easy exchangeability of optical elements is critical because the actual surgery of implanting the lens in the first place, as well as variances in the manner in which the eye heals after implantation, potentially create distortions which may not stabilize for several months after the operation. Therefore, the ability to measure and to compensate for the distortion(s) optimally takes place several months after surgery and cannot typically be predicted prior thereto. Since the same surgical wound is used for both the primary and secondary operations, additional distortion due to wound healing would not be anticipated as a result of the second operation.
[0022] Furthermore, the ability to exchange optical elements of a multicomponent or compound intraocular lens can be economical compared to removing, modifying, and re-implanting a single component lens, as well as easier to perform.
[0023] The MC-IOL has four surfaces available for modification, two piano and two convex. Preferably, the modification is made only to the piano surfaces to avoid interfering with the convex side which may already be used for correction of astigmatism (cylinder) or used as a multifocal lens surface. The same preference applies to the CIOL, which has two surfaces available for modification, one piano and the other convex.
[0024] The inventor of this application also developed a system for correcting optical aberrations in the MC-IOL, as described, for example, in U.S. Pat. No. 6,413,276, for conducting measurements to determine any residual or new aberrations present in an operated eye after the biological healing parameters have stabilized, as well as to correct any errors in sphere, cylinder, or cylindrical axis, and for modifying one, two, or more existing lens elements within the implanted optical system based on the conducted measurements.
[0025] In conventional multi-component intraocular lens designs, the surgical procedure required to implant the intraocular lens components requires a high level of surgeon skill. For example, implantation of the removable component of the lens requires the surgeon to directly visualize the placement of the lens in order to match the notches with the flanges. Further, removal of the removable lens component requires a special forceps tool for grabbing the base lens, and releasing the tabs holding the sandwich and cap lens together with the base lens (see, for example, the system described in U.S. Pat. No. 5,968,094).
[0026] Historically intraocular lens systems used a rigid one piece poly methyl methacrylate (PMMA) lens. The PMMA lens is approximately six millimeters in diameter. Because the PMMA lens is rigid, insertion of the PMMA intraocular lens generally requires a seven or eight millimeter incision to be inserted into the eye. In contrast, a flexible or foldable lens can be manipulated and compacted to a much smaller size. Once compacted, the multi-component intraocular lens can be delivered using a relatively smaller incision, for example, about three millimeters or less. By using a smaller incision, the patient reaps optical and practical benefits. From an optical standpoint, any time incisions are made to the cornea, the cornea loses some of its natural globularity due to imperfections caused by the incisions and the resultant trauma. The imperfections in the cornea lead to induced astigmatism, or optical aberrations caused by irregularities in the shape of the cornea. By minimizing the size of the corneal incision, a surgeon may also minimize the amount of induced astigmatism. Even though the three-component design simplifies the process of correcting induced astigmatism, minimizing the amount of induced astigmatism remains a primary goal for all intraocular surgeries.
[0027] As a practical matter, by making a smaller incision, the surgeon reduces the amount of actual trauma to the eye, thus reducing the occurrence of complications and decreasing the time for recovery. These advantages are further realized if the surgeon is able to perform the intraocular surgery using an incision small enough to heal without the use of stitches, wherein the incision is small enough to allow the eye's natural ocular pressure to hold the incision together during the healing process.
SUMMARY OF THE INVENTION
[0028] It is an aspect of this invention to overcome the above-described drawbacks of the related art.
[0029] In particular, it is an aspect of this invention to provide a multi-component intraocular lens system with components that are removable after placement in the eye. It is an additional aspect of the present invention to provide a multi-component intraocular lens system with foldable components in order to minimize trauma to the eye. Trauma is minimized by allowing the use of a delivery system for the foldable lens which requires an incision smaller than the unfolded diameter of the foldable lens.
[0030] It is a further aspect of this invention to provide a multi-component intrabcular lens system with components designed to simplify the surgical procedure for intraocular lens component insertion. An embodiment of the present invention includes a multi-component intraocular lens, wherein the base lens is attached with haptics, and the top and mid lenses are assembled outside the eye. The top and mid lenses may include projections designed to lock into place with flanges of the base lens. The intraocular lens system allows assembly without the use of special equipment or techniques for securing the top and mid lenses to the base lens. The intraocular lens system also does not require that the surgeon performing the operation be able to see or visualize the insertion of the top and mid lenses. Rather, in the present invention, the surgeon merely slides the folded mid/top lens assembly into the eye, unfolds the assembly in the eye, and slides the assembly across the base lens component until each projection aligns with a corresponding flange.
[0031] It is an aspect of the present invention to provide a modified multi-component intraocular lens implanted in an optical system of a human eye, including three or more removable components, with each component being foldable, and two of the removable components being connected to each other by a flange and slot.
[0032] It is a further aspect of the present invention to provide a multi-component intraocular lens for an eye, including a foldable base intraocular lens component, a foldable removable lens component, and a foldable mid intraocular lens component. The foldable removable lens component is attached to the foldable mid intraocular lens component by a notch along the circumference of the foldable removable lens component.
[0033] It is yet another aspect of the present invention to provide a system for the administration of pharmacological agents through an intraocular lens system capable of the time-delayed release of medicine into the eye over a predetermined, and/or adjustable period of time.
[0034] The use of an adjustable intraocular lens allows adjustment or exchange of optical elements, both spherical and cylindrical, independent of any additional wound healing or significant calculation error to fine-tune, reverse, or replace any of the original optical features.
BRIEF DESCRIPTION OF THE FIGURES
[0035] In the drawings:
[0036] FIG. 1 is a plan view of the base, mid, and top lens components of a currently known multi-component intraocular rigid lens;
[0037] FIG. 2 is an exploded side view of the assembled base, top, and mid lenses of the currently known multi-component intraocular rigid lens shown in FIG. 1 ;
[0038] FIGS. 3A-3B are exploded views of a two component compound intraocular lens;
[0039] FIGS. 4A-4B are top and side views, respectively, of a type of compound intraocular lens-top lens component;
[0040] FIGS. 5A-5B are top and side views, respectively, of a type of compound intraocular lens-top lens component;
[0041] FIG. 6 is a side view of a compound intraocular lens implanted within a human eye ciliary sulcus;
[0042] FIG. 7 is a side view of another compound intraocular lens implanted within a human eye using the anterior chamber angle as support;
[0043] FIG. 8 is a side view of a sulcus mounted compound intraocular lens implanted within a human eye with a previously implanted single component conventional intraocular lens mounted in the capsular bag;
[0044] FIG. 9 is a side view of an anterior chamber mounted compound intraocular lens implanted within a human eye with a previously implanted single component conventional intraocular lens mounted in the capsular bag;
[0045] FIG. 10 is a side view of an anterior chamber mounted compound intraocular lens on a support secured in the posterior chamber and is implanted within a human eye with a previously implanted single component conventional intraocular lens mounted in the capsular bag;
[0046] FIG. 11 is a side view of an iris fixated compound intraocular lens in the anterior chamber that is implanted within a human eye with a previously implanted single component conventional intraocular lens mounted in the capsular bag;
[0047] FIG. 12 is a top view, with an enlarged side view cutaway, of the base component of a foldable multi-component intraocular lens according to an embodiment of the present invention;
[0048] FIG. 13 is a top view of the base component of a foldable multi-component intraocular lens according to another embodiment of the present invention;
[0049] FIGS. 14A and 14B are an exploded top view and an exploded side view, respectively, of the mid lens replaceable component of a foldable multi-component intraocular lens according to an embodiment of the present invention;
[0050] FIG. 15 is an exploded top view of the top lens component of a foldable multi-component intraocular lens according to an embodiment of the present invention; and
[0051] FIG. 16 is a side view of the inventive assembly when the top lens is inserted into the mid lens according to an embodiment of the present invention.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT
[0052] FIG. 12 shows a top or plan view of the intraocular foldable base lens 100 in a preferred embodiment of the present invention. The base lens 100 is similar to the MC-IOL base lens illustrated in FIG. 3 . The base lens 100 is preferably manufactured from acrylic or silicone materials, but the base lens 100 can be manufactured from any suitable foldable material. The base lens 100 has a diameter ranging from 1.00 to 8.00 millimeters, but preferably is between 5.50 and 6.50 millimeters, and has an optical aperture ranging from 3.0 millimeters to 7.0 millimeters, with a preferable optical aperture of 5.5 millimeters.
[0053] As mentioned above, the base lens 100 has a diameter ranging from 1.00 to 8.00 millimeters, and is preferably composed of foldable material. Accordingly, the insertion of the base lens 100 into the eye requires an incision therein which is less than half as large as the diameter of the base lens 100 .
[0054] The base lens 100 attaches to the eye by at least one haptic 120 . In FIG. 12 , the base lens 100 is secured to the eye by at least one, but preferably two haptics 120 , however, this is merely one embodiment of the present invention, and other embodiments may use one or more haptics 120 to secure the base lens 100 to the eye.
[0055] The haptics 120 illustrated in FIG. 12 have a span ranging from 5.0 millimeters to 15.0 millimeters. In a system where the base lens 100 has two haptics extending outward, the two haptics each have a preferable span of 12.0 to 1 3.0 millimeters. The preferable length of the haptics 120 depends on the number of haptics extending from the base lens 100 . Each haptic 120 extends outward from the base lens 100 , and is tilted from between 10 to 20 degrees, in either direction, relative to a plane taken across the base lens, preferably having a 15 degree positive tilt.
[0056] The base lens 100 includes one or more flanges 105 disposed on and extending outwardly away from the body of the base lens 100 , preferably forming a perpendicular angle with the plane of the base lens, however the flanges 105 could extend outward from the body of the base lens at any angle from 45 degrees to 135 degrees. In a preferred embodiment, such as the embodiment illustrated in FIG. 12 , two flanges 105 are disposed on either side of the base lens 100 . However, the invention is not limited to this embodiment, as more flanges 105 may be disposed in various locations around the base lens 100 .
[0057] Each flange 105 has a slot 110 designed or configured to receive or accept an assembly of a top lens 300 and a mid lens 200 therein, which will be described in more detail herein. The slot 110 illustrated in FIG. 12 is in the shape of a parallelogram, however other shaped slots, such as elliptical, oval, trapezoidal, rounded rectangular, or any other known geometric shape are considered to be within the scope and pervue of the present invention.
[0058] The base lens incorporated into another embodiment of the present invention is illustrated in FIG. 13 . The base lens 102 is similar to the base lens 100 , except for a groove 130 defined in the base lens 100 and extending along the entire outer periphery of the base lens 102 , and four attachment points 140 , which serve to attach the optical region 150 to the base lens 102 . Although four attachment points 140 are illustrated here, embodiments with more attachment points or fewer attachment points are also considered to be within the scope and pervue of the invention. In all other aspects, the base lens 102 is the same as the base lens 100 illustrated in FIG. 12 .
[0059] In an embodiment of the present invention, the base lens 100 is infused with chromophores, which absorb light in a portion of the light spectrum. For example, the base lens could be infused with chromophores to absorb light from the ultraviolet wavelength portion of the light spectrum, typically between 380 and 389 nm. By absorbing light in the ultraviolet wavelength portion of the spectrum, the intraocular lens system reduces eye glare, enhances vision capabilities, and helps protect the eye from potentially harmful ultraviolet rays. Although ultraviolet light is exemplified here, other color chromophores, which are used to block other wavelengths of light, are also considered within the scope and pervue of the invention.
[0060] The foldable MC-IOL includes two or more additional refractive components, including an assembly of the top lens 300 and the mid lens 200 , described more fully herein. One embodiment of the mid lens 200 , hereinafter interchangeably referred to as the “middle” lens, the “cap” lens, or the “removable component” lens, is illustrated in FIGS. 14A and 14B . The mid lens 200 allows spherical adjustments from −4.00 D to +4.00 D in 0.25 D increments. In an embodiment of the present invention, the top lens 300 carries the astigmatic correction, which can range, for example, from 0.00 D to 5.00 D cylinder in 0.25 D increments and has an orientation projection 305 . The present values are presented merely for illustrative purposes, and other possible ranges for the cylinder at various sphere values are considered to be within the scope and pervue of the invention.
[0061] Like the base lens 100 , the top lens 300 may be constructed from acrylic, silicone, or any other material suitable for manufacturing a foldable intraocular lens. The top lens 300 has a central thickness ranging from 0 . 1 millimeters to 0.4 millimeters, and a diameter ranging from 1.50 to 8.50 millimeters, but preferably is between 5.50 and 7.00 millimeters. The top lens 300 features an optical aperture ranging from 3.0 millimeters to 7.0 millimeters, with a preferable optical aperture of 5.5 millimeters.
[0062] The mid lens 200 and/or the top lens 300 may serve multiple purposes depending on the specific embodiment and the specific nature of the problem to be solved. For example, the top lens 300 and/or the mid lens 200 may correct myopia, presbyopia, or astigmatism. The top lens 300 and/or the mid lens 200 may also be used to correct cosmetic defects in the eye. The top lens 300 and/or the mid lens 200 may also be tinted to protect the eye from ultraviolet rays, or blue light, or to reduce glare, or to change the color of the eye for cosmetic or other purposes. The top lens 300 and/or the mid lens 200 , like the base lens 100 , may also be constructed in a manner which allows the top lens 300 and/or the mid lens 200 to absorb light in the ultraviolet wavelength portion of the light spectrum, for the purpose of achieving the same goals as mentioned above.
[0063] In an embodiment of the present invention, the top lens 300 and/or the mid lens 200 may be designed to change the light-gathering aspects of the eye to improve night vision. A lens with these characteristics has potential use for military applications, such as low light or telescopic use, or for underground workers, or in any other application where the patient desires reversibly enhanced night vision, or vision enhancement in a specific area of the spectrum. For example, athletes such as baseball players may desire amber-tinted lenses to improve their ability to perform the tasks critical to their sport, such as seeing the ball. Lenses designed for this purpose could be removed when the patient no longer desires the enhanced vision characteristic, for example when the military application is finished, or the athlete's season or career ends.
[0064] In another embodiment of the present invention, the top lens 300 and/or the mid lens 200 may be used to deliver pharmacological compounds, such as medicines, into the eye. The top lens 300 and/or the mid lens 200 in this embodiment feature a system for delivering a compound into the eye over a predetermined period of time. At the end of the predetermined time period, the surgeon removes the top lens 300 and/or the mid lens 200 , and replaces the top lens 300 and/or the mid lens 200 with a new lens for delivering a compound into the eye, if needed. In this way, the patient may conveniently receive delivery of a compound directly into the inner portions of the eye, while minimizing the risk to the patient, and simplifying the delivery of the compound. Because this treatment does not require recurring action by the patient, the treatment avoids the problem of patient non-compliance, which is critically important to the treatment of chronic eye disorders, such as glaucoma, diabetes, and macular degeneration.
[0065] FIG. 14A illustrates a top view of the mid lens 200 of an embodiment of the present invention. The mid lens 200 includes one or more projections 210 extending horizontally from the body of the mid lens 200 , preferably in the plane parallel to the edge of the mid lens 200 , but optionally at any angle from 150 to 180 degrees in either direction. Each projection 210 may extend outward from the lens ranging from 0.5 to 5.0 millimeters from the outer edge of the mid lens 200 . Each projection 210 may also have varying lengths depending on the shape and number of projections. The projections are illustrated in FIG. 14A as trapezoidal, but any shape which would accomplish the stated purpose of fitting into slot 110 of the flange 105 extending from the base lens 100 , for example, rectangular, triangular, half-oval, notched, ridged, serrated, or any other suitable geometric shape, is considered to be within the scope and pervue of the present invention. Additionally, any shape, indentation, marking, notching, or surface treatment of the flange 105 , including, for example, ribbing, roughening, adding bumps, notches, and indentations, are considered to be within the scope and prevue of the present invention. Likewise, the use of any adhesive material on the flange, for example, glues, Velcros, cements, resins, pastes, or any other adherent, is also considered to be within the scope and pervue of the present invention.
[0066] The mid lens 200 also comprises a side portion 250 which extends upward, and terminates at a lip 225 , as illustrated in FIG. 14B . The side portion 250 and lip 225 extend along the outer circumference of the mid lens 200 , thereby defining a notch 230 . Although the lip 225 is illustrated in FIG. 14B as having a relatively squared off end, the lip 225 may be configured to any suitable shape which does not prevent the formation of the notch 230 , such as, for example, a rounded end, an angled end, or a pointed end. Further, although not illustrated in FIG. 14B , the lip 225 may also optionally be surface treated to have at least one of bumps, ridges, bevels, serrated teeth, gouges, notches, impressions, recesses, or other such surface treatments that are suitable for use in a notch. Additionally, although the notch 230 is illustrated as substantially defining a right angle between the side portion 250 and the lip 225 , the angle formed between the notch 230 and the lip 225 may range from 45 degrees to 135 degrees.
[0067] Prior to insertion into the eye, the top lens 300 (described further herein with respect to FIG. 15 ) engages the notch 225 , such that a seal is formed between the notch 225 and the top lens 300 , and which holds the mid lens 200 and the top lens 300 together as a single assembly. The top lens 300 includes a groove 320 defined in a surface of the top lens 300 , and extends along the circumference of the outer periphery of the top lens 300 . The groove 320 extends along the circumference of the top lens 300 , except for the location of the compression slots 315 , as shown in FIG. 15 . Although four compression slots are illustrated here, embodiments with more compression slots or fewer compression slots are also considered to be within the scope and pervue of the invention. Groove 320 and a series of compression slots 315 allow easier fitting of the top lens 300 into the mid lens 200 . In other embodiments, the groove 320 could be replaced with other slots or channels defined in the periphery of the lens, and the invention should not be considered to be limited to this specific embodiment.
[0068] The top lens 300 also includes one or more end notches 305 . In FIG. 15 , two end notches 305 are illustrated, but varying numbers of end notches, or no end notches at all, are considered to be within the scope of the invention. The end notches 305 are raised slightly from the surface of the top lens 300 , and can be configured to be any one of notches, bumps, ridges, or indentations. The notches could also be of various shapes, sizes, and lengths. The top lens 300 is oriented so that, when the top lens 300 is inserted into the mid lens 200 , as discussed below, the raised projections or notches 305 face the mid lens 200 or may also project away from the mid lens 200 . The notches or projections 305 can provide directional and axial orientation for the top lens, similar to the axis orientation marks 85 of FIG. 5 .
[0069] The surgeon performing the operation or the lens manufacturer assembles the mid lens 200 and the top lens 300 outside the eye to a predetermined axis orientation to correct the astigmatism, and then inserts the completed assembly into the eye as one folded piece. A side view of the completed assembly of the top lens 300 and the mid lens 200 is illustrated in FIG. 16 . It is noted that in FIG. 16 , the angles and sizes have been exaggerated in order to illustrate the relationship between the top lens 300 and the mid lens 200 . It is also noted that, although in FIG. 16 , the side portion of top lens 300 is flush with the side region 250 of the mid lens 200 , and the bottom portion of top lens 300 is flush with the top portion of the mid lens 200 , this fitting is not required for the assembly of the top lens 300 and mid lens 200 . That is, embodiments in which the side portion of the top lens 300 is not flush with side region 250 of the mid lens are considered to be within the scope and pervue of the invention.
[0070] Once the base lens 100 has been inserted into and mounted within the eye, the surgeon inserts the top lens 300 and the mid lens 200 assembly into the base lens 100 by sliding a projection 210 into a slot 110 of a corresponding flange 105 of the base lens 100 . When attaching the assembly of the top lens 300 and the mid lens 200 to the base lens 100 , the surgeon does not need to visually see the individual pieces line up together. Instead, projection 210 is designed to slide into place with the slot 110 . That is, the surgeon unfolds the assembly of the top lens 300 and the mid lens 200 , and then slides the assembly across the base lens 100 until a first projection 210 lines up with a first slot 110 . Once a projection 210 lines up with a slot 110 , the projection 210 catches in the slot 110 , and the surgeon will feel the two pieces lock into place. Once the first projection 210 is in place in the corresponding first slot 110 , if more projections are present in the mid lens 200 , then the surgeon adjusts the mid lens 200 and the top lens 300 until the other projection(s) 210 line up with the other slot(s) 105 . Once all projections 210 have been inserted into their corresponding slots 110 , the assembly of the top lens 300 and the mid lens 200 is secured in the base lens 100 , and the procedure is completed.
[0071] In the event that the assembly formed by the mid lens 200 and the top lens 300 requires replacement, the surgeon may perform a disassembly procedure as discussed herein. First, a cannula containing visco elastic material would be introduced into the eye and positioned at the interface between the lens assembly (mid lens 200 and top lens 300 ) and the base lens 100 . The injection of visco elastic causes the mid 200 /top 300 lens assembly to elevate, thus disengaging the projections 210 from the slots 110 in the base lens 100 . The original lens assembly would then be removed from the eye, and a new lens assembly placed into the eye and attached to the base lens 100 similar to as described above in the primary operation.
[0072] While the invention has been described in conjunction with specific embodiments therefor, it is evident that various changes and modifications may be made, and the equivalents substituted for elements thereof without departing from the true scope of the invention. In addition, many modifications may be made to adapt a particular situation or material to the teachings of the invention without departing from the scope thereof. Therefore, it is intended that this invention not be limited to the particular embodiment disclosed herein, but will include all embodiments within the spirit and scope of the disclosure.
[0073] For example, the mid lens 200 may also have additional spherical power ranging from −9.50 D to 9.50 D in 0.25 D increments, and may be either monofocal or multifocal. The top lens 200 may also be constructed from acrylic, silicone, or any other material suitable for crafting a foldable intraocular lens. The mid lens has a plano-convex lens with a central thickness ranging from 0.1 to 0.3 millimeters, and a diameter ranging from 1.5 to 8.5 millimeters, preferably between 6.0 and 6.5 millimeters, and an optical clear aperture ranging from 5.0 to 6.0 millimeters, preferably 5.5 mm. Similar to the base lens 100 and the top lens 300 , the mid lens 200 may also be manufactured in a manner to allow absorption of light in the ultraviolet wavelength portion of the light spectrum, or other portions of the light spectrum for which it may be clinically important to absorb light, such as the blue light portion.
[0074] Also, the mid lens 200 may have at least one bevel 210 formed along an outer edge thereof, allowing the mid lens 200 to fit into the opening 110 of the base lens 100 . The mid lens 200 has a projection/notch 225 , 230 that allows compression of the top lens 300 in order for the top lens 300 to fit inside the projection/notch 225 , 230 of the mid lens 200 . Prior to insertion into the eye, the surgeon or manufacturer places the top lens 300 into the mid lens 200 , and seals the top lens under the notch 225 around the entire circumference of the mid lens. The assembly is then ready for insertion into the eye of the patient.
[0075] The three piece system (i.e. the base lens 100 , the mid lens 200 , and the top lens 300 ) described herein has a spherical power range of −20.00 D to +40.00 D and accuracy of ±0.25 D. The three piece system has an adjustable cylindrical power of 5.00 D, and adjustable spherical power of ±9.00 D. Its maximum central thickness is 1.88 millimeters, but could be as thick as 4.0 millimeters. The optical element diameter ranges from 1.00 millimeters to 8.00 millimeters. The optical aperture ranges from 3.0 to 7.0 millimeters, with an optimal optical aperture of 5.5 millimeters.
[0076] Any of the base, top, and/or mid lens components may be coated with chemicals to decrease their cellular reactivity, such as heparin or other surface passivation techniques to prevent building of cellular debris at the optical interface. Moreover, any of the lens components may be configured with a multifocal corrective component of any of several varieties: derefractive or refractive, bull's eye or aspheric, depending upon the desired optical characteristics. Additionally, extra components beyond the basic base, top, and mid components may be added to help with optical aberrations or other focusing refinements. In an embodiment of the present invention, additional top lenses may be added to the base lens 100 , and attached in the same manner as the assembly of the top 300 and the mid lens 200 described above.
[0077] In another embodiment of the present invention, a telescopic lens can be introduced into the lens system for the treatment of macular degeneration. If the base lens 105 illustrated in FIG. 13 is used, then the surgeon can cut the attachment points 140 while the lens is in the eye, and remove the central optic 150 of the base lens 105 . The surgeon can then implant a telescopic assembly, for example a Lipschitz telescopic assembly, in place of the optic portion of the base lens 105 , to allow optical correction for macular degeneration.
[0078] By using specific predetermined combinations of lens powers for each of the three components, it is possible to achieve a large variety of possible corrective power while requiring only a minimum number of different lenses to be manufactured. By placing small degrees of spherical construction in each of the three optical components, a surgeon can, from a very limited inventory of lenses, construct all of the corrections needed to achieve optical powers from −20.00 D to +40.00 D of spherical correction, and from 0.0 to 5.0 D of cylindrical correction in any axis, all in standard 0.25 D steps.
[0079] Optical aberrations and abnormalities present after implantation of the intraocular lens are identified by measuring the optical system using, for example, wave front technology. A surface modifier may be used to modify either a surface of the eye itself, or a component of the intraocular lens system. If a component requires modification or replacement, the surgeon can remove the component, alter the component or replace it with another, and reinsert the component through the same wound which was used to implant the lens. This process is described more fully in U.S. Pat. No. 6,413,276, “Modified Intraocular Lens and Method of Correcting Optical Aberrations Therein,” by the same inventor.
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The present invention discloses a multi-component intraocular lens implanted in an optical system of a human eye, including one or more foldable removable components, each component being foldable. One component acts as a base lens, including a flange with an aperture. Another component acts as a mid lens, including a tab which engages the aperture. A third component acts as a top lens, which engages the mid lens. Because the lens components are foldable, they may be inserted into the eye using an incision smaller than the diameter of the unfolded lens. The removable components may be used to correct various medical conditions of the eye, as well as to improve and enhance vision, and for cosmetic purposes.
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PRIORITY INFORMATION
This application claims priority from U.S. Provisional Application Ser. No. 60/655,678 filed Feb. 22, 2005, which is incorporated herein by reference in its entirety.
BACKGROUND OF THE INVENTION
Organic Light Emitting Diodes (OLEDs) are useful in electronic displays, building lighting, signage, and other applications where efficient, lightweight, thin form-factor light sources are needed. An OLED is formed by sandwiching a fluorescent or phosphorescent organic film between two electrodes, at least one of which is transparent. Holes from the anode and electrons from the cathode recombine in the organic film and produce light. If the organic film is a polymer film the device is a polymer-OLED or p-OLED. It is known in the art how to improve efficiency of OLEDs and p-OLEDs by inclusion of various other layers in the sandwich structure, including but not limited to hole injection layers, hole transport layers, buffer layers, electron injection layers, electron transport layers, hole blocking layers, electron blocking layers, exciton blocking layers, optical layers to increase light extraction efficiency, and the like. It is also known in the art that the properties of the organic film, or emissive layer, must be carefully designed to 1) allow transport of holes, 2) allow transport of electrons, 3) prevent non-radiative decay of the excited state, and 4) ensure that no irreversible chemical reactions occur during device operation. Requirements 1-3 relate to device efficiency and requirement 4 relates to device lifetime. The emissive layer will often be comprised of several substances or components, including one or more charge carriers, a fluorescent or phosphorescent material, and a more or less inert matrix.
While theory suggests that OLEDs and p-OLEDs can have high efficiencies, commercial devices still have lower efficiencies than conventional fluorescent bulbs. In practice, the efficiency of a device is dependent on color and is related to the sensitivity of the human eye, so that green devices are inherently more efficient than red or blue emitting devices, however, improvement in efficiency of all colors is desired. One cause of low efficiency is energy transfer from the excited emissive compound (whether it be fluorescent or phosphorescent, small molecule, or polymer) to a material having a lower energy excited state. Materials with lower energy excited states may be, for example, impurities, defects, or excimers. It often occurs that the matrix has a first triplet excited state that is lower in energy or only slightly above the emissive material's excited state and a first singlet-excited state that is higher than the emissive material's excited state. It would be desirable to reduce or eliminate energy transfer from the desired excited state to other lower energy excited states and to eliminate energy transfer from the desired excited state to the triplet state of the matrix material.
The decreasing brightness of OLEDs and p-OLEDs as a function of time is the major obstacle to commercial application. Many factors affect lifetime. An important factor appears to be the redox stability of the emissive layer (that is, the stability of the reduced and oxidized states of the materials in the emissive layer). While not wishing to be bound by theory, it is believed that as holes propagate through the emissive layer they take the form of cations or radical cations. A radical is a molecule having an odd number of electrons and may be charged (an anion or cation) or neutral (a free radical). Radicals are generally more reactive than molecules with an even number of electrons. As electrons propagate through the emissive layer, they take the form of anions or radical anions. Radical cations may dissociate into a cation and a free radical, while radical anions may dissociate into an anion and a free radical, Cations, radical cations, anions, radical anions, and free radicals are all reactive species and may undergo unwanted chemical reactions with one another or with nearby neutral molecules. Such chemical reactions alter the electronic properties of the emissive layer and can lead to decreases in brightness, efficiency, and (ultimately) device failure. For this reason, it would be desirable to reduce or eliminate chemical reactions of these active species in OLEDs and p-OLEDs.
Even the most promising p-OLED materials are limited by short lifetimes. For example, copolymers of methylene-bridged polyphenylenes (also called polyfluorenes) and other arylene units, Q (such as 4,4′-triphenylamine, 3,6-benzothiazole, 2,5(1,4-dialkoxyphenylene), or a second bridged biphenyl unit) are frequently used in p-OLED applications. While green emitting p-OLEDs based on such polyfluorene copolymers have been reported to have lifetimes of over 10,000 hours, red and blue emitting p-OLEDs based on these systems are shorter lived. Lifetime is generally measured as the time to half brightness at a set current density, starting at 100 cd/m 2 . In fact, the lifetimes of the best polyfluorene blue phosphors are not suitable for commercial p-OLED applications. For this reason, it would be desirable to improve emissive materials, especially those that emit in the blue color range.
General structures 1 and 2 for polyphenylene (top, General Structure 1) and methylene bridged polyphenylene (bottom, General Structure 2), where Q is an arylene.
In polyarylene-type green and red emissive polymers (including polyfluorene as a subclass of polyarylene) the emissive center is typically a special repeat unit selected to have a first singlet-excited state of appropriate energy to emit green or red. In polyarylene type blue emissive polymers (including polyfluorenes) the emissive center is typically one or more adjacent phenylene (or bridged biphenylene) repeat units. In this case, the phenylene (or bridged biphenylene) backbone has the lowest singlet-excited state out of all the repeat units or other materials present. That is, the majority repeat unit is the emitter. This means that excited states spend most of their time on the majority repeat unit. Since excited states are more reactive than ground states the majority repeat units are prone to undergo undesired reactions.
SUMMARY OF THE INVENTION
One aspect provided in the present invention are polymer materials having twisted biarylene units that increase the first singlet- and triplet-excited states relative to similar polymers lacking such sterically twisted structures.
Another aspect provided in the present invention is a polymer material having sterically twisted biarylene units that are suitable as host matrixes for fluorescent and phosphorescent emitters for use in p-OLED applications.
Another aspect provided in the present invention is an oligomeric maternal comprised of sterically twisted biarylene units that are suitable as host matrixes for fluorescent and phosphorescent emitters for use in p-OLED applications.
Another aspect provided in the present invention is a copolymer material comprised of sterically twisted biarylene repeat units and fluorescent or phosphorescent repeat units.
Another aspect provided in the present invention is a copolymer comprised of 1) sterically twisted biarylene repeat units, 2) fluorescent or phosphorescent repeat units, and 3) hole and/or electron transport repeat units.
It is another objective of the present invention to provide OLED and p-OLED devices with improved brightness and/or lifetime.
DETAILED DESCRIPTION OF THE INVENTION
One object of the present invention is to provide a blue emissive polymer with a long lifetime. The lifetime to half brightness starting at 100 cd/m 2 should be greater than 1,000 hours, preferably greater than 2,000 hours, more preferably greater than 5,000 hours, even more preferably greater than 10,000 hours, and yet more preferably greater than 20,000 hours. P-OLED devices are often tested at higher initial brightness as an accelerated ageing test. The lifetime to half brightness starting at 1,000 cd/m 2 should be greater than 100 hours, preferably greater than 200 hours, more preferably greater than 500 hours, even more preferably greater than 1,000 hours, and yet more preferably greater than 2,000 hours.
While not wishing to be bound by theory, the short lifetime of current state-of-the-art blue emissive polyphenylenes and bridged polyphenylene is likely due to the polymer serving as the emissive center. If the polymer itself has the lowest lying singlet level, then it must carry the exciton (excited state) for a longer period of time than if it transfers its energy to an emitter with a lower level. Having this exciton reside on the polymer for long periods of time has several deleterious effects. First, since the excited state is a very chemically reactive species, an opportunity is provided for the majority of repeat unit of the polymer backbone to react irreversibly. Second, the time that the excited state spends on the main polymer repeat unit is increased, further increasing the chance of side reactions. Third, it is more difficult to protect an excited state that is spread across the whole polymer backbone than one isolated on an occasional (typically from 10 mol % to 1 mol % or less) emissive repeat unit. Finally, it is more difficult to change the color of emitted light (that is, to prepare a polymer modified to emit a different color) if the majority polymer repeat unit is emitting than if a minority polymer repeat unit is emitting.
Designing a useful polymer in which the bulk of the backbone structure does not serve as the emitting unit in p-OLED applications has met with limited success. Lower energy green and red phosphors have been achieved from methylene-bridged polyphenylene copolymers because the lower energy lowest lying singlet-energy levels of the individual polymer units are higher than that of the emissive repeat unit. This suggests that excitons that are formed on the polymer units within these green or red systems are short lived because they quickly transfer their energy to the lower energy emissive repeat units, giving rise to longer lifetimes. This is not the case with higher energy blue phosphors because the lowest singlet-energy levels of the individual polymer units are comparable to those of the emissive repeat units. This means that excitons reside for longer periods on the backbone units of blue phosphors leading to deleterious side reactions, which accounts for the shorter lifetimes of these systems.
Electronic conjugation is a key component to the energy level of polymer repeat units with more conjugated systems having lower energies. In this context, there are two contributing factors to conjugation: 1) the conjugation of the repeat unit itself, and 2) the conjugation of the repeat unit with adjacent aromatic units. Both of these contributing factors can be seen in polyfluorene copolymers (compare Structures 3 and 4). In these systems, the methylene bridge of the fluorene unit holds two adjacent phenylene units in a planar configuration (zero twist) giving rise to the maximum possible conjugation between these two units and the lowest possible energy. Additionally, the fluorene
units in these systems generally have only small hydrogen substituents at positions ortho to the polymer backbone, which also give rise to increased conjugation and lower energy. In typical polyphenylene systems one or two out of the four ortho positions is substituted with a straight chain alkyl or alkoxy group, causing some twist. In the practice of the present invention groups larger than n-alkyl are used, or three or four of the ortho positions are substituted, and larger twists, approaching 90° are generated, and a significant increase in bandgap results.
A key aspect of this invention are sterically twisted polyarylene polymer systems that offer higher energy repeat units. This is accomplished by decreasing both the conjugation of the polyarylene repeat by forcing adjacent aryl groups out of planarity. In General Structure 5 the twist angle between the rings shown depends on the size of substituents R 2 , R′ 2 , R 6 and R′ 6 .
The rings will have a large enough twist (called herein a “Sterically Twisted Biarylene” (STB) group, unit, or repeat unit) to be useful for the practice of the present invention if:
1) at least two of R 2 , R′ 2 , R 6 and R′ 6 are not —H and
at least one of R 2 , R′ 2 , R 6 and R′ 6 is selected from the group consisting of —CR 7 R 8 R 9 , —OR 10 —NR 10 R 11 , —SR 10 , —SiR 11 R 12 R 13 , and bridging with either R 3 , R′ 3 , R 5 and R′ 5 respectively, where R 7 is selected from the group consisting of —H, alkyl, aryl, heteroalkyl, heteroaryl, fluoro, chloro, alkoxy, aryloxy, cyano, fluoroalkyl, fluoroaryl, where R 8 and R 9 are independently selected from the group consisting of alkyl, aryl, heteroalkyl, heteroaryl, fluoro, chloro, alkoxy, aryloxy, cyano, fluoroalkyl, fluoroaryl, where R 10 is selected from the group consisting of —CR 7 R 8 R 9 , and where R 12 and R 13 are selected independently from the group consisting of —H, alkyl, aryl, heteroalkyl, heteroaryl, fluoroalkyl, and fluoroaryl,
or
2) at least three of R 2 , R′ 2 , R 6 and R′ 6 are not —H,
and optionally, any of R 2 , R′ 2 , R 6 and R′ 6 may form a bridge or multiple bridges with R 3 , R′ 3 , R 5 and R′ 5 respectively, and any R 3 , R′ 3 , R 5 and R′ 5 may form a bridge or multiple bridges with R groups on repeat units adjacent to those shown in General Structure 1, and any carbon atom and its associated R group in the rings of General Structure 1 may be replaced by nitrogen to form a heterocycle,
and any of R 7 , R 8 , R 9 R 10 , and R 11 may form a bridge or multiple bridges with any other R group, and where here and throughout fluoroalkyl and fluoroaryl may be mono, di, poly, or per fluorinated.
R 3 , R′ 3 , R 5 and R′ 5 may be any group, including but not limited to H, alkyl, aryl, heteroalkyl, heteroaryl, fluoro, chloro, alkoxy, aryloxy, cyano, fluoroalkyl, fluoroaryl, ester, amide, imide, thioalkyl, thioaryl, alkylketone, and arylketone.
Examples of bridging groups between R 2 and R 3 , R′ 2 and R′ 3 , R 5 and R 6 , and R′ 5 and R′ 6 are —CR 7 ═CR 7 —CR 7 ═CR 7 —, —CR 7 ═CR 7 —CR 7 ═N—, —CH 2 CH 2 CH 2 CH 2 —, —OCH 2 CH 2 O—, ═N—S—N=(i.e. the arylene group is benzothiadiazole), and —S—CH═CH—,
A non-limiting example of R 3 bridging to an adjacent repeat unit is:
In the above structure R 6 is methyl and R′ 2 is isopropyl.
In one embodiment of the present invention is provided a polymer comprising on the average at least one dyad per chain of the structure:
where R 30 , R 31 , R 32 , R 33 , R 34 , R 34 , R′ 30 , R′ 31 , R′ 32 , R′ 33 , R′ 34 , and R′ 35 are independently selected from the group consisting of hydrogen, alkyl, aryl, heteroalkyl, heteroaryl, fluoroalkyl, fluoroaryl, alkylketone, aryl ketone, alkoxy, and aryloxy,
X and X′ are independently selected from the group consisting of C, N, O, Si, P, and 1,
if X is C and R 35 and R′ 35 are H then R 30 and R 31 are not H,
if X is N or P then R 30 is nil and R 3 , has a secondary or tertiary carbon bonded to X,
if X′ is N or P then R′ 30 is nil and R 31 has a secondary or tertiary carbon bonded to X′,
if X is O or S then R 30 and R 31 are nil and R 32 has a secondary or tertiary carbon bonded to X,
if X′ is O or S then R′ 30 and R′ 31 are nil and R′ 32 has a secondary or tertiary carbon bonded to X′,
A 33 , A 34 , A 35 , A′ 33 , A′34, and A′ 35 , are independently-selected from C or N, where if A is N the corresponding R is nil,
any of R 30 -R 33 independently may be bridging with one another,
R 34 may be bridging with R 35 ,
any of R′ 30 -R′ 33 independently may be bridging with one another,
R′ 34 may be bridging with R′ 35 ,
and any of R 33 , R 34 , R′ 33 and R′ 34 may be bridging with a repeat unit adjacent to the dyad.
In this embodiment the R groups may form saturated or unsaturated fused rings. For example, forming naphthyl or phenanthryl repeat units. In order to maintain a sufficient twist the number of R groups ortho to the central dyad bond must be three or four, or if only two then at least one of the R groups should be larger than a simple straight chain alkyl, and in the case of X═C should have a tertiary or quaternary carbon as X, and in the case of O, N, S, or P, should have a secondary or tertiary carbon bonded to X (that is to the O, N, S, or P respectively).
In order to maintain good charge transport properties it is desirable that a significant portion of the repeat units be arylene or other conjugated units (e.g. ethylene, acetylene, arylamine, thiophene), preferably more than 25% of the units will be arylene or other conjugated units, more preferably more than 45% and most preferably more than 65%.
In order to maintain a high bandgap a significant portion of the dyads should be sterically twisted dyads represented by Structure 7, preferably more than 10% of the dyads, more preferably more than 20%, even more preferably more than 30%, yet more preferably more than 40%. Higher amounts of sterically twisted dyads may be incorporated into the instant polymers, including but not limited to 50% of the dyads, 75% of the dyads, and even 100% of the dyads. Note that a homopolymer may have 50% of the dyads twisted, or more. Note that a homopolymer may have a random regio-chemistry such that not all dyads are head-to-head or head-to-tail, and the number of twisted dyads may have a statistical distribution.
Particular non-limiting examples of sterically twisted biarylene polymers are given by:
As in the example immediately above the arylene group may be a bicyclic or polycyclic fused ring group, and may contain heteroatoms.
The polymers may be prepared by any of various aryl-aryl coupling methods, preferably by Suzuki coupling. The general monomer structure is:
where X and Y are selected independently from Cl, Br, I, B(OH) 2 , B(OR 12 ) 2 , and OS(O) 2 R 13 , where R 12 is alkyl, aryl, and the two R 12 may be bridging to form a ring, and R 13 is alkyl, aryl, fluoroalkyl and fluoroaryl, preferably fluoroalkyl.
X and Y may also be selected from MgX, ZnX, Li, Sn(R 14 )3 and the like, where X is halogen, for example, for use in Yamamoto coupling polymerization, Negishi coupling polymerization, or Stille coupling polymerization, where R 14 is selected independently from H, halide, and alkyl.
The singlet and triplet states of polymers comprising sterically twisted arylene repeat units are higher than those of conventional polyarylenes, polyphenylenes, and polyfluorenes. The singlet energy may be greater than approximately 3 eV (413 nm), preferably greater than about 3.1 eV (400 nm), and more preferably greater than about 3.2 eV (388 nm).
Polymers comprising sterically twisted biarylene segments may also contain emissive repeat units with singlet energy in the visible, IR or UV range. For example, the emissive repeat unit may have peak emission of about 410 nm to 450 nm n that will emit blue light. These blue emissive repeat units may be present at a relatively small mole fraction, preferable less than 10 mole %, more preferably less than 8 mole %, even more preferably less than about 6 mole %, yet more preferably less than 5 mole %. Lower levels of blue emissive repeat units may also be practical, including less than 4 mole %, less than 2 mole %, less than 1 mole % and even less than 0.5 mole %.
There are various ways to improve the stability of emissive units of the proposed invention. Such emissive repeat units may be protected, using methods known in the art, to prevent reaction of these units with one another or other components of the emissive layer. For example, the emissive repeat unit may have large inert substituents including but not limited to alkyl, aryl, heteroalkyl, and heteroaryl. Particular examples of such inert substituents include but are not limited to t-butyl, phenyl, pyridyl, cyclohexyloxy, and trimethylsilyl. Attaching inert substituents at reactive positions on the unit can also stabilize emissive units. For example, it is known that the triphenylamine cations reacts primarily at the 4, 4′, and 4″-positions of the phenylene units (those para to the nitrogen). It is also known that substituting these positions with, for example, alkyl groups prevents these reactions and greatly increases the lifetime of the radical cation. One skilled in the art will know how to find the reactive positions by making and testing chemical model compounds or by computational modeling, and how to substitute these reactive positions with inert substituents like alkyl (e.g. methyl, t-butyl) or fluoro, or to replace the reactive —CH═ group with —N═ (e.g. replace phenyl with pyridyl). Emissive units can also be made stable if they are able to delocalize charge over a larger number of atoms. For example, a triphenylamine cation is more stable than an allyldiphenylamine cation since the charge on the former delocalizes over three phenyl rings, as opposed to only two phenyl rings in the latter. Finally, incorporating bulky groups on adjacent repeat units can protect emissive repeat units.
This combination of twisting of adjacent arylene units, transfer of energy to a minority emissive repeat unit, and protection of emissive units leads to longer OLED and p-OLED device lifetimes. Additionally, raising the singlet- and triplet-energy levels of the polymer or oligomer by sterically twisting reduces or eliminates non-radiative pathways and increases brightness and efficiency.
One embodiment of this invention involves a homopolymer or copolymer having a molecular weight of greater than about 1,000 comprising a twisted biphenyl unit having the structure:
where R2, R′2, R6 and R′ 6 are as defined above, for example, R2, R′2, R6 and R′16 are all i-propyl.
In one aspect of the present invention the Sterically Twisted Biarylene (STB) polymers are non-linear and contain branch points. One advantage of non-linear polymers is that polymer mixtures or blends are easier to prepare. For example, if two dendrimeric or hyperbranched polymers have dissimilar cores but similar shells they will tend to be miscible. Another advantage is that the central core is protected by an outer shell structure. A further advantage is that the electronic properties of the core and one or more shells may be varied independently, for example, a hyperbranched polymer might have an emissive core, a hole transporting inner shell, and an electron transporting outer shell. Light branching or crosslinking also may be advantageous for control of MW and viscosity.
A non-limiting example of a STB polymer having a branched structure is given by:
The branched polymers of the present invention may be prepared by the inclusion of a trifunctional or polyfunctional monomer along with the difunctional monomers. For example, Structure 13 may be prepared by Suzuki coupling of the following monomers and endcapping agent:
The degree of branching may be controlled by adjusting the relative amount of tribromophenylamine. It will be also understood that the molecular weight is controlled by the relative amount of endcapping agent and the ratio of diboronic ester monomers and dibromo monomers. One unusual feature of Suzuki polymerization is that the monomer ratio giving the highest MW is often offset in favor of the diboronic ester. This is likely due to some homocoupling of boronic esters. One reasonably skilled in the art will know how to adjust the monomer ratio, the amount of endcapping agent, and the amount of crosslinking monomer to obtain a higher or lower MW.
The present invention also relates to linear polymers comprising sterically twisted arylene units and reactive end groups or side groups that may be induced to form non-linear structures through reaction at the reactive end groups or side groups. Polymers having reactive side groups are disclosed in U.S. Pat. Nos. 5,539,048 and 5,830,945 incorporated herein in full by reference. Polymers having reactive end groups are disclosed in U.S. Pat. Nos. 5,670,564; 5,824,744; 5,827,927; and 5,973,075 all incorporated herein in full by reference.
Non-limiting examples of STB polymers having a reactive side group are given by:
Branched, hyperbranched, and dendritic polymer may also have reactive groups.
In addition to formation of branched structures, polymers having reactive side groups or reactive end groups may be crosslinked into an insoluble network, sometimes called thermosets. Crosslinked polymers offer several advantages over uncrosslinked polymers, especially for applications in the area of OLEDs and p-OLEDs. For example, p-OLEDs typically consist of multiple layers polymers, each being very thin, typically between 50 nm and 1,000 nm. During fabrication, polymer layers must be deposited over previously formed polymer layers. The underlying layer must not dissolve in or be disturbed by the polymer solution being applied to form the upper layer. One method to prevent disturbance of the lower layers is to crosslink the lower layers prior to application of upper layers. The non-linear, crosslinked layers are impervious to solvent and subsequent processing steps.
Polymers and co-polymers of the present invention may be linear, branched, hyperbranched, dentritic, graft, comb, star, combinations of these or any other polymer structure. Polymers of the present invention may be regio-regular, regio-random or combination. Polymers of the present invention may be head-to-head, head-to-tail, or mixed head-to-head/head-to-tail. Co-polymers of the present invention may be alternating, random, block, or combination of these. Polymers of the present invention may be chiral or contain chiral repeat units. Any combination of chiral repeat units is contemplated, including all chiral units of a single handedness, a racemic mixture of units, or a mixture (e.g. from partially resolved chiral monomers). Chiral units may be desirable to induce polarization of the emitted light. Polarized OLEDs and p-OLEDs may have application in LCD backlighting, eliminating the need for one of the LCD display polarizers. Since polarizers absorb some of the incident light elimination of a polarizer can increase efficiency.
In one embodiment of the present invention a polymer comprises at least one Sterically Twisted Biarylene (STB) repeat unit, at least one luminescent compound, L, and optionally other repeat units Q.
The luminescent dye may be incorporated into the polymer in any fashion. Non-limiting examples of structural types include:
Where X is as defined above,
Q is nil, or any conjugated repeat unit,
where structures I-V are copolymers they may be any combination of alternating, block, or random, L is any luminescent compound or group, and where if L is part of a polymer chain backbone as in structure I L is divalent, if L is attached to a polymer as in structures II-V L is monovalent, and if part of a blend as in structure V, zero valent (i.e. not sharing any bonds with the STB polymer chain) and in Structure II L may be chemically attached directly to the aromatic ring or to any of R 2 , R′ 2 , R 6 and R′ 6 . The structure may represent homopolymers, for example the STB units and Q are perfectly alternating, co-polymers comprising any number of types of repeat units, random, block, regio-regular, regio-random, graft, comb, branched, hyperbranched, dendritic, crosslinked or any combination of structures.
Non-limiting examples of conjugated repeat units, Q, include:
In structure I the luminescent unit, L, is a divalent unit, and is part of the main chain. In structure II luminescent unit, L, is a monovalent unit appended from any position of the STB unit, including any position on the biarylene moiety and any position on any of the bridging moieties. In structure III the luminescent unit, L, is a monovalent unit appended from at least one of the repeat units Q. In structure IV the luminescent unit, L, is an end group. In structure V the luminescent compound is not chemically attached to the polymer, but is present as a component of a polymer blend or mixture. In structure V the luminescent compound may be a small molecule that is dissolved in the polymer matrix. In another embodiment of structure V the luminescent compound is an oligomer or polymer blended in with the STB containing polymer. Where L is part of a blend or mixture other compounds may be present to increase solubility or compatibility of L with the STB containing polymer. L need not be fully soluble or compatible with the STB containing polymer if the fabrication method results in a non-equilibrium state wherein L is trapped in the polymer and kinetically prevented from crystallizing or separating.
There will be at least one STB unit on the average in each polymer chain, however, preferably there are at least 10 mol % STB units, more preferably at least 20 mol % STB units, and most preferably at least 25 mol % STB units. There may be up to 99.99 mol % STB units. There may be anywhere between 0 and 99 mol % Q units, preferably between 0 and 50 mol %. There may be 0.01 to 50 mol % luminescent units L, more preferably between about 0.1 and 25 mol %, even more preferably between about 0.2 and 15 mol % luminescent L units, and most preferably between about 0.5 mol % and 5 mol % luminescent L units.
In the compositions of the present invention the luminescent component, L, will have an emission at longer wavelength (lower energy) than the STB polymer component. As is known in the art (see for example, M. D. McGehee, T. Bergstedt, C. Zhang, A. P. Saab, M. B. O'Regan, G. C. Bazan, V. I. Srdanov, and A. J. Heeger, Adv. Materials, 1999, 11(6), 1349-1354) if a luminescent material of lower energy is embedded in a matrix that is luminescent at higher energy (in the absence of L), then energy is transferred from the matrix to the luminescent material and emission from the luminescent material dominates. This seems to be especially effective in EL devices where luminescence from the matrix may be completely absent, being transferred with high efficiency to L, even when luminescence from both matrix and L are present in the photoluminescent spectrum. It is sometimes said that the luminescence of the matrix is quenched by L.
For the practice of the present invention all or part of the luminescence of the matrix may be quenched by L, preferably 20%, more preferably 40%, even more preferably 60%, yet more preferably 80%, even yet more preferably 90%, even more preferably 95%, and most preferably more than 99% of the matrix luminescence is quenched (or otherwise reduced) by the presence of L. It may be that within experimental error 100% of the luminescence of the matrix is quenched by L.
Transfer of energy to a luminescent component is desirable because 1) the luminescent component may be protected to reduce or eliminate chemical reactions of the excited state, 2) energy does not reside on the majority backbone repeat unit making undesirable chemical reaction of the majority repeat units less likely, and 3) a single matrix repeat unit may be used with various luminescent repeat units to generate many colors.
Luminescent materials, groups, dyes, or pigments may be selected from any luminescent material, group, dye or pigment known in the art. A non-limiting example of a luminescent dyes is stilbene:
where each ring may have 0-5 R 17 groups which may be monovalent or divalent, or may provide a link to a polymer, and where any two R 17 -R 19 taken together may be bridging. Monovalent R means the group R has only one linking bond. Non-limiting examples of monovalent R are methyl, hexyloxy, and 4-t-butylphenyl. Divalent R means the group R has two linking bonds. Non-limiting examples of divalent R are —CH 2 — (methylene), —CH 2 CH 2 CH 2 —(1,3-propylene), 1,2-phenylene, and —OCH 2 CH 2 O— (ethylenedioxy). For example, a specific monovalent stilbene is (R 17 is alkyloxy, R 18 is cyano, and a second R 17 is divalent alkyl providing a link to the polymer chain):
a specific divalent stilbene, where two of the divalent R are bridging (R 17 and R 18 are bridging and additional two R 17 provide links to the polymer chain), is:
Similarly, other non-limiting examples of luminescent dyes are: anthracene, tetracene, phenanthrene, naphthalene, fluorene, binaphthalene, biphenyl, terphenyl, quaterphenyl, bisthiophene, biquinoline, bisindene, and the like, where any of the hydrogens may be independently substituted by monovalent or divalent R, or may provide a link to a polymer, where any two R taken together may be bridging.
Non-limiting specific examples of luminescent dyes include:
Additional luminescent dyes are disclosed in U.S. Pat. No. 6,723,811 incorporated herein by reference.
It will be understood by one reasonably skilled in the art that for luminescent materials that are phosphorescent, that is, for those that emit from a triplet level, the relevant energy level of the STB polymer is also the triplet level. That is, the lowest triplet level of the STB polymer must have a higher energy than the triplet of the luminescent material. This limit on the triplet level is much more restrictive, since the triplet is nearly always lower than the singlet level. Nevertheless, the triplet level is expected to increase with the singlet level, and a “bluer” or higher energy triplet emitter can be supported with the STB polymers of the present invention than with the corresponding less twisted or untwisted polymer. For example, it may be possible to realize a green triplet emitter with a STB polymer where the corresponding untwisted or less twisted polymer cannot because its triplet is too low. Thus in one embodiment of the present invention a phosphorescent emitter is bound to or mixed with a STB polymer. For example, a green emitting iridium bisphenylpyridine emitter is coordinated to an acetylacetone group linked to a STB polymer to provide a green emitting EL phosphor:
where the mole ratio of STB/triphenylamine/Ir repeat units is 74/22/4, and the STB and Ir containing repeat units are regio-random.
One way to determine if a luminescent compound is useful in the practice of the present invention is to compare the visible emission spectrum of the polymer in the presence of L to that of the polymer in the absence of L. Useful L will effectively quench the polymer matrix photoluminescence or electroluminescence. Thus the emission spectrum of the polymer in the presence of L will have average energy in the visible range (400 nm to 650 nm) red-shifted by at least 4 nm from the polymer without L, more preferably at least 8 nm, even more preferably at least 12 nm, and most preferably at least 20 nm. Because the wavelength scale is not linear in energy it may be preferable to use energy units where the emission spectrum of the polymer in the presence of L will have average energy in the visible range (400 nm to 650 nm) red-shifted by at least 0.025 eV from the polymer without L, more preferably at least 0.050 eV, even more preferably at least 0.075 eV, and most preferably at least 0.125 eV.
An example of such a comparison is given in McGehee et al. where a europium complex quenches the emission of a polyphenylene polymer. Examples are given of poor quenching and essentially complete quenching of photoluminescence (see FIG. 3 in McGehee et al.).
In other words, because the luminescent compound emits at lower energy than the STB repeat units, excited STB repeat units will transfer their energy to the luminescent compound. The reverse process is thermodynamically unfavorable and thus the excited state energy is funneled to the luminescent compound. If the STB repeat units have the lowest excited state energy of any of the repeat units in the chain then they may emit.
If L is a compound or repeat unit it may simply be omitted from the blend or polymer composition. It is noted that if L is part of the polymer (for example, as a repeat unit, a side group, or an end group) the comparison will necessarily be to a different polymer lacking any L groups or units, for example, if L is a side group or end group it may be replaced with H or phenyl. In the case that L is part of the polymer there may be other unavoidable changes that could also affect the emission spectrum, for example, molecular weight, or distance between STB units, however, typically the mol % L will be low and such effects will be minimal.
Another way to determine the ability of a luminescent compound, group or repeat unit L to be useful in the practice of the present invention is to compare the visible emission spectrum of a luminescent model compound L′ having phenyl groups where the luminescent compound was attached to the polymer chain, with the visible emission spectrum of a STB model compound Ph-STB-Ph, having a single STB unit terminated with phenyl groups. L′ will be identical to L where L is a compound not attached to the STB polymer chain. To be useful L must have a lower emission energy than Ph-STB-Ph.
Yet another method is to compare the spectra of L″ and H-STB-H, where L″ is a model of L terminated with H, and H-STB-His a model of the STB unit terminated with H. The spectrum of L″ should be lower in energy than the spectrum of H-STB-H.
The above methods for determining the if an L compound is useful in the practice of the present invention does not depend on any particular theory or mechanism of EL device operation. One theoretical argument suggests that in an EL device comprised of a high energy emitter and a low energy emitter, emission solely from the low energy emitter may result from transfer of excited state energy from high energy emitter to low energy emitter. An alternative theoretical argument suggests that emission solely from the low energy emitter may result from recombination of holes and electrons directly on the low energy emitter, and that transfer of excited state energy from high energy emitter to low energy emitter is not important. No matter which, if any, theory is correct, useful L may be selected by the methods described above.
In another embodiment the luminescent compound, unit, or group L, will be protected through incorporation of sterically bulky groups. The bulky groups protect L by preventing close approach to another L or polymer chain. The stabilizing effect of bulky groups is well known and it will be understood by one reasonably skilled in the art how to design a molecule L to have steric bulk.
In another embodiment the luminescent compound, unit or group L, will be protected through the placement of inert groups at active positions. For example, it is well known that the radical cation of triphenylamine is very reactive and reacts rapidly with neutral triphenylamine to form tetraphenylbenzidene. However, substitution of the three hydrogens para to the nitrogen with methyl results in the very stable tri-p-tolylamine radical cation.
It will be understood by one reasonably skilled in the art how to determine active positions in a material, for example, by alkylation and location of the alkyl groups, and to prepare protected versions of those materials. Protective groups include but are not limited to, alkyl, aryl, halo (preferably F and Cl), cyano, alkoxy, aryloxy, heteroalkyl, and heteroaryl.
Degradation will be lower if the polymer is below T 8 during use of the device. Thus L will be protected by use of relatively stiff repeat units and side chain, and avoiding flexible groups such as long alkyl chains.
The STB polymers of the instant invention may have repeat units, side groups or end groups that aid in charge transport. These repeat units or groups may aid electron transport or hole transport Non-limiting examples of hole transport units are triarylamines, benzidenes, and dialkoxyarenes. Some of the non-limiting examples of repeat unit Q shown above are good hole transport units. Non-limiting examples of electron transport units are oxadiazoles, benzoxazoles, perfluoroarenes, and quinolines. Some of the non-limiting examples of repeat unit Q shown above are good electron transport units. Any of the divalent structures shown for Q may be used as monovalent groups, e.g. end groups or side groups, by replacing one of the two linkages with —H or -Ph (i.e. phenyl). The amount of charge transport units or groups may vary from zero to 99%, preferably less than 75%, more preferably less than 50%. Useful amounts of charge transport groups include about 5 mol %, 10 mol %, 15 mol %, 20 mol %, 25 mol %, 30 mol % and 35 mol %. One skilled in the art will know how to prepare a series of polymers having various amounts of charge transport units and test their properties by measurement of charge mobility, for example, by time of flight measurement, or by measuring the efficiencies of p-OLEDs prepared from them. It has been suggested that a good luminescent layer will carry electrons and holes equally well, and it is desirable to adjust hole and electron mobility to be equal through addition or subtraction of charge transport units or groups.
The STB polymers of the instant invention may be used in layers of OLEDs and p-OLEDs other than the luminescent layer, for example, in a charge transport layer. As is known in the art, the charge carrying ability of a conjugated polymer may be enhanced by the incorporation of easily reducible repeat units (enhanced electron transport), or easily oxidizable repeat units (enhances hole transport), or both. Polymer compositions comprising easily oxidizable triarylamines are disclosed in U.S. Pat. No. 6,309,763 which is incorporated herein by reference. Polymer compositions comprising electron transport units are disclosed in U.S. Pat. No. 6,353,083 which is incorporated herein by reference. Additional carrier transporting repeat units useful in the practice of the present invention are disclosed in U.S. 2002/0064247 and U.S. 2003/0068527 also incorporated herein by reference.
The charge carrying layers of OLEDs and p-OLEDs may have additional functionality, for example, but not limited to, blocking charge carriers of the opposite type, blocking excitons, planarizing the structure, providing means for light to escape the device, and as buffer layers.
When used as any layer in an OLED or p-OLED the polymers and oligomers of the present invention may be blended or mixed with other materials, including but not limited to, polymeric or small molecule charge carriers, light scatterers, crosslinkers, surfactants, wetting agents, leveling agents, T 8 modifiers, and the like. For example, it may be desirable to blend an emissive polymer of the present invention with a hole transporting polymer. Or it may be desirable to blend a polymer of the present invention that emits at relatively high energy with a small molecule emitter or a polymeric emitter that also functions as an electron transport material.
The monomers of the present invention may be prepared by any methods known in the art. Patent application U.S. 2004/0135131 discloses many aryl compounds and their synthesis and is incorporated herein by reference.
The polymers of the instant invention may be prepared by any method of aryl coupling polymerization, including but not limited to, Colon reductive coupling of aryldihalides with zinc or other reducing metals catalyzed by nickel or other transition metal, Yamamoto reductive coupling of aryldihalides with an equivalent of nickel (O), Yamamoto coupling of aryl halides and aryl grignards with a nickel catalyst, Stille coupling of aryl halides with aryl tin reagents typically catalyzed with Pd, Suzuki coupling of aryl halides with aryl boronic acids or esters catalyzed with Pd metal, Pd complexes or salts, Negishi coupling of aryl halides with aryl zinc reagents typically catalyzed with Pd, Kumada catalytic coupling of aryl halides with aryl grignards or aryl lithium reagents, oxidative coupling of electron rich aryls as for example described in a review by Kovacic and Jones, Chemical Reviews, 1987, vol. 87, pp 357-379, and the like. Examples of Yamamoto and Colon coupling are disclosed in U.S. 2004/0170839 and U.S. 2002/0177687 which are incorporated herein by reference.
The polymers of the instant invention also may be prepared by any other methods, such as, but not limited to Diels-Alder type condensation of a bis-diene with a bis-dienophile as disclosed for example by Schilling et al, Macromolecules , Vol. 2, pp 85-88, 1969, incorporated herein by reference.
The polymers of the instant invention also may be prepared by graft and block methods, for example, wherein an intermediate polymer or oligomer is first formed and arms or chain extensions of another type of polymer are grown off the intermediate polymer. Graft co-polymers and block co-polymers may be useful, for example, to control the polymer morphology, or to prevent close approach of polymer chains, or crystallization. Grafts and blocks also may be used to control charge transport, for example, by incorporation of grafts or blocks of hole and/or electron transporting chains, Luminescent groups may be incorporated through the use of grafting or block copolymerization.
Monomers useful for the practice of the present invention include, but are not limited to, compositions represented by:
where R 2 , R 3 , R 5 , R 6 , R′ 2 , R′ 3 , R′ 5 , and R′ 6 are as defined above, R m may be independently hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl; R n may be independently alkylene, substituted alkylene, and 1,2-arylene; Z 1 and Z 2 are independently chosen from the group consisting of halogen atoms, —ArCl, —ArBr, —ArI, —COR m , ArCOR m , boron dihalides, borontrihalide salts, boronic acids, boronic esters,
where the boronic acids or esters may be, but are not limited to
—B(OR m ) 2 ,—ArB(OR m ) 2 ,
Non-limiting examples of R m are ethyl, phenyl, and 2-pyridyl. Non-limiting examples of R n are ethylene (—CH 2 CH 2 —), propylene (—CH 2 CH 2 CH 2 —), tetramethylethylene, and 1,2-phenylene. A non-limiting example of a borontrihalide salt is the tetrabutylammonium salt of —BF 3 (−).
Monomers useful for preparing the polymers of the present invention include:
where Z 1 and Z 2 are independently chosen from the group consisting of halogen atoms, —ArCl, —ArBr, —ArI, —COR m , ARCOR m , B(OR m ) 2 , —ArB(OR m ) 2 ,
wherein m, n, Ar, X, X′, A 33 -A 35 , A′ 33 -A′ 35 , R 30 -R 35 , and R′ 30 -R′ 35 , are as defined above.
Monomers may be prepared by any method. For example,
terphenyl monomers may be prepared by Suzuki coupling followed by bromination to dibromomonomer and conversion of the dibromide into the diboronic ester. The known 1,4-diiodo-2,5-diisopropylbenzene may also be used as a monomer, or converted to a diboronic acid or ester. The known 4,4″-dibromoterphenyl may be alkylated or dialkylated to give a dibromo monomer, and this may be converted to a diboronic acid or ester monomer. Other monomers and their method of preparation will be apparent to one reasonably skilled in the art.
Any of the dibromo-monomers may be polymerized with, for example, toluene 2,5-bis(1,3,2-dioxaborolane-2-yl), and 4-t-butyl-4′,4″-dibromotriphenylamine (typically 5 to 20 mol %) using Pd(PPh 3 ) 4 (0.5 mol %) and Na 2 CO 3 (2 eq) in toluene/water or in dimethylacetamide. It is preferred to add benzene boronic acid as an endcap.
It is desirable for the polymers of the present invention to have good electron and hole transport properties. It is therefore desirable to use co-polymers comprising STB units and good hole transporting and/or electron transporting units. Good hole transporting units will be relatively easy to oxidize, show reversible electrochemistry, and be relatively stable in the oxidized state. Hole transport units should have higher bandgap than the emitter. Preferably the hole transport unit will impart upon the polymer a reversible oxidation in the range of 0.2 to 2 V vs the Ag/AgNO 3 reference electrode (about 1 to 2.8 V vs the normal hydrogen electrode (NHE)) when measured, for example, by cyclic voltammetry (CV), either in solution or as a film in an electrolyte that can swell the film (for example acetonitrile), and at a scan rate of about 10 mV/sec. Preferably the CV peak-to-peak separation will be less than 80 mV, more preferably less than 70 mV and most preferably less than 60 mV.
Electron transport units should be relatively easy to reduce, show reversible electrochemistry, have higher bandgap than the emitter, and be relatively stable in the reduced state. Preferably the hole transport unit will impart upon the polymer a reversible oxidation in the range of between −1.3 and −2.8V vs the Ag/AgNO 3 reference electrode (about −0.5 to −2 V vs NHE when measured, for example, by cyclic voltammetry (CV), either in solution or as a film in an electrolyte that can swell the film, and at a scan rate of about 10 mV/sec. More preferably in the range −1.5 to −2.5 V vs Ag/AgNO 3 . Preferably the CV peak-to-peak separation will be less than 80 mV, more preferably less than 70 mV and most preferably less than 60 mV.
As used herein luminescent means the property of emitting light upon stimulation. Stimulation may be by electromagnetic radiation of any frequency, including visible light (photoluminescent), X-rays, gamma rays, infra-red, and ultra-violet, by electron beam, by heat or by any other energy source. Luminescent and photoluminescent include fluorescent and phosphorescent Fluorescence is luminescence having a short decay time, and generally refers to luminescence from an excited singlet state to the ground state, or any highly allowed transition. Phosphorescence is luminescence having a long decay time, and generally refers to luminescence from an excited triplet state to a singlet ground state, or to a forbidden transition.
As used herein the term transition metals includes group IIIB, IVB, VB, VIB, VIIB, VIII, IB and IIB elements.
As is well known in the art most polymers may be subdivided into repeat units in more than one way. For the polyarylenes of the present invention it is sometimes convenient to divide the polymer into simple arylene units, and sometimes into biaryl units. The heuristic division into biaryl units helps to visualize the twisting of two adjacent aryl units by their ortho substituents. The scope of the present invention is in no way limited by the particular selection of repeat units discussed here. Likewise, a given polymer may often result from more than one set of monomers. The scope of the present invention is in no way limited by the particular selection of monomers used in the examples.
Dyad as used herein refers to two aryl repeat units, where the ortho substituents are those ortho to the bond joining the two aryl units. In counting dyads in a polyarylene each aryl unit will appear in two dyads.
A secondary carbon is one which is directly bonded to exactly two other carbon atoms: A tertiary carbon is one which is directly bonded to exactly three other carbon atoms. A quaternary carbon is one which is directly bonded to exactly four other carbon atoms.
Although the present invention has been described in terms of preferred and alternate embodiments, it is intended that the present invention encompass all modifications and variations that occur to those skilled in the art, upon consideration of the disclosure herein, those embodiments that are within the broadest proper interpretation of the claims and their requirements.
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Luminescent polymers having sterically twisted arylene repeat units are provided, which are particularly suited as electroluminescent polymers. Monomers necessary for the synthesis of the sterically twisted polyarylene are provided, as are electroluminescent device utilizing these polymers.
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RELATED APPLICATION
This application claims priority to and all the benefits of U.S. Provisional Application No. 60/278,912, filed on Mar. 26, 2001.
FIELD OF THE INVENTION
The invention relates to a vehiclular mid structural module. More particularly, this invention relates to a vehicular module incorporating a tray assembly for securing a plurality of components to a mid region of the frame of a motor vehicle.
BACKGROUND OF THE INVENTION
According to conventional motor vehicle construction, multiple components are installed to the frame assembly separately of one another in the rear interior area of a vehicle passenger compartment. These components are typically packaged and shipped separately from various suppliers to a vehicle assembly site.
In particular, the installation of various vehicle components into the rear interior area of the motor vehicle can be difficult due to the needs for installing individual components in confined and restricted spaces. Individual installation of these components at a main vehicular assembly line slows the vehicle construction, is time-consuming, and is costly. As a result, there is a need for a more efficient system for assembly of the rear interior portion of the motor vehicle.
In many instances, a rear tray is a structural component of the motor vehicle. Not only does the tray provide a surface to which various components may be secured, it also adds to the structural integrity of the frame. It does so by maintaining the rear windshield in its proper position. To fulfill such requirements, the tray must be structurally reinforced. Structural reinforcement is accomplished by using tens of sheet metal pieces that are bonded or otherwise secured to the tray. This adds extra weight to the motor vehicle.
SUMMARY OF THE INVENTION
A vehicular mid structural module secures a plurality of components to a motor vehicle frame and adds structural integrity thereto. The vehicular assembly includes a tray having a bottom surface, a top surface, a front edge, a back edge, and a pair of sides extending between the front edge and the back edge. The tray includes a plurality of receiving apertures for mounting a plurality of components thereto. The vehicular assembly also includes a support member that is fixedly secured to the tray. The support member extends between the tray and the frame of the motor vehicle to support and strengthen the tray.
BRIEF DESCRIPTION OF THE DRAWINGS
Advantages of the invention will be readily appreciated as the same becomes better understood by reference to the following detailed description when considered in connection with the accompanying drawings wherein:
FIG. 1 is a perspective view of a motor vehicle including a module according to one embodiment of the invention, a decklid, and a rear windshield;
FIG. 2 is a perspective view of the module according to one embodiment of the invention;
FIG. 3 is a rear perspective view of the motor vehicle and a plurality of receiving apertures formed along a sidewall thereof;
FIG. 4 is a partially exploded, perspective view of the module of one embodiment of the invention;
FIG. 5 is a bottom view of the module of one embodiment of the invention;
FIG. 6 is a rear perspective view of the module of one embodiment of the invention; and
FIG. 7 is a cross-sectional view along lines 7 — 7 in FIG. 4 .
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT
Referring to FIG. 1 , a motor vehicle is generally shown at 10 . A rear portion 12 of the vehicle 10 extends between a rear seating area 14 and a rear bumper 16 , and is bounded by a pair of sidewalls (B or C pillar regions) 18 extending between the rear seating area 14 and the rear bumper 16 . A vehicular module, generally indicated at 20 , includes a tray 22 and a support member 24 . The tray 22 extends between the sidewalls 18 upon installation inside the vehicle 10 . The tray 22 , along with the support member 24 , supports a later-installed seat back portion 25 of a seat structure 27 , which is positioned over a vehicle frame 29 . Optionally, the seat back portion 25 of the seat structure 27 may be secured directly to the support member 24 before the tray 22 and the support member 24 are installed inside the vehicle 10 . The tray 22 and the support member 24 also serve to increase vehicle stiffness against side impacts. A decklid 26 and a rear windshield 28 , both of which are mounted to the tray 22 (as described in further detail below), are also shown.
Referring to FIG. 2 , the support member 24 is generally an inverted U-shape and includes a pair of side support arms 30 , 32 and a top support member 34 extending therebetween in the bight of the U. The top support member 34 defines a middle segment 36 and a pair of top member ends 38 , 40 . The middle segment 36 defines a recessed portion 42 extending along the length of the top support member 34 . The recessed portion 42 is formed to complementarily receive the tray 22 for attachment thereto. The support member 24 and the tray 22 may be bonded, fastened or otherwise attached as known by those skilled in the art. An upper mount 44 and a lower mount 46 are provided on each of the top member ends 38 , 40 for attachment of the support member 24 to the sidewalls 18 of the vehicle 10 . The upper mount 44 may also support a rear speaker assembly, generally indicated at 85 (as shown in FIG. 5 ).
The tray 22 includes a generally L-shaped front edge 52 , a back edge 54 , and a pair of side edges 56 , 58 extending between the front edge 52 and the back edge 54 . The tray 22 further defines a pair of generally circular-shaped apertures 60 , 62 therethrough for receiving a speaker (as seen in FIG. 3 ). The tray 22 also defines a generally rectangular-shaped cavity 64 therethrough for receiving an additional vehicle component. The tray 22 further includes a mount 65 on each of the sides 56 , 58 for mounting the tray 22 within the apertures 50 .
Referring to FIG. 3 , a plurality of support member-receiving apertures 48 and a tray-receiving aperture 50 are formed in the opposite sidewalls 18 . It will be appreciated that the number of upper 44 and lower 46 mounts and the number of complementary receiving apertures 48 , 50 may vary depending on the design of the tray 22 and the support member 24 .
Referring to FIG. 4 , the tray 22 has a top surface 66 and an underside 68 . The underside defines a series of reinforcing or structural ribs integrally molded or formed therein. The tray 22 defines a pair of head restraint mounts 70 , 72 adjacent to the front edge 52 thereof. Each of the head restraint mounts 70 , 72 are shaped to receive a head restraint 73 therein. The tray 22 also includes a pair of oval-shaped mounting apertures 74 , 76 adjacent the back edge 54 thereof for receiving a plurality of air ventilation outlets 78 , 80 . In addition, the tray 22 includes a center mounting aperture 81 for receiving rear windshield mount 82 adjacent to the back edge 54 for supporting the rear windshield 28 . The tray 22 defines a drainage trough 84 adjacent the back edge 54 thereof. The drainage trough 84 is formed to retain any water that collects therein upon opening of the decklid 26 . The tray 22 also defines a plurality of semi-circular shaped apertures 77 for receiving additional vehicle components, such as a child seat restraint attachment member 79 .
Each of the plurality of circular-shaped apertures 56 , 58 formed through the tray 22 receives a speaker assembly 85 including a subwoofer 86 and a grill cover 88 . The plurality of components, including the head restraints 73 , the air ventilation outlets 78 , 80 , the child seat restraint attachment member 79 , the speaker assembly 85 , and a center high mounted stop light (CHMSL) support 91 , is secured to the tray 22 before installation of the tray 22 into the rear seating area 14 of the vehicle 10 .
The side support members 30 , 32 include a seat belt mechanism 90 having a seat belt guide 92 for aligning a seatbelt 94 as it slides therethrough bidirectionally. Referring to FIG. 5 , a seat belt anchor 96 is formed at the bottom surface 68 of the tray 22 .
The bottom surface 68 of the tray 22 also includes a pair of hinge brackets 98 , 100 extending downwardly therefrom. Referring to FIG. 6 , a pair of generally S-shaped decklid hinges 102 , 104 is mounted to the bottom surface 68 of the tray 22 . The decklid 26 is pivotally secured to the decklid hinges 102 , 104 for moving the decklid between an open and a closed position.
Finally, referring to FIG. 7 , the tray 22 includes a rear windshield mount 82 for mounting the rear windshield 28 . In addition the back edge 54 of the tray 22 includes a seal member 106 extending along the length of the back edge 54 . The seal member 106 extends within a channel 83 along a portion of the periphery of a trunk compartment.
The method for installing the vehicular module 20 to the rear portion 12 of the vehicle 10 begins with securing the plurality of components to the tray 22 . The tray 22 includes a plurality of mounting members and receiving apertures for securing such vehicle components thereto. The tray 22 is secured to the support member 24 . The step of attaching the tray 22 to the support member 24 can occur by molding the tray 22 to the support member 24 . Before the final step of attaching the support member 24 to the rear portion 12 of the vehicle 10 , the apertures 48 and apertures 50 must be formed in the B or C pillar region 18 of the vehicle 10 . Finally, the support member 24 and the tray 22 are attached to the B or C pillar region 18 of the vehicle 10 . The rear windshield 28 is mounted to the tray 22 and sealed against the seal 106 extending along the channel 83 .
Alternatively, the step of attaching the support member 24 to the rear portion 12 of the vehicle 10 may be performed prior to the step of connecting the tray 22 to the support member 24 . As a result, the tray 22 and the plurality of components attached thereto can be directly installed to the support member 22 of the vehicle 10 .
The invention has been described in an illustrative manner. It is to be understood that the terminology, which has been used, is intended to be in the nature of words of description rather than of limitation. Many modifications and variations of the invention are possible in light of the above teachings. Therefore, within the scope of the appended claims, the invention may be practiced other than as specifically described.
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A vehicular module ( 20 ) secures a plurality of components to a motor vehicle ( 10 ) having a frame ( 29 ). The vehicular module ( 20 ) includes a tray ( 22 ) and a support member ( 24 ) that is fixedly secured to the tray ( 22 ). The tray ( 22 includes a plurality of receiving apertures for mounting a plurality of components thereto. The support member ( 24 ) engages the frame ( 29 ) of the motor vehicle ( 10 ) to support the tray ( 22 ) and provide structural integrity to the vehicle frame ( 29 ). The module ( 20 ) may be pre-assembled prior to installation to the vehicle frame ( 29 ).
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This is a continuation of application Ser. No. 08/157,360 filed on Nov. 23, 1993, now U.S. Pat. No. 5,403,352.
BACKGROUND OF THE INVENTION
This invention relates to devices which detect and/or treat tachyarrhythmias (rapid heart rhythms), and more specifically, to mechanisms to distinguish among various tachyarrhythmias and to provide appropriate therapies to treat the identified tachyarrhythmias.
Early automatic tachyarrhythmia detection systems for automatic cardioverter/defibrillators relied upon the presence or absence of electrical and mechanical heart activity (such as intra-myocardial pressure, blood pressure, impedance, stroke volume or heart movement) and/or the rate of the electrocardiogram to detect hemodynamically compromising ventricular tachycardia or fibrillation.
In pacemaker/cardioverter/defibrillators presently in clinical evaluation, fibrillation is distinguished from ventricular tachycardia using rate based criteria, In such devices, it is common to specify the rate or interval ranges that characterize a tachyarrhythmia as opposed to fibrillation. However, some patients may suffer from ventricular tachycardia and ventricular fibrillation which have similar or overlapping rates, making it difficult to distinguish low rate fibrillation from high rate tachycardia. In addition, ventricular fibrillation may display R--R intervals which may vary considerably, resulting in intervals that may fall within both the tachycardia and fibrillation rate or interval ranges, or outside both.
Presently available pacemaker/cardioverter/defibrillator arrhythmia control devices, such as the Model 7216A and 7217B pacemaker/cardioverter/defibrillator devices available from Medtronic, Inc., employ programmable fibrillation interval ranges and tachycardia detection interval ranges which are adjacent to one another but do not overlap. In these Medtronic devices in particular, the interval range designated as indicative of fibrillation consists of intervals less than a programmable interval (FDI) and the interval range designated as indicative of ventricular tachycardia consists of intervals less than a programmable interval (TDI) and greater than or equal to FDI. R--R intervals are counted to provide a count of R--R intervals falling within the tachycardia interval range (VTEC) and a count of intervals within the fibrillation range (VFEC). VFEC is a count of how many of the preceding series of a predetermined number (FEB) of R--R intervals is less than or equal to FDI. The VTEC count is incremented in response to R--R intervals that are greater than or equal to FDI but shorter than TDI, is reset to zero in response to intervals longer than or equal to TDI and is insensitive to intervals less than FDI. VTEC is compared to a programmed value (VTNID) and VFEC is compared to a corresponding programmable value (VFNID). When one of the counts equals its corresponding programmable value, the device diagnoses the presence of the corresponding arrhythmia, i.e., fibrillation or tachycardia and delivers an appropriate therapy, e.g., anti-tachycardia pacing, a cardioversion pulse or a defibrillation pulse. In addition, the physician may optionally program the device to require that measured R--R intervals meet a rapid onset criterion before the VTEC count can be incremented and may also optionally program the device to require that a rate stability criterion be met with each successive measured R--R interval in order to increment VTEC and that otherwise VTEC will be reset to zero. This detection system has proven effective in distinguishing between fibrillation and ventricular tachycardia so that appropriate therapies may be delivered. However, in rare instances, the detection methodology may require a sequence of a greater number of rapid heart beats than might optimally be desired to determine whether the rapid rhythm is due to fibrillation or tachycardia. Moreover, an improved level of accuracy in classifying rhythms close to FDI in average R--R interval duration is also believed desirable.
SUMMARY OF THE INVENTION
It is an object of the present invention to provide for accurate detection of and discrimination between tachycardia and fibrillation. It is a further object of the present invention to provide for detection of these arrhythmias in as few heartbeats as possible, consistent with accurate detection.
In accordance with the present invention, it is realized that because of the randomness of intervals between depolarizations during fibrillation or because of the characteristics of a patient's heart rhythms, fibrillation and tachycardia may include such intervals of similar duration. Thus, in a device which defines interval or rate ranges as indicative of fibrillation and tachycardia, intervals falling within the range defined as indicative of fibrillation may in fact be occurring during tachycardia, and vice versa. Moreover, either tachycardia or fibrillation may include intervals in both rate or interval ranges, delaying detection and identification of the arrhythmia.
The present invention addresses these problems by increasing or decreasing the duration of the minimum interval indicative of fibrillation and/or the maximum interval indicative of tachycardia (which, in the disclosed embodiment are essentially the same value) as a function of the measured cycle lengths in a sample of the "N" most recent intervals between depolarizations, that fall within the interval ranges indicative of tachycardia or fibrillation. During the detection of a rhythm containing a series of fast such intervals, the invention determines whether the number of intervals within the interval range indicative of fibrillation exceeds a predetermined number or percentage. If so, the value of the minimum interval indicative of fibrillation is incremented. The invention may also or alternatively determine whether the number of such intervals within the interval range indicative of tachycardia exceeds a predetermined number or percentage. If so, the value of the minimum interval indicative of fibrillation is decremented. Thus, the detection criteria are biased toward detection of fibrillation or tachycardia depending on the relative numbers of measured intervals falling within the associated rate zones. This bias increases the speed of detection by making it more likely that detected intervals will assist in meeting the detection criteria for one of these arrhythmias than the other. In rhythms with average intervals between depolarizations near the minimum interval duration which defines the dividing line between the tachycardia and fibrillation interval ranges, the invention in general reduces the total number of intervals required to satisfy the detection criteria for fibrillation or tachycardia.
BRIEF DESCRIPTION OF THE DRAWINGS
The above and still further objects, features and advantages of the present invention will become apparent from the following detailed description of a presently preferred embodiment, taken in conjunction with the accompanying drawings, and, in which:
FIG. 1 is a diagram illustrating the interval ranges employed for detection of tachyarrhythmias in the disclosed embodiment of the present invention.
FIG. 2 is a simplified block diagram illustrating the components of a device within which the method and apparatus of the present invention may be implemented.
FIGS. 3a and 3b show a simplified flow chart diagram illustrating the functioning of the present invention.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT
In the embodiment of the invention discussed below, the tachycardia and fibrillation detection criteria discussed above in conjunction with the Medtronic Model 7216 and Model 7217 implantable pacemaker/cardioverter/defibrillators are employed, and the following discussion of the present invention should be understood in this context, with the present invention being employed in this embodiment to adjust the dividing point FDI between the interval ranges associated with ventricular tachycardia and ventricular fibrillation. However, while the specific embodiment disclosed below is directed to distinguishing between ventricular tachycardia and fibrillation, it is also believed that the invention may also be usefully be practiced in the context of a device for treating atrial tachyarrhythmias. Moreover, the value of the present invention is not limited to the context of the specific detection criteria disclosed, but is believed workable and valuable in the context of any devices which distinguish between tachycardia and fibrillation using rate or interval based criteria.
FIG. 1 illustrates the relationship between the interval ranges associated with detection of fibrillation and tachycardia, as employed in the context of the present invention. The maximum interval indicative of fibrillation (minimum interval indicative of tachycardia), "FDI p " is defined during programming of the device. The maximum interval indicative of tachycardia, TDI, is similarly defined during programming of the device. As illustrated, an increments to (FDI p plus delta) or decrements from (FDI p minus delta) the value the value of FDI p may occur as part of the detection process including the present invention. Initially, FDI p serves as the current maximum interval indicative of fibrillation (FDI c ). As increments or decrements are made, the incremented or decremented values are used as FDI c . Increments are only allowable up to the point where the incremented value would exceed a maximum value (FDI max ). Decrements are only allowable up to the point where the decremented value would be less than a minimum value (FDI min ).
In the context of the preferred embodiment of the present invention, four or eight preceding R--R intervals less than TDI, for example, may be examined to determine whether the duration of FDI c needs to be incremented or decremented. The value of the increment delta may be, for example, 10 to 30 ms, and the values of FDI max and FDI min may be, for example, FDI c plus 20 to 60 milliseconds and FDI c minus 20 to 60 milliseconds, respectively. Alternatively, the invention may be practiced in a fashion such that FDI p defines either the maximum value or the minimum value of FDI c . For example, the physician may wish to allow the device only to become more biased toward detection of ventricular fibrillation, as compared to detection using the programmed rate interval ranges. In this case, FDI min would be set equal to FDI p .
FDI c may be incremented, for example, in response to more than fifty percent or more of the N intervals being less than FDI c and FDI c may correspondingly be decremented in response to more than fifty percent of the N intervals being greater than or equal to FDI c . Alternatively, more stringent criteria for incrementing and decrementing FDI c may be applied, with incrementing occurring only in response to seventy-five percent or more of the N intervals being less than FDI c and decrementing occurring only in response to seventy-five percent or more of the N intervals being greater than or equal to FDI c . It is anticipated that in greater than or equal to FDI c . It is anticipated that in commercial embodiments of the present invention, some or all of the values and parameters discussed above will be selectable by the physician.
FIG. 2 is a functional schematic diagram of an implantable pacemaker/cardioverter/defibrillator in which the present invention may usefully be practiced. This diagram should be taken as exemplary of the type of device in which the invention may be embodied, and not as limiting, as it is believed that the invention may usefully be practiced in a wide variety of device implementations, including devices having functional organization similar to any of the implantable pacemaker/defibrillator/cardioverters presently being implanted for clinical evaluation in the United States. The invention is also believed practicable in conjunction with implantable pacemaker/cardioverters/defibrillators as disclosed in prior U.S. Pat. No. 4,548,209, issued to Wielders, et al. on Oct. 22, 1985, U.S. Pat. No. 4,693,253, issued to Adams et al. on Sep. 15, 1987, U.S. Pat. No. 4,830,006, issued to Haluska et al. on May 6, 1989 and U.S. Pat. No. 4,949,719, issued to Pless et al. on Aug. 21, 1990, all of which are incorporated herein by reference in their entireties.
The device is illustrated as being provided with six electrodes, 500, 502, 504, 506, 508 and 510. Electrodes 500 and 502 may be a pair of endocardial electrodes located in the ventricle, mounted to a transvenous lead. Electrode 504 may correspond to a remote, indifferent electrode located on the housing of the implantable pacemaker/cardioverter/defibrillator. Electrodes 506, 508 and 510 may correspond to the large surface area defibrillation electrodes located on ventricular, coronary sinus, superior vena cava or subcutaneous leads or to epicardial defibrillation electrodes.
Electrodes 500 and 502 are shown as hard-wired to the 514, auto threshold circuit 516 for providing an adjustable sensing threshold as a function of the measured R-wave amplitude and comparator 518. A signal is generated on R-out line 564 whenever the signal sensed between electrodes 500 and 502 exceeds the present sensing threshold defined by auto threshold circuit 516. As illustrated, the gain on the band pass amplifier 514 is also adjustable by means of a signal from the pacer timing and control circuitry 520 on GAIN ADJ line 566.
The operation of this R-wave detection circuitry may correspond to that disclosed in commonly assigned, copending U.S. patent application Ser. No. 07/612,760, by Keimel, et al., filed Nov. 15, for an Apparatus for Monitoring Electrical Physiologic Signals, incorporated herein by reference in its entirety. However, alternative R-wave detection circuitry such as that illustrated in U.S. Pat. No. 4,819,643, issued to Menken on Apr. 11, 1989 and U.S. Pat. No. 4,880,004, issued to Baker et al. on Nov. 14, 1989, both incorporated herein by reference in their entireties, may also usefully be employed to practice the present invention.
The threshold adjustment circuit 516 sets a threshold corresponding to a predetermined percentage of the amplitude of a sensed R-wave, which threshold decays to a minimum threshold level over a period of less than three seconds thereafter, similar to the automatic sensing threshold circuitry illustrated in the article "Reliable R-Wave Detection from Ambulatory Subjects", by Thakor et al., published in Biomedical Science Instrumentation, Vol. 4, pp 67-72, 1978, incorporated herein by reference in its entirety.
It is preferable that .the threshold level not be adjusted in response to paced R-waves, but instead should continue to approach the minimum threshold level following paced R-waves to enhance sensing of low level spontaneous R-paced R-waves to enhance sensing of low level spontaneous R-waves associated with tachyarrhythmias. The time constant of the threshold circuit is also preferably sufficiently short so that minimum sensing threshold may be reached within 1-3 seconds following adjustment of the sensing threshold equal to 70-80% of the amplitude of a detected spontaneous R-wave. The invention may also be practiced in conjunction with more traditional R-wave sensors of the type comprising a band pass amplifier and a comparator circuit to determine when the band-passed signal exceeds a predetermined, fixed sensing threshold.
Switch matrix 512 is used to select which of the available electrodes are coupled to band pass amplifier 534. Selection of which two electrodes are so coupled is controlled by the microprocessor 524 via data/address bus 540. Signals from the selected electrodes are passed through band-pass amplifier 534 and into multiplexer 532, where they are converted to multi-bit digital signals by A/D converter 530, for storage in random access memory 526 under control of direct memory address circuit 528.
Microprocessor 524 analyzes the digitized EGM signal stored in random access memory 526 to determine the width of the stored R-wave or in conjunction with the tachycardia/fibrillation discrimination function discussed below.
Amplifier 534 may be a broad band pass amplifier, having a band pass extending for approximately 0.5 to 200 hertz. The filtered EGM signal from amplifier 534 is passed through multiplexer 532, and digitized in A-D converter circuitry 530. The digitized EGM data is stored in random access memory 526 under control of direct memory address circuitry 528. Preferably, a portion of random access memory 526 is configured as a looping or buffer memory which stores at least the preceding several seconds of the EGM signal.
The data stored in the buffer memory may be optionally employed to perform R-wave width measurements as disclosed in co-pending U.S. patent application Ser. No. 07/867,931, filed Apr. 13, 1992 by Mader et al., now U.S. Pat. No. 5,312,441, incorporated herein by reference in its entirety and/or to perform the ventricular fibrillation/ventricular tachycardia discrimination function disclosed in pending U.S. patent application Ser. No. 07/750,679 filed Aug. 27, 1991 by Bardy et al., now U.S. Pat. No. 5,193,535, also incorporated herein by reference in its entirety. However, the present invention is readily practiced in devices which do not include such functions, and for purposes of the disclosed preferred embodiment of the present invention it should be assumed that such functions, if available, are programmed off.
The microprocessor also updates counts related to the R--R intervals previously sensed. The counts are incremented on the occurrence of a measured R--R intervals falling within associated rate ranges. As discussed above these ranges may include the ranges illustrated above in FIG. 1 associated with ventricular tachycardia and ventricular fibrillation, and the stored counts may include VTEC and VFEC. These rate ranges may be defined by the programming stored in the RAM 526.
These counts, along with other stored information reflective of the previous series of R--R intervals such as information regarding the rapidity of onset of the detected short R--R intervals, the stability of the detected R--R intervals, the duration of continued detection of short R--R intervals, the average R--R interval duration and information derived from analysis of stored EGM segments are used to determine whether tachyarrhythmias are present and to distinguish between different types of tachyarrhythmias, as discussed above in conjunction with FIG. 1. Other such detection algorithms for recognizing tachycardias are described in the above cited U.S. Pat. No. 4,726,380, issued to Vollmann, U.S. Pat. No. 4,880,005, issued to Pless et al. and U.S. Pat. No. 4,830,006, issued to Haluska et al., incorporated by-reference in their entireties herein. An additional set of tachycardia recognition methodologies is disclosed in the article "Onset and Stability for Ventricular Tachyarrhythmia Detection in an Implantable Pacer-Cardioverter-Defibrillator" by Olson et al., published in Computers in Cardiology, Oct. 7-10, 1986, IEEE Computer Society Press, pp. 167-170, also incorporated by reference in its entirety herein. However, other criteria may also be measured and employed in conjunction with the present invention.
It is envisioned that onset and stability requirements are optional in a device employing the present invention, and preferably are made available as programmable options, which may be deleted by external programmer command. If included, it is believed preferable that the onset criteria be required to met prior to initiating counting of VTEC, and that once met, the criteria will remain satisfied until detection of tachycardia termination. Thus, onset is not intended to be a detection criteria required for redetection of tachycardia, following initial detection. The width criterion, if used, should also be understood to be used both in initial detection of tachycardia and in redetection of tachycardia. This reflects a presumption that following initial detection of ventricular tachycardia, absent a proven return to normal heart rhythm (termination detect), subsequent high ventricular rates should be presumed to be ventricular in origin. The stability criterion, on the other hand, is believed to be appropriate for use both in initial detection of tachycardia and in redetection of tachycardia.
The remainder of the circuitry is dedicated to the provision of cardiac pacing, cardioversion and defibrillation therapies. The pacer timing/control circuitry 520 includes programmable digital counters which control the basic time intervals associated with VVI mode cardiac pacing, including the pacing escape intervals, the refractory periods during which sensed R-waves are ineffective to restart timing of the escape intervals and the pulse width of the pacing pulses. The durations of these intervals are determined by microprocessor 524, and are communicated to the pacing circuitry 520 via address/data bus 540. Pacer timing/control circuitry also determines the amplitude of the cardiac pacing pulses and the gain of band-pass amplifier, under control of microprocessor 524.
During VVI mode pacing, the escape interval counter within pacer timing/control circuitry 520 is reset upon sensing of an R-wave as indicated by a signal on line 564, and on timeout triggers generation of a pacing pulse by pacer output circuitry 522, which is coupled to electrodes 500 and 502. The escape interval counter is also reset on generation of a pacing pulse, and thereby controls the basic timing of cardiac pacing functions, including antitachycardia pacing. The duration of the interval defined by the escape interval timer is determined by microprocessor 524, via data/address bus 540. The value of the count present in the escape interval counter when reset by sensed R-waves may be used to measure the duration of R--R intervals, to detect the presence of tachycardia and to determine whether the minimum rate criteria are met for activation of the width measurement function.
Microprocessor 524 operates as an interrupt driven device, and responds to interrupts from pacer timing/control circuitry 520 corresponding to the occurrence of sensed R-waves and corresponding to the generation of cardiac pacing pulses. These interrupts are provided via data/address bus 540. Any necessary mathematical calculations to be performed by microprocessor 524 and any updating of the values or intervals controlled by pacer timing/control circuitry 520 take place following such interrupts.
In the event that a tachyarrhythmia is detected, and an anti-tachyarrhythmia pacing regimen is desired, appropriate timing intervals for controlling generation of antitachycardia pacing therapies are loaded from microprocessor 524 into the pacer timing and control circuitry 520, to control the operation of the escape interval counter and to define refractory periods during which detection of an R-wave by the R-wave detection circuitry is ineffective to restart the escape interval counter. Similarly, in the event that generation of a cardioversion or defibrillation pulse is required, microprocessor 524 employs the counters to in timing and control circuitry 520 to control timing of such cardioversion and defibrillation pulses, as well as timing of associated refractory periods during which sensed R-waves are ineffective to reset the timing circuitry.
In response to the detection of fibrillation or a tachycardia requiring a cardioversion pulse, microprocessor 524 activates cardioversion/defibrillation control circuitry 554, which initiates charging of the high voltage capacitors 556, 558, 560 and 562 via charging circuit 550, under control of high voltage charging line 552. The voltage on the high voltage capacitors is monitored via VCAP line 538, which is passed through multiplexer 532, and, in response to reaching a predetermined value set by microprocessor 524, results in generation of a logic signal on CAP FULL line 542, terminating charging. Thereafter, delivery of the timing of the defibrillation or cardioversion pulse is controlled by pacer timing/control circuitry 520. One embodiment of an appropriate system for delivery and synchronization of cardioversion and defibrillation pulses, and controlling the timing .functions related to them is disclosed in more detail in co-pending, commonly assigned U.S. patent application Ser. No. 07/612,761, by Keimel, for an Apparatus for Detecting and Treating a Tachyarrhythmia, filed Nov. 15, 1990 and incorporated herein by reference in its entirety. However, any known cardioversion or defibrillation pulse generation circuitry is believed usable in conjunction with the present invention. For example, circuitry controlling the timing and generation of cardioversion and defibrillation pulses as disclosed in U.S. Pat. No. 4,384,585, issued to Zipes on May 24, 1983, in U.S. Pat. No. 4,949,719 issued to Pless et al., cited above, and in U.S. Pat. No. 4,375,817, issued to Engle et al., all incorporated herein by reference in their entireties may also be employed. Similarly, known circuitry for controlling the timing and generation of antitachycardia pacing pulses as described in U.S. Pat. No. 4,577,633, issued to Berkovits et al. on Mar. 25, 1986, U.S. Pat. No. 4,880,005, issued to Pless et al. on Nov. 14, 1989, U.S. Pat. No. 4,726,380, issued to Vollmann et al. on Feb. 23, 1988 and U.S. Pat. No. 4,587,970, issued to Holley et al. on May 13, 1986, all of which are incorporated herein by reference in their entireties may also be used.
In modern pacemaker/cardioverter/defibrillators, the particular anti-tachycardia and defibrillation therapies are programmed into the device ahead of time by the physician, and a menu of therapies is typically provided. For example, on initial detection of tachycardia, an anti-tachycardia pacing therapy may be selected. On re-detection of tachycardia, a more aggressive anti-tachycardia pacing therapy may be scheduled. If repeated attempts at antitachycardia pacing therapies fail, a higher level cardioversion pulse therapy may be selected thereafter. Prior art patents illustrating such pre-set therapy menus of anti-tachyarrhythmia therapies include the above-cited U.S. Pat. No. 4,830,006, issued to Haluska, et al., U.S. Pat. No. 4,727,380, issued to Vollmann et al. and U.S. Pat. No. 4,587,970, issued to Holley et al. The present invention is believed practicable in conjunction with any of the known anti-tachycardia pacing and cardioversion therapies, and it is believed most likely that the invention of the present application will be practiced in conjunction with a device in which the choice and order of delivered therapies is programmable by the physician, as in current implantable pacemaker/cardioverter/defibrillators.
In addition to varying the therapy delivered following a failed attempt to terminate a tachyarrhythmia, it is also known that adjustment of detection criteria may be appropriate. For example, adjustment may comprise reducing the number of intervals required to detect a tachyarrhythmia to allow a more rapid re-detection or by changing the interval ranges to bias detection towards detection of ventricular fibrillation, for example as disclosed in U.S. Pat. No. 4,971,058, issued to Pless et al. and incorporated herein by reference in its entirety.
In the present invention, selection of the particular electrode configuration for delivery of the cardioversion or defibrillation pulses is controlled via output circuit 548, under control of cardioversion/defibrillation control circuitry 554 via control bus 546. Output circuit 548 determines which of the high voltage electrodes 506, 508 and 510 will be employed in delivering the defibrillation or cardioversion pulse regimen, and may also be used to specify a multi-electrode, simultaneous pulse regimen or a multi-electrode sequential pulse regimen. Monophasic or biphasic pulses may be generated. One example of circuitry which may be used to perform this function is set forth in commonly assigned co-pending patent application Ser. No. 07/612,758, filed by Keimel, for an Apparatus for Delivering Single and Multiple Cardioversion and Defibrillation Pulses, filed Nov. 14, 1990, incorporated herein by reference in its entirety. However, output control circuitry as disclosed in U.S. Pat. No. 4,953,551, issued to Mehra et al. on Sep. 4, 1990 or U.S. Pat. No. 4,800,883, issued to Winstrom on Jan. 31, 1989 both incorporated herein by reference in their entireties, may also be used in the context of the present invention. Alternatively single monophasic pulse regimens employing only a single electrode pair according to any of the above cited references which disclose implantable cardioverters or defibrillators may also be used.
FIGS. 3a and 3b illustrate the function of the present invention as embodied in a device as illustrated in FIG. 2, in the form of flow charts. FIG. 3b illustrates the FDI ADJUST functional block 11 of FIG. 3a in more detail.
FIG. 3a illustrates the overall tachyarrhythmia detection function as employed in the disclosed embodiment of the present invention. With the exception of functional block 11, this portion of the tachyarrhythmia detection function corresponds to that employed in the Medtronic Model 7216 and 7217 implantable pacemaker/cardioverter/defibrillators, discussed above. In the context of FIG. 3a, the device should be understood to be operating as a demand pacer, with the detection functions illustrated taking place during the refractory period following the occurrence of a spontaneous or paced R-wave.
The microprocessor waits at 10 for an interrupt indicating the occurrence of a paced or sensed R-wave and in response thereto stores the duration of the preceding R--R interval and increments the value of VFEC or VTEC, if appropriate, using the interval criteria discussed above, based on the value of FDI c and TDI. The microprocessor then determines whether the value of FDI c needs to be incremented or decremented at 11. At 12, the microprocessor determines whether the detection criteria for ventricular fibrillation have been met, i.e., whether VFEC is greater than or equal to VFNID. If ventricular fibrillation is detected, then the scheduled defibrillation therapy is initiated in block 16 and the detection criteria and therapy menus are updated at 18, as described above.
If ventricular fibrillation is not detected at 12, the microprocessor checks at 14 to determine whether the criteria for detection of ventricular tachycardia have been met, i.e. whether VTEC is greater than or equal to VTNID. If ventricular tachycardia is detected, the scheduled ventricular tachycardia therapy is delivered at 16 and the detection criteria and therapy menus are updated at 18, as described above.
If no tachyarrhythmia is detected, if a tachycardia was previously detected, the microprocessor checks at 22 to determine whether a return to sinus rhythm has occurred, i.e. a series of a predetermined number of R--R intervals greater than or equal to TDI. If termination is detected, the detection criteria and therapy menus are updated at 24, as described above.
The flow chart of FIG. 3b illustrates the method by which the value of FDI c is adjusted in block 11 of FIG. 3a, based on the proportion of the N most recent event intervals that are shorter than the FDI c value. Decision block 40 determines whether or not N event intervals less than TDI have been stored since the last updating of the detection criteria due to detection of a tachyarrhythmia or detection of termination of a tachyarrhythmia. If not, the adjustment function is not enabled, and the microprocessor continues with the detection methodology of FIG. 3a. N is intended to be a relatively small number, e.g. four or eight, preferably less than VFNID or VTNID, so detection of fibrillation or tachycardia, as a practical matter will not occur until there has at least been an opportunity for the adjustment function to operate.
If N intervals less than TDI have been detected, decision block 42 determines whether or not a predetermined number of the N intervals are less than the value of FDI c . If a predetermined number M of the of the N stored event intervals are less than FDI c , for example three or more of four, the microprocessor will check at 44 to determine whether FDI c is already at its maximum value. If it is at its maximum value, then it is not altered, and the present value of FDI c is employed in the detection methodology of FIG. 3a. However, if FDI c is not yet at its programmed maximum value, then FDI c is incremented by delta in block 46.
If M of the of the N stored event intervals are not less than FDI c , the microprocessor will check at 43 to determine whether P of the of the N stored intervals are greater than or equal to FDI c , for example three or more of four.
If not, the adjustment function is not enabled, and the microprocessor continues with the detection methodology of FIG. 3a. If P of the N intervals are greater than or equal to FDI c , the microprocessor checks at 48 to determine whether FDI c is already at its minimum value. If it is at its minimum value, then it is not altered, and the present value of FDI c is employed in the detection methodology of FIG. 3a. However, if FDI c is not yet at its programmed minimum value, then FDI c is decremented by delta in block 50.
Through these adjustments of the FDI c , the detection function illustrated in FIG. #a is rendered more sensitive to the trend of the N most recent event intervals. It is thus expected, that in practice the adjustment of the FDI c will prove beneficial in accelerating a detection of ventricular tachycardia or ventricular fibrillation in those cases in which the R--R intervals of the patient's tachyarrhythmia include intervals greater and less than FDI.
After incrementing or decrementing the value of FDI c , the new value is used in subsequent detection functions illustrated in FIG. 3a. The new value of FDI c may be employed in various ways. The simplest manner in which the new value of FDI c may be employed is for subsequent R--R intervals to be classified based on the new value, with the classification of preceding R--R intervals left undisturbed. In this case, the vales of VFEC and VTEC would remain unaltered as a result of the adjustment function, and would simply be subsequently incremented using the new interval ranges defined using the adjusted value of FDI c .
An alternative method of employing the adjusted value of FDI c is to apply the new interval ranges defined by the adjusted value both prospectively and retrospectively. In this case, previously stored R--R intervals would be reexamined, and the VFEC and VTEC counts updated to the values which they would have had if the adjusted value of FDI c had been in effect throughout the detection sequence.
Following a completed detection sequence or detection of termination of a previously detected tachyarrhythmia, the value of FDI c is reset to be equal to FDI p , as part of the procedure for updating the detection criteria in functional blocks 18 and 24 in FIG. 3a. In some embodiments of the invention, the value of FDI p may be different during redetection sequences from the value during initial detection sequences. In such cases, during re-detection sequences, the adjustment function may be employed using FDI c set to the current value of FDI p . Alternatively, in such embodiments and in other embodiments of the invention, the adjustment function may be dispensed with entirely during re-detection sequences.
While the preferred embodiment of the device takes the form of a microprocessor controlled device as illustrated in FIG. 2, in which the various functional steps illustrated in FIGS. 3a and 3b would be implemented in the form of software, the invention may equally well be practiced in the form of a dedicated, full custom digital integrated circuit or, even in the form of an analog circuit, employing analog values as substitutes for the digital values disclosed in conjunction with the above specification.
In addition, while the preferred embodiment disclosed above takes the form of a pacemaker/cardioverter/defibrillator, the enhanced ability to distinguish between various tachyarrhythmias and the improved speed of detection provided by the present invention are also valuable and applicable to devices which are only capable of performing a subset of the various therapies discussed above in conjunction with FIG. 2. For example, the ability to accurately distinguish between ventricular tachycardia and ventricular fibrillation would be valuable in an antitachycardia pacemaker, even without a cardioversion pulse generator, to determine whether anti-tachycardia pacing therapies are appropriate. Similarly, the ability to distinguish between ventricular tachycardia and ventricular fibrillation is valuable in an implantable cardioverter/defibrillator lacking a cardiac pacing function, for example, as in the currently available CPI AICD implantable cardioverter/defibrillators. It should further be kept in mind that while the therapies described for delivery in response to detection of the various arrhythmias discussed are all disclosed in the context of electrical therapies, it is possible that the invention may be embodied in the form of an implantable drug dispenser, wherein one or more of the anti-tachycardia therapies takes the form of injection of a drug locally into the heart or systemically to treat the detected arrhythmia. As such, the above disclosure should be taken merely as an example of an embodiment of the present invention, rather than limiting, when reading the claims which follow.
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An automatic implantable device for detecting and differentiating between tachyarrhythmias in order to therapeutically stimulate the heart in response thereto, particularly for distinguishing fibrillation from tachycardia and to provide appropriate therapies for each condition. The event intervals between successive heart depolarizations are measured, stored and classified as within fibrillation or tachycardia interval ranges. The numbers of intervals falling within the fibrillation and tachycardia interval ranges are employed to distinguish fibrillation from tachycardia. The number of intervals required to detect and discriminate between tachycardia and fibrillation in situations where the tachyarrhythmia includes intervals in both interval ranges is reduced by adjusting the interval ranges as a function of the relative distribution of measured intervals within the interval ranges.
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RELATED APPLICATIONS
This application is a Divisional of U.S. application Ser. No. 11/828,912, filed Jul. 26, 2007, now U.S. Pat. No. 7,488,379 which was a Continuation of U.S. application Ser. No. 10/684,243, filed Oct. 13, 2003, now U.S. Pat. No. 7,367,130, both of which are hereby incorporated by reference.
FIELD OF THE INVENTION
The present invention relates to construction equipment. More particularly, the present invention relates to equipment that is used to lay out dimensional or building lines for workers in the construction industry.
BACKGROUND OF INVENTION
Snap lines have been used in the construction industry for many years for laying out building or dimensional lines. They are easy to use, accurate, and inexpensive. Typically, a snap line is tautly held adjacent or slightly above a surface that is to be marked. The line is then pulled away from the surface and released so that it strikes against the surface, leaving a residual line of powdered material, such as chalk. Over the years, snap line technology has evolved; powdered material is now available in colors other than blue, and housings are better able to retain and protect the powdered material from the elements.
One thing that has not changed over the years, however, is the use and operation of the snap line. That is, the snap line must still be positioned adjacent or slightly above a surface to be marked, pulled away, and then released so that it strikes against the surface to be marked. This works quite well for most surfaces. However, a drawback with existing snap lines is that they are ineffective when weather conditions are less than ideal.
As one may expect, conventional snap lines often do not operate as intended when conditions are wet or damp. Often, the powdered material adheres to the snap line and does not release when the line strikes the surface. Moreover, if some of the powdered material does manage to release from the line upon impact, it does not easily transfer to a surface to be marked, and if transfer does occur, the powdered material can be easily smeared and/or washed away. Thus, whenever wet conditions exist, layout work is essentially halted. This can be problematic in areas where wet conditions such as precipitation and high humidity are common.
SUMMARY OF THE INVENTION
A snap line for use in applying powdered material to a surface. The line comprises at least one strand of material that has been treated with water repellent material. The water repellant material may be applied to the line by conventional techniques and technologies, such as spraying and submersing. The line may be used with existing powdered materials such as the various colored chalks now in use, or it may be used in conjunction with powdered material that has also been treated with water repellent material. In combination, the treated line and powdered material enable a user to apply lines to wet or damp surfaces, or surfaces with shallow puddles thereon in a normal fashion. Advantageously, the treated line and/or powdered material may be used with most existing snap line.
Certain objects, features, and advantages of the present invention will become apparent from the following detailed description thereof taken in conjunction with the accompanying drawings, wherein like reference numerals designate like elements throughout the several views.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 is a perspective view of a snap line apparatus;
FIG. 2 is an illustration depicting a method by which powdered material of the present invention may be treated;
FIG. 3 is another illustration depicting another method by which powdered material of the present invention may be treated;
FIG. 4 is an illustration depicting a method by which a snap line of the present invention may be treated;
FIG. 5 is a schematic representation of process steps by which powdered material of the present invention may be treated; and,
FIG. 6 is a schematic representation of process steps by which an improved snap line may be treated.
DETAILED DESCRIPTION OF THE INVENTION
A typical snap line apparatus is depicted in FIG. 1 . The apparatus 10 includes a housing 12 for holding powdered material and an access door 14 through which powdered material may be added without having to dismantle the housing. The apparatus also has a rotatable handle 16 that may be pivoted between storage and use positions. The handle 16 is operatively connected to a reel (not shown) about which a line 20 is wound. The line 20 includes an attachment ring 22 , which is configured to facilitate attachment of the line 20 to a suitably positioned fastening element (also not shown).
The powdered material used in snap lines is usually available in bulk as a stand-alone product. In addition, powdered material is packaged in differently sized containers, of which a common size is 8-ounces. While the preferred powdered material used in the present invention comprises chalk and/or cementitious dye, it is understood that other powdered materials may be used without departing from the spirit and scope of the invention.
A process by which an improved powdered material may be treated is shown in FIG. 2 . In the figure, a container 30 is depicted as having a cap 32 , which has been removed to expose the powdered material 34 contained therein. Another container 40 is also depicted as having its cap 42 removed to expose water resistant material 44 contained therein. As shown, the water resistant material 44 is added to the container 30 . After an effective amount of water resistant material 44 has been added, and prior to mixing, the container 30 may be closed by reattaching the cap 32 . Although the treated powdered material may be produced using any one of a number of water resistant materials, it is preferred that the water resistant materials are silicone based. More preferably, it has been discovered that a particularly effective silicone-based water resistant material is sold by KIWI Brands under the name of Cavalier® Protect-All™.
FIG. 3 illustrates another process by which an improved powdered material may be treated. Here, a container 30 is depicted as having a cap 32 , which has been removed to expose the powdered material 34 contained therein. Another container 50 is depicted as having a nozzle 52 , which directs water resistant material 54 (preferably Cavalier® Protect-All™) in a predetermined direction as it is expelled or propelled from the container 50 . As shown, the water resistant material 54 is added to the container 30 by directing the water resistant material onto the powdered material. Preferably, enough water resistant material is applied to the powdered material so that the surface is effectively coated. Then, the cap 32 is replaced, and the container is agitated. Then, the cap 32 is removed and the steps of spraying, capping, and agitating are repeated until substantially all of the powdered material 34 has been treated.
As will be understood, the effective amount of water resistant material added to a container of powdered material will depend upon the size of the container. However, with an 8 (eight) ounce container of powdered material, it has been determined that an effective amount of water resistant material is in the range of about 0.5 to 4.0 ounces, and preferably in the range of about 1.0 to 3.0 ounces. It will also be understood that the aforementioned effective amount may differ between powdered materials manufactured by different companies, which may produce their powdered materials according to their own formulae, and manufacturing standards. Note that effective amounts may also be influenced by environmental conditions.
FIG. 4 illustrates a process by which an improved snap line is treated. Here, a container 40 is depicted as having its cap 42 removed to expose water resistant material 44 contained therein. A line 20 is then added to the container 40 so that it may be sufficiently coated. After the line 20 has been sufficiently coated, it is removed and allowed to air dry, or dried by applying gentle heat. Alternatively, water resistant material may be applied to a line 20 by spraying the water resistant material directly onto the line (similar to the method of application as taught in FIG. 3 ).
FIG. 5 illustrates a preferred method by which an improved powdered material may be treated. For this, a separate container may be provided, although it is preferred to use the container in which the powdered material was originally packaged. Then, the water resistant material is added to the container. As mentioned above, for an 8-ounce container, an effective amount of water resistant material is in the range of about 0.5 to 4.0 ounces, and preferably in the range of about 1.0 to 3.0 ounces. Then, the powdered material and the water resistant material are mixed. This can be achieved in numerous ways, such as, for example, by stirring, agitating, or by capping the container and vigorously shaking the container. Then, the mixture is dried. This step, too, can be achieved in numerous ways. For instance, the mixture could be allowed to air dry, or it could be gently heated. Finally, the mixture is combined with a snap line by adding it to a snap line apparatus.
It will be appreciated that the improved powdered material may be produced in a third container, if desired. In this variation, the water resistant material may be added first and then the powdered material may be added.
FIG. 6 illustrates a preferred method by which an improved snap line may be treated. For this, a separate container may be provided, although it is preferred to use the container in which the water resistant material was originally packaged. Then, the line is added to the container so that it is effectively coated. Then, the line is withdrawn from the container and dried. This can be achieved in a number of ways. For example, by air-drying, by forced air-drying, or by gently heating. Finally, the improved line installed into a snap line apparatus, where it may be combined with the improved powdered material.
It will be appreciated that the improved snap line may also be treated in a third container, if desired. In this variation, the untreated line may be added first and then the water resistant material may be added.
While preferred embodiments of the present invention have been shown and described, it should be understood that various changes, adaptations, and modifications may be made therein without departing from the spirit of the invention. For example, it is envisioned that the water repellency could be provided by polytetrafluoroethylene. Changes may be made in details, particularly in matters of shape, size, material, and arrangement of parts without exceeding the scope of the invention. Accordingly, the scope of the invention is as defined in the language of the appended claims.
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A snap line for use in applying powdered material to a surface. The line comprises at least one strand of material that has been coated with water repellent material. The line may be used in conjunction with powder that has also been coated with water repellent material. The line and the powder enable a user to apply lines to wet or damp surfaces in a normal fashion.
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