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BACKGROUND AND SUMMARY OF THE INVENTION
The invention relates to a table top board game suitable for play by one to four players who may range in age from young children to mature, but fun-loving adults.
An object of this invention is a table top board game which permits the players to harmlessly vent their frustrations and angers, not against each other, but against each other's playing pieces which consist of soft molded easily deformable upstanding figurines. The players vent their frustrations and angers by subjecting an opponent's figurine to twisting, cutting, crushing or flattening so as to completely distort the playing piece and cause it to be removed from the playing board.
Another object of this invention is a table top board game in which a player may select any one of four mechanisms for distorting his opponent's playing piece.
Another object of this invention is a table top board game in which various playing piece distortion mechanisms can be operated simultaneously by the rotation of a crank.
Another object of this invention is a table top board game in which soft moldable easily deformable playing pieces may be remolded so that the pieces ca be used repeatedly.
Other objects may be found in the following specification, claims and drawings.
BRIEF DESCRIPTION OF THE DRAWINGS
The invention is illustrated more or less diagrammatically in the following drawings wherein:
FIG. 1 is a top plan view of the table top game board of this invention shown on a reduced scale;
FIG. 2 is a perspective view of a die used in playing the game;
FIG. 3 is a front elevational view of a molded playing piece used in playing this game;
FIG. 4 is a side elevational view of the playing piece of FIG. 3;
FIG. 5 is a top plan view of the game board with the actuating mechanism removed;
FIG. 6 is a top plan view of a playing piece mold;
FIG. 7 is a cross sectional view taken along line 7--7 of FIG. 6;
FIG. 8 is an exploded side elevational view partially in cross section showing a stick of molding material prior to its insertion in the mold;
FIG. 9 is an enlarged top plan view of the operating mechanism housing which is installed on the game board;
FIG. 10 is a cross sectional view taken along line 10--10 of FIG. 9;
FIG. 11 is a cross sectional view taken along line 11--11 of FIG. 9;
FIG. 12 is a cross sectional view taken along line 12--12 of FIG. 9;
FIG. 13 is a cross sectional view taken along line 13--13 of FIG. 9;
FIG. 14 is an enlarged top plan view of the operating mechanism of the game board of this invention;
FIG. 15 is a cross sectional view of the playing figure twisting platform;
FIG. 16 is a bottom elevational view of the playing figure twisting platform of FIG. 15;
FIG. 17 is a cross sectional view taken along line 17--17 of FIG. 14;
FIG. 18 is a cross sectional view taken along line 18--18 of FIG. 14;
FIG. 19 is a side elevational view of a playing piece, shown in phantom lines, lying in a bed mechanism which carries the playing piece under the roller mechanism of FIG. 18;
FIG. 20 is a partial front elevational view, with some parts in cross section, showing the playing piece crushing mechanism;
FIG. 21 is a side elevational view of the mechanism of FIG. 20; and
FIG. 22 is a front elevational view of a playing piece retaining gate.
DESCRIPTION OF THE PREFERRED EMBODIMENTS
An embodiment of the invention is shown in an overview in FIGS. 1 through 4 of the drawings in which 11 is a table top game embodying the novel features of this invention. It includes a game board 13 which is conventionally made of heavy cardboard or pressed board which conventionally may be folded about a center line. A path of travel 15 for playing pieces 17 shown in FIGS. 3 and 4 of the drawings is provided on the top face of the game board 13 by printing, silk screening or any other conventional method. The path of travel 15 includes a number of discrete stations 19 indicated by connected or disconnected circles. The balloon shaped FIG. 21 depicted on the surface of the game board indicates the starting point for the playing pieces. The movements of the playing pieces 17 are controlled by rolling the die 23 shown in FIG. 2. The number which turns up on the die indicates the number of discrete stations 19 to which a playing piece may be moved during any one turn of a player. Some of the discrete stations such as station 24 have lettering which indicates that the player moving his playing piece is permitted to pick up playing pieces 17 of other players which are on target stations such as those indicated by numeral 25 and subject these playing pieces to distortion. The target stations 25 are indicated by multiple concentric circles. Counters 27 are snapped into openings in the playing board and one is provided for each player.
The game board 13 is shown in FIG. 5 prior to the installation of the other parts of the table top game thereon. It has an irregularly shaped design 41 in the center thereof surrounded by a narrow decorative border 43 which may be printed or painted thereon. The design 41 provides a template for installing the mechanical portion of the game on the game board 13. Keyhole slots 45 with rectangular portions are formed in the board to permit attachment of other portion of the table top game to the game board.
FIGS. 6 through 8 of the drawing show a mold 51 used for making and repairing the playing pieces 17. The playing pieces are manufactured using a block 53, shown in FIG. 8, of a soft moldable easily deformable material which is generally sold for children under the generic designation "non-toxic molding material". The mold has a cavity 55 which receives the block of material and two push out pins 57 connected to a mold face 59. The mold face fits inside the mold cavity and provides the figurine shape to the block 53 of molding compound.
The equipment base 71 is shown in FIGS. 9 through 13 of the drawings. It may be conventionally injection molded in the form of a thin piece of plastic having a top surface 73 and a downwardly extending exterior rim 75. Downwardly extending L-shaped feet 77 are formed integrally with the top surface 73 and are positioned to fit through the larger portions of the keyhole slots 45 in the game board 13 so that the equipment base can then be slid to the left as shown in FIG. 5 of the drawings to lock the equipment base in position on top of the game board 13. Portions of the equipment base 71 provide mounting means for the cutting, crushing, twisting and flattening mechanisms to be hereinafter described.
Twisting mechanism 81 is shown in detail in FIGS. 9, 10, 11, 14, 15 and 16 of the drawings. A pivot post 83 for the mechanism is shown in FIGS. 9 and 10 of the drawings. A pair of shouldered tubular stubs 85 shown in FIGS. 9 and 11 of the drawings extend through the top surface 73 of the equipment base 71. A somewhat cross shaped mounting clip 87 is mounted on the stubs 85 through means of its two legs which fit into the tubular stubs. The mounting clip 87 has horizontally extending arms 89, an upstanding center pivot post 91 and a horizontally projecting stop 92 shown most clearly in FIG. 14 of the drawings. A rotatable platform 93, shown most clearly in FIGS. 15 and 16 of the drawings, is mounted for rotation on the pivot post 83 shown in FIG. 10 of the drawings. The platform 93 has a pair of upstanding walls 95 which receive and grip a playing piece 17 standing in position on the platform 93. Ratchet teeth 97 are formed on the bottom surface of the rotatable platform 93 as shown in FIG. 16 of the drawing and these teeth engage a pawl 99 formed in the top surface 73 of the equipment base 71 and shown most clearly in FIG. 9 of the drawings. The purpose of the pawl 99 is to engage the ratchet teeth 97 to limit rotation of the platform 93 to a clockwise direction as shown in FIG. 14 of the drawings. Peripheral ratchet teeth 101 are formed on the circumferential side of the rotatable platform 93 as shown in FIG. 15 of the drawings and these teeth are engaged by a wrench replica 102 shown in FIG. 14 of the drawing to cause clockwise rotation of the rotatable platform 93 as shown in FIG. 14 upon oscillation of the wrench replica 102. The engagement between the wrench replica 102 and the ratchet teeth 101 is brought about by a tooth 103 formed as part of a U-shaped clip 104 attached to the underside of the wrench replica 102.
In order to hold a playing piece 17 in an upright position so that it can be twisted by engagement with the rotating upstanding walls 95 formed on the platform 93, a clothes pin-like device 105 formed of a pair of clothes pin arms 107 is supported on the mounting clip 87 and held together in closing contact by means of two rubber bands 109. When the arms are spread apart, a playing piece 17 may be inserted between the arms 107 and the rubber bands 109 will bring the arms into clamping engagement with the playing piece. With the upper portion of a playing piece 17 clamping in position between the cloths pin arms 107, oscillation of the wrench replica 102 will rotate the platform on which a playing piece 17 is standing in a clockwise direction as viewed in FIG. 14 of the drawings. Because the lower portion of a playing piece is held between the upstanding walls of the platform, the lower portion of the playing piece will rotate with the platform thus twisting the playing piece.
A thickness flattening mechanism 121 is shown in FIGS. 9, 12, 14, 18 and 19 of the drawings. It includes a pair of rails 123 formed integrally with the top surface 73 of the equipment base 71 which rails are located between a pair of upstanding hollow posts 125 extending through openings 127 formed in the top surface 73 of the equipment base 71. The hollow posts need not be formed separately but can be molded integrally with the equipment base 71. A ribbed roller 129 shown most clearly in FIGS. 14 and 18 of the drawings extends between the hollow posts 125 and is biased downwardly by a pair of tension springs 131 each located inside a hollow post 125. Trunnions 133 at the ends of the rib roller 129 extend through vertical slots 135 in the hollow post 125 to engage the ends of the torsion springs 131. The opposite ends of the torsion springs are connected to a rod 137 which extends between the bottoms of the hollow post and is held in position between misaligned bosses 139, the middle boss having a notch formed therein.
A sled 141 shown in FIGS. 14, 18 and 19 has a well 143 which receives a recumbent playing piece 17. The sled rides on the rails 123 beneath the ribbed roller 129. The sled has a stanchion 145 at one end to permit it to be pulled under the roller in a manner to be hereinafter described. As shown in FIG. 18, the roller 129 rides on shoulders 146 formed on the side walls of the sled 141. The shoulders are higher than the thickness of a playing piece 17 at the stanchion end of the sled and are ramped down to the opposite end of the sled where they are lower than the thickness of the playing piece. The roller 129 may be ribbed as shown. The sled 141 may be formed with a mirror image word 147 in the bottom thereof such as the word "splat" as shown in FIG. 14 of the drawings. So that the word "splat" is formed in bas relief on the back of the flattened playing piece. The face of the playing piece would be ribbed in a mirror image of the roller 129.
A playing piece cutting mechanism 151 is shown in detail in FIGS. 9, 13 and 14 of the drawings. A tapered open top mounting post 153 is formed integrally with the top surface 73 of the equipment base 71. A pair of scissor blades 155 and 157 are pivotally mounted on top of the post 153 by means of a locking snap pin 159. The tips of the scissor blades swing over an arcuate rail 161 formed integrally with the equipment base 71. A handle 163 is formed integrally with scissors blade 155 and a handle 165 is formed integrally with scissors blade 167. A hook 167 is formed at the end of the handle 165. An upstanding stanchion 169 is formed integrally with the equipment base 71 and a hook 171 is formed at the upper end of the stanchion. A rubber band 173 connects between hook 171 and hook 167 of the scissors handle 165 to provide a biasing force against the scissors blade 157. A ramp 175 sloping upwardly and outwardly is integrally formed in the equipment base 71 and is engaged by the hook 167 projecting downwardly from the end of the handle 165 to force the handle 165 outwardly of the equipment base 71 as shown most clearly in FIG. 14 of the drawings. The rubber band 173 in addition to providing tension against the blades 155 and 157 of the scissors mechanism also functions as a safety feature to prevent the scissors from coming together and cutting an object such as a child's finger. Instead, the rubber band 173 will stretch beyond its normal extended position to prevent the blades 155 and 157 from coming together when the blades encounter opposition greater than that provided by an easily distortable figurine 17.
Referring now to FIGS. 1, 9, 14, and 20 to 22 of the drawings, a playing piece 17 height crushing mechanism 181 is depicted therein. This mechanism includes a tower 183 having a base 185 which extends laterally of the tower in opposite directions therefrom. The lateral extensions 185 fit under opposed raised ribs 187 formed integrally with the equipment base 71 as shown most clearly in FIG. 21 of the drawings. A spring tab 189 also molding integrally with the equipment base 71 and shown most clearly in FIG. 14 of the drawings engages the base 185 to lock the tower in position. A sprocket wheel 191 is pivotally mounted near the top of the tower on one side thereof. This wheel is held onto the tower by a pair of snap over detents 193 and an arcuate chain guard 195 is formed integrally with the tower. An outwardly extending eccentric stub 197 is formed on the sprocket wheel and a leg replica 199 is pivotally mounted on this eccentric stub. A pants replica 201 snaps over the upper portion of the leg replica as shown most clearly in FIG. 21 of the drawings. A two piece shoe replica 203 fits on the bottom of the leg replica and the inner shoe piece has an inwardly extending guide pin 205 with a hook (not shown) which fits into a guide slot 207 formed in the tower. Sprocket type idler wheels 209 are mounted on the opposite edges of the tower 183. A gate 211 shown in detail in FIG. 22 of the drawings has one post 212 pivotally mounted in an opening in the equipment base 71 and the opposite post has a foot 213 that fits into a converging slot 215 formed in the equipment base to lock the gate in a closed position. The gate prevents the playing piece 17 from moving out from beneath the crushing shoe replica 203 as it is crushed.
An actuating mechanism 221 which simultaneously operates the twisting mechanism 81, the flattening mechanism 121, the cutting mechanism 151 and the crushing mechanism 181 is shown in detail in FIGS. 9, 14, 17, 20 and 21 of the drawings. This actuating mechanism includes a hand operated crank arm 223 having an integral cover 225 which fits over a post 227 formed integrally with the equipment base 71. Located under the cover and over the post 227 is a main drive gear 229. An O-ring 231 is positioned between the drive gear 229 and the crank arm cover 225 to function as a clutch between these two members. The crank arm cover 225, the gear 229 and the O-ring 231 are fastened together by a screw 233 which fits into the post 227. An idler gear 235 is mounted on a post 237 which is formed integrally with the equipment base 71. The idler gear 235 meshes with a gear 239 mounted on a post 240 formed integrally with the equipment base 71. The gear 239 has an upstanding eccentric stub 241 shown in FIG. 14. The idler gear 235 also has a spur gear 242 of reduced diameter which engages a gear 243 mounted on a post 245 formed integrally with the equipment base 71. The gear 243 has an upstanding eccentric post on the top thereof and an arcuate partial gear 249 on the lower side thereof which engages a clicker 251 held by posts 253 on the equipment base 241. The clicker makes sounds as the scissor blades 155 and 157 close. Sprocket teeth 255 formed on gear 229 engage a bead chain 257 which rotates the sprocket wheel 191 of the crushing foot tower 183.
A plastic cover 259 snaps into openings 260 in the equipment base 71 to enclose and cover the gears and bead chain.
As can be seen most clearly in FIG. 14, drive link 261 in the shape of a fanciful arm and hand connects the eccentric stub 241 on gear 239 to the wrench replica 102 of the playing piece twisting mechanism 81. A drive link 263 connects the eccentric post 247 of the gear 243 to post 145 on the sled 141 of the figurine flattening mechanism 121 to move it back and forth under the roller 129. Another drive link 265 also in the shape of a fanciful arm and hand is connected to the eccentric post 247 of the gear 243 and to the handle 163 of the scissors blade 155 of the playing piece cutting mechanism 151. The playing piece height crushing mechanism 181 is actuated by movement of the bead chain 257 which is moved by engagement with the sprocket teeth of main gear drive 229. Thus, it can be appreciated that clockwise rotation of the crank arm 223 of the actuating mechanism 221 operates all of the playing piece distortion mechanisms.
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A table top board game including a game board having a plurality of playing pieces. Each playing piece is formed of a soft moldable easily deformable material in the shape of an upstanding figurine. A mold is provided for molding new playing pieces and repairing playing pieces which have been deformed during the course of the game. A path of travel for the playing pieces is depicted on the game board. This path of travel includes a series of discrete stations each of which is spaced apart a sufficient distance from another station so that a station can receive one of the playing pieces without that playing piece interfering with another playing piece positioned on an adjacent station. The playing piece cutting mechanism includes a scissors-like mechanism having a pair of blades one of the blades being movable relative to the other blade by a link which is driven by the crank operated mechanism. The twisting mechanism includes a clothes pin-like playing piece grasping mechanism to hold one end of a playing piece and a wrench-like mechanism to engage the opposite end of a playing piece and to twist it relative to the end held fixed. The crushing mechanism includes a boot-like mechanism which is reciprocated up and down on the top of a playing piece and the flattening mechanism includes a grooved roller which runs over a playing piece from head to toe.
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BACKGROUND AND SUMMARY OF THE INVENTION
This invention relates to the processing of granular starch for use as a carrier for absorbed functional substances. More particularly, this invention provides a microporous granular starch matrix material useful for absorption and releasable containment of any of a wide variety of useful compositions. Absorbed compositions are released from the porous granular starch matrices by diffusion into surrounding fluids, by mechanical compression, or by chemical degradation of the starch matrix.
It has been known for quite a number of years that digestion of starch in food begins in the mouth on contact with salivary alpha-amylase. Starch digestion is completed in the duodenum of the small intestine where the starch granules come into contact with pancreatic alpha-amylyase and intestinal beta-amylase. Starch granules taken from the duodenum or natural starch granules that have been treated with alpha-amylase or glucoamylase in vitro for a period of time are noted under microscopic examination to have numerous holes or pores ranging over the entire surface. The number, size and depth of the pores depend upon the extent of the enzyme action. As normal digestion continues in the gastrointestinal tract the granule is entirely disintegrated by the alpha-amylase, by the normal beta-amylase of the intestine and by maltase which is also present.
In accordance with the present invention microporous starch granules are used as a carrier for a wide variety of functional substances. The granules are partially hydrolyzed with alpha-amylase and/or glucoamylase and optionally treated chemically to modify structural integrity and surface characteristics. The amylase-treated granules have numerous pores leading from the granule surface to the granule interior giving the treated granules a sponge-like appearance on microscopic examination. Substances can be readily absorbed into the porous granular starch matrix. That property also allows the present porous granular starches to find use as adjuvants for antiperspirants and as bulking agents for foods and drinks.
Use of granular starch matrices in accordance with the present invention allows for the preparation of new forms of art-recognized compounds and compositions having utility in the areas of food/nutrition, topical creams and lotions, cosmetics, agricultural products, and products for human and veterinary medicine. Such novel formulations can be designed to enhance or prolong the functional characteristics of absorbed compositions. For example, substances naturally of a liquid character can be formulated into a powder, paste or cream formulation, more easily adapted for packaging or for practical utility, such as for sustained release of said compositions.
DETAILED DESCRIPTION OF THE INVENTION
The starch matrix materials, in accordance with this invention, are prepared by treating granular starch, typically as a slurry in an aqueous medium, with a glucoamylase or alpha-amylase or a mixture of such enzymes, at temperatures below the gelatinization point of the starch. Enzyme treatment is continued until the granules have a pore volume of about 10% to about 40%, more preferably about 15% to about 25% of granule volume. Any of a wide variety of art-recognized alpha-amylases or glucoamylases including those derived from Rhizopus niveus, Aspergillus niger, and Rhizopus oryzae and Bacillus subtilis and alpha-amylases and glucoamylases of animal origin, can be used. The duration of enzyme treatment necessary to produce microporous starch granules for use in accordance with this invention depends on a number of variables, including the source of starch, species and concentration of amylases, treatment temperature, and pH of the starch slurry. The progress of starch hydrolysis can be followed by monitoring the D-glucose content of the reaction slurry. In a preferred embodiment, the starch hydrolysis reaction is allowed to proceed until about 17 to about 20% of the starch has been solubilized. Starch from any of a wide variety of starch-containing vegetable sources can be used to produce the starch matrices in accordance with this invention, however, economics favor the use of corn starch.
A wide range of pore sizes, granule firmness and structural stability can be produced simply by controlling the degree of starch hydrolysis. However, granular firmness and surface characteristics can be advantageously adjusted by further treatment of the microporous amylase treated starch granules. Although the partially hydrolyzed starch granules have been found to have surprising mechanical strength in the dry state and significant structural integrity in water dispersion, a greater degree of structural integrity can be introduced by treating the microporous granules with an effective amount of a bifunctional starch-reactive chemical cross-linking agent. Any of a variety of art-recognized starch cross-linking agents, including those recognized as food-acceptable by the Food and Drug Administration, can be used. Suitable cross-linking agents include phosphates such as sodium trimetaphosphate, dicarboxylic acids derivatives, particularly C 2 -C 6 dicarboxylic acids including maleic and glutaric acid, phosphorous oxychloride, epichlorohydrin and β,β-dichlorodiethyl ether. Microporous starch granules become more and more resistant to mechanical damage and to swelling and dissolution with increased degree of cross-linking. Starch cross-linking agents are described in my book Starch Chemistry And Technology, second edition, 1984, Academic Press, Inc., New York, New York.
The capacity of microporous starch granules prepared in accordance with this invention to absorb functional substances is dependent upon the compatibility of the surfaces of the starch matrix with the intended absorbate. Thus, the partially hydrolyzed microporous granules can be treated with surface-modifying agents to enhance granule absorptivity. If the substance to be absorbed onto and into the starch matrix has a predominant lipid character, the starch matrix can be treated to render the pore surfaces more lipophilic. The partially hydrolyzed starch granules can be treated with solutions of synthetic polymers, such as methylcellulose, polyvinyl alcohol, poly-N-vinyl-2-pyrrolidone, polyacrylamide, carboxymethylcellulose, carragenan or other food grade gums. After such treatment, the granules, when dried, will take up liquids readily and will easily absorb fatty or lipid substances including oils and creams.
Alternatively absorbency for lipophilic substances can be facilitated by derivatizing starch molecules on the pore surfaces with long fatty acid chains, for example, by reacting the microporous granules with stearyl- or octenyl-succinic acid anhydride. The granule and pore surfaces are thereby rendered more lipophilic and more compatible with absorbates having a predominate lipid character. Absorbency of the granular starch matrices for lipophilic substances can also be enhanced by esterfying the partially hydrolyzed starch granules with long chain fatty acids or derivatives thereof, or by etherification with long chain fatty halides. Treatment with acetic anhydride will also provide some lipophilic character to the partially hydrolyzed granules but a higher level of derivatization is required.
The microporous granular starch matrices prepared in accordance with this invention can be utilized as an absorbent carrier for a wide range of functional substances. Exemplary of substances which can be absorbed into and on the partially hydrolyzed starch granules in accordance with this invention are salad oils, flavors, insect repellents, insecticides, herbicides, perfumes, moisturizers, soaps, waxes, body creams and lotions, vitamins and therapeutic drug substances. Such functional sorbates can be absorbed into the starch matrices of the present invention by either spraying solutions of such substances onto the prepared granular matrices or by adding the granular starch matrix material to solutions of said substances, separating the pore-loaded granules from solution by art-recognized techniques such as filtration or centrifugation and drying the substance bearing granules. The degree of loading of functional substances in the starch matrix can be controlled in part by adjusting the concentration of the functional substance in the solutions used to load the granular matrices. Higher matrix concentrations of the loaded material can be realized using more concentrated solutions of the substance and by repeating the loading procedure. Preferably the substances are absorbed into the starch matrix as their solutions in inert, relatively low boiling solvents which can be removed by evaporation following the absorption-loading of the starch matrix.
Compositions in accordance with the present invention comprising a starch matrix consisting essentially of amylase-treated starch granules having a microporous structure and a functional substance absorbed into said microporous structure can be used in powder form or it can be formulated into liquids, creams, tablets or other forms adapted to the intended usage of the absorbed functional substance. The absorbed substance is released from the microporous starch matrix either upon mechanical compression of the granular formulation or by chemical degradation of the starch matrix. Alternatively the granules can serve as a reservoir for the functional substance from which the substance is released to a surrounding medium simply by diffusion processes, thereby serving as a controlled or slow-release composition for said functional substance.
Microporous starches in accordances with this invention also find use as adjuvants for antiperspirants and as metabolizable bulking agents (i.e., to provide a pulpy texture) to foods and drinks. For that later use the microporous starches can be employed in a cross-linked form utilizing any one of the cross-linking agents herein described, or they can be employed without further chemical modificaion. For many applications the cross-linked material in the diester phosphate form at the levels of 0.1-0.5% are quite satisfactory.
The following examples are presented to illustrate the present invention and should not in any way be construed as a limitation thereof.
EXAMPLE 1
Ten grams of corn starch in 100 milliliters of water was treated with glucoamylase (Zymetec GA-200) from Aspergillus niger for 15 hours at 25° and pH 4.2. The slurry was filtered. The enzyme-treated granular starch was washed and could be used at once to take up flavors and creams and other ingredients. It has been found desirable to stop the enzyme hydrolysis reaction after dissolution of 17-20% of the starch, as can be determined by standard reducing value measurement of the supernatant of the reaction mixture.
A portion of the isolated starch granules was washed with a 0.5% solution of methylcellulose to make it more compatible with lipophilic sorbates. Another portion was dried for later use in absorption of body cream and after shave cream.
Another portion of the partially hydrolyzed starch was treated in water with stirring with 0.1% phosphorus oxychloride, phosphoryl trichloride, in an amount of 0.5 to 0.4% and warmed to 35° while at a pH of 8 to 12 for one hour to cross-link the starch molecules to a small degree. The cross-linked starch granules were washed, filtered and dried for future use in taking up sorbates.
It was found that a very low degree of cross-linking does well to strengthen the porous granule Thus, 100 grams of porous starch in 250 milliliters of water at pH 10.0, adjusted with 1.0N. sodium hydroxide, was stirred slowly during 45 minutes while 50 microliters of phosphoryl chloride dissolved in four milliliters of carbon tetrachloride was slowly added. The pH was maintained over this period by addition of sodium hydroxide solution and then adjusted with dilute (about 1N.) hydrochloric acid to pH 5.5. The slurry was centrifuged, and the precipitated starch derivative washed with water and again centrifuged. This washing was repeated twice more and the starch was finally dried under at 35° in a current of air.
EXAMPLE 2
Twenty grams of dasheen starch in 100 milliliters of water was hydrolyzed with commercial alpha-amylase (enzyme to substrate ratio 1:66) at pH 5.5 and 30° C. for 20 hours with slow stirring. The dispersion was then filtered and washed first with water and then with isopropanol and dried at room temperature (about 25° C.). When these granules were examined microscopically in glycerol-water (ratio 1:1) they showed numerous deep pores distributed over the granules. When some granules were sprinkled as a powder on double sided Scotch tape and shadowed in a vacuum with gold and examined in a scanning electron microscope (JMS-840, JEOL), the granules were seen to have numerous deep pores distributed throughout.
EXAMPLE 3
Ten grams of wheat starch was treated with temperature sensitive Bacillus subtilis alpha-amylase in a 100 milliliter solution of sodium acetate-acetic acid buffer at pH 4.7 and 30° for 6 hours, filtered and washed with water, dried and heated to inactivate the enzyme. The product was used as such or was washed with 0.1% methylcellulose or polyvinyl alcohol solution of 0.1% and dried or was cross-linked with phosphoryl chloride as stated above and dried.
EXAMPLE 4
Ten grams of potato starch in 50 milliliters of a solution of sodium acetate-acetic acid buffer at pH 4.7 was treated with glucoamylase at 30° for 2.5 hours, filtered and washed with water and product subjected to moderate cross-linking using the conditions described in U.S. Pat. No. 2,328,537, Sept. 7, 1944 by George E. Felton and Herman H. Schopmeyer of the American Maize-Products Company. The conditions were adjusted so as to introduce a degree of substitution of 0.01 to 0.5.
EXAMPLE 5
Starch granules were hydrolyzed as in Example 2 above, and the freshly washed product was treated under mild alkaline conditions, about pH 9, with maleic anhydride. The dried product was heated to 100° for 30 minutes to effect a partial Michael condensation and partial cross-linking by way of the carboxyl groups forming ester linkages with hydroxyl groups on the adjacent starch molecules. The partially hydrolyzed starch granules can also be cross-linked with a variety of reagents and by methods referred to in my book Starch Chemistry and Technology referred to above.
EXAMPLE 6
Cassava (tapioca) starch was hydrolyzed with glucoamylase for 6 hours at 30° and pH 5 and the pH of the solution was adjusted to 10.5 by the addition of 3.5% sodium carbonate. Sodium trimetaphosphate was added to a concentration of 2% by weight and the reaction mixture was heated to 50° C. for 1.5 to 2 hours. (Sodium trimetaphosphate is readily available but can be made by heating sodium dihydrogen orthophosphate at 550° C. for 2 hours.) At the end of the reaction the starch slurry is washed with water until the washings are free of reagents and then adjusted to pH 6.5 with hydrochloric acid. The starch product is filtered and dried at 40° C.
EXAMPLE 7
Ten grams of commercial corn starch, pearl starch, in 100 milliliters of water at pH 5.0 was treated at 25° C. for 8 hours with equal amounts of alpha-amylase and glucoamylase in the ratio of starch substrate to total enzyme of 66:1 and the mixture was allowed to stand at 8° C. for 16 additional hours with gentle shaking. The resulting starch granules observed microscopically were seen to have slightly greater Porosity than those treated with either enzyme alone. This might suggest that a shorter reaction time could be employed if mixed enzymes were used. However, commercial amylase and glucoamylase enzymes are known not to be pure and may contain a little of one type when the other type is prepared for commercial customers.
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Amylase treated granular starches provide a microporous matrix material adapted for absorption and releasable containment of functional compositions. The microporous starch granules are chemically derivatized to enhance absorptive and structural properties. Absorbed functional substances are released from the microporous starch matrix under the influence of mechanical compression, by diffusion into a surrounding fluid or as a result of degradation of the granular starch matrix.
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BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention is in the field of watermattresses. More particularly, the present invention is in the field of tube-type watermattresses having an immovable wave-dampening insert.
2. Brief Description of the Prior Art
Watermattresses have been known in the prior art for a long time. To a great many people sleeping on a watermattress offers more comfort than sleeping on conventional bedding. Nevertheless a serious disadvantage of conventional watermattresses is the wave motion of water in the mattress which, although preferred by some, is found objectionable by the majority of persons. In order to reduce or eliminate this unwanted wave motion various devices and means have been employed in the prior art. For example, U.S. Pat. No. 4,301,560 describes the use of lofted polyester fiber as a wave dampening insert in a watermattress. U.S. Pat. No. 4,411,033 describes the use of buoyant floating polyurethane foam insert as wave-dampener in a watermattress. U.S. Pat. Nos. 4,577,356, 4,551,873, 4,399,575, 4,345,348, and 4,247,962 describe the use of wave dampening baffles in watermattresses.
U.S. Pat. No. No. 4,221,013 describes the use of elongated water-filled tubes in a watermattress having a soft-sided (foam) frame of specific construction. When the water-filled tubes are disposed "head-to-toe" in the watermattress, they substantially prevent propagation of wave motion in a side-to-side direction. Inserts, (such as foam or fiber) have also been used in the prior art within the elongated tubes to dampen the propagation of wave motion in the longitudinal direction. A tube-type watermattress which has inserts capable of inhibiting wave motion and providing extra support to the back, "lumbar" area to a person resting on the watermattress is described in our U.S. Pat. No. 5,077,848.
Providing wave dampening inserts and/or baffles in a watermattress, however, is not entirely without problems. For example, baffles welded directly to the vinyl envelope which contains the water usually weaken the overall construction and eventually cause tears and leaks. Inserts, such as foam or fiber, cause their own sets of problems, such as difficulty in draining, and shifting within the water-tight envelope. In order to reduce these problems, techniques were developed in the art to facilitate draining and to anchor or tether baffles and inserts within the interior of the watermattress. Anchoring or tethering structures are described in U.S. Pat. Nos. 5,152,020, and 5,062,170. U.S. Pat. No. No. 5,050,257 describes a fiber-filled watermattress with a drainage manifold positioned beneath the fiber insert to direct water toward a drain valve, to facilitate draining of the watermattress.
With respect to tube-type watermattresses however, the problem of a fiber or foam insert sliding within the tubes, and bunching up ("balling up") within the tube, has not been solved until the present invention. This is so, because, until the present invention, the wave-dampening foam or fiber insert provided in a tube-type watermattress has been allowed to move freely within the mattress. Because users often fill the individual water-containing tubes of a tube-type watermattress at a faucet and then carry the filled tube to the bed (sometimes in a folded U-shaped configuration) or otherwise tend to lift and move the water-containing tubes of such a watermattress, the bunching up or "balling up" of inserts in the tubes is a serious problem in the art. Such bunching up of the insert can also occur over a course of time as a result of normal human activities on the watermattress. The present invention serves to eliminate this problem.
SUMMARY Of THE INVENTION
It is an object of the present invention to provide a wave-dampened tube-type watermattress which is "consumer-friendly" with respect to avoiding problems with the wave-dampening insert when individual tubes of the mattress are drained, filled or moved.
It is another object of the present invention to provide a wave-dampened tube-type watermattress wherein the wave-dampening insert in each tube avoids sliding, and bunching up or bailing-up in the tube as a result of normal human activities on the watermattress or when the tube is drained, filled, lifted at one end or is otherwise moved.
The foregoing and other objects and advantages are attained by a watermattress which includes a plurality of elongated water-filled tubes in a suitable frame, and wherein each tube includes a wave dampening insert of foam or fiber. A base strip made of a substantially flexible material, such as vinyl, is fastened to each end of the tube within the interior of the tube. The wave dampening insert is fastened at a plurality of places along the length of the insert to the base strip, whereby the insert is substantially immobilized and is incapable of sliding or moving around in the tube even when one end of the tube is lifted.
The features of the present invention can be best understood together with further objects and advantages by reference to the following description, taken in connection with the accompanying drawings, wherein like numerals indicate like parts.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 is a perspective view of a tube-type watermattress incorporating the immobilized wave-dampening inserts of the present invention.
FIG. 2 is a cross-sectional view taken on lines 2,2 of FIG. 1.
FIG. 3 is another cross-sectional view taken on lines 3,3 of FIG. 2.
FIG. 4 is a cross-sectional view of a tube of the watermattress containing the immobilized wave dampening insert, analogous to the view of FIG. 2 but showing the tube lifted at one end thereof, as in the process of draining or moving the tube.
FIG. 5 is a partial view of a second embodiment of the tube of the watermattress containing the immobilized wave dampening insert, the view showing attachment of the insert to a retention strip by clips.
FIG. 6 is a partial view of a third embodiment of the tube of the watermattress containing the immobilized wave dampening insert, the view showing attachment of the insert to a retention strip by grommets.
FIG. 7 is a cross-sectional view, analogous to the view of FIG. 2, showing a fourth preferred embodiment of the watermattress of the present invention wherein the immobilized wave dampening insert is fiber.
FIG. 8 is a cross-sectional view, analogous to the view of FIG. 2, showing a fifth preferred embodiment of the watermattress of the present invention wherein the immobilized wave dampening insert of the mattress is foam adapted for lumbar support.
DESCRIPTION OF THE PREFERRED EMBODIMENTS
The following specification taken in conjunction with the drawings sets forth the preferred embodiments of the present invention. The embodiments of the invention disclosed herein are the best modes contemplated by the inventors for carrying out their invention in a commercial environment, although it should be understood that various modifications can be accomplished within the parameters of the present invention.
Referring now to FIGS. 1-4 of the appended drawings, a first preferred embodiment 20 of the watermattress of the present invention is disclosed. The watermattress of the present invention utilizes a plurality of elongated water containers or tubes 22 to provide a "flotation type" sleeping surface. The elongated water containers or tubes 22 are preferably disposed "head-to-toe" in the watermattress (as is shown in the herein described embodiment), although the present invention can also be utilized when the water containers or tubes are disposed cross-wise (not shown) in the watermattress. The watermattress includes a frame 24, which is usually soft-sided and is made from foam. The frame 24 forms a cavity into which the tubes 22 are placed. The frame 24 or cavity includes a bottom panel 26, side panels 28 which form vertical walls, and a top panel 30. Inasmuch as a specific construction of a tube-type watermattress is described in U.S. Pat. No. 4,221,013, a more detailed description of the tube-type watermattress is not considered necessary. The specification of U.S. Pat. No. 4,221,013 is expressly incorporated herein by reference. Quilting and fabric which conventionally covers the watermattress are not shown in the appended drawings. It is noted however, that the present invention pertains to the water containing tubes of the water-mattress, and specifically to the construction and arrangement of wave-dampening inserts therein. Therefore the present invention is not limited by the specific construction of the foam or like soft-sided cavity into which the tubes are placed. Moreover, the present invention is also applicable to tube-type watermattresses which have hard (wood) sides. Each tube 22 has a capped valve 31 to permit filling the tube 22 with water.
Generally speaking, approximately six to nine tubes 22 are used in a watermattress, the exact number depending on the size of the mattress and on the width of the tubes 22.
As is well known in the watermattress industry, the tubes 22 of a tube-type watermattress which are placed head-to-toe substantially prevent transmittal of wave motion from side-to-side. Wave dampening inserts, such as foam or fiber reduce propagation of wave motion along the length of the tubes. The tube-type watermattresses offer other advantages as well. For example, it is generally considered easier to assemble or disassemble, fill, or drain a tube-type watermattress than a single-bladder watermattress of comparable size. These particular advantages are, however accompanied by a serious drawback, in that when draining, filling or carrying an individual tube containing a wave dampening insert, it is quite common for the user to lift one or both ends of the tube thereby causing the insert to shift out of position and at worst to bunch up in the tube. This occurrence renders tube-type watermattresses with inserts of the prior art less than "user-friendly" in a sense, because straightening out and properly repositioning a bunched up insert within the water-filled tube of a watermattress is a difficult, aggravating and sometimes impossible task. Bunching up of the insert can also occur, over an extended course of time of use, as a result of normal human activities on the watermattress.
FIGS. 2, 3 and 4 show the preferred embodiment of the present invention, where, in order to solve the above-noted problem, a foam insert 32 is fastened substantially immovably within the tube 22. Specifically, as is shown in these drawing figures, a base strip or retention strip 34 is attached to the tube 22. The purpose and function of the retention strip 34 is to provide anchor points or tie-down points for substantially immovably fastening the insert 32 within the tube 22. The retention strip 34 itself must be sufficiently securely attached within the tube 22 so that it can perform its function of anchoring the insert 32 and support its weight when one end of the tube 22 is lifted, as is shown in FIG. 4. The preferred manner of constructing and incorporating the retention strip 34 in the tubes 22 is disclosed in the herein described embodiments. Thus, the retention strip 34 is preferably made from vinyl material, preferably from vinyl of approximately the same thickness as the vinyl wall of the tube 22. In this regard it is noted that usually the vinyl wall of tube is of at least 20 mil thickness, and that in the State of California this thickness is mandated by law. The retention strip 34 also needs to be sufficiently wide in order to have the required strength, as described above, and for this reason it is preferably approximately 3 to 3.5 inches wide. The retention strip 34 is welded to the wall of the vinyl tube 22 at each end of the tube 22, proximate to the same welded seam 36 which is utilized to construct the tube 22. As it can be seen from the drawing figures, the rest of the retention strip 34 is not fastened to the tube 22, so that along the length of the tube 22 the retention strip 34 merely rests on the bottom wall 38 of the tube 22.
The wave dampening insert 32 of the first preferred embodiment comprises open cell foam (such as open cell polyurethane foam), which on its upper surface is "convoluted", that is, has egg crate like configuration. The concept of using open cell foam, and specifically convoluted open cell foam as a wave dampening insert, is per se well known in the art. Convoluted foam can be made with state-of-the art convoluting machine, and is available commercially. It should be specifically understood that the height (thickness) of the foam or other insert within the tube 22 depends on the amount of wave suppression desired and does not limit the present invention. Consequently, the foam insert 32 may be high (thick) enough to fill substantially the whole volume of the tube 22, or may only fill the tube 22 partially, as is shown in the drawing figures. In order to provide the desired effect along substantially the entire length of the tube 22, the insert 32 is only slightly shorter than the tube 22, as is shown in FIG. 2.
In accordance with the present invention the insert 32 is disposed above the retention strip 34 and is affixed to the retention strip 34 at several points. In accordance with the preferred embodiment, the insert 32 is attached to the underlying retention strip 34 at five locations, three of which are shown in FIG. 2. Preferably, the points of attaching the insert 32 to the retention strip 34 are evenly spaced along the length of the insert 32, and in the preferred embodiment these points are at approximately twelve inches from one another. It will be readily understood by those skilled in the art that more or less points of attachments, and correspondingly smaller or greater distances between the points of attachment are possible within the scope of the invention.
Referring now primarily to the cross-sectional view of FIG. 3, the preferred mode of attaching the insert 32 to the retention strip 34 is shown. Specifically, polyester twine 40 is used to tie the insert 32 to the strip 34. For this purpose two holes are provided in the strip 34 and also substantially perpendicularly through the insert 32, the twine 40 is led through the holes and is tied into a knot 41 on the top of the insert 32. Instead of polyester twine, twine or string made from other water resistant materials, such as nylon, or even vinyl, could be used for this purpose. An important advantage of using twine or rope is that these materials are soft and therefore do not present a hard object which may be felt by a person resting on the watermattress, even if the person "bottoms out" on the mattress. Those skilled in the art will nevertheless recognize in light of the foregoing disclosure that there are many alternative but presently less preferred means for attaching the insert 32 to the retention strip 34. For example, the partial view of FIG. 5 illustrates a second preferred embodiment wherein a plastic clip 42 (similar in principle of operation to a toggle bolt) affixes the foam insert 32 to the retention strip 34. The partial view of FIG. 6 discloses a third preferred embodiment where a grommet 44 is used to affix the foam insert 32 to the retention strip 34. As it can be seen on the drawing figure, the grommet 44 has two parts which can be affixed to one another by friction fit, or with glue. As it was noted above, however, the preferred method for fastening the insert 32 to the underlying retention strip 34 is by means which include no hard surfaces and therefore cannot be felt by a person resting on the mattress, even if the mattress bottoms out.
FIG. 4 schematically illustrates a tube 22 of the first preferred embodiment 20 in a position in which the tube 22 is when one end of the tube 22 is lifted. Such lifting may occur in connection with draining, or carrying the tube 22, or in order to reach into the cavity of the mattress below the tubes 22. The drawing figure illustrates that the insert 32 is substantially immobilized in the tube 22, it does not shift position, does not bunch up or ball up in the tube 22, and therefore the mattress is "consumer friendly".
FIG. 7 illustrates a fourth embodiment 46 of the watermattress of the invention wherein a fiber pad 48 comprises the wave dampening insert which is tied with polyester twine 40 to the underlying retention strip 34.
FIG. 8 illustrates a fifth preferred embodiment 50. The fifth preferred embodiment 50 is constructed, at least in part, in accordance with the disclosure of our U.S. Pat. No. 5,077,848, the specification of which is incorporated herein by reference. Briefly summarizing those features of this embodiment 50 which are in accordance with the 5,077,848 patent, the insert in the tube 22 is substantially thicker in the center of the tube in the area where a person's back is likely to be located when the person rests on the watermattress. This is best accomplished by affixing a second piece of foam insert 52 on top of a first piece of foam insert 54, thereby forming a unitary insert 55 thus adapted for lumbar support. In accordance with the present invention, the unitary lumbar support insert 55 is affixed at a plurality of places and preferably with polyester twine to the underlying retention strip 34. Presently, six evenly spaced tie-down points are utilized in the herein described preferred embodiment of the tube 2Z having the lumbar support insert
Several modifications of the present invention may become readily apparent to those skilled in the art in light of the foregoing disclosure. Therefore, the scope of the present invention should be interpreted solely from the following claims, as such claims are read in light of the disclosure.
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A watermattress includes a plurality of elongated water-filled tubes in a suitable frame, and each tube includes a wave dampening insert of foam or fiber. A base strip made of a substantially flexible material, such as vinyl, is fastened to each end of the tube. The wave dampening insert is fastened at a plurality of places along the length of the insert to the base strip, whereby the insert is substantially incapable of sliding or moving around in the tube even when one end of the tube is lifted. The foregoing feature prevents the insert from becoming dislocated and distorted in the tube as a result of extended normal use of the watermattress or even when the tube is moved or lifted for the purpose of draining, filling or moving the watermattress, and thereby makes the watermattress user friendly.
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CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] Not Applicable
STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT
[0002] Not Applicable
INCORPORATION-BY-REFERENCE OF MATERIAL SUBMITTED ON A COMPACT DISC
[0003] Not Applicable
BACKGROUND OF THE INVENTION
[0004] 1. Field of the Invention
[0005] The present invention relates generally to inhalation devices. More particularly, the invention concerns a tee type nebulizer device for medicinal use that delivers an aerosol mist of properly sized particles of medicament to the patient at a very rapid rate.
[0006] 2. Discussion of the Prior Art
[0007] Delivery of medication to a patient's lungs by means of jet nebulization has been an accepted procedure in the medical community for many years. Predominantly the device used has been a simple 3-way medical tee with one end interfaced to the patient, the other end open to room air, and the nebulizer component attached to an intermediate third port. Millions of these devices are produced and used annually.
[0008] Published data (Respiratory Care, Vol. 38, No. 38, Aug. 93; and Advance for Respiratory Care Practitioners Aug. 9, 1993) indicate that the most limiting factor in the use of aerosolized medication is the inefficient mist production by currently available commercial nebulizer systems. Research has shown that most state-of-the-art commercial units deliver less than 10% of the original dose of medication to the patient's respiratory tract. (Respiratory Care, Vol. 38, #8, August 1993; and AARC Times, June 1993.)
[0009] Jet nebulization is a process whereby a flow of gas (typically air or oxygen) through a very small orifice creates a partial vacuum in the fluid passageways of the device. This reduction in pressure is sufficient to create a Venturi effect, pulling liquid from a reservoir to mix into the gas stream. This liquid is subsequently changed within the device into aerosol particles.
[0010] Physical constraints in the design of jet nebulizers for medical use are such that the conversion rate of Liquid-to-aerosol is limited to a maximum of approximately 0.35 ml per minute of operation. This is a determining factor that determines the lengthy time (usually in excess of ten minutes) required for delivery of a clinically effective treatment when using any typical present day tee type nebulizer device. Not only is this wasteful, but because of the excessive time required for delivery of a clinically effective treatment, this type device is not user friendly. It is this problem that the present invention seeks to solve by improving the nebulizer design to include special baffling within the tee adapter of the device.
SUMMARY OF THE INVENTION
[0011] It is an object of the present invention to provide an improved tee type nebulizer device that includes a strategically positioned air flow baffle assembly that markedly increases the rate of liquid-to-aerosol conversion. More particularly, due to the positioning and sizing of the air channeling pathways within the air flow baffle assembly, bench studies have shown an increase in rate of aerosol mist production by factors of 200%-300%.
[0012] Another object of the invention is to provide a device of the aforementioned character that is capable of aerosolizing liquid medicaments at a rate of up to 1 milliliter (ml) per minute.
[0013] Another object of the invention is to provide a device of the character described that will aerosolize and deliver a clinically viable patient dose (0.2-0.3 mg Albuterol) from a standard 2.5 mg/3 ml nebulizer charge in 3 minutes or less.
[0014] Another object of the invention is to provide a nebulizer device that is physically small in size for convenience of packaging, storage, dispensing and operation.
[0015] Yet another object of the invention is to provide a medical aerosol device that is operable with either air or oxygen at flow rates between about 5 and about 8 liters per minute (LPM).
[0016] Yet another object is to provide a tee/nebulizer device that, can be used in conjunction with various patient interfaces such as a mouthpiece, face mask, or special nasal mask.
[0017] Another object of the current invention is to provide the capability of readily attaching a commercial filter when needed for exit gas purification prior to atmospheric release.
BRIEF DESCRIPTION OF THE DRAWINGS
[0018] FIG. 1 is a side elevational, exploded view, partly in cross section of a typical prior art tee type nebulizer device.
[0019] FIG. 2 is a generally perspective view of one form of the improved tee type nebulizer device of the present invention.
[0020] FIG. 3 is an enlarged generally perspective exploded view of the body portion of the device shown in FIG. 2 illustrating the positioning of the baffle assembly of the device within the body portion.
[0021] FIG. 4 is a generally perspective view of the baffle assembly shown in FIG. 3 .
[0022] FIG. 5 is an enlarged cross-sectional view taken along lines 5 - 5 of FIG. 2 .
[0023] FIG. 6 is a cross-sectional view taken along lines 6 - 6 of FIG. 5 .
[0024] FIG. 7 is a cross-sectional view taken along lines 7 - 7 of FIG. 5 .
[0025] FIG. 8 is an enlarged cross-sectional view of the nebulizer portion of the device along with the stand therefore.
DETAILED DESCRIPTION OF THE INVENTION
[0026] Referring to the drawings and particularly to FIG. 1 a typical prior art tee type nebulizer device is there shown. As is apparent from a study of FIG. 1 the medical tee “T” serves only as an inter-connecting pathway for gas flow between the nebulizer “N”, the patient “P” (at the mouthpiece), and room air “RA” via an elongated breathing tube “BT” that is attached to the exit port “EP” of the medical tee component. The function of the breathing tubing is to limitedly increase device efficiency.
[0027] Turning now to FIG. 2 of the drawings, one form of the improved tee type nebulizer unit of the present invention for delivering a multiplicity of particles of aerosolized medication to a patient is there shown and generally designated by the numeral 14 . Nebulizer unit 14 here comprises a nebulizer housing 16 having interconnected top, bottom, side and end walls 18 , 20 , 22 , 24 , 26 and 28 respectively that cooperate to define an internal chamber 30 . Bottom wall 20 has a nebulizer port 32 , end wall 26 has an inlet port 34 and end wall 28 has a particle outlet port 36 in communication with the patient “P”.
[0028] Connected to and spanning the top, bottom and side walls 18 , 20 , 22 and 24 is an airflow baffle assembly 40 . Airflow baffle assembly 40 ( FIG. 4 ), which forms an extremely important feature of the invention, is strategically located between nebulizer port 32 and inlet port 34 and functions to divide internal chamber 30 into first and second sub-chambers 42 and 44 respectively ( FIG. 2 ). Airflow baffle assembly includes a baffle plate 40 a having a pair of transversely spaced apart openings 48 formed therein ( FIG. 4 ) and a pair of transversely spaced apart tubular flow directors 50 extending into second sub-chamber 44 . As illustrated in FIG. 2 , tubular flow director 50 provides fluid communication between the first and second sub-chambers.
[0029] Connected to particle outlet port 36 is a conventional patient mouthpiece 52 and connected to nebulizer port 32 is a nebulizer assembly 54 . Nebulizer assembly 54 , which also forms an extremely important aspect of the invention, is in communication with second sub-chamber 44 and functions to convert aerosolizable liquid medicament into an aerosolized medication and to then introduce the aerosolized medication into the second sub-chamber. Nebulizer assembly 54 is operable with air and oxygen at flow rates between about 5 and about 8 liters per minute and when functioning in tandem with assembly 14 , aerosolizes liquid medicaments at a rate of up to 1 milliliter (ml) per minute and uniquely will aerosolize and deliver to the patient a clinically viable patient dose of 0.2-0.3 mg of Albuterol from a standard 2.5 mg/3 ml nebulizer charge in less than 3 minutes.
[0030] Nebulizer assembly 54 here includes a moldable plastic outer body 55 and a moldable plastic central body 56 having a nebulizer orifice 56 a and a deflector element 56 b ( FIGS. 5 , 7 and 8 ). Mounted within the central body portion 56 is an elongated fluid flow tube 60 . Fluid flow tube 60 includes a gas inlet port 62 and a gas outlet port 64 that is in communication with nebulizer orifice 56 a.
[0031] As best seen by referring to FIGS. 2 and 5 , nebulizer body 56 is telescopically receivable over flow tube 60 and includes a plurality of circumferentially spaced ribs 68 that cooperate with the outer wall of the flow tube to define a plurality of fluid flow paths 71 ( FIG. 5 ). When the nebulizer body is in position over the flow tube, the components cooperate to define a transverse fluid passageway 74 that is in communication with the plurality of fluid flow passageways 71 and with gas outlet port 64 . With this construction, when the reservoir 76 is filled with the aerosolizable liquid medicament “LM” and when the fluid flow tube 60 is interconnected with a source of gas under pressure “S” via a connector tube 77 ( FIG. 2 ), the aerosolizable liquid medicament “LM” will, in a manner presently to be described, be aerosolized to produce a multiplicity of particles of aerosolized medication.
[0032] Removably connected to central body portion 58 is a bottom closure assembly 78 that includes a supporting base 80 and an elongated stem 82 that is connected to supporting base 80 in the manner best seen in FIG. 8 of the drawings. As indicated in the drawings, the fluid flow tube is telescopically, sealably receivable within the elongated stem for sealing the gas inlet port 62 thereof. In one form of the invention, supporting base 80 functions to enable proper positioning of nebulizer for automated robotic filling procedures. In this regard, it should be noted that the overall design of the nebulizer unit of the present invention is such that it is fully compatible with an automated robotic assembly process, with automated robotic post-assembly functional testing and quality assurance inspection, and with automatic robotic packaging processes for packaging and shipping the assembled unit in a fashion that meets the needs of the pharmaceutical companies.
[0033] As can clearly be seen by referring to FIG. 2 , when the nebulizer assembly 54 is interconnected with housing 16 , the volume of air surrounding the point of Venturi action “VA” within sub-chamber 44 has been substantially reduced compared to that of the prior art device illustrated in FIG. 1 . Additionally, and quite importantly, this point of mist production is located immediately beneath the air flow passageway 85 carrying fluids to the patient and the air flow passageway 87 that communicates with room air via the exit port 34 .
[0034] In using the device of the invention, when the patient inhales the momentary requirement for air flow to the patient lungs typically far exceeds the 6-8 LPM of gas flow to nebulizer 54 . As depicted in FIG. 5 , upon patient inhalation air is urged to flow through tubular flow directors 50 along a flow path immediately above the port of entry of aerosol from nebulizer 54 into sub-chamber 44 . As this channeled increase in air flow along the edge portions of nebulizer port 32 moves toward the patient, a partial vacuum is created within sub-chamber 44 proximate the area of nebulizer output. This additional partial vacuum, created by the novel baffling assembly 40 , is added to that generated by gas flow through the nebulizer thusly markedly increasing the rate of liquid-to-aerosol conversion. With the proper positioning and sizing of air channeling pathways 50 in the baffle assembly, bench studies have shown an increase in rate of aerosol mist production by factors of 200%-300%.
[0035] Having now described the invention in detail in accordance with the requirements of the patent statues, those skilled in this art will have no difficulty in making changes and modifications in individual parts or their relative assembly in order to meet specific requirements or conditions. Such changes and modifications may be made without departing from the scope and spirit of the invention, as set forth in the following claims.
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An improved tee type nebulizer unit for medicinal use that delivers a mist of properly sized aerosol particles of medicament to the patient. A uniquely configured air flow baffle assembly, which is strategically positioned within the tee of the nebulizer unit, markedly increases the rate of liquid-to-aerosol conversion compared to prior art tee type nebulizer units. More particularly, due to the positioning and sizing of the air channeling pathways within the air flow baffle assembly, an increase in rate of aerosol mist production by factors of 200%-300% is realized.
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BACKGROUND OF THE INVENTION
This is a continuation-in-part application of application Ser. No. 07/627,714, filed Dec. 14, 1990, now U.S. Pat. No. 5,236,412 which was a continuation-in-part of said Ser. No. 07/383,939, now U.S. Pat. No. 5,087,242, filed Jul. 21, 1989 and issued Feb. 11, 1992.
This invention relates to a rehydratable product or membrane especially suitable for use in an iontophoretic bioelectrode system, and to a method of preparing the rehydratable membrane.
Iontophoretic bioelectrodes, used in place of hypodermic needles to inject medications into a person's skin or tissue, typically include a pouch or similar enclosure formed with a wettable barrier or a microporous membrane on one side thereof. See, for example, U.S. Pat. Nos. 4,250,878; 4,419,092; and 4,477,971. A medication solution containing ions to be delivered into the person's skin or tissue is injected into the pouch by means of a hypodermic needle, syringe, etc. When the wettable barrier or membrane is placed against a person's skin and an electric current is supplied to the solution, the ions are caused to migrate from the solution through the wettable barrier or membrane, and into the skin.
A second bioelectrode is used in conjunction with the above-described iontophoretic bioelectrode, but need not include a solution of medicament ions. Rather, the second bioelectrode need only include an element for making contact with the person's skin or tissue (generally in close proximity to the iontophoretic bioelectrode), such as a wettable barrier or membrane containing nontoxic electrolyte for allowing migration of current (of opposite polarity to that of the current supplied to the iontophoretic bioelectrode) between the person's skin or tissue through the contact element to a second current source.
For the iontophoretic bioelectrode described earlier, barriers or membranes are required to retain the solution in the pouch while allowing ions to migrate therethrough. However, such barriers or membranes also inhibit wetting of the skin and thus inhibit the migration of ions to a certain extent, at least as compared to a situation where the solution would be in direct contact with the skin. Also, because of the use of a pouch or similar enclosure to contain the medication solution, a mechanism or structure on the enclosure is necessary for allowing the injection thereinto of the solution. Such structure has typically included some type of orifice containing a plug into which a hypodermic needle or syringe tube may be inserted to allow delivery of the solution through the orifice into the interior of the enclosure, while preventing the outflow of the solution after it has been injected into the enclosure. The requirement of such solution receiving mechanism or enclosure, of course, increases the cost of the bioelectrode and gives rise to potential leakage locations.
In U.S. Pat. No. 5,087,242, and in copending application Ser. No. 07/645,028 filed Jan. 23, 1991, the disclosures of which are both incorporated herein by reference, hydratable bioelectrodes are disclosed in which the need for special solution receiving structure or mechanisms is obviated. Such bioelectrodes include a layer of material for absorbing and holding aqueous solutions when placed in contact therewith, a conductive element disposed in close proximity to the layer of material for receiving an electrical charge to thereby cause ions in the fluid to move to and from the layer of material toward or away from the conductive element, and a support base on which the layer of material and conductive element are mounted. The layer of material may comprise a polymer, a matrix of fibers impregnated or interwoven with a hydratable polymer, or similar ion solution absorbing material. The aforesaid bioelectrode structures provide a simple, inexpensive and easy to use iontophoretic delivery mechanism.
Although U.S. Pat. No. 5,087,242 and the copending parent applications, Ser. Nos. 07/627,714 and 07/645,028 disclose useful methods and apparatus for constructing hydratable bioelectrodes, additional enhancements could be made to the previously disclosed technology in order to prepare hydratable bioelectrodes suitable for use in the practice of iontophoresis.
SUMMARY OF THE INVENTION
It is an object of the invention to provide methods and structures for simple, inexpensive, and skin contour conformable iontophoretic bioelectrodes.
It is also an object of the invention to provide dry iontophoretic bioelectrodes which are capable of efficiently absorbing and holding an aqueous solution when placed in contact therewith.
It is another object of the present invention to concentrate drug in the bioelectrode in a region next to the patient's skin.
Yet another object of the present invention is to provide a bioelectrode more resistant to undesirable effects from formation of electrolysis products or conductive element corrosion products.
It is an additional object of the invention to provide iontophoretic bioelectrodes which may be constructed using conventional equipment.
The above and other objects of the invention are realized in a specific illustrative embodiment of a hydratable bioelectrode for delivering ionized medicament into the skin or tissue of a person or animal. The bioelectrode includes a dry hydratable element for absorbing ionized medicament in aqueous solution when placed in contact therewith, a conductive element mounted in adjacent to the hydratable element for receiving an electrical current to thereby produce an electrical field and cause ionized medicament to move from the hydratable element into the skin or tissue on which the bioelectrode is placed, and means for securing the hydratable element to the conductive element.
In accordance with one aspect of the invention, the hydratable element includes means for separating adjacent sheets of dry hydrogel (sometimes hereafter referred to as "DH") which comprises separation elements such as granules or fibers disposed between each pair of adjacent sheets of DH, with such granules or fibers comprising, for example, sugar crystals, cellulose fibers, etc.
In accordance with another aspect of the invention, the sheets of DH are formed to be relatively stiff to enable maintaining the sheets apart from one another by the separation elements so that when the sheets are exposed to medicament for absorption thereof, there is a greater surface area of the DH sheets in contact with the medicament and thus there is a more rapid complete and uniform absorption. Another alternative is to form fluid channels between the sheets, such as by forming three dimensional patterns on the sheets.
Another embodiment of the invention involves the use of layers of DH's having different aqueous solution absorption properties. Hydrophilic polymers may be crosslinked to different degrees. Crosslinking binds the polymer molecules into a network which can swell with aqueous solution without completely dispersing. An insoluble hydrogel is formed. The degree of swelling and porosity of the hydrogel depends on the number of crosslinks. A highly crosslinked hydrophilic polymer network (sometimes hereafter referred to as "HCDH" for highly crosslinked dry hydrogel) swells to a lesser extent in aqueous solution and is less porous to migrating ionic species than a lightly crosslinked network ("LCDH") of the same polymer. Thus, migration rates of species contained in the DHs can be controlled through adjusting the degree of crosslinking within the DH.
A layer of LCDH may be placed in contact with the conductive element, and a layer of HCDH affixed to the other side thereof so that the less hydrophilic polymer will be placed against the patient's or animal's skin or other tissue during use. This configuration will lessen the impact of undesirable hydrolysis products or corrosion products associated with the conductive member. Alternatively, the conductive member may be placed in contact with the HCDH, so that the highly hydrophilic polymer is placed in contact with the skin. This configuration concentrates medicament in the region next to the skin.
BRIEF DESCRIPTION OF THE DRAWINGS
The above and other objects, features and advantages of the invention will become apparent from a consideration of the following detailed description presented in connection with then accompanying drawings in which:
FIG. 1 (comprised of FIGS. 1A and 1B) shows flow diagram of the method of constructing hydratable bioelectrodes in accordance with the principles of the present invention.
FIG. 2 shows a side, cross-sectional view of a starting product for use in the method illustrated in FIG. 1; and
FIG. 3 is an end, cross-sectional view of an iontophoretic bioelectrode made in accordance with the principles of the present invention.
FIG. 4 is a plan view of one presently preferred electrode of the invention, also illustrating a sheet of hydrogel in accordance with the present invention on the surface of which has been formed a three dimensional pattern which will cause separations between adjacent sheets when stacked.
FIG. 5 is a side, cross-sectional view of a bioelectrode similar to that of FIG. 4, formed of two layers of polymer having different aqueous swelling characteristics.
FIG. 6 is a side, cross-sectional view of a bioelectrode similar to that of FIG. 5, but with the order of layers reversed.
DETAILED DESCRIPTION
FIG. 1 is a flow chart showing the steps of one embodiment of a presently preferred method of producing a hydratable bioelectrode in accordance with the present invention. An exemplary starting material for the method of FIG. 1 is shown in cross section in FIG. 2 to include a mass of gel material 204 sandwiched between two layers of liner material 208 and 212 made, for example, of plastic. A sheet of scrim (mesh material) 216 is disposed in the gel mass generally midway between the two liners 208 and 212. The starting material illustrated in FIG. 2 might illustratively be an inert hydrogel identified as STD-1 or WD-1 which are the products of Nepera, Inc. used as skin dressing for wounds, burns, etc. The particular hydrogels which are presently preferred constitute a polyethylene oxide polymer which is crosslinked, for example, using e-beam radiation, by chemical means, or by other strong radiation such as gamma rays.
However, the starting material could also be another hydrophilic material, such as wet or dry, crosslinked sheets of polyvinyl alcohol, PVA, poly-N-vinyl pyrrolidone or other substituted pyrrolidones, PVP, polyacrylamides such as poly-Nisopropyl acrylamide, NIPPAm, polyhydroxyethyl methacrylate, PHEMA or hydrophilic substituted HEMAs, polysaccharides such as agarose, hydroxy cellulose, HEC, hydroxyethyl methyl cellulose, HPMC, hydroxypropyl cellulose, carboxyethyl cellulose, HPC, hydroxypropyl methyl cellulose, dextrans, modified starches, modified collagens, xanthan gum, modified natural gums, partially neutralized polyelectrolytes such as polyacrylic acid, polyimides, and alginates. It might also be suitable in some circumstances to use copolymer mixtures of the foregoing. However, the preferred polymers are non-ionic or non-electrolyte hydrophilic polymers or copolymers such as PEO, PVP, PAAm, and HEC because these do not contain large numbers of ionizable moieties which would otherwise compete as charge carriers with the drug to be iontophoretically administered.
Referring now to FIG. 1, the first step of the method or process of producing a hydratable bioelectrode is to provide a starting material such as that shown in FIG. 2. From such a stock piece of material, a strip of, for example, six inches by thirteen inches is cut out in a conventional fashion (step 108 of FIG. 1) and then laid flat on a table to allow peeling off of the top liner sheet 208 (steps 112,116 and 120 of FIG. 1). (The term "PEO" used in some of the steps of FIG. 1 means "polyethylene oxide" and the term "WIP" means "work in process".) Although the steps shown in boxes 112,116 and 120 of FIG. 1 are rather specific for peeling off the top liner 208 of the starting material of FIG. 2, it should be understood that any of a variety of approaches could be taken for removing the liner; further starting material without any liner to begin with could be provided and then, of course, steps 112, 116 and 120 would not be necessary.
After step 120 of FIG. 1, the gel mass or layer 204 and remaining liner 212 are wound about a roller device so that the gel layer 204 faces outwardly. The next step in the process is to place a fluoroplastic-coated tray onto a cold table to cool the tray, with the tray being held in place by a vacuum in a conventional fashion. When the tray reaches a steady state temperature of, for example, eighteen degrees Fahrenheit (a temperature below the freezing point of the gel layer), as indicated in step 124, the roller, with gel layer wound thereabout, is aligned along one edge of the cooled tray (step 128) and rolled at a predetermined, controlled rate to cause the outward facing or upper layer of the gel material 204 to freeze and hold onto the tray so that as the roller continues to roll, the thin upper layer (down to the scrim 216) is peeled away from the remainder of the gel on the roller and frozen onto the tray. If no scrim 216 were present in the gel mass 204, the tray temperature, and rate of rolling the roller, would determine the thickness of the layer of gel which is frozen to the tray and peeled from the roller. A layer of gel is now disposed on the tray and another gel layer sandwiched between the scrim 216 and liner 212 remains on the roller.
With the layer of gel on the tray, the tray is placed in a convection drying chamber (step 136) which has been heated to about 55° centigrade. The purpose of this is to dry the gel layer at a temperature which will not cause degradation of the gel (typically about 60° centigrade). The dried hydrogel (DH) layer is then removed from the tray and placed onto a screen and clamped to maintain the planarity of the layer (steps 144 and 148), and the screen is then immersed in a "swelling" solution of water (step 152) containing a stiffening agent such as sugar, for example, 50 grams per liter. The purpose of the stiffening agent will be discussed later. The screen on which the DH layer is placed may illustratively be a perforated fluoro-coated metal sheet, with another screen on top to maintain the flatness of the gel layer.
The screen with DH layer remains submerged in the swelling solution for a sufficient time to allow the layer to absorb solution, swell and expand laterally (step 156). The screen with swollen gel layer is then removed from the swelling solution, blotted dry (step 160) and after sufficient blotting, the screen with gel layer is again placed in the convection drying chamber to further dry the gel layer (step 168). After swelling and the final step of drying, the DH layer will be formed into a sheet having substantially the same length and width dimensions, but the thickness will have decreased substantially from when wet.
In the next stage of the process, granules or fibers are distributed onto the DH sheet to serve as spacers to maintain apart, to the extent possible, adjacent DH sheets which will later be used to form a stack of DH sheets. Individual DH sheets will be fairly stiff, as a result of immersion thereof in the swelling solution with stiffening agent, and so the distribution of granules or fibers, such as sugar, over the DH sheets will serve as spacers when the DH sheets are placed in a stack. Other materials which will form granules useful in connection with the present invention include salt crystals, cellulose, starch, crosslinked particles of polymers, insoluble polymer beads, grains, or ion exchange resins.
One way of distributing the granules or fibers onto the DH sheet is to place the DH sheet onto a conveyor belt and pass it under a granule/fiber dispenser (step 176). It is desired to maintain individual DH sheets separated when in a stack so that when hydrated with iontophoretic medicament, the medicament will be allowed to flow between the sheets and thus be more rapidly and uniformly absorbed by the ultimate gel sheet stack.
In step 180, a fine water vapor or mist is applied to the DH sheet simply to better hold the granules or fibers on the DH sheet surface. The water vapor or mist partially dissolves granules such as sugar causing them to "stick" onto the DH sheet. It is important that too much water vapor or mist not be used so that the granules are not dissolved completely, since, of course, they would then not serve to maintain the DH sheet separated from adjacent sheets.
After securing the granules of fibers onto the DH sheet, the DH sheet is removed from the screen (step 184) and then arranged in a stack with other DH sheets, for a total, for example, of 28 layers (step 186). A sufficient number of layers of DH sheets are included in a stack so that when the DH sheets are incorporated into a bioelectrode such as that shown in FIG. 3, a conductive member 304 which receives electrical current from a current source 308 will not burn the skin or tissue of a person against which the bioelectrode is placed. On the other hand, if too many layers are used to form the stack, then assembly may become too costly.
After the sheets are formed into a stack, the stack is press-cut by a roller press (step 188) which both cuts the stack lengthwise, for example, and also crimps the resulting adjacent edges so cut, although alternative means for binding the layers together could be used, such as an adhesive (e.g., cyanoacrylate), stitches, staples, or welds.
FIG. 3 shows opposite edges 312 and 316 of a DH sheet stack which have been crimped and cut. Note that the edges which are crimped are much thinner than the center portion of the stack which, of course, has not been crimped. In step 190, the stack is then cut perpendicularly to the press-cut made in step 188 to thereby provide plurality of individual stacks of DH sheets, each of which may then be incorporated into a bioelectrode structure such as that shown in FIG. 3 (step 194 or FIG. 1).
In the manner described, a simple iontophoretic bioelectrode is provided in which the ionized medicament may be absorbed into a stack of DH sheets which are part of the bioelectrode. The hydrated sheets may then be placed in direct contact with the skin or tissue of a person or animal for administering the medicament and because the gel sheets are in direct contact, improved wetting of the skin or tissue, and thus more efficient delivery of the ions, is achieved.
In place of granules or fibers as described above, other means for separating adjacent sheets of DH may be used. For example, it is possible to press, form, emboss, machine or otherwise treat each sheet so as to contain a threedimensional pattern. When stacked, such three dimensional patterns cause adjacent sheets to lie in a spaced relationship to one another, thereby providing for rapid and complete hydration when a medicament solution is applied prior to use of the bioelectrode. FIG. 4 is a plan view which illustrates one three dimensional pattern which might be formed on the surface of DH sheets to assist in rapid hydration.
Other modifications may be made to solve other problems which might exist in a particular situation. For example, it is possible to utilize a different type of hydrogel in two or more adjacent layers or similar hydrogels having different hydrophilic properties due to differing degrees of crosslinking. One such construction could advantageously comprise a layer of one or more LCDH sheets of polyethylene oxide (PEO). This layer of LCDH could be secured to a layer of one or more HCDH sheets of PEO, PHEMA, or any of the other hydrophilic polymers listed above.
One embodiment using layers of differing gel structures is shown in FIG. 5. There, a hydratable element includes a layer 502 of a PEO-based LCDH, and a layer 504 of PHEMAbased HCDH. Layer 502 is situated so as to be placed against a patient's skin during use of the bioelectrode, while layer 504 is situated adjacent to and in contact with a conductive element 506. An adhesive member 508 is advantageously applied over the entire assembly in order to serve as a means for affixing the electrode to a patient. Stitches 510 serve as means for securing the hydratable element to the conductive element. Upon application of a medicament solution, the electrode construction of FIG. 5 has the advantage of concentrating drug in the region closest to the patient's skin. Not only does this limit the total amount of drug necessary, but also assists in even distribution and delivery of drug.
Alternatively, the less crosslinked layer might be situated so as to be placed against the patient's skin, and the more highly crosslinked layer situated so as to contact the conductive element, as shown in FIG. 6, where layer 602 of LCDH is shown adjacent to conductive member 606, and layer 604 of a HCDH is shown in position for affixation to a patient's skin. Again, an adhesive member 608 serves as a means for affixing the electrode to a patient, and stitches 610 serve as means for securing the hydratable element to the conductive element. The construction of FIG. 6 would be useful, for example, in situations where undesirable electrolysis products (H+ or OH-) or conductive element corrosion products are formed, by slowing the passage of these unwanted products from the region next to the conductive element to the patient's skin due to a decrease in diffusion coefficient when moving from the region having a looser mesh (lightly crosslinked PEO) to the tighter mesh of the more highly crosslinked gel layers.
Another means for controlling pH changes or removing unwanted ionic species is by incorporating a suitable anion or cation exchange resin, or combination of both anion and cation exchange resins, into the hydrogel. Examples of useful anion exchange resins would utilize amino or quaternary amino groups. Examples of useful cation exchange resins would utilize carboxy or sulfoxy groups. Materials such as PAA, polyethylimine, dextrans, natural gums such as xanthan or alginate, or collagen could each be used in varying applications.
It is to be understood that the above-described arrangements are only illustrative of the application of the principles of the present invention. Numerous modifications and alternative arrangements may be devised by those skilled in the art without departing from the spirit and scope of the present invention and the appended claims are intended to cover such modifications and arrangements.
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A hydratable iontophoretic bioelectrode including a plurality of layers of material capable of absorbing and holding an ionized fluid when placed in contact with the fluid. In one embodiment, a layer of a highly crosslinked dry hydrogel is used with a second layer of a more lightly crosslinked dry hydrogel. When the lightly crosslinked hydrogel layer is located so as to be in contact with the skin during iontophoresis, the medicament ions will be concentrated next to the skin. When the more highly crosslinked layer is located next to the conductive member, the undesirable effects of hydrolysis or corrosion of the conductive member are lessened. In another embodiment, adjacent layers are maintained at least partially out of contact from one another so as to improve the rate of hydration by disposition between the layers of spacing elements such as sugar or other dissolvable particles or cellulose or by forming a three dimensional pattern thereon.
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CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application claims the benefit of application Ser. No. 60/889,098, filed Feb. 9, 2007, under 35 U.S.C. §119(e).
BACKGROUND OF INVENTION
[0002] 1. Field of Invention
[0003] The present invention relates generally to caps for drinking vessels.
[0004] 2. Description of Related Art
[0005] Alcoholic beverages, and particularly mixed beverages, are often served in public restaurants, nightclubs, taverns and bars in open top drinking vessels (e.g., bar glasses and stemware). The uncovered opening of such drinking vessels makes it easy for the bar tender to prepare the beverage. However, the uncovered opening also makes it possible for depraved individuals to add an incapacitating substance such as Rohypnol, for example, to a patron's beverage when they are not closely guarding the drinking vessel (e.g., while conversing with another, dancing etc.).
BRIEF SUMMARY OF THE INVENTION
[0006] In view of the foregoing, the present invention is directed to a cap for covering the open top of a drinking vessel. The cap according to the invention comprises a substantially rigid cover disk assembly dimensioned to span across and substantially cover the open top of the drinking vessel, and a flexible tubular membrane that extends from a bottom side of the cover disk assembly. The membrane is adapted to be rolled down a side wall of the drinking vessel to thereby removably secure the cap thereto. Identifying indicia can be printed on the top side of the cover disk assembly. The beverage within the drinking vessel can be consumed using a drinking straw. When properly deployed, the cap inhibits the introduction of unwanted matter into the drinking vessel.
[0007] The foregoing and other features of the invention are hereinafter more fully described and particularly pointed out in the claims, the following description setting forth in detail certain illustrative embodiments of the invention, these being indicative, however, of but a few of the various ways in which the principles of the present invention may be employed.
BRIEF DESCRIPTION OF THE DRAWINGS
[0008] FIG. 1 is a top plan view of a cap for a drinking vessel according to one embodiment of the invention.
[0009] FIG. 2 is a bottom plan view of the cap shown in FIG. 1 .
[0010] FIG. 3 is a side section view of the cap shown in FIG. 1 taken along the line 3 - 3 .
[0011] FIG. 4 is a bottom perspective view of the cap shown in FIG. 1 .
[0012] FIG. 5 is a perspective view of the cap shown in FIG. 1 deployed on a drinking vessel.
[0013] FIG. 6 is a perspective view of a package containing a cap such as shown in FIG. 1 .
DETAILED DESCRIPTION OF THE INVENTION
[0014] With reference to the accompanying figures, a cap 10 according to the invention comprises a substantially rigid cover disk assembly 20 having a flexible tubular membrane 30 secured thereto and extending therefrom. The tubular membrane 30 is adapted to be stretched so as to extend around and thus entirely surround and envelope an open-top portion of a drinking vessel 40 such as, for example, a pilsner glass, a pint glass, a cocktail glass, a highball glass or other tumbler, a wine glass or other stemware, or a “pop-top” beverage can. The tubular membrane 30 is also adapted to be unrolled down an outer side wall 50 of the drinking vessel 40 such that the cover disk assembly 20 substantially covers the open top of the drinking vessel 40 .
[0015] The cover disk assembly 20 is preferably formed of an upper disk portion 60 and a lower disk portion 70 , which are joined together with a first end portion 80 of the tubular membrane 30 captured therebetween. The upper disk portion 60 and the lower disk portion 70 are preferably joined together using a suitable adhesive. Alternatively, and less desirably, mechanical fasteners such as staples can be used to join the upper disk portion 60 and the lower disk portion 70 together.
[0016] The upper disk portion 60 is preferably formed of a compressed cellulosic material such as paperboard, which may be faced with a thin layer or film of paper or plastic. A top side 90 of the upper disk portion 60 can be printed with decorative and/or informative indicia 100 such as, for example, advertising for products and/or services. The indicia can also be provided on the upper disk portion 60 through the use of adhesive stickers. Preferably, markings can easily be applied to the top side 90 of the upper disk portion 60 using an ink pen or pencil, which allows a patron to further personalize and uniquely identify their beverage.
[0017] The lower disk portion 70 is preferably formed of a moisture resistant material such as plastic. Moisture resistant materials are preferred because beverage contents can splash upwardly against the bottom side 1 10 of the lower disk portion 70 . It will be appreciated that the upper disk portion 60 and/or the lower disk portion 70 could be formed of a variety of different materials (e.g., paperboard, light metals, plastics, wood and/or laminates comprising two or more thereof) to form a substantially rigid cover disk assembly 20 .
[0018] The thickness of the cover disk assembly 20 is not critical, but a thickness within the range of from about 1/16″ (˜1.6 mm) to about ¼″ (˜6.5 mm) is generally believed to be sufficient. In the presently most preferred embodiment of the invention, the cover disk assembly 20 is formed of a flat paperboard upper disk portion 60 having a thickness of about 3/32″ (˜2.4 mm) that is joined to a flat plastic lower disk portion 70 having a thickness of about 1/16″ (˜1.6 mm) using an adhesive.
[0019] The upper disk portion 60 is provided with a first opening 120 through which an end of a drinking straw 130 can be inserted. The first opening 120 is preferably circular in shape and has an inner diameter that is slightly larger than the outer diameter of the drinking straw 130 . It will be appreciated that the shape of the first opening 120 is not critical.
[0020] The lower disk portion 70 is provided with a second opening 140 through which the end of the drinking straw 130 can be inserted. The second opening 140 preferably comprises a plurality of intersecting slits 150 , which thus form flaps 160 that bias against the drinking straw 130 when the drinking straw 130 is inserted through the second opening 140 . The flaps 160 allow the lower disk portion 70 to remain in contact with the drinking straw 130 after the drinking straw 130 has been inserted through the second opening 140 , which minimizes any open area between the drinking straw 130 and the lower disk portion 70 . It will be appreciated that the number of slits and corresponding flaps is not per se critical.
[0021] In the embodiment of the invention shown in FIGS. 1-4 , the second opening 140 through the lower disk portion 70 comprises a pair of intersecting slits 150 , which intersect at about a 90° angle and thus form four flaps 160 that bias against the drinking straw 130 when the drinking straw passes through the second opening 140 . In this embodiment, the slits are provided in a circular recessed area 170 . The recessed area 170 reduces the thickness of the lower disk portion 70 , which allows the flaps 160 to flex more than if the flaps 160 were thicker, and also helps prevent the slits 150 from tearing beyond the area defined by the recessed area 170 . The recessed area 170 also facilitates proper alignment of the upper disk portion 60 with the lower disk portion 70 when the same are joined together. It will be appreciated that an inverse arrangement could be utilized for the first opening and the second opening (i.e., the first opening would include intersecting slits whereas the second opening would be dimensioned sufficiently large enough to allow a drinking straw to pass therethrough).
[0022] The upper disk portion 60 has a first perimeter edge portion 180 . In the embodiment shown in the accompanying figures, the first perimeter edge portion 180 defines a circle. However, it will be appreciated that the shape defined by the first perimeter edge portion 180 is not critical, and that shapes other than circles can be used. For example, the first perimeter edge portion 180 may be adapted to define a polygon, the border of one or more US States, the border of one or more countries, animal and plant shapes or the shape of advertising logos. Although the shape defined by the first perimeter edge portion 180 is not critical, the first perimeter edge portion 180 of the upper disk portion should define a shape sufficiently large to substantially cover the entire opening of a drinking vessel 40 on which the cap 10 is deployed.
[0023] The lower disk portion 70 has a second perimeter edge portion 190 . Preferably, the second perimeter edge portion 190 does not include any points or angles that could pierce or cut the tubular membrane 30 that extends around the second perimeter edge portion 190 . Thus, the second perimeter edge portion 190 preferably defines a circle, an oval or some other shape having rounded corners. In the most preferred embodiment of the invention, the second perimeter edge portion 190 of the lower disk portion 70 defines a shape that is just slightly larger than the shape of the open-top portion of the drinking vessel 40 onto which the cap 10 is to be deployed. As used in this context, the term “slightly larger” means that the second perimeter edge portion 190 of the lower disk portion 70 extends no more than about ¼″ (˜6.4 mm) beyond the rim or top edge of the drinking vessel 40 .
[0024] It will be appreciated that the upper disk portion 60 needs to be at least the same size as the lower disk portion 70 . More preferably, the upper disk portion 60 is larger than the lower disk portion 70 , meaning that the first perimeter edge portion 180 of the upper disk portion 60 is spaced apart from the second perimeter edge portion 190 of the lower disk portion 70 . In the preferred embodiment of the invention illustrated in the accompanying figures, the first perimeter edge portion 180 of the upper disk portion 60 is spaced apart about ¼″ (˜6.4 mm) from the second perimeter edge portion 190 of the lower disk portion 70 .
[0025] The tubular membrane 30 is preferably formed of a stretchy, resilient, flexible material such as a thin film of natural latex rubber, silicone or a polyurethane elastomer. In the preferred embodiment, the membrane 30 is fluid impermeable. Natural latex rubber having a thickness similar to that used in the manufacture of surgical gloves is particularly preferred.
[0026] As noted, the first end portion 80 of the tubular membrane 30 is captured between the upper disk portion 60 and the lower disk portion 70 . Preferably, the adhesive used to join the upper disk portion 60 and the lower disk portion 70 together also helps secure the first end portion 80 of the tubular membrane 30 to the cover disk assembly 20 . The second end portion 200 of the tubular membrane 30 preferably defines a ring, which facilitates rolling the tubular membrane 30 upwardly toward the lower disk portion 70 .
[0027] The tubular membrane 30 is selectively displaceable from a first position to a second position. In the first position, which is shown in FIGS. 1-4 , the tubular membrane 30 is rolled about the ring disposed at the second end portion 200 upwardly toward the lower disk portion 70 . In the second position, which is shown in FIG. 5 , the tubular membrane 30 is unrolled to cover and surround the outer side wall 50 of a drinking vessel 40 and thereby form skirting 210 . The flexible, elastic properties of the tubular membrane 30 cause the skirting 210 to conform to and closely surround the outer side wall 50 of the drinking vessel 40 . When completely unrolled, the skirting 210 preferable has a height “H” of about 2.5″ (˜6.4 cm) to about 4.5″ (˜11.4 cm).
[0028] The cap 10 according to the invention can be packaged in a pouch 220 or other suitable protective enclosure prior to use. Optionally, the pouch can further contain a drinking straw 130 , which may be a telescoping drinking straw. The tubular membrane 30 should be in the first position when placed in the pouch 220 . The pouch 220 containing the cap 10 according to the invention can be kept in a pocketbook or garment pocket until needed. It will be appreciated that the pouch 220 can be imprinted with advertising indicia, making it particularly suitable for use as a promotional product. A variety of sizes of caps 10 can be produced and inventoried for use with drinking vessels having openings of varying size.
[0029] To use the cap according to the invention, a patron or beverage preparer first removes the cap from its protective pouch. The cap is placed onto a drinking vessel containing the beverage. With the tubular membrane in the first position, the cap is placed onto the open-top portion of the drinking vessel such that the lower disk portion is in contact with or nearly in contact with the top portion of the drinking vessel (e.g., the rim or the top of a beverage can). The rolled-up tubular membrane is then grasped and stretched and pulled down around the outer perimeter of the drinking vessel until the lower disk portion of the cover disk assembly adequately covers the open top portion of the drinking vessel. Next, the tubular membrane is unrolled down around the outer side wall of the drinking vessel, thereby surrounding the outer side wall of the drinking vessel with the skirt portion of the tubular membrane as shown in FIG. 5 . If desired, an easy-to-tear, tamper-evident adhesive label can be applied to secure the second end portion of the tubular membrane to the outer side wall of the drinking vessel. A drinking straw is then inserted through the first opening through the upper disk portion and the second opening through the lower disk portion of the cover disk assembly.
[0030] Once deployed, the cap prevents unwanted matter (e.g., insects and drugs) from entering the drinking vessel. The cap inhibits would-be criminals and others from adding unwanted substances to the beverage contained within the drinking vessel. It takes time for a person to unroll, remove, and then redeploy the cap onto a drinking vessel. Furthermore, removing the cap from a drink is a conspicuous act. Finally, in the event that a tamper-proof label has been applied to secure the tubular membrane to the outer side wall of the drinking vessel, removal of the cap from the drinking vessel will be evident.
[0031] It will be appreciated that the deployed cap also helps to minimize spills and broken glassware. The skirt portion of the membrane provides a comfortable non-slip gripping surface.
[0032] Additional advantages and modifications will readily occur to those skilled in the art. Therefore, the invention in its broader aspects is not limited to the specific details and illustrative examples shown and described herein. Accordingly, various modifications may be made without departing from the spirit or scope of the general inventive concept as defined by the appended claims and their equivalents.
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The present invention provides a cap for covering the open top of a drinking vessel. The cap includes a substantially rigid cover disk assembly dimensioned to span across and substantially cover the open top of the drinking vessel, and a flexible tubular membrane that extends from a bottom side of the cover disk assembly. The membrane is adapted to be rolled down a side wall of the drinking vessel to thereby removably secure the cap thereto. Identifying indicia can be printed on the top side of the cover disk assembly. The beverage within the drinking vessel can be consumed using a drinking straw. When properly deployed, the cap inhibits the introduction of unwanted matter into the drinking vessel.
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CROSS-REFERENCE TO RELATED APPLICATION
[0001] This application is a divisional of and claims priority to patent application Ser. No. 11/677,642, filed on Feb. 22, 2007, entitled “Fluid Nutrient Delivery System and Associated Methods,” which itself is a continuation-in-part of patent application Ser. No. 11/126,073, filed on May 10, 2005, entitled “Irrigation System and Associated Methods,” now U.S. Pat. No. 7,198,431, which itself claims priority to provisional application Ser. No. 60/569,262, filed on May 10, 2004, entitled “Irrigation System,” all of which are incorporated by reference hereinto.
FIELD OF INVENTION
[0002] The present invention generally relates to systems and methods for watering and supplying nutrients to plants, and, in particular, to such systems and methods for minimizing water use and maximizing potential crop density by delivering water and nutrients “on demand.”
BACKGROUND
[0003] The need for a self-watering system for plants is well established, since agriculture utilizes approximately 70% of the world's fresh water resources, and many products have been designed and built to satisfy this need to varying degrees. Some systems supply a small continuous amount of water, often referred to as drip irrigation or trickle irrigation, which supply water to the root zone irrespective of the plants' needs. Other systems rely on the moisture level in the soil to signal the need for water. Still others use wicks that bring water to the plant as a result of surface tension and the capillary rise effect.
[0004] Drip irrigation or trickle irrigation is a well-established method of growing crops in arid areas. It is claimed to be 90% efficient in water usage compared to 75-85% for sprinkler systems. The basic drip irrigation system generally consists of a surface tube from which small dripper tubes/emitters are fitted to take water from the supply tube to the roots of the plant on either side of the supply tube. The dripper tube/emitter limits the flow of water to the roots drop by drop based on the viscous resistance to water flow within the emitter/dripper tube. The drip rate is determined by the calculated needs of the specific plants, the soil conditions, anticipated rain fall, and evapotranspiration rate, and can vary from 1 to 4 L/hr per plant.
[0005] The need to estimate the water requirements of the crops or the amount of nutrients to be supplied in the water is seldom exact and invariably leads to wastage of water. It was shown that the roots of plants can control the release of water that is stored behind a thin porous hydrophilic membrane that is believed to become hydrophobic due to the adsorption of organic impurities in the water. The mechanism is not fully understood, though it has been speculated that among the root exudates is a surfactant that opens the pores of the membrane that became hydrophobic due the adsorbed organic impurities in water. The hydrophobic membrane inhibits the flow of water to the plants. However, the roots of the plants exude a variety of chemicals that include a surfactant that open the pores of the membrane by making it hydrophilic. Thus water can now flow to the roots and the membrane becomes hydrophobic when the plant has had enough water.
[0006] It has also been shown that when two reservoirs (one with water and the other containing nutrient solution) with membranes are presented to a plant, the plant can distinguish between the two sources, taking as much water as it needs and as much nutrients as it requires. The ratio of water to nutrient can vary from 2-5 to 1 depending on the concentration of the nutrient solution.
[0007] Several sub-surface systems have been developed that include tubes that are porous or are perforated to permit the continuous slow release of water. However, these hydrophobic tubes, which require a water pressure of up to two atmospheres, do not automatically stop the delivery of water when the plants have had enough or, for example, when it rains.
[0008] One possible reason for the absence of a commercial irrigation system using the membrane system may be the difficulty of obtaining a membrane that can supply the necessary amount of water for new plants or seedlings as well as a fully grown and mature plant that is sprouting and producing fruit and produce. Another possible reason may be the reliance on constant trace amounts of organic solutes in the water, which become adsorbed on the exit walls of the hydrophilic pore channels of the membrane, converting the membrane into a hydrophobic system, which then stops or greatly reduces the flow of water through the membrane. Another reason may be the difficulty of obtaining hydrophilic tubes of suitable wall thickness and diameter that are sufficiently durable to make the process economical.
[0009] The Russian SVET space plant growth system consists of a box greenhouse with 1000 cm 2 growing area with room for plants up to 40 cm tall. The roots were grown on a natural porous zeolite, with highly purified water keeping the roots at the required moisture level. Zero-gravity growth chambers used by NASA have included a microporous ceramic or stainless steel tube through which water with nutrient is supplied to irrigate the greenhouse plants. Systems using porous ceramic, stainless, or hydrophobic membranes to deliver water and/or nutrients to plants are basically a form of drip irrigation where the water/nutrients are always delivered whether the plants need it or not. As will be apparent to one of skill in the art, the ceramic or stainless tubes are thicker and the organic components are adsorbed onto the full length of the channels and cannot be removed by the plant's exudates.
[0010] FIG. 7 shows the flow of water and nutrient solution for a single plant. FIG. 7 , in particular, is a daily record of water flow (in mL/day) through 12 cm 2 of microporous Amerace A-10 fitted to the bottom of two 285-mL identically sized and shaped reservoirs (No. 1 for water and No. 2 for nutrient solution) that were embedded in the potting soil of a well-established Ficus indica (insert), showing the effect on the pattern of water flow when (i) root contact with the membrane was established, and (ii) when the total flow ceased to be greater than the rate of water uptake (after day 24 ). In general, the flow of water is about three times larger than from nutrient solution. It has been shown that a change in the concentration of the nutrient alters the ratio of flow from the two reservoirs. In FIG. 7 , the exudates from the plant's roots convert step 3 back to step 1 in FIG. 8 . This has been shown in an experiment by allowing a membrane to close after a specified volume of water was passed through an Amerace-10 membrane. The exit side of the membrane was then washed with alcohol and the water flow through the membrane resumed and eventually stopped when all the alcohol was washed away and the organic impurities were allowed to be adsorbed onto the exit wall of the pores shown in FIG. 8 .
[0011] Again referring to FIG. 8 , in step 1 , as water leaves the pore of the membrane, it spreads out onto the membrane's surface, which is hydrophilic. A large drop forms and leaves the surface. As the surface becomes coated by the adsorbed hydrophobic impurities in water, the water leaving the capillary pore of the membrane cannot spread out over the surface and a smaller drop can be formed (step 2 ). When further coating continues, there is no room for the water to spread out onto the surface and a greater force is required to push the water through the hydrophobic area shown in step 3 . The membrane is converted from the hydrophilic state to a hydrophobic state. It is made hydrophobic by the adsorption of the organic impurities in the water and/or nutrient solution. This closes the pores and prevents water from leaving the membrane under the prevailing pressure conditions. If the pressure is increased, it becomes possible for the liquid to flow again because the surface tension of water no longer can prevent the water from breaking through the pores.
SUMMARY OF THE INVENTION
[0012] The present invention is directed in one aspect to a system for efficiently delivering an aqueous solution to plants. The system comprises hydrophilic means having a distal portion positionable adjacent a root system of a plant. The hydrophilic means have a lumen therethrough for channeling an aqueous solution from an inlet to the distal portion. The hydrophilic means further have a wall encompassing the lumen. At least a portion of the wall along the distal portion has a porosity adapted for permitting a flow of the aqueous solution therethrough when acted upon by a surfactant root exudate generated by the plant roots' experiencing water stress.
[0013] The system also comprises a reservoir that is adapted for holding the aqueous solution therein. The reservoir is situated in fluid communication with the hydrophilic means inlet.
[0014] The present invention is also directed in another aspect to a method for efficiently delivering an aqueous solution to plants. This aspect of the method comprises the step of positioning a distal portion of hydrophilic means adjacent a root system of a plant as described in the system above. The aqueous solution is introduced into an inlet of the hydrophilic means, and the aqueous solution is channeled from the hydrophilic means inlet to the distal portion.
[0015] The present invention is further directed in another aspect to a method for establishing an efficient system for delivering an aqueous solution to plants. This aspect of the method comprises the step of positioning a distal portion of hydrophilic means adjacent a root system of a plant, as described above.
[0016] A reservoir for holding the aqueous solution therein is provided, with the reservoir in fluid communication with an inlet of the hydrophilic means. A channel is also provided for establishing a flow of the aqueous solution from the reservoir to the hydrophilic means inlet.
[0017] The features that characterize the invention, both as to organization and method of operation, together with further objects and advantages thereof, will be better understood from the following description used in conjunction with the accompanying drawing. It is to be expressly understood that the drawing is for the purpose of illustration and description and is not intended as a definition of the limits of the invention. These and other objects attained, and advantages offered, by the present invention will become more fully apparent as the description that now follows is read in conjunction with the accompanying drawing.
BRIEF DESCRIPTION OF THE DRAWING
[0018] FIGS. 1A and 1B illustrate a dual irrigation tube for supplying water and nutrient to plant roots, in top plan view and cross-sectional view, respectively.
[0019] FIG. 1C is a cross-sectional view of tubing having a supporting spiral inserted thereinto.
[0020] FIG. 2 is a cross-sectional view of a system for irrigating grass.
[0021] FIG. 3 illustrates an exemplary system for growing plants that is operable in a gravity-free environment.
[0022] FIG. 4 is a side perspective view of an embodiment of a tube having holes covered with a hydrophilic membrane.
[0023] FIGS. 5A and 5B illustrate a growth system that includes both surface and subsurface portions, in top plan view and cross-sectional view, respectively.
[0024] FIG. 6 is a chemical diagram of polyhydroxystyrene.
[0025] FIG. 7 (prior art) graphs the flow of water and nutrient solution for a single plant. (•), Water uptake from reservoir No. 1; (∇), nutrient uptake from reservoir No. 2. (From L. A. Errede, Ann. Botany 52, 22-29, 1983.)
[0026] FIGS. 8A-8L (prior art; collectively referred to as FIG. 8 ) are schematic representations of water flow through a microcapillary pathway of a microporous membrane as a function of the extent of hydrophilic area that surrounds the microcapillary outlet, and show how the organic impurities in water are more likely to stick at the exit end of a capillary. In step 1 ( FIGS. 8A-8D ) is shown the initial hydrophilic state of the area that surrounds the microcapillary outlet. D 1 is the diameter of the hydrophilic area, and R 1 is the radius of the drop emerging from the outlet, which is much greater than r, the radius of the microcapillary outlet. Step 2 ( FIGS. 8E-8H ) occurs after some accumulation of hydrophobic solutes at the outer perimeter of the hydrophilic area that rings the microcapillary outlet. Here D 1 >D 2 >2r, and R>R 2 . Step 3 ( FIGS. 8I-8L ) is the ultimate end state when the diameter D f of the hydrophilic area that surrounds the outlet shrinks to twice the radius r of the outlet. Water flow at a given outlet stops when ΔP=2y/R f becomes greater than P f , the applied pressure, where γ is the surface tension of the water. (From L. A. Errede, J. Colloid Interface Sci. 100, 414-22, 1984.)
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT
[0027] A description of the preferred embodiments of the present invention will now be presented with reference to FIGS. 1-8L .
[0028] As used herein, the words “tubes” or “tubing” refer to supply lines for providing water and/or nutrients. As will be appreciated by one of skill in the art, such “tubes” or “tubing” do not necessarily need to be cylindrical, but may be of any suitable shape, and no limitation is intended by the use of these words.
[0029] Described herein are a system and method of supplying water and/or nutrients to the roots of growing plants wherein the water and/or nutrients are released to the plants as needed by the individual plants. Herein the term “plants” should be construed broadly, and can include, for example, grasses. Although not intended as a limitation on the invention, it is believed that when under water stress, plant roots can emit exudates or surfactants that promote the release of water and/or nutrients stored under the conditions described below. Specifically, the plants are supplied water and/or nutrients from supply lines or feeder tubes, at least portions of which are hydrophilic.
[0030] In some embodiments, the tubing may include a plurality of holes that are covered by hydrophilic membranes; in other embodiments, the entire tubing, the below-surface portion thereof, or a significant portion thereof is hydrophilic. In yet other embodiments, the system may include a surface tube that is water-impermeable or hydrophobic, the tube being connected to a plurality of hydrophilic tubes that can be inserted into a support medium for supplying the roots.
[0031] One or more hydrophilic tubes may be inserted into a quantity of support medium such that the tubes are at least partially below the surface of the support media. The support media may be selected from any suitable medium or mixture of media suitable for supporting growing plants and roots. Examples, which are not intended as limitations, of such support media can include sand, soil, Rockwool, polyurethane foam, Fleximat™, SRI cellulose-based growth media, and the like. Other suitable media known in the art, such as continuous-fiber growth media, may also be used.
[0032] In particular embodiments, plants are planted in the support medium and the respective tubes are connected to reservoirs containing water, nutrients, or a mixture thereof. In some embodiments, two tubes may feed a row of plants: a water tube and a nutrient tube. As discussed above, it has previously been shown that the plants are capable of distinguishing between these tubes. Alternatively, nutrient(s) can be added to a water reservoir for distribution through a unitary tube.
[0033] Thin-walled microporous hydrophilic tubes are not known at present to be commercially available for use as irrigation tubing. In a particular embodiment, hydrophilic materials, including Cell-Force™ and Flexi-Sil™, may be made into hydrophilic tubes. Alternatively, some existing hydrophobic thin-walled tubes can be made hydrophilic by a process that uses a water-insoluble hydrophilic polymer (e.g., polyhydroxystyrene, U.S. Pat. No. 6,045,869, incorporated herein by reference; structure illustrated in FIG. 6 ) as a surface coating. Such solutions applied as a coating to and impregnated with microporous hydrophobic plastic tubing have been shown not to clog the pores and to remain hydrophilic for many years. Thus continuous tubes of Tyvek® (a microporous polyethylene material made from very fine, high-density polyethylene fibers, DuPont, Richmond, Va.) in a radius of 5-10 mm (Irrigro-International Irrigation Systems) have been used after being made hydrophilic and have been shown to act as a membrane that is responsive to the roots of plants in a subsurface irrigation system.
[0034] Tyvek® is available in a plurality of styles, each having different properties. Although not intended to be limiting, two particular types have been found to be most beneficial for use in the present invention: 1059B and 1073B.
[0035] As discussed above, it has been shown that hydrophilic membranes can become hydrophobic over time owing to organic impurities in the water adsorbed onto the membrane. Because of the variability of the impurities in water, we have added organic substances to the water which can be adsorbed onto the exit pore walls, making the membrane hydrophobic, and thereby reducing the flow of water or nutrient solution through the membrane. Examples of suitable organic substances include, but are by no means limited to, humic acid, kerosene, turpentine, pinene, paraffin, and hexadecane. In other embodiments, other suitable C8-C16 saturated hydrocarbons may be used. The amounts added ranged from 10 ppb to 10 ppm to the irrigating medium. As will be appreciated by one of skill in the art, in some embodiments, the addition of the organic substance may not be essential, depending on the quality of the water.
[0036] When growing crops in soil, the addition of nutrient on a continuous basis is not essential; however, when growing crops in sand, Fleximat, or Rockwool, a nutrient solution, for example, any suitable nutrient solution known in the art such as those commonly used in hydroponic systems, e.g., Hoegland Solution, Peter's Solution, Miracle-Gro, or other less dyed fertilizer such as Schultz Export may be added to the water supply or may be fed directly to the plants in a separate tube, as described above, and thus the roots of the plant can be allowed to take as much water and nutrient as required. However, for growth in artificial media the inclusion of nutrients and micronutrients is important.
[0037] FIGS. 1A and 1B illustrate a system 10 that uses twin irrigation tubes 11 , 12 for delivering water and nutrient solution to plants 13 growing in a growing medium 14 . In this embodiment 10 , the tubes 11 , 12 are running through the root systems 15 of the plants 13 . It has been found in experiments in both sand and potting soil that the higher the concentration of nutrients used, the smaller the volume of the nutrient solution that is released to the roots 15 , which is illustrative of the water conservation achieved by the current invention.
[0038] It will be understood by one of skill in the art that the tubes 11 , 12 could be provided as a single composite double-lumen tube without departing from the spirit of the invention. The diameters of the two portions could be in a proportion commensurate with a plant's requirements for water versus nutrient, for example, double the size for the water tube, although this is not intended as a limitation.
[0039] In some embodiments, since subsurface thin-walled microporous tubing can be collapsed if sufficient pressure is applied, a spiral 60 comprising, for example, plastic, can be incorporated into a tubing such as tubing 11 or 12 to form a tube 61 that is more resistant to collapsing ( FIG. 1C ).
[0040] FIG. 2 illustrates a system 20 for the irrigation of grass 21 where the subsurface tubes 22 are spaced 1-2 feet apart and are substantially continuously fed with water under low constant pressure, with nutrients added to the aqueous solution as desired.
[0041] The irrigation systems and methods described herein are believed superior to any other watering system currently in use, and further are independent of atmospheric pressure, making them usable for astroculture or micro-gravity conditions, as well as others. In one embodiment of the invention 30 ( FIG. 3 ), for example, a continuous fiber growth medium 31 such as Rockwool or the spongy Fleximat (from Grow-Tech) can be used to support the plants 32 and their roots 33 . In this embodiment 30 , both of the reservoirs 34 comprise a container 35 that has an interior space 36 for holding the water and nutrient solution therein. The containers 35 are formed similar to a bellows, and are movable between an expanded state when containing solution and a retracted state when solution has been removed.
[0042] The containers 35 also comprise a filling inlet 37 that is in fluid communication with the containers' interior space 36 for adding solution thereto. Distribution tubes 38 are also in fluid communication with the containers' interior spaces 36 and with inlets 39 of the hydrophilic tubes 40 . This arrangement provides solution to the tubings' lumina 40 . The distribution tubes 38 also have check valves 41 therein for preventing backflow of solution from the tubes 40 toward the containers' interior spaces 36 .
[0043] Support for plants and their roots can be provided for in the present system under zero gravity, for example, with the use of a monolithic contiguous material such as Rockwool or Fleximat, a spongy hydrophilic porous material made by Grow-Tech or the newly developed artificial sponge such as, for example, Agri-LITE (SRI Enviro-Grow). By using these materials to surround twin microporous hydrophilic irrigating tubes, one supplying water while the other supplying a nutrient solution, it is possible to achieve complete conservation of water and nutrients supplied to growing plants. Such a system can also be applied to arid or desert environments where water conservation is desirable.
[0044] Early laboratory tests showed that using nutrients in water, it was possible to grow tomatoes in sand with Amerace A10 membranes 42 (50% silica gel in polyethylene) glued over holes 43 in a subsurface PVC tube 44 ( FIG. 4 ). The holes 43 in the PVC tube 44 were 12 mm in diameter, spaced 10 cm apart, drilled in 17-mm-ID rigid PVC tubing. The holes 43 are believed to have limited the amount of water and nutrient available to the growing plant, and the system proved to be inadequate when the plants began to bear fruit and needed more membrane area to supply the plants' requirements. Increasing the total surface area of the membrane by drilling and covering more holes improved the system. However, a best mode of practicing the invention at the present time favors the use of a continuous tube. Because of the brittle nature of Amerace, membrane tubes made of this material tended to crack and leak.
[0045] Tyvek® (DuPont) in tube form has been used for irrigation purposes under elevated water pressure for gardens and row crops. However, the hydrophobic nature of the polyethylene material permits it to act as a drip source of water for plants without any control by the exudates of the plant roots. The conversion of a hydrophobic surface to hydrophilic has been described (U.S. Pat. No. 6,045,869) and can be used to make Tyvek® tubing hydrophilic and responsive to the water and/or nutrient needs of the plant. When the tubing has been made hydrophilic by coating and impregnating it with an alcohol solution of polyhydroxystyrene, the tubing was found to be permeable to water at much lower pressures, and showed a decrease in water permeability as the organic compounds in water are adsorbed onto the exit pore walls. This can be considered a “conditioning phase,” during which permeability can be decreased by as much as 80% by the addition of hydrocarbons to the tap water.
[0046] The present invention is believed to be the first to provide a plurality of feeding tubes arranged to extend beneath the surface of a support medium to feed a plurality of plants or a row of plants. Furthermore, a clear advantage of tubes comprising a hydrophilic material is that a greater area of the support medium is fed water and nutrients compared to a single horizontal membrane.
[0047] The invention will now be described by way of examples; however, the invention is not intended to be limited by these examples.
Example 1
[0048] A 4 ft. length of Tyvek® tubing (# 1053 D) was made hydrophilic with an alcoholic solution of polyhydroxystyrene and submerged in a 4.5 ft by 13 cm wide by 10 cm deep planter, covered with soil and connected to a constant supply of nutrient solution at a constant head of 35 cm of water. Ten cherry tomato (Lycopersicon sp.) seedlings were planted at even distances next to the tube where water and nutrients were supplied. Fluorescent lighting was supplied to the plants for 18 hours per day. The average consumption of water was 75±10 mL/hr when the plants were 15 cm high and 125±20 mL/hr when the plants were 25 cm high. When rainfall was simulated by spraying the bed with 100 mL of water, the consumption of water dropped to zero for 2 hours and slowly over the next 3 hours returned to the normal rate. The plants grew to two feet in height, and numerous tomatoes were harvested.
[0049] At the end of the experiment, the system was examined to determine if there was any competition between the plants for space on the membrane. An examination of the root system indicated that the roots encircled the membrane only within about 1-2 inches from the plant stem. This indicates that it should be possible to increase the density of plant growth to an extent that would only be limited by the photochemical flux available and mutual interference.
[0050] When a dual-tube system was used to supply both water and nutrient separately, the ratio of water consumed to nutrient solution consumed was approximately 2.5 to 1 for 8 cherry tomato plants in sand. Again, little or no fluctuations were observed when the size of the plants reached a height of 35 cm.
Example 2
[0051] A continuous irrigation tube can be unnecessary for plants such as grape vines or kiwi vines that are spread apart from each other by distances as much as 20 to 40 cm. In these situations 50 , it is more practical to use a main flexible surface distributing tube 51 of from 20-30 mm ID, out of which are drawn satellite tubes 52 that feed a short length of from 10 to 30 cm, depending of the size of the vine, of thin-walled microporous hydrophilic irrigating tube 53 , closed at its end 54 , surrounding the roots 55 of the vine or bush 56 , as illustrated in FIGS. 5A and 5B .
Example 3
[0052] A tomato plant was planted in potting soil, into which was also placed two 20-cm-long microporous hydrophilic tubes of 1 cm radius. The tubes were connected to reservoirs of water and nutrient which were kept full. The soil remained dry while the plant grew to produce numerous tomatoes.
Example 4
[0053] Another experiment was conducted with Tyvex® tubing (# 1053 B), 1.25 m long and 1 cm radius. The tubing was sealed at one end that was made hydrophilic with a 3% solution of polyhydroxystyrene (Novolac grade from TriQuest) in ethanol. The tubing was submerged in a 1.4-m planter, covered with soil, and connected to a supply of nutrient solution at a constant head of 35 cm of water. Ten cherry tomato (Lycopersicon sp) seedlings were planted at even distanced next to the tube, by which water and nutrients were supplied. The plants grew during the conditioning phase while exposed to fluorescence lighting for 16 hr/day. The average consumption of water was 75±10 mL/hr when the plants were 15 cm in height and 125±20 mL/hr when the plants were 25 cm in height.
[0054] Rainfall was simulated by spraying the bed with 100 mL water, following which the consumption of water dropped to zero for 2 hours and then slowly, over the next 3 hours, returned to the normal rate.
[0055] The plants grew to 60 cm in height, and an abundance of tomatoes was harvested. At the completion of the experiment, the system was examined to determine if there had been any competition between the plants for space on the membrane. An examination of the root system indicated that the roots encircled the membrane only within about 2.5-5 cm from the plant stem. This finding would seem to indicate that it should be possible to increase the density of plant growth to a level only limited by the light flux available and mutual interference.
[0056] It has also been shown that different plants requiring different rates of water and nutrient can grow together with each being satisfied individually without monitoring.
Example 5
[0057] When a dual membrane system was used to supply both water and nutrient separately, the ratio of water consumed to nutrient solution consumed was approximately 2.5 to 1 for 8 cherry tomato plants in sand. Once again, there was little or no fluctuation observed when the size of the tomato plants reached a height of 35 cm.
[0058] A planter 115 cm long, 13 cm wide, and 10 cm deep, was set up in a greenhouse with dual-feed membrane tubes for water and nutrient through the center of a bed comprising 50 cm of Flexmat and 50 cm of rockwool separated by 15 cm of polyurethane foam. The seeds or seedlings of canola ( Brassica sp), beans ( Phaseolus sp), corn ( Zea Mays sp), and tomatoes ( Lycopersicon sp) were planted in each of their respective media and their growth patterns observed. Growth, which was favored in the Fleximat, proceeded normally, except for the polyurethane foam, with each crop growing at its own rate under a light flux of 50-60 mW/cm 2 . Root crops such as carrots ( Daucus carota var sativa sp), radishes ( Raphanus sativus sp), beets ( Beta vulgaris sp), and onions ( Allium sp) were grown in soil and peat, while potatoes ( Solanum tuberosum sp), parsnips ( Pastinaca sativa sp), and parsley ( Petroselinum sativum var tuberosum sp) were grown successfully in vermiculite. A cellulose material (SRI Petrochemical Co.) can also be used as an artificial growth medium.
[0059] It was determined that grass ( Gramineae sp) can be successfully irrigated for 3 successive years with submerged tubular membranes spaced 40-50 cm apart.
Example 6
[0060] In another case, two hydroponic planters (30×30×30 cm) were fitted with a membrane tube for a water/nutrient solution approximately 7 cm from the bottom. The media comprised a soil-less mixture approximately 25-26 cm deep in the planters. This depth allowed the root crops to produce straight tap roots, which is of concern to consumers when purchasing vegetables. One planter was seeded with parsnips ( Daucus carota var. sativa sp). The other planter was seeded with parsley ( Petroselinum sativum var. tuberosum var. tuberosum sp), a dual-purpose crop of foliage and root stocks. Plant competition controlled the over-seeding issue with each planter. The plants received only natural sunlight, reducing the risk of “bolting.” Extreme warm temperatures were a concern for the health of the plants.
[0061] The parsnip roots were straight in growth, and produced a total weight of 38.9 g. The texture and flavor were excellent. The parsley produced straight tap roots, giving a total weight of 38.3 g. The foliage produced had longer petioles than usually purchased, yet the total weight was 58.9 g.
[0062] It will be appreciated by one of skill in the art that plants with varying water requirements can be satisfied by the embodiments of the present invention, wherein one continuous porous hydrophilic irrigating tube is used to allow each plant to take its water requirements independently of the other plants. Such requirements are often needed in greenhouses, where many different plants are cultivated under one roof.
[0063] It has also been shown that a hydrophilic irrigation tube with two channels, one for water and the other for nutrients, can fully satisfy the plants' requirements and also increase the density of the plants, limited only by the sunlight available.
[0064] It has also been shown that commercially available thin-walled microporous hydrophobic tubes can be converted to hydrophilic tubes and thereby become responsive to plants and their roots. Such tubes may include, but are not intended to be limited to, high-pressure irrigation hoses, although their use in the present invention does not require the use of high pressure.
[0065] It has also been shown how a dual-membrane tube can be incorporated into a container for one or more plants so that the plants can be fed on demand both water and nutrients from separate reservoirs and thereby require no attention or supervision as long as there is water available in the tube reservoirs. In a particular embodiment, a diametric ratio of 3:1 for the water tube over the nutrient tube is optimal, although this is not intended as a limitation, and obviously is dependent upon nutrient concentration and plant type.
[0066] It has additionally been shown that water systems that are free of contaminated organic substances and unresponsive in the irrigation system can, by the addition of trace amounts of one or more hydrocarbons to the water supply, become responsive to the irrigation system.
[0067] It has also been shown that the irrigation system of the present invention can be used to replace the emitter in a drip irrigation system, thereby making the release of water and/or nutrient responsive to the roots. In a particular embodiment, a factor of from 100 to 500 has been found for the difference in water volume used between the known drip irrigation systems and that of the present invention.
[0068] Sectors of grass are known to be grown substantially in isolation, for example, on golf courses wherein the greens are formed within soil-filled depressions in the ground and continuously or at predetermined intervals fed with water and nutrients. In such an arrangement, the system of the present invention can ideally provide water and nutrients to the grass roots on an on-demand basis, thereby saving both water and nutrients, and also ensuring optimal sustenance of the greens.
[0069] The following Tables 1-4 include data on experiments conducted indoors (Table 1) and outdoors (Table 2), and the flow rates for water and nutrient (Table 3) and for watering results in series and for single plants (Table 4).
[0000]
TABLE 1
Indoor experimental conditions
Growth
Plant
medium
Feed
Comments
Cherry tomatoes
Soil, sand,
Tap water; nutrient
Greenhouse
vermiculite,
and water a
peat,
Rockwool,
Fleximat d
Radishes, lettuce,
Soil b
Dual tubes
Greenhouse
carrots, tomatoes,
beets, onions,
spinach
Parsnips, parsley,
In separate pots
Nutrient feed
Greenhouse in
potatoes
with
deep pots
Beans c , tomatoes,
vermiculite
Nutrient feed
In greenhouse
canola
Rockwool and
FlexiMat
a Two separate feed lines for water and nutrients.
b Beets did not mature, although the leaves were abundant.
c Bean roots appear to crawl all over the planter and throughout the growth media.
d The system was a model for the growth of plants in the International Space Station.
[0000]
TABLE 2
Outdoor experimental conditions
Plant
Growth medium
Feed
Comments
Zucchini, garlic,
Soil
Water
Garden, good
melons, tomatoes,
results
eggplant, corn a
Grass b
Soil
Water
Visible
improvement
Strawberries
Peat and FlexiMat
Vertical plant
Indoors and
nutrient
outdoors
a Corn, melons did not take and grow.
b Spacing of irrigation tubes of 1. 1.5, and 2 ft (40-50 cm, 10 ft long).
[0000]
TABLE 3
Test of Rockwool and FlexiMat in series for Astroculture a
Test No.
Flows, side A
Flows, side B
Flow Ratio, W/N
1
W 19
N 4.8
4.2
2
N 20.5
W 70.3
3.4
3
W 76
N 14
5.4
4
N 25.4
W 75.1
3.0
5
W 63
N 31
2.0
6
W 66
N 36
1.8
7
N 27
W 74
2.7
a Planter with two tubes, one for water (W), the other for nutrient solution (N). The reservoirs were interchanged periodically to cancel any membrane effects. Flow rates in mL/hr; experiment time March 18 to July 16.
[0000]
TABLE 4
Watering results (mL/hr) for various vegetables (carrots, cherry
tomatoes, onions, beets, radishes, spinach) in potted planters
in two series of five (B and C) compared with single irrigated
plant (X) a
Test No.
Time interval (hr)
X
B
C
1
25
5.4
32.4
16.2
2
25
9.7
41.8
41.7
3
24
9.4
39.4
35.6
4
24
16.9
21.4
31.9
5
26
24.2
23.2
36.3
6
23
8.6
48.9
41.9
7
23.5
5.7
51.7
38.3
8
3
21
30.0
12.0
9
24
7.5
33.7
18.9
10
22.5
26
56
30.4
11
20
12.6
42.3
42.7
a Experiment time, February 19 to June 6.
[0070] Another aspect of the invention is directed to the making of tubing for use with a “water-on-demand” system. In one method, sheets of a low-porosity substance are coated with the aforementioned polyhydroxystyrene, and formed into cylinders by, for example, thermal, ultrasonic, or impulse means.
[0071] Although not intended as a limitation, a possible explanation of the operation of the polyhydroxystyrene polymer ( FIG. 6 ) will now be presented. First, how the polyhdroxystyrene attaches to the membrane: Polyhydroxystyrene has two groups, an hydroxyl (OH), which is hydrophilic and can hydrogen bond with water, and the styrene groups, which include a benzene ring (—C 6 H 4 —) attached to an ethylene group (═CH—CH 2 —), both of which are hydrophobic and can stick to the hydrophobic polyethylene membrane, leaving the hydrophilic (OH) group, which forms a weak hydrogen bond with water.
[0072] As discussed above, the polymer can act as a capillary through the membrane. It has been shown that organic impurities in water are 10 5 -10 6 times more likely to stick at the exit end wall of the capillaries, where there is a gas-liquid-solid equilibrium (i.e., air-water-membrane). The organic impurities are in equilibrium along the walls of the capillary, where the equilibrium is only between liquid and solid. Thus the surface of the exit pores become hydrophobic due to the adsorption of the trace organic impurities in water and/or nutrient solution.
[0073] When a plant is in need of water, it emits chemicals called exudates that can include a surfactant that removes the adhering organic compounds at the exit wall and liquid from the irrigation tube now is allowed to flow. This has been shown for two different membranes in the prior art, as discussed above with reference to FIGS. 7-8L .
[0074] High-purity water is free of organic impurities. Some domestic water supplies are often purified to such an extent that very little organic impurities remain. This would result in pore closure only after a large, and usually unnecessary, volume of water had passed through the membrane. The result would not be suitable because of the time delay between the removal of the organics and their deposition onto the membrane and the closure of the pores. On the other hand, too much organic content in the water could result in a delay in opening the closed pores because of the limited amount of surfactant that is released by the roots.
[0075] It has been found that in general the membrane area needed for a plant is best supplied by a tube of diameter equal to about a 1-cm radius, with a thickness of 0.5 mm maximum and pore sizes of from 0.1 to 5 μm, with a preferred average of 0.4 μm, although this is not intended as a limitation, and other porosity values can be used. This segment of the membrane is to be in contact with the roots of the plant. Short segments of membrane tubing can be supplied with water and/or nutrient solution by smaller diameter tubing, but care must be taken to prevent air locks in the line. Tubing of 1-cm ID would not be considered too large. Since the feed lines are exposed to light (sunlight or artificial lighting), it is necessary to use opaque tubing, or the solar active light will result in algae formation that can eventually block the pores. It is believed that the coating of the hydrophobic membrane is primarily to allow the resulting hydrophilic surface to become hydrophobic and to close the pores. Leaving the inner pore uncoated would restrict the flow of water through the membrane.
[0076] In the foregoing description, certain terms have been used for brevity, clarity, and understanding, but no unnecessary limitations are to be implied therefrom beyond the requirements of the prior art, because such words are used for description purposes herein and are intended to be broadly construed. Moreover, the embodiments of the apparatus illustrated and described herein are by way of example, and the scope of the invention is not limited to the exact details of construction.
[0077] Having now described the invention, the construction, the operation and use of preferred embodiments thereof, and the advantageous new and useful results obtained thereby, the new and useful constructions, and reasonable mechanical equivalents thereof obvious to those skilled in the art, are set forth in the appended claims.
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A method for efficiently delivering an aqueous solution to plants includes positioning a distal portion of a microporous hydrophobic tubing coated with a hydrophilic polymer adjacent a root system of a plant and channeling an aqueous solution from an inlet to the distal portion through a lumen. The tubing along the distal portion has a porosity adapted for permitting a flow of the aqueous solution therethrough when acted upon by a surfactant root exudate generated by the roots due to water stress. The aqueous solution is held in a reservoir, from which it can be channeled to the hydrophilic device's inlet. A nutrient solution can also be channeled to the plant roots via additional tubing.
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BACKGROUND OF THE INVENTION
This application is related to co-pending application. Ser. No. 143,667, entitled Cooking Apparatus Ventilation System, filed by the same inventors on Jan.14, 1988.
Almost every cooking method, such as grilling, frying, boiling, etc., results in the production of smoke, vapors, steam or other by-products which must be removed when the cooking is done indoors. The common arrangement is to locate a hood above the cooking area which confines the smoke or vapors after they have risen. The hood is evacuated through some sort of venting system.
It is the popular style in many restaurants to prepare certain foods at the customer's table rather than in a separate kitchen. The usual arrangement has the customers sitting around three sides of a table, the other side of which contains a cooking surface, usually a griddle. A hood is situated well above the cooking surface to confine the smoke and vapors after they have risen. Because the hood must be placed high enough to be out of the line-of sight of the customers, drafts in the restaurant can drive the smoke and vapors laterally before they reach the confines of the hood, often annoying the customers seated at the table. Also, the presence of a number of hoods throughout the restaurant is not aesthetically pleasing.
One solution to this problem is to provide a suction venting system at or near the cooking surface. A fan or similar means is used to withdraw air through openings at the rear or around the sides of the cooking surface. The smoke and vapors are drawn into the venting system and evacuated outside the room. Examples of these systems are taught in Moeller U.S. Pat. No. 4,291,668 ,Cerola U.S. Pat. No. 4,562,827 , Jenn U.S. Pat. Nos. 3,853,115 and 3,474,724 , and Field U.S. Pat. No.3,712,819.
The major problem with these systems is that the area of the cooking surface must be kept small enough so that smoke and vapors created in the center of the surface will still be entrapped by the suction of the venting system. It is impractical if not impossible to create venting systems with enough suction to draw in all the smoke and vapors created on a large cooking surface. For example, it is common to have restaurant grills as large as five feet by three feet, or even larger. With such a grill, smoke and vapors can be several feet from the nearest vent opening. This inventions solves this problem by directing a horizontal flow of forced air above and across the cooking surface, thereby preventing the smoke and vapors from rising, as well as forcing them into the vent openings. In addition to solving this problem, the invention improves upon the process by recycling a portion of the air, now containing some smoke from the cooking process, back across the food, thereby enhancing the flavor. This is especially true when grilling is being done. None of the prior art cited incorporates this recycling feature.
BRIEF SUMMARY OF THE INVENTION
The invention is a ventilation system incorporated in a cooking apparatus to be used in indoor cooking. The cooking apparatus may be of any type which produces smoke or vapors during the cooking process, including grills, griddles, fryers or individual heating elements. Forced air, as produced by a fan of a compressor, is directed in a full horizontal, planar pattern slightly above the cooking surface, creating a blanket of air which prevents any smoke or vapor from rising vertically. At the same time, this blanket of air directs the smoke and vapors toward the venting channels. A fan or other means is used to created negative pressure in the channels such that the entire quantity of forced air, as well as some room air, is drawn into the venting channels. The majority of this evacuated air is exhausted out of the room, but a small portion of this air is recycled by a fan and duct arrangement back across the cooking surface.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 is an isometric view of the invention as contained in a table, with the forced air means and evacuation means represented by boxes.
FIG. 2 is a cut-away view of a portion of the invention showing the relationship of the grill to the venting channels.
FIG. 3 is a sectional view along line III--III of FIG. 1, showing the forced air ingress means, the grill, the evacuation chamber and the recycling duct.
FIG. 4 is a sectional view similar to FIG. 3, where a compressed air ingress means has been substituted for the forced air ingress means.
DETAILED DESCRIPTION OF THE INVENTION
The particular cooking surface incorporated or used with the invention is not of importance. The term grill will be used throughout this specification to represent any cooking surface or device which produces smoke or vapors, including but not limited to grills, griddles, heating element or frying systems.
As shown in FIG. 1, the invention is typically housed in a large table 90 such that three sides of the table can be used for individual dining. The invention may be placed within any horizontal surface, or may be utilized independently of a table. The invention comprises a grill cooking surface 80 bounded on three sides by two venting channels 70 and a receiving venting channel 72. The remaining side (a long side if the grill is not square) is bounded by the air ingress housing 60. Opposite of the air ingress housing 60, a deflector 71 is situated adjacent to the upper lip of the receiving venting channel 72. Preferably, the upper surface of the venting channels 70 and 72, and the air ingress housing 60 are level with the upper surface of table 90.
Forced air is supplied by a forced air means 50, which can be a fan, blower or compressor, represented by a box in FIG. 1. Air is forced through inlet conduit 40 into the air chamber 41. Air chamber 41 is connected to the bottom of air ingress housing 60. Smoke and vapors are removed by an evacuation fan 51 or similar means, represented by another box in FIG. 1. The evacuation fan 51 draws air through outlet conduit 42 from evacuation chamber 30. Evacuation chamber 30 runs substantially the length of the receiving venting channel 72. In alternate design, the evacuation chamber 30 may be substantially shorter than the length of the receiving venting channel 72. Recycling duct 55 allows a portion of the air in evacuation chamber 30 to be redirected through air chamber 41, into air ingress housing 60, and across grill 80.
The relationship of the venting channels 70 and 72 to the grill 80 is better seen in FIG. 2. The venting channels 70 perpendicular to the air ingress housing 60 are of a general "C" shape such that the short vertical leg becomes a support for the underside of grill 80. The upper horizontal leg forms a lip which creates an ingress channel along the entire edge of the grill 80 and the shape of the venting channel 70 is such that a hollow, extended chamber is formed. This chamber is connected to the evacuation chamber 30 by the receiving venting channel 72 opposite the air ingress housing 60. This receiving venting channel 72 forms the upper portion of evacuation chamber 30. The deflector 71 runs the length of receiving venting channel 72.
Referring now to FIG. 3, grill 80 (shown with burner components 81) spans the distance between evacuation chamber 30 and air ingress housing 60. Air ingress housing 60 is an elongated chamber, closed on each end. Forced air is supplied through inlet conduit 40 and air chamber 41 into the central portion of air ingress housing 60. The only outlet for this forced air is through perforated plate 61, which runs the length of the air ingress housing 60. The perforations insure that the flow of forced air through plate 61 is equal over its entire length. The upper lip of air ingress housing 60 directs the air horizontally across the surface of grill 80, entrapping any smoke or vapor created during cooking. This air is then drawn into venting channels 72 and 70. Deflector 71 creates a larger receiving channel in the direction of the air flow. The smoke and vapors are drawn into evacuation chamber 30, through filters 31 and then through outlet conduit 42, where they are exhausted outside the room. The force, height and direction of the blanket of forced air is such that all of this air is directed at and into the suction region of the venting channels 70 and 72.
The entire quantity of air drawn into evacuation chamber 30 is not exhausted through outlet conduit 42. Recycling duct 55 connects evacuation chamber 30 directly to inlet conduit 40 and air chamber 41. A small recycling fan 53, represented by the box in FIG. 3, which is approximately one-fifth the capacity of evacuation fan 51, draws roughly 20 percent of the air from evacuation chamber 30 and recycles it back through recycling duct 55. This recycled air is then blown back across grill 80 in the normal forced air path.
An alternate embodiment is illustrated in FIG. 4. Instead of a forced air system created by a fan or blower, the blanket of air is created with compressed air. Inlet conduit 40 is replaced by inlet pipe 20 and the air supply means is a compressor. Inlet pipe 20 passes through the air ingress housing 60 and is joined to horizontal air pipe 21 to create a T-shape. Air pipe 21 runs the length of air ingress housing 60, parallel to and a slight distance above the surface of grill 80. Apertures or nozzles 22 are positioned at spaced intervals along air pipe 21. The compressed air is thus directed over the surface of the grill 80, entrapping any smoke or vapors and forcing them into the venting channels 72 and 70. In this embodiment, recycling duct 55 is connected to air ingress housing 60 such that the smoke is admitted below the compressed blanket of air. In this way the smoke is recycled across grill 80, yet remains trapped in the ventilation system.
The efficiency of the device is determined by the relationship between the evacuation fan 51 and the forced air means 50. Both are designed to be adjustable so that each can be independently increased or decreased in response to the situation. In order to insure that all smoke and vapors are removed, the amount of air evacuated through the device is set to be greater than the amount of air forced across the grill 80. Thus all of the forced air will be drawn into the venting channels 70 and 72, as well as some of the ambient room air. The larger the grill 80, the greater is the evacuation required. For a grill size of two feet by three feet, the evacuation fan 51 should be capable of evacuating 1400 cubic feet of air per minute. For a grill of two feet by five feet, the evacuation required is 2100 cubic feet per minute.
Since the invention is designed for indoor use, environmental and energy considerations are important. The source of forced air should be external to the room, since the forced air will be exhausted after passing over the cooking surface. Likewise, the evacuated air should be exhausted externally. It is also beneficial to maintain the settings for the amount of air evacuated to be near the amount of air forced in, so that only so much of the air-conditioned internal air is evacuated as is necessary to maintain the efficacy of the system.
The design of the invention is such that a number of units may be connected to a single forced air means 50 and a single evacuation fan 51. Of course, the capacity of these must necessarily be increased to accommodate the multiple units.
It is also a matter of choice in which direction the air is forced across the grill 80 in relation to table 90. As illustrated, the air is forced away from the person cooking. It is also envisioned that the air can be forced toward the cook.
Another embodiment of the invention allows for vertical adjustment of air ingress housing 60 relative to the surface of grill 80 . In circumstances where the smoke and vapors are produced a distance from the grill surface, for instance if pans or pots are utilized, the air ingress housing 60 can be raised and angled downward. In this way the smoke and vapors are still directed into venting channels 70 and 72 by the blanket of air.
The invention has been described as an integral cooking unit comprising both the cooking apparatus and the ventilation system. Another embodiment of the invention has the cooking apparatus removable from the ventilation system. In this embodiment, various types of cooking surfaces can be interchanged by removing one cooking surface and replacing it with another cooking surface, such that the position of the second surface is properly situated with respect to the ventilation system.
The embodiments set forth above are not exhaustive as to the nature of the invention. One skilled in the art should realize that variations and substitutions of elements are suggested by the disclosure. The full scope of the invention is therefore to be as set forth in the following claims.
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A cooking apparatus ventilation system which evacuates smoke and vapors to allow indoor cooking. Air is evacuated through ventilation channels which surround all but one side of the cooking surface. A layer of air is directed from the fourth side across the cooking surface to push the smoke and vapor into the ventilation channels. A portion of the evacuated air is recycled back across the cooking surface to enhance the flavor of the food being cooked.
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BACKGROUND OF THE INVENTION
[0001] 1. Field of the Invention
[0002] The present invention relates to recovery of volatile organic compound (VOC) fluids during loading or unloading from marine vessels, from petroleum production platforms or vessels or other such facility or location.
[0003] 2. Description of the Related Art
[0004] Vapor recovery units such as those of U.S. Pat. No. 5,050,603 have been provided to recover volatile organic compound (VOC) emissions during or unloading of barges or other vessels from marine vessels, from petroleum production platforms or vessels or other such facility or location. U.S. Pat. No. 5,050,603 is owned by a related company of the assignee of the present application. U.S. Pat. No. 5,050,603 is incorporated herein by reference.
[0005] Typically, such a vapor recovery unit has been ship or barge mounted and traveled in open marine waters from port to port based on service demands. In such an environment, the unit was continually exposed to the marine atmosphere and elements, such as salt water, rain, wind, wave action and the accompanying corrosive nature they presented. In vapor recovery units of this type, a number of the components, including fluid handling mechanical elements such as vessels, tubing, connections and fittings, as well as control elements such as valves, meters and other instrumentation exposed to the marine atmosphere of an ocean or port environment. Further, the unit and its components have been required by their use and purpose to be present in the hazardous zones created by proximity to oil and gas production. Potential leakage of any VOC vapors from the unit in an already hazardous zone in proximity to oil and natural gas production was a problem and safety concern. Additionally, salt air corrosion of components in the unit and the possible leaking of vapors from the unit were undesirable in order to avoid environmental pollution.
[0006] An additional and separate safety concern was present due to the nature of the VOC fluids being transferred to the vapor recovery unit from a cargo tank of a barge or other transport vessel. Concern was present about the hazardous consequences of an explosion in the event one might occur in the equipment of the vapor recovery unit and then be transmitted back through piping and connections from the vapor recovery unit to the vapor space in a cargo tank of the barge or other vessel from which the vapors were being extracted. In transfer of the explosive vapors which accompany VOC fluids from a cargo space to another vessel such as the vapor recovery unit, the hazard of an explosion in the unit spreading back from the vapor recovery unit into another typically larger vapor space on the vessel was a concern.
[0007] Operation of a vapor recovery system such as that of U.S. Pat. No. 5,050,603 was labor intensive in that it was not automated. The operator was required to be present to run the system 24 hours a day during vapor recovery unit operations. The vapor recovery system required a fill time operator to start the system, provide continuous adjustments during operations and shut the system down at the end of vapor recovery operations in connection with a load of oil. The operator was required to have taken specialized training to deal with issues that might arise out of operational problems. Successful operation of the unit was dependent on an operators' detailed knowledge of the process, and equipment settings of the various components. In addition, an operator was required to have mechanical ability to make repairs and adjustments, and instrumentation and control experience, such as record keeping skills in reading and documenting gauge settings and control functions.
[0008] Further, while vapor recovery units according to U.S. Pat. No. 5,050,603 were provided on skids in platform mounted form for mobility purposes, the units were not usable or self-sustaining on arrival at a job site. Outside support was required to be available at the job site in the form of electrical power, compressed air, and diesel fuel, and also of chemicals used in the process, such as methanol. This resulted in additional time and effort having to be spent at the job site in connecting the unit to these required sources and testing these connections during the unit set-up process before the vapor recovery unit was available for use. If the outside support and supplies were not present and available locally at the job site, vapor recovery was typically not available, in the absence of time-consuming prior planning and co-ordination.
[0009] Other systems used in the past for vapor recovery in the oil and chemical industries such as in have included cryogenic gas treatment and recovery by direct refrigeration, light lean oil absorption and activated carbon absorption.
SUMMARY OF THE INVENTION
[0010] Briefly, the present invention provides a new and improved mobile apparatus for recovery of volatile organic compound vapor from a vaporous fluid containing volatile organic compounds during transfer from a storage container for pollution reduction. The mobile volatile organic compound (or VOC) recovery apparatus according to the present invention includes a vapor collection safety unit connected in a fluid transfer conduit from the storage container for receiving the vaporous fluid. The vapor collection safety unit contains a shutdown valve responsive to hazardous conditions to block the fluid transfer conduit. A scrubber unit is connected to the vapor collection safety unit and removes corrosive compounds from the vaporous fluid transferred from the storage container. A compressor unit is connected to the scrubber unit to compress the vaporous fluid after removal of corrosive compounds in the scrubber unit. A liquid-vapor separator module is connected to the compressor unit. The liquid-vapor separator module has a liquid outlet for liquids separated from vaporous fluid received from the compressor unit, and a vapor outlet for vapors separated from vaporous fluid received from the compressor unit. A cooler module is connected to the vapor outlet of the liquid-vapor separator module and cools the vapor received into a recovered volatile organic compound liquid and a recovered volatile organic compound vapor. A vapor scavenger unit is connected to the cooler module for utilizing the recovered volatile organic compound vapor.
[0011] The present invention also provides as a separate aspect from that described above a new and improved mobile apparatus for recovery of volatile organic compound vapor from a vaporous fluid containing volatile organic compounds during transfer from a storage container for pollution reduction. The mobile volatile organic compound (or VOC) recovery apparatus according to the present invention includes a scrubber unit connected to the vapor collection safety unit and removing corrosive compounds from the vaporous fluid transferred from the storage container. A compressor unit is connected to the scrubber unit to compress the vaporous fluid after removal of corrosive compounds in the scrubber unit. A liquid-vapor separator module is connected to the compressor unit. The liquid-vapor separator module has a liquid outlet for liquids separated from vaporous fluid received from the compressor unit and a vapor outlet for vapors separated from vaporous fluid received from the compressor unit. A cooler module is connected to the vapor outlet of the liquid-vapor separator module. The cooler module cools the vapor received into a recovered volatile organic compound liquid and a recovered volatile organic compound vapor. A fluid supply is provided in the apparatus for supplying operating fluid for the apparatus. A vapor scavenger unit is connected to the cooler module to utilize the recovered volatile organic compound vapor.
[0012] The present invention further provides as a separate feature from those described above a new and improved mobile apparatus for recovery of volatile organic compound vapor from a vaporous fluid containing volatile organic compounds during transfer from a storage container for pollution reduction. The mobile volatile organic compound (or VOC) recovery apparatus according to the present invention includes a vapor recovery module which includes a scrubber unit removing corrosive compounds from the vaporous fluid transferred from the storage container; a compressor unit connected to the scrubber unit and compressing the vaporous fluid after removal of corrosive compounds in the scrubber unit; and a liquid-vapor separator module connected to the compressor unit. The liquid-vapor separator module has a liquid outlet for liquids separated from vaporous fluid received from the compressor unit, and a vapor outlet for vapors separated from vaporous fluid received from the compressor unit. A cooler module provided as a part of the vapor recovery module is connected to the vapor outlet of the liquid-vapor separator module to cool the vapor received into a recovered volatile organic compound liquid and a recovered volatile organic compound vapor. A vapor scavenger unit of the vapor recovery module is connected to the cooler module for utilizing the recovered volatile organic compound vapor. According to this aspect of the present invention, a platform has the vapor recovery module mounted therewith; and an enclosure is mounted with the platform and encloses the vapor recovery module.
[0013] The present invention further provides as a separate feature from those described above a new and improved mobile apparatus for recovery of volatile organic compound vapor from a vaporous fluid containing volatile organic compounds during transfer from a storage container for pollution reduction. The mobile volatile organic compound (or VOC) recovery apparatus according to the present invention includes a scrubber unit to remove corrosive compounds from the vaporous fluid transferred from the storage container. The scrubber unit has sensors for monitoring process conditions therein and control members connected therewith for controlling fluid conditions therein. A compressor unit is connected to the scrubber unit and compresses the vaporous fluid after removal of corrosive compounds in the scrubber unit. The compressor unit has sensors for monitoring process conditions therein and control members connected therewith for controlling fluid conditions. A liquid-vapor separator module is connected to the compressor unit, and has a liquid outlet for liquids separated from vaporous fluid received from the compressor unit and a vapor outlet for vapors separated from vaporous fluid received from the compressor unit. The liquid-vapor separator module has sensors for monitoring process conditions therein and control members connected therewith for controlling fluid conditions. A cooler module is connected to the vapor outlet of the liquid-vapor separator module and cools the vapor received into a recovered volatile organic compound liquid and a recovered volatile organic compound vapor. The cooler module has sensors for monitoring process conditions therein and control members connected therewith for controlling fluid conditions. A vapor scavenger unit is connected to the cooler module and utilizes the recovered volatile organic compound vapor. The vapor scavenger unit has sensors for monitoring its process conditions and control members connected for controlling fluid conditions. A processor control computer has a stored established set of state point stored therein to establish operating conditions for the apparatus. The processor control computer monitors the sensors and adjusts the control members of the apparatus according to the established operating conditions.
BRIEF DESCRIPTION OF THE DRAWINGS
[0014] The objects, advantages and features of the invention will become more apparent by reference to the drawings appended thereto, wherein like numerals indicate like parts and wherein an illustrated embodiment of the invention is shown
[0015] FIG. 1 is a schematic block diagram of a vapor recovery unit according to the present invention.
[0016] FIG. 2 is a piping and instrumentation diagram of the vapor recovery unit of FIG. 1 .
[0017] FIG. 3 is a schematic diagram of a vapor collection safety unit of the vapor recovery unit of FIG. 1 .
[0018] FIG. 4 is a plan view of the internal layout of the vapor recovery unit of FIG. 1 .
[0019] FIG. 5 is an isometric view of the vapor recovery unit of FIG. 1 .
[0020] FIG. 6 is a front elevation view of the vapor recovery unit of FIG. 1 .
[0021] FIGS. 7 and 8 are side elevation views the vapor recovery unit of FIG. 1 .
[0022] FIG. 9 is a rear elevation view of the vapor recovery unit of FIG. 1 .
[0023] FIG. 10 is another isometric view of the vapor recovery unit of FIG. 1 .
[0024] FIG. 11 is a schematic diagram depicting the arrangement of FIGS. 11A , 11 B, 11 C, and 11 D.
[0025] FIGS. 11A , 11 B, 11 C, and 11 D when arranged as illustrated in FIG. 11 are an example state point diagram of a vapor recovery unit like that shown in FIG. 1 .
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
[0026] In the drawings, the letter A designates a mobile apparatus according to the present invention for recovery of volatile organic compound vapor from a vaporous fluid containing volatile organic compounds during transfer from a storage container for pollution reduction. The vaporous fluid is typically a hydrocarbon liquid being loaded or unloaded from a storage container, such as a cargo tank. One example of such a cargo tank is a marine vessel, such as a barge or tanker. Another type of cargo tank is a shore-based petroleum tank. It should be understood that the apparatus A may be used with other types of storage containers for bulk storage of hydrocarbons, including those at offshore platforms as well.
[0027] The mobile volatile organic compound (or VOC) recovery apparatus A according to the present invention includes a vapor collection safety unit S connected in a fluid transfer conduit 20 from the storage container for receiving the vaporous fluid. The vapor collection safety unit S contains a shutdown valve 22 ( FIG. 3 ) responsive to hazardous conditions in the apparatus A to block the fluid transfer conduit 20 . In this way, any potential hazard such as fire, flame or incipient explosion in the apparatus A is blocked from passage back to the storage container through the fluid transfer conduit 20 .
[0028] A scrubber unit U ( FIG. 1 ) is connected to the vapor collection safety unit S to remove corrosive compounds from the vaporous fluid transferred from the storage container. A compressor unit C is connected to the scrubber unit U to compress the vaporous fluid after removal of corrosive compounds in the scrubber unit U.
[0029] A liquid-vapor separator module L is connected to the compressor unit U. The liquid-vapor separator module L has a liquid outlet 16 for liquids, at this stage principally water, separated from vaporous fluid received from the compressor unit U. The liquid-vapor separator module L also includes a vapor outlet 26 for vapors, typically principally unliquified hydrocarbons, separated from vaporous fluid received from the compressor unit U.
[0030] A cooler module R is connected to the vapor outlet 26 of the liquid-vapor separator module L and cools the vapor received into a recovered volatile organic compound liquid and a recovered volatile organic compound vapor. As will be set forth, the cooler module R typically takes the form of several sequentially connected cooler stages, each cooling an incoming vapor fluid and separating the incoming vapor into a liquid and a volatile organic compound vapor. A vapor scavenger unit G is connected to the cooler module R for utilizing the recovered volatile organic compound vapor. The utilization may take the form of consumption of the recovered VOC vapors as fuel in an engine or some suitable form of adsorption. In its preferred embodiments, according to the present invention the vapor scavenging unit G is typically a diesel engine adapted to utilize light VOCs as a supplemental fuel which is coupled to either an electricity generator which provides some of the power needed by the apparatus A, or to a hydraulic pump. The present invention also contemplates that the vapor scavenging unit G may take the form of a molecular sieve adsorber capable of absorbing the residual light VOCs.
[0031] The apparatus A also includes a fluid supply F for supplying operating fluid for operation of the other units during vapor recovery operations. When the vapor scavenger unit G takes the form of a diesel engine consuming the volatile organic fluid vapor received from the cooler module R, the fluid supply F includes a fuel supply for the engine. The fluid supply F also includes a supply of coolant supply of coolant fluid for the cooler module R.
[0032] The vapor collection safety unit S, scrubber unit U, compressor unit C, liquid-vapor separator module L, cooler module R, fluid supply F and vapor scavenger unit G take the form of a vapor recovery module M and are mounted on a common platform P of the apparatus. With the present invention, the term “platform” is not restricted to a platform in the sense of a highway flatbed but is intended to include structures for attaching process equipment to a ship or barge or skids after transport by a trailer-type or road transport vehicle over on land. The apparatus A is mounted upon the platform P. As will be set forth, the platform P is typically formed of two separate skid sections, for road transport regulation purposes, which are assembled together to support the apparatus at the job site, whether in a marine vessel or on land.
[0033] According to the present invention, an enclosure E is mounted with the platform P and encloses the vapor recovery module M. The enclosure E is waterproof and weatherproof, being made of steel structure and plates, or comparable materials. The enclosure E is also vented during operations to provide a safe access to operational personnel. The enclosure E also has conventional sensors and associated alarms/indicators suitably placed within it to continuously test the atmosphere, to guarantee the safety of those who enter.
[0034] Tuning now to the vapor collection safety unit S, the shutdown valve 22 ( FIG. 3 ) is a pressure actuated flow control valve of the type furnished with a fail-safe operator, open and closed position limit switches, as well as being capable of manual actuation. The shutdown valve 22 and other instrumentation of the apparatus A is connected to an instrumentation air supply 1 ( FIG. 1 ).
[0035] A position sensor 22 a is associated with the shutdown valve, as are pressure/temperature sensors indicated schematically at 22 b located upstream of the valve 22 on transfer conduit 20 . The sensors 22 a and 22 b monitor conditions relating to the apparatus associated with the shutdown valve 22 and provide data readings to the computer K. The pressure actuated shutdown valve 22 is actuated in response to detection of a hazardous condition such as an abnormal or hazardous temperature or pressure in the apparatus A by the computer K to block the fluid transfer conduit 20 . The shutdown valve 22 may also be actuated manually, as noted.
[0036] The vapor collection safety unit S also includes a suitable pressure/temperature sensor 24 located downstream of the valve 22 in conduit 20 to activate audible and visual alarms 26 in response to detection of either low or high conditions pressure conditions in the transfer conduit 22 . The vapor collection safety unit S also includes a cartridge filter 28 to prevent unwanted particles in the conduit from entering the apparatus A and to reduce plugging potential in a detonation arrestor 30 of the vapor collection safety unit S. It should be understood that a basket strainer might also be used, if desired.
[0037] The cartridge filter 28 is provided with a gauge pressure transmitter 28 a and a differential pressure sensor or transmitter 28 b. The transmitters 28 a and 28 b monitor conditions relating to the apparatus associated with the cartridge filter 28 and provide data readings to the computer K. The gauge transmitter 28 a monitors pressure conditions in the conduit 20 upstream of the filter 28 , while the differential pressure sensor/transmitter 28 b senses and monitors conditions relating to possible blockage or plugging of the filter 28 . A sample valve 28 c is also connected to the filter 28 for testing and sampling purposes.
[0038] The detonation arrestor 30 is preferably of the type intended for use with what are known as “Class D Vapors.” The detonation arrestor includes temperature sensors 30 a and 30 b on inlet and outlet sides, respectively of arrestor element 30 to monitor conditions relating to the arrestor 30 and provide data readings to the computer K. A differential pressure gauge 30 c senses and monitors conditions relating to pressure drop across the arrestor 30 . The vapor collection safety unit S also includes a vacuum relief valve 34 connected to the conduit 20 between the cartridge filter 28 and the arrestor 30 .
[0039] The foregoing equipment and components of the vapor collection safety unit S are mounted in a single skid located on the platform P beneath the conduit 20 leading to the scrubber unit U. A conventional control panel 38 ( FIG. 1 ) is provided for operator annunciation and interface, being mounted on the vapor collection safety unit S. The control panel may include at least a horn, a suitable number of strobe lights for annunciation system alarms and emergency push/pull buttons for shutdowns of the apparatus A as required by the process or by any appropriate governmental regulation.
[0040] In vapor recovery with the apparatus A, a direct refrigeration portion of the process occurs in which the VOC emissions first pass from the storage container through the transfer conduit 20 and the vapor collection safety unit S to the scrubber unit U. Scrubber unit U is a suitable form of caustic scrubber where potential corrosive or sulfurous components of the type which may be present in the hydrocarbons in the vapor stream are removed. Flow of the vapor from the storage container and the vapor collection safety unit S through the caustic scrubber is induced by an inline blower 40 ( FIG. 2 ) located downstream of the caustic scrubber U. The blower 40 is fitted with a valve 42 which may be opened by a control mechanism 42 a in response to the computer K to discharge the vapor through vent 18 to atmosphere in an emergency. Manual operating capability of the valve 42 is also provided.
[0041] From the blower, the scrubbed vapor passes to a compressor 44 which boosts the pressure of the vapor stream to a state point of pressure and temperature established by the process control computer K, as will be set forth. The compressed vapors exiting from the compressor 44 are fed to a liquid-vapor separator 50 of the liquid-vapor separator module L. The liquid stream exiting from a liquid outlet 50 a at the bottom of the liquid-vapor separator 50 is essentially hot water, free of oil, which may be recycled.
[0042] A vapor outlet 50 b of the liquid-vapor separator 50 transfers the exiting separated vapor stream through a line 52 so that the separated vapor stream passes through a compressor discharge cooler 54 of the cooler module R, utilizing cooling water from a cooling water supply 55 ( FIG. 1 ) as the cooling medium. The discharge cooler 54 cools the vapor stream to a temperature range established by the process control computer K. A temperature sensor 54 a and a pressure sensor/transmitter 54 b are located upstream in the line 52 of the cooler 54 to provide data readings and indications to the process control computer K.
[0043] The cooled vapor stream from the compressor discharge cooler 54 passes through a line 56 to an after cooler knock-out drum 58 of the cooler module R. A temperature sensor 56 a is located downstream of the cooler 54 to provide data readings and indications to the process control computer K. The cooler knock-out drum 58 is fitted with an oily water drain valve control system 60 including a control valve 62 controlled by the computer K based on readings furnished from a differential pressure transmitter 58 a to drain hydrocarbon liquids and water through conduit 16 associated with the storage container.
[0044] Vapors exit from an outlet 58 b at the top of the knock-out drum 58 and travel through outlet 18 to enter a first high temperature chiller 64 of the cooler module R. In the first high temperature chiller module 64 , the entering vapor is cooled with a low pressure refrigerant which is preferably methanol from a methanol or coolant supply unit 68 of the fluid supply F. The vapor is cooled in the chiller 64 to a temperature range established by the process control computer K to produce a vapor-liquid mixture.
[0045] A differential pressure sensor/transmitter 64 a is connected to the first high temperature chiller module 64 to provide data readings and indications to the process control computer K. A level control valve 66 is controlled by the computer K based on readings from the differential pressure transmitter 64 a to control fluid levels in the chiller 64 .
[0046] The fluid mixture from the chiller 64 is fed to a cold three-phase knock-out drum 68 which is fitted with a hydrocarbon liquid drain system 70 for recovering liquid hydrocarbons. The hydrocarbon liquid drain system 70 includes a differential pressure sensor 72 to provide data readings and indications to the process control computer K and a liquid control valve 74 controlled by the computer K to control fluid levels in the knock-out drum 68 . Liquid hydrocarbons recovered by knock-out drum 68 which are then reinjected into the cargo loading line through a line 76 .
[0047] The vapor portion of the mixture exits from an outlet 68 a at the top of the three-phase knock-out drum 68 and enters a low temperature chiller 80 where it is cooled by low temperature refrigerant to a temperature range established by the process control computer K. A hydrocarbon liquid drain system 82 includes a differential pressure sensor 84 to provide data readings and indications to the process control computer K and a liquid control valve 86 controlled by the computer K to control fluid levels in the low temperature chiller 80 .
[0048] Upon exiting from the low temperature chiller 80 , the gas passes through a gas-gas exchanger 90 where it is further cooled to a temperature range established by the process control computer K and partially condensed by heat exchange with cold expanded vapors. The liquid from control valve 86 travels to an exchanger 92 which serves as a subchiller for refrigeration vapor, as will be described. Exchanger 92 is also connected to chiller 64 and to low temperature chiller 80 .
[0049] The gas from exchanger 90 then travels to a first low temperature accumulator 100 fitted with a hydrocarbon liquid drain system 102 for liquid hydrocarbon recovery. The hydrocarbon liquid drain system 102 includes a differential pressure sensor 104 to provide data readings and indications to the process control computer K and a liquid control valve 106 controlled by the computer K to control fluid levels in the low temperature accumulator 100 . The residual vapors exit from an outlet 100 a at the top of the low temperature accumulator 100 and are fed to a turbo-expander 110 which expands the vapor to a pressure established by the process control computer K. Turbo-expander 110 further cools the vapors to a temperature established by the process control computer K causing further vapor condensation.
[0050] The cooled, expanded vapor-liquid mixture from turbo-expander 110 is fed to a second low temperature accumulator 120 fitted with a hydrocarbon liquid drain system 122 for recovering liquefied hydrocarbons for reinjection into the cargo. The hydrocarbon liquid drain system 122 includes a differential pressure sensor 124 to provide data readings and indications to the process control computer K and a liquid control valve 126 controlled by the computer K to control fluid levels in the accumulator 120 .
[0051] The cold separated vapor from accumulator 120 , typically now mainly methane, with some ethane, propane and butane, exits from an outlet 120 a at the top of the second low temperature accumulator 120 and is used as a cooling medium in the gas-gas exchanger 90 before entering an exchanger 128 which serves as a refrigerant subcooler. Vapor from the exchanger 128 after passage through a flame arrestor 132 enters the vapor scavenging unit G at a temperature and pressure established by the process control computer K.
[0052] Typically, the vapor scavenging unit G takes the form of a diesel engine 134 which is also provided with diesel fuel from a diesel fuel tank 136 of the fluid supply F. Power generated by the diesel engine 134 is used to drive hydraulic pumps which power the rotating equipment of the apparatus A with the possible exception of the blower 40 , and an electricity generator 138 which powers a pump or pumps in the caustic scrubber U; the blower 40 ; and requisite instrumentation and lights for the apparatus A.
[0053] Refrigeration for cooling purposes in the units of the apparatus A is provided by low pressure compressor 140 and high pressure compressor 150 fitted in the conventional manner with ancillary filters, separators, and accumulators associated with such equipment. The compressed refrigerant exiting from the high pressure compressor 150 is fed to a refrigerant condenser 152 via line 154 . The refrigerant condenser 152 is cooled with cooling water. The cooled compressed refrigerant is then fed to a refrigerant accumulator 156 from which it passes via the refrigerant subcooler 128 then via line 160 to the high temperature chiller 64 to provide cooling for the vapor stream.
[0054] Part of the refrigerant exits from the high temperature chiller 64 via line 65 and is routed back to the inlet of the high pressure compressor 150 for recompression and recycling. The remainder of the refrigerant from chiller 64 then flows through line 162 through exchanger 92 to low temperature chiller 80 to provide cooling. The refrigerant exits from chiller 80 through line 85 and is routed through exchanger 92 which serves as a subchiller for refrigeration vapor being returned to the inlet of the low pressure compressor 140 . The low pressure compressor 140 discharges refrigerant in line 142 which routes the refrigerant into the inlet of the high pressure compressor 150 , completing the processing cycle.
[0055] The apparatus A is a complete, self-contained vapor processing plant, and as such weighs about 180,000 pounds when fully loaded with operating fluids. To support this weight and provide a rigid mounting to a barge, the vapor recovery module M is supported by the platform P which is constructed of carbon steel I-beams 200 of suitable size, designed with cross bracing and welded together to form a 20 foot wide by 48 foot long base 202 in the disclosed embodiment. The base 202 is preferably made from two separate skids 203 a and 203 b, each forty eight feet long, one being eleven feet wide and the other being nine feet wide. This is done to allow for shipping to a barge or other location for installation as each of the two skids of the base 203 a and 203 b can be shipped separately and within current transport regulations.
[0056] The skids 203 a and 203 b when connected to form the base 202 have a floor 204 ( FIG. 4 ) mounted to form the platform P. The floor 204 ( FIG. 4 ) of the platform is made from a suitable number of carbon steel deck plate members, which are welded together to form an interlocking pattern upon the I-beams 200 of the base 202 . Appropriately located floor drains are installed in the deck plates of the floor 204 , and have threaded couplings that may be plugged when the apparatus A is moved after installation on a barge, or when otherwise necessary.
[0057] The enclosure E is formed from a frame of carbon steel tube members 210 of suitable size and strength that are welded in positions so that they extend upwardly around the perimeter of the base 202 . Cross-members or supports as required are welded as needed for strength and to provide mounting locations for a set of panels or side wall members 214 . The side wall members 214 form side walls on side and end wall segments of the enclosure E. The side wall members 214 are bolted or otherwise mounted to the tube members 210 in order to be removable for maintenance. The junctures of the side panels 214 with the tube members 210 are provided with elastomer seals to prevent water entry or exit and provide protection for the equipment of the apparatus A mounted within the enclosure B. The enclosure E is provided with a suitable number of fore and aft marine doors 216 and 218 , respectively, together with various hinged smaller panels as may be required to be opened during preparation for operation of the apparatus A, or for access to inlet or outlet ports or connection points associated with components of the apparatus A.
[0058] The enclosure E is provided with a roof 220 formed of roof panels 222 mounted above the side wall members with appropriate supports and bracing, if required. The roof panels 222 are sloped and are also removable for maintenance. The sloped roof panels 222 are also removably mounted by bolts to the tube members of the framework of the enclosure B. As with the side wall members 214 , the roof panels 222 are provided with elastomer seals at their mounting with other components of the enclosure E. The tubes 210 of the framework and both the side wall panels 214 and roof panels 222 of the enclosure E are painted with a suitable weather resistant marine epoxy.
[0059] A ventilator fan 230 is mounted in an upper portion 232 of end side panel 214 to draw in and circulate air within the interior of enclosure S, while an outlet vent 234 is mounted in an upper portion 236 of an opposite end side panel to allow outlet circulation of air from the enclosure E. Suitable hoods or canopies 238 are mounted above the fan 230 and vent 234 to prevent entry of rain or other weather elements into the enclosure E.
[0060] The apparatus A is mounted within the enclosure E as a self-supporting and self-contained unit, and provides all its own support services. The generator 138 is installed on a power take off from the diesel engine 134 , allowing supply of the electrical power necessary to support operations of the apparatus A. Diesel fuel in fuel tank 136 and coolant chemicals in coolant supply unit 67 of the fluid supply F are stored in the enclosure E in tanks designed for that purpose. Compressed air is supplied by an onboard air compressor of the instrumentation air system 1 . These features allow the apparatus A capable of transport or movement from ship to land based operations or the opposite in a short period of time. The required automated functions are located in the enclosure E, eliminating the requirement of a separate and additional remote operations building.
[0061] In the mobile volatile organic compound (or VOC) recovery apparatus according to the present invention the component units of the vapor recovery module M have sensors for monitoring vapor recovery process conditions, including pressure sensors and temperature sensors, and control members including valves for controlling fluid flow and transfer conditions in the apparatus A. The apparatus A also includes a processor control computer K which has a stored established set of state points for the components of the vapor recovery module M to establish operating conditions for the apparatus A.
[0062] FIGS. 11A , 11 B, 11 C, and 11 D represent an example state point diagram of operating conditions for the apparatus A. The processor control computer K monitors the sensors and adjusts the control members of the apparatus A according to established operating conditions, such as those depicted in the state point diagram of the composite FIGS. 11A , 11 B, 11 C, and 11 D. It should be understood that the parameters values of temperature, pressure and the like are given by way of example. The computer K has an associated operator interface panel 250 with operator touch screen for monitoring and control purposes.
[0063] The computer K in a preferred embodiment of the present invention takes the form of a programmable logic controller, such as an Allen-Bradley Model PLC-5, or a programmable automation controller, such as an Allen-Bradley CompactLogix Model L43. The computer K permits user or operator selection of automatic, manual, or maintenance modes of vapor recovery operation. The computer K also permits conventional step sequencer logic for start-up control and provides safety interlocks to meet safety and other regulations.
[0064] It should be understood that other types of process control computers, such as personal computers, microprocessors or process controller may be used, if desired. The computer K receives input data from many sensors associated with units in the apparatus A, analyzes and monitors such data. In addition the computer K contains programmed therein an established set of state points and other parameters to establish operating conditions for the apparatus A. Based on the established set of state points and parameters, as well as the data readings from the temperature and pressure sensors in the apparatus A, the computer K sends signals to mechanical and electrical control members or valves to adjust system operation and efficiency.
[0065] According to the present invention, automation of vapor recovery operations allows for more efficient operations. It also eliminates the need for a full time operator and thus can afford a considerable saving of personnel costs. The computer K also permits independent recording of performance to determine both efficiency of the system and compliance with regulatory mandates.
[0066] In addition, the computer K prevents equipment damage by sensing problems with system operations before a major problem presents itself that could otherwise cause damage to person and property. Further, the computer K monitors and regulates the safety systems present into the apparatus A.
[0067] The control system associated with the computer includes sensors located throughout the unit to monitor a complex set of parameters to tell the logic controller how the system is working. As has been set forth, the state point diagram depicted in the drawings is an illustrative example of established operating conditions. The sensors in the apparatus A involved in vapor recovery operations take the form of pressure transmitters mounted inline, either differential pressure transmitters or gauge pressure transmitters. Also, where desired, conventional visual indicators may be located in the vapor recovery unit in conjunction with the pressure transmitters and elsewhere for operator observation and monitoring. In a preferred embodiment, the sensors are of the type available as Rosemount 3051 S series.
[0068] The differential pressure transmitters previously described herein serve as level controllers, to furnish data readings and direct the computer K to automatically drain a knockout vessel of condensed hydrocarbons or flow more refrigerant into a heat exchanger. The pressure transmitters of the apparatus A monitor process pressure conditions and provide data readings to the computer K for monitoring purposes during vapor recovery operations. The temperature sensors/transmitters of the apparatus A permit monitoring of process temperature conditions, and provide temperature data readings to the computer K for that purpose. In a preferred embodiment, the sensors are of the type available as Rosemount 248.
[0069] The control system of the apparatus A operates under of the computer K, and contains servomechanisms and valve operators to automatically adjust vapor recovery operations based on input values detected by the various pressure and temperature sensors previously discussed. The computer system K has associated with it the control members or mechanisms in the form of valves of the apparatus S as described above.
[0070] An operator interface panel 250 of the computer K displays in real time data about present vapor recovery operations. A preferred display on the operator interface panel 250 takes the form of a piping and instrumentation diagram of the system on a touch screen display. The operator interface panel 250 allows the operator to make manual adjustments to settings and controls as required. The operator interface panel 250 also displays both real time and saved data on current and past operations.
[0071] The operator interface panel 250 allows control of operation of control members such as valves and servomechanisms, such as those described above, to properly control the vapor collection safety unit S, scrubber unit U, compressor unit C, liquid-vapor separator module L, cooler module R, fluid supply F and vapor scavenger unit G of vapor recovery module M The operator interface panel 250 includes an industrial monitor with appropriate software, and mouse and keyboard controls mounted on the front of the panel. It should be understood that a touch screen may be used instead of an industrial monitor
[0072] If desired, a slave computer unit may also be provided. In such a case, the slave unit can be any suitable computer that capable of receiving signals from the controller of the computer K. Such a slave unit would usually be located in the vicinity of the control center and operator interface panel 250 .
[0073] According to the present invention, the term “volatile organic compounds” (VOC) refers to hydrocarbon or hydrocarbon derived compounds containing from 1 to 12 carbon atoms.
[0074] The term “light VOCs” refers to hydrocarbon or hydrocarbon derived compounds having from 1 to 4 carbon atoms. Further, according to the present invention, the term “light hydrocarbons” refers to C 4 and lighter hydrocarbons.
[0075] The apparatus A is particularly suited for use in the oil and chemicals industry for recovery of volatile organic compounds from a process stream containing such compounds. The mobile volatile organic compound (or VOC) recovery apparatus A according to the present invention meets or exceeds current safety standards for operation in the petroleum industry and marine operations on an oil barge or tanker as defined by United States Coast Guard Regulation and American Bureau of Shipping.
[0076] By enclosing the system in the water-tight, vented enclosure E, the mobile volatile organic compound (or VOC) recovery apparatus according to the present invention meets current regulatory standards, prevent corrosive damage to sensitive equipment by atmospheric elements, and prevent water damage to controls and a safe environment for operators.
[0077] The mobile volatile organic compound (or VOC) recovery apparatus A according to the present invention increases utilization and availability of VOC recovery by allowing a system to be transferred to active equipment and locations that are in current need of such a system. An apparatus according to the present invention eliminate the cost of separately providing at those locations supplies used by the system and support services such as fuel and coolant.
[0078] The mobile volatile organic compound (or VOC) recovery apparatus A according to the present invention includes an automated VOC vapor recovery system to eliminate the constant attention of an operator, reducing labor costs and making the system safer to operate.
[0079] Having described the invention above, various modifications of the techniques, procedures, material, and equipment will be apparent to those in the art It is intended that all such variations within the scope and spirit of the appended claims be embraced thereby.
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A self-contained unit which is automated for safety and efficiency recovers emissions present as a result of loading volatile organic compositions at marine or land based vessels or terminals. The unit is enclosed for protection of its components from wind, weather and the saltwater marine environment, while including venting for protection against possible vapor build-up. The unit also includes required support services and materials, and also includes structure for protection against transfer of explosion back into the cargo vessel or terminal.
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CROSS-REFERENCES TO RELATED APPLICATIONS
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STATEMENT AS TO RIGHTS TO INVENTIONS MADE UNDER FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT
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REFERENCE TO A “SEQUENCE LISTING,” A TABLE, OR A COMPUTER PROGRAM LISTING APPENDIX SUBMITTED ON A COMPACT DISK
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BACKGROUND OF THE INVENTION
The present invention relates to oximeters, and in particular to determining a pulse rate by multiple mechanisms in a detected waveform from a pulse oximeter.
Pulse oximetry is typically used to measure various blood chemistry characteristics including, but not limited to, the blood-oxygen saturation of hemoglobin in arterial blood, the volume of individual blood pulsations supplying the tissue, and the rate of blood pulsations corresponding to each heartbeat of a patient. Measurement of these characteristics has been accomplished by use of a non-invasive sensor which scatters light through a portion of the patient's tissue where blood perfuses the tissue, and photoelectrically senses the absorption of light in such tissue. The amount of light absorbed at various wavelengths is then used to calculate the amount of blood constituent being measured.
The light scattered through the tissue is selected to be of one or more wavelengths that are absorbed by the blood in an amount representative of the amount of the blood constituent present in the blood. The amount of transmitted light scattered through the tissue will vary in accordance with the changing amount of blood constituent in the tissue and the related light absorption. For measuring blood oxygen level, such sensors have typically been provided with a light source that is adapted to generate light of at least two different wavelengths, and with photodetectors sensitive to both of those wavelengths, in accordance with known techniques for measuring blood oxygen saturation.
Known non-invasive sensors include devices that are secured to a portion of the body, such as a finger, an ear or the scalp. In animals and humans, the tissue of these body portions is perfused with blood and the tissue surface is readily accessible to the sensor.
U.S. Pat. Nos. 6,083,172, 5,853,364 and 6,411,833 show multiple methods of calculating a pulse rate in a pulse oximeter, with a “best rate” module which arbitrates between the pulse rate calculations to select a best rate based on confidence levels associated with each. The confidence levels are calculated using various metrics to determine the reliability of the different pulse rate calculations. Also, U.S. Pat. No. 5,524,631 shows a fetal heart rate monitor that uses multiple parallel filter paths to identify the fetal heart rate, and uses a figure of merit operation to weight the different heart rate estimates.
N-100. The N-100 technology, dating to around 1985, accepted or rejected pulses based on pulse history of the size of pulses, pulse shape, expected time to occur (frequency) and ratio of R/IR.
In particular, the N-100 found pulses by looking for a signal maximum, followed by a point of maximum negative slope, then a minimum. The processing was done in a state machine referred to as “munch.” Each maximum was not qualified until the signal passed below a noise threshold, referred to as a noise gate. This acted as an adaptive filter since the noise gate level was set by feedback from a subsequent processing step to adapt to different expected signal amplitudes. The pulses are then accepted or rejected in a “Level3” process which was a filter which adapts to changing signals by comparing the amplitude, period and ratio-of-ratios (ratio of Red to IR, with Red and IR being expressed as a ratio of AC to DC) of a new pulse to the mean of values in a history buffer, then determining if the difference is within a confidence level. If the new pulse was accepted, the history buffer was updated with the values for the new pulse. The level3 process acted as an adaptive bandpass filter with center-frequency and bandwidth (confidence limits) being adapted by feedback from the output of the filter.
N-200. The N-200 improved on the N-100 since it could be synchronized with an ECG, and included ECG filtering. The N-200 also added interpolation to compensate for baseline shift between the time of measuring the pulse maximum and minimum. The N-200 included other filtering features as well, such as a “boxcar” filter which computed the mean of a varying number of signal samples.
The N-200, after various filtering and scaling steps, applies the digitized signals to a “boxcar” filter, which computes the mean of N samples, where N is set by feedback from a subsequent processing step according to the filtered heart rate. New samples are averaged into the boxcar filter, while the oldest samples are dropped. The boxcar length (N) is used to set three parameters: a pulse threshold, absolute minimum pulse and small pulse. An ensemble-averaging (a.k.a “slider”) filter then produces a weighted average of the new samples and the previous ensemble-averaged sample from one pulse-period earlier. The samples are then passed to a “munch” state machine and a noise gate, like the N-100. An interpolation feature is added to the N-100 process, to compensate for changes in the baseline level. Since the minimum and maximum occur at different times, a changing baseline may increase or decrease the minimum and not the maximum, or vice-versa.
“Ensemble averaging” is an integral part of C-Lock, which is NELLCOR's trademark for the process of averaging samples from multiple pulses together to form a composite pulse. This process is also known as “cardiac-gated averaging.” It requires a “trigger” event to mark the start of each pulse.
BRIEF SUMMARY OF THE INVENTION
The present invention is a pulse oximeter which determines multiple heart rates, and selects between them based on the metrics of only one of the heart rate calculations. A primary heart rate calculation method is selected, and is used unless its metrics indicate questionable accuracy, in which case an alternative rate calculation is available and is used instead.
In one embodiment, the primary heart rate calculation method does not use an ensemble averaged waveform, while the alternative heart rate calculation does use an ensemble averaged waveform. The alternative heart rate calculation is used if the primary calculation has disqualified its most recently detected pulse.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 is a block diagram of an oximetry system incorporating an embodiment of the invention.
FIG. 2 is a diagram of the software processing blocks of an oximeter including an embodiment of the present invention.
FIG. 3 is a context diagram of the pulse rate calculation subsystem.
DETAILED DESCRIPTION OF THE INVENTION
FIG. 1 illustrates an embodiment of an oximetry system incorporating the present invention. A sensor 10 includes red and infrared LEDs and a photodetector. These are connected by a cable 12 to a board 14 . LED drive current is provided by an LED drive interface 16 . The received photocurrent from the sensor is provided to an I-V interface 18 . The IR and red voltages are then provided to a sigma-delta interface 20 incorporating the present invention. The output of sigma-delta interface 20 is provided to a microcontroller 22 which includes a 10-bit A/D converter. Controller 22 includes flash memory for a program, and EEPROM memory for data. The processor also includes a controller chip 24 connected to a flash memory 26 . Finally, a clock 28 is used and an interface 30 to a digital calibration in the sensor 10 is provided. A separate host 32 receives the processed information, as well as receiving an analog signal on a line 34 for providing an analog display.
Design Summary The design of the present invention is intended to deal with unwanted noise. Signal metrics are measured and used to determine filter weighting. Signal metrics are things that indicate if a pulse is likely a plethysmograph or noise, such as frequency (is it in the range of a human heart rate), shape (is it shaped like a heart pulse), rise time, etc. A similar technique was used in the Nellcor N200, described in the background of this application. The new design adds a number of different features and variations, such as the use of two ensemble averagers as claimed in the present invention.
Details of the architecture are shown in the diagram of FIG. 2 . This design calculates both the oxygen saturation, and the pulse rate, which are described separately below.
I. Oxygen Saturation Calculation.
A. Signal Conditioning—The digitized red and IR signals are received and are conditioned in this block by (1) taking the 1st derivative to get rid of baseline shift, (2) low pass filtering with fixed coefficients, and (3) dividing by a DC value to preserve the ratio. The function of the Signal Conditioning subsystem is to emphasize the higher frequencies that occur in the human plethysmograph and to attenuate low frequencies in which motion artifact is usually concentrated. The Signal Conditioning subsystem selects its filter coefficients (wide or narrow band) based on hardware characteristics identified during initialization.
Inputs—digitized red and IR signals Outputs—Pre-processed red and IR signals
B. Pulse Identification and Qualification—The low pass filtered and digitized red and IR signals are provided to this block to identify pulses, and qualify them as likely arterial pulses. This is done using a pre-trained neural net, and is primarily done on the IR signal. The pulse is identified by examining its amplitude, shape and frequency, just as was done in the Nellcor N-100. An input to this block is the average pulse period from block D. This function is similar to the N-100, which changed the upfront qualification using the pulse rate. The output indicates the degree of arrhythmia and individual pulse quality.
Inputs—(1) Pre-processed red and IR signals, (2) Ave. pulse period, (3) Lowpass Waveforms from the low pass filter. Outputs—(1) Degree of arrhythmia, (2) pulse amplitude variations, (3) individual pulse quality, (4) Pulse beep notification, (5) qualified pulse periods and age.
C. Compute Signal Quality Metrics—This block determines the pulse shape (derivative skew), period variability, pulse amplitude and variability, Ratio of Ratios variability, and frequency content relative to pulse rate.
Inputs—(1) raw digitized red and IR signals, (2) degree of arrhythmia, individual pulse quality, pulse amplitude variation (3) pre-processed red and IR signals, (4) average pulse period.
Outputs—(1) Lowpass and ensemble averaging filter weights, (2) metrics for sensor off detector, (3) Normalized Pre-processed waveforms, (4) percent modulation.
D. Average Pulse Periods. This block calculates the average pulse period from the pulses received.
Inputs—Qualified pulse periods and age. Outputs—Average pulse period.
E1. Lowpass Filter and Ensemble Averaging—Block E1 low pass filters and ensemble averages the signal conditioned by block A, and normalized by block C, for the pulse rate identification. The weights for the low pass filter are determined by the Signal Metrics block C. The signal is also ensemble averaged (this attenuates frequencies other than those of interest near the pulse rate and its harmonics), with the ensemble averaging filter weights also determined by Signal Metrics block C. Less weight is assigned if the signal is flagged as degraded. More weight is assigned if the signal is flagged as arrhythmic because ensemble-averaging is not appropriate during arrhythmia. Red and IR are processed separately, but with the same filtering weights. The filtering is delayed approximately one second to allow the signal metrics to be calculated first.
The filters use continuously variable weights. If samples are not to be ensemble-averaged, then the weighting for the previous filtered samples is set to zero in the weighted average, and the new samples are still processed through the code. This block tracks the age of the signal—the accumulated amount of filtering (sum of response times and delays in processing). Too old a result will be flagged (if good pulses haven't been detected for awhile).
Inputs—(1) normalized pre-processed red and IR signals, (2) average pulse period, (3) low pass filter weights and ensemble averaging filter weights, (4) ECG triggers, if available, (5) IR fundamental, for zero-crossing triggers. Outputs—(1) filtered red and IR signals, (2) age.
F. Estimate Filtered Waveform Correlation and Calculate Averaging Weight—this uses a noise metric similar to that used in the N100 and N200 described above, and doesn't use feedback. The variable weighting for the filter is controlled by the ratio-of-ratios variance. The effect of this variable-weight filtering is that the ratio-of-ratios changes slowly as artifact increases and changes quickly as artifact decreases. The subsystem has two response modes. Filtering in the Fast Mode targets an age metric of 3 seconds. The target age is 5 seconds in Normal Mode. In Fast Mode, the minimum weighting of the current value is clipped at a higher level. In other words, a low weight is assigned to the newest ratio-of-ratios calculation if there is noise present, and a high weight if no noise is present.
Inputs—(1) filtered red and IR signals and age, (2) calibration coefficients, (3) response mode (user speed settings). Outputs—averaging weight for ratio-of-ratios calculation.
H. Calculate Saturation—Saturation is calculated using an algorithm with the calibration coefficients and averaged ratio of ratios.
Inputs—(1) Averaged Ratio-of-Ratios, (2) calibration coefficients. Outputs—Saturation.
II. Pulse Rate Calculation.
E2. Lowpass Filter and Ensemble Averaging—Block E2 low pass filters and ensemble averages the signal conditioned by block A, for the pulse rate identification. The weights for the low pass filter are determined by the Signal Metrics block C. The signal is also ensemble averaged (this attenuates frequencies other than those of interest near the pulse rate and its harmonics), with the ensemble averaging filter weights also determined by Signal Metrics block C. Less weight is assigned if the signal is flagged as degraded. More weight is assigned if the signal is flagged as arrhythmic since filtering is not appropriate during arrhythmia. Red and IR are processed separately. The process of this block is delayed approximately one second to allow the signal metrics to be calculated first.
The filters use continuously variable weights. If samples are not to be ensemble-averaged, then the weighting for the previous filtered samples is set to zero in the weighted average, and the new samples are still processed through the code. This block tracks the age of the signal—the accumulated amount of filtering (sum of response times and delays in processing). Too old a result will be flagged (if good pulses haven't been detected for awhile).
Inputs—(1) pre-processed red and IR signals, (2) average pulse period, (3) Lowpass filter weights and ensemble averaging filter weights, (4) ECG triggers, if available, (5) IR fundamental, for zero-crossing triggers. Outputs—(1) filtered red and IR signals, (2) age.
I. Filtered Pulse Identification and Qualification—This block identifies and qualifies pulse periods from the filtered waveforms, and its results are used only when a pulse is disqualified by block B.
Inputs—(1) filtered red and IR signals and age, (2) average pulse period, (3) hardware ID or noise floor, (4) kind of sensor. Outputs—qualified pulse periods and age.
J. Average Pulse Periods and Calculate Pulse Rate—This block calculates the pulse rate and average pulse period.
Inputs—Qualified pulse periods and age Outputs—(1) average pulse period, (2) pulse rate.
III. Venous Pulsation
K. Detect Venous Pulsation—Block K receives as inputs the pre-processed red and IR signal and age from Block A, and pulse rate and provides an indication of venous pulsation as an output. This subsystem produces an IR fundamental waveform in the time domain using a single-tooth comb filter which is output to the Ensemble Averaging filters.
Inputs—(1) filtered red and IR signals and age, (2) pulse rate. Outputs—Venous Pulsation Indication, IR fundamental
IV. Sensor Off
L. Detect Sensor-Off and Loss of Pulse Amplitude—The Pulse Lost and Sensor Off Detection subsystem uses a pre-trained neural net to determine whether the sensor is off the patient. The inputs to the neural net are metrics that quantify several aspects of the behavior of the IR and Red values over the last several seconds. Samples are ignored by many of the oximetry algorithm's subsystems while the Signal State is not either Pulse Present or Sensor Maybe Off. The values of the Signal State variable are: “Pulse Present, Disconnect, Pulse Lost, Sensor Maybe Off, and Sensor Off.”
Inputs—(1) metrics, (2) front-end servo settings and ID Outputs—Signal state including sensor-off indication
Pulse Rate Calculation Subsystem
The subsystem averages qualified pulse periods from the Pulse Identification and Qualification subsystem. It outputs the average period and the corresponding pulse rate.
The oximetry algorithm contains two instances of this subsystem. The first instance receives input from the Pulse Identification and Qualification instance whose input waveform have been processed by the Signal Conditioning subsystem, then lowpass filtered, but not ensemble averaged, by the Ensemble Averaging subsystem. The second instance of the Pulse Rate Calculation subsystem receives input from two instances of the Pulse Identification and Qualification subsystem, the one described above and a second instance that receives input that has been ensemble averaged.
Selection of Pulse Period Source
One instance of the subsystem receives qualified pulse periods from two sources. The subsystem selects which of these two sources to use for its pulse rate calculation based solely on analysis of only one source, the “primary” source. The oximetry algorithm designates the Pulse Identification and Qualification instance that does NOT receive ensemble-averaged waveforms as the primary source, and designates the other Pulse Identification and Qualification instance as the “alternate” source of qualified pulse periods. Qualified pulse periods from the alternate source are only used if the most recent pulse from the primary source was rejected. When a qualified pulse period is received from the primary source, it is always used to update the pulse-rate calculation, and will prevent qualified pulse periods from the alternate source from being used until the primary source once again rejects a pulse period.
Calculation of Average Pulse Period and Pulse-Rate Estimate
When the subsystem uses a Qualified_Pulse_Period, it updates its average pulse period, Avg_Period, using a pulse-based, variable-weight IIR filter, then computes its Rate output from Avg_Period. The steps for this filtering operation are:
r t =(60/Δ t )/Qualified_Pulse_Period 1.
k =Consecutive_Qualified/max(| r t −r t−1 |, |r t−1 −r t−2 |, |r t−2 −r t−3 |, 1.0) 2.
x =bound(min(Avg_Period t−1 , Qualified_Pulse_Period), ¾ seconds, 2 seconds)/7 seconds 3.
If Rate_Age>10 seconds, x =min( x* Rate_Age/10 seconds, 0.3) 4.
k =max(1/Total_Qualified, min( k, x )) 5.
If Avg_Period t−1 < >0 Avg_Period t =Avg —Period t−1 *(Qualified_Pulse_Period/Avg_Period t−1 ) k 6.
If Avg_Period t−1 =0 Avg_Period t =Qualified_Pulse_Period 7.
Rate=(60/Δ t )/Avg_Period t 8.
Rate_Age=Rate_Age+ k* (Qualified_Period_Age−Rate_Age) 9.
where:
r t is the pulse rate corresponding to Qualified_Pulse_Period, in BPM the t−1 subscript denotes the previous qualified pulse. Δt is the oximetry algorithm's sample interval in seconds 60/Δt is the number of samples per minute x is a filter weight that targets a 7-second response time for typical adult pulse rates. k is the final filter weight, based on both x and the differences between consecutive values of r t . During the first few pulses, k is increased to at least 1/Total_Qualified so that the initial qualified pulses will be weighted equally.
Consecutive_Qualified is the number of consecutive qualified pulses, and Total_Qualified is the total number of pulses qualified since the subsystem was reinitialized. Both Consecutive_Qualified and Total_Qualified are incremented each time a Qualified_Pulse_Period is used, before k is calculated. Consecutive_Qualified is set to zero when a pulse is rejected by the pulse-period source currently in use.
The update formula for Avg_Period t , in step 6 above, is a geometric average of Avg_Period t , and Qualified_Pulse_Period. Geometric averaging helps to keep the subsystem responsive to large pulses-to-pulse period variations, and large, sustained changes in pulse rate.
Once Rate is initialized to a non-zero value, Rate_Age is incremented every sample, whether or not Rate is updated.
Context Diagram
FIG. 3 is a context diagram of the pulse rate calculation subsystem. The subsystem updates its Avg_Period and Rate outputs from Qualified_Pulse_Periods. It uses Qualified_Pulse_Periods from the Alternative_Period_Source only if it last received a Notify_Pulse_Rejected from the primary source. It updates its Rate_Age output based on Qualified_Period_Age. When Rate is updated, the subsystem sets its Pulse_Rate_Updated flag. The Reinitialize input tells the subsystem to reinitialize itself. Increment_Rate_Age notifies the subsystem to increment its Rate_Age every sample once Rate is initialized.
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A pulse oximeter which determines multiple heart rates, and selects between them based on the metrics of only one of the heart rate calculations. A primary heart rate calculation method is selected, and is used unless its metrics indicate questionable accuracy, in which case an alternative rate calculation is available and is used instead.
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CROSS-REFERENCE TO RELATED APPLICATIONS
This application is a U.S. national phase application of International Application No. PCT/CN2013/085854, filed on Oct. 24, 2013, which claims priority to Chinese Application No. 201310129691.0, filed on Apr. 12, 2013, the contents of which are incorporated herein by reference in their entireties.
TECHNICAL FIELD OF THE INVENTION
The present invention relates to the technical field of optical films, and in particular, to a composite optical reflective film for a backlight source system and a preparation method thereof.
BACKGROUND OF THE INVENTION
Liquid crystal display (LCD) technology is one of the most commonly used display technologies at present, and has dominated a prevailing technical position in the flat panel display field for a certain period. Liquid crystal molecules itself are not luminous, and images or characters displayed thereby are the results of modulating the light sent by the backlight source, and the backlight source is an important component determining the display performance of the liquid crystal display, and the brightness of the backlight source directly determines the display brightness on an LCD surface.
A liquid crystal backlight source system is primarily comprised of a light source, a light guide plate, various kinds of optical diaphragms and structural members. Its development tends towards the diversification of size and light-weighting, and requirement of high brightness. Current types of backlight sources mainly contain electro luminescence (EL), cold cathode fluorescent tube (CCFL), light emitting diode (LED), etc., which are divided into a side-light type and an end backlight type according to different positions thereof. Along with the development of the LCD modules, the side-light type CCFL backlight source of high brightness and thin thickness becomes a main stream. But due to its significant large power consumption, it cannot meet the requirements of energy conservation and a portable information product. Therefore, how to improve the backlight source brightness to further increase the LCD brightness without increasing the power consumption has become one of the main challenges of the development.
The major optical diaphragm of the liquid crystal backlight system comprises a reflective film of which the effect is to reflect light emitted from the light source at high efficiency without losses to a light emitting direction of the backlight source thus to reduce light losses and reach objects of raising brightness of the backlight or decreasing power consumption, a diffusion film and a brightness enhancement film.
How to improve the optical property of the reflective film to increase the reflectivity, making the light emitted by the light source be utilized to the highest degree, thereby reducing loss, is the important problem to be solved now in the art. Moreover, in actual applications, it is also required that the reflective film be stable in the ultraviolet resistant performance upon prolonged use; and when the temperature gradient is higher, the dimension deformation difference of the reflective film is small, and does not affect its assembly and use.
SUMMARY OF THE INVENTION
In order to overcome defects of lower reflectivity and easy deformation of the existing optical reflective film, the present invention provides a composite optical reflective film and a preparation method thereof. The composite optical reflective film of this invention has good dimension stability, is not easy to warp and deform, has a higher reflectivity, has a simple preparation process, and is easy to operate.
In order to solve the abovementioned technical problem, the present invention provides the following technical solution:
A composite optical reflective film, wherein the reflective film comprises a transparent diaphragm (or called a bottom transparent diaphragm, also known as a bottom diaphragm) and a reflective diaphragm having two sides, the reflective diaphragm is spliced on one side to the transparent diaphragm with an adhesive, and the other side of the reflective diaphragm is coated with a reflective coating; and the adhesive consists of a phenolic resin, an inorganic powder filler and a solvent. The adhesive forms an adhesive layer.
The thickness of the transparent diaphragm is 100-250 μm, and the thickness of the reflective diaphragm is 75-250 μm. Preferably, the thickness of the transparent diaphragm is 120-150 μm, 170-230 μm, 188 μm or 200 μm; and the thickness of the reflective diaphragm is 75-120 μm, 100-170 μm, 180-230 μm, 150 μm, 188 μm or 200 μm.
Furthermore, the reflective diaphragm is a white reflective diaphragm, and the reflective coating is an ultraviolet-resistant highly reflective coating. That is to say, the reflective coating has a higher reflectivity and an ultraviolet resistance function.
Furthermore, the material of the ultraviolet-resistant highly reflective coating comprises silane-crosslinked polyolefin, zinc oxide and/or titanium dioxide, and the content of zinc oxide and/or titanium dioxide is 50-70% (weight percentage).
Adding higher content of zinc oxide and titanium dioxide into the abovementioned ultraviolet-resistant highly reflective coating, can increase the reflective effect and improve the reflectivity. The weight ratio of titanium dioxide and zinc oxide is 2-4:1.
Furthermore, in the adhesive, the weight ratio of the phenolic resin, inorganic powder filler and solvent is 100:80-150:40-80.
The phenolic resin is preferably an thermosetting phenolic resin, further preferably a high ortho thermosetting phenolic resin; the inorganic powder filler (also called inorganic filler for short) is one of or a combination of at least two of zirconium powder, iron powder, carbon powder, boron powder, silicon powder, boron carbide and silicon carbide; the solvent is selected from ethyl acetate or ethanol. During the use, the adhesive (also called composite adhesive) can be prepared by adding the phenolic resin and the inorganic powder filler into the solvent and mixing them homogeneously at the room temperature. At the room temperature, the composite adhesive has higher bonding strength due to the polarity effect of the phenolic resin, and a stable structure which can keep the bonding strength thereof is formed in a high temperature environment because of the reaction between the inorganic filler and the phenolic resin. Therefore, the composite reflective film provided by the present invention can be resistant to high temperature. Due to effects of the adhesive and the dimensional stabilization of the bottom diaphragm, the reflective film is not easy to deform, so that a backlight module can also keep its dimension and stable mechanical performance in the temperature gradient environment.
The high ortho thermosetting phenolic resin can be prepared by the following method: reacting phenol with formaldehyde with the catalyst of the zinc oxide; and vacuum dehydrating them after the reaction is terminated, to provide the product when the gelling temperature of the system is 80° C., and the gelling time is 100-150 s; wherein the molar fraction ratio of the phenol, formaldehyde and zinc oxide may be 1:1.2-1.8:0.03-0.06.
Furthermore, the material of the white reflective diaphragm comprises polyethylene terephthalate (PET), and 10-25% of nano-modified inorganic fillers are homogeneously dispersed in the material; and the material of the bottom transparent diaphragm is selected from polycarbonate (PC), polypropylene (PP) or polyethylene terephthalate (PET).
The nano-modified inorganic filler comprises an inorganic particle, and an outer surface of the inorganic particle has a surface layer formed by the modified coating material. The inorganic particle is selected from one of or a combination of at least two of titanium dioxide, barium sulfate, calcium carbonate and zinc oxide, the modified cladding material is silicon dioxide and/or aluminum oxide, the weight of the coating material is 0.5-1% of the inorganic particle, and the percentage is the weight percentage. The material of the bottom transparent diaphragm is preferably PET, which has good mechanical performance, an appropriate thickness, a low hot-shrinkage rate, and good dimension stability.
Furthermore, 0.3% of the hindered amine photostabilizer and 0.3% of the benzotriazole ultraviolet absorbent are added in the ultraviolet-resistant highly reflective coating, and the percentage is the weight percentage. Utilizing the cooperative effect of the above-mentioned photostabilizer and the ultraviolet absorber reaches a highly-efficient ultraviolet resistant effect.
Furthermore, the material of the bottom transparent diaphragm is selected from PET, PP or PC; the adhesive consists of high ortho thermosetting phenolic resin, inorganic powder filler and solvent to form a composite adhesive; the ultraviolet-resistant highly reflective coating is the compound of silane-crosslinked polyolefin, titanium dioxide and zinc oxide; and the hindered amine photostabilizer and the benzotriazole ultraviolet absorbent are also added in the ultraviolet-resistant highly reflective coating.
Furthermore, the weight ratio of the high ortho thermosetting phenolic resin, inorganic powder filler and solvent in the composite adhesive is 100:80-150:40-80; the content of titanium dioxide and zinc oxide in the ultraviolet-resistant highly reflective coating is 50-70% (weight percentage). Preferably, the weight ratio of the high ortho thermosetting phenolic resin, inorganic powder filler and solvent in the composite adhesive is 100:80:40, 100:100:50, 100:120:60, or 100:150:80.
Furthermore, the materials of the bottom transparent diaphragm and white reflective diaphragm are PET, nano-modified titanium dioxide or barium sulfate are homogeneously dispersed within the white reflective diaphragm, and a modified cladding material is silica and/or alumina.
A preparation method of the above-mentioned composite optical reflective film, includes the following steps:
(1) providing a polyester base material, white masterbatch and foaming masterbatch, after crystallization and drying, to an extruder for melt plastification, and then to produce a cast sheet by filtration, tape casting and cooling;
(2) longitudinally stretching and transversely stretching the cast sheet prepared in step (1), with a stretching ratio of 3-4;
(3) applying a corona treatment on a stretched sheet prepared in step (2) when stretching, and activating the surface of the sheet to increase surface wetting tension to obtain a reflective diaphragm; and
(4) cutting the reflective diaphragm prepared in step (3) into narrow reflective diaphragm, coating with an adhesive after unreeling, compositing with a bottom transparent diaphragm, coating a reflective coating on the other face of the reflective diaphragm, and drying by baking to obtain the composite optical reflective film.
The abovementioned polyester base material, white masterbatch, foaming masterbatch, and bottom transparent diaphragm can be bought in the market directly, can also be self-prepared according to demands; adding the foaming masterbatch in the reflective diaphragm can improve the reflectivity thereof, reduce the diaphragm density and reduce the cost simultaneously; and the reflective coating materials and adhesive can also be self-prepared according to the raw material ratio.
Compared with the prior art, the reflective diaphragm and bottom diaphragm of the reflective film provided by the present invention have excellent dimension stability, even if at high temperature or under larger temperature gradient, the warping deformation will not occur on the diaphragm; and its ultraviolet-resistant highly reflective coating has an excellent ultraviolet resistant effect, and a high content of inorganic particles in the reflective coating can improve the reflectivity of the diaphragm, can also improve the brilliance of the backlight module assembled from the composite reflective film simultaneously. The preparation method of the reflective film is simple to process and easy to operate.
BRIEF DESCRIPTION OF THE DRAWING
FIG. 1 is a structural diagram of a composite optical reflective film provided by the present invention, wherein 1 represents an ultraviolet-resistant highly reflective coating, 2 represents a white reflective diaphragm, 3 represents an adhesive layer, and 4 represents a bottom transparent diaphragm.
DETAILED DESCRIPTION OF THE INVENTION
As shown in FIG. 1 , the present invention provides a composite optical reflective film, including a bottom transparent diaphragm 4 which is provided with a white reflective diaphragm 2 on one side thereof, wherein the white reflective diaphragm 2 is coated with an ultraviolet-resistant highly reflective coating 1 on one side and composited with the bottom transparent diaphragm 4 via an adhesive on another side, and the adhesive forms an adhesive layer 3 .
A method for preparing the composite optical reflective film of this invention comprises the following steps:
(1) providing a polyester base material, white masterbatch and foaming masterbatch, after crystallization and drying, to a single-screw extruder or a twin-screw extruder for melt plastification; after passing through a melt pipe filter, tape casting onto a chill roller through a clothes-hanger type long slot die; quickly cooling the polyester melt below a glass transition temperature on the chill roller with uniform rotation, to form a cast sheet with the uniform thickness in a glassy state;
(2) longitudinally stretching the cast sheet prepared in step (1) in a heated state by a longitudinal stretching machine with a stretching ratio of 3-4; and then entering into a transverse-stretch oven to stretch the cast sheet in a width direction with a ratio consistent with the longitudinal stretching ratio;
(3) applying a corona treatment on a stretched sheet prepared in step (2) during stretching, and activating the surface of the sheet, to increase surface wetting tension to obtain a reflective diaphragm; and
(4) cutting the reflective diaphragm prepared in step (3) into narrow reflective diaphragm, coating with an adhesive after unreeling, compositing with a bottom transparent diaphragm, coating a reflective coating on the other face of the reflective diaphragm, and drying by baking to obtain the final product (the composite optical reflective film).
The following methods are used to test performances of the composite optical reflective films:
Reflectivity: the higher the reflectivity of the film, the better the performance, a ColorQuest XE spectrophotometer produced by Hunterlab Company is adopted to test its reflectivity by an integrating sphere d/8° structure under a D65 light source condition, the reflectivity data is the weighted average value of the reflectivity of every wavelength with the interval of 10 nm at 400-700 nm, and the weighted value corresponds to an energy distribution curve of the D65 light source.
Luminance: the diaphragm is assembled respectively in a direct type and side entrance type backlight modules of 31.5 inches, and the luminance test is carried out by instrument BM-7A luminance photometer of Japan Topcon Corporation, the manufacturer of the test platform is Suzhou Fstar Scientific Instrument Co., Ltd., the model is FS-5500G, and the average luminance value for 9 points is tested under 1° of the viewing angle in 500 mm distance when the backlight is normally lighted; and three diaphragms are taken in each test, and the average value is taken after the luminance tests.
The smoothness of the film: (1) one sheet of film is cut apart to be placed on horizontal glass, and it will be suitably attached to the glass and no waviness will be seen if the smoothness is good; (2) the film is cut apart along a central axis thereof, and no gap will be observed when the two halves of films are placed against each other if the smoothness is good; and (3) the film is unfolded after winding for a period of time, and it will not be warped or crimped.
Warpage: the warpage test is carried out on the final product of film according to the GBT 25257-2010 optical functional film warpage measuring method. Three pieces of samples of A4-size are chosen for each sample to carry out the warpage test, the samples are placed on a smooth glass testing platform, and the maximum warpage height is tested by a steel ruler.
The present invention are further described in details with reference to the specific embodiments below, Tinuvin770, Tinuvin622, Tinuvin744 of Switzerland Ciba-Geigy Company or Sanol770, Sanol744 of Japan Sankyo Chemical Company and the like can be selected as the hindered amine photostabilizers (HALS) in the embodiments, and UV326, UV327, UV328, UV329 and the like can be selected as benzotriazole ultraviolet absorbers.
Example 1
A composite optical reflective film of the present invention comprised a bottom transparent diaphragm provided with a white reflective diaphragm on one side thereof, the white reflective diaphragm was coated with an ultraviolet-resistant highly reflective coating on one side and composited with the bottom transparent diaphragm by an adhesive on the other side, and an adhesive formed the adhesive layer.
The material of the bottom transparent diaphragm was hyperviscous PET (namely the PET hyperviscous material) with a thickness of 120 μm, and the thickness of the reflective diaphragm was 100 μm; the adhesive was a compound of the high ortho thermosetting phenol resin, inorganic zirconium-borosilicon powders (zirconium powders, boron powders and silicon powders were mixed according to a weight ratio of 3:1:1) and ethanol solvent, with a weight ratio of 100:120:60; the ultraviolet-resistant highly reflective coating was a compound of silane-crosslinked polyolefin, titanium dioxide and zinc oxide with a content of 50% of titanium dioxide and zinc oxide; and the ultraviolet-resistant highly reflective coating was also added with 0.3% of the hindered amine photostabilizer and 0.3% of the benzotriazole ultraviolet absorber.
Example 2
A composite optical reflective film of the present invention comprised a bottom transparent diaphragm provided with a white reflective diaphragm on one side thereof, the white reflective diaphragm was coated with an ultraviolet-resistant highly reflective coating on one side and composited with the bottom transparent diaphragm by the adhesive on the other side, and the adhesive formed the adhesive layer.
The material of the bottom transparent diaphragm was PC with a thickness of 170 μm, and the reflective diaphragm had a thickness of 120 μm; the adhesive was a compound of the high ortho thermosetting phenol resin, inorganic zirconium borosilicate powders (zirconium powders, boron powders, silica powders were mixed according to a weight ratio of 3:1:1) and an ethyl acetate solvent, with the weight ratio of 100:80:40; the ultraviolet-resistant highly reflective coating was a compound of silane-crosslinked polyolefin, titanium dioxide and zinc oxide, with the content of 60% of titanium dioxide and zinc oxide; and the ultraviolet-resistant highly reflective coating was also added with 0.3% of the hindered amine photostabilizer and 0.3% of the benzotriazole ultraviolet absorber.
Example 3
A composite optical reflective film of the present invention comprised a bottom transparent diaphragm provided with a white reflective diaphragm on one side thereof, the white reflective diaphragm was coated with an ultraviolet-resistant highly reflective coating on one side and composited with the bottom transparent diaphragm by an adhesive on the other side, and the adhesive formed adhesive layer.
The material of the bottom transparent diaphragm was PP with a thickness of 230 μm, and the thickness of the reflective diaphragm was 200 μm; the adhesive consisted of the high ortho thermosetting phenol resin, inorganic zirconium-borosilicon powders (zirconium powders, boron powders and silicon powders were mixed according to a weight ratio of 3:1:1) and ethyl acetate solvent, with a weight ratio of 100:150:80; the ultraviolet-resistant highly reflective coating was a compound of silane-crosslinked polyolefin, titanium dioxide and zinc oxide with a content of 70% of titanium dioxide and zinc oxide; and the ultraviolet-resistant highly reflective coating was also added with 0.3% of the hindered amine photostabilizer and 0.3% of the benzotriazole ultraviolet absorber.
Example 4
A composite optical reflective film of the present invention was also provided, wherein the reflective film comprised a transparent diaphragm and a reflective diaphragm, the reflective diaphragm was spliced to the transparent diaphragm through an adhesive, and the adhesive formed adhesive layer. The other face of the reflective diaphragm was coated with a reflective coating.
The material of the bottom transparent diaphragm was PC with a thickness of 100 μm, and the thickness of the reflective diaphragm was 75 μm; the adhesive was a compound of the high ortho thermosetting phenol resin, iron powders and ethyl acetate solvent, with a weight ratio of 100:150:80; the ultraviolet-resistant highly reflective coating was a compound of silane-crosslinked polyolefin, titanium dioxide and zinc oxide with a content of 60% of titanium dioxide and zinc oxide (the weight ratio of the titanium dioxide and zinc oxide was 2:1); and the ultraviolet-resistant highly reflective coating was also added with 0.3% of the hindered amine photostabilizer and 0.3% of the benzotriazole ultraviolet absorber.
Example 5
A composite optical reflective film comprised a transparent diaphragm and a white reflective diaphragm, the white reflective diaphragm was spliced to the transparent diaphragm through an adhesive, the adhesive formed adhesive layer, and the other face of the reflective diaphragm was coated with a reflective coating.
The material of the bottom transparent diaphragm was PP with a thickness of 250 μm, and the thickness of the reflective diaphragm was 250 μm; the adhesive was a compound of the high ortho thermosetting phenol resin, boron carbide, and silicon carbide (boron carbide and silicon carbide were mixed according to a weight ratio of 2:1) and ethanol solvent, with a weight ratio of 100:120:60; the ultraviolet-resistant highly reflective coating was a compound of silane-crosslinked polyolefin, titanium dioxide and zinc oxide with a content of 50% of titanium dioxide and zinc oxide (the weight ratio of titanium dioxide and zinc oxide was 3:1); and the ultraviolet-resistant highly reflective coating was also added with 0.3% of the hindered amine photostabilizer and 0.3% of the benzotriazole ultraviolet absorber.
Example 6
A composite optical reflective film comprised a transparent diaphragm and a white reflective diaphragm, the white reflective diaphragm was spliced to the transparent diaphragm through an adhesive, and the other face of the reflective diaphragm was coated with an ultraviolet-resistant highly reflective coating.
The material of the bottom transparent diaphragm was PET with a thickness of 150 μm, and the thickness of the reflective diaphragm was 150 μm; the adhesive was a compound of the high ortho thermosetting phenol resin, carbon powders and silicon powders (carbon powders and silicon powders were mixed according to a weight ratio of 3:1) and ethanol solvent, with a weight ratio of 100:80:40; the ultraviolet-resistant highly reflective coating was a compound of silane-crosslinked polyolefin, titanium dioxide and zinc oxide with a content of 50% of titanium dioxide and zinc oxide (the weight ratio of titanium dioxide and zinc oxide was 4:1); and the ultraviolet-resistant highly reflective coating was also added with 0.3% of the hindered amine photostabilizer and 0.3% of the benzotriazole ultraviolet absorber.
Example 7
A composite optical reflective film comprised a bottom transparent diaphragm and a white reflective diaphragm, the white reflective diaphragm was composited with the bottom transparent diaphragm through an adhesive, and the other face of the white reflective diaphragm was coated with an ultraviolet-resistant highly reflective coating.
The material of the bottom transparent diaphragm was PET with a thickness of 170 μm, and the thickness of the reflective diaphragm was 180 μm; the adhesive consisted of the thermosetting phenol resin, inorganic zirconium-borosilicon powders (zirconium powders, boron powders and silicon powders were mixed according to a weight ratio of 3:1:1) and ethyl acetate solvent, with a weight ratio of 100:100:50; the white reflective diaphragm had 10% of nano-modified titanium dioxide homogeneously dispersed therein, the surface modified cladding material of titanium dioxide was a mixture of silicon dioxide and aluminum oxide, and the weight of the cladding material was 1% of titanium dioxide; the ultraviolet-resistant highly reflective coating was a compound of silane-crosslinked polyolefin, titanium dioxide and zinc oxide with a content of 50% of titanium dioxide and zinc oxide; and the ultraviolet-resistant highly reflective coating was also added with the hindered amine photostabilizer and the benzotriazole ultraviolet absorber.
Example 8
A composite optical reflective film comprised a bottom transparent diaphragm and a white reflective diaphragm, the white reflective diaphragm was composited with the bottom transparent diaphragm through an adhesive, the other face of the white reflective diaphragm was coated with an ultraviolet-resistant highly reflective coating, and the adhesive formed adhesive layer.
The material of the bottom transparent diaphragm was PP with a thickness of 200 μm, and the thickness of the reflective diaphragm was 230 μm; the adhesive consisted of the high ortho thermosetting phenol resin, inorganic zirconium-borosilicon powders (zirconium powders, boron powders and silicon powders were mixed according to a weight ratio of 3:1:1) and ethyl acetate solvent, with a weight ratio of 100:80:80; the white reflective diaphragm had 25% of nano-modified barium sulfate homogeneously dispersed therein, the modified cladding material of barium sulfate was aluminum oxide, and the weight of the cladding material was 0.5% of barium sulfate; the ultraviolet-resistant highly reflective coating was a compound of silane-crosslinked polyolefin, titanium dioxide and zinc oxide with a content of 60% of titanium dioxide and zinc oxide; and the ultraviolet-resistant highly reflective coating was also added with the hindered amine photostabilizer and the benzotriazole ultraviolet absorber.
Example 9
A composite optical reflective film comprised a bottom transparent diaphragm and a white reflective diaphragm, the white reflective diaphragm was composited with the bottom transparent diaphragm through an adhesive, the other face of the white reflective diaphragm was coated with an ultraviolet-resistant highly reflective coating, and the adhesive formed adhesive layer.
The material of the bottom transparent diaphragm was PC with a thickness of 188 μm, and the thickness of the reflective diaphragm was 188 μm; the adhesive consisted of the high ortho thermosetting phenol resin, inorganic zirconium-borosilicon powders (zirconium powders, boron powders and silicon powders were mixed according to a weight ratio of 3:1:1) and ethyl acetate solvent, with a weight ratio of 100:150:60; the white reflective diaphragm had 15% of nano-modified calcium carbonate homogeneously dispersed therein, and the modified cladding material of calcium carbonate was silicon dioxide; the ultraviolet-resistant highly reflective coating was a compound of silane-crosslinked polyolefin, titanium dioxide and zinc oxide with a content of 70% of titanium dioxide and zinc oxide; and the ultraviolet-resistant highly reflective coating was also added with the hindered amine photostabilizer and the benzotriazole ultraviolet absorber.
Comparative Example 1
The composite optical reflective film was prepared according to the abovementioned method, the material of the bottom transparent diaphragm was PET with a thickness of 188 μm, and the thickness of the reflective diaphragm was 188 μm; the adhesive was epoxy resin; the white reflective diaphragm had nano-modified titanium dioxide homogeneously dispersed therein, and the modified cladding material of titanium dioxide was silicon dioxide and aluminum oxide; the ultraviolet-resistant highly reflective coating was a compound of silane-crosslinked polyolefin, titanium dioxide and zinc oxide with a content of 50% of titanium dioxide and zinc oxide; and the ultraviolet-resistant highly reflective coating was also added with the hindered amine photostabilizer and the benzotriazole ultraviolet absorber.
The composite optical reflective film selected an ordinary adhesive for usage, which had poor dimension stability. The performance test result is included in Table 1.
Comparative Example 2
The composite optical reflective film was prepared according to the abovementioned method, the material of the bottom transparent diaphragm was PET with a thickness of 188 μm, and the thickness of the reflective diaphragm was 188 μm; the adhesive consisted of the high ortho thermosetting phenol resin, borosilicon powders and ethyl acetate solvent, with a weight ratio of 100:100:50; the white reflective diaphragm had nano-modified titanium dioxide homogeneously dispersed therein, and the modified cladding material was silicon dioxide and aluminum oxide; the ultraviolet-resistant highly reflective coating was a compound of silane-crosslinked polyolefin, titanium dioxide and zinc oxide with a content of 30% of titanium dioxide and zinc oxide; and the ultraviolet-resistant highly reflective coating was also added with the hindered amine photostabilizer and the benzotriazole ultraviolet absorber.
The content of titanium dioxide and zinc oxide in the ultraviolet-resistant highly reflective coating of the reflective film was lower, and the reflective effect was poor. The performance test result is included in Table 1.
Comparative Example 3
The E6D6 type reflective film was produced by Toray Company in Japan.
TABLE 1
Performance test table of the composite optical
reflective film provided by the examples and the
comparative examples of the present invention:
Side entering
Direct
average
average
luminance
luminance
Reflective film
Reflectivity
Warpage
(cd/m 2 )
(cd/m 2 )
Example 1
98.5%
1.4 mm
4865
2675
Example 2
99.1%
0.8 mm
4923
2720
Example 3
99.7%
0.8 mm
4990
2787
Example 4
99.1%
0.8 mm
4919
2722
Example 5
98.5%
1.2 mm
4866
2667
Example 6
98.6%
1.2 mm
4865
2680
Example 7
98.4%
0.9 mm
4868
2669
Example 8
99.2%
0.8 mm
4930
2718
Example 9
99.7%
0.9 mm
4987
2779
Comparative
98.4%
2.0 mm
4866
2677
example 1
Comparative
97.8%
1.0 mm
4823
2612
example 2
Comparative
96.5%
1.9 mm
4850
2612
example 3
According to the performance test results of the reflective film in Table 1, it might be concluded that the composite optical reflective film provided by the present invention had higher reflectivity with respect to the reflective film provided by the comparative examples; according to the warpage data of comparative example 1 and comparative example 3, it might be concluded that the smoothness of the reflective film provided by the present invention was better and the warpage data was lower; and comparative example 2 used the adhesive provided by the present invention, therefore the warpage data was also lower. In the aspect of luminance, as the reflective film had been developed up to now, the improvement space for luminance was very little, and generally, improving by 2-3% was a very significant improvement. The luminance of the composite optical reflective film provided by the embodiments 1 to 9 of the present application ranged from 2667 to 2787, with the average value of 2713, which, compared with the luminance value of the reflective film provided by the comparative example 2 and comparative example 3, was improved by 3.8%. Compared with the technical solution recited in the present application, the technical solution provided by comparative example 1 just used different adhesives, so the luminance value was not obviously reduced, but the warpage data was higher. Accordingly, the composite optical reflective film provided by the present invention had better overall performances.
The above described is just the preferable embodiments of the present invention and is not intended to limit the protection scope of the present invention. All equivalent alterations and modifications made according to the present invention will fall within the scope of the claims of the present invention.
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The present invention provides a composite optical reflective film for a backlight source system and a preparation method therefor. The composite optical reflective film comprises a transparent diaphragm and a reflective diaphragm, wherein the reflective diaphragm is spliced to the transparent diaphragm through an adhesive, and the other face of the reflective diaphragm is coated with a reflective coating. The composite optical reflective film has good dimension stability, is not easy to warp and deform, has a higher reflectivity, has a simple preparation process and is easy to operate.
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CROSS-REFERENCE TO RELATED APPLICATIONS
This application is a National Phase application claiming the benefit of the international PCT Patent Application No. PCT/CA2013/050782, filed on Oct. 15, 2013, in English, which claims priority to U.S. Provisional Application No. 61/714,087, filed on Oct. 15, 2012, the entire contents of which are incorporated herein by reference.
FIELD
The present disclosure relates to an apparatus and method for making edible containers. In particular, the present disclosure relates to an apparatus and method for making edible food containers having a pocket or cavity formed therein. The present disclosure also relates to a method for filling the edible food container.
BACKGROUND
The making of edible bread containers have been in existence for a very long time. People have wrapped all sorts of foodstuffs in pliable flatbreads for centuries. As well small loaves have been sliced open or hollowed out in order to be filled with a variety of foodstuffs. These breads in effect serve to transport and contain food.
All of the above attempts have serious disadvantages. In the case of the wraps made out of flatbreads, it takes a minimum of 3 folds to achieve a tube like structure capable of containing food. However these folds still represent open seams where leakage is always a possibility. Also, certain areas in particular the bottom the wrap is several layers thick, resulting in mouthfuls of bread without any filling. Furthermore, as the bread is being eaten, the structural integrity of the tube is compromised and the contained food substances often end up in places other than the mouth.
Simply slicing a loaf of bread requires at least 3 surfaces to be cut before the bread can be opened. These are open seams for food to fall out. Consider also that since there is no cavity for the filling, the gap between the sliced bread is even wider. As well, the interior of the bread is more soft and absorbent so it provides less moisture resistance. Hollowing out the loaf may alleviate some of the aforementioned problems but it will require time, skill and a very good idea of what to do with the scrap bread.
Most edible containers being produced requires that the dough be made into flat sheets which are then cut into predetermined shapes prior to having them cooked on some supporting framework or molds. These techniques are successful in producing relatively stiff and brittle containers (ice cream cones, tacos, etc.) bearing little resemblance to bread.
Furthermore, loaf breads are made generally made by baking leavened dough on a bread pan that may or may not have walls but definitely it will have an open top. The exposed part of the dough during baking allows not only for the moisture and other gasses to escape but also for the formation of the characteristics (caramelization, color, crunchiness, etc.) of the particular crust as determined by the dough recipe. Lastly the dough is free from any compression forces preventing the loaf to rise and expand.
There are some patents that propose the use of bread dough for producing edible containers.
U.S. Pat. No. 4,656,935 describes an apparatus and method to produce oval boat-shaped buns with a central depression designed specifically for an open faced sandwich.
U.S. Pat. No. 4,313,964 uses a female form and a male form that are locked together during the cooking process with a vent port on either of the male or female form. A vent was placed at the apex of the male form to allow for the release of gases and excess dough but this vent is inadequate for gas release. It may in fact create a defect in the eventual cone at the worst possible location, its bottom. Another problem the vent poses is that during compression to coax the dough into the cone shaped cavity, the dough will more likely escape through this vent.
U.S. Pat. No. 5,336,511 describes a technique using two male molds, a forming one and a cooking one in conjunction with a female mold. The dough is first, partially cooked with the female and the male forming molds together. At this point the source of heat is from the female mold only. The male forming mold is then replaced by a heated male cooking mold and the rest of the cooking of the resultant cone is completed with both forms in place. Again this method like the previously described one fails to prevent compression of the bread during cooking and also fails to provide adequate venting of moisture.
U.S. Pat. No. 7,895,940 uses one female form and two male forms (namely, a heated mandrel and a baking insert). The method involves inserting the heated mandrel into the female form holding the dough bolus, to partially cook and to partially form the cone shape. The partially cooked dough is to retain enough of a self-supporting shape to allow the heated mandrel to be removed and replaced by the baking insert, as shown in their FIG. 6 . In this case, the guide pins with the wing nuts serve to centre the baking insert relative to the female form as well as to hold the insert off the female form to create the space for the dough to expand and for vapors to escape. The wing nuts serve to place an upper limit to the vertical movement of the insert. This is supposed to encourage the uncooked dough to expand up the sides during the final baking phase to form the shape of the end product. This, however, may be a rather haphazard means of producing the final dimension of the end product. For example, the initial partly formed cone may be torn apart during the final baking as the uncooked dough is forced up the sides. This continuous movement during the cooking process may result in the formation of various cracks, fissures and other open seams in the bread.
Therefore, it would be beneficial to provide a more uniform and consistent food container having a substantially seamless cavity (or cavities), and having less cracks and fissures. Accordingly, the present disclosure is related to a more efficient, yet simpler apparatus and method for creating edible food containers out of bread.
SUMMARY
The present disclosure provides an apparatus for making edible containers which includes a hollow female mold for holding a flowable food product and a male mold insertable into the hollow female mold. The two molds when assembled define a gap of preselected thickness so that when assembled with the food product in the female mold, the gap is filled with the food product in the shape of the final edible container produced once the food product is cooked or baked. An alignment and positioning mechanism is provide that keeps the two mold sections aligned but allows them to move with respect to each other during heating so that when the food product expands, the two molds can move with respect to each other while still keeping the two mold sections aligned with each other so the final edible container keeps its same general shape before and after cooking. Thus, an embodiment of an apparatus for making an edible container, comprises:
at least one female mold having a hollow body and an entrance into the hollow body;
at least one male mold having a body with a first end portion adapted for insertion into the hollow body of the female mold and a second end located exterior to the hollow body when the first end portion is inserted into the hollow body, the at least one female mold and the at least one male mold having a shape and size such when the at least one male mold is inserted into the at least one female mold, a gap of preselected width is formed between an inner surface of the hollow body of the female mold and an outer surface of the male mold;
an alignment and positioning mechanism for aligning the at least one female mold and the at least one male mold for assembling the at least one female mold and the at least one male mold together; and
wherein in operation, a flowable food product is placed into the hollow body of the female mold, and upon aligning and positioning the at least one male mold the male mold is inserted into the at least one female mold whereupon the at least one male mold displaces the flowable food product between the at least one female and male mold with the flowable food product located in the gap for defining a wall thickness of an edible container formed by heating the flowable food product located in the gap, and wherein, and wherein the alignment and positioning mechanism is configured to permit unrestricted movement of the at least one male and female molds with respect to each other while maintaining an alignment between the at least one male mold and the at least one female mold upon heating and expansion of the flowable food product.
A further understanding of the functional and advantageous aspects of the disclosure can be realized by reference to the following detailed description.
BRIEF DESCRIPTION OF DRAWINGS
The following is a description of the apparatus for making edible containers, reference being had to the accompanying drawings, in which:
FIG. 1 is a sectional view of an apparatus according to the present disclosure wherein a predetermined amount of dough has been placed in the outer mold (hereinafter, also referred to as a female mold), and also showing an inner mold (hereinafter, also referred to as a male mold) partially inserted;
FIG. 2 is a sectional view of an apparatus according to the present disclosure wherein the male mold is completely inserted within the female mold;
FIGS. 3 to 9 are views showing one embodiment of cooking process;
FIG. 10 is a top view of one embodiment of a female mold;
FIG. 11 is a top view of one embodiment of a male mold;
FIG. 12 is a side view of one embodiment of a female mold;
FIG. 13 is a side view of one embodiment of a male mold;
FIG. 14 is an exploded view of a set of a plurality of male and female molds;
FIG. 15 is an exploded view of an apparatus according to a first alternative embodiment of the present disclosure;
FIG. 16 is an exploded view of an apparatus according to a second alternative embodiment of the present disclosure;
FIG. 17 is an exploded view of an apparatus according to a third alternative embodiment of the present disclosure;
FIG. 18 is a side elevation view of the apparatus shown in FIG. 17 ;
FIG. 19 is a side elevation view of the apparatus of FIG. 18 , as assembled; and
FIG. 20 is a sectional view of an alternate apparatus according to the present disclosure wherein the guide pins 16 are on the male form and their corresponding holes on the female form.
DETAILED DESCRIPTION
Various embodiments and aspects of the disclosure will be described with reference to details discussed below. The following description and drawings are illustrative of the disclosure and are not to be construed as limiting the disclosure. Numerous specific details are described to provide a thorough understanding of various embodiments of the present disclosure. However, in certain instances, well-known or conventional details are not described in order to provide a concise discussion of embodiments of the present disclosure.
The figures are not to scale and some features may be exaggerated or minimized to show details of particular elements while related elements may have been eliminated to prevent obscuring novel aspects. Therefore, specific structural and functional details disclosed herein are not to be interpreted as limiting but merely as a basis for the claims and as a representative basis for teaching one skilled in the art to variously employ the present disclosure. For purposes of teaching and not limitation, the illustrated embodiments are directed to apparatuses and methods for making edible containers having a cavity or cavities formed therein.
Referring to FIG. 1 , an apparatus for making a flatbread container having a cavity according to one embodiment of the present disclosure is shown at 10 . The apparatus 10 has a female form 12 with the interior in the shape of a cone with the smaller diameter forming the bottom and ends in a dome. The larger diameter will be the top and will form the opening. If desired, non-stick coatings and other releasing agents may be used.
The apparatus 10 includes a hollow male form 14 whose exterior shape mirrors that of the interior of the female form 12 such that when the two forms 12 and 14 are assembled as facilitated by the guide pins 16 and their corresponding holes 18 , there is a resultant pre-specified volume 20 formed between forms 12 and 14 . The apparatus 10 includes flanges 22 and 24 , extending outwardly from female form 12 and male form 14 , respectively, and the guide pins 16 and their corresponding holes 18 are formed in the flanges 22 and 24 , respectively, with flange 22 being located at the top of the female form 12 and flange 24 being located at the top of male form 14 . The guide pins 16 centre the male form 14 relative to that of the female 12 and allows movement in the vertical direction while keeping the two molds aligned with each other. More specifically, the guide pins 16 serve to centre the male form 14 with respect to the female form 12 to shape and form the dough as well as to maintain the shape during cooking while allowing the dough to expand. The dimension of the end product is determined by the pre-formed dough rather than by the expansive forces of cooking. It is noted that in addition to dough, the present device is useful for any flowable food product.
In a specific embodiment disclosed herein, the guide pins 16 are shown on the flanges 22 of the female form 12 ( FIGS. 10 and 12 ) and their corresponding holes 18 shown on the flanges 24 of on the male form 14 ( FIGS. 11 and 13 ). However, these can be reversed with the same effect as shown in FIG. 20 , and the present disclosure is also related to such an alternative embodiment.
In one embodiment, the apparatus 10 includes a silicone o-ring 26 located in flange 24 around the upper open end of male mold 14 to allow for compression to initially form the dough into a uniform specific size and shape as well as to facilitate the removal of the excess dough prior to the cooking process. The silicone ring sits within an annular compartment around the peripheral upper opening of the of the male mold 14 . Silicone o-ring is not permanently attached so that silicone rings of different thicknesses may be interchanged to accommodate the different viscosities of dough being used.
Still referring to FIG. 1 , a predetermined amount of dough 28 is placed in the bottom of mold 12 , which may be slightly more than the volume of the aforementioned space defined between molds 12 and 14 such that when the male form 14 is placed in position and inserted into mold 12 , the dough completely fills the volume defined between the male and female molds. The excess dough may be trimmed off and returned to the dough vat for reuse.
One embodiment of a process for making a flat bread container of the present disclosure are shown in FIGS. 3 to 9 . The male mold 14 is lifted off to allow various gases and vapors to escape ( FIG. 3 ), and the female mold 12 is heated to the desired cooking temperature ( FIG. 4 ). When the bread is half cooked the male form 14 is put back in as the heat is removed from the female form 12 , as shown in FIGS. 5 and 6 .
The entire mold complex including both the male and female forms 14 and 12 as well as the half cooked dough is now inverted, as shown in FIG. 7 . Referring to FIGS. 8 and 9 , heat is now applied to the male form 14 to finish the cooking as the female form 12 is lifted off to allow the gases and vapors to escape. The flaring conical shape of the interior of the female form 12 , gravity and the optional use of non-stick coatings as well as releasing agents help ensure that all the half cooked bread stays on the male form 14 . A gentle tap or a shake may also allow the half cooked bread to disengage the female form 12 and stay on the male mold 14 .
Although the method described above involves a single male and a single female form, a plurality of these forms as well as automation can be used to make the process more cost effective. Referring to FIG. 14 , one embodiment of an apparatus having a plurality or array of the female forms 12 and a plurality of the male forms 14 is shown generally at 30 . In this specific embodiment, the flanges 22 on the female forms 12 at the ends of the array are provided with alignment guide pin 16 which are received into corresponding holes 18 ′ to attach the plurality of the female molds 12 to the flange 24 ′ of the male forms 14 In the embodiment shown in FIG. 14 , the flange 24 ′ on the male forms 14 may be in the form of one single tray 32 , and the holes 18 ′ are located at each corner of the tray 32 to receive the alignment pins 16 from the female mold flanges. Furthermore, the plurality of the female molds 12 may be provided with one of more optional fins 29 connecting the neighboring female molds near the downstream end thereof. Optional fins 29 may be present in order to provide more stability by holding the female forms 12 more securely. It will be appreciated that individual female and male mold forms 12 and 14 respectively may be configured so that any number of the molds may be attached to each other depending on the overall size of the mold array desired. Specifically, the flanges on each of the male and female molds may be shaped in such a way that they snap fit to flanges on several other molds in order to releasably attach them to each other.
As with the single molds described earlier, the cooking process may be carried out by forming the shaped dough product using the molds, then removing the female mold and cooking the dough on the male mold, or it may be reversed with the cooking carried out on the male form first followed by cooking on the female form.
Alternately the dough could be cooked with both the male and female forms in place with the heat applied evenly on both forms at the same time or on one form at a time. The alignment guide pins 16 in holes 18 , 18 ′ allow for molds 12 and 14 to move with respect to each other thus allowing the bread to rise and for vapors to vent especially when the male form 14 is removed once the cooking is completed and the female form 12 still has residual heat, or vice versa. Cooking of the dough can also be done by leaving it on either form (see FIG. 4 or FIG. 9 ) and baking it.
The present disclosure is also directed to an apparatus for making loaf breads having a desired pocket or cavity, into which food stuff can be filled in. Referring to FIG. 15 , one exemplary embodiment of such an apparatus is shown at 40 . The apparatus 40 includes a female baking form or mold 42 that is comprised of three separate parts A, B and C that can come apart easily and fit together with precision and a male baking form or mold 44 . In the embodiment shown in FIG. 15 , parts A, B and C of the female mold 42 have flanges 46 A, 46 B and 46 C, respectively.
The first part or part A forms the base (or the bottom of the bread) and has a pre-selected number of upright longitudinal pins 47 extending upwardly from the flange 46 A. The pins 47 are of sufficient length and diameter to prevent the other pieces of the female mold 42 from moving in any direction other than the longitudinal direction of the pins themselves. In one embodiment, there may be at least three pins 47 . For example, the embodiment shown in FIG. 15 features six longitudinal pins 47 .
The second part B of the female form 42 has the function to form one side surface of the bread, the particular side with the opening to the space within the bread. The part B has a flange 46 B with holes 48 of appropriate diameter and location to receive therein the longitudinal pins 47 of part A. Extending upwardly from one end of flange 46 B is a vertical plate 50 with an opening 51 whose perimeter mirrors the perimeter of the vertical plate 50 . The distance between the perimeter of plate 50 and the opening 51 determines the eventual dough thickness prior to baking. This thickness can be altered to any specification requirement by making the opening 51 smaller or larger. The plate 50 may also have vent holes 52 to release excess dough. The opening 51 itself will have walls extending outwards to form a hollow tube-like structure 54 which in turn will serve as a guide to center and keep centered the male form 44 when it is assembled with the female mold 42 .
The third part C of mold 42 has a flange 46 C and a top or lid section 57 , which serve to define or form the last four remaining surfaces of the bread loaf being produced. The flange 46 C also has holes 48 ′ to receive the upright pins 47 therein. The lid 57 has an entrance zone 56 , configured to be in alignment with plate 50 . The entrance zone 56 also has vent holes 52 ′ matching with the vent holes 52 of the plate 50 . The lid 57 may also have a handle 55 . When all the parts of mold 42 are assembled together the entire exterior surface of the bread dough is defined.
The hollow male mold 44 is provide with a stop 58 such that when it is fully inserted into the female form 42 , a volume with desired dimensions is formed for defined between molds 42 and 44 . The stop 58 in FIG. 15 is the base of the male form 44 , which being larger than the opening 51 prevents the male form 44 being pushed too far into female mold 42 .
The parts of the male and female molds that are in contact with the dough may have non-stick coatings applied thereto. When the three parts A, B and C of the female form 42 are completely assembled, part C may be treated with a releasing agent (as an example oil spray) as needed.
In operation, a premeasured amount of dough is placed into the female form 42 via the opening 51 , or it can be placed inside part C before part C is assembled in place with parts A and B. The male form 44 is then inserted to force the dough to be thoroughly distributed into the volume defined between forms 42 and 44 . Excess dough will be expelled out through the vent holes 52 , 52 ′ and returned to the dough mix to be reused. Prior to baking, part C is removed and to facilitate its removal without damaging or changing the shape of the dough, releasing agents may be applied and used, or the dough may be frozen.
Although the method described produces a single pocket, multi pocketed loaves can be made by using multiple male forms or using a single male form with multiple projections. One exemplary embodiment is shown in FIG. 16 , where the apparatus for making multiple pocketed loaves is generally shown at 60 . In this embodiment, the male mold 64 is similar to the male mold 44 shown in FIG. 15 , except that it is divided into two compartments 66 and 68 with a volume or space 65 formed therebetween. The volume 65 in FIG. 19 extends all the way to the base or stop 58 , thereby creating in essence two independent male forms, which provide the two separate compartments 66 and 68 . In FIG. 16 , the space 65 is shown in the horizontal position corresponding to the orientation of they assembled molds 42 and 44 in when in use, which would result in two separate pockets with one atop of the other in the final baked product. However, the male mold 44 may be configured so that the space 65 is in the vertical position and create two separate side by side pockets in the final baked product, if desired.
FIG. 16 also shows an alternate embodiment of a female mold 62 which includes part A and part B of mold 42 shown in FIG. 15 combined into a single unit. In this alternative embodiment, the female mold 62 has the first part 62 A which forms the bottom surface and one side surface of the bread loaf, while the second part 62 B forms the remaining four surfaces of the bread loaf. The first part 62 A has a pre-selected number of longitudinal pins 47 extending upwardly, with all other remaining structure similar to that of the female mold 42 part B shown in FIG. 15 . Likewise, the structure of the second part 62 B is substantially similar to that of female mold part C shown in FIG. 15 .
The present disclosure is also directed to another alternative embodiment of an apparatus for making any breads. Referring to FIGS. 17-19 the apparatus shown at 70 comprises a female baking mold 72 , a male Insert 74 , and an optional lid 76 . A single unit is shown in FIGS. 17-19 , but for economy multiple units could be strung together.
The female baking mold 72 has flange 71 to provide holes 73 for pins 77 on the male insert 74 and pins 79 on the optional lid 76 . The flange 71 is notched to facilitate easier removal of the male Insert 74 and the lid 76 . Handles may also be placed on the flange or rim of any of the parts of female baking mold 72 , the male Insert 74 and the optional lid 76 to facilitate separation.
The male Insert 74 forms the specified volume within the dough and also determines the dough thickness. These dimensions can be adjusted by using detachable sleeves 81 over the male form 74 in FIG. 17 . The detachable sleeve 81 is a larger male form which fits over the existing one to increase the size of the pocket and to decrease the thickness of the dough. The wall 80 in FIG. 17 supporting the male form can be smaller in dimension than the corresponding wall on the baking tray portion of female form 72 so that the baked product can be removed more easily. The flange 75 has pins 77 and holes 73 ′ to accommodate female baking mold 72 and the lid 76 .
The optional lid 76 acts to compress the dough to ensure it covers the male insert 74 completely. It may be vented to remove excess dough. It may also be indented to fit the opening of the baking tray of female form 72 .
In operation, a pre-measured amount of dough is put into the female baking mold 72 . Then, the male insert 74 is placed firmly over it, followed by the lid 76 if present.
In the case where the dough is high in viscosity, the female baking mold 72 may be under-filled prior to the placing of the male insert 74 into the female mold 72 . Afterwards, more dough may be added and then the lid 76 may be used to compress the dough to ensure there is total coverage and that there is no empty space under the lid 76 . Clips may be used on the flanges 71 and 75 to secure the molds 72 and 74 together firmly when needed. The lid 76 may be removed for the baking process or, if desired, the assembled molds may be flipped over and the female baking mold 72 removed instead, for the cooking process.
In the case the dough has a low viscosity, it could be placed into the baking tray 72 with the male insert 74 already in position. The use of the lid 76 for the cooking process is optional.
The method of baking using the molds disclosed herein may also be carried out by using other dough such as puff pastry dough or donut dough and even crepe batter may be used to make other products. Automation and using multiple forms would increase the cost effectiveness of the method.
A tool used for filling the female forms with dough may be provided which has almost the same cross sectional shape as the male molds but with slightly smaller dimensions to allow ease of insertion into the space. In addition, the tool may be open ended at both ends and have a top is made with two (2) hinges such that both sides can be opened to gain access to the interior to place the desired filling. The two flaps that determine the top when closed leave a space between them when closed which allows for the use of a matching spatula to close the exterior open end at the same time while withdrawing the tool, thus depositing the filling. Alternatively, the top could be left open without the flaps.
As used herein, the terms, “comprises” and “comprising” are to be construed as being inclusive and open ended, and not exclusive. Specifically, when used in this specification including claims, the terms, “comprises” and “comprising” and variations thereof mean the specified features, steps, or components are included. These terms are not to be interpreted to exclude the presence of other features, steps, or components.
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The present disclosure provides an apparatus for making edible containers which includes a hollow female mold for holding a flowable food product and a male mold insertable into the hollow female mold. The two molds when assembled define a gap of preselected thickness so that when assembled with the food product in the female mold, the gap is filled with the food product in the shape of the final edible container produced once the food product is cooked or baked. An alignment and positioning mechanism is provide that keeps the two mold sections aligned but allows them to move with respect to each other during heating so that when the food product expands, the two molds can move with respect to each other while still keeping the two mold sections aligned with each other so the final edible container keeps its same general shape before and after cooking.
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FIELD OF THE INVENTION
This invention relates to a novel group of compounds and more particularly to a novel group of compounds particularly well suited as sweeteners in edible foodstuff.
DESCRIPTION OF THE PRIOR ART
Sweetness is one of the primary taste cravings of both animals and humans. Thus, the utilization of sweetening agents in foods in order to satisfy this sensory desire is well established.
Naturally occuring carbohydrate sweeteners such as sucrose, are still the most widely used sweetening agents. While these naturally occurring carbohydrates, i.e., sugars, generally fulfill the requirements of sweet taste, the abundant usage thereof does not occur without deleterious consequence, e.g., high caloric intake and nutritional imbalance. In fact, often times the level of these sweeteners required in foodstuffs is far greater than the level of the sweetener that is desired for economic, dietetic or other functional consideration.
In an attempt to eliminate the disadvantages concomitant with natural sweeteners, considerable research and expense have been devoted to the production of artificial sweeteners, such as for example, saccharin, cyclamate, dihydrochalcone, aspartame, etc. While some of these artificial sweeteners satisfy the requirements of sweet taste without caloric input, and have met with considerable commercial success, they are not, however, without their own inherent disadvantages. For example, many of these artificial sweeteners have the disadvantages of high cost, as well as delay in the perception of the sweet taste, persistent lingering of the sweet taste, and very objectionable bitter, metallic aftertaste when used in food products.
Since it is believed that many disadvantages of artificial sweeteners, particularly aftertaste, is a function of the concentration of the sweetener, it has been previously suggested that these effects could be reduced or eliminated by combining artificial sweeteners such as saccharin, with other ingredients such as aspartame or natural sugars, such as sorbitol, dextrose, maltose, etc. These combined products, however, have not been entirely satisfactory either. Some U.S. Patents which disclose sweetener mixtures include for example, U.S. Pat. No. 4,228,198; U.S. Pat. No. 4,158,068; U.S. Pat. No. 4,154,862; and U.S. Pat. No. 3,717,477.
Accordingly, much work has continued in an attempt to develop and identify compounds that have a sweet taste and which will satisfy the need for better lower calorie sweeteners. Search continues for sweeteners that have intense sweetness, that is, deliver a sweet taste at low use levels and which will also produce enough sweetness at low levels to act as sole sweetener for most sweetener applications. Furthermore, the sweeteners sought must have good temporal and sensory qualities. Sweeteners with good temporal qualities produce a time-intensity sweetness response similar to natural sweeteners without lingering. Sweeteners with good sensory qualities lack undesirable off tastes and aftertaste. Furthermore, these compounds must be economical and safe to use.
In U.S. Pat. No. 3,798,204, L-aspartyl-O-t-butyl-L-serine methyl ester and L-aspartyl-O-t-amyl-L-serine methyl ester are described as sweet compounds having significant sweetness.
In U.S. Pat. No. 4,448,716 metal complex salts of dipeptide sweetners are disclosed. In the background of this patent a generic formula is described as an attempt to represent dipeptide sweeteners disclosed in five prior patents: U.S. Pat. No. 3,475,403; U.S. Pat. No. 3,492,131; Republic of South Africa Pat. No. 695,083 published July 10, 1969; Republic of South Africa Pat. No. 695,910 published Aug. 14, 1969; and German Pat. No. 2,054,554. The general formula attempting to represent these patents is as follows: ##STR4## wherein R represents the lower alkyls, lower alkylaryls and cycloalkyls, n stands for integers 0 through 5, R 1 represents (a) phenyl group, (b) lower alkyls, (c) cycloalkyls, (d) R 2 .
Where R 2 is hydroxy, lower alkoxy, lower alkyl, halogen, (e) (S(O) m (lower alkyl) where m is 0, 1 or 2 and provided n is 1 or 2, (f) R 3 .
Where R 3 represents an hydroxy or alkoxy and (g) single or double unsaturated cycloalkyls with up to eight carbons. These compounds also are not entirely satisfactory in producing a high quality sweetness or in producing a sweet response at lower levels of sweetener.
Dipeptides of aspartyl-cysteine and aspartylmethionine methyl esters are disclosed by Brussel, Peer and Van der Heijden in Chemical Senses and Flavour, 4, 141-152 (1979) and in Z. Lebensm. Untersuch-Forsch, 159, 337-343 (1975). The authors disclose the following dipeptides:
α-L-Asp-L-Cys(Me)-OMe
α-L-Asp-L-Cys(Et)-OMe
α-L-Asp-L-Cys(Pr)-OMe
α-L-Asp-L-Cys(i-Pr)-OMe
α-L-Asp-L-Cys(t-But)-OMe
α-L-Asp-L-Met-OMe
In U.S. Pat. No. 4,399,163 to Brennan, et al. sweeteners having the following formulas are disclosed: ##STR5## and physiologically acceptable cationic and acid addition salts thereof wherein
R a is CH 2 OH or CH 2 OCH 3 ;
R is a branched member selected from the group consisting of fenchyl, diisopropylcarbinyl, d-methyl-t-butylcarbinyl, d-ethyl-t-butyl-carbinyl, 2-methylthio-2,4-dimethyl-pentan-3-yl, di-t-butylcarbinyl, ##STR6##
In a related patent, U.S. Pat. No. 4,411,925, Brennan, et al. disclose compounds of the above general formula with R being defined hereinabove, except R a is defined as methyl, ethyl, n-propyl or isopropyl.
U.S. Pat. No. 4,375,430 to Sklavounos discloses dipeptide sweeteners which are aromatic sulfonic acid salts of L-aspartyl-D-alaninoamides or L-aspartyl-D-serinamides.
European Patent Application No. 95772 to Tsau describe aspartyl dipeptide sweeteners of the formula: ##STR7## wherein R' is alkyl of 1 to 6 carbons, and R 2 is phenyl, phenylalkenyl or cyclohexylalkenyl, wherein the alkenyl group has 1 to 5 carbons. Closely related is U.S. Pat. No. 4,439,460 to Tsau, et al. which describes dipeptide sweeteners of the formula: ##STR8## wherein n is an integer from 0 to 5, and R 1 is an alkyl, alkylaryl or alicyclic radical. Similar such compounds are described in many related patents, the major difference being the definition of R 2 .
In U.S. Pat. No. 3,978,034 to Sheehan, et al. R 2 is defined as cycloalkenyl or phenyl. U.S. Pat. No. 3,695,898 to Hill defines R 2 as a mono- or a di-unsaturated alicyclic radical. Haas, et al. in U.S. Pat. No. 4,029,701 define R 2 as phenyl, lower alkyl or substituted or unsubstituted cycloalkyl, cycloalkenyl or cycloalkadienyl, or S(O) m lower alkyl provided that n is 1 or 2 and m is 0 or 2. Closely related are U.S. Pat. Nos. 4,448,716; 4,153,737; 4,031,258; 3,962,468; 3,714,139; 3,642,491; and 3,795,746.
U.S. Pat. No. 3,803,223 to Mazur, et al. describe dipeptide sweeteners and anti-inflammatory agents having the formula: ##STR9## wherein R is hydrogen or a methyl radical and R' is a radical selected from the group consisting of alkyl, or ##STR10## wherein Alk is a lower alkylene radical, X is hydrogen or hydroxy, and Y is a radical selected from the group consisting of cyclohexyl, naphthyl, furyl, pyridyl, indolyl, phenyl and phenoxy.
Goldkamp, et al. in U.S. Pat. No. 4,011,260 describe sweeteners of the formula: ##STR11## wherein R is hydrogen or a lower alkyl radical, Alk is a lower alkylene radical and R' is a carbocyclic radical. Closely related is U.S. Pat. No. 3,442,431.
U.S. Pat. No. 4,423,029 to Rizzi describes sweeteners of the formula: ##STR12## wherein R is C 4 -C 9 straight, branched or cyclic alkyl, and wherein carbons a, b and c have the (S) configuration.
European Patent Application No. 48,051 describes dipeptide sweeteners of the formula: ##STR13## wherein
M represents hydrogen, ammonium, alkali or alkaline earth,
R represents ##STR14##
R 1 represents methyl, ethyl, propyl;
R 2 represents --OH, or CH 3 ;
* Signifies an L-optical configuration for this atom.
Dutch Patent Application No. 7207426 discloses L-aspartyl-3-fenchylalanine methyl ester as a sweetening agent.
U.S. Pat. No. 3,971,822 to Chibata, et al., disclose sweeteners having the formula: ##STR15## wherein R' is hydrogen or hydroxy, R 2 is alkyl of one to five carbon atoms, alkenyl of two to three carbon atoms, cycloalkyl of three to five carbon atoms or methyl cycloalkyl of four to six carbon atoms and Y is alkylene of one to four carbon atoms.
U.S. Pat. No. 3,907,366 to Fujino, et al. discloses L-aspartyl-aminomalonic acid alkyl fenchyl diester and its physiologically acceptable salts as useful sweeteners. U.S. Pat. No. 3,959,245 disclose the 2-methyl cyclohexyl analog of the abovementioned patent.
U.S. Pat. No. 3,920,626 discloses N-α-L-aspartyl derivatives of lower alkyl esters of O-lower-alkanoyl-L-serine, β-alanine, α-aminobutyric acid an D-β-aminobutyric acid as sweeteners.
Miyoshi, et al. in Bulletin of Chemical Society of Japan, 51, p. 1433-1440 (1978) disclose compounds of the following formula as sweeteners: ##STR16## wherein R' is H, CH 3 , CO 2 CH 4 , or benzyl and R 2 is lower alkyl or unsubstituted or substituted cycloalkyl.
European Patent Application No. 128,654 describes gem-diaminoalkane sweeteners of the formula: ##STR17## wherein m is 0 or 1, R is lower alkyl (substituted or unsubstituted), R' is H or lower alkyl, and R" is a branched alkyl, alkylcycloalkyl, cycloalkyl, polycycloalkyl, phenyl, or alkyl-substituted phenyl, and physically acceptable salts thereof.
U.S. Pat. No. 3,801,563 to Nakajima, et al. disclose sweeteners of the formula: ##STR18## wherein R' is a branched or cyclic alkyl group of 3 to 8 carbon atoms, R 2 is a lower alkyl group of 1 to 2 carbon atoms and n is a integer of 0 or 1.
European Patent Application No. 34,876 describes amides of L-aspartyl-D-amino acid dipeptides of the formula: ##STR19## wherein R a is methyl, ethyl, n-propyl or isopropyl and R is a branched aliphatic, alicyclic or heterocyclic member which is branched at the alpha carbon atoms and also branched again at one or both of the beta carbon atoms. These compounds are indicated to be of significant sweetness.
In the Journal of Medicinal Chemistry, 1984, Vol. 27, No. 12, pp. 1663-8, are described various sweetener dipeptide esters, including L-aspartyl-α-aminocycloalkane methyl esters.
The various dipeptide esters of the prior art have been characterized as lacking significant stability at low pH values and/or thermal stability. These characterstics have limited the scope of use of these sweeteners in food products which are of low pH values or are prepared or served at elevated temperatures.
Accordingly, it is desired to find compounds that provide quality sweetness when added to foodstuffs or pharmaceuticals at low levels and thus eliminate or greatly diminish the aforesaid disadvantages associated with prior art sweeteners.
SUMMARY OF THE INVENTION
The present new compounds are amides of aspartic acid and certain amines which are characterized by the presence of a thietanyl substituent and are low caloric sweeteners possessing a high order of sweetness with pleasing taste and a high order of stability to acid pH and elevated temperatures compared to known dipeptide sweeteners.
This invention provides new sweetening compounds represented by the formula: ##STR20## wherein
A is hydrogen, alkyl containing 1-3 carbon atoms, hydroxyalkyl containing 1-3 carbon atoms, alkoxymethyl wherein the alkoxy contains 1-3 carbon atoms or carbalkoxy wherein the alkoxy group contains 1-3 carbon atoms;
A' is hydrogen or alkyl containing 1-3 carbon atoms;
A and A' taken together with the carbon atom to which they are attached form cycloalkyl containing 3-4 carbon atoms;
Z is --CH 2 CH 2 --; --CH═CH; ##STR21##
Y is thietanyl or alkyl-substituted thietanyl containing up to a total of 8 carbon atoms;
B' is H or an amino protecting group with the proviso that when Z is ##STR22## B' is not H.
and food acceptable salts thereof.
DESCRIPTION OF THE PREFERRED EMBODIMENTS
In accordance with the present invention, the preferred compounds are those wherein the thietanyl moiety is substituted with at least one lower alkyl group; preferably a beta-position on the thietanyl ring, i.e., the β or β' carbon atoms. Among these the preferred are thietanyl moieties disubstituted in the beta position with alkyl groups. Particularly preferred are thietanyl groups which are alkyl substituted in the β,β and β',β' positions, i.e., tetramethyl thietanyl. Of the alkyl groups, the most preferred is methyl. Thus, preferred thietanyl groups include 2,4-dimethyl-; 2,2-dimethyl-; 2,2,4-trimethyl-; 2,4,4-trimethyl-; 4,4-dimethyl-; β-isopropyl-; β,β'-diethyl-; β-tertiarybutyl-; and 2,2,4,4-tetramethylthietanyl groups. In all cases, the thietanyl moieties may contain up to a total of 8 carbon atoms including the four ring carbon atoms. The preferred thietanyl groups are attached to the remainder of the present new compounds at the 3-position.
Also preferred are compounds in which Z is --CH 2 --CH 2 --, --CH═CH--; --CH(OH)--CH 2 -- and ##STR23## Of these, compounds in which Z is --CH═CH-- are also useful intermediates for preparing those in which Z is --CH 2 --CH 2 --. Compounds in which Z is ##STR24## are also useful intermediates for preparation of compounds in which Z is --CH(OH)--CH 2 --. When Z is ##STR25## it is preferred that B' is an amino protecting group in order to avoid any possible internal cyclization with the amino group. In both cases, such preparations are effected by known reduction techniques;
When Z is other than ##STR26## it is preferred that B' is H.
The amino protecting group representative of the substituent B' in Formula I is an electron-withdrawing protecting group. Exemplary protecting groups include COCF 3 , COOCl 3 , and CONAr--X, wherein Ar is aryl, X is NO 2 , CN, COOR", COR", SO 2 R", halo, carboxy, SO 3 H, SO 3 R", SO 2 NR"R", SO 2 NH R", SO 2 NH 2 , CONR"R", CONHR", CONH 2 , SOR", ##STR27## OR", OSO 2 R", OCF 3 , CH 2 OR", CH(OR") 2 , COCF 3 , CF 3 , CH 2 CF 3 , CCl 3 , C t F 2t+1 , and the like;
wherein
each R" is the same or different and is C 1 -C 12 alkyl and
t is an integer from 1-6.
Preferable X groups are CN, COOC 2 H 5 , COOCH 3 , SO 2 CH 3 or COCH 3 groups.
The term aryl when used hereinabove signifies a 6-10 membered aromatic ring compounds and includes phenyl, α-naphthyl, β-naphthyl and the like.
These novel compounds are effective sweetness agents when used alone or in combination with other sweeteners in an ingesta, e.g., foodstuffs or pharmaceuticals. For example, other natural and/or artificial sweeteners which may be used with the novel compounds of the present invention include sucrose, fructose, corn syrup solids, dextrose, xylitol, sorbitol, mannitol, acetosulfam, thaumatin, invert sugar, saccharin, thiophene saccharin, meta-aminobenzoic acid, metahydroxybenzoic acid, cyclamate, chlorosucrose, dihydrochalcone, hydrogenated glucose syrups, aspartame (L-aspartyl-L-phenylalanine methyl ester) and other dipeptides, glycyrrhizin and stevioside and the like. These sweeteners when employed with the sweetness agents of the present invention, it is believed, could produce synergistic sweetness responses.
Furthermore, when the sweetness agents of the present invention are added to ingesta, the sweetness agents may be added alone or with nontoxic carriers such as the abovementioned sweeteners or other food ingredients such as acidulants and natural and artificial gums. Typical foodstuffs, and pharmaceutical preparations, in which the sweetness agents of the present invention may be used are, for example, beverages including soft drinks, carbonated beverages, ready to mix beverages and the like, infused foods (e.g. vegetables or fruits), sauces, condiments, salad dressings, juices, syrups, desserts, including puddings, gelatin and frozen desserts, like ice creams, sherbets, icings and flavored frozen desserts on sticks, confections, toothpaste, mouthwash, chewing gum, cereals, baked goods, intermediate moisture foods (e.g. dog food) and the like.
In order to achieve the effects of the present invention, the compounds described herein are generally added to the food product at a level which is effective to perceive sweetness in the food stuff and suitably is in an amount in the range of from about 0.0005 to 2% by weight based on the consumed product. Greater amounts are operable but not practical. Preferred amounts are in the range of from about 0.001 to about 1% of the foodstuff. Generally, the sweetening effect provided by the present compounds are experienced over a wide pH range, e.g. 2 to 10 preferably 3 to 7 and in buffered and unbuffered formulations.
It is desired that when the sweetness agents of this invention are employed alone or in combination with another sweetner, the sweetener or combination of sweeteners provide a sucrose equivalent in the range of from about 2 weight percent to about 40 weight percent and more preferably from about 3 weight percent to about 15 weight percent in the foodstuff or pharmaceutical.
A taste procedure for determination of sweetness merely involves the determination of sucrose equivalency. Sucrose equivalence for sweeteners are readily determined. The amount of a sweetener that is equivalent to a given weight percent sucrose can be determined by having a panel of tasters taste solutions of a sweetener at known concentrations and match its sweetness to standard solutions of sucrose.
In order to prepare compounds of the present invention, several reaction schemes may be employed. The general reaction scheme involves amide formation between an acylating derivative of aspartic acid and amines of Formula II:
H.sub.2 N--C(A)(A')--Z--Y
wherein A, A', Z and Y have the same meaning as previously described. Acylating derivatives of aspartic acid are well-known and include, for example, aspartic anhydride, including mixed anhydrides with lower alkanoic acids and half-esters of aspartic acid. In the amide-forming reactions, it is preferred to employ protecting groups which preclude undesired side reactions as exemplified in the following sequence: ##STR28##
In these, group B' is an amino protecting group, B is a carboxyl protecting group and the remaining groups have the same meaning as previously described. A variety of protecting groups known in the art may be employed. Examples of many of these possible groups may be found in "Protective Groups in Organic Synthesis" by T. W. Green, John Wiley and Sons, 1981. Among the preferred groups that may be employed are benzyloxycarbonyl for B' and benzyl for B. When A includes a free hydroxy group suitable protecting groups can be employed as known in the art.
Coupling of compounds with general formula II to compounds having general formula III employs established amide-forming techniques. One such technique uses dicyclohexylcarbodiimide (DCC) as the coupling agent. The DCC method may be employed with or without additives such as 4-dimethylaminopyridine or copper(II). The DCC coupling reaction generally proceeds at room temperature, however, it may be carried out from about -20° to 50° C. in variety of solvents inert to the reactants. Thus suitable solvents include, but are not limited to, N,N-dimethylformamide, methylene chloride, toluene and the like. Preferably the reaction is carried out under an inert atmosphere such as argon or nitrogen. Coupling usually is complete within 2 hours but may take as long as 24 hours depending on reactants.
Various other amide-forming methods can be employed to prepare the desired compounds using suitable derivatives of the free-carboxy group in compounds of structure II, e.g., acid halide, mixed anhydride with acetic acid and similar derivatives. The following illustrates such methods using aspartic acid as the amino dicarboxylic acid.
One such method utilizes the reaction of N-protected aspartic anhydrides with the selected amino compound of formula III. Thus compounds of formula III can be reacted directly in inert organic solvents with L-aspartic anhydride having its amino group protected by a formyl, carbobenzloxy, or p-methoxycarbobenzloxy group which is subsequently removed after coupling to give compounds of general formula I. The N-acyl-L-aspartic anhydrides are prepared by reacting the corresponding acids with acetic anhydride in amounts of 1.0-1.2 moles per mole of the N-acyl-L-aspartic acid at 0° to 60° C. in an inert solvent. The N-acyl-L-aspartic anhydrides are reacted with preferably 1 to 2 moles of compounds of formula III in an organic solvent capable of dissolving both and inert to the same. Representative solvents are ethyl acetate, methyl propionate, tetrahydrofuran, dioxane, ethyl ether, N,N-dimethylformamide and benzene. The reaction proceeds smoothly at 0° to 30° C. The N-acyl group is removed after coupling by catalytic hydrogenation with palladium on carbon or with HBr or HCl in a conventional manner. U.S. Pat. No. 3,879,372 discloses that this coupling method can also be performed in an aqueous solvent at a temperature of -10° to 50° C. and at a pH of 4-12.
Compounds of Formula II, that is the amino compounds, can be prepared by art-recognized procedures.
In any of the previous synthetic methods the desired products are preferably recovered from reaction mixtures by crystallization. Alternatively, normal or reverse-phase chromatography may be utilized as well as liquid/liquid extraction or other means.
The desired compounds of formula I are usually obtained in the free acid form; they may also be recovered as their physiologically acceptable salts, i.e., the corresponding amino salts such as hydrochloride, sulfate, hydrosulfate, nitrate, hydrobromide, hydroiodide, phosphate or hydrophosphate; or the alkali metal salts such as the sodium, potassium, lithium, or the alkaline earth metal salts such as calcium or magnesium, as well as aluminum, zinc and like salts.
Conversion of the present new compounds of formula I into their physiologically acceptable salts is carried out by conventional means, as for example, bringing the compounds of formula I into contact with a mineral acid, an alkali metal hydroxide, an alkali metal oxide or carbonate or an alkaline earth metal hydroxide, oxide, carbonate or other complexed form.
These physiologically acceptable salts can also be utilized as sweetness agents usually having increased solubility and stability over their free forms.
It is known to those skilled in the art that the compounds of the present invention having asymmetric carbon atoms may exist in racemic or optically active forms. All of these forms are contemplated within the scope of the invention.
The compounds of the present invention have one asymmetric site, which is designated by an asterisk(*) in the formula below, and at least one pseudo-asymmetric site which is designated by a double asterisk(**): ##STR29##
There may also be asymmetric sites in Z and Y depending on the nature of the substituents. Whenever A is identical to A', the compounds of the present invention have one asymmetric site, designated by the asterisk, in the dicarboxylic acid moiety, and may have others depending upon the nature of Z and Y. Although both the D and L forms are possible, the preferred compounds are those in which the dicarboxylic acid group is in the L-configuration. Whenever the groups A' and A are different, the carbon atoms designated by the double asteriks become asymmetric centers and the compounds of the present invention will contain at least two asymmetric centers. Regardless, the configuration around each of the asymmetric sites, whenever present, may exist in either the D and L forms, and all possible stereoisomers are contemplated to be within the scope of the present invention. Since the aspartyl group is in the L-configuration, whenever an asymmetric center is present at any of the other possible asymmetric sites, the compounds of the present invention are diastereomers, which can be separated, if desired, by art-recognized techniques, as, for examples, chromatography. However, mixtures of at least two stereoisomers will also exhibit sweetness properties and are useful as sweeteners.
The following examples further illustrate the invention.
EXAMPLE 1
N-alpha-L-aspartyl-2-amino-4-(2,2,4,4-tetramethylthietan-3-yl)trans-3-butene
A. Homologation of diethylmalonate
To a stirring mixture of NaH (12.49 g, 0.52 mol) in 300 mls of anhydrous THF at 0° C. under argon, was added 50 g (0.312 mol) of diethyl malonate. The reaction stirred for 0.5 hours as hydrogen gas evolved. Once the complete formation of the anion was certain, 25.17 mls (23.09 g, 0.312 mol) of ethyl formate was added dropwise over a period of ten minutes. The solution was allowed to stir for two hours and was then quenched by the addition of 200 mls of saturated ammonium chloride. The reaction was extracted three times with 100 ml portions of diethyl ether. The organic portions were combined and washed once with saturated sodium bicarbonate, once with water, and dried over anhydrous magnesium sulfate. The ethereal solution was filtered, concentrated, and purified by flash chromatography to yield the desired product as a colorless oil.
B. 2,4-Dihydro-2,4-dimethyl-3-formylpentane
The homologated diester (25 g, 0.136 mol) was placed in a two-necked flask along with 135 mls of diethyl ether at -78° C. under argon. 5 Equivalents of methylmagnesium bromide (226 mls, 0.68 mol) was then added slowly to the well-mixed solution. The reaction stirred for two hours when 200 mls of saturated ammonium chloride was introduced to the reaction. After fifteen minutes of agitation, the mixture was extracted three times with 100 ml portions of diethyl ether. The ethereal extracts were combined and washed once with 100 mls of saturated sodium bicarbonate, and once with 100 mls of water. The organic layers were combined, dried over magnesium sulfate, filtered, and concentrated. Chromotographic purification resulted in the isolation of the desired di-carbinol.
C. 2,4-Dibromo-2,4-dimethyl-3-formylpentane
To a magnetically stirred solution of N-bromosuccinimide (28.48 g, 0.16 mol) in THF (500 mls), a solution of triphenylphosphine (41.92 g, 0.16 mol) in THF was added dropwise; and exothermic reaction resulted with a white solid separating. To this suspension, a solution of dicarbinol (12 g, 0.08 mol) in THF, was added and stirring was continued until the solid went into solution. The mixture was concentrated in vacuo and the residue was treated with water and ether. The organic layer was separated, washed with water, dried over magnesium sulfate, and concentrated to afford the desired product.
D. 1-(2,4-Dibromo-2,4-dimethyl-3-pentyl)buten-1-ol
To a magnetically stirred solution of 6.05 g (0.05 mol) of 1-bromopropene in 200 mls of Trapp mixture (THF/diethylether/pentane 4:1:1) was cooled under argon to -120° C. After ten minutes of stirring, tert-butyl lithium (59 mls, 0.001 mol) was added to the mixture. The product from the previous reaction (12.87 g, 0.045 mol) was added and stirring continued for fifteen minutes at -78° C. and for twenty minutes at room temperature. The mixture was quenched by pouring into a separatory funnel containing 0.01 mol of acetic acid, saturated sodium chloride and methylene chloride. The organic layer was separated, dried over magnesium sulfate, and concentrated to afford the desired allylic alcohol.
E. 1-(2,4-Dibromo-2,4-dimethyl-3-pentyl)-2-butenyl-1-(2,2,2-trichloroacetimidate)
A flame dried three necked flask containing a solution of 15 g (0.046 mol) of 1-(2,4-dibromo-2,4-dimethyl-3-pentyl)-2-buten-1-ol in 45 mls of anhydrous THF (1M) at 0° C. under argon was treated portionwise with a hexane slurry of 0.37 g (0.0092 mol) of potassium hydride (a 35% dispersion in mineral oil which had been washed twice with hexane). After stirring for ten minutes, hydrogen evolution ceased. The yellow alkoxide solution was transferred, via a double needle syringe, to a solution of 4.6 mls (0.046 mol) of trichloroacetonitrile in 100 mls of diethyl ether at 0° C. under argon. The resulting mixture darkened quickly and was allowed to stir at 0° C. for 2 hours. The mixture was taken up in 200 mls of 1% ethanolic hexane and shaken vigorously for two minutes. Dark insoluble material precipitated and was promptly filtered. The filtrate was then concentrated to afford the crude acetimide.
F. 2,2,2-Trichloro-N-[2-methyl-3-butenyl-4-(2,4-dibromo-2,4-dimethyl-3-pentane)-1
A solution of crude imidate (21.6 g, 0.046 mol) in 200 mls of xylene was brought to reflux and monitored by IR. After 3 hours, the isomerization was complete. Concentration in vacuo afforded the crude acetamide.
G. Preparation of 2-amino-4-(2,2,4,4-tetramethyl thietanyl)-3-butene
Sodium metal (2.12 g, 0.092 mol) was dissolved in 50 mls of anhydrous methanol and the mixture was then cooled to 0° C. Hydrogen sulfide gas was passed through the mixture until a saturated solution was obtained. Then the crude acetamide (0.046 mol) was added dropwise in methanol while continuing to allow hydrogen sulfide to pass through the reaction mixture. After the addition was complete, the reaction was stirred for two hours at 0° C., allowed to warm to room temperature and stirred overnight. After pouring the mixture into water, it was extracted with diethyl ether and the extracts washed with 1M HCL and saturated sodium chloride. After drying over magnesium sulfate, filtering and concentration resulted in the product which was used without purification.
H. Preparation of Dipeptide
To a three necked flask equipped with an overhead stirrer, was added 0.98 g (0.0046 mol) of 2-amino-3-butenyl-4-(1,1,3,3-tetramethylthietane) in 10 mls of water. The solubility of the amine was enhanced by the addition of 4 mls of THF. The flask was cooled to 0° C. and 0.80 g (0.0046 mol) of NTA was added in small portions. A pH of 11 was recorded prior to the NTA addition and decreased to a range of 8.5-9.5 during the addition. Once the addition was complete, the pH stabilized at 10.5. After 2 hours of stirring, the mixture was acidified with concentrated HCl to a pH of 4.5. The mixture was filtered through Celite, washed through with 25 mls of methanol, and concentrated in vacuo. The crude product was purified by reversed phase flash chromotography using 70% methanol-water as an eluant to afford the desired product as a white solid.
Using the foregoing procedure, the following products are obtained from corresponding starting compounds:
N-α-L-aspartyl-2-amino-2-methyl-4-(2,2,4,4-tetramethylthietan-3-yl)-trans-3-butene;
N-α-L-aspartyl-2-amino-2-methyl-4-(2,4-dimethylthietan-3-yl)-trans-3-butene;
N-α-L-aspartyl-2-amino-2-methyl-4-(2,2-dimethylthietan-3-yl)-trans-3-butene;
N-α-L-aspartyl-2-amino-2-methyl-4-(2,2,4-trimethylthietan-3-yl)-trans-3-butene;
N-α-L-aspartyl-2-amino-2-methyl-4-(2,4,4-trimethylthietan-3-yl)-trans-3-butene;
N-α-L-aspartyl-2-amino-2-methyl-4-(4,4-dimethylthietan-3-yl)-trans-3-butene;
N-α-L-aspartyl-2-amino-2-methyl-4-(β,β'-diethylthietan-3-yl)-trans-3-butene;
N-α-L-aspartyl-2-amino-2-methyl-4-(β-tertbutylthietan-3-yl)-trans-3-butene;
N-α-L-aspartyl-2-amino-4-(2,4-dimethylthietan-3-yl)-trans-3-butene;
N-α-L-aspartyl-2-amino-4-(2,2-dimethylthietan-3-yl)-trans-3-butene;
N-α-L-aspartyl-2-amino-4-(2,2,4-trimethylthietan-3-yl)-trans-3-butene;
N-α-L-aspartyl-2-amino-4-(2,4,4-trimethylthietan-3-yl)-trans-3-butene;
N-α-L-aspartyl-2-amino-4-(4,4-dimethylthietan-3-yl)-trans-3-butene;
N-α-L-aspartyl-2-amino-4-(β,β'-diethylthietan-3-yl)-trans-3-butene;
N-α-L-aspartyl-2-amino-4-(β-tertbutylthietan-3-yl)-trans-3-butene;
N-α-L-aspartyl-2-amino-1-methoxy-4-(2,2,4,4-tetramethylthietan-3-yl)-trans-3-butene;
N-α-L-aspartyl-2-amino-1-hydroxy-4-(2,2,4,4-tetramethylthietan-3-yl)-trans-3-butene;
N-α-L-aspartyl-2-amino-4-(2,2,4,4-tetramethylthietan-3-yl)-trans-3-butenoic acid methyl ester;
N-α-L-aspartyl-1-amino-1-[2-(2,2,4,4-tetramethylthietan-3-yl)-trans-ethenyl]cyclopropane.
EXAMPLE 2
N-Alpha-L-aspartyl-2-amino-4-(2,2,4,4-tetramethylthietan-3-yl)butane
Method A
The product from Part F of Example 1 is treated with H 2 gas at 45 psi over 5% Pd/C until reduction of the double bond is completed and the product is obtained from the reaction mixture by filtration and evaporation.
Method B
The crude acetamide from paragraph F, Example 1, was dissolved in 100 mls of ethanol and placed in an ultrasound bath. This vessel was then purged with argon. Cyclohexadiene (10 equiv.) was added, followed by 0.1 equivalents of 10% Pd/C. Ultrasound was commenced for one-half hour. After one half hour the reaction was completed, as indicated by TLC. The solution was filtered through Celite and concentrated to afford the desired product which was used to prepare the saturated analogue of the product from step H.
The reaction product is then converted to the dipeptide by the procedure of paragraphs 7 and 8 of Example 1.
Using these procedures, the following products are produced from the corresponding unsaturated compound.
N-α-L-aspartyl-2-amino-2-methyl-4-(2,2,4,4-tetramethylthietan-3-yl)butane;
N-α-L-aspartyl-2-amino-2-methyl-4-(2,4-dimethylthietan-3-yl)butane;
N-α-L-aspartyl-2-amino-2-methyl-4-(2,2-dimethylthietan-3-yl)butane;
N-α-L-aspartyl-2-amino-2-methyl-4-(2,2,4-trimethylthietan-3-yl)butane;
N-α-L-aspartyl-2-amino-2-methyl-4-(2,4,4-trimethylthietan-3-yl)butane;
N-α-L-aspartyl-2-amino-2-methyl-4-(4,4-dimethylthietan-3-yl)butane;
N-α-L-aspartyl-2-amino-2-methyl-4-(β,β'-diethylthietan-3-yl)butane;
N-α-L-aspartyl-2-amino-2-methyl-4-(β-tertbutylthietan-3-yl)butane;
N-α-L-aspartyl-2-amino-4-(2,4-dimethylthietan-3-yl)butane;
N-α-L-aspartyl-2-amino-4-(2,2-dimethylthietan-3-yl)butane;
N-α-L-aspartyl-2-amino-4-(2,2,4-trimethylthietan-3-yl)butane;
N-α-L-aspartyl-2-amino-4-(2,4,4-trimethylthietan-3-yl)butane;
N-α-L-aspartyl-2-amino-4-(4,4-dimethylthietan-3-yl)butane;
N-α-L-aspartyl-2-amino-4-(β,β'-diethylthietan-3-yl)butane;
N-α-L-aspartyl-2-amino-4-(β-tertbutylthietan-3-yl)butane;
N-α-L-aspartyl-2-amino-1-methoxy-4-(2,2,4,4-tetramethylthietan-3-yl)butane;
N-α-L-aspartyl-2-amino-1-hydroxy-4-(2,2,4,4-tetramethylthietan-3-yl)butane;
N-α-L-aspartyl-2-amino-4-(2,2,4,4-tetramethylthietan-3-yl)butanoic acid methyl ester;
N-α-L-aspartyl-1-amino-1-[2-(2,2,4,4-tetramethylthietan-3-yl)-ethyl]cyclopropane.
EXAMPLE 3
(2,2,4,4-Tetramethyl thietanyl) N-alpha-L-aspartyl-2-amino isobutyrate
A. N-Boc-2-amino isobutyric acid
2-amino isobutyric acid was N-Boc protected as described in the literature in 62% yield. (J. Miss. Acad. Sci. 29, 13, 1984).
B. (2,2,4,4-tetramethyl thietanyl) N-Boc-2-amino isobutyrate
The N-protected amino acid (3.7 g, 18.3 mmol) was dissolved in 1,2-dichloroethane (50 ml) at 0° C. under argon. A solution of N,N-dimethylamino pyridine (0.5 equiv.) and 2,2,4,4-tetramethyl thietanyl alcohol (1 equiv.) in 1,2-dichloroethane (10 ml) was added. Lastly, dicyclohexylcarbodiimide (1.1 equiv.) was added as a solid. After five days of stirring at room temperature, the urea was removed by filtration and the filtrate was hi-vacuum rotary evaporated and then diluted with petroleum ether (50 ml). The solution was clarified again by filtration and the filtrate was hi-vacuum rotary evaporated to a paste. Column chromatography on silica gel with 6:1 petroleum ether/ethyl acetate gave the pure product (4.4 g) in 81% yield as a white crystalline solid. The structure of the product was confirmed by 300 MHz proton and carbon NMR and FAB mass spectrometry. NMR (CDCl 3 ) δ 1.44 (s, 9H), 1.54 (s, 6H), 1.55 (d, 12H), 5.0 (s, 1H).
C. (2,2,4,4-tetramethyl thietanyl)2-Aminoisobutyrate
A fresh solution of trimethylsilyl iodide was prepared at 0° C. under argon by dissolving 1.47 g of sodium iodide in 20 ml of acetonitrile. Then 1.26 ml of trimethylsilyl chloride was added and and the mixture was stirred until a yellowish color developed over 0.5 hours. The N-Boc protected amino ester from above, 1.14 g, was dissolved in 75 ml of chloroform at 0° C. and 13.84 ml of the trimethylsilyl iodide solution was added via syringe. The reaction was stirred for 2 hours to room temperature and then quenched with 20 ml methanol and hi-vacuum rotary evaporated to a solid. The solid was washed with diethyl ether and characterized to be the ammonium iodide salt of the desired product. Yield: 1.4 g.
D. (2,2,4,4-tetramethyl thietanyl) N-Alpha-L-aspartyl-2-aminoisobutyrate
The salt from above, 360 mg, was dissolved in 6 ml of water of 0° C. and adjusted to pH 9.1 with 1N NaOH. 276 mg of N-thiocarboxy-L-aspartic acid anhydride (NTA) was added as a solid slowly while the pH was maintained at 9.0-9.2 with the addition of 1N NaOH. Upon completion of addition of the NTA the pH was adjusted as above for 3 hours. When stabilized, 3 ml of methanol was added and the solution was acidified with 2% hydrochloric acid to pH 4.5. After stirring for 0.5 hours, the mixture was hi-vacuum rotary evaporated to give 680 mg of a solid. The solid was dissolved in methanol and filtered. The filtrate was concentrated to a paste and redissolved in water and applied to an AG-1×4 acetate form ion exchange column. The product eluted with pure water and was hi-vacuum rotary evaporated to give 125 mg of a white solid. The product was characterized by FAB mass spectrometry.
Using these procedures, the following products are produced from the corresponding starting compounds.
(2,4-dimethylthietanyl) N-α-L-aspartyl-2-aminoisobutyrate;
(2,2-dimethylthietanyl) N-α-L-aspartyl-2-aminoisobutyrate;
(2,2-dimethylthietanyl) N-α-L-aspartyl-2-aminoisobutyrate;
(2,2,4-trimethylthietanyl) N-α-L-aspartyl-2-aminoisobutyrate;
(2,4,4-trimethylthietanyl) N-α-L-aspartyl-2-aminoisobutyrate;
(4,4-dimethylthietanyl) N-α-L-aspartyl-2-aminoisobutyrate;
(β,β'-diethylthietanyl) N-α-L-aspartyl-2-aminoisobutyrate;
(β-tert-butylthietanyl) N-α-L-aspartyl-2-aminoisobutyrate;
(2,2,4,4-tetramethylthietanyl) N-α-L-aspartyl-2-amino-1-hydroxymethylpropionate;
(2,2,4,4-tetramethylthietanyl) N-α-L-aspartyl-2-amino-1-methoxymethylpropionate;
(2,2,4,4-tetramethylthietanyl) N-α-L-aspartyl-1-aminocyclopropylcarboxylate.
EXAMPLE 4
A. 3,3-Diisopropyl methyl acrylate
To a dry flask under argon was added diethyl phosphono methyl acetate (1.1 equiv.) in dry benzene. Sodium hydride (60% dispersion in oil) (1.1 equiv.) was added. The solution was warmed to 60° C. until evolution of hydrogen was complete (1.5 h) and a clear mixture was obtained. Diisopropyl ketone (1 equiv.) was dissolved in dry benzene and added to the 60° C. solution from above so as to maintain a gentle reflux. After 1 hour the solution as evaporated to a paste and the residue distilled at reduced pressure to afford the desired product.
B. Gamma, gamma-dibromo diisopropyl methyl acrylate
The product from above was treated with N-bromo succinimide (2.1 equiv.) in dry carbon tetrachloride at 60° C. and when thin layer chromatography indicated no remaining starting material the solution was filtered and rotary evaporated. The oil was carried onto the next step without purification.
C. Gamma, gamma-dibromo diisopropyl methyl acrylate
The unsaturated ester from above was dissolved in a 1:1 mixture of water and dimethylformamide. The solution was treated with chromium sulfate. (A. Zurauiyah and C. E. Castro, Org. Syn. 49, 98, 1969). Aqueous ammonium sulfate workup and ether extraction followed by distillation gave the desired product.
D. Gamma, gamma-dibromo diisopropyl acetic acid
The ester from above in chloroform at 0° C. was treated with the required amount of reagent prepared as described below. A fresh solution of trimethylsilyl iodide was prepared at 0° C. under argon by dissolving 1.47 g of sodium iodide in 20 ml of acetonitrile. Then 1.26 ml of trimethylsilyl chloride was added and the mixture was stirred until a yellowish color developed over 0.5 hours. Workup was done with methanol and high vacuum rotary evaporation to give the crude product which was purified by filtration through neutral alumina with ether.
E. 2,2,4,4-Tetramethyl thietanyl acetic acid
Sodium metal (1 mol) was dissolved in dry methanol (500 ml) at 10° C., and hydrogen sulfide gas was passed through the mixture until it was saturated. The dibromo acid from above (0.33 mol) was added dropwise in methanol while containing to allow hydrogen sulfide to pass into the solution. After 2 hours at the cold temperature the reaction was stirred at room temperature overnight. After pouring into water and ether extraction the aqueous layer was acidified with dilute acetic acid and re-extracted with ether. After drying with magnesium sulfate and rotary evaporation, cooling produced a solid. This material was washed with a minimum of petroleum ether to give a low melting solid.
F. Anhydride Formation
2,2,4,4-tetramethyl thietanyl acetic acid (1 equiv.) was dissolved in dichloromethane at room temperature. Dicyclohexylcarbodiimide (0.5 equiv.) was added and the contents of the flask stirred for 3 days. The urea was removed by filtration and the filtrate was evaporated. The residue was taken up in petroleum ether and refiltered. The clarified filtrate was evaporated and distilled at 0.5 mm Hg. The product anhydride was characterized by IR spectroscopy.
G. Acylation--Decarboxylation
D-alanine (20 g) was dissolved in dimethyl formamide (400 ml) and treated with chlorotrimethylsilane (26.8 g) and stirred at room temperature (1H) until a homogeneous solution was obtained. Meanwhile, N-alpha- t butyloxycarbonyl beta- t butyl L-aspartic acid (58 g) was dissolved in a 1:1 mixture of dimethylformamide and tetrahydrofuran (880 ml), cooled to -15° C., and treated with N-methyl morpholine (22.4 ml) and isobutyl chloroformate (26.2 ml). After 10 minutes of activation the precooled solution of D-alanine silyl ester from above was added via double syringe. N-methyl morpholine (22.4 ml) was added again. The reaction was warmed to room temperature slowly and stirred for four hours then acidified to pH 2 with aqueous hydrochloric acid. The product was extracted with chloroform and washed with dilute acid and water several times. After drying with magnesium sulfate and rotary evaporation a white solid was obtained when crystallized with diethyl ether.
N-Boc-L-aspartic acid beta-t-butyl ester alpha-DL-alanine (1 equiv.) was stirred at room temperature under argon with triethylamine (3 equiv.) and N,N-dimethylamino pyridine (0.08 equiv.). The anhydride from F, above (1.5 equiv.) was added and the mixture stirred neat for 3 days. Aqueous dilute acetic acid was added and the mixture extracted with ethyl acetate. The organic layer was washed with ethyl acetate. The organic layer was washed with water and dilute sodium hydrogen carbonate. Drying with magnesium sulfate followed by rotary evaporation gave a semi-solid. Chromatography on silica gel with 2:1 petroleum ether/ethyl acetate afforded the product, N-Boc-L-aspartic acid beta-t-butyl ester alpha-DL-2-amino 4-(2,2,4,4-tetramethyl)thietanyl-3-butanone.
Similarly, using the appropriate starting materials, the following compounds were prepared:
N-Boc-L-aspartic acid-β-t-butyl ester-α-DL-2-amino-4-(2,4-dimethylthietanyl)-3-butanone;
N-Boc-L-aspartic acid-β-t-butyl ester-α-DL-2-amino-4-(2,2-dimethylthietanyl)-3-butanone;
N-Boc-L-aspartic acid-β-t-butyl ester-α-DL-2-amino-4-(2,2,4-trimethylthietanyl)-3-butanone;
N-Boc-L-aspartic acid-β-t-butyl ester-α-DL-2-amino-4-(2,4,4-trimethylthietanyl)-3-butanone;
N-Boc-L-aspartic acid-β-t-butyl ester-α-DL-2-amino-4-(4,4-dimethylthientanyl)-3-butanone;
N-Boc-L-aspartic acid- β-butyl ester-α-DL-2-amino-4-(β,β'-diethylthietanyl)-3-butanone;
N-Boc-L-aspartic acid-β-t-butyl ester-α-DL-2-amino-4-(β-t-butylthientanyl)-3-butanone;
N-Boc-L-aspartic acid-β-t-butyl ester-α-DL-2-amino-2-methyl-4-(2,2,4,4-tetramethyl)thietanyl-3-butanone;
N-Boc-L-aspartic acid-β-t-butyl ester-α-DL-2-amino-1-methoxy-4-(2,2,4,4-tetramethyl)thietanyl-3-butanone;
N-Boc-L-aspartic acid-β-t-butyl ester-α-(DL)-2-amino-1-hydroxy-4-(2,2,4,4-tetramethylthietanyl)-3-butanone;
N-Boc-L-aspartic acid-β-t-butyl ester-α-(DL)-2-amino-4-(2,2,4,4-tetramethylthietanyl)-3-oxybutanoic acid methyl ester;
N-Boc-L-aspartic acid-β-t-butyl ester-α-(DL)-1-amino-1-[(1-oxo-2-(2,2,4,4-tetramethylthietanyl)ethyl]cyclopropane.
EXAMPLE 5
N-alpha-L-aspartyl-DL-2-amino 4-(2,2,4,4-tetramethyl thietanyl) 3-butanol
The amido ketone from Paragraph G, Ex. 4, was dissolved in 95% ethanol at 0° C. Cerium trichloride (hydrate, 2 equiv.) was added and followed by the addition of sodium borohydride (2 equiv.). The milky solution was stirred for one hour to room temperature and then poured into sufficient water and ethyl acetate to break the emulsion. The organic layer was dried and rotary evaporated to give a white solid which was recrystallized with ether/petroleum ether. The pure product was characterized by FAB mass spectrometry.
The protected dipeptide was treated with 2.1 equiv. of trimethylsilyl iodide as described in Part D. The crude reaction mixture was evaporated to a paste and chromatographed on C 18 reversed phase silica with methanol and water. It was found that severe insolubility in methanol of the C 2 L-diastereomers continually precipitated them out of solution. Thus, isolation of the pure sweet dipeptide was an enrichment of the C 2 D-diastereomers.
Using these procedures, the following products are produced from the corresponding precursors.
N-α-L-aspartyl-DL-2-amino-4-(2,4-dimethylthietanyl)-3-butanol;
N-α-L-aspartyl-DL-2-amino-4-(2,2-dimethylthietanyl)-3-butanol;
N-α-L-aspartyl-DL-2-amino-4-(2,2,4-trimethylthietanyl)-3-butanol;
N-α-L-aspartyl-DL-2-amino-4-(2,4,4-trimethylthietanyl)-3-butanol;
N-α-L-aspartyl-DL-2-amino-4-(4,4-dimethylthietanyl)-3-butanol;
N-α-L-aspartyl-DL-2-amino-4-(β,β'-diethylthietanyl)-3-butanol;
N-α-L-aspartyl-DL-2-amino-4-(β-t-butylthietanyl)-3-butanol;
N-α-L-aspartyl-DL-2-amino-2-methyl-4-(2,2,4,4-tetramethylthietanyl)-3-butanol;
N-α-L-aspartyl-DL-2-amino-1-hydroxy-4-(2,2,4,4-tetramethylthietanyl)-3-butanol.
N-α-L-aspartyl-DL-2-amino-1-methoxy-4-(2,2,4,4-tetramethylthietanyl)-3-butanol;
N-α-L-aspartyl-DL-2-amino-4-(2,2,4,4-tetramethylthietanyl)-3-hydroxybutanoic acid methyl ester;
N-α-L-aspartyl-1-amino-1-[1-hydroxy-2-(2,4,4,4-tetramethylthientanyl)ethyl]cyclopropane.
All thin layer (TLC) separations were done with Analtech silica (GF) plates and Analtech reverse phase bonded plates. The preparative chromatography was performed on slurry packed flash columns employing J. T. Baker 40 um flash silica. Reversed phase C 18 silica from J. T. Baker was used for de-blocked dipeptide purification.
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This invention is directed to food sweeteners of the formula: ##STR1## wherein A is hydrogen, alkyl containing 1-3 carbon atoms, hydroxyalkyl containing 1-3 carbon atoms, alkoxymethyl wherein the alkoxy contains 1-3 carbon atoms or carbalkoxy wherein the alkoxy group contains 1-3 carbon atoms;
A' is hydrogen or alkyl containing 1-3 carbon atoms;
A and A' taken together with the carbon atom to which they are attached form cycloalkyl containing 3-4 carbon atoms;
Z is --CH 2 CH 2 --; --CH═CH; ##STR2## Y is thietanyl or alkyl-substituted thietanyl containing up to a total of 8 carbon atoms;
B' is H or an amino protecting group with the proviso that when Z is ##STR3## B' is not H; and food acceptable salts thereof.
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BACKGROUND OF THE INVENTION
[0001] 1. Field of the Invention
[0002] The present application relates to the separation of a sheet of brittle material through fluid impact, and more particularly, to crack initiation and propagation along a score line in response to the application of fluid energy applied to the brittle material.
[0003] 2. Description of Related Art
[0004] Two methods are conventionally employed for cutting or shaping a sheet of brittle material, such as a glass, amorphous glass, glass-ceramic or ceramic material, to form a piece with a desired configuration or geometry. The two methods include a mechanical-based method and a thermal-based method (e.g., laser).
[0005] The first conventional method involves mechanical scribing of the sheet by a hard device (such as a diamond or tungsten tip) to score the surface of the brittle material, which is then broken along the score line in response to a significant bending moment applied to the material. The sheet is generally bowed out-of-plane in both the horizontal and vertical (traveling) directions due to stress distribution inside the sheet. Typically, the bending moment is applied by physically bending the brittle material about the score line. However, the amount of bending movement and amount of movement of the sheet must be carefully controlled since bending can result in multiple break origins along the score line and can even result in crack out (i.e., cracks extending away from the score line). With large sheets, the degree of bow tends to increase, making the bending separation more difficult and uncontrollable. Bending also creates disturbances to the sheet shape (due to its bowed shape), with the bending process causing flattening of the sheet during the bending, and then releasing the sheet after separation. This potentially contributes significantly to sheet stress. Under worst case, bending separation will not work if the sheet bow is too high. In addition, bending separation provides an opportunity for edge rubbing to take place (especially in sheets with greater bows), which generates chips along the edges.
[0006] The second conventional technique involves laser scribing, such as described in U.S. Pat. No. 5,776,220. Typical laser scribing includes heating a localized zone of the brittle material with a continuous wave laser, and then immediately quenching the heated zone by applying the coolant, such as a gas, or a liquid such as water. The separation of laser scribed material can be achieved either by mechanical breaking using bending as with the mechanical scribing, or by a second higher energy laser beam. The use of the second higher energy laser beam allows for separation without bending. However, the separation is slow and often it is difficult to control crack propagation. The second laser beam also creates thermal checks and introduces high residual stress.
[0007] Notably, physical/mechanical contact with the sheet, such as tapping the sheet along a score line with a hard, sharp probe to promote a crack and separation, carries some risk of damage and/or chipping to the glass sheet. Further, after crack separation, there is a risk of the two newly-formed edges rubbing together and causing edge damage, such as chipping.
[0008] Therefore, the need exists for the fast, repeatable and uniform separation that allows minimized bending of a sheet of brittle material, and that minimizes manipulation of the sheet and that minimizes physical contact of a hard object with the glass sheet. The need also exists for a minimized disturbance separation that can be used during vertical forming process (on the draw) or during horizontal forming (e.g., float glass). The need also exists for reducing the twist-hackle distortion commonly associated with aggressive bend induced separation, and improve separation edge quality. The need exists for the consistent separation of a brittle material along a score line, without requiring physical bending of the material, or the introduction of extreme temperature gradients. There is a particular need for the separation of a pane from a continuously moving ribbon of brittle material within very short period of time (less than 1 second), while reducing imparted disturbances which can propagate upstream along the ribbon.
[0009] Accordingly, an apparatus and method are desired solving the aforementioned problems and having the aforementioned advantages.
SUMMARY OF THE INVENTION
[0010] The present invention provides for the fast separation of a brittle material through application of fluid (e.g., water, air) to a score line without requiring application of a bending moment and without the need for contacting the glass sheet with a hard or sharp probe, through impact loading without generating significant shear motion. The present system also provides for the fast, repeatable and uniform separation of a pane of brittle material from a continuously moving ribbon of the brittle material, while reducing the introduction of disturbances into the ribbon. The present system further allows for a separation of a sheet of brittle material which reduces twist-hackle commonly observed in aggressive bending moment induced separation, and therefore improve edge quality and reduce glass particle caused by separation. The present system can be used for separating a stationary, independent or fixed sheet of material. However, particular applicability has been found for separating a pane from a ribbon of material, and further applicability has been found for separating a pane of glass from a moving ribbon of glass.
[0011] In one aspect of the present invention, a method of separating a sheet of brittle material includes directing an energized stream of fluid against the sheet along the score line with sufficient fluid energy to initiate and propagate a crack along the score line.
[0012] In yet another aspect of the present invention, an apparatus for separating a sheet having a score line includes a fluid application device having a nozzle supported and positioned to direct energized/compressed fluid at the sheet along the score line for crack initiation and propagation along the score line.
[0013] An object of the present invention is to separate a brittle sheet, such as glass, by a single burst of air, as part of a clean and repeatable process.
[0014] Additional features and advantages of the invention are set forth in the detailed description which follows, and will be readily apparent to those skilled in the art from that description or recognized by practicing the invention as described herein. For purposes of description, the following discussion is set forth in terms of glass manufacturing. However, it is understood the invention as defined and set forth in the appended claims is not so limited, except for those claims which specify the brittle material is glass.
[0015] It is to be understood that both the foregoing general description and the following detailed description are merely exemplary of the invention, and are intended to provide an overview or framework for understanding the nature and character of the invention as claimed below. Also, the above listed aspects of the invention, as well as the preferred and other embodiments of the invention discussed and claimed below, can be used separately or in any and all combinations.
[0016] The accompanying drawings are included to provide a further understanding of the invention, and are incorporated in and constitute a part of this specification. The drawings illustrate various embodiments of the invention, and together with the description serve to explain the principles and operation of the invention. It should be noted that the various features illustrated in the figures are not necessarily drawn to scale. In fact, the dimensions may be arbitrarily increased or decreased for clarity of discussion.
DESCRIPTION OF THE DRAWINGS
[0017] FIGS. 1 and 2 are a perspective schematic view and a front view showing an apparatus for forming a ribbon of brittle material.
[0018] FIG. 3 is an enlarged view of an edge of the ribbon.
[0019] FIG. 4 is a front elevational schematic view of modified stationary apparatus.
DETAILED DESCRIPTION OF EMBODIMENTS
[0020] In the following detailed description, for purposes of explanation and not limitation, example embodiments disclosing specific details are set forth in order to provide a thorough understanding of the present invention. However, it will be apparent to one having ordinary skill in the art having had the benefit of the present disclosure, that the present invention can be practiced in other embodiments that depart from the specific details disclosed herein. Moreover, descriptions of well-known devices, methods and materials may be omitted so as not to obscure the description of the present invention.
[0021] The present apparatus and method provides for the impact induced separation of a brittle material without requiring gross bending of the brittle material. The present apparatus and method further avoids using a single high force blow with a hard object to cause crack propagation. The present apparatus and method also provides a way to control separation time and edge quality. In one configuration (see FIGS. 1-2 ), the present invention provides for the separation of a pane of a brittle material from a moving ribbon of the material, without introduction of disturbances which can propagate upstream in the ribbon. In another configuration (see FIG. 4 ), a glass sheet was cut into smaller sized sheets in a static/stationary batch-type operation. For purposes of description, the apparatus of FIG. 3 is initially set forth as separating a glass pane from a moving ribbon of glass.
[0022] FIG. 1 is a schematic diagram of glass fabrication apparatus 10 of the type typically used in the fusion process. The apparatus 10 includes a forming isopipe 12 , which receives molten glass (not shown) in a cavity 11 . The molten glass flows over the upper edges of the cavity 11 and descends along the outer sides of the isopipe 12 to a root 14 to form the ribbon of glass 20 . The ribbon of glass 20 , after leaving the root 14 , traverses fixed edge rollers 16 which engage bulbous edge portions 36 of the glass sheet 20 . The ribbon 20 of brittle material is thus formed and has a length extending from the root 14 to a terminal free end 22 . Such draw down sheet or fusion processes, are described in U.S. Pat. No. 3,338,696 (Dockerty) and U.S. Pat. No. 3,682,609 (Dockerty), and herein incorporated by reference. It is noted, however, that other types of glass fabrication apparatus can be used in conjunction with the invention, such as laminated down draw, slot draw and laminated fusion processes, as well as horizontal and float-type glass fabrication apparatus.
[0023] As the glass ribbon 20 travels down from the isopipe 12 , the ribbon changes from a supple, for example 50 millimeter thick liquid form at the root 14 , to a stiff glass ribbon of approximately 0.03 mm to 2.0 mm thickness, for example, at the terminal end 22 , and having a width of 1000 mm or greater.
[0024] A scribing assembly 40 is used to form a score line 26 on the first side 32 of the ribbon 20 . The scribing assembly 40 includes a scribe and in certain configurations, a scoring anvil. For purposes of description, the scribe and the scoring anvil are described in terms of travel on a common carriage 100 shown in FIG. 2 . The carriage 100 can be movable relative to a frame 102 , wherein the movement of the carriage can be imparted by any of a variety of mechanism including mechanical or electromechanical, such as motors, gears, rack and pinion, to match the velocity vector of the ribbon 20 . A load assembly 80 loads the glass sheet to facilitate and accelerate separation through faster crack propagation. Loads can be varied as desired for optimal results, eg., 2 pounds to 80 pounds. Preferably, the loads are at least about 0.2 lb/in (i.e., about 10 pounds per 1300 mm wide sheet) or higher such as 25-80 pounds force to assist in obtaining quick separation, such as less than 1 second or even 0.5 seconds.
[0025] As shown in FIG. 3 , fluid application device 70 is used to compress fluid and direct a stream of fluid under pressure against the unscored side of the glass sheet in alignment with the score line 76 . The stream is applied to the glass as a single burst of energized fluid, and when the air is used, is very clean and efficient. The application device 70 can be mounted on the carriage 100 or on a similar device therebelow, with the carriage 100 , scribing assembly 40 , and the fluid application device 70 being controlled by a controller 77 . The application device 70 is configured to suddenly release compressed/pressured fluid 71 towards the scored glass sheet 20 from the non-score side.
[0026] A preferred profile of the nozzle of the application device is generally a narrow rectangular slot with length parallel to the score line, although other profiles, such as a circle or oval, can be used. Notably, the length/width ratio affects the separation. The recommended range for the disclosed nozzle is between 10 and 20, and more preferably is between 15-20, with a higher ratio being generally better. Nonetheless, if the ratio is too high, it can divert the compressed fluid too much to initiate the crack. A slot length from 2″ to 6″ and a width from 0.125″ to 0.25″ were successfully used to cause an acceptably fast separation of less than 1 second in a sheet width of 1300 mm and sheet thickness of 0.7 mm. The distance between the nozzle and glass surface may be another significant parameter affecting separation. If the nozzle is too close, it can cause edge damage and sheet vibration after separation. If the nozzle is too far away, separation may not happen. However, a preferred distance may vary depending on operating parameters, the type and thickness of the glass, and related factors. In any case, edge guides or edge restraining devices are recommended to prevent a separated edge from freely moving and also from abrading an adjacent edge. It may be important that an initial burst of fluid be provided for effective separation. It is contemplated that the emitted stream could be sufficient to cause a shock wave.
[0027] As the fluid 71 hits the surface of the glass sheet 20 , a dynamic localized load is applied onto the contact area, as generally illustrated by the arrows in FIG. 3 . The resultant stress in the neighborhood of the impact area is tensile at location 74 near the score line side surface 72 and compressive at the impact side surface 73 , as schematically illustrated in FIG. 3 . The local stress leads to concentrated tensile stress at the crack tip (2-D) or the crack front (3-D). The crack propagates through the thickness of sheet and mode 1 fracture occurs when the dynamic bending stress is greater than a critical value, which results in a dynamic stress intensity factor exceeding the critical stress intensity factor in the glass sheet. The crack propagation along the score line is aided by the vibration induced by the fluid impact. High speed video process analysis clearly shows the separation of sheet without obvious visible lateral sheet motion and bending.
[0028] The stress intensity factor is generally a function of the structure and crack geometries, the applied bending stress, and the crack size. The illustrated application device ejects a stream of fluid 71 against the glass sheet 20 on a side opposite the score line 26 as the application device 70 is moved along the score line 26 , with the stream 71 having a narrow width in a direction perpendicular to the score line and potentially a slightly wider shape in a direction along the score line. It is contemplated that the fluid pressure, the duration of application, and the location and distance of device 70 may be varied along the width of the sheet 20 and/or the stream 71 may be pulsed to create optimal crack-initiating characteristics. It is contemplated that the present arrangement works best if the impact is on the opposite side of the score line because tensile stress is induced at the score line side while compressive stress is produced on the other side. It is also contemplated that tensioning the sheet makes the transition of the impact energy more efficient and therefore helps the separation.
[0029] By way of example, when the fluid 71 is a gas, such as air, a pressure of about 300 psi flowing through a nozzle opening of about 3/16″×5″ (or 1″ diameter) works well to separate glass sheet. Advantageously, gas, such as air, provides for a very clean separation process. When the fluid 71 is a liquid such as water, a pressure of about 500 psi flowing through a nozzle opening of about 1/16×4″ (or 3/16″ diameter) will work well to separate glass sheet.
[0030] FIG. 4 shows a schematic presentation of a batch process for cutting a glass sheet 20 such as for cutting a larger sheet into smaller sheets. Glass sheet 20 is held vertically by three clamps 75 from the top. Vacuum cups 76 at the bottom apply downward force to the sheet. After scoring, a pneumatic fluid application device 70 strikes the glass sheet 20 with compressed fluid, such as air, for a very short period of time from the non-scored glass side. The applicator device 70 is moved along the score line 26 to cause separation. The process/equipment variables affecting the separation can be controlled by a controller 77 operably connected to the fluid application device. The process/equipment variable include: the fluid pressure, release time, orifice profile, distance from the device to the glass surface, application location, fluid temperature and viscosity, and the downward force on the sheet. It is contemplated that these will be optimally controlled for best results in the separation process. Initial test using compressed air yielded promising results, since separation was consistent and instantaneous (less than one second) for a sheet 1300 mm wide. Initial fracture edge analysis demonstrated a pattern similar to that of other known separation processes, but there were no contact area damages.
[0031] While the invention has been described in conjunction with specific exemplary embodiments thereof, it is evident that many alternatives, modifications, and variations will be apparent to those skilled in the art in light of the foregoing description. Accordingly, the present invention is intended to embrace all such alternatives, modifications, and variations as fall within the spirit and broad scope of the appended claims.
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A sheet of brittle material, such as glass, flat or bowed, is separated along a score line by applying fluid energy (compressed gas or liquid) through a fluid applicator such as a nozzle or directional fluid motivator, into a scored sheet material. A separation time of less than 1 second is possible with smooth edge quality. The brittle material can be in the form of a moving ribbon of glass sheet or a stationary sheet. A load (tension) can be applied transverse to the score line to enhance crack propagation along the score line. A controller controls the fluid pressure, release time and other process parameters for best results, depending on material properties and structure.
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BACKGROUND OF THE INVENTION
In the alkaline refining of polymeric carbohydrates and particularly in the processing of natural products containing cellulose, hemicellulose is dissolved into the caustic solution. As used herein, the term hemicellulose should be understood to include all those organic compounds which during the course of the alkali treatment are dissolved into such a caustic solution. The hemicellulose-containing caustic liquors resulting from such treatment can usually be recirculated into the process, but the content of hemicellulose in the circulating liquor gradually increases until finally it reaches a state of equilibrium. At this stage the amount of hemicellulose entering the refining process in the alkali solution equals that removed by the refining treatment. This means that the amount of hemicellulose introduced into the process in the starting material equals that removed from the process with the refined product, with the result that refining is frustrated and the removal of hemicellulose in fact does not occur. Thus, in order for refining of the pulp to occur, hemicellulose-containing liquor must be continuously removed from the process by one means or the other, and the removal must be compensated for by the addition of a like amount of fresh alkali. The removed solution can be treated to regenerate the alkali present therein, but otherwise it must be destroyed or used for other purposes.
This process is particularly important, for example, in the manufacture of viscose products and cellulose derivatives from pulp, where, in most cases, the first step is mercerisation; that is, steeping treatment of the cellulosic material with concentrated alkali solutions which usually contain more than 17% sodium hydroxide. This treatment results in the dissolution of a major proportion of the hemicelluloses and degradation products of the pulp so that a substantially purified cellulose remains. Depending on the degree of refining of the pulp used as raw material in the viscose manufacture, the alpha cellulose content generally varies within the range 89-98% by weight, while the alpha level of unrefined bleached pulps is 85-89% by weight. If the pulp is unrefined or refined to only a small degree, its hemicellulose content is relatively high, and a greater amount of hemicellulose will become dissolved in the steeping liquor during the steeping treatment. To avoid high hemicellulose content in the steeping liquor, most manufacturers of viscose products in the past found it necessary to purify their steeping liquors by dialysis. However, such processes not only require a considerable initial investment and high operating costs, but also yield a large amount of rather dilute NaOH solution that must be concentrated for reapplication, mainly by removal of water by evaporation. Today, because of these disadvantages, only a few manufacturers of viscose products apply dialysis in the purification of their steeping liquors. In the usual case, the hemicellulose-containing liquor is recirculated in the process with only a rather small amount of alkali being taken from the steeping liquor system for use at a later stage (after removal of the fiber fragments and suspended fibers) for dissolution of xanthate which is formed by treating the alkali cellulose with carbon disulfide. Accordingly, after equilibrium has been attained, all of the hemicellulose of the pulp and the low-molecular substances formed during the course of ageing end up in the viscose.
As previously indicated, at equilibrium, the hemicellulose content of the steeping liquor will be proportional to the degree to which the pulp has been refined. For example, the use of a pulp having an alpha-cellulose content of 93-94% will result in a liquor having a hemicellulose content of about 20-25 g/l or even somewhat higher, whereas the utilization of a pulp having an alpha level of approximately 90% yields a liquor having a hemicellulose content of about 50 g/l. Such a high content of hemicellulose in the steeping liquor exercises a detrimental effect on the mercerising power of the alkali with the result that an unduly high amount of carbon disulfide is required in xanthation. Even then, the quality of the viscose may be poor. Thus, preparation of acceptable viscose by most conventional methods has been possible only from fully bleached, more-or-less refined, pulps.
In a departure from such methods, the recently developed so-called SINI process (disclosed and claimed in U.S. Pat. Nos. 3,600,379 and 3,728,330) in which the alkali cellulose is subjected to resteeping and repressing prior to xanthation by application of a steeping solution with a NaOH content lower than 15%, has proved very efficient and makes it possible to manufacture high quality viscose even from unrefined pulp. However, where unrefined pulp is employed in the process, the concentration of hemicellulose in the circulating steeping liquor will become so high that utilization of unrefined pulp is impracticable unless the hemicellulose is removed from the steeping liquor. It can be estimated that the content of hemicellulose in the two steeping liquor systems of the SINI process will rise to 100 g/l, if unrefined pulp is utilized as raw material.
SUMMARY OF THE INVENTION
Accordingly, it is an object of the present invention to provide a convenient process for removing hemicellulose from circulating caustic liquors, principally originating in the alkaline refining of pulp or viscose manufacture, so as to permit a recirculation of the caustic solution into such processes.
It is another object of the invention to remove hemicellulose from hemicellulose-containing caustic solutions by means other than dialysis.
A further object of the invention is to reduce hemicellulose content to a fraction of the initial hemicellulose in a circulating caustic solution.
A still further object of the invention is to make it possible to utilize low-alpha pulps in the manufacture of viscose, by preventing the hemicellulose content of the steeping liquor from rising to a level that would occasion disturbances.
These and other apparent objects of the present invention are accomplished by adding to a hemicellulose-containing caustic liquor, a sufficient amount of ethanol to cause the hemicellulose to precipitate from the caustic liquor, separating said precipitate from the caustic liquor and recovering a substantial purified caustic liquor.
DESCRIPTION OF THE PREFERRED EMBODIMENTS
According to the present invention the precipitation and subsequent removal of hemicellulose from a caustic liquor is carried out by adding to the liquor one or more organic compounds which are miscible with water and sodium hydroxide solutions and having a boiling point below 100°C. Included among such compounds are alcohols and ketones such as methanol and acetone, but the preferred precipitating agent will be ethanol. While the use of ethanol alone produces the best results, any of the precipitating agents described above may be mixed to cause the intended precipitation. Methanol seems to precipitate the hemicellulose at least as thoroughly as does ethanol, but the precipitate formed is more difficult to separate by centrifugation.
The amount of precipitating agent depends on how completely the hemicellulose should be removed from the caustic solution. The precipitation of hemicellulose begins with even a small addition of ethanol, for example; however, if it is desired to remove at least 2/3 of the hemicellulose present in the solution, the amount of ethanol added must be at least half of the volume of the caustic solution. If the amount of ethanol equals the volume of caustic solution, 90-95 per cent of the hemicellulose may be precipitated. In some cases, depending on the nature of the pulp, it may be necessary to employ an amount of precipitating agent twice as large as the volume of caustic solution.
The precipitated hemicellulose can be removed from the solution by ordinary techniques of separation such as, for example, filtration, sedimentation and decantation, centrifugation and the like. Owing to the finely divided precipitate, centrifugation is most appropriate although even then the most finely divided substance may not be completely removed from the solution.
The precipitation and centrifugation can be effected at any desired temperature, although tests have indicated that the results are slightly impaired when the temperature is raised from 20° to 35°C. Considerable lowering of the temperature significantly improves the separation of the hemicellulose. Thus, the results obtained at +5°C are markedly better than those noted at room temperature.
The separation of the precipitate from the mother liquor can be improved by adding flocculation aids thereto in connection with the precipitation. Any of the conventional flocculants may be used for this purpose including, for example, polyacrylamide, polyamines, polyethyleneimide and the like.
The mother liquor from which the major proportion of hemicellulose has been removed by precipitation and centrifugation, may be treated subsequently as follows: The temperature is raised as required to 20°-90°C, and the organic precipitating agent distilled off, with or without the application of reduced pressure (5-700 mmHg), and stored for reuse. At this stage, some water usually also evaporates, which is advantageous from the aspect of the process as a whole. The caustic liquor is now fully clear and contains only a minor proportion (5-40%) of the hemicellulose present prior to precipitation. The clear caustic liquor is returned to the steeping liquor system of the process; if required, it may be concentrated by addition of fresh alkali.
In a conventional viscose process, steeping is effected either in batches ("sheet steeping") or continuously ("slurry steeping"). In sheet steeping, the major proportion of the steeping liquor is recovered in a relatively pure condition ("yellow liquor") whereas the solution separated from the sheets by pressing ("press liquor") contains a large amount of various substances dissolved from the pulp. The method presented in this invention is particularly suitable for the purification of this type of liquor. Experiments have shown that the hemicellulose content in press liquor varies from 10 to 35 g/l when the alpha cellulose content of the pulp varies between 93 and 85 percent, and pure 19% NaOH solution is used in steeping. If press liquor is reused several times repeatedly for the steeping of new batches of the same pulp, the content of hemicellulose may rise to 25...150 g/l.
In slurry steeping, yellow and press liquor are usually not separated from each other in the process. However, also in slurry steeping, the content of hemicellulose in the circulating steeping liquor rises to the same level as quoted above unless significant amounts of alkali are removed from the process.
In the SINI viscose process previously alluded to, the alkali cellulose is subjected to a second steeping just before xanthation. Here the NaOH-concentration of the steeping solution is lower than 15% by weight, preferably 10-12%. However, the present invention makes it possible to purify the press or circulation liquors from both the first and second steeping stage of this process. It should be understood that usually the hemicellulose is more readily precipitated from the first steeping liquor than from the second one, owing at least in part to the higher content of NaOH in the first steeping liquor. Usually no more than about 65 per cent of the hemicellulose can be precipitated from the second steeping liquor unless the precipitation is carried out at a temperature significantly lower than normal. In the SINI process, a proportion of the alkali entering along with the alkali cellulose from the first into the second steeping liquor system, must be returned to the liquor system of the first steeping stage and in this connection it must be concentrated from the level of 10-13% by weight to 18-23%; this can be effected in part by evaporation of water in conjunction with the distillation of ethanol, and/or concentration by addition of fresh alkali prior to the precipitation of the hemicellulose. In the latter case the precipitancy of the hemicellulose improves at the same time.
The content of sodium hydroxide in the alkali solution to be purified imposes no limitation on the applicability of the method. For example, in a circulation steeping such as found in a conventional viscose process, the content of NaOH ranges from 17 to 23 per cent by weight, and in the second steeping liquor obtained in the SINI process the NaOH-content amounts to 10-15% by weight; however, the present invention is applicable also in conjunction with the manufacture of other types of cellulose derivatives, such as cellulose ethers, in which case the NaOH-content of the steeping solution may be considerably higher, even 40 percent by weight.
The major proportion of the hemicellulose in the circulation steeping liquor of a conventional viscose process and in the first steeping liquor of the SINI process is gamma cellulose, whereas the hemicellulose of the second SINI-liquor consists mainly of beta cellulose. Both types of hemicellulose, and particularly that obtained from the second steeping stage, are well adapted to recirculation into the viscose process. In such case ethanol, for example, should first be removed by distillation, followed by dissolution of the remaining alkaline hemicellulose precipitate into water or dilute alkali and utilization of the resulting solution in the dissolution of xanthate to yield viscose.
The following examples will further illustrate the invention.
EXAMPLE 1.
Dissolving pulp with an alpha cellulose content of 93.4% was mercerised in sheet form at 25°C for 60 minutes utilizing a NaOH solution containing 19% NaOH by weight and 10.7 g/l hemicellulose. The yellow liquor was drained off and the press liquor recovered. The NaOH content of the press liquor was 17.4% and hemicellulose content 23.3 g/l. Ethanol was added at room temperature to this press liquor in ratios 1:1 and 1:1.5 and the precipitates formed were separated from the solutions by centrifugation for 15 seconds at a rotation speed of 2000 rpm, the average radius being 12 cm. After separation of the precipitate from the mother liquor, the ethanol was distilled off the mother liquor at a temperature of 30°C and a pressure of 10 mmHg. Some water was removed from the solution along with the ethanol and consequently the NaOH content of the alkali solution rose to 22-23%. It was found that 76% and 63% of the hemicellulose was precipitated when the ratio of the press liquor to ethanol was 1:1 and 1.5:1 respectively.
EXAMPLE 2.
The alkali cellulose from Example 1 was aged at 25°C for 42 hours, and subsequently resteeped with NaOH solution which contained 11.2% NaOH by weight and 12.8 g/l of hemicellulose. The yellow liquor was drained off and the press liquor recovered. It contained 20.5 g/l of hemicellulose and 10.7% NaOH by weight. This liquor was mixed with ethanol in ratios 1.5:1, 1:1 and 1:1.5 and the precipitates formed were separated from the mother liquor by centrifugation for 15 seconds at a rotation speed of 5000 rpm. In these experiments, 55.7, 63.9 and 75.6% of the hemicellulose in the press liquors was removed.
EXAMPLE 3.
NaOH solution of 50% concentration was added to the press liquor from Example 2, which contained 10.7% NaOH by weight and 20.5 g/l of hemicellulose, thus raising the NaOH content of the solution to 18.5% by weight. The hemicellulose content was then 19.7 g/l. This solution was mixed with ethanol in ratios 1.5:1 and 1:1 and the hemicellulose precipitated was separated as in Example 2. In these experiments, 60.2% and 72.2% respectively, of the hemicellulose was precipitated indicating that a greater proportion of the hemicellulose is precipitated at a higher NaOH concentration.
EXAMPLE 4.
A sample of circulation steeping liquor was taken from a rayon staple plant where a slurry steeping process is applied. The NaOH content of the steeping liquor was 18.4% by weight and it contained 51.8 g/l of hemicellulose. In the precipitation experiments the steeping liquor:ethanol ratios were as follows: 2:1, 1.5:1, 1:1, 1:1.5 and 1:2. The hemicellulose precipitated was removed from the mother liquor by centrifugation for 15 seconds at a rotation speed of 2000 rpm. The results are given in Table 1.
Table 1______________________________________Steeping Liquor/ Hemicellulose NaOH content afterethanol removed distillation of ethanol______________________________________vol/vol % % 2:1 60.3 22.51.5:1 79.3 22.2 1:1 82.7 23.61:1.5 84.4 23.6 1:2 83.5 24.7______________________________________
EXAMPLE 5
Bleached unrefined softwood sulphate pulp (alpha cellulose content 85.2%) was steeped in sheet form with 21% NaOH solution for 1 hour at 25°C. The press liquor recovered contained 19.2% of NaOH by weight and 30.3 g/l of hemicellulose. After aging for 48 hours at 35°C the alkali cellulose was resteeped with 12% NaOH solution. The press liquor recovered contained 12.2% of NaOH and 16.6 g/l of hemicellulose. The press liquors from both steepings were treated separately as described in Example 1. The results are presented in Table 2.
Table 2______________________________________ Press liquor/ ethanol Centrifuging Precipitated vol/vol rpm sek %______________________________________Press liquor 1 2:1 2000 15 72.3 1.5:1 2000 15 81.6 1:1 2000 15 88.7 1:1.5 2000 15 85.0 2:1 5000 15 74.9 1.5:1 5000 15 83.6 1:1 5000 15 93.9 1:1.5 5000 15 86.8Press liquor 2 1.5:1 5000 15 26.2 1:1 5000 15 73.1 1:1.5 5000 15 62.8______________________________________
These results indicate that in all series of experiments the highest percentage of hemicellulose was precipitated at the press liquor:ethanol ratio 1:1.
Unless otherwise indicated, all expressions of percentages or amounts used herein are to be on a weight basis.
The invention may be embodied in other specific forms without departing from the spirit or essential characteristics thereof. The present embodiments are therefore to be considered in all respects as illustrative and not restrictive, the scope of the invention being indicated by the appended claims rather than by the foregoing description, and all changes which come within the meaning and range of equivalency of the claims are therefore intended to be embraced within.
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Hemicellulose is removed from hemicellulose containing caustic solutions by adding thereto a sufficient amount of ethanol to precipitate the hemicellulose. The caustic solutions are generally obtained in the manufacture of viscose products or, more broadly, in processing natural products containing cellulose.
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CROSS REFERENCE TO RELATED APPLICATIONS
[0001] Applicant claims priority under 35 U.S.C. §119(e) of provisional U.S. Patent Application Ser. No. 60,814,755 filed on Jun. 19, 2006, which is incorporated by reference herein.
FIELD OF INVENTION
[0002] An apparatus to lock the threaded rod of any tool employing a threaded rod axially disposed with a cylindrical structure circumferentially enveloping at least a portion of the threaded rod, wherein the threaded rod is used to adjust the clearance between the gripping means of the tool.
STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT
[0003] No federal funds were used to develop or create the invention disclosed and described in the patent application.
REFERENCE TO SEQUENCE LISTING, A TABLE, OR A COMPUTER PROGRAM LISTING COMPACT DISK APPENDIX
[0004] Not Applicable
BRIEF DESCRIPTION OF THE DRAWINGS
[0005] FIG. 1 provides a side view of a first embodiment of the present invention.
[0006] FIG. 2 provides a detailed, partial cutaway view of a portion of the rod handle of the first embodiment of the present invention.
[0007] FIG. 3 provides a detailed, partial cutaway view of a portion of the rod handle of a second embodiment of the present invention.
[0008] FIG. 4 provides a detailed, perspective view of the threaded rod used with the second and third embodiments of the present invention.
[0009] FIG. 5 provides a side view of a third embodiment of the present invention.
[0010] FIG. 6 provides a detailed view of the distal end of the rod handle of the third embodiment of the present invention.
[0011] FIG. 7A provides a cross-sectional view of the rod handle showing the engagement ball in the third embodiment seated in an axial groove of the threaded rod.
[0012] FIG. 7B provides a cross-sectional view of the rod handle showing the engagement ball in the third embodiment not seated in an axial groove of the threaded rod.
[0000]
DETAILED DESCRIPTION - LISTING OF ELEMENTS
Element Description
Element Number
Gripping Tool
1
Engagement Surface
2
Threaded Rod
3
Threaded Rod Grip
4
Screw
5
Rod Handle
6
Non-Rod Handle
7
Threaded Chamber
8
Intentionally Left Blank
9
Axial Groove
10
Engagement Ball
11
Jaw Release Lever
12
Jaw Clearance
13
Spring Mechanism
14
Spring Band
15
Annular Groove
16
DETAILED DESCRIPTION
[0013] The invention described herein provides an improvement to adjustable gripping tools. The invention provides a means to lock the threaded rod 3 of any tool employing a threaded rod 3 axially disposed with a cylindrical structure circumferentially enveloping at least a portion of the threaded rod 3 , wherein the threaded rod 3 is used to adjust the clearance between the engagement surfaces 2 of the gripping tool 1 . In the specific embodiments disclosed and described herein, the present invention has been applied to the structure disclosed in U.S. Pat. No. 2,641,149, but as noted above, the present invention applies to the entire class of tools employing a threaded rod 3 axially disposed with a cylindrical structure circumferentially enveloping at least a portion of the threaded rod 3 wherein the threaded rod is used to adjust the jaw clearance 13 , and is not limited by the specific embodiments described and disclosed herein.
[0014] Referring now to the drawings, wherein similar reference numerals designate similar or identical elements, FIG. 1 shows a first embodiment of the present invention. The embodiment employs a screw 5 mounted on the handle through which the threaded rod 3 passes, which handle is hereinafter referred to as the rod handle 6 , to adjust the jaw clearance 13 , as is well known in the prior art. As shown in FIG. 2 , the rod handle 6 is fitted with a threaded chamber 8 that is oriented transverse with respect to the threaded rod 3 . The screw 5 passes through the threaded chamber 8 and engages the threaded rod 3 when the screw 5 is tightened, so that the screw 5 locks the position of the threaded rod 3 and does not allow the threaded rod 3 to rotate. The threaded rod grip 4 is positioned at the distal end of the threaded rod 3 and provides the user interface for rotating the threaded rod 3 . Once the jaw clearance 13 has been set (by adjusting the position of the threaded rod 3 ) and the gripping tool 1 has been engaged with the object desired to be gripped, the jaw release lever 12 may be used to release the engagement surface 2 from the gripped object, as is well known in the prior art.
[0015] As shown in FIGS. 1 and 2 , the threaded chamber 8 is positioned towards the interior portion of the gripping tool 1 and extends from the rod handle 6 towards the non-rod handle 7 so that it is protected from foreign objects on one side by the rod handle 6 and on the opposite side by the non-rod handle 7 . In the specific embodiment shown in FIG. 2 , the end of the screw 5 which engages the threaded rod 3 is blunt. However, in alternative embodiments that end of the screw 5 may be pointed, and the pitch of the point may be fashioned to emulate the pitch of the threads on the threaded rod 3 so that when the screw 5 is fully engaged with the threaded rod 3 , the screw 5 does not damage the threads on the threaded rod 3 . The opposite end of the screw 5 , which provides the user interface, is fashioned to allow the user to tighten and loosen the screw 5 easily as needed. This end of the screw 5 may be fashioned so that the user may tighten and loosen the screw with the user's bar hands, or it may be fashioned so that another tool is needed to securely tighten the screw 5 . The screw 5 is of such an axial dimension as to not interfere with the operation of the rod handle 6 and non-rod handle 7 when the jaw clearance 13 is at the minimum allowed by the gripping tool 1 and the engagement surfaces 2 are in the locked position. When the threaded rod 3 is set for a desired jaw clearance 13 , the screw 5 may then be tightened to engage the threaded rod 3 so that the threaded rod 3 does not rotate. Therefore, the jaw clearance 13 remains constant even after a plurality of engagements and disengagements of the gripping tool 1 with the gripping target. The jaw clearance 13 will remain constant when the screw 5 is engaged with the threaded rod 3 regardless of the tool being moved, inadvertent attempts by the user to rotate the threaded rod 3 , or changes in the environment of the type that would normally cause the threaded rod 3 to rotate a certain amount (resulting in a change in the jaw clearance 13 ), such as placement in and removal from a tool storage device, or any other stimuli that might cause jaw clearance 13 to change. When the screw 5 is engaged with the threaded rod 3 , the threaded rod 3 will not rotate until the screw 5 has been loosened and disengaged from the threaded rod 3 .
[0016] In the second and third embodiments, shown in FIGS. 3 and 5 in which the present invention has again been applied to the gripping tool 1 disclosed in U.S. Pat. No. 2,641,149, an engagement ball 11 in cooperation with axial groove 10 fashioned in the threaded rod 3 is employed to prevent the threaded rod 3 from inadvertently being rotated. The threaded rod 3 , shown in detail in FIG. 4 , is fashioned with a plurality of axial groves 10 disposing a radial portion of the threads on the threaded rod 3 at predetermined circumferential positions around the periphery of the threaded rod 3 . In the embodiment shown in FIGS. 7A and 7B , the threaded rod 3 is fashioned with an axial groove 10 every ninety degrees, in another embodiment the threaded rod 3 is fashioned with an axial groove 10 every one hundred eighty degrees, but the present invention is not limited by the number or location of axial grooves 10 fashioned in the threaded rod 3 . As seen in FIG. 3 , in the second embodiment the engagement ball 11 is mounted on the rod handle 6 and biased in the radial direction towards the threaded rod 3 by a spring mechanism 14 . As see in FIG. 6 , in the third embodiment the engagement ball 11 is biased in the radial direction towards the threaded rod 3 by a spring band 15 . Any biasing means known to those skilled in the art may be used to bias the engagement ball 11 towards the threaded rod 3 , and therefore the scope of the present invention is not limited by choice of biasing means.
[0017] The number and location of axial grooves 10 fashioned in the threaded rod 3 and the threads of the threaded rod 3 may cooperate so that the rotation of the threaded rod 3 from one axial groove 10 to an adjacent axial groove 10 will affect the jaw clearance 13 by a predetermined amount at a constant pressure of the engagement surfaces 2 on the item to be gripped. For example, in one embodiment, the threads and the axial grooves 10 on the threaded rod 3 could be fashioned so that rotating the threaded rod 3 from one axial groove 10 to the adjacent axial groove 10 caused the jaw clearance to change by 1/32 of an inch at an engagement surface 2 pressure of 100 pounds per square inch. This type of embodiment will be especially useful in applications where the user of the gripping tool 1 uses the gripping tool 1 to grip objects of known thicknesses. This is one example of an infinite number of embodiments of this type, and modifications and variations will occur without departing from the spirit and scope of the present invention. The present invention extends to any arrangement of axial grooves 10 and threads on a threaded rod 3 of a gripping tool 1 wherein the rotation of the threaded rod 3 from one axial groove 10 to an adjacent axial groove 10 changes the jaw clearance 13 by a predetermined amount at a given engagement surface 2 pressure on the gripped object.
[0018] In the second embodiment, as shown in FIG. 3 , the disclosed biasing means is an enclosed spring mechanism 14 mounted on the interior side of the rod handle 6 . The spring mechanism 14 directly communicates with the engagement ball 11 to bias the engagement ball 11 radially towards the threaded rod 3 . The spring mechanism 14 urges the engagement ball 11 to seat within an axial groove 10 fashioned in the threaded rod 3 .
[0019] In the third embodiment as shown in FIGS. 5 , 6 , 7 A, and 7 B, the biasing means is a spring band 15 circumferentially engaging at least the axial portion of the rod handle 6 in which the engagement ball 11 is positioned. The spring band 15 communicates directly with the engagement ball 11 by biasing it radially towards the threaded rod 3 . The spring band 15 may be made flush with the rod handle 6 by fashioning an annular groove 16 in the rod handle 6 having the same axial and radial dimensions as the spring band 15 .
[0020] In the third embodiment, the engagement ball 11 communicates with the threaded rod 3 through a hole in the distal portion of the rod handle 6 , as easily may be seen in FIG. 6 . The hole in the rod handle 6 may be fashioned so that if the threaded rod 3 is entirely removed from the rod handle 6 the engagement ball 11 will not be dislodged, yet also allow the engagement ball 11 to move in a radial direction towards the threaded rod 3 by an amount sufficient to ensure the engagement ball 11 will adequately seat within an axial groove 10 . In an arrangement not shown, the second embodiment may also employ a hole through the distal portion of the rod handle 6 , and the hole in the rod handle 6 may be fashioned to achieve the same functionality as described above for the third embodiment. In that arrangement, the spring mechanism 14 would be located further (in a radial direction) from the threaded rod 3 when compared to the location of the spring mechanism 14 as shown in FIG. 3 .
[0021] In both the second and third embodiments, when the engagement ball 11 is rotationally aligned with an axial groove 10 in the threaded rod 3 (as shown for the third embodiment in FIG. 7A ), the biasing means acts on the engagement ball 11 and forces the engagement ball 11 to seat in the axial groove 10 . To unseat the engagement ball 11 from the axial groove 10 , the threaded rod 3 must be turned with enough force to overcome the radial biasing force that the biasing means places on the engagement ball 11 and the relevant frictional forces. As is readily apparent, the threaded rod 3 will require less force to rotate when the engagement ball 11 is not seated in one of the axial grooves 10 (i.e., when the engagement ball 11 is engaged with the threads of the threaded rod as shown for the third embodiment in FIG. 7B ) than the force required to rotate the threaded rod 3 when the engagement ball 11 is seated in an axial groove 10 . The extra force required to rotate the threaded rod 3 when the engagement ball 11 is seated in an axial groove 10 ensures the threaded rod 3 will not be inadvertently rotated if the gripping tool 1 or the threaded rod grip 4 is accidentally contacted by the user or another object. If the rotational force applied to the threaded rod grip 4 is large enough to overcome the biasing force the biasing means communicates to the engagement ball 11 in the radial direction when seated in an axial groove 10 and the relevant frictional forces, the engagement ball 11 will be dislodged from the axial groove 10 . The threaded rod 3 may then more easily be rotated until the engagement ball 11 is again rotationally aligned with an axial groove 10 , at which point the engagement ball 11 will again seat within the axial groove 10 . While the engagement ball 11 is seated in one of the axial grooves 10 , the jaw clearance 13 for the locked position of the gripping tool 1 will remain constant since the threaded rod 3 will not rotate without dislodging the engagement ball 11 from an axial groove 10 .
[0022] The amount of force the biasing means communicates to the engagement ball 11 will vary depending on the particular embodiment, according to the application for which the gripping tool 1 is designed. Therefore, the amount of force the biasing means communicate to the engagement ball 11 (and subsequently, the amount of rotational force required to dislodge the engagement ball 11 from an axial groove 10 in which the engagement ball 11 is seated) in no way limits the scope of the present invention. Additionally, the specific dimensions and/or shape of the axial grooves 10 formed in the threaded rod 3 in no way limit the scope of the present invention. The present invention includes an embodiment of axial grooves 10 in which the axial grooves 10 are fashioned so that more rotational force is required to rotate the threaded rod 3 when the engagement ball 11 is seated within an axial groove 10 than when the engagement ball 11 is not seated within an axial groove.
[0023] The radial biasing force placed on the engagement ball 11 by the biasing means may be predetermined to such a quantity so that a plurality of engagements and disengagements of the gripping tool 1 , normal wear and tear, placement and removal of the gripping tool 1 in a storage container, transporting the gripping tool 1 , or any other contemplated stimulus will not change the jaw clearance 13 , while simultaneously allowing the threaded rod 3 to be rotated without the assistance of another tool. That is, the biasing force communicated to the engagement ball 11 by the biasing means may be adjusted to whatever value is convenient for a particular application; and this includes a value that allows the user to rotate the threaded rod 3 with the user's bare hands. In this way, the second and third embodiments prevent the threaded rod 3 from being inadvertently rotated. The second and third embodiments also prevent the jaw clearance 13 from drifting (i.e., any inadvertent change in the jaw clearance 13 over time that result from use of the gripping tool 1 ) as typically caused by normal engagement and disengagement of the gripping tool 1 , or any other variables which might cause unwanted rotation of the threaded rod 3 . Because the threaded rod 3 in several embodiments of the present invention may be adjusted with the user's bare hands and does not require additional tools or adjustments to other moving parts to secure the position of the threaded rod 3 , unlike previous designs, the present invention secures the position of the threaded rod 3 while still retaining the ease of purposeful adjustment of the threaded rod 3 that is available in tools not employing the present invention.
[0024] The present invention applies to any and all tools that use a threaded rod 3 to adjust the jaw clearance 13 , including but not limited to lockable pliers, C-clamps, rod hangers with threaded engagement surfaces 2 , and the like.
[0025] It should be noted that the present invention is not limited to the specific embodiments pictured and described herein, but is intended to apply to all similar apparatuses for securing the jaw clearance 13 of gripping tools 1 . Modifications and alterations from the described embodiments will occur to those skilled in the art without departure from the spirit and scope of the present invention.
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A gripping tool is disclosed. The gripping tool comprises a rod handle having a first and second end, wherein said rod handle first end is coupled to an engagement surface, and wherein said rod handle second end is adapted to receive an adjustment means; a non-rod handle having a first and second end, wherein said non-rod handle first end is coupled to an engagement surface, wherein said non-rod handle second end provides a user interface, and wherein said non-rod handle is engaged to and movable relative to said rod handle; and a securing means adapted to secure the position of said adjustment means, wherein said securing means engages said adjustment means in a manner different than the manner in which said rod handle receives said adjustment means, and wherein said adjustment means controls the distance between said engagement surfaces.
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CLAIM FOR PRIORITY
This application is a divisional of U.S. Ser. No. 10/693,584, filed Oct. 24, 2003 which claims priority from U.S. Ser. No. 60/421,359 filed Oct. 25, 2002 and U.S. Ser. No. 60/421,486 filed Oct. 25, 2002.
TECHNICAL FIELD
This document relates to late transition metal catalysts for olefin oligomerizations and to methods for making and using these catalysts.
BACKGROUND OF THE INVENTION
Alpha-olefins, especially those containing 6 to 20 carbon atoms, are important items of commerce. They are used as intermediates in the manufacture of detergents, as monomers (especially in linear low-density polyethylene), and as intermediates for many other types of products. Consequently, improved methods of making these compounds are desired. Especially desired, is a process capable of making a range of linear α-olefins such as 1-butene and 1-hexene.
Most commercially produced α-olefins are made by the oligomerization of ethylene, catalyzed by various types of compounds, see for instance B. Elvers, et al., Ed. Ullmann's Encyclopedia of Industrial Chemistry, Vol. A13, VCH Verlagsgesellschaft mbH, Weinheim, 1989, p. 243-247 and 275-276, and B. Cornils, et al., Ed., Applied Homogeneous Catalysis with Organometallic Compounds, A Comprehensive Handbook, Vol. 1, VCH Verlagsgesellschaft mbH, Weinheim, 1996, p. 245-258. The major types of commercially used catalysts are alkylaluminum compounds, certain nickel-phosphine complexes, and a titanium halide with a Lewis acid such as AlCl 3 . In all of these processes, significant amounts of branched internal olefins and diolefins are produced. Since in most instances these are undesirable and often difficult to separate, these byproducts are avoided commercially.
SUMMARY
Invention catalyst systems, suitable for solution- or slurry-phase oligomerization reactions to produce α-olefins, comprise a Group-8, -9, or -10 transition metal component (catalyst precursor) and an activator. Invention catalyst precursors can be represented by the general formula:
where M is a Group-8, -9, or -10 transition metal, especially Fe, Co and Ni; N is nitrogen; P is phosphorus; Y is a hydrocarbyl bridge in which four or more carbon atoms connect between the nitrogen and phosphorus atoms; R 1 , R 2 , R 3 and R 4 are independently hydrocarbyl radicals such as C 1 -C 40 aliphatic radicals, C 3 -C 40 alicyclic radicals, C 6 -C 40 aromatic radicals or combinations of these; X is independently a hydride radical, a hydrocarbyl radical, or hydrocarbyl-substituted organometalloid radical; or two X's are connected and form a 3 to 50 atom metallacycle ring. When Lewis-acid activators such as methylalumoxane, aluminum alkyls, alkylaluminum alkoxides or alkylaluminum halides that are capable of donating an X ligand, as described above, to the transition metal component are used, or when the ionic activator is capable of extracting X, one or more X, which may optionally be bridged to one another, may additionally be independently selected from a halogen, alkoxide, aryloxide, amide, phosphide or other anionic ligand, provided that the resulting activated catalyst contains as least one M-H or M-C bond into which an olefin can insert.
DEFINITIONS
The term “hydrocarbyl radical” is sometimes used interchangeably with “hydrocarbyl” throughout this document. For purposes of this disclosure, “hydrocarbyl radical” encompasses C 1 -C 50 radicals. These radicals can be linear, branched, or cyclic, and when cyclic, aromatic or non-aromatic. Thus, the term “hydrocarbyl radical”, in addition to unsubstituted hydrocarbyl radicals, encompasses substituted hydrocarbyl radicals, halocarbyl radicals, and substituted halocarbyl radicals, as these terms are defined below.
Substituted hydrocarbyl radicals are radicals in which at least one hydrogen atom has been substituted with at least one functional group such as NR″ 2 , OR″, PR″ 2 , SR″, BR″ 2 , SiR″ 3 , GeR″ 3 and the like or where at least one non-hydrocarbon atom or group has been inserted within the hydrocarbyl radical, such as O, S, NR″, PR″, BR″, SiR″ 2 , GeR″ 2 , and the like, where R″ is independently a hydrocarbyl or halocarbyl radical. The functional group can be an organometalloid radical.
Halocarbyl radicals are radicals in which one or more hydrocarbyl hydrogen atoms have been substituted with at least one halogen or halogen-containing group (e.g. F, Cl, Br, I).
Substituted halocarbyl radicals are radicals in which at least one hydrocarbyl hydrogen or halogen atom has been substituted with at least one functional group such as NR″ 2 , OR″, PR″ 2 , SR″, BR″ 2 , SiR″ 3 , GeR″ 3 and the like or where at least one non-carbon atom or group has been inserted within the halocarbyl radical such as O, S, NR″, PR″, BR″, SiR″ 2 , GeR″ 2 , and the like where R″ is independently a hydrocarbyl or halocarbyl radical provided that at least one halogen atom remains on the original halocarbyl radical. The functional group can be an organometalloid radical.
In some embodiments, the hydrocarbyl radical is independently selected from methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl, octadecyl, nonadecyl, eicosyl, heneicosyl, docosyl, tricosyl, tetracosyl, pentacosyl, hexacosyl, heptacosyl, octacosyl, nonacosyl, triacontyl, propenyl, butenyl, pentenyl, hexenyl, heptenyl, octenyl, nonenyl, decenyl, undecenyl, dodecenyl, tridecenyl, tetradecenyl, pentadecenyl, hexadecenyl, heptadecenyl, octadecenyl, nonadecenyl, eicosenyl, heneicosenyl, docosenyl, tricosenyl, tetracosenyl, pentacosenyl, hexacosenyl, heptacosenyl, octacosenyl, nonacosenyl, triacontenyl, propynyl, butynyl, pentynyl, hexynyl, heptynyl, octynyl, nonynyl, decynyl, undecynyl, dodecynyl, tridecynyl, tetradecynyl, pentadecynyl, hexadecynyl, heptadecynyl, octadecynyl, nonadecynyl, eicosynyl, heneicosynyl, docosynyl, tricosynyl, tetracosynyl, pentacosynyl, hexacosynyl, heptacosynyl, octacosynyl, nonacosynyl, or triacontynyl isomers. For this disclosure, when a radical is listed it indicates that radical type and all other radicals formed when that radical type is subjected to the substitutions defined above. Alkyl, alkenyl and alkynyl radicals listed include all isomers including where appropriate cyclic isomers, for example, butyl includes n-butyl, 2-methylpropyl, 1-methylpropyl, tert-butyl, and cyclobutyl (and analogous substituted cyclopropyls); pentyl includes n-pentyl, cyclopentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, 1-ethylpropyl, and neopentyl (and analogous substituted cyclobutyls and cyclopropyls); butenyl includes E and Z forms of 1-butenyl, 2-butenyl, 3-butenyl, 1-methyl-1-propenyl, 1-methyl-2-propenyl, 2-methyl-1-propenyl and 2-methyl-2-propenyl (and cyclobutenyls and cyclopropenyls).
The transition metal component can also be described as comprising at least one ancillary ligand that stabilizes the oxidation state of the metal. Ancillary ligands serve to enforce the geometry around the metal center. In this disclosure, ancillary ligands have a backbone that comprises nitrogen and phosphorus bridged to each other by at least 4 atoms.
For purposes of this disclosure, oligomers include about 2-75 mer units. A mer is defined as a unit of an oligomer or polymer that originally corresponded to the olefin that was used in the polymerization reaction. For example, the mer of polyethylene would be ethylene.
Abstractable ligands are ligands that are removed from the catalyst precursor to activate it. They are sometimes assigned the label X in this disclosure. X are independently hydride radicals, hydrocarbyl radicals, or hydrocarbyl-substituted organometalloid radicals; or two X's are connected and form a 3-to-50-atom metallacycle ring. When Lewis-acid activators such as methylalumoxane, aluminum alkyls, alkylaluminum alkoxides or alkylaluminum halides that are capable of donating an X ligand, as described above, to the transition metal component are used, or when the ionic activator is capable of extracting X, one or more X, which may optionally be bridged to one another, may additionally be independently selected from a halogen, alkoxide, aryloxide, amide, phosphide or other anionic ligand, provided that the resulting activated catalyst contains as least one M-H or M-C connection in which an olefin can insert.
In some structures throughout this specification the ligand-metal connection is drawn with an arrow indicating that the electrons originally came from the ligand. At other times, connection is shown by drawing a solid line. One of ordinary skill in the art recognizes that these depictions are interchangeable.
C 6 F 5 is pentafluorophenyl or perfluorophenyl.
For purposes of this document, the term “comprising” is interchangeable with “including”.
DETAILED DESCRIPTION
In one embodiment of this invention, the catalyst precursor can be represented by the following formula:
where M, N, P, R 1 , R 2 , R 3 , R 4 and X are defined above, and R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , and R 12 are independently hydrogen, fluorine, or C 1 -C 20 hydrocarbyl radicals. The organic group connecting between N and P takes the place of Y, the hydrocarbyl bridge.
In other invention embodiments, R 1 and R 2 are independently C 1 -C 12 hydrocarbyl radicals, C 1 -C 6 hydrocarbyl radicals, or methyl radicals. In these or other embodiments, R 3 and R 4 are independently C 6 -C 20 hydrocarbyl radicals, C 6 -C 12 hydrocarbyl radicals, aromatic radicals, cyclohexyl radicals, or phenyl radicals.
Specific, invention catalyst precursor examples are illustrated by the following formula where some components are listed in Table 1. For Y, alkylenes are diradicals and include all isomers of bridge length 4 or greater, for example, hexylene includes 1,6-hexylene, 2,5-hexylene, 2-methyl-1,5-pentylene, 3-methyl-1,5-pentylene, 4-methyl-1,5-pentylene, 1,5-hexylene, 3,6-hexylene, 2-ethyl-1,4-butylene, 3-ethyl-1,4-butylene, 4-ethyl-1,4-butylene, and 1,4-hexylene. To illustrate members of the transition metal component, select any combination listed in Table 1. For example, by choosing the first row components, the transition metal compound would be 1-(N,N-dimethylamino)-4-(P,P-dimethylphosphino)butylene nickel dichloride. By selecting a combination of components from Table 1, an example would be 2-(N,N-dimethlamino)-2′-(P,P-dicyclohexylphosphino)biphenyl nickel dibromide. Any combination of components may be selected.
R 1 , R 2 , R 3 , and R 4
Y
X 1 and X 2
M
Methyl
Butylene
chloride
nickel
Ethyl
Pentylene
bromide
iron
Propyl
Hexylene
iodide
cobalt
Butyl
Heptylene
methyl
palladium
Pentyl
Octylene
ethyl
platinum
Hexyl
Nonylene
propyl
ruthenium
Heptyl
Decylene
butyl
osmium
Octyl
Undecylene
pentyl
rhodium
Nonyl
Dodecylene
hexyl
iridium
Decyl
Tridecylene
heptyl
Undecyl
Tetradecylene
octyl
Dodecyl
Pentadecylene
nonyl
Tridecyl
Hexadecylene
decyl
Tetradecyl
Heptadecylene
undecyl
Pentadecyl
Octadecylene
dodecyl
Hexadecyl
Nonadecylene
tridecyl
Heptadecyl
Eicosylene
tetradecyl
Octadecyl
Heneicosylene
pentadecyl
Nonadecyl
Docosylene
hexadecyl
Eicosyl
tricosylene
heptadecyl
Heneicosyl
tetracosylene
octadecyl
Docosyl
pentacosylene
nonadecyl
Tricosyl
hexacosylene
eicosyl
Tetracosyl
heptacosylene
heneicosyl
Pentacosyl
octacosylene
docosyl
Hexacosyl
nonacosylene
tricosyl
Heptacosyl
triacontylene
tetracosyl
Octacosyl
cyclohexylene
pentacosyl
Nonacosyl
cyclooctylene
hexacosyl
Triacontyl
cyclodecylene
heptacosyl
Ethenyl
cyclododecylene
octacosyl
Propenyl
2,2′-biphenyl
nonacosyl
Butenyl
butenylene
triacontyl
Pentenyl
penentylene
hydride
Hexenyl
hexenylene
phenyl
Heptenyl
heptenylene
benzyl
Octenyl
octenylene
phenethyl
Nonenyl
nonenylene
tolyl
Decenyl
decenylene
methoxy
Undecenyl
undecenylene
ethoxy
Dodecenyl
dodecenylene
propoxy
Ethynyl
hexynylene
butoxy
Propynyl
heptynylene
dimethylamino
Butynyl
octynylene
diethylamino
Pentynyl
nonynylene
methylethylamino
Hexynyl
decynylene
phenoxy
Heptynyl
undecynylene
benzoxy
Octynyl
dodecynylene
allyl
Nonynyl
butadienylene
1,1-dimethyl allyl
Decynyl
pentadienylene
2-carboxymethyl allyl
Undecynyl
hexadienylene
acetylacetonate
Dodecynyl
heptadienylene
1,1,1,5,5,5-hexa-
fluoroacetylacetonate
Phenyl
octadienylene
1,1,1-trifluoro-
acetylacetonate
Benzyl
nonadienylene
1,1,1-trifluoro-5,5-di-
methylacetylacetonate
Phenethyl
decadienylene
Tolyl
undecadienylene
both X 1 and X 2
Cyclobutyl
dodecadienylene
catecholate
Cyclopentyl
hexatrienylene
3,5-dibutylcatecholate
Cyclohexyl
octatrienylene
3,6-dibutylcatecholate
Cycloheptyl
decatrienylene
3,6-dibutyl-4,5-
dimethoxycatecholate
Cyclooctyl
dodecatrienylene
3,6-dibutyl-4,5-
dichlorocatecholate
Cyclononyl
3,6-dibutyl-4,5-
dibromocatecholate
Cyclodecyl
1,3-propylene
Cyclododecyl
1,4-butylene
R 3 and R 4 can further independently be defined as one of the following substituents:
where R′ are independently, hydrogen or C 1 -C 50 hydrocarbyl radicals. Additionally, any two adjacent R′ may independently be joined to form a saturated or unsaturated cyclic structure.
Y can further be defined as one of the following bridging groups:
where R′ is as defined above, A is a non-hydrocarbon atom or group (i.e. C═O, C═S, O, S, SO 2 , NR*, PR*, BR*, SiR* 2 , GeR* 2 and the like where R* is independently a hydrocarbyl or halocarbyl radical), E is a Group-14 element including carbon, silicon and germanium, x is an integer from 1 to 4, and y is an integer from 0 to 4.
Common activators are useful with this invention: alumoxanes, such as methylalumoxane, modified methylalumoxane, ethylalumoxane and the like; aluminum alkyls such as trimethyl aluminum, triethyl aluminum, triisopropyl aluminum and the like; alkyl aluminum halides such as diethyl aluminum chloride and the like; and alkylaluminum alkoxides.
The alumoxane component useful as an activator typically is an oligomeric aluminum compound represented by the general formula (R″—Al—O) n , which is a cyclic compound, or R″(R″—Al—O) n AlR″ 2 , which is a linear compound. In the general alumoxane formula, R″ is independently a C 1 -C 20 alkyl radical, for example, methyl, ethyl, propyl, butyl, pentyl, isomers thereof, and the like, and “n” is an integer from 1-50. Most preferably, R″ is methyl and “n” is at least 4. Methylalumoxane and modified methylalumoxanes are most preferred. For further descriptions see, EP 279586, EP 561476, WO94/10180 and U.S. Pat. Nos. 4,665,208, 4,908,463, 4,924,018, 4,952,540, 4,968,827, 5,041,584, 5,103,031, 5,157,137, 5,235,081, 5,248,801, 5,329,032, 5,391,793, and 5,416,229.
The aluminum alkyl component useful as an activator is represented by the general formula R″AlZ 2 where R″ is defined above, and each Z is independently R″ or a different univalent anionic ligand such as halogen (Cl, Br, I), alkoxide (OR″) and the like. Most preferred aluminum alkyls include triethylaluminum, diethylaluminum chloride, triisobutylaluminum, tri-n-octylaluminum and the like.
When alumoxane or aluminum alkyl activators are used, the catalyst-precursor-to-activator molar ratio is from about 1:1000 to 10:1; alternatively, 1:500 to 1:1; or 1:300 to 1:10.
Additionally, discrete ionic activators such as [Me 2 PhNH][B(C 6 F 5 ) 4 ], [Bu 3 NH][BF 4 ], [NH 4 ][PF 6 ], [NH 4 ][SbF 6 ], [NH 4 ][AsF 6 ], [NH 4 ][B(C 6 H 5 ) 4 ] or Lewis acidic activators such as B(C 6 F 5 ) 3 or B(C 6 H 5 ) 3 can be used, if they are used in conjunction with a compound capable of alkylating the metal such as an alumoxane or aluminum alkyl. Discrete ionic activators provide for an activated catalyst site and a relatively non-coordinating (or weakly coordinating) anion. Activators of this type are well known in the literature, see for instance W. Beck., et al., Chem. Rev., Vol. 88, p. 1405-1421 (1988); S. H. Strauss, Chem. Rev., Vol. 93, p. 927-942 (1993); U.S. Pat. Nos. 5,198,401, 5,278,119, 5,387,568, 5,763,549, 5,807,939, 6,262,202, and WO93/14132, WO99/45042 WO01/30785 and WO01/42249.
Invention catalyst precursors can also be activated with cocatalysts or activators that comprise non-coordinating anions containing metalloid-free cyclopentadienide ions. These are described in U.S. Patent Publication 2002/0058765 A1, published on 16 May 2002.
When a discrete ionic activator is used, the catalyst-precursor-to-activator molar ratio is from 1:10 to 1.2:1; 1:10 to 10:1; 1:10 to 2:1; 1:10 to 3:1; 1:10 to 5:1; 1:2 to 1.2:1; 1:2 to 10:1; 1:2 to 2:1; 1:2 to 3:1; 1:2 to 5:1; 1:3 to 1.2:1; 1:3 to 10:1; 1:3 to 2:1; 1:3 to 3:1; 1:3 to 5:1; 1:5 to 1.2:1; 1:5 to 10:1; 1:5 to 2:1; 1:5 to 3:1; 1:5 to 5:1.
The catalyst-precursor-to-alkylating-agent molar ratio is from 1:10 to 10:1; 1:10 to 2:1; 1:10 to 25:1; 1:10 to 3:1; 1:10 to 5:1; 1:2 to 10:1; 1:2 to 2:1; 1:2 to 25:1; 1:2 to 3:1; 1:2 to 5:1; 1:25 to 10:1; 1:25 to 2:1; 1:25 to 25:1; 1:25 to 3:1; 1:25 to 5:1; 1:3 to 10:1; 1:3 to 2:1; 1:3 to 25:1; 1:3 to 3:1; 1:3 to 5:1; 1:5 to 10:1; 1:5 to 2:1; 1:5 to 25:1; 1:5 to 3:1; 1:5 to 5:1.
The catalyst systems of this invention can additionally be prepared by combining in any order, the bidentate ligand:
where N, P, Y, R 1 , R 2 , R 3 and R 4 are as previously defined and a Group-8, -9, or -10 halide salt which may optionally be coordinated by solvent (for example NiX 2 or NiX 2 .MeOCH 2 CH 2 OMe where X=Cl, Br or I) in an activator-compound solution (for example methylalumoxane dissolved in toluene). The reactants may be added in any order, or even essentially simultaneously.
Invention catalyst precursor solubility allows for the ready preparation of supported catalysts. To prepare uniform supported catalysts, the catalyst precursor should significantly dissolve in the chosen solvent. The term “uniform supported catalyst” means that the catalyst precursor or the activated catalyst approach uniform distribution upon the support's accessible surface area, including the interior pore surfaces of porous supports.
Invention supported catalyst systems may be prepared by any method effective to support other coordination catalyst systems, effective meaning that the catalyst so prepared can be used for oligomerizing olefin in a heterogeneous process. The catalyst precursor, activator, suitable solvent, and support may be added in any order or simultaneously. In one invention embodiment, the activator, dissolved in an appropriate solvent such as toluene is stirred with the support material for 1 minute to 10 hours. The total volume of the activation solution may be greater than the pore volume of the support, but some embodiments limit the total solution volume below that needed to form a gel or slurry (about 100-200% of the pore volume). The mixture is optionally heated to 30-200° C. during this time. The catalyst can be added to this mixture as a solid, if a suitable solvent is employed in the previous step, or as a solution. Or alternatively, this mixture can be filtered, and the resulting solid mixed with a catalyst precursor solution. Similarly, the mixture may be vacuum dried and mixed with a catalyst precursor solution. The resulting catalyst mixture is then stirred for 1 minute to 10 hours, and the catalyst is either filtered from the solution and vacuum dried, or vacuum or evaporation alone removes the solvent.
In another invention embodiment, the catalyst precursor and activator are combined in solvent to form a solution. The support is then added to this solution and the mixture is stirred for 1 minute to 10 hours. The total volume of this solution may be greater than the pore volume of the support, but some embodiments limit the total solution volume below that needed to form a gel or slurry (about 100-200% pore volume). The residual solvent is then removed under vacuum, typically at ambient temperature and over 10-16 hours. But greater or lesser times are possible.
The catalyst precursor may also be supported in the absence of the activator, in which case the activator is added to the liquid phase of a slurry process. For example, a solution of catalyst precursor is mixed with a support material for a period of about 1 minute to 10 hours. The resulting catalyst precursor mixture is then filtered from the solution and dried under vacuum, or vacuum or evaporation alone removes the solvent. The total volume of the catalyst precursor solution may be greater than the pore volume of the support, but some embodiments limit the total solution volume below that needed to form a gel or slurry (about 100-200% of the pore volume).
Additionally, two or more different catalyst precursors may be placed on the same support using any of the support methods disclosed above. Likewise, two or more activators may be placed on the same support.
Suitable solid particle supports typically comprise polymeric or refractory oxide materials. Some embodiments select porous supports (such as for example, talc, inorganic oxides, inorganic chlorides (magnesium chloride)) that have an average particle size greater than 10 μm. Some embodiments select inorganic oxide materials as the support material including Group-2, -3, -4, -5, -13, or -14 metal or metalloid oxides. Some embodiments select the catalyst support materials to include silica, alumina, silica-alumina, and their mixtures. Other inorganic oxides may serve either alone or in combination with the silica, alumina, or silica-alumina. These are magnesia, titania, zirconia, and the like. Lewis acidic materials such as montmorillonite and similar clays may also serve as a support. In this case, the support can optionally double as the activator component. But additional activator may also be used.
As well know in the art, the support material may be pretreated by any number of methods. For example, inorganic oxides may be calcined, and/or chemically treated with dehydroxylating agents such as aluminum alkyls and the like.
Some embodiments select the carrier of invention catalysts to have a surface area of 10-700 m 2 /g, or pore volume of 0.1-4.0 cc/g, and average particle size from 10-500 μm. But greater or lesser values may also be used.
Invention catalysts may generally be deposited on the support at a loading level of 10-100 micromoles of catalyst precursor per gram of solid support; alternately from 20-80 micromoles of catalyst precursor per gram of solid support; or from 40-60 micromoles of catalyst precursor per gram of support. But greater or lesser values may be used. Some embodiments select greater or lesser values, but require that the total amount of solid catalyst precursor does not exceed the support's pore volume.
Additionally, oxidizing agents may be added to the supported or unsupported catalyst as described in WO 01/68725.
Process
In the invention oligomerization processes, the process temperature may be −100° C. to 300° C., −20° C. to 200° C., or 0° C. to 150° C. Some embodiments select ethylene oligomerization pressures (gauge) from 0 kPa-35 MPa or 500 kPa-15 MPa.
The preferred and primary feedstock for the oligomerization process is the α-olefin, ethylene. But other α-olefins, including but not limited to propylene and 1-butene, may also be used alone or combined with ethylene.
Invention oligomerization processes may be run in the presence of various liquids, particularly aprotic organic liquids. The homogeneous catalyst system, ethylene, α-olefins, and product are soluble in these liquids. A supported (heterogeneous) catalyst system may also be used, but will form a slurry rather than a solution. Suitable liquids for both homo- and heterogeneous catalyst systems, include alkanes, alkenes, cycloalkanes, selected halogenated hydrocarbons, aromatic hydrocarbons, and in some cases, hydrofluorocarbons. Useful solvents specifically include hexane, toluene, cyclohexane, and benzene.
Also, mixtures of α-olefins containing desirable numbers of carbon atoms may be obtained. Factor K from the Schulz-Flory theory (see for instance B. Elvers, et al., Ed. Ullmann's Encyclopedia of Industrial Chemistry, Vol. A13, VCH Verlagsgesellschaft mbH, Weinheim, 1989, p. 243-247 and 275-276) serves as a measure of these α-olefins' molecular weights. From this theory,
K=n (C n+2 olefin)/ n (C n olefin)
where n(C n olefin) is the number of moles of olefin containing n carbon atoms, and n(C n+2 olefin) is the number of moles of olefin containing n+2 carbon atoms, or in other words the next higher oligomer of C n olefin. From this can be determined the weight (mass) fractions of the various olefins in the resulting product. The ability to vary this factor provides the ability to choose the then-desired olefins.
Invention-made α-olefins may be further polymerized with other olefins to form polyolefins, especially linear low-density polyethylenes, which are copolymers containing ethylene. They may also be homopolymerized. These polymers may be made by a number of known methods, such as Ziegler-Natta-type polymerization, metallocene catalyzed polymerization, and other methods, see for instance WO 96/23010, see for instance Angew. Chem., Int. Ed. Engl., vol. 34, p. 1143-1170 (1995); European Patent Application, 416,815; and U.S. Pat. No. 5,198,401 for information about metallocene-type catalysts, and J. Boor Jr., Ziegler-Natta Catalysts and Polymerizations, Academic Press, New York, 1979 and G. Allen, et al., Ed., Comprehensive Polymer Science, Vol. 4, Pergamon Press, Oxford, 1989, pp. 1-108, 409-412 and 533-584, for information about Ziegler-Natta-type catalysts, and H. Mark, et al., Ed., Encyclopedia of Polymer Science and Engineering, Vol. 6, John Wiley & Sons, New York, 1992, p. 383-522, for information about polyethylene.
Invention-made α-olefins may be converted to alcohols by known processes, these alcohols being useful for a variety of applications such as intermediates for detergents or plasticizers. The α-olefins may be converted to alcohols by a variety of processes, such as the oxo process followed by hydrogenation, or by a modified, single-step oxo process (the modified Shell process), see for instance B. Elvers, et al., Ed., Ullmann's Encyclopedia of Chemical Technology, 5th Ed., Vol. A18, VCH Verlagsgesellschaft mbH, Weinheim, 1991, p. 321-327.
A set of exemplary catalyst precursors is set out below. These are by way of example only and are not intended to list every catalyst precursor that is within the scope of the invention.
Several structures are shown along with their corresponding name.
EXAMPLES
The following examples are presented to illustrate the discussion above. Although the examples may be directed toward certain embodiments of the present invention, they do not limit the invention in any specific way. In these examples, certain abbreviations are used to facilitate the description. These include standard chemical abbreviations for the elements and certain, commonly accepted abbreviations, such as: Me=methyl, Ph=phenyl, Cy=cyclohexyl, MAO=methylalumoxane, COD=cyclooctadiene and DME=ethylene glycol dimethyl ether.
All preparations were performed under an inert nitrogen atmosphere using standard Schlenk or glovebox techniques, unless mentioned otherwise. Dry solvents (toluene, diethyl ether, pentane, methylene chloride) were purchased as anhydrous solvents and further purified by passing them down an alumina (Fluka) column. Ethylene (99.9%) was purchased from BOC (Surrey, United Kingdom). 2-(N,N-dimethlamino)-2′-(dicyclohexylphosphino)biphenyl and 2-(N,N-dimethlamino)-2′-(diphenylphosphino)biphenyl were purchased from Strem Chemicals, Inc. Tetramethyltin, nickel(II) bromide ethylene glycol dimethylether complex, and dichloro(1,5-cyclooctadiene)palladium(II) were purchased from Aldrich Chemical Company. Deuterated solvents were dried with CaH and vacuum distilled prior to use.
Some compounds prepared are illustrated below:
Preparation of 2-(N,N-dimethlamino)-2′-(dicyclohexylphosphino)biphenyl nickel dibromide (Compound 1)
CH 2 Cl 2 (25 ml) was added to a Schlenk flask containing 2-(N,N-dimethlamino)-2′-(dicyclohexylphosphino)biphenyl (2.00 g, 5.10 mmol) and (DME)NiBr 2 (1.23 g, 4.0 mmol) in a dry box. A dark blue solution formed immediately upon mixing. This solution was stirred for 20 hours. Then, it was filtered and recrystallized from CH 2 Cl 2 /pentane. The product was washed three times with an additional 15 ml of pentane and dried for 1 hour under vacuum. A blue powder was isolated in 49.0% yield. The product was soluble in CH 2 Cl 2 . 1 H NMR indicates that it is paramagnetic. Anal. Calcd for (C 26 H 36 NPBr 2 Ni): C, 51.02%; H, 5.94%; N, 2.29%; P, 5.06%. Found: C, 50.72%; H, 6.10%; N, 2.12%; P, 5.02%. The IR (cm −1 , KBr): 272, ν(Ni—Br). This compound has also been characterized by x-ray crystallography.
Preparation of 2-(N,N-dimethlamino)-2′-(diphenylphosphino)biphenyl nickel dibromide (Compound 2)
CH 2 Cl 2 (25 ml) was added to a Schlenk flask containing the 2-(N,N-dimethlamino)-2′-(diphenylphosphino)biphenyl (2.00 g, 5.2 mmol) and (DME)NiBr 2 (1.30 g, 4.2 mmol) in a dry box. A green solution formed immediately upon mixing. This solution was stirred for 20 hours. Then, it was filtered and recrystallized from CH 2 Cl 2 /pentane. The product was washed three times with an additional 15 ml of pentane and dried for 1 hour under vacuum. A green powder was isolated in 69.3% yield. The product was soluble in CH 2 Cl 2 . 1 H NMR indicates that it is paramagnetic. Anal. Calcd for (C 26 H 24 NPBr 2 Ni): C, 52.03%; H, 4.08%; N, 2.33%; P, 5.16%. Found: C, 1.20%; H, 4.24%; N, 2.14%; P, 5.29%.
Preparation of 2-(N,N-dimethylamino)-2′-(dicyclohexylphosphino)biphenyl palladium methy chloride (Compound 3)
(COD)PdCl 2 (2.0 g, 7.0 mmol) was mixed with tetramethyltin (1.16 ml, 8.4 mmol) in CH 2 Cl 2 (50 ml) at room temperature. The mixture was stirred overnight until the bright yellow color of the precursor had vanished. The resulting mixture was filtered through Celite yielding a pale yellow solution. The solvent was removed from the that solution, leaving behind an off-white solid, (COD)PdClMe, which was washed twice with diethyl ether and dried under vacuum. A solution of the white (COD)PdClMe complex (0.775 g, 0.0029 mol dissolved in CH 2 Cl 2 ) was reacted with 2-(N,N-dimethlamino)-2′-(dicyclohexylphosphino)biphenyl (1.78 g, 0.0045 mol). As a result, a light yellow palladium complex formed. 1 H NMR (250 MHz, CD 2 Cl 2 , δ ppm): 0.88-2.94 m (22H, 2×C 6 H 11 ); 1.06 d (3H, PdCH 3 , J PH =2.5 Hz); 2.87 s (6H, 2×CH 3 ); 6.75-7.68 m (8H, 2×C 6 H 4 ). Anal. Calcd for (C 27 H 39 NPClPd): C, 58.91%; H, 7.16%; N, 2.55%; P, 5.63%. Found: C, 59.21%; H, 7.31%; N, 2.38%; P, 5.41%.
Oligomerization Reactions
Oligomerization reactions were run in 300 mL HastelloyC Parr reactor equipped with a mechanical stirrer. Catalyst (dissolved in 75 ml toluene) was added to the reactor under argon. Ethylene was added to the reactor at 100 psig, and then the reactor was vented to maintain an atmosphere of ethylene. Methylalumoxane solution (Albemarle, 30 wt % in toluene) was then cannulated in to the reactor. This process caused catalyst activation to be completed in the presence of the monomer. After activation, the ethylene pressure was adjusted to the desired value. It was attempted to maintain the reactor temperature at room temperature; but in cases where the exotherm was very large, higher reaction temperatures were reached. After the reaction had run for an hour, the reactor was cooled in an acetone/dry ice bath and vented. The reaction was quenched with methanol. A sample of the product solution was analyzed by GC/MS after adding nonane as an internal standard. In the case of supported transition metal compounds, silica-loaded samples were prepared by adding a solution of the transition metal complex in methylene chloride to silica followed by overnight drying of the silica under vacuu. MAO was added to the reactor solution prior to adding the supported transition metal compound. The results of the oligomerization reactions are tabulated below in Table 2.
TABLE 2
Oligomerization Examples
Final Rxn
C 2
Tempera-
Activity
Catalyst a
(psig)
ture (° C.)
(mol C 2 /mol Ni · hr)
Product
1
820
40
226,200
Linear C 4 to C 14
(K* = 0.60) b
1
100
30
26,700
Primarily C 4 and C 6
(linear)
1
800
25
155,000
Primarily C 4 and C 6
(linear) c
2
800
30
130,000
C 4
2
100
30
8095
C 4
a 0.0075 mmol of catalyst
b *K is based on C 14 /C 12 molar ratio for all isomers.
c After removing all volatiles at room temperature under vacuum, traces of higher oligomers were observed by NMR in the residue with 84 mol % of terminal olefins; GC/MS of the same residue showed C 16 to C 24 oligomers.
While certain representative embodiments and details have been shown to illustrate the invention, it will be apparent to skilled artisans that various process and product changes from those currently disclosed may be made without departing from this invention's scope. The appended claims define the invention's scope.
All cited patents, test procedures, priority documents, and other cited documents are fully incorporated by reference to the extent that this material is consistent with this specification and for all jurisdictions in which such incorporation is permitted.
Certain features of the present invention are described in terms of a set of numerical upper limits and a set of numerical lower limits. This specification discloses all ranges formed by any combination of these limits. All combinations of these limits are within the scope of the invention unless otherwise indicated.
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A series of novel late transition metal catalysts for olefin oligomerization have been invented. The catalysts demonstrate high activity and selectivity for linear α-olefins.
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CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This is a continuation-in-part of U.S. patent application Ser. No. 09/128,052, filed Aug. 3, 1998, the disclosure of which is incorporated by reference herein.
TECHNICAL FIELD
[0002] The present invention relates generally to nucleic acid chemistry and to the chemical synthesis of oligonucleotides. More particularly, the invention relates to an improved method for synthesizing oligonucleotides wherein carbonates are used as hydroxyl-protecting groups and “alpha-effect” nucleophiles such as peroxides are used in the deprotection thereof. The invention has utility in the fields of biochemistry, molecular biology and pharmacology, and in medical diagnostic and screening technologies.
BACKGROUND
[0003] Solid phase chemical synthesis of DNA fragments is routinely performed using protected nucleoside phosphoramidites. S. L. Beaucage et al. (1981) Tetrahedron Lett. 22:1859. In this approach, the 3′-hydroxyl group of an initial 5′-protected nucleoside is first covalently attached to the polymer support. R.C. Pless et al. (1975) Nucleic Acids Res. 2:773 (1975). Synthesis of the oligonucleotide then proceeds by deprotection of the 5′-hydroxyl group of the attached nucleoside, followed by coupling of an incoming nucleoside-3′-phosphoramidite to the deprotected hydroxyl group. M. D. Matteucci et al. (1981) J. Am. Chem. Soc. 103:3185. The resulting phosphite triester is finally oxidized to a phosphorotriester to complete the internucleotide bond. R. L. Letsinger et al. (1976) J. Am. Chem. Soc. 98:3655. The steps of deprotection, coupling and oxidation are repeated until an oligonucleotide of the desired length and sequence is obtained. This process is illustrated schematically in FIG. 1 (wherein “B” represents a purine or pyrimidine base, “DMT” represents dimethoxytrityl and “iPR” represents isopropyl.
[0004] The chemical group conventionally used for the protection of nucleoside 5′-hydroxyls is dimethoxytrityl (“DMT”), which is removable with acid. H.G. Khorana (1968) Pure Appl. Chem. 17:349; M. Smith et al. (1962) J. Am. Chem. Soc. 84:430. This acid-labile protecting group provides a number of advantages for working with both nucleosides and oligonucleotides. For example, the DMT group can be introduced onto a nucleoside regioselectively and in high yield. E. I. Brown et al. (1979) Methods in Enzymol. 68:109. Also, the lipophilicity of the DMT group greatly increases the solubility of nucleosides in organic solvents, and the carbocation resulting from acidic deprotection gives a strong chromophore, which can be used to indirectly monitor coupling efficiency. M. D. Matteucci et al. (1980) Tetrahedron Lett. 21:719. In addition, the hydrophobicity of the group can be used to aid separation on reverse-phase HPLC. C. Becker et al. (1985) J. Chromatogr. 326:219.
[0005] However, use of DMT as a hydroxyl-protecting group in oligonucleotide synthesis is also problematic. The N-glycosidic linkages of oligodeoxyribonucleotides are susceptible to acid catalyzed cleavage (N. K. Kochetkov et al., Organic Chemistry of Nucleic Acids (New York: Plenum Press, 1972)), and even when the protocol is optimized, recurrent removal of the DMT group with acid during oligonucleotide synthesis results in depurination. H. Shaller et al. (1963) J. Am. Chem. Soc. 85:3821. The N-6-benzoyl-protected deoxyadenosine nucleotide is especially susceptible to glycosidic cleavage, resulting in a substantially reduced yield of the final oligonucleotide. J. W. Efcavitch et al. (1985) Nucleosides & Nucleotides 4:267. Attempts have been made to address the problem of acid-catalyzed depurination utilizing alternative mixtures of acids and various solvents; see, for example, E. Sonveaux (1986) Bioorganic Chem. 4:274. However, this approach has met with limited success. L. J. McBride et al. (1986) J. Am. Chem. Soc. 108:2040.
[0006] Conventional synthesis of oligonucleotides using DMT as a protecting group is problematic in other ways as well. For example, cleavage of the DMT group under acidic conditions gives rise to the resonance-stabilized and long-lived bis(p-anisyl)phenylmethyl carbocation. P. T. Gilham et al. (1959) J. Am. Chem. Soc. 81:4647. Protection and deprotection of hydroxyl groups with DMT are thus readily reversible reactions, resulting in side reactions during oligonucleotide synthesis and a lower yield than might otherwise be obtained. To circumvent such problems, large excesses of acid are used with DMT to achieve quantitative deprotection. As bed volume of the polymer is increased in larger scale synthesis, increasingly greater quantities of acid are required. The acid-catalyzed depurination which occurs during the synthesis of oligodeoxyribonucleotides is thus increased by the scale of synthesis. M. H. Caruthers et al., in Genetic Engineering: Principles and Methods , J. K. Setlow et al., Eds. (New York: Plenum Press, 1982).
[0007] Considerable effort has been directed to developing 5′-O-protecting groups which can be removed under non-acidic conditions. For example, R. L. Letsinger et al. (1967) J. Am. Chem. Soc. 82:7147, describe use of a hydrazine-labile benzoyl-propionyl group, and J. F. M. deRooij et al. (1979) Real. Track. Chain. Pays-Bas. 98:537, describe using the hydrazine-labile levulinyl ester for 5′-OH protection (see also S. Iwai et al. (1988) Tetrahedron Lett. 2:5383; and S. Iwai et al. (1988) Nucleic Acids Res. 16:9443). However, the cross-reactivity of hydrazine with pyrimidine nucleotides (as described in F. Baron et al. (1955) J. Chem. Soc. 2855 and in V. Habermann (1962) Biochem. Biophys. Acta 55:999), the poor selectivity of levulinic anhydride and hydrazine cleavage of N-acyl protecting groups (R. L. Letsinger et a. (1968), Tetrahedron Lett. 22:2621) have made these approaches impractical. H. Seliger et al. (1985), Nucleosides & Nucleotides 4:153, describes the 5′-O-phenyl-azophenyl carbonyl (“PAPco”) group, which is removed by a two-step procedure involving transesterification followed by P-elimination; however, unexpectedly low and non-reproducible yields resulted. Fukuda et al. (1988) Nucleic Acids Res. Symposium Ser. 19, 13, and C. Lehmann et al. (1989) Nucleic Acids Res. 17:2389, describe application of the 9-fluorenylmethylcarbonate (“Fmoc”) group for 5′-protection. C. Lehmann et al. (1989) report reasonable yields for the synthesis of oligonucleotides up to 20 nucleotides in length. The basic conditions required for complete deprotection of the Fmoc group, however, lead to problems with protecting group compatibility. Similarly, R. L. Letsinger et al. (1967), J. Am. Chem. Soc. 32:296, describe using the p-nitrophenyloxycarbonyl group for 5′-hydroxyl protection. In all of the procedures described above utilizing base-labile 5′-O-protecting groups, the requirements of high basicity and long deprotection times have severely limited their application for routine synthesis of oligonucleotides.
[0008] Still an additional drawback associated with conventional oligonucleotide synthesis using DMT as a hydroxyl-protecting group is the necessity of multiple steps, particularly the post-synthetic deprotection step in which the DMT group is removed following oxidation of the internucleotide phosphite triester linkage to a phosphorotriester. It would be desirable to work with a hydroxyl-protecting group that could be removed via oxidation, such that the final two steps involved in nucleotide addition, namely oxidation and deprotection, could be combined.
[0009] The problems associated with the use of DMT are exacerbated in solid phase oligonucleotide synthesis where “microscale” parallel reactions are taking place on a very dense, packed surface. Applications in the field of genomics and high throughput screening have fueled the demand for precise chemistry in such a context. Thus, increasingly stringent demands are placed on the chemical synthesis cycle as it was originally conceived, and the problems associated with conventional methods for synthesizing oligonucleotides are rising to unacceptable levels in these expanded applications.
[0010] The invention is thus addressed to the aforementioned deficiencies in the art, and provides a novel method for synthesizing oligonucleotides, wherein the method has numerous advantages relative to prior methods such as those discussed above. The novel method involves the use of neutral or mildly basic conditions to remove hydroxyl-protecting groups, such that acid-induced depurination is avoided. In addition, the reagents used provide for irreversible deprotection, significantly reducing the likelihood of unwanted side reactions and increasing the overall yield of the desired product. The method provides for simultaneous oxidation of the internucleoside phosphite triester linkage and removal of the hydroxyl-protecting group, eliminating the extra step present in conventional processes for synthesizing oligonucleotides; the method also avoids the extra step of removing exocyclic amine protecting groups, as the reagents used for hydroxyl group deprotection substantially remove exocyclic amine protecting groups. In addition, the method can be used in connection with fluorescent or other readily detectable protecting groups, enabling monitoring of individual reaction steps. Further, the method is useful in carrying out either 3′-to-5′ synthesis or 5′-to-3′ synthesis. Finally, because of the far more precise chemistry enabled by the present invention, the method readily lends itself to the highly parallel, microscale synthesis of oligonucleotides.
SUMMARY OF THE INVENTION
[0011] It is accordingly a primary object of the invention to provide a novel method for synthesizing oligonucleotides which addresses and overcomes the above-mentioned disadvantages of the prior art.
[0012] It is another object of the invention to provide a novel method for synthesizing oligonucleotides in which individual nucleoside monomers are added to a growing oligonucleotide chain using carbonates as hydroxyl-protecting groups and “alpha effect” nucleophiles as deprotecting reagents.
[0013] It is still another object of the invention to provide such a method in which hydroxyl group deprotection and oxidation of the internucleotide phosphite triester linkage are carried out simultaneously, in a single step.
[0014] It is yet another object of the invention to provide such a method in which deprotection and oxidation are conducted in aqueous solution at neutral or mildly basic pH.
[0015] It is an additional object of the invention to provide such a method in which removal of hydroxyl protecting groups during oligonucleotide synthesis is irreversible.
[0016] It is a further object of the invention to provide such a method in which the desired oligonucleotide can be synthesized in either the 3′-to-5′ direction or the 5′-to-3′ direction.
[0017] Still a further object of the invention is to provide such a method in which individual oligonucleotides are synthesized within the context of a highly dense, substantially parallel oligonucleotide array on a substrate surface.
[0018] Still an additional object of the invention is to provide nucleoside reagents useful in conjunction with the novel synthetic methods.
[0019] Additional objects, advantages and novel features of the invention will be set forth in part in the description which follows, and in part will become apparent to those skilled in the art upon examination of the following, or may be learned by practice of the invention.
[0020] The invention is premised on the discovery that rapid and selective removal of suitable 5′-OH or 3′-OH protecting groups following phosphoramidite condensation can be achieved by employing nucleophiles, and particularly peroxy anions, that exhibit an “alpha effect” under neutral or mildly basic conditions. Further, it has now been discovered that rapid and selective deprotection can be achieved under such conditions by employing carbonate groups for 5′-OH or 3′-OH protection. Deprotection of nucleoside carbonates using peroxy anions can be conducted in aqueous solution, at neutral or mild pH, resulting in quantitative removal of the carbonate group and concomitant and quantitative oxidation of the internucleotide phosphite triester bond. Oligonucleotides synthesized using the novel methodology can be isolated in high yield and substantially free of detectable nucleoside modifications.
[0021] The term “alpha effect,” as in an “alpha effect” nucleophilic deprotection reagent, is used to refer to an enhancement of nucleophilicity that is found when the atom adjacent a nucleophilic site bears a lone pair of electrons. As the term is used herein, a nucleophile is said to exhibit an “alpha effect” if it displays a positive deviation from a Brønsted-type nucleophilicity plot. S. Hoz et al. (1985) Israel J. Chem. 26:313. See also, J. D. Aubort et al. (1970) Chem. Comm. 1378; J. M. Brown et al. (1979) J. Chem. Soc. Chem. Comm. 171; E. Buncel et al.(1982) J. Am. Chem. Soc. 104:4896; J. O. Edwards et al. (1962) J. Amer. Chem. Soc. 84:16; J. D. Evanseck et al. (1987) J. Am. Chem Soc. 109:2349. The magnitude of the alpha effect is dependent upon the electrophile which is paired with the specific nucleophile. J. E. McIsaac, Jr. et al. (1972), J. Org. Chem. 37:1037. Peroxy anions are example of nucleophiles which exhibit strong alpha effects.
[0022] In one general aspect, the invention features a method, in an oligonucleotide synthesis, for removing a protecting group from a protected nucleoside, by reacting the protected nucleoside or protected nucleotide with a nucleophile that exhibits an alpha effect at conditions of mildly basic pH, and particularly at conditions of pH 10 or less.
[0023] The invention provides for efficient solid-phase synthesis of oligonucleotides of lengths up to 25 nucleotides and greater. Treatment using an alpha effect nucleophile according to the invention for removal of carbonate protecting groups is irreversible, resulting in breakdown of the carbonate and formation of CO 2 . Moreover, because such treatment results in concomitant oxidation of the internucleotide bond and substantial removal of exocyclic amine protecting groups, the method of the invention obviates the need for a separate oxidation step and a post-synthesis deprotection step to remove any exocyclic amine protecting groups that may be used.
[0024] In another general aspect, the invention features a method for making an oligonucleotide array made up of array features each presenting a specified oligonucleotide sequence at an address on an array substrate, by first treating the array substrate to protect the hydroxyl moieties on the derivatized surface from reaction with phosphoramidites, then carrying out the steps of (a) applying droplets of an alpha effect nucleophile to effect deprotection of hydroxyl moieties at selected addresses, and (b) flooding the array substrate with a medium containing a selected protected phosphoramidite to permit coupling of the selected phosphoramidite onto the deprotected hydroxyl moieties at the selected addresses, and repeating the steps (a) and (b) to initiate and to sequentially build up oligonucleotides having the desired sequences at the selected addresses to complete the array features. In a variation on the aforementioned method, the droplets applied may comprise the protected phosphoramidite, and the alpha effect nucleophile may be used to flood the array substrate.
[0025] In the array construction method according to the invention, the deprotection reagents are aqueous, allowing for good droplet formation on a wide variety of array substrate surfaces. Moreover, because the selection of features employs aqueous media, small-scale discrete droplet application onto specified array addresses can be carried out by adaptation of techniques for reproducible fine droplet deposition from printing technologies. Further, as noted above, the synthesis reaction provides irreversible deprotection resulting in evolution of CO 2 , and thus quantitative removal of protecting groups within each droplet may be achieved. The phosphoramidite reactions are carried out in bulk, employing an excess of the phosphoramidite during the coupling step (b), allowing for exclusion of water by action of the excess phosphoramidite as a desiccant.
DETAILED DESCRIPTION OF THE FIGURES
[0026] [0026]FIG. 1 schematically illustrates conventional 3′-to-5′ oligonucleotide synthesis using DMT as a 5′-OH protecting group, and separate deprotection and oxidation steps.
[0027] [0027]FIG. 2 schematically illustrates 3′-to-5′ oligonucleotide synthesis using the method of the invention.
[0028] [0028]FIGS. 3A and 3B compare the conventional deprotection reaction in which DMT is used as a hydroxyl-protecting group (FIG. 3A) and the deprotection reaction in which the reagents of the invention are employed (FIG. 3B).
[0029] [0029]FIG. 4 schematically illustrates a method for synthesizing a 5′-carbonate-3′-phosphoramidite monomer of the invention.
[0030] [0030]FIG. 5 schematically illustrates a method for synthesizing a 3′-carbonate-5′-phosphoramidite monomer of the invention.
[0031] [0031]FIG. 6 sets forth the HPLC results obtained for a mixed-sequence oligonucleotide synthesized in Example 4, part (D).
[0032] [0032]FIG. 7 sets forth the MALDI TOF results obtained for the same mixed-sequence oligonucleotide.
DETAILED DESCRIPTION OF THE INVENTION
[0033] DEFINITIONS AND NOMENCLATURE:
[0034] It is to be understood that unless otherwise indicated, this invention is not limited to specific reagents, reaction conditions, synthetic steps, or the like, as such may vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting.
[0035] It must be noted that, as used in the specification and the appended claims, the singular forms “a,” “an” and “the” include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to “a protecting group” includes combinations of protecting groups, reference to “a nucleoside” includes combinations of nucleosides, and the like. Similarly, reference to “a substituent” as in a compound substituted with “a substituent” includes the possibility of substitution with more than one substituent, wherein the substituents may be the same or different.
[0036] In this specification and in the claims which follow, reference will be made to a number of terms which shall be defined to have the following meanings:
[0037] The term “alkyl” as used herein, unless otherwise specified, refers to a saturated straight chain, branched or cyclic hydrocarbon group of 1 to 24, typically 1-12, carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, pentyl, cyclopentyl, isopentyl, neopentyl, hexyl, isohexyl, cyclohexyl, 3-methylpentyl, 2,2-dimethylbutyl, and 2,3-dimethylbutyl. The term “lower alkyl” intends an alkyl group of one to six carbon atoms, and includes, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, pentyl, cyclopentyl, isopentyl, neopentyl, hexyl, isohexyl, cyclohexyl, 3-methylpentyl, 2,2-dimethylbutyl, and 2,3-dimethylbutyl. The term “cycloalkyl” refers to cyclic alkyl groups such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.
[0038] The term “alkenyl” as used herein, unless otherwise specified, refers to a branched, unbranched or cyclic (in the case of C 5 and C 6 ) hydrocarbon group of 2 to 24, typically 2 to 12, carbon atoms containing at least one double bond, such as ethenyl, vinyl, allyl, octenyl, decenyl, and the like. The term “lower alkenyl” intends an alkenyl group of two to six carbon atoms, and specifically includes vinyl and allyl. The term “cycloalkenyl” refers to cyclic alkenyl groups.
[0039] The term “alkynyl” as used herein, unless otherwise specified, refers to a branched or unbranched hydrocarbon group of 2 to 24, typically 2 to 12, carbon atoms containing at least one triple bond, such as acetylenyl, ethynyl, n-propynyl, isopropynyl, n-butynyl, isobutynyl, t-butynyl, octynyl, decynyl and the like. The term “lower alkynyl” intends an alkynyl group of two to six carbon atoms, and includes, for example, acetylenyl and propynyl, and the term “cycloalkynyl” refers to cyclic alkynyl groups.
[0040] The term “aryl” as used herein refers to an aromatic species containing 1 to 5 aromatic rings, either fused or linked, and either unsubstituted or substituted with 1 or more substituents typically selected from the group consisting of amino, halogen and lower alkyl. Preferred aryl substituents contain 1 to 3 fused aromatic rings, and particularly preferred aryl substituents contain 1 aromatic ring or 2 fused aromatic rings. Aromatic groups herein may or may not be heterocyclic. The term “aralkyl” intends a moiety containing both alkyl and aryl species, typically containing less than about 24 carbon atoms, and more typically less than about 12 carbon atoms in the alkyl segment of the moiety, and typically containing 1 to 5 aromatic rings. The term “aralkyl” will usually be used to refer to aryl-substituted alkyl groups. The term “aralkylene” will be used in a similar manner to refer to moieties containing both alkylene and aryl species, typically containing less than about 24 carbon atoms in the alkylene portion and 1 to 5 aromatic rings in the aryl portion, and typically aryl-substituted alkylene. Exemplary aralkyl groups have the structure —(CH 2 ) j —Ar wherein j is an integer in the range of 1 to 24, more typically 1 to 6, and Ar is a monocyclic aryl moiety.
[0041] The term “electron withdrawing” denotes the tendency of a substituent to attract valence electrons of the molecule of which it is a part, i.e., an electron-withdrawing substituent is electronegative.
[0042] The term “heterocyclic” refers to a five- or six-membered monocyclic structure or to an eight- to eleven-membered bicyclic structure which is either saturated or unsaturated. The heterocyclic groups herein may be aliphatic or aromatic. Each heterocycle consists of carbon atoms and from one to four heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur. As used herein, the terms “nitrogen heteroatoms” and “sulfur heteroatoms” include any oxidized form of nitrogen and sulfur, and the quaternized form of any basic nitrogen. Examples of heterocyclic groups include piperidinyl, morpholinyl and pyrrolidinyl.
[0043] The term “halo” or “halogen” is used in its conventional sense to refer to a chloro, bromo, fluoro or iodo substituent.
[0044] As used herein, the term “oligonucleotide” shall be generic to polydeoxynucleotides (containing 2-deoxy-D-ribose), to polyribonucleotides (containing D-ribose), to any other type of polynucleotide which is an N-glycoside of a purine or pyrimidine base, and to other polymers containing nonnucleotidic backbones, providing that the polymers contain nucleobases in a configuration which allows for base pairing and base stacking, such as is found in DNA and RNA.
[0045] It will be appreciated that, as used herein, the terms “nucleoside” and “nucleotide” will include those moieties which contain not only the known purine and pyrimidine bases, but also modified purine and pyrimidine bases and other heterocyclic bases which have been modified (these moieties are sometimes referred to herein, collectively, as “purine and pyrimidine bases and analogs thereof”). Such modifications include methylated purines or pyrimidines, acylated purines or pyrimidines, and the like.
[0046] By “protecting group” as used herein is meant a species which prevents a segment of a molecule from undergoing a specific chemical reaction, but which is removable from the molecule following completion of that reaction. This is in contrast to a “capping group,” which permanently binds to a segment of a molecule to prevent any further chemical transformation of that segment.
[0047] “Optional” or “optionally” means that the subsequently described circumstance may or may not occur, so that the description includes instances where the circumstance occurs and instances where it does not. For example, the phrase “optionally substituted” means that a non-hydrogen substituent may or may not be present, and, thus, the description includes structures wherein a non-hydrogen substituent is present and structures wherein a non-hydrogen substituent is not present.
[0048] Oligonucleotide Synthesis using Carbonate Protection and Irreversible Nucleophilic Deprotection:
[0049] In a first embodiment, the invention pertains to a method for synthesizing an oligonucleotide on a solid support, wherein a carbonate is used as a hydroxyl-protecting group and an alpha effect nucleophile is used to bring about deprotection. The novel synthesis is based on a simple, two-step method of (1) coupling a hydroxyl-protected nucleoside monomer to a growing oligonucleotide chain, and (2) deprotecting the product, under neutral or mildly basic conditions, using an alpha effect nucleophilic reagent that also oxidizes the internucleotide linkage to give a phosphotriester bond. The coupling and deprotection/oxidation steps are repeated as necessary to give an oligonucleotide having a desired sequence and length.
[0050] In the initial step of the synthesis, then, an unprotected nucleoside is covalently attached to a solid support to serve as the starting point for oligonucleotide synthesis. The nucleoside may be bound to the support through its 3′-hydroxyl group or its 5′-hydroxyl group, but is typically bound through the 3′-hydroxyl group. A second nucleoside monomer is then coupled to the free hydroxyl group of the support-bound initial monomer, wherein for 3′-to-5′ oligonucleotide synthesis, the second nucleoside monomer has a phosphorus derivative such as a phosphoramidite at the 3′ position and a carbonate protecting group at the 5′ position, and alternatively, for 5′-to-3′ oligonucleotide synthesis, the second nucleoside monomer has a phosphorus derivative at the 5′ position and a carbonate protecting group at the 3′ position. This coupling reaction gives rise to a newly formed phosphite triester bond between the initial nucleoside monomer and the added monomer, with the carbonate-protected hydroxyl group intact. In the second step of the synthesis, the carbonate group is removed with an alpha effect nucleophile that also serves to oxidize the phosphite triester linkage to the desired phosphotriester.
[0051] More specifically, for 3′-to-5′ synthesis, a support-bound nucleoside monomer is provided having the structure (I)
[0052] wherein:
[0053] ∘ represents the solid support or a support-bound oligonucleotide chain;
[0054] R is hydrido or hydroxyl, wherein when R is hydrido, the support-bound nucleoside is a deoxyribonucleoside, as will be present in DNA synthesis, and when R is hydroxyl, the support-bound nucleoside is a ribonucleoside, as will be present in RNA synthesis; and
[0055] B is a purine or pyrimidine base. The purine or pyrimidine base may be conventional, e.g., adenine (A), thymine (T), cytosine (C), guanine (G) or uracil (U), or a protected form thereof, e.g., wherein the base is protected with a protecting group such as acetyl, difluoroacetyl, trifluoroacetyl, isobutyryl, benzoyl, or the like. The purine or pyrimidine base may also be an analog of the foregoing; suitable analogs will be known to those skilled in the art and are described in the pertinent texts and literature. Common analogs include, but are not limited to, 1-methyladenine, 2-methyladenine, N 6 -methyladenine, N 6 -isopentyladenine, 2-methylthio-N 6 -isopentyladenine, N,N-dimethyladenine, 8-bromoadenine, 2-thiocytosine, 3-methylcytosine, 5-methylcytosine, 5-ethylcytosine, 4-acetylcytosine, 1-methylguanine, 2-methylguanine, 7-methylguanine, 2,2-dimethylguanine, 8-bromoguanine, 8-chloroguanine, 8-aminoguanine, 8-methylguanine, 8-thioguanine, 5-fluorouracil, 5-bromouracil, 5-chlorouracil, 5-iodouracil, 5-ethyluracil, 5-propyluracil, 5-methoxyuracil, 5-hydroxymethyluracil, 5-(carboxyhydroxymethyl)uracil, 5-(methylaminomethyl)uracil, 5-(carboxymethylaminomethyl)-uracil, 2-thiouracil, 5-methyl-2-thiouracil, 5-(2-bromovinyl)uracil, uracil-5-oxyacetic acid, uracil-5-oxyacetic acid methyl ester, pseudouracil, 1-methylpseudouracil, queosine, inosine, 1-methylinosine, hypoxanthine, xanthine, 2-aminopurine, 6-hydroxyaminopurine, 6-thiopurine and 2,6-diaminopurine.
[0056] The protected monomer to be added has the structure of formula (II)
[0057] in which B and R are as defined above with respect to the support-bound nucleoside of structural formula (I), and R 1 is COOR 3 , such that a carbonate group —OCOOR 3 is present at the 5′ position. R 3 is generally substituted or unsubstituted hydrocarbyl, including alkyl, aryl, aralkyl, alkaryl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, optionally containing one or more nonhydrocarbyl linkages such as ether linkages, thioether linkages, oxo linkages, amine and imine linkages, and optionally substituted on one or more available carbon atoms with a nonhydrocarbyl substituent such as cyano, nitro, halo, or the like. Preferred carbonate groups —OCOOR 3 are aryl carbonates, i.e., R 3 is aryl. Suitable aryl carbonates include, for example, o-nitrophenylcarbonyl, p-phenylazophenylcarbonyl, phenylcarbonyl, p-chlorophenylcarbonyl, 5′-(α-methyl-2-nitropiperonyl)oxycarbonyl (“MeNPOC”), and 9-fluorenylmethylcarbonyl (“Fmoc”). Particularly preferred aryl carbonates have the structure Ar—L—O—(CO)—O— wherein Ar is an aromatic moiety, typically a monocyclic aromatic moiety such as a phenyl group, optionally substituted with one or more electron-withdrawing substituents such as halo, nitro, cyano, or the like, and L is a lower alkylene linkage. Preferred alkyl carbonate substituents are fluorinated alkyl carbonates such as 2,2,2-trichloro-1,1-dimethylcarbonyl (“TCBOC”) and cyano-substituted alkyl carbonates such as 1,1-dimethyl-2-cyanoethyl carbonate
[0058] R 3 may also be a fluorescent or colored moiety. Preferably, in this embodiment, R 3 becomes fluorescent or colored upon cleavage of the carbonate —OCOOR 3 , but is neither fluorescent nor colored when bound to the nucleoside in carbonate form. In this way, when the carbonate protecting group R 1 is removed, the reaction may be monitored by detecting a fluorescent or colored cleavage product. Alternatively, R 3 may be fluorescent or colored when bound to the nucleoside in carbonate form, such that the presence of the newly attached monomer can be immediately detected. Examples of fluorescent and colorimetric species that may be employed include, but are not limited to: xanthenes such as fluoresceins, eosins and erythrosins, with preferred fluorescein compounds exemplified by 6-carboxy-fluorescein, 5- and 6-carboxy-4,7-dichlorofluorescein, 2′7′-dimethoxy-5- and 6-carboxy-4,7-dichlorofluorescein, 2′,7′-dimethoxy-4′,5′-dichloro-5- and 6-carboxyfluorescein, 2′7′-dimethoxy-4′5′-dichloro-5- and 6-carboxy-4,7-dichlorofluorescein, 1′2′7′8′-dibenzo-5- and 6-carboxy-4,7-dichlorofluorescein, 2′7′-dichloro-5- and 6-carboxy-4,7-dichlorofluorescein, and 2′4′,5′,7′-tetrachloro-5- and 6-carboxy-4,7-dichlorofluorescein; rhodamines such as tetramethylrhodamine and Texas Red®; benzimidazoles; ethidiums; propidiums; anthracyclines; mithramycins; acridines; actinomycins; merocyanines; coumarins such as 4-methyl-7-methoxycoumarin; pyrenes; chrysenes; stilbenes; anthracenes; naphthalenes such as dansyl, 5-dimethylamino-1-naphthalenesulfonyl; salicylic acids; benz-2-oxa-1-diazoles (also known as benzofurans), including 4-amino-7-nitrobenz-2-oxa-1,3-diazole; fluorescamine; and 4-methylumbelliferone.
[0059] R 2 is a phosphorus derivative that enables coupling to a free hydroxyl group. Preferred phosphorus derivatives are phosphoramidites, such that R 2 has the structure (III) (III)
[0060] wherein X is NQ 1 Q 2 in which Q 1 and Q 2 may be the same or different and are typically selected from the group consisting of alkyl, aryl, aralkyl, alkaryl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, optionally containing one or more nonhydrocarbyl linkages such as ether linkages, thioether linkages, oxo linkages, amine and imine linkages, and optionally substituted on one or more available carbon atoms with a nonhydrocarbyl substituent such as cyano, nitro, halo, or the like. Preferably, Q 1 and Q 2 represent lower alkyl, more preferably sterically hindered lower alkyls such as isopropyl, t-butyl, isobutyl, sec-butyl, neopentyl, tert-pentyl, isopentyl, sec-pentyl, and the like. Most preferably, Q 1 and Q 2 both represent isopropyl. Alternatively, Q 1 and Q 2 may be linked to form a mono- or polyheterocyclic ring having a total of from 1 to 3, usually 1 to 2 heteroatoms and from 1 to 3 rings. In such a case, Q 1 and Q 2 together with the nitrogen atom to which they are attached represent, for example, pyrrolidone, morpholino or piperidino. Usually, Q 1 and Q 2 have a total of from 2 to 12 carbon atoms. Examples of specific —NQ 1 Q 2 moieties thus include, but are not limited to, dimethylamine, diethylamine, diisopropylamine, dibutylamine, methylpropylamine, methylhexylamine, methylcyclopropylamine, ethylcyclohexylamine, methylbenzylamine, methylcyclohexylmethylamine, butylcyclohexylamine, morpholine, thiomorpholine, pyrrolidine, piperidine, 2,6-dimethylpiperidine, piperazine, and the like.
[0061] The moiety “Y” is hydrido or hydrocarbyl, typically alkyl, alkenyl, aryl, aralkyl, or cycloalkyl. Preferably, Y represents: lower alkyl; electron-withdrawing β-substituted aliphatic, particularly electron-withdrawing β-substituted ethyl such as β-trihalomethyl ethyl, β-cyanoethyl, β-sulfoethyl, β-nitro-substituted ethyl, and the like; electron-withdrawing substituted phenyl, particularly halo-, sulfo-, cyano- or nitro-substituted phenyl; or electron-withdrawing substituted phenylethyl. Most preferably, Y represents methyl, β-cyanoethyl, or 4-nitrophenylethyl.
[0062] The coupling reaction is conducted under standard conditions used for the synthesis of oligonucleotides and conventionally employed with automated oligonucleotide synthesizers. Such methodology will be known to those skilled in the art and is described in the pertinent texts and literature, e.g., in D. M. Matteuci et al. (1980) Tet. Lett. 521:719 and U.S. Pat. No. 4,500,707. The product of the coupling reaction may be represented as structural formula (IV), as follows:
[0063] In the second step of the synthesis, the product (IV) is treated with an “alpha effect” nucleophile in order to remove the carbonate protecting group at the 5′ terminus, thus converting the moiety —OR′ to —OH. The alpha effect nucleophile also oxidizes the newly formed phosphite triester linkage —O—P(OY)—O— to give the desired phosphotriester linkage
[0064] Advantageously, this step is conducted in an aqueous solution at neutral pH or at a mildly basic pH, depending on the pKa of the nucleophilic deprotection reagent. That is, and as will be explained in further detail below, the pH at which the deprotection reaction is conducted must be above the pKa of the deprotection reagent for the reagent to be effective. Typically, the reaction is conducted at a pH of less than about 10.
[0065] In a preferred embodiment, the nucleophilic deprotection reagent that exhibits an alpha effect is a peroxide or a mixture of peroxides, and the pH at which deprotection is conducted is at or above the pKa for formation of the corresponding peroxy anion. The peroxide may be either inorganic or organic. Suitable inorganic peroxides include those of the formula M + OOH − , where M is any counteranion, including for example H + , Li + , Na + , K + , Rb + , Cs + , or the like; and lithium peroxide or hydrogen peroxide can be particularly suitable. Suitable organic peroxides include those of the formula ROOH, where R is selected from the group consisting of alkyl, aryl, substituted alkyl and substituted aryl. More particularly, the organic peroxide will have one of the following three general structures (V), (VI) or (VII)
[0066] in which R 4 through R 10 are generally hydrocarbyl optionally substituted with one or more nonhydrocarbyl substituents and optionally containing one or more nonhydrocarbyl linkages. Generally, R 4 through R 10 are independently selected from the group consisting of hydrido, alkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, alkenyl, cycloalkenyl, alkynyl aralkynyl, cycloalkynyl, substituted aralkyl, substituted cycloalkyl, substituted cycloalkylalkyl, substituted alkenyl, substituted cycloalkenyl, substituted alkynyl substituted aralkynyl, substituted cycloalkynyl; t-butyl-hydroperoxide or metachloroperoxybenzoic acid can be particularly suitable. As a specific example, the m-chloroperbenzoic acid (mCPBA) peroxy anion exhibits a strong alpha effect towards the p-chlorophenylcarbonate electrophile, and that, accordingly, the peroxyanion of mCPBA is a particularly effective deprotection reagent for removal of p-chlorophenylcarbonate protecting groups.
[0067] The product of this simultaneous deprotection and oxidation step may thus be represented as follows:
[0068] wherein B, R and Y are as defined earlier herein. This latter reaction also gives rise to the by-products R 3 O and carbon dioxide, insofar as nucleophilic attack of the peroxide deprotection reagent cleaves the carbonate linkage as follows:
[0069] The use of a peroxy anion to effect simultaneous removal of the carbonate protecting group and oxidation of the internucleotide linkage also removes, to a large extent, exocyclic amine-rotecting groups such as acetyl, trifluoroacetyl, difluoroacetyl and trifluoroacetyl moieties. Thus, an added advantage herein is the elimination of a separate post-synthetic reaction step to remove exocyclic amine-protecting groups, as is required with conventional methods of synthesizing oligonucleotides. Elimination of this additional step significantly decreases the time and complexity involved in oligonucleotide synthesis.
[0070] An additional advantage of peroxy anions as deprotection reagents herein is that they may be readily activated or inactivated by simply changing pH. That is, the effectiveness of peroxides as nucleophiles is determined by their pKa. In buffered solutions having a pH below the pKa of a particular peroxide, the peroxides are not ionized and thus are non-nucleophilic. To activate a peroxide and render it useful as a deprotection reagent for use herein, the pH is increased above the pKa so that the peroxide is converted to a nucleophilic peroxy anion. Thus, one can carefully control the timing and extent of the deprotection reaction by varying the pH of the peroxide solution used.
[0071] [0071]FIG. 2 schematically illustrates 3′-to-5′ synthesis of an oligonucleotide using the method of the present invention. In the figure, the moiety “Arco” (“aryloxycarbonyl”) represents the carbonate protecting group p-chlorophenylcarbonyl. As may be seen, deprotection and oxidation occur simultaneously. The synthesis may be contrasted with that schematically illustrated in FIG. 1, the prior, conventional method employing DMT protection and separate oxidation and deprotection steps. A further advantage of the invention is illustrated in FIG. 3. As shown therein, in FIG. 3A, protection and deprotection of hydroxyl groups using DMT is a reversible process, with the DMT cation shown being a relatively stable species. Thus, using DMT as a protecting group can lead to poor yields and unwanted side reactions, insofar as the deprotection reaction is essentially reversible. FIG. 3B illustrates the irreversible deprotection reaction of the present invention, wherein nucleophilic attack of the peroxy anion irreversibly cleaves the carbonate moiety, i.e., the O-p-chlorophenylcarbonyl group, giving rise to carbon dioxide and the p-chlorophenol anion. The reaction is not “reversible,” insofar as there is no equilibrium reaction in which a cleaved protecting group could reattach to the hydroxyl moiety, as is the case with removal of DMT.
[0072] As explained earlier herein, the method of the invention also lends itself to synthesis in the 5′-to-3′ direction. In such a case, the initial step of the synthetic process involves attachment of a nucleoside monomer to a solid support at the 5′ position, leaving the 3′ position available for covalent binding of a subsequent monomer. In this embodiment, i.e., for 5′-to-3′ synthesis, a support-bound nucleoside monomer is provided having the structure (IX) (IX)
[0073] wherein ∘ represents the solid support or a support-bound oligonucleotide chain, R is hydrido or hydroxyl, and B is a purine or pyrimidine base. The protected monomer to be added has the structure of formula (X)
[0074] wherein the carbonate protecting group is present at the 3′ position, i.e., R 1 is COOR 3 where R 3 is as defined previously, and R 2 represents a phosphorus derivative that enables coupling to a free hydroxyl group, preferably a phosphoramidite having the structure (III)
[0075] wherein X and Y are as defined earlier herein. The coupling reaction in which the nucleoside monomer becomes covalently attached to the 3′ hydroxyl moiety of the support bound nucleoside is conducted under reaction conditions identical to those described for the 3′-to-5′ synthesis. This step of the synthesis gives rise to the intermediate (XI)
[0076] As described with respect to oligonucleotide synthesis in the 3′-to-5′ direction, the coupling reaction is followed by treatment of the product (XI) with an alpha effect nucleophile in order to remove the carbonate protecting group at the 3′ terminus, thus converting the moiety —OR 1 to —OH, and to oxidize the internucleotide phosphite triester linkage to give the desired phosphotriester linkage.
[0077] The two-step process of coupling and deprotection/oxidation is repeated until the oligonucleotide having the desired sequence and length is obtained. Following synthesis, the oligonucleotide may, if desired, be cleaved from the solid support.
[0078] The synthetic methods of the invention may be conducted on any solid substrate having a surface to which chemical entities may bind. Suitable solid supports are typically polymeric, and may have a variety of forms and compositions and derive from naturally occurring materials, naturally occurring materials that have been synthetically modified, or synthetic materials. Examples of suitable support materials include, but are not limited to, polysaccharides such as agarose (e.g., that available commercially as Sepharose®, from Pharmacia) and dextran (e.g., those available commercially under the tradenames Sephadex® and Sephacyl®, also from Pharmacia), polyacrylamides, polystyrenes, polyvinyl alcohols, copolymers of hydroxyethyl methacrylate and methyl methacrylate, silicas, teflons, glasses, and the like. The initial monomer of the oligonucleotide to be synthesized on the substrate surface is typically bound to a linking moiety which is in turn bound to a surface hydrophilic group, e.g., to a surface hydroxyl moiety present on a silica substrate.
[0079] Synthesis of Oligonucleotide Arrays:
[0080] In a related embodiment, the invention features a method for making an oligonucleotide array made up of array features each presenting a specified oligonucleotide sequence at an address on an array substrate. First, the array substrate is treated to protect the hydroxyl moieties on the derivatized surface from reaction with phosphoramidites or analogous phosphorus groups used in oligonucleotide synthesis. Protection involves conversion of free hydroxyl groups to —OR 1 groups, i.e., to carbonate-protected species. The method then involves (a) applying droplets of an alpha effect nucleophile to effect deprotection of hydroxyl moieties at selected addresses and oxidation of the newly formed internucleotide phosphite triester linkages, followed by (b) flooding the array substrate with a medium containing a selected nucleoside monomer having the structure of either Formula (II) (for 3′-to-5′ synthesis) or Formula (X) (for 5′-to-3′ synthesis). Step (a), deprotection/oxidation, and step (b), monomer addition, are repeated to sequentially build oligonucleotides having the desired sequences at selected addresses to complete the array features. In a variation on the aforementioned method, the applied droplets may comprise the selected nucleoside monomer, while the alpha effect nucleophile is used to flood the array substrate; that is, steps (a) and (b) are essentially reversed.
[0081] In the array construction method according to the invention, the deprotection reagents are aqueous, allowing for good droplet formation on a wide variety of array substrate surfaces. Moreover, because the selection of features employs aqueous media, small-scale discrete droplet application onto specified array addresses can be carried out by adaptation of techniques for reproducible fine droplet deposition from printing technologies.
[0082] Novel Compositions of Matter:
[0083] The invention additionally provides protected nucleoside monomers as novel compositions of matter useful, inter alia, in the synthesis of oligonucleotides as described herein. The novel monomers have the structural formulae (II) and (X)
[0084] wherein:
[0085] B is a purine or pyrimidine base, as described previously herein;
[0086] R is hydrido or hydroxyl;
[0087] R 1 is COOR 3 wherein R 3 is as described previously herein, such that the moiety OR 1 represents a carbonate-protected hydroxyl group; and
[0088] R 2 is a phosphorus derivative phosphorus derivative that enables coupling to a free hydroxyl group, and is preferably a phosphoramidite having the structure (III)
[0089] wherein X and Y are as defined earlier herein.
[0090] Reagent (II), used for 3′-to-5′ synthesis, is readily prepared by reaction of the unprotected nucleoside with the haloformate R 3 O—(CO)—Hal wherein Hal represents halo, typically chloro, and R 3 is as defined previously, in the presence of a base effective to catalyze the nucleophilic reaction, e.g., pyridine. This step results in a 5′-carbonate, as follows:
[0091] The intermediate so prepared is then phosphitylated with the phosphoramidite PX 2 (OY) wherein X and Y are as defined earlier, resulting in conversion of the 3′-hydroxyl moiety to the desired substituent —O—PX(PY), i.e., —OR 2 :
[0092] A specific example of this synthesis is illustrated schematically in FIG. 4, wherein “Arco” represents the aryloxycarbonyl group p-chlorophenylcarbonyl, iPr represents isopropyl, and B is either N 6 -benzoyl-protected deoxyadenine, N 4 -Fmoc-protected deoxycytidine, N 2 -isobutyryl-protected deoxyguanine or thymine. In the initial step of the reaction, the unprotected base is reacted with 4-chlorophenyl chloroformate in the presence of pyridine to give the carbonate-protected 5′-OH, followed by phosphitylation using (iPr 2 N) 2 PO(CH 2 ) 2 CN, i.e., P-cyanoethyl-N,N-diisopropylamino phosphoramidite.
[0093] Reagent (X), used for 5′-to-3′ synthesis, may be prepared by first synthesizing a 5′-protected nucleoside using a conventional 5′-OH protecting group such as DMT. This 5′-protected nucleoside is then reacted with the haloformate R 3 O—(CO)—Hal, which, as above, is done in the presence of a base effective to catalyze the nucleophilic reaction, e.g., pyridine. The DMT group is then removed with acid, resulting in the 3′-carbonate intermediate
[0094] Subsequent reaction with the phosphoramidite results in conversion of the 5′-hydroxyl moiety to the desired substituent —O—PX(PY), i.e., —OR 2 :
[0095] A specific example of this synthesis is illustrated schematically in FIG. 5, wherein, as in FIG. 4, “Arco” again represents the aryloxycarbonyl group p-chlorophenylcarbonyl, iPr represents isopropyl, and B is either N 6 -benzoyl-protected deoxyadenine, N 4 -Fmoc-protected deoxycytidine, N 2 -isobutyryl-protected deoxyguanine or thymine. In the initial step of the reaction shown in FIG. 4, the 5′-O-DMT-protected base is reacted with 4-chlorophenyl chloroformate in the presence of pyridine to give the 3′ carbonate, followed by DMT removal using trichloroacetic acid and subsequent phosphitylation using β-cyanoethyl-N,N-diisopropylamino phosphoramidite.
[0096] It is to be understood that while the invention has been described in conjunction with the preferred specific embodiments thereof, that the description above as well as the example which follows are intended to illustrate and not limit the scope of the invention. Other aspects, advantages and modifications within the scope of the invention will be apparent to those skilled in the art to which the invention pertains.
[0097] Experimental:
[0098] The practice of the present invention will employ, unless otherwise indicated, conventional techniques of synthetic organic chemistry, biochemistry, molecular biology, and the like, which are within the skill of the art. Such techniques are explained fully in the literature.
[0099] The following examples are put forth so as to provide those of ordinary skill in the art with a complete disclosure and description of how to prepare and use the compounds disclosed and claimed herein. Efforts have been made to ensure accuracy with respect to numbers (e.g., amounts, temperature, etc.) but some errors and deviations should be accounted for. Unless indicated otherwise, parts are parts by weight, temperature is in ° C. and pressure is at or near atmospheric.
[0100] All patents, patent applications, journal articles and other references mentioned herein are incorporated by reference in their entireties.
EXAMPLE 1
PROTECTION AND DEPROTECTION OF DEOXYTHYMIDINE
[0101] (A) General Procedures:
[0102] Nuclear resonance spectra ( 1 H, 13 C and 31 P NMR) were recorded on a Varian VXR-300 spectrometer. Tetramethylsilane was used as an internal reference for 1 H and 13 C NMR. An external capillary containing 85% H 3 PO 4 was used as a reference for 31 P NMR. Downfield chemical shifts were recorded as positive values for 31 P NMR. Thin layer chromatography was performed on HF254 silica gel plates (Merck) in: CH 2 Cl 2 /MeOH, 9:1 (Solvent A), CH 2 Cl 2 /MeOH, 8:2 (Solvent B), ethyl acetate/THF/Et 3 N (45/45/10, v/v/v) (Solvent C). Pyridine, dichloromethane, and benzene were freshly distilled over CaH 2 . Acetonitrile was distilled over P 2 O 5 (solid), followed by calcium hydride, and stored over molecular sieves. Hexanes and pentanes were distilled. 5′-O-(4,4′- Dimethoxytrityl)-6-N-((di-N-butylamino)methylene)-2′-deoxyadenosine and 2-N-(di-N-butylamino)methylene-2′-deoxyguanosine were prepared according to published procedures. Protected nucleoside-derived CPG was obtained from Applied Biosystems Inc.
[0103] (B) Synthesis of 5′-O-Nucleoside Carbonates:
[0104] The syntheses were conducted generally as follows. Deoxythymidine (2 mmol) was co-evaporated with anhydrous pyridine (2×20 ml), then redissolved in dry pyridine (40 ml). The corresponding chloroformate (2.2 mmol ) was added and the mixture stirred at room temperature (25° C.) for 2 hr. The reaction was quenched with water (1 ml), then concentrated. The residual pyridine was removed by co-evaporation with toluene (40 ml).
[0105] The resulting residue was then dissolved in CHCl 3 (50 ml) and extracted with brine (40 ml). The aqueous layers were back-extracted with CHCl 3 (30 ml). The organic layers were combined, concentrated, and then loaded onto a silica gel column (100 g). The column was eluted with CH 2 Cl 2 using a methanol gradient. The isolated products were evaporated to foams.
[0106] This scheme was used to synthesize a series of alkyl and aryl 5′-O- carbonates of deoxythymidine from the corresponding chlorofonnates. In all cases, the best yields for the 5′-protected nucleoside were obtained when the reactions were performed at room temperature in pyridine using a slight excess of the chloroformate (1.1 eq). Under these conditions, good regioselectivity was observed with most chloroformates. Table 1 sets forth isolated yields of the 5′-protected nucleosides:
TABLE 1 ISOLATED YIELDS OF 5′-PROTECTED DEOXYTHYMIDINE WITH VARIOUS ALKYL AND ARYL CHLOROFORMATES AT ROOM TEMPERATURE IN PYRIDINE 5′-Carbonate Protected Thymidine Isolated Yield Cl 3 C(CH 3 ) 2 COCO 2 -dT (1a) 87% [5′-O-TCBOC-dT] [5′-O-Fmoc-dT] (1b) 90% 2-(NO 2 )C 6 H 4 OCO 2 -dT (1c) 35% [5′-O-oNPh-dT] C 6 H 5 N═NC 6 H 4 OCO 2 -dT (1d) 50% [5′-O-PAP-dT] C 6 H 5 OCO 2 -dT (1e) 60% [5′-O-Ph-dT] 4-(Cl)C 6 H 4 OCO 2 -dT (1f) 60% [5′-O-pClPh-dT]
[0107] The results were as follows.
[0108] 5′-O-(2,2,2-Trichloro- 1,1-Dimethylcarbonyl)Deoxythymidine (5′-O-TCBOC-dT, 1 a ):
[0109] Yield 87%. R F (A)=0.40, R F (B)=0.70. 1 H NMR (CDCl 3 +DMSO-D 6 ) δ:7.33 (d, 1, H 6 ), 6.34 (t, J=7 Hz, 1, H 1′ ), 4.45-4.08 (m, 4, H 3′ , H 4′ , H 5,5′ ,) 2.32-2.1 (m, 2, H 2,2′ ), 1.94-1-93 (m, 6, C-(CH 3 ) 2 ),1.88 (s, 3, C 5 5—CH 3 ). 13 C NMR (CDCl 3 +DMSO-D 6 ) δ: 163.27 (C-4),150.93 (0-(CO)—O), 149.68 (C-2),134.21 (C-6), 109.71 (C-5), 104.37 C—Cl 3 ), 88.64 (C—Me 2 ), 83.39 (C-4′), 82.94 (C-1′), 62.96 (C-3′), 66.4 (C-5′), 20.02,19.95 (C—(CH 3 ) 2 ), 11.6 (C 5 —CH 3 ).
[0110] 5′-O-(9-Fluorenylmethylcarbonyl)Deoxythymidine (5′-O-Fmoc-dT, 1 b ):
[0111] Yield 90%. R F (A)=0.41, R F (B)=0.74. 1 H NMR (CDCl 3 +DMSO-D 6 ) δ: 7.72-7.28 (m, 9, Fmoc+H 6 ), 6.36 (t, J=7 Hz, 1, H 1′ ), 4.54-4.11 (m, 3, CHCH 2 (Fmoc), H 3 ′, H 4 ′, H 5,5′ ) 2.35-2.06 (m, 2, H2,2′) 1.79 (s, 3, C 5 —CH 3 ). 13 C NMR (CDCl 3 +DMSO-D 6 ) δ: 163.87 (C-4), 154.58 (C-2), 150.28 (O—(CO)—O), 142.76, 142.71, 140.91, 127.04, 126.82, 124.59, 119.75 (Fmoc), 134.89 (C-6), 110.55 (C-5), 84.29 (C-4′), 83.76 (C-1′), 69.47 (C-3′), 66.92 (C-5′), 46.3 (Fmoc), 39.86 (C-2′), 12.13 (C 5 —CH 3 ).
[0112] 5′-O-(-o-Nitrophenylcarbonyl)Deoxythymidine (5′-O-oNPh-dT, 1 c ):
[0113] Yield 35%. R F (A)=0.41, R F (B)=0.68. 1 H NMR (CDCl 3 ) δ: 8.21 (d, 1, H 6 ), 7.89-7.53 (m, 4, aryl), 6.37 (t, J=7 Hz, 1, H 1′ ), 4.53-4.17 (m, 4, H 3′ , H 4′ , H 5,5′ ), 2.33-2.03 (m, 2, H 2,2′ ) 1.79 (s, 3, C 5 5—CH 3 ). 13 C NMR (CDCl 3 ) δ: 164.3 (C-4), 153.04 (O—(CO)—O), 152.21 (C-2), 144.68, 142.1, 136.5, 128.36, 126.65, 125.68 (C 6 H 4 ), 136.33 (C-6), 111.05 (C-5), 85.44 (C-1′), 84.62 (C-4′), 71.54 (C-5′), 69.67 (C-3′), 40.15 (C-2′), 12.4 (C 5 —CH 3 ).
[0114] 5′-O-(-p-Phenylazophenylcarbonyl)Deoxythymidine (5′-O-PAP-dT, 1 d ):
[0115] Yield 50%. R F (A)=0.41, R F (B)=0.75. 1 H NMR (CDCl 3 ) δ: 7.94-7.28 (m, 10, H 6 6+aryl(PAP)), 6.31 (t, J=7 Hz, 1, H 1′ ), 4.5-4.12 (a, 4, H 3′ , H 4′ , H 5,5′ ), 2.33-2.19 (m, 2, H 2,2′ ), 1.86 (s, 3, C 5 —CH 3 ). 13 C NMR (CDCl 3 ) δ: 164.44 (C-4), 152.33 (O—(CO)—O), 152.1 (C-2), 152.86, 152.16, 150.55, 150.23, 131.05, 128.84, 123.86, 122.54, 121.21 (PAP), 135.56 (C-6), 110.92 (C-5), 84.65 (C-1′), 83.55 (C-4′), 70.13 (C-5′), 67-53 (C-3′), 39.73 (C-2′), 11.93 (C 5 —CH 3 ).
[0116] 5′-O-(Phenylcarbonyl)Deoxythymidine (5′-O-Ph-dT, 1 e ):
[0117] Yield 60%. R F (A)=0.41, R F (B)=0.71. 1 H NMR (CDCl 3 ) δ: 7.54-7.19 (m, 6, H 6 +aryl), 6.34 (t, J=7 Hz, 1, H 1′ ) 4.52-4.12 (m, 4, H 3′ , H 4′ , H 5,5′ ), 2.3-2 (a, 2, H 2,2′ ), 1.78 (s, 3, C 5 —CH 3 ). 13 C NMR (DMSOd- 6 +(CD 3 ) 2 CO) δ: 164.36 (C-4), 152.21 (O—(CO)—O), 151.35 (C-2), 154.2, 130.42, 126.97, 121.99 (C 6 H 4 ), 136.61 (C-6), 111.11 (C-5), 85.44 (C-1′), 84.84 (C-4′), 71.73 (C-5′), 68.83 (C-3′), 40.21 (C-2′),12.5 (C 5 —CH 3 ).
[0118] 5′-O-(p-Chlorophenylcarbonyl)Deoxythymidine (5′-O-pC1Ph-dT, 1 f ):
[0119] Yield 60%. R F (A)=0.42, R F (B)=0.73. 1 H NMR (CDCl 3 ) δ: 7.9 (d, 1, H 6 ), 7.44-7.16 (m, 5, aryl), 6.34 (t, J=7 Hz, 1, H 1′ ), 4.6-4.12 (m, 4, H 3′ , H 4′ , H 5,5′ ). 2.3-2.05 (m, 2, H 2,2′ ), 1.74 (s, 3, C 5 —CH 3 ). 13 C NMR (CDCl 3 ) δ: 164.4 (C-4), 153.23 (O—(CO)—O), 151.4 (C-2), 149.39, 139.86, 129.73, 122.23 (C 6 H 4 ), 136.6 (C-6), 111.1 (C-5), 85.41 (C- 1 ′), 84.8 (C-4′), 71.52 (C-3′), 67.53 (C-5′), 40.25 (C-2′), 12.49 (C 5 CH 3 ).
[0120] (C) Synthesis of 5′-O-DMT-3′-O-R-Deoxythymidines:
[0121] The 3′-hydroxyl group of 5′-O-DMT-deoxythymidine was protected with phenyloxycarbonyl ( 2 a ), benzoyl ( 2 b ), and acetyl ( 2 c ), as follows. 5′-O-(4,4′-Dimethoxytrityl)-deoxythymidine (1 mmol) was co-evaporated 3 times with anhydrous pyridine, then redissolved in 20 ml of pyridine. Corresponding chloroformates (1.1 mmol) were added to the nucleoside mixture. After stirring for 6 hr, the reaction was quenched with water (100 ml) and concentrated. Residues of pyridine were removed by co-evaporation with toluene (2×20 ml).
[0122] The resulting gum was dissolved in CH 2 Cl 2 , extracted with 10% aqueous NaHCO 3 , and dried over Na2SO 4 . After concentration, the product was loaded onto a silica gel column (50 g) and eluted with CH 2 Cl 2 using a methanol gradient (0-3%). Product fractions were collected and concentrated to a foam.
[0123] The results were as follows.
[0124] 5′-O-(4,4′-Dimethoxytrityl)-3′-O-Phenylcarbonyl Deoxythymidine ( 2 a ):
[0125] Yield 80%. R F (A)=0.74, R F (B)=0.91. 1 H NMR (CDCl 3 ) δ: 7.65-6.83 (m, 18, H 6 +DMTr+aryl), 6.57 (t, J=7 Hz, 1, H 1′ ), 5.45 (m, 1, H 3′ ) 4.34 (m, 1, H 4′ ), 3.79 (s, 6, OCH 3 ), 3.54 (m, 2, H 5,5′ ), 2.72-2.52 (m, 2, H 2,2′ ), 1.41 (s, 3, C 5 —CH 3 ).
[0126] 5′-O-(4,4′-Dimethoxytrityl)-3′-O-Benzoyl Deoxythymidine ( 2 b ):
[0127] Yield 90%. R F (A)=0.72, R F (B)=0.91. 1 H NMR (CDCl 3 ) δ: 8.07-6.85 (m, 18, H 6 +DMTr+aryl), 6.58 (t, J=7 Hz, 1, H 1′ ), 5.45 (m, 1, H 3′ ), 4.14 (m, 1, H 4′ ), 3.79 (s, 6, OCH 3 ), 3.57 (m, 2, H 5,5′ ) 2.63 (m, 2, H 2,2′ ), 1.42 (s, 3, C 5 —CH 3 ).
[0128] 5′-O-(4,4′-Dimethoxytrityl)-3′-O-Acetyl Deoxythymidine ( 2 c ):
[0129] Yield 90%. R F (A)=0.67, R F (B)=0.89. 1 H NMR (CDCl 3 ) δ: 7.62 (s, 1, H 6 ),7.4-6.82 (m, 13, DMTr), 6.46 (t, J=7 Hz, 1, H 1′ ), 5.45 (m, 1, H 3′ ), 4.14 (m, 1, H 4′ ), 3.78 (s, 6, OCH 3 ), 3.47 (m, 2, H 5,5′ ), 2.45 (m, 2, H 2,2′ ) 2.08 (s, 3, CO—CH 3 ), 1.39 (s, 3, C 5 —CH 3 ).
[0130] (D) Nucleoside Deprotection by Peroxy Anions:
[0131] Deprotection reactions were carried out using peroxy anions on alkyl and aryl 5′-O-carbonates of deoxythymidine synthesized as described above. The reactions were monitored by TLC for complete conversion of the starting material to deoxythymidine. A wide variety of peroxy anions, known to exhibit strong alpha effects, were screened for their ability to cleave 5′-O-carbonates of deoxythymidine. Peroxy anion solutions active in cleavage of the 5′-O-carbonates were buffered at a variety of pH conditions. The cleavage activity of these peroxy anion solutions was shown to be rapid only at pH conditions above the pKa for the formation of the anion. The ability of peroxy anion solutions A, B, C, D and E to completely deprotect the 5′-O-carbonates of deoxythymidines 1 a - 1 f is summarized in Table 2.
[0132] Solution A: 3.1% LiOH.H 2 O (10 mL), 1.5 M 2-amino-2-methyl-1-propanol (“AMP”), pH 10.3 (15 mL), 1,4-dioxane (50 mL), 30% H 2 O 2 (12 mL), pH 12.0.
[0133] Solution B: 3.1% LiOH.H 2 O (10 mL), 1.5 M 2-amino-2-methyl-1-propanol (“AMP”), pH 10.3 (15 mL), dimethyl sulfoxide (“DMSO”) (50 mL), 30% H 2 O 2 (12 mL), pH 12.0.
[0134] Solution C: 3.1% LiOH.H 2 O (10 mL), 1.5 M 2-amino-2-methyl-1-propanol (“AMP”), pH 10.3 (15 mL), 1,4-dioxane (50 mL), 30% H 2 O 2 (12 mL), pH 12.0, m-chloroperbenzoic acid (“mCPBA”) (1.78 g), pH 9.6.
[0135] Solution D: H 2 O (10 mL), dioxane (50 mL), 2.5 M Tris (15 mL), H 2 O 2 (12 mL), mCPBA (1.78 g), pH 9.0.
[0136] Solution E: H 2 O (10 mL), dioxane (50 mL), 2.5 M Tris (15 mL), t-butyl-OOH (0.1 M), pH 9.0.
TABLE 2 TIMES REQUIRED FOR COMPLETE CONVERSION OF PROTECTED NUCLEOSIDES 1A THROUGH 1F USING PEROXY ANION SOLUTIONS A, B, C, D AND E 5′-Carbonate-dT Reaction Completion Times for Deprotection Solutions Compounds A B C D E 1a <1 min <1 min <12 min — — 1b >1 hr <1 min >3 hr — — 1c <1 min <1 min <1 min — — 1d <1 min <1 min <1 min <1 min >12 hr 1e <1 min <1 min <1 min <2 min <12 hr 1f <1 min <1 min <1 min <1 min <12 hr
[0137] (E) Selectivity of Various Peroxy Anion Solutions for Deprotection of Carbonates:
[0138] As described in part (C) of this example, the 3′-hydroxyl group of 5′-O-DMT-deoxythymidine was protected with a phenyloxycarbonyl ( 2 a ), a benzoyl ( 2 b ), and an acetyl ( 2 c ) group. The stability of these 3′-protecting groups was determined by TLC using deprotection conditions C and D (Table 2). Under both these conditions, the phenyl carbonate was completely removed in less than 2 min. The 3′-benzoyl group was completely stable under both conditions for 140 min. The 3′-acetyl group was cleaved to a small extent (less than 3%) over the 140 min exposure to deprotection condition A (pH 10.0). The 3-benzoyl group was completely stable for the 140 min exposure to condition B.
[0139] (F) Selectivity of Deprotection on Solid-Support Attached Nucleosides:
[0140] The demonstration of stability at the 3′ position was then extended to the succinate linker commonly used for the attachment of nucleosides to Controlled Pore Glass, as follows. 5′-DMT-deoxythymidine attached to Long Chain Alkyl Amine Controlled Pore Glass (LCAA/JCPG) through a 3′-succinate linkage was obtained from a commercial source. This solid-support attached nucleoside was then exposed to deprotection conditions A through D. The stability of the 3′-linkage was determined spectrophotometrically based upon the evolution of the trityl cation during subsequent treatment with toluene sulfonic acid in anhydrous acetonitrile. Deprotection conditions A and B gave complete cleavage of the 3′-succinate in 20 min. Deprotection conditions C and D gave less than 2% cleavage of the 3′-succinate after 20 hrs.
EXAMPLE 2
Simultaneous Oligothymidylate Deprotection and Internucleotide Bond Oxidation by Peroxy Anions
[0141] (A) Oligonucleotide Synthesis on Controlled Pore Glass:
[0142] Oligonucleotides were synthesized on CPG using an automated DNA synthesizer (ABI model 380A). The synthesis cycle used for 5′-DMT protected nucleoside phosphoramidites (Cycle 1) is shown in Table 4. This cycle was initially modified for the use of 5′-carbonate protected nucleoside phosphoramidites simply by substituting the alternative deprotection mixtures for the 3% TCA solution (Step 8, Table 4) and varying the exposure times. For the synthesis of longer sequences using 5-carbonate protected nucleoside phosphoramidites, it was necessary to separate the deprotection mixture into a two-component system (Table 3). The separation of the deprotection mixture was accomplished using the capping ports on the synthesizer, and thus necessitated elimination of the capping step from the synthesis cycle. Table 4 shows the optimized cycle for synthesis using 5′-carbonate protected nucleoside phosphoramidites (Cycle 2):
TABLE 3 TWO-COMPONENT SYSTEM FOR STORAGE OF DEPROTECTION SOLUTION C Solution 30% H 2 O 2 (10 ml), LiOH (280 mg), dioxane (7.5 ml), 2.5 M C-1 Tris-Base (15 ml), water (42.5 ml) Solution 50-60% mCPBA (1.78 g), dioxane (42.5 ml) C-2
[0143] [0143] TABLE 4 OLIGONUCLEOTIDE SYNTHESIS CYCLES Cycle 1 Cycle 2 Step # Function Reagent Time, sec. Time, sec. 1 Wash Acetonitrile 25 25 2 Coupling Amidite (0.15 M, 30 eq) 2 × 30 2 × 30 Tetrazole (0.5 M, 120 eq) in Anhydrous Acetonitrile 3 Wash Acetonitrile 5 5 4 Capping N-Methylimidazole/2,6- 40 — Lutidine/Acetic Anhydride/ THF (1/1/1/2, vol/vol/vol/ vol) 5 Oxidation 0.1 M I 2 in THF/Lutidine/ 30 — Water (80/40/2, vol/vol/vol) 6 Wash Acetonitrile 25 — 7 Wash Dichloromethane (Cycle 1) 25 25 1,4-Dioxane (Cycle 2) 8 Deblock 3% TCA in CH 2 Cl 2 2 × 30 480 (Cycle 1) 1:1 mix of Solution C-1 & Solution C-2 from Table 3 (Cycle 2) 9 Wash Dichloromethane (Cycle 1) 25 25 1,4-Dioxane (Cycle 2)
[0144] (B) Analysis of Oligonucleotides by HPLC:
[0145] The oligonucleotides synthesized on the solid support were deprotected with concentrated ammonium hydroxide (55° C., 24 hr). The ammonium hydroxide solutions were removed from the support and evaporated to dryness. The crude oligonucleotides were reconstituted in distilled water and stored at −20° C.
[0146] HPLC analysis was performed by ion-exchange HPLC (Nucleogen 60-7DEAE, 4 mm ID ×125 mm). Oligonucleotides were eluted from the column with a LiCl gradient (0.0-0.7 M) in a water/acetonitrile (60/40, v/v) buffer containing sodium acetate (0.002 M, pH 6.0).
[0147] (C) Solid-support Deprotection of 5′-O-Carbonates of Thymidine:
[0148] The deprotection efficiency of peroxy-anion solutions on oligonucleotides was determined by the synthesis of oligothymidylate tetramers. The 5′-O-arylcarbonates of deoxythymidine (see part (B) of Example 1, compounds 1 a through 1 f ) were converted to the corresponding 3′-O-(2-cyanoethyl)- N,N-diisopropylphosphoramidite by procedures described generally in A. D. Barone et al. (1984) Nucleic Acids Res. 12:4051, as follows.
[0149] Synthesis of the 2-cyanoethyl-N,N,N′,N′-tetraisopropyl-phosphorodiamidite phosphine was performed according the procedure described in A. Kraszewski et al. (1987) Nucleic Acids Res. 18:177. The resulting product was purified by distillation from CsF. The product was obtained in 60% yield. Purity was confirmed by 31 P NMR (CDCl 3 ) δ: 123.8 ppm.
[0150] Thymidyl-3′-5′-deoxythymidine was synthesized on solid-support using 5′-O-dimethoxytrityl-3′-O- (2-cyanoethyl)-N,N-diisopropylaminodeoxythymidinephosphoramidite. The dimer was elongated to a trimer using a 5′-O-aryloxycarbonyl-3′-O-(2-cyanoethyl)-N,N-diisopropylaminodeoxythymidinephosphoramidite and synthesis cycle 1 (Table 4). Deprotection of the carbonate was then attempted using deprotection mixture C, at 1 min increments, from 1-15 min. The extent of deprotection was determined by the yield of the subsequent coupling reaction using a standard 5′-DMT-dT phosphoramidite. Deprotection efficiency for the 5′-O-arylcarbonate was determined using ion-exchange HPLC. The percent deprotection was calculated by integration and normalization of peak areas for the corresponding trimers and tetramers, assuming quantitative coupling reactions. The optimum deprotection time and extent of deprotection for each aryloxycarbonyl group is summarized in Table 5.
TABLE 5 OPTIMUM DEPROTECTION TIMES DETERMINED FOR 5′- ARYLCARBONATES OF THYMIDINE ON CONTROLLED PORE GLASS USING DEPROTECTION SOLUTION C 5′-Carbonate dT Optimum Deprotection Deprotection Compounds Time Efficiency 1c 5 min 80% 1d 1 min 94% 1e 7 min 98% 1f 3 min] 98%
[0151] (D) Solid Support Synthesis and Internucleotide Bond Oxidation:
[0152] Several oligothymidylate tetramers were synthesized on Controlled Pore Glass using 5′-O-p-chlorophenyloxycarbonyl-3′-O-(2-cyanoethyl)-N,N-diisopropylaminodeoxythymidine-phosphoramidite. These syntheses were performed on a 1 μmol scale using an automated DNA synthesizer. The only modification from the standard 1 μmol synthesis cycle (Cycle 1, Table 4) was the use of deprotection mixture C (7 min) in place of 3% TCA in dichloromethane. The resulting tetramers were compared to oligothymidylate tetramers synthesized using the standard DMT protected phosphoramidites of thymidine. These tetramers were then analyzed using ion-exchange HPLC. There were no detectable differences in the yield or purity of any of the oligomers.
[0153] Oligothymidylate tetramers were then synthesized using this same synthesis cycle, which was again modified by the removal of the iodine oxidation step. This concomitant deprotection and oxidation cycle produced tetramers of identical yield and purity to the standard DMT phosphoramidite synthesis. Decomposition of MCPBA in the presence of LiOH results in the deprotection mixture being effective for only a few hours. In order to synthesize longer sequences, it was necessary to separate the deprotection mixture into a two component system (Table 3). This was accomplished using the capping ports on the automated DNA synthesizer. Separating the LiOH from the mCPBA and mixing just prior to deprotection allows the reagents to remain effective for several days. Oligonucleotide synthesis using 5′-O-arylcarbonate nucleoside phosphoramidites was carried out with and without acetic anhydride capping. No adverse effects on the yield of final product or increases in the appearance of n-1 products were observed in absence of capping. This is contrary to what is seen with the use of DMT protected phosphoramidites in the absence of capping. Anion-exchange HPLC profiles of crude synthesis products of oligothymidylate decamers were produced. Product purity and yield of full-length oligonucleotides, using peroxyanion deprotection of 5′-O-carbonates in absence of acetic anhydride capping and iodine oxidation (Cycle 2, Table 4), were comparable to or better than those obtained using DMT phosphoramidites and the standard synthesis cycle.
EXAMPLE 3
Peroxy Anion Deprotection of 5′-O-DMT-protected Cytosine, Adenine, Uracil, Thymidine and Guanosine Nucleosides
[0154] The unprotected heterocyclic bases cytosine and adenine are susceptible to N-oxidation by peracids and peroxides under stringent conditions, and oxidative reactions that result in ring cleavage of uracil, thymidine and guanosine in the presence of highly concentrated peroxides at elevated temperatures have been described. 5′-O-DMT-protected nucleosides, N-protected with a (di-N-butylamino)methylene group, were dissolved in deprotection mixture C and allowed to react for 24 hrs. The tritylated nucleosides were extracted from the aqueous deprotection mixture with CHCl 3 and analyzed by 13 C NMR and TLC. Neither formation of N-oxides nor attack at the 5,6-double bond of thymidine (leading to ring cleavage) was detected.
EXAMPLE 4
Synthesis of Mixed Oligonucleotides
[0155] This example demonstrates extension of the method of the invention to synthesis of mixed oligonucleotide sequences, employing substituted aryl carbonate protected phosphoramidite synthons, and following each coupling reaction by treatment with a mixture of peroxy-anions at mild pH (less than 10) to deprotect and concomitantly oxidize the internucleotide linkage.
[0156] The method is high-yielding, and effective for the four main 2′-deoxynucleotides. Synthesis in both the 3′-5′ direction and the 5′-3′ direction were carried out, with equal effect.
[0157] (A) Protected Phosphoramidite Synthesis:
[0158] Generally, the protected nucleoside phosphoramidites were prepared as follows. The 3′- or 5′-protected nucleoside (5.00 mmol) and tetrazole (175 mg, 2.50 mmol) were dried under vacuum for 24 h and then dissolved in trichloromethane (100 mL). 2-cyanoethyl-N,N,N′,N′-tetraisopropyl phosphane (2.06 mL, 6.50 mmol) was added in one portion and the mixture stirred over 1 hour. The reaction mixture was washed with sat. NaHCO 3 (150 mL) and brine (150 mL), dried over MgSO 4 and applied directly to the top of a silica column equilibrated with hexanes. The dichloromethane was flashed off the column with hexanes, and the product eluted as a mixture of diastereoisomers using 1/1 hexanes/ethyl acetate then ethyl acetate. After evaporation of solvents in vacuo and coevaporation with dichloromethane, products were isolated as friable, white, glassy solids in yields varying from 70% to 90%.
[0159] The four 5′-aryloxycarbonyl-3′-nucleoside phosphoramidites were prepared by the straightforward two-step procedure shown generally in FIG. 4. In a first step, commercially available base protected 2′-oligodeoxynucleosides were selectively aryl carbonate protected at the 5′ position by treatment with 4-chlorophenyl chloroformate in dilute anhydrous pyridine to yield 5′-aryloxycarbonyl protected compounds in moderate to good yield. The use of more concentrated reaction mixtures resulted in an increase in the amounts of isolated 3′- and 3′, 5′-bis-aryloxycarbonyl-protected materials. In a second step, the resulting compounds were phosphitylated using the method described in Barone et al., supra, to furnish high yields following column chromatography.
[0160] Synthesis of the four 3′-aryloxycarbonyl-5′-nucleoside phosphoramidites were prepared by the three-step procedure shown in FIG. 5.
[0161] (C) Deprotection Mixture:
[0162] The deprotection mixture was formulated in two parts, which were mixed immediately prior to use. Solution F: 3.1% w/v lithium hydroxide monohydrate (10 mL), 1.5 M 2-amino-2-methyl-1-propanol pH 10.3 (15 mL), 1,4 dioxane (17.5 mL). Solution G: 1,4-dioxane (32.5 mL), 50- 83% 3-chloroperbenzoic acid (1.78 g), 30% hydrogen peroxide (12 mL). The initial pH of the deprotection mixture was 9.6±0.05. For pH dependence studies, the initial deprotection mixture was altered by varying the strength of the lithium hydroxide solution.
[0163] (D) Synthesis of Mixed-sequence Oligonucleotides:
[0164] A series of model oligodeoxynucleotides was synthesized, having sequences 3′-T 3 AT 2 AT 3 -5′, 3′-T 3 CT 2 CT 3 -5′, 3′-T 3 GT 2 GT 3 -5′, 3′-TACGT-5′, 3′TACGTACGT-5′, 3′-TA 7 T-5′, 5′-TACGT-3′, 5′-TACGTACGT-3′, and 5′-CAGTTGTAAACGAGTT-3′. HPLC analysis was performed as described in Example 2, part (B); HPLC traces of the all products confirmed the results.
[0165] The HPLC obtained for 5′-CAGTTGTAAACGAGTT-3′ is shown in FIG. 6. The calculated molecular weight for 5′-CAGTTGTAAACGAGTT-3′ is 4921.1; the actual molecular weight determined using MALDI (Matrix Absorption Laser Desorption Ionization) TOF (Time of Flight) analysis was 4921.9. The MALDI TOF spectrum is shown in FIG. 7.
[0166] (E) Stability of Base Protecting Groups in the Deprotection Mixture:
[0167] The stability of the standard base protecting groups A Bz , C Bz , and G ibu during exposure to the deprotection mixture was tested by incubating 5′-DMT base-protected deoxynucleosides at room temperature with a large excess of the deprotection mixture. The extent of cleavage of the base protecting groups over time was measured by TLC. The approximate T ½ values for A Bz , C Bz , and G ibu were approximately ½ hour, 2 hours, and 1 day, respectively, and unlikely to present difficulties for syntheses.
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The invention provides a method for synthesizing oligonucleotides using carbonate protection of hydroxyl groups and nucleophilic deprotection reagents. The deprotection reagents irreversibly cleave the carbonate protecting groups while simultaneously oxidizing the internucleotide phosphite triester linkage, and can be used in aqueous solution at neutral to mildly basic pH. The method eliminates the need for separate deprotection and oxidation steps, and, since the use of acid to remove protecting groups is unnecessary, acid-induced depurination is avoided. Fluorescent or other readily detectable carbonate protecting groups can be used, enabling monitoring of individual reaction steps during oligonucleotide synthesis. The invention is particularly useful in the highly parallel, microscale synthesis of oligonucleotides. Reagents and kits for carrying out the aforementioned method are provided as well.
| 2 |
BACKGROUND OF THE INVENTION
This invention relates to a novel peptide having potent antithrombin activity and, more particularly, to a synthetic peptide analogous to residues 54-75 of heparin cofactor II.
Heparin cofactor II (HCII) is an inhibitor of thrombin in plasma that is activated by dermatan sulfate or heparin. It is a 65,600 dalton glycoprotein member of the serpin (serine protease inhibitor) superfamily. The full sequence of 480 amino acids of the mature protein is disclosed by Blinder et al., Biochemistry 27, 752-759 (1988).
A short internal repeat amino acid sequence (Glu-Asp-Asp-Asp-Tyr-X-Asp, in which X=Ile or Leu) within HCII, beginning with Glu-56 and Glu-69, respectively, has been identified by Hortin et al., J. Biol. Chem. 261 (34), 15827-15830 (1986). These sequences flank two tyrosine residues at positions 60 and 73, respectively, which were shown to be sulfated in a human hepatoma-derived cell line (HepG2).
Further background information on HCII can be had by reference to the following illustrative papers: Tollefsen et al., J. Biol. Chem. 257, 2162-2169 (1982); Parker and Tollefsen, Ibid. 260, 3501-3505 (1985); and Hortin et al., Am. J. Clin. Pathol. 89, 515-517 (1988).
BRIEF DESCRIPTION OF THE INVENTION
In accordance with the present invention a novel synthetic peptide is provided which has potent antithrombin activity: This synthetic peptide has the following amino acid sequence: ##STR2##
The novel 22-residue peptide is analogous to residues 54-75 of human heparin cofactor II (HCII) except that Ser-68 is replaced by Ala (residue 15 in the present peptide). For convenience, this novel peptide can also be designated HCII(54-75)[Ser(68)→Ala]. It has been found that this novel peptide potently inhibits thrombin's clotting activity but not its amidolytic activity versus small chromogenic substrates. This finding of inhibitory activity by binding to a noncatalytic site is unlike most proteinase inhibitors which complex with the active site of the enzyme. See, for example, Travis and Salvesen, Ann. Rev. Biochem. 52, 655-710 (1983).
The potent antithrombin activity of the 22-residue synthetic peptide was further demonstrated by comparison with tryptic fragments of 12 and 10 residues prepared from the parent peptide but which had little anticlotting activity.
The synthetic thrombin inhibitor of the present invention also provides a novel molecular probe for investigating the specificity of thrombin's interactions with inhibitors and substrates.
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 of preferred embodiments taken in conjunction with the accompanying drawings in which:
FIG. 1 is a graphical representation which shows inhibition of fibrinogen clotting by the novel 22-residue synthetic peptide. Fibrinogen clotting times (S=seconds) in the presence of varying concentrations (μM) of the peptide were determined with a fibrometer following addition of thrombin. Each concentration of peptide was assayed in triplicate. Error bars indicate standard deviations.
FIG. 2 is a gel pattern which shows inhibition by the peptide of FIG. 1 of thrombin's cleavage of fibrinogen. Thrombin was added in the indicated amounts (U/ml) to solutions of fibrinogen and varying amounts (μM) of the peptide. After incubation for 30 minutes, clots were solubilized in sample buffer and aliquots were analyzed by sodium dodecylsulfate polyacrylamide gel electrophoresis. The mass of molecular weight markers in kDa and the identities of fibrinogen chains are indicated on the left and right sides, respectively.
The novel 22-residue synthetic peptide of this invention can be prepared by known solution and solid phase peptide synthesis methods. Thus, in accordance with conventional solution phase peptide synthesis, the peptide chain can be prepared by a series of coupling reactions in which the constituent amino acids are added to the growing peptide chain in the desired sequence. The use of various N-protecting groups, e.g., the carbobenzyloxy group or the t-butyloxycarbonyl group (BOC), various coupling reagents, e.g., dicyclohexylcarbodiimide or carbonyldimidazole, various active esters, e.g., esters of N-hydroxyphthalimide or N-hydroxy-succinimide, and various cleavage reagents, e.g., trifluoroacetic acid, HCL in dioxane, boron-tris-(trifluoroacetate) and cyanogen bromide, and reaction in solution with isolation and purification of intermediates is well-known classical peptide methodology.
The preferred peptide synthesis method follows conventional Merrifield solid-phase procedures. See Merrifield, J. Amer. Chem. Soc. 85, 2149-54 (1963) and Science 150, 178-85 (1965). This procedure, though using many of the same chemical reactions and blocking groups of classical peptide synthesis, provides a growing peptide chain anchored by its carboxy terminus to a solid support, usually cross-linked polystyrene, styrenedivinylbenzene copolymer or p-methylbenzhydrylamine polymer. This method conveniently simplifies the number of procedural manipulations since removal of the excess reagents at each step is effected simply by washing the polymer.
Further background information on the established solid phase peptide synthesis procedure can be had by reference to the treatise by Stewart and Young, "Solid Phase Peptide Synthesis," W. H. Freeman & Co., San Francisco, 1969, and the review chapter by Merrifield in Advances in Enzymology 32, pp. 221-296, F. F. Nold, Ed., Interscience Publishers, New York, 1969; and Erickson and Merrifield, The Proteins, Vol. 2, p. 255 et seq. (ed. Neurath and Hill), Academic Press, New York, 1976.
In order to illustrate specific preferred embodiments of the invention in greater detail, the following exemplary laboratory preparative work was carried out.
Example
Solid phase peptide synthesis was carried out to provide a novel 22-residue synthetic peptide having the following amino acid sequence: ##STR3##
Materials and Methods
Materials: Reagents were obtained from the following sources: t-butyloxycarbonyl amino acids from Bachem, t-butyloxycarbonyl-L-(β-benzyl)-aspartic acid phenylacetamidomethyl resin from Applied Biosystems, solvents from Burdick & Jackson, trifluoroacetic acid from Pierce Chemical, human thrombin, bovine thrombin, and Ancrod (protease from venom of Agkistrodon rhodostoma) from Sigma Chemical, human fibrinogen from Helena, 1,000 U/ml solution of heparin from Organon, trypsin (treated with tosylphenylalaninylchloromethyl ketone) from Worthington Biochemicals, and chromogenic substrates S-2366 (pyroglutamylprolylarginyl-para-nitroanilide) and S-2288 (D-isoleucylprolylarginyl-para-nitroanilide) from Helena.
Peptide Preparation: Peptide synthesis was performed using an Applied Biosystems 430A synthesizer. Coupling steps employed activation of protected amino acids as their symmetric anhydrides. Sidechain protection of α-N-t-butoxycarbonyl-blocked amino acids was effected by the following groups: O-benzyl for Asp, Glu; O-orthobromobenzyloxycarbonyl for Tyr; ortho-chlorobenzyloxycarbonyl for Lys. Deprotection of the synthetic peptide and cleavage from the resin were performed by Immuno-Dynamics Inc. using anhydrous HF. The peptide was purified by reverse-phase HPLC using a 1×25 cm Vydac 218TP octadecylsilica column with a gradient of increasing acetonitrile in 0.05% trifluoroacetic acid. Tryptic peptides were prepared by cleaving 60 mg of peptide with 1 mg trypsin in 100 ml NH 4 HCO 3 . The digest was ultrafiltered through a Centricon-10 unit (Amicon) to remove the trypsin. The two tryptic peptides were purified by reverse-phase HPLC. Purified peptides were prepared as aqueous solutions for assays of activity. Compositions of peptides and concentrations of peptide solutions were determined by vapor-phase hydrolysis with 6N HCl for 24 h at 110° C. Amino acids were quantitated with a Beckman 6300 analyzer, with standardization of recovery using a norleucine internal standard. The composition of the novel 22-residue synthetic peptide thus prepared was: Asp 8.0, Thr 0.0, Ser 0.0, Glu 4.0, Pro 0.0, Gly 1.0, Ala 1.1, Val 0.1, Met 0.0, Ile 1.8, Leu 1.9, Tyr 1.4, Phe 1.0, His 0.0, Lys 1.0, Arg 0.0. All values were within 0.2 of expected theoretical integer values, except the value for Tyr is low due to losses during hydrolysis. The determined ε 280 =2,380 in water at 24° C. and theoretical M r =2,638 for the novel 22-residue synthetic peptide.
Fibrinogen Clotting Assays: Peptides were mixed with a solution of fibrinogen and clotting was initiated by addition of thrombin to a concentration of 0.4 U/ml. The total volume was 0.25 ml with a final composition of 1 mg/ml fibrinogen, 125 mM NaCl, 10 mM Hepes, pH 7.4, 6 mM sodium citrate, 10 mM CaCl 2 , and 1% polyethylene glycol. All reagents were equilibrated to 37° C. before mixing. The endpoint of clotting was established using a Precision fibrometer with an electro-mechanical probe. Clotting times were related to a standard curve of clotting times versus thrombin concentration.
Amidolytic Assays of Thrombin: Aliquots of thrombin were added to a solution containing varying amounts of synthetic peptide and 0.2 mM chromogenic substrate (S-2366 or S-2288) in 140 mM NaCl, 10 mM Hepes, pH 7.4, 1 mg/ml polyethylene glycol. Hydrolysis of the substrate at room temperature was monitored at 405 nm with a Hitachi U-2000 spectrophotometer.
Fibrinogen Cleavage Assay: Inhibition of thrombin's cleavage of fibrinogen was assessed by including varying amounts of synthetic peptide in 0.1 ml reactions containing 1 mg/ml fibrinogen and 0.005-0.1 U/ml thrombin. Final ionic conditions were: 130 mM NaCl, 10 mM Hepes adjusted to pH 7.4 with NaOH, and 6 mM sodium citrate. Reactions were incubated for 30 min at 37° C. Resulting clots were solubilized by adding an equal volume of 4% sodium dodecylsulfate, 10% 2-mercaptoethanol, 20% glycerol and heating the mixture for 2 min at 100° C. Aliquots (60 μl) of each sample were analyzed by polyacrylamide gel electrophoresis using the system of Laemmli as in previous work by Hortin et al., J. Biol. Chem. 261, 15827-15830 (1986). Protein bands in gels were visualized by staining with 0.1% Coomassie brilliant blue R.
Results
The novel 22-residue synthetic peptide, HCII(54-75)[Ser(68)→Ala], was found to be an effective inhibitor of thrombin's clot-forming activity in a system containing purified fibrinogen and human thrombin (FIG. 1). Measurements of clotting time showed progressive inhibition of clotting by increasing amounts of peptide. Comparison of these results to a standard curve of thrombin concentration versus clotting time indicated that 50% inhibition of thrombin's effect was produced by a peptide concentration of 2.8 μM. (According to the standard curve of thrombin concentration, addition of half the standard amount of thrombin to the assay system yielded clotting in 54 sec.)
Tryptic fragments of 12 and 10 residues, prepared from the 22-residue synthetic peptide, had little anticlotting activity compared with the parent peptide. No significant changes in clotting time were produced by concentrations of tryptic peptides 10-fold higher than the IC 50 of the parent peptide. Results with the tryptic peptides thus did not localize functional sites in the 22-residue peptide. However, the results with the tryptic peptides served as a control for nonspecific effects of peptides added to the system. Heparin added to a final concentration of 10 U/ml also had no effect on clotting time in this system, and this served an important control that the fibrinogen preparation did not contain significant amounts of HCII, which might be activated by polyanions such as the synthetic peptide.
Clotting of fibrinogen by the snake venom proteinase, Ancrod, was not affected by addition of the 22-residue synthetic peptide, even at a concentration of 20 μM (Table 1). This result indicated that changes in clotting times induced by the synthetic peptide were not due to interference with fibrin polymerization, and that the inhibitory effect was selective for thrombin.
Although the 22-residue synthetic peptide inhibited thrombin's action in the clotting assay, the peptide, even at relatively high concentrations, had little effect on thrombin activity measured with two chromogenic substrates. In the presence of 14 μM synthetic peptide, action of thrombin on the substrate S-2366 under the conditions described in Materials and Methods, above, yielded a rate of hydrolysis of 8.2±0.2 μmol/L min (mean±S.D. for triplicate analyses) and 8.2±0.1 μmol/L min without peptide. Similar results were obtained with the substrate S-2288; the rate of hydrolysis was 10.1±1.1 μmol/L min with 14 μM peptide and 9.7±0.3 μmol/L min for control reactions. These results indicated that the peptide was not blocking thrombin's active site. The peptide's inhibition of clotting must then result from binding to a noncatalytic site on thrombin so as to impede interactions with the larger physiological substrate, fibrinogen.
TABLE 1______________________________________Clotting activity of Ancrod:Lack of Effect of HCII(54-75)[Ser(68) → Ala]Clotting of fibrinogen by Ancrod was determined using afibrometer. Varying amounts of ancrod were assayed induplicate to standardize clotting time versus activity.Clotting times in the presence of peptideHCII(54-75)[Ser(68) → Ala] are shown as the mean ±standard deviation (N = 4). HCII(54-75)-Ancrod [Ser(68) → Ala] Clotting timeU/ml μM seconds______________________________________0.10 0 24.5 ± 1.60.10 10 25.2 ± 0.90.10 20 25.5 ± 0.5Standards0.05 0 43.90.10 0 24.50.20 0 16.00.40 0 10.5______________________________________
The effects of the 22-residue synthetic peptide on thrombin's cleavage of fibrinogen was assessed directly by polyacrylamide gel electrophoresis to determine whether thrombin's release of fibrinopeptide A from the α-chain and fibrinopeptide B from the β-chain were inhibited in parallel (FIG. 2). Excision of the fibrinopeptides decreased the apparent molecular weight of the α and β-chains by about 2,000. The Aα-chain of the fibrinogen used in this test is represented by two bands (lane 9), both of which were converted by thrombin to products about 2,000 daltons smaller (lanes 1 and 5). The Bβ-chain likewise was converted to the slightly smaller β-chain although higher concentrations of thrombin are required to complete this cleavage efficiently. Thrombin is known to act more rapidly on the Aα-chain so that, at low concentrations of thrombin, the Aα-chain is cleaved preferentially. At higher concentrations of thrombin both the Aα and Bβ-chains are cleaved. The 22-residue peptide inhibited the ability of thrombin to cleave both the Aα and Bβ-chains (lanes 2-4 and 6-8). This test indicates that, even though the peptide does not block thrombin's active site, it inhibits thrombin's excision of both fibrinopeptides from fibrinogen.
Amino acids are shown herein by standard three letter abbreviations as follows:
______________________________________Abbreviated Designation Amino Acid______________________________________Ala AlanineCys CysteineAsp Aspartic acidGlu Glutamic acidPhe PhenylalanineGly GlycineHis HistidineIle IsoleucineLys LysineLeu LeucineMet MethionineAsn AsparaginePro ProlineGln GlutamineArg ArginineSer SerineThr ThreonineVal ValineTrp TryptophanTyr Tyrosine______________________________________
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. It is intended that all such other examples be included within the scope of the appended claims.
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A novel synthetic peptide with potent antithrombin activity is provided which has the following amino acid sequence: ##STR1##
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FIELD AND BACKGROUND OF THE INVENTION
The invention relates to a method for marking workpieces and to a device to execute the method, using a probe intended for measuring machines, particularly multicoordinate measuring machines and particularly a measuring probe with a chuck for one or several tracer pins.
Marking machines are already known which are similar in their mechanical design to the three-coordinate measuring machines. However, in their overall construction, such marking machines are considerably more simple and rugged than the measuring machines because, basically, marking requires less accuracy than measuring.
For instance, the marking machine can absorb without problems the forces occurring in marking whereas themeasuring machine, due to its mechanical construction and its application, is not suited therefor.
Since the workpieces to be marked often differ greatly from each other as rough parts according to the respective manufacturing process and the marking operation is geared to desired values, the possibility to operate marking machines by the NC method is very remote. The tool, e.g. a scriber, is normally connected to the chuck and the overall mechanism of the marking machine. The latter is fed to the workpiece in accordance with the given control data.
But the scriber does not detect the workpiece contour and therefore travels with increased force over material accumulations.
The essential disadvantages of the known marking machine are:
they are suited exclusively for the marking of simple geometric elements such as circles and straight lines;
due to the machine design, the accuracy attainable is relatively poor;
the wear of the scriber is relatively great;
the workpieces to be scribed must be aligned mechanically; and
automatic marking is possible only with restrictions because the machine is not controlled by the workpiece.
The three coordinate measuring machines, suited per se for marking from the aspect of their precision, are not usable, however, for the reason that they offer no possibility of absorbing forces and that they can handle only small tool weights due to the measured value pickup system present.
SUMMARY OF THE INVENTION
The invention provides a method for the marking of workpieces which avoids the above mentioned disadvantages of the conventional marking machines and which is easy to execute while permitting the marking of any configurations with great accuracy. It is also an object of the invention to provide a mechanically simply designed device for the execution of the method.
According to the invention, these problems are solved in that a voltage is applied to a scriber and that the scriber, as it moves across the surface of the workpiece, draws a line thereon through burning by means of voltage spark-over and current flow between the tip of the scriber and the surface of the workpiece. The tip of the scriber may be inserted in a measuring probe of a multicoordinate measuring machine, with the interposition of an electrical insulation between it and the probe.
The advantage of this marking method is contactless, low-force marking of lines on workpiece surfaces. It is optional to apply an AC or DC voltage to the scriber tip. The strength of the line made is essentially a function of the current set, of the quality of the scriber tip, and of the position of the scriber tip relative to the surface normal. The device for the execution of the method, using a probe intended for multicoordinate measuring machines, provides, according to the invention, that there be inserted in the probe a pin whose scriber tip, electrically insulated against the probe, is connected to a voltage source in such a manner that the scriber tip carries a potential; and a voltage is present between scriber tip and workpiece surface. The scriber tip may be connected to an AC-fed voltage source which may again be turned on and off by a switch. Advantageously, there is between the scriber tip and the workpiece surface facing it a constant air gap of 0.1 to 0.5 mm.
This device according to the invention makes contactless marking possible in a technically simple manner. Since the scriber tip is connected to a voltage source, a fine arc is drawn between the scriber tip and the workpiece surface of the part to be marked when a voltage is applied, generating a thin line equivalent to a mechanically scribed line. The characteristic typical of the probe of the three-coordinate measuring machine permits the maintenance of contact between scriber tip and workpiece due to the readjustment behavior, even in the event of surface deviations. The three-coordinate measuring machine, thus used as a marking machine, controls the scriber tip through the coordinates known to it. The tip is defined through the known calibration by means of a prepared auxiliary calibrating ball or by the tip setting procedure by means of a calibrating cube with holes. The strength of the line made is essentially a function of the current set, of the quality of the scriber tip and of the position of the tip relative to the surface normal. The surface quality and the material to be marked also affect the durability of the scriber tip. This means that workpieces with poor surfaces, such surfaces as rolled, or with hammer impressions, etc., require high marking currents. Where long marking lines are involved, there also results under these conditions increased burning of the scriber tip, automatically leading to a broadening of the line made.
To counteract this wear and at the same time provide a good possibility to replace the scriber tip quickly, the tip is made of metal, preferably tungsten, and retained in an axial hole in the pin by a cross pin, or a cross screw, according to a further development of the invention.
The pin is separated in its area facing the probe and both mutually and coaxially facing ends may be joined to each other by an interposed adapter of electrically insulating material. The advantage of this design is that both the probe and the marking machine are electrically insulated against the scriber tip, thereby preventing basically in particular personal injury through electrical shock.
In another embodiment of the invention, the scriber tip may be disposed axially movable within a coil connected to a voltage source reduced to low voltage by a transformer, the scriber tip working at an impressed frequency on the workpiece surface due to the action of a compression spring. The advantage of this design is, first, that only a low voltage gets to the scriber tip, which excludes personal injury alsop when the scriber tip is touched unintentionally. When voltage is applied, a current transfer from the scriber tip to the workpiece surface takes place. At the same time, to coil generates an electrical field through which the scriber point is lifted off perpendicularly from the workpiece surface against the force of the spring. This motion of the scriber tip is immediately reversed by the marking of the arc. This mechanical resonant circuit thus realized causes a line composed of dots to be drawn on a workpiece surface when the probe is moved across it. At an appropriately high frequency of 50 Hz to about 200 Hz a solid line may appear also.
In further developments of the invention, the scriber tip may be made of a ceramic material and have an axial hole to guide a thin wire which exits at the tip and is connected to a voltage source so that the wire end carries a potential and a voltage prevails between the end of the wire and the workpiece surface disposed with spacing. The wire may be refed automatically in accordance with its burn-off rate. In this embodiment of the invention an electrically insulating ceramic tip is utilized which is retained spaced from the workpiece surface. A line is drawn on the workpiece surface due to the burning of the inserted wire whose end carries a potential, leading to a spark-over at the voltage applied between the wire and the workpiece surface.
In all cases of marking there is a burn-out of the surface with very shallow depth.
Accordingly, it is an object of the invention to provide an improved method for the marking of workpieces using a scriber tip which comprises applying a voltage to the scriber tip as it is moved across a workpiece surface so that it causes a line to be drawn thereon due to the burning produced by the voltage spark-over and current flow between the scriber tip and the workpiece surface.
A further object of the invention is to provide a device for the execution of the method for marking workpieces using a probe intended for measuring machines and in particular a multicoordinate measuring machine and comprising a measuring probe having a tracer pin chuck with a pin in the chuck having a scriber tip and with means electrically insulating the tip from the probe and including a voltage source connected to the tip in such a manner that the scriber tip carries a potential and a voltage prevails between the scriber tip and the workpiece.
A further object of the invention is to provide a simple and easy and inexpensive method for marking workpieces and to a new and useful device for accomplishing the method which is simple in design, rugged in construction and economical to manufacture.
The various features of novlety 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 preferred embodiments of the invention are illustrated.
BRIEF DESCRIPTION OF THE DRAWINGS
In the drawings:
FIG. 1 is an elevational view of a scriber in a probe, partly in section and constructed in accordance with the invention;
FIG. 2 is a view similar to FIG. 1 of another embodiment of the invention showing the scriber tip disposed axially movable in a coil; and
FIG. 3 is a view similar to FIG. 1 of still another embodiment of the invention showing a ceramic tip of different design with inserted wire.
DESCRIPTION OF THE PREFERRED EMBODIMENTS
Referring to the drawings in particular in accordance with the invention a method for marking a workpiece uses a scriber tip 6 and it comprises applying a voltage to the scriber tip, for example from a voltage source 9 using a circuit which is connected to the tip and to a workpiece of surface 11. The voltage is applied as the tip 6 is moved across the workpiece surface so that it causes a line to be drawn on the surface due to the burning effected by the voltage spark-over and current flow between the scriber tip and the workpiece surface.
Shown in FIG. 1 is the lower part of a measuring probe 1, as usually employed in three-coordinate measuring machines. Clamped in chuck 2 of probe 1 is a pin 3 in coaxial extension of the probe. Th pin 3 is separated in its upper area and consequently consists of two parts. Inserted between the two parts of pin 3 is an adapter 4 of electricity insulating material. The lower part of pin 3 has an axial hole 5, into which the scriber tip 6, such as of tungsten, is inserted from below. The scriber tip 6 is kept in place by a transversely inserted screw 7. The central part 8 of pin 3 is connected to a voltage source 9. In the embodiment example according to FIG. 1, a DC voltage source 9 is shown. Also provided is a switch 10, by means of which the voltage can be turned on and off. When the switch 10 is closed, the scriber tip 6 carries a potential. Since the workpiece surface is also connected to the voltage source, a voltage prevails between the marking tip 6 and the workpiece surface 11. The scriber tip 6 is constantly at a defined spacing from the workpiece surface 11 so that an air gap 12 exists between workpiece 11 and scriber tip 6. A current spark-over now occurs between the scriber tip 6 and the workpiece surface 11, which leads to a low depth burn-out of the workpiece surface. If the probe 1 is simultaneously moved transversely, a thin marking line will appear on the workpiece surface 11 according to given machine data.
The embodiment example according to FIG. 2 shows a solution with a low voltage of about 10 to 12 V. This is achieved with an AC source by the interposition of a transformer. The lower part 13 of a pin 3, or its central part 8, is disposed axially movable in the center of a coil 14. Again, the scriber tip 6 is inserted into an axial hole 5 in the lower part. The top of the lower part of pin 3 is acted upon by a compression spring 15 supported by the upper part 16 of the pin. The compression spring 15 causes the scriber tip 6 to rest on the workpiece surface 11. Now, the coil 4 is connected to the AC voltage source 17 on the one hand and to the lower part 13 of pin 3 on the other. Due to the simultaneous electrical connection of the workpiece surface 11 to the voltage source 17, a voltage is applied in the operating state between the scriber tip 6 and the workpiece surface 11.
If the scriber tip 6 is now caused to contact the workpiece surface 11, the potential at the scriber tip 6 collapses and and the voltage applied to the coil 14 generates in known manner, a magentic field with the current flowing through, with the consequence that the lower part 13 of pin 3 moves upwardly against the force of the compression spring 15, thereby lifting the scriber tip 6 off the workpiece surface 11. This interrupts the current flow between the scriber tip 6 and the workpiece surface 11 with the consequence that the lower part 13 of pin 3, together with the scriber tip 6, pushed back onto the workpiece surface 11 again by the compression spring 15. This process repeats when voltage is applied at an impressed frequency which may be between 50 and 200 Hz. If the probe together with the pin 3 and the scriber tip 6 is moved transversely across a workpiece surface 11, a marking line is generated on it. The coil 4 in FIG. 4 is joined mechanically to the pin 3 by a yoke 25. To produce an axial motion of the lower pin part 13 relative to the pin 3, a bolt 24 is attached axially to the pin 3 which immerses centrally through the spring 15 into a recess 23 on the face of the lower pin part 13.
In FIG. 3, the scriber tip 18 is designed as a guide tip of a ceramic material, into which is machined an axial hole 19 with lateral exit. Inserted in this hole is a very thin wire about 2 to 3 one hundredth of a millimeter in diameter. The wire 20 ends approximately flush with the guide tip 18 which ends a slight distance above the workpiece surface 11. In the embodiment example according to FIG. 3, a voltage is again applied to the thin wire 20 so that a potential prevails between the wire end 20 and the workpiece surface 11. The voltage source 17 can be turned on and off by a switch 10. Since in operating condition the thin wire will burn off at the guide tip 19, the wire 20 is automatically refed, e.g. from a spool 21 by a motor 22.
While specific embodiments of the invention have 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 for the marking of workpieces and a device for the execution of the method, uses a probe intended for multicoordinate measuring machines and having a chuck for tracer pins. A scriber is inserted in the probe which is connected to a voltage source so that a voltage prevails between the scriber tip and workpiece surface and a fine line is drawn due to the burn-off through voltage spark-over and current flow.
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BACKGROUND OF THE INVENTION
The invention relates to the manufacture of molded bodies by pressing finely divided material with a binder in general and more particularly to an improved method of this type for manufacturing molded bodies, as well as an appropriate machine for carrying out the method.
In the manufacture of molded bodies of the kind under discussion, especially in the manufacture of chip boards, organic binders, for instance, in the form of resins of the most varied kind, are usually used. In certain cases, particularly at elevated temperature, these resins present difficulties if they are in contact with the oxygen in the air. The resins can be subjected, for instance, to undesired oxidation which can go as far as the danger of explosion. This can also be brought about by the fact that the binders secrete vapors during the setting process which, together with the oxygen of the air, result in an explosive mixture.
SUMMARY OF THE INVENTION
Starting from this problem, it is an object of the present invention to develop a method of this nature in such a manner that separation of the material from the ambient atmosphere is provided during the pressing and setting.
According to the present invention, this problem is solved by carrying out the pressing and setting in a gas atmosphere different from air.
Obviously, the difficulties which resulted from the continuous access of air in the conventional method, are eliminated thereby. The invention, however, comprises not only the avoidance of possible detrimental effects of the presence of air but, in addition, also provides a possible positive effect of the gas atmosphere which is different from air, on the setting of the binder and the formation of the molded body. It is conceivable, for instance, that certain binding processes are catalyzed by the presence of a certain gas or that through the presence of such gas at the surface of the molded body being formed, setting processes deviating from the interior take place there in a desired manner.
In most cases, however, the binder and/or the material will be sensitive to oxygen at high temperatures, so that the method will be one in which the oxygen concentration in the gas atmosphere does not exceed, at most, a very low value.
A gas for the purpose under discussion, which is easy to handle particularly because its density is higher than that of air, is carbon dioxide. A less expensive alternative is nitrogen. It, however, is lighter than air and accordingly requires appropriate equipment. In some cases it is sufficient to replace the oxygen component of the air in the vicinity of the pressing zone, to a considerable part, with nitrogen, in order to obtain a sufficient reduction of the reactivity of the air.
If the requirements as to the purity of the gas atmosphere surrounding the pressing zone are less stringent, in some cases it is sufficient to surround the pressing zone by a stream of the gas, for instance, by providing gas outlet openings on one side of the pressing zone and suction openings for the gas on the opposite side and to make sure that the entire pressing zone is in the resulting flow.
Depending on the design of the press, the pressing zone may also be surrounded by a tray that can be filled with the gas.
The carbon dioxide embodiment is thought to be the safest embodiment. Furthermore, it can also be realized in practice relatively simply, however, provided that the entire press is arranged in a pit which can be filled with the gas and the upper edge of which extends at least to above the pressing zone.
In both above-mentioned cases a gas is used, of course, which is heavier than air and is able to displace air from the tray or the pit without escaping into the ambient atmosphere to an appreciable extent. Carbon dioxide meets these requirements.
The installation of a hood can be considered if the gas is lighter than air. Panels such as chip board can be produced continuously in the form of webs. In certain critical cases it may be necessary to install the continuous press, with its feeding and removal equipment entirely in the pit if the material must also be in the gas atmosphere in the charging section and the discharging section. As a result, the pit and the amount of gas to be fed in must, of course, be very large and other handling problems in the charging and discharging section occur also. Therefore, if it is only necessary to maintain the gas atmosphere in the pressing zone proper, the charging section and the discharging section can be also situated outside the pit or tray or hood and can be sealed from the gas atmosphere.
In many cases the seal need not be perfect, if the gas, as for instance, in the case of carbon dioxide, is not poisonous or explosive. Provision must merely be made that excessive amounts of gas are not lost from the pit through overflow at the points where the lower forming belt enters or leaves the pit.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 shows a vertical longitudinal section through a press for the continuous manufacture of chip board, with two revolving forming belts, which is arranged in a pit.
FIG. 2 shows a corresponding view in which the pressing zone is arranged in a tray and the chasrging and discharging section of the lower forming belt are arranged outside the tray.
FIG. 3 shows a side view of a molding press in which the pressing zone proper is arranged in a tray.
FIG. 4 shows a view corresponding to FIGS. 1 and 2 of an embodiment with a gas stream enclosing the pressing zone.
DETAILED DESCRIPTION
The press 30 of FIG. 1 comprises an upper forming belt 1 and a lower forming belt 2 which revolves endlessly in the directions indicated around the cylinders 3 and 4 and 5 and 6. The cylinders 3 and 4 and 5 and 6 have horizontal axes parallel to each other. The cylinders 4 and 6 are driven.
Between the cylinders 3 and 4, above the lower section of the forming belt 1, a support structure 7 in the form of a heavy plate is arranged. Below the upper section of the forming belt 2 a support structure 8 is arranged opposite the support structure 7. The support structures 7 and 8 are connected to each other laterally outside the forming belts 1 and 2 by strong anchors. The forming belts 1 and 2 are braced, a rolling motion in their forward travel, against the sides of the support structures 7 and 8 facing each other, by roller chains 9. The roller chains 9 return in suitable slots in the support structure 7 and 8. The pressing zone proper, 10, is formed between the suport structures 7 and 8.
The lower forming belt 2 is longer than the upper forming belt 1 and forms, ahead of the pressing zone 10, as seen in the travel direction, a charging section 11, in which a bed of material, from which the panel is to be formed, is placed on the lower forming belt 2. After the pressing zone 10, as seen in the travel direction, a discharge section 12 is provided, in which the finished panel 14 is taken from the lower forming belt 2.
The bed 13 placed on the lower forming belt 2 is taken along by the lower forming belt 2 in its forward travel and is compressed between this belt and the forming belt 1 in the pressing zone 10. The pressure and, if applicable, the heat, required for setting are transferred via the roller chains 9 and the forming belts 1 and 2 from the support structure 7 and 8 to the bed 13, whereby the compacted sheet web 14 is formed.
The entire press 30 is located in a pit 16 situated below the floor 15 of the room which has a feed line 17 for feeding a gas (indicated by dots), for instance, carbon dioxide, as well as a suction line 18 by means of which the gas can be drawn from the pit 16 if desired, for instance, if maintenance work is to be undertaken.
The upper edge of the pit, i.e., the level of the floor 15, is above the lower section of the forming belt 1, so that the material of the bed 13 is situated below the gas level when the pit 16 is filled with gas, and is separated from the ambient air atmosphere.
Arranging the press 30 in the pit 16 has advantages because the gas cannot spread in the factory room. However, the cost for this arrangement is relatively high.
In FIG. 2, another embodiment is shown, in which the press 30 is arranged in a tray 20 which sits on the floor 15 of the room. In the embodiment according to FIG. 2 the entire press is furthermore not arranged in the tray 20; only the region of the pressing zone 10 is in the tray while the charging region 11 and the discharging region 12 are located outside the tray 20. At the points 19 and 21 where the lower forming belt 2 passes through the walls of the tray 20, seals are provided; the upper seal 19, especially on the entrance side, cannot be a hermetic seal since it has to pass the loose bed 13.
In FIG. 3, an ordinary, not continuous, molding press 40 with two mold halves 23 and 24 which are pressed together is shown. In the region of the pressing zone between the two mold halves 23 and 24, a tray 25 is provided, by means of which a gas atmosphere can be maintained in the vicinity of the pressing zone when the tray is supplied with gas.
Also in the embodiments of FIGS. 2 and 3, suitable devices for filling and emptying the trays 20 and 25 with the gas are provided, of course.
In FIG. 4, the press 30 is shown again. This time, however, no part is located in a container with a stationary amount of gas as in the other embodiments. Instead, the pressing zone 10 is surrounded by an enclosing gas stream. The gas is fed in through nozzles 26 at the press entrance and through other nozzles 27 along the sides of the press between the forming belts 1 and 2 and is optionally collected again on the exit side by means of a suction nozzle 28. While the gas in this embodiment does not bring about an absolute separation from the air atmosphere, it can still have an adequate effect as a protective gas if the requirements are less stringent. Covers or channels, not shown, may be provided along the edges of the web which hold the gas stream together.
Instead of a tray open at the top as in FIGS. 2 and 3, a hood which is closed at the top may also be provided if the gas is lighter than air and has a tendency to escape upward.
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In order to manufacture molded bodies by pressing finely divided material with a binder while the binder sets, such as to avoid problems caused because of contact of the binder or vapors therefrom with oxygen, the pressing and setting is carried out in a gas atmosphere different from air.
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FIELD OF THE INVENTION
The present invention relates to a transversely mountable power train for a vehicle comprising a power take off, and more particularly but not exclusively to such a transversely mountable power train for an amphibious vehicle. The invention also relates to a vehicle having a transversely mounted power train with a power take off.
1. Description of the Relevant Art
In an amphibious vehicle it is advantageous to use a transverse power train for driving the rear wheels of the vehicle, because the power train does not extend far forward of the rear wheels. The weight of the power train is therefore positioned towards the back of the vehicle, which is necessary for good vehicle performance when the vehicle is in marine mode. Furthermore, the position of the power train maximizes the space available towards the front of the vehicle for the passenger compartment.
In a conventional mid-engined vehicle having a transverse power train, there is usually no power take off. However, in the case of an amphibious vehicle, it is usually necessary to provide power to a marine propulsion unit, for example a water jet or propeller, positioned at the rear of the vehicle, and therefore a power take off is required.
2. Summary of the Invention
It is an object of the invention to provide a power take off from a transverse power train, which is suitable for powering a marine propulsion unit of an amphibian vehicle.
According to a first aspect of the invention, there is provided a power train for a vehicle comprising an engine and gearbox adapted for mounting transversely within the vehicle, characterised in tat a power take off means is mounted to an input shaft of the gearbox for rotation therewith, the power take off means being arranged externally of a casing of the gearbox.
According to a second aspect of the invention, there is provided a vehicle having a power train in accordance with the first aspect of the invention. Preferably the vehicle is an amphibious vehicle and the power take off drives a marine propulsion unit of the vehicle.
BRIEF DESCRIPTION OF THE DRAWINGS
Several embodiments of the invention will now be described, by way of example only, with reference to the accompanying drawings in which:
FIG. 1 Is a perspective view of a conventional transverse power train for a vehicle;
FIG. 2 is a cross-sectional view through part the transmission of the conventional power train of FIG. 1;
FIG. 3 is a perspective view of a first embodiment of a transverse power train for a motor vehicle having a power take off in accordance with the invention;
FIG. 4 is a plan view, partly in cross-section, of part of the transverse power train of FIG. 3;
FIG. 5 is a cross-sectional view through part of the transmission of the power train of FIGS. 3 and 4;
FIG. 6 is a view similar to that of FIG. 4 but showing a modified embodiment in which the transmission comprises a manual change gearbox;
FIG. 7 is a schematic plan view of a further embodiment of a transverse power train with power take off in accordance with the invention;
FIG. 8 is a view similar to that of FIG. 7 showing a yet further embodiment of a transverse power train with power take off in accordance with the invention.
DETAILED DESCRIPTION
FIG. 1 shows a known transverse power train for a vehicle (not shown). The power train comprises an engine 92 and a transmission 40 which provides drive to the rear wheels (not shown) of a vehicle via drive shafts 68 , 69 . The transmission comprises a gearbox and an integrated final drive unit.
FIG. 2 shows part of the transmission 40 of the power train of FIG. 1. A drive tube 12 , which is mounted in bearings 14 , runs axially of the transmission 40 and provides an input to the gearbox of the transmission. A driven sprocket 16 at one end of the drive tube 12 is connected to a driving sprocket (not shown) which is driven by the engine 92 via a torque converter (not shown), by means of an endless chain or toothed belt 18 , shown in dotted outline.
An axle shaft 20 is axially mounted inside, and concentric with, the drive tube 12 , and receives power from the final drive (not shown) of the transmission. The transmission has a casing 22 , which is apertured at 24 , and a circular boss 26 extends into the transmission from the periphery of the aperture 24 The boss 26 terminates in a shoulder 28 which extends into the aperture. Bearings 30 , which locate against the shoulder 28 , mount the end of the axle shaft 20 in the boss 26 of the casing 22 . The axle shaft 20 extends through the aperture 24 and is connected to a constant velocity joint 32 which provides drive to one of the rear wheels of the vehicle (not shown). An oil seal 34 seals between the boss 26 and the axle shaft 20 , and protects the bearings 30 .
A first embodiment of a transverse power train in accordance with the invention will now be described with reference to FIGS. 3 to 5 . Parts in common with the conventional power train of FIGS. 1 and 2 are given the same reference numerals.
The power train is similar to the power train of FIG. 1 and comprises an engine 92 and a transmission 40 . The transmission comprises a automatic gearbox 41 and a final drive unit 96 which provides drive to the rear wheels of the vehicle (not shown) via drive shafts 68 , 69 . The crankshaft 94 of the engine, a part of which can be seen in FIG. 4, is arranged parallel with and overlapping an input shaft, in the form of a drive tube 42 , of the gearbox 41 . This arrangement is commonly known as a wrap around transmission.
In accordance with the invention, a power take off in the form of a sprocket 65 is secured to the drive tube 42 of the gearbox for rotation therewith. As is shown in FIGS. 3 and 4, the power take off can be used to provide drive to a marine propulsion unit 88 of an amphibious vehicle. In the embodiment shown, the drive is provided via a decoupler 76 . The decoupler 76 has a driven sprocket 78 connected to the power take off sprocket 65 by means of an endless belt or chain 80 , shown in dotted outline. Alternatively, the power take off could use a gear drive. A cardan shaft 82 connects the drive from the decoupler 76 to a pair of bevel gears 84 . An impeller 86 of a jet drive 88 (FIG. 3) is driven by a drive shaft 90 from one of the bevel gears 84 .
The attachment of the power take off sprocket 65 to the input shaft 42 of the gearbox is shown in more detail in FIG. 5 which shows part of the transmission 40 . The transmission 40 is similar to the conventional transmission 40 described above with reference to FIG. 2 but has been adapted to provide a power take off. As in the conventional transmission 40 already described, the drive tube 42 runs axially of the transmission 40 and provides drive to the gears (not shown) of the gearbox. A driven sprocket 46 at one end of the drive tube 42 is connected to a driving sprocket 47 (see FIG. 4) by means of an endless chain 48 , shown in dotted outline. The driven sprocket 46 is formed on a flange 50 at the left-hand end (as viewed) of the drive tube 42 . The driving sprocket 47 is itself driven from the engine via a fluid flywheel such as a torque converter 95 .
The transmission 40 is housed in a casing 52 which is modified from the standard casing 22 , previously described with reference to FIG. 2 . The aperture 24 of the casing 22 is increased in size to form a new aperture 54 . The aperture 54 is circular and a flanged spigot 55 with an internal diameter 56 is bolted 57 around the periphery of the aperture 54 .
A spacer ring 58 is attached by threaded screws 59 to the flange 50 and extends through the aperture 54 . The spacer ring 58 has an external diameter 60 , an internal diameter 62 and a power take off sprocket 65 formed on the periphery of the spacer ring 58 , in a position outside the transmission casing 52 remote from the flange 50 of the driven sprocket 46 .
Bearings 64 locate on the external diameter 60 of the spacer ring 58 and abut a shoulder 61 of the spacer ring 58 . The bearings 64 are mounted in the aperture 54 in the casing 52 , on the internal diameter 56 of the flanged spigot 55 . An oil seal 66 seals the spacer ring 58 against the flanged spigot 55 and protects the bearings 64 .
As in the conventional transmission 40 , an axle shaft 20 is axially mounted inside, and concentric with, the drive tube 42 , and receives power from the final drive 96 of the transmission 40 . The axle shaft 20 extends through the aperture 54 and is connected to a constant velocity joint 70 , which provides drive to one of the rear wheels of the vehicle (not shown). The spacer ring 58 extends beyond the end of the axle shaft 20 , and the sprocket 65 is positioned around the outer casing of the constant velocity joint 70 . Although constant velocity joints are shown, other types of articulating rotating joints could be used.
Bearings 72 locate on the internal diameter 62 of the spacer ring 58 abutting a shoulder 63 , and mount the end of the axle shaft 20 . An oil seal 74 seals between the internal diameter 62 and axle shaft 20 and protects the bearings 72 .
Although the power train has been described above as having transmission with an automatic gearbox, this is not essential to the invention and the gearbox can be of any suitable type. For example the gearbox could be a semi-automatic gearbox, a manual change gearbox, an automated manual change gearbox or a continuously variable transmission unit. These types of gearbox are well known in the art and so need not be described in any detail.
FIG. 6 shows a modification to the first embodiment in which the gearbox is a manual change gearbox. In this arrangement, drive is transferred from the engine crankshaft 94 to the driving sprocket 47 via a flywheel 135 and a friction clutch assembly 136 . The friction clutch 136 is disengaged by movement of a release lever 137 in the direction of arrow A. The release lever may be moved manually by a driver of the vehicle in a conventional manner.
Alternatively, the release lever can be moved by means of a hydraulic or electronic actuator when operation of the gearbox and/or the clutch is automated or semi-automated, including sequential shift transmissions, as is known in the art.
A power take off sprocket 65 is attached to the input shaft 142 of the gearbox in a manner similar to that described above in relation to the previous embodiment. The input shaft 142 drives the gearbox via an input gear indicated schematically at 143 whilst an output gear of the gear box is indicated schematically at 144 . The construction of the gearbox is otherwise conventional and so is not shown in any detail.
As with the previous embodiment, the power take off can be used to drive the impeller 86 of a marine propulsion unit 88 via a decoupler 76 .
A second embodiment of a transverse power train with power take off in accordance with the invention is shown in FIG. 7 . Parts in common with the embodiment shown in FIGS. 3 to 5 are given the same reference numerals but increased by 200.
In this embodiment, the transmission 240 , which comprises a gearbox 241 and a final drive unit 296 , is mounted substantially in line with the transverse engine 292 . The final drive unit 296 providing drive to left and right wheels 297 , 298 of the vehicle via drive shafts 268 , 269 respectively. V joints or other articulating rotating joints would normally be required in these drive shafts 268 , 269 but are omitted in FIG. 7 for clarity.
Indicated schematically in dotted lines are the crankshaft 294 of the engine and an input shaft 242 of the gearbox 241 . The gearbox can be of any suitable type. For example the gearbox may be an automatic, semi-automatic, manual or automated manual gearbox. A drive coupling unit 236 is provided between the engine and the gearbox to transfer drive from the crankshaft of the engine to the input shaft of the gearbox. The drive coupling unit may be a friction clutch or a fluid flywheel depending on the type of gearbox used in the transmission.
In accordance with the invention, a power take off sprocket 265 is mounted for rotation with the input shaft 242 of the gearbox 241 . In this embodiment, the power take off sprocket is mounted to the end of the input shaft farthest from the engine. The power take off sprocket may be connected to the input shaft by any suitable means such as by means of a spacer ring (not shown) as described with reference to FIG. 5 above. Those skilled in the art will understand that it will be necessary to provide suitable sealing between the gearbox casing and the input shaft or the power take off sprocket spacer to ensure that fluid within the transmission does not leak out, and bearings will also be necessary to support the input shaft and the power take off sprocket.
The power take off sprocket 265 can be used to provide drive to a marine propulsion unit of an amphibious vehicle in a manner similar to that described above in relation to FIGS. 3 to 5 . To this end the power take off sprocket 265 is connected to a driven sprocket 278 of a decoupler by means of an endless chain or belt 280 . The decoupler and the remainder of the power take off drive line to the marine propulsion unit have been omitted in this Figure for clarity.
A third embodiment of a transverse power train with power take off in accordance with the invention is shown in FIG. 8 . Parts in common with the embodiment shown in FIGS. 3 to 5 are given the same reference numerals but increased by 300.
The power train of the third embodiment is similar to that of the second embodiment except that the power take off sprocket 365 in this arrangement is attached to the gearbox input shaft 342 toward the end of the shaft which is closest to the engine. As shown in FIG. 8, the power take off sprocket 365 is attached to the input shaft 342 between an end 353 of the gearbox casing and the drive coupling unit 336 . As with the previous embodiments, the gearbox can be of any suitable type, and the drive coupling unit can be a fluid flywheel or a friction clutch as required.
The power take off sprocket 365 can be used to provide drive to a marine propulsion unit of an amphibious vehicle in a manner similar to that described above in relation to FIGS. 3 to 5 . To this end the power take off sprocket 365 is connected to a driven sprocket 378 of a decoupler by means of an endless chain or belt 380 . The decoupler and the remainder of the power take off drive line to the marine propulsion unit have been omitted for clarity.
Although not shown in FIG. 8, a cowling or bell housing may be provided between the gearbox and the engine to enclose the drive coupling unit 336 and the take off sprocket 365 , an opening in the cowling or bell housing being provided to enable the chain or belt 380 to extend outwardly to the decoupler sprocket 378 .
The above described embodiments all provide a compact and cost effective means of providing a power take off from a transverse engine and transmission unit which has particular application in an amphibious vehicle where it is necessary to provide drive for a marine propulsion unit.
By providing the power take off from the input shaft of the gearbox, it is possible for the marine propulsion unit to be driven whilst the gearbox is in neutral when there will be no drive to the road wheels. However, in certain gearbox constructions, the input shaft does not rotate when the gearbox is in neutral. In such cases, it will be necessary to have a gear engaged when providing drive to the marine propulsion unit and to provide at least one decoupler in the drive line to the road wheels so that drive to the wheels can be decoupled when the amphibious vehicle is in marine mode. Also, the decoupler on the power take off to the marine drive is not essential to the concept of the invention, and may therefore be omitted and replaced by continuous drive means in road mode.
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A PTO (power take off) sprocket 65 driving belt or chain 80 is attached to input shaft 42 of a transversely mounted vehicle gearbox 40 . The driving face of sprocket 65 is outside casting 52 ; its driven part 58 is attached to sprocket 46 by bolts 59 , running in bearing 64 in flanged spigot 55 . Shaft 42 is driven through sprocket 46 by belt or chain 48 . Decouplers may be fitted to wheel drive shafts, and to the PTO drive at 76 . FIGS. 3, 4 , and 6 show automatic and manual gearboxes mounted alongside engines; FIG. 5 also shows marine jet drive 88 , bevel gears 84 , and Cardan shaft 82 . FIG. 7 shows in-line transmission 240 . FIG. 8 shows a sandwich PTO 365 with manual gearbox 341 and clutch assembly 336 ; or automatic gearbox 341 and torque converter 336 . Applications are disclosed to semi-automatic, sequential shit automated manual, and CVT gearboxes.
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FIELD OF THE INVENTION
The present invention relates to a device for turning the pages of a bound document, particularly of a book, a magazine, an index file or a journal, in order to make pages accessible or to take a picture of these pages, that has a support on which the document is placed, some means arranged for separating one page from the other pages of the document by suction, and some means for holding the pages which are to be turned and for turning the separated page in order to bring it onto a stack of turned pages, said support being formed by two movable trays connected together by at least one rod, and with the document being placed on a roughly horizontal plane so as to be set on the pages forming the cover of the document, the visible pages being presented towards the top.
BACKGROUND OF THE INVENTION
At present devices already exist that enable turning the pages of a document automatically, for example, in order to photocopy or digitize it.
Such a device is described, for example, in the U.S. Pat. No. 4,943,502. This device has two transparent trays on which the document is set in such a way that the pages of the document are turned downward. Between the trays is a slot below which are two adjacent cylinders, one of which has suction holes. The document is held by a movable template so that it can be moved with respect to the trays. In order to turn a page, the document is pushed by means of the template in the direction of the slot. A page of this document is sucked by the cylinders provided with suction holes. This page turns between the two cylinders and penetrates into a housing situated below the cylinders. When the document continues to advance under the effect of the movement of the template, the page is withdrawn from the housing and placed on the side of the already turned pages.
This device has a certain number of disadvantages. Given that the sheets execute a trajectory around the suction cylinder, the device cannot be used for certain types of paper. In particular, it is not possible to turn board-bound pages. Moreover, a document must necessarily be open before beginning to turn the pages. Furthermore, if it contains a board-bound inset, the machine becomes immobilized. Because of the face downward position of the document and the curvature to which the pages are subjected, they can be damaged or destroyed, particularly when the pages which are presented are pressed by the weight of the document against the holding device. This device is therefore not suitable for old and/or valuable documents. Furthermore, given that the template must be suited to the dimensions of the document, the device is not very practical for dealing with documents with different formats. With the document turned downward, it is necessary to integrate in the support structure an apparatus which can do photocopies or digitization. This means that it is necessary to choose a given type of apparatus and that it is practically impossible later to change it without designing a completely new machine.
Another device, intended particularly for handicapped people, is also known through the French Patent FR 2 713 149. This device has two trays, mounted independently from one another using elastic means, on which the document is set. Each tray can apply the pages of a document against at least one finger. These fingers are retractable. The page turning component is a roller provided with a pressing device and has some means of lateral translation in order to go from one edge of the document to the other. The main disadvantage of this execution is connected with the fact that since the trays for holding the document are independent but connected by elastic means, it is very difficult to manage the force applied to the document between the trays and the retractable fingers.
The device to which the U.S. Pat. No. 4,691,909 relates has two movable trays which are inclined toward one another and on which the document is set. The page is held open by a device with rods that rest on the visible pages. A roller capable of turning is brought into forced contact against the document. It turns in one direction and can take several sheets. It brings these sheets against a squeezing member and then turns in the reverse direction in order to eliminate the extra pages. In a rocking movement, the roller and the squeezing member send the turned page onto the other side. This page falls back by its own weight, and it is regained by the rod device.
In these last two devices, the page turning component turns the pages and carries them along by friction on their surface, which can damage sensitive pages or even erase the contents at the point of friction. The page separation process requires the page carried along to be flexible so that it can become convex when it is pushed from its end towards its bound part. The effectiveness of the separation of the pages by friction and by relative movement is greatly dependent on the type of paper and on the surface condition of the paper. This type of page separation has difficulty guaranteeing that only a single page is turned at a time. Furthermore, the page holding fingers or rods have support points concentrated over a small area, which can mark or damage the document. These objects are also a problem with regard to the visibility of the pages.
U.S. Pat. No. 5,471,277 relates to a device for reading a document, provided with a page turner arranged for installation on a photocopier, a fax, or the like, which has a support table for the document and a page turner in the form of a belt made of dielectric material associated with an electrical field generator in order to attract the page electrostatically.
GB 2 207 423 relates to an apparatus for turning the pages of a document, which has a table on which the document is set open, some means for applying a frictional force to the upper page in order to raise it and allow air to insert itself between this page and the next one. The insertion of a horizontally movable transparent plate in the space thus created turns the raised page.
SUMMARY OF THE INVENTION
The present invention proposes to remedy the disadvantages of the known devices of prior art by realizing a device making it possible to turn the pages, from left to right or from right to left, of any type of document and of any form of bound work, regardless of the stiffness, the porosity, and the fragility of the pages, and which can be adapted easily to the chosen application.
Furthermore, the automatic working of this device automatically detects the case of grasping of a single page, of failure to grasp a page, of grasping multiple pages, of the end of the document, of flexible or stiff pages, and adapts itself to their specific handling without requiring human intervention.
These aims are attained by a device as defined in the preamble, and which is characterized by the fact that the means for separating the pages of the document entail a perforated hollow element which houses a diaphragm formed by two parts which are movable with respect to one another, each of these parts being provided with an open zone and a closed zone to enable orienting the direction of the suction flow and changing its flow rate and its speed by movement of one of the parts with respect to the other.
Advantageously, the perforated hollow element is movable with respect to the trays.
In a preferred embodiment of the invention, the perforated hollow element is provided with closing means arranged so as to longitudinally limit the suction surface.
In the preferred embodiment, the rod connecting the two trays pivots around a horizontal shaft, this horizontal shaft being vertically movable, which synchronizes the movement of the movable trays, and a compression component is arranged so as to counterbalance the weight of the elements supported by said horizontal shaft.
The trays advantageously have means for immobilizing their relative position, and each tray is connected with a horizontal return element arranged so as to allow the centering of the document.
Preferably, each tray is formed by a box having a planar upper surface provided with holes and at least one suction intake. This upper surface of the boxes can be provided with a mask suited to the size of the document whose pages are to be turned.
In one embodiment, the means for turning a page of the document comprise at least one transparent plate which is movable with respect to the trays.
In a variant, the means for turning a page of the document can comprise two transparent plates arranged in parallel planes, which are movable with respect to one another and with respect to the trays.
The device, moreover, has some means of inspection arranged so as to measure the dimensions of the document and the number of pages taken, as well as some means for measurement of the suction pressure in the perforated hollow element.
In all the embodiments, one or each transparent plate has a duct arranged, on an edge roughly parallel to the binding of the document, so as to expel air in the direction of the pages of said document, as well as at least one movable duct, perpendicular to said binding of the document, also arranged so as to expel air in the direction of the pages of said document.
According to the use of the device, the perforated hollow element can be equipped with a removable filtering element in order to protect the turned pages from contamination.
When the device is intended for taking a picture of the turned pages of the document, it has some means of recording these images.
BRIEF DESCRIPTION OF THE DRAWINGS
The present invention and its advantages will be better understood with reference to a preferred but non-limiting embodiment of the invention and to the appended drawing in which:
FIG. 1 is an overall diagrammatic view of the device according to the present invention,
FIG. 2 is a section of a part of the device of FIG. 1 , and
FIGS. 3 a and 3 b are sections of the element of FIG. 2 in different positions.
DETAILED DESCRIPTION
With reference to FIG. 1 , device 100 according to the present invention has support structure 10 , in which are arranged support 11 for the document whose pages are to be turned, means 12 for holding the pages to be turned and for turning the separated page, means 13 for inspection of the pages which have been turned or are to be turned, means 14 for separating the pages to be turned and means 15 for recording images.
Support 11 for the document has two trays 16 connected together by means of rod 17 . In a more detailed manner, each tray 16 is mounted on horizontal rail 18 which allows it to slide along a longitudinal axis with respect to the device. These horizontal rails are themselves connected with a carriage (not represented) which slides in vertical rail 20 , which ensures a linear guidance of the trays. Rod 17 is articulated about its center. This center, which is materialized by shaft 21 , can be moved in vertical guide 22 by means of a motor. In this way, the trays can be moved either in two opposite directions or in the same direction. In other words, when one of the trays is raised, the other can either be lowered around the center of rod 17 or also raised along vertical rail 20 .
Each horizontal rail 18 is also connected with vertical bar 24 running in the vicinity of articulated rod 17 . This rod is provided with means of immobilization 25 arranged in the vicinity of each of the vertical bars in such a way that when these means are actuated, they hold the bars and thus keep them from moving. Furthermore, compression component 9 connected to vertical rail 22 makes it possible to counterbalance the weight of the elements supported by horizontal shaft 21 . In this way, trays 16 remain in their relative position regardless of the force applied to them.
Each tray is formed by box 26 whose roughly planar upper surface is provided with many small holes 27 , and which has one or more suction intakes 28 . This box can furthermore be provided with perforated mask 29 whose perforations coincide with holes 27 so that these holes are stopped by the cover of the document whose pages are to be turned, or by the mask. This makes suitable holding of the document possible and prevents leaks due to suction through the unstopped holes. Furthermore, centering of the document on the trays is ensured by horizontal return elements 19 connected with trays 16 .
Means 12 for holding the pages to be turned and for turning the separated page entails at least one transparent plate or, in the example represented, two transparent plates 30 , for example, made of glass, which are placed above the document. These plates can slide in a plane parallel to the pages of the document and in a direction perpendicular to the binding of this document. To this effect, they are connected with translational guiding elements which are known and are not represented.
The edge of the transparent plate which is in contact with the page of the document to be turned has duct 33 connected to a blower so that air is blown in the direction of the pages in order to push the sheet to be turned by a cushion of air. This makes it possible to turn the pages of the document very delicately and therefore to avoid any risk of damaging the documents, even particularly fragile ones, in particular by avoiding any friction with the page. Duct 33 can be placed on only one of the plates or on both of them, and the blower can be operated in one of the ducts or both as a function of the direction in which the pages are turned.
It is also possible to provide only one transparent plate 30 which covers the whole document during picture taking. In this case, it is desirable to provide a component for holding the pages of the document so that the document does not close by itself.
Means 14 for separating the pages of the document are composed of suction means 34 and means 35 for movement of these suction means. In the embodiment illustrated, they make it possible to turn the pages from left to right or from right to left. It is possible, however, to produce a machine with reduced dimensions if it only has to turn the pages in one direction.
Suction means 34 , illustrated in more detail in FIGS. 2 , 3 a and 3 [sic: 3 b ], are formed by a perforated hollow element which can take the form of tube 36 provided with diaphragm 37 . Tube 36 has many holes 38 having a flared peripheral zone in the form of a suction cup. According to a preferred embodiment, the holes are arranged in a staggered manner on the lower surface of the tube so as to ensure optimal grasping of the sheets to be turned. Diaphragm 37 is formed by two parts 39 and 40 which are movable with respect to one another, and which can be produced in the form of tubes sliding into tube 36 , each of these tubes being provided with a closed zone and an open zone such as a slot extending over an angular zone less than 180°, so that the rotation of one of the tubes with respect to the other makes it possible to close the diaphragm completely or to open it. Tubes 39 and 40 forming the diaphragm are supported by bearings.
These suction means 34 also have some closing means in order to longitudinally limit the suction surface. In the example represented, these closing means are formed by two movable sleeves 44 arranged at each end of tube 36 in such a way that holes 38 of said tube 36 can be stopped by a page of the document, by the diaphragm, or by one or the other of the sleeves. As in the case of mask 29 on the box, these sleeves ensure optimal suction. Furthermore, in order to protect the turned pages from contamination by particles or bacteria, perforated tube 36 can be equipped with a removable filtering element.
Means 35 for movement of these suction means include two rails, vertical rail 46 and horizontal rail 47 , as well as driving motors. When a page is sucked up, tube 36 is displaced according to a relative movement with respect to the page that is obtained by the combination of a vertical movement and a horizontal movement.
Means of inspection 13 essentially makes it possible to make sure that a single page of the document is turned at a time. These means of inspection includes first telemeter 48 a which takes a measurement of the number of pages grasped by the page separation means as well as second telemeter 48 b making it possible to determine the exact position and size of the document.
The device also has means 50 for measurement of the pressure in suction means 34 . In effect, when a page is sucked up, the pressure varies according to a determined curve. If a page has not been able to be grasped correctly, the pressure will remain constant, and the curve will not correspond to the conventional curve, and this will be detected.
The pressure measurement means 50 also makes it possible to distinguish a standard page of the document from a page which is different, such as, for example, a flexible page from a stiff page. In effect, a flexible sheet bends slightly around the tube of the suction means and stops a certain number of holes 38 , which generates a determined pressure curve. When two standard sheets are taken at the same time, the pressure curve is practically identical to the curve for one sheet. By contrast, the number of pages measured by telemeter 48 a differs. When a stiff sheet is grasped, it bends less than a standard sheet and stops fewer holes 38 of suction means 34 . The pressure curve will be different from the conventional curve. Thus, it will be possible to not take into account the measurement made by telemeter 48 a.
Image recording means 15 can be adapted to the chosen application. In effect, the pages can be photographed or scanned and digitized. According to a concrete embodiment, these recording means can include digital camera 51 which is stationary or movable and mounted so that it can move above the document on a set of rails connected with the support structure. This camera takes a picture of each double page, digitizes it and transmits it to a storage and/or processing system such as a computer (not represented).
Device 100 of the invention can also have mechanism 53 for separation of pages 54 , in the form of a duct perpendicular to the binding of the document. Air is blown from this duct in a direction parallel to the binding, which has the effect of slightly separating the pages by introducing a small cushion of air between them. This very greatly reduces the friction between the pages and increases the reliability of the device by preventing several pages from being taken at the same time.
When one wishes to turn the pages of a document, one places it open or closed on support 11 . In closed position, the document is placed on a single tray 16 of the support, for example, on the right when the document is turned from left to right [sic], in such a way that the binding of the document is in the vicinity of the edge of this tray. When the document is open, each of the cover pages is arranged on a tray in such a way that the binding is placed between these two trays. The two cover pages of the document are held in place by suction through holes 27 of box 26 . This ensures suitable holding of the document while requiring no complex mechanical parts.
If one starts with a closed document, telemeter 48 b is moved in order to determine the exact position and size of the document. The cover page is then opened. If one starts with the document open, the document is positioned on the two trays, telemeter 48 a is moved longitudinally along the machine and measures at each point the distance between the telemeter and the document. This makes it possible to determine the position of the edges of a page as well as the position of the middle of the document.
The connection between trays 16 is such that regardless of the number of pages on each of the trays, the upper page of each part of the document is situated roughly in the same plane. In effect, [on] the side of the document with more pages and therefore the thicker side, the tray will be pressed downward. Thus, the two visible pages of the document will be roughly in the same plane.
The trays are locked in position by means of immobilization device 25 so that the pages of the document remain in the same plane when the document is moved away from plates 30 .
In order to turn the pages from right to left, trays 16 are raised simultaneously until they press the document with a determined pressure against right transparent plate 30 of the device. The visible double page can then be dealt with, that is to say, photographed or scanned. In order to turn the page and thus allow the next double page to be dealt with, trays 16 are lowered simultaneously a distance such that the document cannot close up by itself, and the pages which have a tendency to turn are retained by one of transparent plates 30 . The plates are then moved towards the left so that the left plate retains the pages of the document which have a tendency to close up, and the right plate has its free edge more to the right than the document. As can be seen in FIG. 1 , a space is created between the two plates. This space is sufficiently wide to allow passage for suction means 34 . These means are lowered and operated such that the edge of the right page is sucked up by tube 36 , diaphragm 37 being adjusted so as to be suited to the stiffness of the pages.
The rotation of this diaphragm 37 in tube 36 of the suction means, as illustrated by FIGS. 3 a (open position) and 3 b (closed position), allows the suction force to be adjusted. In effect, if the slot of the diaphragm is such that it faces a small number of holes of the exterior tube, the suction force will be distributed over a very small number of holes, and will be greater. This is used when it is necessary to turn very stiff or heavy pages, such as board-bound cover pages or stiff inserts. On the other hand, when the open zone of the diaphragm is in contact with a large number of holes, the force per hole is relatively small. This mode of utilization is suitable for the interior pages of a document, which are generally flexible.
Adjustment of the suction force can be done manually, as a function of the grade of the paper of the document whose pages are to be turned. It can also be done automatically. In this case, the turning of the diaphragm is managed by motors which automatically adjust the angle of opening as a function of the paper.
Suction means 34 is then displaced according to a movement whose trajectory is obtained by the combination of a vertical movement and a horizontal movement. The two tubes 39 and 40 forming diaphragm 37 are also turned inside tube 36 such that the line bisecting the angle of opening of the diaphragm is always in contact with the same zone of the page to be turned. This bisecting line is oriented perpendicularly to the page during movement of the page to be turned. This becomes all the more important, the stiffer the page.
When suction means 34 has grasped a batch of one or more pages and this batch has been raised, telemeter 48 a measures the number of pages grasped. If an insert whose thickness differs from that of conventional pages is grasped, this can be detected by means of measurement of the pressure in the suction means.
If one or more pages have been grasped simultaneously, suction means 34 is stopped, and the pages possibly taken are released. Another attempt is then begun.
The suction means are moved until they are arranged above the plane defined by right transparent plate 30 . This plate is then moved towards the left.
When transparent plate 30 is sufficiently inserted under raised page 54 , the suction means release the page by stopping the suction. This page-is carried along by the movement of the transparent plate. This movement is coordinated with the movement of the left plate which holds the document open. When the transparent plate entirely covers the document, the movements of the plates are stopped. Trays 16 are raised in such a way as to flatten the pages of the document against the transparent plates or to move the document a chosen distance closer to plates 30 when one does not wish to flatten the document. A picture of the two open pages is taken. The transparent plates are then moved towards the right so as to regain their initial position. A cycle is then begun again.
Blower duct 33 arranged on the edge of transparent plates 30 blows air before the plate comes in contact with the page to be turned. Thus, the page is pushed by a cushion of air and does not come in contact with the plate. It is possible in this way to deal with a particularly valuable and/or fragile document. This same duct can also blow air during the page separation phase.
Numerous parameters can be adjusted on device 100 according to the invention. In particular, the pressure applied on the document against transparent plates 30 can be suited to the document. Thus, for fragile documents or those with bindings of mediocre quality, the document can be simply placed open on support 11 with no pressure applied. The picture of the document taken by recording means 15 can be worked on by computer means in order to correct the deformations due to lack of flatness of the document.
This device has numerous advantages with respect to the similar devices of the prior art.
First of all, it makes it possible to use documents with practically any format without it being necessary to perform tedious manual adjustments. According to a concrete embodiment, the document can have any size including the format A 6 and the format A 1 . It also automatically adapts itself to a wide variety of paper grades or thicknesses. Furthermore, the documents can be naturally placed closed on support 11 without it being necessary to position them in a particular manner.
Moreover, it can be used to turn the pages of particularly fragile documents, allowing old or rare documents to be digitized or copied, for example.
The speed of movement of the different components can be increased or slowed down as a function of the fragility of the pages of the document. All the movements of the components can be motorized.
Since trays 16 can be moved vertically, it is possible to press the document against the transparent plates in such a way that the two pages are flat. For documents with a fragile binding, it is also possible to leave a certain distance between the document and the transparent plates. In this case, the distance must merely be close enough to prevent the pages from turning by themselves.
The means of inspection make it possible to ensure that all the pages will be turned one after the other, one page at a time.
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The invention concerns an automatic device for turning the pages of a bound document comprising a support ( 11 ) whereon is arranged the document, means ( 14 ) for separating by suction one page from the other pages to be turned and for turning the separated page to bring it on a pile of turned pages. The support ( 11 ) consists of two mobile trays ( 16 ) mutually linked by a rod ( 17 ), each tray consisting of a box ( 26 ) whereof the upper side is provided with small holes ( 27 ) cooperating with the suction intake orifices ( 28 ). The means ( 14 ) for separating the document pages consist of suction means ( 34 ), displaced by the combination of a vertical movement and a horizontal movement, consisting of the perforated recessed element ( 36 ) provided with a diaphragm ( 37 ). Said perforated element ( 36 ) is provided with holes ( 38 ) and the diaphragm ( 37 ) comprises two mobile parts for orienting the direction of the suction flow and modify its flow rate and its speed. Said suction means ( 34 ) also comprise mobile closure means ( 44 ) for longitudinally delimiting the suction surface. The means ( 14 ) for turning a page of the document comprise two mobile transparent plates ( 30 ) arranged in parallel planes. Control means ( 13 ) enable to measure the dimensions of the document and the number of pages turned.
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CROSS REFERENCE TO RELATED APPLICATIONS
[0001] The present application claims priority to provisional application No. 61/330,040, filed Apr. 30, 2010.
FIELD OF THE INVENTION
[0002] The present invention relates to garments that include targeted shape control zones.
BACKGROUND OF THE INVENTION
[0003] Many women have parts of their bodies that they are unhappy with, making them have an insecure feeling when wearing certain clothing. Foundation garments have been worn for a very long time to address this problem. Better known today as shapewear, these foundation garments include body briefs, bodysuits, brassieres, control top panty hose, control panties, control briefs, control slips, control camisoles, control tanks, hip slips, waist shapers, corsets, garter belts, and girdles.
[0004] Shapewear are undergarments designed to change the wearer's shape, producing a more fashionable, slim figure and to enhance the natural curves of the body. Take for example control briefs. They are designed to lift a wearer's bottom, flatten the tummy and add shape and form to the thighs.
[0005] Shapewear is typically categorized according to the level or shape control offered —for instance, light, medium or firm. Generally, shapewear can be categorized into four different support levels:
Light Control shapewear garments, which offer a slight touch of control without binding. These are typically chosen by women of all sizes who want to appear firmer, but not necessarily smaller. Moderate Control shapewear garments may have light control panels built in, offering control with a touch of compression. These are typically chosen by women who want to look more toned. Firm Control shapewear garments are the most popular with a support level that gives the maximum amount of compression and control. These are typically chosen by women seeking to appear slimmer and more toned.
[0009] Extra Firm Control shapewear garments offer the highest level of support. These garments will most likely have reinforced panels and possibly boning.
[0010] Shapewear garments typically have a single control material covering an entire section of the garment. For example, in a typical shapewear tank, a single control panel material forms the tummy, side and back areas of the garment. This results in a shapewear garment that has the same control properties for all sections of the garment. However, women do not necessarily need a consistent amount of shaping across body parts. For example, a woman may want a shapewear garment to firmly flatten her stomach but give only light control to her thighs.
SUMMARY OF THE INVENTION
[0011] The present invention provides a shapewear garment, i.e. a tank top or panties, that is capable of delivering different shape control properties to different regions of a wearer's body by employing multiple shape control panels with varying degrees of stretch. These shape control panels are each positioned in the garment to be adjacent to specific body parts and to constrict and shape those body parts.
[0012] One embodiment of the present invention is configured as panties. In this embodiment, the multiple shape control panels include a tummy/midriff panel, corresponding to the abdominals of the wearer, two opposed lateral side panels, corresponding to the oblique abdominals of the wearer, a back panel corresponding to the back of the wearer, and a chest panel, corresponding to the chest of the wearer.
[0013] The control panel material for each of the panels is selected to provide a desired amount of stretch to the particular location of that panel. In the tank top embodiment, the control panel material used for the tummy/midriff panel and back panel portion are selected to have a greater degree of stretch than the side panels, thereby providing a greater degree of restriction in the tummy/midriff and back areas for the wearer.
[0014] Another embodiment of the present invention is configured as panties. In this embodiment, the multiple shape control panels include front control panels, which correspond to the right and left lower abdominals of the wearer, side control panels, which correspond to the upper thighs of the wearer and wrap around the wearer's back side to correspond also to the lower buttocks of the wearer, and rear control panels, which correspond to the right and left central and upper buttocks of the wearer.
[0015] Like in the tank top embodiment, the material that comprises each panel in the panties embodiment is selected to provide a desired of constriction and shaping depending upon the body part where it is positioned. The desired constriction and shaping for each body part varies. The control panel material used for the front and rear panel portions is selected to have a greater degree of stretch than the side panel portions, which thereby provides a greater degree of restriction in the front and rear areas for the wearer.
BRIEF DESCRIPTION OF THE DRAWINGS
[0016] The figures are for illustration purposes only and are not necessarily drawn to scale. The invention itself, however, may best be understood by reference to the detailed description which follows when taken in conjunction with the accompanying drawings in which:
[0017] FIG. 1 is a plan view of an outer front side of a garment of the present invention;
[0018] FIG. 2 is a plan view of an outer back surface of a garment of the present invention;
[0019] FIG. 3 is a plan view of an outer front surface of a garment according to a second aspect of the present invention;
[0020] FIG. 4 is a plan view of an inner front surface of a garment according to the second aspect of the present invention;
[0021] FIG. 5 is a plan view of an outer back surface of a garment according to the second aspect of the present invention; and
[0022] FIG. 6 is a plan view of an inner back surface of a garment according to the second aspect of the present invention.
DESCRIPTION OF THE INVENTION
[0023] The present invention will next be illustrated with reference to the figures. Such figures are intended to be illustrative rather than limiting and are included herewith to facilitate the explanation of exemplary features of embodiments of the present invention. Unless otherwise noted, the figures are not to scale, and are not intended to serve as engineering drawings.
[0024] Shapewear undergarments have become a very popular fashion item. However, since currently available shapewear garments utilize a single control material that covers an entire section of the garment, i.e., a single control panel material forms the tummy, side and back areas of the garment, the shapewear garment is only capable of delivering the same control properties for all sections of the garment and thus to all parts of the wearer. This is not always an ideal situation because many times the wearer has different control needs corresponding to different body parts/locations. Because of this, there is a need to provide a garment that has the ability to provide different control properties to different body parts/locations.
[0025] The present invention addresses such a need. Specifically, the present invention provides garments, i.e., a tank top and panties, that have targeted shape control zones that, when worn, provide differing amounts of shape control to different body parts/locations.
[0026] As shown for example in FIGS. 1-2 , the present invention achieves this unique targeted shape control by providing a garment 1 having multiple shape control panels. These multiple shape control panels include a tummy/midriff panel portion 3 corresponding to the abdominals of the wearer, two opposed lateral side panel portions 4 , 5 corresponding to the oblique abdominals of the wearer, and a back panel portion 6 corresponding to the back of the wearer. The garment also includes a chest panel portion 2 for covering the chest of the wearer. Preferably, the chest panel portion is constructed of a single layer of fabric, but however may also be constructed as a shape control panel similar to the other panels 3 , 4 , 5 and 6 .
[0027] Each of these panel portions 2 , 3 , 4 , 5 and 6 are preferably constructed of multiple fabric layers. These multiple fabric layers typically include an outer fabric layer and a control panel material attached to the inner, body facing surface of the outer fabric layer. An inner fabric layer is also preferably provided. Although the figures show a specific shape and configuration of the panel portions, one of skill in the art will readily recognize from the instant disclosure that the specific shape and positioning of these panel portions can be altered to provide control and/or compression to any desired area of the wearer's body. Preferably, the outer fabric layer (and inner fabric layer) is selected from any fabric, such as lace, circular knit, warp knit, woven, cotton, nylon, polyester, elastane, or any combination thereof.
[0028] The control panel material for each of the panels 3 , 4 , 5 , and 6 is selected to provide a desired amount of stretch to the particular location of that panel. For example, as shown in the garment 1 of FIGS. 1 and 2 , i.e., a tank top, the control panel material used for the tummy/midriff panel portion 3 and back panel portion 6 is selected to have a greater degree of stretch than the side panel portions 4 and 5 , thereby providing a greater degree of restriction in the tummy/midriff and back areas for the wearer. The control panel material used for the side panel portions 4 and 5 is preferably selected to offer a degree of control and/or compression less than that of the tummy/midriff panel portion 3 and back panel portion 6 .
[0029] The control panel material can be attached to the inner body facing surface of the outer fabric layer by sewing, adhesive bonding, ultra sonic bonding, or any other means known in the art to attach fabric materials together. The control panel material is preferably a power mesh/net material, such as spandex or nylon/Lycra® blend, a stretch tricot material, a cotton/spandex knit material, a poly/spandex knit material, or any other material that can provide the desired control and/or compression.
[0030] For example, it is preferred that control panel material used in the side panel portions 4 , 5 is stretch mesh fabric having a weight of 75 g/m 2 , and a 180% length/85% width elongation under a 10 lb load. This material is preferred because it is a lightweight mesh that provides light support and control.
[0031] The control panel material used in the other panel portions 2 , 3 and 6 is preferably a stretch tricot material, a cotton/spandex knit material or a poly/spandex knit material having a weight 125-180 g/m 2 , and a 75-270% length/100-150% width elongation under a 10 lb load. These materials are preferred because they have everyday wearability characteristics, comfortable stretch properties, and a modulus of elasticity that assists in the overall smoothing appearance of the wearer's body.
[0032] FIGS. 3-6 show the garment of the present invention configured as panties 10 having multiple shape control panels. Specifically, FIG. 3 is a plan view of an outer front surface of the panties 10 ; FIG. 4 is a plan view of an inner front surface of the panties 10 of FIG. 3 ; FIG. 5 is a plan view of an outer back surface of the panties 10 of FIG. 3 ; and FIG. 6 is a plan view of an inner back surface of the panties 10 of FIG. 5 .
[0033] In the example shown in FIGS. 3 and 5 , the panties 10 have an outer fabric layer. An inner fabric layer may also be provided. Preferably, the outer fabric layer (and inner fabric layer) is selected from any fabric, such as lace, circular knit, warp knit, woven, cotton, nylon, polyester, elastane, or any combination thereof.
[0034] As shown in FIGS. 4 and 6 , the multiple shape control panels are located on an inner body-facing surface of the outer fabric layer and include front control panels 12 , 13 , side control panels 14 , 15 , and rear control panels 16 , 17 . The front control panels 12 , 13 correspond to the right and left lower abdominals of the wearer. The side control panels 14 , 15 are two opposed lateral side panel portions that correspond to the upper thighs of the wearer and wrap around the wearer's back side to correspond also to the lower buttocks of the wearer. The two rear control panels 16 , 17 correspond to the right and left central and upper buttocks of the wearer.
[0035] The control panel material for each of the panels 12 , 13 , 14 , 15 , 16 and 17 is selected to provide a desired amount of restriction and/or control. For example, as shown in the panties 10 of FIGS. 3-6 , the control panel material used for the front and rear panel portions 12 , 13 , 16 , 17 is selected to have a greater degree of stretch than the side panel portions 14 , 15 , which thereby provides a greater degree of restriction in the front and rear areas for the wearer. The control panel material used for the side panel portions 14 and 15 is preferably selected to offer a degree of control and/or compression less than that of the front and rear panel portions 12 , 13 , 16 , 17 .
[0036] The control panel material is preferably attached to the inner body facing surface of the outer fabric layer by sewing, adhesive bonding, ultra sonic bonding, or any other means known in the art to attach fabric materials together so as to reduce the visibility of any panty lines. The control panel material is preferably a power mesh/net material, such as spandex or nylon/Lycra® blend, a stretch tricot material, a cotton/spandex knit material, a poly/spandex knit material, or any other material that can provide the desired control and/or compression.
[0037] For example, and similar to the embodiment of FIGS. 1-2 , it is preferred that control panel material used in the side panel portions 14 , 15 is stretch mesh fabric having a weight of 75 g/m 2 , and a 180% length/85% width elongation under a 10 lb load. This material is preferred because it is a lightweight mesh that provides shaping and lift for the wearer.
[0038] The control panel material used in the other panel portions 12 , 13 and 16 , 17 is preferably a stretch tricot material, a cotton/spandex knit material or a poly/spandex knit material having a weight 125-180 g/m 2 , and a 75-270% length/100-150% width elongation under a 10 lb load. These materials are preferred because they have everyday wearability characteristics, comfortable stretch properties, and a modulus of elasticity that assists in the overall smoothing appearance of the wearer's body.
[0039] It should be noted that although the number of layers of material in the presently preferred embodiment of the garment has been described herein with respect to a particular number of layers, the actual number of layers in the garment may vary based on specific requirements of the garment being constructed, such as for a particular weight garment for a certain season of use. Accordingly, the number of layers of material shown in the presently preferred embodiment of FIGS. 1-6 is merely illustrative and in no way excludes other combinations of layers that may be employed by one of ordinary skill in the art to achieve the benefits of the present invention.
[0040] Although the present invention has been described in relation to particular embodiments thereof, many other variations and modifications will become apparent to those skilled in the art. As such, it will be readily evident to one of skill in the art based on the detailed description of the presently preferred embodiment of the garment explained herein, that different types of garments can be realized.
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A garment comprised of a first shape control panel, which is comprised of a first material, with a first degree of stretch and a second shape control panel, which is coupled to the first shape control panel. The second shape control panel is comprised of a second material, with a second degree of stretch. The second degree of stretch is different than the first degree of stretch.
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CROSS REFERENCE TO RELATED APPLICATIONS
This application is a 35 USC § 371 National Phase Entry Application from PCT/KR2007/001307, filed Mar. 16, 2007, and designating the United States. This application claims priority under 35 U.S.C. § 119 based on Korean Patent Application No. 10-2006-0026110 filed Mar. 22, 2006, which is incorporated herein in its entirety.
FIELD OF THE INVENTION
The present invention relates to a method for preparing clopidogrel 1,5-naphthalenedisulfonate or hydrate thereof.
BACKGROUND OF THE INVENTION
Clopidogrel (methyl(S)-(+)-α-(2-chlorophenyl)-6,7-dihydrothieno[3,2-a]pyridine-5(4H)-acetate) of formula (IV), which has inhibiting activity against platelet agglutination, is a useful vascular diseases therapeutic for treating peripheral artery diseases such as stroke, thrombosis and embolism, as well as ischemic heart diseases such as myocardial infarction and angina pectoris:
Clopidogrel, an optically active dextrorotatory compound, however, is an oil phase which is unstable under moist and high temperature conditions and is difficult to be purified to the level of required for pharmaceutical use.
Accordingly, acid addition salts of clopidogrel, which are stable solid and easy to purify, have been developed. Clopidogrel 1,5-naphthalenedisulfonate (napadisilate (INN)), one of the most stable acid addition salts, has been disclosed in International Publication No. WO 2005/097804, wherein clopidogrel 1,5-naphthalenedisulfonate is prepared by reacting the free base form of clopidogrel with 1,5-naphthalenedisulfonic acid.
However, 1,5-naphthalenedisulfonic acid used in the above method (Armstrong acid) is a strong acid having a pK a1 value of −3.37 and a pK a2 of −2.64, and is not suitable for use in the preparation of high quality clopidogrel 1,5-naphthalenedisulfonate due to its corrosiveness, handling in a bulk production process and tendency to color the product red. Accordingly, there has been a need for an improved method of preparing clopidogrel 1,5-naphthalenedisulfonate.
The present inventors have found that clopidogrel 1,5-naphthalenedisulfonate can be beneficially prepared by reacting a clopidogrel acid addition salt with a 1,5-naphthalenedisulfonate, which is not acidic nor corrosive.
SUMMARY OF THE INVENTION
It is an object of the present invention to provide a new method of preparing clopidogrel 1,5-naphthalenedisulfonate, which can ameliorate the problems associated with the conventional methods.
In accordance with an aspect of the present invention, there is provided a method for preparing clopidogrel 1,5-naphthalenedisulfonate of formula (I) or a hydrate thereof, which comprises:
reacting a clopidogrel-acid addition salt of formula (II)
with disodium 1,5-naphthalenedisulfonate of formula (III) or its hydrate
in water, or a mixture of water and an organic solvent, wherein HX is an acid capable of reacting with clopidogrel to form an acid addition salt excluding naphthalenedisulfonate.
DETAILED DESCRIPTION OF THE INVENTION
The method of the present invention is characterized in that disodium 1,5-naphthalenedisulfonate, which is non-corrosive and non-acidic is used as a starting material, instead of 1,5-naphthalenedisulfonic acid.
The inventive method of preparing clopidogrel 1,5-naphthalenedisulfonate of formula (I) or a hydrate thereof may be carried out by adding the clopidogrel-acid addition salt of formula (II) and disodium 1,5-naphthalenedisulfonate of formula (III) to water or a water-organic solvent mixture to obtain a solution or a suspension; stirring the solution or the suspension at a temperature ranging from 0° C. to the boiling point of the solvent used, preferably from room temperature to the boiling point of the solvent used.
Examples of the organic solvent which may be used in the present invention include water-miscible solvents selected from the group consisting of C 1-3 alcohols such as methanol, ethanol, isopropanol; ketones such as acetone, methyl ethyl ketone, methyl isobutyl ketone; alkyl acetates such as methyl acetate, ethyl acetate, isopropyl acetate; acetonitrile; tetrahydrofuran; and 1,4-dioxane; as well as water-immiscible solvents selected from the group consisting of C 6 or higher alkanes such as n-hexane, n-heptane, n-octane, isooctane; dialkyl ethers such as diethyl ether, diisopropyl ether; chloroalkanes such as dichloromethane, 1,2-dichloroethane, chloroform; aromatic solvents such as benzene and toluene; and a mixture thereof. Among those, water-miscible solvents, methanol, ethanol, isopropanol, acetone, methylethylketone, methyl isobutyl ketone, methyl acetate, ethyl acetate, isopropyl acetate, acetonitrile, tetrahydrofuran and 1,4-dioxane are preferred, and methanol, ethanol, isopropanol and acetone are more preferred.
Although the water-organic solvent mixture may have any organic solvent content, the preferred amount of the organic solvent is less than 95% by volume based on the mixture, which helps the removal of the incidental salt.
Disodium 1,5-naphthalenedisulfonate of formula (III) or its hydrate may be employed in an amount ranging from 0.45 to 0.7 mole per mole of clopidogrel acid addition salt of formula (II).
The clopidogrel acid addition salt of formula (II) may be any of those disclosed by European Patent No. 0281459 or International Publication No. WO 2004/074215. Representative examples of the clopidogrel acid addition salt include inorganic acid salts such as hydrochloride, hydrobromide, hydroiodide, hydrogen sulfate, phosphate, perchlorate and nitrate; sulfonates such as methanesulfonate, ethanesulfonate, 1,2-ethanedisulfonate, benzenesulfonate, p-toluenesulfonate, camphorsulfonate, laurylsulfonate, 2-naphthalenesulfonate; alkyl sulfates such as methyl sulfate and ethyl sulfate; organic acid salts such as acetate, oxalate, trifluoroacetate, propionate, benzoate, citrate, tartarate, succinate, malonate, lactate, malate, maleate and fumarate. Preferred among the above are hydrochloride, hydrobromide, hydrogen sulfate, camphorsulfonate and benzenesulfonate of clopidogrel.
The present invention will be described in further detail with reference to Examples. However, it should be understood that the present invention is not restricted by the specific Examples.
Preparation of clopidogrel 1,5-naphthalenedisulfonate monohydrate
EXAMPLE 1
1.0 g of clopidogrel hydrochloride (2.8 mmol) was dissolved in a mixture of 10 ml of methanol and 10 ml of distilled water, and 515 mg of disodium 1,5-naphthalenedisulfonate monohydrate (95%, 1.4 mmol) was added thereto. The resulting solution was stirred at room temperature for 15 hours, and then at 5° C. for 2 hours. The resulting precipitates were filtered under a reduced pressure, washed with 1 ml of a mixture of methanol and distilled water (1/2, v/v), and dried at 50° C. for 4 hours, to obtain 1.1 mg of the title compound (yield: 85%) as a white powder.
M.p.: 221-224° C. (reported value: 223-225° C.);
Water contents (Karl-Fisher titrator): 1.9%; (theoretical value: 1.90%)
Purity (HPLC): 98.7% (purity of standard product: 99.3%)
EXAMPLE 2
3.0 g of clopidogrel hydrochloride (8.4 mmol) and 1.54 g of disodium 1,5-naphthalenedisulfonate monohydrate (95%, 4.2 mmol) were suspended in a mixture of 20 ml of isopropanol and 10 ml of distilled water and the suspension was homogenized at 70° C. The resulting solution was slowly cooled; and stirred at room temperature for 15 hours, and then at 5° C. for 2 hours. The resulting precipitates were filtered under a reduced pressure, washed with 3 ml of a mixture of isopropanol and distilled water (2/1, v/v), and dried at 50° C. for 4 hours, to obtain 3.5 g of the title compound (yield: 88%) as a white powder.
M.p.: 220-224° C. (reported value: 223-225° C.);
Water contents (Karl-Fisher titrator): 1.80%; (theoretical value: 1.90%)
EXAMPLE 3
3.0 g of clopidogrel hydrobromide (7.4 mmol) and 1.37 g of disodium 1,5-naphthalenedisulfonate monohydrate (95%, 3.7 mmol) were suspended in a mixture of 20 ml of isopropanol and 10 ml of distilled water, and the suspension was homogenized at 70° C. The resulting solution was slowly cooled; and stirred at room temperature for 15 hours, and then at 5° C. for 2 hours. The resulting precipitates were filtered under a reduced pressure, washed with 3 ml of a mixture of isopropanol and distilled water (2/1, v/v), and dried at 50° C. for 4 hours, to obtain 3.2 g of the title compound (yield: 91%) as an white powder.
M.p.: 221-224° C. (reported value: 223-225° C.);
Water contents (Karl-Fisher titrator): 2.0%; (theoretical value: 1.90%)
EXAMPLE 4
5.0 g of clopidogrel besylate (10.4 mmol) and 1.92 g of disodium 1,5-naphthalenedisulfonate monohydrate (95%, 5.2 mmol) were suspended in a mixture of 20 ml of methanol and 15 ml of distilled water and the suspension was homogenized at 60° C. The resulting solution was slowly cooled; and stirred at room temperature for 15 hours, and then at 5° C. for 2 hours. The resulting precipitates were filtered under a reduced pressure, washed with 6 ml of a mixture of methanol and distilled water (1/1, v/v), and dried at 50° C. for 4 hours, to obtain 4.6 g of the title compound (yield: 94%) as a white powder.
M.p.: 220-224° C. (reported value: 223-225° C.);
Water contents (Karl-Fisher titrator): 1.75%; (theoretical value: 1.90%)
EXAMPLE 5
5.0 g of clopidogrel besylate (10.4 mmol) and 1.92 g of disodium 1,5-naphthalenedisulfonate monohydrate (95%, 5.2 mmol) were suspended in a mixture of 30 ml of isopropanol and 15 ml of distilled water and the suspension was homogenized at 70° C. The resulting solution was slowly cooled; and stirred at room temperature for 15 hours, and then 5° C. for 2 hours. The resulting precipitates were filtered under a reduced pressure, washed with 6 ml of a mixture of isopropanol and distilled water (2/1, v/v), and dried at 50° C. for 4 hours, to obtain 4.2 g of the title compound (yield: 86%) as a white powder.
M.p.: 220-224° C. (reported value: 223-225° C.);
Water contents (Karl-Fisher titrator): 1.8%; (theoretical value: 1.90%)
EXAMPLE 6
3.0 g of clopidogrel (+)-(1S)-camphor-10-sulfonate (5.4 mmol) and 998 mg of disodium 1,5-naphthalenedisulfonate monohydrate (95%, 2.7 mmol) were suspended in a mixture of 20 ml of isopropanol and 10 ml of distilled water and the suspension was homogenized at 70° C. The resulting solution was slowly cooled; and stirred at room temperature for 15 hours, and then at 5° C. for 2 hours. The resulting precipitates were filtered under a reduced pressure, washed with 3 ml of a mixture of isopropanol and distilled water (2/1, v/v), and dried at 50° C. for 4 hours, to obtain 2.4 g of the title compound (yield: 92%) as a white powder.
M.p.: 220-223° C. (reported value: 223-225° C.);
Water contents (Karl-Fisher titrator): 2.0%; (theoretical value: 1.90%)
EXAMPLE 7
3.0 g of clopidogrel (−)-(1R)-camphor-10-sulfonate (5.4 mmol) and 998 mg of disodium 1,5-naphthalenedisulfonate monohydrate (95%, 2.7 mmol) were suspended in a mixture of 20 ml of isopropanol and 10 ml of distilled water and the suspension was homogenized at 70° C. The resulting solution was slowly cooled; and stirred at room temperature for 15 hours, and then at 5° C. for 2 hours. The resulting precipitates were filtered under a reduced pressure, washed with 3 ml of a mixture of isopropanol and distilled water (2/1, v/v), and dried at 50° C. for 4 hours, to obtain 2.3 g of the title compound (yield: 88%) as an white powder.
M.p.: 221-224° C. (reported value: 223-225° C.);
Water contents (Karl-Fisher titrator): 1.75%; (theoretical value: 1.90%)
EXAMPLE 8
3.0 g of clopidogrel hydrogen sulfate (7.1 mmol) and 1.32 g of disodium 1,5-naphthalenedisulfonate monohydrate (95%, 3.6 mmol) were suspended in a mixture of 20 ml of isopropanol and 10 ml of distilled water and the suspension was homogenized at 70° C. The resulting precipitates were slowly cooled; and stirred at room temperature for 15 hours, and then at 5° C. for 2 hours. The resulting precipitates were filtered under a reduced pressure, washed with 6 ml of a mixture of isopropanol and distilled water (2/1, v/v), and dried at 50° C. for 4 hours, to obtain 3.2 g of the title compound (yield: 94%) as a white powder.
M.p.: 220-223° C. (reported value: 223-225° C.);
Water contents (Karl-Fisher titrator): 1.7%; (theoretical value: 1.90%)
EXAMPLE 9
1.0 g of clopidogrel hydrogen sulfate (2.4 mmol) and 439 mg of disodium 1,5-naphthalenedisulfonate monohydrate (95%, 1.2 mmol) were suspended in a mixture of 5 ml of methanol and 10 ml of distilled water and the suspension was homogenized at 70° C. The resulting solution was slowly cooled; and stirred at room temperature for 15 hours, and then at 5° C. for 2 hours. The resulting precipitates were filtered under a reduced pressure, washed with 6 ml of a mixture of isopropanol and distilled water (2/1, v/v), and dried at 50° C. for 4 hours, to obtain 3.2 g of the title compound (yield: 94%) as a white powder.
M.p.: 220-223° C. (reported value: 223-225° C.);
Water contents (Karl-Fisher titrator): 1.7%; (theoretical value: 1.90%)
EXAMPLE 10
1.0 g of Clopidogrel hydrogen sulfate (2.4 mmol) and 439 mg of disodium 1,5-naphthalenedisulfonate monohydrate (95%, 1.2 mmol) were dissolved in 10 ml of distilled water; and stirred at room temperature for 15 hours, and then at 5° C. for 2 hours. The resulting precipitates were filtered under a reduced pressure, washed with 3 ml of distilled water, and dried at 50° C. for 4 hours, to obtain 0.9 g of the title compound (yield: 84%) as a white powder.
M.p.: 220-223° C. (reported value: 223-225° C.);
Water contents (Karl-Fisher titrator): 2.0%; (theoretical value: 1.90%)
EXAMPLE 11
1.0 g of Clopidogrel hydrogen sulfate (2.4 mmol) and 439 mg of disodium 1,5-naphthalenedisulfonate monohydrate (95%, 1.2 mmol) were suspended in a mixture of 7 ml of toluene and 10 ml of distilled water; and stirred at room temperature for 15 hours, and then at 5° C. for 2 hours. The resulting precipitates were filtered under a reduced pressure, washed with 3 ml of distilled water, and dried at 50° C. for 4 hours, to obtain 0.9 g of the title compound (yield: 84%) as a white powder.
M.p.: 221-224° C. (reported value: 223-225° C.);
Water contents (Karl-Fisher titrator): 1.9%; (theoretical value: 1.90%)
EXAMPLE 12
1.0 g of Clopidogrel hydrogen sulfate (2.4 mmol) and 439 mg of disodium 1,5-naphthalenedisulfonate monohydrate (95%, 1.2 mmol) were suspended in a mixture of 7 ml of diethyl ether and 10 ml of distilled water; and stirred at room temperature for 15 hours, and then at 5° C. for 2 hours. The resulting precipitates were filtered under a reduced pressure, washed with 3 ml of distilled water, and dried at 50° C. for 4 hours, to obtain 0.91 g of the title compound (yield: 85%) as a white powder.
M.p.: 221-224° C. (reported value: 223-225° C.);
Water contents (Karl-Fisher titrator): 1.8%; (theoretical value: 1.90%)
As discussed above, the present invention provides an easy method for preparing clopidogrel 1,5-naphthalenedisulfonate or its hydrate on a large scale, in which disodium 1,5-naphthalenedisulfonate, a non-corrosive and non-coloring starting material is used without any of the problems encountered in the conventional method.
While the invention has been described with respect to the above specific embodiments, it should be recognized that various modifications and changes may be made to the invention by those skilled in the art which also fall within the scope of the invention as defined by the appended claims.
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The present invention relates to a method for preparing clopidogrel 1,5-naphthalenedisulfonate or a hydrate thereof, which comprises reacting a clopidogrel-acid addition salt with disodium 1,5-naphthalenedisulfonate or its hydrate in water, or a mixture of water and an organic solvent. High quality clopidogrel 1,5-naphthalenedisulfonate can be prepared by the inventive method by way of using non-corrosive disodium 1,5-naphthalenedisulfonate.
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FIELD OF THE INVENTION
[0001] The present application is in the field of plant extracts for pharmaceutical compositions as acetylcholinesterase inhibitors useful as neuroprotectors, to manage depressive states and cognitive deficits of diverse etiologies, and for the treatment of neurodegenerative conditions, such as Alzheimer and Parkinson diseases, and the sequel from ischemic events.
BACKGROUND OF THE INVENTION
[0002] The differentiation of a normal healthy ageing and pathologic conditions common to the elderly is not always clear-cut. Ageing is, essentially, a degenerative process that culminates with neural death. Chronic neurodegenerative diseases are characterized by a progressive and irreversible neuronal loss in specific brain areas, as a result of neuronal injury consequent to a complex interaction of genetic and environmental factors.
[0003] Cognitive deficits are frequently associated with ageing and a core sign in dementias, with a global prevalence predictable to increase with the increasing life expectancy. Dementias affect approximately 5% of older people at 65, and 20% of those over 80 years old Among most common chronic-degenerative diseases are the Parkinson Disease (PD), affecting 1% of population over 65 years of age, and the Alzheimer Disease (AD) which became the commonest form of dementia in the elderly, affecting 2% of this group in developing countries. The current treatment for Alzheimer disease is based on acetylcholinesterase inhibitors (AChEIs), used for the mild and moderate stages of the disease. The ideal Ache would be well tolerated, of convenient administration, would induce a selective and sustained inhibition in the brain, besides showing selectivity to the isoforms of the enzyme of most relevance in AD, especially in the cortex and hippocampus. AChEIs such as this are not currently available.
[0004] Vascular dementia, resulting from small and recurring brain infarcts, is responsible for approximately 20% of all dementias pathologically confirmed. The prevalence of vascular dementia in individuals older than 64 years of age is estimated to be 1.0% whereas that of AD in 2.4%. In fact, vascular dysfunction responsible for changes in small vessels and hypo perfusion may precede the dementia in AD, strongly suggesting that cerebral ischemia has an important role in the majority of degenerative dementias. The world faces a prevalence of dementia of an epidemic nature associated with the increasing life spam, and brain ischemia may be one of the major contributing factors. The cost of cerebral ischemia, and of the associated pharmaceutical market, may be assessed by the following numbers: cerebral-vascular diseases are responsible for 5.4 millions of death/year (10% of the total), consuming £21 billion or approximately 3% of the health system costs in the European community in 2003; this costs raised to £34 billion if informal care and productivity losses are included; the anticipated costs of cerebro-vascular accidents in the US economy between 2005 and 2050 is U$ 2.2 trillion). Although historically seen as an inevitable consequence of ageing, it is now well accepted that the consequences of cerebral ischemia are prone to both prevention and treatment.
[0005] Relevant to this application, it has been shown that a combination of memantine (NMDA antagonist) and donezepil (AChEI) has a better outcome than any of the drugs given alone in the treatment of both vascular dementia (moderate and severe) and the latter stages of AD (Rossom, R., Adityanjee, Dysken, M., 2004. Efficacy and tolerability of memantine in the treatment of dementia. Am J Geriatr Pharmacother, 2: 303-312.). In fact, several approaches indicate that multi or bi-functional compounds may result in higher effectiveness as neuroprotective agents than those with a single mechanism of action. It has been argued that the historical difficulty for the development of better psychiatric drugs was the valorization of few targets as pharmacologic mechanism of actions and the unlikely belief in a single abnormal molecule as cause of complex illnesses. This notion is perfectly compatible with the demonstration that neurodegenerative phenomena are multifactorial in nature, determining a renewed interest in plant drugs having more than an active ingredient, and/or compounds with innovative and multiple mechanisms of action, and/or by the synergic interaction of these various active compounds.
[0006] Depression is another mental disturb common in the elderly, in general considered a chronic, recurrent, potentially fatal pathology that affects 20% of the global population. Our data show a clear antidepressant-like effect of the extract, demonstrated in three animal models, in a dose range lower than that presenting promnesic properties. The data show that the antidepressant activity depends on norepinephrine, and possibly not of serotonin, as well as involving the participation of dopamine D1 receptors and β adrenergic. Normalization of the hypothalamic-pituitary-adrenal axis (HPA) is related to the success of antidepressant treatment, and the data indicate that the compounds may normalize the HPA axis in an animal model of depression associated with repetitive stress. (Roth, B. L., Sheffler, D. J., Kroeze, W. K., 2004. Magic shotguns versus Magic bullets: selectively non-selective drugs for mood disorders and schizophrenia. Nat Rev Drug Discov, 3: 353-359). Given that depression includes cognitive deficits and can either trigger or influence the progression of neurodegenerative diseases, the antidepressive properties of the compounds add to its overall therapeutic value in neurodegenerative diseases.
[0007] The medical and scientific literatures identify physical exercise as a preventive measure not only to cardiovascular diseases, but also cancer, depression and neurodegenerative diseases.
[0008] Ptychopetalum olacoides Bentham (PO) (Olacaceae) is a plant most commonly used as a “nerve tonic” in the Amazon, now also found in herbals in Brazil, Europe and USA. “Nerve tonic”, “stimulating nerves,” or simply “tonics” are found in many traditional medical systems, commonly used by the elderly or those convalescent from disease in general and specifically from those that affect the central nervous system (such as stroke lack of concentration, memory lapses), and/or during periods of intense physical or mental stress. In addition to articles of the medical literature specifically, the patent literature also has a number of publications devoted to herbal medicines using Ptychopetalum olacoides Bentham (PO) (Olacaceae).
[0009] JP9235237A (1997) describes the invention relating to the use of a composition comprised of Muirapuama and Cordyceps sinensis Sacc. The composition is allegedly capable to enhancing functions and effectively acting on a state of deteriorated physical strength due to a stress. The Muirapuama can be used as an extract and the daily dose thereof for an adult is about 10-5000 mg expressed in terms of the amount of the raw crude drug. The Cordyceps sinensis Sacc. can be used as an extract or a fluid extract and the dose thereof administered is about 50-1000 mg.
[0010] JP2000119187A (2000) describes the invention relating to the use of a composition obtained by formulating Muirapuama or its essence. The effective daily dose for an adult is preferably about 10-500 mg expressed in terms of the amount of the raw crude drug. Furthermore, a water-soluble vitamin, a xanthin derivative, a crude drug, an excipient, a pH adjustor, etc., may be formulated.
[0011] WO0072861A1 (2000) and U.S. Pat. No. 6,746,695 B1 (2004) describe methods for extracting and purifying bioactive substances from various plants and herbs. More specifically the invention relates to methods of extracting and separating bioactive substances from various plants and herbs, such as Kava root, Byrsonima species, Aesculus californica, Crataegus mexicana, Simmondsia chinensis, Pfaffia species, Alternanthera repens, Bursera species, Turnera species, Perezia species, Heimia salicifolia, Psidium species, Enterlobium species, Ptychopetalum olacoides, Liriosma ovata , and Chaunochiton kappleri , using supercritical fluid extraction and/or fluorocarbon solvent extract. The invention further relates to separation of bioactive substances contained in extracts using packed column supercritical fluid chromatography or HPLC, where dense gas with or without modifiers is the mobile phase. The invention also relates to pharmaceutical preparations and dietary supplements which may be prepared with the extracted bioactive substances and use of such pharmaceutical preparations and dietary supplements to treat various human aliments.
[0012] Brazilian PI0102185-0 (2001) describes the use of the product comprising extract as an antioxidant or as a cerebral vasodilator agent, pharmaceutical composition comprising such product for the prophylaxis or treatment of vascular disorders and disturbances caused by the inappropriate presence of free radicals, the method for prophylaxis or treatment of cerebrovascular disorders and disorders caused by the inappropriate presence of free radicals using the product and use of that product to produce a pharmaceutical composition for prophylaxis or treatment of vascular disorders and disturbances caused by the inappropriate presence of free radicals. The invention addresses the use of a product of plant extracts including the species Trichilia sp, Paullinia cupana (Sapindaceae), Ptychopetalum olacoides (Olacaceae) and Zingiber officinale (Zingiberaceae).
[0013] Brazilian P10102184-2 (2001) describes the use of extract as an antidepressant and anxiety disorders, pharmaceutical composition comprising such product for the treatment or prevention of depression and/or anxiety disorders, the method for treatment or prevention of depression and/or anxiety disorders using the product and use of that product to produce a pharmaceutical composition for treatment or prevention of depression and/or anxiety disorders. The invention is the use of an extract product comprising the inlet species Trichilia sp (preferably from Trichilia catigua ) Paullinia cupana (Sapindaceae), Ptychopetalum olacoides (Olacaceae) and Zingiber officinale (Zingiberaceae).
[0014] Brazilian P10102186-9 (2001) describes use of the product comprising extract as agent, pharmaceutical composition comprising such product for the treatment or prevention of thromboembolic disorders, the method for treatment of thromboembolic disorders using the product and use of this product for production of a pharmaceutical composition for treatment or prevention of thromboembolic disorders. The invention is the use of a product extracts inlet including the species Trichilia sp (preferably the kind catigua ) Paullinia cupana (Sapindaceae), Ptychopetalum olacoides (oliacaceae) and Zingiber officinale (Zingiberaceae).
[0015] Brazilian PI0307647-4 A2 (2003) describes the invention of the extraction process of the chemical and pharmaceutical compositions. This paper describes the use of ethanol extracts of plants of the family Olacaceae as a chemical and/or pharmaceutical compositions for the prevention and treatment of chronic degenerative disorders of the central nervous system based on verification testing of biological activity for therapeutic purposes desired. The ethanol extracts endowed with biological activity are obtained using ethyl alcohol/water in proportions varying between 50 and 95% ethyl alcohol, characterized by the presence of a chemical marker substance or guide called pov-2. It also described a process of obtaining and identification of the substance guide pov-2 from plants of the family Olacaceae.
[0016] U.S. Pat. No. 6,746,695 (2004) describes methods of extracting and purifying bioactive substances from various plants and herbs. More specifically the invention relates to methods of extracting and separating bioactive substances from various plants and herbs, such as Kava root, Byrsonima species, Aesculus californica, Crataegus mexicana, Simmondsia chinensis, Pfaffia species, Alternanthera repens, Bursera species, Turnera species, Perezia species, Heimia salicifolia, Psidium species, Enterlobium species, Ptychopetalum olacoides, Liriosma ovata and Chaunochiton kappleri , using supercritical fluid extraction and/or fluorocarbon solvent extract. The invention further relates to separation of bioactive substances contained in extracts using packed column supercritical fluid chromatography or HPLC where dense gas with or without modifiers is the mobile phase. The invention also relates to pharmaceutical preparations and dietary supplements which may be prepared with the extracted bioactive substances and use of such pharmaceutical preparations and dietary supplements to treat various human ailments. Another embodiment of the invention is directed to formula and compositions comprising a combination of extracted phytochemicals from Turnera species and Pfaffia species, with or without muira puama (a crude drug derived from various species including Ptychopetalum olacoides, Liriosma ovata , and Chaunochiton kappleri for use as a health tonic and to support sexual function.
[0017] JP2005350391A (2005) describes the use of one or two or more species selected from the group consisting of plants of the genus Picrorhiza , plants of the Apocynum L., Catharanthus roseus (L.) Don, or the like, plants of the genus Iris , plants of the genus Rubus , plants of the genus Gossypium , plants of the genus Cynamchum , plant of the genus Tylophora , plants of the family Cactacea, plant of the genus Ceratostigma , plants of the genus Hyoscyamus, Hercampure; Gentianella alborosea (Gilg), Hernandia peltata, Ptychopetalum olacoides and pyroligneous acid are applied as an active ingredient. Thereby, neurocyte apoptosis by the Alzheimer's disease can be suppressed to carry out the prophylaxis of the Alzheimer's disease, suppress the progression of the Alzheimer's disease and treat the Alzheimer's disease.
[0018] Brazilian PI0605812-4 A2 (2006) describes the use of combination of extracts from pfaffia ( Pfaffia sp.), maripuama ( Ptychopetalum olacoides ) and white lily ( Lilium candidum ) in improvement of specific skin changes; in particular the use of a mixture of concentrated extracts of pfaffia ( Pfaffia sp.) puama ( Ptychopetalum olacoides ) and lily ( Lilium candidum ), presented as a hidroglicolic extract pure or mixed with other extracts and/or ingredients in cosmetic preparations and pharmaceuticals for treatment and improvement of the physiological and aesthetic of the region around the eyes, as dark circles or hyperpigmentation, edema or swelling, fat pads and the formation of fine wrinkles to the around the eyes, where this effect is achieved through mechanisms of action that lead to anti-inflammatory activities, decongestants, draining, lipolytic and restorative.
[0019] Applicant has shown that Ptychopetalum olacoides contains bioactive compounds with central action. dissertation of Ionara Rodrigues Siqueira (Contribution to the ethnopharmacology of Ptychopetalum olacoides Bentham: psychopharmacological properties. Masters Thesis, Masters in Biological Sciences—Physiology, Presented in November 1997, UFRGS, Brazil) and the following articles: Elisabetsky, E., Smith, I. R., 1998. Is there a psychopharmacological meaning for traditional tonics? IN: Prendergast H. D., Etkin N., Harris D. R. Houghton P. J (eds), Plants for Food and Medicine, 373-385. Royal Botanical Gardens, Kew and Siqueira, I. R., Lara, D. R., Silva, D., Gaieski, F. S., Nunes, D. S., Elisabetsky, E., 1999. Psychopharmacological properties of Ptychopetalum olacoides BENTHAM (Olacacea). Pharm Biol, 36 (5): 327-334).
[0020] Despite the range of indications (referred to but not specified or associated with biological data to substantiate the indications) and procedures for the extraction of bioactive compounds (generally referred to but not named) from Ptychopetalum reported in the literature, there is no mention or suggestion of the psychopharmacological properties and neurochemical data described bellow for P. olacoides extracts or that have the following pharmacological properties useful in preventing and/or treating degenerative diseases of the central nervous system. Such uses are described and claimed in this application.
SUMMARY OF THE INVENTION
[0021] The plant extract and composition of the present application is related to innovative mechanisms of action in line with the latest approaches to development of antidepressant drugs. The extract increases endurance, a pattern likely to result from an altered and more effective energy consumption (glycogen sparing along with increased fatty acid burning), and protection from muscle damage (decreased CK and LDH during exercise). These properties add to the overall therapeutic value of this extract in treating and or preventing neurodegenerative diseases.
[0022] The present application seeks to provide an ethanolic extract of Ptychopetalum olacoides obtained from a source selected from a group consisting of: stems, barks, leaves, roots and combinations thereof.
[0023] The present application also seeks to provide a pharmaceutical composition comprising: (a) an effective amount of an extract of Ptychopetalum olacoides , and (b) pharmaceutically acceptable excipients. The pharmaceutical composition comprising from 0.001% to 99% of extract of Ptychopetalum olacoides.
[0024] The present application also seeks to provide a method for treating or preventing diseases, dysfunctions and disorders of the central nervous system; neurodegenerative disorders and sequel from vascular dementia in a patient by administering an effective amount of an extract of Ptychopetalum olacoides.
BRIEF DESCRIPTION OF THE DRAWINGS
[0025] FIG. 1 shows the effect of Ptychopetalum olacoides extract (POEE) and eserine on G1 (A) and G4 (B) AChE isoforms in mouse hippocampus. SAL=saline; ESE=Eserine. All assays were performed in triplicate for five separate experiments. Each value represents mean±S.E.M. *P<0.05 vs. control (saline and DMSO).
[0026] FIG. 2 shows the effect of Ptychopetalum olacoides extract (POEE) and eserine on G1 (A) and G4 (B) AChE isoforms in mouse frontal cortex. SAL=saline; ESE=Eserine. All assays were performed in triplicate for five separate experiments. Each value represents mean±S.E.M. *P<0.05 vs. control (saline and DMSO).
[0027] FIG. 3 shows the effect of Ptychopetalum olacoides extract (POEE) and eserine on G1 (A) and G4 (B) AChE isoforms in mouse striatum. SAL=saline; ESE=Eserine. All assays were performed in triplicate for five separate experiments. Each value represents mean±S.E.M. *P<0.05 vs. control (saline and DMSO).
[0028] FIG. 4 shows the Lineweaver-Burk representation of G1 AChE (A) and G4 AChE (B) inhibition by Ptychopetalum olacoides extract (POEE) in the hippocampus with acetylthiocholine as substrate. Double reciprocal plot was constructed by plotting 1/V against 1/S analyzed over a range of substrate concentrations (0.01-0.075 mM) in the absence and in the presence of Ptychopetalum olacoides extract (POEE) (30, 100, 300 and 1000 μg/mL). The plot represents the means of five experiments (n=5).
[0029] FIG. 5 shows the effects of Ptychopetalum olacoides extract (POEE) on AChE activity in mice hippocampus CA1 (A), CA3 (B) and striatum (C). SAL=saline; GALA=Galanthamine. Optical density (OD) is expressed in pixels. Data are presented as means±S.E.M. (n=5). *P<0.05 vs. control (DMSO).
[0030] FIG. 6 shows the effects of Ptychopetalum olacoides extract (POEE) on AChE activity in mice hippocampus (CA1 and CA3) and striatum.
[0031] FIG. 7 shows the effect of Ptychopetalum olacoides extract (POEE) ex vivo on G1 (A) and G4 (B) AChE isoforms in mouse hippocampus. SAL=saline; GALA=Galanthamine. All assays were performed in triplicate. Each value represents mean±S.E.M. *P<0.05 vs. control (DMSO).
[0032] FIG. 8 shows the effect of Ptychopetalum olacoides extract (POEE) ex vivo on G1 (A) and G4 (B) AChE isoforms in mouse frontal cortex. SAL=saline; GALA=Galanthamine. All assays were performed in triplicate. Each value represents mean±S.E.M. *P<0.05 vs. control (DMSO).
[0033] FIG. 9 shows the effect of Ptychopetalum olacoides extract (POEE) ex vivo on G1 (A) and G4 (B) AChE isoforms in mouse striatum. SAL=saline; GALA=Galanthamine. All assays were performed in triplicate. Each value represents mean±S.E.M. *P<0.05 vs. control (DMSO).
[0034] FIG. 10 shows the western blotting analysis for AChE immunocontent in total membranes from the mice hippocampus (A), and frontal cortex (B). Bands of the equivalent molecular weights (65 kDa for AChE) are illustrated on the top of the each histogram where bars indicate the bands quantifications by scanned autoradiographic films. Density is expressed as means±S.E.M. of five samples of whole hippocampus and frontal cortex for each treatment group. *P<0.05, vs. control (saline).
[0035] FIG. 11 shows the western blotting analysis for AChE immunocontent in synaptosomal fractions from the mice hippocampus (A) and frontal cortex (B). Bands of the equivalent molecular weights (65 kDa for AChE) are illustrated on the top of the each histogram where bars indicate the bands quantifications by scanned autoradiographic films. Density is expressed as means±S.E.M. of five synaptosomal samples hippocampus and frontal cortex for each treatment group. *P<0.05, vs. control (saline).
[0036] FIG. 12 shows the effect of Ptychopetalum olacoides extract (POEE) 800 mg/kg administrated for 14 days in adult mice on step-down inhibitory avoidance task (LTM, 24 h training-test interval). DMSO=dimethyl sulphoxide 20%; Sal=saline; Aβ 1-42 =β-amyloid (1-42) peptide fragment; PO=standardized ethanol extract of Marapuama (N=12/group). Each column represents latencies (s) median (interquartile ranges) of training (light columns) or test (gray columns) latencies. ## p<0.05 test×training latencies for each treatment, Wilcoxon. **p<0.05× controls (PBS+Sal) test latencies, Mann-Whitney/Kruskal-Wallis; $ p<0.05 for Aβ 1-42 +Sal×Aβ 1-42 +PO test latencies, Wilcoxon.
[0037] FIG. 13 shows the effects of Ptychopetalum olacoides extract (POEE) on spontaneous locomotor activity: (A) exploration (first 3 min) and (B) locomotion (final 5 min). Each column represents the mean±SEM. N=12. ANOVA/Duncan's test.
[0038] FIG. 14 shows the brain-derived neurotrophic factor (BDNF) levels in mice hippocampus. Results are expressed as mean±SEM. N=5 per group. ANOVA/Duncan's test.
[0039] FIG. 15 shows the effects of Ptychopetalum olacoides extract (POEE) (200 mg/kg) and apomorphine 3 mg/kg (APO) on MPTP-induced tremors in C57BL/6 mice. The intensity of tremors was scored 0-5 by independent observers immediately after the second dose of MPTP. Evaluation was done every 3 min for a period of 45 min. N=5, mean±SEM, *P≦0.05 or # P≦0.01 vs. control, Kruskai Wallis/Mann Whitney.
[0040] FIG. 16 shows the effects of Ptychopetalum olacoides extract (POEE) (25 or 50 mg-kg) and apomorphine 3 mg/kg (APO) on BALB/c mice MPTP induced tremor. The intensity of tremors was scored as 0-5 by independent observers immediately after the second dose of MPTP. Evaluation was done every 3 min for a period of 45 rain. N=6, mean±SEM, *P≦0.05 or # P≦0.01 vs. control, Kruskal Wallis/Mann Whitney.
[0041] FIG. 17 shows the effects of Ptychopetalum olacoides extract (POEE) (25 and 50 mg/kg) and apomorphine 3 mg/kg (APO) on BALB/c mice MPTP-induced catalepsy. Assessment of catalepsy was undertaken 3 h after the treatment of MPTP. Results given are mean±S.E.M (five times for each animal), *P≦0.05× controls sal×sal or # P≦0.1× controls MPTP. Kruskal Wallis/Mann Whitney. n=6.
[0042] FIG. 18 shows the effects of Ptychopetalum olacoides extract (POEE) (25 and 50 mg/kg) and apomorphine 3 mg/kg (APO) on BALB/c mice MPTP-induced akinesia. Assessment of akinesia was undertaken 4 h after the treatment of MPTP. Results given are mean±S.E.M (five times for each animal), *P≦0.05× controls sal×sal or # P≦0.01× controls MPTP. Kruskal Wallis/Mann Whitney. n=6.
[0043] FIG. 19 shows the effect of different doses of Ptychopetalum olacoides extract (POEE) (25 and 50 mg/kg) and apomorphine 3 mg/kg (APO) on the swimming ability of BALB/c mice was tested in warm water (27±2° C.) on the third day following the treatment of MPTP. Swim-scores were recorded on a performance intensity scale of 0-3 for all the animals for 10 min. Results given are mean±0.05 or # p≦0.01 vs. control MPTP. Kruskal Wallis/Mann Whitney, n=6.
[0044] FIG. 20 shows the effect of different doses of Ptychopetalum olacoides extract (POEE) (25 and 50 mg/kg) and apomorphine 3 mg/kg (APO) on the swimming ability of BALB/c mice was tested in warm water (27±2° C.) on the seventh day following the treatment of MPTP. Swim-scores were recorded on a performance intensity scale of 0-3 for all the animals for 10 min. Results given are mean±S.E.M., *p≦0.05 or #p≦0.01 vs. control MPTP. Kruskal Wallis/Mann Whitney, n=6.
[0045] FIG. 21 shows the effect of different doses of Ptychopetalum olacoides extract (POEE) (25 and 50 mg/kg) and apomorphine 3 mg/kg (APO) on the swimming ability of BALB/c mice was tested in warm water (27±2° C.) on the fourteenth day following the treatment of MPTP. Swim-scores were recorded on a performance intensity scale of 0-3 for all the animals for 10 min. Results given are mean±S.E.M. Kruskal Wallis/Mann Whitney, n=6.
DETAILED DESCRIPTION OF THE INVENTION
[0046] The invention will be described for the purposes of illustration only in connection with certain embodiments; however, it is to be understood that other objects and advantages of the present invention will be made apparent by the following description of the drawings according to the present invention. While a preferred embodiment is disclosed, this is not intended to be limiting. Rather, the general principles set forth herein are considered to be merely illustrative of the scope of the present invention and it is to be further understood that numerous changes may be made without straying from the scope of the present invention.
[0047] The present application describes extract of Ptychopetalum olacoides (olacaceae) as an active ingredient useful in preparing medicines, or pharmaceutical compositions, for the treatment or prevention of diseases, dysfunctions and disorders of the central nervous system, such as depressive and neurodegenerative disorders such as Alzheimer's and Parkinson's diseases.
[0048] The extract of this application not only fulfill several of the desired aspects described above for the ideal anticholinesterase agent, but also shows neuroprotective properties, consisting in a new prototypic anticholinesterase class of compounds. Adding to previous promnesic properties for the extract, it is noteworthy that the anticholinesterasic properties of these compounds are not the only pharmacodynamic basis for ameliorating diverse types of memories, since dopamine D 1 , adrenergic β and serotonin 5HT 2A receptors are also involved in the identified promnesic and anti-amnesic properties. Moreover, the reversion of MK801-induced amnesia is suggestive of modulation of glutamate NMDA receptors, which play central roles in neuronal death and several neurodegenerative processes. Therefore the present extract, with promnesic, anti-amnesic and neuroprotective properties, containing innovative AChEI compounds that moreover modulate other receptors (glutamate, adrenergic, dopaminerfic and serotonergic) of renowned relevance for pro-cognitive, neuroprotective and antidepressive properties is perfectly in line with the cutting edge therapeutic approaches for neurodegenerative conditions. Neuroprotective properties of the compounds were demonstrated by a marked antioxidant activity in brain areas relevant to cognition, its capacity to protect hippocampus slices submitted to ischemia (oxygen and glucose deprivation model), the increased resilience to in vivo hypoxia, the reversion of tremors, akinesia and catalepsy induced by MPTP (an experimental model for Parkinson's Disease) and the reversal of β-amilóide changes (an experimental model for Alzheimer's Disease). The above mentioned modulation of neurotransmitters systems by the extract, especially glutamate and dopamine, are also relevant for neuroprotection.
[0049] As evidenced by the examples detailed below, the extract is efficacious in inhibiting brain cholinesterases, thereby augmenting the synaptic acetylcholine availability and consequently all functions dependent on cholinergic stimulation. Such functions include, neuroprotection, memory facilitation to various types of memory, reversal of amnesias induced by different neurotransmitter antagonists, protection against isquemic and oxygen reactive species.
[0050] The appropriate dosage of one or more active ingredients according to the present application can vary from about 0.001 mg/kg/day to about 5000 mg/kg/day, particularly from about 200 mg/kg/day to about 400 mg/kg/day, divided into one or more times a day.
[0051] Another embodiment of this application consists in a pharmaceutical composition containing an effective amount of extract of Ptychopetalum olacoides , in pharmaceutically acceptable excipients. The pharmaceutical compositions according to the present application can be liquid, semisolid or solid and can be adapted for any route of enteral or parenteral administration, either immediate release or modified. In particular achievement, said pharmaceutical composition is adapted for oral administration, particularly in the form of tablets, capsules, tinctures, emulsions, liposomes, microcapsules or nanoparticles.
[0052] Excipients suitable for the pharmaceutical composition of the present application are, for example and without limitation, those cited in the book Remington's Pharmaceutical Sciences, Mack Publishing publisher American, European Pharmacopoeia or the Brazilian Pharmacopoeia. Another object according to the present invention includes a method for preventing or treating disease, treating disease or neurodegenerative disorders such as Parkinson's disease and Alzheimer's disease or vascular dementia or cognitive deficits seen in older people, comprising supplying a patient in need with an effective amount of the extract o Ptychopetalum olacoides extract and/or a pharmaceutical composition containing such compounds.
[0053] The following examples serve to illustrate aspects of the present invention without having, however, any limiting character. We present tests with the extract of Ptychopetalum olacoides just for ease of presentation, without limitation only for this product.
EXAMPLES
I. Characterization of Acetylcholinesterase Inhibition in Relevant Brain Areas and Acetylcholinesterase Isoforms
I.I. In Vitro
[0054] Because there is evidence that AChE-Is differentially inhibit the two major AChE molecular isoforms are found in the brain. (the cytosolic globular monomer (G1) and membrane bound globular tetramer (G4), and because these isomeric forms have different cellular distribution and functional significance in synaptic transmission (Brimijoin, S., 1983. Molecular forms of acetylcholinesterase in brain, nerve and muscle: nature, localization and dynamics. Prog Neurobiol 21:291-322), and since in healthy human brain, G1 and G4 AChE isoforms are responsible for 80% of total cholinesterase activity (Atack, J. R., Perry, E. K., Bonham, J. R., Candy, J. M., Perry, R. H., 1986. Molecular forms of acetylcholinesterase and butyrylcholinesterase in Alzheimer's disease resemble embryonic development: a study of molecular forms. Neurochem Int, 21:381-396), whereas in AD brain there is a selective loss of G4 and a relative sparing of G1 (Siek, G. C., Katz, L. S., Fishman, E. B., Korosi, T. S., Marquis, J. K., 1990. Molecular forms of acetylcholinesterase in subcortical areas of normal and Alzheimer disease brain. Biol Psychiatry 27, 573-580; Schegg, K. M., Harrington, L. S., Neilsen, S., Zweig, R. M., Peacock, J. H., 1992. Soluble and membrane-bound forms of brain acetylcholinesterase in Alzheimer's disease. Neurobiol Aging 13, 697-704), the following experiments characterize the inhibitory effect of Ptychopetalum olacoides extract in mouse hippocampus, frontal cortex, and striatum (brain areas relevant for cognition), taking into account specificities for G1 and G4 isoforms. Additionally, the nature of inhibition was determined in hippocampus.
[0055] AChE isoform sources: Male (CF1) adult (2 months old, 35-45 g) albino mice were sacrificed by guillotine, then the brains were quickly removed, cleaned with chilled saline, and cerebral structures dissected out over ice. The hippocampus, frontal cortex, and striatum were homogenized in 20, 10 and 20 volumes of buffer (0.01 M Tris-HCl buffer, pH-7.2 and 0.16 M sucrose), respectively, and centrifuged at 5000×g at 4° C. for 15 min (Eppendorf Centrifuge 5415R). The resulting supernatants were used as the G1 source (Das, A., Dikshit, M., Nath, C., 2001. Profile of acetylcholinesterase in brain areas of male and female rats of adult and old age. Life Sci 68, 1545-1555). The pellet was suspended in 1% Triton-X 100 (1% w/v in 0.5 M potassium phosphate buffer, pH-7.5) and centrifuged at 100,000×g at 4° C. in a Hitachi Refrigerated Centrifuge for 60 min. The supernatant was collected and used as the G4 source (Das, A., Dikshit, M., Nath, C., 2001. Profile of acetylcholinesterase in brain areas of male and female rats of adult and old age. Life Sci 68, 1545-1555).
[0056] AChE activity: Determination of AChE activity was adapted from the colorimetric method originally described by Ellman et al. (Ellman, G. L., Courtney, K. D., Andre, V. Jr., Featherstone, R. M., 1961. A new and rapid colorimetric determination of acetylcholinesterase activity. Biochem Pharmacol 7, 27-30). Briefly, 33 μL of 10 mM DTNB, 68 μL of Tris-HCl buffer, 100 μL of Ptychopetalum olacoides extract (0-1000 μg/mL), 33 μL of enzymatic material (3 μg/μL of protein for G1 or G4 AChE) were added to microplates followed by 33 μL of 0.8 mM ATC. The incubation solution contained the butyrylcholinesterase inhibitor tetraisopropyl pyrophosphoramide (iso-OMPA) at a final concentration of 100 μM in order to specifically measure AChE activity. The microplate was read at 415 nm every 30 s for 2.5 min (Microplate Reader Model 680, Bio-Rad Laboratories, UK). Experiments were performed in triplicate. AChE activities are expressed as μmol of acetylthiocholine hydrolyzed/hour/milligram of protein (μmol ATC/h/mg protein). The total enzymatic activity was determined and POEE IC 50 was obtained using the software package Prism Graph Pad 5.0 (Graph Pad Inc., San Diego, USA).
[0000]
TABLE 1
Effect of Ptychopetalum olacoides extract on Km (μg/mL) and
V max (μmol ATC/h/mg protein) of hippocampus G1 and G4 AChE.
V max
[POEE]
(μmol ATC/h/mg
Km
(μg/mL)
protein)
(μg/mL)
G1 AChE
0
5.86
7.91
30
6.27
9.14
100
6.11
10.63
300
5.68
11.06
1000
6.45
12.84
G4 AChE
0
6.05
8.29
30
5.74
7.61
100
4.11
6.0
300
4.36
6.05
1000
4.43
6.37
V max and Km were measured on Lineweaver-Burk double reciprocal plots varying the concentration of the substrate ATC from 0.01 to 0.075 mM, and using increasing Ptychopetalum olacoides extractconcentrations (0, 30, 100, 300 and 1000 μg/mL) in hippocampus.
[0057] Kinetics analysis: To determine the type of enzyme inhibition, Lineweaver-Burk double reciprocal plots were produced by varying the concentration of the substrate ATC from 0.01 to 0.075 mM in the hippocampus. Plots were used to determine Km and V max for Ptychopetalum olacoides extract using 0, 30, 100, 300 and 1000 μg/mL. Specific activities are expressed as μmol ATC/h/mg protein.
[0058] Protein assay: The protein content was determined as described by Lowry et al. (Lowry, O. H., Rosebrough, N. J., Farr, A. L., Randall, R. J., 1951. Protein measurement with the folin phenol reagent. J Biol Chem 193, 265-275), using bovine serum albumin (BSA) as standard.
[0059] Statistical analysis: The data were analyzed by one way analysis of variance (ANOVA) followed by Duncan's post hoc test. P<0.05 was adopted as the least significant level.
Results:
[0060] FIGS. 1 , 2 and 3 show the effects of Ptychopetalum olacoides extract (0-1000 μg/mL) on G1 and G4 from hippocampus, frontal cortex and striatum, respectively. Ptychopetalum olacoides extract mostly inhibits (P<0.05) G1 in hippocampus (75%), and G4 in frontal cortex (58%) and striatum (75%).
[0061] The kinetic analysis shown at Table 1 and FIG. 4 indicates that Ptychopetalum olacoides extract-induced inhibition in hippocampus is of a competitive nature for G1 and uncompetitive for G4.
I.II. Ex-Vivo
[0062] A huge impediment for developing drugs for treating CNS diseases is the blood-brain barrier (BBB) and the extent to which a drug can readily penetrate the BBB determines its bioavailability (Anekonda, T. S. and Reddy, P. H., 2005. Can herbs provide a new generation of drugs for treating Alzheimer's disease? Brain Res Rev, 50: 361-376). The following experiments characterize histochemically the effect of different doses of Ptychopetalum olacoides extract on AChE activity at differents brain areas in mice orally treated with the compounds in Formula (I). The experiments prove the anticholinesterase effects of the compounds in Formula (I) in the desired sites after oral treatment.
[0063] Complementing the in vitro analysys, the effects of oral treatment with Ptychopetalum olacoides extract was analysed in the acetylcholinesterase isoforms G1 and G4 obtained from hippocampus, frontal cortex and striatum.
[0064] In addition, western blotting analysis were performed to measure the effects of Ptychopetalum olacoides extract in the acetylcholinesterase immunocontent in mice hippocampus and frontal cortex. The experiment show that the compounds do not affect the immunocontent, demonstrating that there is a functional inhibition rather than an effect in the enzyme syntheses.
[0065] Experimental groups and drug administration: Ptychopetalum olacoides extract was dissolved in a 20% DMSO solution. Groups of mice (N=5) were treated orally (by gavage) with a single dose of saline, galanthamine (5 mg/kg), DMSO 20%, and Ptychopetalum olacoides extract (300 or 800 mg/kg). All drugs were given as 0.1 mL/10 g body weight.
[0066] Preparation of Brain Slices: Ninety minutes after drug administration, under deep anesthesia (i.p. sodium thiopental 60 mg/kg), the animals were transcardially perfused with saline followed by a cold 4% paraformaldehyde solution in 0.1 M phosphate buffer (PB), pH 7.4. After complete perfusion brains were removed, post-fixed in the same fixative solution at room temperature for 4 hours, and sectioned (coronal sections; 50 μm) with a vibratome (Leica, Germany). The sections were collected in PB.
[0067] Histochemistry procedure: The free-floating sections were carefully washed in 0.1 M tris maleato buffer, pH 6 (TMB) and processed for AChE histochemistry as described by Karnovsky and Roots (Karnovsky, M. J. and Roots, L., 1964. A “direct-coloring” thiocoline method for cholinesterases. J Histochem Cytochem, 12: 219-221). Each section was incubated during 4 h at room temperature and protected from light in microplates filled with 3 ml of the following solution: acetylthicholine iodide 2.5 mM, TMB 0.1 M sodium citrate, 30 mM copper sulfate, 5 mM potassium ferricyanide in distilled water. Cupric ferrocyanide (Karnovsky's precipitate) and cuprous thiocholine iodide (resulting from ferricyanide and cupric ions reduced by thicholine) are the expected histochemical products. Immediately after incubation, sections were rinsed 3 times in TMB, dehydrated in ethanol, cleared with xylene, and covered with balsam and a coverslip. Experiments included brains from all experimental groups, and the entire procedure were carefully executed to ensure that all sections were submitted to exactly the same histological steps, identical incubation medium and same incubation time. Therefore eventual differences in histochemistry reaction or changes in the background levels among the various groups were kept as minute as possible.
[0068] Optical densitometry: Hippocampus (CA1 and CA3), striatum (caudate putamen, CPu), basolateral amygdaloid nucleus anterior (BLA) and lateral entorhinal cortex (LEnt) were identified according to Franklin and Paxinos Atlas (Franklin, K. B. J. and Paxinos, G. T., 1996. The mouse brain in stereotaxic coordinates, Academic Press, San Diego), with the following coordinates: interaural 2.34 at 1.10 mm, bregma −1.46 at −2.70 mm for CA1/CA3, interaural 2.34 at 1.50 mm, bregma −1.46 at −2.30 mm for CPu, BLA and LEnt. These areas were selected for its relevance to cognition and/or abundant cholinergic afference. The intensity of the AChE histochemistry was assessed by semi-quantitatively denstitometric analysis (Xavier, L. L., Viola, G. G., Ferraz, A. C., Da Cunha, C., Deonizio, J. M., Netto, C. A., Achaval, M., 2005. A simple and fast densitometric method for the analysis of tyrosine hydroxylase immunoreactivity in the substantia nigra pars compacta and in the ventral tegmental area. Brain Res Brain Res Protoc, 16:58-64; Winkelmann-Duarte, E. C., Todeschin, A. S., Fernandes, M. C., Bittencourt, L. C., Pereira, G. A., Samios, V. N., Schuh, A. F., Achaval, M. E., Xavier, L. L., Sanvitto, G. L., Mandarim-de-Lacerda, C. A., Lucion, A. B., 2007. Plastic changes induced by neonatal handling in the hypothalamus of female rats. Brain Res , 19:20-30), using a Nikon Eclipse E-600 (Japan, Tokyo) microscope coupled to a Pro-Series High Performance CCD camera and the Image Pro Plus Software 6.0 (Media Cybernetics, CA, USA). The digitized images from selected areas (left and right brain sides) were converted to an 8-bit gray scale (0-255 gray levels), and lighting conditions and magnifications were held constant throughout the analysys. 100× magnification was used for CA1 and CA3 and 40× magnification for CPu, BLA and LEnt. The optical density (OD, pixels) was measured in 325.5 μm2 squares delimited at CA1 and CA3, and 8053.9 μm2 squares at CPu, BLA and LEnt. Selected squares were free from blood vessels or procedure-induced tissue marks. ODs were obtained from at least 40 slices from each animal, with the average OD/area used as individual OD. Investigators were unaware of the slice source (experimental groups) being analysed. The optical density (OD) was calculated in accordance with our previous published protocol (Xavier, L. L., Viola, G. G., Ferraz, A. C., Da Cunha, C., Deonizio, J. M., Netto, C. A., Achaval, M., 2005. A simple and fast densitometric method for the analysis of tyrosine hydroxylase immunoreactivity in the substantia nigra pars compacta and in the ventral tegmental area. Brain Res Brain Res Protoc, 16:58-64).
[0069] Preparation of total and synaptosomal membranes: Ninety minutes after drug administration mice were sacrificed by decapitation and the hippocampus and frontal cortex were dissected out in ice to obtain total and percoll purified synaptosomal membranes as previously described (Cunha, R. A., Johansson, B., Constantino, M. D., Sebastião, A. M., Fredholm, B. B., 1996. Evidence for high-affinity binding sites for the adenosine A2A receptor agonist [3H]CGS 21680 in the rat hippocampus and cerebral cortex that are different from striatal A2A receptors. Naunyn Schmiedeberg's Arch Pharmacol 353, 261-271). Briefly, brain structures were dissected and homogenized (5%, w/v) in 0.32 M sucrose, 10 mM HEPES, pH 7.4 (sucrose buffer), using a homogenizer. The suspension was centrifuged at 3,000 rpm for 2 min, and supernatants were spun at 14,000 rpm for 12 min. The upper white layer of the pellet (P2) was removed and resuspended in 5% SDS with a protease cocktail inhibitor (Sigma, São Paulo/Brazil). Alternatively, a purified hippocampal synaptosomal suspension was isolated using the Percoll method described elsewhere (Dunkley et al., 1986) by resuspending P2 in 500 μL of 45% (v/v) Percoll solution in Krebs (140 mM NaCl, 5 mM KCl, 25 mM HEPES, 1 mM EDTA, 10 mM glucose, pH 7.4), centrifuged at 14,000 g for 20 minutes min at 4° C. The top layer (synaptosomal fraction) was collected in 1 mL Krebs solution, washed and the synaptosomal fraction was centrifuged again at 14,000×g for 2 min at 4° C. and the pellet was ressuspended in 5% SDS with a protease cocktail inhibitor (Sigma, São Paulo/Brazil). The samples were frozen at −70° C.
[0070] Western blotting analysis: After defrost, the protein determination of the synaptosomal and total membranes from hippocampus and frontal cortex were carried out by using Bicinchoninic acid assay using bovine serum albumin (BSA) as standard (Pierce, São Paulo/Brazil). Samples were diluted to a final protein concentration of 2 μg/μL in SDS-PAGE buffer; 40 μg (20 μL) of samples and 20 μL of a dual color pre-stained molecular weight standard (Bio-Rad, Porto Alegre, Brazil) were separated by SDS-PAGE (10% concentrating gel). After electro-transfer, the membranes were blocked with Tris-buffered saline 0.1% Tween-20 (TBS-T) containing 3% BSA. After blocking, the membranes were incubated for 24 h at 4° C. with mouse anti-AChE antibody (1:1000, Chemicon Int., São Paulo/SP, Brazil). After primary antibody incubation, membranes were washed in TBS-T and incubated with horseradish peroxidase-conjugated secondary antibodies for 2 h at room temperature and developed with ECL (Amersham, São Paulo/Brazil). The autoradiographic films were scanned and densitometric analyses were performed using public domain NIH Image Program (http://rsb.info.nih.gov/nih-image/). As an additional control of the protein loading, membranes were stained with Ponceau S or mouse anti-GAPDH antibody (1:1000).
[0071] AChE activity: Determination of AChE activity was adapted from the colorimetric method originally described by Ellman et al. (Ellman, G. L., Courtney, K. D., Andre, V. Jr., Featherstone, R. M., 1961. A new and rapid colorimetric determination of acetylcholinesterase activity. Biochem Pharmacol 7, 27-30) as described above for in vitro studies.
[0072] Statistics: The data are expressed as means±S.E.M. One way analysis of variance (ANOVA) followed by the Duncan multiple group comparison was used to image analysis. Paired Student t-test was used to validate methods against positive controls. Significance was set at P<0.05.
Results:
[0073] FIG. 5 shows AChE histochemistry intensity, expressed in optical density (OD). Ptychopetalum olacoides extract 800 mg/kg significantly (P<0.05) decreased OD in CA1 (0.08±0.01), CA3 (0.14±0.01), and CPu (0.13±0.01), as compared to DMSO (CA1: 0.10±0.01; CA3: 0.17±0.01; and CPu: 0.17±0.01). AChE inhibition corresponded to 33%, 20% and 17% on CA1, CA3 and CPu, respectively. FIG. 6 illustrated this result.
[0074] FIGS. 7A-B , 8 A-B and 9 A-B show the effects of Ptychopetalum olacoides extract (800 mg/kg) on G1 and G4 from hippocampus, frontal cortex and striatum, respectively. Ptychopetalum olacoides extract mostly inhibits (P<0.05) G1 and G4 (−70%) in hippocampus, and G4 in frontal cortex (62%) and striatum (75%).
[0075] FIGS. 10A-B and 11 A-B show the effects of Ptychopetalum olacoides extract on the AChE immunocontent in total membranes and synaptosomal membranes from the hippocampus and frontal cortex. No significant changes were induced by Ptychopetalum olacoides extract 800 (mg/kg) in hippocampus and frontal cortex total membranes or synaptosomal membranes.
II. Alzheimer's Disease Model
[0076] Alzheimer's disease is pathologically characterized by the presence of extracellular plaques of β-amyloid peptide (Aβ) (Glenner, G. G. and Wong, C. W., 1984. Alzheimer's disease: initial report of the purification and characterization of a novel cerebrovascular amyloid protein. Biochem Biophys Res Commun, 120(3):885-90; Masters, C. L., Multhaup, G., Simms, G., Pottgiesser, J., Martins, R. N., Beyreuther, K., 1985. Neuronal origin of a cerebral amyloid: neurofibrillary tangles of Alzheimer's disease contain the same protein as the amyloid of plaque cores and blood vessels. EMBO J. 4(11): 2757-63), and intracellular tangles of hyperphosphorylation tau protein (Ballatore, C., Lee, V. M., Trojanowski, J. Q., 2007. Tau-mediated neurodegeneration in Alzheimer's disease and related disorders. Nat Rev Neurosci, 8(9): 663-72; Braak, H. and Braak, E., 1998. Evolution of neuronal changes in the course of Alzheimer's disease. J Neural Transm Suppl, 53:127-40). These changes result in loss of forebrain cholinergic neurons and pronounced acetylcholine reduction (Bartus, R. T., Dean, R. L., Beer, B., Lippa, A. S., 1982a. The cholinergic hypothesis of geriatric memory dysfunction. Science 217, 408-417), although, the connections between these pathological hallmarks and mechanism by which Aβ causes neuronal injury and cognitive impairment is not yet clearly understood (Pimplikar, S. W., 2009. Reassessing the amyloid cascade hypothesis of Alzheimer's disease. Int J Biochem Cell Biol, 41(6): 1261-8; Jhoo, J. H., Kim, H. C, Nabeshima, T., Yamada, K., Shin, E. J., Jhoo, W. K., Kim, W., Kang, K. S., Jo, S. A., Woo, J. I., 2004. Beta-amyloid (1-42)-induced learning and memory deficits in mice: involvement of oxidative burdens in the hippocampus and cerebral cortex. Behav Brain Res , 155(2):185-96).
[0077] The following experiments investigate whether chronic oral administration of Ptychopetalum olacoides extract protects mice from the learning and memory deficits induced by intracerebroventricular (icv) β-amyloid protein-(1-42), a mice model of AD. Experiments show that treatment with Ptychopetalum olacoides extract for 15 days already attenuates the consequences of icv β-amyloid.
[0078] BDNF (brain-derived neurotrophic factor) and its receptor are involved in cholinergic cell survival, maintenance and axonal growth (Bibel, M. and Barde, Y. A., 2000. Neurotrophins: key regulators of cell fate and cell shape in the vertebrate nervous system. Genes Dev, 14(23): 2919-37; Chao, M. V., 2003. Neurotrophins and their receptors: a convergence point for many signaling pathways. Nat Rev Neurosci 4: 299-309), stimulate choline acetyltransterase (ChAT) activity (Auld, D. S., Mennicken, F., Quirion, R., 2001. Nerve growth factor rapidly induces prolonged acetylcholine release from cultured basal forebrain neurons: differentiation between neuromodulatory and neurotrophic influences. J Neurosci 21: 3375-3382; Berse, B., Szczecinska, W., Lopez-Coviella, I., Madziar, B., Zemelko, V., Kaminski, R., Kozar, K., Lips, K. S., Pfeil, U., Blusztajn, J. K., 2005. Expression of high affinity choline transporter during mouse development in vivo and its upregulation by NGF and BMP-4 in vitro. Brain Res Dev Brain Res 157: 132-140) and have been implicated in neurodegenerative disorders (Mattson, M. P. and Magnus, T., 2006. Ageing and neuronal vulnerability. Nat Rev Neurosci 7: 278-294). Therefore, an additional experiment was performed to evaluate whether chronic oral administration of Ptychopetalum olacoides extract alters BDNF levels in hippocampus. The experiment show that BDNF is not altered either by β-amyloid in this mice model of AD, nor by Ptychopetalum olacoides extract treatment for 15 days. Therefore the protection afforded by the Ptychopetalum olacoides extract treatment against β-amyloid induced cognitive deficits is more likely to be mediated by its anticholinesterase properties and the same receptors (D1 and β that mediate its promnesic activity.
[0079] Experimental design: Ptychopetalum olacoides extract was dissolved in a DMSO 20% (v/v) solution. After Aβ 1-42 or PBS administration i.c.v, groups of mice (N=12) were treated orally (by gavage) for 14 consecutives days with a single dose of saline (0.9 g %), DMSO 20%, or Ptychopetalum olacoides extract (800 mg/kg). All drugs were given as 0.1 mL/10 g body weight. Cognitive deficit was assessed using step-down inhibitory avoidance task and hippocampal BDNF levels was measured by immunoassay. The effects of treatments on locomotion were evaluated.
[0080] Intracerebroventricular injection of β-Amyloid peptide: The administration of β-amyloid (1-42) peptide fragment (Aβ 1-42 ) was performed according to the procedure established by Laursen & Belknap (Laursen, S. E. and Belknap, J. K., 1986. Intracerebroventricular injections in mice. Some methodological refinements. J Pharmacol Methods, 16(4): 355-7). The peptide was prepared as stock solution at a concentration 500 μM in sterile 0.1M phosphate-buffered saline (PBS) (pH 7.4), aliquot and stored at −20° C. Aβ 1-42 (400 μmol/mouse) or control solution (PBS) were administered by intracerebroventricular (i.c.v.) route using a microsyringe with a 28-gauge stainless-steel needle 3.0 mm long (Hamilton). In brief, the needle was inserted unilaterally 1 mm to the right of the midline point equidistant from each eye, at an equal distance between the eyes and the ears and perpendicular to the plane of the skull. The injection volume (4 μL) of Aβ 1-42 or PBS was delivered gradually. Mice exhibited normal behaviour within 1 min after injection. The injection placement or needle track was visible and was verified at the time of dissection. The present Aβ 41-42 is comparable to that of previous literature (Kim, H. S., Cho, J. Y., Kim, D. H., Yan, J. J., Lee, H. K., Suh, H. W., Song, D. K., 2004. Inhibitory Effects of Long-Term Administration of Ferulic Acid on Microglial Activation Induced by Intracerebroventricular Injection of β-Amyloid Peptide (1-42) in Mice. Biol Pharm Bull, 27(1): 120-121; and Yan, J. J., Cho, J. Y., Kim, H. S., Kim, K. L., Jung, J. S., Huh, S. O., Suh, H. W., Kim, Y. H., Song, D. K., 2001. Protection against b-amyloid peptide toxicity in vivo with long-term administration of ferulic acid. British J Pharmacol 133: 89-96). The behavioral performance was evaluated 14 days after the only administration of Aβ.
[0081] Locomotion: Twenty four hours before step-down inhibitory avoidance task, the locomotor activity was avaliated. Number of crossings were automatically recorded in activity cages (45×25×20 cm, Albarsch Electronic Equipment), equipped with three parallel photocells (Creese, I., Burt, D. R., Snyder, S. H., 1976. Dopamine receptor binding predicts clinical and pharmacological potencies of antischizophrenic drugs. Science, 192(4238):481-483). Mice were individually placed in the activity cages and the crossings were recorded for 8 min, being the first 3 min of exploratory and the 5 final minutes of locomotor activity.
[0082] Step-down inhibitory avoidance performance: The test used was adapted from Netto and Izquierdo (Netto, C. A. and Izquierdo, I., 1985. On how passive is inhibitory avoidance. Behav Neural Biol 43: 327-330) and from Maurice et al. (Maurice, T., Hiramatsu, M., Itoh, J., Kameyama, T., Hasegawa, T., Nabeshima, T., 1994. Behaviour evidence for modulation role of σ ligands in memory process. I. Attenuation of dizocilpine (MK-801)-induced amnesia. Brain Res 647: 44-56). Fourteen days after Aβ 1-42 injection, mice were trained on a one-trial step down inhibitory avoidance task. Mice were habituated in the dim lighted room for at least 60 min before the experiments. The inhibitory avoidance apparatus was a plastic box (30 cm×30 cm×40 cm), with a platform (5 cm×5 cm×4 cm) fixed in the center of the grid floor. Each mouse was placed on the platform and the latency to step down (four paws on the grid), was automatically recorded in the training and test sessions. In the training session, mice received a scrambled foot shock (0.3 mA for 15 s) upon stepping down. The test session was performed 24 h later (long-term memory—LTM), with the same procedure except that no shock was administered after stepping down; an upper cut-off time of 300 s was set.
[0083] Analysis of BDNF tissue levels: To measure the amount of BDNF in each sample, Promega BDNF Emax ImmunoAssay System was employed (Promega Co., Madison, Wis., USA), according to manufacturer's recommendations. Briefly, hippocampus (n=5 per group) were individually homogenized in lysis buffer [containing, in mM: 137 NaCl, 20 Tris-HCl (pH 8.0), Igepal (1%), glycerol (10%), 1 PMSF, 0.5 sodium vanadate, 0.1 EDTA and 0.1 EGTA] and centrifuged at 14,000 rpm at 4° C. during 3 min. Supernatant was diluted in sample buffer and incubated on 96-well flat-bottom plates previously coated with anti-BDNF monoclonal antibody (1:1000). After blocking (with Promega 1× Block and sample buffer), plates were incubated with polyclonal anti-human antibody for 2 h and horseradish peroxidase for 1 h. Then, color reaction with tetramethyl benzidine was quantified in a plate reader at 450 nm; the standard BDNF curve ranged from 0-500 pg/mL.
[0084] Protein assay: Total protein concentration was measured by Lowry's method using bovine serum albumin as a standard (Lowry, O. H., Rosebrough, N. J., Farr, A. L., Randall, R. J., 1951. Protein measurement with the folin phenol reagent. The Journal of Biological Chemistry 193, 265-275).
[0085] Statistical analysis: Locomotor activity and BDNF levels are expressed as mean±SEM and statistical significance were determined by one-way ANOVA followed by post hoc Duncan's test. Step-down latencies are expressed as medians [interquartile ranges]. Data were analyzed by Kruskal-Wallis non-parametric analysis of variance; comparisons among treatment groups were completed through Mann-Whitney U-test (two-tailed), and within treatment groups by the Wilcoxon test. P<0.05 was considered statistically significant.
Results:
[0086] FIG. 12 shows that icv Aβ 1-42 (400 μmol/mouse) impaired mice performance in the inhibitory avoidance (P<0.05), and that Ptychopetalum olacoides extract treatment for 15 days attenuated such impairment (P<0.05).
[0087] FIG. 13 shows that Ptychopetalum olacoides extract did not alter the locomotion, which could mask the results of such analysis.
[0088] FIG. 14 shows that no significant changes were seen in hippocampus BDNF levels either with Aβ 1-42 or Ptychopetalum olacoides extract.
III. Parkinson's Disease Model
[0089] Parkinson's Disease (PD) is characterized by a progressive and irreversible loss of dopamine neurons at the nigro-striatal area. The reasons for this specific death are unclear, it has been suggested that neuronal death is linked to excitotoxic lesions, oxidative stress and a byproduct of dopamine metabolism (Martignoni, E., Blandini, F., Godi, L., Desideri, S., Pacchetti, C., Mancini, F., Nappi, G., 1999. Peripheral markers of oxidative stress in Parkinson's Disease. The role of L-Dopa. Free Radic Biol Med., 27(3-4):428-37; Dauer, W., Przedborski, S., 2003. Parkinson's disease: mechanisms and models. Neuron, 39(6):889-909).
[0090] The MPTP (1-methyl-4-fenyl-1,2,3,6-tetrahydropiridine) neurotoxin mimics in animals de effects of PD, reproducing various symptoms (such as akinesica, rigidity and catalepsy) as well as the neurodegeneration at substantia nigra (Beal, M. F., 2001. Experimental models of Parkinson's disease. Nat Rev Neurosci 2:325-34), consolidating a valid animal model of PD.
[0091] Given that traditional uses of P. olacoides include tremors, and considering the antioxidative and neuroprotective properties of the extract from which the compounds in formula (I) were obtained, the purpose of the following experiments was to evaluate the effects of such compounds in the MPTP model of PD in mice.
[0092] FIG. 15 shows that acute treatment with Ptychopetalum olacoides extract reduced the intensity of tremors at 21 min (P≦0.01), as well as its duration (from 45 min in controls to 39 min for C57BL/6 mice treated with the compounds).
[0093] FIG. 16 shows that acute treatment with Ptychopetalum olacoides extract reduced the intensity of tremors; while control Balb/c mice treated with MPTP show a continuous tremor of 3.7±0.0 at 18 min, and tremors that lasted over 45 min (H(5)=27.8, P<0.01). Likewise with C57BL/6 mice, Balb/c mice treated with Ptychopetalum olacoides extract 25 mg/kg showed tremors with median score of 1.4±0.2 at 9 min (P≦0.01). Total tremor duration was not affected by Ptychopetalum olacoides extract or apomorphine.
[0094] FIG. 17 shows that acute treatment with Ptychopetalum olacoides extract reduced akinesia (H(5)=23.5, P<0.01), with latency equal to 9.9±2.1 seg in mice treated with 25 mg/kg kg, and 11.1±1.7 seg in those treated with 50 mg/kg, in comparison to 62.5±12.8 of controls.
[0095] FIG. 18 shows that acute treatment with Ptychopetalum olacoides extract reduced catalepsy (H(5)=26.1, P<0.01) with 8.2±1.2 seg in mice treated with 25 mg/kg, and 4.5±1.6 seg in those treated with 50 mg/kg, in comparison to 51.8±16.7 of controls.
[0096] The detrimental effects of MPTP in Balb/C mice swimming capacity can be seen in FIGS. 19-21 , at the 3 rd day (H(5)=20.7, P<0.01), and 7 th day (H(5)=19.6, P<0.01) post treatment, with complete recovery after 14 days.
[0097] FIG. 19 shows that acute treatment with Ptychopetalum olacoides extract 50 mg/kg protected mice from the MPTP effect at day 3 post MPTP.
[0098] FIG. 20 shows that acute treatment with Ptychopetalum olacoides extract 50 mg/kg protected mice from the MPTP effect at day 7 post MPTP.
[0099] FIG. 21 shows that at day 14 post MPTP there are no significant differences in treatment groups.
[0100] Animals: Male adult mice, C57BL/6 and BALB/c strain (FEEPS) were used and maintain with water and foot ad libitum under controlled environment.
[0101] Treatments in C57BL/6: MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) 50 mg/kg (2×25 mg/kg) was administered intraperitonially (i.p.), twice, 1 h apart. Saline, DMSO 20%, Ptychopetalum olacoides extract 200 mg/kg (2×100 mg/kg) and apomorphine 3 mg/kg (2×1.5 mg/kg) were given 30 min before each MPTP administration. The animals received the first injections at 8:00 h and the second at 9:00 h. The volume of injection was 0.1 ml/g body weight. N=5.
[0102] Treatments in BALB/c: MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) 60 mg/kg (2×30 mg/kg) was administered intraperitonially (i.p.), twice, 16 h apart. Saline, DMSO 20%, Ptychopetalum olacoides extract 50 mg/kg (2×25 mg/kg), POEE 25 mg/kg (2×12.5 mg/kg) and apomorphine 3 mg/kg (2×1.5 mg/kg) were given 30 min before each MPTP administration. The animals received the first injections at 17:00 h and the second at 09:00 h the next day. The volume of injection was 0.1 ml/g body weight. N=6.
[0103] Tremor in C57BL/6 and in BALB/c: Tremors were observed immediately after the administration of the second MPTP dose, with animals placed in a clear Plexiglas box (20 cm×20 cm×20 cm) for 45 min; tremor scores were noted every 3 min, with the highest score considered for the period. Tremors were quantified on a modified intensity-score basis in a scale of 0-5 as described earlier (Hoabam, R., Sindhu, K. M., Chandra, G., Mohanakumar, K. P., 2005. Swim-test as a function of motor impairment in MPTP model of Parkinson's disease: a comparative study in two mouse strains. Behavioural Brain Research 163:159-167): 0, no tremor; 1, occasional muscle twitches or slight tremor which is barely visible at the head region; 2, moderate, intermittent tremor restricted to the head region; 3, visible tremor with occasional quiescent periods affecting the anterior region; 4, continuous tremor, restricted to the extremities and head; 5, continuous, gross, whole body tremor. N=5-6.
[0104] Akinesia in BALB/c: Akinesia was measured by noting the latency in seconds (s) of the animals to move all four limbs and the test was terminated if the latency exceeded 180 s. Each animal was initially acclimatized for 5 min on a wooden elevated (30 cm) platform (40 cm×40 cm) used for measuring akinesia in mice. Using a stopwatch, the time taken (s) by the animal to move all the four limbs was recorded. This exercise was repeated five times for each animal. N=5-6.
[0105] Catalepsy in BALB/c: The term implies the inability of an animal to correct an externally imposed posture. Catalepsy was measured by placing the animals on a flat horizontal surface with both the hind limbs on a square wooden block (3 cm high) and the latency in seconds was measured to move the hind limbs from the block to the ground. This exercise was repeated five times for each animal. N=5-6.
[0106] Swim-test in BALB/c: Swim-test was carried in water tubs (40 cm length×25 cm width×16 cm height). The depth of water was kept at 12 cm and the temperature was maintained at 27±2° C. The animals were wiped dry immediately after the experiment using a dry towel and returned to cages kept at 27±2° C. Swim-score scales were recorded and the following parameters analyzed by an investigator blind to the treatment, with the software The Observer® XT5.0 (Noldus Information Technology, Wageningen, The Netherlands: 0, hind part sinks with head floating; 1, occasional swimming using hind limbs while floating on one side; 2, occasional floating/swimming only; 3, continuous swimming. Swim-test was carried out on different days (3°, 7°, 14° days) after MPTP. N=6.
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Plant extracts for pharmaceutical compositions as acetylcholinesterase inhibitors useful as neuroprotectors, to manage depressive states and cognitive deficits of diverse etiologies, and for the treatment of neurodegenerative conditions, such as Alzheimer's and Parkinson's diseases, and the sequel from ischemic events.
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PRIORITY CLAIM
[0001] This application is a continuation of U.S. application Ser. No. 13/995,425, filed Jun. 18, 2013, which is a U.S. national stage filing of International Appl. PCT/EP2011/073638, filed on Dec. 21, 2011, which claims priority to European Patent Application No. 10196359.3, filed Dec. 21, 2010, the entire contents of which are being incorporated herein by reference.
FIELD OF THE INVENTION
[0002] The present invention relates to a container and a pouch. The container and pouch 5 are preferably mutually shaped so that the pouch fits tightly into the container. The container comprises a closure for closing the container and preferably is adapted to maintain the pouch in an open state in a position where its opening is facing upwardly. In addition, the closure comprises a lid, allowing re-closable access to the contents stored in the pouch.
BACKGROUND
[0003] A common pouch in a container kit comprises fitting a pouch in a container. To gain access t the content stored in the pouch, one needs to open the container and then open the pouch. The pouch may be closed by a plastic clip. Closing is done in the reverse manner. Drawbacks of such a pouch in a container kits are numerous and some of them are: unconvenient for consumers, especially if used frequently, because pouch and container are not fitted together; the opening and closing process is time and effort consuming; pouring content from the pouch in container kit is difficult if not impossible; contents stored often spills outside the kit; hygiene and contamination is often a concern; the pouch is often smaller than the internal volume of the container, which results in lost storing capacity; it may be difficult to serve content from the pouch when little content is left.
[0004] U.S. Pat. No. 5,165,568 relates to an automatically resealing container consisting of an interior paperboard box and an external resealing bag of flexible plastic film. The film is associated with closure flaps of the box such that when the flaps are reclosed, the film is pressed together outside the box to provide a nearly airtight seal. The single external film bag provides the dual function of protecting the contents as well as the exterior of the box. This device may require a two-step closing as the flaps may have to be guided into a slit during closing. Thus, the closing procedure proves to be delicate and to require vigilance of the user.
[0005] US 2008/0179357 relates to a package designed to facilitate the use of squeeze bottle or other dispensers for wet products such as mayonnaise. The package consists of an external semi-rigid bottle or container, a bottle pouch placed inside the external container and food product. The bottle pouch has a peelable primary seal area and a secondary membrane with lines of weakness for ready opening of the pouch when the pouch flaps are pulled over the side of the bottle or during dispensing. Dispensing of the contained product happens by applying pressure on the external bottle.
[0006] As can be understood from this document, this device is designed to contain wet products, but cannot be hermetically reclosed after peeling of the pouch. The device remains constantly opened, therefore the product remains in prolonged contact with air which may lead to hygene issues.
[0007] Hence, an improved pouch in a container kit would be advantageous.
OBJECT OF THE INVENTION
[0008] It is a further object of the present invention to provide an alternative to the prior art 15 and in particular to provide a pouch in container kit providing safe storage of and easy access to substances in the pouch.
SUMMARY
[0009] Thus, the above described object and several other objects are intended to be 20 obtained in a first aspect of the invention by providing a pouch in a container kit comprising a pouch and a container adapted to receive the pouch. The container comprises a body part having one or more side walls and a bottom forming an open ended container, wherein the one or more sides walls defines an opening positioned opposite to the bottom. The container further comprises a closure with a lid. The pouch comprises a top having flaps. The pouch may be inserted through the opening into the body part of the container. During use of the kit, the flaps are folded around distal end(s) of the one or more side walls and the closure is adapted to accommodate the distal end(s) of the one or more side walls with the flaps folded around to provide a closure of the container with the pouch arranged internally.
[0010] The invention is particularly, but not exclusively, advantageous for obtaining the effect of the container storing the pouch in a manner where easy access to the content of the pouch may be obtained without opening of closing of the pouch, as access to the content in the pouch is gained by the lid. In addition, the pouch may be maintained in the container due to the folding of flaps over the distal ends of the walls. Furthermore, by having the pouch maintained in the container with flaps folded around distal end(s), one may easily pour as well as scoop the content out.
[0011] The pouch in a container kit is convenient, easy and faster to open and re-close, pouring is easy, without or with reduced product spilling outside the container, more hygienic, pouch and container sizes are well optimised, dispensing is easy even with small quantities of product left in the pouch. The pouch itself can be designed in different manners depending on actual needs or preferences. Corner cuts, hole, sealing profile and pouch can be given different designs.
[0012] The kit may be used in several manners. Typically, a consumer may purchase a prefilled pouch and a container in an initial buy. The pouch may be arranged in the container or delivered separate from the container. Later, the consumer will preferably only purchase the pouch and re-use the container. Although an advantageous effect of the invention is that the consumer may be provided with prefilled pouches, the invention may also be utilised in a manner where e.g. the consumer purchase an empty pouch and fills the pouch with the desired substance themselves, or from a bulk container at the grocery for instance.
[0013] According to preferred embodiments of the pouch in a container kit the pouch may comprise four side walls thereby defining a box shape and the top may be folded into a gusset form by folding along folding lines. The folding line may preferably comprise:
[0014] horizontal folding lines encircling the pouch (ie: a peripheral folding line around the pouch), first vertical folding lines along the edges of the side walls
[0015] a pair of oblique folding lines on two opposite side walls extending from intersections between a horizontal folding line and a vertical folding line to an intersection between the oblique folding lines, and
[0016] second vertical folding lines extending from the intersection between the oblique folding lines and upwardly to an upper edge of the side walls in question.
[0017] In addition, the flaps are preferably tapered having their largest width at the onset of the flaps. However, the flaps may alternatively be rectangular.
[0018] In an embodiment, embodiments, the pouch may comprise four side walls thereby defining a box shape and the top having two flaps only.
[0019] In an embodiment, the comprises at least a reinforcement tongue which is formed by two curvilinear cuts each extending between the edge of the side walls and the flap folding lines respectively.
[0020] In an embodiment, the pouch may be closed by sealing the flaps together. Preferably the sealing is provided by a heat sealing, a gluing or the like.
[0021] In container kits according to the present invention, the container may comprise retaining means for retaining the closure in its position where it closes the container.
[0022] The closure may comprise a frame to which the lid is rotatably connected, the lid further comprises a lock in the form of a flap that extends down to and snaps on to a rim of the closure.
[0023] In many advantageous embodiments of the invention, the pouch may be made more flexible that the container.
[0024] The kit may preferably comprise securing means for fixing tightly the pouch relatively to container. Such securing means may ease the assembly of the kit as the securing means provides a fixation of the pouch inter alia while the closure is not applied to the container. The securing means may preferably comprise: a knob on the container and a corresponding opening in a flap, Velcro arranged on the container and on a flap, glue such as reversible glue provided on the container and/or on a flap.
[0025] In a second aspect the invention relates to a container comprising a body part having one or more side walls and a bottom forming an open ended container. The one or more side walls define an opening positioned opposite to the bottom and through which a pouch may be inserted into the body part. The container further comprises a closure with a lid and the closure being adapted to accommodate the distal end(s) of the one or more side walls with flaps formed in an opening of the pouch being folded around the distal end(s) to provide a closure of the container with the pouch arranged internally.
[0026] In a third aspect the invention relates to a pouch comprising a top having flaps. At least the top of the pouch is foldable so as to close the pouch and the flaps are adapted to be folded around distal ends of side walls of a container while the distal ends of the side walls are accommodated by a closure of the container into which the pouch is arranged.
[0027] It is noted 1 that features presented in relation to the various aspect are compatible and may be combined among the various aspects of the invention.
[0028] In addition/the flaps may preferably be provided in different ways. For instance/the flaps may advantageously be provided during manufacturing of the pouch.
[0029] Alternatively/the flaps may be provided during use of the pouch—e.g. by the consumer cutting corners/breaking perforations or the like upon or prior to instertion of the pouch in the container.
[0030] The various aspects are particular useful for reducing the amount of waste material as the container may be re-used and the pouch being the replaceable part may be optimized so as to avoid production of superfluous waste material.
[0031] The instant container and pouch may be used in several areas. Non-limiting examples are storing and dispensing of dry consumable products. Dry consumable products include for instance all types of powdered or particulate products such as infant formula/infant cereals/soluble coffee/soluble coffee mixes/soluble tea/soluble chocolate powder for beverages/and other powdered beverages; grocery products such as flour/oat flakes/breakfast cereals/sugar/rice/pastal ground coffee, tea leaves; flaky products such as seasoning/or culinary powder.
BRIEF DESCRIPTION OF THE FIGURES
[0032] The invention and in particular different embodiments thereof will now be described in more detail with regard to the accompanying figures. The figures show manners of implementing the present invention and are not to be construed as being limiting to other possible embodiments falling within the scope of the attached claim set.
[0033] FIG. 1 is a three dimensional view showing separately a pouch and a container for 35 a preferred embodiment of a pouch in a container kit according to the present invention.
[0034] FIG. 2 is a three dimensional view showing schematically initial steps for preparing the pouch in a container kit of FIG. 1 for use.
[0035] FIG. 3 is a three dimensional view showing schematically steps for preparing the pouch in a container kit of FIG. 1 for use, the step being subsequent to the step shown in FIG. 2 .
[0036] FIG. 4 is a three dimensional view showing schematically pouch in a container kit shown in FIG. 1 during use.
[0037] FIG. 5 is a three dimensional view showing a pouch according to the present invention in an open state, together with an .
[0038] FIG. 6 is a three dimensional view showing a further pouch according to the present invention with two flaps only, the pouch is shown in close state to the left, and in open state to the right.
[0039] FIG. 7 is a three dimensional view showing yet a further pouch according to the present invention with two flaps only, the pouch is shown in close state to the left, and in open state to the rights.
[0040] FIG. 8A is a perspective view showing another embodiment of a pouch according to the present invention, when closed. FIG. 8B is a front view of the pouch depicted at FIG. 8A . FIG. 8C is a magnified view of the corner of the pouch of FIG. 8A , in the open state, showing a reinforcement tongue.
DETAILED DESCRIPTION
[0041] Referring to FIG. 1 , an embodiment of the invention is disclosed, which comprises a pouch 1 and a container 2 . As indicated on FIG. 1 , the pouch 1 is box-shaped with a flat rectangular bottom with side lengths I and w. The top 3 of the pouch is gusset-shaped and the distance from the bottom of the pouch 1 to the gusset-shaped top is hp.
[0042] As indicated in FIG. 1 the container 2 match the size of the pouch 1 , that is the internal dimensions of the container are selected so as to be sufficiently close to I, w to provide a firm fit of the pouch 1 inside the container 2 while still allowing an easy insertion of the pouch 1 in the container 2 . The height hp of the pouch 1 may be similar to or smaller than the height he of the container 2 depending on the implementation of the gusset form of the top 3 . This will be disclosed in greater details with reference to FIG. 5 .
[0043] The gusset shape of the top 3 is formed by folding the open end (20, in FIG. 5 ) of the pouch 1 so as to close the pouch 1 . The part of the pouch 1 being folded ranges from folding lines 21 a and 21 g and upwardly. As shown in FIG. 5 , the top 3 has flaps 10 a - d which will be disclosed in further details below. Typically, the upper parts of two opposite sides are folded inwardly along folding lines ( 21 a - f in FIG. 5 ) provided as indentations where after the remaining upper parts of the two remaining sides are folded inwardly to form the gusset. Suitable sealing—shown with numeral 9 in FIG. 1 —in the form of glue or heat welding is provided at the top of the gusset 3 to provide a sealed closing of the pouch 1 .
[0044] As the flaps 10 a - d is to be folded around the distal ends of the side walls 4 a of the container, the sealing 9 should be selected so that the pouch 1 may be pealed opened without destroying the flaps 1 Oa-d nor the pouch 1 .
[0045] The container 2 comprises a body part 4 having four sides walls 4 a and a bottom 4 b forming an open container. The sides walls 4 a defines an opening 24 , positioned opposite to the bottom 4 b, through which the pouch may be inserted into the body part 4 .
[0046] The container 2 further comprising a closure 5 detachable arranged to close the opening of the container 2 . When the pouch is located in the container, the flaps are folded around the distal (relatively to the bottom 4 b ) ends of the side walls 4 a as shown in e.g. FIGS. 3 and 4 . Closing of the container 2 is provided by the closure 5 being adapted to accommodate the distal ends of the side walls 4 a with the flaps 10 - a - d being folded around. This accommodation is provided by the skirt portion 13 of the closure 5 . By providing a firm fit between the closure 5 , the flaps 1 Oa-d and the the distal end(s) of the side wall 4 a, fixation of the pouch 1 relatively to the container 2 is possible. Once the pouch 1 is situated in the container 2 , the flaps 10 a - d folded and the closure 5 applied, the pouch in a container kit is ready for use.
[0047] The closure 5 is retained in its closing position by use of two locks 6 which are hingedly arranged on the closure 5 and clicks onto an edge of the container 2 . In addition, the container comprises a knob 26 on the front side of the container 2 and an equally arranged knob 26 on the opposite side of the container, the purpose of which is disclosed below.
[0048] The closure 5 comprises a rectangular shaped lid 7 . The lid 7 can rotate about an edge of the lid 7 relatively to the remaining parts of the closure 5 . The lid 7 further comprises a lock 8 in the form of a flap that extends down to and snaps on to a rim of the closure 5 . The lid 7 is preferably an integral part of the closure 5 . Thus, the closure as presented in FIG. 1 comprises a frame to which the lid is rotatably connected, the frame is the part of the closure that maintains its position relatively to the container 2 during use.
[0049] The pouch 1 is preferably made from a plastic material and the thickness of the 10 plastic material is chosen so as to allow sufficient flexibility to allow insertion of the pouch 1 into the container 2 , which may require some squeezing while still allowing sufficient strength to avoid breakage during e.g. transportation. The container 2 is also preferably made from a plastic material and the thickness of the plastic material for the container 2 is chosen so that the container is more rigid than the pouch 1 . By selecting the thickness of the materials in this manner, a pouch in a container kit is obtained in which the relatively more vulnerably pouch is protected by the container 2 from being punctured or ruptured.
[0050] The pouch 1 shown in FIG. 1 is shown in a closed state and prior to use. The upper 20 corners 25 (see e.g. FIG. 5 ) of the closing area, that is the area composed by the flaps ( 10 a - d ), have been removed thus providing four flaps upon opening of the pouch 1 . This will be disclosed in further details below.
[0051] Use of the pouch in a container kit will now be described with reference to FIGS. 2-4 .
[0052] FIG. 2 shows removal of the closure 5 from the container. The locks 6 are released and the closure is removed from the container 2 as indicated by the arrow shown on top of the lid 7 . The pouch 2 is pealed open by breaking the seal 9 . It is noted that although the peal open procedure is shown in a situation where pouch 1 is not in the container 2 , the procedure may be carried out while the pouch 1 is situated inside the container 2 with no closure 5 applied.
[0053] FIG. 3 shows how to make the pouch in a container kit ready for use once the pouch 35 1 has been located in the container 2 .
[0054] With reference to the drawing shown to the left in FIG. 3 , the top 3 is opened. This opening is provided by breaking the seal 9 , thereby releasing the four flaps 1 Oa-d. These four flaps 10 a - d are each folded around the edge of the opening of the container 2 until they extend along the sides 4 a of the container as shown to the right in FIG. 3 . The openings 11 provided in the two flaps 10 c and 10 d are each squeezed over the knobs 26 to attach the flaps to the sides of the container 2 . The knob 26 on the container and a corresponding opening 11 in a flap constitutes securing means, that will assist in keeping the pouch positioned in the container at least during application of the closure 5 . This may be particular usefull if a pouch 1 is used that has a smaller height hp than the height of the container he. The opening 11 , may be provided as a hole or as a puncture e.g. a cross shaped puncture, that allows the knob to be pressed through the opening 11 . Alternatively, the securing means may be provided by glue, preferably being reversible glue or Velcro provided on the wall of the container and the flaps (in case of glue it may be sufficient to provide glue to only the container wall or the flap).
[0055] Having the flaps attached to the container 2 and further maintained by the closure 5 allows keeping the pouch opened permanently, therefore avoiding time and effort consuming process of opening and closing the pouch each time one wants to consume the dry consumable products contained in the pouch. Hygienic issues and contamination are avoided due to the lid 7 . This will be disclosed in greater details with reference to the FIG. 4 .
[0056] Once the flaps are folded and attached to the sides of the container 2 , the closure is brought into its position to close the container as indicated by the arrow shown to the right in FIG. 3 . Finally, the locks 6 are engaged and the pouch in a container kit is ready for use.
[0057] The closure 5 , the pouch 1 and the body part 4 of the container are preferably 30 mutually adapted to provide a sealed pouch in a container kit. Various degrees of sealing are provided spanning from powder tight to prevent powdered material from escaping the container to fluid tight preventing fluids from being spilled from the container. The sealing to be obtained (in case a sealed kit is aimed at) is a sealing of the lid 7 , and a sealing between the container 2 and the closure 5 .
[0058] The sealing of the lid is obtained by providing a recess in the closure 5 adapted to breceive an edge provided along the rim of the lid 7 . Such a kit will at least provide a powder tight seal. If a fluid tight seal is desired a gasket may be arranged in the recess. Sealing between the closure 5 and the body part 4 is provided by the flaps 10 a - d folded around an edge 12 provided at the upper end of the body part and mating with a corresponding recess provided in the skirt portion 13 . Thereby a sealing being at least powder tight is provided when the closure 5 is provided to the body part 4 of the container. If a fluid tight seal is aimed at this may be provided by electing the material of the pouch as—or coat the part of the pouch contacting the edge 12 and the recess of the closure with a suitable sealing material e.g. rubber.
[0059] Use the pouch in a container kit is shown in FIG. 4 . Initially, the lock 8 is dis-engaged followed by rotation of the lid 7 into a position where access to the content stored in the pouch is available; cf. the right drawing in FIG. 4 . Once the lid is opened, the content may be dispensed e.g. by use of a spoon as shown in the right drawing of FIG. 4 or the container 2 may be tilted whereby the content may be poured from container 2 . Thereby, the product is easily accessible for the consumer, even when little content is left.
[0060] FIG. 5 is a three dimensional view showing a pouch according to the present invention in an open state with outwardly folded flaps 10 a - d . The pouch 1 is box shaped and comprising four side walls 23 a - d . The pouch 1 also comprises a bottom (not shown) that is provided by folding and gluing or welding parts of the side walls a-d to form a sealed bottom in a manner well known to a skilled person. Numeral 24 indicates powdered material arranged in the pouch 1 .
[0061] As indicated in the figure, the pouch 1 is provided with folding lines 21 a - f provided as indentations in the pouch 2 . The folding lines comprises:
[0062] horizontal folding lines ( 21 a, 21 g ) encircling the pouch ( 1 )
[0063] first vertical folding lines ( 21 e, 21 f ) along the edges of the side walls ( 4 a )
[0064] a pair of oblique folding lines ( 21 c, 21 b ) on two opposite side walls ( 4 a ) extending from intersections between a horizontal folding line and a vertical folding line to an intersection between the oblique folding lines, and
[0065] second vertical folding lines ( 21 d ) extending from the intersection between the oblique folding lines ( 21 c, 21 b ) and upwardly to an upper edge of the side walls ( 4 a ).
[0066] The top 3 is thereby provided with the gusseted shape by folding along the folding lines 21 a - f in the following manner:
[0067] each side 23 a and 23 b are simultaneously folded inwardly along the folding ines 21 a - f; during this folding the flaps 1 Oa-d are not outwardly folded.
[0068] as the folding along the folding lines 21 a - f takes place, a folding along a further folding line 21 g (that may be omitted) on each of the remaining sides gradually takes place.
[0069] at the end of the folding process, the flaps 1 Oa-d are abutting each other and e.g. a heat sealing or gluing may be applied to provide the sealing 9 .
[0070] The result of the folding is that the folding lines 21 a, 21 f and 21 g (if present) becomes outer edges of the pouch 2 and the folding lines 21 b and 21 c becomes internal corners as shown in FIG. 1 left drawing.
[0071] As shown in FIG. 5 , the flaps 1 Oa-d are provided by removal of the upper corners 25 of the folded sealed pouch 1 . Thereby, flaps 10 are tapered having their largest width at the onset of the flap, that is at folding lines 21 i,h.
[0072] The removal of the upper corners 25 is provided by two oblique cuts each extending from the edge formed between two side walls 23 a - d to an upper edge of the side wall in question 23 a - d . This is shown as a magnified view in FIG. 5 where the crosshatched areas indicate material being cut-away (the magnified view of FIG. 5 shows the contrary to the full FIG. 5 the flaps in a non-folded state). It is noted, that the removal of the corners may also be done after the top 3 has been folded although the removal of the corners preferably is done during manufacturing of the pouch 1 . It is also noted that the size and the shape of the flaps 1 Oa-d is determined by the cut and e.g. the height of the flap is determined by the depth of the cut hf shown in FIG. 5 . Typically, the cut is rounded off to avoid sharp corners (indicated by R in FIG. 5 ).
[0073] The flaps can be implemented in different ways. For instance, the corners 25 to be removed may be provided by perforations allowing the corners 25 to be removed when desired, including also after folding. In addition, the flaps may be provided by cutting—or providing perforations—along folding lines 21 e, f whereby no corners are removed. A further way of providing flaps includes providing graphical indications as to where to cut to remove the corners 25 . Thereby the provision of the flaps may be provided by the user.
[0074] The upper corners 25 are as said above preferably removed during manufacturing of the pouch 1 . According to a preferred way of manufacturing the pouch 1 , the pouch is made from an unfolded and flat piece of flexible material e.g. plastic, aluminium, cardboard, paper or the like. Folding lines and corner cuts are provided to the piece of plastic where after, the piece of plastic is folded into the box shape shown in FIG. 5 (the flaps are still not folded) in a conventional manner. The pouch 1 is filled with the desired content and the top part is folded into the gusset shape and sealed. Thereafter the pouch is ready for use. Flap folding lines 21 i and 21 h assisting in folding the flaps 10 a - d around the distal ends of the side walls 4 a may be provided at the onset of the flaps 10 a - d.
[0075] Alternatively, the corner cuts may be provided after the top is folded into its gusset form by cutting away the two top corners of the pouch 1 .
[0076] The opening 11 is punched into the top 3 of the pouch 1 . The corner cuts and opening 11 are made above the above the seal area 9 . This is to preserve the tightness of the pouch 1 .
[0077] By cutting the corners, one eliminates the excess material and when the pouch 9 is open it creates four flaps. These flaps can be easily folded over the rims of the container 1 once the pouch is inside the container 2 . The small opening 11 in the longer flaps can be used to attach the flaps on the exterior of the container by use of the knob 26 . The closure 5 with to lock 6 on the smaller sides retain the closure 5 on the container 2 . By clipping the closure 5 , a tightly closed container is obtained with a well-fixed pouch inside. Various openings can be designed on the interior of the lid to allow pouring, scooping, etc.
[0078] Refering now to FIGS. 8A , 8 B and 8 C, a tongue 27 can be provided for during the formation of the flaps in order to prevent tearing the pouch when opening. Tongue 27 is shaped along the edge of the side walls 23 a - d during the removal of the upper corners 25 . This is shown as a magnified view in FIG. 8 . The tongue 27 is formed by two curvilinear cuts 27 a, 27 b each extending between the edge 21 f of the side walls 23 a, 23 c and the flap folding lines 21 i, 21 h respectively. The cut 27 b is made according to an angle alpha a defined between the folding line 21 i and the tangent to the curvilinear cut 27 b that goes through the extremity of the tongue 27 . Preferably, α the angle a is an integer comprised between 10° and 45°, most preferably 30°. Preferably, the curvilinear cut 27 b has a radius of curvature comprised between 4 and 10 mm, and most preferably 6 mm. The cut 27 a is symmetrical to cut 27 b, in order to provide tongue 27 , and each corner of the pouch can be provided with a similar tongue, as shown on FIG. 8A . The tongue 27 reinforces the corners of the pouch and prevents a weakness point at the flap onset. This helps preventing the the pouch from tearing along the edges e-h of the side walls 23 a - d when opening of the pouch.
[0079] As shown on FIG. 8B , the cuts 27 can be made in a single step, using the appropriately shaped knife, on the folded and sealed pouch. In other words, once the pouch 1 is formed and its bottom is sealed, the pouch is filled with the food product. Then the open ended top 3 of the pouch is folded, then sealed. And finally, the flaps 10 a - d and the tongues 27 are formed by cutting off the material 25 , above the seal 9 .
[0080] The above disclosure of the pouch in container kit has focussed on a kit where the pouch 1 comprises four flaps ( 10 a - d ) each being folded or foldable around a corresponding distal end of a side wall of the container 2 . However, the invention is not limited to kits with four flaps and/or a top being folded into a gusset shape. In another embodiment shown in FIG. 6 , the top 3 only comprises two flaps 10 a and 10 b which are foldable to close the top of the pouch 1 .
[0081] FIG. 6 is a three dimensional view showing a further pouch according to the present invention with two flaps only, the pouch is shown in close state to the left, and in open state to the right. As shown in FIG. 6 (right figure) the pouch 1 is similarly to the pouch disclosed in relation to FIG. 5 box shaped with a closed bottom. Reference numerals introduced in the preceding figures are used for identical or similar structural elements in FIG. 6 . The pouch 1 of FIG. 6 has folding lines 21 a - g assisting in providing the desired folding. The folding of the pouch 1 is as disclosed in relation to FIG. 5 and sealing is providing by gluing or heat sealing 9 at the top 3 . As indicated in FIG. 6 , only two flaps 10 a and 10 b are provided, and these flaps are provided at the longer sides opposite to each other of the pouch 1 . The flaps may alternatively be provided at the shorter sides of the pouch 1 . The width of the flaps WF 10 a,b may be selected as indicated in FIG. 6 to be shorter than the width of the side WS. The height of the flaps 1 Oa,b HF is selected so as to provide a sufficient folding around the distal ends of the container 2 (similarly as for the other embodiments disclosed herein).
[0082] FIG. 7 is a three dimensional view showing yet a further pouch according to the present invention with two flaps only, the pouch is shown in close state to the left, and in open state to the rights. Reference numerals introduced in the preceding figures are used for identical or similar structural elements in FIG. 7 , although for instance the folding of the sides of the pouch 1 is done a different manner than what is disclosed in relation to FIG. 5 e.g.
[0083] The pouch 1 of FIG. 7 may have folding lines 21 a - f assisting in providing the desired 15 folding. The folding of the pouch 1 is then as disclosed in relation to FIG. 5 except that the folding due to the location of the folding lines 21 a - c are located at the bottom of the pouch 1 whereby the pouch 1 by folding along folding lines 21 a - f as in FIG. 5 provides a pouch 1 with the shape indicated in FIG. 7 left side. Please note, that the pouch 1 of FIG. 7 left has a bottom shape that has been provided by e.g. heat sealing or gluing 29 and that if the sealing or gluing is not provided, the bottom shape will be gusset shaped.
[0084] Sealing of the pouch 1 of FIG. 7 is providing by gluing or heat sealing 9 at the top 3 . As indicated in FIG. 7 , only two flaps 10 a and 10 b are provided, and these flaps are provided at the longer sides opposite to each other of the pouch 1 . The flaps may alternatively be provided at the shorter sides of the pouch 1 as disclosed in relation to FIG. 6
[0085] Thus, although the above disclosure has focussed on a pouch in container kit wherein the container and pouch having four side walls, the container 2 and/or the pouch may be provided with another number of walls, e.g. the pouch may be tubular shaped (to preferably accommodate a pouch as disclosed in FIG. 8 ) with only one side wall, shaped with three side walls etc. Similarly, the container may be tubular shaped etc.
[0086] As indicated above, the material for the container 2 and the pouch 1 may advantageously be selected so that the container 2 may prevent the pouch 1 from being punctured or ruptured. Although this is not a specific requirement, it has been found in relation to the present invention that suitable non-limiting examples for the material of the pouch 1 are: plastic, aluminium, paper, cardboard or the like and combinations thereof; and that suitable non-limiting examples for the material of the container are: plastic, aluminium, paper, cardboard, glass or the like and combinations thereof. In a specific preferred embodiment of the pouch in a container kit, the container is made from plastic and the pouch is made from aluminium.
[0087] Although the present invention has been described in connection with the specified embodiments, it should not be construed as being in any way limited to the presented examples. The scope of the present invention is set out by the accompanying claim set. In the context of the claims, the terms “comprising” or “comprises” do not exclude other possible elements or steps. Also, the mentioning of references such as “a” or “an” etc. should not be construed as excluding a plurality. The use of reference signs in the claims with respect to elements indicated in the figures shall also not be construed as limiting the scope of the invention. Furthermore, individual features mentioned in different claims, may possibly be advantageously combined, and the mentioning of these features in different claims does not exclude that a combination of features is not possible and advantageous.
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The present invention relates to a container and a pouch. The container and pouch is preferably mutually shaped so that the pouch fits tightly into the container. The container comprises a closure for closing the container and preferably being adapted to maintain the pouch in an open state in a position where its opening is facing upwardly. In addition, the closure comprises a lid, allowing re-closable access to the contents stored in the pouch.
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BACKGROUND OF THE INVENTION
The present invention relates to a two dimensional drive system, and more precisely relates to a two drive system whose moving body is driven in a plane by fluid pressure.
Conventionally, there have been several drive systems which are driven by fluid pressure. Hydraulic cylinder units, air cylinder units, rodless cylinder units, etc. have been known as pressure driven drive systems. In the conventional drive systems, moving bodies, which are attached to cylinder rods or to driven parts, are linearly driven by selectively supplying fluid, e.g. oil, air, to chambers in units.
However, the conventional drive systems have a disadvantage. Namely, their moving bodies are allowed linear movement only. They cannot be allowed two dimensional movement.
SUMMARY OF THE INVENTION
An object of the present invention is to provide a two dimensional drive system, which is capable of two dimensional movement.
To achieve the object, the two dimensional drive system of the present invention has three basic structures.
Firstly, the first basic structure comprises:
a pair of X-guides being arranged parallel in an X-direction;
a pair of Y-guides being arranged parallel in a Y-direction perpendicular to the X-direction;
an X-rod being arranged parallel to the X-guides, each end of the X-rod is slidably attached to each Y-guide;
a Y-rod being arranged parallel to the Y-guides, each end of the Y-rod is slidably attached to each X-guide;
an X-piston section being provided at the midway of the X-rod, the diameter of the X-piston section is greater than that of the X-rod;
a Y-piston section being provided at the midway of the Y-rod, the diameter of the Y-piston section is greater than that of the Y-rod; and
a moving body having an X-chamber in the X-direction through which the X-rod is pierced, and a Y-chamber in the Y-direction through which the Y-rod is pierced, whereby the moving body is capable of moving on the X- and Y-rods, the X-chamber being divided into two subchambers by the X-piston section, the Y-chamber being divided into two subchambers by the Y-piston section,
wherein the moving body is capable of moving in a plane by selectively supplying fluid to each subchamber.
Secondly, the second basic structure comprises:
a pair of X-guides being arranged parallel in an X-direction;
a pair of Y-guides being arranged parallel in a Y-direction perpendicular to the X-direction;
a first X-rod being arranged parallel to the X-guides, each end of the first X-rod is slidably attached to each Y-guides;
a first Y-rod being arranged parallel to the Y-guides, each end of the first Y-rod is slidably attached to each X-guides;
a first X-piston section being provided at the midway of the first X-rod, the diameter of the first X-piston section is greater than that of the first X-rod;
a first Y-piston section being provided at the midway of the first Y-rod, the diameter of the first Y-piston section is greater than that of the first Y-rod;
an X-cylinder section having a first X-chamber in the X-direction through which the first X-rod is pierced whereby the X-cylinder section is capable of moving on the first X-rod, the first X-chamber being divided into two first X-subchambers by the first X-piston section;
a Y-cylinder section having a first Y-chamber in the Y-direction through which the first Y-rod is pierced whereby the Y-cylinder section is capable of moving on the first Y-rod, the first Y-chamber being divided into two first Y-subchambers by the first Y-piston section;
a second X-rod being provided on the X-cylinder section and arranged in the X-direction;
a second Y-rod being provided on the Y-cylinder section and arranged in the Y-direction;
a second X-piston section being provided at the midway of the second X-rod, the diameter of the second X-piston section is greater than that of the second X-rod;
a second Y-piston section being provided at the midway of the second Y-rod, the diameter of the second Y-piston section is greater than that of the second Y-rod; and
a moving body having a second X-chamber in the X-direction through which the second X-rod is pierced, and a second Y-chamber in the Y-direction through which the second Y-rod is pierced, whereby the moving body is capable of moving on the second X- and Y-rods, the second X-chamber being divided into two second X-subchambers by the second X-piston section, the second Y-chamber being divided into two Y-subchambers by the second Y-piston section,
wherein the moving body is capable of moving in a plane by selectively supplying fluid to the first X-subchambers, the second X-subchambers, the first Y-subchambers and the second Y-subchambers.
Thirdly, the third basic structure comprises:
a pair of X-guides being arranged parallel in an X-direction;
a pair of Y-guides being arranged parallel in a Y-direction perpendicular to the X-direction;
an X-rod having an X-chamber in the X-direction, the X-rod being arranged parallel to the X-guides, each end of the X-rod is slidably attached to each X-guide;
a Y-rod having a Y-chamber in the Y-direction, the Y-rod being arranged parallel to the X-guides, each end of the Y-rod is slidably attached to each X-guide;
an X-piston being movably provided in the X-chamber, the X-piston dividing the X-chamber into two subchambers;
a Y-piston being movably provided in the Y-chamber, the Y-piston dividing the Y-chamber into two subchambers; and
a moving body being pierced by the X- and Y-rods so as to move thereon, the moving body is connected to the X- and Y-pistons so as to move on the X- and Y-rods together therewith,
wherein the moving body is capable of moving in a plane by selectively supplying fluid to each subchamber.
In the two dimensional drive system of the present invention, by selectively supplying fluid to the subchambers, the moving body can be executed two dimensional movement in a plane.
Further scope of applicability of the present invention will become apparent from the detailed description given hereinafter. However, it should be understood that the detailed description and specific examples, while indicating preferred embodiments of the invention, are given by way of illustration only, since various changes and modifications within the spirit and scope of the invention will become apparent to those skilled in the art from this detailed description.
BRIEF DESCRIPTION OF THE DRAWINGS
Embodiments of the present invention will now be described by way of examples and with reference to the accompanying drawings, which are given by way of illustration only, and thus are not limitative of the present invention, and in which:
FIG. 1 is a perspective view of a drive system of a First Embodiment;
FIG. 2 is a plan view of the First, Embodiment;
FIG. 3 is a partially perspective view of a Second Embodiment;
FIG. 4 is a plan view of a Third Embodiment;
FIG. 5 is a plan view of a Fourth Embodiment;
FIG. 6 is a partially perspective view of a Fifth Embodiment;
FIG. 7 is partially sectional view of the Fifth Embodiment;
FIG. 8 is a partially perspective view of a Sixth Embodiment;
FIG. 9 is a partially sectional view of the Sixth Embodiment;
FIG. 10 is a plan view of a Seventh Embodiment;
FIG. 11 is a plan view of a Eighth Embodiment; and
FIG. 12 is a partially sectional view of the Eighth Embodiment.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
Preferred embodiments of the present invention will now be described in detail with reference to the accompanying drawings.
First Embodiment
An First Embodiment will be explained with reference to FIGS. 1 and 2.
A base 10 is formed like a frame.
X-guides 12a and 12b are made of metal shafts. The X-guides 12a and 12b are provided above the base 10 and arranged in the X-direction. Ends of the X-guides 12a and 12b are fixed to boxes 14, which are provided at corners of the base 10, by bolts 16.
X-travellers 18a and 18b are slidably attached to the X-guides 12a and 12b. The X-travellers 18a and 18b include slide bearings (not shown) so as to prevent abrasion between the X-travellers 18a and 18b and the X-guides 12a and 12b.
A Y-rod 22 is a metal shaft. The ends of the Y-rod 22 are respectively fixed at the X-travellers 18a and 18b. Therefore, the X-travellers 18a and 18b can be moved together in the X-direction.
Y-guides 24a and 24b are made of metal shafts. The Y-guides 24a and 24b are provided above the base 10 and arranged in the Y-direction perpendicular to the X-direction. Ends of the Y-guides 24a and 24b are also fixed to the boxes 14 by bolts 16.
Y-travellers 26a and 26b are slidably attached to the Y-guides 24a and 24b. The Y-travellers 26a and 26b also include slide bearings (not shown) so as to prevent abrasion between the Y-travellers 26a and 26b and the Y-guides 24a and 24b.
A X-rod 28 is a metal shaft. The ends of the X-rod 28 are respectively fixed at the Y-travellers 26a and 26b. Therefore, the Y-travellers 26a and 26b can be moved together in the Y-direction.
A slider 30, which is an example of moving bodies, is a cross-shaped block. The slider 30 has an upper section 32 and a lower section 34. There is formed an X-chamber 35, which is bored in the X-direction, in the upper section 32; there is formed a Y-chamber 37, which is bored in the Y-direction, in the lower section 34. The X-rod 28 is pierced through the X-chamber 35; the Y-rod 22 is pierced through the Y-chamber 37, so that the X-rod 28 and the Y-rod 22 are crossed in the slider 30. By this structure, the slider 30 can be moved on the X-rod 28 and the Y-rod 22 and can execute two dimensional movement in a plane 36, which is rounded by the X-guides 12a and 12b and the Y-guides 24a and 24b. Robot heads, tools, work, etc. can be attached to the slider 30.
In the upper section 32 of the slider 30, there is provided an X-piston section 38 at the center of the X-rod 28. The diameter of the X-piston section 38 is greater than that of the X-rod 28. The X-piston section 38 divides the X-chamber 35 into subchambers 40a and 40b. Compressed air, which is an example of fluid, is selectively supplied to the subchambers 40a and 40b from a compressor (not shown) via ports 42. By selectively supplying compressed air to the subchambers 40a and 40b, the slider 30 selectively moves on the X-rod 28 in the X-direction, so that the Y-rod 22 and the X-travellers 18a and 18b move together in the X-direction. Note that, the moving stroke of the slider 30 in the X-direction may be defined by the length of the subchambers 40a and 40b.
The structure of the lower section 34 of the slider 30 is the same as the upper section 32 thereof. Namely, there is provided a Y-piston section, which corresponds to the X-piston section 38, at the center of the Y-rod 22. The diameter of the Y-piston section is greater than that of the Y-rod 22. The Y-piston section divides the Y-chamber 37 into subchambers 40c and 40d. Compressed air is selectively supplied to the subchambers 40c and 40d from the compressor via ports 44. By selectively supplying compressed air to the subchambers 40c and 40d, the slider 30 selectively moves on the Y-rod 22 in the Y-direction, so that the X-rod 28 and the Y-travellers 26a and 26b move together in the Y-direction. Note that, the moving stroke of the slider 30 in the Y-direction may be defined by the length of the subchambers 40c and 40d. By combining the X- and Y-directional movement, the slider 30 can execute two dimensional movement in the plane 36.
Stoppers 46 are detachably fixed on the X-rod 28 and the Y-rod 22 so as to limit the movement of the slider 30. To adjust the stroke of the slider 30, the stoppers 46 can be slid on the X-rod 28 and the Y-rod 22.
Second Embodiment
A Second Embodiment will be explained with reference to FIG. 3. Note that, the Second Embodiment is a modified embodiment of the First Embodiment, so components, which are the same as ones in the First Embodiment, are assigned the same symbols, and the explanation thereof will be omitted.
A slider 30 has four block sections 100, two cylinder sections 102a in which Y-chambers are formed, and two cylinder sections 102b in which X-chambers are formed.
Y-rods 22 are respectively pierced through the cylinder sections 102a; X-rods 28 are respectively pierced through the cylinder sections 102b. With this structure, the blocks 100 and the cylinder sections 102a and 102b can be moved together as a single slider 30. Note that, the Y-chambers formed in the cylinder sections 102a are, as well as the First Embodiment, respectively divided into two subchambers by Y-piston sections (not shown), which are respectively provided at the center of each Y-rod 22; the X-chambers formed in the cylinder sections 102b are, as well as the First Embodiment, also respectively divided into two subchambers by X-piston sections(not shown), which are respectively provided at the center of each X-rod 28.
In the present embodiment, thrust force applying to the slider 30 is twice as great as that of the First Embodiment. With greater thrust force, even if a plane 36 is inclined or vertical, the slider 30 can be driven easily.
Third Embodiment
A Third Embodiment will be explained with reference to FIG. 4. Note that, the Third Embodiment is also a modified embodiment of the First Embodiment, so components, which are the same as ones in the First Embodiment, are assigned the same symbols, and the explanation thereof will be omitted.
First timing belts 202a and 202b, which constitute X-restraining means, are arranged parallel to Y-guides 24a and 24b. The first timing belt 202a engages with first timing pulleys 204a and 204b; the first timing belt 202b engages with first timing pulleys 204c and 204d. The timing pulleys 204a, 204b, 204c and 204d constitute the X-restraining means with the first timing belts 202a and 202b. The timing pulleys 204a, 204b, 204c and 204d are accommodated in boxes 14.
Second timing belts 206a and 206b, which constitute Y-restraining means, are arranged parallel to X-guides 12a and 12b. The second timing belt 206a engages with second timing pulleys 208a and 208b; the second timing belt 206b engages with second timing pulleys 208c and 208d. The timing pulleys 208a, 208b, 208c and 208d constitute the Y-restraining means with the second timing belts 206a and 206b. The timing pulleys 208a, 208b, 208c and 208d are accommodated in boxes 14.
X-travellers 18a and 18b are respectively connected to the second timing belts 206a and 206b by connecting members 210. With this structure, the second timing belts 206a and 206b are driven by the movement of the X-travellers 18a and 18b.
Y-travellers 26a and 26b are respectively connected to the first timing belts 202a and 202b by connecting members 210. With this structure, the first timing belts 202a and 202b are driven by the movement of the Y-travellers 26a and 26b.
By providing the X-restraining means, the inclination of the X-rod 28 with respect to the X-axis can be prevented; by providing the Y-restraining means, the inclination of the Y-rod 22 with respect to the Y-axis can be prevented. Therefore, positioning accuracy of a slider 30 can be higher. Additionally, vibration and noise during high speed operation can be prevented.
Fourth Embodiment
A Fourth Embodiment will be explained with reference to FIG. 5. Note that, the Fourth Embodiment is also a modified embodiment of the First Embodiment, so components, which are the same as ones in the First Embodiment, are assigned the same symbols, and the explanation thereof will be omitted.
First racks 302a and 302b, which constitute X-restraining means, are arranged parallel to Y-guides 24a and 24b.
First pinions 304a and 304b, which constitute X-restraining means, are respectively engaged with the first racks 302a and 302b. The first pinions 304a and 304b are capable of rotating on the first racks 302a and 302b.
A first shaft 306, which constitutes X-restraining means, is arranged in the X-direction, and rotatably pierced through a hollow cylindrical X-rod 28, a slider 30 and Y-travellers 26a and 26b. The first pinions 304a and 304b are respectively fixed at each end of the first shaft 306.
Second racks 308a and 308b, which constitute Y-restraining means, are arranged parallel to X-guides 12a and 12b.
Second pinions 310a and 310b, which constitute Y-restraining means, are respectively engaged with the second racks 308a and 308b. The second pinions 310a and 310b are capable of rotating on the second racks 308a and 308b.
A second shaft 312, which constitutes Y-restraining means, is arranged in the Y-direction, and rotatably pierced through a hollow cylindrical Y-rod 22, the slider 30 and X-travellers 18a and 18b. The second pinions 310a and 310b are respectively fixed at each end of the second shaft 312.
By the movement of the X-travellers 18a and 18b, the second pinions 310a and 310b rotate on and along the second racks 308a and 308b. While, by the movement of the Y-travellers 26a and 26b, the first pinions 304a and 304b rotate on and along the first racks 302a and 302b.
By providing the X-restraining means, the inclination of the X-rod 28 with respect to the X-axis can be prevented; by providing the Y-restraining means, the inclination of the Y-rod 22 with respect to the Y-axis can be prevented. Therefore, positioning accuracy of the slider 30 can be higher. Additionally, vibration and noise during high speed operation can be prevented.
Note that, the X-rod 28 and the Y-rod 22 are filled with lubricant, e.g. grease, so that abrasion and noise, which are caused between the inner faces of the rods 22 and 28 and the outer circumferential faces of the shafts 306 and 312.
Fifth Embodiment
A Fifth Embodiment will be explained with reference to FIGS. 6 and 7. Note that, components, which are the same as ones in the prior embodiments, are assigned same symbols, and the explanation thereof will be omitted.
Each end of a first X-rod 402 is Y-travellers 26a and 26b. There is provided a first X-piston section 416, whose diameter is greater than that of the first X-rod 402, at the midway thereof.
Each end of a first Y-rod 404 is X-travellers 18a and 18b. Similarly to the first X-piston section 416, there is provided a first Y-piston section, whose diameter is greater than that of the first Y-rod 404, at the midway thereof.
In an X-cylinder section 406, a first X-chamber 418 is formed in the X-direction. The first X-rod 402 is pierced through the first X-chamber 418, so that the X-cylinder section 406 is capable of moving on and along the first X-rod 402. The first X-chamber 418 is divided into two first X-subchambers 420a and 420b by the first X-piston section 416. By selectively supplying compressed air to the first X-subchambers 420a and 420b, a slider 30 is capable of moving on and along the first X-rod 402 in the X-direction together with the X-cylinder section 406.
In a Y-cylinder section 408, a first Y-chamber 418, as well as the X-cylinder section 406, is formed in the Y-direction. The first Y-rod 404 is pierced through the first Y-chamber, so that the Y-cylinder section 408 is capable of moving on and along the first Y-rod 404. The first Y-chamber is also divided into two first Y-subchambers by the first Y-piston section. By selectively supplying compressed air to the first Y-subchambers, the slider 30 is capable of moving on and along the first Y-rod 404 in the Y-direction together with the Y-cylinder section 408.
A second X-rod 410 is arranged in the X-direction. Both ends of the second X-rod 410 are respectively fixed at supporting pieces 412a and 412b, which are provided on the X-cylinder section 406. There is provided a second X-piston section 422, whose diameter is greater than that of the second X-rod 410, at the midway of the second X-rod 410.
A second Y-rod 414 is arranged in the Y-direction. Both ends of the second Y-rod 414 are respectively fixed at supporting pieces 412c and 412d, which are provided on the Y-cylinder section 408. Similarly to the second X-rod 410, there is provided a second Y-piston section, whose diameter is greater than that of the second Y-rod 414, at the midway of the second Y-rod 414.
The slider 30 has a block section 100 and cylinder sections 102a and 102b. In the cylinder section 102b, a second X-chamber 424 is formed in the X-direction. The second X-rod 410 is pierced through the second X-chamber 424. With this structure, the slider 40 is capable of moving on the second X-rod 410 and the second Y-rod 414. In the cylinder section 102b, as well as the cylinder section 102a, a second Y-chamber is formed in the Y-direction. The second Y-rod 414 is pierced through the second Y-chamber.
The second X-chamber 424 in the cylinder section 102b is divided into two second X-subchambers 426a and 426b by the second X-piston section 422; the second Y-chamber in the cylinder section 102a is, as well as the second X-chamber 424, divided into two second Y-subchambers by the second Y-piston section. By supplying compressed air to the second X-subchambers 426a and 426b and the second Y-subchambers, the slider 30 is capable of moving in the X- and the Y-directions on the second X-rod 410 and the second Y-rod 414.
By supplying compressed air to the first X-subchambers 420a and 420b, the first Y-subchambers, the second X-subchambers 426a and 426b and the second Y-subchambers, the slider 30 is capable of two dimensional movement in a rectangle plane 36. In comparison with foregoing embodiments, positioning points of the slider 30 can be increased. Namely, the slider 30 can be located at four points in the X- and the Y-directions, so that 16 positioning points can be defined in the plane 36. In each foregoing embodiment, positioning point is four, so the present embodiment has four times as many positioning points as they have.
Sixth Embodiment
A Sixth Embodiment will be explained with reference to FIGS. 8 and 9. Note that, components, which are the same as ones in the prior embodiments, are assigned the same symbols, and the explanation thereof will be omitted.
An X-rod 502 and a Y-rod 504, which are pierced through a slider 30, are formed like hollow cylinders.
There are respectively provided an X-piston 506 and a Y-piston 508 in the X- and the Y-rods 502 and 504. The pistons 506 and 508 are made of magnet and capable of moving in the X- and the Y-directions.
The Y-rod 504 has a Y-chamber 510. The Y-chamber 510 is divided into two subchambers 512a and 512b by the Y-piston 508. Compressed air may be supplied to the subchambers 512a and 512b via air-ports 514, which are respectively provided in Y-travellers 26a and 26b. By selectively supplying compressed air to the subchambers 512a and 512b, the Y-piston 508 can be selectively moved in the Y-direction. Note that, symbols 518 show seal rings. The X-rod 502 has the same structure, so that the X-piston 506 can be selectively moved in the X-direction by selectively supplying compressed air to two subchambers, which are in the X-rod 502 and divided by the X-piston 506, via air-ports 516, which are respectively provided in X-travellers 18a and 18b. Note that, the length of the stroke of the piston 506 and 508 may be defined by the length of the X- and the Y-rods 502 and 504.
The slider 30 is made of one of magnetizable materials, so that the slider 30 is magnetically connected to the pistons 506 and 508. The slider 30 is capable of moving in the X- and Y-directions together with the pistons 506 and 508. With this structure, the slider 30 is moved in the X- and Y-directions in a plane 36 by selectively supplying compressed air to the subchambers. In the present embodiment, the pistons 506 and 508 are made of magnet, and the slider 30 is made of magnetizable materials but the present invention is not limited to above described structure. For example, the pistons 506 and 508 may be made of magnetizable materials, and the slider 30 may be made of magnet. Furthermore, the pistons 506 and 508 and the slider 30 are connected not only by magnetic force but mechanical couplers.
Seventh Embodiment
A Seventh Embodiment will be explained with reference to FIG. 10. Note that, the Seventh Embodiment is a modified embodiment of the sixth Embodiment, so components, which are the same as ones in the prior embodiments, are assigned the same symbols, and the explanation thereof will be omitted.
In the present embodiment, the drive system, whose basic structure is the same as the drive system of the Sixth Embodiment, has X-restraining means and Y-restraining means.
The X-restraining means has first timing belts 202a and 202b and first timing pulleys 204a, 204b, 204c and 204d; the Y-restraining means has second timing belts 206a and 206b and first timing pulleys 208a, 208b, 208c and 208d.
Also in the present embodiment, the inclination of an X-rod 502 with respect to the X-axis can be prevented by the X-restraining means; the inclination of a Y-rod 504 with respect to the Y-axis can be prevented by the Y-restraining means. Therefore, positioning accuracy of a slider 30 can be higher. Additionally, vibration and noise during high speed operation can be prevented.
Eigth Embodiment
A Eighth Embodiment will be explained with reference to FIGS. 11 and 12. Note that, the Eighth Embodiment is also a modified embodiment of the sixth Embodiment, so components, which are the same as ones in the prior embodiments, are assigned the same symbols, and the explanation thereof will be omitted.
In the present embodiment, the drive system, whose basic structure is the same as the drive system of the Sixth Embodiment, has X-restraining means and Y-restraining means.
The X-restraining means has first racks 302a and 302b, first pinions 304a and 304b and a first shaft 306. Note that, a X-piston 602 has a hollow cylindrical shape, and a first shaft 306 is pierced therethrough.
The Y-restraining means has second racks 308a and 306b, second pinions 310a and 310b and a second shaft 312. Note that, a Y-piston 604 has a hollow cylindrical shape, and a second shaft 312 is pierced therethrough.
Also in the present embodiment, the inclination of an X-rod 502 with respect to the X-axis can be prevented by the X-restraining means; the inclination of a Y-rod 504 with respect to the Y-axis can be prevented by the Y-restraining means. Therefore, positioning accuracy of a slider 30 can be higher. Additionally, vibration and noise during high speed operation can be prevented.
Preferred embodiments of the present inventions have been described above but the present invention is not limited to the embodiments, for example, oil pressure can be applied to the drive system instead of air pressure. It should be appreciated that the present invention can modified without deviating the scope of the claims.
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An object of the present invention is to provide a two dimensional drive system driven by fluid pressure. The drive system of the present invention comprises: a pair of X-guides; a pair of Y-guides; an X-rod whose each end is slidably attached to each Y-guide; a Y-rod whose each end is slidably attached to each X-guide; an X-piston section being provided at the midway of the X-rod; a Y-piston section being provided at the midway of the Y-rod; and a moving body having an X-chamber through which the X-rod is pierced and a Y-chamber through which the Y-rod is pierced, the X-chamber being divided into two subchambers by the X-piston section, the Y-chamber being divided into two subchambers by the Y-piston section. With this structure, the moving body is capable of moving in a plane by selectively supplying fluid to each subchamber.
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This application is a continuation-in-part of application Ser. No. 10/695,735, filed Oct. 23, 2003, now U.S. Pat. No. 6,849,707, which, in turn, claims benefit of priority of the filing date of Provisional Application No. 60/453,334, filed Feb. 28, 2003.
RIGHTS OF THE GOVERNMENT
The invention described herein may be manufactured and used by or for the Government of the United States for all governmental purposes without the payment of any royalty.
BACKGROUND OF THE INVENTION
The present invention relates to a new quinoxaline-containing hyperbranched ether-ketone polymers.
Dendritic macromolecules such as dendrimers and hyperbranched polymers are a new class of highly branched polymers that have distinctly different properties from their linear analogs. Both dendrimers and hyperbranched polymers have much lower solution and melt viscosities than their linear analogs of similar molecular weights. They also have a large number of chain-ends whose collective influence dictates their overall physical and/or chemical behaviors. These features are attractive in terms of processability and offering flexibility in engineering required properties for specific applications. However, there is a practical advantage that hyperbranched polymers have over dendrimers at “raw material” level. Although dendrimers have precisely controlled structures (designated as generations), their preparations generally involve tedious, multi-step sequences that are impractical and costly in scale-up production. Synthesis of a hyperbranched polymer, on the other hand, is a one-pot process. Large quantities of hyperbranched polymers can be easily produced from AB x (x≧2) monomers.
Because of their excellent thermal and mechanical properties, as well as their optical and electronic characteristics, aromatic, fused heterocyclic polymers such as polyquinoxalines and polybenzoxazoles continue to attract considerable attention. However, they have limited processability due to the nature of fused ring systems. Their insolubility and their softening temperatures are generally above their degradation temperatures. Chemical modification on the these materials, for example, by the use of solubilizing pendants or flexible units in the main chain, has been successful to improve their processability, allowing the optimization of their properties as a function of processability. Another viable approach to achieving this objective is to incorporate the elements of local rigidity and global randomness into the macromolecular architecture. Local rigidity provides the thermal, electronic and optical characteristics of the aromatic fused systems while global randomness frustrates entanglement of the polymer chains, leading to greater solubility. Dendritic structures clearly embody these qualities. However, as noted previously, hyperbranched structures have greater synthetic practicality.
Accordingly, it is an object of the present invention to provide novel quinoxaline-containing hyperbranched poly(ether-ketones).
It is another object of the present invention to provide novel end-capped quinoxaline-containing hyperbranched poly(ether-ketones).
It is another object of the present invention to provide a novel method for preparing end-capped quinoxaline-containing hyperbranched poly(ether-ketones).
Other objects and advantages of the invention will be set forth in part in the description which follows, and in part will be obvious from the description, 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.
SUMMARY OF THE INVENTION
In accordance with the present invention there is provided a quinoxaline-containing hyperbranched ether-ketone polymer having repeating units of the formula:
Also provided is an end-capped quinoxaline-containing hyperbranched ether-ketone polymer having repeating units of the formula:
wherein n represents the degree of polymerization for the parent hyperbranched polymer, x represents the degree of endgroup functionalization, x has a value of 0.05 to 1.0, and G is selected from the group consisting of
and aliphatic carboxylic acids having 2 to 16 carbon atoms, i.e., C q H 2q+1 COOH, wherein q has a value of 1 to 15.
DETAILED DESCRIPTION OF THE INVENTION
The quinoxaline-containing hyperbranched ether-ketone polymer of this invention is prepared by polymerization of the corresponding AB 2 monomer
Preparation of the AB 2 monomer, 2,3-bis(4-phenyloxyphenyl)-6-quinoxaline carboxylic acid, is described in co-pending application Ser. No. 10/695,730, filed Oct. 23, 2003.
Polymerization of the AB 2 monomer can be conducted in polyphosphoric acid (PPA) at a polymer concentration of about 5 weight percent at a temperature of about 130° C. Preliminarily it is helpful to describe the chemistry of phosphoric acids and strong phosphoric acids or polyphosphoric acids as follows: As used herein the term “phosphoric acid(s)” means commercial phosphoric acid(s) containing 85–86% H 3 PO 4 . The strong phosphoric acids, or polyphosphoric acids referred to as PPA (polyphosphoric acid) are members of a continuous series of amorphous condensed phosphoric acid mixtures given by the formula
H n+2 P n O 3n+1
or
HO—PO 3 H n H
where the value of n depends on the molar ratio of water to phosphorus pentoxide present.
In its most general definition, polyphosphoric acid composition can range from distributions where the average value of n is less than unity, giving rise to a mobile liquid, to high values of n, where the polyphosphoric acid is a glass at normal temperatures. Because the species of polyphosphoric acid are in a mobile equilibrium, a given equilibrium composition can be prepared in many ways. For instance, the same distribution or polyphosphoric acid composition could be prepared by either starting with concentrated orthophosphoric acid (H 3 PO 4 , n=1) and driving off water or by starting with phosphorus pentoxide (P 2 O 5 ) and adding an appropriate amount of water.
All polyphosphoric acid compositions can be described as a ratio of P 2 O 5 and water by reducing the various species present (on paper) to P 2 O 5 and water. We will then use the convention that polyphosphoric acid composition will be expressed in terms of a P 2 O 5 content (as a percentage) defined as P 2 O 5 content
=(weight of P 2 O 5 )/(weight of P 2 O 5 +weight of water)×100.
Thus, the P 2 O 5 content of pure orthophosphoric acid could be derived by reducing one mole of H 3 PO 4 to 0.5 moles P 2 O 5 +1.5 moles H 2 O. Converting to weights gives the P 2 O 5 content as
(0.5*142)/((0.5*142)+(1.5*18.01))=72.4%
Similarly, the P 2 O 5 content of commercial polyphosphoric acid can be derived in the following way. Polyphosphoric acid is available commercially in two grades, 105% and 115%. These percentages refer to H 3 PO 4 content, which means that 100 g of the two grades contain 105 and 115 grams of H 3 PO 4 . The P 2 O 5 content of 115% polyphosphoric acid can then be calculated knowing the P 2 O 5 content of 100% H 3 PO 4 .
(115*0.724)/100=83.3%
We have found that the rate of polymerization can be accelerated by adding about 25% additional phosphorus pentoxide (relative to the weight of PPA) to the polymerization mixture, as shown in the examples which follow.
Due to the availability of large number of end-groups, the end-functionalization of hyperbranched polymers can be utilized to tailor their physical properties for various applications. The number of reactive end-groups is equal to the degree of polymerization plus one (DP+1). A sufficient quantity of the selected endcapping compound is added to the polymerization mixture to provide about 5 to 99 mol % endcapping. The hyperbranched polymers can be endcapped using a variety of endcapping compounds, for example, but not limited to, 3,5-dihydroxybenzoic acid, 3-sulfobenzoic acid, 4-sulfobenzoic acid and 2,3-diphenylquinoxaline-6-carboxylic acid. 2-thiophenecarboxylic acid, 4-dimethylaminobenzoic acid, cyclohexanecarboxylic acid, acetic acid through and including palmitic acid, and the like. For example, endcapping the hyperbranched polymer with 3,5-dihydroxybenzoic acid provides 3,5-dihydroxyphenylcarbonyl moieties as chain-end units
which, in turn, can be modified with allylbromide to provide the diallyl-terminated hyperbranched polymer having 3,5-di-allyloxyphenylcarbonyl moieties as chain-end units:
Other reactive endgroups, such as propargyl and glycidyl functions, can be prepared from the 1,3-dihydroxyphenyl-terminated derivative using similar reactions.
The hyperbranched polymers of this invention are suitable for use in applications where the material will be subject to high service temperatures.
The following examples illustrate the invention:
EXAMPLE 1
Polymerization of 2,3-bis(4-phenyloxyphenyl)-6-quinoxaline-carboxylic acid (AB 2 monomer) in PPA at 130° C.
Into 250 mL resin flask equipped with a high-torque mechanical stirrer and nitrogen inlet and outlet, a pressure regulator, and an addition port, polyphosphoric acid (PPA, 60 g) was charged. The PPA was degassed under reduced pressure by freezing in liquid nitrogen and melting in warm water several times. Then the monomer, 2,3-bis(4-phenyloxyphenyl)-6-quinoxaline-carboxylic acid (3.0 g, 5.9 mmol), was introduced. As soon as the monomer was added and the stirring started, the mixture became deep blue-purple. The mixture was heated to 130° C. and kept at this temperature for 48 h. Although the mixture had become deep red, its viscosity was not significantly increased. The reaction mixture was allowed to cool to 60–70° C. and water was added to precipitate the polymer. The resulting mixture was warm at 60–70° C. overnight under the nitrogen. The resulting bright yellow solids were collected by suction filtration, washed with diluted ammonium hydroxide, and large amount of water. The polymer was finally dried under reduced pressure (0.05 mmHg) at 200° C. for 150 h to give essentially quantitative yield: [η]=0.07 dL/g (0.5% solution in MSA at 30.0±0.1° C.). Anal. Calcd. for C 33 H 20 N 2 O 3 C, 80.47%; H, 4.09%; N, 5.69%; O, 9.75%. Found: C, 78.69%; H, 4.34%; N, 5.27%; O, 10.81%.
EXAMPLE 2
Polymerization of AB 2 Monomer in PPA/P 2 O 5 at 130° C.
Into a 250 mL resin flask equipped with a high-torque mechanical stirrer, nitrogen inlet and outlet, a pressure regulator and an addition port, PPA (83% assay, 80 g) was placed and stirred with dried nitrogen purging at 100° C. for 10 h. The monomer 2,3-bis(4-phenoxyphenyl)-6-quinoxaline-carboxylic acid (4.0 g) was added and heated to 130° C. until it become a homogeneous mixture. It usually took about 1 h. The color of mixture became dark brown. P 2 O 5 (20.0 g; 25 wt % relative to PPA used) was then added in one portion and the temperature was maintained at 130° C. for 24 h. The mixture became very viscous after 2 h at 130° C. and started to stick to the stirring rod. At the end of the reaction, water was added into the flask. The resulting precipitates were collected by suction filtration, washed with diluted ammonium hydroxide followed by a large amounts of water, stirred in boiling water for 100 h, and finally dried in the presence of phosphorous pentoxide under reduced pressure (1 mmHg) at 200° C. for 48 h. The yield was essentially quantitative (>99% yield). Its intrinsic viscosity is 0.56 dL/g (MSA, 30±0.1° C.). Anal. Calcd. for C 33 H 19 N 2 O 3 : C, 80.47%; H, 4.09%; N, 5.69%; O, 9.75%. Found: C, 80.08%; H, 4.57%; N, 3.69%; O, 10.34%.
EXAMPLE 3
Polymerization of AB 2 Monomer in PPA/P 2 O 5 at 160° C.
Into a 100 mL resin flask equipped with a high torque mechanical stirrer, nitrogen inlet and outlet, a pressure regulator and an addition port, PPA (83% assay, 40 g) was placed and stirred with dried nitrogen purging at 100° C. for 10 h. The monomer, 2,3-bis(4-phenyloxyphenyl)-6-quinoxaline-carboxylic acid (1.80 g, 3.5 mmol) and P 2 O 5 (10.0 g) were added and the mixture heated to 130° C. until it become a homogeneous mixture. It took about 3 h. The mixture was then heated at 160° C. and it soon stuck to the stirring rod, rendering further efficient stirring/mixing impossible. It took around 3 h. At the end of the reaction, water was added into the reaction vessel. The resulting lumps were broken up with the aid of a Waring blender, and the polymer product was collected by suction filtration, washed with diluted ammonium hydroxide and then with a large amount of water, stirred in boiling water for 100 h, and finally dried in the presence of phosphorous pentoxide under reduced pressure (1 mmHg) at 200° C. for 48 h. The yield was essentially quantitative (>99% yield). The polymer was insoluble in most organic solvents and only formed gel in methanesulfonic acid (MSA). Anal. Calcd. for C 33 H 19 N 2 O 3 : C, 80.47%; H, 4.09%; N, 5.69%. Found: C, 78.34%; H, 4.34%; N, 5.27%.
EXAMPLE 4
Polymerization in 1:10 w/w Mixture of P 2 O 5 /Methanesulfonic Acid (PPMA) at 110° C.
Into a 100 mL 3-necked round bottom flask equipped with a mechanical stirrer, nitrogen inlet and outlet, the monomer 2,3-bis(4-phenoxyphenyl)-6-quinoxaline-carboxylic acid (1.0 g, 1.96 mmol) and PPMA (10 mL) were added and heated to 110° C. for 8 h. The color of mixture became dark purple. The mixture was poured into ice water. The resulting purple precipitates were collected by suction filtration, washed with diluted ammonium hydroxide and then with large amount of water, stirred in boiling water for 48 h, and finally dried in the presence of phosphorous pentoxide under reduced pressure (1 mmHg) at 200° C. for 48 h. The yield was essentially quantitative (>99% yield). Its intrinsic viscosity was 0.50 dL/g (MSA, 30±0.1° C.). Anal. Calcd. for C 33 H 19 N 2 O 3 : C, 80.47%; H, 4.09%; N, 5.69%; O, 9.75%. Found: C, 78,12%; H, 4.33%; N, 5.27%; O, 10.77%.
The polymerization results are summarized in Table 1.
TABLE 1 Polymerization Conditions and Yields of Polymer P 2 O 5 Temp. Time Example Media (wt %) a (° C.) (h) [η] dL/g b Yield (%) 1 PPA 0 130 48 0.07 ~97 2 PPA 25 130 24 0.56 >99 3 PPA 25 160 3 Gel >99 4 MSA 10 110 8 0.50 >99 a Relative to the amount of PPA used. b Intrinsic viscosity measured in methanesulfonic acid (MSA) at 30 ± 0.1° C.
Thermal Properties. The T g 's of the polymers were determined by DSC. The thermograms were obtained on powder samples after they had been heated to 400° C. and cooled to 20° C. with heating and cooling rate of 10° C./min. The T g value was taken as the mid-point of the maximum baseline shift from the second run. The polymer samples (Examples 1–4), which were prepared from different reaction conditions, displayed T g 's at 149° C., 113° C., not detectable, 91° C., in that order. Thermogravimetric analysis of these polymers showed that they were heat-resistant; temperatures at which a 5% weight loss was observed were in the range of 505–525° C. in air and 515–536° C. in helium, respectively.
EXAMPLE 5
Preparation of 3,5-dihydroxy-terminated polyetherketonequinoxaline
Into a 250 mL resin flask equipped with a high torque mechanical stirrer, nitrogen inlet and outlet, a pressure regulator and an addition port, PPA (83% assay, 80 g), P 2 O 5 (20.0 g; 25 wt % relative to PPA used) were placed and heated to 130° C. until it became homogeneous. After the reaction medium had been allowed to cool to 100° C., the monomer, 2,3-bis(4-phenoxyphenyl)-6-carboxyquinoxaline (4.0 g, 3.92 mmol) and the end-capper 3,5-dihydroxybenzoic acid (1.21 g, 7.84 mmol) were added at the same time. The color of mixture became deep purple. The mixture was heated at 130° C. for 2 h, and at 160° C. for 24 h. When the polymerization was terminated, the mixture was moderately viscous. It was allowed to cool to 100° C. (still fluid) to facilitate pouring into water. The resulting precipitates were collected by suction filtration, washed with diluted ammonium hydroxide and then with a large amounts of water, Soxhlet-extracted with water for 50 h and then with methanol for additional 50 h, and finally dried in the presence of phosphorous pentoxide under reduced pressure (1 mmHg) at 100° C. for 48 h. The yield was essentially quantitative (>99% yield). The reduced viscosities at 0.5 g/dL were 0.09 dL/g (NMP, 30±0.1° C.) and 0.21 dL/g (MSA, 30±0.1° C.). Anal. Calcd. for C 40 H 24 N 2 O 6 : C, 76.43%; H, 3.85%. Found: C, 76.05%; H, 4.28%.
EXAMPLE 6
Preparation of 3,5-diallyl-terminated polyetherketonequinoxaline
Into a 100 mL three-necked, round-bottomed flask equipped with a magnetic stirrer, nitrogen inlet, a condenser, and an addition port, hydroxyl-terminated hyperbranched polymer (example 5; 3.5 g, 5.57 mmol), potassium carbonate (4.0 g, 28.90 mmol), allyl bromide (3.37 g, 27.86 mmol), and dimethylacetamide (50 mL) were placed. The reaction mixture was then heated and maintained at 90–100° C. for 16 h. During this time period, the orange solution became light yellow in color and homogeneous. After it had been allowed to cool down on its own, the mixture was filtered through a cake of Celite 545 to remove any insoluble salts. The filtrate was poured into a beaker containing 5% hydrochloric acid (300 mL) and the mixture was warmed up to around 60–70° C. for 2 h. The white powder was collected, air-dried, dissolved in dichloromethane, precipitated in methanol, collected, and dried under the reduced pressure in the presence of phosphorus pentoxide at 50° C. for 48 h. The yield was essentially quantitative. [η]=0.13 dL/g. Anal. Calcd. for C 46 H 32 N 2 O 6 : C, 77.95%; H, 4.55%; N, 3.95%; O, 13.54%. Found: C, 77.82%; H, 4.49%; N, 3.67%; O, 13.45%.
Having thus described exemplary embodiments of the present invention, it should be noted by those skilled in the art that the disclosures herein are exemplary only and that alternatives, adaptations and modifications may be made within the scope of the present invention.
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An end-capped quinoxaline-containing hyperbranched ether-ketone polymer having repeating units of the formula:
wherein n represents the degree of polymerization for the parent hyperbranched polymer, x represents the degree of endgroup functionalization, x has a value of 0.05 to 1.0, and G is selected from the group consisting of
and alkyl having 2 to 16 carbon atoms, and a method for preparing the polymer are provided.
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This invention relates generally to a device for cleaning stays of the type that are used on a sailboat for holding the mast in a fixed position.
BACKGROUND OF THE INVENTION
Stays that are commonly in the form of wound cables are used on sailboats for holding masts in fixed position. These stays, or guide wires as they are sometimes called, generally extend from the mast at various positions, most usually from an upper portion, to a point on the deck or hull of the boat. Commonly, these stays require frequent cleaning due to corrosion, rust and the collection of salt and dirt. This has been traditionally a manual operation requiring an individual to climb to the upper portions of the stays and hand clean them with handheld cleaning items such as cloths.
Several prior art patents have been directed to apparatus and devices for cleaning stays and these include U.S. Pat. Nos. 1,219,051; 1,407,674; 1,748,900; 3,116,811 and 3,791,330. These prior cleaning apparatus range from the simplistic device of the U.S. Pat. No. 3,791,330 patent to the rather complicated mechanism of U.S. Pat. No. 3,116,811. These prior art cleaning devices, however, have had problems either because the devices tend to wind the pulling cord or halyard around the stay, or the devices are mechanically complicated, unreliable and expensive to manufacture.
SUMMARY
According to this invention there is provided a stay cleaning device which comprises in combination a cleaning unit housing and a cleaning unit mounted therein.
The cleaning unit housing is adapted to be moved up and down along the length of the stay in fixed angular position. That is to say, the housing does not rotate around the axis of the stay. A cleaning unit including a stay cleaning means such as a brush is mounted in the housing and is permitted to freely rotate around the axis of the stay. When the housing is moved up and down the length of the stay in a fixed angular position, the cleaning unit is free to rotate with the wind of the stay and thus the stay is cleaned.
A halyard which is normally used on a sailboat for lifting the sails into position to catch the wind, can be used to tow the cleaning unit up and down along the length of the stay. In addition to the halyard, other lines that are normally used on a sailboat can be used for this towing purpose when connected to the cleaning unit.
It was an object of this invention to provide a stay cleaning device which would be reliable, and which would eliminate as many moving parts as possible.
Another object of this invention is a provision of a stay cleaning device that is relatively compact and could be operated with existing equipment on a sailboat.
A still further object of this invention was to provide a stay cleaning device which would not wind a halyard or line to which it was attached around the stay.
These and other objects of the invention were accomplished by the provision of a stay cleaning device wherein a simple housing can be moved up and down along the length of the stay in fixed angular position while a cleaning unit within the housing is free to rotate with the wind of the stay.
DESCRIPTION OF THE DRAWINGS
The invention will be more fully understood and described in connection with the drawings wherein:
FIG. 1 is a view in perspective of the stay cleaning device according to this invention shown in an open position;
FIG. 2 is a rear view of the device shown in FIG. 1.
FIG. 3 is an exploded assembly view showing the cleaning unit of the stay cleaning device of this invention;
FIG. 4 is a perspective view showing the assembled cleaning unit in cleaning position on a stay; and
FIG. 5 is a view in cross-section taken on line 5--5 of FIG. 4.
DETAILED DESCRIPTION OF THE INVENTION
Referring now to the drawings, there is shown a stay cleaning device 10 according to the invention. The stay cleaning device 10 includes a cleaning unit housing 11 and a cleaning unit 12 which is assembled of several different components. As shown in FIG. 4, cleaning unit housing 11 is adapted to be moved up and down the length of a stay 13 in a fixed angular position, that is to say it will not rotate with respect to the axis of the stay. Cleaning unit 12 on the other hand is mounted in housing 11 for free angular rotation around the axis of the stay so that it can follow the wind of the stay.
Cleaning unit 12 includes sector 14, and a like sector 15 which form halves of the cleaning unit. The sectors 14 and 15 include a slot 16 and a corresponding ridge 17 on the opposite side of the sector to provide alignment of the two sectors 14 and 15. In the middle of each sector 14 and 15 is a groove 18. Adapted to be placed in groove 18 is a brush assembly 19 which includes brush mounting base 20 and a brush 21 which has a concave surface 22.
Biasing spring 23 is provided to fit behind brush assembly 19 to force the brush assembly outwardly in the direction of the brush bristles 22. Biasing spring 23 can be fastened to brush base 20 by means of a fastener 24 which can be inserted through hole 25 in the biasing spring 23 and imbedded in brush base 20. Adapted to be positioned on the ends of sector 13 are bearing plates 26 and 27. These bearing plates in turn can be fixed by fasteners 28 which pass through holes 29 and are imbedded in the material of sectors 14 and 15. Fastened to sector 14 are spring clips 30 which are adapted to mate with spring clip retainer groove 31 in the mating sector 15.
housing 11 has a cylindrical interior section 32 into which cleaning unit 12 is inserted. Sectors 14 and 15 of cleaning unit 12 are assembled together by means of the spring clips 30 in sector 14 being snapped into spring clip retainer grooves 31 in sector 15. Similarly, ridges 17 fit into groove 16 on the opposite sector resulting in the formation of the fully assembled cleaning unit 12. The two halves of housing 11 are hinged together by hinges 33 fastened with hinge pins 34. The housing is locked together by locking flanges 35 which are locked by fastener 36.
At each end of housing 11 are pulling flanges 37 provided with holes 38. Housing 11 is further provided with side flanges 39 which in turn are provided with elongate holes 40.
Housing 11 is also provided with a threaded water inlet 41 to which a fitting 42 can be fixed.
In operation, after the two halves of cleaning unit 12 are placed over a stay 13 and the assembly closed and locked with spring clips 30 being engaged with retainer grooves 31, housing 11 is placed over cleaning unit 12 and closed and secured by fastener 36 through locking flanges 35. Brush 21 is forced by biasing spring 23 in contact with the wind of stay 13. Halyards or lines can be connected to flanges 37 whereby the cleaning device can be moved up and down along the length of the stay by pulling as shown in FIG. 4. Since the brush 21 is in contact with the wind of stay 13, the cleaning unit which is free to rotate within the interior cylindrical section 32 of housing 11 will rotate on bearing plates 26. Because the introduction of water to the interior housing 11 during the cleaning operation may be helpful to promote cleaning and remove debris that is brushed from the stay, such may be introduced during the cleaning operation through part 41 and fitting 42.
Housing 11 may also be positioned and moved up and down stay 13 by means of a boat hook 43 (as shown on dotted lines on FIG. 4) which can be inserted through elongate slots 40.
In accordance with an object of the invention, the parts of the cleaning device can be easily manufactured of desirable materials. Both the housing and the sectors of the cleaning unit can be made by means of injection molded plastics, composite materials such as filled plastics and/or metal or other materials with machining capabilities to create the structures described herein. The same is true of brush base 20. It is preferred to have bearing plates 26 manufactured of teflon materials because of their durability and lubricity.
The invention may be embodied in other specific forms without departing from the spirit or essential characteristics thereof. The present embodiments are therefore to be considered in all respects as illustrative and not restrictive, the scope of the invention being indicated by the appended claims rather than by the foregoing description; and all changes which come within the meaning and range of equivalency of the claims are therefore intended to be embraced therein.
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A cleaning unit including a stay cleaning means such as a brush is mounted in the housing and is permitted to freely rotate around the axis of the stay. When the housing is moved up and down the length of the stay in a fixed angular position, the cleaning unit is free to rotate with the wind of the stay and thus the stay is cleaned.
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BACKGROUND OF THE INVENTION
1. Field of the Invention
This invention relates to a sun visor arrangement for shielding vehicle occupants from sun glare, and more particularly, to a convenient arrangement in which the visors may be positioned either adjacent the windshield or adjacent the door to provide shielding from sun glare as the position of the vehicle relative to the sun varies.
2. Description of the Prior Art
The prior art has long provided sun visors which are movable from a windshield position to a side window or door position. Further, the prior art has disclosed arrangements in which such shifting between windshield and door positions has been provided for both the driver and the passenger side of the vehicle. The prior art has also included sun visor arrangements which include right, left and center visors extending across the full width of the windshield of the vehicle.
However, none of the prior art visor arrangements with which the applicant is familiar have provided the versatility and convenient arrangement of the sun visor structure of this invention.
Further, in prior art visor arrangements, it is usually necessary for the driver or other occupant to shift his head to the side or to duck to allow the visor to clear his head when moving between its windshield and side door positions. By the visor mounting arrangement of this invention, the visor path is such that it clears the occupant's head without requiring the occupant to change the position of his head.
It is an object of this invention to provide an improved sun visor arrangement including left, center and right visors in which, in cases where the steering wheel is on the left side, the left visor may be moved to a position adjacent the left door of the vehicle and the center visor may be moved into the position previously occupied by the left visor. In cases where the steering wheel is on the right side of the vehicle, the right visor would be moved to a position adjacent the right door and the center visor would then be moved into the position previously occupied by the right visor.
It is a further object of this invention to provide such a sun visor arrangement having a center visor construction which includes a stowage bracket conveniently serving as a receptacle for receiving the free end of the driver's visor to hold that visor in position when the three visors are in their normal windshield position.
It is a further object of this invention to provide such a stowage bracket construction on the center visor wherein the pin of the driver's visor received in the stowage bracket is automatically released therefrom when the center visor is moved towards its outer position.
It is a further object of this invention to provide a visor mounting arrangement whereby the visor follows a path which enables it to clear the head of the vehicle's occupant without requiring the occupant to change the position of his head.
SUMMARY OF THE INVENTION
In carrying out the invention, in one form thereof, as applied to a left-hand-steer vehicle, three pivoted visors are arranged along the windshield of a vehicle such as a truck. The left and right visors are movable from positions adjacent the windshield to positions adjacent the left and right doors, respectively, to provide shielding from sun glare as the vehicle moves along a curving road and its relation to the sun varies. The pivotal mounting of the left visor, that is, the visor on the driver's side of a left-hand-steer vehicle, is arranged so that when the left visor is moved between its windshield and door positions it follows an arcuate path raising the visor above the driver's head and eliminating the need to duck. The center visor, which in a left-hand-steer vehicle is movable between its center position and a position at the left end of the windshield, is constructed at its left side to provide a stowage bracket for receiving a rod extension of the left visor for holding the free end of the left visor in position. Further, this stowage bracket is formed so that should the center visor be pivoted towards its left-hand position before the left visor is moved from its windshield position, the bracket automatically releases itself from the rod extension of the left visor. In a right-hand-steer vehicle, the arrangement would be reversed so that the center visor is movable between its center position and a position at the right end of the windshield.
BRIEF DESCRIPTION OF THE DRAWINGS
For a better understanding of the invention, reference may be had to the accompanying drawings in which:
FIG. 1 is an elevation view showing the arrangement of the sun visors of this invention adjacent the windshield of a portion of a vehicle such as a truck cab;
FIG. 2 is a view similar to FIG. 1, showing the left and center visors in their alternate positions;
FIG. 3 is an enlarged elevation view of a portion of the left visor showing the pivotal mounting arrangement thereof;
FIG. 4 is a top view of the portion of the left visor and its mounting shown in FIG. 3;
FIG. 5 is a sectional view taken along the line 5--5 in FIG. 4;
FIG. 6 is an elevation view of a portion of the left-hand end of the center visor, showing its mounting arrangement;
FIG. 7 is a view taken along the line 7--7 in FIG. 6; and,
FIG. 8 is a top view of the portion of the center visor shown in FIG. 6.
DESCRIPTION OF THE PREFERRED EMBODIMENT
Referring to FIG. 1, which illustrates the invention as applied to a left-hand-steer vehicle, there is shown a sun visor arrangement for a vehicle, for example, a truck cab. In the particular arrangement shown in FIG. 1, three sun visors 10, 12 and 14 are shown positioned along the width of the windshield of the vehicle. The visors are shown in their vertical, that is, sun-shielding position, but, in accordance with common practice, they are movable about horizontal axes to a horizontal position adjacent the roof of the vehicle. While in the form shown three sun visors are employed because, in the particular application shown where the visors are employed in a relatively wide truck cab, three such visors are desirable to cover the entire width of the windshield, it will become apparent as this description proceeds that in its essential aspects the invention is equally applicable to a more narrow vehicle in which only two sun visors are employed.
The left-hand visor 10, that is, the visor at the driver's side of a left-hand-steer vehicle, is mounted at 16 for movement from the position shown in FIG. 1 adjacent the windshield to the position shown in FIG. 2 where the visor 10 is positioned adjacent the side of the vehicle, that is, adjacent the left door. The center visor 12 is mounted as shown at 18 for movement from the position shown in FIG. 1 where the visor is adjacent the center portion of the windshield to a second position shown in FIG. 2 wherein the center visor is at the left-hand side of the vehicle, that is, essentially in the position previously occupied by the left-hand visor 10. The right-hand visor 14 is mounted, as shown at 20, for movement from a first position adjacent the right-hand side of the windshield as shown in FIG. 1, to a second position adjacent the side of the vehicle, that is, adjacent the right door.
In FIGS. 3, 4 and 5, details of the mounting arrangement for the left-hand visor 10 are shown, the visor including a horizontally extending rod 22 about which the visor is movable between a vertical position adjacent the windshield and a horizontal position adjacent the top of the vehicle. The rod 22 includes at its left end an upwardly bent portion 24 which is formed, for reasons discussed below, to extend at an angle of approximately 45 degrees with the horizontal. For supporting the visor, a mounting bracket 26, adapted to be mounted on the roof 28 of the vehicle, is provided. The bracket includes a somewhat triangular-shaped plate 30. The plate 30 includes a plurality of holes 32 for receiving screws (not shown) to mount the bracket 26 on the frame of the vehicle. The bracket 26 further includes a tubular portion 34, formed integral with the plate 30, which extends at an angle α with respect to the plate 30. The angle α is approximately 45 degrees. In addition to the arrangement of the tubular portion 34 at an angle of approximately 45 degrees with the plate 30, the bracket 26 is formed and mounted so that the tubular portion 34 extends along a plane approximately mid-way between the plane of the windshield and the plane of the left door or side of the vehicle.
The visor 10 is movable about the axis provided by the above-described mounting arrangement between the position shown in FIG. 1 adjacent the windshield and the position shown in FIG. 2 where this visor is adjacent the side of the vehicle. Because of the construction of the mounting bracket 26 and its position on the roof of the vehicle, the visor 10 in moving between its first and second positions, that is, between its position adjacent the windshield and its position adjacent the side of the vehicle, is caused to move along an arcuate path generally indicated by the dashed line 36 in FIG. 2. The visor therefore reaches its highest point approximately mid-way in its travel between its two positions and thereby provides an elevated position of the visor which enables it to clear the head of the driver, indicated at 38, without requiring the driver to duck beneath the visor during such movement.
The mounting arrangement for the center visor is shown in more detail in FIGS. 6-8. As there shown, the center visor 12 includes a horizontally extending rod 40 about which the visor is movable from a vertical position adjacent the windshield to a horizontal storage position adjacent the roof of the vehicle. The rod 40 includes at its left end an upwardly extending generally vertical portion 42 about which the visor 12 pivots in moving from its first position adjacent the center of the windshield, as shown in FIG. 1, to its second position adjacent the left-hand side of the windshield, as shown in FIG. 2.
A mounting bracket 44 is provided for supporting the center visor 12 and providing for its pivotal movement. The mounting bracket includes a plate 46, similar to the plate 30. The plate 46, like the plate 30, includes a plurality of holes 48 for mounting the bracket 44 on the roof of the vehicle. To provide for pivotal movement of the visor 12, the mounting bracket 44 further includes a tubular member 50 formed integral with the plate 46. The tubular member 50 in its mounted position occupies a generally vertical position so that the portion 42 of the rod 40, which extends through the tubular member 50, also is supported in a generally vertical position. The visor 12 therefore moves about the vertical axis provided by the tubular member 50 and the vertical portion 42 between its center and left-hand positions.
The right-hand visor 14 is similar in construction and mounting to the left-hand visor 10, being essentially a mirror image thereof, and this visor and its mounting arrangement need therefore not be described in detail. A bracket 52, which is mounted on the roof of the vehicle, is provided at the adjacent ends of the visors 12 and 14 for supporting the free end of the rod 40 of the center visor 12 and the free end of the rod 54 of the right-hand visor 14.
A significant aspect of the invention is the arrangement for supporting the free end of the rod 22 of the left-hand visor 10. This arrangement is shown in FIG. 1 and in FIGS. 6-8. Referring particularly to FIGS. 6-8, the center visor 12 includes a member 56 positioned at the left-hand end of the rod 40 of the center visor. The member 56 includes an elongated opening 58 at the top portion thereof through which the vertical portion 42 of the rod 40 extends. The member 56 further includes, at the left-hand end thereof and on the portion thereof facing away from the windshield, an elongated recess 60. The recess 60 is made of such size that the right-hand end of the rod 22 of the left-hand visor 10 is received therein with a snap or friction fit so that when the left-hand and center visors 10 and 12, respectively, are in the position shown in FIG. 1, the right-hand end of the visor 10 is supported by the member 56. While the member 56 has been shown and described as being mounted on the left-hand end of rod 40, it will be apparent that the member 56 could be formed integral with the rod 40 if desired.
The location of the elongated recess 60 and its position relative to the visors is important to the successful movement of the visors between their several positions. Thus, as indicated above, the elongated recess 60 is formed in the member 56 so that when the visors are in their vertical position, in which the visors may be moved from the position shown in FIG. 1 to those shown in FIG. 2, the recess 60 faces away from the windshield, that is, towards the rear of the vehicle, and is located beyond the axis 42 about which the center visor 12 pivots. Should the driver or one of the occupants of the vehicle move the center visor 12 from its first position, as shown in FIG. 1, toward its second position, as shown in FIG. 2, before the left-hand visor 10 has been moved from its first to its second position, that is, when the end of the rod 22 is still within the recess 60, the end of the rod 22 will be automatically released from engagement with the recess 60 of the member 56 as soon as the initial turning movement of the center visor 12 toward its second position is begun. Thus, the member 56 provides a convenient and effective means for supporting the free end of the visor 10, but at the same time insures that immediate release of the rod of this visor as soon as movement of the center visor 12 begins.
It can be seen from the above description that the sun visor arrangement of this invention provides substantial versatility in meeting varying road conditions and further provides a convenient mounting arrangement and an easy shifting of the visors from one position to another. Thus, when the vehicle is travelling along a curving road where the position of the vehicle relative to the sun may repeatedly change so that the sun is at one time in line with the windshield of the vehicle and at other times in line with one side or the other of the vehicle, the driver or passenger of the vehicle may quickly and easily and conveniently shift the appropriate visor or visors to provide a shield from the sun. Moreover, the driver, on a curving road, may move both the left-hand visor 10 and the center visor 12 to their second positions, shown in FIG. 2, so that as the vehicle changes course and, as a result, the rays of the sun shift between the windshield and the side of the vehicle, the driver is continuously shielded from the sun's glare. On a relatively straight road, where the sun's position may be steadily in line with the windshield, the visors may be placed in the positions shown in FIG. 1 so that both the driver and the passenger are fully shielded from the sun's glare. When the left-hand visor 10 is moved between its first and second position, its mounting arrangement, as described above, is such that it moves along an arcuate path causing the visor to move to a somewhat elevated position mid-way in its travel and thereby to clear the head of the driver. The right-hand visor 14 is similarly mounted so as to clear the head of the passenger. Further, as described above, the support for the free end of the left-hand visor 10, provided by the member 56, is so arranged that should the center visor 12 be moved towards its second position before the movement of the left-hand visor has begun, the end of the rod 22 of the left-hand visor is automatically released from its engagement with the member 56.
While a particular embodiment of this invention has been described in detail as applied to a left-hand-steer vehicle, it is apparent that the invention is equally applicable to right-hand-steer vehicles. In the latter application, of course, the relationship of the visors would be reversed so that, for example, the member 56 on the center visor would be arranged to receive the end of a rod on the right-hand visor. In the specification and claims, the terms "left" and "right" are used for convenience and clarity, but it is intended that the claims apply equally to left-hand-steer and right-hand-steer vehicles.
Further, while the invention provides its maximum benefits as applied to vehicles of such width that the three-visor arrangement is utilized, it is also applicable to arrangements in which only two visors are employed.
While a particular embodiment of the applicant's invention has been shown and described, the specific construction may be modified without departing from the scope of the invention, and it is intended by the appended claims to cover all such modifications as come within the spirit and scope of this invention.
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A sun visor arrangement is disclosed which includes three pivoted visors arranged along the windshield of a vehicle such as a truck. The left and right visors are movable from positions adjacent the windshield to positions adjacent the left and right doors, respectively, to provide shielding from sun glare as the vehicle moves along a curving road and its relation to the sun varies. The pivotal mounting of the outer visors are arranged so that when an outer visor is moved between its windshield and door positions it follows an arcuate path raising the visor above the occupant's head. In a left-hand-steer vehicle, the center visor is constructed at its left side to provide a stowage bracket for receiving a rod extension of the left visor for holding the free end of the left visor in position. This stowage bracket is formed so that should the center visor be pivoted towards its left-hand position before the left visor is moved from its windshield position, the bracket automatically releases itself from the rod extension of the left visor.
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TECHNICAL FIELD
[0001] The present invention concerns a method for transforming a biomass, into at least one biochar.
BACKGROUND
[0002] By biochar, it is meant according to the invention, a stable carbon-rich solid derived from a heat treatment of a biomass suitable for numerous industrial applications. Thus, it constitutes, but is not limited to, a combustible with a high calorific value, representing a new alternative in the field of renewable energies. It also constitutes a fertilizer for agricultural use for soil amendment. It also constitutes a product intended for the chemical industry, for example as a catalyst. It is further an excellent adsorber and constitutes a purifier, a decolorant, a decontaminant and/or a deodorant, usable in numerous industrial fields. It may be shaped in any format depending on its destination, such as a powder, grains . . .
[0003] The method of the invention is described more specifically with reference to a lignocellulosic biomass, but by analogy, it may be applied to other biomasses.
[0004] Methods for transforming a lignocellulosic biomass into combustibles are already known involving in particular a torrefaction step. The torrefaction of a biomass consists in heating it gradually to a moderate temperature, generally between 190° C. and 250° C., in an oxygen-free atmosphere, and possibly under pressure. This treatment results in an almost complete elimination of water from the biomass and in a partial modification of its molecular structure, causing a change of some of its properties. In particular, this heat treatment produces a depolymerization of hemicellulose, making the torrefied biomass almost hydrophobic and friable, while improving its calorific value.
[0005] Thus, the document EP2287278A2 describes a method for torrefying a lignocellulosic biomass comprising a step of drying the biomass so as to remove about 95% of moisture, then a torrefaction step in a reactor brought to a temperature of 100-1000° C. in theory, 220-300° C. in practice, at a pressure of 1-50 bar, preferably 5-20 bar, in an oxygen-free atmosphere, and finally a step of cooling the torrefied biomass, this method providing for a gas recycling system.
[0006] There is also known according to the document WO2013/003615A2, a device for torrefying a hemicellulose-rich biomass such as wood, and a method for treating this biomass implemented in this device, comprising a biomass drying step, a torrefaction step carried out at a temperature of 200-250° C., at a pressure of at least 3 bar, in an inert atmosphere, and a cooling step. The device is constituted by a vertical body in which is disposed a superposition of plates constituting treatment compartments of the biomass. These compartments are equipped with apertures for allowing the biomass, being treated or already treated, to flow and the treatment gases or products may be evacuated via pipes in order to be recycled.
[0007] According to the article J. Wannapeera and N. Worasuwannarak, Journal of Analytical and Applied Pyrolysis 96 (2012) 173-180, the authors have studied, on a laboratory scale, namely on a few grams, the effect of pressure in a method for transforming, by torrefaction, a biomass based on Leucaena leucocephala , a tropical tree. This method comprises the following steps:
The biomass is shredded then ground into particles of a size <75 μm; The particles are dried afterwards in a vacuum oven at 70° C. for 24 h; The particles are placed in a reactor under inert atmosphere, which is then introduced and maintained in a furnace at a temperature of 200-250° C. and a pressure of 1-40 bar, for 30 min; After these 30 min, the reactor is immersed in water in order to stop the reaction; The product derived from this carbonization is dried in an oven for 2-3 h then analyzed.
[0013] The highest values of the higher calorific value (HCV) are obtained for a solid derived from a torrefaction at a temperature in the order of 250° C. and a pressure of 40 bar. These works have highlighted the favorable effect of pressure on torrefaction reactions in these conditions.
[0014] Known torrefaction treatments under pressure such as those described before produce solids having a high lower calorific value (LCV), generally in the order of 19 to 23 MJ/kg. The LCV of a solid obtained according to the method described in EP2287278A2 is actually in this order. The authors state herein that their torrefaction method would result in a mass reduction of 30% with a loss of 10% of the overall energy, which means that the energy of the obtained solid, corresponding to 90% of the energy of the initial dried biomass, is concentrated in 70% of the mass of the initial dried biomass, which leads to a concentration of the LCV per unit mass of 0.9/0.7, namely 1.28. The reported biomass drying ratio being 5%, equivalent to that of a commercial wood granulate whose LCV is in the order of 15 to 18 MJ/kg, the LCV of the obtained solid according to EP2287278A2 is in the order of 19 to 23 MJ/kg. Besides, these values are those reported by numerous developers in this field.
[0015] However, there is still a growing need to develop methods which are more effective and less energy-consuming, with investments which are less expensive, easier to control and which allow to obtain a combustible with a better quality.
[0016] The authors of the present invention have discovered that the implementation of a torrefaction in specific conditions allows initiating a spontaneous exothermic phenomenon, producing a combustible solid whose LCV is very high, much higher than that of combustibles resulting from the transformation methods discussed before. Moreover, this combustible solid has a very high carbon content, generally higher than 80% by mass and a reduced oxygen content, in the order of 10% by mass or less. The authors have also observed that this phenomenon would occur with numerous types of biomass.
[0017] This exothermic phenomenon is prevented in known methods because it is considered as an unfavorable factor in the energy balance. The authors of the invention have actually demonstrated that it is the development of this phenomenon which allows producing a biochar which is more carbon-rich, and therefore more calorific.
[0018] Two conditions are essential so that this phenomenon occurs. They lie in an accurate control of the grain-size distribution of the involved biomass and in the drying of the latter before the torrefaction step, this drying having to be complete. Hence, the prior drying step has to retrieve all moisture from the biomass, in order to reach a moisture content close to 0, and always lower than 10% by mass. The more the treated biomass is close to the anhydrous condition, the more the method is effective.
BRIEF SUMMARY
[0019] Thus, the invention concerns a method for transforming a biomass into at least one biochar, comprising the following steps of:
[0020] (a) Providing a ground and dried biomass, said biomass containing at least 30% of a lignocellulosic biomass, by mass relative to the dry mass of said ground and dried biomass;
[0021] (b) Heating progressively this biomass at a temperature higher than 140° C. and lower than 350° C., in an oxygen-free inert gas stream, at a pressure comprised between 1 and 40 bar;
[0022] (c) Allowing the reaction to proceed by maintaining the temperature in the 300-700° C. range and the pressure in the 1-40 bar range,
[0023] And optionally,
[0024] (d) Cooling the biomass derived from step (c) at a temperature of at most 100° C. in an oxygen-free inert gas stream, and
[0025] (e) Collecting the biochar.
[0026] This method allows obtaining a solid presenting characteristics which in particular make it an effective combustible, whose carbon concentration is higher than 85% by mass and whose LCV is comprised between 25 and 35 MJ/kg, from a wood whose carbon concentration is in the order of 45% by mass, whose oxygen concentration is in the order of 45% by mass and whose LCV is in the order of 17 MJ/kg. This method also leads to a very considerable reduction of the oxygen content, which reaches values in the order of 10% by mass, resulting in an equivalent reduction of the overall mass of the combustible product.
[0027] By transformation of a biomass into at least one biochar, it is meant according to the invention, that one or more combustible gas(es) is/are co-produced. They may be injected at step (b) of the method, and also be used to supply any other thermal or chemical installation.
[0028] The step (b) of the method brings the matter to a temperature at least higher than the water boiling temperature at the working pressure, the moisture content of the matter treated in the subsequent steps is therefore almost zero, and preferably zero.
[0029] Prior to disclosing the invention in more detail, some terms used within the text are defined hereinafter and the methods for analyzing the different measured parameters are given hereinafter.
[0030] By lignocellulosic biomass, it is meant according to the invention, organic matters essentially of vegetable origin comprising at least one constituent selected among hemicellulose, cellulose, lignin, carbonhydrates and oligosaccharides. As example, a biomass according to the invention is selected among or derived from products and by-products of forestry, agricultural and agri-food activities.
[0031] Unless otherwise stated, the indicated temperatures are the core temperatures of the treated biomass.
[0032] The moisture content of the biomass represents its water content; it is expressed as a percentage by mass of water relative to the mass of the raw biomass. Several methods allow measuring it, the one retained by the authors of the present invention is the Karl-Fisher method, well known from those skilled in the art. A ground biomass sample is maintained for 24 hours in dehydrated methanol under stirring then the moisture content is determined by means of the Metrohm 870KF Trinito plus volumetric titration apparatus.
[0033] In the context of this method, essential characteristics of a biochar, for example when it is used as a combustible product, are its moisture content, its lower calorific value (LCV), its ash content and its elemental composition (ultimate analysis).
[0034] Its moisture content is measured by means of the above-described method.
[0035] The calorific value of a combustible represents the amount of energy contained in a unit mass of the combustible. The lower calorific value (LCV) and the higher calorific value (HCV) are distinguished. They comply with the definitions and are measured, in accordance with the ISO 1928 standard.
[0036] The HCV is measured in an IKA C 5000 combustion calorimeter.
[0037] Afterwards, the LCV is calculated from an elemental composition of the biomass. An elemental analysis of this biomass is carried out in a FISONS EA 1108 apparatus.
[0038] The ash content of the combustible is obtained by incinerating the ground sample. Heating is carried out by steps up to 815° C. and maintained at this temperature until obtaining ashes which are weighted afterwards. The ash content is expressed as a mass percentage relative to the mass of the sample.
[0039] As said before, the authors have observed that the physical state of the biomass subjected to the heating step (b) is important in order to reach the performances of the method of the invention. They have further observed that it is preferable to supply the method with a matter presenting a low grain-size dispersion. Hence, the biomass has to be ground beforehand and is advantageously in the form of particles with various shapes, but with homogenous dimensions. Thus, the particles derived from this grinding operation may be in the form of grains, chips, sticks, needles and/or any other aspect. Regardless of their shapes, it is important that the dimensions of the particles are substantially homogenous. By particles with homogenous dimensions, it is meant that at least 50%, preferably at least 60%, even better, at least 70% by weight and more, of the particles, relative to the dried mass, are constituted of particles whose smallest dimension is of at least 0.5 mm. This smallest dimension corresponds to the thickness. Preferably, the largest dimension of said particles whose smallest dimension is of at least 0.5 mm, is of at most 40 mm. For illustration, the particles may be in the form of grains whose dimensions vary from 0.5-5 mm, chips or needles with a thickness of 0.5-3 mm and a length of at most 40 mm, still better with a length of 10-25 mm. It is preferable that the particles are as homogenous as possible, in terms of dimensions as said before, but also in terms of shape. Thus, we will opt for a grinding which produces a matter being mainly in the form of grains and of which preferably at least 50% of the mass relative to the mass of the dry biomass have a size varying from 0.5-4 mm. In another variant, we will select a grinding which produces a matter being mainly in the form of chips and/or needles and of which preferably at least 50% by mass relative to the mass of the dry biomass have a thickness of at least 0.5 mm and a length of at most 40 mm; advantageously the matter in the form of chips and/or needles of which at least 50% have a thickness varying from 0.5-3 mm and/or a length of 10-25 mm.
[0040] A too high proportion of fine particles results in a considerable production of tars which might be prejudicial to the effectiveness of the method. A too high proportion of large particles weakens the efficiency of the method in that these particles cannot be converted effectively into biochar.
DETAILED DESCRIPTION
[0041] The method of the invention responds advantageously to the characteristics described hereinafter, considered individually or in combination. They contribute to an increase of the effectiveness of the method.
[0042] Step (b) may be carried out in two steps, one step (b1) according to which the biomass is preheated at a temperature of at least 120° C., preferably of at least 130° C. and, even better, of at least 140° C., and one step (b2) according to which the biomass preheated at step (b1) is heated at a temperature of at least 220° C., preferably 230° C., and even of at least 240° C.
[0043] At step (b1), preferably, the temperature is set between 180 and 220° C. and/or the pressure is set between 3 and 14 bar.
[0044] At step (b2), preferably, the temperature is set between 240 and 300° C. and/or the pressure is set between 3 and 14 bar.
[0045] The steps (b1) and (b2) may partially overlap.
[0046] At the end of step (b), the solid is in the conditions of an initiation of a spontaneous carbonization reaction. At step (c), the temperature is controlled so as to be maintained between 300 and 700° C., preferably, it is maintained between 350 and 500° C., even better between 350 and 400° C.
[0047] The method of the invention may be conducted in batch or continuously. In batch, steps (b) and (c) are carried out in the same enclosure. Preferably, the method is implemented continuously, the steps (b) or (b1) and (b2), (c), and (d) being performed in at least two different compartments. According to one variant of the method of the invention, the steps (b) or (b1) and (b2), (c), and (d) are carried out in different compartments, respectively, a first, and possibly a second, a third and a fourth compartments. A priori, this variant is more effective and economical, in particular it allows recovering the heat of the gases produced at steps (b) and (c), and possibly recycling them, upstream of the method. In addition, it allows a more regular operation of the installations where the method is implemented with a more constant regulation. Alternatively, steps (b) and (c) may be performed in the same compartment. Also, step (b) may be carried out inside a boiler of an electrical and/or heat generation unit.
[0048] Advantageously, the different compartments are equipped with the following means:
[0049] The first compartment, for implementing step (b1), is equipped with convective and/or fluidized-bed preheating means and with temperature control means; preferably, the heat transfer is performed by convection.
[0050] The second compartment, for implementing step (b2), is equipped with convective, conductive and/or radiating heating means and with temperature control means; preferably, the heat transfer is performed by radiation.
[0051] The third compartment, for implementing step (c), is equipped with temperature and pressure control means. In particular, all useful temperature control means are eligible to balance the amount of heat produced by the reactions with the thermal load.
[0052] The fourth compartment, for implementing step (d), is equipped with convective and/or conductive cooling means.
[0053] As indicated before, in a continuous implementation of the method, the gases are recycled; thus the heat emitted by the exothermic phenomenon at step (c) in the third compartment is recovered and recycled in either one of the first and second compartments and/or for drying the necessary biomass at step (a). It is also possible to provide for a circulation of the gases generated by steps (b2) and (c) countercurrentwise to the matter.
[0054] In such a variant, the method may be implemented without any supply of external inert gas. Thus, it is possible to consider it as fully autonomous in terms of energy, from the upstream steps, including the treatment of the fresh biomass, till the downstream steps, including the shaping of the combustible solid and, in this case, a cogeneration unit will be preferably installed.
[0055] In the method of the invention, at step d), the treatment time varies in the range from 50 seconds to 3 minutes. Hence, the short reaction times are another advantage of the method of the invention.
[0056] The method of the invention applies to the transformation of any biomass. Preferably, the biomass is lignocellulosic. In particular, it is intended to the conversion of any lignocellulosic biomass derived from products and by-products of forestry, agricultural and agri-food activities.
[0057] The invention also concerns the biochar which can be obtained by the method defined hereinabove. In particular, it presents a lower calorific value (LCV) of at least 25 MJ/kg, preferably of at least 30 MJ/kg, which may reach 35 MJ/kg and in this, it constitutes a very calorific combustible.
[0058] The invention is illustrated hereinafter by examples of treatment of biomasses of various origins, by a batch transformation method.
[0059] Prior to step c), that is to say at the inlet of the reactor, all examples are carried out in the following conditions.
[0060] 10 to 15 kg of biomass, ground and dried, are loaded in an AISI 310S type stainless steel tube, with a 200 mm diameter and 1800 mm height. The tube is filled with nitrogen and its inertization (complete absence of oxygen) is controlled. Afterwards, a gaseous nitrogen current, preheated at a temperature of about 200° C., is passed in order to completely dry the matters, which is checked on the one hand by a measurement of temperature within the matter, which, in all cases, should be higher than the boiling temperature of water, and on the other hand, by a measurement of the composition of the gas. The drying time varies from 1 h to 1 h30, it allows reaching a moisture content of 0.
[0061] Finally, the reactor is placed under a nitrogen pressure and the progressive heating of the walls of the reactor is started, which initiates the reactive transformation.
Example 1: Method for Transforming Softwood Sawdust and Shavings According to the Invention—Pressure 40 bar
[0062] Shavings coming from a framework manufacture, at least 70 to 80% of which are in the form of needles with a 1 mm thickness and 20 mm length, and fine softwood sawdust with a particle-size distribution of 0.2-0.5 mm are subjected to the preparation protocol hereinabove.
[0063] Afterwards, the resistances of the reactor are brought progressively to a temperature of 250° C., then 270° C. At 160° C., a slight overall exothermicity is observed, and the exothermic phenomenon takes off from 270° C. causing a spontaneous rise of temperature up to 700° C.
[0064] Afterwards, the product is cooled at a temperature lower than 100° C.; about 30 minutes are necessary.
[0065] The product derived from this transformation resembles to a very porous and very friable carbon foam. These characteristics are as follows:
[0066] The obtained average LCV is of 32.5 MJ/kg, locally reaching 35 MJ/kg. The variation of the LCV that can be observed results from the batch implementation of the method.
[0067] The obtained overall energy efficiency is of 84.8%, 20% of which are in the gas stream and 80% in the solid stream. The obtained mass yield to the anhydrous mass is of 46.2%.
Example 2: Method for Transforming Softwood Sawdust and Shavings According to the Invention—Pressure 10 Bar
[0068] Shavings coming from a framework manufacture, at least 70 to 80% of which are in the form of needles with a 1 mm thickness and 20 mm length, and fine softwood sawdust with a particle-size distribution of 0.2-0.5 mm are subjected to the preparation protocol hereinabove.
[0069] Afterwards, the resistances of the reactor are brought progressively to a temperature of 250° C., then 270° C. At 160° C., a slight overall exothermicity is observed, then the exothermic phenomenon takes off from 270° C. causing a rise of temperature up to 400° C.
[0070] Afterwards, the product is cooled at a temperature lower than 100° C.; about 30 minutes are necessary.
[0071] The thus obtained characteristics of the combustible product are as follows:
[0072] The obtained average LCV is of 32.5 MJ/kg, locally reaching 34.7 MJ/kg.
[0073] The obtained overall energy efficiency is of 86.5% and the obtained mass yield to the anhydrous mass is of 51.6%.
Example 3: Method for Transforming Hardwood Sawdust—Pressure 5 Bar
[0074] Hardwood sawdust, namely a 80/20 mixture of beech and oak, coming from a stairs and doors manufacture, with a particle-size distribution of 0.1-0.8 mm, are subjected to the preparation protocol hereinabove.
[0075] Afterwards, the resistances of the reactor are brought progressively to a temperature of 250° C., then 280° C. At 280° C., a very marked spontaneous exothermic reaction is observed. The reaction brings the temperature to 510° C.
[0076] Afterwards, the product is cooled at a temperature lower than 100° C.; about 30 minutes are necessary.
[0077] The thus obtained characteristics of the combustible product are as follows:
[0078] The obtained average LCV is of 33.1 MJ/kg, locally reaching 33.7 MJ/kg.
[0079] Through this transformation, an overall energy efficiency of 77.0% and a mass yield to the anhydrous mass of 43.3%, are obtained.
[0080] The authors have observed a considerable production of tars induced by a significant presence of fine particle-size matter.
Example 4: Method for Transforming <<Run-of-Mine>> Fresh Matters—Pressure 10 Bar
[0081] A fresh biomass, essentially constituted by birch freshly cut and shredded with leaves, twigs and barks, is dried in open air, then ground and dried. Its average thickness is in the order of 15 mm, with a 25 mm length. It is subjected to the preparation protocol hereinabove.
[0082] Afterwards, the resistances of the reactor are brought progressively to a temperature of 250° C., then 270° C. The exothermic phenomenon takes off from 270° C., causing a rise of temperature up to 500° C.
[0083] Afterwards, the product is cooled at a temperature lower than 100° C.; about 30 minutes are necessary.
[0084] The thus obtained characteristics of the combustible product are as follows:
[0085] The obtained average LCV is of 30.5 MJ/kg, locally reaching 31.1 MJ/kg.
[0086] Through this transformation, an overall energy efficiency of 65.3% and a mass yield to the anhydrous mass of 42.1%, are obtained.
[0087] In conclusion, while all torrefaction technologies, such as the one constituting the object of the document EP 287278A2, disclose the obtained following results for a wood with 95% of dry matter and a LCV of 17 MJ/kg: a mass reduction of 30%, an obtained LCV of 21 MJ/kg and an energy concentration factor per unit of overall mass of 1.28, the method of the invention shows a mass reduction of 55%, an obtained LCV of at least 30 MJ/kg, which provides an energy concentration per unit of overall mass of 1.76.
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The invention concerns a method for transforming a biomass into at least one biochar, comprising the following steps of:
(a) Providing a ground and dried biomass, said biomass containing at least 30% of a lignocellulosic biomass, by mass relative to the dry weight of the ground and dried biomass; (b) Heating progressively this biomass to a temperature higher than 140° C. and lower than 350° C., in an oxygen-free gas stream, under a pressure comprised between 1 and 40 bar; (c) Allowing the reaction to proceed by maintaining the temperature in the 300-700° C. range and the pressure in the 1-40 bar range; (d) Cooling the biomass derived from step (c), at a temperature of at most 100° C., in an oxygen-free gas stream; and (e) Collecting the biochar.
The invention also concerns the thus obtained biochar.
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BACKGROUND OF THE INVENTION
1. Field of the Invention
This invention relates to the composition of a underwater gear; more particularly, this invention relates to the clear, translucent, or colored underwater fishing gear; and most particularly, this invention relates to the use of polymeric-based materials to make fish hooks.
2. State of the Art
The use of fishing devices is known in the prior art. More specifically, metal fishing devices devised and utilized for the purpose of hooking fish are know to consist basically of familiar, expected, and obvious structural configurations, notwithstanding the myriad of designs encompassed by the crowded prior art which has been developed for the fulfillment of countless objectives and requirements.
However, the metal fishing hooks can sometimes be disadvantageous due to their color, appearance, and/or scent. The visual properties of a fish hook device relates to the appearance of the material in water. The enhancement in visual properties is achieved by either reducing the prey's ability to visually perceive the hook, or by the visual appearance of the hook serving to attract the prey in comparison to the appearance displayed by a hook made of a metallic material.
The scent properties of a fish hook device relates to the taste and/or 5 smell of the material to the prey in water. The enhancement in scent properties is achieved by either reducing the scent of the material in comparison to that of a metallic material so that prey are less likely to be wary of the material, and/or enhancing the scent of the material so that prey are attracted to the material.
Therefore, it can be appreciated that there exists a continuing need for a fish hook device that can be used to decrease the disadvantages of a metal fish hook. Accordingly, it is an object of this invention to overcome the aforementioned disadvantages of the metal fish hook.
It is still another object of this invention to use the polymeric fishing devices to provide a medium in which to place a scented material for the purposes of attracting prey.
It is still another object of this invention to surface treat the polymeric fishing devices to modify the scent and/or modify the visual properties of the material.
Additional objectives, advantages, and novel features of the invention will be set forth in the detailed description which follows, and in part will become apparent to those skilled in the art upon examination of the following, or may be learned by practice of the invention.
SUMMARY OF THE INVENTION
This invention relates to the use of polymeric-based materials to make fish hooks for producing clear, translucent, or colored fish hook devices. Additionally, this invention provides for a medium to place scented materials for the purpose of attracting prey.
An aspect of this invention is an underwater fishing component, comprising: a resilient material having an index of refraction substantially the same as that of water. It is preferred that the resilient material be selected from the group of materials consisting of:
polycarbonates
where R is alkylene and n is an integer having a value between 500 and 25,000;
Polyimides
where Ar is aryl and n is an integer having a value between 500 and 25,000;
Polyesters
where R2 and R3 may be the same or different and are alkylene and n is an integer having a value between 500 and 25,000;
Polyurethane
where R5 is alkylene and n is 500 to 25,000;
Polyacetals —[CH 2 —O—R 8 —O] n —
where R8 is alkylene and n is an integer having a value between about 500 and 25,000;
Polyamides
where R9 and R10 may be the same or different and are alkylene and R11 and R12 may be the same or different and are hydrogen or alkyl and n is an integer having a value between about 500 and 25,000;
Polyethers —[R 13 —O—R 14 ] n —
where R13 and R14 may be the same or different and are alkylene and n is an integer having a value between 500 and 25,000;
Polystyrenes
where Ar is aryl and n is an integer between about 500 and 25,000;
Polyacrylates
where R15 is alkyl or cyano (—CN) and n is an integer selected between about 500 and 25,000; and epoxies, polysufone, cyclic olefin copolymer, polyetherimide and nylon.
In an especially preferred embodiment this invention provides a fish hook comprising: a resilient material having an index of refraction substantially the same as that of water.
BRIEF DESCRIPTION OF THE DRAWING
FIG. 1 shows a perspective view of a fish hook with all its parts.
FIGS. 2A-2E shows an alternative shape for the fish hook of this invention.
FIGS. 3A-3E shows an alternative shape for the fish hook of this invention.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT
Definitions
The following definitions are uses to exemplify the invention and not used in any way to limit the scope of the appended claims.
As used herein the word “alkyl” means hydrocarbon radicals having from one to six carbon atoms.
As used herein the word “aryl” means hydrocarbon radicals having an aromatic structure with between one and four alkyl radicals substituted thereon.
As used herein the word “alkylene” means an alkyl radical with at least two sites of substitution.
The Preferred Embodiment
This invention provides underwater fishing components that are substantially transparent under water. The components can be selected from fish hooks, swivels, weights, and connector hardware. This specification will focus on one particularly preferred embodiment, the transparent fish hook.
Referring to FIG. 1, a resilient material is used to make a fish hook device. The fish hook starts with the eye 5 , which is connected to the shank 4 . The shank then connects with the bend 3 and the fish hook device ends with a point 2 that has a barb 1 . The resilient material has an index of refraction substantially the same as or greater than that of water. Moreover, the invention is intended to be used to obtain any prey, either fresh or salt water, which may include, but is not limited to fish, amphibians, reptiles, mammals, or crustaceans.
The resilient material is a polymeric compound, which is either currently available or can be synthesized, that will produce a resilient material which is either optically clear, translucent, or has a tinted color for the purposes of catching prey. In a preferred embodiment, the resilient material is: (1) a clear material which is not easily seen by the prey; (2) a material with an index of refraction close to that of water such that it is not easily seen by the prey; (3) a material which is translucent such that it is not easily seen by the prey, and/or (4) a material which is either clear or translucent but additionally possesses a tinted color in such a manner that it is not easily seen by the prey, or may serve to be attractive to the prey.
Although the invention consists of a product made from substantially the resilient material, the product may include other materials, for example, carbon steel, stainless steel, rustless alloys, and other similar materials. In one particularly preferred embodiment, the fish hook of the invention includes between about 5 wt % and 35 wt % of glass fibers.
In the preferred embodiment, the fish hook is made out of glass, glass fibers, laminated glass, tempered glass, natural quartz, fused quartz, or synthetic quartz. The glass or quartz may be used as an adjunct to the polymeric material, or it may be used as the primary material.
The materials used to make the invention may be selected for different parts of the fish hook, for example, the barb 1 may be the only portion of the fish hook made out of carbon steel with the resilient material and shank 4 are made from a rustless alloy whereas the remainder of the fish hook is made from the resilient material. Moreover, the resilient material may include glass fibers or the like as well as the metallic portions.
The above mentioned polymeric materials include, but are not limited to:
polycarbonates
where R is alkylene and n is an integer having a value between 500 and 25,000;
Polyimides
where Ar is aryl and n is an integer having a value between 500 and 25,000;
Polyesters
where R2 and R3 may be the same or different and are alkylene and n is an integer having a value between 500 and 25,000;
Polyurethanes
where R5 is alkylene and n is 500 to 25,000;
Polyacetals —[CH 2 —O—R 8 —O] n —
where R8 is alkylene and n is an integer having a value between about 500 and 25,000;
Polyamides
where R9 and R10 may be the same or different and are alkylene and R11 and R12 may be the same or different and are hydrogen or alkyl and n is an integer having a value between about 500 and 25,000;
Polyethers —[R 13 —O—R 14 ] n —
where R13 and R14 may be the same or different and are alkylene and n is an integer having a value between 500 and 25,000;
Polystyrenes
where Ar is aryl and n is an integer between about 500 and 25,000;
Polyacrylates
where R15 is alkyl or cyano (—CN) and n is an integer selected between about 500 and 25,000; and
epoxies, polysufones, cyclic olefin copolymers, polyetherimide and nylon.
Other materials can be substituted if they are substantially transparent as seen underwater. Examples include glass, tempered glass, laminated glass, quartz, synthetic quartz and mixtures of quartz and glass.
These polymeric materials may be used as homopolymers, copolymers and/or blends of any of the above mentioned polymers. The morphology of the polymeric materials or mixtures may be linear, branched, hyperbranched, star formation, crosslinked, interpenetrating network, or a mixture of all these molecular forms. Additionally, the polymeric compound may also include additives such as stabilizers, processing aids, or scents. The additives may either be organic, inorganic, or metallic in nature.
Furthermore, several materials may serve the purpose of mediums in which scented material may be carried for the purposes of attracting prey. The scented properties can either reduce the scent in comparison of the metallic materials so that prey are less likely to be wary of the material, or the scented properties can enhance the scent in comparison of the metallic materials so that the prey are attracted to the material.
The fish hook devices may be produced by a variety of methods, including, but not limited to injection molding, solvent casting, compression molding, melt casting, machining, or thermoforming. Additional processes may include various annealing and crosslinking processes and/or surface treatments.
Moreover, as shown in FIGS. 2A-2E, the configuration of the fish hook may encompass a variety of shapes, forms, and sizes. The device may be straight, curved, or reversed and may be of varied size, diameter, or weight. As shown in FIGS. 3A-3E, the shank 11 length and type, the position and type of eye 12 , and the position, type, and number of points 10 and barbs 13 are also not important. For example, the eye may be Ringed Eye or Turned Down Eye. The point may be a straight point, rolled point, bent-in point, or a bent-out point. Furthermore, the distance of the gap and bite ( 6 and 7 in FIG. 1) are also not significant.
This invention has been described by reference to specific examples and embodiments, which will bring alternative embodiments, modifications and variations to the minds of those skilled in the art. The appended claims are intended to encompass all such alternatives, modifications, and variations.
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This invention relates to the use of polymeric-based materials to make fish hooks for producing clear, translucent, or colored fish hook devices. Additionally, this invention provides for a medium to place scented materials for the purpose of attracting prey.
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BACKGROUND OF THE INVENTION
[0001] 1. Field of the Invention
[0002] The invention relates to a corrugating machine for the manufacture of sheets of corrugated board, comprising at least two unroll stands for unwinding webs of material from reels of material; at least one fluting unit for the manufacture of at least one corrugated medium from one of the webs of material; at least one processing equipment for uniting the corrugated medium and at least another web of material to form a web of corrugated board; a cutting station for cutting the sheets of corrugated board from the web of corrugated board; and a method for the manufacture of sheets of corrugated board on a corrugating machine, comprising the steps of providing a corrugating machine which comprises at least two unroll stands for unwinding continuous webs of material as well as at least one processing equipment for producing at least one web of corrugated board from the webs of material; digitally printing at least one web of material on the corrugating machine; and cutting the sheets of corrugated board from the digitally printed web of corrugated board in accordance with the shape and size of digitally imprinted patterns.
[0003] 2. Background Art
[0004] Corrugating machines for the manufacture of single-faced corrugated board or multi-layer corrugated board are for example known from U.S. Pat. No. 5,632,850. There is a frequent demand for printed sheets of corrugated board. Simple and flexible solutions have not been known so far.
SUMMARY OF THE INVENTION
[0005] It is an object of the invention to develop a corrugating machine of the type mentioned at the outset in such a way that simple printing of the corrugated board is possible, in particular for working rather small printing jobs.
[0006] According to the invention, this object is attained in a corrugating machine wherein at least one digital printing system for printing at least one of the webs is disposed between the unroll stands and the cutting station. The gist of the invention resides in digitally imprinting the webs during manufacture of the corrugated board, even before the sheets are cut to size, in a corrugating machine. Prints can be applied to the web rather flexibly, in particular true to pattern. In particular, it is possible to handle rather small printing jobs, imprinting varying patterns on the webs being feasible without exchange of hardware components of the printing system. The patterns can be printed in various directions, in particular lengthwise and crosswise of the web conveying direction, with varying scaling. It is even possible to print a web of single-faced corrugated board on the side of the corrugated medium, which is not feasible when printing cylinders are used. Any subsequent printing of the sheets of corrugated board or printing of reels of material that are kept in the corrugating machine prior to operation can be dropped.
[0007] In a corrugating machine with the printing system disposed upstream of the processing equipment seen in a direction of production, the webs of material are printed while single i.e., not united, in the corrugating machine. This reduces the demands on the printing system because material of comparatively little thickness can be worked.
[0008] With printing taking place upstream of a heater which is anyway necessary for the production of corrugated board, this will automatically provide for the print on the webs of material to dry.
[0009] Printing flexibility is further improved by the possibility of bilateral printing. A single printing unit serves to print bilaterally, or two displaced printing units may be used, a first unit printing one side and a second unit printing the other. The bilateral print can be applied to the united web of corrugated board or even before, with two webs of material being unilaterally imprinted and then united to form the web of corrugated board.
[0010] Details of the invention will become apparent from the ensuing description of several exemplary embodiments, taken in conjunction with the drawing.
BRIEF DESCRIPTION OF THE DRAWING
[0011] [0011]FIG. 1 is a view of a first part of a corrugating machine according to a first embodiment;
[0012] [0012]FIG. 2 is a view of a detail of FIG. 1, on an enlarged scale, in the vicinity of a first web of material;
[0013] [0013]FIG. 3 is a plan view of a detail of the first web of material in the vicinity upstream of a heater in the first part of the corrugating machine;
[0014] [0014]FIG. 4 is a plan view of a detail of the first web of material downstream of the heater in the first part of the corrugating machine;
[0015] [0015]FIG. 5 is a plan view of details of a printed web of material;
[0016] [0016]FIG. 6 is a view of a second part of the corrugating machine according to the first exemplary embodiment;
[0017] [0017]FIG. 7 is a view of a second part of a corrugating machine according to a second exemplary embodiment;
[0018] [0018]FIG. 8 is a view of a first part of a corrugating machine according to a third exemplary embodiment;
[0019] [0019]FIG. 9 is a view of a second part of a corrugating machine according to the third exemplary embodiment;
[0020] [0020]FIG. 10 is a view of a first part of a corrugating machine according to a fourth embodiment; and
[0021] [0021]FIG. 11 is a view of a second part of the corrugating machine according to the fourth embodiment.
DESCRIPTION OF PREFERRED EMBODIMENTS
[0022] The following is a description of a first embodiment of the invention, taken in conjunction with FIGS. 1 to 6 . A corrugating machine as diagrammatically plotted in FIGS. 1 and 6 comprises a machine 1 for the manufacture of single-faced corrugated board. From a first unroll stand 2 , a first web of material 3 is fed to the machine 1 . The webs of material are continuous paper webs. The web of material 3 constitutes a backer web for the corrugated board manufactured on the machine 1 . FIG. 2 is a side view, on an enlarged scale, of the first web of material 3 in detail. It comprises a backer 3 a with a primer 3 b which improves the printing quality. The backer 3 a to primer 3 b thickness ratio is not true to scale in FIG. 2. In practice, the primer 3 b is substantially thinner as compared to the backer 3 a than shown in FIG. 2. The primer 3 b must not necessarily be available in a form applied to the web of material 3 when it is rolled up; it can just as well be applied to the web of material 3 later upon unwinding.
[0023] Between the first unroll stand 2 and the machine 1 , the first web of material 3 passes through a first digital printing unit 4 with an ink jet head 5 which prints the top side of the first web of material in accordance with a printing job. Via a signal line 6 , the printing unit 4 is in connection with an application control unit 7 .
[0024] In the machine 1 , the printed first web of material 3 is united with a second web of material 8 which is supplied from a second unroll stand 9 . When unrolled, the second web of material 8 passes between two adjacent fluted rollers 10 which are allocated to each other for producing a corrugation. After passing there-through, the second web of material 8 is available in the form of a corrugated medium 8 . Then adhesive is applied to the tips of the medium 8 in an adhesive applicator unit 11 , and the medium 8 and the first web of material 3 are pressed together and united in a nip between a nip roller 12 and one of the fluted rollers 10 . Consequently, the machine 1 is a first production unit of a processing equipment 42 for uniting webs of material to form a web of corrugated board. A single-faced web of corrugated board 13 is discharged upwards from the machine 1 and deflected about a deflection roller 14 into a working direction 15 . The machine 1 for the manufacture of single-faced corrugated board is generally known for example from U.S. Pat. No. 5,632,850, GB 2 305 675 A or DE 43 05 158 A1, to which reference is made for details.
[0025] [0025]FIGS. 3 and 4 illustrate details of the first web of material 3 in a plan view. FIG. 3 shows the web of material 3 prior to it passing, in the working direction 15 , through a pre-heater 16 downstream of the deflection roller 14 . The first web of material 3 marginally comprises first marks 17 which are equidistant division marks that extend crosswise of the working direction 15 . Upstream of the pre-heater 16 , two adjacent first marks 17 have a distance a 1 from each other. At regular distances in the working direction 15 , the first web of material further comprises stripes of second marks 18 which are equidistant short division marks that are parallel to the working direction 15 . Upstream of the pre-heater 16 , two adjacent marks 18 have a distance b 1 from each other. FIG. 4 shows the web of material 3 in an illustration similar to FIG. 3 downstream of the pre-heater 16 . The distance between two adjacent first marks 17 is a 2 and the distance between two adjacent second marks 18 is b 2 . Owing to shrinkage of the web of corrugated board 13 after being heated in the pre-heater 16 and owing to the modifications, resulting therefrom, in the dimensions of the web of material 3 , the following applies to the distances: a 2 <a 1 and b 2 <b 1 .
[0026] A reader 19 , which is disposed above the web of corrugated board and thus above the top side of the first web of material 3 that carries the marks 17 , 18 and between the deflection roller 14 and the pre-heater 16 , determines the distances a 1 and b 1 between adjacent marks 17 , 18 . To this end the reader 19 is similar to a bar code scanner. Via a signal line 20 , the reader 19 is in connection with the application control unit 7 .
[0027] A second unroll stand 21 for a third web of material 22 as another liner of the single-faced web of corrugated board 13 is disposed downstream of the machine 1 in the working direction 15 . The corrugated medium 8 , the first web of material 3 which is the backer web, and the third web of material 22 which is the liner web are suitably selected paper webs. In part, it is also usual to call the third web of material 22 the liner web, with the first web of material 3 in this case being called primer web. The webs of material 3 , 8 and 22 are unrolled at a speed of up to 400 m/min.
[0028] Downstream of the second unroll stand 21 , the third web of material 22 is first deviated about a deflection roller 23 so that it runs in the working direction 15 . Then the third web of material 22 is deviated by 180° by another two deflection rollers 24 , 25 so that the side that faces downwards between the deflection rollers 23 and 24 is now turned upwards, the third web of material 22 , downstream of the deflection roller 25 , running counter to the working direction 15 . Downstream of the deflection roller 25 , the third web of material 22 passes through a second printing unit 26 which cooperates with the first printing unit 4 , forming a digital printing system 27 . The side of the third web of material 22 that is turned upwards downstream of the deflection roller 25 is printed by an ink jet head 28 in the printing unit 26 , in accordance with a printing job. The third web of material 22 is also of two-layer design, having a backer and a primer such that the ink jet head 28 of the second printing unit 26 imprints the primer of the third web of material 22 . The primer of the third web of material can also be applied after being unrolled and upstream of the second printing unit 26 .
[0029] For print application control, the second printing unit 26 is in connection with the application control unit 7 via a signal line 29 . After passing the second printing unit 26 , the third web of material 22 , by the aid of another two deflection rollers 30 , 31 , is again deflected substantially by 180° so that downstream of the deflection roller 31 , the third web of material 22 again runs substantially in the working direction 15 .
[0030] Downstream of the deflection roller 31 , the third web of material is fed to the pre-heater 16 . The pre-heater 16 comprises two heating rollers 32 that can be heated and are disposed one on top of the other. The single-faced web of corrugated board 13 and the third web of material 22 run one on top of the other, partially being in contact with the respective heating rollers 32 . An adhesive applicator unit 33 is disposed downstream of the pre-heater 16 , having an adhesive roller 33 which partially dips into an adhesive pan 35 . The medium 8 of the web of single-faced corrugated board 13 is in contact with the adhesive roller 34 .
[0031] Downstream of the adhesive applicator unit 33 , provision is made for a heating contact pressure device 36 which comprises a horizontal hot plate table 37 that extends in the working direction 15 . A continuously driven contact pressure belt 39 is provided above the table 37 ; it is deflected by way of three rollers 38 . A nip 40 is formed between the contact pressure belt 39 and the table, with the web of single-faced corrugated board 13 and the third web of material 22 passing through the nip 40 where they are pressed one upon the other. A corresponding heating device 36 is known from DE 199 54 754 A1. A three-layer web of corrugated board 41 is being formed in the heating device 36 . The heating device 36 and the table 37 constitute a second production unit of the processing equipment 42 for uniting webs of material to form a web of corrugated board 41 .
[0032] [0032]FIG. 5 shows two sections of the printed first web of material 3 as part of the web of corrugated board 41 after discharge from the heating device 36 . Various printing patterns 43 are illustrated, which are necessary for printing certain sizes and types of boxes or cartons. As seen in FIG. 5 by way of example, the printing patterns 43 may differ in dimensions lengthwise or crosswise of the working direction 15 .
[0033] The printing patterns 43 are for example advertising imprints, or instructions in the form of folding or cutting stencils, or printed numbers or dates, or imprints dealing with a certain batch of goods that must be wrapped by the aid of the sheets of corrugated board 62 , 67 . They may be clearly worded, readable information or bar codes. Owing to the possibilities of the digital printing system 27 , printing-pattern- 43 variations are virtually unlimited. It is for instance conceivable to design the patterns 43 so that they represent individual parts of an entire picture which originates when sheets 62 , 67 with these individual parts of printing patterns are joined or when wrappings are produced from these sheets.
[0034] [0034]FIG. 6 illustrates a second part of the corrugating machine, following the discharge of the web of corrugated board 41 from the heating device 36 . At the upstream end of FIG. 6, a second reader 44 is disposed above the web of corrugated board 41 . The reader 44 is in connection with the application control unit 7 via a signal line 45 illustrated by dashes in FIG. 6. The second reader 44 registers the top side of the web-of-material- 3 section seen in FIG. 4. The second reader 44 measures the distances a 2 , b 2 between adjacent first marks 17 and adjacent second marks 18 .
[0035] Downstream of the reader 44 —seen in the working direction 15 —a lengthwise cutting/grooving unit 46 is disposed, consisting of two successive grooving stations 47 and two successive lengthwise cutting stations 48 . The grooving stations 47 have grooving tools 49 which are arranged in pairs one on top of the other, with the web of corrugated board 41 passing there-between. The lengthwise cutting stations 48 have rotatably drivable cutters 50 which are movable into engagement with the web of corrugated board 41 for it to be cut lengthwise. The detailed design of the lengthwise cutting/grooving unit 46 is known from U.S. Pat. No. 6,071,222 and DE 101 31 833 A which reference is made to for further details of design.
[0036] Downstream of the lengthwise cutting/grooving unit 46 —seen in the working direction 15 —provision is made for a shunt 51 where lengthwise cut sections 52 , 53 of the web of corrugated board 41 are separated. The web sections 52 , 53 are then fed to a cross-cutting unit 54 . It comprises a pair of top crosscutting rollers 55 for the top web section 52 and a pair of bottom crosscutting rollers 56 for the bottom web section 53 . The rollers of the pairs of rollers 55 , 56 each have a cutter bar 57 which is perpendicular to the working direction 15 , extending radially outwards. The cutter bars 57 of a pair of crosscutting rollers 55 , 56 cooperate for crosscutting the web sections 52 , 53 . A top conveyor belt 58 is disposed downstream of the top pair of crosscutting rollers 55 ; it is deviated by rotatably drivable rollers 59 . Downstream of the top conveyor belt 58 , provision is made for a place of deposit 60 with a vertical stop 61 where sheets of corrugated board 62 , which have been cut from the web section 52 by means of the crosscutting unit 54 , are piled up, forming a stack 63 . As roughly outlined by an arrow 64 in FIG. 6, the place of deposit 60 is adjustable in height. For further dispatch of the stack 63 , the place of deposit 60 can in particular be lowered as far as to a bottom 65 that supports the corrugating machine.
[0037] Another bottom conveyor belt 66 is disposed downstream of the pair of crosscutting rollers 56 , stacking sheets of corrugated board 67 on another place of deposit 68 ; the sheets are cut from the web section 53 by means of the crosscutting unit 54 . For adaptation to the height of the stack 63 , the bottom conveyor belt 66 can be lifted as roughly outlined by the arrow 68 a.
[0038] Printing the web of corrugated board 41 with patterns 43 takes place as follows: First the webs of material are provided with primers and supplied to the unroll stands 2 and 21 . The primers may also be dropped, in which case a non-coated web of material is made available at the unroll stand 9 . By alternative, the primer can also be applied directly upstream of the printing units 4 , 26 after the webs of material have been unrolled. The marks 17 , 18 are applied by the printing unit 4 . Then the corrugating machine starts running, producing a non-printed web of corrugated board 41 . This continues until the web of corrugated board that is produced has reached the area where it is registered by the second reader 44 . The two readers 19 , 44 then register the distances a 1 , b 1 and a 2 , b 2 of the marks 17 and 18 . The readers 19 , 44 then pass this information to the application control unit 7 . Based on the ratio a 2 /a 1 of the distances of the marks 17 upstream and downstream of the heating devices 16 , 36 , a computer of the application control unit 7 determines a degree of longitudinal shrinkage of the webs of material 3 , 8 , 22 in the working direction 15 , i.e. a modification of the web dimensions in the longitudinal direction between the web in the vicinity of the first printing unit 4 of the printing system 27 on the one hand (reader 19 ) and the web prior to the sheets 62 , 67 being cut on the other hand (reader 44 ). Correspondingly, cross-shrinkage of the webs of material 3 , 8 , 22 is determined by the aid of the ratio of the distances b 1 , b 2 of adjacent marks 18 in the vicinity of the reader 19 on the one hand and in the vicinity of the reader 44 on the other. Determining the cross shrinkage can be dropped as well as the associated marks. The distance parameters a 1 , a 2 , b 1 , b 2 are transmitted by the readers 19 , 44 to the application control unit 7 .
[0039] The degrees of shrinkage of the web of corrugated board 41 in the longitudinal and cross direction, which are determined by the application control device 7 , serve for the application control device 7 to determine scaling factors for the printing pattern 43 that will be applied by the printing units 4 and 26 . The printing units 4 and 26 apply the printing patterns 43 by dimensional reservation so that the desired size of the printing patterns 43 will appear on the web sections 52 , 53 owing to the pre-determined shrinkage of the web. Simultaneously, the application control unit 7 , via signal lines (not shown), controls the lengthwise cutting stations 48 on the one hand and the crosscutting unit 54 on the other in accordance with the printing jobs transmitted by the application control unit 7 to the printing system 27 . The sheets of corrugated board 62 , 67 are cut in such a way that the printing patterns 43 are located at pre-determined places on the sheets 62 , 67 . The printing jobs transmitted from the application control unit 7 to the printing system 27 may involve small or minimal serial manufacture of only few sheets of corrugated board 62 , 67 . Upon modification of the printing job, the lengthwise cutting stating 48 is triggered by the application control unit 7 so that the width of the web sections 52 , 53 is cut correspondingly. Instead of the illustrated cross-cutting unit 54 with pairs of rollers 55 , 56 , use can be made of a cross-cutting unit which is equally triggered by the application control unit 7 , enabling sheets of corrugated board of varying lengths to be cut in the working direction 15 . The sheets of corrugated board 62 , 67 can then be adapted in size perfectly flexibly to the shape and size of the printing patterns 43 of the respective printing jobs.
[0040] If necessary, prior to being printed, the sides of the webs of material 3 , 22 that are to be printed can be cleaned by a corresponding equipment, for instance a compressed air sprayer. Sucking off is conceivable alternatively of blowing off the sides, to be printed, of the webs of material 3 and 22 . Finally, it is also possible to prepare the webs of material 3 , 22 in such a way that they are antistatic, dust being prevented from depositing on the sides that are to be printed. Preferably, printing the webs of material 3 , 22 takes place in an air-conditioned environment. The temperature is kept at less than 40° C. Once the webs of material 3 , 22 have been printed, the printed sides can be sealed by a corresponding protective layer being applied. This type of sealing can take place prior to or after the sheets of corrugated board 62 , 67 are cut.
[0041] [0041]FIG. 7 illustrates a second part of a corrugating machine according to a second embodiment. FIGS. 8 to 11 illustrate further embodiments of corrugating machines. Components that correspond to those described with reference to FIGS. 1 to 6 have the same reference numerals and are not going to be explained in detail again.
[0042] In the corrugating machine according to the second embodiment, a digital printing system 69 is disposed downstream of the heater (not shown). With no relevant shrinkage of the web taking place between the jobs of printing the web of corrugated board 41 and depositing the cut sheets of corrugated board 62 , 67 , the readers 19 , 44 of the first embodiment can be dropped.
[0043] In the second exemplary embodiment, a reader 70 is disposed upstream of the lengthwise cutting/grooving unit 46 , crosswise scanning the web of corrugated board 41 and recognizing the distribution of printing patterns 43 on the web of corrugated board 41 . Signal lines 71 , 72 provide for signalling connection of the reader 70 with the lengthwise cutting stations 48 . Depending on recognition of the printing patterns 43 by the reader 70 , the lengthwise cutting stations 48 are triggered for web sections 52 , 53 to be cut, having a width that corresponds to the arrangement of the printing patterns.
[0044] Another reader 73 is disposed between the lengthwise cutting/grooving unit 46 and the cross-cutting unit 54 , within its range scanning the web sections 52 , 53 of the web of corrugated board in the working direction 15 i.e., lengthwise, and registering the distribution of printing patterns 43 on the web of corrugated board 41 in the working direction 15 . A signal line 74 connects the reader 73 with the cross-cutting unit 54 . Corresponding to what has been said about lengthwise cutting of the web of corrugated board 41 , the reader 73 triggers the cross-cutting unit 54 in such a way that this unit 54 cuts the sheets of corrugated board 62 , 67 in accordance with the distribution of printing patterns in the working direction 15 . By the aid of the readers 70 . 73 , a plane shape of the sheets of corrugated board can be determined, the longitudinal and transverse dimensions of which are adjustable; this plane shape can be cut to size by the lengthwise cutting stations 48 and the cross-cutting unit 54 being correspondingly triggered.
[0045] In variation of the second embodiment, printing units may be provided in addition to the printing system 69 , corresponding to the printing units 4 and 26 of the first embodiment for printing individual webs of material upstream of the machine 1 or the heating device 36 .
[0046] In further variation of the second embodiment, the printing system 69 can be provided with two ink jet heads in such a way that the web of corrugated board 41 is bilaterally printed, i.e. simultaneously on the top and bottom side.
[0047] [0047]FIGS. 8 and 9 show the two parts of a corrugating machine according to a third embodiment. As compared to the first embodiment, the second printing unit 26 misses in the first part, seen in FIG. 8, of the corrugating machine. Also the deviation of the third web of material by the deflection rollers 23 , 24 , 25 , 30 , 31 has been dropped, which is no longer needed. Further, the first reader 19 misses in the third embodiment. The application control unit exists also in this embodiment, however it is not shown. In the corrugating machine of the third embodiment, a first web of material 3 is being printed, having marks 17 , 18 at an initial distance that is given and has been fed into the application control unit of the third embodiment prior to the start of production of the corrugating machine. Therefore the application control unit of the third embodiment knows the distances a 1 , b 1 although they have not been measured by a reader.
[0048] The second part of the third embodiment of the corrugating machine seen in FIG. 9 corresponds to the second part of the corrugating machine of the first embodiment seen in FIG. 6, a difference residing in that the reader 44 of the first embodiment, which evaluates the distance from each other of the marks 17 and the marks 18 , is functionally split into a first reader 75 for determination of the distance of the marks 17 and a second reader 76 for determination of the distance of the marks 18 . Signal lines (not shown) connect the readers 75 , 76 to the application control unit of the corrugating machine of the third embodiment.
[0049] [0049]FIGS. 10 and 11 illustrate the two parts of a corrugating machine of a fourth embodiment. These parts correspond to those of the third embodiment with the difference that the web of corrugated board, in the fourth embodiment, is printed from below instead of from above. Therefore, the printing unit 4 misses in the first part of the corrugating machine of the fourth embodiment. It is replaced by the printing unit 26 which corresponds to the first embodiment, serving for printing the bottom side of the third web of material 22 . Correspondingly, in the second part of the corrugating machine of the fourth embodiment, the readers 75 , 76 are located underneath the web of corrugated board 41 , there registering the printing patterns imprinted by the printing unit 26 . Otherwise, the fourth embodiment corresponds to the third embodiment.
[0050] The readers 19 , 44 , 70 , 73 , 75 , 76 may be embodied as a camera, in particular a CCD camera. In addition to the function described above, the reader 19 still has the function of synchronizing the two printing units 4 , 26 when bilaterally accurately aligned printing is to take place on the web of corrugated board 41 . To this end, the reader 19 registers the time when a certain printing pattern 43 finds itself within in the range of the reader 19 . Depending on the difference of the conveying paths of the web of single-faced corrugated board 13 from the reader 19 as far as to the nip 40 on the one hand and of the third web of material 22 from the ink jet head 28 as far as to the nip 40 on the other hand, the application control unit 7 computes the instant at which the printing unit 26 must print the third web of material 22 for this third web 22 to be printed true to the position of the print on the opposite side of the web of corrugated board, which is the top side of the web of corrugated board 13 that is printed by the printing unit 4 .
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A corrugating machine serves for the manufacture of sheets of corrugated board. It comprises at least two unroll stands for unwinding webs of material. A fluting unit is provided for producing at least one corrugated medium from one of the webs of material. A processing equipment serves for uniting the webs of material to form a web of corrugated board. The sheets of corrugated board are cut to size in a cutting station. At least one digital printing system for printing at least one of the webs is disposed between the unroll stands and the cutting station. One of the webs of material can have a coating for improved printing quality. Methods are specified for digitally printing within the corrugating machine, which, upon printing, allow for any modification of dimensions during manufacture of the web of corrugated board; and which enable synchronized printing of opposite sides of the web of corrugated board to take place; and which enable the sheets of corrugated board to be cut in dependence on a printing job. This ensures rather flexible high-quality printing of the sheets of corrugated board.
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TECHNICAL FIELD
[0001] The invention is in the field of tamper resistant closures for cosmetic products.
BACKGROUND OF THE INVENTION
[0002] Cosmetic products that are damaged, destroyed, or stolen while on store shelves represent a significant cost to cosmetics companies. Generally stores order cosmetic products from the cosmetic manufacturer and place them on store shelves for consumer sale. A significant number of those products are damaged or destroyed while on store shelves, mostly by consumers. In a typical scenario, the consumer wants to better assess the color of the cosmetic product, such as lipstick, that she is considering buying. The consumer removes the cap from the lipstick and applies it to her body somewhere to assess color. Even if the consumer likes the color of the lipstick that was sampled and wants to buy it, the majority of consumers will not purchase the unit they sampled. In most cases the tested, and now damaged, unit will be returned to the store shelf and a new, sealed unit will be selected for purchase. At regular intervals store employees will take stock of the cosmetic products on their shelves and those that are damaged or destroyed are returned to the manufacturer for credit. Returns are not only a cost drain for the cosmetic company but the store that sells their products as well. Stores need employees to collect damaged items, pack and mail them back to the manufacturer, and maintain debit and credit records. Further, cosmetic products that have been tampered with can cause other types of damage in stores. For example, unsealed cosmetic products can spill and create messes, or be used to vandalize store fixtures and other products, so stores are also interested in creating cosmetic products that have adequate tamper resistant packaging.
[0003] With respect to lipsticks in particular, tamper resistant packaging is nothing new. For example, U.S. Pat. No. 4,422,545 is directed to a lipstick container where the entire cap is made of a clear thermoplastic material that enables the consumer to see the color of the lipstick bullet. One problem with this type of cap is that it is still removable by the consumer. Moreover, the cap itself must be clear, which means that one is fairly limited in the types of lipstick designs that can be used. Since lipstick component design is important in an image conscious business and serves to distinguish one brand from another, clear caps may not be desirable.
[0004] U.S. Pat. No. 4,208,144 is directed to another type of lipstick container that enables the consumer to view the color of the lipstick bullet within a narrow range in the middle section of the container. In particular, a plastic cover for the A-shell has a clear section that rests slightly above the intersection of the base portion and A-shell. The clear section has a wider circumference than the lipstick cap. When the cap is placed on the lipstick container, the clear band prevents the cap from completely seating and provides a viewing area for the lipstick bullet. One problem with this type of container is that the cap of the lipstick will not completely fit onto the base when the A-shell cover is in place. Further, viewing the color of the side of the lipstick may not completely satisfy the consumer who is intent on selecting the right lipstick shade because the actual physical lipstick bullet is not viewable.
[0005] U.S. Pat. No. 4,579,134 is directed to another type of tamper resistant lipstick container having a clear cap and a clear mid-portion. The lipstick bullet in retracted form can be viewed through the clear mid-portion. However, When the clear cap is in place, the lipstick bullet is viewed through two transparent layers, which may not provide the most accurate indication of color.
[0006] U.S. Pat. No. 5,257,704 teaches the use of a shrink wrap strip applied to the rotational assembly of the lipstick so that the consumer can remove the cap but cannot propel or repel the lipstick bullet.
[0007] U.S. Pat. No. 5,451,113 teaches another type of tamper resistant package where a clear plastic cover is fitted over the entire lipstick A-shell. The lipstick cap can be placed over the transparent cover if desired. When the consumer wants to look at the color of the lipstick bullet, the cap is removed and the lipstick is viewed through the clear A-shell. One problem with this type of tamper resistant package is that the clear plastic cover adds another layer of thickness to the A-shell and will interfere with the placement of the cap thereon. In some cases, if the lipstick cap is put on with too much force, it may crack.
[0008] U.S.D. 302,054 teaches a transparent A-shell extension through which the lipstick can be extended. While the transparent A-shell facilitates viewing of the lipstick bullet, the fact that the bullet can actually be extended and retracted through the top of A-shell doesn't address the breakage or damage problem at all.
[0009] There is a need for more effective tamper resistant packaging for cosmetic sticks products which caters to the consumer's desire to view the actual color of the stick prior to purchase, and at the same time prevent tampering.
[0010] It is an object of the invention to provide a tamper resistant package for cosmetic stick compositions that provides the consumer with a good view the color of the actual cosmetic product and at the same time prevents tampering.
[0011] It is a further object of the invention to provide a tamper resistant package for cosmetic stick compositions where the tamper resistant portion does not interfere with the operation of the case itself.
[0012] It is a further object of the invention to provide a tamper resistant package for cosmetic stick compositions which is inexpensive.
[0013] It is a further object of the invention to provide a tamper resistant package for cosmetic stick compositions which is easily removed by the consumer after the product is purchased.
SUMMARY OF THE INVENTION
[0014] The invention is directed to a packaged cosmetic stick product comprising a (a) cosmetic composition containing, in a cosmetically acceptable carrier, at least one structuring agent in an amount sufficient to form a solid stick; said stick contained in a (b) a propel/repel container comprised of a (i) base for holding the cosmetic stick product wherein the cosmetic stick is partially extended therefrom, (ii) an A-shell affixed to the base and having length sufficient to completely house the cosmetic stick when it is in the fully retracted position, (iii) an A-shell cover having a length that is less than about 80% of the total length of the A-shell, (iv) a shrink wrap holding the A-shell cover to the A-shell, and (v) a cap for covering the A-shell and the A-shell cover.
BRIEF DESCRIPTION OF THE DRAWINGS
[0015] [0015]FIG. 1: depicts one embodiment of the external appearance of the cosmetic container of the invention, which is in the closed position.
[0016] [0016]FIG. 2: depicts one type of A-shell cover.
[0017] [0017]FIG. 3: depicts the cosmetic container of the invention in the open position with the cap removed and the cosmetic stick fully retracted and not visible in side view.
[0018] [0018]FIG. 4: depicts the container of FIG. 3 wherein the cosmetic stick found therein is fully extended.
[0019] [0019]FIG. 5: is a side cutaway view of the cosmetic container of FIG. 1 showing the A-shell cover of FIG. 2 affixed to the A-shell without shrink wrap and the cosmetic stick in semi-extended position within the base.
[0020] [0020]FIG. 5A: is a side cutaway view of the cosmetic container of FIG. 1 showing the A-shell cover of FIG. 2 affixed to the A-shell with shrink wrap and the cosmetic stick in semi-extended position within the base.
[0021] [0021]FIG. 5B: is a side cutaway view of the cosmetic container of FIG. 1 showing the A-shell cover of FIG. 7 affixed to the A-shell with shrink wrap and the cosmetic stick in semi-extended position within the base.
[0022] [0022]FIG. 6: illustrates is a side cutaway view of one container in accordance with the invention that shows the cosmetic stick partially extended from the base and covered by another type of A-shell cover that rests on the A-shell but is not attached with shrink wrap.
[0023] [0023]FIG. 7: shows the A-shell cover that is depicted in FIGS. 5B and 6.
[0024] FIGS. 8 A-C: illustrate the various components that make up the base.
[0025] [0025]FIG. 8A: depicts the cup for holding the cosmetic stick.
[0026] [0026]FIG. 8B: depicts the dispenser base.
[0027] [0027]FIG. 8C: depicts an outer shell.
[0028] [0028]FIG. 8D: depicts the A-shell.
[0029] [0029]FIG. 9: is a top plan view of the cup, dispenser base, outer shell and A-shell in fully assembled position.
[0030] [0030]FIG. 10: is a top plan view of the cup of FIG. 8A.
[0031] [0031]FIG. 11: is a top plan view of the dispenser base of FIG. 8B.
[0032] [0032]FIG. 12: is a top plan view of the outer shell of FIG. 8C.
[0033] [0033]FIG. 13: is a top plan view of the A-shell of FIG. 8D.
[0034] [0034]FIG. 14: is a side cutaway view of the cosmetic container of the invention having the A-shell cover of FIG. 2 affixed to the A-shell without shrink wrap.
[0035] [0035]FIG. 15: is a side cutaway view of the cosmetic container of the invention having the A-shell cover of FIG. 7 affixed to the A-shell without shrink wrap.
DETAILED DESCRIPTION
[0036] [0036]FIG. 1 depicts the packaged cosmetic product 1 of the invention, which is housed in a container 2 in the closed position. The container has a cap 3 and a base 4 . In FIG. 1 the cap 3 is affixed to the base 4 . The container is a propel/repel container, which means that the container contains a mechanism (to be further described herein) that enables the cosmetic stick to be “propelled” or extended from the base and “repelled” or retracted back into the base when desired.
[0037] The various components that make up the base 4 are illustrated in FIGS. 8 A-C. FIG. 8A depicts a side view what is referred to as a cup 5 , and FIG. 10 is a top plan view of the cup 5 . FIG. 8B depicts the dispenser base 7 in side view and FIG. 12 is a top plan view. FIG. 8C depicts the side view of the outer shell 20 and FIG. 12 a top plan view.
[0038] The cup 5 as shown in FIG. 8A holds the cosmetic stick product 6 , the cosmetic stick being depicted with broken lines.
[0039] The cosmetic stick contains at least one structuring agent or combination of structuring agents in an amount sufficient to enable formation of a cosmetic stick. The term “cosmetic stick” means any self supporting cosmetic composition. The cosmetic stick used in the container of the invention may be anhydrous or aqueous. In the case where the sticks are anhydrous, they typically comprise one or more oily ingredients, such as silicones or organic oils; and the structuring agent, which causes the composition to form its self supporting structure. In addition such sticks may contain particulates and other ingredients to enhance their aesthetic properties. Oily ingredients include volatile and non-volatile silicones as well as organic oils in the form of esters, volatile or non-volatile paraffinic hydrocarbons, triglycerides, and so on. Particulates include include D&C or FD&C organic pigments, inorganic iron oxide pigments, or non-pigmentitious powders such as titanium dioxide, nylon, boron nitride, silica, polyethylene, and so on. Similarly aqueous sticks, which contain water, also may contain, in addition to one or more structuring agents, particulates, and other ingredients to enhance the beneficial properties of the stick. A variety of ingredients are suitable structuring agents including waxes that are animal, vegetable, mineral, or silicone waxes that are capable of providing sufficient viscosity or structure to the composition. Also suitable as structuring agents are polymeric materials including polyamides, ethylene homo- and copolymers, or polymers comprised of other ethylenically unsaturated monomers such as acrylic acid, methacrylic acid, simple esters of acrylic or methacrylic acid, styrene, ethylene, vinyl pyrrolidone, vinyl acetate, urethanes, and so on. Generally, anhydrous sticks preferably contain, by weight of the total composition, about 0.001-95% oily ingredients, about 0.001-99% of one or more structuring agents, and about 0.001-50% of one or more particulates. Aqueous based sticks preferably comprise from about 0.001-85% water, 0.001-30% oily ingredients, 0.001-75% of one or more structuring agents, and 0.001-50% of one or more particulate materials. Examples of suitable cosmetic stick compositions and the ingredients found therein are set forth in U.S. Pat. Nos. 5,505,937; 5,725,845; and 6,162,421; and 6,042,815 all of which are hereby incorporated by reference in their entirety.
[0040] Preferably the cosmetic stick 6 that is used in the container 1 of the invention is prepared in the usual manner by pouring the molten cosmetic product into molds and cooling. The resulting cosmetic stick 6 , also known as a “bullet”, is removed from the mold when hardened and fitted into the cup 5 . The base of the cosmetic stick 6 fits into the cup 5 and the tip of the cosmetic stick is free. Preferably the cup 5 has barbs or splines 8 which assist in anchoring the cosmetic stick 6 in the cup 5 . An example of such barbs is set forth in U.S. Pat. No. 6,116,801, which is hereby incorporated by reference in its entirety. The cup may also contain longitudinally extending ribs 9 . While it is preferred that the cup 5 be circular in cross section, it is possible that the cup 5 may be oval, square, or other shapes. The cup 5 has an outer surface 10 and an inner surface 11 . On the cup 5 outer surface 10 are a pair of cam followers 12 (see FIG. 9), which are generally cylindrical members spaced about 180° apart.
[0041] [0041]FIGS. 8B and 11 illustrate another component of the base 4 which is a dispenser base 13 . The dispenser base 13 is a hollow tubular member which has a first segment 14 of varying diameter, and a second segment 15 of varying diameter, and an external base 16 . Segments 14 and 15 and external base 16 have longitudinal axes in alignment. Segment 14 is formed with a pair of elongated openings 17 terminating at either end by a lateral opening 18 . The openings 17 are generally spaced about 180° apart, with only one such opening being shown. Dispenser base 13 contains a surrounding rib 18 A which contains an underlying lip 19 which circumscribes the dispenser base 13 .
[0042] [0042]FIGS. 8C and 12 depict another component of the base 4 , which is the outer shell 20 . The outer shell 20 is a hollow tubular member having an inside diameter slightly larger than the external diameter of dispenser base 13 . The outer shell 20 contains an external spiral shaped groove 21 formed in the interior surface 22 thereof. The spiral shaped groove 21 communicates between open ends 22 A and 23 of outer shell 20 . Outer shell 20 is positioned over dispenser base 13 as best depicted in FIGS. 14 and 15. Due to the slight dimensional differences between outer shell 20 and dispenser base 13 , the outer shell 20 is rotatable about its longitudinal axis. In this arrangement, the spiral groove 21 is arranged such that it overlies openings 17 and 18 at various positions there along as the outer shell 20 is rotated. The outer shell 20 is retained in position by rib 18 A with underlying lip 19 which fits over open end 22 A of outer shell 20 with the underlying lip 19 fitting over the edges 24 of outer shell 20 .
[0043] The cup 5 , dispenser base 13 , and outer shell 20 are assembled in nested relationship as depicted in FIG. 9.
[0044] [0044]FIG. 8D illustrates an external sleeve 25 referred to as the “A-shell”. The A-shell 25 has an inner diameter 26 that is slightly larger than the external diameter of outer shell 20 . The A-shell 25 is also positioned in a nested relationship with cup 5 , dispenser base 13 , and outer shell 20 as depicted in FIG. 9. Preferably, the outer shell 20 is secured in the A-shell by glue or similar such that it is permanently affixed thereto. Accordingly, then the consumer desires to propel or repel the cosmetic stick in the container, gripping the base 4 with one set of fingers and the A-shell 25 with the other set of fingers, then rotating the A-shell 25 or the base 4 will cause the stick to propel or repel from the container.
[0045] In particular, the A-shell 25 has a bottom edge 27 , which snugly fits against circumferential shelf 28 found on the lower portion 29 of outer shell 20 . The consumer grips A-shell 25 with the fingers of one hand and the external base 16 with the fingers of the other hand. When the external base 16 is rotated in one direction the cosmetic stick 6 is extended from the container 2 . When the external base 16 is rotated in the opposite direction, the cosmetic stick 6 is retracted into the container 2 . Together the parts depicted by FIGS. 8 A-D form the rotational assembly of the container, meaning that the parts work together to enable extension and retraction of the cosmetic stick 6 from the container 2 .
[0046] [0046]FIGS. 2 and 7 depict the types of A-shell covers 30 that may be used with the cosmetic product 1 of the invention. These A-shell covers are generally made of a thermoplastic polymeric material which is preferably transparent either in whole or in part so that the consumer can see the color of the cosmetic stick 6 within the container 2 .
[0047] The A-shell cover 30 of FIG. 2 contains a closed cover 30 A having a shoulder 31 and depending peripheral skirt 31 A. The A-shell cover 30 is preferably completely transparent. The closed cover 30 A has side walls 32 and the depending peripheral skirt 31 A has side walls 33 . The length of the side walls 32 of the closed cover is approximately about the same as the side walls 33 of the depending peripheral skirt 31 A although that configuration is not necessary. The shoulder 31 rests on the top surface 34 of the A-shell 25 as depicted in FIG. 5.
[0048] [0048]FIG. 7 depicts yet another type of A-shell cover 30 B suitable for use with the packaged cosmetic product 1 of the invention. This A-shell cover 30 B has a closed cover 30 C with side walls 34 A and a very small shoulder 35 of a size and shape sufficient to sit directly on the top surface 34 of A-shell 25 . A-shell cover 30 B has a small gripping member 36 . As is depicted in FIG. 6, the shoulder of A-shell cover 30 B rests on the top surface 34 of A-shell 25 and the gripping member 36 extends for a very small distance down into the A-shell 25 internal surface to stabilize the A-shell cover 30 B on the A-shell 25 , preferably by exerting a friction fit. In particular, the gripping member forms a friction fit against the A-shell 25 internal surface to further stabilize this A-shell cover on the top surface 34 of the A-shell.
[0049] In both cases, the thickness of the A-shell cover 30 and 30 B is such that the cap 37 inner surface 38 does not come into contact with the A-shell cover 30 or 30 B. This is important because any additional bulk provided by the A-shell cover or shrink wrap or both will impact how the cap fits onto the container. In particular, if the A-shell cover and shrink wrap provide too much additional bulk, the cap will not fit onto the container, or will have to be forced onto the container. This may cause the cap to crack.
[0050] As is best depicted in FIG. 5A, the A-shell cover is preferably attached to the A-shell by what is referred to as “shrink wrapping” 39 , which is a clear thermoplastic polymeric sealing laminate that holds affixes the A-shell cover to the A-shell. Typically shrink wrap is made from thermoplastic polymeric materials such as polyolefins, polycycloolefins, polyethylene, and the like. If desired, the shrink wrapping 39 that secures the A-shell cover to the A-shell may be imprinted with various indicia such as the lipstick ingredient list, the name of the company manufacturer, and so on. If desired the shrink wrap can have a tearaway tab 40 which enables the consumer who purchases the product to grip the tearaway tab 50 with the fingers and thereby easily remove the shrink wrap 39 . After the shrink wrap 39 is removed, the A-shell cover will loosen and can be removed, and the lipstick can be dispensed from the base in the traditional manner.
[0051] The shrink wrap 39 not only secures the A-shell cover to the A-shell, but also prevents turning of the rotational assembly in, the lipstick base to propel and repel the stick. Until the shrink wrap 39 is removed by the consumer, the lipstick cannot be tested, operated, or tampered with, yet the consumer is fully able to view the bullet color and shape.
[0052] The product of the invention addresses the consumer's need to actually view the color and shape of the cosmetic stick within the container, and even remove the cap of the container but will otherwise prevent any tampering activities. The result is substantial cost savings due to amelioration of damaged goods.
[0053] While the invention has been described in connection with the preferred embodiment, it is not intended to limit the scope of the invention to the particular form set forth but, on the contrary, it is intended to cover such alternatives, modifications, and equivalents as may be included within the spirit and scope of the invention as defined by the appended claims.
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A packaged cosmetic stick product comprising a (a) cosmetic composition containing, in a cosmetically acceptable carrier, at least one structuring agent in an amount sufficient to form a solid stick; said stick contained in a (b) a propel/repel container comprised of a (i) base for holding the cosmetic stick product wherein the cosmetic stick is partially extended therefrom, (ii) an A-shell affixed to the base and having length sufficient to completely house the cosmetic stick when it is in the fully retracted position, (iii) a transparent A-shell cover having a length that is less than about 80% of the total length of the A-shell, (iv) a shrink wrap holding the transparent A-shell cover to the A-shell, and (v) a cap for covering the A-shell and the transparent A-shell cover.
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BACKGROUND OF THE INVENTION
The invention relates to apparatus for the production of directionally solidified castings and castings produced by means of such apparatus.
An inexpensive process in which mold shells having integrated heat sources are used (F. Staub et al, Technische Rundschau Sulzer 3/1988, p. 11) is known for the production of relatively small directionally solidified castings (length in the direction of solidification less than about 15 cm). The integrated heat sources are, for example, additional cavities in the mold shell which, filled with superheated melt, enable casting to be carried out without heating means (susceptors) in the casting chamber. The mold shell itself and the mold thermal insulation which must be used, also contribute to the integrated heat sources.
The mold shell has a bottom aperture which is closed by a flat cooling plate in the casting chamber. Solidification of the melt starts at this aperture during casting. The cooling plate acting as a heat sink and the integrated heat sources form the poles of a temperature field which allows a "uni-directional" heat flow and hence a directional solidification. In the known processes the cooling plate forms a horizontal plane with respect to which the dendrites forming on solidification have a substantially vertical growth direction.
In castings made from nickel based alloys, e.g. for turbine blades for aircraft jet engines, the elongation strengths in the direction of the dendrites and hence the lives of the components during operation are greatly improved as compared with polycrystalline castings. Since the dendrites will be substantially radially oriented in the turbine wheel blades, the wheel must be assembled from individual directionally solidified castings. The production of the wheel would be simplified if it were possible to cast components having directionally solidified zones whose texture structures have different orientations. It is the object of the invention to provide an apparatus which allows the production of such components.
SUMMARY OF THE INVENTION
The cooling attachment applied to the horizontal cooling plate means that the dendrite growth has different orientations in zones. By suitable configuration of the cooling attachment it is possible to manufacture segmental castings which can be assembled to form components in the form of wheels having radially oriented dendrites; alternatively, connected wheel-like components can be cast in which directional solidification results in the formation of dendrites which are aligned at least approximately radially.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 shows a component in the form of a wheel adapted to be produced by the apparatus according to the invention and partially embedded in the mold shell (first exemplified embodiment);
FIG. 2 shows three sectors of the cooling attachment of the first exemplified embodiment;
FIG. 3 is a radial section through the cooling plate, cooling attachment and filled mold shell of the first exemplified embodiment;
FIG. 4 is a variant of the cooling attachment of the first exemplified embodiment;
FIG. 5a shows the cooling attachment of a second exemplified embodiment;
FIG. 5b shows a variant of the second exemplified embodiment;
FIG. 6 shows a third exemplified embodiment in which the casting is a component segment; and
FIG. 7 is a plan view of the cooling plate with the cooling attachment for the third exemplified embodiment.
FIGS. 8a to 10c show different variants of the cooling attachments used for the production of segmental components as in the third exemplified embodiment and which can be assembled from at least two members for each component.
DESCRIPTION OF THE PREFERRED EMBODIMENTS
The component 10 shown in FIG. 1 consists of the radial blades 11, the outer ring 12 and the inner ring 13. A toroidal cavity 3 is integrated in the mold shell 2 and encircles the actual mold shell for the component 10 ring a ring-like manner. (The cavity 3 may also be divided up into sectors forming separate chambers. In this way it is possible to prevent stresses which may occur on solidification.) The melt flows via gate 5 (see FIG. 3-not shown in FIG. 1) via a number of ducts 4 into the torus 3 and then through apertures 31 distributed over the periphery of the outer ring 12 into the central area of the mold shell 2. The torus 3 forms the main part of the heat source integrated in the mold shell. A thermal insulation with which the outer surface of the mold shell 2 must be enclosed is not shown.
On the inside the mold shell 2 has apertures 15 separated from one another by webs 21 of the mold shell 2. As will be seen in FIG. 2, the apertures 15 are closed by members 60 in the form of sectors. These members 60, which are disposed in a ring around a central part 6b, consist of a material having good thermal conductivity, e.g. copper; they serve to dissipate heat on solidification of the melt. As will be seen from the cross-section in FIG. 3, the members 60 are disposed on the cooling plate 6 (connecting line 6a) and are supported with respect to the central part 6b by means of compression springs 61. Radially narrow gaps are provided between the members 60 of the cooling attachment. They permit a change of geometry during volume reduction resulting from the solidification of the casting, the cooling attachment being constructed to yield radially.
Between the heat sink formed by the members 60, on the one hand, and the heat source formed by the superheated melt in the toroidal cavity 3, on the other hand, a radial temperature field forms. After the shock-like start of solidification at the apertures 15 dendrites grow out of a polycrystalline transition zone and follow the temperature field with minor deviations in the blades 11. In this way the wheel-shaped component forms with the required radial orientation of the texture structure.
To enable the mold shell 2 to be fitted quickly onto the cooling members 60, the casting 1 is advantageously given a shape in which the inner ring 13 is slightly conical; the angle 102 between the horizontal 100 and the verticals 101 that the members 60 have at the interface at the apertures 15 should be somewhat smaller than a right angle. Depending upon the component the vertical 101 may also deviate considerably from the vertical (see FIG. 4 where the position of the casting is indicated in dot-dash lines and with the reference 1').
In the second exemplified embodiment (FIGS. 5a and 5b) the members 60 arranged in a ring are again supported with respect to an annular edge 6c via compression springs 61. The two variants illustrated correspond to the two variants of the first exemplified embodiment. Here the directional solidification takes place radially inwards from outside.
The third exemplified embodiment shown in FIG. 6 is a casting 1 having a component 10 in the form of a segment which together with another five components 10 can be assembled to form a component in the form of a wheel. The mold shell (not shown) again comprises not only the cavity for the component 10 but also cavities for the integrated heat sources 3 with the associated connecting lines 4 and 31 and a cavity for a starter base 14 in which the directional solidification develops. The member 60 of the cooling attachment has two flat zones as the interface with the casting 1, these zones including an angle of 30°. Accordingly, on solidification two zones form in the casting with different orientations of dendrite alignment, i.e. by an angle which is at least approximately also 30°. In this case the radial alignment of the dendrites can be achieved only approximately.
The members 60 of the cooling attachment are advantageously mounted on an intermediate plate 65, the connection being so made, for example by means of screws 70, that there is a clearance 71 left for the movement of the screw head. This connection then allows a limited sliding movement of the member 60 about a zero position, of, for example, at least one millimeter. If a plurality of castings are combined to form a cluster, then the cooling attachment can react resiliently owing to the movability of its members 60 in response to small changes in the geometry of the cluster such as occur on heating of the ceramic and on solidification of the melt.
The cooling plate 6 shown in FIG. 7 comprises a cooling attachment with members 60 for a cluster with six components 10 (as in FIG. 6). The mold shell for the cluster is advantageously provided with an annular edge at its base having grooves to form a bayonet lock. The mold shell can be rapidly and securely connected to the cooling system by means of the claws 6d at the sides of the cooling plate 6, these claws forming the co-acting elements for the grooves of the bayonet lock. To enable the rotary movement required for the bayonet lock to be performed, the intermediate plate 65 must be mounted rotatably on the cooling plate 6. To this end, a pin 80 is provided in the center of the cooling plate 6 and engages in a corresponding bore in the intermediate plate 65.
On solidification of the melt the volume decreases by about 2%. This shrinkage in volume is generally accompanied by a change in the geometry of the casting in the form of a contraction. Because of this contraction it is advantageous to assemble the cooling attachment from a plurality of relatively displaceable members 60. Instead of the connected member 60 in the third exemplified embodiment it is preferable to use a cooling attachment comprising 2, 3 or 4 members 60 as shown in FIGS. 8a to 8c (the arrows indicate the displaceability of the members 60). The larger the segment angle of the component 10, i.e., the fewer of such components 10 required for assembling the complete wheel component, the more members 60 must be used in the cooling attachment per component 10.
Instead of making the surfaces of the members 60 flat, they may also be curved as shown in FIGS. 9a and 9b.
To prevent melt from flowing out of the mold shell through the gaps between the members 60, the casting mold must be so devised that the apertures of the mold shell are not situated over these gaps--for example by means of base portions 14' (see FIG. 8a). Other steps may, however, be taken to prevent the melt from flowing away. This is shown with reference to FIGS. 10a to 10c: the gap between two adjacent members 601 and 602 is covered by a roof-shaped projection 605 of the member 601 (see FIG. 10b, which is an enlarged detail of FIG. 10a). The projection 605 bears closely on a small horizontal region of the member 602 in such manner as not to prevent any sliding movement of the member 602 relatively to the member 601.
The individual members 60, 601 and 602 may be mounted on an intermediate plate 65 with connecting means 70 (see FIG. 8a) in the same way as in the third exemplified embodiment. They can also be interconnected by compression springs 603 (see FIG. 10b) as in the first exemplified embodiment.
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The apparatus for the production of directionally solidified castings (10) in a vacuum casting plant comprises a cooling attachment with members (60) between a flat cooling plate (6) and the mold shell (2), by means of which member zones of different orientation of the direction of solidification can be produced in the casting. This apparatus is particularly suitable for the production of components in the form of a wheel--e.g. turbine wheels in aircraft jet engines--in which a radial alignment of the texture structure is advantageous in order to increase strength.
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BACKGROUND OF THE INVENTION
1. Field of the Invention
This invention relates generally to catheters adapted for use in surgical procedures and more specifically to catheters having inflatable balloons.
2. Discussion of the Prior Art
In many surgical procedures it is desirable to introduce an elongate flexible object into a body conduit and to enlarge the distal end of that object at an operative site. Catheters are well known to perform this function, and in one common variety a balloon is disposed at the distal end of the catheter to provide for the desired enlargement. When this balloon is inflated, it typically exceeds the radial diameter of the catheter.
Several surgical procedures, such as embolectomy and angioplasty procedures, take advantage of this balloon catheter construction. In an embolectomy procedure, the distal end of the catheter is introduced beyond a thrombus or embolus, the balloon is inflated, and the catheter with enlarged balloon is withdrawn. In this procedure, the enlarged balloon pushes the thrombus or embolus out of the vessel as the catheter is withdrawn.
In an angioplasty procedure, the balloon of the catheter is inflated in proximity to athroscorotic plaque. In this common procedure, the pressure of the balloon forces the plaque against the vessel walls hereby enlarging the flow path through the vessel. These and other techniques benefiting from balloon catheter technology are disclosed in the following patents which are incorporated herein by reference:
______________________________________U.S. Pat. No. Inventor______________________________________3,438,375 R. Ericson3,866,599 C. Johnson4,217,903 R. Witherow4,254,774 J. Boretos4,823,812 U. Eshel4,913,701 A. Tower5,036,868 A. Berggren______________________________________
In all of these procedures, the initial diameter of the catheter is of particular interest. This elongate flexible structure is typically introduced through long, sometimes torturous, conduits in order to reach the operative site. In some cases, these conduits are quite narrow so that the diameter of the catheter is of critical importance. Such is the case with arteries in the hand of a patient. An embolectomy procedure performed in these environments might require a catheter having a diameter as small as 1 French.
The problem with achieving catheter diameters of this size has been significantly compounded in the case of balloon catheters. With these devices, the balloon structure has typically been provided on the outside of the catheter thereby increasing the diameter of the device. An inflation hole extends through the catheter wall into an inflation lumen of the catheter. The balloon with a cylindrical configuration is disposed over this hole and wound on the catheter body to form a seal on either side of the hole. By pressurizing the inflation lumen, an inflation fluid passes through the hole to inflate the balloon beyond the outer surface of the catheter body.
Attempts have been made to reduce the overall thickness of this balloon structure. The catheter wall has been thinned so that the diameter of the balloon windings can be formed in a recess. This has weakened the catheter walls so that the balloon windings tend to compress the lumen of the catheter. In some instances, metal bushings have been placed over the recess to prevent the collapse of the catheter walls. In such a combination, the total thickness of the catheter is determined by the thickness of four separate structural elements, the catheter wall, the bushing, the balloon and the winding. Since each of these elements has a cylindrical configuration, the wall thickness of each element is doubled in defining the diameter of the total construction. Thus, the catheter body provides two wall thicknesses in the overall diameter of the catheter. Similarly, the bushings, the balloon, the windings and any glue associated with the winding structure each add two thicknesses of material to the diameter of the catheter. As a consequence, eight layers of material have typically contributed to the overall thickness of the catheter.
In spite of the many disadvantages relating to the overall size of such catheters, the methods for constructing the catheter have demanded this configuration. The catheter body has typically been extruded, and any recesses provided in the catheter wall have been machined along with the inflation hole. Bushings have been placed over the recesses. The balloon in the initial form of a cylindrical elastic material has been positioned across the inflation hole and the balloon has been stretched and wound over the bushings. Gluing these windings in place has completed formation of the balloon structure.
Based on this method, typical of the prior art, the entire balloon structure has been formed on the exterior of the catheter body because of its accessibility. The detrimental effect on the overall diameter of the catheter has been accepted without recourse, but it has necessarily limited any possibility of providing balloon catheters in sizes smaller than 2 Fr.
SUMMARY OF THE INVENTION
In accordance with the present invention, an elongate catheter body is provided with an inflation lumen. Importantly, the balloon material is disposed interiorly of the catheter body in the inflation lumen. This material is restrained around a balloon hole which extends through the wall of the catheter into the inflation lumen. The balloon hole may be provided at the distal end of the catheter or in the side wall of the catheter body. When the inflation fluid is introduced into the inflation lumen, the balloon material expands through the balloon hole, outwardly of the catheter body.
When the catheter is initially inserted, the balloon material is disposed interiorly of the catheter body so that the maximum diameter of the catheter is dictated solely by the outside diameter of the catheter wall. There need be no bushings, windings or glue on the outside of the catheter wall to increase this diameter. In its thinnest configuration, the entire catheter structure can be formed with only three thicknesses of material, two thicknesses resulting from the cylindrical catheter wall and a single thickness of elastic material restrained around a side hole in the catheter.
With only three wall thicknesses, as opposed to the eight wall thicknesses of the prior art, significantly smaller diameters of catheters can now be formed making this important technology available in many new areas of the body anatomy.
These and other features and advantages of the present concept will be more apparent with a description of preferred embodiments and the best mode of the invention, and reference to the associated drawings.
DESCRIPTION OF THE DRAWINGS
FIG. 1 is a side view, partially in section, of one embodiment of a balloon catheter of the present invention;
FIG. 2 is an axial cross-section view similar to FIG. 1 showing an additional embodiment of the present invention;
FIG. 2a is a cross-section view taken along lines 2a-2a of FIG. 2;
FIG. 3 is an axial cross-section view similar to FIG. 2 of a further embodiment of the present invention;
FIG. 3a is a radial cross-section view taken along lines 3a-3a of FIG. 3.
FIG. 4 is an axial cross-section view of a further embodiment of the invention which can accommodate introduction of an injectate through the catheter;
FIG. 5 is an axial cross-section view of a further embodiment of the invention including an outer sheath;
FIG. 6 is an axial cross-section view of an embodiment adapted to form more than one radially spaced balloon;
FIG. 7 is a cross-sectional view taken along lines 7--7 of FIG. 6;
FIG. 8 is a cross-sectional view similar to FIG. 7 and illustrating a multiple balloon embodiment providing a full circumferential balloon structure;
FIG. 9 is an axial cross-section view similar to FIG. 6 but illustrating multiple balloons axially spaced;
FIG. 10 is a side view similar to FIG. 1 and illustrating a spiral balloon configuration;
FIG. 11 illustrates a step in a preferred method of manufacture where a mandrel is dipped into an elastomeric material;
FIG. 12 illustrates a further step of the method where the coated mandrel is inserted into a catheter body;
FIG. 13 is a front elevation schematic view of a coextruder adapted for use in a further method of manufacture;
FIG. 13a is a top plan view of the coextruder illustrated in FIG. 13;
FIG. 14 illustrates a method step whereby a laser forms an inflation opening in a catheter body;
FIG. 15 illustrates a method step similar to FIG. 14 wherein a flat point drill is used to form the inflation opening; and
FIG. 16 illustrates a method step wherein a vacuum is applied to the inner balloon structure to separate the balloon from the catheter wall prior to formation of the inflation opening.
DESCRIPTION OF PREFERRED EMBODIMENTS
A catheter is illustrated in FIG. 1 and designated generally by the reference numeral 10. This catheter 10 includes a balloon structure 12 and is representative generally of any elongate medical instrument which is insertable through a body cavity or conduit to provide an inflatable structure at a distal location. Such instruments may include not only catheters but also endoscopes.
In the case of a catheter, a balloon structure is known to provide advantages in both embolectomy and dilatation procedures. In an embolectomy procedure, the catheter is inserted into a vessel and guided so that its distal tip extends beyond an embolus or thrombus. At this location a distal balloon is inflated to fully occupy the interior lumen of the vessel. As the catheter is withdrawn through the incision in the vessel, the balloon pushes the embolus or thrombus thereby removing it from the vessel.
In dilatation procedures, the catheter is inserted into a conduit, such as the urethra, and inflated to push the conduit walls outwardly thereby enlarging or dilating the conduit. In one type of dilatation procedure atherosclerotic plaque coats the interior walls of a vessel and blocks blood flow. In this procedure, the catheter is inserted into the vessel to the point where the blockage occurs. At this location, the balloon is inflated pressing the plaque against the vessel walls thereby dilating the vessel. In all of these cases, the balloon structure provides means for producing a pressure or force exteriorly of the body to perform some function at an operative site within a body conduit.
The catheter 10 will typically include an elongate catheter body 14 having some degree of flexibility. The body 14 is typically formed along an axis 16 which extends between a proximal end 18 and a distal end 21 of the catheter 10. A hub 27 is disposed at the proximal end 18 of the catheter 10 and may include at least one Luer fitting 30. The fitting 30 permits attachment of the catheter 10 to various external systems, such as a source of inflation pressure (not shown).
The catheter body 14 will typically take the form of an elongate cylinder having an outer wall 36 which at least partially defines an inflation lumen 38 that extends from the hub 27 to the balloon structure 12. In many catheters, the inflation lumen 38 will merely be one of several lumens which perform various functions in a particular embodiment of the catheter 10. The opening 34 is configured such that it extends through the catheter wall 36 providing a passage from the inflation lumen 38 through the wall 36 to regions exterior of the catheter 10.
In a preferred embodiment, the balloon structure 12 includes a membrane 41 of elastomeric material, and means for retaining that membrane 41 around the opening 34. In the form illustrated in FIG. 1, this retention means include a bead of glue 43 which fixes the membrane 41 to the catheter wall 36 and any other portions of the catheter body 10 which define the opening 34. The retention means may form a seal around the opening 34 but these sealing characteristics may not be required in a particular embodiment.
In the embodiment illustrated in FIG. 1, the membrane 41 forms a balloon 45 which is operable between a deflated state (shown by the solid lines 47 in FIG. 1) and an inflated state (shown by the dotted lines 50 in FIG. 1).
The balloon structure 12 can be located anywhere along the catheter body 14 but will typically be disposed at the distal end 21 in proximity to an opening 34 in the catheter body 14. In the embodiment illustrated in FIG. 1, this opening 34 is located at the end of the catheter body 14 where the opening 34 is formed in a radial plane and faces axially of the catheter 10. In other embodiments, the opening 34 may be formed in the side of the catheter body as illustrated in FIG. 2.
It is of particular importance to the present invention that in the deflated state, the balloon structure 12 is disposed entirely within the circumferential dimension defining the outer surface of the catheter wall 36. There is no balloon membrane or other elastomeric material or any retention adhesive or windings which exceed this diameter of the catheter wall 36. In the illustrated embodiment, the balloon structure 12 is disposed entirely within the inflation lumen 38 where the bead of glue 43 retains the membrane 41 circumferentially of the lumen 38.
In operation, a source of inflation pressure (not shown) is coupled to the Luer fitting 30 and a pressurizing medium, such as saline, is introduced into the inflation lumen 38. As this inflation medium is pressurized, the membrane 41 associated with the balloon 45 expands through the opening 34 to the inflated state shown by the dotted lines 50. When the inflation medium is withdrawn or depressurized, the elastomeric characteristics associated with the membrane 41 cause it to retract back from the enlarged inflated configuration.
When the balloon 45 is initially inflated, the inflation pressure forces it against the catheter wall 36 forming a seal around the circumference of the opening 34. This seal, designated by the reference numeral 52, may form regardless of any sealing characteristics which may be associated with the retention means, such as the bead of glue 43.
In the embodiment of FIG. 2, the distal end 21 of the catheter body 14 is closed by an end cap 56 which can be molded with, glued to, or otherwise attached to the catheter wall 36. As previously noted, the opening 34 in this embodiment is formed in the side of the catheter body 14 where it extends radially of the catheter wall 36 and faces laterally of the catheter 10.
As in the previous embodiment, the membrane 41 is retained to the catheter wall 36 around the opening 34 and interiorly of the inflation lumen 38. In this particular case, the membrane 41 will have a more planar configuration in axial cross-section than the balloon 45 in the FIG. 1 embodiment. Nevertheless, as the inflation lumen 38 is pressurized, the membrane 41 will expand outwardly through the opening 34 to form the inflated balloon 50. As in the previous case, the inflated balloon 50 will extend in the same direction as the opening 34 which in the case of the FIG. 2 embodiment is laterally of the catheter 10.
The embodiment of FIG. 2 is of particular interest since it provides potentially the most narrow configuration for the catheter 10. In this particular embodiment, the cross-section of the catheter includes only three layers of material. Two of the layers result from the catheter wall 36 but only a single layer of the membrane 41 is required for this embodiment. In contrast, it will be noted that the embodiment of FIG. 1 includes four layers of material, two each associated with the catheter wall 36 and the membrane 41.
With reference to FIG. 2A it will be apparent how this reduced thickness is achieved. As illustrated, the bead 43 which retains the membrane 41 to the catheter wall 36 is formed on only one side of the axis 16. It follow that along any cross-sectional diameter of this embodiment, there is only a single thickness of the membrane 41. Nevertheless, this embodiment forms a fully inflatable balloon 50 as long as the bead 43 fully circumscribes the opening 34.
In the further embodiment of FIG. 2, a lateral balloon such as that illustrated in FIG. 2 can be formed with a radially glue bead 43 similar to that illustrated in FIG. 1. In this case, the opening 34 is formed laterally of the axis 16 as in the FIG. 2 embodiment, but the membrane is provided with the more spherical configuration as in the FIG. 1 embodiment. Although the membrane 43 does not closely circumscribe the opening 34, it is nevertheless attached to those portions of the catheter wall 36 that define the opening 34. This embodiment benefits from ease of manufacture as will be more apparent from the following discussion of manufacturing techniques.
The radial glue bead 43 may be closely spaced to the opening 34 as illustrated in FIG. 3 or it may be distantly spaced from the opening 34 as illustrated in FIG. 4. The only requirement for this relationship between the radial bead 43 and the opening 34 is that the bead 43 be disposed proximally of the opening 34. In the embodiment of FIG. 4 an injection port 61 is provided between the glue bead 43 and the opening 34. This port 61 provides access to lumen 38 and facilitates introduction of an injectate into the catheter 10 and outwardly through the opening 34.
This introduction of an injectate would most easily be accomplished with the balloon 45 in the deflated state shown by the solid lines 47. In this state, the injectate entering the port 61 would be forced between the membrane 41 and the catheter walls 36, as shown by the arrow 63, to exit the catheter 10 through the opening 34.
In the embodiment of FIG. 5, a more conventional catheter is illustrated to include a catheter wall 70 and a balloon 72 which is glued or wound on the outside of the catheter wall 70. In this case, a sheath 74 is provided to enclose the catheter wall 70 as well as the balloon 72. The opening 34 is provided in the sheath 74. As the balloon 72 is inflated (through a lumen formed by the catheter wall 70) it is restricted in all directions by the sheath 74 except in the area of the opening 34. As a result, the balloon 72 expands through the opening 34 forming the seal 52 with the sheath 74. It is apparent that a lateral balloon could also be formed by a lateral opening 34 similar to that illustrated in FIG. 2.
In a further embodiment of the invention, multiple balloons can be formed by providing more than one opening 34 in the catheter wall 36 or sheath 74. The embodiments of FIGS. 6 through 10 are representative of such multiple balloon configurations. In FIG. 6, a pair of radially spaced openings 34a and 34b are formed in the catheter wall 36. In the manner previously discussed, the application of pressure to the inflation lumen 38 results in inflating the membrane 41 through the openings 34a and 34b to form the respective inflated balloons 50a and 50b. These balloons 50a, 50b are radially spaced as best shown in FIG. 7.
Multiple balloons can also be radially spaced to form a single balloon structure that fills the entire circumference around the catheter 10. Such an embodiment is illustrated in FIG. 8 wherein the balloon structure 12 includes three separate balloons 50c, 50d, and 50e formed from a single membrane 41 deployed through respective openings 34c, 34d, and 34e. The resulting balloon configuration provides a substantially constant pressure radially outwardly around the entire circumference of the catheter 10. This embodiment will be of particular interest in dilatation and embolectomy procedures which are typically conducted in a blood vessel, such as that designated by the reference numeral 81.
In the same manner that the balloons 50a-50e are radially spaced, the balloons can also be axially spaced as illustrated in FIG. 9. In this case, a pair of balloons 50f and 50g can be inflated through the respective openings 34f and 34g. Of course various combinations of radially and axially spaced balloons will now be apparent. For example, two of the triple balloon structures illustrated in FIG. 8 could be axially spaced as illustrated in FIG. 9 to provide a substantially constant circumferential pressure at two axial locations.
The embodiment of FIG. 10 illustrates that the openings 34 can be substantially any shape, not just the circular configuration previously discussed. In FIG. 10, the opening is longitudinal in configuration and spirally oriented with respect to the catheter body 14. This opening is divided by several bridges 85 which divide the opening into segments 34h, 34i and 34j. These bridges 85 may be desirable to increase the column strength and structural rigidity of the catheter 10. With the openings divided into segments 34h through 34j, the resulting balloon is also segmented into spiral balloon portions 50h, 50i, and 50j respectively. As with the embodiments of FIGS. 6 through 9, the multiple balloons 50h-50j can be formed from a single membrane 41.
The methods for manufacturing the foregoing embodiments of the concept are quite diverse. The embodiment of FIG. 5 can be most easily manufactured since a large portion of this embodiment is a conventional catheter construction including the catheter wall 70 and the balloon 72 which is wound on the outer surface of the catheter wall 70. This structure is then inserted into the sheath 74 which has been appropriately apurtured to form the opening 34 either laterally or axially of the sheath 74.
Embodiments of the invention which require an elastomeric tube within an outer tube, such as the embodiments of FIGS. 1 and 3 through 10, can be formed in several manners. As illustrated in FIG. 11, a mandrel 81 can be provided with a diameter generally equivalent to the diameter desired for the inflation lumen 38. The length of the mandrel 81 should be such that it can extend from the proximal end 18 of the catheter body 14 to the distal end 21.
A vessel 83 containing the elastomeric material desired for the membrane 41 can be provided and heated to give the material 41 fluid characteristics. Then the distal end of the mandrel 81 can be dipped in the heated material of the membrane 41 to form a coating on the mandrel. This coating can be partially cured to provide it with a more solid configuration for the balloon 45.
Of particular importance to this process is the axial insertion of the coated mandrel 81 into the catheter body 14 as illustrated in FIG. 12. This catheter body 14 can be formed in accordance with conventional extrusion methods. After the balloon 45 is in place, the mandrel 81 can be removed leaving the balloon 45 within the catheter body 14. The step of withdrawing the mandrel 81 can be facilitated by initially coating the mandrel with a release agent so that it can be easily removed, leaving the balloon 45 in place.
This method may be preferred since the end of the balloon 45 is automatically formed in the dipping step of the process. No additional action need be taken in order to close the inflation lumen of the balloon 45. However, as a final step in this process, the distal end of the catheter body 14 will need to be closed if an lateral opening 34 is contemplated. This closure of the catheter body 14 can be accomplished by melting and molding the catheter material over the distal end of the catheter body or otherwise preforming a distal tip and attaching the tip, such as the end cap 56, to the catheter body 14.
A coextrusion process can also be used to form an elastomeric tube within the catheter body 14. As illustrated in FIG. 13, the materials associated with the catheter body 14 and the membrane 41 can be loaded into respective hoppers 83 and 85, heated, and forced by way of respective screws 87, 90 into a crosshead 92. The crosshead 92 is configured in accordance with known techniques to extrude an inner tube from the material in the hopper 85 and an outer tube from the material in the hopper 83. The result is a tubular membrane 41 within a more rigid catheter body 14. This coextrusion can be cut to length and the distal end formed to produce the embodiments of FIGS. 3 and 4. In this process the elastic membrane 41 can to be closed at the distal end in order to form the balloon 45. If a lateral opening 34 is provided, the distal end of the catheter body 14 also can be closed in accordance with methods previously discussed.
If a particular method can accommodate formation of the opening 34 prior to inserting or otherwise forming the elastic membrane 41 within the outer tube 14, this is desirable. For example, in the method of FIG. 12, the lateral opening 34 can be formed prior to insertion of the coated mandrel 81.
If the prior formation of the opening 34 is not possible, that opening needs to be carefully formed in the catheter wall 36 without puncturing the membrane 41. This can be most easily accomplished using a laser 96 which can be carefully operated to control the depth of the cut. By limiting this depth to the thickness of the catheter wall 36, any cutting of the membrane 41 can be avoided.
Another alternative for cutting the catheter wall 36 without penetrating the membrane 41 is to mechanically drill the catheter wall 36 with a flat end drill bit 98, as illustrated in FIG. 15.
This cutting either by the laser 96 or the drill bit 98 can be further facilitated by use of a vacuum 98 to draw the balloon 45 into a collapsed configuration as illustrated in FIG. 16. This will withdraw the balloon 45 from proximity to the catheter wall 36 so that the cutting steps illustrated in FIGS. 14 and 15 need not be as carefully controlled.
The materials associated with the present invention are of particular interest not only to facilitate their functions in a preferred embodiment of the catheter 10, but also to enable the foregoing processes of manufacture. In general the materials associated with the catheter body 14 and the membrane 41 can be any thermoplastic or thermoset material. Depending on the process of manufacture, these materials are formable in that they can be molded. Some of these materials are also extrudable which facilitates the process illustrated in FIGS. 13 and 13a. In most embodiments, both the catheter body 14 and the membrane 41 will be flexible although rigid and semi-rigid configurations may also benefit from the concept.
The material associated with the membrane 41 will typically be more flexible than the material associated with the body 14 which is relied on for additional column strength. The durometer of the material forming the body 14 will preferably be in a range from Shore 5A to Shore 100D. A range of particular advantage occurs from a Shore hardeess of 35D to 100D.
In comparison, the material forming the membrane 41 will preferably have a durometer between Shore 5A and Shore 100D. A preferred range of durometer might be between Shore 25A and Shore 100D. Regardless of the durometer of the material, the flexibility of the catheter 10 is of primary consideration. In embodiments wherein the wall thicknesses of the body 14 and the membrane 41 are quite small, higher durometers such as Shore 50D may still provide the desired flexibility.
The thermoplastic and thermoset materials which are of particular interest for the body 14 include rubbers, elastomers, silicones and polycarbonates. Materials of interest for the membrane 41 include rubber, elastomers including urethanes, polyethylene, polyethyleneterethalate, polyvinylchloride, silicone, nylon and latex.
In a preferred embodiment the catheter body is formed from Hytrel, a trademark of DuPont de Nemours. This material is coextruded with an outside diameter of about 1 Fr. to 10 Fr. and an inside diameter of about 0.005-0.100 inches. The membrane 41 is coextruded from Craton, a trademark of Shell Oil Company. The membrane 41 is coextruded in juxtaposition to the inner surface of the catheter body 14. An inflation lumen of about 0.003-0.080 inches diameter is formed in this particular embodiment so that the membrane 41 has the thickness of about 0.001 to 0.020 inches.
Beyond these considerations, the materials forming the catheter body 14 and the membrane 41 can be selected for their compatibility with each other. Generally it is felt that the materials are compatible if the membrane 41 does not automatically adhere to the material forming the catheter body 14. This permits the membrane 41 to freely move relative to the catheter wall 38 so that it can stretch through and beyond the opening 45 to form the expanded balloon 50. If it is preferrable to use materials which are not compatible in this sense, a release agent can be coextruded or applied to the balloon 45 on the dipped mandrel 81. Such a release agent would typically provide the characteristics required for these otherwise incompatible materials.
Many variations in the concept of this invention will now be apparent to those skilled in the art of balloon catheter design. Certainly different materials can be contemplated for the membrane 41 as well as the catheter body 14. Similarly, steps in the manufacturing processes can be altered all within the skill of the art. Many different embodiments of the invention can be formed by adjusting the various positions for the opening 34 as mentioned with respect to the examples of FIGS. 6-10.
It will also be noted that in a particular catheter construction, multiple lumens can be formed each with its own membrane 41 or balloon 45 which would be independently inflatable and deflatable to achieve the advantages of the present concept. In such an embodiment, multiple balloons could be provided around the circumference of the catheter body 14 in the manner illustrated in FIG. 7. By independently inflating each of the balloons around the circumference, the distal tip of the catheter could be guided in a direction opposite to the inflated balloon. In such an embodiment, the catheter could function not only for embolectomy or dilatation purposes, but also as a guiding catheter.
Given the wide variety of substitutions, all within the breadth of this concept, the broad scope of the invention should not be limited to the drawings and the described embodiments, but should be ascertained only with reference to the following claims.
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A catheter includes a body having tubular walls defining a lumen extending along an axis from the distal end of the body to a proximal end of the body. Portions of the walls define at least one balloon hole extending from the lumen through the walls of the body. Elastomeric material restrained to the hole defining portions interiorly of the body expand outwardly of the (catheter) body to form a balloon when the lumen is pressurized with fluid. The elastomeric material my take the form of a patch or a full lining of the catheter walls defining the lumen. A method for making the catheter includes the step of retaining portions of an elastomeric layer around the hole interiorly of the lumen. A preferred method of manufacturing the catheter includes the step of providing the catheter body and an inner layer of elastomeric sheet material simultaneously in a co-extruder.
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BACKGROUND OF INVENTION
[0001] The present invention relates generally to air conditioning systems for vehicles, and more particularly to secondary loop air conditioning systems.
[0002] In a typical secondary loop air conditioning system for a vehicle, a primary loop may include an engine driven compressor mounted for coupling to a front end accessory drive, a condenser mounted in a condenser, radiator, fan module (CRFM), an accumulator and expansion valve mounted separate from the compressor and condenser, and a refrigerant-to-liquid chiller mounted separately from the other components. The typical secondary loop air conditioning system may also include a secondary loop having a liquid-to-air heat exchanger mounted in a heating, ventilation and air conditioning (HVAC) module, a liquid reservoir and a pump for pumping the liquid through the chiller, heat exchanger and reservoir. While these secondary loop systems provide for some additional flexibility in configuring and operating the air conditioning system, they also add extra components and add additional packaging concerns when locating the components in the vehicle. Moreover, they may still require nearly as much refrigerant in the primary loop as conventional single loop refrigerant systems.
SUMMARY OF INVENTION
[0003] An embodiment contemplates an air conditioning system for a vehicle that may comprise a condenser and an integrated assembly. The condenser may have a first condenser header spaced from a second condenser header, a condenser core extending between the first and second condenser headers, and a refrigerant inlet operatively engaging the first condenser header. The integrated assembly may include a chiller mounted to the first condenser header and having a liquid inlet and a liquid outlet configured to be in fluid communication with a secondary loop of the air conditioning system, an expansion device in fluid communication with the condenser and mounted adjacent to the chiller for directing refrigerant into the chiller, and a refrigerant outlet. Also, a receiver/dryer area may be located in one of the condenser and the integrated assembly.
[0004] An embodiment contemplates an air conditioning system for a vehicle. The air conditioning system may include a refrigerant compressor, a condenser having a first condenser header spaced from a second condenser header, a condenser core extending between the first and second condenser headers, and a refrigerant inlet operatively engaging the first condenser header. The air conditioning system may also include an integrated assembly including a chiller mounted to the first condenser header and having a liquid inlet and a liquid outlet, an expansion device in fluid communication with the condenser and mounted adjacent to the chiller for directing refrigerant into the chiller, and a refrigerant outlet; a pump in fluid communication with the liquid outlet; and a cooler in fluid communication with the pump and the liquid inlet.
[0005] An embodiment contemplates an air conditioning system for a vehicle comprising a primary refrigerant loop and a secondary liquid loop. The primary refrigerant loop may include a refrigerant compressor; a condenser having a first condenser header spaced from a second condenser header, a condenser core extending between the first and second condenser headers, and a refrigerant inlet operatively engaging the first condenser header; an integrated assembly including a chiller mounted to the first condenser header, an expansion device in fluid communication with the condenser and mounted adjacent to the chiller for directing a refrigerant into the chiller, and a refrigerant outlet; and a sub-cool core located between the second condenser header and the integrated assembly and configured to direct the refrigerant from the second condenser header directly into the integrated assembly. The secondary liquid loop may include the chiller having a liquid inlet and a liquid outlet; a pump in fluid communication with the liquid outlet; and a cooler in fluid communication with the pump and the liquid inlet.
[0006] An advantage of an embodiment is that, by locating an integrated expansion device, chiller and receiver/dryer on a condenser header, a compact arrangement of components is created that allows for easier packaging in the vehicle. The number of lines extending between components is reduced. Also, a suction line length can be minimized by integrating the chiller on the same end of the condenser as the compressor is located. The compact arrangement of components for the refrigerant loop, then, allows for a minimal amount of refrigerant to be used in the overall air conditioning system. Moreover, the refrigerant does not enter the passenger compartment. Accordingly, some refrigerants that otherwise might not be suitable for use in a vehicle air conditioning system, such as flammable or mildly toxic refrigerants, may be used.
[0007] An advantage of an embodiment is that multiple cooling point air conditioning systems can be provided with a negligible increase in refrigerant charge versus a single point system. Only one chiller is used versus multiple evaporators for a conventional air conditioning system. This eliminates potential oil trapping issues that may arise with multiple cooling point (double evaporator) systems when a rear unit is turned off.
[0008] An advantage of an embodiment is that the expansion device mounted in the engine compartment with the integrated assembly, so the flow noise from this device is eliminated from the passenger compartment. Moreover, compressor working noise is greatly reduced or eliminated from the passenger compartment since the refrigerant lines do not enter the passenger compartment either.
BRIEF DESCRIPTION OF DRAWINGS
[0009] FIG. 1 is a schematic illustration of a vehicle air conditioning system.
[0010] FIG. 2 is a schematic illustration of an integrated expansion device, chiller and receiver/dryer assembly mounted to a condenser.
[0011] FIG. 3 schematic illustration similar to FIG. 2 , but illustrating a second embodiment.
[0012] FIG. 4 is a schematic illustration similar to FIG. 2 , but illustrating a third embodiment.
[0013] FIG. 5 is a schematic illustration similar to FIG. 2 , but illustrating a fourth embodiment.
DETAILED DESCRIPTION
[0014] Referring to FIG. 1 , a vehicle, indicated generally at 10 , is shown. The vehicle 10 includes an engine compartment 12 and a passenger compartment 14 , with an air conditioning system 16 mounted in portions of the compartments 12 , 14 . The air conditioning system 16 has a primary (refrigerant) loop 18 and a secondary (liquid) loop 20 .
[0015] The primary loop 18 includes a compressor 22 and a refrigerant line 24 leading from a compressor output 26 to a refrigerant inlet 28 of a condenser 30 . The refrigerant lines in FIG. 1 are illustrated as dash-dot-dash lines. The condenser 30 may be part of a condenser, radiator, fan module (CRFM) 31 . The primary loop 18 also includes an integrated expansion device, chiller, receiver/dryer assembly 32 that is mounted to the condenser 30 . The integrated assembly 32 has a refrigerant outlet 36 connected to a suction line 38 leading to an inlet 40 to the compressor 22 , thereby completing the primary loop 18 . Preferably, the integrated assembly 32 is mounted on the same end of the condenser 30 as the compressor 22 is located in order to minimize the length of the suction line 38 . The refrigerant contained in the primary loop 18 does not enter the passenger compartment 14 , and, given the compact arrangement of the components, the loop 18 is relatively small. Thus, types of refrigerants that might not otherwise be desirable for use in a passenger vehicle may be employed.
[0016] The secondary loop 20 includes a chiller 42 of the integrated assembly 32 , an expansion tank 44 , a pump 46 , a cooler 48 , and liquid lines 50 extending between these components. The liquid lines 50 are shown in FIG. 1 as phantom lines to distinguish them from the refrigerant lines. The cooler 48 may be mounted in a HVAC module 52 in the passenger compartment 14 . The liquid in the secondary loop 20 may be, for example, a mix of water and ethylene glycol. Although, the liquid that flows through the secondary loop 20 may be comprised of other types of suitable liquids with desirable thermal transfer properties, if so desired.
[0017] FIG. 2 illustrates the integrated expansion device, chiller, receiver/dryer assembly 32 and condenser 30 of FIG. 1 in more detail. The condenser 30 includes a first condenser header 34 upon which the refrigerant inlet 28 is located. The integrated assembly 32 is mounted to the first condenser header 34 . The condenser 30 also includes a condenser core 54 located above a sub-cool core 56 , which both extend to a second condenser header 58 . The sub-cool core 56 opens to a receiver/dryer area 60 in the integrated assembly 32 .
[0018] The receiver/dryer area 60 includes a desiccant 62 located therein, and opens to an expansion device 64 —which may be, for example, and orifice tube. The orifice device 64 directs the refrigerant into a chiller core 66 of the chiller 42 . Located opposite the chiller core 66 from the expansion device 64 is the refrigerant outlet 36 leading to the suction line 38 . A liquid inlet 68 to, and a liquid outlet 70 from the chiller 42 connect to the liquid lines 50 in the secondary loop. The integrated assembly 32 also includes a charge port 72 and a suction pressure sensor 74 mounted on top. One will note that most components of the refrigerant loop are integrated and packaged into a relatively small area.
[0019] The operation of the air conditioning system 16 will now be discussed relative to FIGS. 1 and 2 . The unnumbered arrows in FIGS. 2-5 represent the direction of flow of refrigerant and liquid into and out of the integrated assembly 32 . The compressor 22 and the pump 46 are driven, causing the refrigerant and the liquid to flow through the primary loop 18 and the secondary loop 20 , respectively.
[0020] In the primary loop 18 , after the refrigerant is compressed in the compressor 22 , the refrigerant flows through the refrigerant line 24 to the refrigerant inlet 28 on the first condenser header 34 . The refrigerant flows through the condenser core 54 , the second condenser header 58 , and the sub-cool core 56 . As with a conventional condenser, heat is transferred from the refrigerant to air flowing through the condenser 30 . From the sub-cool core 56 , the refrigerant flows into the receiver/dryer area 60 containing the desiccant 62 , where moisture is removed from the refrigerant. The refrigerant then flows through the expansion device 64 , dropping the temperature of the refrigerant, before flowing through the chiller 42 . The refrigerant then flows through the refrigerant outlet 36 and the suction line 38 and back to the compressor 22 .
[0021] In the secondary loop 20 , the liquid flows through the liquid inlet 68 and through the chiller core 66 , where heat is transferred to the refrigerant. The liquid then flows through the liquid outlet 70 and through one of the liquid lines 50 to the pump 46 . As the liquid flows past the expansion tank 44 , liquid may be removed from or added to the secondary loop 20 . The pump 46 pumps the liquid through another liquid line 50 to the cooler 48 , where it absorbs heat from air flowing through the HVAC module 52 . The liquid then flows back to the chiller inlet 68 .
[0022] FIG. 3 illustrates a second embodiment. Since this embodiment is similar to the first, similar element numbers will be used for similar elements, but employing 100 -series numbers. FIG. 3 shows an alternate embodiment of the integrated expansion device, chiller, receiver/dryer assembly 32 and condenser 30 shown in FIG. 2 .
[0023] The integrated assembly 132 is still mounted to the first condenser header 134 , but the refrigerant inlet 128 is located on the bottom of the first condenser header 134 while the sub-cool core 156 is located on top of the condenser core 154 . The second condenser header 158 is still on the opposite side of the condenser core 154 from the integrated assembly 132 . The receiver/dryer area 160 and desiccant 162 are still adjacent to and receive refrigerant from the sub-cool core 156 , but now are located above the chiller 142 . The expansion device 164 directs the refrigerant downward from the receiver/dryer area 160 to the chiller core 166 . The refrigerant outlet 136 (connecting to the suction line 138 ) is located below the chiller core 166 . The charge port 172 and the suction pressure sensor 174 are now located near the bottom of the integrated assembly 132 . Also, the liquid inlet 168 is now located below the liquid outlet 170 . The operation of the air conditioning system 116 is essentially the same as in the first embodiment and so will not be discussed further.
[0024] FIG. 4 illustrates a third embodiment. Since this embodiment is similar to the first, similar element numbers will be used for similar elements, but employing 200 -series numbers. FIG. 4 shows another alternate embodiment of the integrated expansion device, chiller, receiver/dryer assembly 32 and condenser 30 shown in FIG. 2 .
[0025] The integrated assembly 232 is still mounted to the first condenser header 234 , but the refrigerant inlet 228 is now located on the bottom of the first condenser header 234 while the sub-cool core 256 is located on top of the condenser core 254 . The second condenser header 258 is still on the opposite side of the condenser core 254 from the integrated assembly 232 , but the receiver/dryer area 260 and the desiccant 262 are located in the second condenser header 258 . The expansion device 264 is mounted on top of the chiller 242 and directs refrigerant downward into the chiller core 266 . The chiller 242 is a plate type of heat exchanger, with the refrigerant outlet 236 extending from the bottom of the chiller 242 . The liquid inlet 268 is located adjacent to the refrigerant outlet 236 , and the liquid outlet 270 is located above the liquid inlet 268 .
[0026] FIG. 5 illustrates a fourth embodiment. Since this embodiment is similar to the first, similar element numbers will be used for similar elements, but employing 300 -series numbers. FIG. 5 shows an alternate embodiment of the integrated expansion device, chiller, receiver/dryer assembly 32 and condenser 30 shown in FIG. 2 .
[0027] The integrated assembly 332 is again mounted to the first condenser header 334 , with a condenser core 354 and sub-cool core 356 mounted between the first condenser header 334 and the second condenser header 358 . An expansion device 364 is mounted adjacent to and receives refrigerant from the sub-cool core 356 . An oil ring 376 is located between the expansion device 364 and the chiller core 366 . The chiller core 366 may be a vertical extrusion. Another oil ring 378 is located above the chiller core 366 , with a snap retainer 380 above the oil ring 378 . The refrigerant outlet 336 extends upward above the snap retainer 380 . Also, the liquid inlet 368 and liquid outlet 370 extend upward above the snap retainer 380 .
[0028] While certain embodiments of the present invention have been described in detail, those familiar with the art to which this invention relates will recognize various alternative designs and embodiments for practicing the invention as defined by the following claims.
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A secondary loop air conditioning system for a vehicle that includes a condenser and an integrated assembly is disclosed. The condenser has a first condenser header spaced from a second condenser header, a condenser core extending between the first and second condenser headers, and a refrigerant inlet operatively engaging the first condenser header. The integrated assembly includes a chiller mounted to the first condenser header and having a liquid inlet and a liquid outlet configured to be in fluid communication with a secondary loop of the air conditioning system, and an expansion device in fluid communication with the condenser and mounted adjacent to the chiller for directing refrigerant into the chiller, and a refrigerant outlet. Also, a receiver/dryer area may be located in one of the condenser and the integrated assembly.
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FIELD
[0001] The present invention relates generally to an apparatus used to tap beer kegs and dispense beer. More specifically the present invention relates to a lightweight portable beer keg tap and beer dispenser operated by CO 2 gas from a compressed gas cylinder.
BACKGROUND OF THE INVENTION
[0002] We can trace the beginning of beer drinking far back beyond the dawn of recorded time. Most likely, a crude form of beer was discovered by accident when someone mixed barley with water and then let it sit long enough for stray yeast cells to settle, triggering fermentation. The Babylonians, Assyrians, Egyptians, Hebrews, Africans, Chinese, Incas, Teutons, Saxons and various wandering tribes all discovered beer by various independent means. The dispensing system used by these early brewers were amphora, mugs and the early equivalent of straws, which were used to sip the liquid beer while avoiding the brewer's residue.
[0003] From the middle ages, when the use of hops made beer clear, until the 1890's, beer was stored in and dispensed from wooden barrels through simple valves and delivered to the drinker mug or glass by gravity flow. From the 1950's to the present most draft beer has been shipped in and dispensed from kegs that are cylindrical, made of stainless steel or aluminum and contain an extractor tube.
[0004] To dispense the beer from the keg a pressurizing gas, air or CO 2 , is forced into the keg through a beer keg tap. The liquid beer is forced out through the extractor tube, flexible hoses and a delivery faucet. Air is very undesirable as a pressurizing gas because the oxygen in air makes beer quickly go stale or sour. Air can be used when the entire keg is to be drunk quickly. Air cannot be used as a pressurizing gas if the keg must be stored and the beer consumed over a period of time.
[0005] There are two general types of beer dispensing systems taught by the prior art. One is a commercial system that uses heavy pressure bottles of compressed carbon dioxide gas operating through regulators and pressure lines to pressurize one or more kegs. The other is a consumer system usually used at a party or picnic that uses an air pump, which may be a hand powered or electrically operated compressor, to pressurize the keg. This is therefore commonly known as a picnic pump system.
[0006] Advantages of the commercial beer dispensing systems include the use of CO 2 dispensing systems that prevent air from coming in contact with the keg beer and thus allowing the keg beer to stay fresh for a longer period of time than when air is used as a pressurizing gas. Another advantage of a commercial beer dispensing system is the ability to control the pressure of the gas supplied to the keg through the use of adjustable regulators and pressure gauges. This feature is a marked advantage over a picnic pump system as it allows the pressure to be finely tuned to the individual type of beer or the specific temperature of the keg to prevent excessive foaming of the dispensed beer as is often encountered in the picnic pump systems.
[0007] Examples of commercial beer dispensing systems may be found in most bars and restaurants. This equipment is cumbersome and industrial. Their ‘rat's nest’ of tubing is a common feature behind bars. These commercial CO 2 dispensing systems weigh hundreds of pounds and can operate dozens of beer keg taps and draft beer dispensers. This equipment is completely unsuitable for use at picnics, parties or for the large and growing number of drinkers who wish to keep a keg of beer at home in their refrigerator so they can have draft beer at home on demand.
[0008] Picnic pumps such as the one taught by U.S. Pat. No. 4,711,377, issued to Brown on Dec. 8, 1987 use a hand-operated air pump. Such pumps are common and exist in hundreds of variations. These pumps are small and lightweight, but they pressurize the beer keg with air, which makes them unsuitable for use with a home keg because contact with the oxygen in air quickly ruins the beer.
[0009] U.S. Pat. No. 5,785,211 teaches a portable electrically powered keg-tapping device for use with regular beer kegs. The electrical compressor is a good replacement for a hand pump, but it does not solve the problem of introducing air into a keg that must be stored and used over a period of time.
[0010] An advantageous beer pumping system would combine the beer preservation and adjustable pressurization available with commercial type systems with the low profile and portability of a picnic pump system. Portable beer dispensing systems, such as the one taught by U.S. Pat. No. 5,199,609, issued to Ash on Apr. 6, 1993, teach the use of a CO 2 bottle packaged in a backpack and connected by pressure tubes to a container of beer. This type of dispenser, and there are many examples in the prior art, is useful for dispensing beer at sporting events, but uses a special small beer tank and thus cannot be of any use to home beer keg owners.
[0011] Another portable beer dispensing system, U.S. Pat. No. 2,571,433, issued to Fine et al. on Oct. 16, 1951, teaches the use of a small pressurized cylinder and a regulator permanently attached to a specialized beer container. However, the specialized beer container is not commercially available. Furthermore the pressurization system is permanently attached to the non commercially available specialized beer container. Additionally, the presence of a cover over the pressurization system does not facilitate precision pressure adjustments for individual types of beer or specific keg temperatures to prevent unwanted foaming. A more useful device will combine all the advantages of a commercial beer pumping system, such as CO 2 pressurization to maintain beer freshness and easy adjustability of the CO 2 pressure to prevent foaming, with the low profile and portability of a picnic pump system. Interestingly, no devices that incorporate all the advantages of a commercial beer pumping system with the low profile and portability of a picnic beer pumping system currently exist.
[0012] This combination would allow for a simple home draft beer system by placing a small, easily adjustable CO 2 pressurized beer pump on any commercially available beer keg. The keg with the beer pump could then be placed in any conventional refrigerator for to keep the beer at a constant drinkable temperature. Currently, home kegs may be kept in refrigerated one keg systems, such as the Beer Baron® sold by Ajex USA, Inc. of Commerce City, Colo., but such “home” draft beer systems are huge, weigh several hundred pounds and are very expensive.
[0013] U.S. Pat. No. 4,180,189, issued to Zurit et al. Dec. 25, 1979 teaches the use of a standard keg tap using a conventional bayonet type of connection to attach the tap to the keg. In addition U.S. Pat. No. 4,180,189 also teaches the use of a pressure inlet to pressurize the beer keg in combination with a Thomas valve designed to prevent back pressure or beer from flowing out of the pressure inlet into the pressure producing source. However, the incorporation of a Thomas valve to help prevent back pressure or beer into the pressure producing has not been rigidly attached to a regulator and a rigidly attached gas canister designed for kegs to be stored in a home refrigerator. The Thomas valve in U.S. Pat. No. 4,180,198 would be designed to prevent back pressure or beer from flowing into a flexible tube used to deliver pressure to the tap, thereby preventing damage to the flexible tube. A desirable invention, in combining all the advantages of a commercial beer pumping system with the low profile and portability of a picnic beer pumping system would have a Thomas valve directly attached to a check valve and furthermore to an easily adjustable pressure regulator and finally attached to a pressurized CO 2 canister.
[0014] It is applicant's belief that none of the above prior art systems have received commercial recognition because they either are too expensive to construct, or are not reliable. None of the above prior art systems solve the problems facing the home keg owner who wishes to tap the keg and still keep the beer fresh over an extended period.
SUMMARY OF THE INVENTION AND ADVANTAGES
[0015] The invention is a beer dispensing system comprising a beer tap connected directly to an adjustable pressure regulator and a small CO 2 pressure bottle. The present invention combines the advantage of the commercial CO 2 beer dispensing system of operating with a full sized beer keg and keeping the beer fresh over a long period with the advantages of the small, lightweight, simple and convenient air operated party pump.
[0016] Yet another advantage of the present invention is that it provides a lightweight and small CO 2 operated beer-dispensing system that does not require the use of cumbersome hoses and pressure tubes.
[0017] Another advantage of the present invention is that it provides a beer dispensing system that will operate with a standard keg in a regular home refrigerator.
[0018] Yet a further advantage of the present invention is that it provides a CO 2 powered beer dispensing system that is small, lightweight, inexpensive and reliable.
[0019] Another advantage of the present invention is that it provides for precision adjustability of the pressure regulator, allowing the user to adjust the pressure of the beer tap for each individual type of beer or specific temperature of the keg, thus preventing the uncontrolled foaming that is often encountered with the picnic pump systems.
BRIEF DESCRIPTION OF THE DRAWINGS
[0020] FIG. 1 shows the major components of the portable beer delivery system of the present invention with the individual parts separated for clarity; and
[0021] FIG. 2 shows the present invention mounted on a beer keg that is stored in a home refrigerator.
DESCRIPTION OF THE PREFERRED EMBODIMENT
[0022] FIG. 1 shows the components of the present invention and how they fit together. The components are shown separated for clarity.
[0023] In FIG. 1 , aluminum alloy CO 2 cylinder 101 is a 16-ounce capacity 800 p.s.i. cylinder that is commercially used to power paint ball guns. It is available from Catalina Cylinders of Trumann, Ariz. They are inexpensive and safe.
[0024] Structurally, outlet 102 of cylinder 101 is attached to and in fluid communication with the inlet of needle valve 103 , which is commercial low-pressure needle valve. Valve 103 has a threaded outlet 105 that is connected to and in fluid communication with the threaded inlet 107 of pressure regulator 111 by means of pressure regulator inlet pipe 109 . Pressure regulator 111 may be any commercial pressure regulator capable of accepting an input pressure of 800 PSI and producing an easily adjustable variable output pressure of from zero to 50 PSI. One example is the model 03G07-222 forged brass regulator sold by the Foxx Equipment Company of Kansas City, Mo. (“Foxx”). Regulator 111 is equipped with two pressure gauges, a low pressure gauge 112 , designed to measure the pressure within the keg, and a high pressure gauge 114 , designed to measure the pressure of the gas cylinder. Regulator 111 is also designed so that the pressure in the keg and the corresponding readout of the low pressure gauge 112 may be varied for each individual type of beer. This is accomplished by simply turning an adjustment device on the regulator 111 to the desired keg pressure. Regulator 111 also has its outlet 113 in threaded connection and fluid communication with inlet 115 of check valve with nipple 117 . Check valve 117 may be a model 03G07-232 brass check valve sold by Foxx. The outlet nipple 119 of check valve 117 mates in fluid communication with rubber Thomas valve 121 and is threadingly attached to and in fluid communication with pressurization inlet 123 of beer keg tap 125 . Beer keg tap 125 may be a universal twist style Sanke Tap® model number 07S07-102 available from Foxx. Beer tap 125 has a standard beer keg tap pressure fitting 127 that is adapted to operable engage a standard beer keg, not shown. Beer tap 125 also has a beer outlet 128 . Beer outlet 128 is connected to and in fluid communication with flexible beer hose 129 and beer delivery faucet 131 . Beer dispensing faucet 131 is attached at its inlet to and in fluid communication with beer hose 129 . Beer dispensing faucet 131 is a standard hand-dispensing faucet having a hand-operating lever 133 and an outlet spout 135 for the delivery of the beer to a cup or glass, not shown. Faucet 131 may be a model 18A03-102 sold by Foxx.
[0025] Functionally, the high pressure CO 2 gas in cylinder 101 passes through needle valve 103 and into pressure regulator 111 where it is reduced in pressure from 800 PSI to about 20 PSI. The low pressure CO 2 then passes out of regulator 111 , through check valve 117 , Thomas valve 121 and beer tap 125 into the beer keg, which it pressurizes in a well-known manner. Beer from the keg flows out through beer tap outlet 128 , through flex tube 129 to faucet 131 where it is dispensed to the drinker.
[0026] The entire invention including the CO 2 weighs less than six pounds and can be used to tap beer from any standard keg.
[0027] FIG. 2 shows the present invention used as a tap for a beer keg in an ordinary kitchen refrigerator. In FIG. 2 , refrigerator 201 contains a beer keg 203 . The portable beer keg tap and dispenser of present invention 205 is shown tapped into the keg. CO 2 tank 207 is attached to valve and regulator and tap assembly 209 , which is attached to keg 203 . Flex line 211 and faucet 203 are attached to tap assembly 209 . Depicted on the tap assembly is the low pressure gauge 112 , designed to measure the pressure within the keg, and the high pressure gauge 114 , designed to measure within the gas cylinder. The refrigerator keeps the beer cold so it will not produce excess foam when it is dispensed. The present invention may operate as shown, vertically, or with the keg laid sideways in the refrigerator and with an insulating barrier placed between the keg and the front of the refrigerator. This embodiment of the invention hides the keg and the dispensing systems so only flex line 211 and faucet 213 is visible. This provides a neat and convenient home draft beer dispenser that would keep the beer fresh; just a commercial system does in a bar.
[0028] Beer must be maintained above freezing and below 42° F. in order to maintain proper freshness and carbonation. The chart below gives the target CO 2 pressure to be set on the regulator for various temperatures to allow 6 weeks of perfectly carbonated beer. Beer is best stored and served below a 40° F. keg temperature.
Keg Temperature & Pressure Chart (for all 100% CO 2 Systems) Keg 35 37-38 38-39 40 41-42 43-44 Temperature (° F.) Internal Keg 10 11 12 13 14 15 Pressure (pounds) Minimum 13 14 15 16 17 18 Applied Pressure (pounds) Maximum 16 17 18 19 20 21 Applied Pressure (pounds
[0029] Depending on the chemical composition of the beer, different beer brands may require various gas pressure adjustments to prevent foaming and to maximize pouring ability. Now more than ever, there is an increased demand for foreign beers with chemical compositions that often vary greatly from region to region. In addition, the explosion of microbreweries in the United States as also altered the once nearly uniform composition of beers available in this country. Standard American lager beers for example are composed of higher water content than that of popular English and Irish beers. The percentage of water in the beers affects the viscosity, and therefore affects the length of time needed for a beer head to settle after pouring at a given pressure. It is therefore necessary to adjust the pressure for each individual type of beer to provide for optimal pouring effectiveness.
[0030] For example, standard American lager beers are poured at a pressure of 10-15 p.s.i., while many of the European beers require that they be poured at a pressure of 5-7 p.s.i.
[0031] Although this specification discloses the best embodiment of the invention known to the inventor, it should not be read as limiting the invention. The invention should be limited only by the appended claims and their equivalents.
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A lightweight beer dispensing system comprising a small carbon dioxide pressure bottle attached directly to an adjustable pressure regulator that can be set to avoid excess foaming is attached directly to a keg tap having a delivery faucet. The invention taps a full size beer keg and uses CO 2 to keep the beer fresh thus avoiding the problem of introducing oxygen into the beer keg.
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BACKGROUND OF THE INVENTION
This invention relates generally to dental tools and pertains more particularly to a special dental removal system for radicular posts/dowels and other intercanal obstructions.
It is common practice in dentistry to place a post and core within an endodontically treated tooth to mechanically enhance the retention of a dental restoration. First the root canal system is cleaned, shaped, and obturated, followed by creating a specific preparation within a root canal for the subsequent placement of a particular post type. The selected post is then seated and retained by cement or adhesives. A dental restoration is subsequently fabricated and cemented or bonded over the post, core and remaining prepared tooth structures. Posts can be fabricated or selected in a variety of geometrical configurations and dental materials. Generally, post-types include parallel, tapered (screw or cast configurations), or fiber posts. Posts vary according to length, diameter, shape, head configurations, and are further selected according to stock versus custom. Post materials utilized range from precious and nonprecious metals to non-metallic posts, such as the new carbon fiber varieties. Furthermore, posts are placed and then retained by reliable cements and new generation, highly retentive bonding agents. In any event, over time, many endodontic cases fail necessitating post removal to facilitate endodontic retreatment procedures and/or prosthetic rehabilitation.
In the past, post removal has been difficult due to lack of effective tools for the task. Historically the procedures for post removal included drilling, vibrating with rotosonics or ultrasonics instruments, or utilizing awkward devices that posed significant limitations and typically sacrificed great amounts of tooth structure; hence, predisposing the root to perforation or subsequent fracture. The aforementioned techniques were employed until the post was loosened and removed. Certain post types and cementing materials retain posts so securely that the techniques described are either unsuccessful, time consuming, or aggressively predispose to irreversible root damage and the loss of the tooth. Finally, the technical inability to remove a post, or perceived inability, has led to countless surgical procedures.
Therefore, there is a need for an improved dental removal system that can be utilized for the safe and effective elimination of dental posts/dowels and other intercanal obstructions.
SUMMARY OF THE INVENTION
A primary objective of this invention is to provide a significantly improved dental removal system for radicular posts/dowels and other intercanal obstructions.
In accordance with a primary aspect of the present invention a dental tool apparatus for use in the removal of a dental post comprises the combination of a pliers having a first end for mounting a post connector and a second end having means for applying a force to said connector, a substantially elongated post connector defined by a shaft having a proximal end with attachment means at said proximal end for attachment to a lever device, and a distal end having an open bore with a stepped diameter and self taping threads in said bore at said end for engaging and threading onto a dental post.
BRIEF DESCRIPTION OF DRAWING
The objects, features and advantages of this invention will be more readily appreciated from the following detailed description, when read in conjunction with the accompanying drawing, in which:
FIG. 1 is a side elevation view of the dental removal system in accordance with an exemplary embodiment of the invention;
FIG. 2 is an enlarged view of the tubular tap connecting device of the dental removal system of FIG. 1;
FIG. 3 is a view taken on line 3--3 of FIG. 2;
FIG. 4 is a side elevation view of the trephine used for machining the coronal most aspect of the exposed intercanal obstruction;
FIG. 5 is a side elevation view of a tooth with a post cemented in place;
FIG. 6 is a view like FIG. 5 showing the prosthetic crown and core removed, and the coronal most part of the post exposed and machined-down utilizing a specific trephine;
FIG. 7 is a view like FIG. 6 showing the removal system of FIG. 1 in position to initiate extrication forces required to remove the posts; and
FIG. 8 is a top plan view of the connecting end of the extracting plier.
DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS
The present invention is directed to and concerns an improved dental removal system for the safe and effective removal of dental posts and other interadicular obstructions. The apparatus is described with reference to preferred embodiments of the invention as illustrated in the drawings. While this invention is described in terms of the best mode for achieving this invention's objectives, it will be appreciated by those skilled in the art that variations may be made in view of these teachings without deviating from the spirit or scope of the invention.
Referring to FIG. 1 of the drawings there is illustrated an exemplary embodiment of an apparatus for removal of dental posts and other intercanal obstructions, in accordance with the present invention, designated generally by the numeral 10. The illustrated apparatus comprises a tubular tap for engaging a post or other canal obstructions, a protective cushion, and an extracting plier. The pliers comprises upper and lower levers 12 and 14 pivotally connected together at a pivot pin 16 so that both levers are on opposite sides of the pivot point. With this connection arrangement, when the ends of the levers on one side of the pivot point are brought together by the screw knob, the opposite end of the levers move apart. This provides a leveraging or separating force as opposed to a gripping force.
The extracting pliers lever units each have a first or connecting end 18 and 20 having provision, such as a bore or slot for receipt of the tubular tap 22 which connects to a post or other intercanal obstruction. The extracting plier is used to mount on the tubular tap and the screw knob applies a leveraged extraction force to a post in a tooth root as will be hereinafter described. A spring latch or retainer member 24 is attached at one end to the upper lever 12 and at the other end secures or holds the tubular tap connector 22 in place within the extracting plier unit.
The extracting pliers levers each have a second end 26 and 28 which is on the longer of the arms of each lever and are used as will be described for force input. An elongated screw 30 is connected between the second ends 26 and 28 of the levers 12 and 14 and functions to pull the second ends of the levers together to spread the first ends 18 and 20 apart and apply force to the tubular tap connector 22. The screw 30 is rotatably mounted in a bore in a plug or pin member 32 at the outer end of the upper lever 12 and is threadably engaged in a threaded bore in a nut 34 in the lower outer end 28. A turning knob or handwheel 36 is mounted on the upper end of the screw 30 to enable finger or hand application of torque to the screw to rotate it and draw the outer ends 26 and 28 of the levers 12 and 14 together and forcing the connecting ends apart.
Referring to FIG. 2, the tubular tap connector 22 is illustrated and comprises an elongated tubular shaft 38 having a bore 40 with an open end 42 with tapping or cutting threads 44 at the open end. The bore is formed with a smaller diameter at the open end for threads 44 with a larger diameter extending from the threads to substantially the other end of the shaft 38. The outer surface of the shaft is formed with an enlarged diameter portion 46 having a rounded bearing portion 48 for engagement with the connecting end 18 of the upper lever 12 of the extracting plier. An enlarged head 50 is formed as a thumb wheel with a knurled surface to grasp and rotate the connector to thread it onto an end of a post. A plurality of cross bores (only one shown) 52 are formed in the thumb wheel for receiving a handle in the form of a rod for applying torque to enhance rotational efficiency of the tubular tap connector.
The tubular tap connector is designed to thread onto the coronal most end of a dental post or other intercanal obstruction as will be subsequently discussed with respect to FIG. 7. The threads 44 are self taping, that is they cut or form threads on the post or any other intercanal obstructions as the engaged tubular tap head is rotated. The tubular tap is threaded, engaged and connected to the post or intercanal obstruction which enables removal tension to be utilized during the extricating process.
Referring to FIG. 4, a trephine in the form of a coring mandrel or hollow drill is illustrated and designated generally by the number 56. This tool comprises an elongated cylindrical body 54 having a tubular cutting tip or end 56. The cutting end 56 is an elongated tubular section having a bore 58 for receiving a dental post or other intercanal obstruction and an annular or peripheral set of cutting teeth 60 for cutting and machining down the most coronal aspect of the post or other type of obstruction. The drill 56 is formed with a tool connector head comprising a flat 62 and a groove 64 for mating with a suitable slow-speed handpiece for rotating the drill for the cutting and machining the coronal most aspect of the post or other obstruction. The trephine drill is provided with one or more indicia rings 65 for identifying a specific drill unit size.
Referring to FIG. 5, the natural tooth's root is illustrated at 66 having an internal cavity or root canal 68 in which has been mounted a post 70 retained by cement or a bonding agent 72. A prosthetic crown 74 is seated on the prepared natural root/crown and is anchored to the post 70 and post head 76 with cement or bonding agent. The post head 76 is typically embedded in the prosthetic crown or build-up core material.
Referring to FIG. 6, the prosthetic crown 74 has been removed and the coronal cement/core 72 has been eliminated exposing the post head 76. The post 70 has a post head 76 which is machined down coronally 78 creating a round specifically sized cylinder. The post head 76 is machined-down at 78 utilizing a tool called a trephine 54 illustrated in FIG. 4. The trephine 54 is positioned such that its cutting edge 60 engages the post head 76 and rotated so the post head 76 is machined down at 78. This action results in forming a round cylinder, as illustrated in FIG. 6 for receiving a tubular tap. The working end 42 of the tubular tap connector 22 is fitted over the rounded cylinder 78 and screwed on and drawn-down over the coronal most end of the post 70. Specific dental burs and/or ultrasonic instruments are used to remove circumferential tooth structure or restorations from around the post or other intercanal obstructions. A specifically sized tool 54 will machine down and size the post head 76 so a correspondingly sized tubular tap 22 can be selected and engage a post or other intercanal obstruction.
The post head 76 is engaged by the open end 42 of the connector 22, such that the threads 44 engage and cut or form threads in the post as the connector is rotated. As soon as the connector has been rotated sufficiently to form a secure connections over a portion of the coronal end of the post 70, the extracting plier may then be activated to pull the tubular tap connector upward with respect to the natural tooth root 66 and thereby pulls the post or obstruction from the root canal 68. A cushion 80 of sufficient diameter protects the natural tooth or prosthetics by evenly distributing the removal loads over the biting surface of the tooth. The extracting pliers lower lever 20 pushes down on the bumper cushion 80 and protects the tooth as illustrated in FIG. 7. Thereafter, the hand knob 36 is rotated, thereby rotating screw 30 so that the outer ends 26 and 28 of the pliers levers are drawn together thereby spreading the levers or jaws 18 and 20. This pulls the tubular tap connector 22 engaging the post 70 which is cemented or bonded 72 from the root canal 68.
Referring to FIG. 8, a top view of the connector end of the extracting plier is illustrated showing a slot 80 through the levers for receiving the tubular tap connector 22. A scalloped recess 82 in the top of the upper lever receives and engages the rounded portion 48 of the connector.
In summary, an exemplary embodiment of a dental removal system for posts/dowels and other obstructions or kit in accordance with the present invention, comprises a Domer Bur, 5 trephines and 5 correspondingly sized tubular taps, variably sized protective cushions, a torque pin, and an extracting plier. Clinically, root canal obstructions can have their coronal ends modified and rounded with the Domer Bur which helps guide the subsequently used instruments. Specifically, post heads can be altered to precise diameters with any particular trephine so a correspondingly sized tubular tap can be rotated to form threads, engage and be drawn down over a particular obstruction.
The extracting plier is mounted to the engaged tubular tap. The extracting plier has two jaws that can progressively open and are controlled by turning the screw knob. As the extracting plier jaws open, force is exerted on the engaged tubular tap as the knob is turned until the obstruction is loosened and removed. Some obstructions can be engaged and removed by just trephines and/or tubular taps without utilizing the extracting plier. Additionally, certain other obstructions can be extracted by using only the extracting plier in conjunction with existing dental and medical instruments other than trephines and tubular taps.
The present post removal system is best employed when ultrasonic efforts are not successful. The post removal system requires that all pulp chamber restorative materials circumferential to the post be removed. These materials include composite, amalgam, bonding agents, and cements.
In the case where a tap strips off the post, a sequentially smaller tap can be used or the procedure restarted again using a smaller trephine bur and corresponding tap.
Cast cores must be reduced in size with high speed burs until a diameter is created slightly larger than dimensions of the interradicular dowel. Caution must be exercised to not over reduce the head of the post which could prevent engaging the post with the smallest tap. The trephine burs should be used on the same axis as the post to prevent over-reduction. If a thin incisal edge of an anterior tooth is encountered, it can be reduced to increase the surface flatness and better distribute the removal loads. Modified wooden tongue depressors can be placed on the incisal edges of adjacent teeth to better distribute and dampen the removal loads.
The extracting plier should never be used on a screw post as its threads typically are engaging lateral dentin and a fractured root is likely to occur. The Domer Bur is used to round off the coronal most aspect of the post. This is important as it guides and directs the trephine and tap over the post and along its axis.
The preferred procedure is to select the largest trephine possible that will just engage the post. Using a high torque, low speed handpiece set in a clockwise direction, drill down over the coronal most aspect of the post approximately three millimeters. Select a silicone cushion of adequate size such that it will not be displaced into the access cavity and will distribute the post removal loads over the biting surface of the tooth evenly. Select the tap corresponding to the trephine size and insert the silicone cushion onto this instrument.
Place the tap onto the coronal most aspect of the rounded post and firmly push in an apical direction, screwing it onto the post with a counter-clockwise rotation. Ideally, the tap should be threaded down over the post approximately three millimeters. Once the tap securely engages the post, the torque pin can be inserted through the head of the tap for added leverage on larger posts, or used to rotate the tap counter-clockwise to unscrew a threaded post. Push the silicone cushion down so it contacts and protects the tooth.
Orient the pliers to the extracting jaws engage the tap. When correctly inserted, one jaw will be against the cushion and the opposing jaw is under the outcropping on the tap. The tubular top's thin metal retention flange is between the outcropping and tap handle.
Holding the Remover firmly with one hand, use the free hand to turn the screw knob clockwise which will open the jaws. As the jaws begin to open, make certain the cushion is properly protecting the tooth. Continue turning the screw know until post loosens and can be removed. If resistance is encountered, a CPR 1 ultrasonic instrument can be held on the tap to encourage post retention failure and allow the knob to be progressively turned.
While we have illustrated and described our invention by means of specific embodiments, it is to be understood that numerous changes and modifications may be made therein without departing from the spirit and the scope of the invention as defined in the appended claims.
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A dental tool apparatus for use in the removal of a dental post and other intercanal obstructions comprises a pliers having a first end for mounting a post connector and a second end for applying a force to the connector a substantially elongate post connector defined by a shaft having a proximal for attachment to a lever device, and a distal end having an open bore having a stepped diameter and self taping threads in the bore at the end for engaging and threading onto a dental post.
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CROSS-REFERENCE TO RELATED APPLICATION(S)
The present application is a 35 U.S.C. §371 national phase conversion of PCT/EP2015/051184 filed on Jan. 22, 2015, which claims priority of European Application No. 14356001.9 filed on Jan. 24, 2014. Applicants claim priority to each of the foregoing patent applications. The PCT International Application was published in the English language.
FIELD OF THE INVENTION
The present invention relates to a novel method for preparing 1-alkyl-3-difluoromethyl-5-fluor-1H-pyrazole-4-carbaldehydes or esters thereof of formula (I) by means of reductive dehalogenation, starting from 1-alkyl-3-chlorodifluoromethyl-5-fluoro-1H-pyrazole-4-carbaldehydes or esters thereof of formula (II)
wherein R 1 is C 1 -C 6 -alkyl and R is H or C 1 -C 6 -alkoxy.
BACKGROUND OF THE INVENTION
1-Alkyl-3-haloalkyl-5-fluoropyrazolecarbaldehydes and esters thereof are important building blocks for preparing plant protection active ingredients, particularly SDHI fungicides.
1-Alkyl-3-difluoromethyl-5-fluor-1H-pyrazole-4-carbaldehydes was so far typically prepared in a multi-stage transformation starting from difluoromethylacetoacetate (WO 2011061205):
Starting material for this transformation, i.e. ethyldifluoracetoacetate, is a rather unstable compound, difficult to purify and which loses its quality during storage. This makes the utilization of this compound, especially on industrial scale, difficult.
The transformation of pyrazolic compounds bearing CF 2 H group is a challenging task as well, since this group is rather unstable under acidic conditions and easily releases fluoride which can damage reaction vessel, especially on a technical scale.
A process for the preparation of esters of 1-alkyl-3-fluoroalkylpyrazole-carboxylic acids via the reduction of 3-chlorodifluoromethylpyrazolic carboxylates was known from WO 2012/010692. Nevertheless, it was not known nor expected that a reductive dehalogenation of CF 2 Cl-group can occur in pyrazoles bearing a halogen atom in position 5 or a carbaldehyde function in position 4 without undesirable effect on said halogen atom in position 5 or carbaldehyde function in position 4. On contrario, the skilled man would expect that the aldehyde group will also at least partially react, and/or that the fluorine atom in position 5 will also at least partially react, as it is shown or suggested in WO 2013/171134 and WO 2004/063165. Indeed WO 2013/171134 shows the reductive elimination of the halogen atom in position 5 of 5-chloro-1-alkyl-3-difluormethylcarbaldehyde, and WO 2004/063165 describes the removal of a chlorine atom in N-aryl-3-methyl-5-chloropyrazole-carbaldehydes.
SUMMARY OF THE INVENTION
It has now surprisingly been found that, under the conditions of the invention, it is possible to selectively remove a halogen atom from a chlorodifluoromethyl group in 1-alkyl-3-chlorodifluoromethyl-5-fluoro-1H-pyrazole-4-carbaldehydes of formula (IIa) or 1-alkyl-3-chlorodifluoromethyl-5-fluor-1H-pyrazole-4-carboxylates of formula (IIb), without affecting or reducing the fluorine atom in position 5, without reducing the carbaldehyde or carboxylate group in position 4 and without attacking the pyrazole ring.
It has also surprisingly been found that the reductive dehalogenation of 5-Fluoro-1-alkyl-3-chlorodifluoroalkyl-1H-pyrazole-4-carbaldehydes and esters thereof leads selectively and in high yield to the 1-alkyl-3-difluoromethyl-5-fluoro-1H-pyrazole-4-carbaldehydes and esters thereof.
It has now been found that 1-alkyl-3-difluoromethyl-5-fluor-1H-pyrazole-4-carbaldehydes or esters thereof of formula (I)
wherein R 1 is C 1 -C 6 -alkyl and R is H or C 1 -C 6 -alkoxy,
can be obtained by reacting 5-fluoro-1-alkyl-3-chlorodifluoromethyl-5-fluoro-1H-pyrazole-4-carbaldehydes or esters thereof of formula (II)
wherein R and R 1 are as stated above,
by means of catalytic hydrogenation and optionally in the presence of a base.
It has now been found that 1-alkyl-3-difluoromethyl-1H-pyrazole-4-carbaldehydes of formula (Ia) or 1-alkyl-3-difluoromethyl-5-fluoro-1H-pyrazole-4-carboxylates of formula (Ib)
where R 1 is C 1 -C 6 -alkyl, and R 2 is C 1 -C 6 -alkoxy,
can be obtained by reacting 5-fluoro-1-alkyl-3-chlorodifluoromethyl-5-fluoro-1H-pyrazole-4-carbaldehydes of formula (IIa) or 1-alkyl-3-chlorodifluoromethyl-5-fluor-1H-pyrazole-4-carboxylates of formula (IIb) respectively
where R 1 , R 2 have the meanings stated above,
by means of catalytic hydrogenation and optionally in the presence of a base.
DETAILED DESCRIPTION OF THE INVENTION
The method according to the invention may be illustrated by the following formula schemes:
where R 1 is C 1 -C 6 -alkyl, and R 2 is C 1 -C 6 -alkoxy.
The radical R 1 is preferably methyl, ethyl, n-propyl, isopropyl, butyl, pentyl, particularly preferably methyl or ethyl, even more preferably methyl.
5-Fluoro-1-methyl-3-difluoromethyl-1H-pyrazole-4-carbaldehyde (II-1) or esters thereof and 5-Fluoro-1-ethyl-3-difluoromethyl-1H-pyrazole-4-carbaldehyde (II-2) or ester thereof are very particularly preferably used as starting material.
The reaction is carried out in the presence of hydrogen. It is possible to use either pure hydrogen or mixtures of hydrogen and an inert gas (up to 1:1), such as nitrogen or argon. The reaction is carried out at pressures of 1 bar to 50 bar, preferably 1 bar to 20 bar and particularly preferably 2 bar to 15 bar.
To scavenge the hydrogen chloride, formed during the reaction, a base is optionally added. As added base, either an inorganic base such as sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, mono-, di- or trisodium phosphate or tripotassium phosphate, sodium hydroxide or potassium hydroxide or an organic base such as triethylamine, tributylamine, diazabicycloundecene (DBU), diazabicyclononene (DBN), pyridine, lutidine, 2-, 3- or 4-picoline or diazabicyclooctane (DABCO) can be used. Preference is given to the use of triethylamine 0.5 to 20 molar equivalents, preferably 0.5 to 5 molar equivalents and particularly preferably 1 to 5 molar equivalents of the base are added, based on the substrate.
In the catalytic hydrogenation for reducing the compound of the general formula (II), any hydrogenation catalyst may be used as catalyst. Suitable catalysts include optionally one or more metals from groups 8-10 of the periodic table on any conventional inorganic support. Examples include noble metal catalysts, such as ruthenium catalysts, palladium catalysts, platinum catalysts and rhodium catalysts, Raney nickel catalysts and Raney cobalt and Lindlar catalysts. In addition to these heterogeneous catalysts, hydrogenations over homogeneous catalysts can, however, also be carried out, for example over the Wilkinson catalyst. The relevant catalysts may be used in supported form, for example on carbon (charcoal or activated charcoal), aluminium oxide, silicon dioxide, zirconium dioxide, calcium carbonate or titanium dioxide. Catalysts of this kind are known per se to those skilled in the art. Particularly preferred are palladium catalysts supported on calcium carbonate. The catalysts may be used either in water-moist or in dried form. The catalyst used is preferably reused for a plurality of conversions. In the method according to the invention, the catalyst is used at a concentration of approximately 0.01 to approximately 30% by weight, based on the halo-1-alkyl-3-fluoroalkyl-1H-pyrazole-4-carbaldehyde of the formula (II) used. The catalyst is preferably used at a concentration of approximately 0.1 to approximately 5% by weight.
In the process according to the invention, the reduction is advantageously carried out in the presence of at least of one additive. Typical additives are, NH 4 OAc, Sodium Acetate, MgF2, NH 4 F, AlF 3 , K 2 CO 3 , Borax. Especially K 2 CO 3 , NH 4 Cl, NH 4 F, CsF or Borax.
The reaction time may be up to 20 hours, depending on the reactivity of the reactants, while the reaction can also be terminated earlier when conversion is complete. Preference is given to reaction times of 3-10 hours.
The reaction is carried out in the presence of a solvent. Suitable solvents are: alcohols, ethyl acetate, isopropyl acetate, THF, methyltetrahydrofuran, dioxane, toluene, hexane, heptane, pentane or petroleum ether. Particular preference is given to the use of methanol, ethanol, DMSO, dimethylacetamide, DMF or NMP.
5-Fluoro-1-alkyl-3-chlorodifluoroalkyl-1H-pyrazole-4-carbaldehydes of the formula (IIa) can be prepared by known methods (cf. J. Het. Chem. 1990, 27, 243, WO 2006/018725 A1, WO 2011/061205 A1, B. Hamper et al. Journal of Organic Chemistry V.57,N21,5680-6, WO 2011061205, WO2013171134 and WO2011131615).
The preparation of compounds could be performed according to the following schema.
where R 1 and R 3 are independently C1-C6-alkyl.
PREPARATION EXAMPLES
Example 1
1-methyl-3-difluoromethyl-5-fluoro-1H-pyrazole-4-carbaldehyde
In an autoclave 10 g of 5-chloro-3-(difluorochlormethyl)-1-methyl-1H-pyrazole-4-carbaldehyde dissolved in 150 ml of THF and 10 g triethylamin and 500 mg of 5% palladium on calcium carbonate were added. The autoclave was flushed with nitrogen and pressurised to 15 bar hydrogen. Reaction mixture in autoclave was stirred at 90° C. for 6 h. After filtration of the catalyst, the solvent was removed under reduced pressure and the product was obtained as a solid and purified via crystallization from mixture isopropanol/water. Yield 7 g, melting point 68-69° C.
Example 2
In an autoclave 10 g of 5-chloro-3-(difluorochlormethyl)-1-methyl-1H-pyrazole-4-carbaldehyde dissolved in 150 ml of THF and 10 g CsF and 400 mg of 150 mg Pd(OH)2 on carbon were added. The autoclave was flushed with nitrogen and pressurised to 15 bar hydrogen. Reaction mixture in autoclave was stirred at 90° C. for 6 h. After filtration of the catalyst, the solvent was removed under reduced pressure and the product was obtained as a solid and purified via crystallization from mixture isopropanol/water. Yield 7 g, melting point 68-69° C.
Example 3
Ethyl 1-methyl-3-difluoromethyl-5-fluoro-1H-pyrazole-4-carboxylate
In an autoclave 10.5 g of Ethyl 1-methyl-3-chlorodifluoromethyl-5-fluoro-1H-pyrazole-4-carboxylate in 100 ml of THF, 6 g Potassium carbonate and 150 mg Pd(OH)2 on carbon support were added. The autoclave was flushed with nitrogen and pressurised to 15 bar hydrogen. Reaction mixture in autoclave was stirred at 100° C. for 6 h. After filtration of the catalyst, the solvent was removed under reduced pressure and the product was obtained as a solid and purified via crystallization from mixture isopropanol/water. Yield 7.2 g.
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The present invention relates to a novel method for preparing 1-alkyl-3-difluoromethyl-5-fluor-1H-pyrazole-4-carbaldehydes or esters thereof of formula (I) by means of reductive dehalogenation, starting from 1-alkyl-3-chlorodifluoromethyl-5-fluoro-1H-pyrazole-4-carbaldehydes or esters thereof Formula (I)
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CROSS REFERENCE TO RELATED APPLICATION
[0001] This application claims priority to Utility patent application Ser. No. 10/985,386 filed Nov. 9, 2004
FIELD OF THE INVENTION
[0002] The present invention relates to apparatus for sharpening a multi-bladed cartridge razor. More specifically, the invention relates to apparatus for use with to sharpen or hone a multi-bladed sharpening razor where multiple blades are retained in a single shaving cartridge. The multi-bladed shaving razor is used for shaving the face, legs, underarm, and other areas of a body where unwanted hair is present. A lubricant comprising of aloe vera gel is utilized to improve the honing process of the blades.
BACKGROUND OF THE INVENTION
[0003] Most safety razors are typically used for shaving the face and other hairy regions of the human body. The razor, consist of a metal and/or plastic handle attached to a multi-bladed cartridge razor head. Generally a multi-bladed razor cartridge is capable of not more than 5 to 10 close shaves before the shaving edges becomes dull and the user must dispose of the cartridge. There is a need for quick and simple means for honing or re-sharpening the blades in order to extend their useful life.
[0004] U.S. Pat. No. 1,540,078 issued May 23, 1924 to W. R. Long discloses a sharpener for a single flat razor blade. With this invention the user places a single blade in the sharpener, and slides the blade over a sharpening surface that sharpens the blade. While this invention sharpens a single blade, it is not intended for sharpening multiple blades, a cartridge of blades and it abrades the blade surface in addition to just removing oxidation from the edge of the blade.
[0005] U.S. Pat. No. 1,588,322 issued Apr. 4, 1924 to T. McAdoo discloses a sharpener for a single flat razor blade. With this invention the user places a single blade in the sharpener, and slides the blade over a sharpening surface that sharpens the blade. While this invention sharpens a single blade, it is not intended for sharpening multiple blades, a cartridge of blades and it abrades the blade surface in addition to just removing oxidation from the edge of the blade.
[0006] U.S. Pat. No. 1,594,246 issued Aug. 28, 1925 to H. W. Dechert discloses a scraper sharpener. With this invention the user places a scraper blade in the sharpener, and slides the blade over the surface of a file to sharpen the edge of the scraper. While this invention sharpens scraper, it is not intended for sharpening multiple blades, a cartridge of blades and it abrades the blade surface in addition to just removing oxidation from the edge of the scraper.
[0007] U.S. Pat. No. 2,458,257 issued Jun. 25, 1946 to A. E. Donovan discloses a holder and sharpener for a single flat razor blade. With this invention the user places a single blade in the holder/sharpener, and slides the blade over a sharpening surface that sharpens the blade. While this invention sharpens a single blade, it is not intended for sharpening multiple blades, a cartridge of blades and it abrades the blade surface in addition to just removing oxidation from the edge of the blade.
[0008] U.S. Pat. No. 5,036,731 issued Aug. 6, 1991 to Fletcher discloses a Razor Sharpening Device that sharpens a single razor blade. With this invention the user places a single blade in the sharpener, and slides the blade over a honing member that sharpens the blade. While this invention sharpens a single blade, it is not intended for sharpening multiple blades, or a cartridge of blades.
[0009] Published US Patent application 2003/0170198 from Williams published Sep. 11, 2003 discloses a shaving gel using a number of ingredients including aloe vera gel for shaving. While this published application discloses the use of aloe vera gel as a lubricant for shaving there is no disclosure where the shaving gel is utilized to sharpen the shaving razor.
[0010] The prior art discloses examples of apparatus for sharpening blades of a razor, but none providing the combination of features disclosed and claimed herein.
BRIEF SUMMARY OF THE INVENTION
[0011] One of the objects of this invention is to provide a new and improved sharpening device for sharpening the cutting edges of a multi-bladed cartridge razor. Other objects of this invention are to provide apparatus that can rapidly sharpen razor blades mounted in a cartridge, which have no moving parts, is compact and durable.
[0012] Razor blades in general become dull when oxidation occurs to the cutting edge. When the oxidation is removed, the cutting edge can be restored or maintained by first applying a soap or aloe vera film onto the sharpening surface and secondly removing the oxidation by sliding the cutting blade edge along a honing or sharpening surface. When only the oxidation is removed, the cutting blade edge can be maintained as long as the razor blade edge is not altered.
[0013] It is another object of this invention to utilize aloe vera gel to lubricate the glass sharpening surface to remove oxidation from the edge of the razor. The aloe vera gel allows the blade to move along the surface of the glass and not bind. The aloe vera further creates a slurry that spreads along the blade to provide even sharpening or honing of the blade.
[0014] In accordance with the present invention, an apparatus is proposed for sharpening the cutting edges of a multi-bladed cartridge razor mounted within a shaving head that is attached to a handle. A liquid aloe vera or soap-dispensing device provides a slurry solution to the sharpening surface to provide lubrication. The sharpening apparatus comprises a housing that holds a sharpening element. The soap or aloe vera dispensing apparatus is a plastic housing with a dispensing end with a cap. The housing includes a substantially elongated flat member. The housing has grooved sidewalls, and an attachment mechanism located along the opposite edges of the bottom member.
[0015] It is another object of the invention to keep the glass or mirror surface exposed to allow the person shaving to utilize the surface to view their reflection while shaving. This give the invention a dual purpose of both providing a sharpening surface and a viewing surface.
[0016] In one embodiment of the invention, a wire or string is attached to eyelet screws to provide a means to store the invention on a showerhead collar or on a wall-mounting bracket.
BRIEF DESCRIPTION OF THE DRAWINGS
[0017] FIG. 1 is an isometric view of the multi-blade sharpening apparatus.
[0018] FIG. 2 is a side view of the multi-blade sharpening apparatus shown with a blade being sharpened.
[0019] FIG. 3 is a top view of the multi-blade sharpening apparatus.
[0020] FIG. 4 is a side view of the multi-blade sharpening apparatus as it might hang within a shower.
[0021] FIG. 5 is a simplified version of the multi-blade sharpening apparatus.
DETAILED DESCRIPTION
[0022] Referring to FIGS. 1 to 3 , there is shown a honing device for a multi-bladed shaving cartridge. In this figure the housing 10 comprises a bottom wall 12 , sidewalls 14 and 16 , end walls 18 , 20 and top plate 22 . Sharpening element 13 as a substantially planar sharpening surface 15 secured to sidewalls 14 and 16 , end walls 18 , and bottom wall 12 . The configuration of the housing is shown as a flat substantially rectangular shape, but various other configurations of the housing are contemplated including square, triangular, round, elliptical and other shapes, as long as the housing allows for a honing surface that allows for the blades of a multi-bladed cartridge to be honed.
[0023] In the preferred embodiment the honing element 13 is comprised of a smooth glass mirrored surface. Other honing elements are contemplated including diamond surfaces, metals, emery paper, sandpaper, stones, or other surfaces. In the preferred embodiment the honing or sharpening is flat, but the shape may be another shape that follows the contour of the blade that is being sharpened. It is further contemplated that the sharpening element 13 has two sides, where one side is used for sharpening, and the opposite side is a mirror used for visual reflection. This allows a person to sharpen the blade(s) on one surface and view themselves while shaving with the other surface. This two sided embodiment allows for degradation of the reflective properties of the sharpening surface without compromising the reflective properties of the reflective surface. While it has been described that the two surfaces have different functions, the two sides can both be mirror surfaces providing twice the number of reflective and sharpening surfaces.
[0024] The material from which the housing 10 is made is not critical and it may suitably be made from a material such as steel or aluminum, wood, or it may be made from plastic. In the preferred embodiment the housing is molded in a plastic material. The plastic material will not rust, is simple to manufacture and can be manufactured with high repeatability with minimal part cost.
[0025] Prior to sharpening, the sharpening process is facilitated by applying a thin coating of liquid soap or aloe vera solution onto the surface 15 from a dispenser 27 as shown in FIG. 3 . The aloe vera or soap dispenser can be a variety of liquid dispensers that can be dry soap, liquid soap, aloe vera, or a spray of a thin aloe vera or soap and water solution. The multi-bladed cartridge razor may be honed or re-sharpened by placing the multi-bladed cartridge razor head within the housing 10 holding handle 26 so the cutting edges in the multi-bladed cartridge razor head is parallel to the sharpening surface 15 , and moving the cartridge 24 along the surface 15 pulled toward the end 20 . In this figure the lubricant dispenser is shown as a separate item it is contemplated that the dispenser is an integrated unit with the blade sharpening housing.
[0026] Referring now to FIG. 4 that shows the blade-honing device on a wall mounted configuration attached to holder 41 or showerhead 42 mounted methods. The mounting is accomplished with a string, or wire that is secured to one or two eyelet screw attachments 33 and 34 shown in FIG. 3 . Wall mounting can be attached with a wall-mounting bracket 41 . The bracket can be made of plastic or metal, and secured to a wall with adhesives or anchored to the wall with a screw or other fastener (not shown). The multi-bladed cartridge-honing device may have a hook or loop molded onto one or more sides for attachment or hooking the apparatus onto the head of a shower or the rail of a shower rod.
[0027] Referring now to FIG. 5 that shows the blade-honing device in its simplified form. In this figure the honing or sharpening surface 13 is shown as a substantially flat piece of mirror. An open mounting hook 33 is formed or cut into the mirror. In this embodiment a user will dispense soap, aloe vera or other lubricant onto the top surface if the glass. The user will then bring a multi-bladed cartridge razor in contact with the glass and stroke the razor on the surface of the glass to remove any oxidation on the razor and or hone the edges of the razor. This embodiment shows a simple open hook so the device can be at least temporarily attached to a showerhead or a shower rod. There are a variety of configurations and embodiments that are contemplated between the embodiment shown in FIGS. 1-3 and the embodiment shown in FIG. 5 .
[0028] Thus, specific embodiments and applications for a multi-blade sharpening apparatus have been disclosed. It should be apparent, however, to those skilled in the art that many more modifications besides those described are possible without departing from the inventive concepts herein. The inventive subject matter, therefore, is not to be restricted except in the spirit of the appended claims
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Apparatus for sharpening and or honing a multi-bladed razor cartridge including a sharpening member, a housing to secure the sharpening member. An aloe vera or soap solution dispenser provides a lubricant to the sharpening member to lubricate the razor and a housing to limit the travel of the razor on the sharpening member. The sharpening and or honing member is made of a mirrored plate glass secured in a channel within the housing
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BACKGROUND OF THE INVENTION
[0001] This invention pertains to inhalation therapy enclosures for small animals.
[0002] In the practice of veterinary medicine, the treatment of diseased or injured animals encompasses administration of medications by injection or by mouth, as well as by inhalation of nebulized medications. Current methods for respiratory therapy through administration of nebulized medications consist of use of a mask held over the nose and mouth of the animal, or by forcing the animal into a closed chamber into which nebulized medication is introduced. Typically, the chamber is an open topped box with a lid held in place to trap the animal inside. Because an animal in compromised health is already under stress, the reaction of an animal to being placed in an open-topped box is to resist this mode of therapy, to become fractious and increasingly stressed and less responsive to therapy. Similarly, the forced placement of a mask over the nose and mouth of a fearful animal is stressful for both animal and veterinarian staff, and results in less successful administration of medication.
[0003] In the administration of general anesthesia to small animals, inhalation of anesthetic gases either must be administered by mask or through placement of the animal into an anesthetic induction chamber into which anesthetic gas is introduced. Again the typical anesthetic induction chamber is an open topped plastic box with a lid. In the case of cats and other small animals, the forced placement of the animal into an open topped box frequently results in fractious behavior by the animal accompanied by elevation of stress in the animal and the veterinary staff.
[0004] An example of an anesthetic induction chamber for animals is shown in U.S. Pat. No. 6,353,076 to French which shows an elongate box with a top lid and an end door.
BRIEF SUMMARY OF THE INVENTION
[0005] The present invention pertains to equipment to assist in the administration of inhalants in the practice of veterinary medicine. Particularly, the invention pertains to administration of nebulized medicaments to small animals such as cats, ferrets, small dogs, rats, birds, small reptiles and like sized pets.
[0006] Uncooperative or medically compromised animal patients are easily treated with inhalation therapy provided the inhalation therapy can be successfully administered. The present invention presents an enclosure for small animals which includes a base with a rear wall and opposing end walls upstanding from edges of the base. The combination of the base, rear wall, and opposing end walls provides a structure with an open top and an open side. A cover assembly is attached to the top of the rear wall by hinges such that the cover can be rotated about the hinges to either close the enclosure or to open the enclosure. Rest brackets extend from the rear wall to provide structures for the open cover to rest against. The cover includes a first panel which serves as the top of the resulting enclosure, and a second panel fixed perpendicularly to the first panel, the second panel providing a front wall for the resulting enclosure. A large portion of each panel is an unbreakable transparent window made of tempered or shatterproof glass or clear acrylic or clear polycarbonate. Latching devices are provided on the base and second panel to retain the cover in place when desired. A port is provided through each of the opposing end walls at a height above the mid-point of the end wall. Each port includes a ribbed tube to which a hose may be attached. The diameter of both ports is substantially equal. When desired to be used for administration of nebulized medications, a hose interconnects the first port with a nebulizer. A second hose may be attached to the port on the opposing sidewall to duct away exhaust exiting the second port.
[0007] The enclosure may also be used as an anesthetic inhalation chamber. In the case of administration of inhalable anesthetic compounds, the port in the first end wall may be connected to tubing coupled to a source of anesthetic gas and the port in the second end wall may be coupled to a hose transmitting the uninhaled gases to a scavenging or recapture system.
[0008] The enclosure may also be used as an oxygen inhalation chamber. In the case of administration of inhalable oxygen, the intake port in the first sidewall may be connected to tubing coupled to a source of oxygen and the exhaust port in the second sidewall may be left open.
[0009] The enclosure may also be configured as a portable pet carrier by substitution of the transparent windows in the cover panels by open cage wall structures such that ventilation is adequate.
[0010] It is a primary object of the invention to provide an enclosure to receive a small animal requiring inhalation therapy which avoids stress in that animal when the animal is placed in the enclosure. It is a further object to provide an enclosure for small animals which the animal will willingly enter. It is also an object of the invention to provide an inhalation therapy enclosure in which nebulized medication may be effectively administered to an ill animal. Another object of the invention is to provide an inhalation therapy enclosure in which the animal is comfortable and unrestrained. It is yet another object of the invention to provide an enclosure for a small animal which allows observation of the animal while enclosed and from which the animal may observe the environment exterior to the enclosure. A further object of the invention is to provide an transportable enclosure into which a pet owner can place his or her pet preparatory to surgery and which can be used to transport the animal to surgery and in which anesthetic can be conveniently administered without further handling of the pet, while allowing the pet to be observed as anesthetic is administered.
[0011] The foregoing and other desirable objects of the invention will be understood from an examination of the detailed description of the invention which follows.
BRIEF DESCRIPTION OF THE SEVERAL VIEWS OF THE DRAWING(S)
[0012] FIG. 1 is a front perspective of a veterinary treatment system for administration of nebulized medication, according to the present invention.
[0013] FIG. 2 is a side plan view of the enclosure of the invention with the cover fully open.
[0014] FIG. 3 is a front elevation of the enclosure invention with the cover fully open.
[0015] FIG. 4 is a cross section view along line 4 - 4 of FIG. 3 .
DETAILED DESCRIPTION OF THE INVENTION
[0016] This invention is an inhalation therapy enclosure for small animals. The invention may be used as an enclosure for administration of nebulized medication, as an anesthetic induction chamber or as an oxygen inhalation chamber. In an alternative embodiment, the invention may be used as a portable pet carrier.
[0017] FIG. 1 discloses a system 2 for administration of nebulized medicaments for treatment of veterinary patients. The medicament may be any drug with the property of being delivered via nebulization or atomization including but not limited to antibiotics, bronchodilators, steroids, insulin, oxygen, or any other medicament that can be absorbed in the oral or nasal mucosa or lungs of an animal, or a drug which may be absorbed transdermally.
[0018] A closable enclosure 4 is coupled to a nebulizer cup 6 containing a liquid medicament to be nebulized. A nebulizer pump 8 is coupled by air duct 10 to the nebulizer cup 6 such that air may be bubbled through the liquid medicament within nebulizer cup 6 to be atomized to a mist or vapor to be passed through intake port 12 in first sidewall 14 into the interior 16 of enclosure 4 . Together the nebulizer pump 8 , nebulizer cup 6 and air duct 10 are a nebulizing apparatus which is well known.
[0019] Enclosure 4 further comprises a base 18 which serves as a bottom of the enclosure 4 , a rear wall 20 and a second sidewall 22 which opposes first sidewall 14 . In the substantially rectangular embodiment of enclosure 4 of FIG. 1 , each of sidewalls 14 , 22 and rear wall 20 is upstanding upon edges of base 18 . A cover 24 is hinged to top edge 26 of rear wall 20 such that cover 24 may pivot about top edge 26 of rear wall 20 from an open position as seen in FIG. 1 to a closed position with the free edge 28 of cover 24 abutted to base 18 at the front 30 thereof.
[0020] Cover 24 comprises a first panel 32 joined at a substantial perpendicular to second panel 34 . First panel 32 is hinged to top edge 26 of rear wall 20 . Second panel 34 could be joined to first panel 32 by a hinge if desired, but in the preferred embodiment of FIGS. 1-3 , second panel 34 is joined to first panel 32 at a fixed angle. Depending on the geometry of sidewalls 14 , 22 , first panel 32 could be joined to second panel 34 over a range of angles from approximately forty-five degrees to approximately one hundred thirty-five degrees.
[0021] When cover 24 is moved to the closed position, in addition to the abutment of free edge 28 to front 30 , first side edge 36 of first panel 32 abuts top edge 38 of first sidewall 14 and second side edge 40 of first panel 24 abuts top edge 42 of second sidewall 22 . In addition, first side edge 44 of second panel 34 abuts front edge 46 of first sidewall 14 and second side edge 48 of second panel 34 abuts front edge 50 of second sidewall 22 . Rabbets 52 along edges 50 , 42 , 40 , 48 and along edges 46 , 38 , 36 , 44 permit a substantially air tight fit of cover 24 to sidewalls 14 and 22 and to base 18 thereby creating a sealed enclosed space within interior 16 of enclosure 4 .
[0022] Exhaust port 54 passes through second sidewall 22 to provide a passageway for exhaled or uninhaled gases to escape. Exhaust port 54 may be located in second sidewall 22 at approximately the same vertical position as that of intake port 12 in first sidewall 14 , generally above the vertical midpoint thereof.
[0023] In the preferred embodiment, the enclosure is rectilinear though other shapes may be employed provided the cover 24 serves as top and a side of the resulting enclosure. The preferred embodiment enclosure 4 encloses a volume of approximately one cubic foot.
[0024] Referring now additionally to FIG. 2 , it can be seen that enclosure 4 comprises rest brackets 56 against which cover 24 may rest when fully open. Brackets 56 serve as stops to limit the travel of cover 24 about hinge 58 . Brackets 56 comprise upwardly extending outwardly angled arms 78 .
[0025] A handle 60 is mounted to cover 24 near its free edge 28 and a pair of latches 62 are fixed to cover 24 upon outer face 64 of second panel 34 such that the bails 66 of latches 62 may capture catches 68 when cover 24 is lowered to its closed position.
[0026] Each of panels 32 , 34 of cover 24 further comprises frames 70 , 72 which are formed with peripheral recesses 74 to permit the resting of panel edges within rabbets 52 of sidewalls 14 , 22 and rear wall 18 .
[0027] Referring now to FIG. 3 , it is seen that each of panels 32 , 34 of cover 24 of enclosure 4 includes a transparent window 80 , 82 of clear acrylic or clear polycarbonate or of glass, preferably tempered or shatterproof glass. The inclusion of windows 80 , 82 provides the ability for veterinary staff to observe a cat or other small animal housed in closed enclosure 4 as anesthesia is administered or as treatment with nebulized medicament is carried out.
[0028] It can also be understood from examination of FIG. 3 that intake port 12 and exhaust port 54 comprise tubes 84 which extend from respective sidewalls 14 , 22 such that flexible hoses may be attached to the tubes 84 of ports 12 and 54 . Tubes 84 may be tapered to ease placement of plastic tubing over them, or they may be provided with annular ribs (not shown) in the conventional manner to assist in frictional retention of tubing to tubes 84 .
[0029] In the case of the use of enclosure 4 as an anesthesia induction chamber, a source of anesthetic gas (not illustrated) may be coupled to one of ports 12 , 54 through conventional hose or tubing so that the anesthetic gas can be passed into the enclosure while uninhaled or exhaled gas may be vented from the port not used for insertion of the anesthetic gas.
[0030] The enclosure 4 may also be used as an oxygen inhalation chamber. In the case of administration of inhalable oxygen, the intake port 12 in the first side end wall 14 may be connected to tubing coupled to a source of oxygen and the exhaust port 54 in the second sidewall 22 may be left open.
[0031] Referring now to FIG. 4 , a cross section view of the enclosure 4 is illustrated. Bracket 56 extends from outer face 86 of rear wall 20 , with the arm 78 of bracket 56 extending upward and away from the plane of outer face 86 . Arm 78 is angled appropriately to parallel the outer face 88 of first panel 32 of cover 24 thereby to provide a stop or rest for cover 24 when it is fully open. It can be seen that first panel 32 joins second panel 34 at a substantial perpendicular and that window 82 is retained in slots 90 of frame 72 of second panel 34 . Window 82 comprises a substantial area of second panel 34 . Similarly, window 80 of first panel 32 makes up a large proportion of the area of first panel 32 and is retained in slots 92 of frame 70 .
[0032] Base 18 is provided with a shelf 94 to receive the tongue 96 of second panel 34 when cover 24 is lowered to the fully closed position. Rabbets 52 allow for a snug and substantially airtight closure of cover 24 in abutment with second sidewall 22
[0033] The foregoing description of the invention has been presented for purposes of illustration and description and is not intended to be exhaustive or to limit the invention to the precise form disclosed. Modifications and variations of the embodiments are possible in light of the above disclosure or such may be acquired through practice of the invention. The embodiments illustrated were chosen in order to explain the principles of the invention and its practical application to enable one skilled in the art to utilize the invention in various embodiments and with various modifications as are suited to the particular use contemplated. It is intended that the scope of the invention be defined by the claims appended hereto, and by their equivalents.
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An inhalation therapy enclosure includes a base with end walls joined by a rear wall. A cover having two panels joined perpendicularly is hinged to the top of the rear wall. When lowered, the cover forms an enclosure with the end wall, rear wall and base. Latches secure the cover to the base. A port in one end wall allows introduction of nebulized medication or anesthesia while a port of equal size in the opposing end wall allows exhaust from the enclosure.
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CROSS-REFERENCE TO RELATED APPLICATIONS
The present application claims the priority of U.S. provisional patent application No. 60/605,854 filed on Aug. 31, 2004 and entitled “Photocatalytic Nanocomposites and Applications Thereof”.
STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT
The U.S. Government has certain rights to the invention based on National Science Foundation Grant No. EEC-94-02989.
FIELD OF THE INVENTION
This invention relates to photocatalyst coated nanotubes and applications thereof including use as a biocide.
BACKGROUND OF THE INVENTION
Certain bacteria can be harmful or even deadly to humans as well as animals. In September 2001, anthrax spores were mailed to several locations via the US Postal Service resulting in twenty-two confirmed or suspected cases of anthrax infection. Because the possibility of a terrorist attack using bioweapons is especially difficult to predict, detect, or prevent in a conventional way, it is crucial to find a solution to nullify a microbial attack.
Currently, there is a lack of efficiency with the conventional method and further developments are necessary to achieve higher biocidal efficiency. Moreover, because of the widespread use of antibiotics and the emergence of more resistant and virulent strains of microorganisms, and furthermore bacterial spores have no metabolism and can withstand a wide range of environmental assaults including heat and UV, there is an immediate need to develop alternative sterilization technologies such as photoelectrochemical sterilization using highly efficient photocatalysts.
Wide band-gap semiconductors can act as sensitizers for light-induced redox processes due to their electronic structure, which is characterized at room temperate by a filled valence band and an empty conduction band. Hydroxyl radicals (OH.) generated by the Titania photocatalyst are very potent oxidants and are nonselective in reactivity.
Titania (TiO 2 ) is currently the photocatalyst of choice for most applications, being the most efficient known photocatalyst. Irradiation of a semiconductor, such as TiO 2 , with light having an energy equal to or greater than the semiconductor material's band gap energy results in the creation of electrons in the semiconductor's conduction band and holes in its valence band. The injection of these electrons and holes into a fluid region surrounding the semiconductor particles causes electrochemical modification of substances within this region. This technology has been used in photocatalytic processes such as the photo-Kolbe reaction in which acetic acid is decomposed to methane and carbon dioxide and the photosynthesis of amino acids from methane-ammonia-water mixtures.
When irradiated TiO 2 particles are in direct contact with or close to microbes, the microbial surface becomes the primary target of the initial oxidative attack. In 1985, Matsunaga and coworkers reported that microbial cells in water could be killed by contact with a TiO 2 —Pt catalyst upon illumination with near-UV light for 60 to 120 min. Later, the same group of workers constructed a practical photochemical device in which TiO 2 particles were immobilized on an acetylcellulose membrane. The loss of membrane structure and membrane functions due to the photochemical oxidation was the root cause of cell death when photocatalytic TiO 2 particles are outside the cell. It was observed that the extent of killing depended on the structure of the cell wall and was inversely proportional to the thickness. The findings of Matsunaga et al. redirected the attention for sterilization and resulted in an attempt to use this technology for disinfecting drinking water and removing bioaerosols from indoor air environments.
A variety of devices for air purification using Titania for photocatalytic degradation of organic impurities and microbial contaminates have been disclosed. The primary metal oxide for these devices is TiO 2 . Typically the challenge was to have the impurity or contaminate in contact with the titania surface for a sufficiently long period of time to effectively remove the desired contaminate and often elaborate systems were designed to increase the effective contact time. In all of these cases, an improvement in the photocatalyst efficiency by increasing the efficiency of the TiO 2 would greatly enhance the effectiveness of these devices. Moreover, the ability to use photocatalysts for air purification using visible light or sunlight, as opposed to conventionally used UV light, is highly desirable.
SUMMARY OF THE INVENTION
The invention is directed to a photocatalyst nanocomposite wherein a surface of a carbon nanotube which preferably provides metallic electrical conductivity is covered with a nanoscale (<1 μm) thick photocatalyst coating layer. The photocatalyst coating is covalently or ionically bound to the nanotube core, and preferably has a thickness of 1 to 10 nm. The photocatalyst can be selected from TiO 2 , ZnO, and Fe 3 O 4 as well as non-metal oxide semiconductors, such as sulfides, selenides, nitrides and carbides. For example, useful non-metal oxide semiconductors include MoS 2 , WS 2 , MoSe 2 , and FeS 2 . The photocatalyst coating is preferably a continuous coating.
The surface of said nanotube preferably includes C and O comprising functionalities derived from oxidation of the surface. For example, the C and O comprising functionalities can comprise C(O)OH, C(O), or (OH) groups.
The invention includes a method of forming the photocatalytic nanocomposite comprising dispersing carbon nanotubes which are then chemically oxidized to produce functional groups on the surface of the nanotubes. The surface functionalized nanotubes are then processed with a metal oxide photocatalyst sol-gel precursor to form a continuous nanoscale metal oxide photocatalyst layer which is covalently or ionically bound to the nanotube surface. The photocatalyst nanocomposite is then preferably heated to a temperature between 350° C. to 550° C. to form the anatase structure of TiO 2 .
The invention also includes a method of destroying biological agents by irradiating the photocatalyst nanocomposite with light having photon energies which equal or exceed the bandgap energy of the photocatalyst nanocomposite and exposing a fluid contaminated with a biological agent to photocatalyst nanocomposites according to the invention. Since the photocatalyst nanocomposite has been discovered to be imparted significant photocatalytic activity using light in the visible spectrum, irradiation in either the visible range or the ultraviolet range or a broad spectrum provides effective destruction of biological agents. Furthermore, the photocatalyst nanocomposite maintains its activity in the dark for long periods of time after irradiation for short periods of time. This feature permits the method to be practiced using intermittent irradiation, so that periods of darkness are interspersed with periods of irradiation. The cycle of dark and irradiation does not have to be periodic.
The invention also includes a system where the photocatalyst nanocomposite is disposed on the surface of a support which can be irradiated to destroy biological contaminates in a fluid exposed to the irradiated photocatalyst nanocomposite. The system can use ambient light from the environment (e.g. sunlight), or can use another light source including a visible light source. A device such as a fan or a pump can also be incorporated into the system to direct the fluid into contact with the photocatalytic nanocomposite.
BRIEF DESCRIPTION OF THE DRAWINGS
A fuller understanding of the present invention and the features and benefits thereof will be accomplished upon review of the following detailed description together with the accompanying drawings, in which:
FIG. 1( a )-( c ) show scanned high-resolution transmission electron microscopy (HRTEM) images of TiO 2 coated multi-walled nanotubes (MWNTs) according to the invention, while FIG. 1( d ) shows the TiO 2 coating fragment after burnout of the MWNT core.
FIG. 2 shows a thermogravimetric analysis (TGA) and thermal differential analysis (DTA) of dried TiO 2 coated MWNTs in air.
FIG. 3 are XRD patterns of raw MWNTs, a TiO 2 -MWNT nanocomposite according to the invention, and TiO 2 coating layers after burnout of MWNTs at 750° C. in air.
FIG. 4 shows a schematic diagram of an exemplary UV chamber for biocidal testing.
FIG. 5( a )-( c ) show examples of the relationship between survival ratio of viable spores and UV irradiated time for control system (a), a system with UV and Degussa P25 TiO 2 (b), and a system with UV and TiO 2 coated carbon nanotubes according to the invention (c).
FIG. 6 shows the degradation of a dye, naphthalenedisulfonic acid, 5-((4,6-dichloro-s-triazin-2-yl)amino)-4-hydroxy-3-(phenylazo)-, disodium salt, by irradiation with visible light in the presence of TiO 2 -MWNT nanocomposite particles according to the invention as indicated by the ratio of the dye concentration to the initial dye concentration as measured by UV-VIS spectroscopy of samples removed from the light.
FIG. 7 shows the degradation of a dye, naphthalenedisulfonic acid, 5-((4,6-dichloro-s-triazin-2-yl)amino)-4-hydroxy-3-(phenylazo)-, disodium salt, in the presence of TiO 2 -MWNT nanocomposite particles according to the invention by the ratio of the dye concentration to the initial dye concentration as determined by UV-VIS spectroscopy for samples of the mixture stored in the dark after irradiated at 365 nm for 10 minutes.
FIG. 8 shows a cylindrical tube embodiment of a system for decontaminating a fluid where the photocatalytic nanocomposite is supported by the inside wall of the tube and is irradiated by external ambient light through an optically transparent window.
DETAILED DESCRIPTION
A photocatalyst nanocomposite comprises a carbon nanotube core, and a nanoscale photocatalyst coating layer covalently or ionically bound to the nanotube core. The coating is disposed on the outside of the nanotube. Previous photocatalyst nanotubes have not involved the chemical bonding of the metal oxide photocatalyst to the carbon nanotubes.
In a preferred embodiment, the photocatalyst coating is a continuous coating. Continuous surface coverage shields the carbon nanotube from direct contact with the environment. Therefore, only the photocatalytically active species, such as TiO 2 , is exposed and the carbon nanotube is used for charge scavenging and storage. The efficacy of photocatalyst coated nanotubes according to the invention as a biocide have been shown to be superior to TiO 2 alone by around a factor of 200 for a given mass of TiO 2 . This can be seen in Table 1 described below where the same mass of TiO 2 has half of the activity of the TiO 2 coated nanotubes according to the invention even though the TiO 2 accounts for only about 0.5% of the mass of the nanocomposite.
The nanotubes can be single wall nanotubes (SWNTs) or multi-wall nanotubes (MWNTs). It is preferred that the nanotubes be metallic nanotubes. In a preferred embodiment, MWNTs, which are generally metallic, are used.
Although described in terms of a photocatalyst layer disposed on nanotube cores, it is possible that other electrically conductive materials can be used together with the nanotubes, or as alternatives to nanotubes. For example, it may be possible for electrically conductive carbon black to replace nanotubes as carbon black provides an electronic band structure similar to the band structure provided by carbon nanotubes. Accordingly, metallic carbon black of nanoscale dimensions can provide similar charge scavenging and storage properties for the nanocomposite. Carbon black has the advantage that it is generally obtainable at a fraction of cost of carbon nanotubes.
The coating layer has a nanoscale thickness, preferably being 1 to 10 nm, and most preferably from 1-5 nm. The advantage of a thin photocatalyst layer is an increase in photocatalytic efficiency. The photocatalytic efficiency is inversely related to the photocatalyst thickness. This is caused by an increasing probability for recombination of the formed electron-hole pair before the hole has migrated to the surface of the photocatalyst as the photocatalyst layer thickness increases. Although described herein generally using the photocatalyst TiO 2 , the photocatalyst can comprise a variety of semiconductors, such as, but not limited to ZnO and Fe 3 O 4 .
Photocatalyst nanocomposites according to the invention can be formed in the following exemplary non-limiting way. MWNTs can be obtained commercially (Alfa Aesar, 3-24 nm outer diameter, 0.5-5 μm). Such commercial nanotubes do not have functional groups on the nanotube surface. The MWNT surfaces can then be chemically treated using a chemical oxidation process to produce surface functionalization, such as using a nitric acid process at a temperature between 120 and 160° C. Other reagents can be used for the oxidation such as sulfuric acid. The functionalized surface is modified so that thin layers of metal oxides can be ionically or covalently attached thereto. Following chemical oxidation, the nanotubes become partially covered with acidic functional groups, C(O)OH, and cabonyl, C(O), and hydroxy, (OH) functional groups.
These groups are used for initiating chemical reactions and adsorption of ions from solution. Sol-gel processing is preferably used for this purpose. For example, a titanium(III) sulfate (99.9+%) solution can be stirred with functionalized MWNTs dispersed H 2 O for 30 minutes to 3 hours. The resulting TiO 2 coated MWNTs can be centrifuged, and dried. The dried TiO 2 coated MWNTs are preferably then heated to a temperature sufficient to result in crystallization of the TiO 2 , such as at 500° C. for at least one hour in air. Transmission electron microscopy has shown that the TiO 2 coating is continuous over the entire nanotube outer surface. The bonding of the TiO 2 to the MWNT provided by the above method provides enhanced photocatalytic efficiency and modification of the properties of the TiO 2 displayed by the invention. Unexpectedly, the bonding of the TiO 2 to the MWNT, (TiO 2 -MWNT), provides significant photocatalytic activity when irradiated with visible light (400 nm to 750 nm) in addition to the conventionally used ultraviolet light. This is surprising because it is well known in the art that TiO 2 is a semiconducting photocatalyst having a room temperature band gap energy of about 3.2 eV. Thus, for room temperature operation, photocatalyst systems prior to the invention using TiO 2 required irradiation with photons having wavelengths less than about 385 nm (UV) to display significant photocatalytic activity.
Although not needed to practice the claimed invention, Applicants, not seeking to be bound to theory, present a mechanism which explains the superior photocatalytic performance demonstrated by nanocomposites according to the invention. The carbon nanotube electronically coupled to the photocatalyst is believed to provide a sink for photogenerated electrons generated by the photocatalyst upon irradiation thus allowing photogenerated holes to enjoy significantly longer lifetimes as compared to when nanotubes are absent. For example, the retardation of the recombination provided by the invention can significantly enhance the biocidal photocatalytic activity provided and permit some efficacy in the dark after the irradiation is turned off.
Photocatalytic composites according to the invention, such as TiO 2 -MWNT, are expected to be useful for a variety of existing photocatalytic processes. In an application having emerging importance, photocatalytic composites according to the invention are expected to be highly useful for the rapid deactivation of biological agent such as spores. Such materials are expected to become a significant tool for cleaning up of contaminated sites and to counter-bioterrorism.
The invention can be embodied as a system for the decontamination of fluids. These systems include photocatalytic nanotubes supported on a substrate surface over which the fluid, either gaseous, i.e. air, or liquid, i.e. water, is contacted. Photons of sufficient energy to match or exceed the band gap of the photocatalyst as modified by the nanotube bound thereto can be directed from a source that is either natural, i.e. sunlight, or artificial, i.e. lamps, which include visible and/or ultraviolet light. FIG. 8 gives a schematic of a system 800 for decontamination of air through a cylindrical tube showing both a side view and an end view. The system 800 includes a support, which is shown as the surface of cylindrical tube 810 , but can also be a flat surface, irregularly shaped surface, fibers, tube bundles, or any other surface that provides mechanical support. The photocatalytic nanocomposite 820 is disposed onto the tube 810 , such as from a suspension of the photocatalytic nanocomposite in a liquid. An adhesive, such as a silane coupling agent, can be used if needed depending upon the chemical nature of the of the surface of the support. A source of photons of that provide photons having energies that meet or exceed the band gap energy of the photocatalytic nanocomposite is provided. As noted above, the required photon energy is less than the minimum photon energy known in the art to be required by the photocatalyst (3.2 eV). This source is displayed as a single window 830 through which ambient light enters the cylindrical tube. The ambient light can be sunlight or from a lamp.
As illustrated in FIG. 8 with a 2 blade fan 840 is used to promote the flow of the fluid for disinfection into the entrance 850 of system 800 onto the surface of the photocatalytic nanocomposite at a rate faster than unaided diffusion to the exit 860 of system 800 . Pumps (not shown) can also be incorporated for use with gases or liquids or any mode of generating a pressure differential can be employed.
Alternatively, to achieve irradiation of the photocatalytic nanocomposite a lamp could be placed within the system 800 , multiple windows may be used, mirrors or optical fibers may be incorporated to direct the light, a transparent support may be used.
EXAMPLES
The present invention is further illustrated by the following specific Examples, which should not be construed as limiting the scope or content of the invention in any way.
Example 1
Synthesis and Characterization of TiO 2 -MWNT Nanocomposites: Commercially available arc-discharged MWNTs (Alfa Aesar, 3-24 nm outer diameter, 0.5-5 μm) were used as templates and the functionalization of the carbon surfaces was performed by chemical oxidation according to a method disclosed by Tsang et al., Nature, vol. 372, pp. 159-162, 1994. Oxidation was performed by dispersing 300 mg of MWNTs in 200 mL of 70% HNO 3 by sonification for 30 minutes followed by refluxed with magnetic stirring at 140° C. for 10 hours. In this manner the MWNT surface was modified so that a thin layers of metal oxides could be attached via sol-gel processing. Although not used in this Example, uniformity of the suspension of the nanotubes in the solution can be aided by stabilizing agents, such as surfactants (e.g. sodium dodecyl sulfate (SDS)) and certain polymers.
The nanotubes obtained had an outer diameter less than 20 nm and their surfaces were partially covered with acidic functional groups. After the oxidation process the MWNT samples were characterized by HRTEM (JEOL 2010F). The walls were damaged and the tips were almost always opened. It was concluded that these opened tubes contained a considerable number of functional groups (C(O)OH, C(O), OH), as indicated by acid base titration and IR spectroscopy. Subsequently, 20 μL of Titanium(III) sulfate (99.9+%) solution was stirred with the surface oxidized MWNTs dispersed in 10 mL of H 2 O for 1 hour and washed with H 2 O repeatedly. The resulting TiO 2 coated MWNTs were centrifuged, dried at 60° C. for two days, and then heat treated at 500° C. for six hours in air for crystallization of the TiO 2 .
After each step of the sol-gel process, samples were collected and the nanostructure was characterized with HRTEM confirming the chemical elements using energy dispersive x-ray spectroscopy (EDS). The heat treatment was performed with thermogravimetric analysis/differential thermal analysis (TGA/DTA, Netzsch STA 449C) monitoring changes in mass and energy of the samples. Both titania coated MWNTs and impurities (TiO 2 nanoparticles and/or TiO 2 coated carbon nanoparticles) were observed. The size of the impurities ranges from several nanometers to tens of nanometers. Since the impurities were considerably smaller than the TiO 2 -MWNT nanocomposite, they were separated by sonification followed by microfiltration, a known process used in non-destructive carbon nanotube purification.
FIGS. 1( a )-( c ) show HRTEM images of TiO 2 coated MWNTs according to the invention, while FIG. 1( d ) shows a TiO 2 coating fragment after burnout of the MWNT core. The sol-gel reaction the samples were dried, and then heat treated to 500° C. for crystallization of the TiO 2 coating. Thermogravimetric characterization and differential thermal analysis shown in FIG. 2 demonstrate a gradually increasing exothermic reaction, which was attributed to changes in the TiO 2 structure since no weight loss was observed.
Pure TiO 2 coating samples were prepared for XRD comparison studies by burning out the carbon from the TiO 2 -MWNTs of Example 1 at 800° C. in air for three hours. TiO 2 coating fragments (see FIG. 1( d )) could be observed after the MWNT removal. FIG. 3 shows the XRD characterization of the untreated MWNTs and the TiO 2 -MWNT. Despite the TiO 2 coating on MWNTs, no TiO 2 patterns could be detected for the nanocomposite. This is likely due to the very thin coating thickness (˜3 nm) of the TiO 2 in the nanocomposite. The titania phase can be assumed to be anatase in analogy to other reports, e.g. sulfate solutions of titanium always give anatase, the metastable form of TiO 2 . Anatase requires heat treating at 920° C. for 1 hour into rutile that is more stable with respect to anatase. Therefore, the nanocomposites produced are anatase composites as the samples were not heat treated to sufficient temperatures to form rutile. After burnout of the MWNTs at 800° C. the presence of anatase was confirmed by XRD as shown in FIG. 3 .
Example 2
Spore Preparation and Biocidal Test: B. cereus ATTC 2 was used as a surrogate of Bacillus anthracis . The bacteria were inoculated in 500 mL Erlenmeyer flasks containing 99 mL of Columbia broth supplemented with 1 mL of 10 mM MnSO 4 .H 2 O. Foam plugs were used to allow air access and prevent contamination. Liquid cultures were incubated for three days at 35±2° C. an orbital incubator-shaker (Model C24, New Brunswick Scientific) at 250 rev/min. Spores were harvested and purified using the lysozyme treatment. The heat shock treatment (80° C., 10 minutes) was applied following the purification process to ensure killing of vegetative cells. Spore suspensions were stored in sterile deionized water and refrigerated at 4° C. until use. Three types of spore suspensions were prepared; (i) the control sample by suspending 10 mL of spore suspension in 20 mL of sterile deionized water, (ii) the experimental sample with 3 mg of commercial TiO 2 nanoparticles (Degussa P25, primarily anatase with BET surface area of 50 m 2 /g and average particle size of 21 nm) into 20 mL of sterile deionized water, sonicating (30 min) in an ice water bath, and adding a volume of 10 mL of spore suspension giving the total amount of 30 mL of spore plus TiO 2 suspension, and (iii) the experimental sample with 0.8 mg of TiO 2 -MWNT nanocomposites (anatase coating with BET surface area of 172 m 2 /g) into 20 mL of sterile deionized water, sonicating, and adding of spore suspension as (ii). Each sample was transferred to a sterile 100×15 mm sterile Petri dish with a sterile magnetic stirring bar.
The UV chamber (shown in FIG. 4 ) comprising a bank of sixteen 350 nm UV lamps (RPR-3500A, Southern New England), a lamp cooling fan, and an adjustable sample holder was used throughout this Example. A magnetic stirrer was placed on the sample holder at the center of irradiation area to provide mixing of experimental suspension. The sample holder was adjusted to give a distance of 10 cm measured from the lamp surface to the initial suspension surface. The UV intensity was measured using a radiometer (Model 30526, Eppley Laboratories Inc.) and a correction coefficient specifically to solar UV was applied. The UV lamps were stabilized for 30 minutes to obtain constant intensity (92 W/m 2 ) before each test.
Samples were collected immediately after the suspension was exposed to UV and subsequently every 30 minutes. For each sampling, a volume of 0.25 mL of the suspension was collected four times, which resulted in the total volume of 1 mL into a sterile culture tube, which was wrapped with aluminum foil. The tube was capped and refrigerated immediately after sampling until use.
The sample was analyzed for survival ratio of B. cereus spores at any sampling time. Colony forming units (CFU) were enumerated by spreading the cultures onto tryptic soy agar plates. The cultures were serially diluted using sterile phosphate buffered saline (PBS) containing 2 mM of the ionic surfactant sodium dodecyl sulfate (SDS). The presence of surfactant in the diluting media was crucial because B. cereus spores tend to agglomerate in water; in following they are often found to be the most hydrophobic among Bacillus species. Experimental studies showed that the coefficient of variation (C V ) of B. cereus CFU was maintained below 10% when 2 mM of SDS was added to the diluting media (PBS). The plated dishes were incubated at 35° C. for 12 hours.
Sample analysis was used to generate the relationship between the survival ratio of viable spores and UV irradiated time. LD 90 values obtained from this relationship were used to characterize the system performance. Also, the decimal reduction time (D values) obtained from the linear portion of the log 10 survival ratio and UV irradiated time plots were used as another characterizing parameter. Both LD 90 and D values were obtained from triplicate experiments of each system, and the mean and standard deviation were reported.
Table 1 shown below summarizes the results for each system. Degussa P25 alone gave no UV enhancing effect on B. cereus spores (LD90s and D values, obtained from UV alone and from UV+Degussa P25 systems, were not significantly different at α=0.05). In contrast, the TiO2-MWNT nanocomposite according to the invention reduced the LD90 and the D value by factors of 1.8 and 2.3 respectively.
TABLE 1
Effect of commercially available TiO 2 particles and
TiO 2 - MWNTs nanocomposites according to the invention
under the presence of solar UV on B. cereus spores (Biocidal tests
were repeated three times)
System
LD 90 (min)
D value (min)
UV
151 ± 41
169 ± 40
UV + Degussa P25 TiO 2
198 ± 41
144 ± 5
UV + TiO 2 - MWNTs nanocomposites
84 ± 29
72 ± 20
For all control experiments, 350 nm UV had an inactivating effect to B. cereus spores. However, a relatively long exposure time was required to achieve 1 log reduction of viable spores. The LD 90 value of 151 minutes and D value of 169 minutes was obtained from triplicate experiments. The plots between spore survival ratio and irradiation time ( FIG. 2( a )) showed the typical shoulder followed by the exponential decay and the tail region. The tail region indicated subpopulation or agglomeration of spores, which could result in a shielding effect.
Degussa P25 has been recognized as an effective photocatalyst for killing several bacteria in previous studies and the failure of Degussa P25 to enhance the solar UV effect on B. cereus spores was due to the spores' high resistance. An experiment was conducted using Degussa P25 under the same protocol to investigate the effect of this commercial TiO 2 on Escherichia coli vegetative cells. The result showed that the commercial TiO 2 , under the solar UV, completely killed E. coli within 1 hour (data not shown). In case of the TiO 2 -MWNT nanocomposite, the enhanced UV effect was observed as the LD 90 and D value decreased dramatically. The biocidal efficiency must be proportional to the specific surface area of photocatalysts and the quantum yield of the photocatalytic system because the number of OH. is proportional to the specific surface area and inversely proportional to the electron-hole recombination rate.
The specific surface areas of each sample were approximately the same (3 mg of Degussa P25 with BET surface area of 50 m 2 /g and 0.8 mg of TiO 2 -MWNT nanocomposite with BET surface area of 172 m 2 /g). The electron trapping mechanism associated with the TiO 2 -MWNT nanocomposite is assumed to be the main contribution in enhancing the biocidal photocatalytic activity mainly due to the retardation of the recombination.
FIG. 5 shows examples of relationship between survival ratio of viable spores and UV irradiated time for a control system comprising spores suspended in deionized water (a), system with UV and Degussa P25 TiO 2 suspended in deionized water (b), and system with UV and TiO 2 coated carbon nanotubes according to the invention suspended in deionized water (c). Error bars indicate standard deviation from triplicate agar plates within the same experiment. The plots between log 10 survival ratio and irradiated time (right-hand side graphs) were fitted using the data within the exponential decay region to calculate the D values. As shown in FIG. 5( c ), the invention is far more effective as compared to the system using TiO 2 alone.
Example 3
Photocatalytic activity of TiO 2 -MWNT in visible light: The photocatalytic activity of TiO 2 -MWNT was displayed by the degradation of a dye in aqueous solution. A 3 mg sample of TiO 2 -MWNT was dispersed in 50 mL of a 5 ppm PROCION RED MX-5B™ (naphthalenedisulfonic acid, 5-((4,6-dichloro-s-triazin-2-yl)amino)-4-hydroxy-3-(phenylazo)-, disodium salt) solution by sonification for 20 minutes. The suspension was then placed under halogen lamps of a total power of 50 W/m 2 which had no output of UV light. Every 20 minutes a sample was removed and the dye concentration was measured by UV-VIS spectroscopy. As can be seen in FIG. 6 , the concentration of dye reduced to approximately half its initial concentration in 100 minutes. Under similar conditions with the Degussa P25 TiO 2 control, no measurable degradation of the dye occurred over the two hour period.
Example 4
Photocatalytic activity of TiO 2 -MWNT in the dark: The photocatalytic activity of TiO 2 -MWNT according to the invention was displayed by the degradation of a dye in aqueous solution. A 1 mg sample of TiO 2 -MWNT was dispersed in 50 mL of a 5 ppm PROCION RED MX-5B™ solution by sonification for 20 minutes. The suspension was then placed under a UV lamps of a total power of 20 W/m 2 for a total of 10 minutes. The suspension was then placed in a dark chamber with stirring. Every two to three days three sample were removed and the dye concentration was measured by UV-VIS spectroscopy. As can be seen in FIG. 7 , the concentration of dye continued to reduce for more than a week with a reduction of the dye concentration to approximately 77% of its original concentration in a week. Under similar conditions with Degussa P25 TiO 2 control, no measurable degradation of the dye occurred.
While the preferred embodiments of the invention have been illustrated and described, it will be clear that the invention is not so limited. Numerous modifications, changes, variations, substitutions and equivalents will occur to those skilled in the art without departing from the spirit and scope of the present invention as described in the claims.
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A photocatalyst nanocomposite which can be used to destroying biological agents includes a carbon nanotube core, and a photocatalyst coating layer covalently or ionically bound to a surface of the nanotube core. The coating layer has a nanoscale thickness. A method of forming photocatalytic nanocomposites includes the steps of providing a plurality of dispersed carbon nanotubes, chemically oxidizing the nanotubes under conditions to produce surface functionalized nanotubes to provide C and O including groups thereon which form ionic or covalent bonds to metal oxides, and processing a metal oxide photocatalyst sol-gel precursor in the presence of the nanotubes, wherein a nanoscale metal oxide photocatalyst layer becomes covalently or ionically bound to the nanotubes.
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CROSS-REFERENCE TO RELATED APPLICATIONS
This is a continuation application, and claims benefit under 35 U.S.C. §120 of U.S. patent application Ser. No. 11/114,929, filed on Apr. 25, 2005, which, pursuant to 35 U.S.C. §119(e), claims priority to both U.S. Provisional Application No. 60/603,171 filed Aug. 20, 2004 and U.S. Provisional Application No. 60/565,316 filed Apr. 26, 2004, the disclosures of which are hereby incorporated by reference.
BACKGROUND OF INVENTION
When drilling or completing wells in earth formations, various fluids typically are used in the well for a variety of reasons. For purposes of description of the background of the invention and of the invention itself, such fluids will be referred to as “well fluids.” Common uses for well fluids include: lubrication and cooling of drill bit cutting surfaces while drilling generally or drilling-in (i.e., drilling in a targeted petroleum bearing formation), transportation of “cuttings” (pieces of formation dislodged by the cutting action of the teeth on a drill bit) to the surface, controlling formation fluid pressure to prevent blowouts, maintaining well stability, suspending solids in the well, minimizing fluid loss into and stabilizing the formation through which the well is being drilled, fracturing the formation in the vicinity of the well, displacing the fluid within the well with another fluid, cleaning the well, testing the well, implacing a packer fluid, abandoning the well or preparing the well for abandonment, and otherwise treating the well or the formation.
As stated above, one use of well fluids is the removal of rock particles (“cuttings”) from the formation being drilled. A problem arises in disposing these cuttings, particularly when the drilling fluid is oil-based or hydrocarbon-based. That is, the oil from the drilling fluid (as well as any oil from the formation) becomes associated with or adsorbed to the surfaces of the cuttings. The cuttings are then an environmentally hazardous material, making disposal a problem.
A variety of methods have been proposed to remove adsorbed hydrocarbons from the cuttings. U.S. Pat. No. 5,968,370 discloses one such method which includes applying a treatment fluid to the contaminated cuttings. The treatment fluid includes water, a silicate, a nonionic surfactant, an anionic surfactant, a phosphate builder and a caustic compound. The treatment fluid is then contacted with, and preferably mixed thoroughly with, the contaminated cuttings for a time sufficient to remove the hydrocarbons from at least some of the solid particles. The treatment fluid causes the hydrocarbons to be desorbed and otherwise disassociated from the solid particles.
Furthermore, the hydrocarbons then form a separate homogenous layer from the treatment fluid and any aqueous component. The hydrocarbons are then separated from the treatment fluid and from the solid particles in a separation step, e.g., by skimming. The hydrocarbons are then recovered, and the treatment fluid is recycled by applying the treatment fluid to additional contaminated sludge. The solvent must be processed separately.
Some prior art systems use low-temperature thermal desorption as a means for removing hydrocarbons from extracted soils. Generally speaking, low-temperature thermal desorption (LTTD) is an ex-situ remedial technology that uses heat to physically separate hydrocarbons from excavated soils. Thermal desorbers are designed to heat soils to temperatures sufficient to cause hydrocarbons to volatilize and desorb (physically separate) from the soil. Typically, in prior art systems, some pre- and post-processing of the excavated soil is required when using LTTD. In particular, excavated soils are first screened to remove large cuttings (e.g., cuttings that are greater than 2 inches in diameter). These cuttings may be sized (i.e., crushed or shredded) and then introduced back into a feed material. After leaving the desorber, soils are cooled, re-moistened, and stabilized (as necessary) to prepare them for disposal/reuse.
U.S. Pat. No. 5,127,343 (the '343 patent) discloses one prior art apparatus for the low-temperature thermal desorption of hydrocarbons. FIG. 1 from the '343 patent reveals that the apparatus consists of three main parts: a soil treating vessel, a bank of heaters, and a vacuum and gas discharge system. The soil treating vessel is a rectangularly shaped receptacle. The bottom wall of the soil treating vessel has a plurality of vacuum chambers, and each vacuum chamber has an elongated vacuum tube positioned inside. The vacuum tube is surrounded by pea gravel, which traps dirt particles and prevents them from entering a vacuum pump attached to the vacuum tube.
The bank of heaters has a plurality of downwardly directed infrared heaters, which are closely spaced to thoroughly heat the entire surface of soil when the heaters are on. The apparatus functions by heating the soil both radiantly and convectionly, and a vacuum is then pulled through tubes at a point furthest away from the heaters. This vacuum both draws the convection heat (formed by the excitation of the molecules from the infrared radiation) throughout the soil and reduces the vapor pressure within the treatment chamber. Lowering the vapor pressure decreases the boiling point of the hydrocarbons, causing the hydrocarbons to volatize at much lower temperatures than normal. The vacuum then removes the vapors and exhausts them through an exhaust stack, which may include a condenser or a catalytic converter.
In light of the needs to maximize heat transfer to a contaminated substrate using temperatures below combustion temperatures, U.S. Pat. No. 6,399,851 discloses a thermal phase separation unit that heats a contaminated substrate to a temperature effective to volatize contaminants in the contaminated substrate but below combustion temperatures. As shown in FIGS. 3 and 5 of U.S. Pat. No. 6,399,851, the thermal phase separation unit includes a suspended air-tight extraction, or processing, chamber having two troughs arranged in a “kidney-shaped” configuration and equipped with rotating augers that move the substrate through the extraction chamber as the substrate is indirectly heated by a means for heating the extraction chamber.
In addition to the applications described above, those of ordinary skill in the art will appreciate that recovery of adsorbed hydrocarbons is an important application for a number of industries. For example, a hammermill process is often used to recover hydrocarbons from a solid. One recurring problem, however, is that the recovered hydrocarbons, whether they are received by either of the methods described above or whether by another method, can become degraded, either through the recovery process itself, or by the further use of the recovered hydrocarbons.
This degradation may result in pungent odors, decreased performance, discoloration, and/or other factors which will be appreciated by those having ordinary skill in the art. What is needed, therefore, are methods and apparatuses for improving the properties of recovered hydrocarbons.
SUMMARY OF INVENTION
In one aspect, the present invention relates to a method of treating a hydrocarbon fluid that includes contacting the hydrocarbon fluid with an effective amount of ozone.
In another aspect, the present invention relates to a method for separating contaminants from a contaminated material that includes the steps of supplying the contaminated material to a processing chamber, moving the contaminated material through the processing chamber, heating the contaminated material by externally heating the processing chamber so as to volatilize the contaminants in the contaminated material, removing vapor resulting from the heating, wherein the vapor comprises the volatilized contaminants, collecting, condensing, and recovering the volatilized contaminants, and contacting the volatilized contaminants with an effective amount of ozone.
In yet another aspect, the present invention relates to a system for separating contaminants from a material that includes a processing chamber, a heat source connected to the processing chamber adapted to vaporize hydrocarbons and other contaminants disposed on the material, a condenser operatively connected to an outlet of the process chamber and adapted to condense the vaporized hydrocarbons and other contaminants, and an ozone source operatively connected to the condenser.
Other aspects and advantages of the invention will be apparent from the following description and the appended claims.
BRIEF DESCRIPTION OF DRAWINGS
FIG. 1 a is a GC/MS trace of an untreated sample of hydrocarbon fluid;
FIG. 1 b is a GC/MS trace of a sample of hydrocarbon fluid treated in accordance with one embodiment of the present invention;
FIG. 2 a is an extracted ion scan of an untreated sample of hydrocarbon fluid; and
FIG. 2 b is an extracted ion scan of a sample of hydrocarbon fluid treated in accordance with one embodiment of the present invention.
FIG. 3 shows an apparatus for ozone treatment in accordance with one embodiment of the invention.
DETAILED DESCRIPTION
In one or more aspects, the present invention relates to methods and apparatuses for treating hydrocarbons. In particular, aspects of the present invention relate to methods and apparatuses for treating hydrocarbons that have been recovered from solid materials.
As noted above, a number of prior art methodologies for recovering adsorbed hydrocarbons from “cuttings” (i.e., rock removed from an earth formation) are currently used by hydrocarbon producers. While the present invention is not limited to this industry, the embodiments described below discuss the process in that context, for ease of explanation. In general, embodiments of the present invention may be applied to any “cracked” hydrocarbon fluid. A “cracked” hydrocarbon fluid is one where at least some of the “higher” alkanes present in a fluid have been converted into “smaller” alkanes and alkenes.
A typical prior art process for hydrocarbon recovery, as described above, involves indirectly heating a material having absorbed hydrocarbons causing the hydrocarbons to volatilize. The volatized hydrocarbon vapors are then extracted, cooled and condensed. As a result of the heating process, even at low temperatures, a portion of the recovered hydrocarbon fluid may be degraded. As used herein, the term degraded simply means that at least one property of the hydrocarbon fluid is worse than a “pure” sample. For example, a degraded fluid may be discolored, may have a pungent odor, or may have increased viscosity. “Recovered” hydrocarbons, as used herein, relate to hydrocarbons which have been volatized off of a solid substrate and condensed through any known method.
In a first embodiment, the present invention involves contacting a cracked hydrocarbon fluid with a stream of ozone. Ozone is known as an oxidizing agent, and previous studies have shown that ozone does not react with saturated compounds such as alkanes and saturated fatty acids. It is also known that ozone will react with unsaturated compounds such as alkenes, unsaturated fatty acids, unsaturated esters and unsaturated surfactants. The present inventors have discovered that by passing ozone through cracked hydrocarbons, improved hydrocarbon fluids may result. In particular, the present inventors have discovered that a reduction in odor and an improved coloration may occur. Reducing odor is of significant concern because of the increased regulation of pollution in hydrocarbon production.
Embodiments of the present invention involve contacting a hydrocarbon fluid with an effective amount of ozone. An “effective amount,” as used herein refers to an amount sufficient to improve a desired property (such as odor or color) in a hydrocarbon fluid. One of ordinary skill in the art would appreciate that the effective amount is a function of the concentration of the contaminants and the volume of the hydrocarbons to be treated.
Without being bound to any particular mechanism, the present inventors believe that the present invention operates through a chemical reaction known as ozonolysis. The reaction mechanism for a typical ozonolysis reaction involving an alkene is shown below:
Thus, in the reaction, an ozone molecule (O 3 ) reacts with a carbon-carbon double bond to form an intermediate product known as ozonide. Hydrolysis of the ozonide results in the formation of carbonyl products (e.g., aldehydes and ketones). It is important to note that ozonide is an unstable, explosive compound and, therefore, care should be taken to avoid the accumulation of large deposits of ozonide.
The efficacy of ozone as an agent to improve at least one property of a hydrocarbon fluid was investigated. In this embodiment, recovered hydrocarbons were used. One suitable source for the recovered hydrocarbons is described in U.S. patent application Ser. No. 10/412,720, which is assigned to the assignee of the present invention. That application is incorporated by reference in its entirety.
Another suitable source of recovered hydrocarbons is described in U.S. Pat. No. 6,658,757, which is assigned to the assignee of the present invention. That patent is incorporated by reference in its entirety. These two methods of obtaining recovered hydrocarbons are merely examples, and the scope of the present invention is not intended to be limited by the source of the hydrocarbon fluid to be treated.
In one embodiment, a 500 ml sample of recovered hydrocarbon was placed in a cylinder. Ozone was bubbled through the cylinder at a rate of 8 g per day. Commercial ozone generators are available from a variety of vendors. For this particular embodiment, a Prozone PZ2-1 ozone generator sold by Prozone International Inc. (Hunstville, Ala.) was used. The top of the cylinder remained open to the air, in order to avoid a build up of ozonide. However, a vacuum blower could also be used to continuously purge the ozonide. In this embodiment, it was discovered that by contacting the ozone with the recovered hydrocarbons for 48 hours, substantial improvement in the color and the odor of the recovered hydrocarbons was seen. As a baseline, a similarly sized sample of recovered hydrocarbon had air bubbled through it for the same period of time.
After 48 hours, the two samples were analyzed by GC/MS. FIGS. 1 a and 1 b show the results. FIG. 1 a is a GC/MS scan of the recovered hydrocarbon that had air bubbled through it, while FIG. 1 b is a GC/MS scan of the recovered hydrocarbon that was treated with ozone. Inspection of the scans reveals that the traces are very similar. This was expected as these samples comprise mostly saturated hydrocarbons which do not react with ozone.
FIGS. 2 a and 2 b which are extracted ion scans (i.e., second MS analysis) of the two samples, however, show that ozonolysis has an effect on the recovered hydrocarbons. In FIG. 2 a (the untreated sample), large amounts of xylene (panel 1 ) and benzene derivatives (panel 2 ) are present. In FIG. 2 b (the treated sample), however, these peaks are not present, indicating that the ozone has selectively attacked the carbon-carbon double bonds present in these molecules. In contrast, panels 3 of FIG. 2 a and FIG. 2 b show that the saturated hydrocarbon C 11 H 24 , remains unchanged after ozonolysis. The reduction of the amount of unsaturated hydrocarbons leads to improved performance, odor, and color in the recovered hydrocarbon fluid.
To further understand the chemistry behind the reaction, the untreated fluid (i.e., recovered hydrocarbon contacted only with air) and the treated fluid were tested and analyzed on a GC/MS for paraffins, iso-paraffins, aromatics, napthenics, olefins, aldehydes, ketones, and acids (the latter three collectively called “other compounds”). The results are summarized in the table below:
TABLE 1
GC/MS data for treated vs. untreated fluid
Compound
Untreated Fluid
Treated Fluid
Paraffin
20.69%
21.71%
Iso-paraffin
27.56%
32.14%
Aromatics
13.27%
10.67%
Naphthenics
23.48%
16.57%
Olefins
2.97%
3.69%
Other compounds
11.94%
15.22%
The above table illustrates that the unsaturated aromatics and naphthenics are attacked by ozone, reducing their concentration in the treated fluid. These samples also contain low amounts of olefins. While the analysis does not show a reduction in olefin concentration, this is most likely due to the error inherent in the analysis.
In order to increase the reactivity of the ozone, a number of changes can be incorporated into the process. For example, the reaction vessel may be slightly pressurized in order to increase the solubility of the ozone in the hydrocarbon fluid. 7-8 psi is a preferred range, but those of ordinary skill will recognize that depending on the application, higher pressures may be used. Further, because the ozonolysis reaction is believed to be driven by the surface area of the ozone bubbles, ultrasonic systems may be used to decrease the size of individual ozone bubbles, leading to increased contact, which, in turn, increases the rate of the ozonolysis reaction. In addition, those having ordinary skill in the art will appreciate that another way to get improved contact is by using long, narrow columns of fluid, and passing the ozone through such a column.
The removal of organochlorine substances or microorganisms may also be accomplished by a cavitation phenomenon using ultrasound and injections of ozone, peroxides, and/or catalysts, such as within JP-900401407 (Ina Shokuhin Kogyo), JP-920035473 (Kubota Corp.), JP-920035472 (Kubota Corp.) and JP-920035896 (Kubota Corp.). Further the use of ultrasound with or without ozone is reported for the treatment of sewage sludge. Thus, it is contemplated that the combination of ozone and ultrasound (either low frequency or high frequency) may provide additional benefits to the treatment process described herein. For example, a tank with a sparger for ozone and a source for ultrasound may provide enhanced processing of the recovered oil. Alternatively, a continuous flow process (either concurrent flow or counter flow) in which ultrasound is introduced is contemplated as being within the scope of the present invention.
Depending on the particular amount of hydrocarbon liquid to be treated, a selected amount of ozone per day may be used. Further, the methods and apparatuses of the present invention may be used as a batch process, whereby barrels of hydrocarbon fluids are transported to a different location for ozone treatment, or they may be used in a continuous recovery process, whereby the ozone is added during the recovery process. Those having ordinary skill will recognize that continuous recovery may be used in either the process described in U.S. patent application Ser. No. 10/412,720 or U.S. Pat. No. 6,658,757.
FIG. 3 illustrates an apparatus in accordance with an embodiment of the present invention. FIG. 3 shows an embodiment of an apparatus 90 for improving the properties of recovered hydrocarbons from wellbore cuttings 100 . In the embodiment shown in FIG. 3 , cuttings 100 contaminated with, for example, oil-based drilling fluid and/or hydrocarbons from the wellbore (not shown) are transported to the surface by a flow of drilling fluid returning from the drilled wellbore (not shown). The contaminated cuttings 100 are deposited on a process pan 102 . In some embodiments, the cuttings 100 may be transported to the process pan 102 through pipes (not shown) along with the returned drilling fluid. In other embodiments, the cuttings 100 may be, for example, processed with conveying screws or belts (not shown) before being deposited in the process pan 102 . The process pan 102 is then moved into a process chamber 103 via, for example, a fork lift (not shown separately in FIG. 3 ). For example, in some embodiments of the invention, the process pan 102 may be rolled in and out of the process chamber 103 on a series of rollers.
In other embodiments, the process pan 102 may be moved vertically in and out of the process chamber 103 with, for example, hydraulic cylinders. Accordingly, the mechanism by which the process pan 102 is moved relative to the process chamber 103 is not intended to be limiting. Moreover, some embodiments of the apparatus 90 may comprise a plurality of process chambers 103 and/or a plurality of process pans 102 . Other embodiments, such as the embodiment shown in FIG. 3 , comprise a single process pan 102 /process chamber 103 system. Furthermore, the number of process pans 102 and process chambers 103 need not be the same.
The process chamber 103 includes, in some embodiments, a hydraulically activated hood (not shown) that is adapted to open and close over the process chamber 103 while permitting the removal or insertion of the process pan 102 . After the process pan 102 has been inserted into the process chamber 103 , the hydraulically activated hood (not shown) may be closed so as to “seal” the process chamber 103 and form an enclosed processing environment. The hood (not shown) may then be opened so that the process pan 102 may be removed.
After the process pan 102 has been positioned in the process chamber 103 , heated air, which has been heated by a heating unit 112 (which may be, for example, a propane burner, electric heater, or similar heating device), is forced through the contaminated cuttings 100 so as to vaporize hydrocarbons and other volatile substances associated or adsorbed thereto. The heated air enters the process chamber 103 through, for example, an inlet duct 120 , pipe, or similar structure known in the art. The heated air, which may be heated to, for example, approximately 400° F., is forced through the process pan 102 by, for example, a blower (not shown).
However, a blower may not be necessary in some embodiments if the pressure in the air circulation system is maintained at a selected level sufficient to provide forced circulation of the heated air through the contaminated cuttings 100 . As the heated air is forced through the process pan 102 , the air volatilizes the hydrocarbon and other volatile components that are associated with the cuttings 100 . The hydrocarbon rich air then exits the bottom of the process chamber 103 through, for example, an outlet duct 122 and passes through a heat recovery unit 108 . The heat recovery unit 108 recaptures some of the heat from the hydrocarbon rich air and, for example, uses the recaptured heat to heat additional hydrocarbon free air that may then be recirculated through the process chamber 103 through the inlet duct 120 . Some hydrocarbons, water, and other contaminants from the contaminated cuttings 100 may be directly liquefied as a result of the forced-air process. These liquefied hydrocarbons, water, and/or other contaminants flow out of the process chamber 103 and through a process chamber outlet line 106 .
After passing through the heat recovery unit 108 , the hydrocarbon rich air is drawn through a series of filters 124 that are adapted to remove particulate matter from the air. The hydrocarbon rich air is then passed through an inlet 126 of a first condenser 110 . Note that the inlet 126 of the first condenser 110 is typically operated under a vacuum to control the flow of hydrocarbon rich air. The vacuum at the inlet 126 may be produced, for example, by a vacuum pump (not shown separately in FIG. 3 ).
The first condenser 110 further comprises cooling coils (not shown separately in FIG. 3 ) adapted to condense the volatilized hydrocarbons (and, for example, an water vapor and/or other contaminants) in the hydrocarbon rich air into a liquid form. The liquefied hydrocarbons and contaminants are then removed through, for example, a condenser outlet 128 that conveys the liquefied hydrocarbons and contaminants to an oil/water separator 116 . The apparatus 90 may also comprise, for example, pumps (not shown) that may assist the flow of liquefied hydrocarbons and contaminants from the condenser outlet 128 to the oil/water separator 116 .
After passing through the first condenser 110 , the cooled air then flows through a second series of filters and cooling coils 130 and into a second condenser 111 that operates at or near atmospheric pressure. The second condenser 111 boosts the pressure of the ambient airflow, and any additional condensate is removed from the process stream through an outlet 132 that transports the additional condensate to the oil/water separator 116 .
An ozone generator 142 is connected to the oil/water separator 116 . The ozone generator 142 is arranged to provide a selected amount of ozone (usually selected in grams per day) into the oil/water separator 116 . In a preferred embodiment, the oil/water separator 116 comprises long, narrow columns, so that the contact area of the ozone is increased. Further, in some embodiments, an ultrasonic system (not separately shown) is coupled to the oil/water separator 116 to increase the ozone contact area. Further, in certain other embodiments, the oil/water separator 116 may be placed under pressure to increase the amount of ozone that can dissolve in the system. The oil/water separator 116 may further comprise a vent 144 to allow built up gases to evacuate the system, or may be attached to a vacuum blower, for example. Those having ordinary skill in the art will recognize that although the above embodiment describes a multi-condenser system, some embodiments contemplate the use of only a single condenser. Those having ordinary skill will appreciate that the ozone generator is operatively coupled to a recovered hydrocarbon fluid, and that the operative coupling may take place in a variety of ways.
In an alternative embodiment, contaminated material (i.e., solids containing adsorbed hydrocarbons) may first be screened to remove stones, rocks, and other debris, and then deposited into a feed hopper. The contaminated material may be fed directly into a feed hopper, or fed from a feed hopper into a lump breaker by a horizontal conveyor belt. From the lump breaker, the contaminated material is discharged onto an inclined conveyor belt for delivery to a feed hopper that directs the contaminated material to rotary paddle airlock valves.
Upon passing through the airlock valves, the contaminated substrate drops into an extraction chamber (also referred to as “processing chamber”) and is moved through the extraction chamber by an auger screw. As the contaminated material moves though the extraction chamber, the contaminated material is indirectly heated by a combustion system that supplies heat to the extraction chamber from burners located externally and underneath the extraction chamber. The contaminated substrate remains physically separated from the combustion system by the extraction chamber's steel shell.
An enclosure referred to as “firebox” houses the extraction chamber and burners of the combustion system. As eluded to above, the firebox derives its heat by the combustion of commercially available fuels. The heat can be varied so that the temperature of the contaminated substrate is elevated to the point that the contaminants in the contaminated material are volatilized.
The treated substrate is then passed through a rotary airlock valve at the end of the extraction chamber and become available for rewetting and reintroduction to the environment. The volatilized contaminants are removed from the extraction chamber and directed to a vapor handling system.
The volatilized water and contaminants generated in the extraction chamber are subject to a vapor/gas condensation and clean-up system for the purpose of collection and recovery of the contaminants in liquid form. An ozone generator may then be operatively connected to the contaminants, which comprise hydrocarbon fluids, in order to treat the fluid. The vapor/gas condensation and clean-up system preferably includes a plurality of steps. First, the hot volatilized vapors/gases from the extraction chamber are cooled through direct contact water sprays in a quench header and the water required by the quenching process is provided by spray nozzles spaced at regular intervals along the quench header.
Second, the vapor/gas stream is then directed through one or more knock-out pots to remove residual particulate matter and large water droplets. Third, the vapor stream is subjected to a water impinger to further remove finer particulate matter and smaller water droplets. Fourth, the relatively dry vapor/gas stream of non-condensable gases is subject to one or more mist eliminators for aerosol removal. Fifth, the vapor/gas stream may be passed through a high efficiency air filtration system to remove any submicron mists or particles still remaining in the vapor/gas stream.
Glass media may be used in the filter system to filter material down as a microlite, and, as such, the filters remove liquid mist down to a 0.05 micron level. Finally, the vapor/gas stream may be subjected to a final polishing in a series of carbon absorption beds and subsequently vented to the atmosphere or returned to the burners of the combustion system. The ozone generator may be attached at a number of positions in the above embodiments, but should preferably be attached in a fashion to avoid placing significant heat on the ozonide formed during the ozonolysis reaction, to reduce the chance of an explosion.
In addition, those having ordinary skill in the art will recognize that the rate (i.e., the amount of ozone per day) may be varied, depending on a particular application in order to optimize treatment of recovered hydrocarbon fluids. Further, the reaction time (i.e., the length of time that the hydrocarbon fluids are subjected to ozone) may vary depending on the particular application. Still further, the extent of reaction (i.e., the amount of double bonds broken) may vary, depending on the amount of degradation that has occurred, and the desired end properties of the hydrocarbon fluid. Advantageously, embodiments of the present invention provide an improvement in at least one property of a “cracked” hydrocarbon fluid.
While the invention has been described with respect to a limited number of embodiments, those skilled in the art, having benefit of this disclosure, will appreciate that other embodiments can be devised which do not depart from the scope of the invention as disclosed herein. Accordingly, the scope of the invention should be limited only by the attached claims.
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A method of treating a hydrocarbon fluid that includes contacting the hydrocarbon fluid with an effective amount of ozone. A method for separating contaminants from a contaminated material includes supplying the contaminated material to a processing chamber, moving the contaminated material through the processing chamber, heating the contaminated material by externally heating the processing chamber so as to volatilize the contaminants in the contaminated material, removing vapor resulting from the heating, wherein the vapor comprises the volatilized contaminants, collecting, condensing, and recovering the volatilized contaminants, and contacting the volatilized contaminants with an effective amount of ozone.
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TECHNICAL FIELD
[0001] The present disclosure is directed to systems and methods for the production of seams to seal lids onto cans, particularly seaming metal lids and cans in the food and beverage industries.
BACKGROUND
[0002] A variety of can seaming apparatus are presently available for seaming lids onto metal cans in the food and beverage industries. Particularly for smaller cans with smaller lids, pneumatic sealing devices are preferable in terms of cost reduction and setup time. However, one existing difficulty in devices using air pressure to drive pivoting arms equipped with seam rollers into a can seaming area is in maintaining the high accuracy necessary to drive the roller into the correct position at the seaming area to produce a sufficient seam.
[0003] Typically, an air cylinder drives the seam roller into the seaming area. However, maintaining a consistent dimensional deformation throughout the seaming area is difficult to achieve with air cylinders in conventional designs. Existing methods use a sequence of two seam rollers to form the lips of the lid and the can into the required seal. Low pressure in the air system driving the seam rollers or an inadequate dwell time in the seaming process lead to discontinuity in the seam area. This causes dimensional variations in the seam area. Additionally, if the seam producing rollers travel too far into the seam forming area or not far enough, an inadequate seam is formed. These inaccuracies frequently lead to leakage and contamination of contents within the can. Such cans are not acceptable for further processing or sale, which leads to inefficiencies in the canning process and production of canned foods and beverages.
[0004] The repeatable seam apparatus disclosed herein is intended to overcome one or more of the problems discussed above.
SUMMARY OF THE EMBODIMENTS
[0005] One embodiment disclosed herein is a can seaming apparatus that includes a seaming arm pivotably attached to a shaft of the can seaming device. A seam roller is attached to one end of the seaming arm, and a cam system is attached to the other end of the seaming arm distal to the seam roller.
[0006] The cam system of the can seaming apparatus may include a rotating cam, a cam follower and an actuator. The actuator may rotate the cam about an axis, with the rotating cam providing a force on the cam follower that is in mechanical contact with the perimeter of the rotating cam. The cam follower may be operatively attached to an end of the seaming arm distal the seam roller. The force provided to the cam follower may be transferred to the seaming arm through direct contact, and therefore pivoting the seaming arm about the shaft of the can seaming device. The pivot force provided at one end of the seaming arm may swing the other end of the seaming arm, containing the seam roller, into a seaming area of a can and lid assembly.
[0007] In an embodiment which features an actuator in the cam system, the actuator may be a pneumatic actuation device. In other embodiments, the actuator may be an electric motor or a programmable controller.
[0008] Similarly, the cam follower may be an eccentric cam follower, thus allowing for fine tune adjustments to the cam system driving the seaming arms and seam rollers of the can producing apparatus. This may allow for smooth and repeatable can seaming operation.
[0009] Furthermore, the cam system may include a separate single-lobed rotating cam for each actuation device. In some embodiments, the can seaming apparatus may include a plurality of seam rollers. In this representative embodiment, the can seaming apparatus may further include multiple seaming arms. As such, the cam system of the can seaming apparatus might include a rotating cam with two or more lobes. The number of lobes may correspond to the number of seam rollers in operation of the can seaming apparatus.
[0010] The can seaming apparatus may include a height adjustment device attached to the seaming arm. This may provide for adjustment of the vertical positioning of the seam roller. In some cases, this height adjustment device may be a manually turnable knob, where turning the knob in either direction may cause the seam roller to be positioned higher or lower on its vertical axis. The height of the seam roller may be specified according to industry standards for producing acceptable can seams. The height adjustment device may allow for easy adjusting, and therefore repeatable fine tune adjustments of the positioning of the seam roller into a proper seam area of the can and lid assembly. This particular embodiment may contribute to producing repeatable and highly accurate can seams with the can seaming apparatus. The cam seaming device may further include a can lifting device to lift a can and lid assembly into contact with the seaming chuck.
[0011] It may be desirable for specific embodiments that the bearing of the rotating cam is aligned with the rotational axis of the can and lid assembly. In other embodiments, the bearing of the cam may rotate at an axis that is offset from the rotational axis of the can and lid assembly.
[0012] Another embodiment disclosed herein is a method of producing a seam on a can and lid assembly. The method includes providing a seam roller that is attached to one end of a seaming arm. The seaming arm may be pivotably secured to a shaft. A cam system may be provided, and may include a rotating cam that is mechanically associated with a cam follower and an actuator. The cam system may be operatively associated with a second end of the seaming arm that is distal to the first end containing the seam roller. The actuator may actuate the cam system to drive the rotating cam, which may provide a sliding force on the cam follower that is in contact with the perimeter of the rotating cam. This contact may transfer a force from the rotating cam to the second end of the seaming arm, which may cause a repeatable swinging motion of the seaming arm about the shaft, and therefore engage the seam roller into contact with the can and lid assembly.
[0013] As used herein, a means for actuating the cam system may include pneumatic actuation means. Alternatively, the actuating means include means for an electric motor or means for programmable controls.
[0014] The method may further include adjusting the cam system by selecting a specific eccentric cam and cam follower. This may allow for producing a highly accurate and repeatable can seam.
[0015] In other embodiments, the method may include driving a single lobe rotating cam of the cam system with an actuator. Alternatively, the method may include driving a multiple lobe rotating cam with an actuator.
[0016] A height adjustment device may allow for fine tuning of the vertical height of the seam roller with respect to the can and lid assembly. Such positioning of the seam roller may be specified by industry standards, and furthermore may be easily adjusted with the height adjustment device, therefore allowing the user to produce accurate and repeatable can seams.
[0017] The method may further include rotating the cam around the rotational axis of the can and lid assembly. In another embodiment, the method may include rotating the cam at an axis that is offset from the rotational axis of the can and lid assembly.
BRIEF DESCRIPTION OF THE DRAWINGS
[0018] FIG. 1 is a perspective view of a can seaming apparatus as disclosed herein.
[0019] FIG. 2 is a perspective view of several components of a can seaming apparatus from an upper point of view.
[0020] FIG. 3 is a perspective view of a seaming area for a can and lid assembly and a can seaming apparatus.
[0021] FIG. 4 is a perspective view of a seaming area for a can and lid assembly and a can seaming apparatus.
[0022] FIG. 5 is a perspective view of the engagement of a seam roller with a seaming area of a can and lid assembly.
[0023] FIG. 6 is a perspective view of a cam system that drives components of the can seaming apparatus of FIG. 2 .
[0024] FIG. 7 is a perspective view of several components of a can seaming apparatus from a lower point of view.
[0025] FIG. 8 is an additional view of a cam system of a can seaming apparatus from an upper and rear point of view.
[0026] FIG. 9 is a front plan view of a can seaming apparatus and elevation device.
DETAILED DESCRIPTION
[0027] Unless otherwise indicated, all numbers expressing quantities of ingredients, dimensions, reaction conditions and so forth used in the specification and claims are to be understood as being modified in all instances by the term “about”.
[0028] In this application and the claims, the use of the singular includes the plural unless specifically stated otherwise. In addition, use of “or” means “and/or” unless stated otherwise. Moreover, the use of the term “including”, as well as other forms, such as “includes” and “included”, is not limiting. Also, terms such as “element” or “component” encompass both elements and components comprising one unit and elements and components that comprise more than one unit unless specifically stated otherwise.
[0029] FIG. 1 illustrates one embodiment of a can seaming apparatus 100 . The FIG. 1 embodiment features a pneumatically actuated cam that can be deployed against a pivoting arm equipped with a specialized roller to repeatedly produce a pressure tight seam in a can. Particularly, the disclosed can seam producing device uses both a highly accurate cam system and a linearly actuated slide, pneumatically driven or otherwise, to deploy the cams. The various embodiments feature a metal cam with an adjustable cam follower in order to achieve precise dimensional control in the seaming process. An adjustment feature on the cam follower enables an operator to finely tune the engagement of both seaming rollers, producing a controllable seam between the can and the lid. The disclosed systems can be retrofitted on existing pneumatic only driven can sealers. The described systems can also operate as a standalone can sealing device.
[0030] FIG. 2 is a perspective view from an upper vantage point of the seam producing device 100 . In use, a can and lid assembly 104 to be seamed is brought into contact with a seaming chuck 103 . The seaming chuck 103 includes apparatus configured to secure the can and lid assembly 104 in an operative position with respect to the seam producing device 100 . A motor 111 spins a shaft connected to the seaming chuck 103 at a sufficient speed to accomplish a selected number of complete revolutions in a given time frame, as required for the fabrication of an acceptable seam. The can/lid assembly 104 is held in place by the seaming chuck 103 and rotates with the motor-driven shaft of the seaming chuck 103 . As both the can/lid assembly 104 and seaming chuck 103 are rotating, seam rollers 101 and 102 are brought into the area of the can/lid assembly 104 where a seam is to be formed. Formation of the can seam is accomplished in two operations. Separate rollers are therefore required. In the first operation the first seam roller engages the lip of the can and the curled outer section of the can lid and initiates the seaming process by forming the can and lid into a mutually engaged curl. The second operation involves a second roller with a different form that finishes a double envelopment seam by forming the results of the first operation into a tightly compressed band with overlapping metal from both the can and the lid. When properly aligned, the above processes form a permanent hermetic seal.
[0031] Height adjustment devices 107 , 108 are threaded and fit into a likewise threaded portion of the seaming arms 105 , 106 . The height adjustment devices 107 , 108 provide for the height of the seam rollers 101 , 102 to be very accurately oriented vertically with respect to the chuck 103 and can/lid assembly 104 . The seaming arms 105 , 106 can be rotated about pivots 114 , 115 (hidden). Rotary actuators 109 , 110 are located at the far end of the seaming arms 105 , 106 from the seam rollers 101 , 102 . The rotary actuators 109 , 110 , in conjunction with certain cam embodiments described in detail below, drive the seaming arms 105 , 106 into and out of an operative position.
[0032] In one embodiment, a single cam rotating on its own bearing and having a cam axis coincident with the axis of the can/lid assembly 104 and the seaming chuck 103 , or offset a given distance from this axis, can actuate the seam rollers 101 , 102 to provide an accurate seam. In a single cam embodiment the cam will have two or more lobes corresponding to the number of seam rollers 101 , 102 . For example, FIG. 3 illustrates the location and position of the driving cam 121 in a single cam embodiment. This cam has a center of rotation located coincident with the center of rotation of the seaming chuck 103 .
[0033] In other embodiments, a separate cam with a single lobe may be provided for each separate rotary actuator 109 , 110 . In this alternative embodiment, each separate cam can be mounted on its own separate bearing. In either embodiment, the rotating cam or cam system is driven separately from the can rotating system and can be sequenced on command. The cam or cam system can be driven by a pneumatic device, by an electric motor device, or another commonly used actuation method. The cam or cam system may be controlled, for example, with commands from a programmable controller. As described in detail below, adjustable cam followers 117 , 118 for each of the arms carrying seaming rollers 101 , 102 allow an operator to precisely adjust the resulting seam to a given specification.
[0034] In the case of a pneumatically actuated cam, the cam can be deployed against a pivoting arm equipped with a specialized roller to repeatedly produce a pressure tight seal in a can. An air pressure driven slide can be actuated to bring a shaped cam into contact with a rolling element mounted on a swiveling arm. On the opposite end of the arm, a specially constructed seam roller 101 , 102 is brought into a fixed distance from the edge of the can/lid interface.
[0035] FIG. 4 is a perspective view of the seaming area. The seaming chuck 103 is attached to a shaft 113 driven by the motor 111 . Seam roller 101 performs the first of two operations required to fabricate a proper seam. The seam roller 101 is brought into an accurate and repeatable position in relation to the seam area 112 of the can/lid assembly 104 . Accuracy in positioning the seam roller 101 at a fixed distance from the edge of the can/lid assembly 104 is critical to the formation of a proper seam. Upon completion of the first operation, the initial seam roller 101 is retracted and the second seam roller 102 is brought into an accurate and repeatable position in relation to the seam area 112 . The second seam roller has a different special construction to produce the final formation of the seam. The height adjustment devices 107 , 108 control the position of their respective vertically aligned seam rollers 101 , 102 . Both seam rollers 101 , 102 require exact dimensional control.
[0036] FIG. 5 illustrates the engagement of seam roller 101 into seaming area 112 . The seaming chuck 103 and can/lid assembly 104 rotate together for this first operation by seam roller 101 . The seam roller 102 is disengaged, as shown by the gap between the seam roller 102 and the lip of the can/lid assembly 104 .
[0037] FIG. 6 illustrates the cam system that drives the seaming arms 105 , 106 in a rotating fashion to bring the seam rollers 101 , 102 into the desired accurate and repeatable position. In one embodiment, rotary actuators 109 , 110 drive the driving cams 116 , 119 in a continuous rotation. The cam followers 117 , 118 in contact with the rotating driving cams 116 , 119 transfer the rotary motion imparted to the cams 116 , 119 by the rotary actuators 109 , 110 into linear motion by pushing the seaming arms 105 , 106 about pivots 114 , 115 . Consequently, the seaming arms 105 , 106 attached to the seam rollers 101 , 102 push the seam rollers 101 , 102 into the rotating seaming area 112 . The seaming action is accomplished by deforming the can and lid interface in a controlled manner. Gross adjustment of the seam rollers 101 , 102 is accomplished by loosening the rotary actuators 109 , 110 and moving them in a lateral mode, thereby increasing or decreasing the relative position between seam rollers 101 , 102 and the seaming area. Once gross adjustment is completed, the rotary actuators 109 , 110 are re-tightened. The cam followers 117 , 118 have eccentric base mounts, allowing for fine adjustment of the relative position between the seam rollers 101 , 102 and the seaming area 112 . Such adjustments are made in anticipation of conforming to well-established industry parameters.
[0038] FIG. 7 illustrates a perspective view from the lower vantage point of the seam producing apparatus, showing the driving cam 116 and corresponding cam follower 117 and the driving cam 119 and corresponding cam follower 118 .
[0039] FIG. 8 provides an additional view of the driving cam 116 and cam follower 117 connected to the seaming arm 106 . In operation, the driving cam 116 rotates and the rotation is traced by the cam follower 117 . With the cam follower 117 attached to the seaming arm 106 , the tracing action causes the seaming arm 106 to pivot about the pivot 115 . This repeatable and accurate action places a first seam roller 101 (not shown on FIG. 8 ) into contact with the seaming area 112 of the can/lid assembly 104 . The second seam roller 102 is then put in contact with the seaming area 112 of the can/lid assembly 104 to complete a seam. The seaming arms 105 , 106 may be provided to have carefully selected lengths, so that force is multiplied at the seam rollers 101 , 102 , thereby lessening radial forces on the cam followers 117 , 118 and the driving cams 116 , 119 .
[0040] The adjustability of the driving cams 116 , 119 attached to the rotary actuators 109 , 110 in combination with the eccentric based cam followers 118 , 117 make the final specifications of the produced seam controllable within the range of 0.001 inch, according to some embodiments. In other embodiments, the can seam is repeatable to within 0.003 inch.
[0041] As shown in FIG. 9 , the can seamer 100 may be implemented in conjunction with a can elevation device that raises a can/lid assembly 104 from the conveyor surface to engage the seaming chuck 103 . The filled can/lid assembly 104 is required to rotate in concert with the rotating seaming chuck 103 . The FIG. 9 can elevation device embodiment features a table 120 that engages the bottom of the filled can/lid assembly 104 . Contained within the table 120 is a bearing (hidden) that allows the table 120 to follow the rotation of the seaming chuck 103 . The can/lid assembly 104 located on the table 120 is raised by a pneumatic cylinder 121 , or other lifting means. The pneumatic cylinder 121 is configured to bring the filled can/lid assembly 104 into engagement with the seaming chuck 103 prior to the full extension of the pneumatic cylinder. An externally controlled pressure source then allows the operator to produce an accurate axial force engaging the filled can/lid assembly 104 with the seaming chuck 103 which is useful for the accurate reproduction of the formed seam.
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A can seaming apparatus and methods of forming a seam on a can and lid assembly is disclosed. The apparatus comprises one or more seaming arms pivotably attached to a shaft, a seam roller attached to one end of each seaming arm and a cam system. The cam system comprises one or more cams associated with the end of each seaming arm opposite the seam roller. Force is transferred to each seaming arm through rotation of the one or more cams. The seaming arm then pivots and moves the associated roller into a seaming area of a can and lid assembly to create a seam.
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Botanical/commercial classification: Rosa hybrida /Shrub Rose Plant.
Varietal denomination: cv. Meijeunom.
SUMMARY OF THE INVENTION
The new variety of Rosa hybrida shrub rose plant of the present invention was created by artificial pollination wherein two parents were crossed which previously had been studied in the hope that they would contribute the desired characteristics. The female parent (i.e., the seed parent) was ‘The Fairy’ variety (non-patented in the United States). Such female parent was formed by the cross of the ‘Paul Crampel’ variety (non-patented in the United States) and the ‘Lady Gay’ variety (non-patented in the United States). The male parent (i.e., the pollen parent) of the new variety was an unnamed seedling (non-patented in the United States). The parentage of the new variety can be summarized as follows:
‘The Fairy’×Unnamed Seedling.
The seeds resulting from the above pollination were sown and small plants were obtained which were physically and biologically different from each other. Selective study resulted in the identification of a single plant of the new variety.
It was found that the new Shrub Rose plant of the present invention possesses the following combination of characteristics:
(a) abundantly forms in clusters on a nearly continuous basis attractive semi-double cup-like fragrant ivory-white blossoms that self clean well, (b) exhibits a spreading ground cover growth habit, (c) forms glossy medium green foliage that contrasts well with the blossom coloration, (d) develops well following asexual reproduction, (e) is highly resistant to Black Spot, Powdery Mildew, and Rust; and (f) is particularly well suited for providing attractive ornamentation as a mass planting and when grown in containers.
The new variety well meets the needs of the horticultural industry. It can be grown to advantage as ornamentation in parks, gardens, public areas, and in residential settings where attractive ornamentation is desired. It is particularly well suited for growing in small areas.
The new variety of the present invention also can be readily distinguished from other rose varieties. For instance, ‘The Fairy’ female parent forms dissimilarly colored light pink blossoms and displays a taller growth habit. The ‘Meipadan’ variety (U.S. Plant Pat. No. 15,487) displays a similar growth habit and also forms white blossoms; however, unlike the new variety, this comparative variety forms much larger blossoms that possess single petalage. The ‘Meidarin’ variety (U.S. Plant Pat. No. 13,291) also displays a similar growth habit, combined with less hardiness, and the formation of vibrant orange blossoms.
The characteristics of the new variety have been found at Waso, Calif., U.S.A., and near West Grove, Pa., U.S.A., to be homogeneous and stable and to be strictly transmissible by asexual propagation, such as budding, grafting, and the rooting of cuttings from one generation to another. The new variety reproduces true to type by such asexual propagation. Good plant development has been observed regardless of the mode of asexual propagation.
The new variety has been named ‘Meijeunom’, and is being marketed under the IVORY DRIFT trademark.
BRIEF DESCRIPTION OF THE PHOTOGRAPHS
The accompanying photographs shown, as nearly true as it is reasonably possible to make the same in a color illustrations of this character, a typical flowering plant of the new variety. The illustrated rose plant of the new variety was approximately three years of age and was observed during June, 2006 while growing outdoors on ‘Dr. Huey’ rootstock near West Grove, Pa., U.S.A.
FIG. 1 shows the typical flowering specimen of the new variety wherein the compact spreading ground cover growth habit is illustrated.
FIG. 2 shows a close view of the attractive ivory-white blossoms in various stages of opening, as well as the foliage of the new variety.
DETAILED DESCRIPTION
The chart used in the identification of colors is that of The Royal Horticultural Society (R.H.S. Colour Chart), London, England. The description is based on the observation of three-year-old specimens of the new variety during June 2006 while growing outdoors on ‘Dr. Huey’ rootstock near West Grove, Pa., U.S.A.
Class: Landscape Shrub. Plant:
Height.— Approximately 30 to 45 cm on average at the end of the growing season. Width.— Approximately 55 to 65 cm on average at the end of the growing season. Habit.— Low rounded mound.
Branches:
Color.— Young stems: Yellow-Green Group 144C with highlights of Red Group 53C. Adult wood: Yellow-Green Group 144A. Thorns.— Size: approximately 1 cm in length from base to point on average. Configuration: commonly sharply pointed with the tip nearly perpendicular to the stem and pointing upward. Quantity: typically approximately 4 to 5 over a stem length of 10 cm. Color: near Yellow-Green Group 151A on young stems and near Brown Group 200D on mature wood and more glaucous.
Leaves:
Length.— Varies widely with number of leaflets, for a five-leaflet leaf approximately 7 to 8 cm including the petiole on average, and for a seven-leaflet leaf approximately 9 to 10 cm including the petiole on average. Width.— For a five-leaflet leaf approximately 4.5 to 5 cm on average at the widest point, and for a seven-leaflet leaf approximately 7 to 7.5 cm on average at the widest point. Leaflets.— Number: 3 (rarely), 5 (more commonly), 7 (more typically), and 9 (rarely). Arrangement: alternate and pinnate. Shape: typically elliptical to broadly elliptical, with an attenuate base, and commonly with a broadly acute to rounded tip. Margins: serrulate. Texture: glabrous on the upper and under surfaces and papyraceous. Overall appearance: small, dense, medium green in coloration, and glossy. Color (young foliage): upper surface; near Green Group 137A. under surface: near Green Group 138A with some darkening to Green Group 137C. Color (adult foliage): upper surface: near Green Group 139A. under surface: near Green Group 138with some lightening to Green Group 137C. Petioles.— Length: approximately 20 mm on average. Diameter: approximately 1.4 mm on average. Color: Yellow-Green Group 144C. Stipules.— Length: approximately 20 mm on average. Width: approximately 8 mm on average. Color: near Yellow-Green Group 144C towards the middle, and near Green Group 137A at the edges.
Inflorescence:
Number of flowers.— Commonly 10 to 15 per stem in a cluster. Peduncle.— Approximately 15 to 20 mm in length on average, and approximately 1.5 to 2 mm in diameter on average. Sepals.— Typically five in number, approximately 7 to 11 mm in length on average, approximately 6 mm in width on average, near Yellow-Green Group 144B on the inner and outer surfaces, and with a few generally lanceolate-shaped foliaceous extensions at the edges which commonly are approximately 7 to 11 mm in length and approximately 2.5 to 4.5 mm in width. Buds.— Shape: Ovoid. Size: very small, and approximately 1 cm in length and width on average as the calyx breaks. Color: as the bud cracks the petals are Yellow Group 13C on the upper and under surfaces. Flower.— Form: semi-double. Shape: cup-like when fully open. Diameter: approximately 4 to 4.5 cm on average when fully open. Color newly opened: upper surface: Yellow Group 4D at the apex and Yellow Group 4A towards the base. under surface: Yellow Group 4D at the apex and Yellow Group 4A towards the base. Color fully opened: upper surface: near Yellow Group 11D with a small amount of Yellow Group 11A at the base. under surface: primarily near Yellow Group 11D. Color stability: there is a considerable change in coloration from the time of first opening to petal drop. Fragrance: slight and fruity. Petal shape: obovate to narrowly obovate to narrowly obcordate. Petal number: commonly approximately 22 to 26 on average under normal growing conditions. Petaloids: commonly 1 to 3 per blossom, irregularly shaped, approximately 20 mm in length, and approximately 8 mm in width. Petal texture: glabrous, membranaceus, relatively thin, and semi-transparent. Petal margin: entire, and tends to be slightly revolate. Petal apex: obtuse. Petal base: narrowly cuneate. Petal size: commonly approximately 2 to 2.5 cm in length on average, and approximately 2.3 to 2.5 mm in width on average. Petal drop: very good with the petals detaching cleanly and freely before drying. Stamen number: approximately 55 to 60 on average. Filaments: typically approximately 6 mm in length, and approximately 1 mm in diameter. Pollen: present and near Yellow-Orange Group 22A in coloration. Pistils: approximately 30 on average. Styles: approximately 3 mm in length on average, and approximately 1 mm in width on average. Receptacle: slightly glaucous, commonly approximately 2.5 to 2.8 mm in size when the flower is completely open, and near Green Group 138A in coloration. Hips: rarely observed. Lasting quality: commonly approximately 7 to 8 days on the plant, and approximately 5 to 6 days when cut and placed in a vase.
Development:
Vegetation.— Vigorous and procumbent thin branches with upright thin shoots and a generally restrained growth. Blossoming.— Abundant and substantially continuous. Resistance to diseases.— Excellent with respect to Black Spot, Powdery Mildew, and Rust. Formation of hips/seeds.— Sparsely formed. Hardiness.— Proven hardy in U.S.D.A. Hardiness Zone No. 5. Heat tolerance.— Testing is underway.
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A new and distinct variety of shrub rose plant is provided which forms in abundance on a nearly continuous basis attractive semi-double cup-like fragrant ivory-white blossoms that self clean well. A spreading ground cover growth habit is displayed. Forms glossy medium-green foliage that contrasts nicely with the blossom coloration. The resistance to Black Spot, Powdery Mildew, and Rust is excellent. The new variety is particularly well suited for providing ornamentation in small areas. It performs well as a mass planting and when grown in containers.
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BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates generally to systems for the filling, transport, and emptying of liquid containers More particularly, the invention concerns a novel, corrosion resistant liquid extraction apparatus that includes a novel plastic valve that can be removably connected to a liquid transport container. In turn, the valve can be interconnected with a specially configured, corrosion-resistant, plastic coupler that operates the valve in a manner to enable fluid to be extracted from the container.
2. Discussion of the Prior Art
The storage and transport of liquids and particularly the storage and transport of hazardous liquids have long presented substantial problems. For many years liquids were stored and transported in throwaway type metal and plastic containers. Typically, such containers were provided with a threaded liquid outlet port, which, after the container was filled, was closed, by some type of threaded cap. The use of these types of containers was costly, inefficient and often hazardous, particularly when the containers were used to store and transport potentially dangerous chemicals.
In recent years substantial efforts have been made to develop new systems to improve container and drum management capabilities, minimize user exposure to hazardous materials and address emerging governmental regulations. These efforts have resulted in the development of several different types of reusable systems for transferring liquid formulations from returnable closed drums and containers. As a general rule, these systems to a greater, or lesser extent, simplify drum emptying, minimize operator hazards, improve cleanliness and eliminate costly waste inherent in prior art disposable container systems. One of the most advanced of such improved systems was developed by and is presently commercially available from Micro Matic, Inc. of Northridge, Calif.
The Micro Matic system, which is described in U.S. Pat. No. 5,901,747 issued to the present inventor, basically comprises a two-part system that includes a coupler operated extractor valve which can be interconnected with a conventional drum via existing threaded connections and a cooperating coupler which connects to the extractor valve to allow drum emptying through the use of a remote pumping system. The extractor valve apparatus includes a valve body and a down tube connected to the valve body, which extends to the bottom of the drum to permit the complete transfer of liquid from the drum.
Another Micro Matic prior art liquid transfer system is described in U.S. Pat. No. 5,944,229 also issued to the present inventor. This invention concerns a novel, tamper-proof, safety valve system that includes a tamper evident valve closure cap that must be broken before liquid can be removed from the container.
The Micro Matic systems, while representing the best of the current state of the art liquid transfer systems, have certain drawbacks which are sought to be overcome by the system of the present invention More particularly, the metal valve and coupler assemblies of the Micro Matic systems are of a relatively complex design making them somewhat difficult and costly fabricate. Further, in some respects these metal assemblies are not well suited for use with various types of hazardous and highly corrosive chemicals that are frequently stored and transported.
As will be better appreciated from the discussion that follows, unlike the prior art Micro Matic systems, the novel valve and coupler of the improved system of the present invention are of an elegantly simple design and are uniquely constructed from a corrosive resistant plastic that is substantially impervious to most corrosive liquids. Additionally, the improved system provides a customer unique, key type coupler-valve mating interface that precludes removal of the drum contents by unauthorized persons
SUMMARY OF THE INVENTION
It is an object of the present invention to provide a novel liquid transfer system that includes a valve and coupler assembly of unique design for use in extracting hazardous fluids from a transport container. More particularly, it is an object of the invention to provide a liquid transfer system of the aforementioned character that includes a novel valve and coupler assembly that is of a simple design and is uniquely constructed from a corrosive resistant plastic that is substantially impervious to most corrosive liquids.
Another object of the invention is to provide a system of the character described which improves container and drum management while at the same time significantly reducing the material and labor costs inherent in the fabrication of the prior art liquid transfer systems.
Another object of the invention is to provide a liquid transfer system, which includes a novel plastic valve mechanism, which can be readily removably connected to a container such as a metal or plastic drum, and a novel, plastic coupler mechanism that can be removably coupled with the plastic valve mechanism for operating the valve mechanism. An important aspect of the liquid transfer system resides in the fact that the valve mechanism is specially configured so that only a coupler of a special, mating configuration can be interconnected with the valve mechanism. In this way, couplers and valves can be custom designed for individual users and use of or tampering with containers belonging to the individual user by users of similar systems is positively prevented.
Another object of the invention is to provide a fluid transfer system of the aforementioned character, which is highly reliable in operation, has a long useful life and is easy to use with a minimum amount of instruction being required.
Another object of the invention is to provide a system of the character described in the preceding paragraphs, which is inexpensive to produce and requires minimum maintenance.
In summary, the novel liquid transfer system of the present invention includes a valve and coupler assembly of unique design and a remote pump means that can be connected to the coupler to extract hazardous fluids from a transport container. The plastic valve of the system comprises a valve body that is connected to the container, which includes a coupler receiving portion and a hollow skirt portion, the hollow skirt portion having a spiral groove formed therein. An insert having a central bore is sealably received within the skirt portion for rotational movement by the coupler between a first valve closed position and a second valve open position. A down tube assembly is connected to the valve body and includes a stem portion that is sealably received within the central bore of the insert. The coupler of the liquid transfer system, which includes a fluid outlet passageway in communication with the fluid passageway of the down tube assembly, can be conveniently, removably connected to the valve body for imparting rotation to the insert. The plastic valve further includes a radially outwardly extending protuberance that is closely receivable within said spiral groove of the skirt portion of said valve body and the coupler receiving portion of the valve body is provided with circumferentially spaced openings which receive circumferentially spaced blades provided on the coupler. The insert of the plastic valve, in turn, includes upstanding fingers that are engagable by the spaced-apart blades when the coupler is connected to said valve body. In one form of the invention, the coupler also includes a downwardly extending first sleeve, an upwardly extending second sleeve telescopically received within the first sleeve and biasing means for yieldably resisting telescopic movement of the second sleeve into the first sleeve.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 is a generally perspective, exploded view of one form of the liquid transfer system of the invention showing the fluid container broker away to reveal internal construction.
FIG. 2 is a generally perspective exploded view of one form of the coupler assembly and valve assembly of the invention.
FIG. 3 is a greatly enlarged fragmentary top plan view of a portion of the system shown in FIG. 1 .
FIG. 4 is a view taken along lines 4 — 4 of FIG. 3, partly broken away to show internal construction.
FIG. 5 is a cross-sectional view taken along lines 5 — 5 of FIG. 4 .
FIG. 6 is a cross-sectional view taken along lines 6 — 6 of FIG. 4 .
FIG. 7 is a planer projection of the upper portion of the valve assembly of the invention and the lower portion of the coupler assembly showing the manner in which the coupler blades interact with the valve assembly.
FIG. 8 is a view similar to FIG. 3 but showing the coupler moved into a valve open position.
FIG. 9 is a cross-sectional view similar to FIG. 4, but showing the valve assembly in a valve open configuration.
FIG. 10 is a cross-sectional view taken along lines 10 — 10 of FIG. 9 .
FIG. 11 is a cross-sectional view taken along lines 11 — 11 of FIG. 9 .
FIG. 12 is a planer projection similar to FIG. 7, but showing the valve assembly having been moved into a valve open configuration.
FIG. 13 is a generally perspective, exploded view of an alternate form of the valve and coupler assembly of the invention.
FIG. 14 is a top plan view of the assembly shown in FIG. 13, partly broken away to show internal construction.
FIG. 15 is a generally perspective, exploded view of yet another embodiment of the invention.
FIG. 16 is a top plan view of the embodiment shown in FIG. 15 partly broken away to show internal construction.
FIG. 17 is a generally perspective view of still another form of the coupler and valve assembly of the invention.
FIG. 18 is a top plan view of the assemblage shown in FIG. 17 partly broken away to shown internal construction.
DESCRIPTION OF THE INVENTION
Referring to the drawings and particularly to FIG. 1, one form of the apparatus is there shown interconnected with a conventional liquid transport container “C”. Container “C” includes interconnected top, bottom and side walls “T”, “B”, and “S” respectively that define a liquid reservoir “R”. The apparatus of the invention here comprises a valve assembly 20 that is threadably connected with top wall “T” of the container, a coupler assembly 22 that can be removably interconnected with valve assembly 20 and a remotely located pumping means “P” for pumping the liquid “L” from the transport container. As best seen in FIG. 2, valve assembly 20 comprises a valve body 24 that is threadably connected to top wall “T” of container “C” by conventional threads 26 formed on the valve body. Valve body 24 includes a tubular shaped skirt portion 28 that is provided with a plurality of circumferentially spaced, curved grooves 30 , the purpose of which will presently be described. The top wall 24 a of valve body 24 is provided with a plurality of circumferentially spaced irregularly shaped openings 32 which here are generally fan shaped.
Valve assembly 20 farther includes a generally cylindrically shaped insert 36 that is rotatably received within skirt portion 28 of valve body 24 . In a manner presently to be described, insert 36 can be moved by the coupler assembly 22 from a first valve closed position to a second valve open position. As best seen in FIG. 6, insert 36 is provided with a central, generally cylindrically shaped bore 38 that telescopically receives upper portion 42 a of stem 42 which forms a part of a down tube assembly generally designated by the numeral 44 (FIG. 2 ). Down tube assembly 44 also includes a flange portion 45 that is interconnected with skirt 28 of valve body 24 in the manner shown in FIG. 6 . As indicated in FIG. 6, stem 42 is connected to and extends both upwardly and downwardly from flange 46 . The upper portion 42 a of the stem, which carries an elastomeric O-ring 43 , is sealably received within central bore 38 of insert assembly 36 , while the lower portion 42 b extends downwardly within reservoir “R”. As indicated in FIG. 2, the upper portion 42 a of stem 42 is provided with a plurality of circumferentially spaced fluid passageways 46 . As will presently be described, when the coupler assembly 22 is interconnected with the valve assembly and is rotated into the valve-open position, fluid passageways 46 will move into communication with an outlet passageway formed in coupler assembly 22 , which, in turn, communicates with the pumping means “P” (FIG. 1 ).
Turning particularly to FIGS. 2 and 6, the novel coupler assembly of the present invention can be seen to comprise an upper gripping portion 22 a having finger gripping segments 22 b and a lower, downwardly extending, generally tubular portion 22 b . Affixed to portion 22 b of the coupler assembly are circumferentially spaced blade-like members 50 which engage circumferentially spaced surfaces 52 formed on a plurality of upstanding, finger-like portions 54 that comprise a part of insert 36 .
As indicated in FIG. 4, when the coupler assembly 22 is mated with the valve assembly, the generally fan shaped blades 50 will be received within the fan shaped openings 32 and the edges thereof will engage walls 52 of fingers 54 upon rotation of the coupler. With this construction, rotation of coupler assembly 22 relative to valve assembly 24 will cause blades 50 to impart rotation to insert 24 between the first valve closed position shown in FIG. 6 and the second valve open position shown in FIG. 11 . In this regard, it is to be noted that protuberances 40 of insert 36 are received within curved grooves or slots 30 so that, upon rotation of insert 36 by the coupler assembly 22 , protuberances 40 will move along grooves 30 urging downward movement of insert 36 from the valve closed position shown in FIG. 6 to the valve open position shown in FIG. 11 (see also FIGS. 7 and 12 ).
As indicated in FIG. 6, when the valve is in the closed position, a valve seat-engaging sleeve 56 formed on coupler assembly 22 will sealably engage a valve seat 58 formed on upper stem portion 42 a . When the valve is in the valve open position illustrated in FIG. 11, it is to be noted that outlet passageways 46 provided in stem portion 42 a can freely communicate with outlet passageway 60 formed in coupler assembly 22 and with the pumping means (FIG. 1 ). Accordingly, when the valve is in the valve open position shown in FIG. 11, upon urging of the pumping means, the liquid “L” can be drawn from the container “C” upwardly through the down tube assembly in the direction of the arrow 61 in FIG. 11, through outlet passageways 46 , into passageway 60 and then outwardly of the apparatus in a direction toward the pump means “P”. Pump means “P” can comprise any suitable commercially available pump of a character well understood by those skilled in the art.
As illustrated in FIGS. 6 and 11, coupler assembly 22 includes a downwardly extending sleeve 64 which telescopically receives an upwardly extending sleeve 66 . Sleeve 66 terminates in an end wall 66 a that engages the top of valve seat 58 . Disposed within sleeves 64 and 66 is biasing means for yieldably resisting telescopic movement of second sleeve 66 into first sleeve 64 . This biasing means is here provided in the form of a conventional coil spring 68 . As indicated in FIG. 11, as the coupler assembly is rotated into the valve open position there shown, spring 68 will be compressed in a manner that will urge coupler 22 to return to its upward, valve closed position as shown in FIG. 6 .
With the construction described in the preceding paragraphs, as the coupler assembly is rotated relative to the valve assembly, from the position shown in FIGS. 3 and 4 to the position shown in FIGS. 8 and 9, valve seat engaging sleeve 56 will move telescopically downwardly over the upper portion 42 a of stem 42 against the urging of the biasing means or spring 68 . When the coupler assembly reaches the position shown in FIG. 11, valve seat engaging sleeve 56 will have moved telescopically downwardly relative to stem portion 42 a to a position where outlet passageways 46 are in fluid communication with passageway 60 formed in coupler assembly 22 . With the apparatus in the valve-open position, energization of pump “P” will, of course, cause fluid to be drawn from the container “C” outwardly of the apparatus in the direction toward pump “P”. Rotation of coupler assembly 22 in the opposite direction will, of course, cause the apparatus to return to the valve closed position shown in FIG. 6 where sleeve 56 will sealably engage valve seat 58 .
Turning to FIGS. 13 and 14, an alternate form of the apparatus of the invention is there shown. This form of the invention is similar in most respects to that shown in FIGS. 1 through 12 and like numerals are used to identify like components. However, in the embodiment of the invention shown in FIGS. 13 and 14, the circumferentially spaced openings 71 formed in the valve body are of a slightly different configuration as are the blades 73 of the coupler assembly. More particularly, as indicated in FIG. 13, blades 73 are provided with a plurality of key-like shoulders 73 a that are closely received within the keyhole-like openings 71 provided in the valve assembly. It is apparent that, unless the coupler is provided with the correctly configured blades, the coupler cannot be used in conjunction with the valve body 24 of the character shown in FIG. 13 .
Turning to FIGS. 15 and 16, still another form of the apparatus of the invention is there shown. Once again, this apparatus is similar to that previously described and like numerals are used to identify like components. In the embodiment of the invention shown in FIGS. 15 and 16, the circumferentially spaced openings 75 formed in the valve assembly are of a different configuration from that shown in FIGS. 1 through 12, but are similar to those shown in FIGS. 13 and 14. Similarly, the blades 77 formed on the coupler assembly are of a different configuration from those shown in FIGS. 1 through 12. However, the blades in the apparatus shown in FIGS. 15 and 16 are of similar configuration to those shown in FIGS. 13 and 14. Although this is the case, as indicated by the arrow 79 in FIG. 15, in this latest embodiment of the invention, the coupler is rotated in a counterclockwise direction rather than a clockwise direction to move valve assembly from a valve closed position to a valve open position. Once again, with this important distinction, unless the coupler is provided with properly configured blades 77 , the coupler cannot be used with the valve assembly having the configuration shown in FIG. 15 .
Referring next to FIGS. 17 and 18, yet another form of the apparatus of the invention is there shown. Again, this form of the apparatus is similar in most respects to the apparatus previously described and like numerals are used in FIGS. 17 and 18 to identify like components. In this latest embodiment of the invention, it is to be noted that the operating blades 81 of the coupler assembly and the openings 83 provided in the valve assembly are once again of a different configuration. More particularly, as best seen in FIG. 17, blades 81 include a central radially outwardly extending protuberance 81 a that is received within a notch-like opening 83 a that forms a part of each of the blade receiving openings of the valve assembly.
It is clear from a study of FIGS. 13 through 18 that the coupler assemblies as well as the valve assemblies can be specially configured for particular customer so that only couplers belonging to that customer can be used to operate valves belonging to the customer.
It is to be understood that the configuration of the blades and openings of the apparatus shown in the drawings is only exemplary, and that any number of mating configurations of blades and openings can be provided to the customer.
Having now described the invention in detail in accordance with the requirements of the patent statutes, those skilled in this art will have no difficulty in making changes and modifications in the individual parts or their relative assembly in order to meet specific requirements or conditions. Such changes and modifications may be made without departing from the scope and spirit of the invention, as set forth in the following claims.
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A liquid transfer system that includes a valve and coupler assembly of unique design for use in extracting hazardous fluids from a transport container. The system includes a novel valve and coupler assembly that is of a simple design and is uniquely constructed from a corrosive resistant plastic that is substantially impervious to most corrosive liquids.
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BACKGROUND OF THE INVENTION
This invention relates to an automobile suspension system, more particularly to an automobile suspension system which can offer safety and comfort to the occupants in the automobile by a hydraulic system and a resilient body unit in accordance with the speed of the automobile and various conditions of the road.
Referring to FIG. 1, a very common independent automobile suspension system includes a supporting rod 11 interposed between an automobile wheel and the automobile body. A hydraulic shock absorber is installed in the supporting rod 11. A shock absorbing spring 12 is sleeved on the upper portion of the supporting rod 11.
In a case where the shock absorbing action of the spring 12 is sufficient to provide comfort, when the automobile is steered, the automobile is apt to sway or even tilt. When the material of the spring 12 is selected to reduce the sway of the automobile to a safe degree, the shock absorbency of the spring 12 is insufficient to provide comfort. As a consequence, safety and comfort cannot be simultaneously obtained.
SUMMARY OF THE INVENTION
It is therefore the main object of this invention to provide an automobile suspension system which can offer safety and comfort to the occupants in the automobile by a hydraulic system and a resilient body unit in accordance with the speed of the automobile and various conditions of the road.
According to this invention, an automobile suspension system includes a suspending hydraulic cylinder interposed between the automobile body and an automobile wheel, a tensing hydraulic cylinder attached to the automobile body, an absorbing hydraulic cylinder attached to the automobile body, a hydraulic piping system intercommunicating these hydraulic cylinders, and a processing system sensing road conditions and driving situations to adjust the height of the corners of the automobile body, so as to offer shock-absorbency and anti-sway effects.
BRIEF DESCRIPTION OF THE DRAWING
Other features and advantages of this invention will become apparent in the following detailed description of a preferred embodiment of this invention, with reference to the accompanying drawings, in which:
FIG. 1 illustrates a conventional automobile suspension system;
FIG. 2 illustrates an automobile suspension system of this invention when the automobile is unloaded;
FIG. 3 illustrates the automobile suspension system of this invention when the automobile has just been loaded with one or more people;
FIG. 4 illustrates the automobile suspension system of this invention after the automobile has been loaded with one or more people;
FIG. 5 illustrates the automobile suspension system of this invention when the automobile is accelerated;
FIG. 6 illustrates the automobile suspension system of this invention when the automobile wheel rolls onto concave ground, such as potholes and divots;
FIG. 7 illustrates the automobile suspension system of this invention when the automobile wheel rolls onto convex ground, such as raised bumps and road debris;
FIG. 8 illustrates the automobile suspension system of this invention when the automobile body is in an unbalanced condition;
FIG. 9 illustrates the automobile suspension system of this invention when the automobile has just been unloaded; and
FIG. 10 illustrates the automobile suspension system of this invention when the automobile body is lowered.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT
Referring to FIG. 2, an automobile suspension system of this invention includes a suspending hydraulic cylinder 2, a tensing hydraulic cylinder 3, an absorbing hydraulic cylinder 4, a hydraulic piping system 5 and a processing system 6.
The suspending hydraulic cylinder 2 has a suspending cylinder body 21 connected pivotally to the bottom of the automobile body, a suspending piston rod 22 connected pivotally to the swing arm (C) of an automobile wheel (B), and a suspending piston 23 connected to the suspending piston rod 22 defining an oil storing space thereabove.
The tensing hydraulic cylinder 3 includes a tensing cylinder body 31 connected securely to the automobile body, which has an upper chamber 311 and a lower chamber 312. As illustrated, the tensing cylinder body 31 has a thin upper wall portion defining the upper chamber 311, and a thick lower wall portion defining the lower chamber 312, between which a shoulder 313 is formed. An upper tensing piston 32 is disposed slidably in the thin upper wall portion of the tensing cylinder body 31, while a lower tensing piston 33 is disposed slidably in the thick wall portion of the tensing cylinder body 31. A tensing spring 34 is interposed between the upper tensing piston 32 and the lower tensing piston 33 in the tensing cylinder body 31. An upper oil storing space 35 is defined above the upper tensing piston 32 in the tensing cylinder body 31, while a lower oil storing space 36 (see FIGS. 4-9) is defined below the lower tensing piston 33 in the tensing cylinder body 31.
The absorbing hydraulic cylinder 4 includes an absorbing cylinder body 41 connected securely to the automobile body, an upper absorbing piston 42 disposed slidably in the upper portion of the absorbing cylinder body 41, a lower absorbing piston 43 disposed slidably in the lower portion of the absorbing cylinder body 41, an absorbing spring 44 interposed between the upper absorbing piston 43 and the lower absorbing piston 43 in the absorbing cylinder body 41. An upper oil storing space 45 (see FIGS. 3, 7) is defined above the upper absorbing piston 42 in the absorbing cylinder body 41, while a lower oil storing space 46 (see FIGS. 4-9) is defined below the lower absorbing piston 43 in the absorbing cylinder body 41.
The hydraulic piping system 5 includes an oil tank 51, an oil pump 52, an accumulator 53 and a two-way valve 54. Oil is fed from the oil tank 51 to the two-way valve 54 through a first conduit (D), on which the oil pump 52 and the accumulator 53 are installed. A second conduit (E) intercommunicates the oil storing space 24 of the suspending hydraulic cylinder 2 and the upper oil storing space 35 of the tensing hydraulic cylinder 3. A fourth conduit (G) intercommunicates the two-way valve 54 and the lower oil storing space 36 of the tensing hydraulic cylinder 3. A fifth conduit (H) intercommunicates the two-way valve 54 and the lower oil storing space 46 of the absorbing hydraulic cylinder 4. The oil in the two-way valve 54 can be returned to the oil tank 51 through a sixth conduit (I). A seventh conduit (J) intercommunicates the second conduit (E) and the upper oil storing space 35 of the tensing hydraulic cylinder 3. A first check valve 57 is installed on the seventh conduit (J), so as to limit the oil flow from the upper oil storing space 35 of the tensing hydraulic cylinder 3 to the oil storing space 24 of the suspending hydraulic cylinder 2 through the seventh conduit (J). An eighth conduit (K) intercommunicates the third conduit (F) and the upper oil storing space 45 of the absorbing hydraulic cylinder 4 and is equipped with a second check valve 58 which limits the oil flow from the oil storing space 24 of the suspending hydraulic cylinder 2 to the upper oil storing space 35 of the tensing hydraulic cylinder 3 through the eighth conduit (K). A ninth conduit (L) intercommunicates the oil storing space 24 of the suspending hydraulic cylinder 2 and the two-way valve 54. A first damper 55 is installed on the second conduit (E) so as to stabilize the spring movement of the tensing spring 34, while a second damper 56 is installed on the third conduit (F) so as to stabilize the spring movement of the absorbing spring 44.
The processing system 6 is a logical circuit unit which receives the signals from a plurality of sensors (S), which are provided on the automobile body or the steering wheel. When the automobile is accelerated or steered, the logical circuit unit signals the two-way valve 54, in response to the signals from the sensors (S), to open the fifth conduit (H) Three piston-position sensors 61, 62 and 63 are respectively installed on the suspending hydraulic cylinder 2, the tensing hydraulic cylinder 3 and the absorbing hydraulic cylinder 4, so as to determine the positions of the pistons 23, 32, 33, 42 and 43.
When nobody is in the automobile, the automobile suspension system of this invention is in the position shown in FIG. 2. In this situation, the lower tensing piston 33 is positioned at the lower end of the interior chamber of the tensing hydraulic cylinder 3. The upper tensing piston 32 is positioned near, but not in contact with the shoulder 313 of the tensing cylinder body 31. The upper absorbing piston 42 is positioned at the upper end of the interior chamber of the absorbing hydraulic cylinder 4, while the lower absorbing piston 43 is positioned at the lower end of the interior chamber of the absorbing hydraulic cylinder 4.
Referring to FIG. 3, when one or more persons enter the automobile, when the suspending piston 23 of the suspending hydraulic cylinder 2 moves upward to impel oil toward the tensing hydraulic cylinder 3 and the absorbing hydraulic cylinder 4, so as to push the upper tensing piston 32 downward to contact the shoulder 313. The absorbing spring 44 is therefore compressed by the upper absorbing piston 42.
Referring to FIG. 4, after the automobile has been loaded with one or more people, the piston-position sensor 62 installed on the tensing hydraulic cylinder 3 detects the engagement of the upper tensing piston 32 with the shoulder 313, the processing system 6 signals the two-way valve 54 to open the fourth conduit (G). The opening of the fourth conduit (G) permits the flow of the oil in the accumulator 53 into the lower oil storing space 36 of the tensing hydraulic cylinder 3, causing the lower tensing piston 33 to move upward, moving the upper tensing piston 32 away from the shoulder 313. Once the upper tensing piston 32 has returned to the normal position shown in FIG. 2, the processing system 6 stops the movement of the lower tensing piston 33. On the other hand, when the piston-position sensor 63 detects the separation of the upper absorbing piston 42 from the upper end of the interior chamber of the absorbing hydraulic cylinder 4, the processing system 6 signals the two-way valve 54 to open the fifth conduit (H), so that the lower absorbing piston 43 is activated hydraulically to move upward until the upper absorbing piston 42 returns to the upper end of the interior chamber of the absorbing hydraulic cylinder 4. At this time, because the upper tensing piston 32 and the upper absorbing piston 42 are in the same positions as they are shown in FIG. 2, the suspending piston 23 is also located at the normal position shown in FIG. 2. In other words, the height of the automobile body is adjusted to the same level, whether the automobile is loaded or not.
Referring to FIG. 5, when the automobile speed reaches 60 km/hour, the processing system 6 signals the two-way valve 54 to open the fifth conduit (H), so that the lower absorbing piston 43 is moved upward a preset distance. When the automobile speed continues to increase to another predetermined value, the lower absorbing piston 43 further compresses the tensing spring 44. Accordingly, the higher the automobile speed, the greater the resistance to the upward movement of the suspending piston 23, thereby increasing driving safety. The upper absorbing piston 42 is fixed at the upper end of the interior chamber of the absorbing hydraulic cylinder 4 during the compression process of the absorbing spring 44 by the lower absorbing piston 43. That is to say, there is no change of the height of the automobile body during the compression of the absorbing spring 44. This constancy of height is considered to be a feature of this invention.
Referring to FIG. 6, when the automobile wheel (B) rolls onto concave ground, the suspending piston 23 of the suspending hydraulic cylinder 2 moves downward, so as to increase the volume of the oil storing space 24 of the suspending hydraulic cylinder 2. But the upper absorbing piston 42 cannot move upward at the same time and cannot squeeze oil into the oil storing space 24 of the suspending hydraulic cylinder 2 through the third conduit (F). Therefore, oil is squeezed into the oil storing space 24 of the suspending hydraulic cylinder 2 by the spring action of the tensing spring 34. In this case, because oil flows from the upper oil storing space 35 of the tensing hydraulic cylinder 3 through the second conduit (E) and the seventh conduit (J), oil can be rapidly injected into the oil storing space 24 of the suspending hydraulic cylinder 2, so that the automobile wheel (B) can maintain contact with the concave surface without jolting the automobile. With the first check valve 57 installed on the seventh conduit (J), after the automobile wheel (B) has rolled over a concave surface feature, oil returns slowly from the oil storing space 24 of the suspending hydraulic cylinder 2 to the upper oil storing space 35 through the second conduit (E), so as to prevent the high-speed restoring movement of the suspending piston 23, which would jolt the occupants in the automobile uncomfortably.
Referring to FIG. 7, when the automobile wheel (B) rolls onto a convex surface feature like a raised bump, the suspending piston 23 of the suspending hydraulic cylinder 2 moves upward to squeeze the oil therein toward the tensing hydraulic cylinder 3 and the absorbing hydraulic cylinder 4. At the same time, the upper tensing piston 32 moves downward until it contacts the shoulder 313, allowing the oil flowing from the oil storing space 23 of the suspending hydraulic cylinder 2 to enter rapidly the absorbing hydraulic cylinder 4 through the third conduit (F) and the eighth conduit (K). With the second check valve 58 installed on the eighth conduit (K), after the automobile wheel (B) has rolled over a convex surface feature, the absorbing spring 44 pushes the upper absorbing piston 42 upward, so that oil flows slowly from the absorbing hydraulic cylinder 4 through the eighth conduit (K). The slow movement of the oil from the absorbing hydraulic cylinder 4 prevents vibrating of the automobile body.
Referring to FIG. 8, when the sensors (S) detect unbalance of the automobile body which can result from steering, braking or acceleration, the suspending piston 23 of the suspending hydraulic cylinder 2 tends to move upward, thus squeezing the oil therefrom into the tensing hydraulic cylinder 3 and the absorbing hydraulic cylinder 4. At the same time, the upper tensing piston 32 moves a small distance to contact the shoulder 313 and cannot continue to move, thus causing the remainder of the oil from the suspending hydraulic cylinder 2 to flow entirely into the absorbing hydraulic cylinder 4. When the downward movement of the upper absorbing piston 42 is detected, the piston-position sensor 63 signals the processing system 6, which causes the oil from the accumulator 53 to move upward through the fifth conduit (H), thereby pushing the lower absorbing piston 43 upward. As a result, the displacement of the suspending piston 23 is very small. The small displacement of the suspending piston 23 diminishes the inclination of the automobile during steering, braking and acceleration of the automobile.
Referring to FIG. 9, when the automobile stops and is unloaded, the suspending cylinder body 21 moves upward relative to the automobile wheel (B), so as to increase the volume of the oil storing space 24 of the suspending hydraulic cylinder 2. In this situation, the tensing spring 34 urges the upper tensing piston 32 to move upward, so as to squeeze the oil from the tensing hydraulic cylinder 3 to the suspending hydraulic cylinder 2. In a case where the automobile is parked, when the upward movement of the upper tensing piston 32 is detected, the piston-position sensor 62 signals the processing system 6 to open the two-way valve 54, so as to return the oil in the lower oil storing space 36 of the tensing hydraulic cylinder 3 and in the lower oil storing space 46 of the absorbing hydraulic cylinder 4 to the oil tank 51. Finally, all the pistons 23, 32, 33, 42 and 43 return to the normal positions shown in FIG. 2.
Referring to FIG. 10, when the automobile advances rapidly with good road conditions, the driver can manually actuate the piston-position sensor 63 to open the ninth conduit (L), so that the oil in the suspending hydraulic cylinder 2 flows back to the oil tank 51 through the ninth conduit (L) and the sixth conduit (I). In this way, the automobile body is lowered, steadying the ride.
With this invention thus explained, it is apparent that numerous modifications and variations can be made without departing from the scope and spirit of this invention. It is therefore intended that this invention be limited only as indicated in the appended claims.
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An automobile suspension system includes a suspending hydraulic cylinder interposed between the automobile body and an automobile wheel, a tensing hydraulic cylinder attached to the automobile body, an absorbing hydraulic cylinder attached to the automobile body, a hydraulic piping system intercommunicating these hydraulic cylinders, and a processing system sensing road conditions and driving situations to independently adjust the height of the corners of the automobile body, so as to offer shock-absorbing and anti-sway effects.
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CONTRACTUAL ORIGIN OF THE INVENTION
[0001] The present invention was conceived and developed under U.S. Government Contract No. DE-AC09-96SR18500 awarded by the U.S. Department of Energy. The Government has rights in this invention.
BACKGROUND OF THE INVENTION
[0002] 1. Field of the Invention
[0003] This invention relates a novelty toy item that is self-luminescent, without the need for bulbs or batteries. The toy is formed of a transparent plastic rod suffused with a fluorescent substance. The substance fluoresces in response to ambient light and the flouresced light is subject to internal reflection within the rod, with the flouresced light being substantial emitted at one or both ends of the rod. The end of the rod may be manufactured in a variety of shapes-such as a conical tip, multi-point star, sphere, or fiber optic bundle-to produce a wide variety of toy wands.
[0004] 2. Related Art
[0005] A variety of toys in the form of wands are known to exist. U.S. Pat. Nos. 4,891,32 and 3,707,055 are representative of the art in the field of toy wands. These conventional devices obtain their illumination from a miniature, incandescent light bulb power by a battery contained in the body of the device. These devices suffer the drawback of all battery-powered toys—both the batteries and bulbs must be regularly replaced with regular usage.
[0006] Similarly, toys that utilize self-luminescent components are also known to exist. U.S. Pat. No. 4,655,721 discloses a small self-illuminating element within the opaque body of a toy doll. This small element produces glowing features on the exterior of the toy doll, such as eyes, mouths, hearts or weapons. Additionally, U.S. Pat. No. 5,092,809 discloses a pinwheel toy where the pinwheel blades are composed of a transparent plastic containing a fluorescent dye.
[0007] Despite this prior art, self-luminescent toy wands, composed entirely of fluorescent suffused plastic, are not known.
SUMMARY OF THE INVENTION
[0008] It is an object of this invention to provide a device useful in creating a source of light without the need for batteries or light bulbs.
[0009] It is a further object of this invention to provide a self-luminescent toy wand capable of creating a visually stimulating light display at at least one end of the wand.
[0010] It is an additional object of this invention to provide a self-luminescent presentation pointer capable of creating a visually stimulating point source of light.
[0011] These and other objects are provided by a device that is an elongated rod of substantially transparent material, the rod having a length and cross-sectional width and having a first end and a second end, the transparent material being suffused with a fluorescent substance or dye, wherein said length, width and fluorescent substance are selected such that light impinging the surface of the rod undergoes substantial internal reflection in the rod, and wherein at least said first end is capable of emitting the reflected light energy to create a stimulating visual display.
BRIEF DESCRIPTION OF THE DRAWINGS
[0012] [0012]FIG. 1 is a schematic diagram illustrating the presentation pointer embodiment of the current invention.
[0013] [0013]FIG. 2 is a schematic diagram illustrating a multi-point star wand embodiment of the current invention.
[0014] [0014]FIG. 3 is a schematic diagram illustrating two-ended baton embodiment of the current invention.
[0015] [0015]FIG. 4 is a schematic diagram illustrating a magic wand embodiment utilizing fiber optics as the means of fluoresced light presentation.
DESCRIPTION OF THE PREFERRED EMBODIMENTS
[0016] The features and preferred embodiments of the present invention are best illustrated in the accompanying drawings. The drawings are illustrative only and are not to scale. Any critical dimensions as described herein can be determined by those skilled in the art.
[0017] [0017]FIG. 1 illustrates a simple wand 10 according to the current invention. An alternate use for this embodiment would be as a presentation pointer-as a substitute for lighted or non-lighted pointers or conventional laser presentation pointers. The wand is an elongated rod 12 having a first end 14 and a second end 15 . The first end 14 is shaped into a conical point to focus the maximum light energy display. While a simple conical point at the first end 14 is shown in FIG. 1, the current invention envisions variations on this single point theme to include such designs as spirals, arrows and corkscrews. FIG. 1 also illustrates the use of a focusing mirror 16 at the second end 15 , to assist in focusing more light energy towards the first end 14 . Furthermore, the wand 10 may be provided with a grip 18 suitably adapted to secure the focusing mirror 16 and to provide a comfortable handhold for a user.
[0018] [0018]FIG. 2 illustrates a multi-point star wand 20 embodiment according to the current invention. This embodiment consists of an elongated rod 12 having a multi-point first end 22 and a second end 15 . The multi-point first end 22 consists of a plurality of radiating points, preferably shaped to focus and display light energy along each edged surface and at each tip of the multi-point star.
[0019] [0019]FIG. 3 illustrates a baton 30 embodiment according to the current invention. This embodiment consists of an elongated rod 12 having a substantially spherical first end 32 and a substantially spherical second end 34 . Said substantially spherical first end 32 and second end 34 are shaped to allow a soft glow display of light energy. Additionally, at least one of these said spherical ends could optionally contain etchings that will enhance visual display.
[0020] [0020]FIG. 4 illustrates an optical fiber wand 40 embodiment according to the current invention. This embodiment consists of an elongated rod 12 having an optical fiber first end 42 and a second end 15 . This optical fiber first end 42 consists of a plurality of optical fibers arranged to produce a pleasing light display. The current invention envisions that the length, number and color of individual optical fibers may be changed to produce a virtually limitless variety of visual displays and effects.
[0021] In all of the aforementioned preferred embodiments, the elongated rod 12 may be made out of a wide variety of transparent or substantially transparent substances. A nonexclusive list of such substances includes glasses, polycarbonates, methacrylates, acrylics, and other natural and manmade materials. The choice of the substances depends on factors such as the particular use conceived and intended user. Transparent resins are preferred when weight and safety are the primary concerns-such as when children are the intended users.
[0022] In all the aforementioned preferred embodiments, rod 12 is a right circular rod for all or substantially all of its length. Meaning, a cross-section taken at right angles to the longitudinal axis of the rod 12 will be a circle. Deviations from this shape, such as an oval cross-section, may be desirable for specific applications.
[0023] In all the aforementioned preferred embodiments, rod 12 is suffused with a fluorescent dye (not shown). The term dye, as used herein, is intended to include any colored, luminescent or fluorescent substance. Furthermore, references herein to light or light energy emitted by this substance includes all reflected, luminesced and fluoresced energy. The purpose and effect of the dye is described below. The dye should be selected such that it is compatible with the material of the rod 12 selected.
[0024] In the preferred embodiments, the dye is suffused throughout or substantially throughout the rod 12 . The dye is intended to be active in and reactive to visible light. The use of dyes or substances that are active in or reactive to near-visible light are also considered within the scope of the invention.
[0025] While not wishing to be bound by a single theory, it is believed that the invention works as follows. Light from any source, including ambient light, passes into the material of the rod 12 . The light at a particular wavelength (or relatively small range of wavelengths) is reflected by the dye or causes the dye to fluoresce. As can be determined by those skilled in the art, the dye, rod length and circumference are determined so that a substantial portion of the reflected or fluoresced light will undergo total or substantially total internal reflection. The light is thus transmitted and concentrated at the ends of the rod 12 , and displayed as determined by the particular embodiment.
[0026] In all of the aforementioned embodiments where there is one primary light emitting end (specifically FIGS. 1, 3 and 4 ), a focusing mirror 16 may be placed over the second end 15 . This focusing mirror 16 is designed to reflect the light energy which would otherwise escape out the second end 15 back into the rod and add to the light energy being emitted from the first ends ( 14 , 22 and 42 , respectively).
[0027] An important feature of the current invention is that it is, in all its preferred embodiments, a completely passive device. While there must be some source of light or energy, as from ambient light, the device requires no power source and no dedicated light source. The current invention has been found to be quite efficient at collecting and focusing light energy under very low ambient light conditions. This feature gives rise to another potential embodiment of the current invention as an emergency directional indicator. During an emergency situation, where reliable light and energy sources may not be available, pre-placed indicators similar to the embodiment in FIG. 1, with an arrow-shaped first end 14 , would be valuable in directing people towards an exit.
[0028] While the preferred embodiments of the present invention have been illustrated and described, it will be apparent to those of ordinary skill in the art that various changes, modifications or variations (especially in the fluorescent dye or substance selected) may be easily made, to provide a wide range of potential uses, without deviating from the scope of the invention.
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A novelty item in the form of a rod suffused with a fluorescent substance. The substance fluoresces in response to ambient light and the flouresced light is subject to internal reflection within the rob, with the flouresced light being substantial emitted at one or both ends of the rod. The concentration of the light enables a variety of uses, such as a broad range self-illuminating toy wands as a luminescent professional, presentation pointer.
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CROSS REFERENCE TO RELATED APPLICATIONS
[0001] The present application is a continuation U.S. patent application Ser. No. 13/203,040, filed Jan. 31, 2012, which is a U.S. National Phase Application pursuant to 35 U.S.C. §371 of International Application No. PCT/US2010/060022 filed Dec. 13, 2010, which claims priority to Swedish Patent Application No. 0950958-9 filed on Dec. 15, 2009. The entire disclosure contents of these applications are herewith incorporated by reference into the present application.
TECHNICAL AREA
[0002] The present invention relates to a medicament delivery device comprising a dose setting function.
BACKGROUND
[0003] Medicament delivery devices such as injectors are sometimes provided with functions where a specific dose can be set by the user, which dose may be varied within a range.
[0004] Quite often this dose setting function is performed by turning a knob or wheel at the distal end of the device whereby it is moved in the distal direction. When performing a subsequent injection, the knob is pushed linearly in the proximal direction. One such injector is disclosed in the document U.S. Pat. No. 6,221,053 in which the distal dose knob of the injector is threaded out of a rod barrel tube as a dose is set. Thus the distance the knob is moved in the distal direction is directly related to the dose quantity to be delivered.
[0005] One drawback with that type of solution is that if larger doses are to be delivered the dose knob has to be moved quite a long distance in the distal direction, which means that it might be difficult for a user to push the dose knob in the proximal direction during injection.
SUMMARY
[0006] The aim of the present invention is to remedy the drawbacks of the state of the art medicament delivery devices and to provide a device by which it is possible to set a desired or required dose in a simple and intuitive way.
[0007] This aim is obtained by a medicament delivery device according to the features of the independent patent claim. Preferable embodiments of the invention are subject of the dependent patent claims.
[0008] According to a main aspect of the invention it is characterised by a medicament delivery device comprising a housing having opposite distal and proximal ends; a medicament container holder releasably connected to said housing; a medicament container arranged inside said medicament container holder; a threaded plunger rod arranged to pass through a first inner wall of the housing and arranged to act on a stopper in the medicament container; a lead screw member coaxially connected to the threaded plunger rod by co-acting first slidably-and-rotatably-locked means; wherein said device further comprises a nut coaxially connected to the threaded plunger rod by a treaded engagement between them, connected to the lead screw member by co-acting non-slidable-and-rotatable means, and connected to the housing by co-acting second slidably-and-rotatably-locked means; a primary dose member coaxially rotatable on the lead screw member when the device is in a non-activated state and connected to the lead screw member by co-acting third slidably-and-rotatably-locked means when the device is in an activated state; a locking member fixedly connected to the housing and releasably connected to the lead screw member by co-acting locking means; a first spring force means arranged between the first inner wall of the housing and the nut, wherein the first spring force means is in a pre-tensioned state when said locking means are engaged and the device is in the non-activated state; a secondary dose member rotatably connected to said primary dose member via a pinion gear; dose setting means connected to the primary dose member by co-acting fourth slidably-and-rotatably-locked means, such that when the device is to be set from the non-activated state to the activated state, the dose setting means are manually manipulated in a pre-determined direction, whereby the locking means are released and the lead screw member is distally moved a pre-determined distance by the first spring force means independent of the size of a dose to be set.
[0009] According to a further aspect of the invention, said primary and said secondary dose members are provided with indicia.
[0010] According to another aspect of the invention, the locking means comprises a proximally pointing and radial flexible lever arranged on the locking member, an annular ledge on the circumferential surface of the lead crew member, and the circumferential inner surface of the secondary dose member; such that when the first spring force means is in a pre-tensioned state, the circumferential inner surface of the secondary dose member forces the flexible lever radial inwardly in contact with the ledge; and when the dose setting means are manually manipulated, the secondary dose member is rotated to a position wherein the flexible lever is radial outwardly flexed into a longitudinal groove on the inner circumferential surface of the secondary dose member.
[0011] According to yet a further aspect of the invention, the locking member comprises on its distal circumferential surface a distally pointing stop member, and wherein the secondary dose member comprises on its proximal circumferential surface a first and a second proximally pointing stop members arranged to interact with the stop member of the locking member.
[0012] According to yet another aspect of the invention, the non-slidable-and-rotatable means comprises ratchet arms and radial inwardly directed arms on the nut, grooves on the outer circumference of wheels on the proximal end of the lead screw member, and an annular groove between the wheels, wherein the ratchet arms cooperate with the grooves for giving an audible signal when the lead screw member is rotated; and wherein the radial inwardly directed arms cooperate with the annular groove such that the lead screw member and the nut are slidably locked and rotatable in relation to each other.
[0013] According to a further aspect of the invention, the first slidably-and-rotatably-locked means comprises radial inwardly directed ledges on the inner surface of the proximal end of the lead screw member, and longitudinally extending grooves on the plunger rod, wherein the grooves cooperate with the radial inwardly directed ledges such that the lead screw member and the plunger rod are rotationally locked and slidable in relation to each other.
[0014] According to another aspect of the invention, the second slidably-and-rotatably-locked means comprises grooves on the outer circumferential side surface of the nut, and longitudinal ribs on the inner surface of the housing, wherein the grooves cooperate with the longitudinal ribs such that the nut and the housing are rotationally locked and slidable in relation to each other.
[0015] According to yet a further aspect of the invention, the third slidably-and-rotatably-locked means comprises splines on the outer circumferential surface of the lead screw member, and corresponding splines arranged on the inner circumferential surface of the primary dose member, wherein the splines cooperate with corresponding splines such that the lead screw member and the primary dose member are rotationally locked and slidable in relation to each other.
[0016] According to yet another aspect of the invention, the dose setting means comprises a clutch plate provided with a first annular ratchet, a dose setting knob provided with a second annular ratchet, and a second spring force means arranged between a second inner wall of the housing and a proximal surface of the clutch plate, such that clutch plate is distally urged and the first and the second ratchet are abutting each other, and which dose setting knob protrudes through the distal end of the housing.
[0017] According to a further aspect of the invention, the fourth slidably-and-rotatably-locked means comprises longitudinally extending grooves on the outer circumferential surface of the primary dose member, and radial inwardly directed protrusions on the inner surface of the clutch plate, wherein the longitudinally extending grooves cooperate with radial inwardly directed protrusions such that the primary dose member and the clutch plate are rotationally locked and slidable in relation to each other.
[0018] According to another aspect of the invention, the plunger rod is arranged to be proximally moved a distance corresponding to a set dose to be delivered by manually manipulating the dose setting knob when the device is in the activated state.
[0019] There are a number of advantages with the present invention. Because the lead screw, e.g. the manually operating delivery means, protrudes outside the housing with the same length independent of the set dose quantity the manual dose delivery operation is the same independent of set dose, i.e. the lead screw member has always the same position when a dose has been set.
[0020] Compared to the state of the art medicament delivery devices, this solution is a great advantage for the user or patient who suffers of dexterity problems. Also when not in use, the lead screw member is inside the medicament delivery device and locked. The unlocking of the lead screw member is performed when said dose setting knob is turned to an initial position, preferably a zero-dose position.
[0021] These and other features and advantages will become apparent from the detailed description and from the accompanying drawings.
BRIEF DESCRIPTION OF THE FIGURES
[0022] In the detailed description reference will be made to the accompanying drawings in which
[0023] FIGS. 1 a,b are a cross-sectional view of a medicament delivery device according to the present invention;
[0024] FIG. 2 is an exploded view of the medicament delivery device of FIGS. 1 a,b;
[0025] FIG. 3 is a detailed view of a dose-setting mechanism comprised in the present invention;
[0026] FIG. 4 is a further detailed view of the dose-setting mechanism comprised in the present invention; and
[0027] FIG. 5 is yet a further detailed view of the dose-setting mechanism comprised in the present invention; and
[0028] FIGS. 6 , 7 a , 7 b , 8 a , and 8 b are cross-sectional view of different functional positions.
DETAILED DESCRIPTION
[0029] In the present application, when the term “distal part/end” is used, this refers to the part/end of the injection device, or the parts/ends of the members thereof, which under use of the injection device is located the furthest away from the medicament injection site of the patient. Correspondingly, when the term “proximal part/end” is used, this refers to the part/end of the injection device, or the parts/ends of the members thereof, which under use of the injection device is located closest to the medicament injection site of the patient.
[0030] The medicament delivery device 10 according to the drawings comprises a generally elongated housing 12 having opposite distal and proximal ends. The elongated housing being e.g. divided in a proximal 12 a and a distal part 12 b. The proximal end of the housing is arranged with fastening means such as e.g. threads 14 on its inner surface, which fastening means cooperate with corresponding fastening means such as outwardly threads 16 on a distal end of a medicament container holder 18 , providing a releasable connection. Inside the medicament container holder a medicament container 20 can be placed. The proximal end of the medicament container holder 18 is arranged with a threaded neck 22 for connection of a medicament delivery member such as an injection needle 24 , a mouthpiece, a nozzle or the like, FIG. 2 .
[0031] When received by a user, the medicament delivery device 10 is provided with a releasably attachable protective cap 26 . At the distal end of the medicament container holder a sleeve-shaped container support 28 is inserted for holding and supporting the medicament container 20 when inserted, FIG. 2 . At the proximal end of the housing a first inner wall 30 is arranged, which wall is provided with a central passage 32 , FIG. 1 b . The central passage is arranged with a distally directed tubular flange 34 , FIG. 1 a . A threaded plunger rod 36 extends in the longitudinal direction through the central passage 32 with a proximal end adjacent a stopper 38 inside said medicament container 20 , FIG. 1 a . The proximal end of the plunger rod 36 is further arranged with a plunger rod tip 40 , FIG. 2 .
[0032] The device further comprises a lead screw member 58 coaxially connected to the threaded plunger rod by co-acting first slidably-and-rotatably-locked means; and a nut 44 coaxially connected to the threaded plunger rod by a treaded engagement between them. The nut also being connected to the lead screw member by co-acting non-slidable-and-rotatable means, and to the housing by co-acting second slidably-and-rotatably-locked means.
[0033] The first slidably-and-rotatably-locked means comprises radial inwardly directed ledges 57 on the inner surface of the proximal end of the lead screw member, and longitudinally extending grooves 42 on the plunger rod, FIG. 2 , wherein the grooves cooperate with the radial inwardly directed ledges 57 such that the lead screw member and the plunger rod are rotationally locked and slidable in relation to each other.
[0034] The non-slidable-and-rotatable means comprises ratchet arms 50 and radial inwardly directed arms 51 on the nut 44 , grooves 56 on the outer circumference of wheels 54 on the proximal end of the lead screw member, and an annular groove 53 between the wheels 54 , wherein the ratchet arms 50 cooperate with the grooves 56 for giving an audible signal when the lead screw member is rotated; and wherein the radial inwardly directed arms 51 cooperate with the annular groove 53 such that the lead screw member and the nut are slidably locked and rotatable in relation to each other, FIG. 3 .
[0035] The second slidably-and-rotatably-locked means comprises grooves 52 on the outer circumferential side surface of the nut 44 , FIG. 3 , and longitudinal ribs on the inner surface of the housing (not shown), wherein the grooves cooperate with the longitudinal ribs such that the nut and the housing are rotationally locked and slidable in relation to each other.
[0036] The nut 44 comprises a threaded central passage 46 which cooperates with the threads of the plunger rod, FIG. 2 , thereby forming the threaded engagement between them.
[0037] The device also comprises a primary dose member 66 coaxially rotatable on the lead screw member when the device is in a non-activated state and connected to the lead screw member by co-acting third slidably-and-rotatably-locked means when the device is in an activated state. The third slidably-and-rotatably-locked means comprises splines 60 on the outer circumferential surface of the lead screw member; and corresponding splines 64 arranged on the inner circumferential surface of the primary dose member, wherein the splines 60 cooperate with corresponding splines 64 such that the lead screw member and the primary dose member are rotationally locked and slidable in relation to each other, FIGS. 2 and 3 .
[0038] The device further comprises:—a locking member 96 fixedly connected to the housing and releasably connected to the lead screw member by co-acting locking means;—a first spring force means 48 arranged between the first inner wall 30 of the housing and the nut, wherein the first spring force means is in a pre-tensioned state when said locking means are engaged and the device is in the non-activated state; and—a secondary dose member 90 rotatably connected to said primary dose member 66 via a pinion gear 94 , FIG. 3 .
[0039] The device also comprises dose setting means connected to the primary dose member by co-acting fourth slidably-and-rotatably-locked means, such that when the device is to be set from the non-activated state to the activated state, the dose setting means are manually manipulated in a pre-determined direction, whereby the locking means are released and the lead screw member is distally moved a pre-determined distance by the first spring force means independent of the size of a dose to be set.
[0040] The dose setting means comprises a clutch plate 74 provided with a first annular ratchet 76 , a dose setting knob 84 provided with a second annular ratchet 82 , and a second spring force means 78 arranged between a second annular inner wall 80 of the housing and a proximal surface of the clutch plate, such that clutch plate is distally urged and the first and the second ratchet are abutting each other, and which dose setting knob protrudes through the distal end of the housing, Figs. la and 4 . The fourth slidably-and-rotatably-locked means comprises longitudinally extending grooves 70 on the outer circumferential surface of the primary dose member 66 , and radial inwardly directed protrusions 72 on the inner surface of the clutch plate 74 , wherein the longitudinally extending grooves 70 cooperate with radial inwardly directed protrusions 72 such that the primary dose member and the clutch plate are rotationally locked and slidable in relation to each other, FIGS. 2 and 3 . The distal end of the lead screw member 58 protrudes through the dose setting knob 84 , and is at its distal end arranged with a dose injection button 86 , FIGS. 2 and 7 b . Outside the dose injection button 86 a spin ring 88 is rotatably arranged, FIG. 2 .
[0041] The locking means comprises:—a proximally pointing and radial flexible lever 102 arranged on the locking member,—an annular ledge 62 on the circumferential surface of the lead crew member, and—the circumferential inner surface of the secondary dose member, FIG. 2 . The secondary dose member 90 is also arranged with teeth 92 arranged around its circumference, which teeth cooperate with teeth on the pinion gear 94 , which is journalled in the housing as well as the locking member 96 via a locking lever bracket, FIG. 3 . Further the primary dose member 66 is arranged with a gear segment 98 , which also cooperate with the pinion gear 94 , FIG. 3 . A certain part of the lead screw member 58 is arranged with the splines 60 on its outer circumferential surface, FIG. 2 ; which splines have a lesser diameter than the proximal part of the lead screw member, thereby creating the annular ledge 62 , FIG. 2 . The locking member 96 also comprises on its distal circumferential surface a distally pointing stop member 95 , and the secondary dose member 90 comprises on its proximal circumferential surface a first 91 and a second 93 proximally pointing stop member arranged to interact with the stop member of the locking member, FIG. 4 .
[0042] The proximal part of the primary dose member 66 and the secondary dose member 90 are arranged with a circumferential band containing numbers or indicia 68 which are used to indicate dose size through a dose window on the housing, as will be explained below, FIG. 3 .
[0043] The device is intended to function as follows. When delivered to the user, the device is in the non-activated state wherein a medicament container 20 has been inserted in the medicament container holder 18 in the proximal end of the device, FIG. 1 , the first spring force means is in a pre-tensioned state and said locking means are engaged, wherein the circumferential inner surface of the secondary dose member 90 forces the flexible lever 102 radial inwardly in contact with the ledge 62 .
[0044] When the device is to be used the protective cap 26 is removed and the dose setting means are manually manipulated for setting the device from the non-activated state to the activated state by rotating the dose setting knob 84 counter clockwise until activating indicia as e.g. two zeros are visible through the window of the housing. The rotation of the dose setting knob 84 causes the clutch plate 74 and thereby the primary dose member 66 to rotate due to the engagement between the co-acting fourth slidably-and-rotatably-locked means, and due to the connection between the first 76 and the second 82 ratchets. However, the lead screw member is not rotated since the third slidably-and-rotatably-locked means 60 , 64 are not in engagement, i.e. the splines 60 on the outer circumferential surface of the lead screw member and the corresponding splines 64 arranged on the inner circumferential surface of the primary dose member 66 are not in engagement. The secondary dose member 90 also rotates due to the connection between the gear segment 98 of the primary dose member 66 and the teeth 92 of the secondary dose member 90 through the pinion gear 94 . The rotation of the secondary dose member 90 is stopped when its second proximally pointing stop member 93 abuts the distally pointing stop member 95 . This causes a longitudinal groove on the inner circumferential surface (not shown) of the secondary stop member to be aligned with the flexible lever 102 whereby the flexible lever is radial outwardly flexed into the groove and thereby moved out of contact with the ledge 62 of the lead screw member 58 . This causes the lead screw member 58 to move a pre-determined distance in the distal direction due to the force of the spring 48 acting on the nut 44 , which in turn is attached to the lead screw member 58 . The splines 60 on the outer circumferential surface of the lead screw member and the corresponding splines 64 arranged on the inner circumferential surface of the primary dose member are then engaged to each other. Because of the movement of the nut 44 , the plunger rod 36 is also moved. The distal end of the lead screw member 58 and its dose injection button 86 now protrude distally out of the housing said predetermined distance and independent of the size of the dose to be set.
[0045] The device is now in the activated state and ready for setting a required dose of medicament, FIGS. 7 a and 7 b.
[0046] When setting a dose, the plunger rod is arranged to be proximally moved a distance corresponding to a set dose to be delivered by manually manipulating the dose setting knob. The dose setting knob 84 is rotated in the clockwise direction which also rotates the primary dose member 66 clockwise indicating the dose that is being dialled. At the same time the primary dose member 66 rotates the lead screw member 58 clockwise due to the engagement between the co-acting third slidably-and-rotatably-locked means 60 , 64 ; and the lead screw rotates the plunger rod due to the engagement between the co-acting first slidably-and-rotatably-locked means, driving the plunger rod 36 through the nut 44 because of the threaded engagement between them, thereby moving the plunger rod 36 proximally. The secondary dose member 90 also rotates due to the connection between the gear segment 98 of the primary dose member 66 and the teeth 92 of the secondary dose member 90 through the pinion gear 94 . The rotation of the secondary dose member 90 is stopped when its first proximally pointing stop member 91 abuts the distally pointing stop member 95 , which indicates the maximum dose the device can deliver e.g. two indicia as e.g. a seven and a zero are visible through the dose window. In any case, the set dose is visible through the dose window of the housing. At this point the device is ready for an injection.
[0047] Moreover, if the user attempts to dial past the maximum dose the device can deliver or if the user attempts to dial pass the activating indicia, the connection between the first annular ratchet 76 and the second annular ratchet will function as a clutch.
[0048] When the dose is set, a medicament delivery member 24 is attached to the proximal end of the device, such as e.g. an injection needle. It is however to be understood that other types of medicament delivery members may be used in order to deliver a dose of medicament. The medicament delivery member is then placed at the delivery site and the user presses the dose injection button 86 in the proximal direction the predetermined distance that the distal end of the lead screw member 58 and its dose injection button 86 protrudes distally out of the housing and which said predetermined distance is independent of the size of the dose to be delivered. This causes the lead screw member 58 to move in the proximal direction as well as the nut 44 and the plunger rod 36 . This proximal movement of the plunger rod 36 causes it to act on the stopper 38 of the medicament container 20 whereby a dose of medicament is expelled through the medicament delivery member 24 . When the lead screw member 58 has reached a certain distance inside the housing, the flexible lever 102 of the locking member is again moved in contact with the ledge 62 of the lead screw member 58 , FIG. 8 . The medicament delivery member may now be removed and discarded.
[0049] When a subsequent dose is to be performed, the above described procedure is performed and can be repeated until the medicament container is emptied.
[0050] It is to be understood that the embodiment described above and shown in the drawings is to be regarded only as a non-limiting example of the invention and that it may be modified in many ways within the scope of the patent claims.
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A dose setting mechanism for a medicament delivery device is presented having a pinion mounted to a locking member where the axis of rotation of the pinion is offset and parallel to the longitudinal axis of the housing containing the dose setting components. Primary and secondary dose members are engaged with the pinion to indicate a set dose of medicament.
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CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This claims priority to U.S. Application Ser. No. 60/729,940, filed on Oct. 25, 2005.
TECHNICAL FIELD
[0002] In general, this disclosure related to printing systems and methods of printing on substrates.
BACKGROUND
[0003] Droplet ejection devices are used for depositing droplets on a substrate. Ink jet printers are a type of droplet ejection device. Ink jet printers typically include an ink supply to nozzle path. The nozzle path terminates in a nozzle opening from which ink drops are ejected. Ink drop ejection is controlled by pressurizing ink in the ink path with an actuator, which may be, for example, a piezoelectric deflector, a thermal bubble jet generator, or an electro statically deflected element. A typical printhead has an array of ink paths with corresponding nozzle openings and associated actuators, such that drop ejection from each nozzle opening can be independently controlled. In a drop-on-demand printhead, each actuator is fired to selectively eject a drop at a specific pixel location of an image as the printhead and a printing substrate are moved relative to one another. In high performance printheads, the nozzle openings typically have a diameter of 50 microns or less, e.g., around 35 microns, are separated at a pitch of 100-300 nozzle/inch, have a resolution of 100 to 3000 dpi or more, and provide drop sizes of about 1 to 70 picoliters or less. Drop ejection frequency can be 10 kHz or more.
[0004] Printing accuracy is influenced by a number of factors, including the size and velocity uniformity of drops ejected by the nozzles in the head and among multiple heads in a printer. The drop size and drop velocity uniformity are in turn influenced by factors such as the dimensional uniformity of the ink paths, acoustic interference effects, contamination in the ink flow paths, and the actuation uniformity of the actuators.
SUMMARY
[0005] Generally, the invention relates to printing systems and methods of printing on substrates, In an aspect, a method of printing one or more images using a printhead, the method includes moving a substrate on a transporter, providing a printhead configured to print a plurality of print lines in a direction, rotating an image to an image angle (i.e., about 45 degrees) relative to the direction of the print lines,and printing the image rotated to an image angle onto the substrate.
[0006] Implementations may include one or more of the following features. The method can include moving the transporter to a transporter angle (i.e., about 45 degrees) relative to the printhead, the transporter angle substantially equals the image angle.
[0007] In another aspect, a method of printing one or more images on a substrate using a printhead, the method includes moving a substrate on a transporter in a direction, rotating at least two orifices on a printhead to an orifice angle (i.e., about 45 degrees) relative to the transporter, the printhead configured to print a plurality of print lines in a direction substantially parallel to the direction of the transporter, rotating an image to an image angel relative to the print lines, and printing the image rotated to an image angle.
[0008] Implementations can include one or more of the following features. The method can include orifices that are parallel it a side of the printhead, or orifices that are rotated to the orifice angle relative to a side of the printhead.
[0009] In an aspect, a printing system includes a printhead configured to print a plurality of print lines in a direction, a transporter for moving a substrate relative to the printhead, and an image rotated to an image angle (i.e., about 45 degrees) relative to the direction of the print lines, the printhead prints the image onto the substrate.
[0010] Implementations can include one or more of the following features. The printing system can include the transporter being rotated to a transporter angle relative to printhead and the transporter angle substantially equals the image angle. The printing system can include and image database for storing images, a digital imager for processing the image, or a computer network through which the image travels to the printhead. The system can also include an ink reservoir or a control unit to control functions. of the printhead, The printhead can include at least two orifices rotated to an orifice angle relative to the transporter. The orifices can be parallel to a side of the printhead or rotated to the orifice angle relative to a side of the printhead.
[0011] These printing systems and methods of printing create less noticeable jet-out artifacts. A jet-out artifact is a black space left through an image when a jet becomes inoperative and stops depositing ink. Also, when printing rotated images, if either the transporter or the orifices are rotated, the substrates may be printed closer together. Furthermore, printing rotated images increases jet sustainability. Since more jets are used to print rotated images than are used to print parallel or perpendicular images, it is less likely that jets will dry out or clog. If a jet dries out or clogs, a jet-out artifact may be left on the image.
DESCRIPTION OF DRAWINGS
[0012] FIG. 1 is a block diagram of a printing system
[0013] FIG. 2 a is a top view of an image on a substrate.
[0014] FIG. 2 b is top view of a rotated image of FIG. 2 a rotated on a substrate.
[0015] FIG. 3 a is a top view of the image of FIG. 2 a with a jet-out artifact.
[0016] FIG. 3 b is a top view of the rotated image of FIG. 3 a with a jet-out artifact.
[0017] FIG. 4 is a block diagram of a printing system with a printhead, a rotated image, and a rotated transporter.
[0018] FIGS. 5 a & b are bottom views of a printhead with orifices parallel to a side of the printhead.
[0019] FIGS. 6 a & b are bottom views of a printhead with orifices aligned at an angle relative to a side of the printhead.
[0020] FIG. 7 is a block diagram of a printing system with a printhead similar to FIG. 5 b printing a rotated image on a substrate traveling along the transporter.
[0021] FIG. 8 is a block diagram of a printing system with a printhead similar to FIG. 6 b printing a rotated image on a substrate traveling along the transporter.
DETAILED DESCRIPTION
[0022] Referring to FIG. 1 , a printing system 10 includes an imaging system 12 for printing one or more images 14 on a substrate 16 . The imaging system 12 includes a digital imager 18 for processing images 14 stored in a image database 20 and provided to the digital imager 18 via a local area network 22 . In other implementations, the images 14 can be delivered from the database via wide area network (e.g., Internet). The imaging system 12 converts an image 14 into a format compatible with a printhead 24 . In this embodiment, the image database may include a library of images 14 stored on a server 26 . Other servers 27 may be connected to the network 22 for storing and sending images 14 .
[0023] More specifically, and discussed in greater detail below, digital imager 18 processes the images 14 by electronically rotating the image 14 relative to the print lines before sending the image 14 to a printhead 24 . The printhead 24 prints the image 14 onto a substrate 16 traveling on the transporter 28 , which in this embodiment includes a conveyor belt that moves along rollers 30 . Additionally, the printing system 10 includes an ink reservoir 32 to store one or more inks, and in this embodiment, includes a control unit 34 for performing different functions, such as monitoring the ink level, managing data transfers, sensing a jet-out, or controlling the temperature of the ink.
[0024] The printing system 10 may print one image 14 on one substrate 16 , or multiple images on one substrate 16 . In a preferred embodiment, the printing system 10 prints one or more images 14 on multiple substrates 16 traveling along the transporter 28 .
[0025] By rotating an image to be printed on a substrate, jet-out artifacts are less noticeable. If a jet dries out or clogs, a jet-out artifacts may be left on the image. A jet-out artifact is a blank space left through an image when a jet becomes inoperative an stops depositing ink (see FIGS. 3 a and 3 b below). For higher print resolution, an array of printhead orifices may be rotated (see FIGS. 6 a and 6 b below).
[0026] Referring to FIG. 2 a, an image 104 is printed in a substrate 108 , in this embodiment, and alphanumeric image (“ABC”) with the print lines 112 perpendicular to the image 104 . In other embodiments, the print lines 112 parallel to the image 104 .
[0027] Referring to FIG. 2 b, an image 104 is rotated to an image angle θ 116 relative to the print lines 112 . The image 104 is neither perpendicular nor parallel to the print lines 112 . The image angle 116 may be between 0 and 90 degrees, preferably between 5 and 35 degrees or 55 and 85, more preferably between 35 and 55 degrees, 90 and 180 degrees, preferably between 95 and 125 degrees or 145 and 175, more preferably between 125, and 145 degrees; 180 and 270 degrees, preferably between 185 and 215 degrees or 235 and 265, more preferably between 215 and 235 degrees; or 270 and 360 degrees, preferably between 275 and 305 degrees or 325 and 355, more preferably between 305 and 325 degrees. In this embodiment, the image angle 116 is about 35 degrees relative to the print lines 112 .
[0028] As shown in FIGS. 3 a and 3 b, when the image 104 is rotated to an angle, such that the image 104 is neither parallel nor perpendicular to the print lines (not shown), a jet-out artifact 120 is less noticeable to the human eye. For example, FIG. 3 a shows an image 104 on a substrate 108 , where the image 104 is perpendicular to the print lines (not shown). In FIG. 3 a, a jet-out artifact 120 is more noticeable to the human eye because the jet-out may leave white space through the entire length of the image 104 . Moreover, the human eye is more sensitive to horizontal and vertical lines, thus a horizontal or vertical jet-out artifact 120 is more noticeable.
[0029] In addition to less noticeable jet-out artifacts, printing rotated images increases jet sustainability. Since more jets are used to print rotated images than are used to print parallel or perpendicular images, it is less likely that jets will dry out or clog. For example, if rows of text are printed and the rows are parallel to the print lines, the jets corresponding to the spaces between the rows of text will not be used, On the other hand, if the rows of text are rotated to angle relative to the print lines, most, if not all, of the jets will be used because the spaces between the rows are no longer parallel to the print lines.
[0030] Conversely, in FIG. 3 b, when the image 104 is rotated to an angle relative to the print lines (not shown), a jet-out artifact 120 is less noticeable. The jet-out artifact 120 may leave white space only through a portion of the image 104 on the substrate 108 rather than the entire length of the image 104 . Also, the human eye is less sensitive to angled lines, and may not perceive the jet-out artifact 120 . Thus, in one embodiment, the image is an image rotated such that it is neither parallel nor perpendicular relative to the print lines.
[0031] FIG. 4 depicts a printing system 200 including a printhead 204 , transporter 208 rotated to a transporter angle α 212 , and a substrate 216 with and image 220 rotated to an angle θ 224 . As shown in FIG. 4 , for substrates 216 with an orientation (i.e., business cards), the transporter 208 may be rotated such that the rotated image 220 aligns with the orientation of the substrate 216 . In one embodiment, the transporter angle 212 substantially equals the image angle 224 . In one embodiment, the transporter angle 212 and image angle 224 are about 45 degrees. For other applications, the transporter angle 212 may by different from the image angle 224 . In some embodiments, the transporter angle 212 and image angle are between 0 and 90 degrees, preferably between 5 and 35 degrees or 55 and 85, more preferably between 35 and 55 degrees; 90 and 180 degrees, preferably between 95 and 125 degrees or 145 and 175, more preferably between 125 and 145 degrees; 180 and 270 degrees, preferaly between 185 and 215 degrees or 235 and 265, more preferably between 215 and 235 degrees; or 270 and 360 degrees, preferably between 275 and 305 degrees or 325 and 355, more preferably between 305 and 325 degrees.
[0032] In FIG. 5 a, an embodiment of a printhead 300 has a single row of orifices 304 aligned parallel to a side of the printhead 300 . In another embodiment, as depicted in FIG. 5 b, a printhead 300 may have multiple rows of orifices 304 parallel to a side of the printhead 300 .
[0033] Referring to FIGS. 6 a and 6 b, to achieve higher print resolution, a printing system 200 may have orifices on a printhead 204 rotated to an orifice angle. FIGS. 6 a and 6 b show printheads 300 with orifices 304 that are aligned at an orifice angle φ 304 relative to a side of the printhead 300 . In FIG. 6 a, a printhead 300 , while FIG. 5 b depicts a printhead 300 with multiple rows of rotated orifices 304 .
[0034] FIG. 7 shows a printing system 400 with a printhead 404 , a transporter 408 , and substrates 412 traveling along the transporter 408 . The printhead 404 with parallel orifices as shown in FIG. 5 b is rotated to an angle, such that the orifices are at an orifice angle β 416 .
[0035] Similarly, the printing system 500 in FIG. 8 shows a printhead 504 , a transporter 508 , and substrates 512 traveling along the transporter 508 . FIG. 8 uses the printhead 504 of FIG. 6 b, in which the orifices are rotated to an angle φ on the printhead 504 and an image 516 is rotated. In one embodiment, the printhead 504 is placed perpendicular to the transporter 508 . In another embodiment, the printhead 504 may be rotated relative to the transporter 508 , such that both the printhead 504 and the orifices are rotated.
[0036] In some embodiments of FIG. 7 or 8 , the orifice angle and image angle are between 0 and 90 degrees, preferably between 5 and 35 degrees or 55 and 85, more preferably between 35 and 55 degrees; 90 and 180 degrees; preferably between 95 and 125 degrees or 145 and 175, more preferably between 125 and 145 degrees; 180 and 270 degrees, preferably between 185 and 215 degrees, or 235 and 265, more preferably between 215 and 235 , degrees; 270 and 360 degrees, preferably between 275 and 305 degrees or 325 and 355, more preferably between 305 and 325 degrees.
[0037] In some embodiments of FIG. 7 or 8 , the printing system may print rotated images on a paper web that are cut out of the paper web, such as business cards or wrappers. Similarly, in other embodiments, the printing system may print rotated images on one or more sheets of food products, like confectionery or dough, which are subsequently cut into smaller pieces.
[0038] Other embodiments are within the scope of the claims. For example, although printing system is shown having one imaging system, in other applications, a number of imaging systems associated with the same or different transporter may by connected to the computer network.
[0039] The printing systems may be used to print on substrates of any shape, such as round, rectangular, planar, or nonplanar. Some types of substrates may include food products, such as confectionery, gum, cookies, crackers, yogurt, ice cream, and pastries. Other substrates may include paper products, such as envelopes, stationery, business cards, as well as foil wrappers, candy wrappers, food packaging, textiles, plastic products, or round shaped objects, like golf balls. Also, the substrate may be a paper web. The images printed on the substrates may be text, graphic, or any combination thereof.
[0040] Other embodiments may use other printing systems, such as rotary printing, drum printing, thermal bubble jet printing, continuous ink jet, laser printing, and helical printing.
[0041] Referring to FIG. 7 , the printing system 400 may include a sensor (not shown) that detects the edge of a substrate 412 , at which time the sensor signals the printhead 404 to start printing. If substrates 412 are being printed close together, the printhead 404 may abruptly stop printing on a first substrate when the sensor detects the second substrate, leaving an incomplete image on the first substrate. In such circumstances, software can be used to overlay consecutive images to move the images closer together. The printhead can then continue printing the first substrate after the sensor signals the printhead to start printing the second substrate.
[0042] Before the images are rotated, they have a rectangular orientation. The images are then rotated and have a skewed rectangular orientation. To make the images rectangular for bitmap rasterization, the skewed regions are filled with zeros. These skewed regions cause the consecutive images to be further apart and make it difficult to print on substrates close together on a conveyor. To move the images closer together, the images are overlaid and combined by “or” logic function. For example, image 2 overlays image 1 and covers a few pixels of image 1 . The “or” logic function ensures that the pixels in image 1 that are overlaid by image 2 will still be printed. The images can also be slanted after they are rotated, which permits the images to be overlaid even closer together.
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Printing systems and method of printing on substrates are provided. A method of printing one or more images using a printhead, the method including moving a substrate on a transporter, providing a printhead configured to print a plurality of print lines in a direction, rotating an image to an image angle relative to the direction of the print lines, and printing the image rotated to an angle onto the substrate.
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BACKGROUND OF THE INVENTION
[0001] 1. Field of the Invention
[0002] The present invention relates generally to the field of brushes for applying coloring matter to hair, and more specifically to a brush, which applies such matter as, defined in this application and retracts to prevent the bristles from bending and becoming deformed. The brush having an elongate handle portion connected to a retractable bristle support rack having two ends and a plurality of perpendicularly protruding bristles, the bristles preferably being flexible and resilient, and protruding to form maximum bristle length.
[0003] 2. Description of the Prior Art
[0004] There have long been brushes for applying and removing various materials to and from work surfaces. A problem with these prior art brushes when used for applying coloring matter to hair is that after use the bristles will bend and become deformed if not properly stored.
[0005] Koffler, U.S. Pat. No. 4,730,361, issued on Mar. 15 th , 1988, discloses a hair brush for lifting and shaping hair, having rows of bristles tapered across their width, but uniform along their length. This tapering causes the hair to be contacted by successively shorter rows of bristles. The longer rows first lift and shape the hair, and then the shorter rows smooth and pat the hair. A problem with Koffler after used for applying coloring matter to hair and cleaned, if not stored properly the bristles will bend and become deformed.
[0006] Pessis, U.S. Pat. No. 4,998,315, issued Mar. 12 th , 1991, disclose a nail polish brush having an essentially cylindrical cluster of bristles tapered at its distal end to give a sharper tip, and contoured to conform to the curvature of the nail. The taper is intended to fit the nail to make possible a uniform single stroke application. A problem with Pessis after used for applying coloring matter to hair and cleaned, if not stored properly the bristles will bend and become deformed.
[0007] Marino, U.S. Pat. No. 4,590,637, issued on May 27 th , 1986, discloses a paint brush having the across-width taper of Koffler. The taper from one broad bristle face to the other is supposed to make the brush more versatile, so that the ends can fit more easily into corners and edges. A problem presented by the Marino design, if used for applying hair coloring matter, is the same as that of Koffler, namely, if the brush is not properly stored the bristles can bend and become deformed.
[0008] Poole, U.S. Pat. No. 3,349,781, issued on Oct. 31 th , 1987, discloses a hair coloring method and brush for creating color streaks in hair. The brush has spaced apart tufts of bristles to produce discrete and distinct streaks having sharply defined edges. A problem with Poole after used for applying coloring matter to hair and cleaned, if not stored properly the bristles will bend and become deformed.
[0009] Fuentes, U.S. Pat. No. 2,610,637, issued on Sep. 16 th , 1952, reveals a combined comb and brush structure. The body of the structure has row of comb teeth extending from a concave edge portion so that their free extremities define an arcuate path. The arcuate path of the comb teeth conforms to the curvature of a person's head. There is a flat face on either side of the concave edge. Bristles protrude from one of these faces and are radically spaced from the free ends of the comb teeth. A problem with Koffler after used for applying coloring matter to hair and cleaned, if not stored properly the bristles will bend and become deformed.
[0010] It is thus an object of the present invention to provide a brush for applying hair coloring matter to a head of hair that is retractable in order to preserve the bristles.
[0011] It is finally an object of the present invention to provide such a brush which is of reliable design, and simple and inexpensive to manufacture.
SUMMARY OF INVENTION
[0012] The present invention accomplishes the above-stated objectives, as well as others, as may be determined by a fair reading and interpretation of the entire specification.
[0013] A brush is provided for applying coloring matter to hair, including a retractable rack having two ends for holding a row of bristles, the ends of the bristles forming an essentially flat tip surface. The tip surface portion has two sides and is located midway between the rack ends.
[0014] The retractable bristle rack is comprised of stainless steel with the bristle crimped. The rack is housed in the brush, which is molded from thermoplastic material. Preferably, the thermoplastic material is chosen from polypropylene and polyethylene.
[0015] In another aspect, the retractable bristle rack is comprised of molded thermoplastic material. Preferably, the thermoplastic material is chosen from polypropylene and polyethylene. Molding with thermoplastic material is preferred because it has a very low cost and allows the use of conventional industrial molding techniques.
BRIEF DESCRIPTION OF THE DRAWINGS
[0016] Various other objects, advantages, and features of the invention will become apparent to those skilled in the art from the following discussion taken in conjunction with the following drawings, in which:
[0017] FIG. 1 shows the top view of the retractable hair coloring brush, in the retracted position.
[0018] FIG. 2 shows a left-handed side elevation view thereof;
[0019] FIG. 3 shows a right-hand side elevation view thereof;
[0020] FIG. 4 shows the bottom view thereof;
[0021] FIG. 5 shows a front elevation view thereof;
[0022] FIG. 6 shows the a right-hand side elevation view of the retractable mounting rack as it would appear outside of the brush thereof;
[0023] FIG. 7 shows the top view of the retractable hair coloring brush, in the extended position
[0024] FIG. 8 shows a left-handed side elevation view thereof;
[0025] FIG. 9 shows a right-hand side elevation view thereof;
[0026] FIG. 10 shows the bottom view.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
[0027] As required, detailed embodiments of the present invention are disclosed herein; however, it is to be understood that the disclosed embodiments are merely exemplary of the invention, which may be embodied in various forms. Therefore, specific structural and functional details disclosed herein are not to be interpreted as limiting, but merely as a basis for the claims and as a representative basis for teaching one skilled in the art to variously employ the present invention in virtually any appropriately detailed structure. Reference is now made to the drawings, wherein like characteristics and features of the present invention shown in the various FIGURES are designated by the same reference numerals.
Preferred Embodiments
[0028] Referring to the Figures, a brush 10 is disclosed for applying coloring matter to hair. The term “coloring matter” for purposes of this application is understood to include all substances, which are used to color, bleach, highlight, frost, paint, or produce any hair coloring special effects.
[0029] A brush 10 depicted in FIGS. 1 through 6 has an elongate handle 11 portion and stores a retractable bristle support rack 20 . An extending/retracting button 12 is accessible from the top of the brush.
[0030] The retractable bristle support rack 20 depicted in FIGS. 6 through 10 has two ends 22 and 24 , a longitudinal bristle mounting face 26 and a plurality of bristles 30 . Bristles 30 protruding perpendicularly from mounting face 26 , are substantially uniformly thick, flexible and resilient per unit length. Bristles 30 are straight of equal length and either crimped or molded to the retractable bristle support rack.
[0031] The brush is used to transfer hair product from the bristle members to the lock of hair.
[0032] Although not illustrated, the hair product is a coloring product that is packaged as a cream or paste and prepared in a bowl or an automatic mixing device.
[0033] It will be apparent to those skilled in the art that various modifications and variations can be made to the structure and methodology of the present invention without departing from the scope and spirit of the invention. In view of the foregoing, it is intended that the present invention cover modifications and variations of this invention, provided they fall within the scope of the following claims and their equivalents.
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A brush for applying coloring matter to hair includes a retractable bristle rack having two ends for holding a row of bristles, the ends of the bristles forming an essentially flat tip surface portion.
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BACKGROUND
[0001] The invention relates to a computed tomography apparatus which includes a radiation source which emits a conical radiation beam, which apparatus involves a helical relative motion between the radiation source and the examination zone. The invention also relates to a computer program for such a computed tomography apparatus.
[0002] A computed tomography apparatus of this kind is known already from WO 9936885 (PHQ 98020). The helix and the detector unit which detects the conical radiation beam to the other side of an examination zone are proportioned in such a manner that the detector unit detects all rays of the radiation beam which extend through two neighboring segments of the helix which face the radiation source or extend between these segments. The reconstruction utilizes only the measuring data from the detector unit which is associated with the rays in the measuring window thus defined.
[0003] Upon its entry into the conical radiation beam, an arbitrary point in the examination zone is irradiated from a direction which is 180° opposed to the direction wherefrom it is irradiated upon its departure from the radiation beam. Because each point in the examination zone is irradiated only through an angular range of exactly 180°, this method is very susceptible to scanning errors.
[0004] This susceptibility is reduced in a computed tomography apparatus which is known from U.S. application Ser. No. 09/368,850 (PHD 98086); the computed tomography apparatus disclosed therein is distinct from the previously mentioned known computed tomography apparatus in that the measuring data used for the reconstruction is situated within a measuring window which is a factor of 2n+1 larger in relation to the distance between two neighboring turns of the helix, n being an integer number amounting to at least 1. According to this method each point of the examination zone is irradiated from an angular range of (2n+1). 180°. The susceptibility to scanning errors is then less pronounced. This advantage is achieved at the expense of the fact that the object to be examined is irradiated by a factor of 2n+1 longer (with the same speed of rotation). In the case of a moving object, this fact may give rise to motional unsharpness. Moreover, it may give rise to specific artefacts in the reconstructed CT image.
SUMMARY
[0005] It is an object of the present invention to provide a computed tomography apparatus in which the described problems are mitigated. This object is achieved in accordance with the invention by means of a computed tomography apparatus which includes
[0006] a scanning unit which includes a radiation source and a detector unit which is connected thereto in order to detect a conical radiation beam, emitted by the radiation source, after its passage through an examination zone or an object present therein,
[0007] a drive device for producing a relative motion in the form of a helix, consisting of a rotation about an axis of rotation and an advance in the direction parallel to the axis of rotation, between the scanning unit and the examination zone or the object,
[0008] the helix and the detector unit being proportioned in such a manner that the detector unit simultaneously detects all rays of the radiation beam within a first measuring window whose edges, being offset relative to one another in the direction of the axis of rotation, are defined by lines which originate from the radiation source and intersect two segments of the helix which are offset over the distance (2n+1)p in the direction of the axis of rotation, where n is an integer number ≧1 and p corresponds to the axial offset of two neighboring turns of the helix,
[0009] and a reconstruction unit for reconstructing a CT image which corresponds to the spatial distribution of the absorption within the examination zone from the measuring data acquired by the detector unit within the first measuring window,
[0010] the measuring data derived from rays which extend within a second measuring window being assigned a weight for the reconstruction which differs from that assigned to the measuring data from rays which extend outside the second measuring window but inside the first measuring window, and the second measuring window being situated, viewed in the direction of the axis of rotation, at the center of the first measuring window and its mutually offset edges being defined by lines which originate from the radiation source and intersect two segments of the helix which are offset over the distance (2m+1)p in the direction of the axis of rotation, where m is an integer number and 0≦m≦n.
[0011] Thus, like in the latter known computed tomography apparatus, in accordance with the invention measuring data is acquired from rays which are situated within a (first) measuring window which (measured in the direction of the axis of rotation) is a factor of 2n+1 larger than the distance between two neighboring turns of the helix. During the reconstruction, however, measuring data from a second, smaller measuring window which is centrally situated with respect to the first measuring window is assigned a weighting factor which differs from that assigned to the measuring data acquired outside the second measuring window but within the first measuring window.
[0012] The invention is based on the idea that the examination zone can be completely reconstructed from the measuring data acquired in the first measuring window as well as from the measuring data acquired in the second measuring window. When the CT images formed by such different reconstruction are added, the described problems are more or less suppressed. A reduced susceptibility to scanning errors is achieved (in comparison with a computed tomography apparatus with a measuring window between two neighboring turns) and the motional unsharpness and any other artefacts are reduced (in comparison with a computed tomography apparatus with a measuring window which extends across several turns of the helix). Because of the linearity of the reconstruction method, the processing of the measuring data is equivalent, depending on whether this data was acquired in the second measuring window or only in the first measuring window, to the weighted summing of the two CT images separately reconstructed from the CT data of the first and the second measuring window, respectively.
[0013] The principle on which the invention is based can also be extended to more than two measuring windows as indicated in claim 2. A prerequisite in this respect is that the first measuring window must extend across a range of at least 5p in the axial direction (n≧2) and that the further window is smaller than the first window and larger than or smaller than the second window.
[0014] The possibility for selection of the weights with which the measuring data derived from the various measuring windows enter the reconstruction as disclosed in claim 3 enables the weights to be adapted to different conditions in the examination zone. If there is a high risk of motional unsharpness, it makes sense to attach more weight to the measuring data acquired in the second measuring window. Otherwise it is effective to put less emphasis on this measuring data.
[0015] The measuring data from the two windows can in principle be processed in an identical way, that is, if their different weight is ignored. However, in conformity with claim 4 it is also possible to process the measuring data in different ways. This is because, when the second measuring data is bounded by neighboring turns of the helix (m=0), the filtering of the measuring data from this window can be carried out as described in U.S. application Ser. No. 09/663,634 (PHD 99123), thus resulting in an enhanced image quality.
[0016] Claim 5 describes a computer program for the reconstruction unit of a computed tomography apparatus which enables implementation of the invention in a computed tomography apparatus.
DRAWINGS
[0017] The invention will be described in detail hereinafter with reference to the drawing. Therein:
[0018] [0018]FIG. 1 shows a computed tomography apparatus in accordance with the invention,
[0019] [0019]FIG. 2 shows a flowchart of the method carried out by means of such a computed tomography apparatus,
[0020] [0020]FIG. 3 shows the location in space of the radiation source and the edge rays of the measuring window relative to the helix,
[0021] [0021]FIG. 4 shows a development of the detector unit, and
[0022] [0022]FIG. 5 shows the course of the lines along which a one-dimensional filtering is performed during the reconstruction.
DESCRIPTION
[0023] The computed tomography apparatus as shown in FIG. 1 includes a gantry 1 which is capable of rotation about an axis of rotation 14 which extends parallel to the z direction of the co-ordinate system shown in FIG. 1. To this end, the gantry is driven at a preferably constant angular speed by a motor 2 . A radiation source S, for example, an X-ray tube, is mounted on the gantry. The X-ray source is provided with a collimator device 3 which forms a conical radiation beam 4 from the radiation produced by the radiation source S, that is, a radiation beam which has a finite dimension other than zero in the direction of the z axis as well as in a direction perpendicular thereto (that is, in the x-y plane).
[0024] The radiation beam 4 traverses an object (not shown) which is present in an examination zone 13 . The examination zone 13 is shaped as a cylinder. After having traversed the examination zone 13 , the X-ray beam 4 is incident on a detector unit 16 which is mounted on the gantry 1 and includes a number of detector rows which are offset in the z direction. Each detector row is arranged in a plane which extends perpendicularly to the z direction and comprises a plurality of detector elements, each of which detects a respective ray and delivers corresponding measuring data. The detector unit 16 may be arranged on an arc of circle around the axis of rotation 14 , but other detector geometries are also feasible; for example, it may be arranged on an arc of circle around the radiation source S.
[0025] The angle of aperture α max of the radiation beam 4 (the angle of aperture is defined as the angle enclosed by a ray of the beam 4 which is situated at the edge in the x-y plane relative to the plane defined by the radiation source S and the axis of rotation 14 ) then determines the diameter of the examination zone. The examination zone 13 , or an object present therein, for example, a patient accommodated on a patient table, can be displaced parallel to the z axis. The speed of such displacement in the z direction is constant and preferably adjustable.
[0026] The measuring data acquired by the detector unit 16 is applied to an image processing computer 10 which reconstructs therefrom the absorption distribution in the part of the examination zone 13 which is irradiated by the radiation cone 4 in order to reproduce it, for example on a monitor 11 . The two motors 2 and 5 , the image processing computer 10 , the radiation source S and the transfer of the measuring data from the detector unit 16 to the image processing computer 10 are controlled by a suitable control unit 7 .
[0027] When the motor 5 stands still and the motor 2 rotates the gantry, a circular scanning motion of the radiation source S and the detector unit occurs. The control unit 7 , however, can also activate the motors 2 and 5 simultaneously, that is, in such a manner that the ratio of the speed of advancement of the examination zone 13 to the angular velocity of the gantry is constant. In this case the radiation source S and the examination zone 13 move relative to one another along a helical trajectory.
[0028] The acquisition of measuring data by means of the computed tomography apparatus as shown in FIG. 1 and the reconstruction of a CT image from such measuring data will be described in detail hereinafter with reference to the flowchart which is shown in FIG. 2.
[0029] After the initialization in the step 100 , the motors 2 and 5 are activated and the radiation source S is switched on. The measuring data subsequently acquired in the step 101 , being dependent on the attenuation of the radiation beam in the examination zone, is transferred from the detector unit 16 to a memory of the reconstruction unit 10 .
[0030] [0030]FIG. 3 shows the geometrical conditions during the acquisition of the measuring data. In this respect it is assumed that the radiation source S moves along a trajectory 17 in the form of a helix around the stationary examination zone which is not shown in FIG. 3, even though it actually performs only a circular motion and the examination zone or the object to be examined is displaced. However, this assumption is permissible because only the relative motion between the X-ray source and the examination zone is of relevance.
[0031] The radiation beam 4 used for the reconstruction is limited to a first measuring window. The lines or edge rays of the radiation beam 4 which are shown in the drawing and originate from the radiation source intersect the edges of said measuring window which are mutually offset in the direction of the axis of rotation and also intersect two of the turns of the helix which face the radiation source. Thus, only rays which coincide with the edge rays shown or are situated between these edge rays are evaluated for the measurement. The measuring window is situated symmetrically relative to the radiation source S. The turns of the helix which define the edge of the measuring window are situated at a distance 3p from one another in the direction of the axis of rotation, where p is the distance between two neighboring turns of the helix.
[0032] [0032]FIG. 4 shows a development of the detector unit 16 ; for the sake of clarity, the dimensions of the detector unit are shown at a significantly enlarged scale in the direction of the axis of rotation in comparison with its dimensions in the direction perpendicular thereto. The reference numerals 163 and 164 denote the edges of the first measuring window on the detector unit which are mutually offset in the direction of the axis of rotation. Because of the slope of the helix, said edges do not extend horizontally but are inclined. If the detector 16 were curved around the radiation source S instead of around the axis of rotation 14 , or if it were flat, the edges 163 and 164 would not be straight as shown in FIG. 4.
[0033] [0033]FIG. 4 also shows a second measuring window whose edges which are offset in the direction of the axis of rotation 14 are denoted by the reference numerals 161 and 162 . The edges are defined by the lines which originate from the radiation source S and puncture the two turns inside the first measuring field and these edges at the same time.
[0034] An arbitrary point in the examination zone is projected onto a detector element upon its entry into the first measuring window, which detector element is situated, for example, on the lower edge 164 (in that case the ray on which the point is situated punctures a turn of the helix). Subsequently, this point is projected onto a detector element on the line 162 (in that case the ray through the point punctures a neighboring turn) which bounds the second measuring window in the downward direction. After having traversed a further radiation range of 180°, this point is projected onto a detector element on the upper edge 161 of the second measuring window (where the ray punctures the next turn). When this point has been irradiated through an angular range amounting to 540° overall by the radiation source S, it is projected onto a detector element which is situated on the upper edge 163 of the first measuring window (the ray then intersects the upper turn).
[0035] The path of the radiation beam 4 which is compatible with the first measuring window can be realized by appropriate configuration of the collimator 3 . If this is not possible so that the radiation beam 4 irradiates the entire rectangular zone of the detector 6 , the limitation to the measuring window is realized by excluding the measuring data from detector elements which are situated in the shaded zones outside the lines 163 and 164 from the reconstruction.
[0036] The measuring data acquired in the step 101 correspond (that is, possibly after smoothing and logarithmation) to the line integral of the attenuation along the ray along which it has been measured. If necessary, in this step all measuring data can be weighted with the cosine of the angle which is enclosed by the relevant ray relative to a plane perpendicular to the axis of rotation. However, when the cosine has practically the value 1 for all rays (because the angle is very small), such weighting can be dispensed with.
[0037] All measuring data M is characterized by a (scalar) quantity which corresponds to the line integral of the attenuation and by the position of the rays along which it has been acquired. Each ray is characterized by the three parameters (β, γ, s) listed below.
[0038] The parameter β characterizes the direction of a normal from the radiation source position to the axis of rotation 14 in an (x,y) plane which extends perpendicularly to the axis of rotation. All rays in the radiation beam shown in FIG. 3 thus have the same parameter β. After more than one revolution of the radiation source, β will be larger than 2π.
[0039] The parameter γ is the angle enclosed by the relevant ray in the (x,y) plane, perpendicular to the axis of rotation 14 , relative to the said normal. All rays within a fan beam parallel to the axis of rotation have the same value γ. In FIG. 3 such a fan beam is defined by the line 400 and the (edge) rays which connect said line to the radiation source (S).
[0040] The parameter s represents the height co-ordinate of the ray, that is, it indicates the position in which the relevant ray passes between two turns of the helix. All rays which intersect the same turn of the helix have the same value s. The edge rays of the first measuring window are characterized by the parameter s=±0.75 p; the edge rays of the second measuring window have the parameter s=±0.25 p.
[0041] Each ray is thus characterized by a point in the three-dimensional (β, γ, s) parameter space. The acquisition of the CT data thus constitutes a sampling of the so-called object function (in this case of the line integral of the attenuation) in a multitude of sampling points which are comparatively uniformly distributed in the (β, γ, s) parameter space. The sampling in this parameter space, however, is not optimally suitable for the further processing.
[0042] Therefore, in the step 102 a so-called rebinning operation is performed in a parallel beam geometry. Therein, a data set M(θ, t, s) which represents the object function at the grid points of a regular Cartesian grid in a three-dimensional (θ, t, s) parameter space is calculated by resorting and re-interpolation from the acquired measuring data M(β, γ, s):
[0043] The parameter θ therein indicates the direction of a fan beam which is parallel to the axis of rotation in a plane perpendicular to the axis of rotation. The rays in fan beams which extend parallel to the axis of rotation and to one another have the same parameter θ. Like the parameter β, the parameter θ may also become larger than 2π.
[0044] The parameter t denotes the distance between a fan beam and the axis of rotation; the fan beams which are situated to one side of the axis of rotation then have a negative value of t whereas the fan beams situated to the other side have a positive value of t. The maximum value of t corresponds to the radius of the examination zone 13 .
[0045] The parameter s once more is the height co-ordinate.
[0046] Except for the use of a second measuring window, the method described thus far is known from the cited U.S. application Ser. No. 09/368,850. However, whereas in conformity with the known method the further processing of the measuring data takes place independently of its position within the (first) measuring window, the measuring data in accordance with the invention is further processed in dependence on whether or not it is associated with rays which also extend through the second measuring window.
[0047] Therefore, in the step 103 it is checked whether the absolute value s of the measuring data M(θ, t, s) is larger than 0.25 p (where p corresponds to the distance between neighboring turns of the helix). If so, the rays associated with this measuring data extend within the first measuring window, but outside the second measuring window. In this case in the step 104 a one-dimensional filtering operation is applied to all CT data which have the same value of θ and s but different values of t.
[0048] This filtering operation is illustrated in FIG. 5. FIG. 5 shows a plane parallel to the θ axis in the cartesian (θ, t, s) parameter space; the parameter s is the ordinate (normalized to the value p) and the parameter t (normalized to the radius R of the examination zone) is the abscissa. The dotted and dot-dash lines connect the successive grid points or measuring data subjected to a common filtering operation. Such lines extend horizontally for all measuring data for which the value s is between 0.25p and 0.75p as well as for those where it lies between −0.75p and −0.25p, for example, the lines 201 and 202 .
[0049] All measuring data situated within the second measuring window (that is, measuring data whose parameter s is not larger than 0.25p and not smaller than −0.25p) are subjected to a filtering operation in the block 105 ; however, the measuring data which are situated on a horizontal line are not subjected to one-dimensional filtering, but only the measuring data of rays which are interconnected by more or less inclined lines 203 , 204 and 205 in FIG. 5. This filtering method is described in detail in U.S. application Ser. No. 09/663,634 whereto explicit reference is made. This filtering operation results in a given improvement of the image quality.
[0050] The measuring data acquired outside the second measuring window (but inside the first measuring window) is weighted with a weighting factor w 1 (block 106 ) and the measuring data acquired within the second measuring window and filtered in the step 105 is weighted with a second weighting factor w 2 (block 107 ). In the step 108 the attenuation in the individual points of the examination zone is derived by backprojection from the measuring data thus filtered and weighted. For each point in the examination zone the rays are then determined which have irradiated this point of the examination zone from an angular range of 3π. The measuring data associated with these rays is weighted with w 1 or w 2 so as to be summed, that is, after a further interpolation, if necessary. The image thus reconstructed is reproduced and stored in a suitable manner. The method is thus terminated (block 109 ).
[0051] The weighting factors w 1 and w 2 can be iteratively preset by the user. However, they can also be automatically preset as a function of the part of the body to be imaged.
[0052] When the weighting factor w 1 =0 (or small in comparison with w 2 ), only measuring data from the second measuring window will be used for the reconstruction. This results in a CT image which has a low level of motional unsharpness, but an increased susceptibility to scanning errors. When the weighting factor w 2 is chosen to be twice as large as the weighting factor w 1 , the linearity of the reconstruction method ensures that the same conditions will be obtained as when a first CT image were reconstructed from all measuring data acquired in the first window and this CT image were added to a second CT image which is reconstructed exclusively from the measuring data acquired in the second measuring window. The signal-to-noise ratio is then better and the effect of scanning errors is reduced; however, this advantage is achieved at the expense of the fact that any motional unsharpness becomes more pronounced.
[0053] When the weighting factors w 1 and w 2 are equal, essentially the same conditions will be obtained as when a uniformly weighted CT image were reconstructed from all measuring data acquired in the first measuring window. The signal-to-noise ratio is then optimum, but the risk of motional unsharpness is even higher.
[0054] Contrary to what is shown in FIG. 2, the measuring data from the second measuring window can also be filtered in the same way as the measuring data from the first measuring window, that is, along parallel lines in the t, s plane (FIG. 5). The branching operation 103 must then be performed only after the uniform filtering. Small reductions of the image quality, however, will have to be accepted in that case.
[0055] It has been assumed in the foregoing that the dimensions of the first measuring window in the direction of the axis of rotation correspond to three times the distance p of the turns of the helix. The dimensions of the measuring window, however, may also amount to 3p, 5p or in general to (2n+1)p, where n is an integer number. In that case at least two further measuring windows of the dimensions (2m+1)p and (2k+1)p can be defined (and possibly even more measuring windows), m and k then being different positive integer numbers which are smaller than n. The measuring data from such different measuring windows can be assigned different weighting factors for the reconstruction.
[0056] As has already been explained, the same results are obtained when a CT image is reconstructed from all measuring data acquired in a respective measuring window and when this CT image is added to the CT image or the CT images which can be reconstructed from the measuring data of the other measuring window or measuring windows.
[0057] The invention has been described with reference to the preferred embodiment. Obviously, modifications and alterations will occur to others upon reading and understanding the preceding detailed description. It is intended that the invention be construed as including all such modifications and alterations insofar as they come within the scope of the appended claims or the equivalents thereof.
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The invention relates to a computed tomography apparatus in which the measuring data acquired in a first measuring window enter the reconstruction with a weight other than that of the measuring data that can be acquired in a second measuring window, the second measuring window being situated centrally relative to the first measuring window and being smaller than the first measuring window. Depending on the weighting of the measuring data, the resultant CT image exhibits either smaller motional artefacts or a spatially more uniform noise.
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BACKGROUND OF THE INVENTION
This invention relates to a structure used for assembling rail members together to form a pool table.
In the past, a pool table has included a part called an insert or iron which is assembled between two adjacent rail members of a pool table. The iron is usually enclosed in a molded decorative cover and a pocket is secured to the table beneath the iron.
Currently, the pocket insert has included opposite end pins which are inserted into mating holes in the ends of the adjacent rail members. In order to hold the pins securely in the mating holes, it is necessary to drill and tap transverse apertures in the pins. These apertures will line up with apertures which have been drilled in the bottom surfaces of the rail members for receiving screws. It is the current practice that the screws be inserted and the apertures drilled on the bottom side of the rail members for aesthetic reasons. Thus, it has been necessary to turn the rail members and insert upside down during assembly so that the screws can be inserted.
When the entire rectangular assembly has been completed, the assembly is turned right side up.
The resulting rectangular frame which must be turned right side up, requires the strength of two men to manipulate it.
SUMMARY OF THE INVENTION
An object of this invention is to provide a unique pocket insert which can be securely assembled with the rail members while the rectangular frame is right side up. Thus, the need for two men to turn over the frame has been eliminated.
Another object of the present invention is to provide a novel pocket structure that secures the rail members of a pool table without the need for separate fasteners. Consequently, the need for drilling apertures in the pin means and rail member is no longer required. This causes a significant reduction in the time and money needed to assemble a pool table.
BRIEF DESCRIPTION OF THE DRAWINGS
The features of the present invention which are believed to be novel are set forth with particularity in the appended claims. The organization and manner of operation of the invention, together with further objects and advantages thereof, may best be understood by reference to the following description taken in connection with the accompanying drawings in which like reference numerals identify like elements, and in which:
FIG. 1 is a perspective view of a pool table incorporating the present invention;
FIG. 2 is an exploded view, also in perspective, showing the manner of engagement between a pocket insert structure and the associated rail members;
FIG. 3 is a plan view of the assembled pocket in place;
FIG. 4 is a side elevational view;
FIG. 5 is an enlarged fragmentary sectional view taken along line 5--5 in FIG. 3 showing a modified form of the invention; and
FIG. 6 is a sectional view taken along line 6--6 in FIG. 1.
DETAILED DESCRIPTION OF THE INVENTION
Referring now to FIG. 1, there is shown a pool table 4, which is comprised of a plurality of sets of adjacent rail members 20, 22, which fit together to form a rectangular frame 6 adapted to be positioned on a frame 7 of the table. Pocket inserts 8 constructed in accordance with the present invention are fitted between each pair of rail members 20, 22 in the manner described in detail below. The pocket inserts are provided at the sides and corners of the table and are essentially identical except for the differences in shape of the side and corner pockets.
FIG. 2 shows the innovative pocket insert 10 which comprises a body 11 of the desired shape and opposite laterally extending end pins 12 and 14 having flanges 16 and 18. Adjacent rail members 20 and 22 are formed with apertures or bores 24 and 26 respectively including intersecting slots 28 and 30 extending from bottom surfaces of the rail members for receiving the pins 12 and 14 respectively. The apertures 24 and 26 are slightly larger than the pin means 12 and 14 and the slots 28 and 30 are slightly wider than the flanges 16 and 18, but the dimensions are such as to provide a snug fit.
As best seen in FIGS. 3 and 4, each flange 16 and 18 is parallel to an upstanding plane which is inclined at a small angle 33 with the vertical axis. The slot 30 in the adjacent rail member 22 is vertical. Consequently, when the flange 18 is inserted into the slot 30, a side or interference or abutment surface 19 of the flange 18 will bind with a side or interference or abutment surface 31 of the slot 30 when the parts are finally secured to the frame 7 of the table as described below.
The friction caused by the interference of the flange 18 and the slot 30, at varying angles, will serve to securely bind the pocket insert 10 with respect to the rail member 22. The pin 12, flange 16, bore 24 and slot 28 are formed in the same manner to provide an interference fit for securing the pocket insert and rail member 20 with respect to each other.
During assembly of the structure of the present invention, the rail members may first be loosely arranged right side up and in a rectangular pattern on top of the table frame 7. Then the pocket inserts 10 may be easily assembled between each pair of adjacent rail members simply by inserting the pins 12 and 14 into the mating bores 24 and 26. Finally, the rail members are tightly drawn down against and secured with respect to the table frame 7 by a plurality of screws 34 as shown in FIG. 6. The screws 34 are spaced around the table frame in a known manner.
When the installation is complete, the interfering surfaces 19 and 31 of the pin means flanges and slot portions of the complementary openings in the rail members are urged into tight engagement to promote a rigid connection between the pocket insert and the rail members. It is to be understood that the pin means and complementary rail member openings could be formed with other non-circular or polygonal cross-sectional configurations for presenting interfering surfaces and locking the inserts 8 against rotation or turning around the axes of the pins. Furthermore, the axes of the pins 12 and 14 and of the bores 24 and 26 may be inclined slightly relative to each other to provide interfering surfaces along their length to further enlarge the rigidity of the final assembly. This modification is shown in FIG. 4.
As seen in FIGS. 3 and 6, in accordance with a further aspect of the invention, when the rail member 20 is finally firmly secured, the flanges 16 and 18 will be forced toward a vertical position. As a result, the body 11 of the pocket insert 10 will be inclined upward, as desired, two or three degrees relative to the horizontal plane of the rail members.
As seen in FIG. 5, another embodiment of the invention in which elements corresponding to those described above are designated by the same reference numerals with the suffix "a" added. In this embodiment, the pin means 14a has ribs 36 provided on one side of its flange 18a for obtaining the desired thickness of the flange. The flange of the pin not shown corresponding to the pin 12 and flange 16 is also provided with the ribs 36. The use of the ribs 36 reduces the area of surface contact for facilitating initial insertion of the flanges 16a and 18a in the slots while still providing for an interference fit in the final assembly.
While particular embodiments of the invention have been shown and described in detail, many changes may be made without departing from the spirit and scope of the appended claims.
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A pocket structure for assembly between two adjacent rail members of a pool table comprising a pocket defining insert having non-circular pin means extending from opposite ends thereof that fit and bind in apertures in the rail members to snugly secure them together in the desired position when the rail members are secured to a pool table frame.
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FIELD OF THE INVENTION
[0001] This invention relates to dust-free stabilizer compositions for plastics, more especially polyvinyl chloride (PVC), in granular form, the composition being substantially free from the plastics for which it is intended.
PRIOR ART
[0002] Stabilizers are added to thermoplastics during processing in order to increase their stability. These stabilizers may be lead, cadmium, barium, calcium, tin and zinc compounds, more especially salts and metal soaps, and others. Apart from the stabilizers themselves, the stabilizer compositions also consist of lubricants, such as fatty acid esters, waxes, paraffins, etc., and fillers, such as chalk, kaolin, titanium dioxide, etc. Other auxiliaries, such as flow modifiers, may also be present in the stabilizer compositions.
[0003] The stabilizer compositions are incorporated in the plastics in powder form by the processor, the plastics also being present in powder form or in the form of very fine granules. The powder form of both components to be incorporated, i.e. the plastic and the stabilizer compositions, is favorable for obtaining a uniform and homogeneous mixture.
[0004] However, if the stabilizer compositions are present as powders for incorporation in the plastics, serious disadvantages arise. Since, as can be seen from the examples mentioned above, the stabilizer compositions often contain physiologically harmful constituents which should not be inhaled, special safety measures have to be taken during the processing of powder-form stabilizer compositions. Accordingly, totally encapsulated installations have been developed for the completely dust-free processing of the powder-form stabilizer composition from delivery to the final mixture of plastic and stabilizer composition and beyond. However, such installations are very expensive both in regard to initial cost and in regard to ongoing maintenance.
[0005] Another disadvantage of powder-form stabilizer compositions lies in the risk of explosion because they contain a significant percentage of organic compounds. Accordingly, special measures have to taken to avoid dust explosions.
[0006] For these reasons, it is known that stabilizer compositions can be made up in such a way that the advantages of the powder form are retained without having to accept any of their disadvantages.
[0007] To this end, the stabilizer compositions are converted into granules which the user processes in a special apparatus. The granules are introduced together with the plastic powder into a heating/cooling powder mixer with a vertical axis of rotation in which stirrer blades rotate at high speeds, typically 2,000 r.p.m. The stirrer reduces the stabilizer granules into a fine powder and, at the same time, mixes this powder with the plastic powder. About 2 to 8 parts by weight of the stabilizer compositions are mixed with 100 parts by weight of plastic powder in this way. Under the effect of mechanical shearing and the resulting friction, the temperature in the mixer rises very quickly so that it is important not to exceed a certain mixing time because other the plastic plasticizes and a partially plasticized block is obtained instead of the required powder mixture.
[0008] The mixture drops from the powder mixer into a tubular, horizontally arranged cooler with a longitudinal, i.e. likewise horizontally arranged, stirrer shaft on which stirrer blades are provided. In the cooler, the powder mixture is cooled to around 30 to 40° C. and is then directly further processed or transported to a storage silo.
[0009] The temperatures mentioned relate to the most common application in which PVC powder is mixed with a stabilizer composition. Temperatures of 145 to 210° C. are applied during processing, for example in an extruder or injection molding machine. By contrast, the typical plasticization temperature which must not be exceeded in the powder mixer is about 140° C.
[0010] Various supply forms which can be processed in the apparatus mentioned above are known. Thus, the stabilizer compositions can be cold-compacted by pressure to form granules. To obtain particularly dust-free compositions, correspondingly high pressures are of advantage. However, the high density achieved in this way leads to poor dispersibility of the granules in the plastic.
[0011] In addition, it is known that stabilizer compositions can be used in the form of flakes. To this end, the corresponding metal soaps are produced from the metal oxides and fatty acids in a melt reactor at temperatures of 130 to 150° C. These metal soaps often have an indefinable composition. After addition of fusible and infusible additives, a viscous melt with a temperature of 140° C. is obtained and is applied to a flake-forming roller to obtain flakes. The flakes are not uniform in shape and, in addition, are mechanically relatively unstable so that a product with a significant, unwelcome dust content is obtained.
[0012] Accordingly, it is more favorable to produce pellets rather than flakes from the melt. To this end, drops of the hot melt are applied by a punch to a cooling bed which may be formed by a cooled steel belt. Pellets have the advantage that they are almost completely dust-free and easier to disperse in the plastic powder because no mechanical pressure has been applied to produce the pellets. The pellets have a diameter of about 3 to 4 mm.
[0013] Although pellets have the advantage of being dust-free and easy to process, stabilizer compositions with high metal contents, especially lead salt contents, as necessary for cable plastics for example, cannot be produced in the form of pellets because stabilizer compositions such as these are difficult to melt. Plastics intended for the sheathing of electrical cables require stabilizer compositions containing 50 to 70% by weight or even up to 75% by weight of lead sulfate. Although fatty alcohols can be added, for example in quantities of 5 to 10% by weight, to the stabilizer compositions to reduce their viscosity, so that the composition can be pelleted, the presence of fatty alcohols is undesirable in cable compounds and even intolerable in the case of flexible PVC. The problems to do with the fusibility of the stabilizer composition do not arise with lead contents of less than 50% by weight so that fatty alcohols do not have to be added.
[0014] In addition, DE-A-34 29 766 describes a granular stabilizer for PVC and a process for its production. The process starts out from a powder-form stabilizer mixture and a solid organic binder. The binder is used in a quantity of 2 to 15 parts by weight to 100 parts by weight of the powder-form stabilizer composition. The binder may also be a typical constituent of the stabilizer mixture, for example lead stearate, or even a low-melting wax. It is important that the binder is added in a quantity which is smaller than the “critical liquid absorption” of the powder-form stabilizer composition defined in the cited document.
[0015] In a first step, the powder-form stabilizer mixture is size-reduced to so-called “primary particles” of which the particle size is not discussed. However, it may be concluded from the size-reducing machines used, for example high-speed mills, that the particle sizes are in the nanometer range. During its size reduction, the powder-form stabilizer mixture is mixed with the binder mentioned either in the dry state or in the presence of solvents, so that the surface of the primary particles is covered by binder.
[0016] In a second step, the coated primary particles obtained are granulated to particle sizes of 0.1 to 2 mm by melting of the surface layer, i.e. at a higher temperature than the melting point of the binder, optionally after removal of the solvent. The end product consists of granules each made up of several primary particles which in turn are individually covered by the binder.
[0017] Although, as a result of the drastic size reduction of the stabilizer mixture into primary particles, favorable dispersion behavior in the plastic is obtained by virtue of the very small particle size, the considerable effort involved in the drastic size reduction is a disadvantage. If typical constituents of the stabilizer mixture, for example lead stearate, are used as the binder, as proposed in the cited document, the effort involved in avoiding explosions of the “high-dust” powder is a disadvantage. In view of their very large relative surface, the primary particles also have a tendency towards dust explosions against which suitable measures have to be taken. For example, the size reduction of the starting materials to primary particles could be undertaken in the presence of a solvent although this does have the disadvantage that, after this process step, the solvent has to be removed by distillation in another step before the primary particles are granulated.
[0018] A process for the production of additives for plastics and the corresponding additives in granular form are known from WO-A-87 00543. Here, the binder—which is referred to in this document as “wax”—is added to the other constituents in molten form in several fractions, i.e. gradually, in a high-speed mixer. When the first fraction of the binder is added, the individual powder particles take on a thin coating of the binder. When the other fractions of the binder are added, the “waxed” particles undergo aggregation so that the granules obtained consist entirely of the binder mentioned, for example glycerol monostearate, in which the other particles are embedded as in a matrix. Accordingly, in the production of these granules, the binder has to be added in the molten state, i.e. at a temperature above the melting temperature. In addition, during the incorporation of these additive granules in the plastic for which they are intended, the binder again has to be completely melted to ensure uniform dispersion in the plastic.
[0019] In addition, DE-A-2 031 445 describes a process for the granulation of auxiliaries for stabilizing halogen-containing vinyl polymers. To produce the granules, molten binder is again added to the other components.
DESCRIPTION OF THE INVENTION
[0020] The problem addressed by the present invention was to provide a stabilizer composition for plastics, more particularly PVC, which would be dust-free during transportation and on delivery, would be as readily dispersible in the plastic as powder-form compositions and would allow high inorganic lead salt contents without the addition of fatty alcohols. The composition would readily disintegrate into powder in the mixer so that it could be incorporated in the plastic without any dispersion problems.
[0021] This problem has been solved by the stabilizer composition mentioned at the beginning which is characterized in that each agglomerate grain consists of several particles of the stabilizer composition and is completely surrounded by a layer of a binder which contains the lowest-melting component of the stabilizer composition, the interior of the agglomerate grain being poor in this binder and containing the above-mentioned particles of the stabilizer composition in a flowable state. In the context of the invention, the term “agglomerate” is used synonymously with the term “granules”. Accordingly, the terms “agglomeration” and “granulation” are synonyms, as are the terms “agglomerator” and “granulator”.
[0022] Accordingly, the present invention relates to dust-free stabilizer compositions for plastics in agglomerate form, the composition being substantially free from the plastics for which it is intended, each agglomerate grain consisting of several particles of the stabilizer composition and being completely surrounded by a layer of a binder which contains the lowest-melting component of the stabilizer composition, the interior of the agglomerate grain being poor in this binder and containing the above-mentioned particles of the stabilizer composition in a flowable state.
[0023] In a preferred embodiment, polyvinyl chloride is used as the plastic.
[0024] The granules (agglomerates) according to the invention are substantially spherical in shape with a compact outer solid layer consisting of the binder mentioned. FIG. 1 is a schematic section through one such agglomerate grain. The powder-form stabilizer composition is located within the outer layer 1 in a non-caked, i.e. loose and flowable, form. Accordingly, the outer shell corresponds to a pack for the powder-form product. Each agglomerate grain contains virtually the entire formulation of the stabilizer composition so that troublesome separation cannot occur. In the prior art, such separation occurs relatively quickly in powder-form stabilizer compositions, for example simply through the transportation of the compositions, because the densities of the individual powder particles are very different. It should be remembered that both lead compounds and purely organic compounds, such as waxes and fatty acid derivatives, are or may be present in compositions of the type in question.
[0025] When the agglomerate grains according to the invention are incorporated by mixing in the plastic powder at normal temperatures, i.e. not at elevated temperature, the outer layer 1 breaks apart and the powder particles 2 flow out of the outer layer 1 and are dispersed in the plastic powder (FIG. 2). Accordingly, despite the total absence of dust, the dispersion behavior of the powder particles in the plastic is equivalent to that of known powder-form stabilizer compositions. The agglomerate grains according to the invention have the further advantage that no heating is required for incorporation. It is sufficient to incorporate the agglomerate grains in the plastic powder by mixing at low temperature in a cold mixer. The outer solid layer of binder breaks apart solely under the effect of mechanical stress and releases the powder-form mixture. Basically, there is no need here for incorporation with a high-speed mixer at elevated temperatures, for example about 140° C., as is the case in the prior art. This high temperature required in the prior art is necessary for completely melting the binder so that the individual solid particles of the stabilizer composition can be dispersed. However, since—according to the invention—the particles are present in flowable form inside each agglomerate grain, the binder does not have to melt, and certainly not completely, during incorporation of the agglomerate grains according to the invention. It is sufficient for the outer layer to break up so that the powder flows out.
[0026] In addition, there is no need in accordance with the invention for the starting materials for the stabilizer composition to be size-reduced to primary particles in a first step. The particle size in which the components of the stabilizer compositions are normally supplied guarantees good dispersibility in the plastic. Since there is no need to melt the stabilizer compositions, as there is in the known process for producing pellets, high lead salt contents can also be accommodated in the composition. The absence of dust is achieved by the coating of the agglomerates with the lowest-melting component of the stabilizer composition.
[0027] Another advantage of the stabilizer composition according to the invention is that no additional binder is used for agglomeration because the percentages by weight of the components in the stabilizer composition are not altered by the agglomeration process.
[0028] In a preferred embodiment, the lowest-melting component makes up from 1 to 20% by weight and more particularly from 5 to 10% by weight of the stabilizer composition. The optimal value in each individual case depends upon the percentages of the other constituents of the stabilizer composition. In another embodiment, the lowest-melting component has a melting point below 100° C. Accordingly, low temperatures are sufficient for the agglomeration process.
[0029] In another embodiment of the invention, the binder contains a lubricant for the processing of plastics. However, other low-melting components of the stabilizer composition may also be used as binder for the agglomerate according to the invention.
[0030] Another embodiment of the invention is characterized in that the binder contains a lubricant from the group consisting of C 8-24 fatty acids, C 12-24 fatty alcohols, esters of C 8-24 fatty acids and C 6-24 fatty alcohols, esters of C 8-24 fatty acids and polyhydric alcohols containing 4 to 6 hydroxyl groups and hydroxystearic acid esters. The compounds mentioned may be used both individually and in the form of mixtures with one another.
[0031] Suitable C 8-24 fatty acids are both native and synthetic, linear saturated compounds of this class. If fatty acid mixtures are used, they may contain small quantities of unsaturated fatty acids, with the proviso that the melting point of such mixtures is always above 25° C. Examples of fatty acids which may be used as a solid fusible component are caprylic, capric, lauric, tridecanoic, myristic, pentadecanoic, palmitic, margaric, stearic, behenic and lignoceric acid. Fatty acids containing hydroxyl groups, such as 12-hydroxystearic acid, are also suitable. Fatty acids such as these can be obtained from naturally occurring fats and oils, for example through lipolysis at elevated temperature and pressure and subsequent separation of the fatty acid mixtures obtained, optionally followed by hydrogenation of the double bonds present. Technical fatty acids are preferably used here. They are generally mixtures of different fatty acids of a certain chain length range with one fatty acid as the main constituent. C 12-18 fatty acids are preferably used.
[0032] The C 12-24 fatty alcohols suitable as the fusible component are linear saturated representatives of this class of substances which all have a melting point above 25° C. Corresponding fatty alcohols may be obtained inter alia from naturally occurring fats and oils by transesterification with methanol, subsequent catalytic hydrogenation of the methyl esters obtained and fractional distillation. Synthetic fatty alcohols obtained, for example, by oxo and Ziegler synthesis may also be used. Examples of such fatty alcohols are lauryl, myristyl, cetyl, stearyl and behenyl alcohol. These compounds may be used individually and in admixture with one another. Technical fatty alcohols are preferably used. They are normally mixtures of different fatty alcohols of a limited chain length range in which one particular fatty alcohol is present as the main constituent.
[0033] The above-mentioned esters of C 8-24 fatty acids and C 6-24 fatty alcohols should meet the requirement that their melting point is above 25° C. Suitable starting materials for the production of these fatty alcohol/fatty acid esters are the fatty acids and fatty alcohols already described in detail in the foregoing. The esters may additionally contain C 6-11 fatty alcohols, i.e. for example n-hexanol, n-octanol and n-decanol, as alcohol component. The esters mentioned may be obtained by known methods of organic synthesis, for example by heating stoichiometric quantities of fatty acid and fatty alcohol to 180-250° C., optionally in the presence of a suitable esterification catalyst, such as tin grindings, and in an inert gas atmosphere, and distilling off the water of reaction. Examples of esters suitable for use in accordance with the invention are stearyl caprylate, stearyl caprate, cetyl laurate, cetyl myristate, cetyl palmitate, n-hexanol stearate, n-octyl stearate, lauryl stearate, stearyl stearate, stearyl behenate, behenyl laurate and behenyl behenate. It is important in this connection to bear in mind that these esters are normally produced from technical starting materials which, in turn, are mixtures so that the corresponding esters are also mixtures.
[0034] Suitable starting materials for the production of the above-mentioned esters of C 8-24 fatty acids and alcohols containing 4 to 6 hydroxyl groups are, again, the fatty acids already described in the foregoing. The alcohol component may be selected, above all, from aliphatic polyols containing 4 to 12 carbon atoms, for example erythritol, pentaerythritol, dipentaerythritol, ditrimethylol propane, diglycerol, triglycerol, tetraglycerol, mannitol and sorbitol. These polyesters may be full esters in which all the hydroxyl groups of the polyol are esterified with fatty acid. However, polyol partial esters containing one or more free hydroxyl groups in the molecule are also suitable. These fatty acid polyol esters may also be obtained by known methods of organic synthesis by esterification of the polyols with stoichiometric or sub-stoichiometric quantities of free fatty acids. Examples of such polyol fatty acid esters are the stearic acid and stearic acid/palmitic acid full esters of erythritol, pentaerythritol and diglycerol, the dilaurates of dipentaerythritol, ditrimethylolpropane, triglycerol, mannitol and sorbitol, the distearates of erythritol, pentaerythritol, dipentaerythritol and tetraglycerol and the so-called sesquiesters of pentaerythritol, dipentaerythritol, mannitol and sorbitol in whose production 1.5 mol fatty acid, more particularly palmitic and/or stearic acid, is used to 1 mol polyol. The polyol fatty acid esters mentioned are generally mixtures simply because of the particular starting materials used. In this case, too, only products with a melting point above 25° C. may of course be considered.
[0035] One particular group of possible low-melting components in the context of the present invention are the esters of hydroxystearic acid. This is because both compounds in which the hydroxystearic acids are esterified through their carboxyl group with a mono- or polyhydric alcohol and compounds in which they are esterified with fatty acids through their hydroxyl group are suitable for use. Derivatives of 12-hydroxystearic acid which may be obtained, for example, from the fatty acid component of hydrogenated castor oil are preferred. Derivatives of the first-mentioned type include 12-hydroxysteric acid esters of the fatty alcohols described in detail in the foregoing and 12-hydroxystearic acid full and partial esters with polyols containing 2 to 6 hydroxyl groups and 2 to 12 carbon atoms, more particularly those derived from ethylene glycol, 1,2- and 1,3-propylene glycol, the isomeric butylene glycols, 1,12-dodecanediol, glycerol, trimethylolpropane, erythritol, pentaerythritol, ditrimethylolpropane, dipentaerythritol, diglycerol, triglycerol, tetraglycerol, mannitol and sorbitol. Examples of such esters are the 12-hydroxystearic acid full esters of ethylene glycol, 1,3-propylene glycol, erythritol and pentaerythritol, the di-12-hydroxystearates of pentaerythritol, dipentaerythritol, diglycerol, tetraglycerol and sorbitol and the 12-hydroxystearic acid sesquiesters of pentaerythritol, dipentaerythritol and mannitol. Another member of this group is hydrogenated castor oil which is known to be a triglyceride mixture with a fatty acid component mainly consisting of 12-hydroxystearic acid. 12-Hydroxystearic acids of the second type are esterification products of 12-hydroxystearic acid and the C 8-24 fatty acids already described in detail in the foregoing. Within this group of 12-hydroxystearic acid derivatives, particular significance attaches to the esterification product of 12-hydroxystearic acid and behenic acid because it has the characteristic property of dispersing the stabilizer composition so thoroughly in plastic melts that its use enables the quantities in which the other components of the stabilizer composition are normally used to be considerably reduced. In addition, this esterification product has such a favorable melting point of 60° C. that the agglomerates according to the invention can be produced at correspondingly low temperatures. On the other hand, the melting point is high enough to allow the agglomerates to be stored without caking together or showing signs of exudation, even at summer temperatures.
[0036] In another embodiment of the present invention, the binder contains glycerol monostearate. A stabilizer composition of this type enables the other components to be coated with the inexpensive glycerol monostearate at relatively low temperatures. In addition, glycerol monostearate is a very good lubricant in polyvinyl chloride. Finally, glycerol monostearate is highly compatible with other additives incorporated in polyvinyl chloride.
[0037] It is pointed out that the term “glycerol monostearate” encompasses both pure glycerol monostearate and mixtures containing various quantities of glycerol di- and tristearate, depending on the purity of the glycerol monostearate. Typical values are 40-50% monostearate, 30-43% distearate and 8-10% tristearate.
[0038] For the purposes of the disclosure, reference is expressly made to the “stabilizers”, “stabilizing aids”, “lubricating stabilizers”, “lubricants” and “resin modifiers” mentioned in DE-A-34 29 766 which may be present in the agglomerate according to the invention. The lowest-melting component forms the binder for coating the other components of the stabilizer composition.
[0039] In a preferred embodiment, 95% of the particle size of the agglomerates according to the invention is at most 4 mm and more particularly from 0.5 to 2 mm.
[0040] The present invention also relates to a process for the production of a dust-free stabilizer composition for plastics, more particularly for PVC, the composition being substantially free from the plastics for which it is intended and the dust-free stabilizer composition being produced by agglomeration of a mixture of the powder-form composition in an agglomerator/mixer at a temperature substantially equal to the melting point of the lowest-melting component.
[0041] A process such as this is already known from the above-cited DE-A34 29 766.
[0042] Here, the above-stated problem addressed by the invention is solved by agglomeration of a mixture in which each particle consists of only one material and by introduction of all the components of the mixture to be agglomerated into the agglomerator/mixer in solid form.
[0043] In contrast to the prior art where the binder is often added to the other components in molten form for agglomeration, it is important in the process according to the invention that all the components, i.e. the binder included, are introduced into the agglomerator in solid rather than molten form. The agglomerates obtained in this way are not agglomerates in which the solid particles are embedded in a solid matrix consisting of the binder. Instead, the agglomerate grains according to the invention which contain only an outer layer of the binder are obtained, the interior of each agglomerate grain being poor in the binder and containing the solid other components of the stabilizer composition in powder, flowable and uncaked form.
[0044] The agglomeration process itself is accompanied by relatively slow stirring so that no significant increase in temperature is caused by the stirring. The agglomeration process takes place at about the melting point of the binder, i.e. the lowest-melting component. Since the slow stirring precludes any increase in temperature through friction, it is recommended to use a heated mixer which has the advantage that the required temperature can be adjusted relatively exactly. In addition, it is favorable to heat the mixer slowly. This promotes the formation of the agglomerate grains according to the invention. Accordingly, the mixer used is not the dry-blend friction mixer otherwise used in the prior art which rotates relatively quickly and heats the mixture to be agglomerated through friction.
[0045] In one advantageous embodiment, the entire mixture to be agglomerated is introduced into the agglomerator/mixer in only one step in contrast to the prior art.
[0046] For illustration purposes, a typical agglomerate grain according to the prior art is schematized in section in FIG. 3. It can clearly be seen that the individual solid particles 2 of the stabilizer composition are embedded in a solid sphere of the binder 1 as in a matrix. This agglomerate grain cannot be dispersed by mechanical action alone as the agglomerate grains according to the invention can. Instead, the binder 1 has to be fully melted to enable the powder particles to be dispersed in the plastic.
[0047] Accordingly, the process according to the invention corresponds less to granulation by the processes known from the prior art and more to a pill coating process as used in the pharmaceutical industry for completely enveloping solid particles, i.e. for coating. In contrast to the pill coating process, several small powder particles rather than a single large particle are encapsulated in a skin consisting of the binder.
[0048] In addition, in the process according to the invention, in contrast to the process according to DE-A-34 29 766, the stabilizer composition is granulated without any pretreatment with the binder present in the composition.
[0049] At least one of the components of the stabilizer composition preferably has a melting point below 100° C. This component serves as binder for completely enveloping the other components during the agglomeration process.
[0050] In another embodiment of the process according to the invention, the agglomeration process is carried out in a mixer, more particularly a heating/cooling mixer, at temperatures of up to 100° C. and more particularly at temperatures of 60 to 80° C. In addition, in the practical application of the process, it is of advantage to carry out agglomeration for only a short time because otherwise the mixture becomes too viscous so that the necessary motor power increases too greatly. The optimal time—which is also dependent upon the agglomeration temperature adjusted—can easily be determined by practical tests. A “heating/cooling mixer” in the context of the invention is understood to be a mixer or agglomerator in which one section can be heated and the other section cooled. The process is initially carried out in the heated mixer, the product obtained there being cooled down to the required temperature in the cooling section.
[0051] In another advantageous embodiment, the agglomeration process is carried out in a mixer with wall-sweeping strippers. Caking of the agglomerates on the walls is easily avoided in this way. For the same reason, the agglomeration process is carried out in a mixer with bottom scrapers.
[0052] It has also proved to be of advantage to use mixers with a certain height-to-diameter ratio. A height-to-diameter ratio of 0.1 to 0.5 is advantageous.
[0053] The invention is illustrated by the following Examples and Comparison Example.
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A dust-free stabilizer additive for use in plastics, the additive comprising agglomerates containing: (a) a plurality of stabilizer composition particles; and (b) a binder composition encapsulating the stabilizer composition, the binder composition containing at least one binder component having a melting point lower than a melting point of the stabilizer composition particles.
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BACKGROUND OF THE INVENTION
Space debris is growing at a rapid rate and poses a hazard to future space vehicles. Although the probability of collision is low, collision speeds could be hypervelocity with the possibility of destruction of space structure.
Space debris can be conveniently grouped into three categories. The first is mission related debris. Inactive payloads, expended satellites, shrouds, clamps, and separation components are examples of debris within this category. A second category is launch related debris resulting from spent rocket stages, combustion products of the rocket stages (primarily aluminum oxide from solid propellants), and paint flakes. Unlike the first category, most of the debris within the second category is small and has less momentum than debris with greater mass. Nevertheless, the large oxide particles, at velocities of several kilometers per second, have the impact effect of a bullet, and enough force to destroy unprotected payloads. The third category of debris results from fragmentation. Collisions, explosion, breakups, and antisatellite (ASAT) testing contribute to this group. Sizes of debris in this group range from the very small untrackable objects to large, locatable objects.
Debris build-up patterns follow exploration of space and debris belts are forming along space trails. As documented in the literature, there is more debris in low earth orbit (LEO) as this was the first region explored and later used operationally. Additionally, all subsequent exploratory and operational missions go through this region, regardless of their final destination, leaving additional debris deposits. This, combined with the natural slow gravitational decay process which brings all the near-earth debris "home," makes the LEO the most debris littered region.
A second region of high interest is at geosynchronous altitude. A strategically placed payload at this altitude remains relatively fixed over a given position on earth. With minimal station keeping efforts and the need for only a single ground control station, a single satellite can provide constant coverage for almost half of the globe. This makes the geosynchronous altitude a prime parking site for communication and surveillance systems.
Many solutions for the elimination and/or control of space debris within the critical regions discussed are being proposed and have been developed. These solutions relate generally to structural hardening, avoidance, debris retrieval, earth reentry, transfer to dump regions, treaty/agreement, and collectors. Structural hardening has been a traditional solution to prevent penetration damage. This solution, however, has two shortcomings. First, space debris travels at hypervelocities (as high as 15 km/sec), well outside traditional hardening regimes. Technology for developing hardened structure does not exist at these velocities. Secondly, any hardening approach will most likely increase the system's total weight thereby increasingly launch cost and straining the capacity of current launch systems.
Avoidance schemes are being proposed in which orbital payloads would use thrusters to dodge debris on impact trajectories. These schemes, however, project tremendous fuel consumption, which for current satellites in unacceptable. Dodging debris would also require the development of sensor systems to detect and trace debris.
The debris retrieval concept has already been shown to be successful, at least in limited applications. U.S. Pat. No. 4,775,120 to Marwick describes an extraterrestrial transportation apparatus and method in which items could be crash transported to a low earth orbit crash-load capturing satellite for subsequent relocation. U.S. Pat. No. 4,750,692 to Howard relates to a satellite retrieval apparatus comprising a tethered grappling unit having deployable arms with catching ropes and Velcro hook strips on the ends thereof. On impacting the target, the catching ropes envelop the target and each other. The grappling unit is then retrieved along with the target satellite. In addition, a recent Shuttle mission retrieved an inactive satellite which was then repaired and returned to service. The drawback with this concept is the expense of retrieval and difficulty of the operation. Only high valued space debris would qualify for such a debris clearing solution.
Earth reentry involves using the last remaining onboard fuel to project the satellite into a decay orbit. One drawback with this concept is that energy needed to put a satellite into a decay orbit is significant, in many cases more than current satellites have onboard. The prior art provides several alternatives to the use of on-board fuel to project a satellite into a decay orbit. For example, U.S. Pat. No. 4,707,979 to Gutsche describes a method to produce and utilize propulsion forces on objects or devices by the controlled release of energy derived from absorbed radiation. U.S. Pat. No. 4,408,563 to Swales et al relates to a method of separating and ejecting a reentry body from a booster rocket. A pair of diametrically opposed rockets attached to the base of the re-entry body are ignited and provide thrust at an angle resulting in separation velocity and spin to the re-entry body. And, U.S. Pat. No. 3,427,808 to Butcher describes a method and apparatus to generate pressurized gas for satellite propulsion. A quantity of solid or liquid material which is decomposible into the gas state is provided, and either thermal decomposition, photolysis, or radiolysis are employed for the decomposition process. Even if future satellites were somehow required to carry a decay orbit propulsion reserve, this solution again is limited only to the payload category of debris and does little to mitigate the other two categories. Another drawback to this concept is the reentering payload impact location, which can have undesired political and safety implications.
Akin to the reentry concept is the concept of transfer of space debris to a dump orbit or region. Recognizing the burden placed on the propulsion system to cause reentry, especially for satellites in orbits other than the LEO, the concept is to move geosynchronous satellites from their strategic position when they become of little use. This concept also solves the impacting debris problem of the reentry solution, yet does little for the other categories of debris and raises the question of determining suitable junkyard regions.
Efforts to legislate away the space debris problem have had little success. Currently, some LEO regions have been set aside for space developing nations to use. Requirements of restricting solid rocket propulsion systems, eliminating blow away clamps, and similar requirements are being considered.
Overall, the existing and proposed solutions to eliminate or control space debris appear inadequate. None appear able to ensure safe, debris-free missions.
It is therefore the object of the present invention to provide a method to clear space debris to allow for safe orbits for spacecraft flight.
It is another object of the present invention to clear the space debris without resorting to expensive spacecraft to track, collect, and transport the debris.
It is another object of the present invention to clear space debris without creating additional debris in the form of solid by-products of detonation.
SUMMARY OF THE INVENTION
The object of the present invention are accomplished by the following methods, steps, and embodiments. A space debris clearing device would be launched aboard the Shuttle or an expendable launch vehicle. It would be placed in or near an orbit which is considered to be highly populated with debris. The device would be made of a castable energetic material this not requiring a casing which would create more debris. The shape of the device would meet specific clearing requirements. The device would be remotely detonated using a laser or other means. Upon detonation, an impulse, cased by the expanding detonation products, would be imparted to the debris, thereby, pushing the debris into a reentry or an earth escape trajectory. The device is not intended to blow up debris, (which would cause more debris), or to collect any debris.
BRIEF DESCRIPTION OF THE DRAWINGS
FIGS. 1 and 2 are a conceptual view of the present invention showing detonation and clearance of space debris.
FIG. 3 is a graph showing realistic altitudes for debris clearing devices to impart escape or reentry velocities.
DESCRIPTION OF PREFERRED EMBODIMENTS
Referring in more detail to the drawings, as shown in FIG. 1, space vehicle 14 is launched from the Earth 10 toward the orbiting ring of space debris 12 and detonates a blast 16 therethrough as shown in FIG. 1.
Such blast 16 creates an opening 18 in the orbiting ring of space debris 12 for the payload of space vehicle 14 (FIG. 1) i.e., satellite 20 as shown in FIG. 2.
This satellite 20 as well as the larger orbiting space debris objects are tracked by tracking station 22, as shown in FIG. 2.
The invention relates to the placement, deployment, and detonation of energetic materials in space to provide clear paths through a region for spacecraft travel, or to clear operating regions within a given orbit. The invention accomplishes these goals without an increase in space debris associated with an explosive destruction of the debris.
The energetic materials comprised of oxygen balanced, non-metallic, crystalline high explosives and polymer binders may take two preferred forms. First, the energetic materials may be in the form of specifically tailored charges of material. Second, the energetic materials may be dispersed in a cloud to increase the area affected, as the specific application may direct. Because the charges are either castable (requiring no container) or dispersed, and tailored to achieve complete combustion to gaseous products, no debris creating solid by-products of detonation would occur. Reference to "castable" means the charges could be specifically shaped and initiated to produce a directed impulse to improve effectiveness. Specific application is a criterion to determine shape.
The clearing of space debris could be accomplished prior to launch of a new satellite, or as the debris problems become more pronounced. It is envisioned that future satellites could have a charge on-board so that as the satellite approaches a region of high debris concentration, a charge could be launched to clear a path for the satellite through the debris. FIGS. 1 and 2 illustrate the concept.
Neglecting atmospheric effects, the impulse needed to cause a 1 gram debris particle in a circular orbit to hit the ground is 0.1094 N-sec from 370 km altitude and 0.2357 N-sec from 850 km. From geosynchronous altitude, about 35,863 km, the impulse needed to cause a 1 gram object to reach escape velocity is 1.2771 N-sec.
The equation defining impulse derivable from energetic material in space is: ##EQU1## Where: I=impulse per square meter of target projected area
w=charge mass
Q 0 =charge energy (assumed to be 4000 KJ/kg)
R=range between charge and debris particle
This equation shows that the impulse is inversely proportional to the square of the range. The term "I" in the equation is in impulse per unit projected area of debris. At a given range, the change in velocity imparted to a debris particle is inversely proportional to the radius of the particle, assuming spherical particles of identical density but different sizes. The reason for this is that larger particles have a greater mass to projected area ratio than smaller particles. These factors greatly limit the practical range over which energetic materials can be used to clear debris from orbit, since both range and particle size affect the change in velocity of a given debris particle. Different changes in velocity result in different orbit changes. Therefore, a single charge of energetic material might cause some debris particles to reenter, others to achieve escape velocity, and still others to have their orbits changed without either escape or reentry. The problem is further complicated by non-circular initial debris particle orbits and the fact that debris particles might be located in all directions around a single energetic material charge.
FIG. 3 presents a qualitative picture of the possible effective limits of the energetic material debris clearing concept. Debris at LEOs would require small velocity changes and therefore a small charge mass to cause reentry. As the altitude increases, the charge mass needed to force a given debris particle to reenter would increase. On the other hand, debris at very high altitudes would only require small velocity increases to achieve escape velocities. At lower debris particle altitudes more energy would be needed to escape earth's gravity, requiring increased charge mass. The two curves in FIG. 2 provide a breakeven intersection. Selection of reentry or escape options is based on payload limitations of the launch vehicle delivering the energetic material.
There are two basic classes of targets. The first is a specific region of space with unknown debris particles. In this application, a given region of space would require clearing to allow either a clear path or a safe operating region. This region is to be cleared regardless of debris. The second class of target is a specific debris object. This target would be trackable and could be targeted by a specifically designed device to provide sufficient impulse to move the object from its current orbit.
Based on the target type, its location, and device limitations, one of three basic debris delta velocity strategies would be attempted. The first strategy is to slow the debris and cause it to reenter the earth's atmosphere. The second strategy is to increase velocity to escape velocity causing the debris to escape earth's orbit, and the third is to simply change its velocity and cause the debris to enter a new orbit.
As mentioned above, the energetic materials would be specifically tailored charges. Table 1 provides representative ingredients. Table 2 provides a representative formulation.
TABLE 1______________________________________OxidizersAmmonium perchlorate (AP)Cyclotetramethylene tetranitramine (HMX)Cyclotrimethylene trinitramine (RDX)Ammonium nitrate (AN)BindersNitrocellulose (PNC)Polypropylene glycol(PPG)Hydroxy-terminated polybutadiene (HTBP)PlasticizersNitroglycerin (NG)Trimethylolethane trinitrate (TMETN)Curing Agents______________________________________
TABLE 2______________________________________INGREDIENT WT %______________________________________Nitrocellulose 51Nitroglycerin 43Curing Agents 6______________________________________
Deployment options include any current or future lift systems (shuttle, expendable launch systems), as well as potentially specifically designed spacecraft which would incorporate such a device.
Various initiation options are available. Initiation options, however, would be required to uniformly initiate the device without increasing debris. Because the device is composed of material which will combust with the application of a threshold energy, a gallium arsenide laser could provide such an initiation energy source.
For regional cleaning, a spherical charge would be deployed to clear a specific region. The charge mass required would be dependent on the volume of the region and the mass and amount of debris. For example, to clear a 1000 cubic meter region containing 500 objects with an average debris particle mass of 0.001 kg at a circular orbital altitude of 2100 kilometers, a charge mass of 377 kilograms would be required if the charge energy was 4000 kilojoules per kilogram.
For specific debris object removal, Table 3 relates to orbital altitudes and approximate charge masses required to cause a 20 kilogram, 0.5 meter square aluminum plate, (0.025 meters thick), debris object to either reenter or escape earth's orbit given that the device is within 2 meters at detonation.
TABLE 3______________________________________Orbital Altitude (km) vs. Charge Mass (kg) Reentry Escape______________________________________ 500 130 3890 1500 (LEO) 460 3640 2100 600 3540 6500 1240 284021000 1770 195029000 1780 171035740 (GEO) 1800 1570______________________________________
Table 3 also provides specific applications of the space debris clearing device. For example, to cause the 20 kilogram debris object at a low earth orbit (LEO) of 1500 kilometers to escape would require a charge mass of 3640 kilograms, but only 460 kilograms to reenter. The same debris object orbiting at a geosynchronous orbit (GEO) of 35740 kilometers would require 1570 kilograms of charge of cause escape, but 1800 kilograms to force reentry. These cases assume a circular orbit. Elliptical orbits where the orbiting body's velocity is continuously changing would vary the above. Therefore, debris orbital characteristics are an important parameter in selecting the most advantageous (based on charge mass) delta velocity strategy.
A shaped charge of energetic material could be used against specific debris objects, increasing the effectiveness. It would allow directed detonation products and thereby reduce the overall charge mass needed to achieve a specific objective. For example, using a semi-spherical shape charge located 2 meters from a 20 kilogram aluminum debris object orbiting at 1500 kilometers would require only 230 kilograms of energetic material to force reentry. The same object orbiting at 3570 kilometers would require a mass of 785 kilograms to force escape from orbit. This halves the charge mass required.
Another alternative is to disperse the energetic material prior to detonation. This would provide an increased volume detonation source and reduce the distance from detonation to debris object, thereby increasing the velocity change to a given debris particle.
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The space debris clearing device of the invention, following launch and placement in or near an orbit considered to be highly populated with debris, is intended to clear the debris allowing safe paths and orbits for space assets. The device is made of a castable, energetic material, and shaped to meet specific clearing requirements. Once in position the device is remotely detonated, and an impulse, caused by the expanding detonation products, is imparted to the debris, pushing the debris into a reentry or earth escape trajectory.
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CROSS REFERENCE TO RELATED APPLICATION
[0001] This application claims priority to U.S. Provisional Application Serial No. 61/775,425 filed Mar. 8, 2013; the contents of all of which are hereby incorporated by reference herein in their entirety into this disclosure.
TECHNICAL FIELD
[0002] The subject disclosure relates to a bib, and in particular a combined bib and storage device.
BACKGROUND
[0003] Conventionally, an infant bib is worn hanging from the neck and extends over the chest to protect clothing from the spilling of food or drink. Traditionally, a caregiver has various items to transport when taking an infant away from the home. A few examples carried for a feeding time may include a bib, formula and snacks, etc. Because of the special needs of a young infant, a caregiver oftentimes has to carry a bag or the like to transport the various items around during the day.
[0004] Thus, there is a long-standing need to have a bib configured to address these needs.
BRIEF DESCRIPTION OF THE DRAWINGS
[0005] Various exemplary embodiments of this disclosure will be described in detail, wherein like reference numerals refer to identical or similar components or steps, with reference to the following figures, wherein:
[0006] FIG. 1 shows a front view of an exemplary convertible bib according to the subject disclosure.
[0007] FIG. 2 shows a rear view of an exemplary convertible bib according to the subject disclosure.
[0008] FIG. 3 shows an adjustable fastener attached to the bib.
[0009] FIG. 4 depicts a full side cross section view of the bib.
[0010] FIG. 5 illustrates the bib position in use during meal time.
[0011] FIGS. 6-11 show the folding down and storage of the first panel of the bib.
[0012] FIG. 12 illustrates a partial cross section view of the storage container of the bib.
[0013] FIGS. 13-14 depict the storage container including another item for storage in addition to the first panel
DETAILED DESCRIPTION
[0014] Particular embodiments of the present invention will now be described in greater detail with reference to the figures.
[0015] FIG. 1 illustrates an exemplary convertible bib 10 having a combined bib and storage container 20 with an adjustable fastener 40 attached thereto. As described in more detail later, the convertible bib 10 is foldable and can be collapsed down and stored in the storage container 20 .
[0016] Various items can also be conveniently stored in the storage container 20 according to this subject disclosure. The convertible bib 10 can be portably stored in a small bag and conveniently carried by a caregiver. Various items can be secured in the storage container 20 , such as, but not limited to, a spoon, travel size wet wipes, squeezable baby food containers, hand sanitizer, etc., for use while dining away from home.
[0017] The convertible bib 10 includes a first panel 12 having a collar 13 disposed at a first end adapted to extend around the neck of a user. The collar 13 may include two sub-collar portions 13 a, 13 b that extend around the neck of the infant and are adapted to secure the convertible bib 10 to the infant.
[0018] A first closure device 14 including at least two mating fastening portions 14 a, 14 b may be disposed at the top end of the collar portions 13 a, 13 b to connect the collar 13 around the neck of the user. The closure device 14 provides an adjustable means by which the collar portions 13 a, 13 b can be incrementally adjusted and secured to the first collar portion 13 a to the second collar portion 13 b around the neck of the wearer and to remain securely on the neck. The closure device 14 can be one or more metal snaps, plastic snaps, buttons and button holes, hook-and-loop fasteners (e.g. VELCRO®), zippers, magnets sewn into the collar with polarities arranged for magnetic attraction and closure, and/or any other suitable closure mechanism in accordance with this subject disclosure.
[0019] As shown in FIG. 2 , the first panel 12 extends from the collar 13 portion downward and attaches to a top edge 24 a of a rear panel 24 in the storage container 20 . The storage container 20 includes a front panel 22 and a rear panel 24 .
[0020] Referring to FIGS. 1-2 and 4 , the front panel 22 and the rear panel 24 of the storage container 20 include an unattached open mouth 26 portion. The remainder of the sides 22 b of the front panel 22 , and the remainder of the sides 24 b of the rear panel 24 are attached to each other along their respective sides 22 b, 24 b and define an open pocket 21 into which various items may be stored. The pocket 21 is designed to catch various items during feeding, such as capturing food particles, liquids, and/or other items during the feeding process.
[0021] The various panels of the convertible bib 10 are comprised of a material that can be easily cleaned and washed after use. That is, the convertible bib 10 can be comprised of a polymer, fabric and/or any other suitable material according to this subject disclosure. The material of the convertible bib 10 can be protective water-repellant and stain-resistant layer. The protective water-repellant and stain-resistant layer can cover, or make up, each surface of the convertible bib 10 and/or selected surfaces of the convertible bib 10 .
[0022] As shown in FIG. 4 , the top edge 22 a of the front panel of the storage container 20 , and the top edge 24 a of the rear panel 24 of the storage container 20 can include mating closure elements of a second closure device 30 . A first closure element 30 a of the second closure device 30 may be disposed on the inside of the seam disposed at the top of the front panel 22 . A second closure element 30 b of the second closure device 30 may be disposed on the inside of the seam disposed at the top of the rear panel 24 . The first closure element 30 a faces the second closure element 30 b. When the storage container 20 is to be secured closed, the first closure element 30 a is matingly secured to the second closure element 30 b.
[0023] As before, the second closure device 30 can be one or more metal snaps, plastic snaps, buttons and button holes, hook-and-loop fasteners (e.g. VELCRO®), zippers, magnets sewn into the collar with polarities arranged for magnetic attraction and closure, and/or any other suitable closure mechanism in accordance with this subject disclosure.
[0024] Various seams 50 can be sewn by various stitches 60 into the edges of the bib to reinforce the edges from tear. Likewise, the edges of the bib can be folded over or built up to provide added rigidity to the edges of the bib 10 .
[0025] FIG. 5 shows an adjustable fastener 40 . The adjustable fastener 40 can be attached to the convertible bib 10 at any suitable location. The adjustable fastener 40 can be composed of a first closure element 40 a and a second closure element 40 b. In use, the first closure element 40 a faces the second closure element 40 b for adjustable attachment purposes. The adjustable fastener 40 can securely attach the convertible bib 10 to another object, such as an infant carrier, a stroller, a belt loop and/or any other object intended to carry the convertible bib 10 .
[0026] FIG. 5 shows an exemplary configuration of use for the convertible bib 10 . That is, the convertible bib 10 is secured around the infant's neck such that the pocket 21 opens outwardly from the front of the convertible bib 10 and acts as a tap to catch any spillage of food or liquid or during mealtime that would otherwise fall into the infants lap during meal time. As shown, the front panel 22 is slightly opened forward.
[0027] After mealtime has been completed, the convertible bib 10 can be folded downward and placed into the storage container 20 . Although not shown, it is contemplated that the storage container 20 can include one or more dividers.
[0028] FIGS. 6-12 depict the folding and storage of the first panel 12 of the convertible bib 10 into the storage container 20 . In more detail, in FIGS. 6-9 , the first panel 12 of the convertible bib 10 is shown incrementally folded over and placed into the storage container 20 of the convertible bib 10 .
[0029] In FIGS. 10-12 , the storage container 20 is shown secured closed. That is, the first and second closure elements 30 a and 30 b of the second closure device 30 are shown secured closed thereby preventing the contents within the pocket 21 from falling out of the storage container 20 . FIG. 12 shows a partial cross section of the first panel 12 folded and stored within the storage container 20 .
[0030] FIGS. 13-14 further demonstrate that various other items 70 may be conveniently stored and secured within the pocket 21 in addition to the first panel 12 , such as spoons, snacks, toys, juices or the like.
[0031] The bib is constructed to be easily cleaned. At a suitable location, such as a wash basin, the convertible bib 10 can be opened and conveniently washed and made ready for its next use. The advantage of the convertible bib 10 is in its ability to catch spillage and to keep the infant's clothing clean and protected. The convertible bib 10 may designed aesthetically pleasing and fashionable.
[0032] The illustrations and examples provided herein are for explanatory purposes and are not intended to limit the scope of the appended claims. It will be recognized by those skilled in the art that changes or modifications may be made to the above described embodiment without departing from the broad inventive concepts of the invention. It is understood therefore that the invention is not limited to the particular embodiment which is described, but is intended to cover all modifications and changes within the scope and spirit of the invention.
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A bib having a first panel and a storage container. The first panel has a collar constructed in a first end. The storage container has a first and a second side, an upper opening and a lower closed end. The first panel also has a second end which is attached to an upper end of the second side of the storage container in order to capture spillage while the bib is in use. The first panel can also be folded down into the storage container and secured by a fastener about the upper opening of the storage container.
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CROSS-REFERENCE TO RELATED APPLICATION
[0001] This application claims the benefit under 35 U.S.C. § 119(e) of copending provisional application Nos. 60/377,286, filed May 2, 2002, and 60/377,285, filed May 2, 2002.
BACKGROUND OF THE INVENTION
FIELD OF THE INVENTION
[0002] The invention relates to an apparatus for producing a printing form, such as a printing plate, which has a device for feeding a printing-form blank to a circumferential surface of a rotatable cylinder, a device for releasably fixing the printing-form blank to the circumferential surface, and a device for producing ink-accepting image points or pixels on the surface of the printing-form blank in accordance with a printing image. The pixel-producing device has a device for treating the printing-form blank with a medium stored in a container.
[0003] German Published, Non-Prosecuted Patent Application DE 32 39 580 A1, corresponding to U.S. Pat. No. 4,507,167, describes a device for changing printing film for a printing press, wherein previously imaged films are singly separated from a stacking or pile table by a suction roller and, with a transport device, are conducted through a stationary fixing container to a form cylinder. Following a printing operation, the film is guided into a storage device. A fixing liquid is received in the stationary fixing container. The fixing liquid or bath serves for making the previously imaged film ready for printing.
[0004] German Published, Non-Prosecuted Patent Application DE 29 42 772 A1, corresponding to U.S. Pat. No. 4,270,485, shows a liquid developer device wherein a medium conveyed on an endless belt is provided with a charge image and is subsequently moved over a developing bath. In this regard, liquid developer is conveyed to the developing bath by a pump. The liquid developer emerges with a gentle flow from interspaces between developing electrodes. The spent developer is guided back to a storage container via an outlet. The distance between the developing electrodes and the medium is set at a fixed value.
[0005] In a method for removing non-image areas from electro-photographic planographic printing plates disclosed in German Published, Non-Prosecuted Patent Application DE 39 33 156 A1, a processing fluid is provided which is stored in a stationary container. The impedance of the processing fluid is determined or registered by a sensor. Signals issuing from the sensor serve for deriving actuating signals which cause the processing fluid to be refilled by pumps. A planographic printing-plate blank is exposed to the processing fluid by spraying devices or in a dip processing zone.
[0006] In German Published, Non-Prosecuted Patent Application DE 32 44 870 A1, corresponding to U.S. Pat. No. 4,420,363, a single-bath etching device for processing a gravure printing plate is described, wherein an inspection solution is sprayed on a printing-plate blank in a test area. The process parameters for an etching machine are determined based upon measurable effects of the inspection liquid. In that way, it is possible to control the rotational speed of a plate or form cylinder whereon the gravure printing-plate or printing-form blank is accommodated.
[0007] A common factor in the heretofore-known structures of the prior art is that, by providing conveyor devices for the printing forms, and the fixed configuration of the processor baths, the structures become voluminous, expensive in terms of material and costs, and not very flexible. That applies in particular when printing-form blanks of different construction are to be treated with varying processes.
SUMMARY OF THE INVENTION
[0008] It is accordingly an object of the invention to provide an apparatus for producing a printing form or plate, which overcomes the hereinafore-mentioned disadvantages of the heretofore-known devices of this general type and which affords a compact construction with great flexibility.
[0009] With the foregoing and other objects in view, there is provided, in accordance with the invention, an apparatus for producing a printing form, comprising a device for feeding a printing-form blank to a circumferential surface of a rotatable cylinder, a device for releasably fixing the printing-form blank to the circumferential surface, and a device for producing ink-accepting image points or pixels on the surface of the printing-form blank in accordance with a printing image. The pixel-producing device has a device for treating the printing-form blank with a medium stored in a container. The container is movable relative to the cylinder.
[0010] In accordance with another feature of the invention, the container is able to be brought up to the cylinder.
[0011] In accordance with a further feature of the invention, the container is disposed underneath the cylinder.
[0012] In accordance with an added feature of the invention, the medium stored in the container is a liquid.
[0013] In accordance with an additional feature of the invention, the container is positionable in a vertical direction. Thus, in an upper position of the container, the printing-form blank disposed on the cylinder is in contact with the liquid.
[0014] In accordance with yet another feature of the invention, the medium stored in the container is a powdery medium.
[0015] In accordance with yet a further feature of the invention, the apparatus further includes a device for discharging the printing form. The discharging device is disposed in horizontal direction on a side of the cylinder opposite to a side thereof whereon the feeding device is disposed.
[0016] In accordance with yet an added feature of the invention, the discharging device includes a magazine for accommodating at least two printing forms.
[0017] In accordance with yet an additional feature of the invention, the discharging device has a printing-form storage device that is swivellable about an axis extending parallel to the axis of rotation of the rotatable cylinder.
[0018] In accordance with still another feature of the invention, the apparatus further includes an endless belt for conveying the medium from the container to the surface of the printing form blank.
[0019] In accordance with still a further feature of the invention, the endless belt is a textile, absorbent, and driven belt guidable over deflection rollers and, in one sector of the circumferential surface, is looped around the printing form blank for being set on and set off the printing form blank.
[0020] In accordance with still an added feature of the invention, one of the deflection rollers is positionable in a direction tangential to the cylinder.
[0021] In accordance with still an additional feature of the invention, the container is formed with different chambers separated from one another and filled with liquids. The belt dips into the liquid in one of the chambers.
[0022] In accordance with another feature of the invention, at least one of the container and the belt is positionable in horizontal direction and possibly in vertical direction for moving to a predetermined chamber.
[0023] In accordance with a further feature of the invention, the belt is guidable over at least one roller that is rotatably mounted on the container.
[0024] In accordance with a concomitant feature of the invention, the container, the cylinder and the pixel-producing device for accepting printing ink are integrated into a printing press.
[0025] According to the invention, the container is disposed so as to be movable relative to a printing-form cylinder. Imaging technology and equipment for print preparation are thereby present in only one device. The apparatus according to the invention needs only little overall space. With the movable container, all the fluids and media utilized for the print preparation can be provided for application to the printing-form blank. A printing form or plate in a clamping device is therefore made completely ready for use in a printing press.
[0026] A compact construction can be achieved due to the possibility that the container with the medium for treating a printing-form blank can be guided up to the printing-form cylinder. The apparatus can be constructed for treating conventional printing-plate blanks or sleeve-shaped printing form blanks. In this regard, the apparatus may be formed of modules which implement individual process steps. Such process steps are, for example, infeeding the printing-form blank for clamping it onto the cylinder, imaging or forming an image on the printing-form blank, aftertreating the imaged printing-form blank, releasing it from the cylinder, and removing it again. The modules and the functions thereof can be respectively connected up in accordance with the differently performable process steps. Depending upon the requirements of the respective process step, process media and/or cleaning media, such as liquids, pastes or powders, can be brought up in one or more containers to the printing-form blank. The apparatus can serve for treating various types of printing-form blanks for wet and dry offset printing. For example, if required, a silicone-coated printing-form or printing-plate blank for dry offset printing can be imaged, i.e., have an image formed thereon, and then aftertreated by mechanical devices, or a printing plate for wet offset printing can be treated chemically and subsequently washed with water. Such an apparatus can be set up and operated in a printshop or press room. It is possible to integrate the apparatus into a printing press, in particular an offset printing press. The printing-plate blank or printing-form blank can be processed and developed, respectively, on the cylinder, making it possible to process a printing-form blank which has already been edge-bent, in that it is then imaged and made ready for printing in a clamping device. Making ready for printing includes processes such as developing, drying and burning in the image on a printing-form blank. When erasable and rewriteable printing forms are used, the apparatus can additionally include an erasing device for erasing the imaging that had been produced for a previous print job.
[0027] The container with the medium can advantageously be disposed for movement in the vertical direction underneath the printing-form cylinder. A plurality of containers with various media can be provided, or one container with chambers, wherein various media are stored. The level of the medium in the container or in the chambers can be monitored and regulated or controlled. In the construction of a container with chambers, the latter can be positioned in vertical and horizontal direction so that the printing form located on the printing-form cylinder dips partly into the medium. A device for discharging a treated printing-form blank can be disposed on the opposite side of a feeding device. It is advantageous for the discharge device to include a magazine for accommodating at least two printing forms. A printing-form storage that is swivellable about an axis extending parallel to the axis of rotation of the cylinder can be provided in the discharge device.
[0028] By providing an endless belt for conveying a medium from a container to the surface of a printing-form blank, a compact construction can likewise be achieved. The belt can be formed of a textile, absorbent material and can be guided over deflection rollers in a manner that the belt loops or wraps around a sector of the circumferential surface of the Printing-form blank. If one of the deflection rollers is positionable, the belt can be set on and off the circumferential surface. In one embodiment, the container can have chambers which are filled with different liquids. By positioning the container, the belt can selectively dip into the liquid in one of the chambers.
[0029] Other features which are considered as characteristic for the invention are set forth in the appended claims.
[0030] Although the invention is illustrated and described herein as embodied in an apparatus for producing a printing form, it is nevertheless not intended to be limited to the details shown, since various modifications and structural changes may be made therein without departing from the spirit of the invention and within the scope and range of equivalents of the claims.
[0031] The construction and method of operation of the invention, however, together with additional objects and advantages thereof will be best understood from the following description of specific embodiments when read in connection with the accompanying drawings.
BRIEF DESCRIPTION OF THE DRAWINGS
[0032] [0032]FIG. 1 is a diagrammatic, side-elevational view of an embodiment of the apparatus according to the invention for producing a printing form, having a vertically adjustably movable processor bath;
[0033] [0033]FIG. 2 is a view similar to FIG. 1 showing another embodiment of the apparatus according to the invention, having a fully automatic printing-form discharge device;
[0034] [0034]FIG. 3 is a further view similar to FIG. 1 showing a further embodiment of the apparatus according to the invention, having an automatic printing-form depositing device and an integrated plate cleaning device;
[0035] [0035]FIG. 4 is an additional view similar to FIG. 1 showing an additional embodiment of the apparatus according to the invention, having a device for applying and removing material capable of being exposed;
[0036] [0036]FIG. 5 is yet another view similar to FIG. 1 showing yet another embodiment of the apparatus according to the invention, provided with a double-chambered container;
[0037] [0037]FIG. 6 is yet a further view similar to FIG. 1 showing yet a further embodiment of the apparatus according to the invention, having a flexible belt and a horizontally adjustable processor bath; and
[0038] [0038]FIG. 7 is yet an additional view similar to FIG. 1 showing yet an additional embodiment of the apparatus according to the invention, provided with a triple-chambered container.
DESCRIPTION OF THE PREFERRED EMBODIMENTS
[0039] Referring now to the figures of the drawings in detail and first, particularly, to FIG. 1 thereof, there is seen a diagrammatic view of an embodiment of an apparatus for producing a printing form, wherein a printing-form cylinder 1 is rotatably mounted between side walls 2 , only one of which is shown. Non-illustrated conventional devices for holding and clamping a printing-form blank 3 on an outer cylindrical or circumferential surface of the cylinder 1 are provided on the printing-form cylinder 1 . These conventional devices may include mechanical clamping devices, which act upon ends of the printing-form blank 3 , or devices making use of a technology based upon vacuum, which act over the entire area of the printing-form blank 3 . An electric motor may be provided in order to drive the printing-form cylinder 1 . The setting or position of the rotational angle of the printing-form cylinder 1 is registered by a rotary encoder. An inclined or obliquely-set placement and guide table 4 is provided for placement of printing-form blanks manually. The printing-form blanks can be fed by hand in such a manner that they meet the device for holding and clamping at the end of the placement and guide table 4 . Underneath the placement and guide table 4 , there is an imaging unit 5 including an imaging head 6 , an oblique support 7 , a linear guide 8 and a worm or spindle drive 9 . The imaging unit 5 contains an array of individually activatable lasers having beams 10 which are directed towards the surface of the printing-form blank 3 . The imaging unit 5 can be positioned in a direction parallel to the axis of rotation of the printing-form cylinder 1 by the linear guide 8 and the worm drive 9 , so that the beams 10 can reach the entire surface to be imaged on the printing-form blank 3 . A container 11 with a processor bath 12 is disposed underneath the printing-form cylinder 1 .
[0040] The container 11 is positionable in a vertical direction represented by a double-headed arrow 15 , in guides 13 and 14 belonging to the side walls 2 , by a motor 16 and a spindle or screw 17 . Either a gear or chain drive, which is coupled with an electric motor, can be provided for displacing the container 11 vertically. The vertical positioning of the container 11 can be controlled based upon the thickness of the printing-form blank 3 , for which purpose appropriate detectors for the height of the container 11 are provided. Rollers 18 , which are rotatably mounted between the side walls of the container 11 , are provided in an upper region of the container 11 . The rollers 18 are aligned parallel with the axis of rotation of the printing-form cylinder 1 and can be set against the surface of the printing-form blank 3 . For this purpose, the rollers 18 can be spring-mounted on the container 11 . The rollers 18 extend over the entire length of the printing-form cylinder 1 , and dip into the liquid in the processor bath 12 . Depending upon what is required, the liquid of the process bath 12 or the entire container 11 can be provided in such a way as to be replaceable. The level of the liquid in the processor bath 12 can be regulated.
[0041] In order to produce a finished printing form, a printing-form blank 3 with a photosensitive layer can be brought onto the placement and guide table 4 and moved forward in a direction towards the form cylinder 1 to such an extent that the holding device on the printing-form cylinder 1 grips the leading edge of the printing-form blank 3 . During rotation of the printing-form cylinder 1 , the printing-form blank 3 is placed around the circumferential surface of the printing-form cylinder 1 . The rear or trailing end of the printing-form blank is likewise held by a holding device. By applying a tensile stress between the holding devices at the leading and trailing edges of the printing-form blank 3 , the latter is clamped smoothly onto the circumferential surface of the printing-form cylinder 1 . The imaging unit 5 is then started up. While the printing-form cylinder 1 rotates, and the imaging unit 5 is positioned in the axial direction, the lasers are switched on and off in accordance with a printing image. During imaging, the rollers 18 of the container 11 are set off the surface of the printing-form blank 3 . The beams 10 produce printing ink-accepting or dampening solution-accepting points or pixels by removal or changes in the adhesive characteristics of the photosensitive layer. After the imaging operation, the imaging unit 5 is movable into a parked position, and protective devices for optical elements become effective. For this purpose, the imaging unit 5 is movable away from the printing-form cylinder 1 . In a further step, the height of the container 11 is adjusted so that the rollers 18 come to rest on the surface of the printing-form blank 3 . While the printing-form cylinder 1 rotates, the rollers 18 are entrained or carried along by friction. In order to clean the printing-form blank 3 , the rollers 18 serve for scooping liquid 12 out of the container 11 to the surface of the printing-form blank 3 . Due to contact with the liquid 12 , particles which are produced by the removal operation during the imaging are removed from the surface of the printing-form blank 3 . The printing form is therefore produced ready to print and can be removed from the printing-form cylinder 1 . Depending upon the requirements of the process, the liquid 12 in the container 7 is adjusted with respect to the composition and the characteristics thereof. For example, in addition to the cleaning action described hereinabove, the liquid 12 can display a developer action, so that points or pixels exposed by the beams 10 or unexposed points or pixels go into solution. One variant or different embodiment includes a photosensitive layer which is applied to the surface of a printing-form blank 3 before imaging, for which purpose the container 11 filled with photosensitive material and having the rollers 18 is moved against or into contact with the printing-form cylinder 1 .
[0042] In the following description, elements having a function equivalent to that already described in relation to FIG. 1 are identified by the same reference numerals.
[0043] [0043]FIG. 2 illustrates a different embodiment or variant of the device for removing the printing-form blank 3 from the apparatus for producing a printing form. Following the imaging and cleaning of a printing-form blank 3 , the container 11 is moved downwardly, so that there is sufficient clearance for a removal device 19 underneath the printing-form cylinder 1 . The removal device 19 is provided with guide elements 20 for the printing-form blanks 3 , so as to ensure that no damage to the imaging occurs during the conveyance of the finished printing forms. The removal of a finished printing form from the printing-form cylinder 1 can be carried out fully automatically. For this purpose, the holding and clamping devices on the printing-form cylinder 1 are released. By rotating the printing-form cylinder 1 , the completely finished printing form is conveyed outwardly along the guide elements 20 . It is possible to convey the printing form into a magazine which is constructed for accommodating a set of printing forms for one printing image. The delivery of a printing form on the rear side of the apparatus for producing a printing form can be carried out at the same time as a new printing-form blank 3 is supplied on the placement and guide table 4 oppositely disposed on the front side of the apparatus.
[0044] [0044]FIG. 3 illustrates a further different embodiment or variant of the apparatus for producing a printing form. As in FIG. 2, the container 11 is in a lower position, moved away from the printing-form cylinder 1 . In order to deliver completely finished imaged printing forms, a pivotable printing-form storage 21 is provided on the rear side of the apparatus. The pivot axis 22 of the storage 21 extends parallel to the axis of rotation of the printing-form cylinder 1 and is coupled with the side walls 2 . In a pivoted-in state, the printing plate storage 21 is located at least approximately tangentially to the printing-form cylinder 1 . In this position, a completely finished printing form can automatically be conveyed from the surface of the printing-form cylinder 1 onto the printing-form storage 21 . The ability to pivot permits adaptation to different thicknesses of the printing forms, improved removal by hand and accessibility to the interior of the apparatus for servicing when necessary. In this embodiment or variant of the apparatus according to the invention, a replaceable cleaning module 23 with a rotating brush 24 is additionally provided. The brush 24 is disposed on a swivelling lever 25 , which permits the brush 24 to be set on and off the printing-form blank 3 . The particles removed from the surface of the printing-form blank 3 by the brush 24 are sucked away, a guard 26 preventing the particles from contaminating the liquid 12 in the container 7 .
[0045] [0045]FIG. 4 shows an added different embodiment or variant of the apparatus according to the invention, provided with a semiautomatic printing-form feeder 27 . In this different embodiment or variant, a series of printing-form blanks 3 can be made-ready in a magazine. This can be done while a printing-form blank 3 is being treated in the apparatus. The printing-form blanks 3 which are provided are removed automatically from the magazine and fed to the printing-form cylinder 1 . A respective removal slot on the magazine lies at least approximately tangentially to the printing-form cylinder 1 . The magazine is constructed to be pivotable or swivellable, in order to move the respective removal slot into the removal position. In the different embodiment or variant according to FIG. 4, a coating module 28 is also provided. The coating module 28 serves for applying materials capable of being exposed before they are imaged, if the intention is not to use a previously prepared printing-form blank 3 . The container 11 with the rollers 18 acts as a developer and cleaning device here, the container 11 being filled with developer and cleaning liquid. A dryer module 29 serves for curing material capable of being exposed and/or for the thermal aftertreatment of the printing-form blank 3 . For the case wherein sleeve-shaped printing-form blanks 3 are to be used, at least one opening is provided in a side wall in order to feed and remove the sleeve-shaped printing-form blanks 3 . A special feature of the different embodiment or variant of the apparatus according to FIG. 5 is in the provision of the container 11 with two chambers 30 and 31 with different liquids 32 and 33 . The liquids 32 and 33 can be photosensitive materials, developer liquid, fixing liquid or cleaning liquid. According to this variant embodiment, the container 11 can be positioned both in the vertical direction 15 and in the horizontal direction 34 . The container 11 is positioned automatically based upon the type of printing form to be produced, the characteristics of which are entered into the control system of the apparatus beforehand in the form of data or are determined in advance by sensors. Following the selection of the required horizontal position, the container 11 is moved in the vertical direction 15 so that the printing-form blank 3 dips into the chamber 30 or 31 having the correct liquid 32 or 33 therein. As shown, for example, in FIG. 6, the container 11 can be positioned in the horizontal direction 34 , in guides belonging to the side walls 2 , by a motor and a worm or spindle 35 . In an upper region of the container 11 , rollers 36 are provided, which are rotatably mounted between the sidewalls of the container 11 . The rollers 36 extend over the entire length of the printing-form cylinder 1 . The rollers 36 are aligned parallel to the axis of rotation of the printing-form cylinder 1 . The rollers 36 dip into the liquid in the processor bath 12 . Depending upon the requirement, the liquid of the processor bath 12 or the entire container 11 can be provided so as to be replaceable. The level of the liquid in the processor bath 12 can be regulated. The apparatus further has a series of deflection rollers 37 to 40 , which are mounted in the side walls 2 . A textile absorbent belt 41 is placed around the rollers 36 in the container 11 and around the deflection rollers 37 to 40 . The deflection roller 40 is constructed so as to be adjustable in the tangential direction 42 of the printing-form cylinder 1 , in order to be able to set the belt 41 on and off the surface of the printing-form blank 3 .
[0046] During the imaging operation by the imaging unit 5 , the belt 41 is set off the surface of the printing-form blank 3 . The beams 10 produce printing ink-accepting or dampening solution-accepting points or pixels due to removal or changes in the adhesive characteristics of the photosensitive layer. Following the imaging operation, the imaging unit 5 can be moved into a parked position, protective devices for optical elements then becoming effective. For this purpose, the imaging unit 5 can be moved away from the printing-form cylinder 1 . In a further step, by positioning the deflection roller 40 , the belt 41 is set on the surface of the printing-form blank 3 . The belt 41 impregnated with cleaning liquid is moved over the surface of the printing-form blank 3 at a differential speed with respect to the rotating form cylinder 1 . For this purpose, at least one of the deflection rollers 37 to 40 is driven. Due to the action of the cleaning liquid and due to the mechanical wiping action of the belt 41 , particles which have been produced during imaging with the imaging unit 5 are removed from the surface of the printing-form blank 3 . As the belt 41 passes through the container 11 , the particles are surrendered to the cleaning liquid, the belt 41 picking up fresh cleaning liquid. The positioning of the container 11 in the horizontal direction 34 permits the tension of the belt 41 to be controlled, and movement to a service position for replacing the container 11 or the liquid 12 . The finished printing form has thus been produced ready for printing and can be removed from the printing-form cylinder 1 . Depending upon the requirements of the process, the liquid 12 in the container 11 is set or adjusted with respect to the composition and characteristics thereof. For example, the liquid 12 , in addition to the cleaning action described hereinabove, can provide a developer action, so that points or pixels exposed by the beams 10 or unexposed points or pixels go into solution.
[0047] A special feature of the different embodiment or variant of the apparatus according to FIG. 7 is in the construction of the container 11 with three chambers 43 , 44 and 45 with different liquids 46 , 47 and 48 , respectively, disposed therein. The liquids 46 to 48 can be photosensitive materials, developer liquid, fixing liquid or cleaning liquid. According to this different embodiment or variant, the container 11 can be positioned both in the vertical direction 49 and in the horizontal direction 34 . The container 11 is positioned automatically based upon the type of printing form to be produced, the characteristics of which are entered in advance into the controls of the device in the form of data or are determined in advance by sensors. Following the selection of the required horizontal position, the container 11 is moved in the vertical direction 49 so that the printing-form blank 3 dips into one of the chambers 43 to 45 containing the correct liquid 46 to 48 , respectively.
[0048] The aforedescribed variants or different embodiments constitute only exemplary embodiments, which can be modified and combined as desired. The apparatus can be quite compact, requiring a small area for the erection thereof, so that it is possible to provide the apparatus in a pressroom or print shop, and it being therefore possible for the operation of the apparatus to be performed from the operating desk of a printing press. In the control of the apparatus, use may be made of data which is also used in controlling the printing press. The apparatus is suitable for processing all types of printing forms, such as rewriteable printing forms, conventional aluminum plates, printing forms in film or sleeve form, precoated printing forms, and printing forms which are coated and cleaned in the apparatus. The apparatus can be integrated into printing units of a printing press.
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An apparatus for producing a printing form includes a device for feeding a printing-form blank to a circumferential surface of a rotatable cylinder, a device for releasably fixing the printing-form blank to the circumferential surface, and a device for producing ink-accepting image points or pixels on the surface of the printing-form blank in accordance with a printing image. The pixel-producing device has a device for treating the printing-form blank with a medium stored in a container. The container is disposed so as to be movable relative to the cylinder.
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FIELD OF THE INVENTION
[0001] The present invention relates generally to powder application, and more particularly to a device and method for applying powder to the body.
BACKGROUND OF THE INVENTION
[0002] Body powders are applied to the skin's surface. The body powder may be used to dry the skin and/or interact with the skin cells. The body powder may act as an astringent, an antiperspirant, fungicide or other medicinal purpose. The body powder may also incorporate a fragrance to provide a perfume or cologne.
[0003] Typically, Body powder is applied by squeezing a bottle or shaking a bottle containing the powder upside down. The powder grains pass through a perforated top of the bottle directly onto the skin or are collected in the palm of the hand. The user then rubs the powder on the skin. Excess powder may be released into the air or fall to the ground. In addition, one may need to continuously apply powder.
[0004] Accordingly, a device, method, and system is needed to easily and efficiently apply body powder. In addition, the device, method and system may need to be easily storable and transportable. Further, the device, method, and system may need to dry and brush the skin of foreign particles while applying the body powder. Still further, the device, method and system may need to be cleanable and refillable.
BRIEF DESCRIPTION OF THE DRAWINGS
[0005] The above and other objectives and advantages of the present invention will be apparent upon consideration of the following detailed description, taken in conjunction with the accompanying drawings, in which like reference numbers refer to like parts throughout, and in which:
[0006] FIG. 1A is a perspective view of the powder applicator 100 according to a first exemplary embodiment of the present invention.
[0007] FIG. 1B is a profile view of the powder passing through the powder applicator walls 104 according to an exemplary embodiment of the present invention.
[0008] FIG. 2 is a perspective view of the powder applicator 100 with container 200 according to a second exemplary embodiment of the present invention
[0009] FIG. 3 is a flow chart of the powder application according to a first exemplary method embodiment 300 of the present invention.
[0010] FIG. 4 is a flow chart of cleaning and refilling of powder applicator 100 according to a second exemplary method embodiment 400 of the present invention.
DETAILED DESCRIPTION OF THE INVENTION
[0011] Referring to FIG. 1A , the powder applicator 100 is made of walls 104 that allows a body powder 102 stored in the powder applicator 100 to pass through to an outer surface of the powder applicator 100 . The body powder 102 may be a variety of powders applied to the skin, for example but not limited to, talcum powder, cornstarch, fragrance powders, medicated powders, a combination of the forgoing powders, and/or any other suitable powder(s). The user rubs the outer surface of the walls 104 of the powder applicator 100 against the skin. The outer surface may brush the skin of foreign particles, for example but not limited to, sand, dirt, and dead skin. The walls 104 also allow body powder 102 to pass through and be applied to the skin. The powder applicator 100 may be used, for example, at the beach to remove sand from the skin.
[0012] According to the first exemplary embodiment, the powder applicator 102 may be made of a cotton fabric stitched together in a pocket shape. An aperture 108 may be provided for the powder applicator 100 to allow empting and/or refilling of the powder applicator 100 . The aperture 108 may include a hook and loop fasteners seam 110 to allow the aperture 108 to remain closed during use but allow for quick access for refilling the powder applicator 100 . The powder applicator 100 may use other suitable fasteners to provide closing of the aperture 108 , for example but not limited to, snaps, zippers, drawstrings, or press and lock fasteners. The powder applicator 100 may also be designed without an aperture 108 to provide a limited use applicator. According to this embodiment, the powder applicator 100 would be filled during manufacturing and disposed by the user once the powder applicator 100 is emptied.
[0013] Referring to FIG. 1B , the powder applicator 100 is made of fabric walls 104 that allows a body powder 102 stored in the powder applicator 100 to pass through to an outer surface of the powder applicator 100 . The fabric may be selected based on the desired amount of body powder 102 released and the grain size of the body powder 102 . For example, increasing the porosity of the fabric will increase the amount of body powder 102 released. The fabric may be of a variety of materials, for example, the fabric may be a 100 percent blend of cotton fiber. The fabric material may be made of a material the wicks water from the skin. In another embodiment the fabric may be of a synthetic fiber, for example, spandex or elastane. The fabric material may be made of a material that does not readily absorb water and provides a relative dry surface. In another embodiment, the fabric may be a material that has unidirectional characteristics that allow the powder and moisture to pass to the outside of the powder applicator 100 but prevents moisture from flowing in the opposite direction into the powder applicator 100 . One skilled the art will appreciate that other suitable material with similar properties as fabric walls 104 may be used in embodiments of the present invention. The powder applicator 100 may also be made with a combination of fabric and rigid portion and is not limited to a pocket shape. For example, a rigid handle or container may be incorporated into the design. In another example, the powder applicator 100 may have the shape of a seahorse, starfish, surfboard, life vest or other aesthetic shape.
[0014] Referring to FIG. 2 , the powder applicator 100 may include a container 200 . The container 200 may be used to provide for storage and transportability of the powder applicator 100 when not in use. The container 200 may be made of a material that prevents the passage of body powder 102 . A container aperture 204 may be provided for placing the powder applicator 102 within the container 200 . The container aperture 204 may include a drawstring fasteners seam 206 to allow the container aperture 204 to remain closed during storage and/or transporting. The container 204 may use other fasteners to provide closing of the container aperture 204 , for example but not limited to snaps, hook and loop, zipper, press and lock fasteners, or any other suitable fastener(s). Excess powder 202 remains inside the container 200 and may be disposed of or inserted back into the powder applicator 100 . The container 200 may be made of a fabric that prevents the passage of powder or a rigid or semi rigid material, for example, plastic or leather. The container 200 may be made of a combination of fabric with a plastic lining.
[0015] FIG. 3 is a flow chart of the powder application according to a first exemplary method embodiment 300 of the present invention. The user removes powder applicator 100 from container 200 (block 302 ). The user rubs the outer surface of powder applicator 100 against the skin (block 304 ). The outer surface of powder applicator 100 brushes off foreign particles, for example sand (block 306 ). Body powder 102 passes through powder applicator's walls 104 and is applied to the skin (block 308 ). The amount of powder dispensed may be dependent on fabric and powder characteristics. Moisture on the skin is pushed or wicked away (block 310 ). Moisture on the skin may be accomplished by some of the body powder 102 absorbing moisture and falling off the skin from repeated brushes. The powder applicator 100 is reinserted into container 200 for later use and/or transport (block 312 ).
[0016] FIG. 4 is a flow chart of cleaning and refilling of the powder applicator according to a second exemplary method embodiment of the present invention. The aperture 108 to the powder applicator 100 is opened (block 402 ). Excess body powder 102 from the powder applicator 100 is removed through the aperture 108 (block 404 ). The powder applicator 100 is washed (block 406 ). This action may include, for example, washing the powder applicator 100 in a washing machine, sink, for by shaking or dry cleaning. The powder applicator 100 is allowed to dry (block 408 ). The powder applicator 100 is refilled with fresh body powder 102 (block 410 ). The powder applicator 100 is now recharged and ready for future use.
[0017] It will be understood that the foregoing is only illustrative of the principles of the invention and that various modifications can be made by those skilled in the art without departing from the scope and spirit of the invention. Accordingly, such embodiments will be recognized as within the scope of the present invention. Various aspects disclosed in the exemplary embodiments may be incorporated with aspects disclosed in other exemplary embodiments without departing from the scope of the invention. Persons skilled in the art will also appreciate that the present invention can be practiced by other than the described embodiments, which are presented for purposes of illustration rather than of limitation and that the present invention is limited only by the claims that follow.
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Apparatus and methods for application of body powder are disclosed. The apparatus and methods disclosed may have a body powder stored within a porous fabric material. As the fabric material is rubbed against the skin surface the powder is released onto the skin.
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RELATED APPLICATIONS
This application is a continuation of U.S. application Ser. No. 10/989,803, filed on Nov. 17, 2004, which relies for priority upon International Application No. PCT/US03/20628 filed on Jul. 1, 2003, which claims the benefit of U.S. Provisional Application Ser. No. 60/429,137, filed Nov. 26, 2002, the contents of which are herein incorporated by reference in their entirety.
BACKGROUND OF THE INVENTION
It has been discovered that magnesium diboride is a superconductor with a transition temperature of approximately 40 K. Magnesium diboride can be made by the reaction of elemental magnesium and boron. The result of this process is a fine powder which is commercially available. Experiments on small crystals of this material have demonstrated high current-carrying capabilities at high magnetic fields, properties which could make MgB2 very useful in applications such as magnetic resonance imaging (MRI) where large powerful magnets are required. Magnesium diboride, however is an intractable material with respect to the usual drawing processes for forming the continuous wires required for such applications.
Magnesium diboride wires have been formed by a “powder-in-tube” process in which a tube of cladding material is filled with the fine powder and the composite tube is then drawn to smaller diameter. (S. Jin et al, high Critical Currents in Iron-clad Superconducting MgB2 Wires, Nature, Vol. 410, 63 (2001)). This process is expensive and may not lead to optimum properties in the fabricated wire.
Another approach to forming MgB2 wires has been to convert boron filaments by reaction with magnesium vapor. Boron filaments are formed in a continuous chemical vapor deposition (CVD) process; 100 micron diameter boron filaments on a 12 micron tungsten substrate are commercially available in lengths exceeding several kilometers. Segments of these filaments were reacted with magnesium vapor in sealed tantalum tubes. (Canfield et al, Superconductivity in Dense MgB2 Wires, Phys. Rev. Lett., Vol. 86, 2424 (2001)). The filament segments retained the shape of wires after conversion to MgB2, and exhibited good superconducting properties. However, the resulting wires were fragile and difficult to handle.
One objective of the invention disclosed below is to form a boron substrate which can be converted to magnesium diboride in continuous wire form while still retaining both good superconducting properties and good mechanical properties such as handleability.
Another aspect of the superconducting behavior of MgB2 is the effect of impurities. Impurity sites can enhance the current-carrying capability of a superconductor by “pinning” magnetic vortices; the restrained vortices allow the sample to retain a zero electrical resistance. (Canfield and Bud'ko, Physics World, 29, Jan.
2001.) Impurities which have been found useful for enhancing the properties of MgB2 include magnesium oxide, carbon, silicon carbide and titanium diboride.
Another objective of this invention is to provide a continuous boron substrate doped in a controlled manner by chemical vapor deposition with atomic species which will, upon conversion of the boron to MgB2, form “pinning” sites which will enhance the current-carrying capability of the resulting superconductor.
SUMMARY OF THE INVENTION
In this invention, chemically doped boron coatings are applied by chemical vapor deposition to silicon carbide fibers; these coated fibers are then exposed to magnesium vapor to convert the doped boron to doped magnesium diboride. The silicon carbide fibers are the commercially available SCS-9 or 9A (nominal 3 mil diameter) or SCS-6 (5.6 mil diameter). These silicon carbide fibers exhibit high mechanical properties with tensile strength typically in excess of 500 kpsi and Young's modulus in excess of 50 mpsi. The SCS fibers have a carbonaceous surface layer which enhances the use of the fibers in composite applications. Silicon carbide fibers can also be produced without a carbon-rich surface layer. The chemically doped boron coatings are produced by the controlled addition of a dopant vapor to the gas stream normally used to deposit boron. In this way the concentration of the dopant in the coating can be controlled. For example, addition of titanium tetrachloride vapor to the roughly stoichiometric hydrogen and boron trichloride mixture normally used to deposit boron will result in the deposition of boron doped with titanium diboride, and the concentration of the titanium diboride can be controlled through the vapor pressure of titanium tetrachloride. When the (B/TiB2)-coated SiC is then exposed to magnesium vapor at high temperature, the result is a robust SiC fiber coated with magnesium diboride doped with titanium diboride.
Another useful dopant for magnesium diboride is magnesium oxide. This can be produced by adding controller amounts of B3O3Cl3 to the gas stream used for boron deposition. The oxygen-doped boron thus produced will convert to magnesium oxide-doped magnesium diboride upon processing as above.
Silicon carbide has been shown to be a useful dopant for magnesium diboride. The doped MgB2 was prepared in pellet form by the reaction of a mixture of boron, magnesium and silicon carbide powders in sealed tubes. Boron made by chemical vapor deposition (by the hydrogen reduction of boron trichloride) can be doped with controlled amounts of silicon carbide by the addition of metered amounts of an organosilane such as methyltrichlorosilane to the plating gas during the deposition process. Hence, a more convenient method of forming a continuous SiC-doped MgB2 wire is a process which includes forming a continuous SiC-doped boron substrate by chemical vapor deposition and subsequently converting the substrate to doped MgB2 by reaction with magnesium. The chemical vapor deposition process provides a means of fabricating a continuous substrate of controlled composition with a uniform dispersion of the dopant.
Similarly, carbon as a dopant can be incorporated into continuous MgB2 wires through a process as described above where a hydrocarbon is added to the plating gas during boron deposition instead of an organosilane.
Boron-containing coatings on silicon carbide are known (Suplinskas et al, U.S. Pat. No. 4,481,257) but their application is limited to enhancing the bonding in composites in which the silicon carbide provides the reinforcement. The application to the formation of superconducting wires is novel.
The doped boron coatings may be deposited on substrates other than silicon carbide fiber. Tungsten wires, molybdenum wires and carbon monofilament, for example, can be used for boron deposition and could be used as well for the deposition of doped boron. In this case, the specific mechanical property enhancement due to the use of silicon carbide would not result, but the improvement in superconducting properties such as superconducting critical current density and upper critical magnetic field would still be obtained after the coatings are reacted with magnesium to form magnesium diboride. The conversion to magnesium diboride has been illustrated by using the process of Caulfield et al, but other means of converting the doped boron to a superconductor are possible; for example, the continuous doped boron could be passed through a batch of molten magnesium. The method used for the reaction of the boron with magnesium is separate from the invention described here.
DETAILED DESCRIPTION OF THE EMBODIMENTS
Example 1
SCS-9 fiber, 3 mils in diameter, was passed through a reactor normally used for the deposition of continuous boron fiber. The continuous silicon carbide fiber enters the reactor at the top through a mercury gas seal and electrode, and exits at the bottom of the reactor through a similar seal/electrode. Fiber emerging from the bottom of the reactor is taken up on a variable speed take-up reel. The rate of fiber traverse through the reactor was 20 feet per minute. Reactant gases are admitted at the top of the reactor and exhausted at the bottom. Metered flows of 3.1 liters per minute of hydrogen and 4.2 liters per minute of boron trichloride were passed through the reactor. The silicon carbide was resistively heated by an electric current produced between mercury gas seals/electrodes at the top and bottom of the reactor. At a current of 200 milliamps, the silicon carbide fiber was heated to 1100-1300 degrees Celsius. The hydrogen flow was then directed to pass through a bubbler (coarse glass frit) containing liquid titanium tetrachloride. The bubbler was immersed in an ice-water bath; a thermocouple immersed in the TiCl4 read 3% C. The hydrogen/titanium tetrachloride mixture emerging from the bubbler was then mixed with the boron trichloride and passed through the reactor. The diameter of the fiber emerging from the reactor was approximately 3.3 mils compared to the 3 mil SCS-9 entering the reactor. A sample of this coated fiber was collected on the take up spool.
Examination of the collected sample showed a smooth uniform adherent coating approximately 4 microns thick. Auger analysis of the coating showed it to consist of approximately 90% boron and 10% titanium. Sections of this fiber were sealed in tantalum tubes with magnesium and heated to 950% C for one hour in the laboratory of Doug Finnemore at Iowa State University by the method described by Caulfield et al (loc.cit.). These converted fibers were superconducting with a transition temperature of about 39% K. Subsequent measurements showed a critical current density of 5 million amps per square centimeter at 5% K and a magnetic field of 0.1 Tesla. Similar measurements on superconductors made from pure boron gave maximum values of approximately 600,000 amps per square centimeter. The wires thus produced were handleable and could be bent around a half inch diameter without breaking.
Example 2
Silicon carbide fiber, 3 mils in diameter, was passed through the reactor described above. The rate of fiber traverse through the reactor was 20 feet per minute. Metered flows of 3.1 liters per minute of hydrogen and 4.2 liters per minute of boron trichloride vapor were passed through the reactor. The silicon carbide fiber was resistively heated to approximately 1100 degrees C. by a current of 162 milliamps. A portion of the hydrogen flow could be diverted through a bubbler (coarse glass frit) containing liquid methyltrichlorosilane at a temperature of 27-34 degrees C. In a series of experiments as described in the table below, the percentage of the total hydrogen flow that was diverted to the bubbler was varied systematically. In all cases, smooth adherent coatings 2-4 microns thick were formed on the silicon carbide. The composition of the coatings was determined by Energy Dispersive X-ray Analysis on a scanning electron microscope. The atomic percent silicon found in each case is noted in the table. The data demonstrates that controlled doping of the boron coatings was accomplished.
Experiment
% Flow
Atomic
Number
through Bubbler
% Silicon
1
0
0
2
18
1.5
3
36
5.0
4
55
6.3
5
73
8.1
Example 3
Silicon carbide fiber, 3 mils in diameter, was passed through the reactor described above. The rate of fiber traverse through the reactor was 20 feet per minute. Metered flows of 3.1 liters per minute of hydrogen and 4.2 liters per minute of boron trichloride vapor were passed through the reactor. The silicon carbide fiber was resistively heated by the passage of electrical current in the range 162-178 milliamps as indicated in the table below. A metered flow of methane gas in the range of 0-950 standard cubic centimeters per minute (SCCM) could be added to the reactor in addition to the hydrogen and boron trichloride. A series of experiments was performed in which the current and methane flow were varied as described in the table. In all cases, smooth adherent coatings 2-4 microns thick were formed on the silicon carbide. The composition of the coatings was determined by Energy Dispersive X-ray Analysis on a scanning electron microscope. The atomic percent carbon found in each case is noted in the table. The data demonstrates that controlled doping of the boron coatings was accomplished.
Sample Number
Methane (SCCM)
Current (ma)
Atomic % Carbon
1
0
165
0
2
250
162
1.5
4
500
170
3.3
6
950
178
6.3
DOCUMENTATION
These experiments are described in detail in my laboratory notebook entitled “B for superconductors” on pages 3-114.
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A chemically doped boron coating is applied by chemical vapor deposition to a silicon carbide fiber and the coated fiber then is exposed to magnesium vapor to convert the doped boron to doped magnesium diboride and a resultant superconductor.
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CROSS-REFERENCE TO RELATED APPLICATIONS
This application claims the benefit of U.S. Provisional Application No. 60/116,474, filed Jan. 20, 1999, which is incorporated by reference herein.
STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH DEVELOPMENT
This invention, in part, was made with Government support under ATP grant 70NANB5H1140 awarded by the National Institute of Standards and Technology. The United States Government may have certain rights in this invention.
BACKGROUND OF THE INVENTION
This invention relates to melt processing of olefin polymers and more particularly relates to melt extrusion and pelletization of elastomeric propylene polymers.
Extrusion of thermoplastic crystalline olefin polymers is well known in the art. Extrusion of these polymers is widely practiced from laboratory-scale test units to full-size commercial equipment. Extruders typically are used to convert polymer powder formed in a polymerization reactor to melted strands that may be chopped into pellets. Extruders also are used to blend polymer with additive materials such as stabilizers, anti-oxidants, and acid scavengers such that additives are well dispersed into the polymer. In a typical extruder apparatus, normally-solid polymer is transported through a barrel by action of a rotating screw. The polymer typically is heated by mechanical action and externally-applied heat through zones in the extruder barrel. Additives may be blended with the polymer in the screw-agitated process, and melted polymer which incorporate such additives is extruded through an orifice or die into strands, fibers, or sheets.
In a conventional extrusion process for a crystalline thermoplastic polymer, such as isotactic polypropylene, the final extruder barrel zone temperature is maintained above the polymer melting point. Cyrstalline isotactic polypropylene has a narrow temperature melting range with rapid crystallization upon cooling. If this material flows through the last extruder zone and die and falls below the polymer crystallization temperature, the isotactic polypropylene would solidify in the barrel and at the extruder orifice. This would result in excessively high torque on the extruder and high barrel pressures and, ultimately, would shut down the extruder. Thus, in a conventional extrusion process for crystalline propylene polymer, the last extruder zone temperature must be high enough to prevent polymer freezing in the barrel.
There is now a class of partially crystalline olefin polymers with a broad melting range, which may exhibit elastomeric properties. In order to incorporate additives and form into pellets, these polymers should be processed in an extruder. If these partially-crystalline polymers are extruded in a conventional manner in which the barrel exit temperature is above the polymer melting temperature, the resulting extruded polymer strand has no rigidity and is very sticky. Such a sticky strand does not easily feed into a pelletizer and may wrap around the cutting blades of a pelletizer. Even when some polymer strands get to the cutting blades, the blades may not cut completely through the strand.
This invention permits melt processing and subsequent formation of polymer pellets of such a polymer with a broad melting range without these problems.
SUMMARY OF THE INVENTION
A method to melt process a thermoplastic, partially-crystalline, olefin polymer in a multi-temperature stage extruder wherein the polymer has a broad melting temperature range comprises setting the temperature profile of the extruder such that a portion of the polymer crystallizes in the extruder and passing the resulting partially-crystallized polymer through an extruder die.
DESCRIPTION OF THE INVENTION
The method of this invention permits melt processing of a thermoplastic, partially-crystalline, olefin polymer which has a broad melting temperature range. Melt processing such a polymer through an extruder using conventional techniques in which polymer exits the extruder in a fully-melted state, produces a polymer strand which has little if any rigidity and is very sticky. As a result the strand is difficult to feed into a pelletizer and would stick to and wrap around the take-up rollers instead of feeding to the cutting blades.
In the method of this invention, such a thermoplastic, partially-crystalline, olefin polymer preferably is melted in an initial stage of an extruder, but the extruder temperature profile is set such that the polymer partially crystallizes at least at the last extruder zone. A partially-crystallized polymer is extruded into a strand which has sufficient rigidity to feed satisfactorily into a pelletizer. An adequate polymer strand is firm, typically translucent, has low stickiness, and is readily pelletized. Such strands do not significantly stick together in a collection container.
A typical thermoplastic, partially-crystalline, olefin polymer useful in this invention has a broad melting temperature range of over 50° C. and up to about 200° C. A broad melting temperature typically indicates the compositions contain a minor amount of crystallizable material within a matrix of amorphous material.
In describing this invention, melting ranges and crystallization temperature are measured using Differential Scanning Calorimetry (DSC). Using DSC to measure melting characteristics of a polymer useful in this invention shows a range of melting in a polymer in which crystalline phase will be present in a melted phase. In contrast to a DSC measurement of an isotactic polypropylene which shows a narrow temperature range of melting, polymers useful in this invention will show a broad melting range of over 50° C. and up to about 200° C. Typical melting ranges are about 100 to 150° C. The melting range typically is measured as the width of the crystalline melting endotherm as observed in the DSC. The melting range is sufficiently broad to permit a minor amount of crystalline phase to be incorporated within a major amount of a flowable non-crystalline matrix phase at a temperature within the melting range. A flowable polymer will pass through an extruder without using significant pressure or torque. Although melted polymer exists throughout the melting range, typically the melting temperature as measured by DSC (T m ) is the maximum peak (or inverse peak) of the DSC thermogram heating at 20° C./min. This should correspond to the temperature at which the largest portion of crystalline material melts.
Another temperature measurable by DSC is the crystallization temperature (T c ) which is determined by cooling a totally melted polymer and determining the maximum peak (or inverse peak) in the DSC cooling at 10° C./min. As the polymer is cooled, it passes through a supercooled phase before crystallization occurs. Thus the T c will be lower than the T m . Polymers used in this invention may have a T c 20 to 100° C. (typically 30 to 90° C.) lower than the T m . Typically, polymers useful in this invention will be sticky if rapidly cooled from a total melt phase because a solid supercooled phase is produced which does not include significant amounts of crystalline phase.
Olefin-based polymers useful in this invention include polymers of ethylene, propylene and C 4 -C 8 olefins having a broad melting range. Partially crystalline olefin polymers having a broad melting range include elastomeric propylene polymers and propylene-ethylene copolymers which may have up to 50 mole % of ethylene.
Propylene polymers useful in this invention should have about 10 to about 30 percent crystallinity which corresponds to m4 values (as measured by 13 C NMR) of about 25 to 55%. The isotactic pentad (m4) content is the percentage of isotactic stereosequences of five contiguous stereocenters as measured by 13 C NMR. The m4 of a statistically atactic polypropylene is about 6.25% while that of a highly isotactic polypropylene approaches 100%. Typical polymers useful in this invention have a crystallinity of 15 to 25% at room temperature (20° C.) which corresponds to m4 values of about 25 to 45%. Typical melting temperatures for useful propylene polymers are about 75 to about 155° C., preferably about 100 to about 150° C. Typical crystallization temperatures for useful propylene polymers are about 45 to about 120° C., preferably about 80 to about 110° C.
At the exit zone of an extruder in the process of this invention, crystallized polymer is incorporated into a matrix of flowable non-crystalline phase. Thus, after such polymer passes through the extruder exit zone, the polymer will solidify into a form which possesses sufficient physical integrity to be formed into films, strands, or pellets
In a preferable process of this invention, suitable polymer is passed through an extruder device such that the barrel temperature at the beginning of the extruder is sufficiently above the melting temperature, T m , such that a total melt phase is present and in which appropriate polymer additives and stabilizers may be incorporated completely. Thus, the barrel temperature at the beginning of the extruder is set higher than T m and below a temperature at which the polymer is degraded. A typical beginning temperature zone would be about 5° C. to about 20° C. higher than T m and preferably about 10° C. to about 20° C. higher than T m . For a typical polymer with a T m of about 150° C., the first extruder heat zones may be about 160-170° C.
Temperature along the barrel is decreased such that in the last barrel heat zone the temperature is at or below the crystallization temperature, T c , which permits partially crystallized polymer to exit the extruder. Thus, the final temperature zone in the extruder is set lower than T c but sufficiently high to permit flow of the polymer through the extruder exit or die. A typical final temperature zone would be about 5° C. to about 15° C. lower than T c and preferably about 5° C. to about 10° C. lower than T c . For a typical polymer useful in this invention with a T c of about 95-110° C., the final barrel temperature typically is set to about 90-100° C.
The temperature profile for a particular suitable polymer useful in this invention must be set to permit partial crystallization in the final extruder stage while maintaining sufficient polymer flowability. Temperatures for a high melt flow rate (low molecular weight) polymer would be lower than a lower melt flow polymer to achieve partial crystallization in the final stage. Also, suitable polymers filled with inert materials such as talc and calcium carbonate will require a higher temperature to maintain flowability.
Extruders useful in this invention are well known in the art. Useful barrel polymer extruders have a plurality of temperature zones that may be independently set along the length of the extrusion barrel. A typical extruder has about 3 to about 20 or more temperature zones and preferably has about 4 to about 15 zones. Since the polymer is cooling as it passes through the barrel, heat must be transferred from the polymer through the barrel wall. Longer extruders may be preferred to permit more efficient heat transfer from the polymer to the barrel in this process. Although a screw extruder, in which a rotating screw device in the extruder barrel provides the necessary force to transport the polymer through the apparatus, is preferred, a static mixer also may be used, in which polymer is transported by an external pump.
Preferable polymers useful in this invention include propylene polymers which exhibit elastomeric properties such as tending to regain its shape upon extension or exhibiting a positive power of recovery at 100%, 200% and 300% elongation. The preferable polymer useful in this invention is an elastomeric propylene based polymer described in U.S. Pat. No. 5,594,080, incorporated by reference herein. The elastomer polymer formed according to this disclosure, has regions of isotactic and atactic structures which produces a polymer with a broad melting range. Such polymers have a high molecular weight and a narrow molecular weight distribution and are homogeneous in composition with typical melting points of 50 to 145° C.
Typical polymers useful in this invention are propylene polymers that may be homopolymers or copolymers of propylene with minor amounts of ethylene or other alpha-olefin. Introduction of comonomers typically decreases the processing temperatures. These polymers may be extruded according to this invention, but at lower barrel temperatures appropriate to the melting and crystallization temperatures of the copolymer.
Also, these polymers may be combined with inert fillers such as talc, calcium carbonate, barium carbonate, and the like and extruded according to the method of this invention. Typically, filled polymers will have higher processing temperatures than unfilled polymers. But these filled compositions still may be extruded according to this invention with the barrel temperatures set appropriately higher.
This invention is illustrated, but not limited by, the following examples:
EXAMPLES 1-6
A series of extrusion runs was performed using a single screw 125-5 V Brabender extruder with five temperature zones. Elastomeric polypropylene polymers were obtained which had been prepared according to U.S. Pat. No. 5,324,080 having physical properties listed in Table II. Samples of these polymers were cryo-ground with dry ice in a Wiley mill, desiccant dried, stabilized (0.2 wt %. Ultranox® 2714A) and pelletized by melt processing through the Brabender extruder into strands which were chopped into pellets. All polymers from Examples 1-6 were able to be extruded and pelletized according to this invention. Results are presented in Table I.
TABLE I
Zone
1
2
3
4
5
Example 1
Set Temp. ° C. 1
160
100
90
90
90
Actual Temp. ° C 2
158
98
96
92
107 3
Torque = 65-75 m · g;
Rotation = 77 rpm;
Pellet Yield = 4.3 Kg
Example 2
Set Temp. ° C. 1
160
100
90
90
90
Actual Temp. ° C. 2
162
111
97
94
112 3
Torque = 61-80 m · g;
Rotation = 77 rpm;
Pellet Yield = 5.6 Kg
Example 3
Set Temp. ° C. 1
160
100
90
90
90
Actual Temp. ° C. 2
162
105
89
99
119 3
Torque = 82 m · g;
Rotation = 80 rpm;
Pellet Yield = 4.9 Kg
Example 4
Set Temp. ° C. 1
160
100
90
90
90
Actual Temp.° C. 2
156
101
92
104
126 3
Torque = 70 m · g;
Rotation = 82 rpm;
Pellet Yield = 4.1 Kg
Example 5
Set Temp. ° C. 1
155
85
75
75
75
Actual Temp. ° C. 2
156
85
79
82
100 3
Torque = 63-71 m · g;
Rotation = 80 rpm;
Pellet Yield = 13.0 Kg
Example 5 used a higher MFR polymer that required a lower final stage
temperature for partial crystallization.
Example 6
Set Temp.° C. 1
200
180
170
160
—
Actual Temp.° C. 2
156
101
92
104
—
Torque = 61 m · g;
Rotation = 100 rpm;
Pellet Yield = 14.5 Kg
The polymer composition in Example 6 was filled with 55 wt. % calcium
carbonate, which required a higher final stage temperature.
1 Barrel temperature machine setting.
2 Actual barrel temperature measured by a thermocouple.
3 Actual temperature measured by thermocouple inserted into flowing polymer exiting the die.
TABLE II
Tensile
Tensile
Elongation
MFR 1
T m 2
T c
m4 3
Density
Strength 4
Modulus 4
at Break 4
Ex.
(g/10 min.)
° C.
° C.
(%)
Mw
Mn
Mw/Mn
(g/ml)
(MPa)
(MPa)
(%)
1
15.5
147
88
43
221
55
4.0
0.8666
14.6
14.7
878
30-165
2
16.2
149
80
46.3
238
60.8
3.9
0.8692
16.9
17.6
792
70-160
3
8.1
150
78
44.6
252
71.8
3.5
0.8671
17.5
14.9
1170
58-170
4
1.5
151
64
35.3
370
134
2.8
0.8648
8.67
7.64
726
58-170
5 5
47.7
151
76
36.5
159
44.4
3.6
0.8668
6.74
8.51
1250
28
55-160
39.4
189
45.1
4.2
6
1.9
7
88
25.9
318
111
3.0
0.8645
6.47
4.29
873
70-165
6A 6
6.54
8.23
1037
1 ASTM D1238 Condition L
2 T m = maximum peak in DSC; crystalline melting range = endotherm width observed in DSC
3 13 C NMR
4 ASTM D638 at 23° C.
5 Data for MFR, m4, and molecular weight shown for each component of composite.
6 6A shows properties of a 55 wt % calcium carbonate filed composition.
7 No definitive endotherm peak maximum.
Run A and Example 7
Two runs of composite polymer samples of elastomeric polypropylene prepared according to U.S. Pat. No. 5,324,080 were processed through a Brabender single-screw extruder. The composite had an average melt flow rate (MFR) of 16 g/10 min. and m4 content of 34%. This composite had a melting range of 40-165 and a T m of 151 and a T c of 102 as measured by DSC. In Run A, the temperature profile of the extruder was set for conventional polymer with the exit temperature high enough to assure the exiting polymer was completely melted. In Example 7, the temperature profile was set such that the polymer composition in the last temperature zone contained crystallized polymer. Details of these experiments are shown in Table III below:
TABLE III
Zone
1
2
3
4
5
Run A
Set Temp. ° C. 1
160
155
155
155
—
Actual Temp. ° C 2
159
153
156
154
—
Torque = 12 m · g;
Rotation = 100 rpm;
Example 7
Set Temp. ° C. 1
100
100
100
100
—
Actual Temp. ° C. 2
100
100
100
100
—
Torque = 9 m · g;
Rotation = 100 rpm;
1 Barrel temperature machine setting.
2 Actual barrel temperature measured by a thermocouple.
3 Actual temperature measured by thermocouple inserted into flowing polymer exiting the die.
Strands of polymer exiting the die were directed to a water bath followed by a rotating blade pelletizer in each experiment. In Run A, the polymer did not pelletize well and the strand balled up between the pelletizer blades and stuck together. In Example 7, the strand was translucent out of the diehead and pelletized well. If an additive package were to be included in the composition used in Example 7, preferably, the initial extruder zones would be operated at above the polymer melting temperature to assure good additive dispersion.
|
A method to melt process a thermoplastic, partially-crystalline, olefin polymer in a multi-temperature stage extruder wherein the polymer has a broad melting temperature range comprises setting the temperature profile of the extruder such that a portion of the polymer crystallizes in the extruder and passing the resulting partially-crystallized polymer through an extruder die.
| 1 |
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to gels and mixed gels of hyaluronic acid (HA), formulations containing them and methods for preparing them.
2. The Prior Art
Hyaluronic acid is a well known, naturally occurring polysaccharide containing alternating N-acetyl-D-glucosamine and D-glucuronic acid monosaccharide units linked with β1→4 bonds and the disaccharide units linked with β1→3 glycoside bonds. Hyaluronic acid usually occurs as the sodium salt. The molecular weight of HA is generally within the range of 50,000 up to 8×10 6 and even higher.
The prior art describes the cross-linking of HA with the use of 1,2,3,4-diepoxybutane in alkaline medium at 50° C. (T. C. Laurent, K. Hellsing, and B. Gelotte, Acta Chem. Scand. 18 [1984], No 1, 274-5). The product obtained by that method is a gel which substantially swells in water.
It is also known that divinyl sulfone (DVS) is used for cross-linking polysaccharides, especially cellulose (U.S. Pat. No. 3,357,784).
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 is a graphical representation of the experimental data set forth in Example 3 below; and
FIG. 2 is a graphical representation of the experimental data set forth in Example 4 below.
SUMMARY OF THE INVENTION
In one aspect thereof, the present invention provides highly swollen gels of cross-linked hyaluronic acid.
In another aspect, the invention provides mixed cross-linked gels of hyaluronic acid and other hydrophillic polymers.
In yet another aspect, the invention provides cross-linked gels of hyaluronic acid and other polymers filled with various substances.
In still another aspect, the invention provides cross-linked gels of hyaluronic acid containing low molecular weight substances covalently attached to the macromolecules.
In still yet another aspect, the invention provides various formulations containing cross-linked hyaluronic acid gels.
Finally, the invention provides the methods of preparing the products of the invention.
The present invention is based on the observation that divinyl sulfone (DVS) reacts readily with HA in aqueous alkaline solutions at room temperature, i.e., about 20° C., thereby providing cross-linked HA gels. As used herein, the term HA means hyaluronic acid and its salts such as the sodium, potassium, magnesium, calcium, etc. salts. These gels swell in water and water containing media. The swelling ratio depends upon the degree of cross-linking of the gel. We have found that the degree of cross-linking can be controlled by changing several factors including the molecular weight of the HA, its concentration in the reaction mixture, the alkali concentration and the polymer/DVS ratio. The reaction is very fast and in most cases a strong gel can be obtained in several minutes. The swelling ratio of these gels can be from 20 up to 8000, and more, depending upon the reaction parameters.
It has also been found that the swelling ratio of cross-linked HA gels is substantially greater than the swelling ratio of cross-linked gels of other polysaccharides obtained under the same reaction conditions. This can probably be explained by the unique nature of HA (as compared to other polysaccharides) and its water solutions. We have found that in water, a large molecule of HA forms a very flexible, long random coil which takes up an extremely large volume in the solution. For example, the specific volume of a hydrated HA molecule in a physiological salt solution is about 2-6×10 3 ml/g. That means that in a quite low concentration water solution of HA, a steric exclusion phenomenon occurs which will substantially affect not only the physico-chemical properties of the solution, but the reaction of the HA with low molecular weight substances as well. In other words, the nature of the HA solutions affects the degree of cross-linking and the behavior of the cross-linked gel, in a manner quite unlike anything that occurs with other polysaccharides.
We have also found that this unique property of HA to give highly swollen cross-linked gels can be used to effect modification of the properties of cross-linked gels made of mixtures of HA with other hydrophillic polymers. These polymers include other polysaccharides, synthetic and natural, such as hydroxyethyl cellulose, carboxymethyl cellulose, xanthan gum, chondroitin sulfate, heparin, proteins of various types, such as collagen, elastin, albumin, a globulin, etc., sulfated proteins such as keratin sulfate and sulfated aminoglycosaminoglycans, synthetic water-soluble polymers, such as polyvinyl alcohol and its co-polymers, co-polymers of poly-(hydroxethyl)methacrylate and the like. In other words, any polymer soluble in water or water alkaline solutions and containing groups capable of reacting with DVS, namely, hydroxyl, amino or sulfyhydryl groups, can be used to obtain highly swollen cross-linked mixed gels of HA.
We have further found that useful products can easily be obtained by carrying out the cross-linking reaction of HA in the presence of low-molecular weight substances containing reactive groups of the mentioned types.
Another type of material according to the present invention is a cross-linked hydrophillic gel filled with various water insoluble substances including hydrocarbons, such as petrolatum; an oil or fat such as beeswax, conconut oil or lanolin, pigments, such as kaolin, ferric oxide; insoluble dyes, polymers, such as polyethylene, polyetrafluro ethylene, etc. In this type of product fine particles of a filler are immobilized in a gel network or in what we call a "polymer cage". This latter product can be very useful for several purposes which will be discussed in more detail below.
DESCRIPTION OF THE PREFERRED EMBODINEMT
The processes by which the hereinabove described products are obtained will now be discussed in detail.
In order to obtain a cross-linked HA gel, a sample of sodium hyaluronate or hyaluronic acid from any source is dissolved in dilute alkaline solution. The molecular weight of HA can be from 50,000 up to 8×10 6 and even higher. The molecular weight affects the reation--the higher the molecular weight the greater the possibility to obtain a cross-linked gel.
The alkali concentration in the reaction mixture can be from 0.005M to 0.5M and higher. The lower limit is dictated by the necessity to have the pH of the medium not lower than 9 and the upper limit by the hydrolysis of HA in an alkaline solution. Usually, a decrease in alkali concentration results in gels with a greater swelling ratio, probably because a small amount of DVS takes part in the cross-linking reaction.
The concentration of HA in the starting solution can vary from 1% by weight up to 8% by weight and higher. When the concentration is below the lower limit, a cross-linked gel cannot be obtained even at a low HA/DVS ratio. When the concentration is too high, the solution becomes so viscous that it is difficult to handle it. The HA concentration substantially affects the swelling behavior of the gels (FIG. 1). It was found that the shape of the curve for the swelling ratio--the HA concentration dependence is essentially the same for various HA/DVS ratios but the lower this ratio (i.e., more DVS in the mixture), the less the swelling ratio of the cross-linked gel for the same concentration of HA in the starting mixture.
We have found that HA/DVS in the reaction mixture is another parameter which can be conveniently used to control the swelling ratio of the cross-linked HA gel. An increase in the ratio results in highly swollen soft gels (the swelling ratio is about 4000 and higher) whereas hard and less swollen gels are obtained when this ratio is decreased. In general, the HA/DVS weight ratio can be from 15:1 to 1:5 and lower.
The cross-linking reaction is usually carried out at room temperature, i.e., about 20° C., but it can be performed at a lower or higher temperature, if desired. However, it should be kept in mind that HA can degrade relatively rapidly in alkaline solutions at elevated temperatures and, if such degradation occurs, the decrease in MW can affect the properties of the obtained gels.
The cross-linking reaction is relatively fast and strong gels are formed usually in several minutes when the HA concentration is high enough and the HA/DVS ratio is low. But even at low HA concentration in the reaction mixture, the gel formation starts usually 5-10 minutes after addition of DVS. We have found that in most cases one hour is enough for completion of the cross-linking reaction.
Another method of controlling the swelling ratio of cross-linked HA gels involves adding neutral salt to the reaction mixture. We have found that the swelling ratio of the gels obtained in the presence of water soluble neutral salts, such as the chlorides, sulfates, phosphates and acetates of alkali metals, decreases with the increase of salt concentration. A salt can be used in concentration up to 20 wt. % and higher, depending upon the nature of the salt and its effect on the solubility of HA in the reaction mixture.
To obtained cross-linked gels of other hydrophillic polymers the same reaction conditions as for HA can be used. The swelling ratio of these gels can be conveniently controlled by incorporating HA into the gel structure. When the mixed gels are obtained, the composition of the polymer mixture can vary over a broad range depending on the swelling ratio of the cross-linked gel desired. The preferred content of HA in the mixture is from 5 to 95 wt. %.
Cross-linked gels of HA or other polymers or mixed cross-linked gels filled with inert substances are obtained by incorporating these substances into the reaction mixture before the addition of DVS. These inert substances are, preferably, water-insoluble liquids or solid substances. Examples of such substances are petrolatum and kaolin. To obtain a filled cross-linked gel, a chosen substance (based on a consideration of the desired properties of the gel) is emulsified or dispersed in an alkaline solution of HA or other polymer or mixture of HA with other polymer or polymers and DVS is added to the mixture. The amount of DVS and the other parameters of the reaction are selected depending upon the desired properties of the gel. The relative amount of filler in the gel can vary over a broad range and is from 1 to 95 wt. % calculated on the total amount of polymers and filler, preferably from 5 to 90 wt. %.
Cross-linked gels containing low molecular weight substances such as drugs, dyes and others covalently attached to the macromolecular network are obtained, preferably by incorporating the named substances into an HA or HA and other polymers solution before the addition of DVS. An example of such a substance is carminic acid, an FDA approved substance for use in food and drug preparations.
It is probably the presence of a glucosidic moiety of the carminic molecule which takes part in the cross-linking reaction with DVS. It should be understood that a great number of substances can be used to obtain a modified cross-linked gel of this type. The only essential feature of these substances is that they contain chemical groups with active hydrogen atoms reactive to DVS. The amount of such low molecular weight substances which can be used in the reaction depends upon the desired level of that substance in the gel. This amount can be in the range of from 1 to 99 wt. % as calculated on polymer content in the gel, preferably, 5 to 90 wt. %.
The cross-linked HA and mixed gels obtained according to the present invention can be used for many purposes. We have found that these highly swollen gels are very useful in cosmetic formulations and can be considered as water-retaining and water-delivering ingredients in these formulations.
As HA is known to be a biologically tolerable polymer in the sense that it does not cause any immune or other kind of response when introduced into a human body, the cross-linked HA gels can be used for various medical applications. The cross-linked gels modified with other polymers or low molecular weight substances can be used as drug delivery devices. For example, we have found that heparin introduced in a cross-linked HA gel retains its antithrombogenic activity.
We have also found that cross-linked gels of HA can slow down the release of a low molecular weight substance dispersed therein but not covalently attached to the gel macromolecular matrix.
The domain of the cross-linked hyaluronic acid (alone or co-polymerized with other polyanionic or neutral polymers) forms a molecular cage. In this cage, hydrophilic or hydrophobic molecules of various pharmacological or biological activity can be dispersed. Thus, the cage constitutes a depot for these substances of various molecular size. The substances contained in the domain of the molecular cage will be delivered into the environment by diffusion. The delivery process is controlled by such factors as the exclusion volume effect and the pore size of the molecular cage and by the molecular interaction between the polymeric network and the substance contained therein. Thus, the molecular cage forms a depot for the controlled delivery of drugs or other substances to the skin or other tissues.
There is one additional property of the cross-linked HA gels which makes them potentially very useful as drug delivery devices. The swelling ratio of these gels in water depends substantially upon the salt concentration in the medium and decreases several times with an increase in salt concentration. This means that a gel swollen in water will contract substantially when introduced into the body (because of the normal salt content of the body fluids and tissues), thus delivering its contents, i.e., an incorporated drug, into the body tissue.
The cross linked gels filled with various substances can also be used in cosmetic formulations. For example, a gel with petrolatum incorporated therein gives all the benefits of using petrolatum in cosmetic formulations without the unpleasant greasy feeling which is normally observed with petrolatum containing formulations.
DETAILED DESCRIPTION OF THE INVENTION
The present invention is described in more detail in the following examples, wherein all parts given are by weight unless otherwise indicated. These examples are given merely by way of illustration and are not intended to limit the invention as set forth in the claims.
EXAMPLE 1
This example illustrates the effect of varying HA molecular weight on the cross-linking reaction.
0.3410 g. of sodium hyaluronate obtained from rooster combs (intrinsic viscosity in 0.15M solution of NaCl [η] 3850, MW about 2.5×10 6 ) was mixed with 8.1840 g. of 0.2M NaOH solution to give a 4% by weight solution after stirring for 30 minutes. Then, 0.0721 g. of DVS was stirred into the solution. The weight ratio HA/DVS was about 4.7. A strong gel formed in about 15 minutes. The gel was left for one hour and then put into one liter of distilled water. The gel was left to swell in water overnight. Then it was broken into small particles by vigorous stirring in water. The gel particles were filtered off and washed several times with water. Colorless, water clear particles were obtained. To determine the swelling ratio of the gel, a sample weighing about 1 g. was centrifuged in a glass filter at 3,000 rpm for two hours. Then the particles left on the filter were hydrolyzed with 2 ml of 1N H.sub. 2 SO 4 solution for three hours at 95°-98° C. The clear solution obtained was neutralized upon cooling with 2 ml of 1N NaOH solution and the glucuronic acid content was determined by the carbazole method (An Automated Method For The Determination Of Hexuronic Acids, Analytical Biochemistry, 2, 517-558 [1965]). The HA content in the starting gel was calculated and the swelling ratio was expressed as 100/[HA]%, where [HA]% is a percent of HA in the swollen gel.
The swelling ratio in water of the gel obtained was 820.
This example was repeated with the exception that the solution of HA in alkali was kept at room temperature for 24 hours. This led to a HA hydrolysis. The intrinsic viscosity [η] of the polymer was 1064 which corresponded to a MW of about 0.5×10 6 . A cross-linked gel could not be obtained from this polymer at the HA/DVS ratio used above.
The example with the degraded HA was repeated but the HA/DVS ratio used was about 2. A cross-linked gel was obtained which had a swelling ratio in water of 2910.
EXAMPLE 2
This example illustrates the effect of alkali concentration on the cross-linking of HA.
A sample of HA with a MW of about 3×10 6 was dissolved in a calculated amount of 0.2M NaOH solution to give 4% viscous solution to which DVS was added in an amount providing an HA/DVS ratio of about 5:1. The cross-linking and treatment of the gel was carried out as described in the preceding example. The swelling ratio of the gel in water was 990.
The example was repeated but the alkali concentration was 0.01M. A gel was obtained with a swelling ratio in water of 3640. Thus, a decrease in the alkali concentration in the reaction mixture results in a gel with substantially greater swelling in water.
EXAMPLE 3
This example illustrates the effect of varying the HA concentration in the starting mixture on the swelling behavior of the resulting gel.
Eight solutions of sodium hyaluronate in 0.2M sodium hydroxide solution were prepared with the HA concentration being 2.0, 2.5, 3.0, 3.5, 4.0, 5.5, 8.0 and 10.0% by weight respectively. To each solution a calculated amount of DVS was added to have a weight ratio of HA/DVS about 1 (molar ratio about 0.33). The cross-linked gels were obtained as described in the above examples and treated accordingly. The swelling ratio was determined for each sample and plotted against starting HA concentration. The results are shown in FIG. 1.
EXAMPLE 4
This example illustrates the effect of varying the HA/DVS ratio on the swelling behavior of the resulting gel.
Six solutions of sodium hyaluronate in 0.2M sodium hydroxide solution were prepared with a concentration of 4.0% by weight. To each solution a calculated amount of DVS was added to have the following HA/DVS ratios: 0.2, 0.3, 0.5, 1.0, 1.5 and 2.0 mole/mole. The cross-linked gels were obtained and treated as described in the preceding examples. The swelling ratio was determined for each sample and plotted against HA/DVS ratio in the reaction mixture. The results are shown in FIG. 2.
EXAMPLE 5
This example illustrates the effect of sodium chloride in the reaction mixture on the swelling ratio of the cross-linked gel.
Two samples of the cross-linked HA gel were prepared with the use of the above described procedure. Sodium hyaluronate concentration in 0.2M sodium hydroxide was 4% by weight. The HA/DVS ratio was about 5:1, the reaction time one hour. To the second reaction mixture sodium chloride was added in an amount to have a 1.0 molar salt concentration. The swelling ratio of the first gel was 2380, whereas the gel obtained in the presence of salt had a swelling ratio in water of 650.
EXAMPLE 6
This example illustrates the cross-linking of hydroxyethyl cellulose with the use of DVS.
0.4312 g. of air-dry hydroxyethyl cellulose (Cellosize QP-100000®, Union Carbide) was dissolved with stirring in 10.3 g. of 0.2N sodium hydroxide to give 4% by weight. 0.0855 g. of DVS was stirred into this solution (polymer/DVS ratio was about 5:1 by weight) and the mixture was left for one hour at room temperature. A cross-linked gel was obtained which was processed as described in Example 1. To determine the polymer concentration in the gel and, hence, the swelling ratio, a weighed sample of the gel was put into acetone, kept overnight, washed several times with acetone and dried in a vacuum oven at 50° C. to a constant weight. The swelling ratio of the gel obtained was 43 which is substantially less than for cross-linked HA gel obtained under the same reaction conditions.
EXAMPLE 7
This example illustrates the cross-linking of xanthan gum with the use of DVS.
0.4935 g. of air-dry xanthan gum (Kelzan®, Kelco) was dissolved in 11.3 g. of 0.2M sodium hydroxide solution to give a 4% by weight solution. To this solution 0.0718 g. of DVS was added (the polymer/DVS ratio was about 7:1 by weight). The mixture was kept for an hour at room temperature. The cross-linked gel finally obtained was put into a large volume of water, left to swell overnight and broken into small pieces which were extensively washed with water.
The swelling ratio of the gel determined by the weight method described in the preceding example was 526, which is substantially less than for cross-linked HA gel obtained under the same reaction conditions.
EXAMPLE 8
This example illustrates the cross-linking of a cationic water-soluble cellulose polymer with the use DVS.
0.5483 g. of a cationic cellulose polymer obtained by chemical modification of hydroxyethyl cellulose (Polymer Ucare JR®, Union Carbide) was dissolved in 13.71 g. of 0.2M sodium hydroxide solution to give a 4% by weight solution to which 0.0849 g. of DVS was added (the polymer/DVS ratio was about 6.5:1). The reaction mixture was left to stand for an hour at room temperature and the gel obtained was processed and analyzed as described in the preceding example. The swelling ratio of the gel in water was 386, which is substantially less than that for a cross-linked HA gel obtained under the same reaction conditions.
EXAMPLE 9
This example illustrates the cross-linking of carboxymethyl cellulose with the use of DVS.
0.4703 g. of carboxymethyl cellulose sodium salt (9H 4F, Hercules) was dissolved in 11.76 g. of 0.2M NaOH to give a 4% by weight solution to which 0.0651 g. of DVS was added (the polymer/DVS ratio was about 7:1). The reaction mixture was kept for an hour at room temperature and the gel obtained was processed and analysed as described in the preceding example. The swelling ratio in water was 893, which is more than that obtained for other cellulosic polymers but less than for cross-linked HA gel.
EXAMPLES 10-13
These examples illustrate mixed cross-linked gels made of HA and carboxymethyl cellulose and the effect of the HA content on the swelling ratio of the gels.
In each example, sodium hyaluronate and carboxymethyl cellulose 9H4F were dissolved in 0.2M sodium hydroxide solution in such amounts as to provide specific ratios of the two polymers In all cases the total polymer concentration was 4% by weight and the polymer/DVS ratio was about 5:1. The gels were obtained and processed as described above. The polymer content in the gels was determined as described in Example 1, with the exception that the hexosamine concentration (instead of glucoronic acid) was determined by a known method (A Rapid Procedure for the Estimation of Amino Sugars on a Micro Scale, Analytical Biochemistry 15, 167-171 [1966]) in the hydrolyzate. The polymer content was calculated from the HA concentration and the ratio of the two polymers.
______________________________________ HA Content in the Starting Swelling Ratio Mixture, Wt. % in Water______________________________________Example 10 70 8196Example 11 50 6757Example 12 20 1117Example 13 0 623______________________________________
As can be seen from these data, an increase in the HA content in the starting mixture results in an increase in the swelling ratio of the resulting gels.
EXAMPLE 14
This example illustrates mixed cross-linked gels obtained from HA and collagen. 0.2531 g. of dry sodium hyaluronate was dissolved in 2.5 ml of 0.1M sodium hydroxide solution. 0.063 g. of collagen obtained from human umbilical cord was dissolved in 2.3 ml of 0.1M acetic acid and the two solutions were combined. The total polymer concentration was 6 wt. % and the weight ratio HA/collagen was about 4:1. 0.05 g. of dry KCl was dissolved in the mixed solution and DVS was stirred into the reaction mixture in an amount providing a polymer/DVS ratio of about 5:1. The reaction mixture was kept at room temperature for an hour and the gel obtained was treated as described above. The polymer content in the swollen gel was calculated from the HA content which was found by the glucuronic acid assay. A strong and resilient gel was obtained which had a swelling ratio in water of 321.
EXAMPLE 15
This example illustrates a mixed cross-linked HA-collagen gel with a higher content of collagen and a lower swelling ratio than the gel described in Example 14.
0.2544 g. of sodium hyaluronate was dissolved in 3.5 ml of 0.2M sodium hydroxide solution. 0.1192 g. of collagen obtained from human umbilical crod was dissolved in 1.5 ml of 0.2M acetic acid solution and the solutions were combined. The total polymer concentration was 7.5 wt. % and the weight ratio HA/collagen was about 2:1. 0.05 g. of sodium chloride was dissolved in the mixed solution to which 0.1189 g. of DVS was added, thus providing a polymer/DVS ratio of about 3:1 by weight. The gel was obtained and processed as described in the preceding example. A strong gel was obtained with a swelling ratio of 35.
EXAMPLE 16
This example illustrates a mixed cross-linked gel of HA and heparin.
0.2968 g. of dry sodium hyaluronate was dissolved in 6.92 g. of 0.2M sodium hydroxide solution to give a 4 wt. % solution to which 0.0503 g. of heparin was added. The heparin content calculated on the basis of the total amount of polymers was 14.5 wt. %. 0.0590 g. of DVS was stirred into the mixture. The reaction was carried out for an hour at room temperature. The obtained gel was processed as described in the preceding examples. The swelling ratio of the gel was 625.
EXAMPLE 17
This example illustrates a cross-linked hydroxyethyl cellulose gel filled with petrolatum.
0.5292 g. of dry hydroxyethyl cellulose was dissolved in 10.58 g. of 1M sodium hydroxide solution and 1.058 g. of white petrolatum was stirred into the solution. The petrolatum/polymer ratio was about 2. A solution of 0.1771 g. of DVS in 1.0 g. of 1M sodium hydroxide solution was added to the emulsion with vigorous stirring. The reaction mixture was left for an hour at room temperature and the gel obtained was treated as described in the above examples. To find the petrolatum content in the gel, a gel sample was digested with 2 ml of 1N H 2 SO 4 at 95° C. for three hours. Then 2 ml of 1N NaOH was added to the mixture followed by 4 ml of xylene to extract the petrolatum. The extract was dried off in vacuum and the residue was weighed. The calculated petrolatum content in the gel was 6 wt. %.
EXAMPLE 18
This example illustrates a mixed HA-carboxymethyl cellulose gel filled with petrolatum.
0.1830 g. of dry sodium hyaluronate and the same amount of carboxymethyl cellulose were dissolved in 9.1 g. of 0.2N sodium hydroxide solution to give a 4 wt. % solution of polymer. 0.3660 g. of petrolatum was stirred into the solution and 0.0730 of DVS was added to the resulting emulsion with vigorous stirring. The polymer/DVS ratio was about 5:1. The reaction mixture was left for an hour at room temperature. The obtained gel was processed as described in the preceding example. The swelling ratio of the gel determined through hexosamine content was 738 and the petrolatum content determined as in the preceding example was 0.1 wt. %.
EXAMPLE 19
This example illustrates a cross-linked HA gel filled with kaolin.
0.2700 g. of dry sodium hyaluronate was dissolved in an amount of 0.2N sodium hydroxide solution sufficient to obtain a 4 wt. % solution of the polymer. 0.5400 g. of kaolin was stirred into the solution. 0.0540 g. of DVS was added to the suspension and the reaction mixture was left for an hour at room temperature. The gel formed was left to swell in a large volume of water. The highly swollen gel was broken into small particles by pushing it through a syringe with a needle. The particles were extensively washed with water. Milky white, highly swollen particles were obtained. The concentration of solids in the gel was 0.064 wt. %.
EXAMPLE 20
This example illustrates a cross-linked HA gel containing carminic acid covalently attached to the macromolecular network.
0.20 g. of dry sodium hyaluronate and 0.04 g. of carminic acid were dissolved in 5.0 ml of 0.2M sodium hydroxide solution to give an approximately 4 wt. % solution of polymer. 0.40 g. of DVS was added to the solution (polymer/DVS ratio was 1:2) and the mixture was left for an hour at room temperature. The gel obtained was processed as described in the preceding examples.
Red colored transparent gel particles were obtained and the color did not disappear after extensive washing with water. The swelling ratio in water determined by the weight method was 115.
EXAMPLE 21
This example illustrates the effect of salt concentration in water on the swelling behavior of a cross-linked HA gel.
A cross-linked HA gel was obtained as described in the preceding examples with an HA concentration in 0.2M NaOH of 4 wt. %; HA/DVS ratio 5:1, at room temperature for one hour. The gel particles were put into water and aqueous sodium chloride solution of different concentrations and the swelling ratios were determined. The following results were obtained:
______________________________________NaCl Concentration, M Swelling Ratio______________________________________Water 9900.05 4130.15 3840.50 2191.00 176______________________________________
EXAMPLE 22
This example illustrates the biological activity of a mixed HA-heparin cross-linked gel.
Fine particles of the mixed HA-heparin cross-linked gel prepared according to Example 16 were mixed with normal human plasma in amounts providing concentrations of cross-linked HA of 0.01, 0.02 and 0.04% and the clotting time of the samples increased respectively by 1.4, 2.8 and 5.0 times. Identical concentrations of non-heparin containing, cross-linked gel particles had no effect on clotting time.
These data indicate that heparin does not lose the ability to inhibit thrombin-catalyzed fibrin formation when it is incorporated into a cross-linked gel structure.
EXAMPLE 23
This example illustrates a product containing cross-linked HA gel particles useful for cosmetic formulations.
A cross-linked HA gel was prepared as described in Example 1 under the following reaction conditions: HA concentration 3.0 wt. %, sodium hydroxide concentration 0.2M, HA/DVS ratio about 3:1, room temperature, time one hour. The gel was allowed to swell in a large volume of water overnight, then was broken into small particles by pushing through a syringe with a needle of 181/2 gauge and then through a syringe with a needle of 251/2 gauge. The particles were thoroughly washed with water. Optically clear, colorless particles were obtained. the swelling ratio of the gel was 1980. The HA concentration of the filtered gel particles was 0.025 wt. %. These particles were used in mixtures with high molecular weight polyethylene oxide (Polyox® Coagulant, Union Carbine) and soluble sodium hyaluronate (Hyalderm®, Biomatrix, Inc.) of the following composition:
______________________________________ Parts By Weight:Ingredients Mixture 1 Mixture 2 Mixture 3______________________________________Cross-linked gel 90 80 75Hyladerm ® (1% solution 5 2 14of sodium hyaluronate)Polyox ® 1% solution 5 4 11in waterWater -- 14 --______________________________________
All of these formulations had the appearance of homogeneous viscous liquids even though they were heterogeneous by the nature of the ingredients. When appled to the skin they gave a very soft, silky feel.
EXAMPLE 24
This example illustrates a moisturizing eye cream containing a cross-linked HA gel according to the present invention.
______________________________________ % By Weight______________________________________A. Carbopol ® 940 (B. F. Goodrich) 0.4 Mixture #3 (Example 23) 10.0 Water 83.33 (Croda, Inc.)M. 1.05 (Croda, Inc.)M. 0.5 Solulan ® C-24 (Amerchol Co.) 1.8 Roban ® 1.0 Crodamol ® PMP (Croda, Inc.) 0.5 Glucam ® E-10 (Americhol) 0.7 Preservative 0.3C. Triethanolamine 0.4 Fragrance 0.1______________________________________
This formulation is prepared in separate stages, as follows: Part A of the mixture was prepared by dispersing the Carbopol® in water and then stirring in the other components. All the part B components were mixed together and heated to 70° C. Parts A and B were then combined and the triethanolamine and fragrance were added. The resulting cream was stable and smooth and had good moisturizing qualities and an excellent feel on the skin.
EXAMPLE 25
This example illustrates the use of the petrolatum filled cross-linked gel in a hand lotion.
______________________________________ % By Weight______________________________________A. Carbopol ® 0.25 Carboxymethylcellulose 2.00 9H4F, 1% water solution Product of Example 18 60.00 Water 36.70B. Robane ® 0.20 Cochin ® 0.10 Preservative 0.30C. Triethanolamine 0.25 Fragrance 0.20______________________________________
This formulation was prepared as the one described in the preceding example. The resulting lotion was rich with excellent moisturizing qualities and did not give a greasy feeling on the skin.
The ingredients noted in Examples 24 and 25 by trademark are identified as follows:
______________________________________Volpo-5 ® Oleth-5 (polyethylene glycol ether of oleyl alcohol)Volpo-3 ® Oleth-3 (polyethylene glycol ether of oleyl alcohol)Solulan ® C-24 Choleth-24 (polyethylene glycol ether of Cholesterol)Crodamol ® PMP (propoxylated myristyl pro- pionate) PPG-3 Myristyl Ether PropionateGlucam ® E-10 Methyl gluceth-10 (poly- ethylene glycol ether of methyl glucose)______________________________________
EXAMPLE 26
This example illustrates the slow release of a low molecular weight substance dispersed in a matrix of cross-linked hyaluronic acid.
In this experiment, a radioactive labelled substance, hydroxytryptamine binoxolate, 5-[1,2- 3 H(N)]-, was used. 5 μl of a 40 μM solution of the substance was mixed with 5 μl of cross-linked HA gel particles (HA concentration in the gel 0.131%) and water, respectively. The mixtures were put into dialysis tubes and dialyzed against 0.15M NaCl solution for 24 hours. For the mixture of the labelled substance and the cross-linked gel, 54% of the starting amount of the labelled material was left in the dialysis tube, whereas only 10% remained for the water solution. This demonstrates that the cross-linked gel of HA slows down the release of the low molecular weight substance by a factor of more than 5 times.
Variations and modifications can, of course, be made without departing from the spirit and scope of the invention.
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Disclosed are cross-linked gels of hyaluronic acid, alone or mixed with other hydrophilic polymers and containing various substances or covalently bonded low molecular weight substances and processes for preparing them. These products are useful in numerous applications including cosmetic formulations and as drug delivery systems.
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FIELD OF THE INVENTION
[0001] The present invention relates to methods for treating or preventing gastritis or gastric injury by administering an amylin or an amylin agonist. The present invention also relates to the treatment of pain, fever, inflammation, arthritis, hypercoagulability, or other conditions for which a non-steroidal anti-inflammatory drug would be indicated, comprising administering an amylin or an amylin agonist in conjunction with a non-steroidal anti-inflammatory drug. Pharmaceutical compositions comprising an amylin or an amylin agonist and a non-steroidal anti-inflammatory agent are also described by the present invention.
BACKGROUND
[0002] Publications and other materials including patents and patent applications used to illuminate the specification are hereby incorporated by reference.
[0003] Amylin
[0004] The structure and biology of amylin have previously been reviewed. See, for example, Rink et al., Trends in Pharmaceutical Sciences, 14:113-118 (1993); Gaeta and Rink, Med. Chem. Res., 3:483-490 (1994); and, Pittner et al., J. Cell. Biochem., 55S:19-28 (1994).
[0005] Amylin is a 37 amino acid protein hormone. It was isolated, purified and chemically characterized as the major component of amyloid deposits in the islets of pancreases of human Type II diabetics (Cooper et al., Proc. Natl. Acad. Sci., USA 84:8628-8632 (1987)). The amylin molecule has two important post-translational modifications: the C-terminus is amidated, and the cysteines in positions 2 and 7 are cross-linked to form an N-terminal loop. The sequence of the open reading frame of the human amylin gene shows the presence of the Lys-Arg dibasic amino acid proteolytic cleavage signal, prior to the N-terminal codon for Lys, and the Gly prior to the Lys-Arg proteolytic signal at the C-terminal position, a typical sequence for amidation for protein amidating enzyme, PAM (Cooper et al., Biochm. Biophys. Acta, 1014:247-258 (1989)). Amylin is the subject of United Kingdom patent application Ser. No. 8709871, filed Apr. 27, 1987, and corresponding U.S. Pat. No. 5,367,052, issued Nov. 22, 1994.
[0006] In Type 1 diabetes, amylin has been shown to be deficient, and combined replacement with insulin has been proposed as a preferred treatment over insulin alone in all forms of diabetes. The use of amylin and other amylin agonists for the treatment of diabetes mellitus is the subject of U.S. Pat. No. 5,175,145, issued Dec. 29, 1992. Pharmaceutical compositions containing amylin and amylin plus insulin are described in U.S. Pat. No. 5,124,314, issued Jun. 23, 1992.
[0007] Amylin is primarily synthesized in pancreatic beta cells and is secreted in response to nutrient stimuli such as glucose and arginine. Studies with cloned beta-cell tumor lines (Moore et al., Biochem. Biophys. Res. Commun., 179(l) (1991)), isolated islets (Kanatsuka et al., FEBS Letts., 259(l), 199-201 (1989)) and perfused rat pancreases (Ogawa et al., J. Clin. Invest., 85:973-976 (1990)) have shown that short pulses, 10 to 20 minutes, of nutrient secretagogues such as glucose and arginine, stimulate release of amylin as well as insulin. The molar amylin:insulin ratio of the secreted proteins varies between preparations from about 0.01 to 0.4, but appears not to vary much with acute stimuli in any one preparation. However, during prolonged stimulation by elevated glucose, the amylin:insulin ratio can progressively increase (Gedulin et al., Biochem. Biophys. Res. Commun., 180(1):782-789 (1991)). Thus, amylin and insulin are not always secreted in a constant ratio.
[0008] It has been discovered and reported that certain actions of amylin are similar to non-metabolic actions of CGRP and calcitonin; however, the metabolic actions of amylin discovered during investigations of this recently identified protein appear to reflect its primary biologic role. At least some of these metabolic actions are mimicked by CGRP, albeit at doses which are markedly vasodilatory (see, e.g., Leighton et al., Nature, 335:632-635 (1988)); Molina et al., Diabetes, 39:260-265 (1990)).
[0009] The first discovered action of amylin was the reduction of insulin-stimulated incorporation of glucose into glycogen in rat skeletal muscle (Leighton et al., Nature, 335:632-635 (1988)); the muscle was made “insulin-resistant.” Subsequent work with rat soleus muscle ex-vivo and in vitro has indicated that amylin reduces glycogen synthase activity, promotes conversion of glycogen phosphorylase from the inactive b form to the active a form, promotes net loss of glycogen (in the presence or absence of insulin), increases glucose-6-phosphate levels, and can increase lactate output (see, e.g., Deems et al., Biochem. Biophys. Res. Commun., 181(l):116-120 (1991)); Young et al., FEBS Letts, 281(1,2):149-151 (1991)). Amylin appears not to affect glucose transport per se (e.g., Pittner et al., FEBS Letts., 365(1):98-100 (1995)). Studies of amylin and insulin dose-response relations show that amylin acts as a noncompetitive or functional antagonist of insulin in skeletal muscle (Young et al., Am. J. Physiol., 263(2):E274-E281 (1992)). There is no evidence that amylin interferes with insulin binding to its receptors, or the subsequent activation of insulin receptor tyrosine kinase (Follett et al., Clinical Research, 39(1):39A (1991)); Koopmans et al., Diabetologia, 34:218-224 (1991)).
[0010] It is believed that amylin acts through receptors present in plasma membranes. Studies of amylin and CGRP, and the effect of selective antagonists, suggest that amylin acts via its own receptor (Beaumont et al., Br. J. Pharmacol., 115(5):713-715 (1995); Wang et al., FEBS Letts., 219:195-198 (1991 b)), counter to the conclusion of other workers that amylin may act primarily at CGRP receptors (e.g., Chantry et al., Biochem. J., 277:139-143 (1991)); Galeazza et al., Peptides, 12:585-591 (1991)); Zhu et al., Biochem. Biophys. Res. Commun., 177(2):771-776 (1991)). Amylin receptors and their use in methods for screening and assaying for amylin agonist and antagonist compounds are described in U.S. Pat. No. 5,264,372, issued Nov. 23, 1993.
[0011] While amylin has marked effects on hepatic fuel metabolism in vivo, there is no general agreement as to what amylin actions are seen in isolated hepatocytes or perfused liver. The available data do not support the idea that amylin promotes hepatic glycogenolysis, i.e., it does not act like glucagon (e.g., Stephens et al., Diabetes, 40:395-400 (1991); Gomez-Foix et al., Biochem J., 276:607-610 (1991)). It has been suggested that amylin may act on the liver to promote conversion of lactate to glycogen and to enhance the amount of glucose able to be liberated by glucagon (see Roden et al., Diabetologia, 35:116-120 (1992)). It is most likely that amylin has no direct effect on liver cells. (Pittner, R. A., Eur. J. of Pharm. ( 1997) (in press)).
[0012] In fat cells, contrary to its action in muscle, amylin has no detectable actions on insulin-stimulated glucose uptake, incorporation of glucose into triglyceride, CO 2 production (Cooper et al., Proc. Natl. Acad. Sci., 85:7763-7766 (1988)), epinephrine-stimulated lipolysis, or insulin-inhibition of lipolysis (Lupien and Young, “Diabetes Nutrition and Metabolism—Clinical and Experimental,” Vol. 6(l), pages 1318 (February 1993)). Amylin thus exerts tissue-specific effects, with direct action on skeletal muscle, and indirect (via supply of substrate) effects on liver, while adipocytes appear “blind” to the presence or absence of amylin.
[0013] It has also been reported that amylin can have marked effects on secretion of insulin. In isolated islets (Ohsawa et al., Biochem. Biophys. Res. Commun., 160(2):961-967 (1989)), in the perfused pancreas (Silvestre et al., Reg. Pept., 31:23-31 (1991)), and in the intact rat (Young et al., Mol. Cell. Endocrinol., 84:R1-R5 (1992)), some experiments indicate that amylin inhibits insulin secretion. Other workers, however, have been unable to detect effects of amylin on isolated β-cells, on isolated islets, or in the whole animal (see Broderick et al., Biochem. Biophys. Res. Commun., 177:932-938 (1991) and references therein).
[0014] Amylin or amylin agonists potently inhibit gastric emptying in rats (Young et al., Diabetologia 38(6):642-648 (1995)), dogs (Brown et al., Diabetes 43(Suppl 1):172A (1994)) and humans (Macdonald et al., Diabetologia 38(Suppl 1):A32 (abstract 118)(1995)). Gastric emptying is reportedly accelerated in amylin-deficient type 1 diabetic BB rats (Young et al., Diabetologia , supra; Nowak et al., J. Lab. Clin. Med., 123(1):110-6 (1994)) and in rats treated with the selective amylin antagonist, AC187 (Gedulin et al., Diabetologia, 38(Suppl 1):A244 (1995). Methods for reducing gastric motility and slowing gastric emptying comprising the administration of an amylin agonist (including amylin) are the subject of U.S. patent application Ser. No. 08/118,381, filed Sep. 7, 1993, and U.S. patent application Ser. No. 08/302,069, filed Sep. 7, 1994 (and corresponding PCT application, Publication No. WO 95/07098, published Mar. 16, 1995). The effect of amylin on gastric emptying appears to be physiological (operative at concentrations that normally circulate). Supraphysiological levels of amylin have also been studied with regard to the inhibition of gastric acid secretion (Guidobono, F., et al., Peptides 15:699-702 (1995)) and in regard to protection from gastritis. (Guidobono et al., Brit. J. Pharm. 120:581-86 (1997)). The latter authors reported that subcutaneous injections of amylin had no effect on ethanol- or indomethacin-induced gastritis in rats, although intracerebroventricular injections did have an effect. The same authors also concluded that any gastroprotective effects of amylin were distinct from effects to inhibit acid secretion.
[0015] Non-metabolic actions of amylin include vasodilator effects which may be mediated by interaction with CGRP vascular receptors. Reported in vivo tests suggest that amylin is at least about 100 to 1000 times less potent than CGRP as a vasodilator (Brain et al., Eur. J. Pharmacol., 183:2221 (1990); Wang et al., FEBS Letts., 291:195-198 (1991)). The effect of amylin on regional hemodynamic actions, including renal blood flow, in conscious rats has been reported (Gardiner et al., Diabetes, 40:948-951 (1991)). The authors noted that infusion of rat amylin was associated with greater renal vasodilation and less mesenteric vasoconstriction than is seen with infusion of human α-CGRP. They concluded that, by promoting renal hyperemia to a greater extent than did α-CGRP, rat amylin could cause less marked stimulation of the renin-angiotensin system, and thus, less secondary angiotensin II-mediated vasoconstriction. It was also noted, however, that during coninfusion of human α- 8-37 CGRP and rat amylin, renal and mesenteric vasoconstrictions were unmasked, presumably due to unopposed vasoconstrictor effects of angiotensin II, and that this finding is similar to that seen during coinfusion of human A-CGRP and human α- 8-37 CGRP (id. at 951).
[0016] Injected into the brain, or administered peripherally, amylin has been reported to suppress food intake, e.g., Chance et al., Brain Res., 539:352-354 (1991)), an action shared with CGRP and calcitonin. The effective concentrations at the cells that mediate this action are not known. Amylin has also been reported to have effects both on isolated osteoclasts where it caused cell quiescence, and in vivo where it was reported to lower plasma calcium by up to 20% in rats, in rabbits, and in humans with Paget's disease (see, e.g., Zaidi et al., Trends in Endocrinol. and Metab., 4:255-259 (1993)). From the available data, amylin seems to be less potent than human calcitonin for these actions. Interestingly, it was reported that amylin appeared to increase osteoclast cAMP production but not to increase cytosolic Ca 2+ , while calcitonin does both (Alam et al., Biochem. Biophys. Res. Commun., 179(l):134-139 (1991)). It was suggested, though not established, that calcitonin may act via two receptor types and that amylin may interact with one of these.
[0017] It has also been discovered that, surprisingly in view of its previously described renal vasodilator and other properties, amylin markedly increases plasma renin activity in intact rats when given subcutaneously in a manner that avoids any disturbance of blood pressure. This latter point is important because lowered blood pressure is a strong stimulus to renin release. Amylin antagonists, such as amylin receptor antagonists, including those selective for amylin receptors compared to CGRP and/or calcitonin receptors, can be used to block the amylin-evoked rise of plasma renin activity. The use of amylin antagonists to treat renin-related disorders is described in U.S. Pat. No. 5,376,638, issued Dec. 27, 1994.
[0018] It has also been found that amylin and amylin agonists have an analgesic effect; methods for treating pain comprising the administration of an amylin or an amylin agonist with or without a narcotic analgesic are described in U.S. application Ser. No. 08/767,169, filed Dec. 16, 1996.
[0019] In normal humans, fasting amylin levels from 1 to 10 pM and post-prandial or post-glucose levels of 5 to 20 pM have been reported (e.g., Hartter et al., Diabetologia, 34:52-54 (1991); Sanke et al., Diabetologia, 34:129-132 (1991); Koda et al., The Lancet, 339:1179-1180 (1992)). In obese, insulin-resistant individuals, post-food amylin levels can go higher, reaching up to about 50 pM. For comparison, the values for fasting and post-prandial insulin are 20 to 50 pM, and 100 to 300 pM respectively in healthy people, with perhaps 3-to 4-fold higher levels in insulin-resistant people. In Type 1 diabetes, where beta cells are destroyed, amylin levels are at or below the levels of detection and do not rise in response to glucose (Koda et al., The Lancet, 339:1179-1180 (1992)). In normal mice and rats, basal amylin levels have been reported from 30 to 100 pM, while values up to 600 pM have been measured in certain insulin-resistant, diabetic strains of rodents (e.g., Huang et al., Hypertension, 19:I-101-I-109 (1991); Gill et al., Life Sciences, 48:703-710 (1991)).
[0020] Non-Steroidal Anti-Inflammatory Drugs
[0021] Non-steroidal anti-inflammatory drugs or agents (NSAIDS) are useful analgesics, however, they have the adverse property of inducing various gastric effects in a large fraction of patients; such gastric effects include gastritis, gastric ulcer, epigastric distress, nausea, vomiting, and hemorrhage. (Woodbury, D. M. and Fingl, E. Analgesic-antipyretics, anti-inflammatory agents, and drugs employed in the therapy of gout , in The Pharmacological Basis of Therapeutics (Goodman, L. S., and Gilman, A., eds.) 325-43 (1975)). Such NSAIDS include salicylate, phenylbutazone, indomethacin, acetominophan, phenacetin, naproxen, and ibuprofen. This side effect is particularly a problem in patients that must continually ingest NSAIDs, such as in patients with chronic inflammatory conditions, such as rheumatoid arthritis.
SUMMARY OF THE INVENTION
[0022] We have discovered that, unexpectedly, amylins and amylin agonists have gastroprotective properties and can prevent the induction of gastritis, and thus treat or prevent gastric injury, such as gastric ulcers, when administered to a subject. The term “amylin” is understood to include compounds such as those defined by Young and Cooper in U.S. Pat. No. 5,234,906, issued Aug. 10, 1993 for “Hyperglycemic Compositions,” the contents of which are hereby incorporated by this reference. For example, the term includes human amylin and species variations of it, referred to as amylin and secreted from the beta cells of the pancreas. “Amylin agonist” is also a term known in the art. The term refers to compounds which mimic effects of amylin. Amylin agonists include “amylin agonist analogues” which are derivatives of amylin which act as amylin agonists. Amylin agonists may act by binding to or otherwise directly or indirectly interacting with an amylin receptor or other receptor with which amylin itself may interact to elicit biological effects of amylin. In addition to those amylin agonists described herein, other useful amylin agonists are identified in U.S. patent application Ser. No. 08/477,849, filed May 30, 1995 and corresponding PCT application Publication No. WO 93/10146, published May 27, 1993, the disclosures of which are hereby incorporated by this reference.
[0023] Thus, in a first aspect of the invention, a method is provided for treating or preventing gastritis or gastric ulceration in a subject, comprising administering to said subject a therapeutically effective amount of an amylin or an amylin agonist, wherein said amylin agonist is not a calcitonin. In one embodiment, said gastritis or gastric ulceration is associated with the administration of a non-steroidal anti-inflammatory drug.
[0024] In the methods of the present invention, the analgesic properties of amylins and amylin agonists will supplement and augment the analgesic properties of NSAIDS, while the gastroprotective effects of amylins and amylin agonists will reduce the propensity of NSAIDS to cause gastritis and ulceration, whether the NSAIDS are being used to treat pain, or for any other purpose.
[0025] Thus, in another aspect of the invention, a method is provided for treating or preventing pain, inflammation, fever, arthritis, hypercoagulability, or other conditions for which an NSAID would be indicated comprising administering to a subject a therapeutically effective amount of an amylin or an amylin agonist, wherein said amylin agonist is not a calcitonin, and a therapeutically effective amount of a non-steroidal anti-inflammatory agent. In another preferred aspect, the invention provides a method of enhancing the analgesic activity of an NSAID in a subject, comprising administering an amylin or an amylin agonist along with said NSAID, wherein said amylin agonist is not a calcitonin. Preferably, said non-steroidal anti-inflammatory agent is selected from the group consisting of salicylate, acetominophen, phenacetin, naproxen, phenylbutazone, indomethacin, and ibuprofen.
[0026] According to the methods of the present invention, the preferred method of administration of said amylin or amylin agonist is not through intramuscular or subcutaneous injection. Most preferably, the amylin or amylin agonist is administered by a route selected from the group consisting of nasal, pulmonary, transdermal, oral, and buccal administration.
[0027] The subject may be any animal, preferably a mammal, and more preferably a human.
[0028] In other aspects of the present invention, a pharmaceutical composition is provided comprising (1) an amylin or an amylin agonist or a pharmaceutically acceptable salt thereof, wherein said amylin agonist is not a calcitonin, and (2) a non-steroidal anti-inflammatory agent in a pharmaceutically acceptable carrier and dose.
[0029] Preferably, said non-steroidal anti-inflammatory agent is selected from the group consisting of salicylate, phenacetin, naproxen, phenylbutazone, indomethacin, and ibuprofen.
[0030] In preferred embodiments of the present invention, the amylin agonist is 25,28,29 Pro-h-amylin.
[0031] Administration of an amylin or an amylin agonist may be by various routes, including subcutaneously, or intramuscularly, or through non-injectable routes of parenteral administration, such as through oral, nasal, pulmonary, transdermal, or buccal routes. Such non-injectable routes of parenteral administration are preferred because of the high potency of the amylin or amylin agonist. Oral administration is especially preferred for orally-active amylin agonists.
BRIEF DESCRIPTION OF THE DRAWINGS
[0032] The invention will be further described with reference to the accompanying drawing in which:
[0033] [0033]FIG. 1 shows the effect of subcutaneous doses of rat amylin to reduce the gastric injury induced by gavage of ethanol into rats.
DETAILED DESCRIPTION OF THE INVENTION
[0034] Amylin agonists may be identified by activity in the gastroprotection assays described below. These compounds may also be assessed by receptor binding and gastric emptying assays described below.
[0035] The nomenclature of various amylin agonist compounds useful in the present invention can be used to indicate both the peptide that the sequence is based on and the modifications made to any basic peptide amylin sequence, such as human amylin. An amino acid preceded by a superscript number indicates that the named amino acid replaces the amino acid normally present at the amino acid position of the superscript in the basic amino acid sequence. For example, “ 18 Arg 25,28 Pro-h-amylin” refers to a peptide based on the sequence of “h-amylin” or “human-amylin” having the following substitutions: Arg replacing His at residue 18, Pro replacing Ala at residue 25 and Pro replacing Ser at residue 28. The term “des- 1 Lys-h-amylin” refers to a peptide based on the sequence of human amylin, with the first, or N-terminal, amino acid deleted.
[0036] Amylin agonists include the following amylin agonist analogues:
[0037] i) An agonist analogue of amylin having the amino acid sequence:
[0038] [0038] 1 A 1 -X-Asn-Thr- 5 Ala-Thr-Y-Ala-Thr- 10 Gln-Arg-Leu-B 1 -Asn- 15 Phe-Leu-C 1 -D 1 -E 1 - 20 F 1 -G 1 -Asn-H 1 -Gly- 25 Pro-I 1 -Leu-Pro-J 1 - 30 Thr-K 1 -Val-Gly-Ser- 35 Asn-Thr-Tyr-Z
[0039] wherein
[0040] Al is Lys, Ala, Ser or hydrogen;
[0041] B 1 is Ala, Ser or Thr;
[0042] C 1 is Val, Leu or Ile;
[0043] D 1 is His or Arg;
[0044] E 1 is Ser or Thr;
[0045] F 1 is Ser, Thr, Gln or Asn;
[0046] G 1 is Asn, Gln or His;
[0047] H 1 is Phe, Leu or Tyr;
[0048] I 1 is Ile, Val, Ala or Leu;
[0049] J 1 is Ser, Pro or Thr;
[0050] K 1 is Asn, Asp or Gln;
[0051] X and Y are independently selected residues having side chains which are chemically bonded to each other to form an intramolecular linkage, wherein said intramolecular linkage comprises a disulfide bond, a lactam or a thioether linkage; and Z is amino, alkylamino, dialkylamino, cycloalkylamino, arylamino, aralkylamino, alkyloxy, aryloxy or aralkyloxy; and provided that when A 1 is Lys, B 1 is Ala, C 1 is Val, D 1 is Arg, E 1 is Ser, F 1 is Ser, G 1 is Asn, H 1 is Leu, I 1 is Val, J 1 is Pro, and K 1 is Asn; then one or more of A 1 to K 1 is a D-amino acid and Z is selected from the group consisting of alkylamino, dialkylamino, cycloalkylamino, arylamino, aralkylamino, alkyloxy, aryloxy or aralkyloxy.
[0052] ii) An agonist analogue of amylin having the amino acid sequence:
[0053] [0053] 1 A 1 -X-Asn-Thr- 5 Ala-Thr-Y-Ala-Thr- 10 Gln-Arg-Leu-B 1 -Asn- 15 Phe-Leu-C 1 -D 1 -E 1 - 20 F 1 -G 1 -Asn-H 1 -Gly- 25 Pro-I 1 -Leu-J 1 -Pro- 30 Thr-K 1 -Val-Gly-Ser- 35 Asn-Thr-Tyr-Z
[0054] wherein
[0055] A 1 is Lys, Ala, Ser or hydrogen;
[0056] B 1 is Ala, Ser or Thr;
[0057] C 1 is Val, Leu or Ile;
[0058] D 1 is His or Arg;
[0059] E 1 is Ser or Thr;
[0060] F 1 is Ser, Thr, Gln or Asn;
[0061] G 1 is Asn, Gln or His;
[0062] H 1 is Phe, Leu or Tyr;
[0063] I 1 is Ile, Val, Ala or Leu;
[0064] J 1 is Ser, Pro, Leu, Ile or Thr;
[0065] K 1 is Asn, Asp or Gln;
[0066] X and Y are independently selected residues having side chains which are chemically bonded to each other to form an intramolecular linkage, wherein said intramolecular linkage comprises a disulfide bond, a lactam or a thioether linkage; and Z is amino, alkylamino, dialkylamino, cycloalkylamino, arylamino, aralkylamino, alkyloxy, aryloxy or aralkyloxy; and provided than when
[0067] (a) A 1 is Lys, B 1 is Ala, C 1 is Val, D 1 is Arg, E 1 is Ser, F 1 is Ser, G 1 is Asn, H 1 is Leu, I 1 is Val, J 1 is Pro and K 1 is Asn; or
[0068] (b) A 1 is Lys, B 1 is Ala, C 1 is Val, D 1 is His, E 1 is Ser, F 1 is Asn, G 1 is Asn, H 1 is Leu, I 1 is Val, J 1 is Ser and K 1 is Asn;
[0069] then one or more of A 1 to K 1 is a D-amino acid and Z is selected from the group consisting of alkylamino, dialkylamino, cycloalkylamino, arylamino, aralkylamino, alkyloxy, aryloxy or aralkyloxy.
[0070] iii) An agonist analogue of amylin having the amino acid sequence:
[0071] [0071] 1 A 1 -X-Asn-Thr- 5 Ala-Thr-Y-Ala-Thr- 10 Gln-Arg-Leu-B 1 -Asn- 15 Phe-Leu-C 1 -D 1 -E 1 - 20 F 1 -G 1 -Asn-H 1 -Gly- 25 I 1 -J 1 -Leu-Pro-Pro- 30 Thr-K 1 -Val-Gly-Ser- 35 Asn-Thr-Tyr-Z
[0072] wherein
[0073] A 1 is Lys, Ala, Ser or hydrogen;
[0074] B 1 is Ala, Ser or Thr;
[0075] C 1 is Val, Leu or Ile;
[0076] D 1 is His or Arg;
[0077] E 1 is Ser or Thr;
[0078] F 1 is Ser, Thr, Gln or Asn;
[0079] G 1 is Asn, Gln or His;
[0080] H 1 is Phe, Leu or Tyr;
[0081] I 1 is Ala or Pro;
[0082] J 1 is Ile, Val, Ala or Leu;
[0083] K 1 is Asn, Asp or Gln; X and Y are independently selected residues having side chains which are chemically bonded to each other to form an intramolecular linkage, wherein said intramolecular linkage comprises a disulfide bond, a lactam or a thioether linkage; and Z is amino, alkylamino, dialkylamino, cycloalkylamino, arylamino, aralkylamino, alkyloxy, aryloxy or aralkyloxy; and provided that when A 1 is Lys, B 1 is Ala, C 1 is Val, D 1 is Arg, E 1 is Ser, F 1 is Ser, G 1 is Asn, H 1 is Leu, I 1 is Pro, J 1 is Val and K 1 is Asn; then one or more of A 1 to K 1 is a D-amino acid and Z is selected from the group consisting of alkylamino, dialkylamino, cycloalkylamino, arylamino, aralkylamino, alkyloxy, aryloxy or aralkyloxy.
[0084] iv) An agonist analogue of amylin having the amino acid sequence:
[0085] [0085] 1 A-X-Asn-Thr- 5 Ala-Thr-Y-Ala-Thr- 10 Gln-Arg-Leu-B 1 -Asn- 15 Phe-Leu-C 1 -D 1 -E 1 - 20 F 1 -G 1 -Asn-H 1 -Gly- 25 Pro-I 1 -Leu-Pro-Pro- 30 Thr-J 1 -Val-Gly-Ser- 35 Asn-Thr-Tyr-Z
[0086] wherein
[0087] A 1 is Lys, Ala, Ser or hydrogen;
[0088] B 1 is Ala, Ser or Thr;
[0089] C 1 is Val, Leu or Ile;
[0090] D 1 is His or Arg;
[0091] E 1 is Ser or Thr;
[0092] F 1 is Ser, Thr, Gln or Asn;
[0093] G 1 is Asn, Gln or His;
[0094] H 1 is Phe, Leu or Tyr;
[0095] I 1 is Ile, Val, Ala or Leu;
[0096] J 1 is Asn, Asp or Gln; X and Y are independently selected residues having side chains which are chemically bonded to each other to form an intramolecular linkage wherein said intramolecular linkage comprises a disulfide bond, a lactam or a thioether linkage; and Z is amino, alkylamino, dialkylamino, cycloalkylamino, arylamino, aralkylamino, alkyloxy, aryloxy or aralkyloxy; and provided that when A 1 is Lys, B 1 is Ala, C 1 is Val, D 1 is Arg, E 1 is Ser, F 1 is Ser, G 1 is Asn, H 1 is Leu, I 1 is Val and J 1 is Asn; then one or more of A 1 to K 1 is a D-amino acid and Z is selected from the group consisting of alkylamino, dialkylamino, cycloalkylamino, arylamino, aralkylamino, alkyloxy, aryloxy or aralkyloxy.
[0097] Preferred amylin agonist compounds, des- 1 Lys-h-amylin, 28 Pro-h-amylin, 25,28,29 Pro-h-amylin, 18 Arg 25,28 Pro-h-amylin, and des- 1 Lys 18 Arg 25,28 Pro-h-amylin, all show amylin activity in vivo in treated test animals. In addition to having activities characteristic of amylin, certain preferred compounds have also been found to possess more desirable solubility and stability characteristics when compared to human amylin. These preferred compounds include 25 Pro 26 Val 28,29 Pro-h-amylin, 25,28,29 Pro-h-amylin (also referred to herein as “AC-0137”), and 18 Arg 25,28 Pro-h-amylin.
[0098] The methods of the present invention employ an amylin or an amylin agonist, for example, amylin receptor agonists such as 18 Arg 25,28 Pro-h-amylin, des- 1 Lys 18 Arg 25,28 Pro-h-amylin, 18 Arg 25,28,29 Pro-h-amylin, des- 1 Lys 18 Arg 25,28,29 Pro-h-amylin, 25,28-29 Pro-h-amylin, des- 1 Lys 25,28,29 Pro-h-amylin, and 25 Pro 26 Val 28,29 Pro-h-amylin. Examples of other suitable amylin agonists include:
[0099] [0099] 23 Leu 25 Pro 26 Val 28,29 Pro-h-amylin;
[0100] [0100] 23 Leu 25 Pro 26 Val 28 Pro-h-amylin;
[0101] des- 1 Lys 23 Leu 25 Pro 26 Val 28 pro-h-amylin;
[0102] [0102] 18 Arg 23 Leu 25 Pro 26 Val 28 Pro-h-amylin;
[0103] [0103] 18 Arg 23 Leu 25,28,29 Pro-h-amylin;
[0104] [0104] 18 Arg 23 Leu 25,28 Pro-h-amylin;
[0105] [0105] 17 Ile 23 Leu 25,28,29 Pro-h-amylin;
[0106] [0106] 17 Ile 25,28,29 Pro-h-amylin;
[0107] des- 1 Lys 17 Ile 23 Leu 25,28,29 Pro-h-amylin;
[0108] [0108] 17 Ile 18 Arg 23 Leu-h-amylin;
[0109] [0109] 17 Ile 18 Arg 23 Leu 26 Val 29 Pro-h-amylin;
[0110] [0110] 17 Ile 18 Arg 23 Leu 25 Pro 26 Val 28,29 Pro-h-amylin;
[0111] [0111] 13 Thr 21 His 23 Leu 26 Ala 28 Leu 29 Pro 31 Asp-h-amylin;
[0112] [0112] 13 Thr 21 His 23 Leu 26 Ala 29 Pro 31 Asp-h-amylin;
[0113] des- 1 Lys 13 Thr 21 His 23 Leu 26 Ala 28 Pro 31 Asp-h-amylin;
[0114] [0114] 13 Thr 18 Arg 21 His 23 Leu 26 Ala 29 Pro 31 Asp-h-amylin;
[0115] [0115] 13 Thr 18 Arg 21 His 23 Leu 28,29 Pro 31 Asp-h-amylin; and,
[0116] [0116] 13 Thr 18 Arg 21 His 23 Leu 25 Pro 26 Ala 28,29 Pro 31 Asp-h-amylin
[0117] Still further amylin agonists, including amylin agonist analogues, are disclosed, and methods for making and using amylin agonists are further specified, in commonly owned U.S. patent application Ser. No. 08/477,849, entitled “Novel Amylin Agonist Peptides and Uses Therefor” filed May 30, 1995 and corresponding PCT application Publication No. WO 93/10146, published May 27, 1993, the disclosures of which are hereby incorporated by this reference.
[0118] The activity of amylin agonists may be evaluated using certain biological assays described herein. The receptor binding assay can identify both candidate amylin agonists and antagonists and can be used to evaluate binding, while the rat gastric-emptying assay can be used to distinguish between amylin agonists and antagonists. Preferably, agonist compounds exhibit activity in the receptor binding assay on the order of less than about 1 to 5 nM, preferably less than about 1 nM and more preferably less than about 50 pM. In the in vivo rat gastric emptying assay-these compounds preferably show ED 50 values on the order of less than about 100 to 1000 μg/rat.
[0119] The receptor binding assay is described in U.S. Pat. No. 5,264,372, issued Nov. 23, 1993, the disclosure of which is incorporated herein by reference. The receptor binding assay is a competition assay which measures the ability of compounds to bind specifically to membrane-bound amylin receptors. A preferred source of the membrane preparations used in the assay is the basal forebrain which comprises membranes from the nucleus accumbens and surrounding regions. Compounds being assayed compete for binding to these receptor preparations with 125 I Bolton Hunter rat amylin. Competition curves, wherein the amount bound (B) is plotted as a function of the log of the concentration of ligand are analyzed by computer, using analyses by nonlinear regression to a 4-parameter logistic equation (Inplot program; GraphPAD Software, San Diego, Calif.) or the ALLFIT program of DeLean et. al. (ALLFIT, Version 2.7 (NIH, Bethesda, Md. 20892)). Munson, P. and Rodbard, D., Anal. Biochem. 107:220-239 (1980).
[0120] Amylins or amylin agonists can be identified, evaluated, or screened by their effects on gastric emptying using the methods described in U.S. applications Ser. No. 08/118,381, filed Sep. 7, 1993, and U.S. application Ser. No. 08/302,069, filed Sep. 7, 1994 (corresponding to PCT Application, Publication No. WO 95/07098), the disclosures of which are hereby incorporated by reference, or other art-known or equivalent methods for determining gastric motility. One such method for use in identifying or evaluating the ability of a compound to slow gastric motility, comprises: (a) bringing together a test sample and a test system, said test sample comprising one or more test compounds, and said test system comprising a system for evaluating gastric motility, said system being characterized in that it exhibits, for example, elevated plasma label in response to the intragastric introduction to said system of that label; and, (b) determining the presence or amount of a rise in plasma label in said system. Positive and/or negative controls may be used as well. Optionally, a predetermined amount of amylin antagonist (e.g., 8-32 salmon calcitonin) may be added to the test system.
[0121] Amylin agonists such as those described above are prepared using standard solid-phase peptide synthesis techniques and preferably an automated or semiautomated peptide synthesizer. Typically, an α-N-carbamoyl protected amino acid and an amino acid attached to the growing peptide chain on a resin are coupled at room temperature in an inert solvent such as dimethylformamide, N-methylpyrrolidinone or methylene chloride in the presence of coupling agents such as dicyclohexylcarbodiimide and 1-hydroxybenzotriazole in the presence of a base such as diisopropylethylamine. The α-N-carbamoyl protecting group is removed from the resulting peptide-resin using a reagent such as trifluoroacetic acid or piperidine, and the coupling reaction repeated with the next desired N-protected amino acid to be added to the peptide chain. Suitable N-protecting groups are well known in the art, with t-butyloxycarbonyl (tboc) and fluorenylmethoxycarbonyl (Fmoc) being preferred herein.
[0122] The solvents, amino acid derivatives and 4-methylbenzhydryl-amine resin used in the peptide synthesizer are purchased from Applied Biosystems Inc. (Foster City, Calif.), unless otherwise indicated. The side-chain protected amino acids are purchased from Applied Biosystems, Inc. and include the following: Boc-Arg(Mts), Fmoc-Arg(Pmc), Boc-Thr(Bzl), Fmoc-Thr(t-Bu), Boc-Ser(Bzl), Fmoc-Ser(t-Bu), Boc-Tyr(BrZ), Fmoc-Tyr(t-Bu), Boc-Lys(Cl-Z), Fmoc-Lys(Boc), Boc-Glu(Bzl), Fmoc-Glu(t-Bu), Fmoc-His(Trt), Fmoc-Asn(Trt), and Fmoc-Gln(Trt). Boc-His(BOM) is purchased from Applied Biosystems, Inc. or Bachem Inc. (Torrance, Calif.). Anisole, methylsulfide, phenol, ethanedithiol, and thioanisole are obtained from Aldrich Chemical Company (Milwaukee, Wis.). Air Products and Chemicals (Allentown, Pa.) supplies HF. Ethyl ether, acetic acid and methanol are purchased from Fisher Scientific (Pittsburgh, Pa.).
[0123] Solid phase peptide synthesis is carried out with an automatic peptide synthesizer (Model 430A, Applied Biosystems Inc., Foster City, Calif.) using the NMP/HOBt (Option 1) system and Tboc or Fmoc chemistry (see, Applied Biosystems User's Manual for the ABI 430A Peptide Synthesizer, Version 1.3B Jul. 1, 1988, section 6, pp. 49-70, Applied Biosystems, Inc., Foster City, Calif.) with capping. Boc-peptide-resins are cleaved with HF (−5° C. to 0° C., 1 hour). The peptide is extracted from the resin with alternating water and acetic acid, and the filtrates are lyophilized. The Fmoc-peptide resins are cleaved according to standard methods ( Introduction to Cleavage Techniques , Applied Biosystems, Inc., 1990, pp. 6-12). Some peptides are also assembled using an Advanced Chem Tech Synthesizer (Model MPS 350, Louisville, Ky.). Peptides are purified by RP-HPLC (preparative and analytical) using a Waters Delta Prep 3000 system. A C4, C8 or C18 preparative column (10μ, 2.2×25 cm; Vydac, Hesperia, Calif.) is used to isolate peptides, and purity is determined using a C4, C8 or C18 analytical column (5μ, 0.46×25 cm; Vydac). Solvents (A=0.1% TFA/water and B=0.1% TFA/CH 3 CN) are delivered to the analytical column at a flowrate of 1.0 ml/min and to the preparative column at 15 ml/min. Amino acid analyses are performed on the Waters Pico Tag system and processed using the Maxima program. The peptides are hydrolyzed by vapor-phase acid hydrolysis (115° C., 20-24 h). Hydrolysates are derivatized and analyzed by standard methods (Cohen, S. A., Meys, M., and Tarrin, T. L. (1989), The Pico Tag Method: A Manual of Advanced Techniques for Amino Acid Analysis , pp. 11-52, Millipore Corporation, Milford, Mass.). Fast atom bombardment analysis is carried out by M-Scan, Incorporated (West Chester, Pa.). Mass calibration is performed using cesium iodide or cesium iodide/glycerol. Plasma desorption ionization analysis using time of flight detection is carried out on an Applied Biosystems Bio-Ion 20 mass spectrometer.
[0124] Peptide compounds useful in the claimed methods may also be prepared using recombinant DNA techniques, using methods now known in the art. See, e.g., Sambrook et al., Molecular Cloning: A Laboratory Manual, 2d Ed., Cold Spring Harbor (1989).
[0125] The compounds referenced above form salts with various inorganic and organic acids and bases. Such salts include salts prepared with organic and inorganic acids, for example, HCl, HBr, H2SO 4 , H 3 PO 4 , trifluoroacetic acid, acetic acid, formic acid, methanesulfonic acid, toluenesulfonic acid, maleic acid, fumaric acid and camphorsulfonic acid. Salts prepared with bases include ammonium salts, alkali metal salts, e.g. sodium and potassium salts, and alkali earth salts, e.g. calcium and magnesium salts. Acetate, hydrochloride, and trifluoroacetate salts are preferred. The salts may be formed by conventional means, as by reacting the free acid or base forms of the product with one or more equivalents of the appropriate base or acid in a solvent or medium in which the salt is insoluble, or in a solvent such as water which is then removed in vacuo or by freeze-drying or by exchanging the ions of an existing salt for another ion on a suitable ion exchange resin.
[0126] Compositions useful in the invention may conveniently be provided in the form of formulations suitable for parenteral (including, intramuscular and subcutaneous) or nasal or transdermal, and/or suitably encapsulated or otherwise prepared by another known methods for oral administration. A suitable administration format may best be determined by a medical practitioner for each patient individually. Suitable pharmaceutically acceptable carriers and their formulation are described in standard formulation treatises, e.g., Remington's Pharmaceutical Sciences by E. W. Martin. See also Wang, Y. J. and Hanson, M. A. “Parenteral Formulations of Proteins and Peptides: Stability and Stabilizers,” Journal of Parenteral Science and Technology , Technical Report No. 10, Supp. 42:2S (1988). Compounds useful in the invention can be provided as parenteral compositions for injection or infusion. Preferably, they are dissolved in an aqueous carrier, for example, in an isotonic buffer solution at a pH of about 4.3 to 7.4. These compositions may be sterilized by conventional sterilization techniques, or may be sterile filtered. The compositions may contain pharmaceutically acceptable auxiliary substances as required to stabilize the formulation, such as pH buffering agents. Useful buffers include for example, sodium acetate/acetic acid buffers. A form of repository or “depot” slow release preparation may be used so that therapeutically effective amounts of the preparation are delivered into the bloodstream over many hours or days following transdermal injection or delivery.
[0127] Preferably, these parenteral dosage forms are prepared according to the U.S. Provisional Patent Application filed Jan. 7, 1997, entitled “Parenteral, Liquid Formulations for Amylin Agonist Peptides,” and include approximately 0.01 to 0.2 w/v%, respectively, of an amylin and/or an amylin agonist in an aqueous system along with approximately 0.02 to 0.5 w/v% of an acetate, phosphate, citrate or glutamate buffer to obtain a pH of the final composition of approximately 3.0 to 6.0 (more preferably 3.0 to 5.5), as well as approximately 1.0 to 10 w/v% of a carbohydrate or polyhydric alcohol stabilizer in an aqueous continuous phase. Approximately 0.005 to 1.0 w/v% of an antimicrobial preservative selected from the group consisting of m-cresol, benzyl alcohol, methyl, ethyl, propyl and butyl parabens and phenol is also present in the preferred formulation of product designed to allow the patient to withdraw multiple doses. A sufficient amount of water for injection is used to obtain the desired concentration of solution. Sodium chloride, as well as other excipients, may also be present, if desired. Such excipients, however, must maintain the overall stability of the amylin, or an amylin agonist. Most preferably, in the amylin and/or amylin agonist formulation for parenteral administration, the polyhydric alcohol is mannitol, the buffer is an acetate buffer, the preservative is approximately 0.1 to 0.3 w/v of m-cresol, and the pH is approximately 3.7 to 4.3.
[0128] The desired isotonicity may be accomplished using sodium chloride or other pharmaceutically acceptable agents such as dextrose, boric acid, sodium tartrate, propylene glycol, polyols (such as mannitol and sorbitol), or other inorganic or organic solutes. Sodium chloride is preferred particularly for buffers containing sodium ions.
[0129] If desired, solutions of the above compositions may be thickened with a thickening agent such as methyl cellulose. They may be prepared in emulsified form, either water in oil or oil in water. Any of a wide variety of pharmaceutically acceptable emulsifying agents may be employed including, for example, acacia powder, a non-ionic surfactant (such as a Tween), or an ionic surfactant (such as alkali polyether alcohol sulfates or sulfonates, e.g., a Triton).
[0130] Compositions useful in the invention are prepared by mixing the ingredients following generally accepted procedures. For example, the selected components may be simply mixed in a blender or other standard device to produce a concentrated mixture which may then be adjusted to the final concentration and viscosity by the addition of water or thickening agent and possibly a buffer to control pH or an additional solute to control tonicity.
[0131] For use by the physician, the compositions will be provided in dosage unit form containing an amount of an amylin or amylin agonist, for example, an amylin agonist with or without an NSAID which will be effective in one or multiple doses to control pain, inflammation, body temperature, blood coagulability, or other targeted biological response at the selected level. Therapeutically effective amounts of an amylin or amylin agonist are those that will alleviate the targeted symptom, or achieve the desired level of control. As will be recognized by those in the field, an effective amount of therapeutic agent will vary with many factors including the age and weight of the patient, the patient's physical condition, the action to be obtained and other factors.
[0132] The therapeutically effective daily dose of amylin or amylin agonist, for the treatment of gastritis and ulcers including h-amylin, 18 Arg 25,28 Pro-h-amylin, des- 1 Lys 18 Arg 25,28 Pro-h-amylin, 18 Arg 25,28,29 Pro-h-amylin, des- 1 Lys 18 Arg- 25,28,29 Pro-h-amylin, 25,28,29 Pro-h-amylin, des- 1 Lys 25,28,29 Pro-h-amylin, and 25 Pro 26 Val 28,29 Pro-h-amylin, will typically be in the range of 0.01 μg/kg/day to about 10 μg/kg/day, preferably between about 0.05 μg/kg/day to about 6.0 μg/kg/day, more preferably between about 1-6 μg/kg/day and even more preferably between about 0.5 μg/kg/day to about 4.0 μg/kg/day administered in single or divided doses.
[0133] The effective daily dose of amylin or amylin agonist in combination with an NSAID to relieve pain, thereby achieving a synergistic effect, including h-amylin, 18 Arg 25,28 Pro-h-amylin, des- 1 Lys 18 Arg 25,28 Pro-h-amylin, 18 Arg 25,28,29 Pro-h-amylin, des- 1 Lys 18 Arg- 25,28,29 Pro-h-amylin, 25,28,29 Pro-h-amylin, des- 1 Lys 25,28,29 Pro-h-amylin, and 25 Pro 26 Val 28,29 Pro-h-amylin, will typically be in the range of 0.01 μg/kg/day to about 10 μg/kg/day, preferably between about 0.05 μg/kg/day to about 6.0 μg/kg/day more preferably between about 1-6 μg/kg/day and even more preferably between about 0.5 μg/kg/day to about 4.0 μg/kg/day administered in single or divided doses. For these indications, the effective daily dose of the NSAID would depend on the agent used, and is comparable to the doses when NSAIDs are used alone. For example, daily doses for salicylate (aspirin) are 150 mg-3.5 g per day, for phenylbutazone 100 mg-600 mg per day, for indomethacin 50 mg-200 mg per day, and for acetaminophen 3 g-6 g per day.
[0134] The effective daily dose of amylin or amylin agonist to reduce the adverse gastric effects of the administration of an NSAID, including h-amylin, 18 Arg 25,28 Pro-h-amylin, des- 1 Lys 18 Arg 25,28 Pro-h-amylin, 18 Arg 25,28,29 Pro-h-amylin, des- 1 Lys 18 Arg- 25,28,29 Pro-h-amylin, 25,28,29 Pro-h-amylin, des- 1 Lys 25,28,29 Pro-h-amylin, and 25 Pro 26 Val 28,29 Pro-h-amylin, will typically be in the range of 0.01 μg/kg/day to about 10 μg/kg/day, preferably between about 0.05 μg/kg/day to about 6.0 μg/kg/day more preferably between about 1-6 μg/kg/day and even more preferably between about 0.5 μg/kg/day to about 4.0 μg/kg/day administered in single or divided doses. For these indications, the effective daily dose of the NSAID would depend on the agent used, and is comparable to the doses when NSAIDs are used alone. For example, daily doses for salicylate (aspirin) are 150 mg-3.5 g per day, for phenylbutazone 100 mg-600 mg per day, for indomethacin 50 mg-200 mg per day, and for acetaminophen 3 g-6 g per day.
[0135] The exact dose to be administered for each indication is determined by the attending clinician and is dependent upon where the particular compound lies within the above quoted range, as well as upon the age, weight and condition of the individual. Those of skill in the art will recognize that other non-daily doses may also be administered. Administration should begin at the first sign of symptoms in the case of gastritis, ulcers or pain, or at the time it is determined that the subject should begin NSAID therapy. Administration may be by injection, preferably subcutaneous or intramuscular. Administration may also be nasally or transdermally. Orally active compounds may be taken orally, however dosages should be adjusted based on their potencies and bioavailabilities, as appropriate.
[0136] The following Examples are illustrative, but not limiting of the methods of the present invention. Other suitable amylins and amylin agonists that may be adapted for use in the claimed methods are also appropriate and are within the spirit and scope of the invention.
EXAMPLE 1
Gastroprotective Properties of Amylin
[0137] The gastroprotective properties of amylin in an animal model for gastritis—the ethanol gavaged rat—are described in this example.
[0138] The effect of amylin on the induction of experimental mucosal damage in rats by gavage of 1 ml absolute ethanol was examined. Mucosal damage was scored between 0 (no damage) and 5 (100% of stomach covered by hyperemia and ulceration) by investigators blinded to the treatment. Rat amylin in saline was injected subcutaneously into fasted conscious male Harlan Sprague Dawley rats at doses of 0, 0.001, 0.01, 0.1, 0.3, 1, 3 or 10 μg (n=12, 5, 5, 5, 9, 9, 5, 6 respectively) 5 min before gavage. Mucosal damage, calculated as percent of scores in the saline-treated controls were, with the above rising subcutaneous doses, respectively: 100.0±8.3%, 95.3±15.2%, 76.6±13.8%, 70.1±10.7%*, 33.9±7.7%**, 59.6±5.8%**, 35.6±11.5%**, 32.9±8.3%** (*P<0.05, ** P<0.001 vs saline control). That is, amylin reduced the injury score by up to 67%, as observed with the 10 μg dose. The ED 50 for the gastroprotective effect of amylin in this experimental system was 0.036 μg/rat ±0.4 log units. The 50% gastroprotective dose of rat amylin (0.036 μg/rat) was predicted to increase circulating amylin concentrations by 1.8±0.4 pM. This prediction was obtained by applying the published relationship between injected subcutaneous dose and peak plasma concentration in rats. Young, A. A. et al., Drug Devel. Res. 37:231-48 (1996). Changes in plasma concentration of amylin of 1.8 pM is within the range of fluctuations reported to occur in normal rodents, indicating that endogenous circulating amylin is likely to exert a tonic gastroprotective effect. Mimicking this physiological effect is unlikely to result in unwanted side effects, as is often the case with administration of unphysiological xenobiotics. The absence of side effects enhances the utility of amylin agonists used for the purposes and in the manner specified herein.
EXAMPLE 2
Time Course of Amylin or Amylin Agonist Analgesic Action
[0139] Male Swiss Webster mice (NIH/Sw) obtained from Harlan (Madison, Wis.) and weighing 20-35 g are group housed with free access to food and water and maintained in a stable environment (12:12 light:dark cycle; 23±1° C.). All animals are habituated to the test room for at least one day prior to any experimentation, and are tested once between 07:30 and 14:00.
[0140] All drugs are dissolved in physiological saline, and given in a dose volume 10 ml/kg body weight.
[0141] The mouse writhing assay procedure used is a modification of a procedure disclosed in Hendershot and Forsaith, J. Pharmacol. Expt. Therap., 125:237-240 (1959). Each mouse is allowed to habituate to the observation box for at least 15 minutes prior to testing. Each mouse is given an intraperitoneal injection of a 2% acetic acid solution to produce a writhing reaction, characterized by a wave of contraction of the abdominal musculature followed by the extension of the hind limbs. The number of writhes per animal is counted during a 10-minute interval starting 5 minutes after acetic acid injection.
[0142] 0.1 mg/kg of amylin or amylin agonist is administered subcutaneously (sc) or intraperitoneally (ip) at 5, 15, 30 and 60 minutes prior to acetic acid injection in mice. Saline injections may be used as a negative control. An NSAID, such as salicylate may be used as a positive control.
[0143] To determine the time course of an amylin or amylin agonist action on visceral pain, the number of writhes per 10 minute period beginning 5 minutes after acetic acid injection are determined for each administration of amylin or amylin agonist and compared to saline-treated animals. To determine the enhancement of NSAID activity in relieving pain, time courses of amylin or amylin agonist administered in conjunction with an NSAID, and an NSAID administered alone, are compared.
EXAMPLE 3
Dose Response of Amylin Action
[0144] The same experimental procedures used in the experiments described in Example 2 are used to determine the dose response of an amylin or amylin agonist in relieving pain, either alone or in conjunction with an NSAID. Subcutaneous and intraperitoneal injections of amylin or amylin agonist (0.001, 0.003, 0.01, 0.1, 1.0 and 10.0 mg/kg) are given 30 minutes prior to acetic acid injection. Saline may be used as a negative control. An NSAID such as salicylate may be used as a positive control.
EXAMPLE 4
[0145] Isobologram Analysis of Interaction of Analgesic Effects of Amylin and NSAIDS
[0146] To further characterize the interaction between amylin and an NSAID, the results of the writhing studies may be graphed in isobolograms according to the method of Berenbaum, “The expected effect of a combination of agents: the general solution,” J. Theor. Biol. 114:413 (1985). The isobologram is a quantitative method for measuring interactions between dosages of drugs that are equieffective in relationship to a common pharmacological endpoint to indicate synergy, additive effect or antagonism. In this instance, the writhing test may be used to estimate a common level of analgesic dose-ratio combination. In an isobologram, areas of dose additional, synergism and antagonism are clearly defined by reference to a theoretical straight (addition) line connecting the points on each axis. According to the isobologram theory, any points falling under the addition line represent enhanced analgesic activity and any points located above the line represent diminished analgesic activity.
EXAMPLE 5
Preparation of 25,28,29 Pro-h-Amylin
[0147] Solid phase synthesis of 25,28,29 Pro-h-amylin using methylbenzhydrylamine anchor-bond resin and N a -Boc/benzyl-side chain protection was carried out by standard peptide synthesis methods. The 2,7 -[disulfide]amylin-MBHA-resin was obtained by treatment of Acm-protected cysteines with thallium (III) trifluoroacetate in trifluoroacetic acid. After cyclization was achieved the resin and side chain protecting groups were cleaved with liquid HF in the presence of dimethylsulfide and anisole. The 25,28,29 Pro-h-amylin was purified by preparative reversed-phase HPLC. The peptide was found to be homogeneous by analytical HPLC and capillary electrophoresis and the structure confirmed by amino acid analysis and sequence analysis. The product gave the desired mass ion. FAB mass spec: (M+H) + =3,949.
EXAMPLE 6
Preparation of 18 Arg 25,28,29 Pro-h-Amylin
[0148] Solid phase synthesis of 18 Arg 25,28,29 Pro-h-amylin using methylbenzhydrylamine anchor-bond resin and N a -Boc/benzyl-side chain protection was carried out by standard peptide synthesis methods. The 2,7 -[disulfide]amylin-MBHA-resin was obtained by treatment of Acm-protected cysteines with thallium (III) trifluoroacetate in trifluoroacetic acid. After cyclization was achieved the resin and side chain protecting groups were cleaved with liquid HF in the presence of dimethylsulfide and anisole. The 18 Arg 25,28,29 Pro-h-amylin was purified by preparative reversed-phase HPLC. The peptide was found to be homogeneous by analytical HPLC and capillary electrophoresis and the structure confirmed by amino acid analysis and sequence analysis. The product gave the desired mass ion. FAB mass spec: (M+H) + =3,971.
EXAMPLE 7
Preparation of 18 Arg 25,28 Pro-h-Amylin
[0149] Solid phase synthesis of 18 Arg 25,28 Pro-h-amylin using methylbenzhydrylamine anchor-bond resin and N a -Boc/benzyl-side chain protection was carried out by standard peptide synthesis methods. The 2,7 -[disulfide] amylin-MBHA-resin was obtained by treatment of Acm-protected cysteines with thallium (III) trifluoroacetate in trifluoroacetic acid. After cyclization was achieved the resin and side chain protecting groups were cleaved with liquid HF in the presence of dimethylsulfide and anisole. The 18 Arg 25,28 Pro-h-amylin was purified by preparative reversed-phase HPLC. The peptide was found to be homogeneous by analytical HPLC and capillary electrophoresis and the structure confirmed by amino acid analysis and sequence analysis. The product gave the desired mass ion. FAB mass spec: (M+H) + =3,959.
EXAMPLE 8
Receptor Binding Assay
[0150] Evaluation of the binding of compounds to amylin receptors was carried out as follows. 125 I-rat amylin (Bolton-Hunter labeled at the N-terminal lysine) was purchased from Amersham Corporation (Arlington Heights, Ill.). Specific activities at time of use ranged from 1950 to 2000 Ci/mmol. Unlabeled peptides were obtained from BACHEM Inc. (Torrance, Calif.) and Peninsula Laboratories (Belmont, Calif.).
[0151] Male Sprague-Dawley rats (200-250) grams were sacrificed by decapitation. Brains were removed to cold phosphate-buffered saline (PBS). From the ventral surface, cuts were made rostral to the hypothalamus, bounded laterally by the olfactory tracts and extending at a 45° angle medially from these tracts. This basal forebrain tissue, containing the nucleus accumbens and surrounding regions, was weighed and homogenized in ice-cold 20 mM HEPES buffer (20 mM HEPES acid, pH adjusted to 7.4 with NaOH at 23° C.). Membranes were washed three times in fresh buffer by centrifugation for 15 minutes at 48,000× g. The final membrane pellet was resuspended in 20 mM HEPES buffer containing 0.2 mM phenylmethylsulfonyl fluoride (PMSF).
[0152] To measure 125 I-amylin binding, membranes from 4 mg original wet weight of tissue were incubated with 125I-amylin at 12-16 pM in 20 mM HEPES buffer containing 0.5 mg/ml bacitracin, 0.5 mg/ml bovine serum albumin, and 0.2 mM PMSF. Solutions were incubated for 60 minutes at 23° C. Incubations were terminated by filtration through GF/B glass fiber filters (Whatman Inc., Clifton, N.J.) which had been presoaked for 4 hours in 0.3% poylethyleneimine in order to reduce nonspecific binding of radiolabeled peptides. Filters were washed immediately before filtration with 5 ml cold PBS, and immediately after filtration with 15 ml cold PBS. Filters were removed and radioactivity assessed in a gamma-counter at a counting efficiency of 77 %. Competition curves were generated by measuring binding in the presence of 10 −12 to 10 −6 M unlabeled test compound and were analyzed by nonlinear regression using a 4-parameter logistic equation (Inplot program; GraphPAD Software, San Diego).
[0153] In this assay, purified human amylin binds to its receptor at a measured IC 50 of about 50 pM. Results for test compounds are set forth in Table I, showing that each of the compounds has significant receptor binding activity.
TABLE I Receptor Binding EC 50 (nM) Assay IC 50 (pM) 1) 28 Pro-h-Amylin 15.0 2) 25 Pro 26 Val 28,29 Pro-h-Amylin 18.0 3) 2,7 Cyclo-[ 2 Asp, 7 Lys]-h-Amylin 310.0 4) 2-37 h-Amylin 236.0 5) 1 Ala-h-Amylin 148.0 6) 1 Ser-h-Amylin 33.0 7) 29 Pro-h-Amylin 64.0 8) 25,28 Pro-h-Amylin 26.0 9) des- 1 Lys 25,28 Pro-h-Amylin 85.0 10) 18 Arg 25,28 Pro-h-Amylin 32.0 11) des- 1 Lys 18 Arg 25,28 Pro-h-Amylin 82.0 12) 18 Arg 25,28,29 Pro-h-Amylin 21.0 13) des- 1 Lys 18 Arg 25,28,29 Pro-h-Amylin 21.0 14) 25,28,29 Pro-h-Amylin 10.0 15) des- 1 Lys 25,28,29 Pro-h-Amylin 14.0
EXAMPLE 9
PHENOL RED GASTRIC EMPTYING ASSAY
[0154] Gastric emptying was measured using a modification (Plourde et al., Life Sci. 53:857-862 (1993)) of the original method of Scarpignato et al. (Arch. Int. Pharmacodyn. Ther. 246:286-295 (1980)). Briefly, conscious rats received by gavage. 1.5 mL of an acoloric gel containing 1.5% methyl cellulose (M-0262, Sigma Chemical Co., St. Louis, Mo.) and 0.05% phenol red indicator. Twenty minutes after gavage, rats were anesthetized using 5% halothane, the stomach exposed and clamped at the pyloric and lower esophageal sphincters using artery forceps, removed and opened into an alkaline solution which was made up to a fixed volume. Stomach content was derived from the intensity of the phenol red in the alkaline solution, measured by absorbance at a wavelength of 560 nm. In most experiments, the stomach was clear. In other experiments, particulate gastric contents were centrifuged to clear the solution for absorbance measurements. Where the diluted gastric contents remained turbid, the spectroscopic absorbance due to phenol red was derived as the difference between that present in alkaline vs acetified diluent. In separate experiments on 7 rats, the stomach and small intestine were both excised and opened into an alkaline solution. The quantity of phenol red that could be recovered from the upper gastrointestinal tact within 29 minutes of gavage was 89±4%; dye which appeared to bind irrecoverably to the gut luminal surface may have accounted for the balance. To compensate for this small loss, percent of stomach contents remaining after 20 minutes were expressed as a fraction of the gastric contents recovered from control rats sacrificed immediately after gavage in the same experiment. Percent gastric emptying contents remaining=(absorbance at 20 min)/(absorbance at 0 min). Dose response curves for gastric emptying were fitted to a 4-parameter logistic model using a least-squares iterative routine (ALLFIT, v2.7, NIH, Bethesda, Md.) to derive ED 50 s. Since ED 50 is log-normally distributed, it is expressed ± standard error of the logarithm. Pairwise comparisons were performed using one-way analysis of variance and the Student-Newman-Keuls multiple comparisons test (Instat v2.0, GraphPad Software, San Diego, Calif.) using P<0.05 as the level of significance.
[0155] In dose response studies, rat amylin (Bachem, Torrance, Calif.) dissolved in 0.15M saline, was administered as a 0.1 mL subcutaneous bolus in doses of 0, 0.01, 0.1, 1, 10 or 100 μg 5 minutes before gavage in Harlan Sprague Dawley (non-diabetic) rats fasted 20 hours and diabetic BB rats fasted 6 hours. When subcutaneous amylin injections were given 5 minutes before gavage with phenol red indicator, there was a dose-dependent suppression of gastric emptying (data not shown). Suppression of gastric emptying was complete in normal HSD rats administered 1 μg of amylin, and in diabetic rats administered 10 μg (P=0.22, 0.14). The ED 50 for inhibition of gastric emptying in normal rats was 0.43 μg (0.60 nmol/kg)±0.19 log units, and was 2.2μ (2.3 nmol/kg)±0.18 log units in diabetic rats.
EXAMPLE 10
TRITIATED GLUCOSE GASTRIC EMPTYING ASSAY
[0156] Conscious, non-fasted, Harlan Sprague Dawley rats were restrained by the tail, the tip of which was anesthetized using 2% lidocaine. Tritium in plasma separated from tail blood collected 0, 15, 30, 60, 90 and 120 minutes after gavage was detected in a beta counter. Rats were injected subcutaneously with 0.1 mL saline containing 0, 0.1, 0.3, 1, 10 or 100 μg of rat amylin 1 minute before gavage (n=8, 7, 5, 5, 5, respectively). After gavage of saline pre-injected rats with tritiated glucose, plasma tritium increased rapidly (t ½ of about 8 minutes) to an asymptote that slowly declined. Subcutaneous injection with amylin dose-dependently slowed and/or delayed the absorption of the label. Plasma tritium activity was integrated over 30 minutes to obtain the areas under the curve plotted as a function of amylin dose. The ED 50 derived from the logistic fit was 0.35 μg of amylin.
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Methods for treating or preventing gastritis or gastric injury are disclosed, comprising administering a therapeutically effective amount of an amylin or an amylin agonist. Methods are also disclosed for the treatment of pain, fever, inflammation, arthritis, hypercoagulability, or other conditions for which a non-steroidal anti-inflammatory drug would be indicated, comprising administering an amylin or amylin agonist in conjunction with administering a therapeutically effective amount of a non-steroidal anti-inflammatory agent. Pharmaceutical compositions comprising an amylin or amylin agonist and a non-steroidal anti-inflammatory drug are also disclosed.
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CROSS-REFERENCE TO RELATED APPLICATION
[0001] This is a Continuation-in-Part application that claims benefit under 35 U.S.C. §120 to application Ser. No. 10/674,268, filed Sep. 29, 2003, entitled “Solubilized CoQ-10” (Attorney Docket No. 33503/US), the contents of which are incorporated herein in their entirety for all purposes.
FIELD OF THE INVENTION
[0002] The present invention relates to the solubilization of coenzyme Q-10 and analogs thereof in monoterpenes, thereby providing increased bioavailability in delivery.
BACKGROUND OF THE INVENTION
[0003] CoQ-10 (coenzyme Q10) is a fat-soluble quinone that is structurally similar to vitamin K and commonly known as ubiquinone. CoQ-10 is found in most living organisms, and is essential for the production of cellular energy. CoQ-10 (2,3 dimethyl-5 methyl-6-decaprenyl benzoquinone) is an endogenous antioxidant found in small amounts in meats and seafood. Although CoQ-10 is found in all human cells, the highest concentrations of CoQ-10 occur in the heart, liver, kidneys, and pancreas. It is found naturally in the organs of many mammalian species.
[0004] CoQ-10 can be synthesized in the body or it can be derived from dietary sources. Situations may arise, however, when the need for CoQ-10 surpasses the body's ability to synthesize it. CoQ-10 can be absorbed by oral supplementation as evidenced by significant increases in serum CoQ-10 levels after supplementation.
[0005] CoQ-10 is an important nutrient because it lies within the membrane of a cell organelle called the mitochondria. Mitochondria are known as the “power house” of the cell because of their ability to produce cellular energy, or ATP, by shuttling protons derived from nutrient breakdown through the process of aerobic (oxygen) metabolism. CoQ-10 also has a secondary role as an antioxidant. CoQ-10, due to the involvement in ATP synthesis, affects the function of almost all cells in the body, making it essential for the health of all human tissues and organs. CoQ-10 particularly effects the cells that are the most metabolically active: heart, immune system, gingiva, and gastric mucosa
[0006] Several clinical trials have shown CoQ-10 to be effective in supporting blood pressure and cholesterol levels. Furthermore, CoQ-10 has also been shown to improve cardiovascular health. CoQ-10 has been implicated as being an essential component in thwarting various diseases such as certain types of cancers. These facts lead many to believe that CoQ-10 supplementation is vital to an individual's well being.
[0007] CoQ-10 is sparingly soluble in most hydrophilic solvents such as water. Therefore, CoQ-10 is often administered in a powdered form, as in a tablet or as a suspension. However, delivery of CoQ-10 by these methods limits the bioavailability of the material to the individual.
[0008] There is a need in the art for an improved methodology to deliver increased amount of bioavailable CoQ-10 to an individual in need thereof.
BRIEF SUMMARY OF THE INVENTION
[0009] The present invention pertains to the surprising discovery that ubiquinone (CoQ-10) and related analogs thereof can be readily dissolved in varying concentrations in monoterpenes. Generally, until the present discovery, most CoQ-10 liquid delivery methods could solubilize only up to about 5% by weight of the CoQ-10 in the “solvent”. Typical solvents included various oils or the CoQ-10 was held in suspension. The present invention provides the ability to solubilize CoQ-10 in monoterpenes in concentrations of up to about 60% (weight to weight) without the need to aggressively heat the solution or with gentle warming. In particular, the solubilization of the CoQ-10 with monoterpenes can be accomplished at ambient temperatures.
[0010] In one aspect, the present invention pertains to compositions that include coenzyme Q-10 or an analog thereof with a sufficient quantity of a monoterpene that is suitable to solubilize said coenzyme Q-10 and a pharmaceutically acceptable carrier. Generally, about 30 to about 45% of the CoQ-10 (by weight) is solubilized in the monoterpene. In particular, the monoterpene is limonene. The compositions of the invention are useful as dietary supplements or as nutriceuticals.
[0011] In particular, the compositions of the invention are included in a soft gelatin (soft gel) capsule. Typically, the soft gelatin capsule includes at least 5% by weight of coenzyme Q-10 or an analog thereof solubilized in a monoterpene. Typical monoterpenes include, for example, perillyl alcohol, perillic acid, cis-dihydroperillic acid, trans-dihydroperillic acid, methyl esters of perillic acid, methyl esters of dihydroperillic acid, limonene-2-diol, uroterpenol, and combinations thereof.
[0012] In another embodiment, the present invention pertains to methods for delivery of an effective amount of bioavailable CoQ-10 to an individual. The method includes providing CoQ-10 solubilized in a monoterpene, such that an effective amount of CoQ-10 is provided to the individual.
[0013] In still another embodiment, the present invention also includes packaged formulations of the invention that include a monoterpene as a solvent for the CoQ-10 and instructions for use of the tablet, capsule, elixir, etc.
[0014] In one aspect, the present invention provides solubilized coenzyme Q-10 compositions that include coenzyme Q-10 or an analog thereof, a sufficient quantity of a monoterpene suitable to solubilize said coenzyme Q-10 or analog thereof, and an acceptable carrier. The compositions provide a percentage of coenzyme Q-10 dosage that is absorbed by an individual of between about 5 percent and about 12 percent of said coenzyme Q-10 or analog thereof that is administered. The ranges of absorbed coenzyme Q-10 are from about 5 percent to about 12 percent, from about 6 percent to about 10 percent, and from about 6.5 percent to about 9.5 percent, based on the dosage of coenzyme Q-10 or analog thereof taken.
[0015] In another aspect, the present invention provides solubilized coenzyme Q-10 compositions that include coenzyme Q-10 or an analog thereof, a sufficient quantity of a monoterpene suitable to solubilize said coenzyme Q-10 or analog thereof, and an acceptable carrier. The compositions provide a bioavailable steady state plasma level of coenzyme Q-10 or an analog thereof of between about 2.5 μg/ml to about 3.5 μg/ml. Suitable ranges of steady state plasma levels of coenzyme Q-10 or analog thereof are from about 2.5 μg/ml to about 3.5 μg/ml, from about 2.75 μg/ml to about 3.25 μg/ml and from about 2.75 μg/ml to about 3.0 μg/ml, based on the dosage of coenzyme Q-10 or analog thereof taken.
[0016] In still yet another aspect, the present invention provides compositions that include solubilized coenzyme Q-10 or an analog thereof, a sufficient quantity of a monoterpene suitable to solubilize said coenzyme Q-10 or analog thereof, and an acceptable carrier. The compositions provide a peak plasma level of coenzyme Q-10 or analog thereof of between about 2.1 μg/ml to about 3.0 μg/ml. Suitable ranges of peak plasma levels of coenzyme Q-10 or analog thereof are from about 2.1 μg/ml to about 3.0 μg/ml, from about 2.2 μg/ml to about 2.8 μg/ml and from about 2.2 μg/ml to about 2.5 μg/ml.
[0017] In another aspect, the present invention pertains to methods for delivery of an effective amount of bioavailable CoQ-10 to an individual. The methods include providing CoQ-10 solubilized in a monoterpene, such that an effective amount of CoQ-10 is provided to the individual so that the dosage absorbed, the steady state plasma levels of coenzyme Q-10, or the peak plasma levels of coenzyme Q-10 are sustained.
[0018] In still another embodiment, the present invention also includes packaged formulations of the invention that include a monoterpene as a solvent for the CoQ-10 and instructions for use of the tablet, capsule, elixir, etc. so that the dosage absorbed, the steady state plasma levels of coenzyme Q-10, or the peak plasma levels of coenzyme Q-10 are sustained.
[0019] While multiple embodiments are disclosed, still other embodiments of the present invention will become apparent to those skilled in the art from the following detailed description, which shows and describes illustrative embodiments of the invention. As will be realized, the invention is capable of modifications in various obvious aspects, all without departing from the spirit and scope of the present invention. Accordingly, the drawings and detailed description are to be regarded as illustrative in nature and not restrictive.
BRIEF DESCRIPTION OF THE FIGURES
[0020] FIG. 1 depicts individual single dose (60 mg) peak absorption curves for solubilized coenzyme Q-10;
[0021] FIG. 2 shows individual daily dose (60 mg/day) steady state plasma coenzyme Q-10 bioavailability curves for the solubilized coenzyme Q-10;
[0022] FIG. 3 provides a graphical representation of single dose peak absorption curves for the solubilized coenzyme Q-10 (60 mg) (upper line, ♦)(Example 5) formulation and Example 6 (30 mg) (lower line, ▪). The Cmax for both formulations occurred at 6 hours. The change in plasma coenzyme Q-10 at Cmax was significantly greater for the solubilized coenzyme Q-10 by a three fold factor. The calculated percentage of dose absorbed at Cmax was 7.95 percent for the solubilized coenzyme Q-10 as compared to 6.04 percent for Example 6; and
[0023] FIG. 4 is a graphical representation of the steady state bioavailability curves for the solubilized coenzyme Q-10 (upper line, ♦)(Example 5) and Example 6 (lower line, ▪) at a daily dose of 60 mg/day. Plasma levels at 7, 14, 21 and 28 days were significant (P<0.01) for the solubilized coenzyme Q-10 formulation.
DETAILED DESCRIPTION
[0024] The present invention pertains to the surprising discovery that ubiquinone (CoQ-10) can be readily dissolved in varying concentrations in monoterpenes. CoQ-10 is found in most living organisms, and is essential for the production of cellular energy. Ubiquinone is a naturally occurring hydrogen carrier in the respiratory chain (coenzyme Q) and structurally, it is a 2,3-dimethoxy-5-methyl-1,4-benzoquinone with a multiprenyl side chain, the number of isoprene units varying depending upon the organism from which it is derived. CoQ-10 analogs include reduced and semi-reduced CoQ-10 and ubiquinone derivatives described, for example, in WO 8803015, the teachings of which are incorporated herein by reference.
[0025] Generally, until the present discovery, most CoQ-10 liquid delivery methods could solubilize only up at most about 10% by weight of the CoQ-10 in the solvent. Typical solvents included oils or the CoQ-10 was held in an aqueous suspension. Alternatively, the CoQ-10 was provided as a solid in a tablet or powder.
[0026] The present invention provides the ability to solubilize CoQ-10 and analogs thereof in monoterpenes, as defined herein, in concentrations of up to about 60% (weight to weight) without the need to heat the solution. In one aspect, the monoterpene solubilizes CoQ-10 from about 0.1 percent by weight to about 45 percent by weight.
[0027] In particular, the solubilization of the CoQ-10 and analogs thereof with monoterpenes can be accomplished at ambient temperatures. In one aspect, from about 5 to about 50 percent (weight CoQ-10/weight solvent) CoQ-10 can be solubilized in a monoterpene. In another aspect, from about 15 to about 40 percent w/w can be solubilized and in still another aspect, from about 20 to about 35 percent w/w CoQ-10 can be solubilized in a monoterpene.
[0028] The phrase “sufficient quantity of a monoterpene suitable to solubilize coenzyme Q-10” is therefore intended to mean that that amount of a monoterpene that will dissolve CoQ-10 under a given set of conditions, generally, those at ambient temperature. This determination should be understood by one skilled in the art and can be determined by methods known in the art, such as by solubility studies.
[0029] One of the particular advantages of utilizing monoterpenes in combination with CoQ-10 and analogs thereof is that the enzyme is dissolved by the monoterpene. That is, many formulations currently in the marketplace have CoQ-10 present as a suspension; a situation where not all the CoQ-10 is dissolved. This reduces efficacy and the bioavailability of the CoQ-10. The present invention eliminates this disadvantage by solubilizing the CoQ-10 in the monoterpene.
[0030] A particular advantage in using monoterpenes is that the CoQ-10 or analog thereof does not have to be heated to dissolve into solution. This is important so that the CoQ-10 or analog thereof does not degrade upon dissolution.
[0031] The term “monoterpene” as used herein, refers to a compound having a 10-carbon skeleton with non-linear branches. A monoterpene refers to a compound with two isoprene units connected in a head-to-end manner. The term “monoterpene” is also intended to include “monoterpenoid”, which refers to a monoterpene-like substance and may be used loosely herein to refer collectively to monoterpenoid derivatives as well as monoterpenoid analogs. Monoterpenoids can therefore include monoterpenes, alcohols, ketones, aldehydes, ethers, acids, hydrocarbons without an oxygen functional group, and so forth.
[0032] It is common practice to refer to certain phenolic compounds, such as eugenol, thymol and carvacrol, as monoterpenoids because their function is essentially the same as a monoterpenoid. However, these compounds are not technically “monoterpenoids” (or “monoterpenes”) because they are not synthesized by the same isoprene biosynthesis pathway, but rather by production of phenols from tyrosine. However, common practice will be followed herein. Suitable examples of monoterpenes include, but are not limited to, limonene, pinene, cintronellol, terpinene, nerol, menthane, carveol, S-linalool, safrol, cinnamic acid, apiol, geraniol, thymol, citral, carvone, camphor, etc. and derivatives thereof. For information about the structure and synthesis of terpenes, including terpenes of the invention, see Kirk-Othmer Encyclopedia of Chemical Technology, Mark, et al., eds., 22:709-762 3d Ed (1983), the teachings of which are incorporated herein in their entirety.
[0033] In particular, suitable limonene derivatives include perillyl alcohol, perillic acid, cis-dihydroperillic acid, trans-dihydroperillic acid, methyl esters of perillic acid, methyl esters of dihydroperillic acid, limonene-2-diol, uroterpenol, and combinations thereof.
[0034] Formulation of the CoQ-10 and analogs thereof can be accomplished by many methods known in the art. For example, the solubilized CoQ-10 or analog thereof can be formulated in a suspension, an emulsion, an elixir, a solution, a caplet that harbors the liquid, or in a soft gelatin capsule. Often the formulation will include an acceptable carrier, such as an oil, or other suspending agent.
[0035] Suitable carriers include but are not limited to, for example, fatty acids, esters and salts thereof, that can be derived from any source, including, without limitation, natural or synthetic oils, fats, waxes or combinations thereof. Moreover, the fatty acids can be derived, without limitation, from non-hydrogenated oils, partially hydrogenated oils, fully hydrogenated oils or combinations thereof. Non-limiting exemplary sources of fatty acids (their esters and salts) include seed oil, fish or marine oil, canola oil, vegetable oil, safflower oil, sunflower oil, nasturtium seed oil, mustard seed oil, olive oil, sesame oil, soybean oil, corn oil, peanut oil, cottonseed oil, rice bran oil, babassu nut oil, palm oil, low erucic rapeseed oil, palm kernel oil, lupin oil, coconut oil, flaxseed oil, evening primrose oil, jojoba, tallow, beef tallow, butter, chicken fat, lard, dairy butterfat, shea butter or combinations thereof.
[0036] Specific non-limiting exemplary fish or marine oil sources include shellfish oil, tuna oil, mackerel oil, salmon oil, menhaden, anchovy, herring, trout, sardines or combinations thereof. In particular, the source of the fatty acids is fish or marine oil (DHA or EPA), soybean oil or flaxseed oil. Alternatively or in combination with one of the above identified carrier, beeswax can be used as a suitable carrier, as well as suspending agents such as silica (silicon dioxide).
[0037] The formulations of the invention are considered dietary supplements useful to the increase the amounts of CoQ-10 and analogs thereof in the individuals in need thereof.
[0038] Alternatively, the formulations of the invention are also considered to be nutraceuticals. The term “nutraceutical” is recognized in the art and is intended to describe specific chemical compounds found in foods that may prevent disease. CoQ-10 or an analog thereof are such compounds.
[0039] The formulations of the invention can further include various ingredients to help stabilize, or help promote the bioavailability of the CoQ-10 and analogs thereof, or serve as additional nutrients to an individual's diet. Suitable additives can include vitamins and biologically-acceptable minerals. Non-limiting examples of vitamins include vitamin A, B vitamins, vitamin C, vitamin D, vitamin E, vitamin K and folic acid. Non-limiting examples of minerals include iron, calcium, magnesium, potassium, copper, chromium, zinc, molybdenum, iodine, boron, selenium, manganese, derivatives thereof or combinations thereof. These vitamins and minerals may be from any source or combination of sources, without limitation. Non-limiting exemplary B vitamins include, without limitation, thiamine, niacinamide, pyridoxine, riboflavin, cyanocobalamin, biotin, pantothenic acid or combinations thereof.
[0040] Vitamin(s), if present, are present in the composition of the invention in an amount ranging from about 5 mg to about 500 mg. More particularly, the vitamin(s) is present in an amount ranging from about 10 mg to about 400 mg. Even more specifically, the vitamin(s) is present from about 250 mg to about 400 mg. Most specifically, the vitamin(s) is present in an amount ranging from about 10 mg to about 50 mg. For example, B vitamins are in usually incorporated in the range of about 1 milligram to about 10 milligrams, i.e., from about 3 micrograms to about 50 micrograms of B 12. Folic acid, for example, is generally incorporated in a range of about 50 to about 400 micrograms, biotin is generally incorporated in a range of about 25 to about 700 micrograms and cyanocobalamin is incorporated in a range of about 3 micrograms to about 50 micrograms.
[0041] Mineral(s), if present, are present in the composition of the invention in an amount ranging from about 25 mg to about 1000 mg. More particularly, the mineral(s) are present in the composition ranging from about 25 mg to about 500 mg. Even more particularly, the mineral(s) are present in the composition in an amount ranging from about 100 mg to about 600 mg.
[0042] Various additives can be incorporated into the present compositions. Optional additives of the present composition include, without limitation, phospholipids, L-carnitine, starches, sugars, fats, antioxidants, amino acids, proteins, flavorings, coloring agents, hydrolyzed starch(es) and derivatives thereof or combinations thereof.
[0043] As used herein, the term “phospholipid” is recognized in the art, and refers to phosphatidyl glycerol, phosphatidyl inositol, phosphatidyl serine, phosphatidyl choline, phosphatidyl ethanolamine, as well as phosphatidic acids, ceramides, cerebrosides, sphingomyelins and cardiolipins.
[0044] L-carnitine is recognized in the art and facilitates transport of materials through the mitochondrial membrane. L-carnitine is an essential fatty acid metabolism cofactor that helps to move fatty acids to the mitochondria from the cytoplasm. This is an important factor as this is where CoQ-10 uptake occurs.
[0045] In one aspect of the present invention, L-carnitine is included in soft gel formulations in combination with CoQ-10 or an analog thereof. Suitable ratios of L-carnitine and CoQ-10 are known in the art and include those described in U.S. Pat. No. 4,599,232, issued to Sigma Tau Industrie Faramaceutiche Riunite S.p.A. on Jul. 8, 1986, the teachings of which are incorporated herein in their entirety. In particular, combinations of limonene, CoQ-10 and L-carnitine in soft gel formulations are of importance. The present invention provides the advantage of solvating large amounts (relative to that of current state of the art) of CoQ-10 in limonene in a soft gel capsule along with an additive, such as L-carnitine.
[0046] As used herein, the term “antioxidant” is recognized in the art and refers to synthetic or natural substances that prevent or delay the oxidative deterioration of a compound. Exemplary antioxidants include tocopherols, flavonoids, catechins, superoxide dismutase, lecithin, gamma oryzanol; vitamins, such as vitamins A, C (ascorbic acid) and E and beta-carotene; natural components such as camosol, carnosic acid and rosmanol found in rosemary and hawthorn extract, proanthocyanidins such as those found in grapeseed or pine bark extract, and green tea extract.
[0047] The term “flavonoid” as used herein is recognized in the art and is intended to include those plant pigments found in many foods that are thought to help protect the body from cancer. These include, for example, epi-gallo catechin gallate (EGCG), epi-gallo catechin (EGC) and epi-catechin (EC).
[0048] The phrase “solubilized CoQ-10 and analogs thereof” is intended to mean that the coenzyme Q-10 is solvated by the lipophilic materials incorporated into the soft gel capsule. Typical capsules that contain CoQ-10 or an analog thereof include the coenzyme or analog as a dry powder or as a suspension of crystals. It is believed that the powder or crystallinity of the coenzyme does not facilitate absorption by the cells. The present invention overcomes this disadvantage by providing formulations wherein the coenzyme is not in a powdered or crystalline form. Microscopic evaluations of the lipophilic formulations do not show crystals of the coenzyme. Consequently, it is believed that the solvated coenzyme can more easily pass into cells. This is highly advantageous in delivering increased amounts of the coenzyme into an individual's physiological make up.
[0049] Any dosage form, and combinations thereof, are contemplated by the present invention. Examples of such dosage forms include, without limitation, chewable tablets, elixirs, liquids, solutions, suspensions, emulsions, capsules, soft gelatin capsules, hard gelatin capsules, caplets, lozenges, chewable lozenges, suppositories, creams, topicals, ingestibles, injectables, infusions, health bars, confections, animal feeds, cereals, cereal coatings, and combinations thereof. The preparation of the above dosage forms are well known to persons of ordinary skill in the art.
[0050] For example, health bars can be prepared, without limitation, by mixing the formulation plus excipients (e.g., binders, fillers, flavors, colors, etc.) to a plastic mass consistency. The mass is then either extended or molded to form “candy bar” shapes that are then dried or allowed to solidify to form the final product.
[0051] Soft gel or soft gelatin capsules can be prepared, for example, without limitation, by dispersing the formulation in an appropriate vehicle (e.g. rice bran oil, monoterpene and/or beeswax) to form a high viscosity mixture. This mixture is then encapsulated with a gelatin based film using technology and machinery known to those in the soft gel industry. The industrial units so formed are then dried to constant weight. Typically, the weight of the capsule is between about 100 to about 2500 milligrams and in particular weigh between about 1500 and about 1900 milligrams, and more specifically can weigh between about 1500 and about 2000 milligrams.
[0052] For example, when preparing soft gelatin shells, the shell can include between about 20 to 70 percent gelatin, generally a plasticizer and about 5 to about 60% by weight sorbitol. The filling of the soft gelatin capsule is liquid (principally limonene, in combination with rice bran oil and/or beeswax if desired) and can include, apart form the antioxidant actives, a hydrophilic matrix. The hydrophilic matrix, if present, is a polyethylene glycol having an average molecular weight of from about 200 to 1000. Further ingredients are optionally thickening agents. In one embodiment, the hydrophilic matrix includes polyethylene glycol having an average molecular weight of from about 200 to 1000, 5 to 15% glycerol, and 5 to 15% by weight of water. The polyethylene glycol can also be mixed with propylene glycol and/or propylene carbonate.
[0053] In another embodiment, the soft gel capsule is prepared from gelatin, glycerine, water and various additives. Typically, the percentage (by weight) of the gelatin is between about 30 and about 50 weight percent, in particular between about 35 and about weight percent and more specifically about 42 weight percent. The formulation includes between about 15 and about 25 weight percent glycerine, more particularly between about 17 and about 23 weight percent and more specifically about 20 weight percent glycerine.
[0054] The remaining portion of the capsule is typically water. The amount varies from between about 25 weigh percent and about 40 weight percent, more particularly between about 30 and about 35 weight percent, and more specifically about 35 weight percent. The remainder of the capsule can vary, generally, between about 2 and about 10 weight percent composed of a flavoring agent(s), sugar, coloring agent(s), etc. or combination thereof. After the capsule is processed, the water content of the final capsule is often between about 5 and about 10 weight percent, more particularly 7 and about 12 weight percent, and more specifically between about 9 and about 10 weight percent.
[0055] As for the manufacturing, it is contemplated that standard soft shell gelatin capsule manufacturing techniques can be used to prepare the soft-shell product. Examples of useful manufacturing techniques are the plate process, the rotary die process pioneered by R. P. Scherer, the process using the Norton capsule machine, and the Accogel machine and process developed by Lederle. Each of these processes are mature technologies and are all widely available to any one wishing to prepare soft gelatin capsules.
[0056] Typically, when a soft gel capsule is prepared, the total weight is between about 250 milligrams and about 2.5 gram in weight, e.g., 400-750 milligrams. Therefore, the total weight of additives, such as vitamins and antioxidants, is between about 80 milligrams and about 2000 milligrams, alternatively, between about 100 milligrams and about 1500 milligrams, and in particular between about 120 milligrams and about 1200 milligrams.
[0057] For example, a soft gel capsule can be prepared by mixing a 35% solution of CoQ-10 and limonene (w/w) (e.g., 104 milligrams of CoQ-10 in 193.14 milligrams of limonene) with between about 0.01 grams and about 0.4 grams (e.g., 0.1 grams) tocopherol, between about 200 grams and about 250 grams (e.g., 225 grams) rice bran oil and between about 0.01 grams and about 0.5 grams betacarotene (e.g. about 0.02 grams). The mixture is then combined with encapsulated within a gelatin capsule as described above.
[0058] The present invention also provides packaged formulations of a monoterpene with CoQ-10 and instructions for use of the tablet, capsule, elixir, etc. Typically, the packaged formulation, in whatever form, is administered to an individual in need thereof that requires and increase in the amount of CoQ-10 in the individual's diet. Typically, the dosage requirements is between about 1 to about 4 dosages a day.
[0059] CoQ-10 has been implicated in various biochemical pathways and is suitable for the treatment of cardiovascular conditions, such as those associated with, for example, statin drugs that effect the body's ability to produce CoQ-10 naturally. CoQ-10 has also been implicated in various periodontal diseases. Furthermore, CoQ-10 has been implicated in mitochondrial related diseases and disorders, such as the inability to product acetyl coenzyme A, neurological disorders, for example, such as Parkinson's disease and, Prater-Willey syndrome.
[0060] The following examples are intended to be illustrative only and should not be considered limiting.
Examples
[0061] Formulations of CoQ-10 can be prepared in the following ratios by mixing the components together and then placing into a soft gel capsule.
[0000]
Component
Example 1
Example 2
CoQ-10
104.09 mg
104.09 mg
Mixed Tocopherols
269.03 mg
269.03 mg
(372 IU/g)
Rice Bran Oil
176.02 mg
—
Natural Beta Carotene
10.05 mg
10.05 mg
(20% by weight)
Yellow Beeswax
20.0 mg
—
D-limonene
—
196.02 mg
Total weight
580 mg
580 mg
[0062] Example 2 demonstrates that the use of limonene solubilizes CoQ-10 without the requirement of beeswax and/or rice bran oil being present. Examples 1 and 2 can be incorporated into soft gel capsules by standard methods known in the art.
[0000]
Component
Example 3
Example 4
CoQ-10
17.95 g
17.95 g
EPAX 2050TG
48.77 g
45.49 g
D-Limonene
35.70 g
35.70 g
5-67 Tocopherol
—
0.86 g
(1000 IU/g)
[0063] Examples 3 and 4 demonstrate that CoQ-10 can be solubilized in scalable quantities. Additives, such as EPAX 2050 TG (an ω-3 oil; 20% EPA/50% DHA as triglycerides, remainder fatty acid/triglycerides; Pronova Biocare) and tocopherols (5-67 Tocopherol; BD Industries) can easily be incorporated into such limonene containing formulations. The resultant mixtures contained approximately 100 mg of CoQ-10 per soft gel capsule. Preparation of the soft gel capsules was accomplished by methods well known in the art.
[0000]
Component
Example 5
Example 6
CoQ-10 (98%)
62.45 mg
62.45 mg
Vitamin E mixed tocopherols
69.19 mg
161.3. mg
(700 mg/g)
D-Limonene
118.1 mg
none
Soybean oil
30.26 mg
none
5-67 Tocopherol
60.0 mg
none
(1000 IU/g)
yellow beeswax
none
15.0 mg
Rice bran oil
none
188.71 mg
Natural beta Carotene
none
7.54 mg
mg/capsule
mg/capsule
[0064] Examples 5 and 6 provide a comparison between soft gel capsules prepared with D-limonene and without D-limonene and enzyme CoQ-10. Examples 5 and 6 will be referred to throughout the following paragraphs to show efficacy in delivery with the use of the monoterpene, D-limonene.
[0065] The single 60 mg dose peak absorption characteristics and the 28-day 60 mg daily dose steady state bioavailability of the solubilized CoQ 10 formulation was determined in five (5) normal male (N=3) and female (N=2) volunteers. The peak absorption study was done over 12 hours. For the control sample, the volunteers were in a rested and fasted condition-minimum eight (8) hours. Serial blood samples were taken at 0, 4, 6, 8, and 12 hours after ingesting 60 mg of a softgel product (either solubilized CoQ 10 (Example 5) or Example 6, a non-solubilized CoQ 10 formulation. In the steady state bioavailability study, daily doses of 60 mg of the solubilized CoQ 10 formulation were taken with breakfast. CoQ 10 in plasma was measured using the hexane extraction and HPLC detection method described in “A New Method to Determine the Level of Coenzyme Q10 in One Drop of Human Blood for Biomedical Research”, Manabu Morita and Karl Folkers, Biochem. Biophys. Res. Commun. 191(3), 950-954, 1993, the contents of which are incorporated herein in their entirety. The solubilized CoQ 10 formulation was a soft gel capsule that contained 60 mg CoQ 10 , 118.1 mg limonene, 30.26 mg soybean oil and vitamin E as described in Example 5. The non-solubilized formulation was a soft gel capsule that contained 60 mg CoQ 10 , 188.71 mg rice bran oil, 161.3 mg vitamin E (and additional additives) as described in Example 6.
[0066] Group mean control plasma CoQ 10 level (0.88±0.13 μg/ml) was in the normal range. Tmax after ingestion of a single 60 mg capsule was in six (6) hours and the mean peak plasma level (Cmax) was 2.28±0.14 μg/ml. The amount of solubilized CoQ 10 absorbed at Cmax was 4,765.51±825.39 μg or 7.96±1.38% of the ingested dose. With daily dosing the plasma solubilized CoQ 10 level increased to a mean plateau level of 2.68±0.15 μg/ml in 14 days and remained fairly constant thereafter. The 28-day plasma level was 2.75±0.22 μg/ml. The solubilized CoQ 10 bioavailability in plasma was 6,498.90±1,634.76 μg, and the area under the plasma time base curve was 42.27±2.29 μg/ml·day. These data demonstrate that the solubilized CoQ 10 formulation was absorbed significantly (p<0.001). The peak absorption of 7.96% of the ingested dose and the steady state bioavailability after 28 days was significantly (p<0.01) greater than that found in Example 6.
[0067] The solubilized CoQ 10 formulation (Example 5) absorption is greater than that of most softgel CoQ 10 products in which CoQ 10 crystals are suspended in a lipid base and those products that provide only a dried powder composition.
Peak Absorption Characteristics and Steady State Bioavailability of Solubilized CoQ 10 formulation
[0068] The use of Coenzyme Q 10 (CoQ 10 ) around the world has surpassed the production capabilities of the Japanese producers. CoQ 10 is also rapidly entering the clinical consumer market with the positive study reports on heart failure, Parkinson's disease, muscular ataxias, low energy genetic syndromes, statin drug inhibition of CoQ 10 synthesis and recent publications that show that CoQ 10 and its precursors in the body inhibit farensyl-transferase and thus turn off the growth and rapid division of cancer cells. With these advances in CoQ 10 research and the conclusions that plasma CoQ 10 levels for clinical efficacy should be raised to about 3.2 μg/ml, more companies have been seeking to develop CoQ 10 products with improved absorption and steady state bioavailability. The absorption of CoQ 10 is not the same for all CoQ 10 products found in the market place. In general dry powder delivery systems have 0.5 to 2% peak absorption. Dry powder CoQ 10 in a lipid base that is incorporated into soft gelatin capsules has better peak absorption (2.0-3.0%). This appears to be dependant on the number and size of the CoQ 10 crystals in the product.
[0069] The following data relate to peak absorption characteristics of a single 60 mg dose and the steady state bioavailability of a daily 60 mg dose for the solubilized CoQ 10 softgel formulation. Both studies were conducted on the same five (5) normal volunteer subjects. Peak absorption and steady state bioavailability characteristics were compared to that of Example 6 which was collected using a similar study design but different volunteers.
Methods
[0070] Five normal volunteers (3 males/2 females) were randomly selected from a screened group of 15 individuals (Table I). The exclusion criteria were: 1) smoker, 2) individual taking a CoQ 10 product, 3) individual with high plasma cholesterol, 4) individual taking drugs known to interfere with endogenous synthesis or CoQ 10 absorption, 5) individual on vegetarian diet, and 6) athlete.
[0000]
TABLE I
Physical Characteristics of Study Volunteers
PLASMA
AGE
HEIGHT
WEIGHT
VOLUME
VOLUNTEER
YEARS
SEX
INCHES
POUNDS
MILLILITERS
PDOB 01
43
F
63.50
147.00
3139.00
RFRE 02
42
M
66.25
170.75
3720.00
AJOH 03
43
M
69.50
205.00
3928.00
SHAL 04
26
M
70.50
192.50
3870.00
NJOH 05
39
F
63.75
126.00
2520.00
[0071] After being fully familiarized with the experimental design and their responsibilities, the volunteers had their questions answered by the principle investigator, and read and signed a volunteer consent form. On day 0 of the study, volunteers reported to the testing facility at 0600 in a rested and fasted state-minimum eight (8) hours. Vital signs were taken, an intercath was placed in a forearm vein, and a control blood sample was collected for determining the control CoQ 10 plasma level. The volunteers were then given a single 60 mg dose of the solubilized CoQ 10 formulation. This was followed by a breakfast consisting of orange juice or milk (2%) with a bagel or cereal. Blood samples were drawn again at hours 4, 6, 8 and 12; vital signs and safety data were collected simultaneously. Starting with day 1 of the study, the volunteers took 60 mg of solubilized CoQ 10 formulation daily for the next 28 days. During this time, volunteers followed their regular diet and activity schedules and returned to the testing facility on days 7, 14, 21, and 28 at 0600 in a rested and fasted condition—minimum eight (8) hours—for the purpose of collecting vital signs and safety data, and to have a venous blood sample collected from which plasma CoQ 10 levels were determined.
[0072] All CoQ 10 samples were collected in vaccutainers containing EDTA to prevent clotting. The samples were cooled in ice water and then centrifuged to separate the plasma from the formed elements. The plasma was pipetted into a sealable transfer container, labeled according to volunteer identification and hour of collection and frozen at −20° centigrade. All plasma samples were shipped overnight in dry ice to an independent laboratory for CoQ 10 analysis. The method used was that as described in Morita & Folkers (supra) hexane extraction and HPLC detection.
[0073] Individual volunteer data points were entered into a Microsoft Excel spreadsheet. Descriptive statistics were used to calculate group means SD and SE. Statistical differences between group control and each group sample for the peak absorption and the steady state weekly levels were determined using a standard t-test for differences between group means. A probability of p≦0.05 was accepted as significant.
Results
[0074] I: Peak Absorption Study
[0075] Individual and group means±SE & SD descriptive statistics data for the 60 mg single dose peak absorption study are presented in Table II and the individual data plotted on a 12 hour time base are shown in FIG. 1 . Control plasma CoQ 10 was variable between volunteers (range=0.77-1.09 μg/ml). The group means±SD was 0.88±0.13 μg/ml. This is considered to be in the normal range. Within four hours after ingesting the solubilized CoQ 10 the plasma levels for the group increased significantly (p≦0.01) to 1.36±0.12 μg/ml. Peak plasma levels occurred at six (6) hours (Tmax) and the maximum plasma concentration (Cmax) was 2.28±0.14 μg/ml. Thereafter plasma CoQ 10 rapidly decreased over the next two hours to a mean level of 1.58±0.23 μg/ml during the rapid tissue uptake period of CoQ 10 . The peak absorption kinetics calculated from the peak absorption data are presented in Table IV.
[0000]
TABLE II
Individual and Group Solubilized CoQ 10 formulation:
Single Dose (60 mg) Peak Absorption Study
Sample Time (Hours)
0
4
6
8
12
Volunteer
1
0.77
1.35
2.09
1.30
1.10
2
1.09
1.56
2.40
1.60
1.46
3
0.92
1.36
2.39
1.90
1.76
4
0.79
1.24
2.16
1.42
1.27
5
0.85
1.28
2.34
1.67
1.45
Mean
0.88
1.36
2.28
1.58
1.41
Standard Error
0.06
0.06
0.06
0.10
0.11
Standard
0.13
0.12
0.14
0.23
0.25
Deviation
P-value
3.24E−05
1.57E−06
0.000766
0.002338
[0076] The amount of CoQ 10 absorbed at Cmax was 4,769.51±825.39 μg. When compared to the ingested dose (60,000 μg), the percent of the dose absorbed at Cmax was 7.95±1.38%. In the first two hours after Cmax an average of 2196.14±523.83 μg was distributed out of the blood and into the body cells. The amount was 46.46±9.85% of that absorbed at Cmax.
[0077] II: Steady State Plasma CoQ 10 Bioavailability
[0078] Individual and group means±SD descriptive statistics data for the 28-day 60 mg/day steady state plasma CoQ 10 bioavailability for the solubilized CoQ 10 formulation are presented in Table III and graphically in FIGS. 2 and 4 . Again there was a variation between volunteers. In seven (7) days the basal plasma CoQ 10 level increased significantly (p≦0.01) to 2.39±0.13 μg/ml. Plasma levels plateaued for each volunteer between the 7th and 14th day and remained fairly constant thereafter ( FIG. 2 ). At the 28th day the group means plasma CoQ 10 level was 2.75±0.22 μg/ml (p≦0.001). The calculated steady state increase in plasma CoQ 10 was 6,458.90±1,634.76 μg at a constant daily dose of 60 mg/day (Table V). In a steady state condition the group mean relative increase in plasma CoQ 10 was 314.42±39.07%. The area under the plasma CoQ 10 and time base curve between days 0 and 28 days (AUC 0-28 day )(AUC denotes area under the curve) is used to equate the CoQ 10 bioavailability. The AUC for this product was 42.27±2.29 μg/ml·day.
[0000]
TABLE III
Individual and Group Solubilized CoQ 10 : Steady State (60 mg/day) Plasma CoQ10 Bioavailability Study
Time (Days)
AUC (0-28
0
7
14
21
28
% Change
day) ug/ml · day
Volunteer
1
0.77
2.20
2.48
2.56
2.67
285.71
42.77
2
1.09
2.30
2.79
2.80
2.78
211.01
38.68
3
0.92
2.52
2.78
3.00
3.10
273.91
42.22
4
0.79
2.42
2.78
2.70
2.68
306.33
42.61
5
0.85
2.49
2.56
2.60
2.50
292.94
45.05
Mean
0.88
2.39
2.68
2.73
2.75
314.42
42.27
Standard Error
0.06
0.06
0.07
0.08
0.10
17.47
1.02
Standard Deviation
0.13
0.13
0.15
0.18
0.22
39.07
2.29
p-value
2.65E−05
3.11E−06
5.13E−06
5.13E−06
[0000]
TABLE IV
Individual and Group Single Dose Peak Absorption Characteristics for Solubilized CoQ 10 formulation
Control
Change
Plasma
Plasma
Plasma
Change in
Rapid Q10
Amt. Q10
% Distributed
Q10
Cmax
Q10
Plasma
Plasma
% of Dose
Distribution
Distributed
of Amt.
ug/ml
ug/ml
ug/ml
Vol ml
Q10 ug
Absorbed
ug/ml
ug
Absorbed
Volunteer
1
0.77
2.09
1.32
3139.00
4143.48
6.91
0.61
1914.79
46.21
2
1.09
2.40
1.31
3720.00
4873.20
8.12
0.80
2976.00
61.07
3
0.92
2.39
1.47
3928.00
5774.16
9.62
0.49
1924.72
33.33
4
0.79
2.16
1.37
3870.00
5301.90
8.84
0.64
2476.80
46.72
5
0.85
2.34
1.49
2520.00
3754.80
6.26
0.67
1688.40
44.97
Mean
0.88
2.28
1.48
3435.40
4769.51
7.95
0.64
2196.14
46.46
SD
0.06
0.06
0.08
268.17
369.12
0.62
0.05
234.26
4.41
SE
0.13
0.14
1.39
599.65
825.39
1.38
0.11
523.83
9.85
[0079] III: Particle and Crystalline Characteristics of Solubilized CoQ 10
[0080] Photomicrographs of solubilized CoQ 10 (Example 5) and Example 6 showed that Example 6 had many small crystals of CoQ 10 , whereas the solubilized CoQ 10 (Example 5) showed no crystals, and appeared to be a homogenous distribution of CoQ 10 molecules in solution.
DISCUSSION
[0081] The study determined the peak single dose (60 mg) absorption characteristics and the steady state plasma CoQ 10 bioavailability in response to a constant daily dose of 60 mg/day for 28 days of solubilized CoQ 10 . The control plasma CoQ 10 data for the small group (N=5) was in the normal range (Tables 1 &2). The plasma CoQ 10 increase at Cmax (2.28±0.14 μg/ml) was significantly (p<0.001) above the control level as was the amount of CoQ 10 added to the plasma at Cmax (Table IV and V).
[0000]
TABLE V
Individual and Group Solubilized CoQ 10 (Example 5):
Steady State (60 mg/day) CoQ 10 Bioavailability Study
Plasma Q
C-CoQ10
28 Day
Change
Plasma Vol
Change
AUC (0-28 day)
ug/ml
ug/ml
ug/ml
ml
ug/ml
% Change
ug/ml · day
Volunteer
1
0.77
2.67
1.90
3,139.00
5,964.10
346.75
42.77
2
1.09
2.78
1.69
3,720.00
6,286.80
255.05
38.68
3
0.92
3.10
2.18
3,928.00
8,563.04
336.96
42.22
4
0.79
2.68
1.89
3,870.00
7,314.30
339.24
42.61
5
0.85
2.50
1.65
2,525.00
4,166.25
294.12
45.05
Mean
0.88
2.75
1.86
3,436.40
6,458.90
314.42
42.27
Standard
0.06
0.10
0.09
267.32
731.09
17.47
1.02
Error
Standard
0.13
0.22
0.21
597.75
1,634.76
39.07
2.29
Deviation
[0082] Peak absorption and steady state bioavailability data were compared between the solubilized CoQ 10 (Example 5) and Example 6. Comparisons were made by examining FIGS. 3 and 4 . These Figures show the peak absorption curves ( FIG. 3 ) and the steady state bioavailability curves ( FIG. 4 ) characteristics of both the solubilized CoQ 10 and CoQ 10sol products plotted on the same time base. Cmax for Example 6 with a 30 mg dose increased 0.53±0.28 μg/ml above the control level. With this change in plasma CoQ 10 1813.33±96.65 μg of CoQ 10 was added to the blood at Cmax. The calculated percent (%) of ingested dose absorbed was 6.04±0.32%. This is significantly less than the 1.48±0.39 ug/ml change in plasma CoQ 10 and the 7.95±1.38% of the 60 mg ingested dose of the solubilized CoQ 10 formulation. Thus, the relative increases in the peak plasma CoQ 10 at Cmax, the amount of CoQ 10 absorbed at Cmax and the percent of ingested dose absorbed at Cmax between the solubilized CoQ 10 (Example 5) and Example 6 formulations were 80, 60 and 40 percent greater respectively for the solubilized CoQ 10 formulation. These data show that Example 6 at a dose of 30 mg is significantly (p<0.01) less absorbed than 60 mg of solubilized CoQ 10 formulation. The steady state bioavailability of Example 6 is also significantly less than that of solubilized CoQ 10 formulation as shown in FIG. 4 .
[0083] At 28 days with a 60 mg daily dose, Example 6 resulted in a group mean steady state plasma CoQ 10 level of 2.26±0.74 μg/ml. This is significantly (p≦0.01) less than the 2.75±0.22 μg/ml measured for the solubilized CoQ 10 formulation using the same 60 mg/day dose. Similarly, the AUCo-28 day for the solubilized CoQ 10 , CoQ 10 was significantly greater (p≦0.01) than that found for Example 6 (42.27±2.29-vs.-29.6±4.61 μg/ml/day). These data comparisons also show that the solubilized CoQ 10 formulation CoQ 10 bioavailability is significantly greater than that of Example 6.
[0084] Not to be limited by theory, as to why the solubilized CoQ 10 formulation (Example 5) has better absorption than Example 6 may be explained by the physical characteristics of the two formulations. Both Example 6 and the solubilized CoQ 10 formulations were made by the same soft gel encapsulating process. The ingredients in the two formulations were different relative to the lipid carrier molecules (Rice bran oil in Example 6 and Soybean oil and D-Limonene oil in the solubilized CoQ 10 formulation (Example 5)). On examination of the two formulations, the contents of both were an oily matrix. The solubilized CoQ 10 formulation appeared to be more liquid (less solids) than Example 6. Example 6 was reddish brown in color due to the beta-carotene. The solubilized CoQ 10 formulation was dark brown in color. Upon microscopic examination Example 6 was found to have small crystals, whereas the solubilized CoQ 10 was devoid of crystals. It is postulated that the solubilized CoQ 10 formulation consists of a larger fraction of single CoQ 10 molecules and exerts a greater osmotic concentration of CoQ 10 outside the intestinal cells, thus a greater driving force for the facilitated diffusion process for CoQ 10 absorption.
[0085] Since the CoQ 10 crystal has a melting point 10° centigrade above body temperature (37° C.) and completely melt to single molecules at 65° centigrade, it is believed that the lower absorption of Example 6 is due to the larger proportion of CoQ 10 crystals in solution and the physiological fact that the body cannot absorb a crystal. Only single molecules in water or lipid solution can be absorbed across the intestinal mucosal membrane or transported across any epithelial cell membrane.
[0086] In summary, the solubilized CoQ 10 formulation peak absorption kinetics and steady state bioavailability is significantly greater than that of Example 6. The 7.95% absorption of the ingested dose makes this a superior composition to provide increased amounts of CoQ 10 to a subject in need thereof.
[0087] Although the present invention has been described with reference to preferred embodiments, persons skilled in the art will recognize that changes may be made in form and detail without departing from the spirit and scope of the invention.
[0088] All literature and patent references cited throughout the application are incorporated by reference into the application for all purposes.
|
The present invention is directed to compositions and methods of delivery of CoQ-10 solubilized in monoterpenes. Use of monoterpenes as dissolving agents, greatly effects the ability to incorporate greater amounts of bioactive CoQ-10 in formulations, such as soft gel capsules.
| 0 |
[0001] This application claims priority from Provisional Application Ser. No. 60/591,657 filed Jul. 28, 2004.
FIELD OF THE INVENTION
[0002] This invention relates to a chair and table combination, in particular a chair arm having a stowable table with an integrated mouse pad. The chair arm is positional relative to the person sitting in the chair thereby allowing the user to position the table in the most ergonomic and comfortable position for operating a keyboard and/or a computer mouse positioned on the table. Furthermore, the chair arm has an armrest allowing the user to rest their arm on the rest while using the computer mouse.
BACKGROUND OF THE INVENTION
[0003] Ergonomics as it relates to computer use is a field in need of innovation. Concerns involving the lack of proper positioning of a persons body while operating a computer keyboard and mouse are growing rapidly. Of particular concern are a person's back and arm position while operating a computer. The operation of a computer primarily involves inputting data through use of a keyboard and the use of a computer mouse for moving a curser and clicking the mouse.
[0004] Typically, these operations are performed in a seated position for long periods of time. Accordingly, these operations are the cause of a great number of stress related injuries. Repetitive motion injuries such as carpel tunnel syndrome and tendonitis are injuries that are common but avoidable with proper ergonomic posture during use of the keyboard and mouse.
[0005] Ergonomic devices have been developed to address these issues. For example, chairs have become high tech with the ability to be positioned to suit the user's needs and comfort level. Also, articulating arms that attach to desktops have been designed to provide support for a users arm while using a keyboard or mouse. Furthermore, mouse pads with a fold out arm that attach to a desktop and a chair desk having a stowable table with a mouse pad have been designed. In particular, these designs address the important and growing issue of relieving the strain put on the users back and arms and wrists. These devices concentrate mainly on supporting the users' arms and wrists while operating a keyboard and mouse. The users' arms and wrists are traditionally positioned on the desk in front of a computer monitor with the mouse pad being to the right of the keyboard. The problem is that there is no easy way to make using the keyboard and mouse comfortable and safe when they are located in a position that forces the user to stretch and bend the arms in positions that cause strain.
[0006] An example of one device addressing the problem of using a computer mouse is shown in U.S. Pat. No. 6,347,771, issued to Lauzon et, Feb. 19, 2002 and entitled “Portable arm and mouse support for use with personal computers”. The device has a jointed arm with a mouse pad on one end and the other end is attached to a desktop. This design presents a problem with stability. In particular, the device is not able to withstand the weight a person will inadvertently put on the arm while positioning him or herself. The device is also cumbersome in that it does not stow away and must be attached and detached when not in use.
[0007] Another such device, U.S. Pat. No. 5,490,710, issued to Dearing et al, Feb. 13, 1996 and entitled “Swing Arm Chair” shows a chair having a stow able table mounted onto a chair arm with an integrated mouse pad. The problem with this design is that it lacks the necessary adjustments to position the table up, down or rotationally so that the table may be usable while using a computer keyboard in conjunction with the mouse. Also, there is no support under the table to provide for any weight that one might put on the table. The mouse pad is in a fixed position and will likely incur strain and fatigue on the wrist because of the inability to position it where it is most comfortable. Finally, another problem is that this chair desk arm is not mountable on the standard office chair.
[0008] In addition, U.S. Pat. No. 6,264,150 issued to Touzani, Oct. 5, 2004, and entitled “Ergonomic bi-level workstation” shows a chair desk with incorporated mouse pad. Many similar problems exist with this device as with that of U.S. Pat. No. 5,490,710 to Benden, et al., Aug. 12, 2003 and entitled “Support apparatus for a chair” in that the table is not positional vertically or horizontally. The mouse pad is in a fixed position to the user's right side thereby forcing the user's arm into a single position that may overtime become uncomfortable.
[0009] Moreover, U.S. Pat. No. 6,311,939 issued to Christensen, Nov. 6, 2001 and entitled “Integrated mouse pad and wrist and arm support” shows a chair arm with an integrated mouse pad that is positional to a limited extent. A problem exists in this design in that the table or mouse pad is not stowable thereby causing a problem of being cumbersome when not in use. Although the arm is positional it has no linear tracking thereby limiting the mouse pad position to a fixed radius from the pivot points.
[0010] Next, U.S. Pat. No. 6,352,303 issued to Hope, Mar. 5, 2002 and entitled “Arm rest mouse pad” shows a mouse pad with almost no means of positioning and no means of stowing it away. This chair mouse pad must be attached and detached when not in use. With the need for maneuverability of an office chair, leaving an extended mouse pad attached to a chair arm would create problems of mobility in the often cluttered and confined environment of computer workstations.
[0011] Finally, U.S. Pat. No. 6,203,109 issued to Bergsten, et al., Mar. 20, 2001 and entitled “Ergonomic arm support” shows multi positional arm supports that are attachable to an office chair. Although this design provides good positioning of the arm supports in relation to the users body and keyboard, it does not provide for a stow able table with integrated mouse pad thereby being limited in its use as only supporting a person's arms. The design does provide for a mouse pad attachment in place of the armrest. This design creates a problem in that the mouse pad would not be hinged or stowable, and would not have the armrest to provide support for the arm while using the mouse.
[0012] In today's workforce and confined environments compactness and speed are essential. In order for a chair arm or desk combination having an integrated mouse pad to be useful it should be quickly accessible, provide ergonomic positioning and have the ability to be quickly stowed away. If the device is cumbersome, unappealing, and too complicated it will not be used. The present invention provides a solution to these needs and other problems, and offers other advantages over the prior art.
SUMMARY OF THE INVENTION
[0013] In accordance with one embodiment of the invention, a stowable work surface and attachment apparatus are used with an existing chair. The attachment apparatus comprise a vertically adjustable post having a first end that is configured and arrange to be attached to a chair, and a second end that is configured and arranged to rotatably support a mounting plate or bracket. The mounting plate, in turn, is operatively and movably connected to one or more arms that are configured and arranged to support the work surface. And the work surface comprises a computer peripheral interface surface and an armrest.
[0014] In another embodiment, a stowable work surface and a portion of the attachment apparatus are used with an exiting chair armpost. In this embodiment, only the mounting plate of the attachment apparatus is used.
[0015] In another embodiment, there are two stowable work surfaces that are movably connected to both sides of a chair. In this embodiment, which may be used with chairs having armposts or chairs without armposts, the work surfaces are configured and arranged so that they may create a substantially continuous work space in front of the chair.
[0016] Still another object of the present invention is to provide a work space that can be separated and stowed along side of a chair when not in use.
[0017] Still another object of the present invention is to provide a work surface that can be removably attached to the frame of an existing wheeled chair thereby converting the chair into a mobile work station.
[0018] Still another object of the present invention is to provide a chair having a stowable work surface capable of supporting a laptop, and movable into a stowed position when not in use.
[0019] Additional advantages and features of the invention will be set forth in part in the description which follows, and in part, will become apparent to those skilled in the art upon examination of the following or may be learned by practice of the invention.
BRIEF DESCRIPTION OF THE DRAWINGS
[0020] FIG. 1 is a front perspective view of the present attachment apparatus assembly with showing the stowable work surface in an extended horizontal position.
[0021] FIG. 2 is a side perspective view of the present attachment apparatus assembly in an extended horizontal position directly in front of a chair.
[0022] FIG. 3 is a side perspective view of the present attachment apparatus assembly with the stowable work surface in a stowed away position to the side of the chair.
[0023] FIG. 4 is an exploded perspective view of the present attachment apparatus assembly.
[0024] FIG. 5 is an exploded perspective view of the attachment apparatus assembly of FIG. 4 showing greater detail of the swing arm mechanism.
[0025] FIG. 6 is a detailed side view of the bracket.
[0026] FIG. 7 is a top view of the attachment apparatus assembly of FIG. 4 showing various positions of the stowable work surface.
[0027] FIG. 8 is a partial perspective view of the second arm positioned in the second block.
[0028] FIG. 9 is an end view of the second block shown from the direction of arrows in FIG. 8 .
[0029] FIG. 10 is a partial perspective view of the first arm with the first block attached to its end.
[0030] FIG. 11 is a side view of the bracket.
[0031] FIG. 11 a is a top view of the bracket with linear tube shown in hidden lines.
[0032] FIG. 12 is a side view of the first arm in an alternate embodiment of attachment apparatus assembly.
[0033] FIG. 12 a is a top view of FIG. 12 .
[0034] FIG. 13 is an exploded perspective view of an alternate embodiment of attachment apparatus assembly FIG. 4 and shows an articulating armrest and a mounting assembly having an adjustable post arm.
[0035] FIG. 14 is a detailed exploded perspective view of the articulating armrest assembly of FIG. 13 .
[0036] FIG. 15 is a perspective view of the alternate embodiment of the arm rest in FIG. 13 .
[0037] FIG. 16 is a perspective view of the alternate embodiment of the mounting assembly shown in FIG. 13 .
[0038] FIG. 17 is an exploded perspective view of an alternate embodiment of present attachment apparatus assembly and shows a glide block assembly and pivot block having linear sliding members.
[0039] FIG. 17 a is a detailed perspective view of the alternate embodiment of the glide block assembly of FIG. 17 .
[0040] FIG. 18 is a detailed perspective view an alternate embodiment of the pivot block shown in FIG. 17 that is attachable to a post arm.
[0041] FIG. 19 is an exploded perspective view of an alternate embodiment of the pivot block shown in FIG. 17 and is attachable directly to an existing chair arm via arm rest mounting bolts.
[0042] FIG. 20 is an exploded view of an alternate embodiment of a means of positioning the present attachment apparatus assembly of FIG. 17 and shows an articulating arm assembly with the pivot block attached.
[0043] FIG. 21 is an exploded view of another alternate embodiment of positioning the attachment apparatus assembly of FIG. 17 showing an extension arm attached to a swivel mechanism on a post arm.
[0044] FIG. 22 is a perspective view of an alternate embodiment of the extension arm of FIG. 21 and shows an extension arm having ball bearing track members instead of nylon linear glides.
[0045] FIG. 23 is an exploded perspective view of an alternate embodiment of the present attachment apparatus assembly showing the extension arm in FIG. 21 having a rotating hinge assembly with stowable work surface attached to it.
[0046] FIG. 24 is an exploded perspective view of another embodiment of the present attachment apparatus assembly.
[0047] FIG. 25 is an another embodiment in which each side of a chair is provided with an attachment apparatus and work surface which, when combined form a work space.
DETAILED DESCRIPTION
[0048] As shown in FIGS. 1, 2 , and 3 the present attachment apparatus assembly is designated in general by the numeral 10 , and includes as its principal components a stowable work surface 12 connected to a mounting plate 20 by means of a first arm 16 and a bracket 14 . The bracket 14 engages the first arm 16 , by means of a linear tube 15 and sleeve bushing 56 and provide a means for the stowable work surface 12 to be swing able and slid able, relative the mounting plate 20 . The mounting plate 20 is connectable to a chair 40 via an adjustable armrest bracket 26 and an arm support 27 . A second arm 18 is connected to the mounting plate 20 and supports the stowable work surface 12 in a horizontal position. A standard armrest 28 is mounted on top of the mounting plate 20 thereby sandwiching the mounting plate 20 between the standard armrest 28 and the adjustable armrest bracket 26 .
[0049] FIGS. 1, 2 , and 3 show various positions of the stow able mouse pad 12 from the stowed away position shown in FIG. 3 to an extended horizontal position directly in front of the chair arm as shown in FIGS. 1 and 2 . FIG. 2 shows the stowable work surface 12 extended and positioned over a user's lap. It will be understood by those skilled in the art that the stowable work surface 12 may be positioned in a myriad of positions.
[0050] FIGS. 4 and 5 show with greater detail exploded views of the present invention showing a stowable work surface 12 in an extended horizontal position. The stowable work surface 12 in phantom as it may appear is connected to a mounting plate 20 by means of a steel rod or first arm 16 and a bracket 14 . The bracket 14 as shown in FIGS. 6, 11 , and 11 a is mounted to the underside of the stowable work surface 12 and comprises a generally plain body and a linear tube 15 having a sleeve bushing 56 that slidably engages the first arm 16 and allows the stowable work surface 12 to relative the mounting plate 20 . The stowable work surface 12 may rotate about a bolt 36 that passes through apertures 39 and 41 of the bracket 14 and thrust washer 38 , respectively. Preferably, the bolt 36 is threaded into a threaded insert 21 located in the underside of the stowable work surface 12 , thereby securing the stowable work surface 12 to the bracket 14 . The thrust washer 38 is positioned between the underside of the stowable work surface 12 and the bracket 14 thereby allowing the stowable work surface 12 to frictionally engage the bracket 14 and to pivot via the bolt 36 and thrust washer 38 . The first arm 16 is mounted to and frictionally engages the mounting plate 20 via a first block 24 , which is attached to the end of the first arm 16 and which frictionally engages the underside of the mounting plate 20 . See, for example, FIG. 5 . It will be understood by those skilled in the art that the first block 24 and is generally disc shaped having a through hole or aperture 25 and two opposing flat sides one of which provides a bearing surface on which the first block 24 rotates. The first block 24 has an aperture 25 extending through the center axis of the first block 24 . A thrust washer 27 may be positioned between the first block 24 and the mounting plate 20 . The first block 24 is attached to and frictionally engages the mounting plate 20 via a bolt 36 which passes through apertures 29 , 27 a , and 25 of the mounting plate 20 , thrust washer 27 , and first block 24 respectively, and which is engaged by a nut 34 . It will be understood by those skilled in the art that by tightening or loosening the nut 34 , the resistance at which the swing arm pivots may be increased or decreased. An additional thrust washer 27 may be placed on the opposing flat side of the first block 24 to ensure a fluid pivoting motion. As shown the mounting plate 20 has a T-shape with the horizontal portion having a leg extending thereabove from the left side of the Tee, which allows a second arm 18 to be offset from the first arm 16 , and which allows the second arm 18 to be perpendicular to or cross over in front of a standard arm rest 28 . The lower portion of mounted plate extension 32 provides support that allows the mounting plate 20 to be secured to an arm rest bracket 26 via the mounting plate bolt holes 48 and arm rest mounting bolts 30 .
[0051] A second arm 18 provides support for a work surface while in a horizontal position and comprises a second arm 18 which is engaged by a second block 22 . The second block 22 is shown in greater detail in FIGS. 8 and 9 . The second block 22 is generally disc shaped having two opposing flat sides. On one flat side a threaded pin or stem 54 extends from the center of the flat portion of the disc, and provides a means for securing the second block 22 to the mounting plate 20 . The second block 22 has through hole or aperture 57 extending through the disc, perpendicular to its center axis. A sleeve bushing 56 comprised of nylon or other low friction material such as polytetraflouroethylene may be is fixed in the hole 57 thereby forming a pillow block through which the second arm 18 may move, allowing the second arm 18 to move into an extended or retracted position. FIG. 3 shows the second arm 18 and the first arm 16 in a retracted position. The second block 22 frictionally engages the bottom of the mounting plate 20 . A thrust washer 38 is may be between the flat bearing surface of the second block 22 and the bottom of the mounting plate 20 . The threaded stud 54 passes through apertures 27 a and 29 of the thrust washer 27 and mounting plate 20 respectively, and is engaged by a nut 34 . By tightening or loosening the nut 34 the resistance at which the second arm 18 pivots may be increased or decreased respectively. An additional thrust washer may be placed on the top side of the mounting plate 20 to ensure a fluid pivoting motion if desired. As shown in FIG. 4 , the mounting plate 20 is positioned between an arm rest 28 and an adjustable arm rest bracket 26 by two mounting bolts 30 , which pass through apertures 50 , 48 of the adjustable armrest bracket 26 , mounting plate 20 and mounting plate extension 32 , respectively. The armrest mounting bolts 30 are threaded into T-nuts 52 located on the underside of the standard armrest 28 . An arm support 27 doubles as a connecting means by which the adjustable armrest bracket 26 and stowable mouse pad 10 are attached to an office chair 40 of the type having a back 42 , a seat 44 , and a support structure 46 . The arm support 27 typically has four slots at its end, providing a means for bolting the arm support to the bottom of the chair seat 44 . It should be noted that the second block 22 need not be limited in use with the second arm 18 only, and may also be used in place of the first block 24 thereby allowing a swingable and slideable first arm 16 as well as a swingable and slidable second arm 18 .
[0052] FIG. 7 shows various positions in phantom of the stowable work surface 12 with corresponding positions of the first arm 16 and second arm 18 . The stowable work surface 12 is shown in four different horizontal positions swinging from left to right and ending with the stowable work surface 12 in a vertical or stowed away position 53 . The second arm 18 is shown in a retracted or stowed away position 58 . From the stowed away position 53 the table may be lifted or swung into a horizontal position, and the second arm 18 extended to provide support for the stowable work surface 12 . The stowable work surface 12 may then be swung into any one of a multitude of positions including but not limited to the four positions shown. It will be appreciated by those skilled in the art that the stowable work surface 12 may also rotate or pivot independently relative to bracket 14 about bolt 36 as described in FIG. 6 , thus allowing even greater positioning capacity.
[0053] FIGS. 13 and 16 shows and alternate embodiment of the present invention having an attachment apparatus 59 that allows the stowable work surface 12 to be connected to a chair 40 that does not have existing arms. Here, a positional arm rest assembly 60 comprises an articulating arm 84 a , 84 b and a rotatable arm rest 76 . A post assembly includes as its principle components a post 68 which connects the stowable work surface 12 to a chair 40 . The arm housing 64 may be provided with a clamp 66 with which to secure the post 68 relative to the housing 64 . The bottom of the housing 64 terminates with a bracket 72 which is provided with mounting slots The post arm 68 is connected to the mounting plate 20 and provides the means to pivot as well as adjust the height of the stowable work surface 12 by engaging the post clamp 66 and a sleeve bearing located inside the arm housing 64 near the bottom. The post clamp 66 has an inside diameter slightly larger than the outside diameter of the post arm 68 thereby allowing it to slide inside the inside diameter of the post clamp 66 . The clamp 66 is of a typical design used on shafts for positioning and holding them in place. Clamp 66 includes a vertical slot 73 with an intersecting bolt hole and a lever with a threaded bolt extending through the hole thereby allowing the post clamp 66 to constrict around the arm 68 by turning the lever and decreasing the diameter of the clamp 66 inside diameter.
[0054] FIG. 14 shows in greater detail the articulating arm 60 in FIG. 13 . The articulating arm 84 a , 84 b allows armrest 76 to rotate and thereby increase positioning capability. The articulating arm comprises a lower arm 84 a and an upper arm 84 b joined together at one end by a pivot pin 86 which allows the two arms to act as a hinge having a common pivot pin. A thrust washer 88 is positioned between the lower 84 a and upper 84 b arms with the pivot pin 86 extending through the thrust washer 88 .
[0055] The upper arm 84 b has a through hole or aperture 90 opposite the end of the pivot pin 86 . The aperture 90 is used as a bushing through which a downwardly depending stem 80 of the arm rest 76 is inserted, allowing the arm rest 76 to be seated and to pivot about the center axis of the aperture 90 at the end of the top arm 84 b . A bushing may be inserted into the through hole or aperture 90 to allow smoother rotation, if desired. The lower arm 84 a has a hole 94 opposite the end of the pivot pin 86 through which the upwardly extending stem 70 of the post projects. As shown, the stem 70 projects through a hole 92 in the center of the mounting plate 20 and extends out the top of the mounting plate 20 and through hole 94 located at the end of the lower arm 84 a opposite the pivot pin. A thrust washer (not shown) may be positioned between the top of the mounting plate 20 and the bottom of the lower arm 84 a . A retainer ring, circlip, or similar fastening may be used on the end of the stem 70 to hold the articulating arm 84 a , 84 b onto the stem 70 .
[0056] FIG. 15 shows a rotatable armrest 76 having a cupped shape that is configured to receive the forearm of a user. The arm rest 76 may be provided with a padded portion 78 made of a resilient material such as foam or sponge rubber which overlays the rigid body of the arm of the armrest 76 . A trunnion 82 is located on the convex or bottom surface of the armrest 76 . The trunnion 82 has a downwardly depending stem 80 inserted into the through hole or aperture 90 located at the end of the upper arm 84 b of the articulating arm 84 a , 84 b.
[0057] FIGS. 17 and 17 a show yet another alternate embodiment of the present invention referred to in general by the numeral 104 . In exploded view the main components of the alternate embodiment, are a stowable work surface 12 that is slid ably connected to a block 96 by means of a first arm 112 . The first arm 112 has a work surface attached to its end by means of a bracket 118 ; the opposing end slidably engages the pivot block. The block 96 is connected to the end of an extension arm 120 . The extension arm 120 is slidably connected to a block 122 . The glide block 122 is mounted to a post 68 a by a swivel base 136 located on the upper end of the post 68 a . The post 68 a is attached to the chair by means of a post arm assembly 59 as previously described. In greater detail the stowable work surface 12 a is shown in an extended vertical folded down position ready to slide back to its stowed away position through a channel 102 . Shown in phantom in FIG. 17 , work surface 12 a is in an extended horizontal position. The stowable work surface 12 may pivot about the vertical and horizontal and is extendable by two linear slide mechanisms the block 96 and the block 122 . The stowable work surface 12 pivots and slides by means of a first arm 112 .
[0058] The first arm 112 is connected to a second arm 114 by bar 116 . The first arm 112 and second arm 114 each have a threaded hole at their respective end for receiving threaded fasteners. The first arm 112 and second arm 114 are connected together after inserting the arms through parallel apertures 100 in the block 96 . The fastening elements 142 includes a shoulder that prevents over-tightening and allows the first arm 112 to rotate, thereby allowing both arms 112 and 114 to slide in unison and maintain the ability of the first arm 112 to also rotate with the shoulder of the fastening element 142 acting as a shaft and the arm hole acting as a bearing. The block 96 is of a rectangular shape having two parallel holes 100 , one located on each end of the block and extending therethrough. Each hole 100 may include a plastic bushing that slidably engages the first arms 112 and 114 . The block 96 also has an opening or channel 102 in the bottom portion of the block and located between the two parallel holes 100 of the block 96 , and closest to the first arm 112 . The channel 102 extends through the block from one side to the other and is generally parallel to the holes 100 . The channel 102 provides an opening in the block 96 so the work surface may be moved into a retracted and stowed position. The block 96 has a through hole 110 extending through the block from top to bottom. The block 76 is mounted to the end of the extension arm 120 by extending a bolt through the throughhole 110 through a nylon washer, and through the block mounting hole located at the end of the extension arm 120 . A nut 34 is screwed onto the end of the bolt thereby frictionally engaging the pivot block 96 with the extension arm 120 with a nylon thrust washer between them. The nut is tightened to increase or decrease the resistance at which the block 96 rotates.
[0059] An arm rest mounting hole 111 is located near the center of the block 96 allowing the stem 80 of the armrest 75 to be inserted in the hole and the trunnion 82 to be seated upon the block thereby allowing the arm rest to pivot. The extension arm 120 comprises a longitudinal flat bar having a top surface and a bottom surface with two ends opposite each other and two sides opposite each other. A block mounting hole 126 is located on one end the opposite end is inserted into a block 122 . The block 122 comprises a top plate 124 and a bottom plate 124 b . The two plates are generally parallel to each other and retain channel elements 128 therebetween. The channel elements 128 are generally rectangular in shape and have a U shaped channel 134 extending the length of the glide. The channel elements 128 may be made of nylon, polytetraflouroethylene, or other material that is used for making a bushing. The U shaped channel 134 has 3 sides a top a bottom and a side. The top and bottom sides are at a distance from each other approximately equal to the thickness of the extension arm 120 . The glides are positioned between the glide plates 124 and 124 b opposite each other one on each side of the plates so that the U shaped channels 134 are facing each other. The channels 134 create a slot into which the end of the extension arm 120 opposite the pivot block mounting hole 115 is inserted. The extension arm 120 slides back and forth inside the channel elements 128 relative to the block 122 . The channel elements 128 are fastened to the glide block plates 124 and 124 b by bolts that extend through apertures 130 in the top plate 124 . The bolts extend through corresponding holes in the channel elements 128 and extend into threaded apertures in the bottom glide plate 124 b (not shown). The block 122 can rotate 360 degrees and is seated on a swivel base 136 . The swivel base 136 is a round disc shaped member having a threaded hole 132 located at its center. The swivel base 136 is located on the top end of a post 68 a . The block 122 is mounted onto the swivel base by a conventional threaded bolt extending through a pivot bolt hole located at the center of the bottom plate 124 b and through a thrust washer and threaded into the threaded hole 132 in the swivel base 136 .
[0060] FIG. 18 shows an alternate embodiment of the present invention having a pivot block 96 as described in FIG. 17 mounted directly to a post 68 . The block is mounted onto the post 68 at throughhole 115 located in the center of the block 96 . The stem 70 of the post arm 68 extends through the hole 115 and extends through the top of the block 96 . The bottom of the block 96 is seated on a seat or shoulder 71 of post 68 . A shroud 140 may be attached to the pivot block by means of screws 144 inserted through apertures 138 in the shroud 140 and screwed into threaded holes 137 in the pivot block. An arm rest may be attached to the top of the shroud 140 . An armrest may also be attached to the pivot block as shown in FIG. 17 .
[0061] FIG. 19 shows another alternate embodiment of the present invention showing the block 96 having an extension 98 extending therefrom. The extension 98 allows the block 96 to be mounted to an adjustable bracket 26 as shown in FIG. 4 . Arm rest mounting bolts 30 extend through the bracket bolt holes 50 (see FIG. 4 ) and through apertures 108 in the pivot block and extension 98 , and into threaded apertures 52 the underside of the arm rest 28 .
[0062] FIG. 20 shows an alternate embodiment of the present invention having an articulating arm 62 interposed between the block 96 and post 68 a . As will be understood, the articulating arm increases the range of motion by which the stowable work surface 12 may be moved. The articulating arm 62 comprises a lower arm 146 and an upper arm 148 joined together by a bolt 154 which allows the two arms to act as a hinge and swivel via the pivot pin 154 . The articulating arm is of a common design and has been shown earlier in FIG. 14 . The lower arm 146 has a hole 150 opposite the its hinged end. The bolt 152 extends through the hole and threads into the threaded hole 132 in the swivel base 136 . A thrust washer 38 may be positioned between the swivel base 136 and the lower arm 146 . The upper arm 148 has a throughhole or aperture 152 located on its end opposite its hinged end. A bolt 36 extends through a hole 162 in block 96 , through the thrust washer 38 and through the throughhole or aperture 152 at the end of the arm 148 and is secured via a nut 34 . The nut is tightened to allow the block to pivot freely with some resistance.
[0063] FIG. 21 shows an alternate embodiment of the present invention having an extension arm 157 with channel elements 156 extending the length of the extension arm 157 and secured to the underside of the arm by fastening elements 160 that extend through apertures 161 in the extension arm 157 and screwed into the channel elements 156 . The channel elements 156 are a longer version of channel elements 128 in FIG. 17 a . The extension arm 157 is configured so that the U shaped channels 163 slide along the edges of a rectangular plate 155 . The plate 155 is rotatably mounted onto the swivel base 136 by bolt 36 which extends through a hole 158 located in the center of the plate 155 through a thrust washer 38 , and into threaded hole 159 located in the center of the swivel base 136 .
[0064] FIG. 22 shows an alternate embodiment of an extension arm 164 that is shaped like a channel having a top and two sides and an interior cavity. Two ball bearing glides 168 are secured to the interior walls of the channel and have mounting flanges 166 that extend towards the interior cavity 166 . The mounting flanges 166 have holes 170 that allow the extension arm 164 to be attached to plate having corresponding holes similar to plate 155 shown in FIG. 21 but with corresponding attachment holes (not shown).
[0065] FIG. 23 shows an alternate embodiment having an extension arm 157 as shown in FIG. 21 with a rotating hinge assembly 171 attached to it. The hinge assembly is a known device used for stowing a desktop to the side of a chair used in classrooms and auditoriums. The mechanics will be briefly described here. A block 172 is mounted to the arm 157 by bolt 176 that extends through a hole 182 located in the center of the block and nut 180 is threaded onto the bolt. The block 172 rotates about the bolt 176 . The block 172 has two hinge pins 178 located at each end of the block which allows a hinge bracket 174 to be mounted and swivel perpendicular to the axis on which the block 172 swivels. The stowable work surface 12 is attached to the hinge bracket thereby allowing the stowable work surface 12 to be flipped up and rotated 180 degrees down and slid back via the extension arm 157 .
[0066] FIG. 24 shows another alternate embodiment of the present invention having an extension arm 192 that does not slide. A block 184 having a block 96 thereto it allows the stowable work surface 12 to slide and rotate. An extension arm 192 is fastened to the swivel base 194 through an aperture 198 on one end of the extension arm 192 . The swivel base has a threaded stud 196 that extends upwardly from the center of the swivel base and extends through the hole 198 on the extension arm and where it is secured by a nut 34 . A thrust washer 134 may be placed between the swivel base 194 and the extension arm 192 to provide a smooth wear resistant surface on which the extension arm 192 may swivel. The block 184 is built in the same fashion as the extension arm shown in FIG. 21 , but shorter in length. The block 184 comprises a plate 186 having two channel elements 188 secured to the underside thereof by conventional fastening elements that are received mounting holes 150 . A thrust washer 134 may be positioned between the block 184 and the block 96 to provide easy and smooth rotation of the pivot block 96 . A standard armrest 28 may be mounted to the pivot block 96 .
[0067] FIGS. 25 and 25 a shows a stowable work surface 12 with a partial oval shape having one flat edge. The stowable work surface 12 has a recess 200 cut into the top that is slightly deeper than the thickness of a mouse pad. A mouse pad 202 is placed in the recess allowing a ridge 204 around the perimeter of the work surface to extend beyond the height of the mouse pad thereby allowing the ridge to prevent a mouse from falling off the stowable work surface 12 . The stowable work surface 12 has a threaded insert 21 threaded into the bottom of the work surface and provides the means for bolting the work surface to the bracket 14 or bracket 118 .
[0068] It is to be understood that even though numerous characteristics and advantages of various embodiments of the present invention have been set forth in the foregoing description, together with details of the structure and function of various embodiments of the invention, this disclosure is illustrative only, and changes may be made in detail, especially in matters of structure and arrangement of parts within the principles of the present invention to the full extent indicated by the broad general meaning of the terms in which the appended claims are expressed.
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An attachment apparatus assembly that is multi positional and attaches to a computer or desk chair is shown. The assembly attaches to a chair by use of an existing chair arm or by using a separate attachment member. The device provides support for the forearm and wrist while operating a computer mouse by allowing the user to rest their forearm on a chair arm that has a stowable work surface on its top surface. The work surface is vertically adjustable and can go from a myriad of horizontal work positions in front of or to the side of the user, and folds down into a stowed away position to the chairs side when not in use. The work surface may be utilized to operate a keyboard from by positioning the work surface over the users lap. In one embodiment the armrest is also horizontally positional.
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CROSS REFERENCE TO RELATED APPLICATIONS
This application claims the benefit of U.S. Provisional Application No. 60/126,203, filed Mar. 25, 1999, and is entitled to this earlier U.S. effective filing date.
FIELD OF THE INVENTION
This invention relates generally to linings for garments. More specifically, it relates to removable liners for garments.
BACKGROUND OF THE INVENTION
Garments made of materials such as wool, or other coarse, loosely woven materials, present several limitations to the wearer. For instance, many people have sensitive skin. Wool and other garment materials, when worn directly against the skin, cause physical discomfort (itching) for a significant percentage of the population. This can lead to irritation and rash, and many people are unable to wear garments made of wool next to their skin.
Most knitted sweaters commercially available to the consumer do not have a lining. Furthermore, lining a sweater or dress with a permanent liner is expensive and time consuming. Consequently, it would be prohibitively expensive to provide linings for commercial garments and even more so for an individual to have all such garments lined after purchase.
Undergarments provide a barrier between the skin and garment, but undergarments that are generally available have limited use for this problem. For instance, a slip can be worn under a wool dress, but this does not provide protection for the arms. Jacket-style undergarments are not generally available.
Therefore, not many options exist for the protection of the arms of those individuals sensitive to wool or other coarse fabrics, that want to wear sleeved garments made of such material.
Similarly, when used to make garments, the looseness of the weave and porosity of many fabrics, provide an incomplete barrier for ultra violet radiation and also limits the ability of these fabrics to provide thermal insulation or an adequate barrier against wind.
SUMMARY OF THE INVENTION
This invention describes removable liners for sleeves, designed to be used with garments that are made of wool or similar materials. Sleeve liners allow individuals sensitive to wool to wear woolen clothing, such as cardigan sweaters over sleeveless or short sleeved shirts or dresses. Sleeve liners also provide a more complete barrier against wind and ultra-violet penetration from the sun or other sources. Sleeve liners also increase the ability of a garment to provide thermal insulation.
It is an object of this invention to greatly expand the potential applications of an individual's existing wardrobe.
It is an object of this invention to expand the uses and applications for a particular garment.
It is an object of this invention to save the wearer the expense of having garments professionally lined. The cost for having even just two sleeves lined can often exceed the price paid for the garment.
It is an object of this invention to provide liners that can be easily removed and used interchangeably in many different garments.
It is an object of this invention to provide liners with fastening means that independently adhere to the garment.
It is an object of this invention to improve the ultra-violet protection afforded by a garment when worn.
It is an object of this invention to improve the wind protection afforded by a garment when worn.
It is an object of this invention to improve the thermal insulation provided by a garment when worn.
In accordance with the above objectives, and others described herein, this invention provides a removable sleeve liner made from a variety of different fabrics. that can be placed within a garment sleeve and easily affixed to the portion of the garment sleeve closest to the body of the garment.
In an embodiment, the liner is provided with the hook portion of hook and fastener fabric such that attachment to the garment can be accomplished independently, e.g., without any modification of the garment.
In further accordance with the above objects, and others described herein, this invention provides a removable liner for inserting in garment sleeves, said liner comprising a tubular material with a shoulder end and a wrist end and a means for fastening said liner to said sleeve proximal to the shoulder end.
DESCRIPTION OF THE DRAWINGS
FIG. 1 is the pattern of the material used to construct the sleeve liner.
FIGS. 2A & 2B are perspective views of the sleeve liner.
FIG. 3A is a perspective view of a sweater as the sleeve liner is being inserted.
FIG. 3B is a view of the inside of a sweater with the sleeve liner in place.
DETAILED DESCRIPTION OF THE INVENTION
The instant invention discloses a removable sleeve liner comprising a sleeve and fasteners. The liner is generally tubular and resembles a typical garment sleeve. Sleeves vary in shape and size, ranging from wide bell shapes to straight, and from the smallest children's sizes to the largest men's sizes. Women's sizes, which are usually intermediate, are also contemplated. Consequently, a variety of sizes and shapes of liner may be manufactured to accommodate the shapes and sizes of typical sleeves.
Referring now to FIG. 2, the liner ( 10 ) has a shoulder end ( 11 ) and a wrist end ( 12 ). In an embodiment, the wrist end ( 12 ) has a smaller circumference than the shoulder end ( 11 ). Typically, the liner is at least 4 inches long and no longer than 40 inches. More typically, the liner is from 18 to 25 inches long. Typically, the liner is at least 4 inches in circumference, but no greater than 34 inches. More typically, the liner is between 8 and 28 inches in circumference.
The liner is identical for the left and right sleeves so the construction of only one unit is illustrated. In an embodiment, the body of the liner itself is made from a single piece of fabric cut to a pattern similar to a sleeve, as shown in FIG. 1 .
The fabric used varies depending on the intended use. When used as a comfort barrier from coarse materials such as wool, the fabric is typically a soft material, commonly available, like that used in lining garments, such as polyester, silk, rayon, nylon, cotton and the like. When the preferred use is as a protective barrier from ultra-violet radiation the liner may be manufactured from fabrics with high SPF values of at least 20, preferrably 30 or greater. When the preferred use includes additional thermal insulation, fabrics in addition to those already referred to, such as polar fleece®, lycra and the like, or quilted material such as thermolitet® or the like may be used, separately or in combinations.
The fabric is folded lengthwise with the “right side” or “shiny side” on the inside and the first long edge ( 5 ) is joined to the second long edge ( 6 ), typically by sewing a seam joining the two sides ( 5 / 6 ) and the corners ( 3 / 4 ) and ( 1 / 2 ) of FIG. 1 .
The sleeve liner so joined ( 10 ) is depicted in FIG. 2 . The edges of the shoulder end ( 11 ) and wrist end ( 12 ) may be finished either by folding the leading edge back toward the “wrong side” or “dull side” of the fabric, and sewing it in place with a seam proximal to the folded edge; or, by sewing separate finishing strips of material ( 7 & 8 ) along the raw edges.
The liner is provided with a means for fastening the liner onto the garment sleeve. The fastener could be of any sort such as snaps hooks or buttons. In a preferred embodiment, the means for fastening is composed of hook and loop fastener fabric (such as that commercially available under the mark “Velcro®”). In a particularly preferred embodiment, shown in FIG. 2, the rectangular strips of the hook portion of the Velcro® ( 9 ) are attached to the liner on the wrong/dull side of the garment at various locations around the perimeter of the shoulder end ( 11 ) and adhere to the garment without requiring attachment of the complimentary loop portion, since the garment fabric itself substitutes for the loop portion and is itself adequate to receive and hold the hook portion.
The means for fastening may be affixed anywhere on the sleeve lining. Preferred locations, either alone or in combination, are: around the perimeter of the shoulder end; along the side seam, or around the perimeter of the wrist end. In an embodiment, the invention has an elastic band incorporated in the seam of the wrist end. Decorative detail, such as lace may also be incorporated upon the liner, preferably at or near the wrist end.
EXAMPLES
1. This invention is to be used to line any sleeved garment including, but not limited to, knitted sweaters and jackets. This example demonstrates the use of the sleeve liner of the instant invention with a knitted sweater, but it is to be understood that the sleeve liner may be used with any garment. The invention will be best understood by reference to the drawings. The invention is designed for use in both sleeves of a garment, but for simplicity only one sleeve is illustrated throughout. FIG. 3A illustrates the liner ( 10 ) being placed inside the right sleeve of a cardigan sweater. The liner attaches to the inside of the sweater at six points by means of small rectangular pieces of the hook portion of Velcrot® ( 9 ) which have been sewn onto the sleeve liner ( 10 ). In this example, it is not necessary to modify the sweater to use the invention. The Velcro® hooks attachment points ( 9 ) on the liner ( 10 ) attach directly to the fabric inside of the knitted cardigan as shown in FIG. 3 B.
The sleeve liner is easily inserted into the sleeve of the sweater by holding the sweater at the shoulder end with one hand and holding the liner at the wrist end in the other hand. The liner is then inserted into the sleeve of the sweater at the shoulder end. With the seam of the liner aligned with the underarm seam of the cardigan, the invention is pushed through until the wrist ends of the liner and the sweater line up. The liner is then attached at the shoulder end by pressing the Velcro hooks on the invention into the fabric at the attachment points.
The sweater may then be worn normally but more comfortably as there is no direct contact between the wearer's arm and the itchy wool of the sleeve. To keep the invention in place when the cardigan is removed the wearer will hold the sleeve lining at the wrist end, with one hand, while pulling their other arm out.
2. In an alternate embodiment, the complementary rectangular loop portions of the Velcro® are employed to produce a stronger attachment between the invention and the garment. In this embodiment the soft side (or loop side) of the Velcro® fastener is attached (by sewing or using self-adhesive loop Velcro® material) to the garment. This embodiment is most useful in cases where the hook Velcro® strips of the invention do not readily adhere to the fabric of the garment. An example would be when the garment is made of a smoother material such as linen, another fabric that some people find uncomfortable.
In the foregoing, the present invention has been described with reference to suitable embodiments, but these embodiments are only for purposes of understanding the invention and various alterations or modifications are possible so long as the present invention does not deviate from the claims that follow.
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This invention discloses a garment sleeve liner useful for improving the comfort or insulating ability of garments. Depending on the application, the liner is made variously from silk, polyester, cotton or quilted fabric. The liner is tubular and designed to fit comfortably within and along a garment sleeve. The liner has means for attaching to the garment affixed to the shoulder end of the liner. A useful means for attaching the liner to the garment is several rectangular pieces of Velcro® affixed to the shoulder end of the liner.
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This is a continuation-in-part application of Ser. No. 07/184,673 filed on Apr. 22, 1988, now abandoned.
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to a process for preparing a di(fluoroalkyl containing group-substituted alkyl) phosphate salt.
The di(fluoroalkyl containing group-substituted alkyl) phosphate salt is useful as a surface active agent, a water- and/or oil-repellent for fiber or paper or an oil resistant agent.
2. Description of the Related Art
Processes for preparing fluoroalkyl containing group-substituted alkyl phosphate esters are disclosed in, for example, Japanese Patent Publications Nos. 7776/1979, 29875/1981 and 48158/1982 and Japanese Patent Kokai Publication No. 64990/1985.
However, the phosphate esters which are obtained by the above processes have wide distribution of composition which contains two or three of a monoalkyl ester, a dialkyl ester and a trialkyl ester. Of these three esters, the di(fluoroalkyl containing group-substituted alkyl) phosphate ester has the highest oil resistance, but is not produced in a high selectivity and contains relatively large amounts of monoalkyl and trialkyl esters. A yield of dialkyl esters is at most about 80% by weight, as described in Examples of Japanese Patent Publication No. 7776/1979. It is desired to increase the selectivity of dialkyl esters.
SUMMARY OF THE INVENTION
An object of the present invention is to provide a process for preparing a fluoroalkyl containing group-substituted alkyl phosphate ester by which a dialkyl ester is produced in a high selectivity.
This and other objects of the present invention are achieved by a process for preparing a di(fluoroalkyl containing group-substituted alkyl) phosphate salt which comprises hydrolyzing a mono-sec.- or tert.-alkyl di(fluoroalkyl containing group-substituted alkyl) phosphate with a base.
DETAILED DESCRIPTION OF THE INVENTION
Illustrative types of the di(fluoroalkyl containing group-substituted alkyl) phosphate salt produced by the process according to the present invention are of the formula:
[R.sub.f --A.sup.1.sub.k --(CH.sub.2).sub.m --O].sub.2 PO--OA.sup.2(I)
wherein each R f is independently a perfluoroalkyl group or ω-hydroperfluoroalkyl group having 3 to 21 carbon atoms,
each A 1 is independently a divalent group which bonds R f to --(CH 2 ) m --,
A 2 is an alkaline metal or an ammonium group which may be substituted with an alkyl and/or hydroxyalkyl group,
k is 0 or 1, and
m is an integer of 1 to 4.
R f in the formula (I) may be linear, branched, cyclic (for example, perfluorocyclohexyl) or combination thereof.
A 1 is, for example, --COO--, --SO 2 , --O--, --(CH 2 ) 3 --O--, --S--, --(CH 2 ) p --NR'--, --CH 2 CH(OR')--, --CO--NR'-- or --SO 2 --NR' in which R' is a hydrogen or an alkyl group having 1 to 5 carbon atoms and p is an integer of 1 to 6.
Specific examples of the di(fluoroalkyl containing group-substituted alkyl) phosphate salt of the formula (I) are:
(C 4 F 9 CH 2 CH 2 O) 2 POONH 2 (C 2 H 4 OH) 2
[(CF 3 ) 2 CF(CF 2 ) 6 CH 2 CH 2 O] 2 POONH 2 (C 2 H 4 OH) 2
(C 8 F 17 CH 2 CH 2 O) 2 POONH 2 (C 2 H 4 OH) 2
(C 6 F 13 CH 2 CH 2 O) 2 POONH 2 (C 2 H 4 OH) 2
(C 10 F 21 CH 2 CH 2 O) 2 POONH 2 (C 2 H 4 OH) 2
(C 12 F 25 CH 2 CH 2 O) 2 POONH 2 (C 2 H 4 OH) 2
(C 14 F 29 CH 2 CH 2 O) 2 POONH 2 (C 2 H 4 OH) 2
(C 8 F 17 CH 2 CH 2 O) 2 POONH 4
(C 8 F 17 CH 2 CH 2 O) 2 POONH(C 2 H 4 OH) 3
[C 8 F 17 SO 2 N(C 2 H 5 )CH 2 CH 2 O] 2 POONH 4
[C 6 F 13 SO 2 N(C 2 H 5 )CH 2 CH 2 O] 2 POONH 4
[C 10 F 21 SO 2 N(C 2 H 5 )CH 2 CH 2 O] 2 POONH 4
[C 12 F 25 SO 2 N(C 2 H 5 )CH 2 CH 2 O] 2 POONH 4
[C 14 F 29 SO 2 N(C 2 H 5 )CH 2 CH 2 O] 2 POONH 4
[C 8 F 17 SO 2 N(C 2 H 5 )CH 2 CH 2 O] 2 POONH 2 (CH 2 CH 2 OH) 2
[C 8 F 17 SO 2 N(C 2 H 5 )CH 2 CH 2 O] 2 POONH(CH 2 CH 2 OH) 3
[C 8 F 17 SO 2 N(C 3 H 7 )CH 2 CH 2 O] 2 POONH 2 (CH 2 CH 2 OH) 2
[C 8 F 17 CON(C 2 H 5 )CH 2 CH 2 O] 2 POONH(CH 2 CH 2 OH) 3
(C 8 F 17 COOCH 2 CH 2 O) 2 POONH 4
(C 8 F 17 SO 2 CH 2 CH 2 O) 2 POONH 4
[C 8 F 17 (CH 2 ) 3 OCH 2 CH 2 O] 2 POONH 4
[C 8 F 17 CH 2 CH(OH)CH 2 O] 2 POONH 4
To prepare the di(fluoroalkyl containing group-substituted alkyl) phosphate salt of the formula (I), an alkyl ester of di(fluoroalkyl containing group-substituted alkyl) phosphate is hydrolyzed with a base. The alkyl ester of di(fluoroalkyl containing group-substituted alkyl) phosphate is preferably of the formula:
[R.sub.f --A.sup.1.sub.k --(CH.sub.2).sub.m --O].sub.2 PO--OR(II)
wherein R is a secondary or tertiary alkyl or alkenyl group having 3 to 9 carbons, and R f , A 1 , k and m are the same as defined above. An alcoholic residue which is formed by the secondary or tertiary alkyl or alkenyl group is easily removed by hydrolysis to form the diester phosphate salt of the formula (I).
Specific examples of the alkyl ester of di(fluoroalkyl containing group-substituted alkyl) phosphate of the formula (II) are:
(C 4 F 9 CH 2 CH 2 O) 2 POOCH(CH 3 ) 2
[(CF 3 ) 2 CF(CF 2 ) 6 CH 2 CH 2 O] 2 POOCH(CH 3 ) 2
(C 8 F 17 CH 2 CH 2 O) 2 POOCH(CH 3 ) 2
(C 6 F 13 CH 2 CH 2 O) 2 POOCH(CH 3 ) 2
(C 10 F 21 CH 2 CH 2 O) 2 POOCH(CH 3 ) 2
(C 12 F 25 CH 2 CH 2 O) 2 POOCH(CH 3 ) 2
(C 14 F 29 CH 2 CH 2 O) 2 POOCH(CH 3 ) 2
(C 8 F 17 CH 2 CH 2 O) 2 POOC(CH 3 ) 3
(C 8 F 17 CH 2 CH 2 O) 2 POOCH 2 CH 2 CH(CH 3 ) 2
[C 8 F 17 SO 2 N(C 2 H 5 )CH 2 CH 2 O] 2 POOCH(CH 3 ) 2
[C 6 F 13 SO 2 N(C 2 H 5 )CH 2 CH 2 O] 2 POOCH(CH 3 ) 2
[C 10 F 21 SO 2 N(C 2 H 5 )CH 2 CH 2 O] 2 POOCH(CH 3 ) 2
[C 12 F 25 SO 2 N(C 2 H 5 )CH 2 CH 2 O] 2 POOCH(CH 3 ) 2
[C 14 F 29 SO 2 N(C 2 H 5 )CH 2 CH 2 O] 2 POOCH(CH 3 ) 2
[C 8 F 17 SO 2 N(C 2 H 5 )CH 2 CH 2 O] 2 POOC(CH 3 ) 3
[C 8 F 17 SO 2 N(C 2 H 5 )CH 2 CH 2 O] 2 POOCH 2 CH 2 CH(CH 3 ) 2
[C 8 F 17 SO 2 N(C 3 H 7 )CH 2 CH 2 O] 2 POOCH(CH 3 ) 2
[C 8 F 17 CON(C 2 H 5 )CH 2 CH 2 O] 2 POOCH(CH 3 ) 2
[C 8 F 17 COOCH 2 CH 2 O] 2 POOCH(CH 3 ) 2
[C 8 F 17 SO 2 CH 2 CH 2 O] 2 POOCH(CH 3 ) 2
[C 8 F 17 (CH 2 ) 3 OCH 2 CH 2 O] 2 POOCH 2 CH(CH 3 ) 2
[C 8 F 17 CH 2 CH(OH)CH 2 O] 2 POOCH(CH 3 ) 2
The base which is used to hydrolyze the alkyl ester of di(fluoroalkyl containing group-substituted alkyl) phosphate of the formula (II) is preferably an alkali hydroxide, an ammonium hydroxide or an amine. Examples of the alkali hydroxide are potassium hydroxide and sodium hydroxide. Examples of the amine are trimethylamine, triethylamine, tripropylamine, tributylamine, triethanolamine, diethylamine, dipropylamine, diethanolamine, ethylamine, propylamine and ethanolamine.
The hydrolysis can be carried out by adding ammonium hydroxide or an amine/water mixture, or an alkali hydroxide/alcohol/water mixture to the alkyl ester of di(fluoroalkyl containing group-substituted alkyl) phosphate. The alcohol which is used in hydrolysis includes a secondary or tertiary C 3 -C 6 alcohol such as isopropyl alcohol, tert.-butyl alcohol, sec.-butyl alcohol, tert.-amyl alcohol, isoamyl alcohol and sec.-amyl alcohol.
The base is used in an amount of at least one equivalent, preferably 1 to 10 equivalents per mole of the alkyl di(fluoroalkyl containing group-substituted alkyl) phosphate.
The pressure during hydrolysis is not critical. Usually, the hydrolysis is carried out under an atmospheric pressure at a temperature of 80° to 100° C. for 2 to 6 hours.
The alkyl ester of di(fluoroalkyl containing group-substituted alkyl) phosphate of the formula (II) can be prepared by reacting a fluoroalkyl containing group-substituted alcohol of the formula:
R.sub.f --A.sup.1.sub.k --(CH.sub.2).sub.m --OH (III)
wherein R f , A 1 , k and m are the same as defined above, with a phosphoryl monoalkoxide dihalide of the formula:
RO--POX.sub.2 (IV)
wherein each X is independently halogen atom, for example, chlorine or bromine and R is the same as defined above.
Specific examples of the alcohol of the formula (III) are:
C 4 F 9 CH 2 CH 2 OH
(CF 3 ) 2 CF(CF 2 ) 6 CH 2 CH 2 OH
C 8 F 17 CH 2 CH 2 OH
C 10 F 21 CH 2 CH 2 OH
C 8 F 17 SO 2 N(C 2 H 5 )CH 2 CH 2 OH
C 8 F 17 SO 2 N(C 3 H 7 )CH 2 CH 2 OH
C 8 F 17 SO 2 N(CH 3 )CH 2 CH 2 OH
In the reaction, a molar ratio of the alcohol of the formula (III) to the phosphoryl monoalkoxide dihalide of the formula (IV) is preferably from 2:1 to 2:1.2. The reaction pressure is not critial. Usually, the reaction is carried out under an atmospheric pressure at 80° to 100° C. for 2 to 4 hours.
The phosphoryl monoalkoxide dihalide of the formula (IV) can be prepared by reacting a secondary or tertiary alcohol of the formula:
ROH (V)
wherein R is the same as defined above, with a phosphoryl trihalide of the formula:
POX.sub.3 (VI)
wherein X is the same as defined above.
It is not preferable to use a primary alcohol instead of the secondary or tertiary alcohol of the formula (V), since the alkyl ester of di(fluoroalkyl containing group-substituted alkyl) phosphate of the formula (II) is hardly hydrolyzed.
As the phosphoryl trihalide of the formula (VI), usually phosphoryl trichloride is used because of its availability, although phosphoryl tribromide and phosphoryl bromide chloride may be used.
A molar ratio of the secondary or tertiary alcohol of the formula (V) to the phosphoryl trihalide of the formula (VI) is preferably about 1:1, preferably 0.9:1 to 1:1. The reaction pressure is not critical. Usually, the reaction is carried out under an atmospheric pressure at a temperature of room temperature (e.g. 20° C.) to 70° C. for 2 to 4 hours.
Therefore, the di(fluoroalkyl containing group-substituted alkyl) phosphate salt of the formula (I) can be prepared by reacting the secondary or tertiary alcohol of the formula (V) with the phosphoryl trihalide of the formula (VI) to produce the phosphoryl monoalkoxide dihalide of the formula (IV), reacting the phosphoryl monoalkoxide halide of the formula (IV) with the fluoroalkyl containing group-substituted alcohol of the formula (III) to produce the alkyl ester of di(fluoroalkyl containing group-substituted alkyl) phosphate of the formula (II), and hydrolyzing the alkyl ester of di(fluoroalkyl containing group-substituted alkyl) phosphate of the formula (II) with the base.
According to the present invention, the di(fluoroalkyl containing group-substituted alkyl) phosphate salt can be prepared in a purity of not less than 90% by weight.
The present invention will be explained further in detail by the following Examples.
EXAMPLE 1
In a 200 ml flask equipped with a stirrer, a Dimroth condenser and a dropping funnel, phosphoryl trichloride (154 g, 1 mol) was charged and isopropyl alcohol (57 g, 0.95 mol) was dropwise added over 30 minutes with stirring. The reaction was exothermic and hydrogen chloride gas evolved. After completing the exothermic reaction, the reaction mixture was heated at 70° C. for one hour to give a colorless liquid mixture containing POCl 3 (1 g), C 3 H 7 OPOCl 2 (175 g) and (C 3 H 7 O) 2 POCl (3 g).
In a one liter flask, a compound (200 g, 0.39 mol) of the formula:
C.sub.n F.sub.n+1 CH.sub.2 CH.sub.2 OH
wherein molar fractions of compounds which have n of 8, 10, 12, 14 and 16 respectively are 55, 26, 12, 5 and 2, was charged. While a temperature was maintained at 80° C., the resultant liquid mixture (37 g) in the above was added with stirring. Hydrogen chloride evolved and the reaction started. The reaction mixture was heated to 95° C. and stirred for 2 hours. Then, water (1.5 g) was added and the reaction mixture was stirred for 2 hours to give a mixture of the following composition:
Diisopropyl mono(fluoroalkyl containing group-substituted alkyl) phosphate: 5% by weight
Monoisopropyl di(fluoroalkyl containing group-substituted alkyl) phosphate: 93% by weight
Tri(fluoroalkyl containing group-substituted phosphate: 2% by weight
The mixture contained no ester having a chlorine atom.
Diethanolamine (65 g) as a hydrolyzing agent was added to the mixture. The mixture was stirred at 95° C. for 3 hours. After cooling, a wax-like solid was obtained. Yield: 297 g. The final product was analyzed by 31 P-NMR spectrum to determine its composition. The result is shown in the Table.
EXAMPLE 2
A wax-like solid was obtained in the same manner as in Example 1 but using tert.-butyl alcohol (70.3 g, 0.95 mol) in place of isopropyl alcohol. Yield: 302 g. A composition of the final product is shown in the Table.
EXAMPLE 3
A wax-like solid was obtained in the same manner as in Example 1 but using tert.-amyl alcohol (83.6 g, 0.95 mol) in place of isopropyl alcohol. Yield: 315 g. A composition of the final product is shown in the Table.
EXAMPLE 4
An aqueous solution was obtained in the same manner as in Example 1 but using sodium hydroxide (20 g) and methyl alcohol (100 g) in place of diethanolamine. Yield: 352 g. A composition of the final product is shown in the Table.
EXAMPLE 5
A wax-like solid was obtained in the same manner as in Example 1 but using diethylamine (30 g) in place of diethanolamine. Yield: 262 g. A composition of the final product is shown in the Table.
EXAMPLE 6
In a 200 ml flask equipped with a stirrer, a Dimroth condenser and a dropping funnel, phosphoryl trichloride (154 g, 1 mol) was charged and isopropyl alcohol (57 g, 0.95 mol) was dropwise added over 30 minutes with stirring. The reaction was exothermic and hydrogen chloride gas evolved. After completing the exothermic reaction, the reaction mixture was heated at 70° C. for one hour to give a colorless liquid mixture containing POCl 3 (1 g), C 3 H 7 OPOCl 2 (175 g) and (C 3 H 7 O) 2 POCl (3 g).
In a one liter flask, a compound (280 g, 0.39 mol) of the formula:
C.sub.8 F.sub.17 SO.sub.2 N(C.sub.2 H.sub.5)CH.sub.2 CH.sub.2 OH
was charged. While a temperature was kept at 80° C., the resultant liquid mixture (37 g) in the above was added with stirring. Hydrogen chloride evolved and the reaction started. The reaction mixture was heated to 95° C. and stirred for 2 hours. Then, water (1.5 g) was added and the reaction mixture was stirred for 2 hours to give a mixture of the following composition:
Diisopropyl mono(fluoroalkyl containing group-substituted alkyl) phosphate: 4% by weight
Monoisopropyl di(fluoroalkyl containing group-substituted alkyl) phosphate: 95% by weight
Tri(fluoroalkyl containing group-substituted alkyl) phosphate: 1% by weight
The mixture contained no ester having chlorine atom.
Diethanolamine (65 g) as a hydrolyzing agent was added to the mixture. The mixture was stirred at 95° C. for 3 hours. After cooling, a wax-like solid was obtained. Yield: 373 g. The final product was analyzed by 31 P-NMR spectrum to determine its composition. The result is shown in the Table.
TABLE______________________________________Example Composition (% by weight)No. Monoester.sup.1 Diester.sup.2 Triester.sup.3______________________________________1 5 93 22 4 92 43 5 92 34 5 95 05 3 92 56 4 95 1______________________________________ Note: .sup.1 Monoester is a mono(fluoroalkyl containing groupsubstituted alkyl) phosphate salt. .sup.2 Diester is a di(fluoroalkyl containing groupsubstituted alkyl) phosphate salt which is a desired compound according to the present invention. .sup.3 Triester is a tri(fluoroalkyl containing groupsubstituted alkyl) phosphate.
In the above Examples, the di(fluoroalkyl containing group-substituted alkyl) phosphate salts are di(2-perfluoroalkyl-ethyl) phosphate salt and di(N-ethyl perfluoroalkanesulfonamidoethyl) phosphate salt. However, it is obvious for those skilled in the art to prepare other di(fluoroalkyl containing group-substituted alkyl) phosphate salts in the same manner as in the Examples. Although the Examples show the processes using diethanolamine, sodium hydroxide or diethylamine as the base, it is also obvious to use other bases since a hydrolysis reaction can be carried out with any base.
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A di(fluoroalkyl containing group-substituted alkyl) phosphate salt which is useful for a surface active agent, a water- and/or oil-repellent for fiber or paper or an oil resistant agent, can be prepared a process which comprises hydrolyzing a mono-sec.- or tert.-alkyl (di(fluoroalkyl containing group-substituted alkyl) phosphate with a base.
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CROSS REFERENCE TO RELATED APPLICATIONS
This is a continuation-in-part application of PCT International Application No. PCT/EP 92/01447 filed on Jun. 26, 1992, the entire contents of which are incorporated herein by reference.
FIELD OF THE INVENTION
This invention relates to a mobile automatic floor cleaner with integrated fresh and soiled liquid compartments, a cleaning rotor to be supplied from the fresh liquid compartment and at least one suction nozzle feeding into the soiled liquid compartment, the fresh and soiled liquid compartments being separated from one another by a fixed partition which allows liquid to pass through from the soiled liquid compartment into the fresh liquid compartment.
BACKGROUND OF THE INVENTION
One such mobile automatic floor cleaner is known from applicants' DE-OS 37 08 087. In this automatic floor cleaner, cleaning liquid containing cleaning concentrate is sprayed from a separate fresh liquid compartment via the rotor onto the floor to be treated. At the same time, the floor is scoured by the rotor. An arm-like water suction nozzle, which follows the rotor as the cleaner moves forward, is used to suck up the soiled water remaining after scrubbing so that, in a single operation, the floor can be thoroughly scrubbed and, at the same time, wiped dry to a certain extent by the suction effect.
The known automatic cleaner has its own drive and its own power supply, i.e. an on-board battery, so that it can be used independently of power points. However, the action radius of the known automatic cleaner is limited by the size of the fresh liquid compartment. Although, in the known cleaner, the partition between the fresh and soiled liquid compartments is also made of filter material to enable the soiled liquid sucked back to pass through the partition into the fresh liquid compartment, so that the fresh liquid compartment is kept full, it has been found in practice that this solution is unsatisfactory because the partition acting as a filter very quickly becomes blocked by soil particles with the result that insufficient soiled liquid passes through the filter into the fresh liquid compartment.
It is also known that the soiled water sucked back can be chemically cleaned in the automatic cleaner itself. However, this solution is unsatisfactory because it involves environmental pollution, besides which the still active cleaning liquid can be neutralized which is also undesirable.
SUMMARY OF THE INVENTION
Accordingly, the problem addressed by the present invention was to improve the automatic cleaner mentioned at the beginning in such a way that its action radius would be considerably increased in an environmentally friendly manner.
According to the invention, this problem has been solved by a mobile automatic floor cleaner of the type mentioned at the beginning which is characterized in that a pressure-equalizing opening is provided in the upper part of the partition and in that an overflow pipe passing through the partition is arranged between the fresh and soiled liquid compartments, the inlet opening of the overflow pipe being situated above the base of the soiled liquid compartment and its outlet opening being situated near the base of the fresh liquid compartment.
By virtue of this construction, the action radius of the automatic floor cleaner can be distinctly improved without the use of ecologically unsafe chemicals. The soiled water returned to the soiled liquid compartment initially sediments therein, i.e. the solid soil particles sink to the bottom of the soiled liquid compartment, while the cloudy soiled liquid free from soil particles passes through the overflow inlet opening arranged at a sufficient height into the fresh liquid compartment when the two compartments are filled to corresponding levels. The flow of liquid from the soiled liquid compartment into the fresh liquid compartment is governed solely by the two filling levels and not by the pressure prevailing in the container because the same pressure prevails in both compartments by virtue of the pressure equalizing opening. Accordingly, hardly any water is lost during the cleaning process so that the automatic floor cleaner has a very large action radius.
In one advantageous embodiment of the invention, a separating plate which separates two zones is provided in the soiled liquid compartment, the soiled water inlet opening being arranged in one zone and the overflow inlet opening being arranged in the other zone. By virtue of this arrangement, the soiled water sucked back passes very slowly into the vicinity of the overflow inlet opening because it first has to flow from one zone via the separating plate into the other zone. The soil particles thus have sufficient time to settle so that effective clarification occurs and no soil particles enter the fresh liquid compartment.
In one particularly practical variant, the separating plate is arranged substantially diagonally in the soiled liquid compartment and/or the separating plate has a rough surface. As a result of these measures, the soiled water sucked back first passes into one of the zones of the soiled liquid compartment, the soil particles immediately sedimenting on the separating plate, particularly under the effect of its rough surface, in addition to which no mixing occurs with the already sedimented soiled water present in the other zone of the soiled liquid compartment.
In another advantageous embodiment of the invention, a filter is arranged at the fresh liquid outlet of the fresh liquid compartment. This has the advantage that any soil particles which have entered the fresh liquid compartment after all cannot leave it and interfere with the cleaning process.
It has been found to be particularly suitable for the filter to be in the form of a filter cylinder with a replaceable filter cover arranged thereon. This filter cylinder has openings in its wall which are covered by the filter cover. The filter is arranged in such a way that it is permanently below the liquid surface. Through the movement of the automatic cleaner and the resulting movement of the water in the fresh liquid compartment, the filter cylinder is continually rinsed free by the swashing movement of the water so that blockages are largely avoided.
In order completely to avoid blockage of the filter cylinder and to replace the associated filter mantle as and when necessary, another embodiment of the invention is characterized in that a reduced pressure monitor is arranged between the filter and the pump connected to the fresh liquid outlet pipe. Accordingly, if no liquid or too little liquid passes through the filter as a result of a blockage, a corresponding reduced pressure is established behind the filter and is detected by the reduced pressure monitor. This reduced pressure monitor is connected to a suitable indicator (optical and/or acoustic) so that the machine operator can replace or clean the filter mantle accordingly.
BRIEF DESCRIPTION OF THE DRAWINGS
The invention is described by way of example in the following with reference to the accompanying drawings, wherein:
FIG. 1 is a perspective view of a mobile automatic floor cleaner according to the invention.
FIG. 2 is a perspective view of part of the liquid container of the automatic floor cleaner with fresh and soiled liquid compartments.
FIG. 3 is a simplified view of a filter for the outlet of the fresh liquid compartment.
FIG. 4 is a simplified side elevation of the liquid container of FIG. 2.
DETAILED DESCRIPTION OF THE INVENTION
The mobile automatic floor cleaner shown in FIG. 1 comprises a movable carriage globally denoted by the reference 1 with rollers 2 and a steering handle 3 with an operating unit (not shown in detail). A large part of the interior of the movable carriage 1 accommodates a liquid tank which is globally denoted by the reference 4 and which is designed to be closed by a cover 5. The liquid tank 4 consists of a fresh water compartment 6 and a soiled water compartment 7, the two compartments being separated from one another by a fixed partition 8.
Shown on the underneath of the carriage 1 is a cleaning rotor 9 designed to be driven by a motor (not shown). Several suction nozzles 10 arranged on a suction arm 11 are provided in the rear lower region of the movable carriage 1, i.e. on that side of the rollers 2 remote from the cleaning rotor 9. A suction hose 12 is attached to the suction arm 11 at one end of suction hose 12, and is attached to fluid inlet connector 13 at an opposite end of suction hose 12. The fluid inlet connector 13 introduces soiled liquid into the soiled liquid compartment 7 of the liquid tank 4.
The design of the liquid tank 4 is crucial to the invention. First of all, a pressure equalizing opening 14 (FIG. 2) is provided in the partition 8 between the fresh and soiled liquid compartments 6 and 7 in the upper part of the tank 4 and, when the suction motor (not shown) located inside the movable carriage 1 is switched on to suck up the soiled water through the suction nozzles 10, the pressure equalizing opening 14 maintains a uniform pressure throughout the liquid tank 4.
The soiled liquid compartment 7 is divided into two zones by a diagonally arranged separating plate 15. The separating plate 15 has merely been outlined to leave the other parts in the tank clearly visible. The soiled water inlet opening, i.e. fluid inlet connector 13, is arranged in the upper zone 16 of the soiled liquid compartment 7 so that the soiled water first passes into the upper zone 16. In addition, a float 17 and a filter sieve 18 are also shown in the upper zone 16 of the soiled water compartment 7 in FIG. 2. Filter sieve 18 allows air drawn into compartment 7 along with the soiled water to escape from within liquid tank 4 into the outside environment. Float 17 is connected to the suction pump (not shown) so that in the event the water level in compartment 7 gets too high, float 17 will cause the suction motor to shut down.
Arranged between the fresh liquid compartment 6 and the soiled liquid compartment 7 is an overflow pipe 19 which passes through the partition 8, running substantially parallel thereto, and which comprises two openings angled through 90°, an inlet opening 20 and an outlet opening 21. The inlet opening 20 is arranged in the soiled liquid compartment 7 above the base thereof, but below the diagonal separating plate 15 in the lower zone 22 of the soiled liquid compartment 7. By contrast, the outlet opening 21 is arranged near the base of the fresh liquid compartment 6.
In addition, a fresh liquid outlet 23 is provided in the fresh liquid compartment 6. A floating suction funnel 24 is arranged at the outlet 23, being provided with a filter in the form of a filter cylinder 25. The filter cylinder 25 has a closed cover and base although an outlet nozzle 26 is provided in the base. The wall 27 of the filter cylinder 25 is heavily perforated although this has not been shown in detail in the drawing. A filter cover 28, preferably of synthetic cloth with a suitable mesh width (30 to 1,000 μm), is drawn over the cylinder 25.
A reduced pressure monitor 30, which again has only been shown in outline in FIG. 3, is connected via a tee between the filter cylinder 25 and a liquid pump 29--shown in outline only in FIG. 3--which transports the fresh liquid from the fresh liquid compartment 6 first through the filter cylinder 25 and then through a fresh liquid outlet pipe 31 to the cleaning rotor 9.
When the automatic cleaner is brought into operation, the liquid tank 4, i.e. both liquid compartments 6 and 7, is completely full. In the illustrated example, the tank 4 has a capacity of around 60 liters. When the suction motor (not shown) is switched on, a uniform reduced pressure is established in the two liquid compartments 6 and 7 under the effect of the pressure equalizing opening 14. The soiled water returned through the suction nozzles 10 passes through the suction hose 12 and the fluid inlet connector 13 into the upper zone 16 of the soiled water compartment 7. The soiled liquid is initially present in the upper zone 16 and does not yet come into contact with the partly clarified liquid situated below the separating plate 15, so that no mixing with the partly clarified liquid takes place. The solid soil particles present in the soiled water settle onto an upper surface of the separating plate 15 which is preferably ribbed.
The liquid from upper zone 16 has to pass through at the lowest point of the separating plate 15, preferably about 2 cm above the base 32 of the tank, in order to enter the lower zone 22 of the soiled water compartment 7. It is during this passage of soiled liquid from upper zone 16 to lower zone 22 that a sedimentation process takes place, i.e. the solid soil particles sink to the bottom of the soiled water compartment 7. The partly clarified, solids-free liquid then flows into lower zone 22 of the soiled water compartment 7. From lower zone 22, the partly clarified liquid then enters inlet opening 20 of overflow pipe 19 and is then discharged through outlet opening 21 into the fresh water compartment 6 at its base, so that the pre-clarified liquor is guided from the soiled water compartment 7 into an end of the fresh water compartment 6 opposite from the filter cylinder 25 and onto the bottom of the fresh water compartment 6.
The tank holds around 60 liters of water, approximately 2 liters being pumped off or taken up per minute. At any given time, the liquid from soiled water compartment 7 takes approximately 30 minutes to flow completely into fresh water compartment 6. This flow rate between compartments 6 and 7 provides ample time for the solid soil particles to settle at the bottom of soiled water compartment 7 once they enter therein, which accounts for the favorable sedimentation result.
The partly clarified liquid in the fresh water compartment 6 is siphoned out by liquid pump 29 through the filter cylinder 25 and pumped onto the surface to be cleaned through the cleaning rotor 9.
When the liquid pump 29 is on, water flows continuously through the filter cylinder 25. After a suitable period of operation and uptake of soil the filter cover 28 becomes clogged. This creates a resistance within filter cylinder 25 which causes the liquid pump 29 to build up a reduced pressure, which is detected by the reduced pressure monitor 30 connected to the fresh liquid outlet pipe 31. The reduced pressure monitor is connected to a visual or audio indicator (not shown) which acts as a signal that the cleaning liquid is exhausted, i.e. overladen with solid soil particles. The filter cover 28 may then be changed by the operator.
Basically, the filter cylinder 25 is arranged in such a way that liquid is continuously pumped out therethrough from fresh water compartment 6. Under the effect of the gentle swashing movements associated with the advance of the cleaner, the filter cover 28 is continually self-rinsed so that it does not clog up as quickly.
The invention is not of course confined to the embodiment illustrated in the drawing. Further embodiments are possible without departing from the basic concept of the invention. Thus, other fittings may be provided to improve sedimentation in the soiled liquid compartment 7 and so on.
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An improved mobile cleaning apparatus is provided having an increased cleaning radius consisting of a movable carriage with integrated fresh and soiled liquid compartments contained therein which are separated by a fixed partition, a cleaning rotor is connected to the fresh liquid compartment at one end of the housing and at least one suction nozzle feeding into the soiled liquid compartment is also provided adjacent to the rotor. A pressure equalizing opening is provided in the upper part of the fixed partition. The fixed partition is also adapted to allow an overflow pipe to pass therethrough having an inlet opening situated in the soiled liquid compartment, and an outlet opening situated in the fresh liquid compartment.
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This application is a continuation of U.S. patent application Ser. No. 10/039,238, filed Dec. 31, 2001, now U.S. Pat. No. 6,863,945.
BACKGROUND OF INVENTION
This invention generally relates to the manufacture of absorbent articles from absorbent material, and in particular to a splice connecting two portions of absorbent material which is useable in articles.
Personal care absorbent articles such as disposable diapers, training pants, other infant care products, other child care products, feminine napkins, panty liners, interlabial pads, other feminine care products, incontinence articles, and other adult care products are typically manufactured using high-speed processing machines which convert a stabilized web or ribbon of a fibrous absorbent material into an article. Each web is pre-formed and provided to the machine as a wound roll or coil. To prevent interruption of the processing machine a trailing end of each coil is spliced to a leading end of the next coil. The resulting interconnected web has sufficient tensile strength so that it may be provided to the machine and processed without breaking at the splice.
One drawback to conventional splicing techniques is that the splice is not fluid permeable and therefore unusable in an article. In the past, fibrous absorbent materials have been joined by an adhesive or, since they do not have smooth surfaces which readily hold an adhesive, by an adhesive tape. Adhesives and tape are substantially impermeable to fluid. They hinder fluid from being absorbed by the absorbent structure of the article and degrade effectiveness of the article. As a result, it is necessary to cull all spliced regions of the absorbent material, or to cull all articles that may incorporate a portion of a spliced region, in order to remove all adhesive or tape. In practice, as many as seven articles are culled per splice, producing a costly loss in efficiency and waste of material.
SUMMARY OF THE INVENTION
In general, a process according to the present invention splices a first portion of absorbent material to a second portion of absorbent material to form a longer, continuous length of absorbent material suitable for uninterrupted sequential infeed to a processing machine. The process comprises the steps of placing a trailing end of the first portion adjacent a leading end of the second portion, and aligning the trailing end of the first portion with the leading end of the second portion. A piece of splicing material is attached to the trailing end of the first portion and the leading end of the second portion. The piece of splicing material has a fluid permeability at least about as great as a fluid permeability of the first portion of absorbent material and at least about as great as a fluid permeability of the second portion of absorbent material.
In another aspect, the present invention comprises a continuous length of absorbent material for uninterrupted sequential infeed to a processing machine. The length includes a first portion of absorbent material having a trailing end and a second portion of absorbent material having a leading end adjacent to and aligned with the trailing end of the first portion of absorbent material. A piece of splicing material is attached to the trailing end of the first portion and the leading end of the second portion of absorbent material. The splicing material has a fluid permeability at least about as great as a fluid permeability of the first portion of absorbent material and at least about as great as the second portion of absorbent material.
In yet a further aspect, a personal care absorbent article according to the present invention has a spliced absorbent material. The article comprises a fluid permeable body side liner for placement adjacent a wearer. An absorbent core is attached to the body side liner for absorbing fluid passing through the liner. The absorbent core includes a first portion of absorbent material, a second portion of absorbent material, and a piece of splicing material attached to the first and second portions of absorbent material. The splicing material has a fluid permeability at least about as great as a fluid permeability of the first portion of absorbent material and at least about as great as the second portion of absorbent material.
Other features of the present invention will be in part apparent and in part pointed out hereinafter.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1A is a fragmentary schematic elevation of a continuous length of absorbent material of a first embodiment of the present invention;
FIG. 1B is a schematic plan of the length of absorbent material shown in FIG. 1A ;
FIGS. 2A and 2B are a schematic elevation and plan, respectively, of a length of absorbent material of a second embodiment;
FIGS. 3A and 3B are views similar to FIGS. 1A and 1B of a third embodiment of the present invention;
FIGS. 4A and 4B are views similar to FIGS. 1A and 1B of a fourth embodiment of the present invention;
FIG. 4C is a view taken on line 4 C- 4 C of FIG. 4A ; and
FIGS. 5A and 5B are views similar to FIGS. 1A and 1B of a fifth embodiment of the present invention.
FIG. 6 is a plot of measured fluid intake rate versus percent saturation in 0.9% saline for a representative example of the invention.
Corresponding reference characters indicate corresponding parts throughout the views of the drawings.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT
The length of material 20 made according to the present invention is useable in absorbent articles, including, but not limited to, disposable diapers, training pants, other infant care products, other child care products, feminine napkins, panty liners, interlabial pads, other feminine care products, incontinence articles, and other adult care products. Typically, the articles are disposable and not intended for washing and reuse. An exemplary article which may include the length of material described herein is disclosed in U.S. Pat. No. 6,160,197 issued Dec. 12, 2000 to Lassen et al. and entitled “Absorbent Article Having A Body-Accommodating Absorbent Core”, which is hereby incorporated by reference. Briefly, the Lassen reference discloses a feminine hygiene product and more particularly a sanitary napkin having a liquid-pervious cover or body side liner, a liquid-impervious baffle or outer cover positioned opposite the body side liner, and an absorbent core positioned between the body side liner and the outer cover.
During manufacture of the absorbent articles, the continuous length of absorbent material 20 is introduced into the processing machine from a suitable supply. For example, the absorbent material may be delivered from a series of supply rolls (not shown), or may optionally be supplied from a upstream inline manufacturing operation.
The first portion of absorbent material 22 has a trailing end 26 . The second portion of absorbent material 24 has a leading end 28 . Typically, the first and second portions 22 , 24 are identical in all respects but they may be different without departing from the scope of the present invention. For example, the second portion 24 may be a different material than the first portion 22 .
The trailing end 26 of the first portion is placed adjacent the leading end 28 of the second portion, and the ends are laterally and vertically aligned as shown in FIGS. 1A and 1B . In the illustrated embodiment, the ends 26 , 28 are placed squarely end-to-end as for a conventional butt joint. The ends may be in engagement, or may be spaced apart by a small gap between the ends. The placing of the ends 26 , 28 at these positions may be done manually, or by automated machine. An end-to-end arrangement results in better product comfort than an arrangement with the ends overlapped because it is thinner and less bulky. Each of the portions 22 , 24 has a first face 30 and an opposite second face 32 . The respective first faces 30 of the first and second portions 22 , 24 are oriented in an identical direction (e.g., vertically upward, as shown in the drawings). Similarly, the respective second faces 32 are oriented in an identical direction (e.g., vertically downward). It is understood that the faces 30 , 32 may be oriented in non-identical directions without departing from the scope of this invention.
A piece of splicing material 40 is positioned adjacent the trailing end 26 of the first portion 22 and the leading end 28 of the second portion 24 for attachment thereto. The piece of splicing material 40 engages at least one of the faces 30 , 32 of each of the ends. For the arrangement shown in FIGS. 1A and 1B , the piece of splicing material 40 is positioned adjacent the first face 30 of the trailing end 26 of the first portion and the first face 30 of the leading end 28 of the second portion.
The relative sizes of the materials may vary. Preferably, the piece of splicing material 40 is slightly narrower than the first and second portions 22 , 24 of absorbent material so that it does not extend beyond the lateral sides of the material, but yet covers a sufficient shear area to produce an effectively strong splice. The piece of splicing material 40 should overlap each portion of absorbent material in the longitudinal direction by a length sufficient to form a strong splice. For example, portions 22 , 24 of absorbent material having a width of about 37 mm may be joined by splicing material having a longitudinal overlap of at least about 25 mm per end (producing a total length of splice of about 50 mm), and more desirably a longitudinal overlap of at least about 50 mm.
In one embodiment, the piece of splicing material 40 is attached to the respective ends 26 , 28 of the first and second portions of absorbent material by compressing the arrangement and applying heat energy. The attachment is made using a compression device (not shown), such as a press, anvil, or set of plates which are pressed together. The heat may originate from either a surface source (such as a heated compression device) or from a hot air source such as a through-air bonding technique. The applications of heat and pressure occur simultaneously for a period of time so that the splicing material and/or a binding agent of the absorbent material soften or begin to melt and bind together upon cooling. As these techniques are conventional and well understood by those of ordinary skill in the art, they will not be discussed in further detail.
Significantly, the piece of splicing material 40 is at least as fluid permeable as the first and second portions 22 , 24 of absorbent material. Therefore, the splice will not hinder passage of fluid to the absorbent material when incorporated into an article. Further, the splicing material has a tensile strength at least as great as a tensile strength of the absorbent material so that the splice is strong and will not rupture when processed into an article.
The first and second portions 22 , 24 of absorbent material may include cellulosic fibers (e.g., wood pulp fibers), other natural fibers, synthetic fibers, superabsorbent material in the form of particles or fibers, binder materials, surfactants, selected hydrophobic materials, or the like, PET fiber, bicomponent fiber, latex, as well as combinations thereof, and other materials suitable to improve absorbent performance and/or web processing. Desirably, the stabilized absorbent material has between 2% and 50% polymer content by weight.
Stabilized absorbent is typically a material capable of retaining fluid to a saturated capacity of at least about 3 g/g and about 10 g of fluid per 0.1 square meter of material as measured by a 0.5 psi saturated capacity test method. Further, the material holds together when dry or at any level of fluid saturation. Dry tensile properties of the material is typically in the range of 0.1-60 kg per cm of material width. Example materials include an airlaid absorbent bonded with a thermally bondable fiber (e.g., bicomponent sheath/core fibers such as KoSa T-255 or Chisso ESC fibers), an airlaid absorbent bonded with dried latex, airlaid absorbents bonded by hydrogen bonding, and wetlaid absorbents.
The absorbent materials are typically formed by employing conventional airlaying techniques, as known in the art. For example, it is common to utilize a fibrous sheet of cellulosic or other suitable absorbent material which is fiberized in a conventional fiberizer, or other shredding or comminuting device, to form discrete fibers. In addition, particles of superabsorbent material are mixed with the discrete fibers. The fibers and superabsorbent particles are then entrained in an air stream and directed to a foraminous forming surface upon which the fibers and superabsorbent particles are deposited to form a fibrous web of absorbent material. In addition, bonding agents or other strengthening components may be incorporated to provide a stabilized web. The web of absorbent material may then be stored or immediately directed for further processing and assembly with other components to produce a final absorbent article.
Other techniques are also employed to form stabilized absorbent webs. Such techniques include: dry-forming techniques, wet-laying techniques, foam-forming techniques, and various wet-forming techniques. The resulting absorbent webs have included absorbent fibers, natural fibers, synthetic fibers, superabsorbent materials, binders, and strengthening components in desired combinations. The stabilized webs may be employed to generate preformed absorbent sheets or layers, and the preformed material may be stored in a preformed supply, such as provided by a supply roll. At an appropriate time, the preformed layer may be delivered from the preformed supply into a manufacturing line.
Suitable stabilized absorbents containing superabsorbent powders for urine absorbing applications typically have a basis weight in the range of about 200-1000 gsm and a web density of about 0.05-0.35 g/cm3. Suitable stabilized airlaid absorbents not containing superabsorbent powders for feminine hygiene or other applications typically have a basis weight in the range of about 100-500 gsm and a web density of about 0.05-0.25 g/cm3. The low density and high basis weight of these materials cause lower than desired roll lengths, forcing the need for a more than desirable number of splices.
Superabsorbent materials are well known in the art, and are readily available from various suppliers. For example, FAVOR 880 superabsorbent is available from Stockhausen, Inc., a business having offices located in Greensboro, N.C., U.S.A.; and DOW 2035 is available from Dow Chemical Company, a business having offices located in Midland, Mich., U.S.A. In one embodiment of the invention, the absorbent material of the portions 22 , 24 has an absorbent capacity of at least about 9 g/g employing 0.9 wt % saline (9 grams of 0.9 wt % saline per gram of absorbent material). It has a tensile strength value of at least about 1.7 N/cm (Newtons per cm of “width” of the material, where the “width” direction is perpendicular to the applied force). However, the web of absorbent material can be provided with a tensile strength value of up to about 100 N/cm, or more.
Desirably, the splicing material of the piece 40 is melt compatible with the binder fiber of the absorbent material. One type of splicing material is a carded web comprising bicomponent fibers used to stabilize absorbent structures. Other polymer options for splicing material include polyethylene, polypropylene, other polyolefins. A web comprised of a blend of polymer fibers may also provide a splicing material of good quality. For example, a bonded, carded web comprised of a blend of bicomponent and polyester staple fibers may be a useful splicing material. Beyond bonded carded webs, the splicing material may include spunbond, meltdown, SMS, BFDL, hydroentangled nonwovens, and other nonwoven material comprised in part of a polymer compatible with the synthetic binding material providing stability to the absorbent material to be spliced. Alternatively, the splicing material may be adhesively covered to assist the thermal bonding of the stabilized absorbent. Desirably, the splicing material has a very permeable, open structure.
The splicing material should not impede fluid intake. Accordingly, the splicing material is desirably more fluid permeable than the absorbent material(s) being spliced together. Further, it is desirable for the absorbent material with the splicing material attached to be about as permeable as absorbent material without the splicing material attached.
The splicing material is sufficiently strong to be processed through the processing machine. Preferably, the splice material has a tensile strength at least as great as a tensile strength of the absorbent material.
A second embodiment 50 of a continuous length of absorbent material includes two pieces of splicing material 40 on opposite faces of the ends is shown in FIGS. 2A and 2B . A second piece of splicing material 40 is placed on the second face 32 of the trailing end 26 of the first portion of absorbent material and the second face 32 of the leading end 28 of the second portion of absorbent material. The second embodiment 50 has the advantage of a stronger splice because in provides more shear area and more cross-sectional area of splice material. Alternatively, the second embodiment may permit use of splicing material pieces having narrower widths without reducing the strength of the splice.
A third embodiment 60 of a continuous length of absorbent material, shown in FIGS. 3A and 3B , places the piece of splicing material 40 on the first face 30 of the trailing end 26 of the first portion and the second face 32 of the leading end 28 of the second portion.
A fourth embodiment 70 of a continuous length of absorbent material, shown in FIGS. 4A , 4 B, and 4 C, wraps the piece of splicing material 40 around both faces 30 , 32 of the ends 26 , 28 .
A fifth embodiment 80 of a continuous length of absorbent material, shown in FIGS. 5A and 5B , places the piece of splicing material 40 in a sandwiched position between overlapping ends 26 , 28 of the first portion and the second portion.
It is understood that other arrangements may be used without departing from the scope of this invention. An adhesive tape may be used in combination with any of these arrangements to further strengthen the splice. However, if such tape is used, it is likely that the manufactured articles containing that tape will need to be culled.
Each end 26 , 28 of the portions of absorbent material is shown with generally square, right angles and the piece of splicing material is shown as having a rectangular shape. However, the absorbent material and piece(s) of splicing material 40 may have other shapes and angles without departing from the scope of this invention. Specifically, the ends 26 , 28 of the portions of absorbent material may be angled or irregularly shaped, and pieces of splicing material 40 may have an irregular shape or a shape which does not match the shape of the ends. Further, the two ends 26 , 28 of the portions of absorbent material need not have corresponding shapes. Gaps between ends 26 , 28 may be large and spanned by the piece of splicing material 40 .
The present invention is illustrated by the following example which is merely for the purpose of illustration and is not to be regarded as limiting the scope of the invention or the manner in which it is practiced. A thermally bonded airlaid absorbent comprised of about 50% superabsorbent polymer, about 45% fluff pulp, and about 5% of KoSa T-255 Merge 35100A 2.2 dpf bicomponent fiber and having basis weight of about 600 gsm and density of about 0.16 g/cc was cut into two pieces. A through air bonded carded web (TABCW) material comprised of 100% Chisso ESC-HR6 3.0 dpf fiber and having basis weight of about 17 gsm was also cut into two pieces. A Carver Press with capability to heat both top and bottom platens compressed the materials at 1000 psi for six seconds at a temperature of about 135 C. The materials were arranged to form a butt splice as shown in FIGS. 2A and 2B (two pieces of splicing material, one for each face). The resulting splice had favorable bonding strength in the dry state, and continued to hold after the splice was fully swollen in 0.9% saline fluid.
Thus the present invention provides a splice which is strong, dry or wet, and which facilitates a fluid intake equal to that of non-spliced absorbent material. Accordingly, manufactured articles which incorporate the splice need not be culled.
It should be readily apparent that any conventional material may be employed to construct the various components incorporated into the method and apparatus of the invention. Such materials can include synthetic polymers, fiberglass-resin composites, carbon fiber-resin composites, metals, metallic composites, ceramic composites, and the like, as well as combinations thereof. The materials are typically selected to provide desired levels of strength, durability, ease of manufacture, and ease of maintenance. Similarly, in the various attachments and securements employed in the constructions of the method and apparatus of the invention, it should be readily apparent that any conventional attachment or securement technique may be employed.
Although various illustrative and representative configurations have been described in detail herein, it is to be appreciated that other variants, modifications and arrangements are possible. All of such variations, modifications and arrangements are to be considered as being within the scope of the present invention.
In view of the above, it will be seen that the several objects of the invention are achieved and other advantageous results obtained.
When introducing elements of the present invention or the preferred embodiment(s) thereof, the articles “a”, “an”, “the” and “said” are intended to mean that there are one or more of the elements. The terms “comprising”, “including” and “having” are intended to be inclusive and mean that there may be additional elements other than the listed elements.
As various changes could be made in the above without departing from the scope of the invention, it is intended that all matter contained in the above description and shown in the accompanying drawings shall be interpreted as illustrative and not in a limiting sense.
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A process for splicing a first portion of absorbent material to a second portion of absorbent material to form a longer, continuous length of absorbent material suitable for uninterrupted sequential infeed to a processing machine. The process includes the steps of placing a trailing end of the first portion adjacent a leading end of the second portion and aligning the ends. A piece of splicing material is attached to the ends. The piece of splicing material has a fluid permeability at least about as great as a fluid permeability of the first portion of absorbent material and at least about as great as a fluid permeability of the second portion of absorbent material.
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This application claims the benefit of U.S. Provisional Application Ser. No. 61/097,005 filed on Sep. 15, 2008, the disclosure of which is hereby incorporated by reference in its entirety.
FIELD OF THE INVENTION
This invention generally relates to chemical vapor deposition (CVD) systems in general and for high surface quantity substrate coating systems in particular.
BACKGROUND OF THE INVENTION
Atmospheric Pressure Chemical Vapor Deposition (APCVD) systems can be used to deposit, either On-Line, i.e. incorporated in a float glass line, or Off-Line, i.e., separate from a float glass line, one or more thin film layers of metal, metal oxide, metal nitrate and other materials at high deposition rates and at line speed v ranging typically from 0.1 m/min to up to 30 m/min onto large area glass substrates. In such APCVD thin film deposition systems, one or more deposition modules are arranged in a serial manner to deposit a given total thickness for each targeted thin film at a chosen line speed. Such APCVD systems can be used to deposit multi-layer films to produce Low-E glass used in the manufacturing of energy efficient (high reflection efficiently of infrared energy) windows, and/or for Transparent Conductive Oxide (TCO) coated glass sheets used for example as substrates for thin film photovoltaic and for display applications. One example of such an On-Line APCVD system can be found in U.S. Pat. No. 6,103,015 and an example of such an Off-Line APCVD system can be found in U.S. Pat. No. 4,595,634.
Other prior art Chemical Vapor Deposition (CVD) systems exist as well that operate either at Atmospheric Pressure (APCVD) or at Low (reduced) Pressures (LPCVD) and may or may not incorporate a continuously operated substrate transport mechanism to deposit at least one CVD thin film onto a wide range of thermally stable substrates. Examples of such thermally stable substrates are Si wafers, flat and bowed glass sheets, partially assembled thin film photovoltaic substrates, display substrates, metal, ceramic and plastic sheets or foils, graphite, carbon-carbon or ceramic tiles, etc. In related LPCVD systems the respective deposition modules are often also called shower heads or injector assemblies and all these names are intended to be used interchangeably in this patent.
During operation, the CVD deposition modules become sufficiently dirty as a result of CVD deposition process as to significantly affect the yield (pinholes and/or coating thickness uniformity) of the coated substrates. Thus, when a given defect threshold is exceeded, the CVD deposition process needs to be stopped because the system is no longer operating in a commercial viable mode. The respective CVD deposition modules must then undergo regular maintenance, i.e. they have to be moved offline, be cleaned, put back into their respective deposition position and reconnected to the process gas supply lines before the CVD deposition process can be resumed.
As a result of this regular deposition module maintenance time, the effective uptime, for example, of prior art On-Line APCVD systems are typically as low as 30-60% for optimum commercial viable system operations. Thus, the available system uptime due to regular deposition module maintenance directly affects the average cost per coated surface area. Further improvements that can minimize the CVD systems down time are therefore desirable.
In some prior art system, this deposition module maintenance frequency issue has sometimes been addressed by adding at least one additional process gas (for example a hydrocarbon gas to act a radical scavenger) to the process chemical mixture needed to achieve a target thin film thickness with a given CVD deposition process that reduces the reaction rate of the chosen process chemistry and allows the deposition process to be spatially more spread out and more uniform in the substrate movement direction. For example, U.S. Pat. No. 5,798,142 describes the influence of C 2 H 4 on the deposition rate reduction of SiO 2 for an APCVD method utilizing SiH 4 , O 2 and N 2 as primary APCVD process chemicals. While such prior art compensation methods can increase the deposition module maintenance interval, these methods typically also result in lower average deposition rates, lower process chemical utilization rates and/or limit which process chemistry can be used and/or which multi layer thin film design can produced on a given CVD deposition system. It can also require special (for example with longer deposition length) designed and manufactured CVD deposition modules to compensate for the lower and spatially more extended deposition area.
Two prior art APCVD deposition systems 30 used for On-Line APCVD deposition of thin films on float glass lines are summarized in FIG. 1 . A float glass line 10 comprises a melting furnace 12 , a tin bath 14 , a high temperature annealing lehr 16 with an inside wall 17 and a low temperature annealing lehr 18 with an inside wall 19 . Raw material enters the melting furnace 12 and a continuous sheet of float glass 20 exits the low temperature annealing lehr 18 of the float glass line 10 which is subsequently cut to required sizes and stored offline for later usages. To change the thickness of the glass sheet 20 , among others, the line speed v of the float glass line 10 need to be adjusted: for example, 2× thinner glass sheet 20 manufacturing requires approximately a 2× faster line speed v and/or a mass throughput change to the melting furnace 12 .
Numbers with a letter “T” or “L” attached indicate that the respective component of the APCVD system is from an APCVD system having an On-Line Deposition Position (deposition position) inside the tin bath 14 section (“T”) or in the high temperature annealing lehr 16 section (“L”) of the float glass line 10 . Numbers without a letter attached represent a generic component with no significant distinction of where the respective component is located on a float glass line 10 and/or include equivalent Off-Line CVD systems. The deposition module 32 moves on a motion control system, for example shown in FIG. 1 as a Rail System (rail system) 34 oriented in the X-axis direction, i.e. perpendicular to Z-axis of the float glass line 10 , also defined as the direction in which the glass sheet 20 or a respective flat substrate or substrate group moves. The prior art rail system 34 has two principal stop locations: one is at the inline deposition position 36 , i.e. over the middle of float glass line, and the other is at the offline maintenance position 38 located on one side (right side shown in FIG. 1 ) of the float glass line 10 where the deposition module 32 is first fully cooled down and then cleaned, serviced and/or maintained.
For prior art Off-Line CVD systems (not shown in FIG. 1 ), the deposition module is moved offline, i.e. to the left or right of the Off-Line system's Z-axis and reinserted from the same side after having been cleaning. Typically, mechanical registration means are used to deliver a respective deposition module 32 back to the deposition position 36 .
Eventually each deposition module of a CVD coating system needs to be serviced to prevent yield problems due to excess particulates falling from more and more polluted sections of the deposition module onto the substrate or substrates underneath. With the prior art solutions the CVD system design and operation balance requirements (to obtain commercial viability) between system cost, maintenance cost, chemical utilization cost, available space on a given process line, etc. limit the lowest achievable cost for a given high volume (high surface area) CVD system.
Thus, there is a need in the art for a solution which allows for increased process uptime and overall cost reduction per coated substrate surface area in high volume production.
SUMMARY OF THE INVENTION
Therefore, it is a first objective of this invention to enable a CVD system with a higher overall uptime.
It is a second objective of this invention to enable a CVD system having a lower average coating cost per coated surface area.
It is a third objective of this invention to enable a CVD system with a lower down time due to deposition modules servicing needs.
It is a forth objective of this invention to enable a CVD system with a higher coating quality performance option.
It is a fifth objective of this invention to enable a quick changeover of a CVD system from one thin film coating type to another.
It is a sixth objective of this invention to simplify the switching back and forth between a normal float glass line and an APCVD coating system on float glass line operation.
It is a seventh objective of this invention to minimize the risk of breaking the float glass sheet during the removal and/or reinsertion a deposition module.
Several preferred embodiments of the present invention enable in general the design and manufacturing of CVD systems with an improved process window, production cost and/or system performance for high volume thin film depositions on a wide variety of temperature compatible substrates and in particular for thin film glass surface coaters. The longer the deposition length and/or the massive a given deposition module is, for a given CVD system, the more commercially beneficial the improvements of the present inventions are. Note that while most of the preferred embodiments of this invention described below are discussed primarily for high throughput On-Line APCVD systems applications, they can easily be adapted, by those skilled in the art, to Off-Line CVD systems for glass and other flat and temperature compatible substrates as well as for other CVD coating systems where at least one substrate advances in a continuous (inline coater) or in a step wise, semi-continuous manner (batch type) and for both CVD system configurations where the substrate entrance and exit locations are either identical or not identical.
This invention can be incorporated in combination with many prior art deposition module designs and CVD process chemistry option and is not limited to any particular deposition module design, CVD process chemistry or CVD operation mode.
One of the key elements of this invention is the recognition that instead of using a single deposition module for each deposition position, the use of a n-element deposition module group with n≧2 for each deposition position of a given CVD system is typically commercially preferable for high volume CVD deposition onto large area flat substrates. During the CVD thin film deposition process each first deposition module of each such deposition module group is located in a respective deposition position and each other deposition module of each such deposition module group is located in an offline standby position or transitioning between two such standby positions, and with at least one such standby position is being empty, i.e. not containing a deposition module of the respective deposition module group and with the numbers of standby position m≧n.
Another key element of this invention is that the motion of all deposition modules forming such a deposition module group is both controlled and constrained through a motion control system, that enables a deposition module exchange process for the deposition position location, which, for the purpose of this invention, is defined as a suitable fast removal of said first deposition module from each deposition module group from its deposition position and its relocation to said at least one empty standby position and a subsequent relocation of one of said other deposition modules of said deposition module group from its offline standby position and its reinsertion to the deposition position, thus creating a new empty standby position.
The preferred motion control system can be manually and/or motor powered, can be manually and/or automatically controlled, can utilize rails, lead screws, pistons, hinges, chains, gear reducers and/or other motion confining and transferring mechanism and it can include a mechanical self aligning guide, a mechanical stop, a limit switch and/or a position feedback sensors. In one preferred embodiment of this invention both a motorized and/or manual power and a manual and automatic controlled rail system is used. The manual powered motion system is a backup system in case of a motor failure to minimize the risk of substrate breakages during such an unscheduled interrupted deposition module exchange operation.
With the present invention, an uptime for the CVD system of 85-95% is achievable for both On-Line and Off-Line CVD system, as well as for the other above outlined inline and batch type CVD deposition systems. In particular, this is accomplishable even for relative short deposition module maintenance cycles, for example of only 8 hours off uninterrupted deposition time between routine maintenance as long as the total deposition modules pair exchange time is shorter than 1 hour, i.e. 8/(8+1)=88%. This is very achievable with process automation even for deposition modules located in the tin bath 14 . Typically, with this invention, a deposition module exchange time of less than a ½ hour can be achieved with optimized automation controls for deposition modules located in the higher temperature lehr 14 section. To minimize the thermal cycling damage to all components and to prevent breakage of the glass sheet 20 proper care has to be taken to minimize rapid thermal shocks during the removal and insertion of the respective deposition modules, with the combination of these constraints limiting in the end how fast the deposition module in the deposition position can be practically be exchanged without causing lifetime or substrate stability issues.
Because the present invention significantly reduces the CVD deposition process restart time, the CVD process uptime is now to a much lesser degree controlled by process chemistry selection, process parameter selections, the design of a particular CVD deposition module, and/or by its location on a CVD processing line. Accordingly, the present invention a much wider, commercially viable, process operation window for a given CVD coating system, which now enables the economical usage of a broader coating type selection, line speed selection, coating material selection, etc. for a CVD system of this invention. Further, the present invention extends the typical usable operational lifetime of a given CVD system, and increases it upgrade capability potential since it can economically accommodate a wider selection of future process chemistry and process parameter updates. It also allows more flexibility to economically manufacture a wider range of large area coating on a wide variety of temperature compatible substrates.
In another preferred embodiment of this invention, a deposition module located in at least one preferred standby position can easily be exchanged, while in said at least one standby positions, with a heat shield that incorporates insulation material and/or an active heating system. Upon using the motion control system to place such a heat shield in the respective deposition position, it allows to substantially convert an APCVD On-Line system back to a normal float glass line system, thereby enabling a fast conversion from one operation mode to the another and possible therefore a more cost efficient, and/or safer process operation for each of such respective system operational modes.
BRIEF DESCRIPTION OF THE DRAWINGS
In order for this invention to be clearly understood and readily practiced, this invention shall be described in conjunction with the drawings set forth herein below with like parts or functions having like numbers.
FIG. 1 shows two prior art APCVD On-Line systems for a float glass line;
FIG. 2 a shows two APCVD On-Line systems of this invention for a float glass line with two standby positions opposite of the float glass line.
FIG. 2 b shows a CVD system of this invention with two standby positions on the same side of the substrate.
FIG. 3 shows a partial section of an APCVD system of this invention.
FIG. 4 shows a cut-away view of part of an APCVD system of this invention.
FIG. 5 shows a perspective view of an APCVD system of this invention.
FIGS. 6 a - 6 f shows the exchange of a heat shield with a deposition module of this invention for an APCVD system.
DETAILED DESCRIPTION OF THE INVENTION
FIG. 2 a shows two preferred APCVD deposition systems 40 of this invention on a float glass line 10 . The preferred APCVD deposition systems 40 comprise at least one deposition module group (n=2) formed by two deposition modules 42 and 44 forming a pair, with each of these deposition modules 42 and 44 moving on a motion control system 45 represented by a rail system 46 in FIG. 2 a . In one preferred embodiment of this invention, the On-Line APCVD system 40 is located in the high temperature annealing lehr 16 section of the float glass line 10 and it optionally includes additional heating sources located underneath and/or above the glass sheet 20 to elevate the temperature of the moving glass sheet 20 to a respective substrate process target temperature before it enters underneath the next deposition module at the next deposition position 50 or while it passed through the deposition position 50 underneath a deposition module to obtain the targeted film thickness for a given line speed v and chosen process parameters. In another preferred embodiment, the APCVD system 40 is located inside the tin bath 14 section. In a further preferred embodiment a multi deposition module holding APCVD system comprises at least one APCVD system 40 T located in the tin bath 14 and at least one APCVD system 40 L is located in the high temperature annealing lehr section 16 . In one preferred embodiment of this invention, the motion control system 45 loops the deposition module from the deposition position 50 to the respective standby position 52 , and then to the standby position 55 from where it moves next to the deposition position 50 , and so forth.
FIG. 2 b shows a cross sectional view of a preferred embodiment of this invention for a CVD system deposition having one or more substantially flat substrates 21 wherein the standby position 52 and the standby position 55 are located on the same side, i.e. to the right of the deposition position 50 . The standby position 52 is preferably also a maintenance position since it allows easier access for deposition position module cleaning than the elevated standby position 55 . The substrate 21 can for example be a continuous moving glass sheet 20 or a continuous flow of cut glass sheets, etc. FIG. 2 b figuratively represents On-Line and Off-Line APCVD system cases, as well as other types of inline and batch type CVD surface coating systems. The two deposition modules 42 and 44 form a preferred minimum deposition module group per this invention, and, unless one or both of them are in a relocation mode, are either located in a deposition position 50 or in one of the two standby position positions 52 or 54 / 55 .
In another preferred embodiment of this invention, when the time for deposition module maintenance comes for said first deposition module of each deposition module group, at least one other deposition module of the same deposition module group has already fully completed its maintenance cycle and is waiting at one of the two standby locations 52 or 54 / 55 . If multiple deposition positions 50 are to be used in a given CVD system, then preferably all of them have such preferred deposition module groups and the deposition module exchange sequence can happen either sequentially for each deposition position 50 or in parallel for all used deposition positions 50 to reduce the overall CVD deposition process downtime. The speed of the deposition module exchange sequence shall preferably be as fast as possible without causing excessive thermal shocks to either a substrate 21 remaining inside the CVD deposition system and/or any other components of the CVD deposition system.
FIG. 2 a shows the preferred embodiments of this invention, where the two offline standby positions 52 and 54 are on opposite sides of the process line. FIG. 2 b on the other hand shows another preferred embodiment of this invention where both standby positions 52 and 55 are located on the same side of the process line, but are separated, for example, by height, i.e. one standby position is located substantially on top of the other one. In a different preferred embodiment of this invention, not shown in any images, the motion control system 45 comprises a rail system which splits into two sub-rails offside the enclosure 47 after a common center rail section leading from the deposition position 50 and with a respective sub-rail selection steering hardware and software system controlling the motion back and forth of the respective deposition modules 42 and 44 between two respective offsite location 52 and 55 and the respective deposition position 50 .
In another preferred embodiment of this invention, as shown in FIG. 2 b for the example of the APCVD system 40 , to minimize thermal shock to any components contained by the enclosure 47 that encloses the deposition position 50 and/to the substrate 21 , the removal/insertion process of the deposition modules from the enclosure 47 comprises at least a three step process. For example, in one preferred embodiment of this invention, the minimal three steps for a preferred deposition module removal process are: Step 1) elevate (shown in FIG. 2 . b ) or withdraw (not shown in FIG. 2 b ) the first deposition module from deposition position 50 through an access port 57 in the enclosure 47 so that its lower edge or opposite side edge is close or preferably slightly outside to the inner respective edge 49 of the enclosure 47 near the access port 57 , i.e. relocate said first deposition module to a first extraction stop position 58 ; Step 2) place at least one heat shield 59 in front of the lower edge or opposite edge of the said first deposition module, i.e. in an access port thermal closure position to increase the thermal insulation between the inside and outside environment of the enclosure 47 near the access port 57 ; and Step 3) fully extract said first deposition module from said enclosure 49 through said access port 57 and relocated it to a free standby position. The preferred deposition module insertion process of this invention is basically the same process in reverse. Alternatively, the first stop location 58 can be slightly outside the enclosure and slightly outside the access port 57 and at least one heat shield 59 is inserted between the deposition module edge closes to the enclosure 49 and end flange of the access port 57 to thermally seal inner and outer environment of the enclosure 49 near the access port 57 .
Note that a preferred heat shield can either be a passive or an active thermal element. For example, a passive heat shield is heat a shield made from ceramic wool, ceramic or other low conducting fiber board and other high efficiency, thermally compatible insulation material. For example, an active heat shield includes at least one electrically powered heating element or a flame heated surface area to provide an increased thermal barrier between the inside and outside of the enclosure 47 near the access port 57 . Preferably an active heat shield is also a passive heat shield. An active heat shield typically allows for using a thinner heat shield than otherwise would be possible with a passive heat shield alone for a given thermal barrier design and is preferably used when the space on the inside of the enclosure 47 above the substrate surface or to the side of the substrate surface is very limited.
FIG. 2 b shows the case where the first deposition module is first elevated a short distance to a first extraction stop position 58 chosen (shown as dashed outline of the deposition module) so that the bottom of the deposition module is slightly above the lower top level 49 of the enclosure 47 . Next, a respectively sized heat shield 59 gets inserted from the left side the enclosure 47 and moved such that it covers the access port 57 in the enclosure 47 . FIG. 2 b shows this heat shield 59 both as not inserted and still located to the left of the enclosure 47 (solid outline) and also as fully inserted into the enclosure 47 from the left side and located slightly below (dashed outline) the lower top level 49 of the enclosure 47 , thus insulating the inside from the outside of the enclosure 47 near the access port 57 . Optional such a heat shield 59 can also be inserted from the same side as the standby locations 52 and 55 . Another preferred heat shield insertion option (not shown in any picture) uses one or two hinged rotatable thermal heat shields 59 that, like window levers, upon an approximately 180 deg rotation around one or two hinges, rotate from next to the access port 57 and close to the top inner surface 49 of the enclosure 47 to underneath said first deposition module located at said first extraction stop position 58 . i.e. to said access port thermal closure position.
A further preferred embodiment includes the lateral shifting of one or two heat shield as more fully detailed below and shown in FIGS. 3-6 . FIG. 3 shows another preferred embodiment of this invention showing an enclosure 47 with four serial positions for deposition positions 50 : two are filled with deposition modules 44 , one with a heat shield 60 and one with no deposition position in the respective deposition position 50 . The deposition modules 44 have an exhaust gas port 61 . The empty deposition position 50 is shown with a closed left and right heat shield 62 and 64 that are located on top of the enclosure 47 . Each deposition module 44 is shown, for example, with two service access ports 69 which allows easy cleaning of the inside of the deposition module 44 , a quick connect system 73 , and on the front and back of the deposition module 44 a support structure 72 mounts comprising one or more adjustable feet 74 which are either adjustable manually or automatically via a motorized system. These feet 74 are used to level the deposition module 44 with respect to the flat substrate 21 when the deposition module 44 is located at the respective deposition position 50 . The quick connect system 73 enables to manually or automatically quickly connect or disconnect the deposition module 44 to a stationary process gas connection system 75 that is connected to process gas lines 77 .
A motion control system 45 (not shown in FIG. 3 ) elevates the deposition module 42 or 44 and moves one or more heat shields 62 and 64 (see FIG. 3 and FIG. 6 ) in such a manner that the substrate 21 is exposed preferably for only a very short time (less than 60 seconds) to outside air through an AP 57 so as to prevent contamination of the substrate 21 and/or its breakage due to higher than normal temperature gradients across its body. In one preferred embodiment, a heat shield 60 is located at the deposition position 50 that is delivered and removed optimally with the same rail system 46 by replacing a respective deposition module 42 or 44 with a heat shield 60 . This optional system feature, when incorporated on an On-Line APCVD system with deposition position located in the high temperature lehr 16 section, allows to operate a float glass line in a normal uncoated mode for extended periods of time, while the APCVD system is either shut down or being serviced (for example for a major component replacement or service problem, or when coated glass production is not desired for extended periods of times).
In one preferred embodiment of this invention, the deposition modules are connected/disconnected through a quick disconnect system 73 to a stationary gas connector 75 connected to the process gas distribution system lines 77 when the deposition modules 42 or 44 are moved from and to the deposition position 50 . In another preferred embodiment, each deposition module 42 and 44 is connected permanently to a process gas distribution system via flexible hoses. For safety reason, the cooling fluid connection to the deposition module 42 and 44 is preferred to be semi-permanent connected. This minimizes the chance that a deposition module 42 or 44 can be overheated while it is being removed from or inserted to a deposition position 50 through an AP 57 in the enclosure 47 and allows decreasing the minimum time internal for safe deposition module exchange operation and therefore increases the overall CVD system productivity.
FIG. 5 shows another preferred embodiment of this invention, that helps to preserve overall floor space where the deposition module motion control system 45 includes a rail system 46 over the standby position 52 and 54 with a mezzanine support structure 103 where a portion of the system support hardware is located, for example as cooling systems 109 , a gas distribution systems 111 and a motion and heating control systems 107 .
Since with this invention higher servicing frequency rates of the deposition modules are no longer significantly affecting a given CVD system's productivity rate, and in addition higher process gas utilization and higher deposition rates can be achieved, an overall production cost reduction is now possible compared to equivalent prior art systems. Coating quality can be also improved, for example, just by more frequently exchanging the deposition modules while still maintaining or improving the production cost. The present invention makes such an abnormal CVD process parameter selection cost efficient and practical.
In one preferred embodiment, the rail system 46 is located overhead, and in another one, it is on the ground. In FIG. 5 , when the deposition module 42 , 44 is not moving, it is located either at the deposition position 50 , i.e. inline with the substrate 21 , or in a standby position 52 , 54 , which is located Off-Line to the right (left) of substrate, towards the end of travel of the rail system 46 . When major servicing is needed a deposition module gets removed and replaced with another deposition module in one of the standby positions. Normally both deposition modules 42 and 44 are loaded on the rail system 46 , but, if needed, only one of these two deposition modules can be installed and the other position can, for example, be empty. This arrangement allows that one of the deposition modules can be totally removed from the rail system 46 and replaced with a substitute deposition module or with a heat shield 60 , as shown in FIG. 3 , FIG. 5 and FIG. 6 a - 6 f . As long as the replacement of the deposition module is completed before the other deposition module is due for servicing, the down time of the CVD system not affected, i.e. it is still just the deposition module exchange time. This invention therefore allows a much higher uptime and productivity for CVD systems, and in particular for coatings of glass sheets 20 when incorporated on a float glass line 10 .
In one preferred embodiment of this invention, each deposition module 42 or 44 can travel to each standby position 52 or 54 / 55 by selecting an appropriate motion control service mode. This feature is beneficial for the installation/removal of a deposition module 42 or 44 and/or a heat shield 60 to/from the rail system 46 and provides more freedom to layout a respective factory or to work within the given access constraints of a pre-existing float glass factory.
The rail system 46 with respective motors, collision avoidance control logic and position sensors allows a quick exchange of a deposition module 42 or 44 between the deposition position 50 and one of the two standby position 52 or 54 / 55 . In this manner the APCVD coating process on the float glass line 10 can quickly resume after a dirty deposition module has been replaced with a clean one and after the clean one has gone through a quick system temperature stabilization time period, together defining the deposition module exchange time. This is quite different from the prior art, shown in FIG. 1 , where the APCVD coating can only be resumed after i) a deposition module 32 has been removed from the deposition position 36 and moved to the standby position 38 , ii) is fully cooled down, iii) is fully serviced (for example cleaned), iv) is returned to the deposition position 36 , and v) has gone through a respective warm up and system temperature stabilization phase. Therefore, the APCVD systems shown in FIGS. 2 a and 2 b , when compared to the prior art APCVD systems shown in FIG. 1 , allows for a much shorter coating service down time. As long as the cool down and maintenance cycle of the offline parked deposition module is less than the usable deposition time of said first deposition module, the coating operation is nearly continuous with this invention. For example, if the deposition module exchange time is 30 min and if the usable deposition time between services is 12 h, the theoretical usable coating up-time for this invention is approximately 12 h/12.5 h=96%. This is significantly better than the prior art systems 30 that can operate only at less than the 12 h/20.5 h=64% theoretical usable coating time for a 30 min startup time and for an 8 h cool down and service time for the removed deposition module 32 .
A detailed view of a cut-out section of the FIG. 3 is shown in FIG. 4 . The bearings 84 mounted on a support frame 86 hold the rollers 82 which are driven in a synchronized manner by a common drive system (not shown in FIG. 4 ). The feet 74 rest on a support bar 88 whose height optionally is adjustable by an adjustment bar 90 that is either adjusted manually or automatically with a motorized system. The height of the adjustment bar 90 can, for example, be adjusted to compensate for the thickness variations of different glass sheets 10 so that the distance between the deposition roof of the deposition module 42 or 44 is at the optimum height separation from the top surface of a flat substrate surface 21 for a given line speed v and process parameters selection.
FIG. 4 illustrates another preferred embodiment of this invention where the support structure 80 has one or more optional heaters 79 a installed underneath the substrate 21 that have electrical outside connections 79 that allow to energize individual heating zones. Preferably the APCVD coating system includes a multi channel temperature control system and the heaters 76 and/or heaters 79 a include respective localized temperature sensors (for example thermocouples or optical pyrometers) that allows to spatially non-uniformly increase the temperature of the substrate 21 in the X-axis direction, so that the net result is a hotter substrate 21 that has optimally a narrower temperature variation along the X-axis.
This provides the ability to reheat and/or to further heat the substrate 21 while underneath the deposition module 42 or 44 and/or to compensate for temperature losses at the sides of the substrate in order to keep the substrate at a more uniform process temperature. A thermal insulating system is located below the heating elements with electrical outside connections 79 and below the rollers 82 to minimize heat loss. In one preferred embodiment of this invention the lower or upper heaters 79 a or 76 contains multi-zone heating elements that can be removed (with appropriate tooling) at least from one side of the frame 80 for replacement while the enclosure 47 is at normal elevated process temperatures. The underneath heaters 79 a also allow compensating for substrate temperature losses occurring while moving underneath the deposition module. The cooling of the substrate 21 by a deposition module in full operation can be in the range of 10-50° C. Therefore, the underneath heaters 79 a are ideally capable of at least compensating for some of these deposition related heat losses and/or to further elevate the substrate temperature, as needed, to reach the next deposition module at the optimum substrate surface temperature.
The heaters 76 that are located underneath the heat shields 62 and 64 and between individual deposition module's and that are energized through the outside electrical connections 78 , further provide spatially resolved thermal heating options to provide additional heating of the substrate 21 while it is traveling between two deposition module's located in series. Together both heating systems allow a greater thermal control and process adjustability. In addition, since the line speed v is typically adjusted for different substrate 21 thicknesses, these underneath and/or above heaters allow more process freedom for tuning an individual APCVD systems 40 for different line speeds v so that they work together in series to produce a targeted multi layer thin film deposition.
A perspective view of an embodiment of this invention for a CVD system 40 L is shown in FIG. 5 . The support structure 101 supports the four overhanging rail systems 46 which move four deposition module pairs 42 and 44 connected through connection joints 71 to extendable support arms 70 between the standby position 52 or 54 and the deposition position 50 . On top of the support structure 101 is a mezzanine floor structure 103 located over the standby position 52 and standby position 54 which can be reached, for example, by one or more ladders 105 . In order to save factory floor space, in one of the preferred embodiments of this invention, some of the CVD systems peripheral system hardware can be located on this mezzanine floor 103 . For example, it can hold the motorized control system 107 for the left and right section of the rail system 46 L, a primary and backup oil-cooling systems 109 for the deposition modules 42 and 44 L and a portion of the process gas delivery systems 111 that uses liquid precursors that need to be vaporized. The main on-side CVD system operator control unit 113 is located preferably on the ground floor to increase overall system safety.
The heat shield 60 is shown with a mounting bracket 121 that optionally stays with the heat shield 60 when it is disconnected from the support arms 70 of the respective rail system 46 . The extendable support arms 70 , which incorporate a vertical motion system also typically incorporate some of the permanent flexible cooling fluid lines as well as some of the electrical control, sending and/or power lines for each respective deposition module. In one preferred embodiment of this invention, the deposition modules 42 and 44 are dual side mounted onto two support arms 70 to decrease the unsupported length distance the deposition modules 42 and 44 , so that the weight and stiffness of the deposition modules 42 and 44 can be reduced compared to one side mounted deposition modules like the prior art deposition modules 32 which are often placed in the tin bath 14 . Together with the one sided mounting of the prior art rail system 34 T, such prior art deposition modules 32 T require more mechanical stiffness and therefore more mass resulting in increased weight, cooling cost and service cycle time. This is important especially for a APCVD system incorporated into a float glass line 10 , where the width of the float glass sheet 20 can be 3-4 m wide and the process temperatures between 500 to 700° C. and the selection of materials able to handle the process environment for extended period of times are limited.
Optionally, some of the power connections of the deposition modules 42 or 44 or of the heat shields 60 are done near the deposition position 50 to simplify the overall wiring of the APCVD system 40 . The deposition modules 42 and 44 are being connected to the exhaust tubing 125 through the exhaust connection tubes 127 which, for example, rotates from 90° to 180° and can be elevated and lowered by a motorized motion mechanism located below the speed controlled exhaust blower unit 129 that regulates the exhaust gas flow level from a respective deposition module 42 or 44 . The motion of these exhaust connection tubes 127 is done in such a manner that they connect or disconnect to the exhaust port 61 of the deposition module 42 and 44 and that they move and rotate out of the way during the exchange phase of the deposition modules 42 and 44 between the deposition position 50 and the standby positions 52 or 54 .
One of the preferred embodiments of this invention is depicted in the figure series FIGS. 6 a - 6 f , where a heat shield 60 is exchanged via an automated process with a deposition module 44 in the deposition position 50 . A similar procedure is preferred for the exchange of two deposition modules 42 and 44 in the deposition position 50 . FIG. 6 a shows that in the first step the replacement deposition module 44 is moved close to the deposition position 50 . Next the heat shield 60 is elevated just slightly above the respective heat shield's 62 and 64 ( FIG. 6 b ). After that the respective heat shield's 62 and 64 are closed quickly ( FIG. 6 c ).
FIG. 6 d shows then the option where the heat shield 60 is moved to the side and over the 76 and parted outside the enclosure 47 . This provides the option of using the space over the heaters 76 as a storage space for the heat shield 60 until it is needed again, as indicated in FIGS. 6 a - 6 f . Alternatively the heat shield 60 can also be removed from the deposition position 50 by connecting it first to the support posts 70 via the connections 71 which are then doing the lifting ( FIG. 6 b ) followed by closing the respective heat shields 62 and 64 and moving the heat shield 60 to the standby position 52 .
In the next step the deposition module 44 is moved into the deposition position 50 ( FIG. 6 e ) where it hovers just barely above the closed respective heat shield 62 and 64 . Next the respective heat shields 62 and 64 are opened and the deposition module 44 is quickly lowered down until its support feet 74 rest on the support bar 88 as shown in more detail in FIG. 4 .
Optionally (not shown in FIG. 6 b ) the front and side section of the process line also have suitable heat shield's that move up or down when the heat shield or deposition module moves up or down so as to minimize any exposure of the substrate 21 with the outside environment.
Therefore this invention facilitates the modification of a portion of a preexisting high temperature annealing lehr 16 to make it adaptable for a CVD coating process that can be turned on and off on demand with respective system reconfigurations. The heat shield 60 is optionally used when the APCVD system 40 is not needed or is down for longer periods of time, and it replaces a section of the removed high temperature annealing lehr 16 in such a manner that the glass sheet 20 (substrate 21 ) cools down in a normal manner when the deposition modules 42 or 44 is not being used. Optionally, the heaters 76 located between the various deposition positions 50 and/or the heaters located underneath the substrate 21 can also be used to control the temperature gradient across (X-axis) and along (Z-axis) said substrate 21 .
In the above described manner, and as modified to handle a quick deposition module exchange for each deposition position 50 , the present invention improves the uptime of a given APCVD system 40 incorporated into a float glass line 10 significantly. In a similar manner, an APCVD system 40 T can obtain an improved uptime as well, however there are no heat shields 62 and 64 and no additional heaters 76 underneath float glass sheet 20 since the tin bath 14 and the respective overhanging tin bath heaters are the only heaters needed in this environment. Respective doors and gas isolation systems to the sides of the tin bath 14 and need to be used to prevent or at least to minimize the exposure of the interior of the tin bath 14 to the outside oxygen rich environment since it will oxidize the hot tin in the tin bath and therefore require additional Hydrogen treatment to reduce the oxidized tin oxide back to tin, all of which cost time and energy and wastes more materials.
Various multi-layer thin film APCVD coatings can be obtained on float glass sheets 20 or other substantially flat substrates at high speed with the present invention. The present invention in not intended to be limited to one or another type of CVD coating or to an On-Line or Off-Line system. Those skilled in the art can adapt the teachings of this invention to other similar CVD thin film deposition process applications, all of which are herewith intended to be included herewith.
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The use of deposition modules groups for each CVD deposition position including at least two deposition modules, together with a Motion Control System that controls and confines the motion of said deposition modules, enables a quick deposition module exchange at the deposition locations of On-Line or Off-Line CVD coating system. This results in a high volume large area CVD coating system that can increase the commercial viability of a given CVD system design through production throughput increases, production cost reductions, overall higher process flexibility and/or improved film quality.
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This is a division of application Ser. No. 215,100, filed on July 5, 1988, which is a continuation-in-part of U.S. Ser. No. 037,484, filed Apr. 13, 1987, now U.S. Pat. No. 4,759,851 which is a continuation of Ser. No. 864,049 filed May 16, 1986, now U.S. Pat. No. 4,659,481, which is a continuation of Ser. No. 545,563, filed Oct. 26, 1983, now abandoned.
FIELD OF THE INVENTION
This invention relates to novel polymeric compositions which are useful for water treatment. These novel compositions are comprised of polymers of αβ ethylenically unsaturated monomer(s), preferably containing carboxylic acid or carboxylic amide functionalities, and amine-containing allyl ether monomers.
BACKGROUND OF THE INVENTION
The present invention is directed to novel polymeric compositions containing pendant functional groups. The polymers are useful for a broad range of water treatment applications. They can be used to control the formation and deposition of scale imparting compounds in water systems such as cooling, boiler, gas scrubbing, and pulp and paper manufacturing systems. They will also find utility as corrosion inhibitors, as well as functioning as chelating agents for various metallic ions in solution.
As described comprehensively in U.S. Pat. No. 4,497,713, scaling and corrosion in cooling waters is a major problem. The term "cooling water" is applied wherever water is circulated through equipment to absorb and carry away heat. This definition includes air conditioning systems, engine jacket systems, refrigeration systems, as well as the multitude of industrial heat exchange operations.
In a cooling water system employing a cooling tower, water is circulated through the heat transfer equipment and subsequently cooled by evaporation of a part of the circulating water as the water is passed over the cooling tower. By virtue of the evaporation which takes place in cooling, the dissolved and suspended solids in the water become concentrated. The circulating water becomes more concentrated than the make-up water due to this evaporation loss.
The make-up water employed for recirculating systems is obtained from surface or well water sources. These waters normally contain a variety of dissolved salts, the abundance and composition of which depend on the source of the water. Generally the make-up water will contain a preponderance of the alkaline earth metal cations, primarily calcium and magnesium, and sometimes iron, and such anions as silicate, sulfate, bicarbonate, and carbonate. As the water is concentrated by the evaporative process, precipitation of a salt will occur whenever the solubility of the particular cation/anion combination is exceeded. If the precipitation occurs at a metal surface, and adheres to it, the resultant deposit is referred to as scale. Some of the factors which affect scale are temperature, rate of heat transfer, water velocity, dissolved solids concentration, cycles of concentration, system retention, and pH of the water.
Preventing the corrosion and scaling of industrial heat transfer equipment is essential to the efficient and economical operation of a cooling system.
Excessive corrosion of metallic surfaces can cause the premature failure of process equipment, necessitating downtime for the repair or replacement.
In addition, the buildup of corrosion products on heat transfer equipment impedes water flow and reduces heat transfer efficiency, thereby limiting production or requiring downtime for cleaning. Reduction in efficiency will also result from scaling deposition which retards heat transfer and hinders water flow.
Scale can also cause rapid localized corrosion and subsequent penetration of metallic surfaces through the formation of differential oxygen concentration cells. The localized corrosion resulting from differential oxygen cells originating from deposits is commonly referred to as "under-deposit corrosion."
With regard to boiler systems, and as described comprehensively in U.S. Pat. No. 4,288,327, the formation of scale and sludge deposits on boiler heating surfaces is the most serious water problem encountered in steam generation. Although external treatment is utilized in an attempt to remove calcium and magnesium ions from the feed water, scale formation due to residual hardness (calcium and magnesium salts) is normally experienced. Accordingly, internal treatment is necessary to prevent, reduce, or inhibit formation of the scale-imparting compounds and their deposition.
Other scale-forming species (phosphate, sulfate, and silicate salts, for example) can form complex insoluble salts, depositing as boiler scale.
Therefore, there is a need in industrial water treatment for materials which can prevent or inhibit the formation of scale and deposits on heat transfer surfaces in boiler systems, and the like.
DESCRIPTION OF THE PRIOR ART
Domba, U.S. Pat. No. 3,989,636, describes novel amino acid-epihalohydrin copolymers with chelating properties. These polymers differ chemically from those of the present invention. The '636 polymers are of the condensation type, whereas the instant polymers are prepared by addition polymerization. This results, in the case of the instant invention, in polymeric chains containing a carbon backbone, whereas in the '636 patent, a backbone containing nitrogen atoms is produced. The molecular weights contemplated by the '636 patent are furthermore well outside the molecular weight range of the novel polymers of the present invention. In addition, the instant polymers are significantly more effective as scale control agents in boiler water treatment, since they reduce scale more effectively than the '636 polymers at dosages far lower than the specific '636 polymers described.
Quinlan, U.S. Pat. No. 3,799,893, describes phosphorous containing compounds which are described as useful for inhibiting scale formation. The compounds described are methylene phosphonates of glycidyl reacted polyalkylene polyamines. These materials are chemically significantly different from the instant polymers: the '893 compounds do not contain carboxylic acid groups; the '893 best mode compounds are not polymers; and, the '893 compounds have nitrogen in the backbone of the structure. For these reasons, the '893 compounds are not considered to be pertinent prior art. Furthermore, although the test conditions for determining scale inhibition are substantially different in '893 and the instant invention, the instant polymers appear to be more effective in scale inhibition at substantially lower dosages than the best mode '893 compounds.
Boffardi, et. al., U.S. Pat. No. 4,018,702 disclose scale and corrosion inhibiting compositions which comprise amine adducts of polymaleic anhydride. The instant invention differs from the '702 patent in a number of significant aspects. The '702 polymers are amides, whereas in the instant invention the amine group is attached to the polymeric chain through a hydrogen-substituted carbon. The instant polymers are significantly more stable in an aqueous environment than the '702 polymers, which would be expected to lose the amine functionality from the polymer chain through hydrolysis. Such hydrolysis is difficult with the instant polymers. Furthermore, the best mode polymers of the '702 patent have a molecular weight of only about 200-300 (Example 1 of '702, the only disclosed example of the preparation of polymer). The molecular weights of the present polymer fall within the range of about 1,000 to about 1,000,000, with the most preferred range being from about 1,500 to about 25,000. Thus, the instant polymers are well outside the range of the '702 polymers. Therefore, the '702 polymers are not considered to be pertinent prior art to the instant invention.
D'Alelio, et. al., Journal of Macromolecular Science-Chemistry, Vol. A6, pp. 513-567 (1972) report on the synthesis and chelating properties of low molecular weight poly(glycidyl methacrylate) reacted with iminoacetic and iminodiacetic acids. Although the D'Alelio polymers have structural similarities to the instant polymers, they are nonetheless chemically distinct. Significantly, the D'Alelio polymers are ester derivatives and suffer from the same hydolytic instability as the '702 compounds. Polymers of the instant invention are stable to hydrolysis in aqueous medium. Therefore, the D'Alelio reference is not considered pertinent prior art to the instant invention.
Lorenc, U.S. Pat. No. 4,457,847, cites the use of carboxyl containing sequestrant polymers to treat hardness in boiler waters to prevent or remove scale formation on heat transfer surfaces.
DETAILED DESCRIPTION OF THE INVENTION
This invention pertains to novel water-soluble copolymers which contain pendant functional groups. Specifically, the novel copolymers of the invention have the structure of Formula I: ##STR1## wherein E in the above formula is the repeat unit remaining after polymerization of a polymerizable monomer, containing pendant carboxylic acid or water-soluble salts thereof, carboxylic amide, lower alkyl (C1-C6) ester, or lower (C1-C6) alkyl hydroxylated ester of such carboxylic acids. Compounds encompassed by E in formula I include polymerized acrylic acid, methacrylic acid, acrylamide, maleic acid or anhydride, itaconic acid, and the like.
It is contemplated that E in Formula I also encompasses mixtures of monomers, provided that they fall within the definition of E given above. One such preferred mixture of monomers is acrylic acid/hydroxypropylacrylate.
R1 in Formula I is an unsubstituted linear or branched lower alkylene group having from about 1 to about 6 carbon atoms, or an hydroxyl substituted linear or branched lower alkylene group having from about 1 to about 6 carbon atoms. R2 and R3 are chosen independently from hydrogen, lower alkylene group containing from about 1 to 5 carbon atoms, hydroxyl substituted lower alkylene group having from about 1 to about 5 carbon atoms, or carboxyl substituted lower alkylene group having from about 1 to about 5 carbon atoms. The above substituents are preferred, but other substituents on the nitrogen capable of chelation are also contemplated. These groups include, but are not limited to, phosphonic acid groups, sulfonic acid groups, and the like.
M and L independently denote hydrogen or a water-soluble cation, e.g., ammonium, alkali metal, organic aminium ion, and the like. It will be readily apparent to those skilled in the art that M and L will be cations only when R2 and R3 contain groups requiring a cation for electrical neutrality, such as carboxyl, phosphonic, or sulfonic acid groups.
The molar ratio of monomers (g:h) in Formula I may fall within the range of 20:1 to 1:10, with a molar ratio (g:h) of about 10:1 to 1:5 being preferred. It is to be understood that molecular weight of the novel copolymers is less a key criterion than that the copolymers be water-soluble. Nonetheless, the number-average molecular weight of the novel water-soluble copolymers of Formula I may fall within the range of 1,000 to 1,000,000, with the number average molecular weight within the range of about 1,500 to about 500,000 being preferred, and the number-average molecular weight within the range of about 1,500 to about 25,000 being most preferred.
The preparation of the monomer(s) designated as (g) in Formula I may be in accordance with well known techniques. For instance, one such possible monomer, acrylic acid, may be prepared by hydrolysis of acrylonitrile or by oxidation of acrolein.
The allyl ether monomer, represented by fragment (h) of Formula I, may be prepared by a ring-opening reaction of an allylic glycidyl ether with ammonia, primary, secondary, or tertiary amines. The ring-opening reaction of amines with the epoxide group of the allylic glycidyl ether is analogous to the ring-opening reaction of allylic glycidyl ethers with reagents such as bisulfites or phosphorous acid, to give sulfonic acids, or salts thereof, or phosphites, respectively, as described thoroughly in Chen, U.S. Pat. Nos. 4,659,481 and 4,659,480. R1 in Formula I is --CH 2 --CHOH--CH 2 --, the allylic glycidyl ether precursor is allyl glycidyl ether (AGE), the preferred allylic glycidyl ether. The reaction is illustrated with AGE and a secondary amine: ##STR2##
AGE will be used hereinafter as the illustrative allylic glycidyl ether for the sake of simplicity, but its use hereinafter is not to be construed as limiting the invention in any way. For example, a methallylic glycidyl ether will also be useful in the present invention.
In the above equation, R 2 , R 3 , M, and L have the same meaning as delineated in Formula I. The following amines, among others, may be employed in the above reaction: ammonia, methylamine, ethylamine, dimethylamine, diethylamine, propylamine, n-butylamine, isopropylamine, isobutylamine, ethanolamine, propanolamine, etc. It is to be understood that the enumeration of the above amines in no way limits the utility of the present invention. Those skilled in the art would recognize the myriad amines which could be utilized to synthesize monomers that would be useful for the present invention.
It is also to be understood that when a tertiary amine is used to synthesize the amine-containing monomer in the above reaction, the third group attached to the nitrogen will be either R2M or R3L, and one equivalent of an inorganic acid, preferably hydrogen chloride, would be needed to achieve a stable product, which in the case of a tertiary amine would be a quaternary ammonium salt. The quaternary ammonium salt would have a permanent positive charge independent of pH. The inorganic acid, preferably hydrogen chloride, needed when a tertiary amine is used could be in any of its readily available forms, i.e., gaseous, aqueous solution, etc.
The carboxylate-containing amines include, but are not limited to, aspartic acid, glycine, sarcosine (n-methyl glycine), iminodiacetic acid (IDA), hydroxyethylglycine, etc. The amines containing carboxylic acids can be utilized in the acid or the salt form. If desired in the salt form, the carboxylic acids are preferably converted to their water-soluble salts with ammonia, organic amines, caustic soda, and the like (as indicated by M and L in Formula I) prior to reaction with the AGE, but the neutralization could also be conducted after the reaction with the AGE, or even after the subsequent polymerization.
The ring opening reaction may be carried out in the absence of solvent, or in a suitable solvent, with water being preferred. The reaction temperature may range from 0° C. to 80° C. Alkaline materials can be used in catalytic amounts to speed the reaction, or to drive the reaction to completion. Preferred as the alkaline material is caustic soda, caustic potash, or soda ash.
During the ring opening reaction, trace amounts of the glyceryl compound may be formed. This can usually be controlled to less than 5 mole %, and is due to hydrolysis of the AGE according to the equation: ##STR3##
If desired, the hydrolysis product (glyceryl allyl ether, GAE) may be removed from the mixed monomer solution via the conventional techniques such as distillation, solvent extraction, and the like. It is to be understood that the method of removal of this, or other impurities, do not in any way limit the practice of our invention. In any case, such methods will be known to those skilled in the art.
The present inventors prefer to utilize the monomer containing the impurities, if any, as it is produced. It may therefore contain minor amounts of GAE. When the GAE is not separated prior to polymerization, it will be incorporated into the polymer along with the primary amine component.
It is to be understood that the above methods of synthesis of the amine containing monomer do not limit the methods of preparation of the said monomer.
After the desired monomers are produced, and isolated if desired, polymerization is conducted. Radical initiation is the preferred means of initiation, and the polymerization may be conducted in any of the media familiar to those skilled in the art, such as solution, suspension, bulk, or emulsion techniques. Any of the well known initiators may be used to polymerize the monomers, such as azo compounds, peroxides, redox couples, persulfates, and the like. Likewise, any of the chain transfer agents familiar to those skilled in the art may be used to control molecular weight. These include, but are not limited to, lower alkyl alcohols such as isopropanol, amines, mercaptans, and the like. Accelerators such as bisulfite or ascorbic acid may also be used. It is to be understood that the aforementioned polymerization methods do not in any way limit the synthesis of polymers useful in our invention. Similarly, the tertiary structure (tacticity, arrangement of monomers in the polymer chain, etc.) of the polymers is not limiting to our invention.
The formation of polymers was confirmed by the following techniques: viscosity increase; gel permeation chromatography; and carbon-13 nuclear magnetic resonance (NMR) spectroscopy. The carbon-13 NMR spectra show the typical broad, polymer-type backbone, with a complex C--C region (35-47 ppm) and C--O--C region (70-75 ppm), with either a trace or no unreacted monomers. Preferred polymers according to our invention are copolymers of the sodium salt of acrylic acid with allyloxyhydroxypropylamino components having the structure of Formula II: ##STR4## wherein the identity of R 2 , R 3 , M and L for the preferred copolymers are as shown in Table I.
TABLE 1______________________________________Structures of the CopolymersCo-polymerExample R.sub.2 R.sub.3 M L Mn______________________________________ 8 CH.sub.2 CH.sub.2 CH.sub.2 COO/H* H Na/-- 2,350 9 CH.sub.2 CH.sub.2 CH.sub.2 COO/H* H Na/-- 3,20010 CH.sub.2 CH.sub.2 H H 2,46911 CH.sub.2 CH.sub.2 H H 2,35012 CH.sub.2 COO CH.sub.2 COO Na Na 4,45013 CH.sub.2 CH.sub.2 COO H Na 4,20014 CH.sub.2 CH.sub.2 COO CH.sub.2 CH.sub.2 COO Na Na 7,000______________________________________ *Results from addition reaction of amino component to acrylic acid, givin terpolymers. For details, see Examples 8 and 9.
Mn, number average molecular weight, was measured by gel permeation chromatography (GPC) using Toyo Soda G-2000 SW or G-4000 SW columns calibrated with polystyrene sulfonate standards in sodium nitrate solution. Molecular weight results from GPC depend on the type of column, conditions and standards used.
Also preferred are copolymers of sodium methacrylate with allyloxyhydroxy propylamino components (Example 15).
Most preferred are copolymers of acrylic acid with glycine, N-(carboxymethyl)-N-[2-hydroxy-3-(2-propenyloxy)propyl], disodium salt (wherein MR2 and R3L in Formula II are both --CH2--COONa), and copolymers of methacrylic acid with 2-propanol, 1-(diethylamino)-3-(2-propenyloxy), (wherein MR2 and R3L in Formula I are both --CH2--CH3).
The copolymers of the instant invention may be used alone or in combination with other additives to inhibit corrosion and control the formation and deposition of scale imparting compounds in water systems. However, they are not limited to use in any specific category of water system. For instance, in addition to boiler and cooling water systems, the copolymers may also be effectively utilized in scrubber systems and the like wherein corrosion and/or the formation and deposition of scale forming salts is a problem. Other possible environments in which the inventive copolymers may be used are for sea water desalinization and dust collecting systems in iron and steel manufacturing. The copolymers are effective in controlling iron-induced fouling in wells or other groundwater systems. The copolymers will also be effective in scale control in cooling systems containing high levels of alum or ferric chloride.
The copolymers may also be used to prevent precipitation of calcium carbonate, calcium sulfate, calcium phosphate, calcium phosphonate, calcium oxalate, barium sulfate, zinc hydroxide, aluminum hydroxide, aluminum oxide, iron oxide, iron hydroxide, ferric chloride, etc, in water systems, They will also be useful, for example, as pigment dispersants, cement dispersants, builders in detergents, and mineral beneficiation aids such as in iron, copper, molybdate mining, etc.
The copolymers of the present invention can also be used with other components in order to enhance the corrosion inhibition and scale controlling properties thereof. For instance, the copolymers may be used in combination with one or more kinds of compounds selected from the group consisting of inorganic phosphates, phosphonic acid salts, organic phosphoric acid esters, and polyvalent metal salts such as those from zinc, chromate, molybdate, and nickel.
The copolymers may be used in combination with conventional corrosion inhibitors for iron, steel, copper, copper alloy, or other metals, conventional scale and contamination inhibitors, metal ion sequestering agents, and other conventional water treating agents.
Exemplary corrosion inhibitors comprise chromates, bichromates, tungstates, molybdates, nitrites, borates, silicates, oxycarboxylic acids, amino acids, catechols, aliphatic amino surface-active agents, benzotriazole, and mercapto benzothiazole.
Scale and contamination inhibitors include lignin derivatives, tannic acids, starches, polyacrylic acids, acrylic acid/hydroxyalkylacrylate copolymers, and acrylic acid/allyloxyhydroxypropylsulfonate copolymers.
Metal ion sequestering agents include ethylenediamine, diethylenetriamine, and the like. and polyaminocarboxylic acids including nitrilotriacetic acid, ethylenediaminetetraaetic acid, diethylenetriaminepentaacetic acid, and hydroxyethylethylenediaminetriacetic acid.
Synergistic effects may occur when the copolymers disclosed in this invention are used in combination with the reagents described above. The novel water soluble copolymers of our invention may contain pendant functional amino carboxylic acid groups. These functional groups are connected to the polymer backbone through the hydrolytically and thermally stable ether linkage. These copolymers have shown unique properties in controlling iron deposition and preventing precipitation of calcium phosphate and calcium carbonate in aqueous systems. The novel copolymers should also find particularly useful application in boiler water treatment, whereby their chelating abilities will allow a reduced dosage of chelating agents, which are commonly used in boiler treatment programs. Furthermore, the presence of the chelating group permanently attached to a polymer chain will minimize the possible corrosion caused by non-bonded chelating agents in various parts of the boiler systems, where corrosion caused by chelating agents could be a problem. The invention is further illustrated by the following specific, but not limiting, examples.
EXAMPLES
Examples 1-7 illustrate the synthesis of the monomers, and Examples 8-15 illustrate synthesis of the copolymers. The monomers of Examples 3 and 4 have not been previously described, and thus have no CAS Registry No. Likewise, the novel copolymers do not have CAS Registry Nos. Examples of the efficacy of the copolymers in aqueous systems are also given.
EXAMPLE 1
Preparation of 2-propanol, 1-(methylamino)-3-(2-propenyloxy) [40987-35-7]
Allyl glycidyl ether (98.5% pure, 196 g, 1.7 mole) was added over a period of 130 minutes to methylamine (40% aqueous solution, 198 g, 2.55 mole), maintaining a reaction temperature of 35 °±4° C. After addition, the reaction mixture was stirred at 35°±1° C. for 30 minutes, then heated at 60°±1° C. for 90 minutes. The reaction mixture was then cooled to room temperature. 2-Propanol, 1-(methylamino)-3-(2-propenyloxy) was collected via vacuum distillation at about 95° C./3 mm Hg.
EXAMPLE 2
Preparation of 2-propanol, 1-(dimethylamino)-3-(2-propenyloxy) [78752-11-1]
Allyl glycidyl ether (98.5% pure, 115 g, 1.0 mole) was added over a period of 130 minutes to dimethylamine (60% aqueous solution, 90 g, 1.2 mole), maintaining a reaction temperature of 25°±2° C. After addition, the reaction mixture was stirred at 30°±3° C. for 30 minutes, then heated at 50°±2° C. for 120 minutes. The reaction mixture was then cooled to room temperature. 2-Propanol, 1-(methylamino)-3-(2-propenyloxy) was collected via vacuum distillation at about 73° C./4 mm Hg.
EXAMPLE 3
Preparation of Glycine, N-(carboxymethyl)-N-[2-hydroxy-3-(2-propenyloxy) propyl], disodium salt
Iminodiacetic acid (98% pure, 34 g, 0.25 mole) was dispersed in 104 ml DI water at room temperature. Sodium hydroxide (50% aqueous solution, 40 g, 0.5 mole) was added over a period of 60 minutes, maintaining a reaction temperature of 10°±2° C. After addition, the reaction mixture was stirred at room temperature for 60 minutes.
The resulting disodium iminodiacetate solution (24.9%, 169.3 g, 0.238 mole) was added over a period of 85 minutes to a mixture of 34 ml DI water and allyl glycidyl ether (98.5% pure, 27.55 g, 0.238 mole), maintaining a reaction temperature of 27°±3° C. After addition, the reaction mixture was stirred at 30° C. for 70 minutes. Glycine, N-(carboxymethyl)-N-[2-hydroxy-3-(2-propenyloxy) propyl], disodium salt was recovered as a 30% active solution.
EXAMPLE 4
Preparation of glycine, N-methyl-N-[2-hydroxy-3-(2 -propenyloxy)-propyl], monosodium salt
N-methyl glycine (98% pure, 32 g, 0.35 mole) was dispersed in 64 ml DI water at room temperature. Sodium hydroxide (50% aqueous solution, 28 g, 0.35 mole) was added over a period of 80 minutes, maintaining a reaction temperature of 5°±2° C. After addition, the reaction mixture was stirred at room temperature for 60 minutes.
The resulting sodium N-methyl glycinate solution (31.6%, 123 g, 0.348 mole) was added over a period of 70 minutes to a mixture of 33 ml of DI water and allyl glycidyl ether (98.5% pure, 40.3 g, 0.348 mole), maintaining a reaction temperature of 20°±2° C. After addition, the reaction mixture was stirred at 25° C. for 100 minutes. Glycine, N-methyl-N-[2-hydroxy-3-(2-propenyloxy)propyl], monosodium salt was recovered as a 40% active aqueous solution.
EXAMPLE 5
Preparation of 2-Propanol, 1-amino-3-(2-propenyloxy) [6967-44-8]
Allyl glycidyl ether (98.5% pure, 185 g, 1.6 mole) was added over a period of 225 minutes to ammonium hydroxide (26% ammonia in water, 629 g, 9.6 mole), maintaining a reaction temperature of 9°±3° C. After addition, the reaction mixture was stirred at 10° C. for 20 minutes, then room temperature for 45 minutes. 2-Propanol, 1-amino-3-(2-propenyloxy) was collected via vacuum distillation at about 120° C./10 mm Hg.
EXAMPLE 6
Preparation of Beta-alanine, N-(2-carboxyethyl)-N-[2-hydroxy-3-(2-propenyloxy)propyl], disodium salt [74988-14-0]
Methyl acrylate (99% pure, 44.2 g, 0.508 mole) was added over a period of 180 minutes to a mixture of 33 ml methanol and 2-propanol, 1-amino-3-(2-propenyloxy) (99.8% pure, 33.4 g, 0.254 mole), maintaining a reaction temperature of 12°±3° C. After addition, the reaction mixture was stirred at room temperature for 11 hours.
48 ml of methanol was added to the resulting beta-alanine, N-(2-carboxyethyl)-N-[2-hydroxy-3-(2-propenyloxy)propyl], dimethyl ester (75%, 92 g, 0.228 mole), and the reaction mixture was cooled to 15° C. Sodium hydroxide (99% pure, 18.5 g, 0.456 mole) was then dissolved in the reaction mixture, maintaining a reaction temperature below 25° C. After dissolution, the batch was stirred at room temperature for 135 minutes. 100 ml of DI water was then added and an exotherm to 31° C. was observed. The reaction mixture was stirred at 20° C. for 180 minutes, before removing the methanol by vacuum distillation. Beta-alanine, N-(2-carboxymethyl)-N-[2-hydroxy-3-(2-propenyloxy)propyl], disodium salt was recovered as a 56% active aqueous solution.
EXAMPLE 7
Preparation of 2-propanol, 1-(diethylamino)-3-(2-propenyloxy) [14112-80-2]
Allyl glycidyl ether (146 g, 1.25 mole) was added over a period of 120 minutes to a solution of diethylamine (97 g, 1.3 mole) in DI water (33 ml), maintaining a reaction temperature of 30°±10° C. After addition, the batch was stirred at 35°±5° C. for 135 minutes, then room temperature overnight. The batch was then heated at 50°±2° C. for 60 minutes before 2-propanol, 1-(diethylamino) 3-(2-propenyloxy) was collected via vacuum distillation at 98° C./3 mm Hg.
Syntheses of copolymers with acrylic acid are illustrated in Examples 8-14.
EXAMPLE 8
Preparation of acrylic acid/2-propanol, 1-(methylamino)-3-(2-propenyloxy)/beta-alanine, N-methyl-N-[2-hydroxy-3-(2-propenyloxy)propyl], terpolymer
2-Propanol, 1-(methylamino)-3-(2-propenyloxy) (Example 1, 12.6 g), water (114.13 g), and isopropyl alcohol (32.09 g) were charged to a suitable reactor and purged with nitrogen. Sodium persulfate (22% aqueous solution, 15.73 g) and acrylic acid (36.77 g) were simultaneously added over a 4 hour period, maintaining a reaction temperature of 87°±4° C. After addition, the reaction mixture was held at 91° C. for 1 hour. The residual isopropyl alcohol was then removed by azeotropic distillation. Sodium hydroxide (50% aqueous solution, 20 g) and 119 ml of water were then added, maintaining the temperature below 40° C.
Under the polymerization conditions, some addition reaction between the secondary amino hydrogen and the free acrylic acid occurred. This was evidenced by the 13 C NMR spectroscopy which indicated a mole ratio of acrylic acid/2-propanol, 1-(methylamino)-3-(2-propenyloxy)/beta-alanine, N-methyl-N-[2-hydroxy-3-(2-propenyloxy)propyl] of 15.6:1.0:1.9 respectively. This corresponds to about 65% of the available amine forming the adduct with acrylic acid.
EXAMPLE 9
Preparation of acrylic acid/2-propanol, 1-(methylamino)-3-(2-propenyloxy)/beta-alanine, N-methyl-N-[2-hydroxy-3-(2-propenyloxy)propyl] terpolymer
Prepared as described in Example 8 except less isopropyl alcohol (19.75 g) and less water (21.59 g) were utilized in the polymerization. This resulted in a higher molecular weight. 13 C NMR analysis of the product was similar to that obtained for Example 8, confirming the terpolymer structure.
EXAMPLE 10
Preparation of acrylic acid/2-propanol, 1-(dimethylamino)-3-(2-propenyloxy) copolymer
Prepared as described in Example 8 utilizing 2-propanol, 1-(dimethylamino)-3-(2-propenyloxy) (Example 2, 13.68 g), water (91.82 g), isopropyl alcohol (21.59 g), sodium persulfate (22% aqueous solution, 16.05 g), and acrylic acid (36.76 g). The hold period after addition was lengthened to 2 hours. After distillation, sodium hydroxide (50% aqueous solution, 20 g) and 119 ml of water were added.
EXAMPLE 11
Preparation of acrylic acid/2-propanol, 1-(dimethylamino)-3-(2-propenyloxy) copolymer
Prepared as described in Example 10 utilizing 2-propanol, 1-(dimethylamino)-3-(2-propenyloxy) (Example 2, 20.52 g), water (105.88 g), isopropyl alcohol (22.91 g), sodium persulfate (22% aqueous solution, 18.23 g), and acrylic acid (36.76 g). After distillation, sodium hydroxide (50% aqueous solution, 20 g) and 130 ml of water were added.
EXAMPLE 12
Preparation of acrylic acid/glycine, N-(carboxymethyl)-N-[2-hydroxy-3-(2-propenyloxy) propyl], disodium salt copolymer
Prepared as described in Example 10 utilizing glycine, N-(carboxymethyl)-N[2-hydroxy-3-(2-propenyloxy)propyl], disodium salt solution (Example 3, 97.04 g), water (105.45 g), isopropyl alcohol (19.54 g), sodium persulfate (22.8% aqueous solution 20 g), and acrylic acid (36.77 g). One hour after addition, tert-butylhydroperoxide (70% aqueous solution, 0.456 g) was added. After distillation, sodium hydroxide (50% aqueous solution, 12 g) and 71 ml of water were added.
EXAMPLE 13
Preparation of acrylic acid/glycine, N-methyl-N-[2-hydroxy-3-(2-propenyloxy)propyl], monosodium salt copolymer
Prepared as described in Example 12 utilizing glycine, N-methyl-N-[2-hydroxy-3-(2-propenyloxy)propyl] monosodium salt solution (Example 4, 56.29 g), water (106.22 g), isopropyl alcohol (31.32 g), sodium persulfate (20.5% aqueous solution, 20 g), acrylic acid (36.77 g), and tert-butylhydroperoxide (70% aqueous solution, 0.418 g). The addition period was lengthened to 5 hours. After distillation, sodium hydroxide (50% aqueous solution, 16 g) and 110 ml of water were added.
EXAMPLE 14
Preparation of acrylic acid/beta-alanine, N-(2-carboxyethyl)-N-[2-hydroxy-3-(2-propenyloxy)propyl], disodium salt copolymer
Prepared similarly to Example 10 utilizing beta-alanine, N-(2-carboxyethyl)-N-[2-hydroxy-3-(2-propenyloxy)propyl], disodium salt solution (Example 6, 30.00 g), water (63.17 g), isopropyl alcohol (21.30 g), sodium persulfate (25% aqueous solution, 12.08 g), acrylic acid (23.34 g), tert-butylhydroperoxide (70% aqueous solution, 0.58 g), and sodium hydroxide (50% aqueous solution, 8.47 g). For this polmerization, the sodium hydroxide was charged simultaneously with the acrylic acid and the sodium persulfate solution; the addition period was shortened to 3 hours; the hold period was lengthened to 3 hours; and the tert-butylhydroperoxide was added 2 hours after addition. After distillation, 95 ml of water was added.
Example 15 illustrates the preparation of a copolymer of methacrylic acid with the product of Example 7.
EXAMPLE 15
Preparation of methacrylic acid/2-propanol, 1-(diethylamino)-3-(2-propenyloxy) copolymer
2-Propanol, 1-(diethylamino)-3-(2-propenyloxy) (Example 7, 16 g, 0.083 mole) and 171 ml DI water were charged to a suitable reactor and purged with nitrogen. Sodium persulfate (20.5% aqueous solution, 20 g) and methacrylic acid (44 g, 0.5 mole) were simultaneously added over a 4 hour period, maintaining a batch temperature of 90°±2° C. 50% aqueous sodium hydroxide (7 g total) was charged during the addition period as needed to maintain polymer solubility. After addition, the batch was held at 90°±2° C. for 1.5 hours. After the hold period, 50% sodium hydroxide (29 g) was charged, maintaining the batch temperature below 30° C.
Table II presents a summary of the physical properties of the copolymers produced in accordance with Examples 8-15.
TABLE II______________________________________Physical Properties of the Copolymers (g/h) Charge Brook-Co- Mole field.sup.apoly- Monomer Monomer Ratio Vis-mer (g) (h) g:h cosity pH M-n.sup.b______________________________________Ex 8 Acrylic Acid Ex 1 6:1 13.5 5.5 2,350Ex 9 " Ex 1 6:1 15.6 5.5 3,200Ex 10 " Ex 2 6:1 21.8 5.5 2,469Ex 11 " Ex 2 4:1 26.3 5.7 2,350Ex 12 " Ex 3 5:1 21.5 4.9 4,450Ex 13 " Ex 4 5:1 17.5 5.1 4,200Ex 14 " Ex 6 6:1 13.4 5.2 --Ex 15 Methacrylic Ex 7 6:1 38.4 9.65 -- Acid______________________________________ .sup.a 25% solutions @ 25° C. .sup.b Number average molecular weight
Table III illustrates the excellent activity of the novel copolymers for deposit control in aqueous systems containing high levels of well water iron. The results are given as percent of soluble iron remaining in solution after specified times. The higher the percent soluble iron, the more effective the scale control of the polymer.
TABLE III______________________________________Deposit Control ActivityWell Water Iron ResultsPercent Soluble IronConditions: 200 ppm Ca.sup.2+ as CaCO.sub.3 ; 100 ppm Mg.sup.2+ asCaCO.sub.3 ; 8 ppm Fe.sup.+2 ; pH 8; 45° C.; 0, 24, 48, 72 hourequilibrationTreatment Treatment Conc 24 48Copolymer (ppm active) 0 hour hour hour 72 hour______________________________________Control 1.85 1.20 1.00 1.00Example 8 10.00 8.80 1.60 1.00 3.70 20.00 96.20 96.30 81.60 96.20 40.00 97.40 95.50 83.70 97.50Example 9 10.00 18.70 1.10 1.00 3.50 20.00 96.60 96.10 82.42 97.20 40.00 96.80 95.60 81.60 97.50Example 10 10.00 10.80 1.20 1.00 2.00 20.00 95.50 70.90 22.70 35.60 40.00 96.40 97.10 81.25 97.50Example 11 10.00 2.80 1.40 1.00 2.00 20.00 96.30 71.80 79.10 88.30 40.00 96.40 97.10 81.25 97.50______________________________________
Table IV illustrates that the copolymers are effective in inhibiting the formation of calcium phosphate, commonly encountered in industrial water systems, such as cooling water systems.
TABLE IV______________________________________Calcium Phosphate InhibitionConditions: 600 ppm Ca.sup.2+ as CaCO.sub.3, 12 ppm PO.sub.4.sup.-3,2 mM NaHCO.sub.3, pH 7.0, 70° C., 18 hour equilibration% InhibitionTreatment Treatment Concentrations (ppm active)Copolymer 5 10 20______________________________________Example 8 9.6 11.3 39.69 11.3 10.9 76.110 5.4 9.2 35.611 4.0 9.4 70.912 3.7 3.7 9.113 8.6 2.7 11.214 5.6 13.5 38.2______________________________________
Table V demonstrates the excellent activity of the novel copolymers in inhibiting the formation of calcium carbonate, another commonly encountered scale-forming agent in various industrial water systems.
TABLE V______________________________________Calcium Carbonate InhibitionConditions: 1105 ppm Ca.sup.2+ as CaCO.sub.3, 1170 ppm CO.sub.3.sup.-2as CaCO.sub.3 pH 9.0, 70° C., 18 hours equilibration,LSI = 3.67 % InhibitionTreatment Treatment Concentrations (ppm active)Copolymer 0.5 1.0 2.0______________________________________Example 8 0.0 23.4 37.59 5.8 29.5 39.410 0.0 18.0 34.611 0.0 10.5 33.612 6.3 31.8 44.613 8.3 31.0 43.014 8.5 35.9 50.2______________________________________
Tables VI and VII show that the copolymers are less effective in dispersing ferric oxide or montmorillonite clay.
TABLE VI______________________________________Ferric Oxide DispersionConditions: 300 ppm Fe.sub.2 O.sub.3, 200 ppm Ca.sup.2+ as CaCO.sub.3,1 mM Nacl, 10 mM NaHCO.sub.3, pH 7.0, 45° C.,18 hours settling% TransmittanceTreatment Treatment Concentrations (ppm active)Copolymer 2.5 5.0 10.0______________________________________Example 8 1.5 2.5 4.39 3.0 4.5 5.010 1.5 1.5 1.511 1.5 1.5 2.012 9.0 15.0 26.013 2.5 5.5 5.514 5.5 9.0 20.5______________________________________
TABLE VII______________________________________Montmorillonite DispersionsConditions: 200 ppm Ca.sup.2+ as CaCO.sub.3, pH 7.0, 1000 ppmmontmorillonite, 18 hours equilibration% TransmittanceTreatment Treatment Concentrations (ppm active)Copolymer 5 10 20______________________________________Example 8 0.0 0.0 0.09 0.0 0.0 0.010 0.0 0.0 0.011 0.0 0.0 0.0______________________________________
Table VII demonstrates the scale control in a boiler water system of a methacrylic acid copolymer (Example 15) in a phosphate precipitation program. Details of typical boiler test conditions can be found in U.S. Pat. No. 4,659,481, col. 17.
TABLE VIII______________________________________Boiler Scale ReductionPrecipitating Phosphate Program900 psig; 4 ppm Ca, 1 ppm Mg (as CaCO3)15 cycles Deposit Weight % ScalePolymer Conc. (ppm) Density (g/ft.sup.2) Reduction______________________________________None -- 8.15 --Ex. 15 2.5 0.99 88Ex. 15 5.0 0.22 97______________________________________ % Scale reduction is calculated from the equation: ##STR5## where DWD is Deposit Weight Density control is the boiler test without polymer
It is to be understood that the above boiler studies in no way limit the utility of the present invention for other boiler treatment programs, such as polymer/phosphate/chelant, coordinated phosphate, etc.
While this invention has been described with respect to particular embodiments thereof, it is apparent that numerous other forms and modifications of this invention will be obvious to those skilled in the art. The appended claims and this invention generally should be construed to cover all such obvious forms and modifications which are within the true spirit and scope of the present invention.
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This invention relates to novel polymeric compositions which are useful for water treatment. These novel compositions are comprised of polymers of α, β ethylenically unsaturated monomer(s), preferably containing carboxylic acid or carboxylic amide functionalities, and amine-containing allyl ether monomers.
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BACKGROUND OF THE INVENTION
The present invention relates generally to spinal fixation systems, such as systems for use in the fixation of the spine for the treatment of various spinal deformities. Specifically, the present invention contemplates a lateral connector assembly for interconnecting an elongated member, such as a rod or tether, with a bone engaging fastener such as a hook, screw or bolt.
The treatment of spinal deformities and injuries has evolved significantly over the last 30 years. Spinal deformities, such as scoliosis and kyphosis, as well as fractures, spondylolisthesis, and other medical indications have been treated using a system of relatively rigid elongated members spanning the vertebral column. In one type of system, the elongated members constitute a plate that has a number of openings or slots through which bone bolts or bone screws extend. The bone engaging fasteners are threaded into different aspects of the vertebra and fixed to the plate to achieve fixation of the elongated plate. In other procedures, elongated rigid rods are joined to screws or hooks embedded in the spine to fix the relative position of each vertebra. In yet further procedures for dynamic stabilization, an at least partially flexible elongate member is joined to bone engaging fasteners embedded in the spine.
In the implantation of any spinal instrumentation, one goal of the surgeon is to minimize the intrusion into the patient, whether by the amount of implants that must be used, the size of the surgical access opening or by the length of time required to fix the implants within the patient. Further, the system must be easy to use and provide the surgeon with confidence that it will provide the desired stabilization after implantation.
While connectors have been provided that offer various degrees of freedom of movement between the elongated member and the bone fastener, there remains a need for providing an improved connection between the bone fastener and the elongated member.
SUMMARY OF THE INVENTION
The present invention provides a connector assembly for connecting a bone engaging fastener to an elongated member. In one aspect the invention includes a connector for joining the bone engaging fastener to a clamp having a channel for holding the elongated member. A compression member is provided to hold the elongated member in the channel and a mechanism is included in the channel to translate the compression force on the elongated member into a locking force to lock the connector to the clamp. In one embodiment, a locking member is provided with an oblique bearing surface that engage the elongated member. In another embodiment, the channel includes an oblique bearing surface that forces the elongated member against a portion of a locking member that locks the connector to the clamp.
In another aspect, the present invention provides a lateral connector assembly for connecting a bone engaging fastener to an elongated member. In one embodiment, the connector assembly includes a lateral connector having a plate portion and a first connection portion, the plate portion defines an opening configured to receive the bone engaging fastener therethrough and the first connection portion defines a first locking surface. The assembly further includes a clamp having a body defining a channel therethrough sized to receive the elongated member therein and a second connection portion defining a connection axis and configured for engagement with the first connection portion of the lateral connector. A variable angle locking member is disposed between the first connection portion and the second connection portion, the variable angle locking member has a second locking surface for engaging the first locking surface of the lateral connector at a plurality of angular orientations, and the variable angle locking member includes a locking member bearing surface opposite the second locking surface. The locking member bearing surface is disposed at least in part within the channel for engaging the elongated member and disposed at an oblique angle with respect to the connection axis. The system further includes a compression member extending between the clamp and the elongated member, the compression member acting to urge the elongated member against the bearing surface.
Further aspects, forms, embodiments, objects, features, benefits, and advantages of the present invention shall become apparent from the detailed drawings and descriptions provided herein.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 is an exploded perspective view of a connector assembly according to one aspect of the present invention.
FIG. 2 is a partially exploded perspective of the connector assembly of FIG. 1 in combination with an elongated member and a bone engagement member.
FIG. 3A is a perspective view of the connector of FIG. 2 in an assembled form.
FIG. 3B is a partial cross-sectional view of the connector of FIG. 3A taken along line 3 B- 3 B.
FIG. 4 is a partial cross-sectional view of an alternative embodiment of a connector assembly according to another aspect of the present invention.
DESCRIPTION OF THE PREFERRED EMBODIMENTS
For the purposes of promoting an understanding of the principles of the present invention, reference will now be made to the embodiments illustrated in the drawings, and specific language will be used to describe the same. It will nevertheless be understood that no limitation of the scope of the invention is intended. Any alterations and further modifications in the described devices, instruments, methods, and any further application of the principles of the invention as described herein are contemplated as would normally occur to one skilled in the art to which the invention relates.
Referring now to FIG. 1 , there is shown a connector assembly 100 according to the present invention. Connector assembly 100 includes a plate portion 110 , a clamp body 150 , a variable angle locking washer 130 and a retaining clip 160 . The plate portion includes an elongated opening 112 and a connection flange 114 with a locking face 116 having a series of radially emanating splines 115 surrounding connection opening 118 . As shown in FIG. 3B , internal connection opening 118 includes an annular groove defining an internal shoulder 120 . The variable angle locking washer 130 includes a locking face 132 having a series of radially emanating splines surrounding opening 138 and configured for interdigitating engagement with splines 115 of locking face 116 . Locking washer 130 further includes a pair of tapering rod bearing surfaces 134 and 136 spaced on either side of opening 138 . Extending between bearing surfaces 134 and 136 , is recessed shoulder 140 .
Clamp body 150 includes a threaded opening 152 extending into a through channel 154 . Extending away from through channel 154 at a substantial perpendicular angle is the connection extension 157 . In the illustrated embodiment, the connection extension extends along a connection axis L 1 and is divided by gap 155 into upper and lower branches. An upper projection 158 is formed on the upper branch and a lower projection 162 is formed on the lower branch. A retaining clip 160 is adapted to slide along gap 155 and engage internal shoulder 120 of the plate portion 110 .
Referring now to FIGS. 2 , 3 A, and 3 B, the connector assembly 100 is shown is an assembled form. Its assembly with be further described below. In FIG. 2 , locking washer 130 has been placed about connection extension 157 of the clamp body 150 . The connection extension 157 extends through opening 138 in locking washer 130 and has been positioned in connection opening 118 . It will be appreciated that gap 155 allows the upper and lower branches of the connection extension 157 to flex inwardly to allow projections 158 and 162 to pass beyond internal shoulder 120 . In the illustrated embodiment, the upper and lower branches are formed such that they have a tendency to resiliently return to the position shown in FIG. 3B , with the projections 158 and 162 disposed in the annular groove behind shoulder 120 . In this manner, the projections 158 and 162 cooperate with shoulder 120 to retain the connection extension in mated contact with the plate portion 110 as shown in FIG. 3B . With the clamp body 150 , locking washer 130 and plate portion 110 in the position shown in FIG. 2 , the retaining clip 160 is passed along gap 155 until its legs are seated behind internal shoulder 120 on plate portion 110 . In this manner, the retaining clip 160 fills gap 155 to lock the assembly together and thereby prevents the upper and lower branches from flexing inward to release the projections 158 and 162 from the annular groove behind shoulder 120 . It will be appreciated that the connection extension 157 , lock washer 130 and plate portion 110 are configured such that in the retained position shown in FIG. 2 , the plate portion 110 may swivel with respect to the lock washer 130 and clamp body 150 . The interconnection between the rectangular shaped shoulder 140 on the lock washer and the rectangular enlarged portion of the connection extension 157 maintains the angular relationship of the lock washer substantially constant with respect to the clamp body 150 . In a one aspect, the connector assembly 100 is preassembled into the retained position of FIG. 2 during the manufacturing process and packaged for use.
In the retained positioned the connector assembly 100 is ready for implantation in a patient. In use, a bone fastener, such as bone screw 210 is implanted in the desired position in the patient. Although not illustrated, it is contemplated that bone screw 210 is implanted into the pedicle of a vertebral body along axis L 3 for a posterior fixation procedure. Further, a plurality of bone screws 210 are implanted in adjacent spinal levels to complete a posterior fixation procedure. Once the bone screws 210 have been implanted, an elongated spinal rod 240 is selected and cut to a length sufficient to span the plurality of bone screws 210 . At least one connector assembly 100 is placed on the rod 240 . The connector assembly 100 is in the retained position such that the plate portion 110 may be rotated with respect to the rod clamp body 150 . The plate portion 110 is rotated such that the opening 112 is in substantial alignment with the bone screw 210 . The upper portion of bone screw 210 is passed through opening 112 in the plate portion 110 . An internally threaded nut 220 is connected to the externally threaded post of the bone screw 210 and is advanced to engage the bone screw to the plate portion 110 .
The externally threaded set screw 230 is threadedly engaged with the internally threaded side walls of opening 152 . Set screw 230 advances along compression axis L 2 as shown in FIG. 3B . As set screw 230 advances along compression axis L 2 , the rod 240 is urged in the direction of compression axis L 2 . In the embodiment shown in FIG. 3B , bearing wall 156 of the clamp channel 154 extends in a plane aligned with axis L 5 that is in substantially parallel alignment with axis L 2 . As rod 240 moves in the direction L 2 along bearing surface 156 , the rod 240 engages a portion of locking member bearing surfaces 134 and 136 that extend into channel 154 . Locking member bearing surfaces 134 and 136 extend in a locking member bearing plane in substantial alignment with axis L 4 . In the illustrated embodiment, axis L 5 of the clamp bearing surface and axis L 4 of the locking member bearing surface intersect to form an acute angle within the channel 154 . In this manner, the channel 154 has a first width substantially aligned with connection axis L 1 adjacent the set screw and opening 152 , and a second width substantially aligned with connection axis L 1 and disposed opposite the set screw 230 . The first width is greater than the second width. The first width is greater than the diameter of rod 240 while the second width is less than the diameter of rod 240 .
In the illustrated embodiment, the sloping wall 156 and corresponding sloping walls 134 and 136 form a channel with side walls that taper from the top, adjacent the set screw, to the bottom of the channel. As the set screw 230 pushes rod 240 into the tapered channel 154 , the set screw compression force is translated by the sloping bearing walls 156 , and locking member bearing walls 134 and 136 into a locking force applied along axis L 1 . In the illustrated embodiment the locking member bearing surfaces 134 and 136 are disposed at an oblique angle with respect to the connection axis L 1 and the compression axis L 2 . The clamp bearing surface is also positioned oblique to connection axis L 1 . This locking force applied against bearing walls 134 and 136 urges the locking member 130 splines into locking engagement with the projecting splines 115 of the connection portion 114 of the plate 110 . It will be appreciated that the set screw compression force on rod 240 causes movement of the locking washer 130 along the locking axis L 1 . Further, movement of the set screw moves rod 240 along bearing surfaces 134 and 136 , and clamp bearing surface 156 toward the bottom of the channel. It will be appreciated that rod 240 is positionable in an infinite number of positions along the bearing surfaces. Moreover, with the locking member 130 fully engaged with the connection portion 114 , further compression force applied by set screw 230 tends to tighten the locking force applied along axis L 1 and to hold rod 230 in a three point contact lock to inhibit movement of the clamp 150 along the rod 240 . The tightened set screw holds the connector assembly in a locked position as shown in FIGS. 3A and 3B . The three point contact lock is formed by the engagement between the rod 240 with the set screw 230 , the clamp bearing wall 156 and the split locking member bearing wall defined by surfaces 134 and 136 . Also, in a plane taken along axis L 1 , the rod is held in a three point lock position between clamp bearing wall 156 and the locking member bearing walls defined by surfaces 134 and 136 that are spaced wider than the width transverse to axis L 1 of the bearing surface 156 .
In a further embodiment shown in FIG. 4 , the clamp body 310 has an internally threaded bore 312 extending along an axis L 6 that is in substantial alignment with axis L 3 of the bone fastener and substantially perpendicular to the locking axis L 2 . Externally threaded set screw 330 is positioned in the bore 312 and exerts a compression force along axis L 6 . The channel of the clamp body is formed substantially as described above. As rod 350 is advanced along axis L 6 into the tapered channel, the rod 350 bears against clamp bearing surface 316 causing the rod to translate along the locking axis L 2 as it slides along the bearing surfaces. Continued compression force along axis L 6 forces the rod 330 against locking member bearing surface 334 and results in translation of the locking member along the locking axis to lock against the connection portion of the plate. It will be appreciated that in the embodiment illustrated in FIG. 4 , the clamp channel is configured to transfer the compressive force of the locking member into a locking force in a substantially perpendicular direction. Further, in the illustrated embodiment, the set screw 330 and axis L 6 extend in a direction that substantially bisects the acute angle between oblique clamp bearing surface 316 extending along axis L 5 and the oblique locking member bearing surface 334 extending along axis L 4 .
Although the above illustrated embodiments have been described in detail for the purpose of illustration and understanding of the principles of the present invention, it is contemplated that the invention may be applied in a variety of spinal stabilization assemblies. For example, in one embodiment the clamp body and locking washer combination of the present invention may be applied to the lateral connector of U.S. Pat. No. 5,976,135 to Sherman et al., incorporated herein by reference in its entirety. In another embodiment the connection portion of the plate member is moveable with respect to the portion of the plate member engaging the bone fastener. The moveable connection portion translates along the connection axis in response to the transmission of the set screw compressive force being translated by a clamp body assembly according to the present invention to translate the rod along the locking axis and thereby move the assembly to a locked position. As set forth in U.S. Pat. No. 6,579,292 to Taylor and U.S. Pat. No. 5,885,285 to Simonson, incorporated herein by reference in their entirety, the moveable connection portion slides along the plate member to capture and hold the bone screw without the need for a separate locking nut. Still further, in another embodiment, the plate member may be substantially ring shaped such that it is joined to a shaft of a bone fastening element.
Although a set screw has been shown as the compression member in the illustrated embodiment, in another embodiment, the compression member is an external nut with internal threading that engages an externally threaded portion of the clamp body. In still a further embodiment, the compression member is one or more tapered sleeves that slide along the rod to lock the rod in the channel.
The connector assembly is useful for rigid rods and flexible connectors. For example, in one embodiment, rod 240 is formed of a rigid material such as titanium or stainless steel. In another embodiment, rod 240 is flexible. In such an embodiment, rod 240 is formed of plastic or a flexible metal. In still a further embodiment, the elongate member is not a rod but a flexible cable or cord that may be tensioned between adjacent spinal levels and connectors. Still further, lateral refers to the connection of the elongated member along one side of the shaft of the bone fixation element such as screw 210 as opposed to fixing the elongated member in line with the axis of the bone screw.
The foregoing outlines features of several embodiments so that those skilled in the art may better understand the aspects of the present disclosure. Those skilled in the art should appreciate that they may readily use the present disclosure as a basis for designing or modifying other processes and structures for carrying out the same purposes and/or achieving the same advantages of the embodiments introduced herein. Those skilled in the art should also realize that such equivalent constructions do not depart from the spirit and scope of the present disclosure, and that they may make various changes, substitutions and alterations herein without departing from the spirit and scope of the present disclosure.
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A lateral connector assembly for connecting a bone engaging fastener to an elongated member, such as a spinal rod includes a lateral connector having an opening for receiving a portion of the bone engaging fastener therethrough. The lateral connector includes a plate portion and an integral yoke portion, which yoke portion is attached to the elongated member by way of a clamp. The lateral connector assembly can include variable angle means between the clamp and the yoke portion of the lateral connector that permits rotation of the lateral connector about an axis projecting outward from the spinal rod. The clamp includes a tapering channel to capture the elongated member and lock the connector assembly.
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CROSS REFERENCE TO RELATED APPLICATIONS
This application is a §365(c) continuation application of PCT/EP2004/002694 filed Mar. 16, 2004, which in turn claims priority to DE Application 103 12 895.6 filed Mar. 22, 2003 and DE Application 102004010975.3 filed Mar. 3, 2004, each of the foregoing applications is incorporated herein by reference.
FIELD OF THE INVENTION
The invention relates to a mixing device for mixing a piece-form, gel-like, pasty, pulverulent, liquid product or the like, which is contained in a film sachet which is soluble in a liquid solvent, with the liquid solvent and optionally at least one further component.
BACKGROUND OF THE INVENTION
In the case of pulverulent cosmetic products which, in order to be used, have to be converted to a liquid-based, in particular water-based, form, for example, it must be ensured that when converting the pulverulent product into the liquid solvent a risk of creating dust for the user does not, as far as possible, take place. Such a risk of creating dust is particularly undesirable and to be avoided if the pulverulent products are strongly acidic, strongly alkaline or chemically active, such as, for example, bleaching powder.
To avoid dust formation, granulation processes have, inter alia, been proposed, for bleaching powders in particular dedusting with oil components. However, besides impaired miscibility of the powder with the liquid components prior to use, these granulation processes with oxidizable components also harbor potential risks, e.g. with regard to reduced storage stability due to the simultaneous presence of oxidizing and oxidizable components. Sometimes, the formulation of components which may be subject to hydrolysis (or in some cases solvatolysis in polar solvents) in oil-based formulations is also of interest.
It has already been proposed to package bleaching powder in a water-soluble film sachet. The powder is then placed in the film sachet into a liquid solvent, the film sachet gradually dissolves and mixing of the powder with the liquid solvent can take place. In practice, however, the delayed solubility of the film sachet has proven to be disadvantageous, i.e. the preparation time is too long and unacceptable for the user.
An object of the invention is therefore to overcome the disadvantages of the prior art. This object is achieved using a mixing device with the features of the present invention. Through a sealable mixing container with a receiving chamber for the product contained in the film sachet and the liquid solvent and the optional further components, internal inserts for the mechanical destruction of the film sachet being provided in the area of the receiving chamber. Here, the mixing mechanism can be used for all aggregate states of the product, in particular piece-form, gel-like, pasty, pulverulent, liquid or the like.
Using such a mixing device, it is possible, after introducing the components and sealing the mixing container, to mechanically destroy and/or to comminute the film sachet containing the pulverulent product, which leads to accelerated dissolution of the film and to a significantly shortened mixing time of the product with the remaining components. Here, the internal inserts in the receiving chamber of the mixing container can in principle be of varying designs where, in the case of the simplest configurations in terms of construction, it is possible to make the internal inserts effective in a simple manner by the mixing device being shaken by the user, which is in any case sensible and useful for increasing the rate of the mixing operation per se.
In order to make the device easier to handle when opening and closing it, it is advantageously provided that the mixing container has a container opening which is sealable by a removable lid. The components to be mixed can then, after the lid has been removed, simply be introduced into the receiving chamber of the mixing container, then the lid can be put back on again.
It is particularly expedient if the internal inserts are formed as an insert arranged in the area of the container opening. After the mixing operation and opening of the container lid, the insert can then be removed from the area of the container opening and the product obtained after mixing can be removed from the container without problems.
According to a first advantageous configuration, it is envisaged that the insert is designed like a lemon squeezer toward the receiving chamber.
Alternatively, it can also be envisaged that the insert is designed like a sieve plate with tapered pins or spikes pointing into the receiving chamber. Furthermore, it can also be envisaged to equip the insert with knife-like elements pointing inwards. In addition, all of the combinations of the specified inserts or others can be envisaged. The film sachet advantageously consists of polyvinyl alcohol or gelatin, but generally of a solid which is soluble in the added liquid solvent to be mixed.
In an advantageous configuration, it is envisaged that the product is a bleaching powder and the liquid solvent is a hydrogen peroxide solution. The mixing device can then be used to prepare a bleaching composition. The further component here is then advantageously a bleaching cream.
The invention also proposes a mixing set with an above-described device and a product contained in a film sachet soluble in a liquid solvent, optionally a receiving container filled with the liquid solvent, and optionally a receiving container filled with a further component.
Cosmetic Portion
In an advantageous embodiment of the present invention, the mixing set according to the invention includes a cosmetic portion. This portion consists of a coating soluble in a liquid solvent, in particular a corresponding film sachet, and a product contained therein.
The set object is achieved in this embodiment according to the invention through the mechanical action in the mixing device and through the specific shape of the film sachet.
In the field of cosmetics, there is a great need for products which should on the one hand be effective and on the other hand should be simple and above all safe for the consumer to handle and use. In the field of hair cosmetics in particular, bleaching and hair-dyeing systems have developed in recent years which are extremely effective but, if handled improperly, for example in cases of contamination with areas of skin or eyes, can lead to irritations or, in extreme cases, even to allergies being triggered. There was therefore a great need to ensure the safety of the handling of such cosmetic formulations and, moreover, to give the consumer a packaging system which is easy to dose by hand and which also allows a mixing or a combining of the required components on site by the consumer.
The prior art already discloses water-soluble sachet-packaged hair cosmetic formulations. DE 196 13 941 A1 describes a method for the preparation of nondusting pulverulent compositions for the bleaching of human hair. The blonding compositions have at least one peroxide compound, which are admixed with suitable thickeners and then packaged in portions in water-soluble sachets for transportation and further processing.
EP-A1-1037589 discloses a composition for the treatment of keratin fibers, consisting of at least one aqueous preparation A and at least one spatially separate preparation B which comprises a constituent which is not storage-stable in preparation A, chosen from the group which is formed by perfume oils, and vitamins, provitamins and derivatives thereof, where the film sachet with preparation B of a material which, when preparation B is added to preparation A, allows a mixing of the components of both preparations at 38° C. within 5 minutes.
U.S. Pat. No. 5,116,388 discloses hair colorants based on oxidation dyes, and bleaches for bleaching hair which are incorporated into polyvinyl alcohol packaging in order to prevent the irritations caused by powder dust.
Although the portioned cosmetic formulations disclosed in the prior art offer improved handleability and a reduction in the dust contamination of the packaged cosmetic preparations, the portions packaged in water-soluble film systems have the disadvantage that they dissolve only slowly in water. Moreover, the water-soluble cosmetic portions disclosed in the prior art, especially in the field of hair cosmetics, have the disadvantage that the portions can slide out of the consumer's hands and possibly burst. It is not uncommon for consumers who use hair cosmetic products to have wet hands or fingers, for example because the hair has been washed just before application, which increases to an extreme degree the risk of cosmetic portions slipping off. Many of the cosmetic individual portions disclosed in the prior art are often sold in a further water-impermeable secondary packaging. The secondary packagings often consist here of smooth film sachets or metal-coated smooth packaging systems, so that the water-soluble PVA cosmetic portions described in the prior art lie flat against the surfaces of the secondary packaging materials and, due to high adhesion forces, do not slide easily out of the secondary packaging container. An object of the embodiment according to the invention is to provide portioned cosmetic preparation in water-soluble and/or water-dispersible film sachets which do not have the abovementioned problems of the prior art.
SUMMARY OF THE INVENTION
It has been found that the abovementioned problems are solved by the special configuration of a portion.
A portion comprising a cosmetic preparation and a water-soluble and/or water-dispersible film sachet, where this film sachet covers the cosmetic preparation and the surface of the film sachet has a square mean value for the roughness of at least 10 μm.
These portions have cosmetic preparations which are covered by water-soluble and/or water-dispersible film sachets. However, film sachets which are completely soluble in water are advantageous. Within the scope of the present embodiment according to the invention, the term “portion” or “cosmetic portion” is used synonymously with the term “portioned cosmetic preparation in water-soluble and/or water-dispersible film sachets”. The portions of the embodiment according to the invention have a film sachet whose surface advantageously has a square mean value for the roughness of at least 10 μm. Preferably, the surface of the film sachet has a square mean value for the roughness of from 10 to 100 μm, particularly advantageously from 10 to 50 μm and in particular from 30 to 35 μm. Within the scope of this embodiment, the term “surface” refers to the flat areas of the film sachet, for example of a polymer film.
The square mean value for the roughness of the film sachet was determined in accordance with DIN 4762/1 using standard commercial surface scanning devices.
Film sachet materials based on polyvinyl alcohol, for example as polymer films which have the roughness values given above are commercially available, from Syntana under the trade name Solublon® PVAL film, type SA 20.
As a result of the fact that the film sachets to be used according to the invention have a significantly rougher surface compared to the film sachets used in this field in the prior art, the three-dimensional macroscopic surface of the film sachet also increases in size. The three-dimensional macroscopic surface additionally takes into consideration the areas which are stretched due to irregularities on the film surface. For the case of an ideally smooth surface, the three-dimensionally macroscopic surface corresponds to the two-dimensional geometric surface. In a further embodiment, the three-dimensional macroscopic surface of the film sachet of the portion is at least 10%, advantageously at least 20%, further advantageously between 20 and 100%, extremely advantageously between 30 and 50%, larger than the two-dimensional geometric surface.
The present embodiment according to the invention thus provides portions comprising a cosmetic preparation and a water-soluble and/or water-dispersible film sachet, where the film sachet covers the cosmetic preparation and the three-dimensional macroscopic surface of the film sachet of the portion is at least 10%, advantageously at least 20%, further advantageously between 20 and 100%, most advantageously between 30 and 50%, larger than the two-dimensional geometric surface.
The three-dimensional surface is determined starting from the reference surface which has the shape of the geometric surface and agrees in terms of its position within the chamber with the main direction of the actual surface.
The three-dimensional macroscopic surface, which is larger than the two-dimensional geometric surface, contributes, inter alia, to an improved solubility in water of the portions according to the invention.
With the portions according to the invention, it is advantageous that at least one surface of the film sachet has a three-dimensional structure, preferably an embossed three-dimensional structure.
The outer surface and/or inner surface of the film sachet can here be provided to at least 50%, preferably at least 70%, further advantageously at least to 90% and in particular essentially completely, with a three-dimensional, preferably embossed, structure.
In the course of the present embodiment according to the invention, the inner surface of the film sachet refers to the flat area which can be in contact with the cosmetic preparation. In the case of the presence of a film sachet, the surface of the film in the inside of the sachet is thus the inner surface and the film surface outside of the inside of the sachet is the outer surface. The outer surface is not in contact with the cosmetic preparation of the portion according to the invention.
In an advantageous embodiment, the structure embossed on a surface of the film sachet is a regular embossed three-dimensional structure in the form of a pattern.
In one advantageous embodiment, the embossed structure has, on the surface, a regular three-dimensional pattern. The regular pattern can here have any imaginable shape, for example squares, rhomboids, punched-in cylinders, ovals, etc. In one advantageous embodiment, the regular pattern consists in a periodically repeating arrangement of raised areas and indentations of the film sachet surface.
The embossed pattern can here influence both the haptic properties of the portion according to the invention and also its dissolution rate. It has therefore proven to be advantageous that the embossed pattern has at least 4, preferably at least 6, particularly advantageously between 8 and 50, further advantageously between 10 and 25, indentations or raised areas per 1 cm 2 of the two-dimensional surface. Embossed indentations or raised areas have, within the scope of the present embodiment according to the invention, in their greatest extension at least a diameter of 2 μm and a depth or height of at least 2 μm, preferably at least 5 μm.
In a further advantageous embodiment, the surface of the film sachet has circular and/or triangular and/or rectangular and/or polygonal indentations.
In a further embodiment, the surfaces of the film sachet can, however, also have parallepiped, round, angular, oval sawtooth-shaped or raised areas triangularly tapering toward the surface.
In one advantageous embodiment, the surface of the film sachet has a grid-like or honeycomb-like three-dimensional structured pattern. These patterns are preferably embossed or stamped onto the coating surface and thus give the surface a three-dimensional profile. In one advantageous embodiment, the film sachet has grid lines as a result of embossing a grid-like or honeycomb-like pattern. The grid lines are advantageously formed by a stringing together of edges limiting the indentations.
The advantageous grid-like patterns are preferably embossed onto the surfaces of the film sachet such that the ratio of the average width of grid line to the maximum extension of the plane of the indentation is less than 20:1, preferably less than 10:1, particularly advantageously less than 1:1, further advantageously less than 0.5:1 and in particular less than 0.25:1.
In the case of embossed patterns in particular, it has proven to be advantageous that the ratio of average diameter of the indentation to the depth of the indentation is less than 20:1, preferably 10:1 to 1:10, in particular 8:1 to 1:1, specifically 6:1 to 4:1.
The portions according to the invention can have film sachets which have an embossed three-dimensional pattern on only one side, in particular only on the outside of the coating surface which is not in contact with the cosmetic preparation. However, it is advantageous for the film sachets to have an embossed three-dimensional structured pattern on both sides, i.e. for both the inside and the outside of the film sachet to bear this pattern.
Preferably, the portions according to the invention have film sachets whose average thickness is 10 to 100 μm, preferably 15 to 50 μm and in particular 20 to 40 μm. The chosen film sachet thicknesses contribute, particularly when the film sachets are water-soluble and/or water-dispersible films, to an optimum dissolution rate in water and additionally to good processing of the films. Thus, it has been found that, particularly in the range of an average film thickness between 10 and 100 μm, that thermal sealing, in particular liquid-tight sealing, can be carried out without problems. The film thickness can here relate to partial areas or advantageously to the entire coating material. The average film thickness refers to the cross section profile and was averaged over the raised areas and indentations along a profile section 1 cm in length. A section of film 1 square centimeter in size (1 cm×1 cm) of the coating material is divided into 5 equal strips (each 2 mm) and in each case the average film thickness is determined along the profile. The average value of the 5 measurements forms the average film thickness. The average film thickness along the cross section profile is determined using video light microscopy.
In an advantageous embodiment, the material of the water-soluble and/or water-dispersible film sachets of the portions according to the invention consists entirely or partially of a thermoplast chosen from the group comprising polyvinyl alcohol (PVA), acetalated polyvinyl alcohol, polyvinylpyrrolidone, polyethylene oxide, gelatin, cellulose, starch and derivatives of the abovementioned substances and/or mixtures of the abovementioned polymers, with polyvinyl alcohol being particularly advantageous.
The polyvinyl alcohols described above are commercially available, for example under the trade name Mowiol® (Clariant) Polyvinyl alcohols which are particularly suitable for the purposes of the present embodiment according to the invention are, for example, Mowiol® 3-83, Mowiol® 4-88, Mowiol® 5-88, Mowiol® 8-88 and Clariant L648.
Further polyvinyl alcohols suitable as material for the film sachet are ELVANOL® 51-05, 52-22, 50-42, 85-82, 75-15, T-25, T-66, 90-50 (trademark of Du Pont), ALCOTEX® 72.5, 78, B72, F80/40, F88/4, F88/26, F88/40, F88/47 (trademark of Harlow Chemical Co.), Gohsenol® NK-05, A-300, AH-22, C-500, GH-20, GL-03, GM-14L, KA-20, KA-500, KH-20, KP-06, N-300, NH-26, NM11Q, KZ-06 (trademark of Nippon Gohsei K.K.).
In a further advantageous embodiment, the film sachet material additionally has polymers chosen from the group comprising acrylic acid-containing polymers, polyacrylamides, oxazoline polymers, polystyrene sulfonates, polyurethanes, polyesters, polyethers and/or mixtures of the above polymers. It is advantageous if the coating material of the portion according to the invention constitutes a partially acetalated polyvinyl alcohol with a degree of hydrolysis of from 70 to 100 mol %, preferably 80 to 96 mol %, particularly advantageously 82 to 94 mol % and in particular 85 to 89 mol %. It is further advantageous that the water-soluble thermoplast used comprises a polyvinyl acetate whose average molecular weight is in the range from 10 000 to 100 000 gmol −1 , preferably from 11 000 to 90 000 gmol −1 , particularly advantageously from 12 000 to 80 000 gmol −1 , in particular from 13 000 to 70 000 gmol −1 and specifically from 20 000 to 40 000 gmol −1 . The average molecular weights were determined by means of gel permeation chromatography. Surprisingly, it has been found that the dissolution rate can be considerably improved through particular selection of the molecular weight.
In a further embodiment, the coating material comprises said thermoplasts in amounts of at least 50% by weight, preferably of at least 70% by weight, particularly advantageously of at least 80% by weight and in particular of at least 90% by weight, in each case based on the weight of the overall coating material.
In a further advantageous embodiment of the present invention, the portions according to the invention have an internal volume of from 5 to 500 cm 3 , preferably from 10 to 200 cm 3 , particularly advantageously from 20 to 100 cm 3 and in particular from 30 to 70 cm 3 . In the field of hair-treatment compositions in particular, portion sizes with an internal volume of from 30 to 70 cm 3 have proven particularly suitable since, on the one hand, they are easy for the end consumer to handle and, on the other hand, due to the limited internal volume, no problems as regards damage to the film sachet caused by the gravitational force of the cosmetic preparation arise.
The internal volume of the portion is the space in the portion which is able to accommodate the cosmetic preparation.
In a further embodiment of the present invention, the film sachet dissolves in water at 20° C. in less than 5 minutes, preferably less than 4 minutes and further advantageously less than 3 minutes and in particular between 2 and 0.5 minutes in water. The dissolution rate was determined by adding 0.07 g of coating material to a beaker containing 7 ml of water. During the dissolution phase, the water was stirred using a magnetic stirrer (60 rpm). The dissolution rate was determined by means of optical methods, starting from the point when the coating material was added to the stirred aqueous solution until complete dissolution (opacity measurement).
Individual doses are perceived by the consumer as being easy. The consumer takes the product in question, doses it and needs to think nothing more about measuring out suitable amounts. However, there may be situations where these supply forms are critical since adaptation of the dosage depending on the situation is no longer possible and thus, for example, one dosage unit is too little, but two units is too much. This problem can be solved by providing multichamber film sachets. The present embodiment according to the invention thus further provides a multichamber film sachet consisting of at least one portion according to the invention.
In a further advantageous embodiment, the multichamber film sachet consists of two or multicomponent individual portions which are joined together via ribs. Ribs here may also be common sealed areas of two adjacent portions.
In a further advantageous embodiment, the multichamber film sachets are such that they have two or three individual portions connected together which advantageously in each case have different cosmetic preparations. A multichamber system for the purposes of the present embodiment according to the invention can thus also be a system, for example, of two dye components (developer and coupler) which are located separately from one another in a multichamber film sachet. Advantageously, the multichamber film sachets according to the invention have two or more compartments in which preferably different cosmetic preparations, in particular hair colorant components, are located. Such multichamber film sachets further simplify dosing for the consumer since, in such a case, only a single packaging unit has to be dissolved in the corresponding use solution.
Cosmetic Preparations
The consistency of the cosmetic preparation which is surrounded by the water-soluble and/or water-dispersible coating is not subject to any particular requirements. Advantageously, the cosmetic preparations are in the form of powders, pastes, emulsions or gels.
The portions according to the invention have proven to be particularly advantageous in the field of hair-treatment compositions. In an advantageous embodiment, the cosmetic preparations are therefore hair-treatment compositions, in particular bleaching or hair colorants.
The water content of the cosmetic preparation is a critical value and should therefore preferably be below 20% by weight, preferably below 12% by weight, particularly advantageously below 8% by weight, further advantageously below 4% by weight, in particular below 2% by weight, in each case based on the total cosmetic preparation.
Bleaching Compositions:
In an advantageous embodiment, the portions according to the invention comprise one or more bleaching compositions as cosmetic preparation.
The principles of bleaching processes are known to the person skilled in the art and described comprehensively in relevant monographs, e.g. by K. Schrader, Grundlagen und Rezepturen der Kosmetika [Fundamentals and formulations of cosmetics], 2nd edition, 1989, Dr. Alfred Hüthig Verlag, Heidelberg, or W. Umbach (Ed.), Kosmetik [Cosmetics], 2nd edition, 1995, Georg Thieme Verlag, Stuttgart, N.Y.
For bleaching human hair—particularly for strand application—solid or paste-like preparations containing solid oxidizing agents are usually mixed directly prior to use with a dilute hydrogen peroxide solution. This mixture is then applied to the hair and rinsed out again after a certain contact time.
The specified preparations which are usually mixed prior to use with a hydrogen peroxide solution are termed below as “bleaching compositions”. All of the amounts listed refer, unless stated otherwise, exclusively to these preparations and are given in percentages by weight, based on the preparation.
Bleaching compositions usually comprise a solid peroxo compound. The choice of this peroxo compound is in principle not subject to limitations; customary peroxo compounds known to the person skilled in the art are, for example, ammonium peroxydisulfate, potassium peroxydisulfate, sodium peroxydisulfate, ammonium persulfate, potassium persulfate, sodium persulfate, potassium peroxydiphosphate, percarbonates, such as magnesium percarbonate, peroxides, such as barium peroxide, and perborates, urea peroxide and melamine peroxide. Among these peroxo compounds, which can also be used in combination, the inorganic compounds are advantageous according to the invention. The peroxydisulfates, in particular combinations of at least two peroxydisulfates, are particularly advantageous.
The peroxo compounds are present in the bleaching compositions advantageously in amounts of 20–80% by weight, in particular in amounts of 40–70% by weight, in each case based on the total bleaching composition.
The bleaching compositions advantageously comprise an alkalizing agent which serves to establish the alkaline pH of the application mixture. Use may be made of the customary alkalizing agents likewise known to the person skilled in the art for bleaching compositions, such as ammonium, alkali metal and alkaline earth metal hydroxides, carbonates, carbamates, hydrogencarbonates, hydroxycarbonates, silicates, in particular metasilicates, and also alkali metal phosphates. In an advantageous embodiment, the bleaching compositions comprise at least two different alkalizing agents. Here, mixtures of, for example, a metasilicate and a hydroxycarbonate may be advantageous.
The bleaching compositions comprise alkalizing agents advantageously in amounts of 10–30% by weight, in particular 15–25% by weight.
In addition, bleaching compositions can comprise amines and/or diamines, for example monoethanolamine, triethanolamine, and 2-amino-2-methyl-1-propanol.
Further amines are ethoxylated coconut amines and derivatives of soya amine, in particular PEG-3 cocamine and dihydroxyethyl soya amine dioleate.
In addition, it has proven advantageous if the bleaching compositions comprise nonionogenic interface-active substances. Here, those interface-active substances which have an HLB value of 5.0 and greater are advantageous. For the definition of the HLB value, reference is made expressly to the details in Hugo Janistyn, Handbuch der Kosmetika und Riechstoffe [Handbook of cosmetics and fragrances], volume III: Die Körperpflegemittel [Bodycare compositions], 2nd edition, Dr. Alfred Hüthig Verlag Heidelberg, 1973, pages 68–78 and Hugo Janistyn, Taschenbuch der modernen Parfümerie und Kosmetik [Pocket book of modern perfumery and cosmetics], 4th edition, Wissenschaftliche Verlagsgesellschaft m.b.H. Stuttgart, 1974, pages 466–474, and the original works cited therein.
Particularly advantageous nonionogenic surface-active substances here are, due to simple processability, substances which are commercially available in pure form as solids or liquids. The definition of purity refers in this connection not to chemically pure compounds. Instead, particularly when the products are natural-based products, it is possible to use mixtures of different homologs, for example with different alkyl chain lengths, as are obtained with products based on natural fats and oils. In the case of alkoxylated products too, mixtures of different degrees of alkoxylation are usually present. The term purity refers in this connection rather to the fact that the chosen substances should be free from solvents, extenders and other accompanying substances.
Advantageous nonionogenic interface-active substances are
alkoxylated fatty alcohols having 8 to 22, in particular 10 to 16, carbon atoms in the fatty alkyl group and 1 to 30, in particular 1 to 15, ethylene oxide and/or propylene oxide units. Preferred fatty alkyl groups are, for example, lauryl, myristyl, cetyl, but also stearyl, isostearyl and oleyl groups. Particularly preferred compounds of this class are, for example, lauryl alcohol having 2 to 4 ethylene oxide units, oleyl and cetyl alcohol having in each case 5 to 10 ethylene oxide units, cetyl and stearyl alcohol, and mixtures thereof having 10 to 30 ethylene oxide units, and the commercial product Aethoxal®B (Henkel), a lauryl alcohol having in each case 5 ethylene oxide and propylene oxide units. Besides the customary alkoxylated fatty alcohols, so-called “terminally capped” compounds can also be used according to the invention. In these compounds, the alkoxy group has no OH group at the end, but is “capped” in the form of an ether, in particular a C 1 –C 4 -alkyl ether. One example of such a compound is the commercial product Dehypon®LT 054, a C 12–18 -fatty alcohol+4.5 ethylene oxide butyl ether. alkoxylated fatty acids having 8 to 22, in particular 10 to 16, carbon atoms in the fatty acid group and 1 to 30, in particular 1 to 15, ethylene oxide and/or propylene oxide units. Preferred fatty acids are, for example, lauric acid, myristic acid, palmitic acid, stearic acid, isostearic acid and oleic acid. alkoxylated, preferably propoxylated and in particular ethoxylated, mono-, di- and triglycerides. Examples of preferred compounds are glycerol monolaurate+20 ethylene oxide and glycerol monostearate+20 ethylene oxide. polyglycerol esters and alkoxylated polyglycerol esters. Preferred compounds of this class are, for example, poly(3)glycerol diisostearate (commercial product: Lameform®TGI (Henkel)) and poly(2)glycerol polyhydroxystearate (commercial product: Dehymuls®PGPH (Henkel). sorbitan fatty acid esters and alkoxylated sorbitan fatty acid esters, such as, for example, sorbitan monolaurate and sorbitan monolaurate+20 ethylene oxide (EO). alkylphenols and alkylphenol alkoxides having 6 to 21, in particular 6 to 15, carbon atoms in the alkyl chain and 0 to 30 ethylene oxide and/or propylene oxide units. Preferred representatives of this class are, for example, nonylphenol+4 EO, nonylphenol+9 EO, octylphenol+3 EO and octylphenol+8 EO.
Particularly preferred classes of nonionogenic interface-active substances are the alkoxylated fatty alcohols, the alkoxylated fatty acids, and the alkylphenols and alkylphenol alkoxylates.
Compositions which have proven particularly advantageous are those which comprise nonionogenic interface-active substances in amounts of 0.5–10% by weight.
In addition, the bleaching compositions can comprise all active ingredients, additives and auxiliaries known in such preparations. In many cases, the colorants comprise at least one surfactant, with both anionic and also zwitterionic, ampholytic and cationic surfactants being suitable in principle. In many cases, however, it has proven to be advantageous to choose the surfactants from anionic, cationic or nonionic surfactants. Anionic surfactants may be very particularly preferred here.
Preferred anionic surfactants are alkyl sulfates, ether carboxylic acid salts having 10 to 18 carbon atoms in the alkyl group and up to 12 glycol ether groups in the molecule, such as C 12 H 25 —(C 2 H 4 O) 6 —CH 2 —COONa, and in particular salts of saturated and specifically unsaturated C 8 –C 22 -carboxylic acids, such as oleic acid, stearic acid, isostearic acid and palmitic acid.
These anionic surfactants should preferably be present in solid form, in particular powder form. Very particular preference here is given to soaps which are solid at room temperature, in particular sodium stearate. These are preferably present in amounts of from 5 to 20% by weight, in particular 10 to 15% by weight.
Suitable nonionic surfactants are, in particular, C 8 –C 22 -alkyl mono- and oligoglycosides and ethoxylated analogs thereof. In particular, the nonethoxylated compounds which are additionally commercially available in powder form have proven to be particularly suitable.
Examples of the cationic surfactants which can be used in the hair-treatment compositions are in particular quaternary ammonium compounds. Preference is given to ammonium halides, such as alkyltrimethylammonium chlorides, dialkyldimethylammonium chlorides and trialkylmethylammonium chlorides, e.g. cetyltrimethylammonium chloride, stearyltrimethylammonium chloride, distearyldimethylammonium chloride, lauryldimethylammonium chloride, lauryldimethylbenzylammonium chloride and tricetylmethylammonium chloride. Further cationic surfactants which can be used according to the invention are the quaternized protein hydrolyzates.
Alkylamidoamines, in particular fatty acid amidoamines, such as the stearylamidopropyldimethylamine obtainable under the name Tego Amid®S 18 are characterized specifically by their good biodegradability as well as a good conditioning effect.
Likewise of very good biodegradability are quaternary ester compounds, so-called ester quats, such as the distearoylethylhydroxyethylammonium methosulfate obtainable in a mixture with cetearyl alcohol under the name Dehyquart®F 75.
The compounds with alkyl groups used as surfactants may in each case be uniform substances. However, it is usually preferred to prepare these substances starting from natural vegetable or animal raw materials, thus leading to mixtures of substances with varying alkyl chain lengths which depend on the particular raw material.
Further active ingredients, auxiliaries and additives are, for example,
nonionic polymers, such as, for example, vinylpyrrolidone/vinyl acrylate copolymers, polyvinylpyrrolidone and vinylpyrrolidone/vinyl acetate copolymers and polysiloxanes, cationic polymers, such as quaternized cellulose ethers and other compounds which are stable as solid and commercially available, zwitterionic and amphoteric polymers which are stable as solids and are preferably obtainable as commercial products, anionic polymers, such as, for example, polyacrylic acids, crosslinked polyacrylic acids and vinyl acetate/crotonic acid copolymers provided these are stable as solids and are preferably available commercially, thickeners, such as agar agar, guar gum, alginates, xanthan gum, gum arabic, karaya gum, carob seed flour, linseed gums, dextrans, cellulose derivatives, e.g. methylcellulose, hydroxyalkylcellulose and carboxymethylcellulose, starch fractions and derivatives, such as amylose, amylopectin and dextrins, clays, such as, for example, bentonite or completely synthetic hydrocolloids, such as, for example, polyvinyl alcohol, structurants, such as glucose, maleic acid and lactic acid, hair-conditioning compounds, such as phospholipids, for example soya lecithin, egg lecithin and cephalins, and silicone oils protein hydrolyzates, in particular elastin, collagen, keratin, milk protein, soya protein and wheat protein hydrolyzates, their condensation products with fatty acids, and quaternized protein hydrolyzates, perfume oils, dimethyl isosorbide and cyclodextrins, dyes for coloring the preparations, active ingredients, such as panthenol, pantothenic acid, allantoin, pyrrolidonecarboxylic acids and salts thereof, cholesterol, fats and waxes, such as spermaceti, beeswax, montan wax, paraffins, fatty alcohols and fatty acid esters, fatty acid alkanolamides, complexing agents, such as EDTA, NTA and phosphonic acids, swelling and penetration auxiliaries, such as carbonates, hydrogencarbonates, guanidines, ureas, and primary, secondary and tertiary phosphates.
The person skilled in the art will choose these further substances according to the desired properties of the compositions.
The bleaching compositions can be prepared by the customary methods known to the person skilled in the art.
One method consists in initially introducing the inorganic components present as a solid, optionally after mixing, e.g. in a Drais mixer, and spraying them with the interface-active composition. This is preferably carried out at room temperature, i.e. at temperatures below about 30° C.; only if the chosen dust-binding components are not in the form of a liquid at these temperatures will elevated temperatures be used.
A further preparation method for the bleaching compositions is the grinding of all components in a ball mill, a ring-roller mill or, in particular, a spindle mill.
Finally, it is possible to prepare the pulverulent bleaching compositions by mixing all of the components and subsequently treating them, preferably at elevated temperatures, in a fluidized bed.
The bleaching compositions can be in liquid, gel-like, paste or powder form.
Preferred cosmetic preparations are bleaching compositions in powder form. It has been found that particularly bleaching powders which have an average particle size below 250 μm, preferably between 50 and 150 μm, are suitable for the portions according to the invention.
The particle sizes were measured using a Coulter counter. The portions according to the invention which comprise bleaching composition as cosmetic preparation are usually mixed directly prior to application with a hydrogen peroxide solution and dissolved in this.
The concentration of this hydrogen peroxide solution is on the one hand determined by the legal stipulations and on the other hand by the desired effect; as a rule 6 to 12 percent strength solutions in water are used. The quantitative ratios of bleaching composition and hydrogen peroxide solution here are usually in the range 1:1 to 1:2, with an excess of hydrogen peroxide solution being chosen particularly if a none too marked bleaching effect is desired.
Hair Colorants:
In a further embodiment, the portions according to the invention comprise hair colorants as cosmetic preparation. The hair colorants are preferably chosen from the group of temporary colorants, semipermanent colorants and permanent hair colorants, in particular chosen from the group of colorants with reactive carbonyl compounds (oxo colorants), oxidation colorants, specifically chosen from developer components or coupler components or the components A or B of an oxo colorant.
Temporary hair colorants are suitable for bringing about temporary colorations on keratin fibers.
For temporary colorations, use is usually made of colorants or tints which comprise so-called direct dyes as coloring component. These are dye molecules which attach directly to the hair and require no oxidative process for developing the color. These dyes include, for example, henna, which has been known since antiquity for coloring bodies and hair. These colorations are generally significantly more sensitive to shampooing than oxidative colorations, meaning that an often undesired nuance shift or even a visible “decoloring” then takes place very much more quickly.
Semipermanent hair colorants are characterized by more strongly marked and more permanent color nuances.
They are resistant to up to 5–6 hair washes. The dyes used must, accordingly, have a high affinity to the keratin and penetrate relatively deeply into the surface of the hair fiber. The most important representatives of this group of dyes are 2-nitro-1,4-phenylenediamine and nitroaniline derivatives. The likewise used so-called arianor dyes are azo or quinoneimine dyes with quaternary ammonium groups. The presence of glycol ethers, cyclohexanol or benzyl alcohol in the solvent system promotes the keratin affinity of the dyes.
Permanent hair colorants are widespread. The permanent hair coloration is largely resistant to the effects of light and weathering and to all customary hair-treatment methods and only needs to be renewed approximately monthly, due to hair regrowth.
The definitions of hair colorants are given in Römpp Lexikon Chemie [Römpp's chemistry lexicon], version 2.0, Stuttgart/New York: Georg Thieme Verlag 1999.
In a particularly preferred embodiment, the portions according to the invention comprise oxidation colorants. Oxidation colorants are usually used for permanent, intense colorations.
Such colorants usually comprise oxidation dye precursors, so-called developer components and coupler components. Under the influence of oxidizing agents or of atmospheric oxygen, the developer components form, with one another or with coupling with one or more coupler components, the actual dyes. For colorations with a natural effect, use is usually made of a mixture of a relatively large number of oxidation dye precursors; in many cases, direct dyes are also used for the nuancing.
The coloring preparation comprising the developer and coupler components and the oxidizing agent—in most cases a hydrogen peroxide preparation—are usually mixed together shortly prior to application. In a preferred embodiment of the present embodiment according to the invention, at least one coloring preparation or one oxidizing agent preparation is located in a portion according to the invention. Preferably, the portions are present separately alongside one another, i.e. as portion comprising colorant preparation, preferably coloring preparation comprising developer and/or coupler components, and as portion comprising oxidizing agent.
The oxidation colorant is particularly preferably present in a multichamber container in which there is, in at least one chamber, a coloring preparation, preferably coloring preparation comprising developer and/or coupler components, and, in at least one other chamber of the container, at least one oxidizing agent preparation.
Developer Component:
Suitable developer components are, for example, p-phenylenediamine derivatives or one of its physiologically compatible salts of the formula (E1)
where
G 1 is a hydrogen atom, a C 1 –C 4 -alkyl radical, a C 1 –C 3 -monohydroxyalkyl radical, a C 2 –C 6 -polyhydroxyalkyl radical, a (C 1 –C 4 )-alkoxy-(C 1 –C 4 )-alkyl radical, a 4-aminophenyl radical or a C 1 –C 4 -alkyl radical which is substituted by a nitrogen-containing group, a phenyl radical or a 4-aminophenyl radical; G 2 is a hydrogen atom, a C 1 –C 4 -alkyl radical, a C 1 –C 3 -monohydroxyalkyl radical, a C 2 –C 6 -polyhydroxyalkyl radical, a (C 1 –C 4 )-alkoxy-(C 1 –C 4 )-alkyl radical or a C 1 –C 4 -alkyl radical which is substituted by a nitrogen-containing group; G 3 is a hydrogen atom, a halogen atom, such as a chlorine, bromine, iodine or fluorine atom, a C 1 –C 4 -alkyl radical, a C 1 –C 4 -monohydroxyalkyl radical, a C 2 –C 6 -polyhydroxyalkyl radical, a C 1 –C 4 -hydroxyalkoxy radical, a C 1 –C 4 -acetylaminoalkoxy radical, a C 1 –C 4 -mesylaminoalkoxy radical or a C 1 –C 4 -carbamoylaminoalkoxy radical; G 4 is a hydrogen atom, a halogen atom or a C 1 –C 4 -alkyl radical or if G 3 and G 4 are in the ortho position relative to one another, they can together form a bridging α,ω-alkylenedioxo group, such as, for example, an ethylenedioxy group.
Examples of the C 1 –C 3 -alkyl radicals specified as substituents in the compounds according to the invention are the groups methyl, ethyl, propyl and isopropyl. Ethyl and methyl are generally preferred alkyl radicals. Advantageous C 1 –C 4 -alkoxy radicals are, for example, a methoxy or an ethoxy group. In addition, preferred examples of a C 1 –C 4 -monohydroxyalkyl group which may be mentioned are a hydroxymethyl group, a 2-hydroxyethyl group, a 3-hydroxypropyl group or a 4-hydroxybutyl group. A 2-hydroxyethyl group is particularly preferred. A particularly preferred C 2 –C 4 -polyhydroxyalkyl group is the 1,2-dihydroxyethyl group. Examples of halogen atoms according to the invention are F, Cl or Br atoms; Cl atoms are very particularly preferred. According to the invention, the other terms used are derived from the definitions given here. Examples of nitrogen-containing groups of the formula (E1) are, in particular, the amino groups, C 1 –C 4 -monoalkylamino groups, C 1 –C 4 -dialkylamino groups, C 1 –C 4 -trialkylammonium groups, C 1 –C 4 -monohydroxyalkylamino groups, imidazolinium and ammonium.
Particularly preferred p-phenylenediamines of the formula (E1) are chosen from p-phenylenediamine, p-tolylenediamine, 2-chloro-p-phenylenediamine, 2,3-dimethyl-p-phenylenediamine, 2,6-dimethyl-p-phenylenediamine, 2,6-diethyl-p-phenylenediamine, 2,5-dimethyl-p-phenylenediamine, N,N-dimethyl-p-phenylenediamine, N,N-diethyl-p-phenylenediamine, N,N-dipropyl-p-phenylenediamine, 4-amino-3-methyl-(N,N-diethyl)aniline, N,N-bis(β-hydroxyethyl)-p-phenylenediamine, 4-N,N-bis(β-hydroxyethyl)amino-2-methylaniline, 4-N,N-bis(β-hydroxyethyl)amino-2-chloroaniline, 2-(β-hydroxyethyl)-p-phenylenediamine, 2-(α,β-dihydroxyethyl)-p-phenylenediamine, 2-fluoro-p-phenylenediamine, 2-isopropyl-p-phenylenediamine, N-(β-hydroxypropyl)-p-phenylenediamine, 2-hydroxymethyl-p-phenylenediamine, N,N-dimethyl-3-methyl-p-phenylenediamine, N,N-(ethyl,β-hydroxyethyl)-p-phenylenediamine, N-(β,γ-dihydroxypropyl)-p-phenylenediamine, N-(4-aminophenyl)-p-phenylenediamine, N-phenyl-p-phenylenediamine, 2-(β-hydroxyethyloxy)-p-phenylenediamine, 2-(β-acetylaminoethyloxy)-p-phenylenediamine, N-(β-methoxyethyl)-p-phenylenediamine and 5,8-diaminobenzo-1,4-dioxane, and their physiologically compatible salts.
According to the invention, very particularly preferred p-phenylenediamine derivatives of the formula (E1) are p-phenylenediamine, p-tolylenediamine, 2-(β-hydroxyethyl)-p-phenylenediamine, 2-(α,β-dihydroxyethyl)-p-phenylenediamine and N,N-bis(β-hydroxyethyl)-p-phenylenediamine.
It may also be advantageous to use, as developer component, compounds which contain at least two aromatic nuclei which are substituted by amino and/or hydroxyl groups.
Among the binuclear developer components which can be used in the coloring compositions according to the embodiment of the invention, mention may be made in particular of the compounds which conform to the following formula (E2), and their physiologically compatible salts:
where:
Z 1 and Z 2 , independently of one another, are a hydroxyl or NH 2 radical which is optionally substituted by a C 1 –C 4 -alkyl radical, by a C 1 –C 4 -hydroxyalkyl radical and/or by a bridge Y or which is optionally part of a bridging ring system, the bridge Y is an alkylene group having 1 to 14 carbon atoms, such as, for example, a linear or branched alkylene chain or an alkylene ring which can be terminated or interrupted by one or more nitrogen-containing groups and/or one or more heteroatoms, such as oxygen, sulfur or nitrogen atoms, and may possibly be substituted by one or more hydroxyl or C 1 –C 8 -alkoxy radicals, or a direct bond, G 5 and G 6 , independently of one another, are a hydrogen or halogen atom, a C 1 –C 4 -alkyl radical, a C 1 –C 4 -monohydroxyalkyl radical, a C 2 –C 6 -polyhydroxyalkyl radical, a C 1 –C 4 -aminoalkyl radical or a direct bond to the bridge Y, G 7 , G 8 , G 9 , G 10 , G 11 and G 12 , independently of one another, are a hydrogen atom, a direct bond to the bridge Y or a C 1 –C 4 -alkyl radical,
with the provisos that
the compounds of the formula (E2) contain only one bridge Y per molecule and the compounds of the formula (E2) contain at least one amino group which carries at least one hydrogen atom.
According to the invention, the substituents used in formula (E2) are defined analogously to the above statements.
Preferred binuclear developer components of the formula (E2) are in particular: N,N′-bis(β-hydroxyethyl)-N,N′-bis(4-aminophenyl)-1,3-diaminopropan-2-ol, N,N′-bis(β-hydroxyethyl)-N,N′-bis(4-aminophenyl)ethylenediamine, N,N′-bis(4-amino-phenyl)tetramethylenediamine, N,N′-bis(β-hydroxyethyl)-N,N′-bis(4-aminophenyl)tetramethylenediamine, N,N′-bis(4-methyl-aminophenyl)tetramethylenediamine, N,N′-diethyl-N,N′-bis(4-amino-3-methylphenyl)ethylenediamine, bis(2-hydroxy-5-aminophenyl)methane, N,N′-bis(4-aminophenyl)-1,4-diazacycloheptane, N,N′-bis(2-hydroxy-5-aminobenzyl)piperazine, N-(4-aminophenyl)-p-phenylenediamine and 1,10-bis(2,5-diaminophenyl)-1,4,7,10-tetraoxadecane and their physiologically compatible salts.
Very particularly preferred binuclear developer components of the formula (E2) are N,N′-bis(β-hydroxyethyl)-N,N′-bis(4-aminophenyl)-1,3-diaminopropan-2-ol, bis(2-hydroxy-5-aminophenyl)methane, N,N′-bis(4-aminophenyl)-1,4-diazacycloheptane and 1,10-bis(2,5-diaminophenyl)-1,4,7,10-tetraoxadecane or one of their physiologically compatible salts.
In addition, it may be advantageous to use a p-aminophenol derivative or one of its physiologically compatible salts as developer component. Particular preference is given to p-aminophenol derivatives of the formula (E3)
where:
G 13 is a hydrogen atom, a halogen atom, a C 1 –C 4 -alkyl radical, a C 1 –C 4 -monohydroxyalkyl radical, a C 2 –C 6 -polyhydroxyalkyl radical, a (C 1 –C 4 )-alkoxy-(C 1 –C 4 )-alkyl radical, a C 1 –C 4 -aminoalkyl radical, a hydroxy-(C 1 –C 4 )-alkylamino radical, a C 1 –C 4 -hydroxyalkoxy radical, a C 1 –C 4 -hydroxyalkyl-(C 3 –C 4 )-aminoalkyl radical or a (di-C 1 –C 4 -alkylamino)-(C 1 –C 4 )-alkyl radical, and G 14 is a hydrogen or halogen atom, a C 1 –C 4 -alkyl radical, a C 1 –C 4 -monohydroxyalkyl radical, a C 2 –C 6 -polyhydroxyalkyl radical, a (C 1 –C 4 )-alkoxy-(C 1 –C 4 )-alkyl radical, a C 1 –C 4 -aminoalkyl radical or a C 1 –C 4 -cyanoalkyl radical, G 15 is is hydrogen, a C 1 –C 4 -alkyl radical, a C 1 –C 4 -monohydroxyalkyl radical, a C 2 –C 6 -polyhydroxyalkyl radical, a phenyl radical or a benzyl radical, and G 16 is hydrogen or a halogen atom.
According to the invention, the substituents used in formula (E3) are defined analogously to the above statements.
Preferred p-aminophenols of the formula (E3) are, in particular, p-aminophenol, N-methyl-p-aminophenol, 4-amino-3-methylphenol, 4-amino-3-fluorophenol, 2-hydroxymethylamino-4-aminophenol, 4-amino-3-hydroxymethylphenol, 4-amino-2-(β-hydroxyethoxy)phenol, 4-amino-2-methylphenol, 4-amino-2-hydroxymethylphenol, 4-amino-2-methoxymethylphenol, 4-amino-2-aminomethylphenol, 4-amino-2-(β-hydroxyethylaminomethyl)phenol, 4-amino-2-(α,β-dihydroxyethyl)phenol, 4-amino-2-fluorophenol, 4-amino-2-chlorophenol, 4-amino-2,6-dichlorophenol, 4-amino-2-(diethylaminomethyl)phenol and their physiologically compatible salts.
Very particularly preferred compounds of the formula (E3) are p-aminophenol, 4-amino-3-methylphenol, 4-amino-2-aminomethylphenol, 4-amino-2-(α,β-dihydroxyethyl)phenol and 4-amino-2-(diethylaminomethyl)phenol.
In addition, the developer component can be chosen from o-aminophenol and its derivatives, such as, for example, 2-amino-4-methylphenol, 2-amino-5-methylphenol or 2-amino-4-chlorophenol.
In addition, the developer component can be chosen from heterocyclic developer components, such as, for example, the pyridine, pyrimidine, pyrazole, pyrazolopyrimidine derivatives and their physiologically compatible salts.
Preferred pyridine derivatives are, in particular, the compounds which are described in the patents GB 1 026 978 and GB 1 153 196, such as 2,5-diaminopyridine, 2-(4-methoxyphenyl)amino-3-aminopyridine, 2,3-diamino-6-methoxypyridine, 2-(β-methoxyethyl)amino-3-amino-6-methoxypyridine and 3,4-diaminopyridine.
Preferred pyrimidine derivatives are, in particular, the compounds which are described in the German patent DE 2 359 399, the Japanese laid-open specification JP 02019576 A2 or in the laid-open specification WO 96/15765, such as 2,4,5,6-tetraamino-pyrimidine, 4-hydroxy-2,5,6-triaminopyrimidine, 2-hydroxy-4,5,6-triaminopyrimidine, 2-dimethylamino-4,5,6-triaminopyrimidine, 2,4-dihydroxy-5,6-diaminopyrimidine and 2,5,6-triaminopyrimidine.
Preferred pyrazole derivatives are, in particular, the compounds which are described in the patents DE 3 843 892, DE 4 133 957 and patent applications WO 94/08969, WO 94/08970, EP-740 931 and DE 195 43 988, such as 4,5-diamino-1-methylpyrazole, 4,5-diamino-1-(β-hydroxyethyl)pyrazole, 3,4-diaminopyrazole, 4,5-diamino-1-(4-chlorobenzyl)pyrazole, 4,5-diamino-1,3-dimethylpyrazole, 4,5-diamino-3-methyl-1-phenylpyrazole, 4,5-diamino-1-methyl-3-phenylpyrazole, 4-amino-1,3-dimethyl-5-hydrazinopyrazole, 1-benzyl-4,5-diamino-3-methylpyrazole, 4,5-diamino-3-tert-butyl-1-methylpyrazole, 4,5-diamino-1-tert-butyl-3-methylpyrazole, 4,5-diamino-1-(β-hydroxyethyl)-3-methylpyrazole, 4,5-diamino-1-ethyl-3-methylpyrazole, 4,5-diamino-1-ethyl-3-(4-methoxyphenyl)pyrazole, 4,5-diamino-1-ethyl-3-hydroxymethylpyrazole, 4,5-diamino-3-hydroxymethyl-1-methylpyrazole, 4,5-diamino-3-hydroxymethyl-1-isopropylpyrazole, 4,5-diamino-3-methyl-1-isopropylpyrazole, 4-amino-5-(□-aminoethyl)amino-1,3-dimethylpyrazole, 3,4,5-triaminopyrazole, 1-methyl-3,4,5-triaminopyrazole, 3,5-diamino-1-methyl-4-methylaminopyrazole and 3,5-diamino-4-(β-hydroxy-ethyl)amino-1-methylpyrazole.
Preferred pyrazolopyrimidine derivatives are, in particular, the derivatives of pyrazolo[1,5-a]pyrimidine of the following formula (E4) and its tautomeric forms if a tautomeric equilibrium exists:
where:
G 17 , G 18 , G 9 and G 20 , independently of each other, are a hydrogen atom, a C 1 –C 4 -alkyl radical, an aryl radical., a C 1 –C 4 -hydroxyalkyl radical, a C 2 –C 4 -polyhydroxyalkyl radical, a (C 1 –C 4 )-alkoxy-(C 1 –C 4 ) -alkyl radical, a C 1 –C 4 -aminoalkyl radical, which may be optionally protected by an acetyl ureido or a sulfonyl radical, a (C 1 –C 4 )-alkylamino-(C 1 –C 4 )-alkyl radical, a di[(C 1 –C 4 )-alkyl]-(C 1 –C 4 )-aminoalkyl radical, where the dialkyl radicals optionally form a carbon cycle or a heterocycle with 5 or 6 chain members, a C 1 –C 4 -hydroxyalkyl radical or a di (C 1 –C 4 )-[hydroxyalkyl]-(C 1 –C 4 )-aminoalkyl radical, the X radicals, independently of each other, are a hydrogen atom, a C 1 –C 4 -alkyl radical, an aryl radical, a C 1 –C 4 -hydroxyalkyl radical, a C 2 –C 4 -polyhydroxyalkyl radical, a C 1 –C 4 -aminoalkyl radical, a (C 1 –C 4 )-alkylamino-(C 1 –C 4 )-alkyl radical, a di [(C 1 –C 4 )alkyl]-(C 1 –C 4 )-aminoalkyl radical, where the dialkyl radicals optionally form a carbon cycle or a heterocycle with 5 or 6 chain members, a C 1 –C 4 -hydroxyalkyl or a di(C 1 –C 4 -hydroxyalkyl)aminoalkyl radical, an amino radical, a C 1 –C 4 -alkyl- or di(C 1 –C 4 -hydroxyalkyl)amino radical, a halogen atom, a carboxylic acid group or a sulfonic acid group, i has the value 0, 1, 2 or 3, p has the value 0 or 1, q has the value 0 or 1 and n has the value 0 or 1, with the proviso that the sum of p+q is not 0, if p+q is 2, n has the value 0, and the groups NG 17 G 18 and NG 19 G 20 occupy the positions (2,3); (5,6); (6,7); (3,5) or (3,7); if p+q is 1, n has the value 1, and the groups NG 17 G 18 (or NG 19 G 20 ) and the group OH occupy the positions (2,3); (5,6); (6,7); (3,5) or (3,7);
According to the invention, the substituents used in formula (E4) are defined analogously to the above statements.
If the pyrazolo[1,5-a]pyrimidine of the above formula (E4) contains a hydroxy group at one of positions 2, 5 or 7 of the ring system, a tautomeric equilibrium exists which is represented, for example, in the following scheme:
Among the pyrazolo[1,5-a]pyrimidines of the above formula (E4) mention may be made in particular of:
pyrazolo[1,5-a]pyrimidine-3,7-diamine; 2,5-dimethylpyrazolo[1,5-a]pyrimidine-3,7-diamine; pyrazolo[1,5-a]pyrimidine-3,5-diamine; 2,7-dimethylpyrazolo[1,5-a]pyrimidine-3,5-diamine; 3-aminopyrazolo[1,5-a]pyrimidin-7-ol; 3-aminopyrazolo[1,5-a]pyrimidin-5-ol; 2-(3-aminopyrazolo[1,5-a]pyrimidin-7-ylamino)ethanol; 2-(7-aminopyrazolo[1,5-a]pyrimidin-3-ylamino)ethanol; 2-[(3-aminopyrazolo[1,5-a]pyrimidin-7-yl)-(2-hydroxy-ethyl)amino]ethanol; 2-[(7-aminopyrazolo[1,5-a]pyrimidin-3-yl)-(2-hydroxy-ethyl)amino]ethanol; 5,6-dimethylpyrazolo[1,5-a]pyrimidine-3,7-diamine; 2,6-dimethylpyrazolo[1,5-a]pyrimidine-3,7-diamine; 3-amino-7-dimethylamino-2,5-dimethylpyrazolo-[1,5-a]pyrimidine;
and their physiologically compatible salts and their tautomeric forms if a tautomeric equilibrium is present.
The pyrazolo[1,5-a]pyrimidines of the above formula (E4) can be prepared as described in the literature by cyclization starting from an aminopyrazole or from hydrazine.
Coupler Components:
The portions according to the invention preferably comprise at least one coupler component. The coupler components used are generally m-phenylenediamine derivatives, naphthols, resorcinol and resorcinol derivatives, pyrazolones and m-aminophenol derivatives. Suitable coupler substances are, in particular, 1-naphthol, 1,5-, 2,7- and 1,7-dihydroxynaphthalene, 5-amino-2-methylphenol, m-aminophenol, resorcinol, resorcinol monomethyl ether, m-phenylenediamine, 1-phenyl-3-methylpyrazol-5-one, 2,4-dichloro-3-aminophenol, 1,3-bis(2,4-diaminophenoxy)-propane, 2-chlororesorcinol, 4-chlororesorcinol, 2-chloro-6-methyl-3-aminophenol, 2-amino-3-hydroxypyridine, 2-methylresorcinol, 5-methylresorcinol and 2-methyl-4-chloro-5-aminophenol.
Coupler components preferred according to the invention are
m-aminophenol and its derivatives, such as, for example, 5-amino-2-methylphenol, N-cyclopentyl-3-aminophenol, 3-amino-2-chloro-6-methylphenol, 2-hydroxy-4-aminophenoxyethanol, 2,6-dimethyl-3-aminophenol, 3-trifluoroacetylamino-2-chloro-6-methylphenol, 5-amino-4-chloro-2-methylphenol, 5-amino-4-methoxy-2-methylphenol, 5-(2-hydroxyethyl)amino-2-methylphenol, 3-(diethylamino)phenol, N-cyclopentyl-3-aminophenol, 1,3-dihydroxy-5-(methylamino)benzene, 3-ethylamino-4-methylphenol and 2,4-dichloro-3-aminophenol, o-aminophenol and derivatives thereof, m-diaminobenzene and derivatives thereof, such as, for example, 2,4-diaminophenoxyethanol, 1,3-bis (2,4-diaminophenoxy)propane, 1-methoxy-2-amino-4-(2-hydroxyethylamino)benzene, 1,3-bis(2,4-diaminophenyl)propane, 2,6-bis(2-hydroxyethylamino)-1-methylbenzene and 1-amino-3-bis(2-hydroxyethyl)aminobenzene, o-diaminobenzene and derivatives thereof, such as, for example, 3,4-diaminobenzoic acid and 2,3-diamino-1-methylbenzene, di- and trihydroxybenzene derivatives, such as, for example, resorcinol, resorcinol monomethyl ether, 2-methylresorcinol, 5-methylresorcinol, 2,5-dimethylresorcinol, 2-chlororesorcinol, 4-chlororesorcinol, pyrogallol and 1,2,4-trihydroxybenzene, pyridine derivatives, such as, for example, 2,6-di-hydroxypyridine, 2-amino-3-hydroxypyridine, 2-amino-5-chloro-3-hydroxypyridine, 3-amino-2-methylamino-6-methoxypyridine, 2,6-dihydroxy-3,4-dimethylpyridine, 2,6-dihydroxy-4-methylpyridine, 2,6-diaminopyridine, 2,3-diamino-6-methoxypyridine and 3,5-diamino-2,6-dimethoxypyridine, naphthalene derivatives, such as, for example, 1-naphthol, 2-methyl-1-naphthol, 2-hydroxymethyl-1-naphthol, 2-hydroxyethyl-1-naphthol, 1,5-dihydroxynaphthalene, 1,6-dihydroxynaphthalene, 1,7-dihydroxynaphthalene, 1,8-dihydroxynaphthalene, 2,7-dihydroxynaphthalene and 2,3-dihydroxynaphthalene, morpholine derivatives, such as, for example, 6-hydroxybenzomorpholine and 6-aminobenzomorpholine, quinoxaline derivatives, such as, for example, 6-methyl-1,2,3,4-tetrahydroquinoxaline, pyrazole derivatives, such as, for example, 1-phenyl-3-methylpyrazol-5-one, indole derivatives, such as, for example, 4-hydroxyindole, 6-hydroxyindole and 7-hydroxyindole, pyrimidine derivatives, such as, for example, 4,6-diaminopyrimidine, 4-amino-2,6-dihydroxypyrimidine, 2,4-diamino-6-hydroxypyrimidine, 2,4,6-trihydroxypyrimidine, 2-amino-4-methylpyrimidine, 2-amino-4-hydroxy-6-methylpyrimidine, and 4,6-dihydroxy-2-methylpyrimidine, or methylenedioxybenzene derivatives, such as, for example, 1-hydroxy-3,4-methylenedioxybenzene, 1-amino-3,4-methylenedioxybenzene and 1-(2-hydroxyethyl)amino-3,4-methylenedioxybenzene.
Coupler components which are particularly preferred according to the invention are 1-naphthol, 1,5-, 2,7- and 1,7-dihydroxynaphthalene, 3-aminophenol, 5-amino-2-methylphenol, 2-amino-3-hydroxypyridine, resorcinol, 4-chlororesorcinol, 2-chloro-6-methyl-3-aminophenol, 2-methylresorcinol, 5-methylresorcinol, 2,5-dimethylresorcinol and 2,6-dihydroxy-3,4-dimethylpyridine.
In a further preferred embodiment, the portions according to the invention comprise nature-analogous hair dye precursors. Dyeing with nature-analogous dyes has been given a lot of attention.
In this method, precursors of the natural hair dye melanine are applied to the hair; these then form nature-analogous dyes in the course of oxidative processes within the hair. Such a method with 5,6-dihydroxyindoline as dye precursor has been described in EP-B1-530 229. In the case of, in particular multiple, application of compositions comprising 5,6-dihydroxyindoline, it is possible to restore the natural hair color in people with gray hair. The coloration can take place here with atmospheric oxygen as the sole oxidizing agent, meaning that it is not necessary to have recourse to further oxidizing agents. In people with originally medium-blond to brown hair, the indoline can be used as the sole dye precursor. For use with people with originally red and, in particular, dark to black hair color, by contrast, satisfactory results can often only be achieved through the co-use of further dye components, in particular special oxidation dye precursors. The precursors of nature-analogous dyes used are preferably those indoles and indolines which have at least one hydroxy or amino group, preferably as substituent on the 6-membered ring. These groups can carry further substituents, e.g. in the form of an etherification or esterification of the hydroxy group or an alkylation of the amino group. In a second preferred embodiment, the colorants comprise at least one indole and/or indoline derivative.
Particularly suitable precursors of nature-analogous hair dyes are derivatives of 5,6-dihydroxyindoline of the formula (VIIa),
in which, independently of one another,
R 1 is hydrogen, a C 1 –C 4 -alkyl group or a C 1 –C 4 -hydroxyalkyl group, R 2 is hydrogen or a —COOH group, where the —COOH group can also be present as a salt with a physiologically compatible cation, R 3 is hydrogen or a C 1 –C 4 -alkyl group, R 4 is hydrogen, a C 1 –C 4 -alkyl group or a group —CO—R 6 in which R 6 is a C 1 –C 4 -alkyl group, and R 5 is one of the groups specified under R 4 ,
and physiologically compatible salts of these compounds with an organic or inorganic acid.
Particularly preferred derivatives of indoline are 5,6-dihydroxyindoline, N-methyl-5,6-dihydroxyindoline, N-ethyl-5,6-dihydroxyindoline, N-propyl-5,6-dihydroxyindoline, N-butyl-5,6-dihydroxyindoline, 5,6-dihydroxyindoline-2-carboxylic acid, and 6-hydroxyindoline, 6-aminoindoline and 4-aminoindoline.
Within this group, particular emphasis is given to N-methyl-5,6-dihydroxyindoline, N-ethyl-5,6-dihydroxyindoline, N-propyl-5,6-dihydroxyindoline, N-butyl-5,6-dihydroxyindoline and in particular 5,6-dihydroxyindoline.
Exceptionally suitable precursors of nature-analogous hair dyes are also derivatives of 5,6-dihydroxyindole of the formula (VIIb),
in which, independently of one another,
R 1 is hydrogen, a C 1 –C 4 -alkyl group or a C 1 –C 4 -hydroxyalkyl group, R 2 is hydrogen or a —COOH group, where the —COOH group can also be present as a salt with a physiologically compatible cation, R 3 is hydrogen or a C 1 –C 4 -alkyl group, R 4 is hydrogen, a C 1 –C 4 -alkyl group or a group —CO—R 6 in which R 6 is a C 1 –C 4 -alkyl group, and R 5 is one of the groups specified under R 4 ,
and physiologically compatible salts of these compounds with an organic or inorganic acid.
Particularly preferred derivatives of indole are 5,6-dihydroxyindole, N-methyl-5,6-dihydroxyindole, N-ethyl-5,6-dihydroxyindole, N-propyl-5,6-dihydroxyindole, N-butyl-5,6-dihydroxyindole, 5,6-dihydroxyindole-2-carboxylic acid, 6-hydroxyindole, 6-aminoindole and 4-aminoindole.
Within this group, emphasis is placed on N-methyl-5,6-dihydroxyindole, N-ethyl-5,6-dihydroxyindole, N-propyl-5,6-dihydroxyindole, N-butyl-5,6-dihydroxyindole and in particular 5,6-dihydroxyindole.
The indoline and indole derivatives can be used in the colorants used within the scope of the method according to the invention either as free bases or in the form of their physiologically compatible salts with inorganic or organic acids, e.g. hydrochlorides, sulfates and hydrobromides. The indole or indoline derivatives are present in these usually in amounts of 0.05–10% by weight, preferably 0.2–5% by weight.
In a further embodiment, it may be advantageous to use the indoline or indole derivative in hair colorants in combination with at least one amino acid or an oligopeptide. The amino acid is advantageously an α-amino acid; very particularly preferred α-amino acids are arginine, ornithine, lysine, serine and histidine, in particular arginine.
Direct Dyes:
In a further embodiment, the portions according to the invention additionally or individually comprise at least one direct dye. Direct dyes often serve to nuance the hair colors and are therefore advantageously added to permanent hair dyes, such as, for example, the abovementioned developer components, coupler components, nature-analogous hair dye precursors or to the components of oxo colorants.
Direct dyes are usually nitrophenylenediamines, nitroaminophenols, azo dyes, anthraquinones or indophenols. Preferred direct dyes are the compounds known under the international names or trade names HC Yellow 2, HC Yellow 4, HC Yellow 5, HC Yellow 6, HC Yellow 12, HC Orange 1, Disperse Orange 3, HC Red 1, HC Red 3, HC Red 10, HC Red 11, HC Red 13, HC Red BN, HC Blue 2, HC Blue 12, Disperse Blue 3, HC Violet 1, Disperse Violet 1, Disperse Violet 4, Acid Violet 43, Disperse Black 9 and Acid Black 52, and also 1,4-diamino-2-nitrobenzene, 2-amino-4-nitrophenol, 1,4-bis(β-hydroxyethyl)amino-2-nitrobenzene, 3-nitro-4-(β-hydroxyethyl)aminophenol, 2-(2′-hydroxyethyl)amino-4,6-dinitrophenol, 1-(2′-hydroxyethyl)amino-4-methyl-2-nitrobenzene, 1-amino-4-(2′-hydroxyethyl)amino-5-chloro-2-nitrobenzene, 4-amino-3-nitrophenol, 1-(2′-ureido-ethyl)amino-4-nitrobenzene, 4-amino-2-nitrodiphenylamine-2′-carboxylic acid, 6-nitro-1,2,3,4-tetrahydroquinoxaline, 2-hydroxy-1,4-naphthoquinone, picramic acid and salts thereof, 2-amino-6-chloro-4-nitrophenol, 4-ethylamino-3-nitrobenzoic acid and 2-chloro-6-ethylamino-1-hydroxy-4-nitrobenzene.
In addition, the compositions according to the invention can comprise a cationic direct dye. In this connection, particular preference is given to
(a) cationic triphenylmethane dyes, such as, for example, Basic Blue 7, Basic Blue 26, Basic Violet 2 and Basic Violet 14, (b) aromatic systems which are substituted by a quaternary nitrogen group, such as, for example, Basic Yellow 57, Basic Red 76, Basic Blue 99, Basic Brown 16 and Basic Brown 17, and (c) direct dyes which contain a heterocycle which has at least one quaternary nitrogen atom, as are specified, for example, in EP-A2-998 908, to which reference is explicitly made at this point.
Preferred cationic direct dyes of group (c) are, in particular, the following compounds:
The compounds of the formulae (DZ1), (DZ3) and (DZ5) are very particularly preferred cationic direct dyes of group (c). The cationic direct dyes which are sold under the trade name Arianor® are advantageous direct dyes.
In a further embodiment, the portions according to the invention additionally comprise naturally occurring dyes, as are present, for example, in henna red, henna neutral, henna black, camomile blossom, sandalwood, black tea, buckthorn bark, sage, logwood, madder root, catechu, sedre and alkanna root.
Oxo Coloring:
In a particularly preferred embodiment, the portions according to the invention comprise components (component A or B) which are used for the oxo coloring.
Oxo colorants offer the possibility of coloring keratin-containing fibers by means of using a combination of
component A) compounds which contain a reactive carbonyl group with component B): compounds chosen from (a) CH-acidic compounds, (b) compounds with a primary or secondary amino group or hydroxy group, chosen from primary or secondary aromatic amines, nitrogen-containing heterocyclic compounds and aromatic hydroxy compounds, (c) amino acids, (d) oligopeptides constructed from 2 to 9 amino acids.
The corresponding coloring method (called oxo coloring below) is described, for example, in the publications WO-A1-99/18916, WO-A1-00/38638, WO-A1-01/34106 and WO-A1-01/47483. Some of the resulting colorations have color fastnesses on the keratin-containing fibers which are comparable with those of oxidation coloring. The nuance spectrum which can be achieved with the gentle oxo coloring is very broad and the coloration obtained often has an acceptable brilliance and color depth. The abovementioned components A and B, referred to below as oxo dye precursors, are generally themselves not dyes, and are therefore, each taken by itself, unsuitable for coloring keratin-containing fibers on their own. In combination, they form dyes in a nonoxidative process. Among compounds of component B, however, it is also possible to use corresponding oxidation dye precursors of the developer type and/or coupler type with or without the use of an oxidizing agent. The method of oxo coloring can thus be directly combined with the oxidative coloring system.
In the course of the oxo coloring, reactive carbonyl compounds are used as component A, which forms the actual dye within the hair, in particular following reaction with a component B. Preferred reactive carbonyl compounds are aldehydes and ketones in which the reactive carbonyl group is present either as carbonyl group or derivatized or masked in such a way that the reactivity of the carbon atom of the derivatized carbonyl group toward the compounds of component B is always present. These derivatives are preferably addition compounds
a) of amines and derivatives thereof with the formation of imines or oximes as addition compound b) of alcohols with the formation of acetals or ketals as addition compound c) of water with the formation of hydrates as addition compound (component A is derived in this case c) from an aldehyde ab) onto the carbon atom of the carbonyl group of the reactive carbonyl compound.
Component A is preferably chosen from compounds according to formula (Ox1),
where
AR is benzene, naphthalene, pyridine, pyrimidine, pyrazine, pyridazine, carbazole, pyrrole, pyrazole, furan, thiophene, 1,2,3-triazine, 1,3,5-triazine, quinoline, isoquinoline, indole, indoline, indolizine, indane, imidazole, 1,2,4-triazole, 1,2,3-triazole, tetrazole, benzimidazole, 1,3-thiazole, benzothiazole, indazole, benzoxazole, quinoxaline, quinazoline, quinolizine, cinnoline, acridine, julolidine, acenaphthene, fluorene, biphenyl, diphenylmethane, benzophenone, diphenyl ether, azobenzene, chromone, coumarin, diphenylamine, stilbene, where the N-heteroaromatics can also be quaternized, R 3 is a hydrogen atom, a C 1 –C 6 -alkyl group, C 2 –C 6 -acyl group, C 2 –C 6 -alkenyl group, C 1 –C 4 -perfluoroalkyl group, an optionally substituted aryl group or heteroaryl group, R 4 , R 5 and R 6 , independently of one another, are a hydrogen atom, a halogen atom, a C 1 –C 6 -alkyl group, C 1 –C 6 -alkoxy group, C 1 –C 6 -aminoalkyl group, C 1 –C 6 -hydroxyalkyl group, a C 1 –C 6 -alkoxy-C 1 –C 6 -alkyloxy group, a C 2 –C 6 -acyl group, an acetyl group, carboxyl group, carboxylato group, carbamoyl group, sulfo group, sulfato group, sulfonamide group, sulfonamido group, C 2 –C 6 -alkenyl group, an aryl group, an aryl-C 1 –C 6 -alkyl group, a hydroxy group, a nitro group, a pyrrolidino group, a morpholino group, a piperidino group, an amino group and ammonio group or a 1-imidazol(in)io group, where the last three groups may be substituted by one or more C 1 –C 6 -alkyl groups, C 1 –C 6 -carboxyalkyl groups, C 1 –C 6 -hydroxyalkyl groups, C 2 –C 6 -alkenyl groups, C 1 –C 6 -alkoxy-C 1 –C 6 -alkyl groups, with optionally substituted benzyl groups, by sulfo-(C 1 –C 4 )-alkyl or heterocycle-(C 1 –C 4 )-alkyl groups,
where also two of the radicals from R 4 , R 5 , R 6 and -Z-Y—R 3 , together with the radical molecule, can form a fused-on optionally substituted 5-, 6- or 7-membered ring, which can likewise carry a fused-on aromatic ring, where the system AR can, depending on the size of the ring, carry further substituents which, independently of one another, can be the same groups as R 4 , R 5 and R 6 ,
Z is a direct bond, a carbonyl group, a carboxy-(C 1 –C 4 )-alkylene group, an optionally substituted C 2 –C 6 -alkenylene group, C 4 –C 6 -alkadienylene group, furylene group, thienylene group, arylene group, vinylenearylene group, vinylenefurylene group, vinylenethienylene group, where Z, together with the —Y—R 3 group, can also form an optionally substituted 5-, 6- or 7-membered ring, Y is a group which is chosen from carbonyl, a group according to formula (Ox2) and a group according to formula (Ox3)
where
R 7 is a hydrogen atom, a hydroxy group, a C 1 –C 4 -alkoxy group, a C 1 –C 6 -alkyl group, a C 1 –C 6 -hydroxyalkyl group, a C 2 –C 6 -polyhydroxyalkyl group, a C 1 –C 6 -alkoxy-C 1 –C 6 -alkyl group, R 8 and R 9 , independently of one another, are a hydrogen atom, a C 1 –C 6 -alkyl group, an aryl group or jointly, together with the structural element O—C—O of the formula (Ox3), form a 5- or 6-membered ring.
Component A is particularly preferably chosen from the group consisting of acetophenone, propiophenone, 2-hydroxyacetophenone, 3-hydroxyacetophenone, 4-hydroxyacetophenone, 2-hydroxypropiophenone, 3-hydroxypropiophenone, 4-hydroxypropiophenone, 2-hydroxy-butyrophenone, 3-hydroxybutyrophenone, 4-hydroxybutyrophenone, 2,4-dihydroxyacetophenone, 2,5-dihydroxyacetophenone, 2,6-dihydroxyacetophenone, 2,3,4-trihydroxyacetophenone, 3,4,5-trihydroxyacetophenone, 2,4,6-trihydroxyacetophenone, 2,4,6-trimethoxyacetophenone, 3,4,5-trimethoxyacetophenone, 3,4,5-trimethoxyacetophenone diethyl ketal, 4-hydroxy-3-methoxyacetophenone, 3,5-dimethoxy-4-hydroxyacetophenone, 4-aminoacetophenone, 4-dimethylaminoacetophenone, 4-morpholinoacetophenone, 4-piperidinoacetophenone, 4-imidazolinoacetophenone, 2-hydroxy-5-bromoacetophenone, 4-hydroxy-3-nitroacetophenone, acetophenone-2-carboxylic acid, acetophenone-4-carboxylic acid, benzophenone, 4-hydroxybenzophenone, 2-aminobenzophenone, 4,4′-dihydroxybenzophenone, 2,4-dihydroxybenzophenone, 2,4,4′-trihydroxybenzophenone, 2,3,4-trihydroxybenzophenone, 2-hydroxy-1-acetonaphthone, 1-hydroxy-2-acetonaphthone, chromone, chromone-2-carboxylic acid, flavone, 3-hydroxyflavone, 3,5,7-trihydroxyflavone, 4,5,7-trihydroxyflavone, 5,6,7-trihydroxyflavone, quercetin, 1-indanone, 9-fluorenone, 3-hydroxyfluorenone, anthrone, 1,8-dihydroxyanthrone, vanillin, coniferyl aldehyde, 2-methoxybenzaldehyde, 3-methoxybenzaldehyde, 4-methoxybenzaldehyde, 2-ethoxy-benzaldehyde, 3-ethoxybenzaldehyde, 4-ethoxybenzaldehyde, 4-hydroxy-2,3-dimethoxybenzaldehyde, 4-hydroxy-2,5-dimethoxybenzaldehyde, 4-hydroxy-2,6-dimethoxybenzaldehyde, 4-hydroxy-2-methylbenzaldehyde, 4-hydroxy-3-methylbenzaldehyde, 4-hydroxy-2,3-dimethylbenzaldehyde, 4-hydroxy-2,5-dimethylbenzaldehyde, 4-hydroxy-2,6-dimethylbenzaldehyde, 4-hydroxy-3,5-dimethoxybenzaldehyde, 4-hydroxy-3,5-dimethylbenzaldehyde, 3,5-diethoxy-4-hydroxybenzaldehyde, 2,6-diethoxy-4-hydroxybenzaldehyde, 3-hydroxy-4-methoxybenzaldehyde, 2-hydroxy-4-methoxybenzaldehyde, 2-ethoxy-4-hydroxybenzaldehyde, 3-ethoxy-4-hydroxybenzaldehyde, 4-ethoxy-2-hydroxybenzaldehyde, 4-ethoxy-3-hydroxybenzaldehyde, 2,3-dimethoxybenzaldehyde, 2,4-dimethoxybenzaldehyde, 2,5-dimethoxybenzaldehyde, 2,6-dimethoxybenzaldehyde, 3,4-dimethoxybenzaldehyde, 3,5-dimethoxybenzaldehyde, 2,3,4-trimethoxybenzaldehyde, 2,3,5-trimethoxybenzaldehyde, 2,3,6-trimethoxybenzaldehyde, 2,4,6-tri-methoxybenzaldehyde, 2,4,5-trimethoxybenzaldehyde, 2,5,6-trimethoxybenzaldehyde, 2-hydroxybenzaldehyde, 3-hydroxybenzaldehyde, 4-hydroxybenzaldehyde, 2,3-dihydroxybenzaldehyde, 2,4-dihydroxybenzaldehyde, 2,4-dihydroxy-3-methylbenzaldehyde, 2,4-dihydroxy-5-methylbenzaldehyde, 2,4-dihydroxy-6-methylbenzaldehyde, 2,4-dihydroxy-3-methoxybenzaldehyde, 2,4-dihydroxy-5-methoxybenzaldehyde, 2,4-dihydroxy-6-methoxybenzaldehyde, 2,5-dihydroxybenzaldehyde, 2,6-dihydroxybenzaldehyde, 3,4-dihydroxybenzaldehyde, 3,4-dihydroxy-2-methylbenzaldehyde, 3,4-dihydroxy-5-methylbenzaldehyde, 3,4-dihydroxy-6-methylbenzaldehyde, 3,4-dihydroxy-2-methoxybenzaldehyde, 3,4-dihydroxy-5-methoxybenzaldehyde, 3,5-dihydroxybenzaldehyde, 2,3,4-trihydroxybenzaldehyde, 2,3,5-trihydroxybenzaldehyde, 2,3,6-trihydroxybenzaldehyde, 2,4,6-trihydroxybenzaldehyde, 2,4,5-trihydroxybenzaldehyde, 3,4,5-trihydroxybenzaldehyde, 2,5,6-trihydroxybenzaldehyde, 4-hydroxy-2-methoxybenzaldehyde, 4-dimethylaminobenzaldehyde, 4-diethylaminobenzaldehyde, 4-dimethylamino-2-hydroxybenzaldehyde, 4-diethylamino-2-hydroxybenzaldehyde, 4-pyrrolidinobenzaldehyde, 4-morpholinobenzaldehyde, 2-morpholinobenzaldehyde, 4-piperidinobenzaldehyde, 2-methoxy-1-naphthaldehyde, 4-methoxy-1-naphthaldehyde, 2-hydroxy-1-naphthaldehyde, 2,4-dihydroxy-1-naphthaldehyde, 4-hydroxy-3-methoxy-1-naphthaldehyde, 2-hydroxy-4-methoxy-1-naphthaldehyde, 3-hydroxy-4-methoxy-1-naphthaldehyde, 2,4-dimethoxy-1-naphthaldehyde, 3,4-dimethoxy-1-naphthaldehyde, 4-hydroxy-1-naphthaldehyde, 4-dimethylamino-1-naphthaldehyde, 4-dimethylaminocinnamaldehyde, 2-dimethylaminobenzaldehyde, 2-chloro-4-dimethylaminobenzaldehyde, 4-dimethylamino-2-methylbenzaldehyde, 4-diethylaminocinnamaldehyde, 4-dibutylaminobenzaldehyde, 4-diphenylaminobenzaldehyde, 4-dimethylamino-2-methoxybenzaldehyde, 4-(1-imidazolyl)benzaldehyde, piperonal, 2,3,6,7-tetrahydro-1H,5H-benzo[ij]quinolizine-9-carboxaldehyde, 2,3,6,7-tetrahydro-8-hydroxy-1H,5H-benzo[ij]quinolizine-9-carboxaldehyde, N-ethylcarbazole-3-aldehyde, 2-formylmethylene-1,3,3-trimethylindoline (Fischers aldehyde or tribase aldehyde), 2-indolealdehyde, 3-indolealdehyde, 1-methylindole-3-aldehyde, 2-methylindole-3-aldehyde, 1-acetylindole-3-aldehyde, 3-acetylindole, 1-methyl-3-acetylindole, 2-(1′,3′,3′-trimethyl-2-indolinylidene)acetaldehyde, 1-methylpyrrole-2-aldehyde, 1-methyl-2-acetylpyrrole, 4-pyridinealdehyde, 2-pyridinealdehyde, 3-pyridinealdehyde, 4-acetylpyridine, 2-acetylpyridine, 3-acetylpyridine, pyridoxal, quinoline-3-aldehyde, quinoline-4-aldehyde, antipyrine-4-aldehyde, furfural, 5-nitrofurfural, 2-theonyltrifluoroacetone, chromone-3-aldehyde, 3-(5′-nitro-2′-furyl)acrolein, 3-(2′-furyl)acrolein and imidazole-2-aldehyde, 1,3-diacetylbenzene, 1,4-diacetylbenzene, 1,3,5-triacetyl-benzene, 2-benzoylacetophenone, 2-(4′-methoxybenzoyl)acetophenone, 2-(2′-furoyl)acetophenone, 2-(2′-pyridoyl)acetophenone and 2-(3′-pyridoyl)acetophenone, benzylidene acetone, 4-hydroxybenzylidene acetone, 2-hydroxybenzylidene acetone, 4-methoxybenzylidene acetone, 4-hydroxy-3-methoxybenzylidene acetone, 4-dimethylaminobenzylidene acetone, 3,4′-methylenedioxybenzylidene acetone, 4-pyrrolidinobenzylidene acetone, 4-piperidinobenzylidene acetone, 4-morpholinobenzylidene acetone, 4-diethylaminobenzylidene acetone, 3-benzylidene-2,4-pentanedione, 3-(4′-hydroxy-benzylidene)-2,4-pentanedione, 3-(4′-dimethylaminobenzylidene)-2,4-pentanedione, 2-benzylidenecyclohexanone, 2-(4′-hydroxybenzylidene)cyclohexanone, 2-(4′-di-methylaminobenzylidene)cyclohexanone, 2-benzylidene-1,3-cyclohexanedione, 2-(4′-hydroxybenzylidene)-1,3-cyclohexanedione, 3-(4′-dimethylaminobenzylidene)-1,3-cyclohexanedione, 2-benzylidene-5,5-dimethyl-1,3-cyclohexanedione, 2-(4′-hydroxybenzylidene)-5,5-dimethyl-1,3-cyclohexanedione, 2-(4′-hydroxy-3-methoxybenzylidene)-5,5-dimethyl-1,3-cyclohexanedione, 2-(4′-dimethylaminobenzylidene)-5,5-dimethyl-1,3-cyclohexanedione, 2-benzylidenecyclopentanone, 2′-(4-hydroxybenzylidene)cyclopentanone, 2-(4′-dimethylaminobenzylidene)cyclopentanone, 5-(4-di-methylaminophenyl)penta-2,4-dienal, 5-(4-diethylamino-phenyl)penta-2,4-dienal, 5-(4-methoxyphenyl)penta-2,4-dienal, 5-(3,4-dimethoxyphenyl)penta-2,4-dienal, 5-(2,4-dimethoxyphenyl)penta-2,4-dienal, 5-(4-piperidinophenyl)penta-2,4-dienal, 5-(4-morpholinophenyl)penta-2,4-dienal, 5-(4-pyrrolidinophenyl)penta-2,4-dienal, 6-(4-dimethylaminophenyl)hexa-3,5-dien-2-one, 6-(4-diethyl-aminophenyl)hexa-3,5-dien-2-one, 6-(4-methoxyphenyl)hexa-3,5-dien-2-one, 6-(3,4-dimethoxyphenyl)hexa-3,5-dien-2-one, 6-(2,4-dimethoxyphenyl)hexa-3,5-dien-2-one, 6-(4-piperidinophenyl)hexa-3,5-dien-2-one, 6-(4-morpholinophenyl)hexa-3,5-dien-2-one, 6-(4-pyrrolidinophenyl)hexa-3,5-dien-2-one, 5-(4-dimethylamino-1-naphthyl)penta-3,5-dienal, 2-nitro-benzaldehyde, 3-nitrobenzaldehyde, 4-nitrobenzaldehyde, 4-methyl-3-nitrobenzaldehyde, 3-hydroxy-4-nitrobenzaldehyde, 4-hydroxy-3-nitrobenzaldehyde, 5-hydroxy-2-nitrobenzaldehyde, 2-hydroxy-5-nitrobenzaldehyde, 2-hydroxy-3-nitrobenzaldehyde, 2-fluoro-3-nitrobenzaldehyde, 3-methoxy-2-nitrobenzaldehyde, 4-chloro-3-nitrobenzaldehyde, 2-chloro-6-nitrobenzaldehyde, 5-chloro-2-nitrobenzaldehyde, 4-chloro-2-nitrobenzaldehyde, 2,4-dinitrobenzaldehyde, 2,6-dinitrobenzaldehyde, 2-hydroxy-3-methoxy-5-nitrobenzaldehyde, 4,5-dimethoxy-2-nitrobenzaldehyde, 6-nitropiperonal, 2-nitropiperonal, 5-nitrovanillin, 2,5-dinitrosalicylaldehyde, 5-bromo-2-nitrosalicylaldehyde, 3-nitro-4-formylbenzenesulfonic acid, 4-nitro-1-naphthaldehyde, 2-nitrocinnamaldehyde, 3-nitrocinnamaldehyde, 4-nitrocinnamaldehyde, 9-methyl-3-carbazolealdehyde, 9-ethyl-3-carbazolealdehyde, 3-acetylcarbazole, 3,6-diacetyl-9-ethylcarbazole, 3-acetyl-9-methylcarbazole, 1,4-dimethyl-3-carbazolealdehyde, 1,4,9-trimethyl-3-carbazolealdehyde, 4-formyl-1-methylpyridinium, 2-formyl-1-methylpyridinium, 4-formyl-1-ethylpyridinium, 2-formyl-1-ethylpyridinium, 4-formyl-1-benzylpyridinium, 2-formyl-1-benzylpyridinium, 4-formyl-1,2-dimethylpyridinium, 4-formyl-1,3-dimethylpyridinium, 4-formyl-1-methylquinolinium, 2-formyl-1-methylquinolinium, 4-acetyl-1-methylpyridinium, 2-acetyl-1-methylpyridinium, 4-acetyl-1-methylquinolinium, 5-formyl-1-methylquinolinium, 6-formyl-1-methylquinolinium, 7-formyl-1-methylquinolinium, 8-formyl-1-methylquinolinium, 5-formyl-1-ethylquinolinium, 6-formyl-1-ethylquinolinium, 7-formyl-1-ethylquinolinium, 8-formyl-1-ethylquinolinium, 5-formyl-1-benzylquinolinium, 6-formyl-1-benzylquinolinium, 7-formyl-1-benzylquinolinium, 8-formyl-1-benzylquinolinium, 5-formyl-1-allylquinolinium, 6-formyl-1-allylquinolinium, 7-formyl-1-allylquinolinium and 8-formyl-1-allylquinolinium, 5-acetyl-1-methylquinolinium, 6-acetyl-1-methylquinolinium, 7-acetyl-1-methylquinolinium, 8-acetyl-1-methylquinolinium, 5-acetyl-1-ethylquinolinium, 6-acetyl-1-ethylquinolinium, 7-acetyl-1-ethylquinolinium, 8-acetyl-1-ethylquinolinium, 5-acetyl-1-benzylquinolinium, 6-acetyl-1-benzylquinolinium, 7-acetyl-1-benzylquinolinium, 8-acetyl-1-benzylquinolinium, 5-acetyl-1-allylquinolinium, 6-acetyl-1-allylquinolinium, 7-acetyl-1-allylquinolinium and 8-acetyl-1-allylquinolinium, 9-formyl-10-methylacridinium, 4-(2′-formylvinyl)-1-methylpyridinium, 1,3-dimethyl-2-(4′-formylphenyl)benzimidazolium, 1,3-dimethyl-2-(4′-formylphenyl)-imidazolium, 2-(4′-formylphenyl)-3-methylbenzothiazolium, 2-(4′-acetylphenyl)-3-methylbenzothiazolium, 2-(4′-formylphenyl)-3-methylbenzoxazolium, 2-(5′-formyl-2′-furyl)-3-methylbenzothiazolium, 2-(5′-formyl-2′-furyl)-3-methylbenzothiazolium, 2-(5′-formyl-2′-thienyl)-3-methylbenzothiazolium, 2-(3′-formylphenyl)-3-methylbenzothiazolium, 2-(4′-formyl-1-naphthyl)-3-methylbenzothiazolium, 5-chloro-2-(4′-formylphenyl)-3-methylbenzothiazolium, 2-(4′-formyl-1-naphthyl)-3-methylbenzothiazolium, 5-chloro-2-(4′-formylphenyl)-3-methylbenzothiazolium, 2-(4′-formylphenyl)-3,5-dimethylbenzothiazolium benzenesulfonate, p-toluenesulfonate, methanesulfonate, perchlorate, sulfate, chloride, bromide, iodide, tetrachlorozincate, methylsulfate, trifluoromethanesulfonate, tetrafluoroborate, isatin, 1-methylisatin, 1-allylisatin, 1-hydroxymethylisatin, 5-chloroisatin, 5-methoxyisatin, 5-nitroisatin, 6-nitroisatin, 5-sulfoisatin, 5-carboxyisatin, quinisatin, 1-methylquinisatin, and any mixtures of the above compounds.
In the compositions according to the invention, very particular preference is given to using benzaldehyde, cinnamaldehyde and naphthaldehyde, and derivatives thereof, in particular with one or more hydroxy, alkoxy or amino substituents as component A. In turn, preference is given here to the compounds according to formula (Ox4),
in which
R 10 , R 11 and R 12 , independently of one another, are a hydrogen atom, a halogen atom, a C 1 –C 6 -alkyl group, a hydroxy group, a C 1 –C 6 -alkoxy group, an amino group, a C 1 –C 6 -dialkylamino group, a di(C 2 –C 6 -hydroxyalkyl) amino group, a di(C 1 –C 6 -alkoxy-C 1 –C 6 -alkyl)amino group, a C 1 –C 6 -hydroxyalkyloxy group, a sulfonyl group, a carboxyl group, a sulfonic acid group, a sulfonamido group, a sulfonamide group, a carbamoyl group, a C 2 –C 6 -acyl group, an acetyl group or a nitro group, Z′ is a direct bond or a vinylene group, R 13 and R 14 are a hydrogen atom or jointly, together with the remaining molecule, form a 5- or 6-membered aromatic or aliphatic ring.
Very particularly preferred compounds of component A are chosen from the group consisting of vanillin, coniferylaldehyde, 2-methoxybenzaldehyde, 3-methoxybenzaldehyde, 4-methoxybenzaldehyde, 2-ethoxybenzaldehyde, 3-ethoxybenzaldehyde, 4-ethoxybenzaldehyde, 4-hydroxy-2,3-dimethoxybenzaldehyde, 4-hydroxy-2,5-dimethoxybenzaldehyde, 4-hydroxy-2,6-dimethoxybenzaldehyde, 4-hydroxy-2-methylbenzaldehyde, 4-hydroxy-3-methylbenzaldehyde, 4-hydroxy-2,3-dimethylbenzaldehyde, 4-hydroxy-2,5-dimethylbenzaldehyde, 4-hydroxy-2,6-dimethylbenzaldehyde, 4-hydroxy-3,5-dimethoxybenzaldehyde, 4-hydroxy-3,5-dimethylbenzaldehyde, 3,5-diethoxy-4-hydroxybenzaldehyde, 2,6-diethoxy-4-hydroxybenzaldehyde, 3-hydroxy-4-methoxybenzaldehyde, 2-hydroxy-4-methoxybenzaldehyde, 2-ethoxy-4-hydroxybenzaldehyde, 3-ethoxy-4-hydroxybenzaldehyde, 4-ethoxy-2-hydroxybenzaldehyde, 4-ethoxy-3-hydroxybenzaldehyde, 2,3-dimethoxybenzaldehyde, 2,4-dimethoxybenzaldehyde, 2,5-dimethoxybenzaldehyde, 2,6-dimethoxy-benzaldehyde, 3,4-dimethoxybenzaldehyde, 3,5-dimethoxy-benzaldehyde, 2,3,4-trimethoxybenzaldehyde, 2,3,5-trimethoxybenzaldehyde, 2,3,6-trimethoxybenzaldehyde, 2,4,6-trimethoxybenzaldehyde, 2,4,5-trimethoxybenzaldehyde, 2,5,6-trimethoxybenzaldehyde, 2-hydroxybenzaldehyde, 3-hydroxybenzaldehyde, 4-hydroxybenzaldehyde, 2,3-dihydroxybenzaldehyde, 2,4-dihydroxybenzaldehyde, 2,4-dihydroxy-3-methylbenzaldehyde, 2,4-dihydroxy-5-methylbenzaldehyde, 2,4-dihydroxy-6-methylbenzaldehyde, 2,4-dihydroxy-3-methoxybenzaldehyde, 2,4-dihydroxy-5-methoxybenzaldehyde, 2,4-dihydroxy-6-methoxybenzaldehyde, 2,5-dihydroxybenzaldehyde, 2,6-dihydroxybenzaldehyde, 3,4-dihydroxybenzaldehyde, 3,4-dihydroxy-2-methylbenzaldehyde, 3,4-dihydroxy-5-methylbenzaldehyde, 3,4-dihydroxy-6-methylbenzaldehyde, 3,4-dihydroxy-2-methoxybenzaldehyde, 3,4-dihydroxy-5-methoxybenzaldehyde, 3,5-dihydroxybenzaldehyde, 2,3,4-trihydroxybenzaldehyde, 2,3,5-trihydroxybenzaldehyde, 2,3,6-trihydroxybenzaldehyde, 2,4,6-tri-hydroxybenzaldehyde, 2,4,5-trihydroxybenzaldehyde, 2,5,6-trihydroxybenzaldehyde, 3,4,5-trihydroxybenzaldehyde, 4-hydroxy-2-methoxybenzaldehyde, 4-dimethylaminobenzaldehyde, 4-diethylaminobenzaldehyde, 4-dimethylamino-2-hydroxybenzaldehyde, 4-diethylamino-2-hydroxybenzaldehyde, 4-pyrrolidinobenzaldehyde, 4-morpholinobenzaldehyde, 2-morpholinobenzaldehyde, 4-piperidinobenzaldehyde, 2-methoxy-1-naphthaldehyde, 4-methoxy-1-naphthaldehyde, 2-hydroxy-1-naphthaldehyde, 2,4-dihydroxy-1-naphthaldehyde, 4-hydroxy-3-methoxy-1-naphthaldehyde, 2-hydroxy-4-methoxy-1-naphthaldehyde, 3-hydroxy-4-methoxy-1-naphthaldehyde, 2,4-dimethoxy-1-naphthaldehyde, 3,4-dimethoxy-1-naphthaldehyde, 4-hydroxy-1-naphthaldehyde, 4-dimethylamino-1-naphthaldehyde, 4-dimethylaminocinnamaldehyde, 2-dimethyl-aminobenzaldehyde, 2-chloro-4-dimethylaminobenzaldehyde, 4-dimethylamino-2-methylbenzaldehyde, 4-diethyl-aminocinnamaldehyde, 4-dibutylaminobenzaldehyde, 4-diphenyl-aminobenzaldehyde, 4-dimethylamino-2-methoxybenzaldehyde, 4-(1-imidazolyl)benzaldehyde and piperonal.
In a second embodiment, in order to expand the color spectrum and also to improve the fastness properties, it may be advantageous to add to the compositions, besides the reactive carbonyl compound (component A), at least one further compound as component B chosen from (a) CH-acidic compounds and (b) compounds with a primary or secondary amino or hydroxy group, chosen from aromatic hydroxy compounds, primary or secondary aromatic amines and nitrogen-containing heterocyclic compounds. CH-acidic compounds have an acidic hydrogen atom bonded to a carbon atom which can be abstracted from the carbon atom using a base.
The CH-acidic compounds of component B are preferably chosen from the group consisting of 1,2,3,3-tetramethyl-3H-indolium iodide, 1,2,3,3-tetramethyl-3H-indolium p-toluenesulfonate, 1,2,3,3-tetramethyl-3H-indolium methanesulfonate, 1,3,3-trimethyl-2-methyleneindoline (Fischer's base), 2,3-dimethylbenzothiazolium iodide, 2,3-dimethylbenzothiazolium p-toluenesulfonate, 2,3-dimethylnaphtho[1,2-d]thiazolium p-toluenesulfonate, 3-ethyl-2-methylnaphtho-[1,2-d]thiazolium p-toluenesulfonate, rhodanine, rhodanine-3-acetic acid, 1,4-dimethylquinolinium iodide, 1,2-dimethylquinolinium iodide, barbituric acid, thiobarbituric acid, 1,3-dimethylthiobarbituric acid, 1,3-diethylthiobarbituric acid, 1,3-diethylbarbituric acid, oxindole, 3-indoxyl acetate, 2-coumaranone, 5-hydroxy-2-coumaranone, 6-hydroxy-2-coumaranone, 3-methyl-1-phenylpyrazolin-5-one, indan-1,2-dione, indane-1,3-dione, indane-1-one, benzoylacetonitrile, 3-dicyanomethyleneindan-1-one, 2-amino-4-imino-1,3-thiazoline hydrochloride, 5,5-dimethylcyclohexane-1,3-dione, 2H-1,4-benzoxazin-4H-3-one, 3-ethyl-2-methylbenzoxazolium iodide, 3-ethyl-2-methylbenzothiazolium iodide, 1-ethyl-4-methyl-quinolinium iodide, 1-ethyl-2-methylquinolinium iodide, 1,2,3-trimethylquinoxalinium iodide, 3-ethyl-2-methylbenzoxazolium p-toluenesulfonate, 3-ethyl-2-methylbenzothiazolium p-toluenesulfonate, 1-ethyl-4-methylquinolinium p-toluenesulfonate, 1-ethyl-2-methylquinolinium p-toluenesulfonate, 1,2,3-trimethylquinoxalinium p-toluenesulfonate, 1,2-dihydro-1,3,4,6-tetramethyl-2-oxopyrimidinium chloride, 1,2-dihydro-1,3,4,6-tetramethyl-2-oxopyrimidinium hydrogensulfate, 1,2-dihydro-1,3,4-trimethyl-2-oxopyrimidinium chloride, 1,2-dihydro-4,6-dimethyl-1,3-dipropyl-2-oxopyrimidinium chloride, 1,2-dihydro-1,3,4,6-tetramethyl-2-thioxopyrimidinium hydrogensulfate and 2-dihydro-1,3,4,5,6-pentamethyl-2-oxopyrimidinium chloride.
The primary and secondary aromatic amines of component B are preferably chosen from the group consisting of N,N-dimethyl-p-phenylenediamine, N,N-diethyl-p-phenylenediamine, N-(2-hydroxyethyl)-N-ethyl-p-phenylenediamine, N,N-bis(2-hydroxyethyl)-p-phenylenediamine, N-(2-methoxyethyl)-p-phenylenediamine, 2,3-dichloro-p-phenylenediamine, 2,4-dichloro-p-phenylenediamine, 2,5-dichloro-p-phenylenediamine, 2-chloro-p-phenylenediamine, 2,5-dihydroxy-4-morpholinoaniline, 2-aminophenol, 3-aminophenol, 4-aminophenol, 2-aminomethyl-4-aminophenol, 2-hydroxymethyl-4-aminophenol, o-phenylenediamine, m-phenylenediamine, p-phenylenediamine, 2,5-diaminotoluene, 2,5-diaminophenol, 2,5-diaminoanisole, 2,5-diaminophenethol, 4-amino-3-methylphenol, 2-(2,5-diaminophenyl)ethanol, 2,4-diaminophenoxyethanol, 2-(2,5-diaminophenoxy)ethanol, 3-amino-4-(2-hydroxyethyloxy)phenol, 3,4-methylenedioxyphenol, 3,4-methylenedioxyaniline, 3-amino-2,4-dichlorophenol, 4-methyl-aminophenol, 2-methyl-5-aminophenol, 3-methyl-4-aminophenol, 2-methyl-5-(2-hydroxyethylamino)phenol, 3-amino-2-chloro-6-methylphenol, 2-methyl-5-amino-4-chlorophenol, 5-(2-hydroxy-ethylamino)-4-methoxy-2-methylphenol, 4-amino-2-hydroxymethylphenol, 2-(diethylaminomethyl)-4-aminophenol, 4-amino-1-hydroxy-2-(2-hydroxyethylaminomethyl)benzene, 1-hydroxy-2-amino-5-methylbenzene, 1-hydroxy-2-amino-6-methylbenzene, 2-amino-5-acetamidophenol, 1,3-dimethyl-2,5-diaminobenzene, 5-(3-hydroxypropylamino)-2-methylphenol, 5-amino-4-methoxy-2-methylphenol, N,N-dimethyl-3-aminophenol, N-cyclopentyl-3-aminophenol, 5-amino-4-fluoro-2-methylphenol, 2,4-diamino-5-fluorotoluene, 2,4-diamino-5-(2-hydroxyethoxy)toluene, 2,4-diamino-5-methylphenetol, 3,5-diamino-2-methoxy-1-methylbenzene, 2-amino-4-(2-hydroxyethylamino)anisole, 2,6-bis(2-hydroxyethylamino)-1-methylbenzene, 1,3-diamino-2,4-dimethoxy-benzene, 3,5-diamino-2-methoxytoluene, 2-aminobenzoic acid, 3-aminobenzoic acid, 4-aminobenzoic acid, 2-aminophenylacetic acid, 3-aminophenylacetic acid, 4-aminophenylacetic acid, 2,3-diaminobenzoic acid, 2,4-diaminobenzoic acid, 2,5-diaminobenzoic acid, 3,4-diaminobenzoic acid, 3,5-diaminobenzoic acid, 4-aminosalicylic acid, 5-aminosalicylic acid, 3-amino-4-hydroxybenzoic acid, 4-amino-3-hydroxybenzoic acid, 2-aminobenzenesulfonic acid, 3-aminobenzenesulfonic acid, 4-aminobenzenesulfonic acid, 3-amino-4-hydroxybenzenesulfonic acid, 4-amino-3-hydroxynaphthalene-1-sulfonic acid, 6-amino-7-hydroxynaphthalene-2-sulfonic acid, 7-amino-4-hydroxynaphthalene-2-sulfonic acid, 4-amino-5-hydroxynaphthalene-2,7-disulfonic acid, 3-amino-2-naphthoic acid, 3-aminophthalic acid, 5-aminoisophthalic acid, 1,3,5-triaminobenzene, 1,2,4-triaminobenzene, 1,2,4,5-tetraaminobenzene, 2,4,5-triaminophenol, pentaaminobenzene, hexaaminobenzene, 2,4,6-triaminoresorcinol, 4,5-diaminopyrocatechin, 4,6-diaminopyrogallol, 1-(2-hydroxy-5-aminobenzyl)-2-imidazolidinone, 4-amino-2-((4-[(5-amino-2-hydroxyphenyl)methyl]piperazinyl)-methyl)phenol, 3,5-diamino-4-hydroxypyrocatechin, 1,4-bis(4-aminophenyl)-1,4-diazacycloheptane, aromatic nitriles, such as 2-amino-4-hydroxybenzonitrile, 4-amino-2-hydroxybenzonitrile, 4-aminobenzonitrile, 2,4-diaminobenzonitrile, amino compounds containing nitro groups, such as 3-amino-6-methylamino-2-nitro-pyridine, picramic acid, [8-[(4-amino-2-nitrophenyl)azo]-7-hydroxynaphth-2-yl]trimethylammonium chloride, [8-((4-amino-3-nitrophenyl)azo)-7-hydroxynaphth-2-yl]trimethylammonium chloride (Basic Brown 17), 1-hydroxy-2-amino-4,6-dinitrobenzene, 1-amino-2-nitro-4-[bis(2-hydroxyethyl)amino]benzene, 1-amino-2-[(2-hydroxyethyl)amino]-5-nitrobenzene (HC Yellow No. 5), 1-amino-2-nitro-4-[(2-hydroxyethyl)amino]benzene (HC Red No. 7), 2-chloro-5-nitro-N-2-hydroxyethyl-1,4-phenylenediamine, 1-[(2-hydroxyethyl)amino]-2-nitro-4-aminobenzene (HC Red No. 3), 4-amino-3-nitrophenol, 4-amino-2-nitrophenol, 6-nitro-o-toluidine, 1-amino-3-methyl-4-[(2-hydroxyethyl)amino]-6-nitrobenzene (HC Violet No. 1), 1-amino-2-nitro-4-[(2,3-dihydroxypropyl)amino]-5-chlorobenzene (HC Red No. 10), 2-(4-amino-2-nitroanilino)benzoic acid, 6-nitro-2,5-diaminopyridine, 2-amino-6-chloro-4-nitrophenol, 1-amino-2-(3-nitrophenylazo)-7-phenylazo-8-naphthol-3,6-disulfonic acid disodium salt (Acid Blue No. 29), 1-amino-2-(2-hydroxy-4-nitrophenylazo)-8-naphthol-3,6-disulfonic acid disodium salt (palatine chrome green), 1-amino-2-(3-chloro-2-hydroxy-5-nitrophenylazo)-8-naphthol-3,6-disulfonic acid disodium salt (Gallion), 4-amino-4′-nitrostilbene-2,2′-disulfonic acid disodium salt, 2,4-diamino-3′,5′-dinitro-2′-hydroxy-5-methylazobenzene (Mordant Brown 4), 4′-amino-4-nitrodiphenylamine-2-sulfonic acid, 4′-amino-3′-nitro-benzophenone-2-carboxylic acid, 1-amino-4-nitro-2-(2-nitro-benzylideneamino)benzene, 2-[2-(diethylamino)ethylamino]-5-nitroaniline, 3-amino-4-hydroxy-5-nitrobenzenesulfonic acid, 3-amino-3′-nitrobiphenyl, 3-amino-4-nitroacenaphthene, 2-amino-1-nitronaphthalene, 5-amino-6-nitrobenzo-1,3-dioxole, anilines, in particular anilines containing nitro groups, such as 4-nitroaniline, 2-nitroaniline, 1,4-diamino-2-nitrobenzene, 1,2-diamino-4-nitrobenzene, 1-amino-2-methyl-6-nitrobenzene, 4-nitro-1,3-phenylenediamine, 2-nitro-4-amino-1-(2-hydroxyethylamino)benzene, 2-nitro-1-amino-4-[bis(2-hydroxyethyl)amino]benzene, 4-amino-2-nitrodiphenylamine-2′-carboxylic acid, 1-amino-5-chloro-4-(2-hydroxyethylamino)-2-nitrobenzene, aromatic anilines and phenols with a further aromatic radical as shown in formula (Ox5)
in which
R 15 is a hydroxy or an amino group which may be substituted by C 1 –C 6 -alkyl, C 1 –C 6 -hydroxyalkyl, C 1 –C 6 -alkoxy or C 1 –C 6 -alkoxy-C 1 –C 6 -alkyl groups, R 16 , R 17 , R 18 , R 19 and R 20 , independently of one another, are a hydrogen atom, a hydroxy or an amino group which may be substituted by C 1 –C 6 -alkyl, C 1 –C 6 -hydroxyalkyl, C 1 –C 6 -alkoxy, C 1 –C 6 -aminoalkyl or C 1 –C 6 -alkoxy-C 1 –C 6 -alkyl groups, and Z″ is a direct bond, a saturated or unsaturated carbon chain optionally substituted by hydroxy groups and having 1 to 4 carbon atoms, a carbonyl group, sulfonyl group or imino group, an oxygen atom or sulfur atom, or a group with the formula (Ox6)
-Q′( CH 2 -Q-CH 2 -Q″ ) 0 (Ox6)
in which
Q is a direct bond, a CH 2 group or CHOH group, Q′ and Q″, independently of one another, are an oxygen atom, an NR 21 group, in which R 21 is a hydrogen atom, a C 1 –C 6 -alkyl group or C 1 –C 6 -hydroxyalkyl group, where also the two groups, together with the remaining molecule, can form a 5-, 6- or 7-membered ring, the group O—(CH 2 ) p —NH or NH—(CH 2 ) p ′—O, in which p and p′ are 2 or 3, and o is a number from 1 to 4,
such as, in particular, 4,4′-diaminostilbene and its hydrochloride, 4,4′-diaminostilbene-2,2′-disulfonic acid mono- or di-Na salt, 4-amino-4′-dimethylaminostilbene and its hydrochloride, 4,4′-diaminodiphenylmethane, 4,4′-diaminodiphenyl sulfide, 4,4′-diaminodiphenyl sulfoxide, 4,4′-diaminodiphenylamine, 4,4′-diaminodiphenylamine-2-sulfonic acid, 4,4′-diaminobenzophenone, 4,4′-diaminodiphenyl ether, 3,3′,4,4′-tetraaminodiphenyl, 3,3′,4,4′-tetraaminobenzophenone, 1,3-bis(2,4-diaminophenoxy)propane, 1,8-bis(2,5-diaminophenoxy)-3,6-dioxaoctane, 1,3-bis(4-aminophenylamino)propane, 1,3-bis(4-aminophenylamino)-2-propanol, 1,3-bis[N-(4-aminophenyl)-2-hydroxyethylamino]-2-propanol, N,N-bis[2-(4-aminophenoxy)ethyl]-methylamine, N-phenyl-1,4-phenylenediamine and bis(5-amino-2-hydroxyphenyl)methane.
The nitrogen-containing heterocyclic compounds of component B are preferably chosen from the group consisting of 2-aminopyridine, 3-aminopyridine, 4-aminopyridine, 2-amino-3-hydroxypyridine, 2,6-diaminopyridine, 2,5-diaminopyridine, 2-(aminoethylamino)-5-aminopyridine, 2,3-diaminopyridine, 2-di-methylamino-6-aminopyridine, 2-methylamino-3-amino-6-methoxypyridine, 2,3-diamino-6-methoxypyridine, 2,6-dimethoxy-3,5-diaminopyridine, 2,4,5-triaminopyridine, 2,6-dihydroxy-3,4-dimethylpyridine, N-[2-(2,4-diaminophenyl)aminoethyl]-N-(5-amino-2-pyridyl)amine, N-[2-(4-aminophenyl)aminoethyl]-N-(5-amino-2-pyridyl)amine, 2,4-dihydroxy-5,6-diaminopyrimidine, 4,5,6-triaminopyrimidine, 4-hydroxy-2,5,6-triaminopyrimidine, 2-hydroxy-4,5,6-triaminopyrimidine, 2,4,5,6-tetraaminopyrimidine, 2-methylamino-4,5,6-triaminopyrimidine, 2,4-diaminopyrimidine, 4,5-diaminopyrimidine, 2-amino-4-methoxy-6-methylpyrimidine, 3,5-diaminopyrazole, 3,5-diamino-1,2,4-triazole, 3-aminopyrazole, 3-amino-5-hydroxypyrazole, 1-phenyl-4,5-diaminopyrazole, 1-(2-hydroxyethyl)-4,5-diaminopyrazole, 1-phenyl-3-methyl-4,5-diaminopyrazole, 4-amino-2,3-dimethyl-1-phenyl-3-pyrazolin-5-one (4-aminoantipyrin), 1-phenyl-3-methyl-pyrazol-5-one, 2-aminoquinoline, 3-aminoquinoline, 8-aminoquinoline, 4-aminoquinaldin, 2-aminonicotinic acid, 6-aminonicotinic acid, 5-aminoisoquinoline, 5-aminoindazole, 6-aminoindazole, 5-aminobenzimidazole, 7-aminobenzimidazole, 5-aminobenzothiazole, 7-aminobenzothiazole, 2,5-dihydroxy-4-morpholinoaniline, and indole and indoline derivatives, such as 4-aminoindole, 5-aminoindole, 6-aminoindole, 7-aminoindole, 5,6-dihydroxyindole, 5,6-dihydroxyindoline and 4-hydroxyindoline. In addition, heterocyclic compounds which can be used according to the invention are the hydroxypyrimidines disclosed in DE-U1-299 08 573. The abovementioned compounds can be used either in free form or else in the form of their physiologically compatible salts, e.g. as salts of inorganic acids, such as hydrochloric acid or sulfuric acid.
The aromatic hydroxy compounds of component B are preferably chosen from the group consisting of 2-methylresorcinol, 4-methylresorcinol, 5-methylresorcinol, 2,5-dimethylresorcinol, resorcinol, 3-methoxyphenol, pyrocatechin, hydroquinone, pyrogallol, phloroglucine, hydroxyhydroquinone, 2-methoxyphenol, 3-methoxyphenol, 4-methoxyphenol, 3-dimethylaminophenol, 2-(2-hydroxyethyl)phenol, 3,4-methylenedioxyphenol, 2,4-dihydroxybenzoic acid, 3,4-dihydroxybenzoic acid, 1-(2,4-dihydroxyphenyl)acetic acid, 1-(3,4-dihydroxyphenyl)acetic acid, gallic acid, 2,4,6-trihydroxybenzoic acid, -acetophenone, 2-chlororesorcinol, 4-chlororesorcinol, 1-naphthol, 1,5-dihydroxynaphthalene, 2,3-dihydroxynaphthalene, 2,7-dihydroxynaphthalene, 6-dimethylamino-4-hydroxy-2-naphthalenesulfonic acid and 3,6-dihydroxy-2,7-naphthalenesulfonic acid.
In a further preferred embodiment, the cosmetic preparations are in the form of a liquid, preferably in the form of a dispersion, emulsion, solution or gel, particularly preferably with a viscosity of from 500 to 4000 mPas, more preferably 5000 to 35 000 mPas, in particular from 10 000 to 35 000 mPas, specifically from 20 000 to 32 000 mPas (Brookfield viscometer LVT-II at 4 rpm and 20° C., spindle 5).
As already described above, the cosmetic preparations preferably have a water content below 20% by weight, preferably below 12% by weight, particularly preferably below 8% by weight, further preferably below 4% by weight, in particular below 2% by weight, in each case based on the total cosmetic preparation.
The liquid coloring systems known from the prior art for keratin materials comprise, as solvent, virtually exclusively water or mixtures of water with low molecular weight alcohols such as ethanol and/or isopropanol. When choosing these solvents, physiological factors firstly play a role, and secondly coloration of the inside of the hair is ensured only with suitable transport media, and a reaction in the case of systems capable of reaction is ensured only with a suitable reaction medium. These conditions are optimally satisfied with water or water/alcohol mixtures. The use of the cited solvents, however, is not only associated with advantages. Upon storage in aqueous or aqueous-alcoholic media, some dyes undergo hydrolysis or dissolve only inadequately. These disadvantages can be overcome in principle through storage in, for example, powder form. However, this type of preparation does not always represent an optimum solution. For example, the finely divided dispersion necessary for extensive dissolving of all components is often not ensured.
In a further preferred embodiment, the hair colorants or hair colorant precursors, in particular component A of the oxo hair colorants, have a solubility in water below 5% by weight, preferably below 2% by weight, in particular below 1% by weight.
Suitable sparingly water-soluble hair colorant precursors are known from the German published specification DE 2932489, which discloses aromatic aldehydes, and from the German patent application DE 196 30 275, which describes vinylogs, aromatic aldehydes. The specified publications describe numerous compounds which only have a limited solubility in water of less than 1 g/l (20° C.). Particular preference is given to the isatin derivatives known from WO 95/24886. Dyes which are chosen from the group of isatin derivatives or of aromatic or vinylog carbonyl compounds are particularly preferred since these dyes are often sparingly soluble in water. These dye precursors are often used for the oxo coloration. Particularly preferred cosmetic preparations comprise 1-allylisatin, 1-diethylaminomethylisatin, 1-diethylaminomethylisatin, 1-piperidinomethylisatin, 4-hydroxy-3-methoxycinnamaldehyde, glutaconaldehyde tetrabutylammonium salt and 2-(1,3,3-trimethyl-2-indolylidene)acetaldehyde.
The dyes or dye precursors preferably have good solubility in oil. For the purposes of the present embodiment according to the invention, oil-soluble substances are understood as meaning substances whose solubility in paraffin oil at 20° C. is above 0.1% by weight.
It has been found that especially for the preparation of low-water cosmetic preparations, in particular low-water hair colorant preparations, oils can additionally be used. Preference is given to using liquid oil components.
Liquid oil components for the purposes of the present embodiment according to the invention are all physiologically compatible mineral, animal, vegetable or synthetic oil components which are liquid at 20° C. Examples of such oil components are, for example, paraffin oils, silicone oils, triglyceride oils, e.g. neatsfoot oil, lard oil, mink oil, olive oil, sunflower oil, almond oil, liquid wax esters, such as, for example, sperm oil, jojoba oil, synthetic esters, such as, for example, glycerol tricaprylate, n-hexyl laurate, isopropyl myristate, 2-ethylhexyl stearate, butyl oleate, synthetic ethers, such as, for example, di-n-octyl ether, synthetic hydrocarbons, such as, for example, diisooctylcyclohexane, squalane, synthetic alcohols, such as, for example, 2-octyldodecanol or 2-hexyldecanol.
The cosmetic preparations particularly preferably additionally comprise an oil chosen from the group
a) mineral oils, preferably paraffin oils, b) vegetable oils, preferably sunflower oil, rapeseed oil, soybean oil, castor oil, c) silicone oils, preferably quaternized silicones, d) esters of C 10 –C 36 -fatty acids, preferably esters of C 14 –C 28 -fatty acids and e) dialkyl ethers with at least one carbon radical which carries 6 or more carbon atoms.
In a further preferred embodiment, the cosmetic formulations advantageously comprise components which, upon dissolution in water, liberate a greater heat of hydration and, on the basis of the development of heat, in particular with hair colorant preparation, lead to improved color absorption. The cosmetic preparations preferably comprise one or more components with an exothermic solubility behavior in water, preferably chosen from the group
a) alkali metal or alkaline earth metal salts, preferably alkali metal or alkaline earth metal halides and/or sulfates, in particular calcium chloride and/or magnesium sulfate and/or dehydrated zeolites and b) low molecular weight polyols, preferably glycerol, propylene glycol or polyethylene glycol.
For the anhydrous, preferably oil-containing, cosmetic formulations, it has surprisingly been found that the viscosity build-up, necessary for the stable finely divided dispersing, of nonpolar or semipolar oils can be achieved through various additives. In a preferred embodiment of the present embodiment according to the invention, the cosmetic preparations have one or more viscosity-regulating additives which are chosen from
a) esters or amides of di-, tri-, tetra- or polyols, in particular dextrin mono- or polyesterified with palmitic acid or N-lauroyl-1-glutamic acid, α,γ-di-n-butylamide, b) esters of di- or oligocarboxylic acids, in particular dibehenylfumaric esters, c) sheet silicates, preferably organically modified, in particular hydrophobically modified, sheet silicates, d) mono- or diglycerides of C 12 –C 22 -fatty acids e) alkali metal, alkaline earth metal and aluminum salts of fatty acids and/or hydroxycarboxylic acids, in particular the lithium salts of C 3 –C 14 -hydroxycarboxylic acids, f) aerosils, preferably SiO 2 and/or TiO 2 , particularly preferably those with an average particle size below 100 μm, in particular below 100 μm, g) polyols, preferably polyethylene glycols and/or polypropylene glycols, particularly preferably polyols with an average molecular weight below 20 000, h) dibenzylidene sorbitols and derivatives thereof, i) copolymers with aminodithiazoles, j) graft copolymers of polyvinylpyridine with sulfonated polyisobutylene, k) crosslinked polyamines and/or polyimines l) polymers chosen from i) rubber-based block copolymers, ii) silicone oils with a viscosity above 2000 mPas, iii) microcrystalline waxes and m) ethylene-vinyl acetate copolymers.
Particularly preferred viscosity-regulating additives for the low-water cosmetic formulations in the portions according to the invention have proven to be dibenzylidene sorbitols and derivatives thereof which are described in U.S. Pat. No. 6,338,841 B1 and whose content is incorporated into the application. Preference is also given to the copolymers with aminodiazoles as described in U.S. Pat. No. 5,472,627 and whose content is explicitly incorporated by reference. Also preferred are graft copolymers of polyvinylpyridine with sulfonated polyisobutylene as described in U.S. Pat. No. 5,328,960 and whose content is incorporated into this application in its entirety. Also preferred are the crosslinked polyamines and/or polyimines as explicitly disclosed in WO 01/46373 A1. Specific preference is likewise given to the esters of di- or oligocarboxylic acids, in particular dibehenylfumaric esters as disclosed in WO 99/51191. Further preferred viscosity-regulating additives are polymers chosen from I) rubber-based block copolymers, II) silicone oils with a viscosity above 2000 mPas, III) microcrystalline waxes as described in WO 98/30193. For the viscosity build-up in low-water hair colorant systems, the lithium salts of C 3 –C 14 -hydroxycarboxylic acids as described explicitly in WO 98/11180 have proven to be particularly advantageous. It is likewise advantageous to use ethylene-vinyl acetate copolymers as described in WO 97/07158 and whose content is incorporated into this application in its entirety.
The cosmetic preparations can, moreover, comprise further active ingredients and auxiliaries.
In many cases, the colorants comprise at least one surfactant, with, in principle, both anionic and also zwitterionic, ampholytic, nonionic and cationic surfactants being suitable. It has proven to be advantageous to choose the surfactants from anionic, zwitterionic or nonionic surfactants.
Suitable anionic surfactants in preparations are all anionic surface-active substances suitable for use on the human body. These are characterized by a water-solubilizing anionic group such as, for example, a carboxylate, sulfate, sulfonate or phosphate group, and a lipophilic alkyl group having about 10 to 22 carbon atoms. In addition, glycol or polyglycol ether groups, ester groups, ether groups and amide groups and also hydroxyl groups, may be present in the molecule. Examples of suitable anionic surfactants are, in each case in the form of the sodium, potassium and ammonium and also the mono-, di- and trialkanolammonium salts having 2 or 3 carbon atoms in the alkanol group,
linear fatty acids having 10 to 22 carbon atoms (soaps), ether carboxylic acids of the formula R—O—(CH 2 —CH 2 O) x —CH 2 —COOH, in which R is a linear alkyl group having 10 to 22 carbon atoms and x=0 or 1 to 16, acyl sarcosides having 10 to 18 carbon atoms in the acyl group, acyl taurides having 10 to 18 carbon atoms in the acyl group, acyl isethionates having 10 to 18 carbon atoms in the acyl group, sulfosuccinic mono- and dialkyl esters having 8 to 18 carbon atoms in the alkyl group and sulfosuccinic monoalkylpolyoxyethyl esters having 8 to 18 carbon atoms in the alkyl group and 1 to 6 oxyethyl groups, linear alkanesulfonates having 12 to 18 carbon atoms, linear alpha-olefinsulfonates having 12 to 18 carbon atoms, alpha-sulfofatty acid methyl esters of fatty acids having 12 to 18 carbon atoms, alkyl sulfates and alkylpolyglycol ether sulfates of the formula R—O—(CH 2 —CH 2 O) x —SO 3 H, in which R is a preferably linear alkyl group having 10 to 18 carbon atoms and x=0 or 1 to 12, mixtures of surface-active hydroxysulfonates according to DE-A-37 25 030, sulfated hydroxyalkyl polyethylene and/or hydroxyalkylene propylene glycol ethers according to DE-A-37 23 354, sulfonates of unsaturated fatty acids having 12 to 24 carbon atoms and 1 to 6 double bonds according to DE-A-39 26 344, esters of tartaric acid and citric acid with alcohols, which constitute addition products of about 2–15 molecules of ethylene oxide and/or propylene oxide onto fatty alcohols having 8 to 22 carbon atoms.
Preferred anionic surfactants are alkyl sulfates, alkylpolyglycol ether sulfates and ether carboxylic acids having 10 to 18 carbon atoms in the alkyl group and up to 12 glycol ether groups in the molecule, and in particular salts of saturated and in particular unsaturated C 8 –C 22 -carboxylic acids, such as oleic acid, stearic acid, isostearic acid and palmitic acid.
Nonionogenic surfactants comprise, as hydrophilic group, e.g. a polyol group, a polyalkylene glycol ether group or a combination of polyol and polyglycol ether group. Such compounds are, for example,
addition products of from 2 to 30 mol of ethylene oxide and/or 0 to 5 mol of propylene oxide onto linear fatty alcohols having 8 to 22 carbon atoms, onto fatty acids having 12 to 22 carbon atoms and onto alkylphenols having 8 to 15 carbon atoms in the alkyl group, C 12 –C 22 -fatty acid mono- and diesters of addition products of from 1 to 30 mol of ethylene oxide onto glycerol, C 8 –C 22 -alkylmono- and oligoglycosides and ethoxylated analogs thereof, and addition products of from 5 to 60 mol of ethylene oxide onto castor oil and hydrogenated castor oil.
Preferred nonionic surfactants are alkyl polyglycosides of the general formula R 1 O-(Z) x . These compounds are characterized by the following parameters.
The alkyl radical R 1 comprises 6 to 22 carbon atoms and can either be linear or branched. Preference is given to primary linear and 2-position methyl-branched aliphatic radicals. Such alkyl radicals are, for example, 1-octyl, 1-decyl, 1-lauryl, 1-myristyl, 1-cetyl and 1-stearyl. Particular preference is given to 1-octyl, 1-decyl, 1-lauryl, 1-myristyl. If so-called oxo alcohols are used as starting materials, compounds with an uneven number of carbon atoms in the alkyl chain predominate.
The alkyl polyglycosides which can be used according to the invention can comprise, for example, only a specific alkyl radical R 1 . Usually, these compounds, however, are prepared starting from natural fats and oils or mineral oils. In this case, the alkyl radicals R present are mixtures corresponding to the starting compounds or corresponding to the particular work-up of these compounds.
Particular preference is given to those alkyl polyglycosides in which R 1 consists
essentially of C 8 - and C 10 -alkyl groups, essentially of C 12 - and C 14 -alkyl groups, essentially of C 8 –C 16 -alkyl groups or essentially of C 12 –C 16 -alkyl groups.
The sugar building block Z which may be used is any mono- or oligosaccharides. Usually, sugars with 5 or 6 carbon atoms, and the corresponding oligosaccharides are used. Such sugars are, for example, glucose, fructose, galactose, arabinose, ribose, xylose, lyxose, allose, altrose, mannose, gulose, idose, talose and sucrose. Preferred sugar building blocks are glucose, fructose, galactose, arabinose and sucrose; glucose is particularly preferred.
The alkyl polyglycosides which can be used according to the invention comprise, on average, 1.1 to 5 sugar units. Alkyl polyglycosides with x values of from 1.1 to 1.6 are preferred. Very particular preference is given to alkyl glycosides in which x is 1.1 to 1.4.
Besides their surfactant effect, the alkyl glycosides also serve to improve the fixing of scent components on the hair. Thus, when it is desirable for the effect of the perfume oil on the hair to last beyond the hair treatment, the person skilled in the art will preferably have recourse to this class of substances as a further ingredient of the preparations according to the invention.
The alkoxylated homologs of the specified alkyl polyglycosides can also be used according to the invention. These homologs can, on average, comprise up to 10 ethylene oxide and/or propylene oxide units per alkyl glycoside unit.
It is also possible to use zwitterionic surfactants, in particular as cosurfactants. Zwitterionic surfactants is the term used for those surface-active compounds which carry at least one quaternary ammonium group and at least one —COO (−) or —SO 3 (−) group in the molecule. Particularly suitable zwitterionic surfactants are the so-called betaines, such as the N-alkyl-N,N-dimethylammonium glycinates, for example cocoalkyldimethylammonium glycinate, N-acylaminopropyl-N,N-dimethylammonium glycinates, for example cocoacylaminopropyldimethylammonium glycinate, and 2-alkyl-3-carboxymethyl-3-hydroxyethylimidazolines having in each case 8 to 18 carbon atoms in the alkyl or acyl group, and cocoacylaminoethyl hydroxyethylcarboxymethyl glycinate. A preferred zwitterionic surfactant is the fatty acid amide derivative known under the INCI name Cocamidopropyl Betaine.
Likewise suitable in particular as cosurfactants are ampholytic surfactants. Ampholytic surfactants are understood as meaning those surface-active compounds which, apart from a C 8 –C 18 -alkyl or acyl group in the molecule, comprise at least one free amino group and at least one —COOH or —SO 3 H group and are capable of forming internal salts. Examples of suitable ampholytic surfactants are N-alkylglycines, N-alkylpropionic acids, N-alkylaminobutyric acids, N-alkyliminodipropionic acids, N-hydroxyethyl-N-alkylamidopropylglycines, N-alkyltaurines, N-alkylsarcosines, 2-alkylaminopropionic acids and alkyl-aminoacetic acids having in each case about 8 to 18 carbon atoms in the alkyl group. Particularly preferred ampholytic surfactants are N-cocoalkylaminopropionate, cocoacylaminoethylaminopropionate and C 12-18 -acylsarcosine.
The cationic surfactants used according to the invention are, in particular those of the quaternary ammonium compound type, the esterquat type and the amidoamine type.
Preferred quaternary ammonium compounds are ammonium halides, in particular chlorides and bromides, such as alkyltrimethylammonium chlorides, dialkyldimethylammonium chlorides and trialkylmethylammonium chlorides, e.g. cetyltrimethylammonium chloride, stearyltrimethylammonium chloride, distearyldimethylammonium chloride, lauryldimethylammonium chloride, lauryldimethylbenzylammonium chloride and tricetylmethylammonium chloride, and the imidazolium compounds known under the INCI names Quaternium-27 and Quaternium-83. The long alkyl chains of the abovementioned surfactants preferably have 10 to 18 carbon atoms.
Ester quats are known substances which comprise both at least one ester function and also at least one quaternary ammonium group as structural element. Preferred ester quats are quaternized ester salts of fatty acids with triethanolamine, quaternized ester salts of fatty acids with diethanolalkylamines and quaternized ester salts of fatty acids with 1,2-dihydroxypropyldialkylamines. Such products are sold, for example, under the trade names Stepantex®, Dehyquart® and Armocare®. The products Armocare® VGH-70, an N,N-bis(2-palmitoyloxyethyl)dimethylammonium chloride, and Dehyquart® F-75 and Dehyquart® AU-35 are examples of such ester quats.
The alkylamidoamines are usually prepared by amidation of natural or synthetic fatty acids and fatty acid cuts with dialkylaminoamines. A further compound suitable according to the invention from this group of substances is the stearamidopropyldimethylamine commercially available under the name Tegoamid® S 18.
Further cationic surfactants which can be used according to the invention are the quaternized protein hydrolyzates.
Likewise suitable according to the invention are cationic silicone oils, such as, for example, the commercially available products Q2-7224 (manufacturer: Dow Corning; a stabilized trimethylsilylamodimethicone), Dow Corning 929 emulsion (comprising a hydroxylamino-modified silicone, which is also referred to as amodimethicone), SM-2059 (manufacturer: General Electric), SLM-55067 (manufacturer: Wacker), and Abil®-Quat 3270 and 3272 (manufacturer: Th. Goldschmidt; diquaternary polydimethylsiloxanes, Quaternium-80).
One example of a quaternary sugar derivative which can be used as cationic surfactant is the commercial product Glucquat® 100, according to INCI nomenclature a “Lauryl Methyl Gluceth-10 Hydroxypropyl Dimonium Chloride”.
The compounds with alkyl groups used as surfactant may in each case be uniform substances. However, it is usually preferred when producing these substances to start from native vegetable or animal raw materials, thus giving rise to mixtures of substances with varying alkyl chain lengths dependent on the particular raw material.
In the case of the surfactants which constitute addition products of ethylene oxide and/or propylene oxide onto fatty alcohols or derivatives of these addition products it is possible to use either products with a “normal” homolog distribution or those with a narrowed homolog distribution. In this connection, “normal” homolog distribution is understood as meaning mixtures of homologs which are obtained during the reaction of fatty alcohol and alkylene oxide using alkali metals, alkali metal hydroxides or alkali metal alkoxides as catalysts. Narrowed homolog distributions are, by contrast, obtained if, for example, hydrotalcites, alkaline earth metal salts of ether carboxylic acids, alkaline earth metal oxides, hydroxides or alkoxides are used as catalysts. The use of products with a narrowed homolog distribution may be preferred.
In addition, the colorants according to the invention can comprise further active ingredients, auxiliaries and additives, such as, for example,
nonionic polymers, such as, for example, vinylpyrrolidone/vinyl acrylate copolymers, polyvinylpyrrolidone and vinylpyrrolidone/vinyl acetate copolymers and polysiloxanes, cationic polymers, such as quaternized cellulose ethers, polysiloxanes with quaternary groups, dimethyldiallylammonium chloride polymers, acrylamide-dimethyldiallylammonium chloride copolymers, dimethylaminoethyl methacrylate-vinylpyrrolidone copolymers quaternized with diethyl sulfate, vinylpyrrolidone-imidazolinium methochloride copolymers and quaternized polyvinyl alcohol, zwitterionic and amphoteric polymers, such as, for example, acrylamidopropyltrimethylammonium chloride/acrylate copolymers and octylacrylamide/methyl methacrylate/tert-butylaminoethyl methacrylate/2-hydroxypropyl methacrylate copolymers, anionic polymers, such as, for example, polyacrylic acids, crosslinked polyacrylic acids, vinyl acetate/crotonic acid copolymers, vinylpyrrolidone/vinyl acrylate copolymers, vinyl acetate/butyl maleate/isobornyl acrylate copolymers, methyl vinyl ether/maleic anhydride copolymers and acrylic acid/ethyl acrylate/N-tert-butylacrylamide terpolymers, thickeners, such as agar agar, guar gum, alginates, xanthan gum, gum arabic, karaya gum, carob seed flour, linseed gums, dextrans, cellulose derivatives, e.g. methylcellulose, hydroxyalkylcellulose and carboxymethylcellulose, starch fractions and derivatives, such as amylose, amylopectin and dextrins, clays, such as, for example, bentonite or completely synthetic hydrocolloids, such as, for example, polyvinyl alcohol, structurants, such as maleic acid and lactic acid, hair-conditioning compounds, such as phospholipids, for example soya lecithin, egg lecithin and cephalins, protein hydrolyzates, in particular elastin, collagen, keratin, milk protein, soya protein and wheat protein hydrolyzates, their condensation products with fatty acids, and quaternized protein hydrolyzates, perfume oils, dimethyl isosorbide and cyclodextrins, solvents and solubility promoters, such as ethanol, isopropanol, ethylene glycol, propylene glycol, glycerol and diethylene glycol, fiber-structure-improving active ingredients, in particular mono-, di- and oligosaccharides, such as, for example, glucose, galactose, fructose, fruit sugars and lactose, quaternized amines, such as methyl-1-alkylamidoethyl-2-alkylimidazolinium methosulfate antifoams, such as silicones, dyes for coloring the composition, antidandruff active ingredients, such as piroctone olamine, zinc omadine and climbazole, photoprotective agents, in particular derivatized benzophenones, cinnamic acid derivatives and triazines, substances for adjusting the pH, such as, for example, customary acids, in particular food acids and bases, active ingredients, such as allantoin, pyrrolidonecarboxylic acids and salts thereof, and bisabolol, vitamins, provitamins and vitamin precursors, in particular those of groups A, B 3 , B 5 , B 6 , C, E, F and H, plant extracts, such as the extracts from green tea, oak bark, stinging nettle, hamamelis, hops, camomile, burdock, horsetail, hawthorn, linden blossom, almond, aloe vera, fir needle, roast chestnut, sandalwood, juniper, coconut, mango, apricot, lemon, wheat, kiwi, melon, orange, grapefruit, sage, rosemary, birch, mallow, lady's smock, wild thyme, yarrow, thyme, melissa, restharrow, coltsfoot, marshmallow, meristem, ginseng and ginger root, cholesterol, consistency regulators, such as sugar esters, polyol esters and polyol alkyl ethers, fats and waxes, such as spermaceti, beeswax, montan wax and paraffins, fatty acid alkanolamides, complexing agents, such as EDTA, NTA, β-alaninediacetic acid and phosphonic acids, swelling and penetration substances, such as glycerol, propylene glycol monoethyl ether, carbonates, hydrogencarbonates, guanidines, ureas, and primary, secondary and tertiary phosphates, opacifiers, such as latex, styrene/PVP and styrene/acrylamide copolymers pearlizing agents, such as ethylene glycol mono- and distearate, and PEG-3 distearate, pigments, stabilizers for hydrogen peroxide and other oxidizing agents, propellants, such as propane-butane mixtures, N 2 O, dimethyl ether, CO 2 and air, antioxidants.
With regard to further optional components and to the amounts of these components used, reference is made expressly to the relevant handbooks known to the person skilled in the art, e.g. Kh. Schrader, Grundlagen und Rezepturen der Kosmetika [Fundamentals and formulations of cosmetics], 2nd edition, Hüthig Buch Verlag, Heidelberg, 1989.
The actual oxidative coloring of the fibers can in principle take place with atmospheric oxygen. However, preference is given to using a chemical oxidizing agent, particularly if a lightening effect on human hair is desired besides the coloring. Suitable oxidizing agents are persulfates, chlorites and, in particular, hydrogen peroxide or its addition products onto urea, melamine and sodium borate. However, according to the invention, the oxidation colorant can also be applied to the hair together with a catalyst which activates the oxidation of the dye precursors, e.g. by atmospheric oxygen. Such catalysts are, for example, metal ions, iodides, quinones or certain enzymes.
Suitable metal ions are, for example, Zn 2+ , Cu 2+ , Fe 2+ , Fe 3+ , Mn 2+ , Mn 4+ , Li + , Mg 2+ , Ca 2+ and Al 3+ . Of particular suitability in this connection are Zn 2+ , Cu 2+ and Mn 2+ . The metal ions can in principle be used in the form of any physiologically compatible salt or in the form of a complex compound. Preferred salts are the acetates, sulfates, halides, lactates and tartrates. The use of these metal salts can both accelerate the development of the coloration and also influence the color nuance in a targeted manner.
Suitable enzymes are, for example, peroxidases, which can considerably enhance the effect of small amounts of hydrogen peroxide. Also of suitability according to the invention are those enzymes which directly oxidize the oxidation dye precursors with the help of atmospheric oxygen, such as, for example, the laccases, or produce in situ small amounts of hydrogen peroxide and in so doing biocatalytically activate the oxidation of the dye precursors. Particularly suitable catalysts for the oxidation of the dye precursors are the so-called 2-electron oxidoreductases in combination with the substrates specific therefor, e.g.
pyranose oxidase and e.g. D-glucose or galactose, glucose oxidase and D-glucose, glycerol oxidase and glycerol, pyruvate oxidase and pyruvic acid or salts thereof, alcohol oxidase and alcohol (MeOH, EtOH), lactate oxidase and lactic acid and salts thereof, tyrosinase oxidase and tyrosine, uricase and uric acid or salts thereof, choline oxidase and choline, amino acid oxidase and amino acids.
The surface of the film sachet is given an embossed structure by heating and pressing, preferably prior to filling the film sachet with a cosmetic preparation.
The coating material is preferably a blow-molded or, in particular, cast polymer film which is embossed in the heated state using a die in order to impart the advantageous surface properties to it. The embossing operation is preferably carried out in such a way that the film is pressed on one side with the die tool so that a three-dimensional structure is embossed on one side and appears again on the opposite side as a “negative”.
The portions according to the invention are usually marketed in a selling unit (kit) containing a mixing set and optionally one or more further preparations and/or cosmetic applications devices. The present embodiment according to the invention thus further provides a kit comprising a mixing set and one or more portions according to the invention.
In a further advantageous embodiment, the kit according to the invention additionally comprises one or more constituents chosen from the group
a) one or more further receiving container(s) comprising at least one further cosmetic preparation, preferably a hydrogen peroxide solution or hydrogen peroxide emulsion or a care lotion; and/or b) one or more safety materials for avoiding the undesired contact between the cosmetic preparation and the human body, preferably gloves.
In a particularly advantageous embodiment, the mixing set according to the invention comprises at least one portion according to the invention with a bleaching powder as preparation, a mixing device, and preferably a plastic bottle containing an aqueous hydrogen peroxide solution or hydrogen peroxide emulsion or hydrogen peroxide dispersion and optionally additionally a care lotion.
In a further advantageous embodiment, the kit according to the invention comprises at least one or more portions according to the invention which comprise bleaching powder as cosmetic preparation, one or more containers comprising a hydrogen peroxide emulsion or hydrogen peroxide dispersion, a mixing device for mixing the components, and safety gloves and optionally one or more highlighting caps or highlighting needles.
In a further advantageous embodiment of the invention, the kit according to the invention comprises at least one or more portions according to the invention comprising a hair colorant, preferably a hair colorant precursor, particularly advantageously component A of an oxo colorant. In addition, the kit comprises a mixing device for mixing the components and preferably additionally one or more portions comprising a further hair coloring component, preferably component B of an oxo colorant and optionally additionally an oxidizing agent preparation (C), which can either be aqueous, e.g. in the case of hydrogen peroxide or in the form of an anhydrous powder, e.g. a hydrogen peroxide adduct onto urea (percarbamide) or onto melamine (melamine perhydrate) or in the form of another percompound, e.g. magnesium peroxide or potassium persulfate.
A further subject-matter is the use of the above-described water-soluble and/or water-dispersible film sachets for portioning cosmetic preparations. The surface of the film sachet has, as already described, a square mean value for the roughness of at least 10 μm. For the purposes of the present embodiment according to the invention, portioning is understood as meaning the dividing of quantitative amounts into suitable handleable sizes, e.g. the amount required for a single hair-coloring or hair-bleaching operation. These quantity units are packaged by means of the coating material to give portions, e.g. to give water-soluble sachets or capsules.
A further subject-matter is the use of a water-soluble and/or water-dispersible film sachet for the portioning of cosmetic preparations which preferably have the roughness values described above. The use takes place in the course of this subject-matter with a coating which has a three-dimensional macroscopic surface which is at least 10%, advantageously at least 20%, further advantageously at least 30% and 50%, larger than the two-dimensional geometric surface.
BRIEF DESCRIPTION OF THE DRAWINGS
The invention is explained in more detail by way of example below by reference to the drawing and working examples. This shows, in each case in a longitudinal section:
FIG. 1 a mixing device according to a first configuration and
FIG. 2 a mixing device according to a second configuration.
DETAILED DESCRIPTION OF THE INVENTION
A mixing device according to the invention is generally indicated in the drawing by 1 . This mixing device 1 has a mixing container 2 which is provided on the upper side with a container opening 3 which can be sealed with a container lid 4 , where in the case of the working example the container lid 4 can be screwed on; a screw thread is indicated by 5 .
As alternatives to the screw connection, a plug connection or a snap-action latch may also be provided.
In the region of the container opening 3 , an insert 6 is placed on the container 2 ; this is curved out like a citrus press into the receiving chamber 7 of the container. This insert 6 can be removed from the container opening in order to fill the receiving chamber of the container 7 , then it can be replaced and then remains firmly positioned after the container lid 4 has been screwed on.
The mixing device 1 designed in this way serves to receive a product 9 contained in a film sachet 8 which is soluble in a liquid solvent, said product preferably being a bleaching powder.
Besides the film sachet 8 filled with the product 9 , a liquid solvent which is able to dissolve the film sachet 8 is introduced into the receiving chamber 7 with an opened mixing container 2 . This liquid solvent is, for example, a hydrogen peroxide solution. This is introduced from a receiving container which is not shown into the receiving chamber 7 of the mixing container 2 . Moreover, a further component, for example a bleaching cream, can also additionally be introduced from a likewise not shown further receiving container into the receiving chamber 7 .
The citrus press-like insert 6 is then placed onto the container opening 3 and the container opening 3 is closed with the lid 4 . If the mixing device 1 is now shaken by the user, the film sachet 8 automatically comes into contact with the citrus press-like insert 6 and in so doing becomes mechanically strained to such an extent that it tears, at least in places. The pulverulent product 9 can then escape directly from the film sachet and mix with the liquid, the fill level for which in the resting state is indicated by 10 . As a result, the rate of the mixing operation is increased significantly, and, moreover, as a result of the comminution or disruption of the film sachet 8 , the latter can also be dissolved more quickly by the liquid solvent. After an adequate mixing time, which depends on the products to be mixed, the mixing container 2 is opened again by removing the lid 4 . The insert 6 is then removed and the finished product can be taken out.
The embodiment according to FIG. 2 differs from that according to FIG. 1 only by virtue of a differently designed insert 6 ′. This insert 6 ′ is constructed like a sieve plate and is provided with tapered pins 11 pointing into the receiving chamber 7 .
Upon shaking the mixing device, the pins 11 penetrate into at least some areas of the film sachet 8 and lead to its partial destruction, meaning that the pulverulent product 9 can escape easily and mix with the liquid solvent.
The invention is of course not limited to the working examples shown. Further configurations are possible without departing from the basic concept. For example, instead of the inserts shown, it is also possible for other internal inserts to be provided for the mechanical action on the film sachet in the receiving chamber; these may also be arranged in a fixed manner within the receiving chamber.
Furthermore, an additional liquid-tight cover can also be attached above the inserts which prevents liquid passing into the space above the inserts during the mixing operation. This cover is then removed together with the inserts when the mixing operation is complete.
Alternatively, it is to be provided that the insert and the lid consist of a single element, which can be produced, for example, in an injection molding process.
As design simplest for the user, such a single-part design is also firmly attached to a seal configured as a sealing ring. In this simplest case, the closure required for using the mixing container requires only a single hand grip.
Moreover, the film sachet can be under superatmospheric pressure, which also informs the user acoustically of the destruction as a result of the mechanical strain by the internal inserts. After the expected pop, it can be assumed that the sachet is torn at least in some areas, and thus the contained product is ready for the mixing operation.
In a further advantageous case, the product contained in the film sachet is a cosmetic preparation and the two together form a cosmetic portion.
Examples of the cosmetic portion:
EXAMPLE 1
A portion according to the invention comprising a bleaching powder with the composition given in Table 1 was prepared.
TABLE 1
Bleaching powder
Raw material
Data in % by wt.
Ammonium persulfate
21.5%
Sodium phosphate
4.0%
Aerosil 200
3.0%
Potassium persulfate
33.0%
Britesil ® C 20
22.0%
Sodium stearate
8.0%
Ceasit ® I
4.0%
Magnesium oxide
2.0%
Magnesium hydroxide carbonate
1.0%
Lanette ® E
1.0%
Idranal ® III
0.5%
The following raw materials were used:
Aerosil® 200: fumed silica (INCI name: Silica) (Degussa) Britesil® C20: sodium silicate; molar ratio SiO 2 :Na 2 O=2.0 Ceasit® I: calcium stearate Lanette®E: sodium cetylstearyl sulfate (ex Cognis) Idranal® III: ethylenediamine-N,N,N′,N′-tetraacetic acid disodium salt
The raw material components of the bleaching powder are mixed and ground until the average particle size is 100 μm.
The bleaching powder is then packaged in a water-soluble PVA polymer film (Solublon, type SA 20 ex Syntana) using a tubular sachet sealing process.
The film sachet has the following properties:
square mean value for the roughness: 30 μm average thickness of the film: 20 μm film material: partially hydrolyzed polyvinyl acetate with a degree of hydrolysis of 96%; cast film; average molecular weight: 36 000 g/mol
The outer and inner surfaces of the polymer film have a three-dimensional structure with a square-shaped pattern. The pattern is formed by a grid with square indentations, meaning that the grid lines are formed by the edges of the indentations.
The depth of the indentation is 0.12 mm. The embossed squares have a diameter of 0.6 mm.
The portion according to the invention comprises 25 g of the abovementioned bleaching powder.
The portion was subsequently dissolved in a hydrogen peroxide dispersion with a composition according to Table 2, at 20° C.:
TABLE 2
Hydrogen peroxide dispersion
Raw materials
Data in % by wt
Lorol ® C16
3.6%
Eumulgin
0.9%
Texapon ® NSO
2.25%
Ammonia (25%)
0.65%
Dipicolinic acid
0.1%
Sodium pyrophosphate
0.03%
Turpinal ® SL
1.5%
Hydrogen peroxide
6%
Water
ad 100%
The following raw material components were used:
Lorol® C 16 : C 16 -fatty alcohol Eumulgin®: Ceteareth-20 Texapon® NSO: sodium lauryl ether sulfate with 2 EO Turpinal® SL: hydroxyethyldiphosphonic acid
It has been found that the portion according to the invention dissolves about 5 times as quickly as the portions known from the prior art with coating materials made of smooth water-soluble films of comparable thicknesses.
The portion according to the invention is contained in a kit together with the following constituents:
a) a mixing device c) a plastic bottle containing a hydrogen peroxide dispersion according to Table 2 d) a conditioner
EXAMPLE 2
Formulation for the Oxo Coloring
Coloring with CH-acidic components and aromatic aldehyde
TABLE 3
Component 1
Component 2
Paraffin oil,
7.5 g
Cetiol ® B
7.5 g
low-viscosity
Cremophor ® RH 40
2.0 g
Dehydol ® LS3
4.0 g
Rheopearl ® KL
0.5 g
Rheopearl ® KL
0.5 g
Both components (1 and 2) were heated to 80° C. with stirring. At this temperature, clear, low-viscosity liquids formed in both cases which, upon cooling to room temperature, thickened to give clear, medium-viscosity gels.
After cooling,
0.75 g of dimethylaminobenzaldehyde 1.2 g of Methocel® E4M and 0.5 g of arginine were homogeneously dispersed into component 1 and 0.85 g of 1,2-dihydro-1,3,4,6-tetramethyl-2-oxopyridinium chloride and 3.6 g of a C 8 –C 10 -fatty alcohol mixture liquid at room temperature (20° C.)
were homogeneously dispersed into component 2.
The following raw materials were used:
Cremophor RH 40: castor oil, hydrogenated with 40-45 ethylene oxide units (INCI name: PEG-40 Hydrogenated Castor Oil) (BASF) Rheopearl®KL: dextrin palmitate ex Miyoshi Kasei Cetiol® B: di-n-butyl adipate Dehydol® LS 3: lauryl alcohol-3 EO ex Cognis Methocel® E 4 M: hydroxypropylmethylcellulose
To prepare a portion according to the invention, component 1 and component 2 were in each case introduced separately into a water-soluble film sachet which has the specification as in example 1, and then thermally sealed to be liquid-tight.
Portion 1 comprising component 1 and portion 2 comprising component 2 were stirred into 80 ml of water at 40° C. This gave a readily flowable emulsion.
A hair tress (Kerling natural white) colored with this formulation in the weight ratio 4:1 for 30 minutes at 32° C. was nuanced an intense magenta color.
EXAMPLE 3
Coloring with Oxidation Dyes
TABLE 4
Paraffin oil, low-viscosity
19.50
g
Dehydol ® LS4
0.25
g
Gelatinization agent GP-1
0.25
g
The following raw material was used:
Gelatinization agent GP-1: N-lauroyl-1-glutamic acid-α,γ-di-n-butylamide ex Ajinomoto Dehydol® LS4: lauryl alcohol-4 EO
The gel was prepared as described in example 2 at 80° C. and cooling to room temperature. 1.2 g of tetraaminopyrimidine sulfate and 0.6 g of methylresorcinol and 2 g of sodium carbonate and 3 g of trisodium phosphate were homogeneously dispersed into the gel with the composition given in Table 4.
The gel was introduced into a film sachet with the coating material specified in example 1 and sealed to be liquid-tight analogously to example 2.
A 5 g portion was prepared which was mixed with 20 g of a commercial 6% strength developer emulsion (Poly Color cream hair color) and 20 g of a 2% strength Natrosol 250 HR swelling in which 0.5 g of ammonium sulfate were dissolved, at room temperature (20° C.).
This emulsion was used to dye a blond hair tress (Kerling natural white) (30 minutes, 32° C.). The nuancing of the tress was a luminous red.
The following raw materials were used:
Natrosol 250 HR: hydroxyethylcellulose ex Aqualon viscosity (1% in H 2 O): 1.5–2.5 Pas (20° C.) viscosity (2% in H 2 O): 30 Pas (20° C.)
EXAMPLE 4
Oxo Coloring
Coloring with Acidic Carbonyl Compounds and Aromatic Amines
TABLE 5
Component 1
Component 2
Cetiol ® 868
2.00
g
Stenol ® 1618
4.00
g
(isooctyl stearate)
Eumulgin B1
0.40
g
Paraffin oil,
14.00
g
Eumulgin ® B2
0.40
g
low-viscosity
p-tolylenediamine
0.88
g
sulfate
Cutina ® GMS
2.00
g
ammonium sulfate
0.20
g
Dehydol ® LS 2
2.00
g
water
34.12
g
with ammonia to pH 9
The following raw materials were used:
Dehydol® LS 2: lauryl alcohol-2 EO Eumulgin® B2: cetylstearyl alcohol with 20 mol of ethylene oxide Stenol® 1618: C 16 /C 18 -fatty alcohol mixture Cutina® GMS: glycerol monostearate ex Cognis Eumulgin® B1: cetylstearyl alcohol with 12 mol of ethylene oxide
The constituents of component 1 were heated to 80° C. 0.6 g of N-allylisatin was dissolved in the hot mixture. Then, with stirring, the mixture was cooled to room temperature. The formulation was packaged in a tubular sachet as in example 2. After dissolving the portion in component 2, the coloring of a blond hair tress (Kerling natural white, 30 minutes, 32° C.) was carried out. The color of the tress was titian red.
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The invention relates to a mixing device for mixing a pulverulent product, which is contained in a film sachet that is soluble in liquid, with said liquid and optionally at least one additional component. The aim of the invention is to accelerate the mixing of pulverulent products, which are packed in film sachets that are soluble in liquid, with a liquid, without the risk of creating dust. This is achieved by a sealable mixing container ( 2 ) comprising a receiving chamber ( 7 ) for the pulverulent product ( 9 ) contained in the film sachet ( 8 ), the liquid and the optional additional component. The receiving chamber ( 7 ) is equipped with fitted components ( 6, 6′ ), which act mechanically on the film sachet ( 8 ).
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BACKGROUND OF THE INVENTION
I. Field of the Invention
The present application relates to the art of recreational devices and, in particular, the present invention seeks to provide a game board apparatus intended to familiarize participants with certain broad principles of business and finance applicable to the construction industry, while affording entertainment and intellectual challenge in the simulated financing of a building project.
II. Description of the Prior Art
While there are many educational games which teach various aspects, such as geographical information, games adapted to familiarize participants with broad legal principles in the acquisition of property, investments, and the purchasing of services and goods, the applicant is not aware of any game which familiarizes participants with the broad business and financial principles applicable to the construction industry. Further, while many previous games have provided entertainment and intellectual challenge, most such games consist of a game board with a plurality of player elements which are moved thereabout around the periphery of the board according to numbers determined by chance, such as the rolling of dice or the rotating of a spinner. Interrelationships between the players themselves are often excluded, and generally the participants are playing along the same course at the same time. These games generally do not involve any decision making steps or any competitiveness between the players aside from the result of chance; and, thus, the participant's ability to make decisions and to choose between various alternatives goes unchallenged.
The prior art games over which the game of the present invention seeks to achieve a substantial improvement and interest in mental stimulation, training and educational experience are typified by the following U.S. Pat. Nos. 2,026,082; 2,780,463; 2,693,961; and 3,367,226.
SUMMARY OF THE INVENTION
The present invention, which will be described subsequently in greater detail, comprises a game board having a plurality of individual playing courses, each of which are individually played by the participants of the game in order to teach the participants broad principles of business and finance associated with the construction industry.
It is therefore a primary object of the present invention to provide a new and improved game involving the simulated construction of a building including the familiarization by the participants of the financial and business principles related to the construction industry.
Another object of the present invention is to provide a game in which skills in analysis, understanding of financial matters, the ability to plan in advance, and simulation of the actual construction industry are provided.
Other objects, advantages and applications of the present invention will become apparent to those skilled in the art of educational games when the accompanying description of one example of the best mode of practicing the invention is read in conjunction with the accompanying drawings.
BRIEF DESCRIPTION OF THE DRAWINGS
The description herein makes reference to the accompanying drawings wherein like reference numerals refer to like parts throughout the several views, and wherein:
FIG. 1 is a plan view of a game board, at an appreciably reduced scale, employed in the described embodiment of the present invention and illustrating twelve separate playing courses;
FIG. 2 is a somewhat enlarged plan view of one example of one of a plurality of individual playing courses illustrated on the game board of FIG. 1;
FIG. 3 is a plan view of one of a plurality of so-called "bulletin" cards which are to be drawn from individually by each participant during selected portions of the game;
FIG. 4 is a plan view of one of a plurality of so-called "backcharge" cards which are to be drawn from individually by each participant during selected portions of the game;
FIG. 5 is one example of a card in a set of twelve cards for each of the twelve courses and indicates certain values associated with various phases of movement by a participant through each playing course;
FIG. 6 is a plan view of script money used in various denominations;
FIG. 7 is one example of a playing piece employed in playing the game;
FIG. 7a is a perspective view of a dice;
FIG. 8 is a front plan view of a so-called "bid" card utilized during the course of the game to provide the participants with a means for selecting which course will be played; and
FIG. 9 is a rear plan view of the "bid" card illustrated in FIG. 8.
DESCRIPTION OF THE PREFERRED EMBODIMENT
Referring now to the drawings and, in particular, to FIG. 1 wherein there is illustrated one example of the present invention in the form of a game board 10. Illustrated on the board is a group of twleve individual playing courses, each of which will be described in greater detail hereinafter. Each of the playing courses represents a particular type of construction project; and as can best be seen in FIG. 2, wherein the course 18 is illustrated in an enlarged fashion, each course is divided into a plurality of sections or spaces. The upper section or spaces 36 state the name of the building project and its approximate cost of construction. Space 38 represents that portion on the course wherein each participant places his bid, a function of which will be described hereinafter. Space 40 represents the starting point in each individual course. As will be described in greater detail hereinafter, each participant, when playing a course, commences at the starting space 40 and moves through each of the numbered spaces 42 through 62, performing the designated state of construction as is associated with the actual construction of a building. For example, on space 42 excavation of the property must be performed, and a particular dollar value is noted in the space 42 so associated with the excavation of this particular course. The next space 44 designates the concrete portion and a dollar amount associated therewith. The next space 46 designates the masonry work and the dollar amount associated therewith. The next space 48 designates the steel and miscellaneous iron associated with the steel work and the dollar amount associated with such steel work. The next space 50 designates carpentry work and the dollar amount associated with such work. The next space 52 represents hollow metal and the dollar amount associated therewith. The next space 54 represents specialties and the dollar amount associated therewith. The next space 56 represents plaster work and lath and the dollar amount associated therewith. The next space 58 represents the work performed in the installation of doors, windows, and glass and the dollar amount associated therewith. The next space 60 represents mechanical matters and the dollar amount associated with the installation of such matters. The next space 62 relates to electrical matters and the dollar amount associated therewith.
Space 64 designates the end of playing for that particular course and is defined as "collect retainage" wherein the participant performs certain acts as described hereinafter. Space 66 illustrates the bidding costs associated with various types of bids in which the participants may make, and space 68 immediately to the right of space 66 is a retainage which the player receives in accordance with the type of bid he makes. This will also be described in greater detail hereinafter.
Referring now to FIG. 1, in addition to the indicia illustrated in FIG. 2 of the drawings with respect to the course 18, the board as aforementioned has a total of twelve courses 12 through 34. Each course has spaces 38 and 40 which designate the positioning spot for the bids and the starting position for the individual course, respectively. Additionally, each space 42 through 62 designates the aforementioned sub-construction portions of the construction of a building or similar project; that is, the spaces 42 through 62 designate respectively the cost for excavation; concrete; masonry; steel & miscellaneous iron; carpentry; hollow metal; doors; windows, glass; lath & plaster; specialties; mechanical work; and electrical work. Similarly, each of the courses has a collect retainage space 64. The dollar amounts associated with each of the spaces 42 through 62 will be described hereinafter with respect to the plurality of job cost construction cards 70 that are illustrated in FIG. 5 of the drawings.
As can best be seen in FIGS. 1 and 2 of the drawings, each of the courses 12 through 34 contains the spaces 66 and 68 respectively indicating the amount at which a party may bid and the retainage that a participant receives if he bids that amount and successfully completes the course for that particular building job. The various bid amounts, which are determined in the manner to be described hereinafter, and the retainage that is associated with bid amounts are as follows for each of the following courses:
1. Course 12: United States Army Corp. of Engineers Flood Retention Basin--approximate cost $6,000,000.
______________________________________BID RETAINAGE______________________________________(a) 5% Below Cost $5,700,000 $570,000(b) 2.5% Below Cost $5,850,000 $585,000(c) Cost $6,000,000 $600,000(d) 2.5% Above Cost $6,150,000 $615,000(e) 5% Above Cost $6,300,000 $630,000(f) 10% Above Cost $6,600,000 $660,000______________________________________
2. Course 14: 3 Story Office Building--approximate cost $6,000,000.
______________________________________BID RETAINAGE______________________________________(a) 5% Below Cost $5,700,000 $570,000(b) 2.5% Below Cost $5,850,000 $585,000(c) Cost $6,000,000 $600,000(d) 2.5% Above Cost $6,150,000 $615,000(e) 5% Above Cost $6,300,000 $630,000(f) 10% Above Cost $6,600,000 $660,000______________________________________
3. Course 16: WSKI Tower--approximate cost $4,000,000.
______________________________________BID RETAINAGE______________________________________(a) 5% Below Cost $3,800,000 $380,000(b) 2.5% Below Cost $3,900,000 $390,000(c) Cost $4,000,000 $400,000(d) 2.5% Above Cost $4,100,000 $410,000(e) 5% Above Cost $4,200,000 $420,000(f) 10% Above Cost $4,400,000 $440,000______________________________________
4. Course 18: State Parking Deck--approximate cost $4,000,000.
______________________________________BID RETAINAGE______________________________________(a) 5% Below Cost $3,800,000 $380,000(b) 2.5% Below Cost $3,900,000 $390,000(c) Cost $4,000,000 $400,000(d) 2.5% Above Cost $4,100,000 $410,000(e) 5% Above Cost $4,200,000 $420,000(f) 10% Above Cost $4,400,000 $440,000______________________________________
5. Course 20: Peach Lane Shopping Center--approximate cost $20,000,000.
______________________________________BID RETAINAGE______________________________________(a) 5% Below Cost $19,000,000 $1,900,000(b) 2.5% Below Cost $19,500,000 $1,950,000(c) Cost $20,000,000 $2,000,000(d) 2.5% Above Cost $20,500,000 $2,050,000(e) 5% Above Cost $21,000,000 $2,100,000(f) 10% Above Cost $22,000,000 $2,200,000______________________________________
6. Course 22: New City Hospital--approximate cost $22,000,000.
______________________________________BID RETAINAGE______________________________________(a) 5% Below Cost $20,900,000 $2,090,000(b) 2.5% Below Cost $21,450,000 $2,145,000(c) Cost $22,000,000 $2,200,000(d) 2.5% Above Cost $22,550,000 $2,255,000(e) 5% Above Cost $23,100,000 $2,310,000(f) 10% Above Cost $24,200,000 $2,420,000______________________________________
7. Course 24: Wastewater Treatment Plant--approximate cost $18,000,000.
______________________________________BID RETAINAGE______________________________________(a) 5% Below Cost $17,100,000 $1,710,000(b) 2.5% Below Cost $17,550,000 $1,755,000(c) Cost $18,000,000 $1,800,000(d) 2.5% Above Cost $18,450,000 $1,845,000(e) 5% Above Cost $18,900,000 $1,890,000(f) 10% Above Cost $19,800,000 $1,980,000______________________________________
8. Course 26: Lakeside Amusement Park--approximate cost $16,000,000.
______________________________________BID RETAINAGE______________________________________(a) 5% Below Cost $15,200,000 $1,520,000(b) 2.5% Below Cost $15,600,000 $1,560,000(c) Cost $16,000,000 $1,600,000(d) 2.5% Above Cost $16,400,000 $1,640,000(e) 5% Above Cost $16,800,000 $1,680,000(f) 10% Above Cost $17,600,000 $1,760,000______________________________________
9. Course 28: 14 Story IZA Building Headquarters--approximate cost $14,000,000.
______________________________________BID RETAINAGE______________________________________(a) 5% Below Cost $13,300,000 $1,330,000(b) 2.5% Below Cost $13,650,000 $1,365,000(c) Cost $14,000,000 $1,400,000(d) 2.5% Above Cost $14,350,000 $1,435,000(e) 5% Above Cost $14,700,000 $1,470,000(f) 10% Above Cost $15,400,000 $1,540,000______________________________________
10. Course 30: Nesmrik County Jail--approximate cost $12,000,000.
______________________________________BID RETAINAGE______________________________________(a) 5% Below Cost $11,400,000 $1,140,000(b) 2.5% Below Cost $11,700,000 $1,170,000(c) Cost $12,000,000 $1,200,000(d) 2.5% Above Cost $12,300,000 $1,230,000(e) 5% Above Cost $12,600,000 $1,260,000(f) 10% Above Cost $13,200,000 $1,320,000______________________________________
11. Course 32: Automotive Assembly Plant--approximate cost $8,000,000.
______________________________________BID RETAINAGE(a) 5% Below Cost $7,600,000 $760,000(b) 2.5% Below Cost $7,800,000 $780,000(c) Cost $8,000,000 $800,000(d) 2.5% Above Cost $8,200,000 $820,000(e) 5% Above Cost $8,400,000 $840,000(f) 10% Above Cost $8,800,000 $880,000______________________________________
12. Course 34: 10 Story Apartment--approximate cost $8,000,000.
______________________________________BID RETAINAGE(a) 5% Below Cost $7,600,000 $760,000(b) 2.5% Below Cost $7,800,000 $780,000(c) Cost $8,000,000 $800,000(d) 2.5% Above Cost $8,200,000 $820,000(e) 5% Above Cost $8,400,000 $840,000(f) 10% Above Cost $8,800,000 $880,000______________________________________
Associated with each course 12 through 34 is a set of cost information cards 70. Each set includes eleven cards numbered 2A through 12A, which corresponds to the numbers 2A through 12A in the spaces 42 through 62 of FIG. 2. The card 70 illustrated in FIG. 2 is typical of the cards of each set. Each card has a designation 72 at the top which names the particular project and its total value. A sub-designation 74 designates the type of job that the participant is working on. For example, in FIG. 5 the card 2A relates to the excavation and has the same dollar amount ($200,000) as indicated in space 42 in FIG. 2. The card 70 has instructions which relate to a number which is obtained by the roll of a dice, as will be explained hereinafter. For example, if the dice is rolled so as to obtain the number 7, the pay amount, as illustrated in FIG. 5, is for $180,000. Other rolls of the dice can result in any one of several numerals which result in the determination of the amount of money that the player must theoretically receive and/or pay out in the course of performing the excavation, all of which will be described in greater detail hereinafter during the description of the game. Each course has a set of cards 70 which includes eleven cards Nos. 2A through 12A. The set of cards 70 associated with the game 12 are as follows and include the following designations:
Course 12: U.S. Army, Value $6,000,000
2A Excavation, Value $300,000; #7 Pay $270,000; Add Pay $270,000; Deduct Pay $285,000; #7 Collect $270,000; Add Collect $285,000; Deduct Collect $255,000
3A Concrete, Value $900,000; #7 Pay $810,000; Add Pay $810,000; Deduct Pay $855,000; #7 Collect $810,000; Add Collect $855,000; Deduct Collect $765,000
4A Masonry, Value $540,000; #7 Pay $486,000; Add Pay $486,000; Deduct Pay $513,000; #7 C/llect $486,000; Add Collect $513,000; Deduct Collect $459,000
5A Steel & Miscellaneous, Value $600,000; #7 Pay $540,000; Add Pay $540,000; Deduct Pay $570,000; #7 Collect $540,000; Add Collect $570,000; Deduct Collect $510,000
6A Carpentry, Value $360,000; #7 Pay $324,000; Add Pay $324,000; Deduct Pay $342,000; #7 Collect $324,000; Add Collect $342,000; Deduct Collect $306,000
7A Hollow Metal, Value $120,000; #7 Pay $108,000; Add Pay $108,000; Deduct Pay $114,000; #7 Collect $108,000; Add Collect $114,000; Deduct Collect $102,000
8A Doors, Windows, Glass, Value $300,000; #7 Pay $270,000; Add Pay $270,000; Deduct Pay 285,000; #7 Collect $270,000; Add Collect $285,000; Deduct Collect $255,000
9A Lath & Plaster, Value $300,000; #7 Pay $270,000; Add Pay $270,000; Deduct Pay $285,000; #7 Collect $270,000; Add Collect $285,000; Deduct Collect $255,000
10A Specialties, Value $180,000; #7 Pay $162,000; Add Pay $162,000; Deduct Pay $171,000; #7 Collect $162,000; Add Collect $171,000; Deduct Collect $153,000
11A Mechanical, Value $1,080,000; #7 Pay $972,000; Add Pay $972,000; Deduct Pay $1,026,000; #7 Collect $972,000; Add Collect $1,026,000; Deduct Collect $918,000
12A Electrical, Value $1,320,000; #7 Pay $1,188,000; Add Pay $1,188,000; Deduct Pay $1,254,000; #7 Collect $1,188,000; Add Collect $1,254,000; Deduct Collect $1,122,000
Course 14: 3 Story Office, Value $6,000,000
2A Excavation, Value $300,000; #7 Pay #270,000; Add Pay $270,000; Deduct Pay $285,000; #7 Collect $270,000; Add Collect $285,000; Deduct Collect $255,000
3A Concrete, Value $900,000; #7 Pay $810,000; Add Pay $810,000; Deduct Pay $855,000; #7 Collect $810,000; Add Collect $855,000; Deduct Collect $765,000
4A Masonry, Value $540,000; #7 Pay $486,000; Add Pay $486,000; Deduct Pay $513,000; #7 Collect $486,000; Add Collect $513,000; Deduct Collect $459,000
5A Steel & Miscellaneous, Value $600,000; #7 Pay $540,000; Add Pay $540,000; Deduct Pay $570,000; #7 Collect $540,000; Add Collect $570,000; Deduct Collect $510,000
6A Carpentry, Value $360,000; #7 Pay $324,000; Add Pay $324,000; Deduct Pay $342,000; #7 Collect $324,000; Add Collect $342,000; Deduct Collect $306,000
7A Hollow Metal, Value $120,000; #7 Pay $108,000; Add Pay $108,000; Deduct Pay $114,000; #7 Collect $108,000; Add Collect $114,000; Deduct Collect $102,000
8A Doors, Windows, Glass, Value $300,000; #7 Pay $270,000; Add Pay $270,000; Deduct Pay $285,000; #7 Collect $270,000; Add Collect $285,000; Deduct Collect $255,000
9A Lath & Plaster, Value $300,000; #7 Pay $270,000; Add Pay $270,000; Deduct Pay $285,000; #7 Collect $270,000; Add Collect $285,000; Deduct Collect $255,000
10A Specialties, Value $180,000; #7 Pay $162,000; Add Pay $162,000; Deduct Pay $171,000; #7 Collect $162,000; Add Collect $171,000; Deduct Collect $153,000
11A Mechanical, Value $1,080,000; #7 Pay $972,000; Add Pay $972,000; Deduct Pay $1,026,000; #7 Collect $972,000; Add Collect $1,026,000; Deduct Collect $918,000
12A Electrical, Value $1,320,000; #7 Pay $1,188,000; Add Pay $1,188,000; Deduct Pay $1,254,000; #7 Collect $1,188,000; Add Collect $1,254,000; Deduct Collect $1,122,000
Course 16: WSKI Tower, Value $4,000,000
2A Excavation, Value $200,000; #7 Pay $180,000; Add Pay $180,000; Deduct Pay $190,000; #7 Collect $180,000; Add Collect $190,000; Deduct Collect $170,000
3A Concrete, Value $600,000; #7 Pay $540,000; Add Pay $540,000; Deduct Pay $570,000; #7 Collect $540,000; Add Collect $570,000; Deduct Collect $510,000
4A Masonry, Value $360,000; #7 Pay $324,000; Add Pay $324,000; Deduct Pay $342,000; #7 Collect $324,000; Add Collect $342,000; Deduct Collect $306,000
5A Steel & Miscellaneous, Value $400,000; #7 Pay $360,000; Add Pay $360,000; Deduct Pay $380,000; #7 Collect $360,000; Add Collect $380,000; Deduct Collect $340,000
6A Carpentry, Value $240,000; #7 Pay $216,000; Add Pay $216,000; Deduct Pay $228,000; #7 Collect $216,000; Add Collect $228,000; Deduct Collect $204,000
7A Hollow Metal, Value $80,000; #7 Pay $72,000; Add Pay $72,000; Deduct Pay $76,000; #7 Collect $72,000; Add Collect $76,000; Deduct Collect $68,000
8A Doors, Windows, Glass, Value $200,000; #7 Pay $180,000; Add Pay $180,000; Deduct Pay $190,000; #7 Collect $180,000; Add Collect $190,000; Deduct Collect $170,000
9A Lath & Plaster, Value $200,000; #7 Pay $180,000; Add Pay $180,000; Deduct Pay $190,000; #7 Collect $180,000; Add Collect $190,000; Deduct Collect $170,000
10A Specialties, Value $120,000; #7 Pay $108,000; Add Pay $108,000; Deduct Pay $114,000; #7 Collect $108,000; Add Collect $114,000; Deduct Collect $102,000
11A Mechanical, Value $720,000; #7 Pay $648,000; Add Pay $648,000; Deduct Pay $684,000; #7 Collect $648,000; Add Collect $684,000; Deduct Collect $612,000
12A Electrical, Value $880,000; #7 Pay $792,000; Add Pay $792,000; Deduct Pay $836,000; #7 Collect $792,000; Add Collect $836,000; Deduct Collect $748,000
Course 18: State Parking Deck, Value $4,000,000
2A Excavation, Value $200,000; #7 Pay $180,000; Add Pay $180,000; Deduct Pay $190,000; #7 Collect $180,000; Add Collect $190,000; Deduct Collect $170,000
3A Concrete, Value $600,000; #7 Pay $540,000; Add Pay $540,000; Deduct Pay $570,000; #7 Collect $540,000; Add Collect $570,000; Deduct Collect $510,000
4A Masonry, Value $360,000; #7 Pay $324,000; Add Pay $324,000; Deduct Pay $342,000; #7 Collect $324,000; Add Collect $342,000; Deduct Collect $306,000
5A Steel & Miscellaneous, Value $400,000; #7 Pay $360,000; Add Pay $360,000; Deduct Pay $380,000; #7 Collect $360,000; Add Collect $380,000; Deduct Collect $340,000
6A Carpentry, Value $240,000; #7 Pay $216,000; Add Pay $216,000; Deduct Pay $228,000; #7 Collect $216,000; Add Collect $228,000; Deduct Collect $204,000
7A Hollow Metal, Value $80,000; #7 Pay $72,000; Add Pay $72,000; Deduct Pay $76,000; #7 Collect $72,000; Add Collect $76,000; Deduct Collect $68,000
8A Doors, Windows, Glass, Value $200,000; #7 Pay $180,000; Add Pay $180,000; Deduct Pay $190,000; #7 Collect $180,000; Add Collect $190,000; Deduct Collect $170,000
9A Lath & Plaster, Value $200,000; #7 Pay $180,000; Add Pay $180,000; Deduct Pay $190,000; #7 Collect $180,000; Add Collect $190,000; Deduct Collect $170,000
10A Specialties, Value $120,000; #7 Pay $108,000; Add Pay $108,000; Deduct Pay $114,000; #7 Collect $108,000; Add Collect $114,000; Deduct Collect $102,000
11A Mechanical, Value $720,000; #7 Pay $648,000; Add Pay $648,000; Deduct Pay $684,000; #7 Collect $648,000; Add Collect $684,000; Deduct Collect $612,000
12A Electrical, Value $880,000; #7 Pay $792,000; Add Pay $792,000; Deduct Pay $836,000; #7 Collect $792,000; Add Collect $836,000; Deduct Collect $748,000
Course 20: Peach Lane Shopping Center, Value $20,000,000
2A Excavation, Value $1,000,000; #7 Pay $900,000; Add Pay $900,000; Deduct Pay $950,000; #7 Collect $900,000; Add Collect $950,000; Deduct Collect $850,000
3A Concrete, Value $3,000,000; #7 Pay $2,700,000; Add Pay $ $2,700,000; Deduct Pay $2,850,000; #7 Collect $2,700,000; Add Collect $2,850,000; Deduct Collect $2,550,000
4A Masonry, Value $1,800,000; #7 Pay $1,620,000; Add Pay $1,620,000; Deduct Pay $1,710,000; #7 Collect $1,620,000; Add Collect $1,710,000; Deduct Collect $1,530,000
5A Steel & Miscellaneous, Value $2,000,000; #7 Pay $1,800,000; Add Pay $1,800,000; Deduct Pay $1,900,000; #7 Collect $1,800,000; Add Collect $1,900,000; Deduct Collect $1,700,000
6A Carpentry, Value $1,200,000; #7 Pay $1,080,000; Add Pay $1,080,000; Deduct Pay $1,140,000; #7 Collect 1,080,000; Add Collect $1,140,000; Deduct Collect $1,020,000
7A Hollow Metal, Value $400,000; #7 Pay $360,000; Add Pay $360,000; Deduct Pay $380,000; #7 Collect $360,000; Add Collect $380,000; Deduct Collect $340,000
8A Doors, Windows, Glass, Value $1,000,000; #7 Pay $900,000; Add Pay $900,000; Deduct Pay $950,000; #7 Collect $900,000; Add Collect $950,000; Deduct Collect $850,000
9A Lath & Plaster, Value $1,000,000; #7 Pay $900,000; Add Pay $900,000; Deduct Pay $950,000; #7 Collect $900,000; Add Collect $950,000; Deduct Collect $850,000
10A Specialties, Value $600,000; #7 Pay $540,000; Add Pay $540,000; Deduct Pay $570,000; #7 Collect $540,000; Add Collect $570,000; Deduct Collect $510,000
11A Mechanical, Value $3,600,000; #7 Pay $3,240,000; Add Pay $3,240,000; Deduct Pay $3,420,000; #7 Collect $3,240,000; Add Collect $3,420,000; Deduct Collect $3,060,000
12A Electrical, Value $4,400,000; #7 Pay $3,960,000; Add Pay $3,960,000; Deduct Pay $4,180,000; #7 Collect $3,960,000; Add Collect $4,180,000; Deduct Collect $3,740,000
Course 22: New City Hospital, Value $22,000,000
2A Excavation, Value $1,1000,000; #7 Pay $990,000; Add Pay $990,000; Deduct Pay $1,045,000; #7 Collect $990,000; Add Collect $1,045,000; Deduct Collect $935,000
3A Concrete, Value $3,300,000; #7 Pay $2,970,000; Add Pay $2,970,000; Deduct Pay $3,135,000; #7 Collect $2,970,000; Add Collect $2,970,000; Deduct Collect $2,805,000
4A Masonry, Value $1,980,000; #7 Pay $1,782,000; Add Pay $1,782,000; Deduct Pay $1,881,000; #7 Collect $1,782,000; Add Collect $1,881,000; Deduct Collect $1,683,000
5A Steel & Miscellaneous, Value $2,200,000; #7 Pay $1,980,000; Add Pay $1,980,000; Deduct Pay $2,090,000; #7 Collect $1,980,000; Add Collect $2,090,000; Deduct Collect $1,870,000
6A Carpentry, Value $1,320,000; #7 Pay $1,188,000; Add Pay $1,188,000; Deduct Pay $1,254,000; #7 Collect $1,188,000; Add Collect $1,254,000; Deduct Collect $1,122,000
7A Hollow Metal, Value $440,000; #7 Pay $396,000; Add Pay $396,000; Deduct Pay $418,000; #7 Collect $396,000; Add Collect $418,000; Deduct Collect $374,000
8A Doors, Windows, Glass, Value $1,100,000; #7 Pay $990,000; Add Pay $990,000; Deduct Pay $1,045,000; #7 Collect $990,000; Add Collect $1,045,000; Deduct Collect $935,000
9A Lath & Plaster, Value $1,100,000; #7 Pay $990,000; Add Pay 990,000; Deduct Pay $1,045,000; #7 Collect $990,000; Add Collect $1,045,000; Deduct Collect $935,000
10A Specialties, Value $660,000; #7 Pay $594,000; Add Pay $594,000; Deduct Pay $627,000; #7 Collect $594,000; Add Collect $627,000; Deduct Collect $561,000
11A Mechanical, Value $3,960,000; #7 Pay $3,564,000; Add Pay $3,564,000; Deduct Pay $3,762,000; #7 Collect $3,564,000; Add Collect $3,762,000; Deduct Collect $3,366,000
12A Electrical, Value $4,840,000; #7 Pay $4,356,000; Add Pay $4,356,000; Deduct Pay $4,598,000; #7 Collect $4,356,000; Add Collect $4,598,000; Deduct Collect $4,114,000
Course 24: Wastewater Treatment Plant, Value $18,000,000
2A Excavation, Value $900,000; #7 Pay $810,000; Add Pay $810,000; Deduct Pay $855,000; #7 Collect $810,000; Add Collect $855,000; Deduct Collect $765,000
3A Concrete, Value $2,700,000; #7 Pay $2,430,000; Add Pay $2,430,000; Deduct Pay $2,565,000; #7 Collect $2,430,000; Add Collect $2,565,000; Deduct Collect $2,295,000;
4A Masonry, Value $1,620,000; #7 Pay $1,458,000; Add Pay $1,458,000; Deduct Pay $1,539,000; #7 Collect $1,458,000; Add Collect $1,539,000; Deduct Collect $1,377,000
5A Steel & Miscellaneous, Value $1,800,000; #7 Pay $1,620,000; Add Pay $1,620,000; Deduct Pay $1,710,000; #7 Collect $1,620,000; Add Collect $1,710,000; Deduct Collect $1,530,000
6A Carpentry, Value $1,080,000; #7 Pay $972,000; Add Pay $972,000; Deduct Pay $1,026,000; #7 Collect $972,000; Add Collect $1,026,000; Deduct Collect $918,000
7A Hollow Metal, Value $360,000; #7 Pay $324,000; Add Pay $324,000; Deduct Pay $342,000; #7 Collect $324,000; Add Collect $342,000; Deduct Collect $306,000
8A Doors, Windows, Glass, Value $900,000; #7 Pay $810,000; Add Pay $810,000; Deduct Pay $855,000; #7 Collect $810,000; Add Collect $855,000; Deduct Collect $765,000
9A Lath & Plaster, Value $900,000; #7 Pay $810,000; Add Pay $810,000; Deduct Pay $855,000; #7 Collect $810,000; Add Collect $855,000; Deduct Collect $765,000
10A Specialties, Value $540,000; #7 Pay $486,000; Add Pay $486,000; Deduct Pay $513,000; #7 Collect $486,000; Add Collect $513,000; Deduct Collect $459,000
11A Mechanical, Value $3,240,000; #7 Pay $2,916,000; Add Pay $2,916,000; Deduct Pay $3,078,000; #7 Collect 2,916,000; Add Collect $3,078,000; Deduct Collect $2,754,000
12A Electrical, Value $3,960,000; #7 Pay $3,564,000; Add Pay $3,564,000; Deduct Pay $3,762,000; #7 Collect $3,564,000; Add Collect $3,762,000; Deduct Collect $3,366,000
Course 26: Lakeside Amusement Park, Value $16,000,000
2A Excavation, Value $800,000; #7 Pay $720,000; Add Pay $720,000; Deduct Pay $760,000; #7 Collect $720,000; Add Collect $760,000; Deduct Collect $680,000
3A Concrete, Value $2,400,000; #7 Pay $2,160,000; Add Pay $2,160,000; Deduct Pay $2,280,000; #7 Collect $2,160,000; Add Collect $2,280,000; Deduct Collect $2,040,000
4A Masonry, Value $1,440,000; #7 Pay $1,296,000; Add Pay $1,296,000; Deduct Pay $1,368,000; #7 Collect $1,296,000; Add Collect $1,368,000; Deduct Collect $1,224,000
5A Steel & Miscellaneous, Value $1,600,000; #7 Pay $1,440,000; Add Pay $1,440,000; Deduct Pay $1,520,000; #7 Collect $1,440,000; Add Collect $1,520,000; Deduct Collect $1,360,000
6A Carpentry, Value $960,000; #7 Pay $864,000; Add Pay $864,000; Deduct Pay $912,000; #7 Collect $864,000; Add Collect $912,000; Deduct Collect $816,000
7A Metal, Value $320,000; #7 Pay $288,000; Add Pay $288,000; Deduct Pay $304,000; #7 Collect $288,000; Add Collect $304,000; Deduct Collect $272,000
8A Doors, Windows, Glass, Value $800,000; #7 Pay $720,000; Add Pay $720,000; Deduct Pay $760,000; #7 Collect $720,000; Add Collect $760,000; Deduct Collect $680,000
9A Lath & Plaster, Value $800,000; #7 Pay $720,000; Add Pay $720,000; Deduct Pay $760,000; #7 Collect $720,000; Add Collect $760,000; Deduct Collect $680,000
10A Specialties, Value $480,000; #7 Pay $432,000; Add Pay $432,000; Deduct Pay $456,000; #7 collect $432,000; Add Collect $456,000; Deduct Collect $408,000
11A Mechanical, Value $2,880,000; #7 Pay $2,592,000; Add Pay $2,592,000; Deduct Pay $2,736,000; #7 Collect $2,592,000; Add Collect $2,736,000; Deduct Collect $2,448,000
12A Electrical, Value $3,520,000; #7 Pay $3,168,000; Add Pay $3,168,000; Deduct Pay $3,344,000; #7 Collect $3,168,000; Add Collect $3,344,000; Deduct Collect $2,992,000
Course 28: 14 Story IZA Building, Value $14,000,000
2A Excavation, Value $700,000; #7 Pay $630,000; Add Pay $630,000; Deduct Pay $665,000; #7 Collect $630,000; Add Collect $665,000; Deduct Collect $595,000
3A Concrete, Value $2,100,000; #7 Pay $1,890,000; Add Pay $1,890,000; Deduct Pay $1,995,000; #7 Collect $1,890,000; Add Collect $1,995,000; Deduct Collect $1,785,000
4A Masonry, Value $1,260,000; #7 Pay $1,134,000; Add Pay $1,134,000; Deduct Pay $1,197,000; #7 Collect $1,134,000; Add Collect $1,197,000; Deduct Collect $1,071,000
5A Steel & Miscellaneous, Value $1,400,000; #7 Pay $1,260,000; Add Pay $1,260,000; Deduct Pay $1,330,000; #7 Collect $1,260,000; Add Collect $1,330,000; Deduct Collect $1,190,000
6A Carpentry, Value $840,000; #7 Pay $756,000; Add Pay $756,000; Deduct Pay $798,000; #7 Collect $756,000; Add Collect $798,000; Deduct Collect $714,000
7A Hollow Metal, Value $280,000; #7 Pay $252,000; Add Pay $252,000; Deduct Pay $266,000; #7 Collect $252,000 Add Collect $266,000; Deduct Collect $238,000
8A Doors, Windows, Glass, Value $700,000; #7 Pay $630,000; Add Pay $630,000; Deduct Pay $665,000; #7 Collect $630,000; Add Collect $665,000; Deduct Collect $595,000
9A Lath & Plaster, Value $700,000; #7 Pay $630,000; Add Pay $630,000; Deduct Pay $665,000; #7 Collect $630,000; Add Collect $665,000; Deduct Collect $595,000
10A Specialties, Value $420,000; #7 Pay $378,000; Add Pay $378,000; Deduct Pay $399,000; #7 Collect $378,000; Add Collect $399,000; Deduct Collect $357,000
11A Mechanical, Value $2,520,000; #7 Pay $2,268,000; Add Pay $2,268,000; Deduct Pay $2,394,000; #7 Collect $2,268,000; Add Collect $2,394,000; Deduct Collect $2,142,000
12A Electrical, Value $3,080,000; #7 Pay $2,772,000; Add Pay $2,772,000; Deduct Pay $2,926,000; #7 Collect $2,772,000; Add Collect $2,926,000; Deduct Collect $2,618,000
Course 30: Nesmrik County Jail, Value $12,000,000
2A Excavation, Value $600,000; #7 Pay $540,000; Add Pay $540,000; Deduct Pay $570,000; #7 Collect $540,000; Add Collect $570,000; Deduct Collect $510,000
3A Concrete, Value $1,800,000; #7 Pay $1,620,000; Add Pay $1,620,000; Deduct Pay $1,710,000; #7 Collect $1,620,000; Add Collect $1,710,000; Deduct Collect $1,530,000
4A Masonry, Value $1,080,000; #7 Pay $972,000; Add Pay $972,000; Deduct Pay $1,026,000; #7 Collect $972,000; Add Collect $1,026,000; Deduct Collect $918,000
5A Steel & Miscellaneous, Value $1,200,000; #7 Pay $1,080,000; Add Pay $1,080,000; Deduct Pay $1,140,000; #7 Collect $1,080,000; Add Collect $1,140,000; Deduct Collect $1,020,000
6A Carpentry, Value $720,000; #7 Pay $648,000; Add Pay $648,000; Deduct Pay $684,000; #7 Collect $648,000; Add Collect $684,000; Deduct Collect $612,000
7A Hollow Metal, Value $240,000; #7 Pay $216,000; Add Pay $216,000; Deduct Pay $228,000; #7 Collect $216,000; Add Collect $228,000; Deduct Collect $204,000
8A Doors, Windows, Glass, Value $600,000; #7 Pay $540,000; Add Pay $540,000; Deduct Pay $570,000; #7 Collect $540,000; Add Collect $570,000; Deduct Collect $510,000
9A Lath & Plaster, Value $600,000; #7 Pay $540,000; Add Pay $540,000; Deduct Pay $570,000; #7 Collect $540,000; Add Collect $570,000; Deduct Collect $510,000
10A Specialties, Value $360,000; #7 Pay $324,000; Add Pay $324,000; Deduct Pay $342,000; #7 Collect $324,000; Add Collect $342,000; Deduct Collect $306,000
11A Mechanical, Value $2,160,000; #7 Pay $1,944,000; Add Pay $1,944,000; Deduct Pay $2,052,000; #7 Collect $1,944,000; Add Collect $2,052,000; Deduct Collect $1,836,000
12A Electrical, Value $2,640,000; #7 Pay $2,376,000; Add Pay $2,376,000; Deduct Pay $2,508,000; #7 Collect $2,376,000; Add Collect $2,508,000; Deduct Collect $2,244,000
Course 32: Automotive Assembly Plant, Value $8,000,000
2A Excavation, Value $400,000; #7 Pay $360,000; Add Pay $360,000; Deduct Pay $380,000; #7 Collect $360,000; Add Collect $380,000; Deduct Collect $340,000
3A Concrete, Value $1,200,000; #7 Pay $1,080,000; Add Pay $1,080,000; Deduct Pay $1,140,000; #7 Collect $1,080,000; Add Collect $1,140,000; Deduct Collect $1,020,000
4A Masonry, Value $720,000; #7 Pay $648,000; Add Pay $648,000; Deduct Pay $684,000; #7 Collect $648,000; Add Collect $684,000; Deduct Collect $612,000
5A Steel & Miscellaneous, Value $800,000; #7 Pay $720,000; Add Pay $720,000; Deduct Pay $760,000; #7 Collect $720,000; Add Collect $760,000; Deduct Collect $680,000
6A Carpentry, Value $480,000; #7 Pay $432,000; Add Pay $432,000; Deduct Pay $456,000; #7 Collect $432,000; Add Collect $456,000; Deduct Collect $408,000
7A Hollow Metal, Value $160,000; #7 Pay $144,000; Add Pay $144,000; Deduct Pay $152,000; #7 Collect $144,000; Add Collect $152,000; Deduct Collect $136,000
8A Doors, Windows, Glass, Value $400,000; #7 Pay $360,000; Add Pay $360,000; Deduct Pay $380,000; #7 Collect $360,000; Add Collect $380,000; Deduct Collect $340,000
9A Lath & Plaster, Value $400,000; #7 Pay $360,000; Add Pay $360,000; Deduct Pay $380,000; #7 Collect $360,000; Add Collect $380,000; Deduct Collect $340,000
10A Specialties, Value $240,000; #7 Pay $216,000; Add Pay $216,000; Deduct Pay $228,000; #7 Collect $216,000; Add Collect $228,000; Deduct Collect $204,000
11A Mechanical, Value $1,440,000; #7 Pay $1,296,000; Add Pay $1,296,000; Deduct Pay $1,368,000; #7 Collect $1,296,000; Add Collect $1,368,000; Deduct Collect $1,224,000
12A Electrical, Value $1,760,000; #7 Pay $1,584,000; Add Pay $1,584,000; Deduct Pay $1,672,000; #7 Collect $1,584,000; Add Collect $1,672,000; Deduct Collect $1,496,000
Course 34: 10 Story Apartment Building, Value $8,000,000
2A Excavation, Value $400,000; #7 Pay $360,000; Add Pay $360,000; Deduct Pay $380,000; #7 Collect $360,000; Add Collect $380,000; Deduct Collect $340,000
3A Concrete, Value $1,200,000; #7 Pay $1,080,000; Add Pay $1,080,000; Deduct Pay $1,140,000; #7 Collect $1,080,000; Add Collect $1,140,000; Deduct Collect $1,020,000
4A Masonry, Value $720,000; #7 Pay $648,000; Add Pay $648,000; Deduct Pay $684,000; #7 Collect $648,000; Add Collect $684,000; Deduct Collect $612,000
5A Steel & Miscellaneous, Value $800,000; #7 Pay $720,000; Add Pay $720,000; Deduct Pay $760,000; #7 Collect $720,000; Add Collect $760,000; Deduct Collect $680,000
6A Carpentry, Value $480,000; #7 Pay $432,000; Add Pay $432,000; Deduct Pay $456,000; #7 Collect $432,000; Add Collect $456,000; Deduct Collect $408,000
7A Hollow Metal, Value $160,000; #7 Pay $144,000; Add Pay $144,000; Deduct Pay $152,000; #7 Collect $144,000; Add Collect $152,000; Deduct Collect $136,000
8A Doors, Windows, Glass, Value $400,000; #7 Pay $360,000; Add Pay $360,000; Deduct Pay $380,000; #7 Collect $360,000; Add Collect $380,000; Deduct Collect $340,000
9A Lath & Plaster, Value $400,000; #7 Pay $360,000; Add Pay $360,000; Deduct Pay $380,000; #7 Collect $360,000; Add Collect $380,000; Deduct Collect $340,000
10A Specialties, Value $240,000; #7 Pay $216,000; Add Pay $216,000; Deduct Pay $228,000; #7 Collect $216,000; Add Collect $228,000; Deduct Collect $204,000
11A Mechanical, Value $1,440,000; #7 Pay $1,296,000; Add Pay $1,296,000; Deduct Pay $1,368,000; #7 Collect $1,296,000; Add Collect $1,368,000; Deduct Collect $1,224,000
12A Electrical, Value $1,760,000; #7 Pay $1,584,000; Add Pay $1,584,000; Deduct Pay $1,672,000; #7 Collect $1,584,000; Add Collect $1,672,000; Deduct Collect $1,496,000
As can best be seen in FIG. 3, the game includes a plurality of so-called "bulletin" cards 80 which the participants utilize throughout portions of the game and which provide the participants with various penalties and/or rewards. The instructions set forth in each of the fifteen "bulletin" cards 80 are as follows:
1. Architectural problem nets you $50,000 for your solutions--collect from owner
2. Owner grants you an additional $10,000 for job completed way ahead of schedule
3. Air pollution equipment owner had to buy from you costs him $80,000--collect $80,000
4. State Fire Marshall tells owner building is not safe--collect $150,000 for additional work you performed to make it safe (from owner)
5. Litigation paid off--collect $40,000 for job extra
6. You have just made $50,000 on the new addition for this job--collect $50,000
7. Collect $100,000 from owner as result of insurance settlement
8. Collect $100,000 from each competitor because judge says collusion was involved
9. Cost saver you proposed earlier nets you $20,000
10. The owner has agreed to pay you $100,000 for your repair of the wall that fell down from wind damage
11. Owner pays you additional $25,000 for engineering services on this building and future adaptations
12. For extra to contract, collect $25,000 from owner
13. Owner wants to pay your invoice you forgot to send--collect $28,000 from him
14. OSHA demands gain you $350,000 for additional work you performed--collect from owner
15. Owner has agreed to pay you $500,000 for new addition
As can be seen in FIG. 4, the game includes a plurality of so-called "backcharge" cards 82 totaling fifteen cards and which include the following instructions which the participants must follow in the manner described hereinafter:
1. Owner says your engineering goof cost him $300,000--pay him
2. Architect tells owner you should have known better--pay owner $200,000 to settle
3. Owner says you failed to meet schedule--you are penalized $100.00 per day--you're 120 days late--pay him $12,000
4. Owner says reason wall fell down is because you used low grade mud instead of mortar--pay him $75,000
5. Owner says you erected steel to wrong elevation--you must pay labor and material $150,000 to fix
6. Your non-compliance to local codes cost you $100,000--pay to owner
7. Labor strikes really do cost money for material and scheduling--pay owner $50,000 and labor and material $50,000
8. You started to erect something with Iron Workers instead of Electricians (Tsk- Tsk-)--goof costs you $45,000 (payable to labor and material)
9. Owner says your labor and material were not to specification--forfeit retainage
10. Material you failed to provide, but was in your contract, costs you $50,000, payable to owner
11. Tsk- Tsk- You were involved in collusion--judge says pay each competitor $100,000
12. Owner caught you substituting cheaper material--pay him $50,000
13. You forgot to tell owner you quoted job delivered only--goof costs you $500,000 to labor and material
14. Electrical fire due to improper wiring--costs you $150,000, payable to labor and material
15. Sub-contractor does not provide item you thought he would--it cost you $350,000, payable to labor and material
As can best be seen in FIGS. 8 and 9, each player is provided with one set of color-coated bid cards 84. The bid cards 84 include specific information which permits the participants to bid on the various construction jobs. As shown in FIG. 8 of the drawings, the face of the bid cards 84 are color-coated so each participant knows which card is his, all of which becomes more clear during the description of the manner in which the game is played. The back side of each bid card includes certain designated information. Each player will have six bid cards. Each bid card 84 has on its back side one of the following notations: 5% below; 2.5% below, 10% above, 5% above, 2.5% above and cost. These six notations correspond to the bidding amount in space 66 in each of the courses 12 through 34, and the manner in which they are used will be described hereinafter.
FIG. 6 is illustrative of the script currency 85 which is utilized during the game, and in the preferred embodiment currency ranging from $1,000 bills to $1,000,000 bills are utilized. Each player would receive ten $1,000 bills; five $5,000 bills; five $10,000; five $20,000 bills; five $50,000 bills; five $100,000 bills; two $500,000 bills; and two $1,000,000 bills. FIG. 7 illustrates a typical game piece 86.
In use the game is set up so that the bulletin cards 80 and the backcharge cards 82 are positioned face down, in two stacks 88 and 90, on the board 10 as shown. In the preferred embodiment four players utilize the game, and each player receives the color-coated set of bid cards 84, each of which includes the aforementioned number of cards having the designations set forth above. Each player is also distributed the aforementioned amount of script currency 85. Any player, or players, may function as both the banker and owner and, in addition to playing, functions in this capacity to take money and give money to each player during the course of the game in the manner to be described.
To commence the game, the players bid on the smallest construction job, which in the present example is either the Course 16 or 18, each having an approximate cost of $4,000,000. Each player bids on the job by secretly selecting one of the bid cards 84 and placing the same, face down, on the bid space 38. After each player has bid, the players all place their bid cards 84 face up, and the lowest bid plays that particular course. The low bids result in the rejection of all bids, and the job is rebid immediately until one of the participants has a low bid. The remaining participants, as well as the first participant who has a low bid, continue to bid on the other courses until each participant has a construction course to play. It is generally recommended that a player not play two jobs at the same time; however, a player is not limited to playing only one job. Playing two jobs at one time may result in the bankruptcy of a player and his withdrawal from and loss of the game.
When each of the participants has a construction job, the game commences with the theoretical construction of the particular project. This is accomplished by first moving a playing piece or token 86 to the starting position 40. Each participant rolls the dice 92 to determine who is to start first, with the highest roll being the participant who moves first. That participant moves to the first stage of construction, that is, the excavation space 42. Each player then rolls the dice to determine his cost for constructing and the payment he receives from the owner. During the roll of the dice 92 if the numbers 2, 6, 8 or 11 turn up, the numbers refer to the "deduct" portion of the card 70, while the numbers 3, 4, 5, 9, 10 and 12 refer to the "add" portion, as shown on the reverse side of the instruction cards 70. The number 7 is an even position.
For example, in the construction of the State Parking Deck, as illustrated in FIG. 2 of the drawings, if a participant rolls a 4 on the $200,000 excavation sub-contract job and since 4 is a "add" number, a reference to the reverse side of card 70 shows that the "add" results in, theoretically, the participant having to pay $180,000 for labor materials in order to achieve or to have the land excavated. Since 4 represents "add," the player collects $190,000 from the owner. Therefore, the player has earned $10,000 for this phase of the game.
Alternately, if the dice roll had been an 8, the participant would have rolled a "deduct." In this situation he would have paid for labor materials $190,000 and would have only collected $170,000 from the owner. This would have been a loss of $20,000 for this portion of the game. The participant who functions as both the owner and banker receives the money from the other participants, as well as money from himself to pay for labor materials, and disburses money from the owner so that each player ends up with a net profit or loss for each particular stage of the game, as aformentioned.
After a participant has played the first section of the game, the next player plays his turn and follows the same procedures. When a player has moved to the next phase, which will be space 44, the concrete phase, the play continues in the same manner as aforementioned. When each player completes his last phase, that is, phase 12A, he moves into the collect retainage box. Prior to moving to the retainage box, he rolls for a bulletin card 80 or a backcharge card 82. An even dice roll, that is, 2, 4, 6, 8, 10 or 12, results in picking a bulletin card 80, while an odd dice roll 3, 5, 7, 9 or 11 results in picking a backcharge card 82. The player draws the selected card and follows instructions given thereon, as aforementioned. The card is then placed to the bottom of the deck drawn from. After following the instructions set forth in the bulletin or backcharge card, the participants complete their last portion of the course by collecting from the owner the retainage corresponding to the amount bid. For example, in the State Park Deck, if the bid was 2.5% below cost, the retainage is $390,000; and this amount would be paid to the participant.
Each of the participants now bids on a new job different from the one completed, and each participant continues to do this until all the jobs have been played or until some time limit, which was previously set by the players, has expired. Any person who cannot at any time pay for his labor and material cost goes into bankruptcy and looses the game. At the end of the game when all the jobs are completed, each player counts up his money, and the player with the most money wins the game.
In order to insure that the game board has a long life, it should be coated with a plastic material, or at a minimum the spaces 40 through 62 which are used to a greater degree should be so coated.
It can thus be seen that the present invention has provided a new and improved game which will provide great stimulus to the participants and provide them with knowledge of the financial and business aspects of the construction business.
While only one form of the present invention has been disclosed, it should be understood by those skilled in the field of such educational games that other forms may be had, all coming within the spirit of the invention and the scope of the appended claims.
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A game wherein each participant is supplied with simulated currency which the player uses to simulate the activities generally associated with the construction industry, such that the participants develop an understanding of the decision making and financial aspects of the construction industry. The game consists of a playing board having a peripheral area marked with spaces that constitute a plurality of individual playing courses, each course being representative of the various steps associated with a construction project, such as constructing a building. Each course is provided with a plurality of instructions which, by the throw of dice by the participant determines his profit and loss during each step of the course.
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This application is a divisional application of U.S. Pat. No. 5,354,406, dated Oct. 11, 1994, entitled Apparatus for Retreading a Tire, which is a continuation-in-part of application Ser. No. 07/908,228, filed Jul. 2, 1992, abandoned; and related to patent application Ser. No. 08/475,570, filed Jun. 7, 1995, entitled Enhanced Treat Mold Expander, and patent application Ser. No. 08/478,006, filed Jun. 7, 1995, entitled Expandable Tread Mold and Method for Retreading Tires.
TECHNICAL FIELD OF THE INVENTION
This invention relates generally to methods and apparatus for retreading a tire casing. More particularly, but not by way of limitation, this invention relates to a tread mold loading machine used to install a plurality of mold segments on retreading material on the exterior of the tire casing.
BACKGROUND OF THE INVENTION
A wide variety of procedures and different types of equipment are available for use in recapping or retreading pneumatic tires. One of the first steps in retreading a worn tire is to remove existing tread material from the tire carcass by buffing. Various procedures are available to apply one or more layers of uncured rubber or retreading material with appropriate bonding agents to the buffed tire carcass. The uncured rubber may also be stitched to the buffed carcass as required. For purposes of this patent application, the term "casing" is used to refer to a buffed tire carcass which has been built up with one or more layers of uncured rubber and other material as required by the retreading equipment and procedures being used to rebuild the worn tire.
In the past, heavy duty mechanical and/or hydraulic closing devices have often been used to install molds which form a new tread in retreading material on a prepared tire carcass or casing. Tire distortion sometimes occurs as the tread molds are closed on the casing. This problem is particularly common if the casing is slightly larger in diameter than desired. In such cases, the prepared tire carcass will often buckle and can thus no longer be used. Damage to a casing during mold installation represents a substantial loss of time and material spent preparing the tire carcass for mold installation.
One method of recapping or retreading tires is illustrated in U.S. Pat. No. 4,767,480, issued Aug. 30, 1988 to Leon C. Goldstein. This patent describes apparatus and methods for retreading which uses a cold process. In this process, a flexible tread mold is stretched over the tire carcass. Subsequently, an envelope is placed over the mold and prepared tire carcass and the entire unit or assembly is placed in a chamber where curing of the rubber is accomplished by inflation of the tire carcass, evacuation of the envelope and pressurization of the chamber and the application of heat.
U.S. Pat. No. 4,588,460, issued May 13, 1986 to Arthur W. McGee, et al. illustrates another method and apparatus for retreading a tire that includes a relatively flexible mold which is formed by a plurality of mold segments. The ends of adjacent mold segments include guides so that the mold, when closed, will form a circle about the casing which will be retreaded. In this process, an elastic band encircles the mold segments for the purpose of holding the mold in position on the tire during handling such as when an envelope is placed over the tire which is ultimately pressurized to force the mold segments into the uncured retread material encircling the tire.
Pneumatic tires may also be recapped or retreaded by installing a continuous replacement tread on a prepared tire carcass. Both uncured and cured or vulcanized rubber compounds have previously been used to provide the continuous replacement tread. Examples of equipment and procedures used to install continuous replacement treads on a tire casing are shown in U.S. Pat. No. 3,976,532 to C. K. Barefoot; U.S. Pat. No. 4,088,521 to P. H. Neal; U.S. Pat. No. 4,036,677 to Carlo Marangouri; and U.S. Pat. No. 4,957,574 to A. R. Clayton, et al.
Most retreading procedures also require the use of a flexible envelope to seal around the tire casing, retread material and tread mold (if used). The complete assembly, including the tire casing, retread material, tread mold (if used) and envelope, are placed in a high pressure, high temperature chamber in preparation for curing the components which comprise the completed tire assembly. The high pressure, high temperature chamber is frequently referred to as an autoclave. Examples of a tire retreading envelope and high pressure, high temperature curing chamber are shown in U.S. Pat. No. 4,309,234 to P. L. Witherspoon. As noted above, U.S. Pat. No. 4,767,480 also contains information on the use of envelopes to assist with curing retreaded tires.
The above listed patents are incorporated by reference for all purposes within this application.
SUMMARY OF THE INVENTION
In accordance with the present invention, the disadvantages and problems associated with previous methods and apparatus for retreading tires including installing tread mold segments on the exterior of tire casings have been substantially reduced or eliminated.
One object of this invention is to provide methods and apparatus for retreading pneumatic tires which eliminate the need for high pressure mold closing equipment. The present invention includes a tread mold loading machine which can install tread molds on a wide range of tire sizes with significant variations in critical tire dimensions without damage to the tire casing. The resulting retreaded tire assembly can be cured in existing hot air chambers.
Another object of the present invention is to provide a method and apparatus for retreading tires that avoids deforming the tire carcass when tread mold segments are placed thereon and thus reduces tire loss during the retreading operation. The present invention allows the use of an adjustable tread mold having a plurality of mold segments which will accommodate variations in casing dimensions. Also, mold segments with a wide variety of different tread designs may be used with the present invention.
The present invention provides, in one aspect, apparatus for retreading a prepared tire carcass or casing having a layer of retreading material located around the exterior thereof. The tread mold loading apparatus or machine includes a plurality of mold segments arranged to be located around the layer of retreading material. The mold segments also include resilient retainers which encircle the tread mold urging the mold segments toward the casing while preparing the tire assembly for curing.
One technical advantage of the present invention is to provide a tread mold loading machine which includes an expandable hub attached to a longitudinal shaft or main axle which may be used to position a prepared tire carcass for installation of tread mold segments. The main axle of the thread mold loading machine allows both longitudinal movement and rotational movement of the prepared tire carcass while mounted on the expandable hub.
Another technical advantage of the present invention includes a plurality of mold segment supporting arms which may be moved inwardly and outwardly with respect to a tire casing to allow installation of a tread mold on the exterior of the tire casing. Each tread mold supporting arm includes a clamp which may be easily engaged and disengaged from the associated mold segment to allow removal of the tire casing and the installed tread mold from the thread mold loading machine. An additional technical advantage of the present invention is that the clamp includes a pair of fingers which are moved by an associated rack and pinion gear. At least one of the fingers can be moved both longitudinally and radially by its associated rack and the pinion gear.
A further object of the present invention is to provide a sensor which will indicate when the tread mold segments have made contact with retreading material on the exterior of the casing. The sensor prevents the application of excessive force to the tire casing by the tread mold loading machine during installation of the tread mold on the casing. The sensor is one of the components which allows the tread mold loading machine to accommodate tire casings with significant variations in critical dimensions without damaging oversized casings.
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 description taken in conjunction with the accompanying drawings in which:
FIG. 1 is a schematic drawing in elevation with portions broken away showing a tread mold loading machine incorporating the present invention;
FIG. 2 is a schematic drawing in section and elevation with portions broken away, taken along line 2--2 of FIG. 1, showing a prepared tire carcass mounted on the tread mold loading machine of FIG. 1;
FIG. 3 is an enlarged fragmentary drawing in section and in elevation with portions broken away showing the bearings and gears associated with the main axle of the tread mold loading machine of FIG. 1;
FIG. 4 is a drawing in section and in elevation with portions broken away showing an expandable hub which may be attached to the main axle of the tread mold loading machine of FIG. 1;
FIG. 5a is a drawing in section and in elevation illustrating a tread mold supporting arm used with the tread mold loading machine of FIG. 1, in its first position which releasably secures a mold segment thereto;
FIG. 5b is a drawing in section and in elevation illustrating the tread mold supporting arm of FIG. 5a in its second position which will release a mold segment therefrom; and
FIG. 6 is an isometric drawing of the tread mold supporting arm of FIG. 5a and 5b engaged with its associated radial arm and guide rails.
DETAILED DESCRIPTION OF THE INVENTION
The preferred embodiments of the present invention and its advantages are best understood by referring to FIGS. 1 through 6 of the drawings, like numerals being used for like and corresponding parts of the various drawings.
Tread mold loading machine 20, as best shown in FIGS. 1 and 2, is provided to install tread mold 200 on the exterior of prepared tire carcass or casing 180. For purposes of this patent application, prepared tire carcass or casing 180 refers to pneumatic tire carcass 182, which has been buffed to remove any old tread material (not shown), and a layer of adhesive or similar bonding agent (not shown) along with retreading material 184 applied to the exterior of carcass 182. Casing 180 may be prepared for retreading using conventional procedures and equipment prior to mounting casing 180 on tread mold loading machine 20.
Tread mold 200 is sometimes referred to as an adjustable mold because it will accommodate casings with variations in critical tire dimensions. The components which comprise tread mold 200 will be described later in more detail. These components include a plurality of mold segments 202 and one or more annular tension springs 204. Mold segments 202 are preferably spaced radially from main axle 22 prior to mounting casing 180 on main axle 22. As shown in FIG. 1, mold segments 202 are positioned by tread mold loading machine 20 to define expanded opening 206 to receive casing 180 therein.
As will be explained later in more detail, an important feature of tread mold loading machine 20 is the ability to move mold segments 202 radially with respect to main axle 22 and casing 180 when mounted thereon. Equally important features of tread mold loading machine 20 include the ability to move casing 180 longitudinally relative to tread mold 200 while mounted on main axle 22 and the ability to rotate casing 180 while mounted on main axle 22.
The various components and subassemblies which comprise tread mold loading machine 20 are secured to, supported by or contained within housing 24, which in turn is attached to and rests upon base 26. Components contained within housing 24 include prime mover or electrical motor 28 and electrical power supply box 30. Control panel 32 is attached to the side of housing 24 and extends outwardly therefrom. Control panel 32 is secured to one end of cable channel and supporting frame 34. The other end of cable channel and supporting frame 34 is secured to housing 24 at opening 35. Electrical cables and other conduits (not shown) may be disposed within cable channel and supporting frame 34 to extend from control panel 32 through opening 35 to the appropriate component contained within housing 24 or secured to housing 24. Cable channel and supporting frame 34 extends at a right angle relative to housing 24 to preferably position control panel 32 exterior from and adjacent to tread mold 200 when casing 180 is mounted on main axle 22.
The embodiment of tread mold loading machine 20 shown in FIGS. 1 and 2 is operated by a combination of electrical and pneumatic power. The various components and functions of tread mold loading machine 20 are controlled by a combination of electrical and/or pneumatic signals as appropriate. If desired, the electrical power functions and electrical control functions could be replaced by pneumatic and/or hydraulic power and control systems. In the same manner many of the components which are operated and controlled by pneumatic systems could be replaced by a hydraulic or electrical system with the exception of inflating casing 180. Since casing 180 is preferably inflated with air pressure while installing or loading tread mold 200 thereon, there are several practical benefits from using the available air supply for other functions and purposes within tread mold loading machine 20. However, for specific applications and designs, these pneumatically operated components could be replaced by hydraulic and/or electrically operated components as desired.
Several of the components and subassemblies which comprise tread mold loading machine 20 are secured to or supported by main axle 22. These components include expandable hub 40, a pair of rotary bearings 60, a pair of linear bearings 70, and hollow drive shaft 80. Rotary bearings 60 and linear bearings 70 are preferably disposed between the exterior of main axle 22 and the interior of hollow drive shaft 80. Head assembly 90 is secured to the front portion of housing 24 by annular plate 92 which is bolted to the front of housing 24. Annular plate 92 and the attached head assembly 90 are concentrically disposed around the exterior of main axle 22. Main axle 22 is supported within housing 24 by annular plate 92 and associated components.
As best shown in FIG. 1, ten sets of radial arms 94 and there associated guide rails 96 and 98 extend outwardly from head assembly 90. Head assembly 90 includes appropriate openings 86 and 88 which extending radially therethrough to secure one end of each set of guide rails respectively 96 and 98 thereto. Additional openings 84 are provided through head assembly 90 to allow the installation of each radial arm 94 between its associated guide rails 96 and 98. As will be explained later in more detail, radial arms 94 are disposed within head assembly 90 in a manner which allows rotation of radial arms 94 in unison with each other.
A plurality of tread mold supporting arms 120 are secured to their associated radial arm 94 and guide rails 96 and 98. Each radial arm 94 is used to position its associated mold supporting arm 120 with respect to casing 180 after casing 180 has been mounted on main axle 22. Since radial arms 94 are rotated in unison with respect to each other, mold supporting arms 120 also move in unison with respect to each other.
Expandable hub 40 is secured to the end of main axle 22 which extends through head assembly 90 and the front of housing 24. Expandable hub 40 provides a portion of the means for releasably mounting prepared tire carcass or casing 180 onto main axle 22. The various components and elements which comprise expandable hub 40 are disposed on the exterior of hollow pipe 42. As best shown in FIG. 4, main axle 22 preferably has a hollow bore 36 extending therethrough and communicating with hollow pipe 42. Air coupling 38 is provided on the end of main axle 22 contained within housing 24 and opposite from expandable hub 40. Expandable hub 40 includes housing 44 with tapered cone 46 slidably disposed therein. Housing 44 and tapered cone 46 are concentrically disposed on the exterior of hollow pipe 42. End 48 of pipe 42, which extends from housing 44, is preferably closed with pipe plug 49. One or more holes 50 are provided in pipe 42 to allow air to enter chamber 52 defined in part by tapered cone 46.
Tire rim 178 and casing 180 are mounted on expandable hub 40 prior to pressurizing chamber 52. If desired, tire rim 178 could be a single unit designed to form a seal with a specific size and type of tire casing. Preferably, tire rim 178 will be formed from multiple segments with an elastomeric band (not shown) surrounding the segments. By using a segmented tire rim 178 and enclosing the exterior of tire rim 178 with an elastomeric band, different sizes of tire casings may be satisfactorily mounted on main axle 22 by the use of expandable hub 40 and the same segmented rim 178.
By directing pneumatic (air) pressure through coupling 38, air will flow through longitudinal bore 36 and hollow pipe 42 into chamber 52 via holes 50. As the air pressure within chamber 52 increases, cone 46 will move towards the end of housing 44 and expand nylon inserts 54 through radial slots 56. As inserts 54 expand radially from housing 44, they will force the segments which comprise tire rim 178 and the associated elastomeric band outwardly to form a fluid tight seal with tire beads 186 provided on the inside diameter of casing 180.
Expandable hub 40 also includes a pair of hose connections 174 and 176. The air pressure flowing through longitudinal bore 36 into chamber 52 is typically 120 to 150 psig. Regulator 172 is provided in air line 170 to reduce this air pressure to approximately 20 psig at hose connection 174 and 176. Sliding valve 173 is provided to control the flow of air pressure to regulator 172. Tire rim 178 will preferably have two valve stems (not shown) to allow inflating casing 180 when mounted on expandable hub 40. Two hose connections 174 and 176 and two valve stems are provided to reduce the time required to inflate casing 180.
Another important feature of the present invention, as best shown in FIGS. 2 and 3, is the cooperation between rotary bearings 60, linear bearings 70 and main axle 22 which allows longitudinal movement of expandable hub 40 relative to housing 24 and the other components which comprise tread mold loading machine 20. Rotary bearings 60 and linear bearings 70 allow expandable hub 40 to be moved longitudinally away from head assembly 90 and its associated mold supporting arms 120. The first position for expandable hub 40 and main axle 22, shown in FIG. 2 by dotted lines, facilitates mounting both tire rim 178 and casing 180 onto expandable hub 40.
Air pressure can be supplied to chamber 52 to expand inserts 54 radiating outwardly to releasably lock tire rim 178 to expandable hub 40. Hose connections 174 and 176 are used to inflate casing 180 to the desired pressure. When casing 180 has been inflated and releasably mounted on expandable hub 40, casing 180, expandable hub 40 and main axle 22 may be moved to their second position in which casing 180 is radially adjacent to mold supporting arms 120 and tread mold 200.
Tread mold 200 is installed or loaded onto retreading material 184 when casing 180 is in its second position. As will be explained later in more detail, after tread mold segments 202 have been released from their respective mold supporting arms 120, expandable hub 40 along with rim 178 and casing 180 may be returned to their first position. In this first position, casing 180 may be deflated along with releasing the pneumatic pressure in chamber 52 which holds segmented rim 178 radially expanded. With casing 180 and expandable hub 40 depressurized, casing 180 with tread mold 200 loaded thereon may be removed from tread loading machine 20. A new casing may then be placed on tire rim 178 and new mold segments loaded onto tread mold supporting arms 120 to repeat the process of installing another tread mold 200 onto another casing 180.
As best shown in FIG. 3, a pair of rotary bearings 60 and a pair of linear bearings 70 are disposed between the exterior of main axle 22 and the interior of hollow drive shaft 80. Linear bearings satisfactory for use with the present invention may be obtained from Boston Gear, a Division of Rockwell International. Rotary bearings satisfactory for use with the present invention may be obtained from INA/Torrington.
Annular collar 62 is disposed on the exterior of hollow drive shaft 80 intermediate the ends thereof. Annular gear 64 is secured to one side of annular collar 62. Annular bearing 66 is secured to the opposite side of annular collar 62 and provides a portion of the means for positioning hollow drive shaft 80 and main axle 22 within housing 24. Annular bearing 66 may be a Rotek Series 3000 bearing available from the Hoesch Group.
One portion 66a of annular bearing 66 is secured to collar 62. The other portion 66b of annular bearing 66 is secured to housing 24 via couplings 68. A plurality of balls 69 are disposed between annular bearing races or portions 66a and 66b. Annular collar 62 cooperates with annular bearing 66 and couplings 68 to allow rotation of hollow drive shaft 80 relative to housing 24. Rotary bearings 60 contained within hollow drive shaft 80 allow rotation of main axle 22 and/or hollow drive shaft 80 relative to each other.
Dust cover 72 is installed on the front of head assembly 90 to protect the bearings and gears associated with main axle 22 and hollow drive shaft 80 from contamination and debris.
Pinion gears 100 are secured to the end of each radial arm 94 which extends into head assembly 90. Flange and bearing assembly 102 is used to secure each radial arm 94 within its respective opening 84 in head assembly 90 and to position each pinion gear 100 adjacent to and contacting annular gear 64. By disposing each pinion gear 100 in contact with annular gear 64, rotation of hollow drive shaft 80 will be translated into rotation of each radial arm 94. Thus, rotation of hollow drive shaft 80 in a clockwise direction is translated into clockwise rotation of radial arms 94. In a similar manner, rotation of hollow drive shaft 80 in a counterclockwise direction will result in counterclockwise rotation of radial arms 94. An important feature of the present invention is that rotation of hollow drive shaft 80 results in rotation of each radial arm 94 in unison with the other radial arms 94.
Sprocket gear 74 is mounted on the exterior of hollow drive shaft 80 spaced longitudinally from flange 62. Drive chain 76 connects sprocket gear 74 with electrical motor 28. Appropriate control signals are transmitted from control panel 32 to electrical motor 28 to cause either clockwise or counterclockwise rotation of hollow drive shaft 80 via drive chain 76 and sprocket gear 74. If desired for specific applications, electrical motor 28 could be replaced with other types of prime movers such as a hydraulic motor or a pneumatic motor.
Each mold supporting arm 120 is engaged with its associated radial arm 94. Mold supporting arms 120 include openings 124, 126 and 128 extending radially therethrough. Opening 126 includes hollow bushing 136 to allow mold supporting arms 120 to slide over the exterior of their respective guide rail 96. In the same manner opening 128 includes hollow bushing 138 which allows mold supporting arms 120 to slide over the exterior of their respective guide rail 98. Threaded bushing 134 is preferably installed into each opening 124 and secured therein by flange 130. Bolts 132 may be used to secure flange 130 and bushing 134 into each opening 124. The interior of bushing 134 contains threads 131 which match threads 102 on the exterior of radial arms 94. Thus, rotation of radial arms 94 by hollow drive shaft 80 is translated by matching threads 102 and 131 into radial movement of mold supporting arms 120, either inwardly or outwardly with respect to main axle 22 and casing 180 when mounted thereon. If desired for selected applications, radial arms 94 could be replaced by a plurality of hydraulic cylinders (not shown) to move mold supporting arms 120 radially inward and outward.
Each mold supporting arm 120 includes housing 122 with clamp assembly 140 partially contained therein. The principal elements of clamp assembly 140 includes a pair of fingers 142 and 144 which extend from housing 122. In FIGS. 5a and 5b, housing 122 is shown with cover 121 removed to better illustrate the components which comprise clamp assembly 140.
Fingers 142 and 144 are securely engaged with their associated racks 152 and 154. Pinion gear 146 is disposed within housing 122 between racks 152 and 154. Matching teeth 148 are provided on the exterior of pinion gear 146 to engage similar teeth 148 on each rack 152 and 154. Thus, by rotation of pinion gear 146, racks 152 and 154 are moved longitudinally with respect to each other. For the embodiment of the present invention shown in FIGS. 5a and 5b, rotation of pinion gear 146 in one direction causes racks 152 and 154 to move their associated fingers 142 and 144 longitudinally towards each other. In the same respect, rotation of pinion gear 146 in the other direction causes movement of fingers 142 and 144 longitudinally away from each other. Such movements are used to engage and disengage each clamp assembly 140 from its associated mold segment 202. Slots 162 and 164 are provided within housing 122 to assist and guide movement of racks 152 and 154 respectively with their associated fingers 142 and 144. If desired, pinion gear 146 and racks 152 and 154 could be replaced by hydraulic cylinders (not shown) to move fingers 142 and 144 with respect to each other.
Rack 152 is similar to rack 154 except end 156 of rack 152 opposite from finger 142 is formed in an arc which defines a radius of curvature matching the radius of curvature of pinion gear 146. Slot 162 contains a longitudinal portion 168 and a portion extending radially therefrom 166. Radial portion 166 of slot 162 cooperates with radial portion or end 156 of rack 152 to allow finger 142 to move both longitudinally and to pivot with respect to pinion gear 146. Thus, pinion gear 146 and racks 152 and 154 are able to move fingers 142 and 144 longitudinally towards and away from each other in addition to pivoting finger 142 away from finger 144. Pivoting finger 142 to its second position shown in FIG. 5b facilitates installation and removal of the associated mold segment 202 which may be releasably secured between fingers 142 and 144.
Heads 143 and 145 are provided respectfully on the end of each finger 142 and 144 extending from housing 122. Heads 143 and 145 have a generally rectangular cross-section which may be inserted into appropriately sized openings (not shown) in the side of each mold segment 202. Another important feature of the present invention is that various types of mold segments may be used with tread mold loading machine 20 by either simply replacing the head on fingers 142 and 144 to match holes in the new mold segments or providing a matching hole in the side of the new mold segments for the existing heads 143 and 145.
As best shown in FIGS. 1 and 6, actuators 158 are positioned on the exterior of each housing 122. Shaft 160 extends from actuator 158 into housing 122. Pinion gear 146 is secured to shaft 160 by key 170. Therefore, when shaft 160 is rotated by actuator 158, pinion gear 146 will rotate and move fingers 142 and 144 either towards each other or away from each other depending upon the direction of rotation of pinion gear 146. Actuator 158 as shown in FIG. 6 is air operated. As previously noted, various components of tread mold loading machine 20 may be either air operated, electrically operated or hydraulically operated. Actuator 158 is an example of an air operated component which could be replaced by an electric motor or a hydraulic motor.
At least one mold supporting arm 120 will preferably include sensor assembly 190 to indicate when the associated mold segment 202 has contacted retreading material 184. As shown in FIG. 6, sensor 190 includes lever 192 mounted on the exterior of housing 122 by slot 193 and pivot pin 194. Slot 193 and pivot pin 194 cooperate to allow limited radial movement and pivoting movement of lever 192 relative to housing 122. End 195 of lever 192 is enlarged for contact with the top portion of tread mold segment 202 associated with the selected mold supporting arm 120 carrying sensor 190.
Limit switch 196 is secured to support arm 120 as part of sensor 190. The other end 197 of lever 192 is positioned adjacent to limit switch 196. In FIG. 6, lever 192 is shown in its first position which would allow end 195 to contact the top portion of an associated mold segment 202 when installed between fingers 142 and 144. In this first position, end 197 of lever 192 engages limit switch 196 to allow rotation of radial arms 94 and corresponding inward movement of all mold supporting arms 120.
When the selected mold segment 202 associated with sensor 190 contacts retreading material 184, the selected mold segment 202 will move upwardly forcing end 195 to move upwardly with respect to pivot pin 194 and rotate end 197 to release limit switch 196. When disengagement between end 197 and limit switch 196 occurs, prime mover or electrical motor 28 will be prevented from further rotation of radial arms 94 to move mold supporting arms 120 inwardly towards casing 180. Sensor 190 thus prevents placing undesired forces on casing 180 if radially inward movement of mold supporting arms 120 continued after mold segments 202 contacted retreading material 184.
Sensor 190 shown in FIG. 6 includes lever 192 and limit switch 196. For some applications limit switch 196 could be mounted directly to housing 122 with plunger 198 positioned above the associated mold segment 202. In this alternative configuration, when the associated mold segment 202 moves upward towards housing 122, it would contact plunger 198 and activate limit switch 196. If desired, more than one mold supporting arm 120 may carry a sensor assembly 190.
Bracket 186 with rod 188 extending therethrough is also attached to the side of at least one mold supporting arm 120. Rod 188 is used to trip additional limit switches (not shown) which define the maximum amount of radial travel for mold supporting arms 120 both inwardly and outwardly with respect to main axle 22. When the selected mold supporting arm 120 has reached the outermost limit of its desired travel, rod segment 188a will contact the upper limit switch. When the selected mold supporting arm 120 has reached its maximum desired radial travel inwardly towards main axle 22, rod segment 188b will activate the inner limit switch. If desired, more than one mold supporting arm 120 may carry rod 188.
FIGS. 1 and 2 show the use of tension springs 204 disposed in grooves on the exterior of mold segments 202. If desired, an elastomeric tension band could also be provided on the exterior of the mold segments 202 between tension springs 204. A tension band is not shown in FIGS. 1 and 2 to allow better illustration of the other components which comprise tread loading machine 20 and tread mold 200. A segmented tread mold with tension springs and an elastomeric band are shown in more detail in co-pending patent application Ser. No. 07/908,228, filed Jul. 2, 1992.
As illustrated in FIG. 1, tread mold 200 is formed of a plurality of segments 202. Ten segments are illustrated, but any number of mold segments can be used as required for the specific tread mold loading machine and the specific tread mold design. Between each of the mold segments, alignment pins (not shown) and alignment receptacles (not shown) may be provided so that the ends of mold segments 202 will align when installed on casing 180 to assure that tread mold 200 is circular in configuration.
The fragmentary view of mold segment 202 in FIG. 2 illustrates more clearly the arrangement of tension springs 204 in mold segments 202. As previously noted, an elastomeric tension band could also be located between tension springs 204 in an annular groove (not shown).
In a process utilizing the apparatus of the invention, tire carcass 182 is prepared to receive retreading material 184. After proper preparation, the layer of retreading material 184 is applied to the outer circumference of casing 180 as shown in FIG. 2 with or without a bonding agent therebetween. After mounting casing 180 on expandable hub 40 and moving expandable hub 40 to its second position, mold segments 202 of tread mold 200 are placed over retreading material 184 with tread pattern 214 engaging the outer surface of retreading material 184.
After assembly of casing 180 and tread mold 200 as described above, a pressure envelope (not shown) is stretched over the assembled tread mold 200 and pressurized to provide the final force for driving tread pattern 214 into the outer surface of retreading material 184. The final assembly including casing 180, tread mold 200 and envelope are then placed in a hot air chamber (not shown) until retreading material 184 is properly cured.
From the foregoing description, it will be appreciated that the apparatus and methods of the present invention, permit retreading of tires without the necessity of distorting the tire carcass or requiring the use of expensive mold stretchers. The operation of loading or installing a tread mold on a prepared tire carcass can be performed simply and quickly to efficiently retread tires.
Although the present invention and its advantages have been described in detail, it should be understood that various changes, substitutions and alterations can be made therein without departing from the spirit and scope of the invention as defined in the following claims.
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Tire recapping or retreading apparatus and method including the use of a tread mold with a plurality of mold segments. A tread mold loading machine is used to position the prepared tire carcass relative to the mold segments and to install the mold segments on the exterior of the tire carcass. The mold segments are retained in place on the exterior of the tire carcass by a tension band. Resilient elastic tension bands or pre-stressed metal tension springs hold the mold segments on the tire carcass after the mold segments have been released from the tread mold loading machine. The use of the tread mold loading machine and the mold segments eliminates distortion of the tire carcass during installation of the tread mold.
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This is a division of application Ser. No. 07/350,426 filed May 11, 1989 now U.S. Pat. No. 4,990,703 which in turn is a divisional of Ser. No. 07/049,916 filed May 15, 1987 now U.S. Pat. No. 4,870,219.
SUMMARY OF THE INVENTION
The present invention is concerned with novel tetrahydronaphthalene and indane derivatives of the formula ##STR2## where X and Y is ##STR3## R 1 is fluorine, chlorine, iodine, o-bromo, m-bromo, lower-alkoxy, acyloxy, nitro, hydroxy, amino, lower-alkylamino, di-lower-alkylamino or phenyl; or lower alkyl in the o- or m-position; R 2 and R 3 are hydrogen, lower-alkyl, trifluoromethyl or halogen with one of R 2 and R 3 being hydrogen, trifluoromethyl or lower-alkyl, R 4 and R 5 are hydrogen, alkyl, alkoxy or halogen; R 6 is hydrogen, halogen, lower-alkyl or --OR 7 ; R 7 is hydrogen, lower-alkyl or acyl; R 8 is hydrogen or lower-alkyl; m is a whole number of from 0 to 5; with the proviso that when m is O and Z is --CH 2 --CH 2 --, R 6 is hydrogen; and with the exception of 1,2,3,4-tetrahydro-1,1,4,4-tetramethyl-6-(α-methylstyryl)naphthalene and its derivatives which are hydroxylated in the terminal phenyl ring.
The compound of formula I are useful as for combatting dermatoses as well as neoplasmas
DETAILED DESCRIPTION
The expression "lower" relates to groups with 1-6 C-atoms. Alkyl and alkoxy groups can be straight-chain or branched such as methyl, ethyl, propyl, isopropyl, butyl, and sec.-butyl and methoxy, ethoxy, propoxy, isopropoxy, butoxy and sec.-butoxy, respectively. Alkyl and alkoxy groups R 4 and R 5 preferably contain from 1 to 10 carbon atoms such as octyl, nonyl, decyl and 2,2-dimethyloctyl and octyloxy, nonyloxy, decyloxy and 2,2-dimethyloctyloxy, respectively. Examples of acyloxy groups are alkanoyloxy groups, preferably loweralkanoyloxy groups containing from 2 to 6 carboratoms such as acetoxy, propionyloxy, butyryloxy, pivaloyloxy and caproyloxy; or aroyloxy groups such as benzoyloxy, p-nitrobenzoyloxy and toluoyloxy; or aralkanoyloxy groups such as phenylacetoxy. Halogen embraces fluorine, chlorine, bromine and iodine.
The compounds of formula I can exist as trans or cis isomers or as cis/trans isomer mixtures. In general, the trans compounds of formula I are preferred.
Of the compounds of formula I there are furthermore preferred those in which X and Y is a group --C(CH 3 ) 2 -- and those in which m=1 or 2 or 3, especially 1. With respect to the substitutents R 2 and R 3 , hydrogen is preferred for R 2 and lower-alkyl, especially methyl, is preferred for R 3 . R 4 is preferably hydrogen or alkyl or alkoxy with up to 10 C-atoms. R 5 and R 6 are preferably hydrogen.
Among the preferred compound of formula I are the following compounds:
Compounds of the formula: ##STR4## wherein n is an integer of from 1 to 3, R 2 , R 3 , R 4 and R 5 are as above,; R 11 , R 12 , R 13 , and R 14 are hydrogen or methyl, R 10 is fluorine, chlorine, iodine, o-bromo or meta-bromo; and R 15 is hydrogen, oxo, lower alkyl, acyloxy, hydroxy or lower alkoxy: and
Compounds of the formula: ##STR5## wherein n, R 2 , R 3 , R 4 , R 5 , R 10 , R 11 , R 12 , R 13 , and R 14 are as above; R 16 and R 17 are hydrogen, oxo, lower alkyl, acyloxy, hydroxy, or lower alkoxy with the proviso that both R 16 and R 17 are not oxo;
Compounds of the formula: ##STR6## wherein n, R 2 , R 3 , R 4 , R 5 , R 11 , R 12 , R 13 , R 14 , R 16 and R 17 are as above; and
Compounds of the formula: ##STR7## wherein n, R 2 , R 3 , R 4 , R 5 , R 11 , R 12 , R 13 , R 14 , R 16 and R 17 are as above; with the proviso that when R 3 is methyl and R 4 is hydrogen, at least one of R 11 , R 12 , R 13 or R 14 is hydrogen;
Compounds of the formula: ##STR8## wherein n, R 2 , R 3 , R 4 , R 5 , R 11 , R 12 , R 13 , R 14 , R 16 and R 17 are as above; and R 18 is lower alkyl with at least one lower alkyl group located in the ortho or meta positions:
Compounds of the formula: ##STR9## wherein n, R 2 , R 3 , R 4 , R 5 , R 11 , R 12 , R 13 , R 14 , R 16 and R 17 are as above; and R 25 is nitro, amino or lower alkylamino;
Compounds of the formula: ##STR10## wherein n, R 2 , R 3 , R 4 , R 5 , R 11 , R 12 , R 13 , R 14 , and R 15 are as above; and R 35 is hydroxy, lower alkoxy or acyloxy; and
Compounds of the formula: ##STR11## wherein n, R 2 , R 3 , R 4 , R 5 , R 11 , R 12 , R 13 , R 14 , and R 16 and R 17 are as above; and R 33 is lower alkoxy or acyloxy; and
Compounds of the formula: ##STR12## wherein n, R 2 , R 3 , R 4 , R 5 , R 11 , R 12 , R 13 and R 14 are as above; and R 27 and R 28 are oxo, acyloxy, hydroxy, or lower alkoxy with the proviso that R 27 and R 28 are not both oxo.
The invention is also concerned with a process for the manufacture of the compounds of formula I, pharmaceutical preparations based on the compounds of formula I, the compounds of formula I in the treatment and prophylaxis of neoplasms and dermatoses as well as the use of the compounds of formula I in the manufacture of pharmaceutical preparations for the treatment and prophylaxis of such conditions.
The compounds of formula I can be manufactured in accordance with the invention by reacting a compound of the general formula ##STR13## with a compound of the general formula ##STR14## in which either A is a residue --CH(R 3 )P + (Q) 3 Y - or
--CH(R 3 )P(O) (OAlk) 2 and B is a residue R 21 --CO--; or
A is a residue R 31 --CO-- and B is a residue --CH(R 2 )P + (Q) 3 Y - or --CH(R 2 )P(O) (OAlk) 2 or --CH(R 21 )MgHal; or
A is a residue --CH(R 31 )MgHal and B is a residue R 2 --CO--; whereby in the above formulae Q is aryl; Y - is the anion of an organic or inorganic acid; Alk is a lower alkyl group; Hal is halogen; R 21 and R 31 are hydrogen, trifluoromethyl or lower-alkyl; and R 1 , R 2 , R 3 , R 4 , R 5 , X, Y, Z and m have the significance given above and the manufacture of 1,2,3,4-tetrahydro-1,1,4,4-tetramethyl-6-(α-methylstyryl)naphthalene and its derivatives which are hydroxylated in the terminal phenyl ring is excluded, whereupon, if desired, a nitro group R 1 is reduced to the amino group, if desired an amino group R 1 is mono- or di-alkylated, if desired an acyloxy group R 1 or R 7 is saponified, a carbonyl group obtained in Z is reduced to the hydroxy group and, if desired, a hydroxy group R 1 or R 7 or a hydroxy group obtained in Z is alkylated or acylated.
The reaction of the compounds of formulae II and III can be carried out according to the known methods of the Wittig, Horner or Grignard reaction.
In the case of the Witting reaction, i.e. with the use of a compound of formula II with A=--CH(R 3 )P + (Q) 3 Y - or of formula III with B=--CH(R 2 )P + (Q) 3 Y - , the components are reacted with one another in the presence of an acid-binding agent, e.g. in the presence of a strong base such as e.g. butyllithium, sodium hydride or the sodium salt of dimethyl sulphoxide, but especially in the presence of an optionally lower alkyl-substituted ethylene oxide such as 1,2-butylene oxide, optionally in a solvent, e.g. in an ether such as diethyl ether or tetrahydrofuran or in an aromatic hydrocarbon such as benzene, in a temperature range lying between room temperature and the boiling point of the reaction mixture.
Of the inorganic acid ions Y - the chloride ion, the bromide ion or the hydrosulphate ion is preferred and of the organic acid ions the tosyloxy ion is preferred. The aryl residue Q is preferably a phenyl residue or a substituted phenyl residue such as p-tolyl.
In the case of the Horner reaction, i.e. with the use of a compound of formula II with A=--CH(R 3 )--P(O) (OAlk) 2 or of formula III with B=--CH(R 2 )--P(O) (OAlk) 2 , the components are condensed with the aid of a base and preferably in the presence of an inert organic solvent, e.g. with the aid of sodium hydride in benzene, toluene, dimethylformamide, tetrahydrofuran, dioxan or 1,2-dimethoxyethane, or also with the aid of a sodium alcoholate in an alkanol, e.g. sodium methylate in methanol, in a temperature range lying between 0° and the boiling point of the reaction mixture.
The alkoxy residues OAlk are especially lower alkoxy residues with 1-6 carbon atoms such as methoxy or ethoxy.
The reaction of a compound of formula II with A=--CH(R 31 )MgHal or of formula III with B=--CH(R 21 )MgHal can be carried out in a manner known per se under the conditions of a Grignard reaction, e.g. in an ether such as diethyl ether or tetrahydrofuran at room temperature and subsequent water-cleavage with acidic agents, e.g. with organic acids such as p-toluenesulphonic acid.
Compounds of formula I which contain an amino group in the phenyl ring (i.e. in which a residue R 1 is amino) are conveniently manufactured via the corresponding nitro compounds. A nitro group present in a compound of formula I can be converted into an amino group in a manner known per se by reduction, e.g. with nascent hydrogen. An amino group present in a compound I can be mono- or di-alkylated in a manner known per se, e.g. by treatment with alkylating agents such as alkyl halides or alkyl sulphates or by reductive alkylation with aldehydes such as formaldehyde or acetaldehyde and sodium cyanoborohydride. The reduction of a carbonyl group contained in Z as well as the alkylation and acylation of hydroxy groups can also be carried out in a manner known per se. For example, a carbonyl group can be reduced to the hydroxy group by treatment with reduction agents such as sodium borohydride.
The compounds of formula I can exist in trans or cis form. In the process they are mainly obtained in the trans form. Cis components which may be obtained can be separated, if desired, in a manner known per se.
The starting materials of formulae II and III, insofar as their preparation is not known or is not described hereinafter, can be prepared in analogy to known methods or to methods described hereinafter.
The compounds of formula I are therapeutically active. In particular, they possess antiseborrhoeic, anti-keratinizing, anti-neoplastic and anti-allergic/anti-inflammatory activity, which can be demonstrated using the test procedures described hereinafter:
(A) The antikeratinizing activity can be determined on the rhino mouse model according to the following procedure. The skin of the rhino mouse is characterized by the presence of keratin-filled utriculi of the epidermis and subcutaneous cysts, both of which are derived from hair follicles. The administration of retinoids leads to a hyperproliferation of the epidermis and of the epithelial lining of the utriculi. The thickening of the epidermis and the reduction in the size of the utriculi lead to a normalization of the altered structure of the epithelial layer. The daily topical application of 0.1 ml/cm 2 skin of the rhino mouse of a 3% acetone solution of an active test compound over a period of 3 weeks or the thrice weekly oral administration in arachis oil over a period of 3 weeks leads to a significant proliferation of the epidermis and a striking reduction of the keratin-filled utriculi.
(B) The activity in the prevention of chemically-induced breast tumours can be determined according to the following procedure. Female Sprague-Dawley rats are kept under temperature-controlled and light-controlled conditions, with free access to drinking water and feed. At the age of 50 days 15 mg of dimethylbenz(a)anthracene disolved in arachis oil are administered to each rat by means of a probang. The treatment with the test compounds begins 1 day after the administration of the carcinogen. The body weights of the test animals are recorded and the tumours are palpated weekly and measured with a vernier caliper. The volumes are calculated according to the formula D/2·d 2 in which D is the larger diameter of the tumour ellipsoid and d is the smaller diameter of the tumour ellipsoid. After 11 weeks the test is terminated and evaluated. In this test there are used in addition to 30 control animals, which receive exclusively normal feed, the following two groups of test animals:
1. 33 rats to which are administered daily 30 mg/kg of test compound mixed with the feed.
2. 36 rats to which are administered daily 90 mg/kg of test compound mixed with the feed.
(C) Furthermore, the activity on tumours can be determined on the transplantable chondrosarcoma of the rat according to the following method. The solid tumour of a donor animal is finely minced and suspended in phosphate buffer/sodium chloride solution. 0.5 ml of the 30% tumour suspension is implanted subcutaneously into albino rats.
The transplanted rats are divided into test groups of in each case 8 animals. The test compounds are suspended in arachis oil and administered orally five times per week for 24 days. The tumours are excised and weighed on day 24. The results are expressed in the quotient C/T which is calculated as follows: ##EQU1## (D) The antimetaplastic activity can also be determined in rats according to the following method. Female Holtzmann rats weighing approximately 100 g are ovarectomized under Thiogenal narcosis after an adaptation period of 8 days and are used in the test after a further 14 days. In each case two animals are placed in a cage with free access to feed which contains approximately 2000 IU of vitamin A determined analytically. Prior to the oral administration of the test compound the animals are treated subcutaneously each day on 6 successive days with 1 μg of estradiol benzoate and 250 μg of testosterone propionate dissolved in 0.1 ml of sesame oil. The parenteral hormone administration leads to the formation of a clear granular stage in the vaginal smear, i.e. a squamous metaplasia. 2 days after the oral administration of the test substance the result of the reaction is again read off on the vaginal epithelium. The area method according to Behrens and Karber is employed to calculate the average effective dosages.
(E) The activity of the compounds I on sebum secretion in rats was determined according to the following procedure. Male rats of approximately 50-60 g body weight were castrated at the age of 21-22 days. One week after this operation the rats were washed in a cleansing solution in order to remove sebum which was excreted prior to the test period. Only the carrier materials used were administered to one group of rats. A further group of rats also simultaneously received 100 μg of testosterone propionate in 0.2 ml of sesame oil per rat and day. To a further group of rats there were administered daily per rat 100 μg of testosterone propionate in 0.2 ml of sesame oil subcutaneously and the test compounds in various dosages in 0.2 ml of propylene glycol orally. The rats were thus-treated for 14 days. On the 15th day the sebum from the skin surface and the pelt was removed by immersing the entire body of the test animals in a determined volume of acetone and bathing therein for 2 minutes. An aliquot of the solvent bath was evaporated and the solid residue was determined gravimetrically. The inhibition of the testosterone-stimulated increase in the serum secretion in comparison to the corresponding values from rats treated only with testosterone propionate was used as the measurement for the activity.
The results of these tests A-E with compounds of formula I are presented in Tables I-V hereinafter.
TABLE I______________________________________(A) Anti-keratinizing activity in the rhino mouse Dosage Diameter of the [mg/kg] utriculus ReductionCompound p.o. [μ] [%]______________________________________a 0 151 400 117 21b 0 161 400 131 19c 0 125 133 91 27 400 61 51d 0 168 133 125 27______________________________________
TABLE II______________________________________(B) Prophylaxis of chemically-induced breast tumours Average Average number of tumour Dosage Rats with tumours per volume perCom- [mg/kg] tumours [% rat [% of rat in mm.sup.3pound p.o. of controls] controls] [% of controls]______________________________________a 30 72 47 22 90 69 42 22b 30 106 87 90 90 99 87 43c 30 92 56 78 90 85 43 32______________________________________
TABLE III______________________________________(C) Activity on transplatable chondrosarcoma of the rat Quotient C/T of tumour weight Dosage of the untreated control [mg/kg] animals and of the treatedCompound p.o. animals______________________________________b 120 1.6c 40 2.0 120 24.0f 120 1.6______________________________________
TABLE IV______________________________________(D) Antimetaplastic activity in the ratCompound Relative activity______________________________________all-Trans-retinoic acid 1a 0.87b 0.77c 1.04______________________________________
TABLE V______________________________________(E) Inhibition of sebum production in the rat Dosage Inhibition of testosterone- [μg/rat] stimulated sebum secretionCompound p.o. [%]______________________________________a 100 67b 100 65e 100 71g 100 71______________________________________ a: (E)6-(p-Fluoro-methylstyryl)-1,2,3,4-tetrahydro-1,1,4,4-tetramethylnaphthlene b: (E)6-(p-Bromo-methylstyryl)-1,2,3,4-tetrahydro-1,1,4,4-tetramethylnaphthaene c: 1,2,3,4Tetrahydro-6-[(E)p-methoxy-methylstyryl1,1,4,4-tetramethylnaphthalne d: 1,1,3,3Tetramethyl-5-[(E)methylstyryl]indane e: (E)6-(p-Iodo-methylstyryl)-1,2,3,4-tetrahydro-1,1,4,4-tetramethylnaphthalne f: (E)6-(p-Chloro-methylstyryl)-1,2,3,4-tetrahydro-1,1,4,4-tetramethylnaphthlene g: 1,2,3,4Tetrahydro-1,1,4,4-tetramethyl-6-(methyl-styryl)-7-octylnaphthalen
The compounds of formula I can be used for the topical and systemic therapy of benign and malignant neoplasms, of premalignant lesions and also for the systemic and topical prophylaxis of the said conditions.
Furthermore, they are suitable for the topical and systemic therapy of acne, psoriasis and other dermatoses which are accompanied by an intensified or pathologically altered cornification, as well as of inflammatory and allergic dermatological conditions. Further, the compounds of formula I can also be used for the control of mucous membrane disorders with inflammatory or degenerative or metaplastic changes.
The pharmaceutical preparations can be administered enterally, parenterally or topically. For enteral administration there are suitable e.g. preparations in the form of tablets, capsules, dragees, syrups, suspensions, solutions and suppositories. Preparations in the form of infusion or injection solutions are suitable for parenteral administration.
The dosages in which the preparations are administered can vary according to the mode of use and route of use as well as according to the requirements of the patients. In general, daily doses of about 0.1-50 mg/kg, preferably 1-15 mg/kg, come into consideration for adults.
The preparations can be administered in one dosage or several dosages. Capsules containing about 5-200 mg of active substance are a preferred administration form.
The preparations can contain inert or pharmacodynamically active additives. Tablets or granulates e.g. can contain a series of binding agents, filler materials, carrier substances or diluents. Liquid preparations can be present, for example, in the form of a sterile solution which is miscible with water. Capsules can contain a filler material or thickening agent in addition to the active substance. Furthermore, flavour-improving additives as well as the substances usually used as preserving, stabilizing, moisture-retaining and emulsifying agents, salts for varying the osmotic pressure, buffers and other additives can also be present.
The previously mentioned carrier substances and diluents can be organic or inorganic substances, e.g. water, gelatine, lactose, starch, magnesium stearate, talc, gum arabic, polyalkylene glycols and the like. It is a prerequisite that all adjuvants used in the manufacture of the preparations are non-toxic.
For topical use the active substances are conveniently used in the form of salves, tinctures, creams, solutions, lotions, sprays, suspensions and the like. Salves and creams as well as solutions are preferred. These preparations intended for topical use can be manufactured by mixing the compounds of formula I as active ingredients with non-toxic, inert, solid or liquid carriers which are usual in such preparations and which are suitable for topical treatment.
For topical use there are suitable conveniently about 0.1-5%, preferably 0.3-2%, solutions as well as about 0.1-5%, preferably about 0.3-2%, salves or creams.
If desired, the pharmaceutical preparations can contain an antioxidant, e.g. tocopherol, N-methyl-γ-tocopheramine, butylated hydroxyanisole or butylated hydroxytoluene.
The following Examples illustrate the invention further. The temperatures are given in degrees Celsius.
EXAMPLE 1
45 g of [1-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-ethyl]-triphenylphosphonium bromide are suspended in 200 ml of 1,2-butylene oxide. After the addition of 8 g of 4-fluorobenzaldehyde the mixture is boiled at reflux for 16 hours. After cooling the clear, yellowish solution is poured into 1 l of methanol/water (6:4) and extracted repeatedly with hexane. The organic phase is washed three times with water and, after drying over sodium sulphate, evaporated. The crystalline residue can be recrystallized from hexane and gives 11.2 g of (E)-6-(p-fluoro-α-methylstyryl)-1,2,3,4-tetrahydro-1,1,4,4-tetramethylnaphthalene in colourless crystals, melting point 99°-101°.
In an analogous manner there are obtained
(E)-6-[p-chloro-α-methylstyryl]-1,2,3,4-tetrahydro-1,1,4,4-tetramethylnaphthalene, melting point 125°-126°;
(E)-6-[p-iodo-α-methylstyryl]-1,2,3,4-tetrahydro-1,1,4,4-tetramethylnaphthalene, melting point 124°-126°;
(E)-6-[p-nitro-α-methylstyryl]-1,2,3,4-tetrahydro-1,1,4,4-tetramethylnaphthalene, melting point 164°-165°;
(E)-6-[2-(4-biphenylyl)-1-methylvinyl]-1,2,3,4-tetrahydro-1,1,4,4-tetramethylnaphthalene, melting point 127°-128°;
(E)-6-[m-fluoro-α-methylstyryl]-1,2,3,4-tetrahydro-1,1,4,4-tetramethylnaphthalene, melting point 72°-73°;
(E)-6-[m-bromo-α-methylstyryl]-1,2,3,4-tetrahydro-1,1,4,4-tetramethylnaphthalene, melting point 98°-99°;
(E)-6-[o-fluoro-α-methylstyryl]-1,2,3,4-tetrahydro-1,1,4,4-tetramethylnaphthalene, melting point 75°-77°;
(E)-6-[o-bromo-α-methylstyryl]-1,2,3,4-tetrahydro-1,1,4,4-tetramethylnaphthalene, melting point 64°-66°;
1,1,3,3-tetramethyl-5-[(E)-α-methylstyryl]indane, melting point 48°-50°;
1,1,3,3-tetramethyl-5-[(E)-α-methyl-p-nitrostyryl]indane, melting point 149°-150°;
5-(p-fluoro-α-methylstyryl)-1,1,3,3-tetramethylindane, melting point 75°-77°;
5-(p-chloro-α-methylstyryl)-1,1,3,3-tetramethylindane, melting point 96°-98°;
5-(p-iodo-α-methylstyryl)-1,1,3,3-tetramethylindane, melting point 129°-131°;
1,1,3,3-tetramethyl-5-[(E)-p-methoxy-α-methylstyryl]indane, melting point 83°-84°;
1,2,3,4-tetrahydro-1,1-dimethyl-6-(α-methylstyryl)naphthalene, melting point 46°-48° (from ethanol);
1,2,3,4-tetrahydro-1,1-dimethyl-7-(α-methylstyryl)naphthalene, melting point 58°-59° (from ethanol);
7-[(E)-p-fluoro-α-methylstyryl]-1,2,3,4-tetrahydro-1,1-dimethylnaphthalene, melting point 64°-65° (from ethanol).
EXAMPLE 2
358 g of [1-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-ethyl]-triphenylphosphonium bromide are suspended in 600 ml of tetrahydrofuran and treated at 0° with 400 ml of n-butyllithium (1.6 molar in hexane). After stirring at 0° for 30 minutes a solution of 78.5 g of p-methoxybenzaldehyde in 200 ml of tetrahydrofuran is added dropwise thereto and the mixture is stirred at room temperature for a further 2 hours. The reaction mixture is subsequently poured into 2 l of methanol/water (6:4) and extracted repeatedly with hexane. The organic phase is washed three times with water and, after drying with sodium sulphate, evaporated. The crystalline residue can be recrystallized from hexane and gives 138 g of 1,2,3,4-tetrahydro-6-[(E)-p-methoxy-α-methylstyryl]-1,1,4,4-tetramethylnaphthalene, melting point 108°-110°.
In an analogous manner there are obtained
p-[2-(5,6,7,8-Tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)propenyl]phenyl acetate, melting point 114°-116°;
m-[2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)propenyl]phenyl acetate, melting point 83°-85°;
o-[2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)propenyl]phenyl acetate, melting point 78°-80°;
1,2,3,4-tetrahydro-1,1,4,4-tetramethyl-1-(α,m-dimethylstyryl)naphthalene, melting point 106°;
1,2,3,4-tetrahydro-1,1,4,4-tetramethyl-6-(α,o-dimethylstyryl)naphthalene, melting point 61°-62°;
1,2,3,4-tetrahydro-1,1,4,4-tetramethyl-6-(α,3,5-trimethylstyryl)naphthalene, melting point 113°-114°;
1,2,3,4-tetrahydro-1,1,4,4-tetramethyl-6-(α,2,5-trimethylstyryl)naphthalene, melting point 72°;
1,2,3,4-tetrahydro-1,1,4,4-tetramethyl-6-(α,2,6-trimethylstyryl)naphthalene, melting point 78°.
EXAMPLE 3
6 g of 6-[p-nitro-α-methylstyryl]-1,2,3,4-tetrahydro-1,1,4,4-tetramethylnaphthalene are dissolved in 200 ml of acetic acid and, after heating to 90°, treated within 2 minutes with 4.5 g of activated iron powder. Thereafter, 60 ml of water are added thereto and, after a further 30 minutes, the mixture is again treated with 60 ml of water. After stirring at 90° for 1 hour the reaction mixture is cooled, diluted with water and extracted with ether. The organic phase is washed with water, dilute soda solution and again with water. After drying with sodium sulphate the organic phase is evaporated and there is obtained a brown oil which is purified by filtration over silica gel (elution agent hexane/acetic acid 4:1). Recrystallization from hexane gives 4.5 g of p-[2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)propenyl]aniline in colourless crystals, melting point 106°-108°.
EXAMPLE 4
320 g of p-[2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)propenyl]aniline are dissolved in 5 ml of acetonitrile and treated at room temperature with 440 mg of acetaldehyde and 190 mg of sodium cyanoborohydride. After 30 minutes the mixture is adjusted to a pH of 6-7 by the addition of acetic acid and 440 mg of acetaldehyde are again added thereto. After stirring at room temperature for 2 hours the reaction mixture is poured into ice-water, made alkaline by the addition of 2N potassium hydroxide solution and extracted with ether. The brownish oil obtained after drying and evaporation of the organic solvent is filtered over silica gel (elution agent hexane/ethyl acetate 9:1) and recrystallized from hexane. There are obtained 280 mg of N,N-diethyl-p-[(E)-2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)propenyl]aniline in colourless crystals, melting point 89°-90°.
EXAMPLE 5
6.1 g of (1,2,3,4-tetrahydro-1,1,4,4-tetramethyl-6-naphthyl) ethyl ketone are dissolved in 25 ml of abs. ether and added dropwise at 0° to a benzylmagnesium chloride solution prepared from 0.6 g of magnesium and 4.3 g of benzyl chloride in 30 ml of abs. ether. After stirring at room temperature for 2 hours the reaction mixture is poured into a saturated ammonium chloride solution, extracted with ether, dried over sodium sulphate and evaporated. The thus-obtained oil is dissolved in 100 ml of toluene and, after the addition of 0.5 g of p-toluenesulphonic acid, boiled at reflux overnight. After cooling the mixture is treated with 10% sodium bicarbonate solution, extracted with ether, dried and evaporated. The residue is purified by filtration over a short column (silica gel, elution agent hexane) and recrystallized from methylene chloride/methanol. There are obtained 3 g of 6-(α-ethylstyryl)-1,2,3,5-tetrahydro-1,1,4,4-tetramethylnaphthalene in colourless crystals, melting point 65°.
EXAMPLE 6
1.1 g of sodium hydride (50% in mineral oil) are washed with abs. pentane, dried and suspended in 20 ml of dimethylformamide. While cooling with ice there is added dropwise thereto a solution of 5.3 g of diethyl benzylphosphonate in 50 ml of dimethylformamide. After 1 hour a solution of 5 g of 1,2,3,4-tetrahydro-1,1,4,4-tetramethyl-6-naphthyl aldehyde in 40 ml of dimethylformamide is allowed to drop in and the mixture is stirred at 40° overnight. The reaction mixture is poured on to ice, extracted repeatedly with ether, dried and evaporated. In order to separate the Z-isomer, the thus-obtained oil is chromatographed (silica gel, elution agent hexane) and recrystallized from hexane. There are obtained 4.1 g of (E)-1,2,3,4-tetrahydro-1,1,4,4-tetramethyl-6-styrylnaphthalene in colourless crystals, melting point 57°-58°.
EXAMPLE 7
In analogy to Example 6, by the Wittig-Horner reaction of 6.8 g of diethyl 5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)methanephosphonate with 2.4 g of acetophenone there are obtained, after recrystallization from methanol, 1.5 g of (E)-1,2,3,4-tetrahydro-1,1,4,4-tetramethyl-6-(β-methylstyryl)naphthalene in colourless crystals, melting point 72°-73°.
The phosphonate used in this Example can be prepared in a simple manner starting from 1,2,3,4-tetrahydro-1,1,4,4-tetramethyl-6-naphthyl aldehyde by reduction with sodium borohydride in ethanol to the corresponding hydroxymethyl compound (melting point 78° from pentane), conversion into the bromomethyl compound (boiling point 125°/0.01 mm) by reaction with phosphorus tribromide and reaction with triethyl phosphite (16 hours, 150°, melting point 55° from hexane).
EXAMPLE 8
In analogy to Example 1, from 20 g of [1-(5,6,7,8-tetrahydro-2-naphthyl)ethyl]triphenylphosphonium bromide and 4 g of benzaldehyde there are obtained, after chromatography (silica gel, elution agent hexane), 4.6 g of 1,2,3,4-tetrahydro-6-(α-methylstyryl)naphthalene as a colourless oil, boiling point about 170°/0.01 mm.
EXAMPLE 9
A solution of diethyl benzylphosphonate in 30 ml of dimethylformamide is added at room temperature to a suspension of 3.7 g of NaH (50% in mineral oil) in 50 ml of dimethylformamide. After stirring at room temperature for 15 minutes a solution of 12.6 g of 7-acetyl-1,1,4,4,6-pentamethyltetralin in 60 ml of dimethylformamide is added dropwise thereto in the course of 2 hours. The reaction mixture is stirred at room temperature overnight and subsequently heated to 60° for a further 1 hour. After cooling the mixture is poured on to ice, extracted with ether, dried and evaporated. After chromatography of the crude product (silica gel, elution agent hexane) and crystallization from hexane there are obtained 3.9 g of 1,2,3,4-tetrahydro-1,1,4,4,7-pentamethyl-6-[(E)-α-methylstyryl]naphthalene in colourless crystals, melting point 75°-77°.
EXAMPLE 10
In analogy to Example 9, from diethyl benzylphosphonate and 5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-3-octyl-2-acetonaphthone there is manufactured 1,2,3,4-tetrahydro-1,1,4,4-tetramethyl-6-(α-methylstyryl)-7-octylnaphthalene, melting point 47°-48° (from hexane).
EXAMPLE 11
In analogy to Example 1, from 7.1 g of [1-(1,1,3,3-tetramethyl-indan-2-on-5-yl)ethyl]triphenylphosphonium bromide and 1.4 g of benzaldehyde there are obtained, after chromatography (silica gel, elution agent hexane/ether=9:1) and recrystallization from hexane, 800 mg of 1,1,3,3-tetramethyl-5-[(E)-α-methylstyryl]-2-indanone, melting point 83°-85°.
The phosphonium bromide used as the starting material can be prepared in a simple manner by the Friedel-Crafts acetylation of 1,1,3,3-tetramethylindanone, reduction of the acetyl group with sodium borohydride and reaction with triphenylphosphonium bromide.
EXAMPLE 12
1.4 g of 1,1,3,3-tetramethyl-5-[(E)-α-methylstyryl]-2-indanone are dissolved in 100 ml of ethanol and treated at room temperature with 6 g of sodium borohydride. After stirring at room temperature for 16 hours the reaction mixture is poured on to ice and extracted repeatedly with ether. The organic phase is washed with saturated sodium chloride solution, dried and evaporated. The residue can be recrystallized from hexane and gives 1.1 g of 1,1,3,3-tetramethyl-5-[(E)-α-methylstyryl]-2-indanol in colourless crystals, melting point 63°-67°.
EXAMPLE 13
2.80 g of 6'-(tert-butyldimethylsiloxy)-5',6',7',8'-tetrahydro-5',5',8',8'-tetramethyl-2-acetonaphthone in 10 ml of abs. THF are added dropwise at 0° to a Grignard solution prepared from 1.90 g of benzyl chloride and 437 mg of Mg shavings in 30 ml of abs. THF. After 15 minutes the mixture is hydrolyzed with H 2 O, extracted with ether and the organic phases are washed thoroughly with H 2 O. After drying and removing the solvent the residue, a viscous oil, is taken up in 20 ml of CH 2 Cl 2 and treated with 150 mg of p-toluenesulphonic acid. After 6 hours the mixture is filtered over silica gel and the crude product is treated at 40° for about 14 hours with 6.3 g of nBu 4 NF·3H 2 O in 20 ml of THF. The reaction product is partitioned between water and ether, and the organic phase is washed with water, dried and evaporated. Filtration over silica gel yields 2.27 g of an oil which contains all three possible double bond isomers. In order to equilibrate this, the oil is treated with 200 mg of p-toluenesulphonic acid in 20 ml of CHCl 3 at 45°-50°. After 24 hours it is chromatographed over a short silica gel column (petroleum ether: AcOEt=7:3) and recrystallized from hexane. A single repetition of the isomerization with the mother liquor yields a total of 1.32 g of 1,2,3,4-tetrahydro-1,1,4,4-tetramethyl-6-[(E)-α-methylstyryl]-2-naphthalenol, m.p. 102°-103°.
The starting material can be obtained as follows:
p-Bromophenylacetic acid is converted by double alkylation, conversion into the acid chloride and tandem Friedel-Crafts reaction of the acid chloride with isobutylene under SnCl 4 or AlCl 3 catalysis into 6-bromo-3,4-dihydro-1,1,4,4-tetramethyl-2(1H)-naphthalenone, from which by NaBH 4 reduction and silylation with TBDMS Cl/imidazole there is obtained [(6-bromo-1,2,3,4-tetrahydro-1,1,4,4-tetramethyl-2-naphthyl)oxy]tert.-butyldimethylsilane. Grignard reaction with acetaldehyde and MnO 2 oxidation yields 6'-(tert-butyldimethylsiloxy)-5',6',7',8'-tetrahydro-5',5',8',8'-tetramethyl-2-acetonaphthone.
EXAMPLE 14
In analogy to Example 13, from benzylmagnesium chloride and 7'-(tert-butyldimethylsiloxy)-5',6',7',8'-tetrahydro-5',5',8',8'-tetramethyl-2-acetonaphthone there is obtained 1,2,3,4-tetrahydro-1,1,4,4-tetramethyl-7-[(E)-α-methylstyryl]-2-naphthalenol, m.p. 89°-91°.
The starting material can be obtained as follows:
m-Bromobenzyl cyanide is converted by double alkylation and basic hydrolysis into 2-(m-bromophenyl)-2-methylpropionic acid which is further converted in analogy to the process steps described in Example 13 via 7-bromo-3,4-dihydro-1,1,4,4-tetramethyl-2(1H)-naphthalenone.
EXAMPLE 15
144 mg of a 50% sodium hydride dispersion are suspended in 3 ml of dimethylformamide and treated with 740 mg of diethyl fluorophenylmethanesulphonate (prepared from benzyl fluoride by radical bromination with N-bromosuccinimide and reaction with triethyl phosphite). After stirring at room temperature for 2 hours 1.15 g of 5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-acetonaphthone are added dropwise thereto and the mixture is heated at 55° overnight. After cooling the mixture is poured into ice-water and extracted with ether. After drying and evaporating the organic phase there are obtained 1.3 g of crude product which is purified by chromatography on silica gel (elution agent hexane/ethyl acetate=99:1) and, after recrystallization from hexane, there are obtained 77 mg of 6-[(Z)-β-fluoro-α-methylstyryl]-1,2,3,4-tetrahydro-1,1,4,4-tetramethylnaphthalene, m.p. 100°.
EXAMPLE 16
In analogy to Example 1, from 19.4 g of [1-(1,1,3,3-tetramethyl-5-indanyl)ethyl]triphenylphosphonium bromide, 6.9 g of ethyl p-formylphenylcarbonate and 200 ml of butylene oxide there are obtained, after filtration of the crude product over silica gel (elution agent hexane/ethyl acetate=19:1), 5 g of ethyl p-[2-(1,1,3,3-tetramethyl-5-indanyl)propenyl]phenylcarbonate as a yellowish oil which solidifies in the cold and which can be recrystallized from hexane. 5 g of the thus-obtained product are dissolved in 50 mg of ethanol and treated with a solution of 7.4 g of potassium hydroxide in 25 ml of water. After stirring at room temperature for 3 hours the mixture is poured into ice-water, acidified with 3N hydrochloric acid, extracted with ethyl acetate and evaporated. After recrystallization of the crude product from hexane there are obtained 2.6 g of p-[2-(1,1,3,3-tetramethyl-5-indanyl)propenyl]phenol in colourless crystals, m.p. 137°.
The ethyl p-formylphenylcarbonate used as the starting material can be prepared in a simple manner by reacting p-hydroxybenzaldehyde with ethyl chloroformate with the addition of triethylamine. Distillation of the crude product gives ethyl p-formylphenylcarbonate as a colourless liquid, b.p. 111°-113°/2.5 mm.
EXAMPLE 17
In analogy to Example 1, from 21.9 g of [1-(1,1,3,3-tetramethyl-indan-2-on-5-yl)ethyl]triphenylphosphonium bromide, 7.6 g of ethyl p-formylphenylcarbonate and 400 ml of butylene oxide there are obtained, after filtration of the crude product over silica gel (elution agent hexane/ethyl acetate=4:1) and recrystallization from hexane/ethyl acetate, 3.4 g of ethyl p-[2-(1,1,3,3-tetramethyl-2-oxo-5-indanyl)propenyl]phenylcarbonate, m.p. 130°-131°.
Hydrolysis of this product with an excess of potassium hydroxide in ethanol/water gives, after recrystallization from ethyl acetate/hexane, 1.7 g of 5-(p-hydroxy-α-methylstyryl)-1,1,3,3-tetramethyl-2-indanone in colourless crystals, m.p. 172°-173°.
EXAMPLE 18
A solution of 1 g of 5-(p-hydroxy-α-methylstyryl)-1,1,3,3-tetramethyl-2-indanone in 10 ml of tetrahydrofuran is added dropwise while cooling with ice to a suspension of 100 mg of lithium aluminium hydride in 5 ml of tetrahydrofuran and the mixture is subsequently left to stir at room temperature for 2 hours. After the dropwise addition of 50 ml of 2N hydrochloric acid at 0° the mixture is extracted with ethyl acetate and the organic phase is washed with water, dried and evaporated. After filtration of the crude product over silica gel (elution agent hexane/ethyl acetate=1:1) it is recrystallized from ethyl acetate/hexane and there are obtained 500 mg of 5-(p-hydroxy-α-methylstyryl)-1,1,3,3-tetramethyl-2-indanol in colourless crystals, m.p. 148°-149°.
EXAMPLE 19
In analogy to Example 2, from [1-(5,6,7,8-tetrahydro-3-methoxy-5,5,8,8-tetramethyl-2-naphthyl)ethyl]triphenylphosphonium bromide and ethyl p-formylphenylcarbonate there is obtained ethyl [p-[(E)-2-(5,6,7,8-tetrahydro-3-methoxy-5,5,8,8-tetramethyl-2-naphthyl)propenyl]phenyl]carbonate m.p. 122°-123°.
Hydrolysis of this product with an excess of potassium hydroxide in ethanol/water gives, after recrystallization from methanol, p-[(E)-2-(5,6,7,8-tetrahydro-3-methoxy-5,5,8,8-tetramethyl-2-naphthyl)propenyl]phenol, m.p. 181°.
EXAMPLE 20
In analogy to Example 5,
from 7-acetyl-6-chloro-1,2,3,4-tetrahydro-1,1,4,4-tetramethylnaphthalene and benzylmagnesium chloride there is obtained (E)-6-chloro-1,2,3,4-tetrahydro-1,1,4,4-tetramethyl-7-(α-methylstyryl)naphthalene m.p. 114°,
from 7-acetyl-1,2,3,4-tetrahydro-6-methoxy-1,1,4,4-tetramethylnaphthalene and benzylmagnesium chloride there is obtained (E)-1,2,3,4-tetrahydro-7-methoxy-6-(α-methylstyryl)-1,1,4,4-tetramethylnaphthalene, m.p. 88°-89°, and
from 7-acetyl-1,2,3,4-tetrahydro-5,8-dimethoxy-1,1,4,4-tetramethylnaphthalene and benzylmagnesium chloride there is obtained (E)-1,2,3,4-tetrahydro-5,8-dimethoxy-6-(α-methylstyryl)naphthalene, m.p. 110°.
The manufacture of dosage forms of the compounds of formula I can be effected in the usual manner, e.g. on the basis of the following Examples.
EXAMPLE A
Hard gelatine capsules can be manufactured as follows:
______________________________________Ingredients mg/capsule______________________________________1. Spray-dried powder containing 75% of 200compound I2. Sodium dioctyl sulphosuccinate 0.23. Sodium carboxymethylcellulose 4.84. Microcrystalline cellulose 86.05. Talc 8.06. Magnesium stearate 1.0Total 300______________________________________
The spray-dried powder, which is based on the active substance, gelatine and microcrystalline cellulose and which has an average particle size of the active substance of <1μ (measured by means of autocorrelation spectroscopy), is moistened with an aqueous solution of sodium carboxymethylcellulose and sodium dioctyl sulphosuccinate and kneaded. The resulting mass is granulated, dried and sieved, and the granulate obtained is mixed with microcrystalline cellulose, talc and magnesium stearate. The powder is filled into size O capsules.
EXAMPLE B
Tablets can be manufactured as follows:
______________________________________Ingredients: mg/tablet______________________________________1. Compound I as a finely milled powder 5002. Lactose powd. 1003. Maize starch white 604. Povidone K30 85. Maize starch white 1126. Talc 167. Magnesium stearate 4Total 800______________________________________
The finely milled substance is mixed with lactose and a portion of the maize starch. The mixture is moistened with an aqueous solution of Povidone K30 and kneaded, and the resulting mass is granulated, dried and sieved. The granulate is mixed with the remaining maize starch, talc and magnesium stearate and pressed to tablets of suitable size.
EXAMPLE C
Soft gelatine capsules can be manufactured as follows:
______________________________________ Ingredients mg/capsule______________________________________1. Compound I 502. Triglyceride 450 Total 500______________________________________
10 g of compound I are dissolved in 90 g of mediumchain triglyceride with stirring, inert gasification and protection from light. This solution is processed as the capsule fill mass to soft gelatine capsules containing 50 mg of active substance.
EXAMPLE D
A lotion can be manufactured as follows:
______________________________________Ingredients:______________________________________1. Compound I, finely milled 3.0 g2. Carbopol 934 0.6 g3. Sodium hydroxide q.s. ad pH 64. Ethanol, 94% 50.0 g5. Demineralized water ad 100.0 g______________________________________
The active substance is incorporated into the ethanol 94%/water mixture under protection from light. Carbopol 934 is stirred in until gelling is complete and the pH value is adjusted with sodium hydroxide.
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The present invention is concerned with novel tetrahydronaphthalene and indane derivatives of the formula ##STR1## useful as for combatting dermatoses as well as neoplasmas.
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This application is a continuation-in-part of application Ser. No. 880,107 filed June 30, 1986 which in turn is a continuation of application Ser. No. 778,575, filed Sept. 20, 1985, both now abandoned, the disclosure of which is incorporated herein by reference.
BACKGROUND OF THE INVENTION
This invention is directed to a guiding catheter for negotiating a tortuous non-linear conduit and to a method for its use.
In many medical procedures, such as percutaneous transluminal angioplasty, it is necessary to advance a catheter through a narrow tortuous blood vessel without damaging the endothelium. A variety of systems are used, such as guide wires, for example, see U.S. Pat. No. 4,436,017, guiding catheters, for example, see U.S. Pat. No. 3,773,034, and everting catheters, for example, see U.S. Pat. No. 4,437,857. A difficulty with commonly used guiding systems is that the procedure is time consuming and requires great skill on the part of the surgeon. Also many systems require the use of a large number of pre-bent guiding tips for accommodating different changes in the path of the vascular system.
The guiding, i.e. steerable, catheter disclosed in U.S. Pat. No. 3,773,034 has at its distal end a steerable tip formed of a flexible, thin, stretchable and contractible material. As the pressure of fluid within the distal end is varied, the steerable tip axially elongates or contracts. One longitudinally extending portion of the tip is restrained from stretching so that an increase in pressure on the fluid in the catheter results in bending of the steerable tip. The restraint may be the walls of the blood vessel or other channel in which the catheter is being inserted or an axially restraining means in the wall of the catheter tip. One disadvantage of this catheter is that if there is a constriction, e.g. caused by the blood vessel walls or improper positioning of the catheter, increased fluid pressure may not cause the desired bending. The degree of bending will be unknown by the person inserting the catheter who will be able to note only the increase in fluid pressure.
There is a need for a device for accessing remote regions of the vascular system without problems associated with current devices.
SUMMARY OF THE INVENTION
The present invention is directed to devices satisfying these needs, as well as novel methods for using these devices. A guiding catheter has incorporated toward its distal end, a flexible member capable of non-uniform elongation to cause the distal end portion to bend and straighten as desired so that it can be maneuvered through and accurately positioned in a tortuous, non-linear conduit containing branches, for example blood vessels. The flexible member comprises interconnected, and preferably braided, filaments with gaps between the filaments. The member has a first configuration that is axially lengthened and a second configuration that is axially shortened. Means are provided to move the member between its first and second configurations. Biasing means are provided to restrict axial lengthening along one side of the flexible member resulting in bending of the catheter tip.
One aspect of this invention comprises a guiding catheter for negotiating a tortuous, non-linear conduit, the catheter having a longitudinal axis, a proximal end, and a distal end, the catheter comprising:
(a) an elongated tubular anchor member having a distal portion and a proximal portion;
(b) an elongated activating member having a distal portion and a proximal portion which extends beyond the proximal portion of the anchor member; and
(c) a flexible member comprising interconnected filaments attached to the outer surface of the distal portion of the anchor member at a first location and also attached to a distal portion of the activating member at a second location, the first and second locations being axially spaced apart from each other, both the anchor member and the activating member being substantially rigid in compression where attached to the flexible member, the flexible member having a first configuration that is axially lengthened and a second configuration that is axially shortened, said flexible member also comprising means for preventing axial lengthening of the flexible member along one side thereof, wherein the flexible member in one of said configurations is bent such that the distal end of the catheter is transverse to the longitudinal axis of the catheter, and in the other said configuration is substantially straight;
and wherein relative axial movement between the anchor member and the activating member reversibly moves the flexible member from one configuration to the other configuration for varying the amount the distal end of the catheter is transverse to the longitudinal axis of the catheter.
Another aspect of this invention comprises a method for accessing a relatively inaccessible region of a tortuous non-linear conduit comprising the steps of:
(a) entering the conduit with a guiding catheter having a longitudinal axis, a proximal end, and a distal end, the distal end being placed first into the conduit, the catheter comprising:
(i) an elongated tubular anchor member having a distal portion and a proximal portion;
(ii) an elongated activating member having a distal portion and a proximal portion which extends beyond the proximal portion of the anchor member; and
(iii) a flexible member comprising interconnected filaments attached to a distal portion of the anchor member at a first location and also attached to a distal portion of the activating member at a second location, the first and second locations being axially spaced apart from each other, both the anchor member and the activating member being substantially rigid in compression where attached to the flexible member, the flexible member having a first configuration that is axially lengthened and a second configuration that is axially shortened, said flexible member also comprising means for preventing axial lengthening of the flexible member along one side thereof, wherein the flexible member in one of said configurations is bent such that the distal end of the catheter is transverse to the longitudinal axis of the catheter and in the other of said configurations is substantially straight,
and wherein the relative axial movement between the anchor member and the activating member reversibly moves the flexible member from one configuration to the other configuration for varying the amount the distal end of the catheter is transverse to the longitudinal axis of the catheter; and
(b) moving the catheter through the conduit toward the inaccessible region while causing relative axial movement between the anchor and activating members for varying the amount the distal end of the catheter is transverse to the longitudinal axis of the catheter for accommodating non-linearity of the conduit.
The flexible member of interconnected, and preferably braided, filaments with gaps between the filaments has a first configuration that is axially lengthened and a second configuration that is axially shortened. Means are provided to restrict axial lengthening (or shortening) along one side of the member so that in either the first or the second configuration, the flexible member is bent, that is the distal end of the catheter is transverse to the longitudinal axis of the catheter. There are two elongated members, a first elongated anchor member attached to the flexible member at a first location of the flexible member and a second elongated activating member attached to the flexible member at a second location of the flexible member. The second location is axially spaced apart from the first location. Relative axial movement between the first and second members moves the flexible member from one of the configurations to the other configuration.
Both members can be accessed from the same end of the device, i.e. both members extend from the proximal portion of the device to the flexible member. Generally the activating members extends from the proximal portion of the device to the distal portion of the flexible member and the anchor member extends to the proximal portion of the flexible member.
The catheter can be rotated by rotating at least the anchor member thereby facilitating manipulation of the catheter along the tortuous conduit and into branch conduits. Thus, the catheter bending is not unidirectional but can occur in any desired direction.
In a preferred embodiment, the flexible member is attached to the outer surface of the anchor member and to the outer surface of the distal portion of the activating member. The flexible member is preferably biased so that it is in its axially lengthened configuration in its at rest state. By "at rest state" is meant the configuration of the member when no force is applied thereto. Relative axial movement between the inner and outer members so that the points at which the flexible member is attached to the anchor and activating members become closer together, results in bending of member by non-uniform axial lengthening of the flexible member. The amount the distal end is bent can be controlled by varying the relative position of the anchor members.
A stop can be provided for limiting the amount the flexible member expands and therefore limiting the degree of bending of the catheter's distal end. The catheter can be provided with a second bending flexible member if desired. The two bendable members can be concentric or can be axially spaced apart. If axially spaced apart, the distal end can assume a double bend or other complex configuration to enable it to traverse complex tortuous conduits and branches.
The region between the inner activating member and the outer anchor member can be used for carrying fluids into a patient or from a patient. The inner member can be solid in cross-section, or can be tubular, and if tubular, the lumen of the inner member can be used for carrying fluids to a patient or from a patient.
BRIEF DESCRIPTION OF THE DRAWINGS
These and other features, aspects, and advantages of the present invention will become better understood from the following description, appended claims, and accompanying drawings where:
FIG. 1A is a side elevation view, partly in section, of a guiding catheter according to the present invention in its substantially straight configuration;
FIG. 1B is a side elevation view, partly in section, of the guiding catheter of FIG. 1A in its bent configuration;
FIG. 2 is a side elevation view, partly in section, of another guiding catheter according to the present invention.
FIG. 3 is a side elevation view, partly in section, of another guiding catheter according to the present invention.
FIG. 4 is a side elevation view, partly in section, of another device according to the present invention in its substantially straight configuration including stop means for limiting the degree of bending of the flexible member.
DETAILED DESCRIPTION OF THE INVENTION
As shown in FIGS. 1A and 1B, a guiding catheter 10 according to the present invention comprises a flexible member 12 of interconnected filaments with gaps therebetween. The catheter 10 has a distal portion 10a and a proximal portion 10b. As shown in FIG. 1A, the flexible member 12 has a first configuration that is substantially straight and axially lengthened, and as shown in FIG. 1B, has a second configuration that is bent and axially shortened.
The flexible member 12 is moved from one configuration to the other configuration by relative axial movement of anchoring member 14 and activating member 15. The flexible member 12 is attached to the anchoring member 14 and activating member 15 at locations 18 and 19 respectively, the two locations being axially spaced apart from each other. Both anchor members 14 and 15 lead into the flexible member 12 from the same direction, i.e. from the proximal portion 10b of the device. Thus the anchoring member 14 is connected to the proximal portion of the flexible member 12 and the activating member 15 is connected to the distal portion of the flexible member 12. The activating member 15 extends from the proximal portion of the anchor member through the distal portion of the anchor member 14.
Relative axial movement between the anchor member 14 and activating member 15 is produced by pulling on activating member 15 while restraining anchor member 14 causing the first 18 and second 19 locations to move closer to each other, resulting in the flexible member 12 moving from its axially lengthened configurations to its axially shortened configuration. Flexible member 12 is provided with a bonding means illustrated as adhesive strip 20 which bonds the interconnecting filaments and prevents axial shortening of the member along the adhesive strip. This results in a moment being produced along the edge of the flexible member causing it to bend as shown in FIG. 1B. Similarly, once the flexible member 12 is in the configuration shown in FIG. 1B, relative axial movement between anchor member 14 and activating member 15 in the opposite direction causes the flexible member 12 to move back to its axially lengthened, substantially straight configuration shown in FIG. 1A.
It is to be understood that relative axial movement results in the change in configuration. For example, to move the flexible member from its axially lengthened, substantially straight configuration shown in FIG. 1A to the axially shortened, bent configuration shown in FIG. 1B, any or all of the following steps can be taken:
(a) Pull (tensile force) on the proximal portion of the activating member 15 with concurrent push (compressive force) on the proximal portion of the anchoring member 14; or
(b) Push (compressive force) on the distal portion 15b of the activating member 15 with concurrent pull (tensile force) on the proximal end of the anchor member 14.
In this application it is to be understood that when force on the activating member is referred to, the concurrent opposite force is applied to the anchor member. Sufficient compressive force can be applied e.g. to the anchor member, by restraining it from motion while the activating member is pulled from its axial end.
Typically, the anchor member 14 is tubular and the activating member 15 is within the lumen of the anchor member 14 for at least part of its length. The tubular anchor member can be circular in cross-section, or can have other cross-sections such as oval, star shaped, or other irregular pattern. As shown in FIGS. 1A and FIGS. 1B, the activating member 15 can also be tubular. As shown in FIG. 3, the activating members can be solid in cross-section.
The anchor and activating members 14 and 15 are formed from a material sufficiently flexible to navigate tortuous paths yet sufficiently rigid in compression and/or tension so that the anchor and activating members are capable, without buckling, of causing the flexible member to move from one configuration to the other. In some embodiments, e.g. where the flexible member is biased (as discussed below) to automatically revert to its axially lengthened configuration, the activating member need not be rigid under compression.
The flexible member 12 is attached or bonded to the anchor members 14 and 15 by any of a variety of techniques, including welding, fusing, heat shrink tubing, or use of an adhesive such as an epoxy based adhesive.
The materials used for the anchor and activating members should be biocompatible materials. By the term "biocompatible" there is meant a material that is non-toxic and noncarcinogenic. Exemplary of materials that can be used are metals such as titanium, medical grade stainless steel, and platinum. Suitable polymeric materials include polyethylene; acrylics; Teflon (Trademark) polytetrafluoroethylene (PTFE); polyesters such as those sold under the trademark Dacron; polysulfones; polyurethane elastomers; silicones; polyolefin elastomers; medical grad epoxy resins; synthetic and natural rubbers; cellulosic materials such as cellulose acetate, cellulose acetate butyrate, and ethyl cellulose; and nylon.
The flexible member 12 is formed of interconnected filaments, preferably formed as a braid, i.e. comprises three or more component strands forming a regular diagonal pattern down its length. The resulting structure resembles a "Chinese finger handcuff" device where a series of interwoven fibers are arranged helically and configured into a tubular shape. Each fiber is capable of simultaneous angular rotation.
Substantially any fiber can be used for the flexible member 12. For medical applications, preferably the flexible member 12 is made from biocompatible materials. Some examples of suitable materials are thermoplastic polyester, polyethylene, thermoplastic soft segment polyurethane, polymethylmethacrylate, polytetrafluorotheylene, silicone polymers, and elastomeric polyurethane polymers. For applications where the device 10 is used in contact with blood, preferably the materials used for the anchor members and the flexible member are polymeric substances that do not promote thrombosis or blood clotting on their surfaces, i.e. the materials are non-thrombogenic.
The flexible member 12 includes means for preventing a longitudinal portion of the flexible member from axially lengthening. For example, the flexible member 12 can include an elongated strip 20 of adhesive along its length for interconnecting the filaments and preventing them from relative movement. Because of the strip 20 of material, the flexible member cannot shorten in the region of the strip 20. Upon relative axial movement between the anchor member 14 and the activating member 15, only a portion of the flexible member 12 shortens, with a resultant bending moment on the distal portion. As shown in FIGS. 1A and 1B, this bending moment results in the flexible member 12 and the distal portion 10a of the catheter 10 being bent so that the distal portion of the catheter is transverse to the longitudinal axis. For this to occur, it is necessary that at least the distal portion of the activating member 15 be sufficiently flexible that it can bend. In addition the anchoring member 14 needs to be sufficiently rigid in compression that when the activating member 15 is pulled relative to the anchoring member 14, the flexible member 12 shortens rather than the anchoring member 14 buckling. Shortening of the flexible member 12 is reversible. For this to occur, it is necessary that the activating member 15 be sufficiently rigid in compression that it does not buckle when the activating member 15 is moved to move the flexible member 12 to its axially lengthened configuration. Thus relative axial movement between the anchoring member 14 and the activating member 15 can reversibly move the flexible member 12 from one configuration to the other configuration for varying the amount the distal end 10a of the catheter 10 is transverse to the longitudinal axis. Other means for preventing lengthening of the flexible member along one side thereof. Any bonding means such as adhesive can be used. A strip of non-stretchable material can be secured to the flexible member, e.g. by adhesion, sewing fusion or the like or incorporated into the flexible member, e.g. by interweaving non-stretchable warp filaments along one edge of the flexible member. The warp filaments can extend beyond the flexible member and act as the activating member (providing the flexible member is biased in its axially lengthened configuration).
Any of the components of a catheter according to the present invention can be made self-lubricating, by incorporating therein a finely divided solid lubricant such as molybdenum disulfide, graphite, tungsten disulfide, molybdenum selenide, or titanium disulfide. Also any of the components can be coated with a lubricant such as PTFE. These lubricating materials greatly facilitate the displacement of the catheter 10 over a mucous surface.
In a catheter according to the present invention, there can be a flexible impervious membrane, preferably in the shape of a band, on the flexible member, the band being substantially impervious to particular liquids and/or gases. In this version of the invention the band, e.g. of natural or synthetic rubber, can be used for preventing flow through a vessel.
A catheter according to the present invention can comprise two or more bendable, flexible members, positioned at the distal end of the catheter.
The flexible member can be biased into either a lengthened or shortened configuration, by, for example, orienting and heat-setting or annealing the braided filaments. By "biased" is meant that the flexible member will at rest be in its first (or second) configuration and will revert to that configuration from any other configuration unless restrained from doing so.
An advantage of the catheter 10 is that the bend at the tip is infinitely variable so that the catheter 10 can be used for navigating substantially all of the turns in a blood vessel system and accommodate differences in the patient's anatomy. Further, the catheter 10 can readily be rotated to bend in any direction and thus can be directed to focus on the entrance of a branch conduit, e.g. the coronary artery from the aorta. This ability to rotate the catheter and then bend the flexible member in the desired direction and to the desired extent is generally unattainable by prior art devices.
FIG. 2 shows another catheter device 30. The catheter 30 includes an outer tubular anchor member 32, an inner tubular anchor member 34 in the lumen of the outer member 32, and a flexible member 36 attached at its distal end 36a by heat shrink tubing 38 to the inner anchor member 34 and attached at its proximal end 36b by adhesive to the outer tubular member 32. As shown in FIG. 2, the inner anchor member 34 is coaxial with the flexible member 36. At the proximal end 36b of the flexible member, the inner anchor member 34 is at about the longitudinal center line of the flexible member 36. However, at the distal end 36a of the flexible member 36, the inner anchor member 34 is offset from the longitudinal center line of the flexible member 36. Thus in the region of the flexible member, the longitudinal axis of the inner tubular member 34 is skewed or transverse relative to the longitudinal center line of the flexible member 36. Because of this skewed configuration, when the inner tubular member 34 is pulled, the flexible member 36 develops a bend and can have the same bent configuration of the catheter 10 shown in FIG. 1B.
FIG. 3 shows another catheter device 40. The catheter 40 includes a tubular anchor member 42 with a flexible member 44 attached at its distal end 42a. Activating member 46 is attached at a point at the distal end 44a of flexible member 44. The activating member 46 is a solid rod which in this embodiment passes outside flexible member 44 and into the lumen of anchoring member 42. It is to be understood that the activating member could be inside the tubular flexible member or woven into it. When activating member 46 is pulled, its point attachment to flexible member 44 causes the flexible member to bend. The flexible member 44 can revert to its substantially straight, axially lengthened, substantially straight configuration by pushing an activating member 46 or the filaments of flexible member 44 can be biased such when the pulling force applied to activating member 46 is removed, the flexible member 44 automatically reverts to its substantially straight configuration.
In some applications, it is desirable to limit the amount the flexible member can bend. For example, if the flexible member is placed into a small diameter blood vessel, it is desirable that the amount that the flexible member can be expanded be limited so that the operator of the device does not inadvertently overexpand the flexible member thereby damaging tissue. The catheter 60 shown in FIG. 4 is particularly adapted for this purpose.
In FIG. 4, the activating member 62 of catheter 60 can be provided with an annular projection 68 that can engage a cooperating radially outwardly projecting ring 69 on the interior of the anchoring member 64. These interengaging stops limit the amount the activating member 62 can be pulled axially, thereby limiting the amount of expansion of the flexible member 66. Flexible member 66 is provided with a strip of adhesive 65 which prevents axial shortening of the flexible member 66 along the strip causing bending of the flexible member 66. The interengaging stops 68 and 69 thus limit the amount of bending of catheter 60. If desired, the stop can be positioned at the proximal end of the device limiting the amount the activating member can move with respect to the anchoring member.
EXAMPLE 1
Guiding Catheter
A guiding catheter 10 as shown in FIGS. 1A and 1B comprises an outer tubular anchoring member 14 which is 50 inches long with an outer diameter of from 80 to 120 mil and an inner diameter of from 70 to 90 mil. The inner tubular activating member 15 is 60 inches long, has an outer diameter of from 68 to 80 mils, and an inner diameter of from 50 to 62 mils. Both tubes can be made of polytetrafluoroethylene or polyethylene. The inner diameter of the outer tube is of course greater than the outer diameter of the inner tube. The flexible member 20 is formed from polyethylene filaments having a diameter of from 6 to 10 mil. The flexible member 20 in its axially lengthened, substantially straight configuration has an outer diameter of 120 mil. The flexible member is bonded to the inner and outer tubes with medical grade epoxy.
Although the present invention has been described in considerable detail with reference to certain preferred versions are possible. Therefore the spirit and scope of the appended claims should not be limited to the description of the preferred versions.
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A guiding catheter has incorporated toward its distal end, a flexible member capable of non-uniform elongation to cause the distal end portion to bend and straighten as desired so that it can be maneuvered through and accurately positioned in a tortuous, non-linear conduit containing branches, for example blood vessels. The flexible member comprises interconnected, and preferably braided, filaments with gaps between the filaments. The member has a first configuration that is axially lengthened and a second configuration that is axially shortened. Means are provided to move the member between its first and second configurations. Biasing means are provided to restrict axial lengthening along one side of the flexible member resulting in bending of the catheter tip.
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RELATED APPLICATION
This application is a division of application Ser. No. 12/125,174, filed on 22 May 2008, now U.S. Pat. No. 7,659,379, which was a continuation in part of Ser. No. 11/983,206 filed on 11 Nov. 2007 and now U.S. Pat. No. 7,595,296, Ser. No. 11/983,215 filed on 11 Nov. 2007 and now U.S. Pat. No. 7,696,171, and Ser. No. 11/983,217 filed on 11 Nov. 2007 and now U.S. Pat. No. 7,776,825, and also claims priority from provisional application Ser. No. 60/939,909, filed on 24 May 2007, all of which applications are incorporated herein by reference in their entirety.
SEQUENCE LISTING
A Sequence Listing is submitted herewith as an ASCII compliant text file throught the Electronic Filing System; the name of the text file is “Mutants of Human Fibroblast Growth Factor Having Increased Stability and/or Mitogenic Potency”; the file was created on May 22, 2008, and is 2 KB in size; this Sequence Listing is incorporated herein by reference in its entirety.
FIELD OF THE INVENTION
The present invention relates to the field of protein engineering and, more particularly, to engineered mutant polypeptides of human fibroblast growth factor 1 (FGF-1) having improved thermal stability and/or improved mitogenic activity.
BACKGROUND OF THE INVENTION
The β-trefoil protein human fibroblast growth factor-1 (FGF-1) is made up of a six-stranded anti-parallel β-barrel closed off on one end by three β-hairpins, thus exhibiting a three-fold axis of structural symmetry. The N- and C-termini β-strands hydrogen bond to each other and are postulated from both NMR and X-ray structure data to represent a structurally-weakened region of the β-barrel. Val mutations within the N- and C-termini β-strands are shown to stabilize the structure and to increase van der Waals contacts by filling local cavities present within this region. Mutations that increase van der Waals contacts between both the N- and C-termini β-strands are associated with significant reductions in the unfolding kinetics, and also increase the cooperativity of unfolding. These results indicate that an important step in the unfolding of FGF-1 involves the melting of the N- and C-termini. A series of stabilizing mutations are subsequently combined and result in a doubling of the ΔG of unfolding. These mutations simultaneously introduce a three-fold symmetric constraint upon the primary structure. The results support the hypothesis that a symmetric primary structure within a symmetric superfold is a solution to achieve a foldable polypeptide. The results also suggest that the β-trefoil is capable of substantial thermal stability. When considering the “function/stability trade-off” hypothesis, the β-trefoil architecture therefore appears capable of diverse functional adaptation.
Accordingly, mutants of human fibroblast growth factor 1 (FGF1) are described that have enhanced stability and mitogenic potency. In comparison to wild-type FGF1, polypeptides having mutations at positions 12 and 134 exhibit enhanced properties of stability and/or mitogenic activity. Enhanced stability may preclude the need for added heparin in formulations of FGF1 for therapeutic use. Additionally, the enhanced thermal stability may translate to a longer shelf-life and minimization of aggregation during storage. The enhanced mitogenicity, which is possibly related to enhanced stability, may provide for use of smaller dosages for equivalent efficacy.
SUMMARY OF THE INVENTION
With the foregoing in mind, the present invention advantageously provides a mutant polypeptide of human FGF1, the polypeptide consisting of SEQ ID NO:1 wherein residue 12 is substituted by cysteine. In other embodiments, this mutant further comprises residue 134 substituted by cysteine, valine or threonine.
The invention also provides a mutant polypeptide of human FGF1, the polypeptide consisting of SEQ ID NO:1 wherein residue 12 is substituted by valine. This mutant may also further comprise residue 134 substituted by cysteine, valine or threonine.
A further embodiment of the invention includes a mutant polypeptide of human FGF1, the polypeptide consisting of SEQ ID NO:1 wherein residue 12 is substituted by threonine. This mutant may further comprise residue 134 substituted by cysteine, valine or threonine.
cysteine. In this embodiment, residues 46, 87 or 134 may be substituted by valine.
Moreover, the present invention includes an isolated nucleic acid comprising a sequence that encodes a human FGF-1 polypeptide containing the amino acid sequence of SEQ ID NO:1 wherein residue 12 is substituted by cysteine. This embodiment may further include the FGF-1 polypeptide wherein residue 134 is substituted by cysteine, valine or threonine.
Also included in the invention is an isolated nucleic acid comprising a sequence that encodes a human FGF-1 polypeptide containing the amino acid sequence of SEQ ID NO:1 wherein residue 12 is substituted by valine. In this preferred embodiment, the encoded FGF-1 polypeptide may further comprises residue 134 substituted by cysteine, valine or threonine.
Yet additionally, the invention includes an isolated nucleic acid comprising a sequence that encodes a human FGF-1 polypeptide containing the amino acid sequence of SEQ ID NO:1 wherein residue 12 is substituted by threonine. This embodiment may further comprise wherein the encoded FGF-1 polypeptide further comprises residue 134 substituted by cysteine, valine or threonine.
BRIEF DESCRIPTION OF THE DRAWINGS
Some of the features, advantages, and benefits of the present invention having been stated, others will become apparent as the description proceeds when taken in conjunction with the accompanying drawings, presented for solely for exemplary purposes and not with intent to limit the invention thereto, and in which:
FIG. 1 is a ribbon diagram of FGF-1, 18 showing the location of positions Lys12 and Pro134; the view on the right is looking down the β-barrel axis; also shown are the turn regions (residues 49-52 and 90-93) related to the N- and C-termini by the pseudo-three-fold axis of symmetry inherent in the β-trefoil architecture;
FIG. 2 is a relaxed stereo diagram of the local structure of FGF-1 in the region of positions Lys12 and Pro134 and including the hydrogen-bonding network; also shown are two small solvent excluded cavities, detectable using a 1.2 Å radius probe;
FIG. 3 is a relaxed stereo diagram showing an overlay of the K12→C, K12→T, and K12→V x-ray structures with WT* (dark grey) in the region of the mutation site; the solvent excluded cavity adjacent to position 12 is filled with each mutation;
FIG. 4 shows a relaxed stereo diagram showing an overlay of the P134→C x-ray structure with WT* (dark grey) in the region of the mutation site; the solvent excluded cavity adjacent position 12 is no longer detectable due to rotation of the Leu14 side chain;
FIG. 5 shows folding and unfolding kinetics “chevron plot” for WT* (●), Lys12→Val (Δ), P134→V(□); and
FIG. 6 shows the results of differential scanning calorimetry studies of K12V/C117V FGF-1 (SEQ ID NO:3) and P134V/C117V FGF-1 (SEQ ID NO:9) in comparison to C117V FGF-1 (“wild-type” FGF-1; SEQ ID NO:1).
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT
The present invention will now be described more fully hereinafter with reference to the accompanying drawings, in which preferred embodiments of the invention are shown. 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 pertains. 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. Any publications, patent applications, patents, or other references mentioned herein are incorporated by reference in their entirety. In case of conflict, the present specification, including any definitions, will control. In addition, the materials, methods and examples given are illustrative in nature only and not intended to be limiting. Accordingly, this invention may be embodied in many different forms and should not be construed as limited to the illustrated embodiments set forth herein. Rather, these illustrated 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. Other features and advantages of the invention will be apparent from the following detailed description, and from the claims.
FIGS. 1 through 6 illustrate various aspects of the present disclosure regarding human fibroblast growth factor-1 (FGF-1), which is a potent human mitogen for a variety of cell types, including vascular endothelial cells, and can stimulate such cells to develop neovasculature capable of relieving ischemia. For this reason, FGF-1 is an angiogenic factor with potential applicability in “angiogenic therapy”. 1-3 FGF-1 belongs to the β-trefoil superfold. 4,5 This molecular architecture is characterized by a pseudo-3-fold axis of structural symmetry, with the repeating motif being a pair of anti-parallel β-strands, known as the “β-trefoil fold”. These repeating structural motifs comprise a total of 12 β-strands that associate to form a six-stranded β-barrel capped at one end by three β-hairpins (forming the “β-trefoil” superfold; FIG. 1 ). Residue positions 13-17 (using the 140 amino acid form of FGF-1 numbering scheme) of the N-termini (β-strand 1), and 131-135 of the C-termini (β-strand 12), hydrogen bond with each other as a pair of anti-parallel β-strands within the six-stranded β-barrel, closely juxtaposing the two termini. When considering the three-fold symmetry of the overall architecture, the N- and C-termini are structurally related to two β-hairpin turns at positions 49-52 and 90-93 ( FIG. 1 ). Thus, the termini in the native structure represent a break in the mainchain continuity that forms the β-barrel.
An analysis of correlated anisotropic thermal factors in a 1.10 Å atom-resolution x-ray structure of FGF-1, has identified the N- and C-termini β-strands (β-strands 1 and 12, respectively) as demarcating a boundary of domain motion within FGF-1 6 . In the solution NMR structure of FGF-1 the interaction between β-strands 1 and 12 is only consistently defined through residue position 133 in β-strand 12, and the remaining positions 134-135 appear largely disordered 7 . Thus, these data are consistent with the N- and C-termini β-strand interaction representing a region of structural weakness in FGF-1 and therefore potentially contributing to the unfolding process. Of additional interest, quenched-flow hydrogen exchange experiments with FGF-1 have shown that the hydrogen bonds linking the N- and C-termini anti-parallel β strands appear to be the first detectable event in the folding of FGF-1, and may provide a structural framework for subsequent folding events. 8 Thus, in addition to unfolding, the interaction of the N- and C-termini β-strands may be a key contributor to the folding of FGF-1.
In an effort to study the contribution of the N- and C-termini β-strands to the stability and folding of FGF-1, Cys mutations were introduced into each β-strand with the intention of linking them through a disulfide bond. In this case, stability and folding studies under oxidizing and reducing conditions might elucidate the contribution of the N- and C-termini β-sheet formation to these processes. Two potential sites for such pair-wise mutations were identified at positions 12 and 134, and 13 and 135, respectively. These two pair wise Cys mutants were constructed and initial stability studies were performed under oxidizing conditions. The Cys13/Cys135 mutant exhibited a substantial decrease in stability and was not studied further. In contrast, the Cys12/Cys134 mutant exhibited a substantial increase in stability, suggesting that the introduced disulfide bond had stabilized the structure. However, repeating the stability studies under reducing conditions resulted in a further gain in stability. Therefore, the increase in stability for the Cys12/Cys134 mutant was due to the substitution of Lys12 and/or Pro134 by Cys and not to disulfide bond formation. As a consequence of this initial result, additional Thr and Val point mutations were constructed at positions 12 and 134 to probe the nature of the stability increase afforded by the Cys mutations. The results of these studies show that the Cys residue, in each case, is not unique and similar or greater increases in stability can be realized with either Thr or Val mutations.
Isothermal equilibrium denaturation, folding and unfolding kinetics, and x-ray structural studies have been utilized in characterizing the effects of Cys, Thr and Val mutations at positions 12 and 134 in FGF-1. The results show that mutations at both positions 12 and 134 contribute to increased stability, with position 12 mutations primarily increasing the rate of folding, and position 134 mutations primarily decreasing the rate of unfolding. The combined position 12 and 134 Val mutation also exhibits a 30-fold increase in mitogenic potency and may find useful application as a “second generation” form of FGF-1 in angiogenic therapy.
Val mutations at the symmetry-related positions of residues 12 and 134 were also studied and in one case (position 95) provide a substantial additional increase in stability. A combined mutation, involving Val mutations at five positions, and introducing a three-fold symmetric constraint at two positions within the FGF-1 structure, results in an increase in stability that doubles the original value of the ΔG of unfolding. This combined mutation is, however, functionally inactive. The results provide additional support to our hypothesis 9 that a symmetric primary structure within a symmetric superfold is a solution to, and not a constraint upon, the protein folding problem. Furthermore, the results also support the “function/stability trade-off” hypothesis 10-14 , and lead us to propose that one property of the β-trefoil superfold (and presumably all the protein superfolds) is the capacity for profound thermal stability, permitting a wide range of adaptive radiation in function.
Materials and Methods
Mutagenesis and Expression
Mutant construction and expression followed previously described procedures. 15-17 Briefly, all studies utilized a synthetic gene for the 140 amino acid form of human FGF-1 18-21 with the addition of an amino-terminal six residue “His-tag” to facilitate purification. 17 In the present study a Cys117 Val mutant form of FGF-1 was chosen as the reference protein for the current set of mutations, and is referred to as WT* in this report. The Cys117 Val mutation has minimal effects upon stability, folding or function of FGF-1 17 but eliminates a surface exposed cysteine residue that can form an intermolecular disulfide bond. The QuikChange™ site directed mutagenesis protocol (Stratagene, La Jolla, Calif.) was used to introduce individual or combination mutations using mutagenic oligonucleotides of 25 to 31 bases in length (Biomolecular Analysis Synthesis and Sequencing Laboratory, Florida State University). All FGF-1 mutants were expressed using the pET21a(+) plasmid/BL21(DE3) Escherichia coli host expression system (Invitrogen Corp., Carlsbad Calif.). Mutant proteins were purified as previously described 17 using nickel-nitrilotriacetic acid (Ni-NTA) chromatography followed by affinity purification using heparin Sepharose™ chromatography (G.E. Healthcare, Piscataway N.J.). Sites for Cys mutations leading to potential disulfide bond formation were identified using the Disulfide by Design program 22 and the x-ray coordinates of wild-type FGF-1. 18
Isothermal Equilibrium Denaturation
Isothermal equilibrium denaturation by guanidine hydrochloride (GuHCl) was quantified using fluorescence as the spectroscopic probe. FGF-1 contains a single buried tryptophan residue (Trp107) that exhibits greater fluorescence quenching in the native versus denatured state. 15, 18 The differential fluorescence between the native and denatured state has been used to quantify the unfolding of FGF-1, in excellent agreement with unfolding as monitored by CD spectroscopy. 15, 23 Fluorescence data were collected on a Varian Eclipse fluorescence spectrophotometer equipped with a Peltier controlled temperature regulator at 298K and using a 1 cm path-length cuvette. Protein samples (5 μM) were equilibrated overnight in 20 mM ADA, 100 mM NaCl, 2 mM DTT pH 6.6 (“ADA buffer”) at 298K in 0.1M increments of GuHCl. Triplicate scans were collected and averaged, and buffer traces were collected and subsequently subtracted from the protein scans. All scans were integrated to quantify the total fluorescence as a function of denaturant concentration. The general purpose non-linear least squares fitting program DataFit (Oakdale Engineering, Oakdale, Pa.) was used to fit the change in fluorescence versus GuHCl concentration data to a six parameter two-state model 24 :
F = F 0 N + S N [ D ] + ( F 0 D + ( S D [ D ] ) ) e - ( Δ G 0 + m [ D ] ) / RT 1 + e - ( Δ G 0 + m [ D ] ) / RT ( 1 )
where [D] is the denaturant concentration, F 0N and F 0D are the 0M denaturant molar ellipticity intercepts for the native and denatured state baselines, respectively, and S N and S D are the slopes of the native and denatured state baselines, respectively. ΔG 0 and m describe the linear function of the unfolding free energy versus denaturant concentration. The effect of a given mutation upon the stability of the protein (ΔΔG) was calculated by taking the difference between the C m values for WT* and mutant proteins and multiplying by the average of the m values, as described by Pace and Scholtz 25 :
ΔΔ G =( C m WT* −C m mutant )( m WT* +m mutant )/2 (2)
Folding Kinetics Measurements
Initial studies using manual mixing indicated that the relaxation times for folding were more appropriate for stopped-flow data collection. Denatured protein samples were prepared by overnight dialysis against ADA buffer containing either 2.5 M or 3.0 M GuHCl (depending upon the overall stability of the mutant). All folding kinetic data were collected using a KinTek SF2000 stopped-flow system (KinTek Corp., Austin Tex.). Folding was initiated by a 1:10 dilution of 40 μM denatured protein into ADA buffer with denaturant concentrations varying in increments of 0.05 M or 0.1 M, to the midpoint of denaturation as determined by the above described isothermal equilibrium denaturation measurements. The data collection strategy was designed to span approximately five half-lives, or >97% of the expected fluorescence signal change between the fully denatured and native states.
Unfolding Kinetics Measurements
Unfolding kinetics measurements were performed using a manual mixing technique. Protein samples (˜30 μM) were dialyzed against ADA buffer overnight at 298K. Unfolding was initiated by a 1:10 dilution into ADA buffer with a final GuHCl concentration of 1.5 to 5.5M in 0.5M increments. All unfolding data were collected using a Varian Eclipse fluorescence spectrophotometer equipped with a Peltier controlled temperature unit at 298K. Data collection times for each protein were designed so as to quantify the fluorescence signal over 3-4 half-lives, or >93% of the total expected amplitude.
Folding and Unfolding Kinetics Analysis
The folding and unfolding characteristics of FGF-1 have previously been described in detail. 26 Briefly, the unfolding kinetic data exhibits an excellent fit to single exponential decay at all denaturant concentrations. The folding kinetic data also exhibit an excellent fit to a single exponential model, but only for denaturant concentrations above approximately 0.6M GuHCl. Below this concentration, the folding kinetic data exhibit bi-exponential properties; with the slow phase being generally independent of denaturant concentration. The fast phase of this biexponential folding regime lies on the extrapolated region of the single-exponential folding data. Thus, the folding constant is derived from a fit to the mono-exponential region and the fast phase of the bi-exponential region. The ΔG values derived from the folding and unfolding kinetic data are in excellent agreement with the values obtained from isothermal equilibrium denaturation data, as well as differential scanning calorimetry. 26
Both folding and unfolding kinetic data were collected in triplicate at each GuHCl concentration; data from at least three separate experiments were averaged in each case. The kinetic rates and amplitudes versus denaturant concentration were calculated from the time dependent change in tryptophan fluorescence using a single exponential model:
l ( t )= A exp(− kt )+ C (3)
Where l(t) is the intensity of fluorescent signal at time t, A is the corresponding amplitude, k is the observed rate constant for the reaction and C is the asymptote of the fluorescence signal. Folding and unfolding rate constant data were fit to a global function describing the contribution of both rate constants to the observed kinetics as a function of denaturant (“Chevron” plot) as described by Fersht 27 :
ln( k obs )=ln( k f0 exp( mf[D ])+ln( k f0 exp( m u [D ])) (4)
where k f0 and k u0 are the folding and unfolding rate constants, respectively, extrapolated to 0M denaturant, mf and m u are the slopes of the linear functions relating ln(k f and ln(k u ), respectively, to denaturant concentration, and [D] is the denaturant concentration.
Crystallization of FGF-1 Mutants, X-Ray Data Collection, Refinement and Cavity Calculations
Purified protein for crystallization trials was dialyzed against 50 mM sodium phosphate, 100 mM NaCl, 10 mM ammonium sulfate, 2 mM DTT pH 7.5 (“crystallization buffer”) and concentrated to 10-16 mg/ml. Crystals were grown at room temperature using the hanging-drop vapor diffusion method with 7 μl drop size and 1 ml of reservoir solution. Diffraction quality crystals grew from reservoirs containing 3.2-4.3 M sodium formate and 0.25-0.5 M ammonium sulfate, with the exception of the Pro134 Cys mutant which grew from 3.6M sodium formate with no added ammonium sulfate.
Diffraction data for all mutants except Pro134 Cys, was collected at the Southeast Regional Collaborative Access Team (SER-CAT) 22-BM beam line (λ=1.00 Å) at the Advanced Photon Source, Argonne National Laboratory, using a MarCCD225 detector (Mar USA, Evanston, Ill.). Pro134 Cys mutant diffraction data was collected using an in-house Rigaku RU-H2R copper rotating anode (λ=1.54 Å) X-ray generator (Rigaku MSC, The Woodlands, Tex.) coupled to an Osmic Purple confocal mirror system (Osmic, Auburn Hills, Mich.) and a MarCCD165 detector (Mar USA, Evanston, Ill.). In all cases, crystals were mounted and maintained in a stream of gaseous nitrogen at 100 K. Diffraction data were indexed, integrated and scaled using the HKL2000 software 28, 29 . His-tagged wild-type FGF-1 (PDB code: 1JQZ) was used as the search model in molecular replacement using the CNS software suite 30 . Model building and visualization utilized the O molecular graphics program 31 . Structure refinement utilized the CNS software suite, with 5% of the data in the reflection files set aside for R free calculations 32 . Quantification of solvent-excluded cavities with the refined mutant structures was performed using the MSP software package 33 .
Mitogenic Assay
The mitogenic activity of certain mutants was evaluated by a cultured fibroblast proliferation assay. NIH 3T3 fibroblasts were initially plated in Dulbecco's modified Eagle's medium (DMEM) (American Type Culture Collection, Manassas Va.) supplemented with 10% (v/v) newborn calf serum (NCS) (Sigma, St Louis Mo.), 100 units of penicillin, 100 mg of streptomycin, 0.25 mg of Fungizone™ and 0.01 mg/ml of gentamicin (Gibco, Carlsbad Calif.) (“serum-rich” medium) in T75 tissue culture flasks (Fisher, Pittsburgh Pa.). The cultures were incubated at 37° C. with 5% CO2 supplementation. At 80% cell confluence, the cells were washed with 5 ml cold 0.14 M NaCl, 5.1 mM KCl, 0.7 mM Na2HPO4, 24.8 mM Trizma base, pH 7.4 (TBS) and subsequently treated with 5 ml of a 0.025% trypsin solution (Invitrogen Corp., Carlsbad Calif.). The trypsinized cells were subsequently seeded in T25 tissue culture flasks at a density of 3.0×104 cells/cm2 (representing 20% confluence). Cell synchronization was initiated by serum starvation in DMEM with 0.5% NCS, 100 units of penicillin, 100 mg of streptomycin, 0.25 mg of Fungizone™ and 0.01 mg/ml of gentamicin (“starvation” medium). Cultures were incubated for 48 hours at 37° C., the medium was then decanted and replaced with fresh medium supplemented with FGF-1 (0-10 μg/ml), and the cultures incubated for an additional 48 hours. After this incubation, the medium was decanted and the cells were washed with 1 ml of cold TBS. 1 ml of 0.025% trypsin was then added to release the cells from the flask surface, and 2 ml of serum-rich medium was added to dilute and inhibit the trypsin. The cells were counted using a hemocytometer (Hausser Scientific Partnership, Horsham Pa.). Experiments were performed in quadruplicate and the cell densities were averaged. The relationship between the cell number and log concentration of added growth factor was fit to a sigmoid function. The midpoint of the fitted sigmoid function represents the concentration of added growth factor necessary to achieve 50% stimulation (EC 50 value), and is used for quantitative comparison of mitogenicity.
Results
Mutant Protein Purification
All mutants were purified with high yield (˜65 mg/L).
Isothermal Equilibrium Denaturation
The thermodynamic parameters for the FGF-1 mutants are listed in Table I. The standard error of ΔG from multiple analyses is approximately 1.0 kJ/mol (0.24 kCal/mol), which is also the typical magnitude of the standard deviation of the fit to the 2-state model (data not shown). Thus, mutational effects upon stability can be reliably measured for values greater than 1 kJ/mol, consistent with previous reports, and the mutational effects upon stability are larger than this standard error in each case.
The substitution of Lys12 by Cys, Thr or Val provides a substantial increase in stability of between −6.9 to −8.1 kJ/mol. The highest midpoint of denaturation is observed for the Val mutant (1.53 M); however, a slight reduction in the ΔG versus denaturant m-value for the Val mutant in comparison to Cys results in a somewhat higher ΔG value for Cys when extrapolated to 0M denaturant (Table I). Overall, therefore, the Cys and Val mutants appear to be approximately equivalent in stability, with Thr slightly less so (but still stabilizing the protein by approximately −7.0 kJ/mol). The substitution of Pro 134 by Cys, Thr or Val also provides a significant increase in stability of between −4.7 to −7.6 kJ/mol. The highest midpoint of denaturation is observed for the Val mutant (1.49 M). In the case of position 134 mutations, the ΔG versus denaturant m-value is not substantially altered (table I), and extrapolation of ΔG to 0M denaturant similarly identifies the Val mutant as the most stable at this position.
Combining Val mutations at positions 12 and 134 results in a −17.7 kJ/mol increase in stability. The simple sum of the individual point mutations predicts an increase in stability of −15.7 kJ/mol; thus, the effects of the combined mutation appear to be largely additive in nature, with the possibility of cooperative interactions providing a modest −2.0 kJ/mol of additional stability.
Folding and Unfolding Kinetics
The results of the folding and unfolding kinetic analyses are listed in table II. The Cys, Thr, and Val mutations at position 12 stabilize the protein by primarily increasing the folding rate constant (4 to 10-fold) with comparatively less-significant (2-fold or less) reduction in the unfolding rate constant. These alterations in the folding and unfolding rate constants are associated with minimal changes in either the folding or unfolding kinetics “m values”.
The results of the Cys, Thr, and Val mutations at position 134 upon the folding and unfolding rate constants are a bit more complex. The Cys mutation achieves its increase in stability primarily through an 8-fold increase in the folding rate constant, and less than 2-fold decrease in the unfolding rate constant. Thus, the stability increase for Cys mutations at positions 12 and 134 are due to similar effects upon folding and unfolding kinetic rate constants (i.e. primarily an increase in folding rate constant). The Thr mutation at position 134 achieves its increase in stability through an equivalent 2-fold increase in folding rate constant and 2-fold decrease in unfolding rate constant. The Val mutation at position 134 achieves its stability increase primarily through a 10-fold decrease in unfolding rate constant, but also through an associated 6-fold increase in folding rate constant. Furthermore, the Val mutation is associated with a 2-fold increase in unfolding kinetics “m value” (which is not observed in either the Cys or Thr mutation; Table II). The double Val mutant at positions 12 and 134 exhibits the 10-fold reduction in unfolding rate constant displayed by the Val mutation at position 134, as well as a 33-fold increase in folding rate constant (an enhancement of the 10-fold increase in folding rate constant exhibited by the Val mutant at position 12). This double mutant retains the 2-fold increase in unfolding kinetics “m value” (in comparison to WT*) displayed by the Val mutation at position 134; there is no substantial change in the folding kinetics “m value” in comparison to WT*.
X-Ray Structures
Diffraction-quality crystals were obtained for the Lys12 Cys, Lys12 Val, Lys12 Thr, Lys12 Val/Asn95 Val and Pro134 Cys mutants (the majority of the position 134 mutations proving to be refractory to crystallization). All structures were refined to acceptable crystallographic residuals and stereochemistry. Crystallographic data collection and refinement statistics for the mutants are listed in Table III. All mutants, except Pro 134 Cys, crystallized in the WT* orthorhombic space group (C222 1 ) with two molecules in asymmetric unit. The Pro 134 Cys mutant crystallized in the monoclinic P2 1 space group with four molecules in the asymmetric unit. These four molecules were successfully positioned using the molecular replacement method and WT* FGF-1 as the search model. The 2F o -F c difference electron density was unambiguous at the mutation site(s), and the mutant structures could be accurately modeled in each case.
Mitogenic Activity
The mitogenic activity (EC 50 ) for representative FGF-1 mutants is summarized in table IV (the WT* Cys117 Val reference protein is essentially identical to wild-type FGF-1 in terms of stability, folding and mitogenic activity). The Cys and Val mutations at position 12 are approximately equivalent to each other in terms of mitogenic activity, and both are approximately 15 times more potent than WT* FGF-1. In contrast, while the Cys and Val mutations at position 134 are similarly equivalent to each other in terms of mitogenic potential, they exhibit only a modest increase in mitogenic activity compared to WT* (Table IV). The combination Val mutation at positions 12 and 134 appears to be largely additive, exhibiting an approximately 30-fold increase in mitogenic activity compared to WT*. The Val mutation at position 95 exhibits a substantial ˜1000-fold reduction in mitogenic activity.
Differential Scanning Calorimetry
Differential Scanning calorimetry studies of K12V/C117V FGF-1 and P134V/C117V FGF-1 were conducted and compared to C117V FGF-1 (“wild-type” FGF-1). We performed thermal denaturation studies of the above mutants using differential scanning calorimetry (DSC). This method permits direct determination of the melting temperature (melting transition midpoint) of a protein. The K12V and P134V point mutations were made in a modified version of wild-type FGF-1 that contains a Cys to Val mutation at position 117. This mutation has no effect upon stability of the protein, however, it eliminates the possibility of disulfide-linked dimers of FGF-1 (which is problematic for DSC analysis). The graph depicted in FIG. 7 shows the derived free energy profile (DG) as a function of temperature for the above mutants and “wild type” FGF-1.
Discussion
The x-ray structure of wild-type FGF-1 exhibits two small solvent-excluded cavities, detectable using a 1.2 Å radius probe, in the region of residues 12, 95 and 134 ( FIG. 2 ) and these appear to be key to understanding the effects of the mutations at these positions. One cavity, adjacent to position 12, and bounded by residues 14, 44 and 46, has a volume of 9 Å3; the other cavity, adjacent to position 134, and bounded by residue positions 14, 95 and 97, has a volume of 8 Å 3 . The WT* Lys residue at position 12 adopts a χ1 angle of −60° (gauche+), which orients the Lys12 side chain away from the adjacent cavity. However, the mutant Cys residue at position 12 adopts a χ1 angle of +60° (gauche−) which positions the side chain Sã towards the nearby cavity ( FIG. 3 ). Both the Thr and Val mutations at position 12 adopt rotamer angles that orient a side chain a methyl group in the same position as the Cys Sã. Thus, each of these small side chains is oriented so as to fill the adjacent cavity with a non-polar moiety. The Lys12 does not appear capable of adopting a gauche− rotamer (and filling the adjacent cavity) due to resulting steric clashes with adjacent residue Leu46. In filling this adjacent cavity, the Cys, Thr or Val residues are oriented to participate in van der Waals contacts with residues in adjacent β-strand 4, and not β-strand 12. Thus, the observed increase in stability with the position 12 mutants does not appear to be associated with stabilizing interactions between the N- and C-termini β-strands.
The X-ray structure of the Cys mutation at position 134 provides an opportunity to understand the structural basis of the increase in stability for mutations at this position. The Cys residue adopts a rotamer angle of −60° (gauche+) ( FIG. 4 ). While generally oriented towards the cavity adjacent to position 134, the mutant Cys Sγ does not appreciably reduce the size of the cavity. However, in response to the introduction of the Cys at position 134, the adjacent residue Leu14 adopts an alternate χ2 angle. This alternative side chain orientation positions one of the Leu Δ methyl groups towards the cavity adjacent to position 12; the result being that this cavity is no longer detectable using a 1.2 Å radius probe. Thus, the mutations at position 134 are capable of reducing the overall cavity space within the local region and increasing van der Waals contacts between β-strand 1 and β-strand 12 (i.e. the N- and C-termini).
In the x-ray structure of the combined Val mutations at positions 12 and 95, the Val at position 12 behaves the same as the Val 12 point mutation, and fills the adjacent cavity ( FIG. 5 ). In response to the Val mutation at position 95, the Pro side chain at position 134 shifts inward towards the cavity adjacent to this position, with the result that it is no longer detectable using a 1.2 Å radius probe. This structural adjustment results in greater van der Waals interactions between residue position 134 and adjacent residues, including Leu14 on β-strand 1. Thus, the Val mutation at position 95 also has the result of improving the van der Waals interaction between β-strands 1 and 12 (i.e. the N- and C-termini).
Mutations at position 134, but not position 12, are unique in increasing the unfolding kinetics “m value” (i.e. cooperativity of unfolding; FIG. 6 ) as well as decreasing the overall unfolding rate constant (table II). An interpretation for an increase in the unfolding kinetics “m value” is that the mutation has introduced stabilizing interactions in the native structure, but not in the folding transition state, as would be expected if additional hydrophobic contacts had been formed in the native structure 34. However, the position 12 mutations have similarly introduced additional hydrophobic contacts in the native state, but have not affected the unfolding kinetics “m value” nor significantly decreased the rate of unfolding. Thus, the distinction is that the mutations that have stabilized interactions between β-strands 1 and 12 are responsible for the decreased unfolding rate constant and increased cooperativity of unfolding. Therefore, it is concluded that early events in the unfolding of FGF-1 likely involve melting of the interaction between β-strands 1 and 12. This interpretation is consistent with the previously described domain motion boundary in FGF-1 involving these β-strands 6, and the solution NMR data indicating partial melting of the interface of β-strand 1 and 12 in FGF-1 at 298K 7 . Stabilizing adjacent N- and C-termini β-strand interactions may prove to be a generally-useful approach to engineering increased thermal stability in β-barrel structures, and appears capable of providing a substantial increase to the stability of the protein.
The Val mutations at positions 12 and 134 are approximately equivalent in their favorable contribution to the stability of the protein (˜−8.0 kJ/mol). FGF-1 exhibits relatively low thermal stability 15,35 , and mutations that stabilize the structure can increase the effective mitogenic potency, presumably due to longer functional half-life 9 . Both of the Val mutations at positions 12 and 134 appear more functionally active than WT*, although the position 12 mutation has a much more dramatic increases in mitogenicity (table IV). The Lys 12 side chain does not directly interact with FGFR (PDB accession 1 E0O), neither does Pro134. Thus, the basis for the difference in mitogenic activity between the 12 and 134 Val mutants (given their near-identical stability increase) is not fully understood. Nonetheless, the combined Lys12 Val/Pro134 Val mutant exhibits the greatest mitogenic activity, approximately 30 times more potent than WT*, and is −17.7 kJ/mol more stable than WT*. Such mutant forms of FGF-1 may find application as “second generation” forms of FGF-1 in angiogenic therapy for the treatment of ischemia 3, 36 .
The results shown in FIG. 6 indicate that the K12V mutation increases the melting temperature by 16.9° C. and the P13V mutation increases the melting temperature by 15.7° C. This is similar to the increase in stability afforded by the addition of heparin (see Copeland (1)); thus, these mutations may obviate the need to add heparin in the formulation of FGF-1 (saving considerable cost and avoiding concerns of infectious agents, since heparin is derived from pig tissue). 35
The Cys, Val and Thr mutations at position 12 exhibit closely-related effects as regards their substantial increase in stability. Similarly, the Cys, Val and Thr mutations at position 134 also exhibit closely-related substantial increases in stability. These similar mutagenic effects observed for the set of Cys, Val and Thr amino acids reflect their related stereochemical properties. Of the 20 common amino acids, the set of Cys, Val, and Thr amino acids comprise a unique set: i.e. they are the only amino acids that contain at least a side chain gamma constituent, but no constituent beyond the gamma position (i.e. no delta, epsilon, etc. constituent). The X-ray structure analyses of the role of the side chain gamma constituent in increasing the protein stability is consistent with this interpretation. Given these data, only representative single and double mutations involving positions 12 and 134 were deemed necessary to evaluate in the functional (i.e. 3T3 mitogenic) assay. All possible combinations of Cys, Val, and Thr single and double mutations at positions 12 and 134 comprise a total set of 15 mutations; however, based on the stability and structural data, we conclude that the single and double Val mutants characterized in the mitogenic assay are appropriately representative of the different combinations of Cys, Val and Thr mutations at these positions. The structure and stability data presented in this application allow us to predict the utility of the various Cys, Val and Thr mutations at positions 12 and 134.
Accordingly, in the drawings and specification there have been disclosed typical preferred embodiments of the invention and although specific terms may have been employed, the terms are used in a descriptive sense only and not for purposes of limitation. The invention has been described in considerable detail with specific reference to these illustrated embodiments. It will be apparent, however, that various modifications and changes can be made within the spirit and scope of the invention as described in the foregoing specification and as defined in the appended claims.
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Mutants of human FGF-1 are disclosed having increased stability and mitogenic potency. In the FGF-1 polypeptide, primarily residue 12 is substituted with cysteine and/or residue 134 is substituted cysteine, valine or threonine to render the polypeptide more stable and/or to increase its mitogenecity.
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This application is a continuation of Ser. No. 08/498,062, filed Jul. 5, 1995, now U.S. Pat. No. 5,636,947.
TECHNICAL FIELD
This invention relates to pneumatic tube carriers and, more particularly, to a pneumatic tube carrier which includes, as an integral part thereof, a sealing apparatus so that liquid, solid or gaseous substances contained within the carrier cannot escape to the outside. As well, substances situated outside of the carrier cannot penetrate the interior of the carrier. Such watertight or airtight qualities are important in the medical industry, especially in the transport of biohazardous or otherwise toxic materials. In those cases, escaping materials can be dangerous. Also, with pneumatic tube systems, leaking materials, particularly fluids, can "gum" or "foul" the interior walls of the tubes, resulting in increased maintenance, degraded performance (less speed, increased power consumption, etc.), and the like.
BACKGROUND ART
The transporting of articles via pneumatic tubes is old and well known. Basically, an object is placed within a container which is then transported by air under either positive or negative pressure from one destination to another. The transport is moved within a closed tube. The interior of the closed tube and the outer dimension of the carrier form a seal, so that the carrier can be propelled between the destinations by a vacuum.
One area of commerce which currently uses the pneumatic tube and the transporting of material via the pneumatic tube on a fairly regular basis is the hospital or biomedical research/manufacturing industry. One particular application of this technology is in the area of transporting blood samples, medicines, intravenous bags, viral samples or other biological or chemical matter between diverse locations within a hospital or laboratory. In that environment, for example, test tubes or vials of liquids are placed within a tube carrier, and are typically secured by foam or clamps within the carrier. The purpose of securing the samples (which are often contained within glass test tubes with rubber stoppers) is to help prevent breakage. When glass breaks or stoppers become dislodged (as can happen when hospital workers fail to properly secure the stopper in the first place), chemical or biological substances can leak into the interior of the carrier. In turn, said substances can leak out of the interior of the carrier, thereby contaminating the interior walls of the tube system. The vials or vessels of liquids, solids or gasses within the carrier can move or shift during transport, which may also lead to breakage. This problem is especially acute, as the carriers are often traveling at speeds in excess of 25 feet per second. Because of the rapid acceleration and deceleration of pneumatic tube carriers, the carrier contents can easily become dislodged, and can break within the carrier, if not for clamps, foam securing means, and the like. Nonetheless, accidents can happen, whereby despite the best efforts toward securing or protecting the interior vessels, they can break, or their stoppers can become dislodged. In fact, dislodged stoppers are a primary problem, due mainly to workers who may inadvertently fail to secure them properly in the first place.
If the leaking substance is of a large enough quantity, the substance (often a fluid) can leak out of the carrier. In that case, the entire tube transport system could become contaminated with the substance. For example, if fluids containing a virus or bacteria sample (for example, the HIV virus or the Ebola bacteria) were to leak out of a carrier, the interior of the vacuum transport tubes could become breeding grounds for the biological specimens--thus contaminating the exteriors of all carriers that pass through the system. Obviously, the recent public concerns over infectious diseases is a primary motivation behind the present invention. Also equally important is that fluids escaping from the carrier can "gum up" the interior of the vacuum tubes, making the smooth passage of the carrier difficult, resulting in enhanced downtime, increased maintenance expense, and increased power consumption (that is, friction would increase within the tube system).
If fluids escape from the vials and/or test tubes, but are contained within the carrier, the aforementioned problems can be mitigated. Of course, other problems can result. For example, a hospital worker may cut his or her hands on a broken vial when they proceed to open the carrier, and dangerous substances contained within the carrier may come in contact with the hospital worker. Also, in the case where toxic, aromatic substances such as toluene or benzene are being transported within vessels contained within the carriers, obviously, the worker would be placed in great danger if he or she opened the carrier under those circumstances. Basically, if a hospital worker opens a carrier expecting to remove sealed vessels and/or containers, and conversely, is presented with spilled contents (which may often be accompanied by broken glass, for example), then, the possibility of infecting the hospital worker or the overall tube system is great. For that reason, a watertight or airtight carrier could facilitate containing the hazardous substances within the carrier, so that vessels which may break or become unsealed in the transport process are contained within the carrier. Of course, problems can still result if workers open a carrier without knowledge of the hazardous conditions within. To safeguard against this event, the carrier could contain an indicator on its exterior that notifies the carrier handler of the interior circumstances--before the carrier is opened. In that case, if the interior contents are, for example, toxic gasses, the carrier may be opened in a controlled, safe environment.
There exists a need in the field to provide a carrier with suitable watertight and airtight properties, such that matter from within the carrier cannot escape to the outside, and matter that has become uncontrollable within the carrier can activate a warning indicator on the exterior of the carrier, so that hospital or other workers who use the carriers will not open carriers with uncontrolled contents (without ample warning that proper measures should be taken). That could be facilitated by a warning signal indicative of a spill or other abnormal condition within the carrier. Such a warning signal may even be a digital output, which can be decoded, to indicate what type of hazard lies within the carrier. Such a warning signal could also trigger a locking mechanism, making the opening of a carrier with spilled interior substances impossible without authorization and a form of key, electronic or otherwise. Also, based on the contents of the carrier, the locking mechanism may be activated so that only certain parties may be able to open the carrier, regardless of whether an uncontrolled substance is contained within. For example, if a dangerous controlled substance such as morphine is being transported, the carrier may be locked, and only certain authorized persons would be able to open the carrier.
Prior art known to the inventor includes U.S. Patent Nos. 4,948,303 to Good, 4,324,511 to Irish, 4,219,290 to Golston, 4,149,685 to Leavelle, and 3,825,210 to Weaver, which are incorporated herein by reference.
U.S. Pat. No. 4,948,303, granted to Good; discloses a pneumatic tube carrier with a reinforced hinge.
U.S. Pat. No. 4,324,511, granted to Irish, discloses a pneumatic tube carrier with an accelerator ring.
U.S. Pat. No. 4,219,290, granted to Golston, discloses a hinged pneumatic tube carrier with an improved side opening mechanism.
U.S. Pat. No. 4,149,685, granted to Leavelle, Apr. 17, 1979, discloses a pneumatic carrier having identical halves and includes means to adjust the latch mechanism.
U.S. Pat. No. Re. 30,882, granted, Mar. 16, 1982, to Leavelle is directed to an adjustable closure mechanism.
U.S. Pat. No. 3,825,210, granted to Weaver, Jul. 23, 1974, discloses a "clamshell" type pneumatic tube carrier of a bullet configuration wherein the seals which substantially fill the tube are not immediately adjacent the ends but are spaced therefrom.
U.S. Pat. No. 242,459, granted to Leaycraft Jun. 7, 1881, which discloses a pneumatic tube carrier having asymmetric hinged halves being continuously urged to a closed position by a spring means.
U.S. Pat. No. 359,456, granted to McLaughlin, Mar. 15, 1887, discloses a pneumatic tube carrier including a spindle or the like for wrapping a paper document for security during transportation from one location to another.
U.S. Pat. No. 452,471, granted to Barri, May 19, 1891, discloses a pneumatic tube apparatus wherein an opening in the surface of the container is created by twisting one coaxial section with respect to the other.
U.S. Pat. No. 769,233, granted to Pfluger, Sept. 6, 1904, discloses a cash box for use with a pneumatic tube wherein an opening in the carrier is exposed by relative twisting of the two coaxial elements.
U.S. Pat. No. 811,915, granted to Hager Feb. 6, 1906, discloses a pneumatic tube carrier including a specific stop member to prevent damage to the cylinders when the two coaxial halves are twisted relative to each other.
U.S. Pat. No. 1,169,553, granted to MacMillan, Jan. 25, 1916, discloses a means for securely latching a pneumatic tube carrier such that it does not accidentally open in transport.
U.S. Pat. No. 1,827,000, granted to Duffin Oct. 13, 1931, discloses a container for a roll of paper wherein the exterior container includes a hinge which connects two halves which are identical with the exception of an internal flap on one side for securing the container in a closed condition.
U.S. Pat. No. 2,251,238, granted to Busch, Jul. 29, 1941, discloses a pneumatic carrier wherein the coaxial halves are twisted with respect to each other to expose a window opening and includes a spring actuated locking device.
U.S. Pat. No. 3,401,902, granted to Gouyou-Beauchamps et al, Sept. 17, 1968, discloses a large dimension open top carriage for use in pneumatic conveying of large objects.
U.S. Pat. No. 3,593,948, granted to McClellan, Jul. 20, 1971, discloses a pneumatic carrier wherein identical halves are hinged together along one edge and includes spring means for urging the two halves to a closed cylindrical configuration for transport.
U.S. Pat. No. 3,761,039, granted to Hazell, Sept. 25, 1973, discloses a pneumatic carrier system including means for transferring documents from one individual carrier to another, enabling the use of sharp corners (transfer stations) in the transport tube itself.
U.S. Pat. No. 4,470,730, granted Sept. 11, 1984, to Wutherich discloses a pneumatic tube carrier having a separate pocket means to separate coinage from paper money during transport.
In general, pneumatic tube systems known in the art include a closed continuous passageway having a predetermined inner cross-sectional dimension where the passageway includes a plurality of curves or bends having a predetermined radius. A fluid, such as air, is controllably forced through the passageway in a loop to move a carrier through the passageway. In order for the carrier to move freely through the passageway, the dimensions, and in particular the length, of the carriers being used have been limited by the inner cross-sectional dimension and curvature radius of the passageway. Pneumatic delivery systems are used extensively for the rapid and efficient transportation of a wide variety of articles. These delivery systems are used in a number of business operations, including banks, hospitals, office buildings, industrial plants, and truck terminals as a few examples.
Pneumatic carriers for use in such delivery systems come in a wide range of sizes and shapes to accommodate the physical articles to be transported in the system. As an example, pneumatic carriers are provided for transporting cash, messages, stock transaction slips, letters, blueprints, electronic data processing cards, x-rays, pharmaceutical supplies, blood samples, narcotics, viral and bacteria cultures, and a variety of other small physical objects. A watertight carrier can be useful for transporting paper documents, by sealing out water or other material that can harm the paper.
In the past, various mechanisms have been utilized as closure devices for pneumatic tube carriers. For example, many such carriers include an end cap that is hinged with respect to a cylindrical hull on one side of the hull and which has a latch that fastens the end cap to the opposite side of the hull in a closed position. Such carriers employ a variety of fasteners, such as snap fasteners, elastic straps with holes that fit over hooks, or straps that may be secured to bendable posts.
Other types of pneumatic tube carriers are of the side opening variety. One conventional form of such a carrier employs two generally semi-cylindrical sections that are hinged along one longitudinal edge. The hinged sections may be swung toward or away from each other to effectuate opening and closing of the carrier hull. Locking is achieved by virtue of the end caps, which may be twisted to effectuate threaded engagement of the caps onto the carrier hull ends when the hinged hull sections have been closed. That is, the end caps are rotated in such a fashion as to be drawn towards each other onto the ends of the hull, thereby immobilizing the hull sections relative to each other. Rotation of the end caps in the opposite direction releases the hull sections and allows them to be opened.
One preferable configuration utilized by many carrier manufacturers is that of a side opening, wherein the two sides are hinged together, and the two sides are held together when the carrier is closed by use of a hook, or detent or indented type locking lip. Such carriers include latching mechanisms to prevent the door from coming ajar or opening during transit, which could cause the carrier to become lodged in the pneumatic tubes and would also allow the contents of the carrier to spill out into the tube system. In addition, the instructions for latching such side opening containers or carriers are simple to follow, so that the container can be easily placed within the tube system. Such hinging and locking mechanisms make waterproofing or sealing the carrier a particularly difficult task, as hinges and locks are embedded within the mold of the carrier, which is generally formed of plastic.
In another type of side opening pneumatic carrier, the access to the carrier is gained by simultaneously pulling and twisting the ends of the carrier to allow the side opening door to be opened. The instructions for such a two-step process are often difficult for many users to follow, and the physical effort and manual dexterity needed to simultaneously pull and twist both ends of the carrier against a spring resistance is often troublesome for many hospital workers.
A need has thus arisen for an improved type of pneumatic carrier which overcomes these and other disadvantages associated with the prior art devices. In particular, a need has arisen for a pneumatic carrier which can be easily opened, but which also maintains a watertight and airtight seal. Also, the carrier must be able to maintain its air and water tightness, despite the fact that it is subjected to a vacuum transport system, and despite the fact that it will be subjected to extreme environmental conditions, such as repeated use, frequent drops, dust and dirt particles, high speed travel and acceleration, and the like. The carrier could also have a supplemental sensor mechanism to indicate that interior abnormal conditions have developed.
SUMMARY OF THE INVENTION
This invention relates to side and/or top-bottom end opening pneumatic carriers for use in pneumatic tube delivery systems, although by way of example, the side opening pneumatic carrier having two semi-cylindrical shells hinged together will be described in detail. Nevertheless, this invention can be readily used for all types of carriers, in all shapes and sizes.
According to a preferred embodiment of the present invention, the two semi-cylindrical shells are designed for movement between an open and closed position by moving the shells in opposing directions (that is, closing the shells) to prevent the carrier's insertion in the delivery system in a partially closed position and to prevent the opening of the carrier during transit within the delivery system. The present invention provides an elongated carrier for carrying material having any length or width. For example, the length can be a few or even twelve inches or more, which in accordance with its construction, is capable of being used in conventional pneumatic systems having an inner cross-sectional dimension and curvature radius designed for accommodating carriers of conventional designs. In particular, the carrier of the present invention has a length sufficient for carrying medical, biomedical or any other industrial supplies, as required in each installation, at hospitals, universities, etc.
It is, therefore, one object of the present invention to provide an improved carrier capable of carrying elongated materials through conventional pneumatic systems which include a closed passageway having a predetermined inner cross-sectional dimension where the passageway includes curves or bends having a predetermined radius. The conventional systems are designed to accommodate carriers of conventional design with a length limited by the predetermined curvature radius of the passageway.
The carrier, according to the present invention, includes two semi-cylindrical mating, elongated members. The two semi-cylindrical members include means for securing the members to each other to provide a closed elongated compartment, each of the members having an outer cross-sectional dimension which is smaller than the inner cross-sectional dimension of the passageway so that the elongated compartment can pass through the curves of the pneumatic system without engaging the inner surface of the passageway, and each of the members further including means for engaging the inner surface of the passageway to accelerate and stabilize the compartment within the passageway, the surface-engaging means having an outer cross-sectional dimension which is generally equal to the predetermined inner cross-sectional dimension of the passageway. A supplemental ring can be installed around the circumference of the carrier (that is, the two semi-cylindrical in their mated, closed position), to provide an enhanced pressure barrier, to help the carrier move throughout the tube system.
Further, according to the present invention, the ends (which may be tapered) of the first and second members can possess frustoconically shaped and have rounded features to facilitate movement of the carrier through the passageway of the pneumatic system. Both members can include elongated intermediate sections formed integrally with smooth and continuous surfaces. Both members include cooperating hinges, locks and overlapping lips for securing themselves to each other, to form an elongated compartment in the direction of the movement of the carrier. By forming a series of supplemental ridges and walls within the carrier, a watertight and/or airtight grommet can be installed and secured within the carrier, to provide a vapor/liquid barrier, which is a principal aspect of the present invention.
Further, according to the present invention, the exterior surface of the carrier may include one or more accelerator rings formed on the perimeter of both members. The accelerator rings have an outer cross-sectional dimension which allows it to engage the inner surface of the passageway to provide stability to the carrier and allow the carrier top be moved in response to the controlled air pressure within the passageway. Each of the accelerator rings has a small width in relationship to the overall length of the closed elongated compartment, and each is located in proximity to the ends of the first and second members.
The present invention provides a relatively easy to open, side opening pneumatic carrier which can't be inserted into the pneumatic tube delivery system in the partially opened condition. The pneumatic carrier will typically be constructed of plastic, and will contain means to secure articles within the carrier during travel. For example, if the carrier is used to transport biomedical or chemical materials, many of which could be dangerous, the carrier will contain either, preferably, a series of clips to retain test tubes, or alternatively, a formed foam rubber insert, that can be slotted, egg crate shaped, formed with slits or other cavities in any shape or size, including being formed with holes which mate with test tubes, circular openings, and so on, so that breakage can be minimized. In addition, the pneumatic carrier is designed to prevent opening of the carrier once it is in transit in the pneumatic tube delivery system. A lock is incorporated for that purpose.
According to the present invention, a side opening pneumatic carrier has two symmetrical shells of concave cross-sectional area, each shell having first and second longitudinal edges and first and second ends. The carrier includes means for securing said symmetrical shells along a first longitudinal edge of said shells, such that the shells are rotatable between a closed position and open position to provide access to the interior of the carrier.
In one embodiment of the present invention, a side opening pneumatic carrier is provided for use in a pneumatic tube delivery system. The carrier includes two plastic semi-cylindrical shells having first and second longitudinal edges, a plastic, hinged, joint arrangement integrally formed with the shells, which joins the shells together along the first longitudinal edges, such that the shells are rotatable between an open and closed position. In the closed position, the second longitudinal edge of each shell mate together. Because the hinge assembly edges are at an offset with respect to one another, the two shells mate completely along their periphery.
The external closure pieces are dimensioned to be closely received within the pneumatic tube delivery system for preventing the entry of the carrier in a partially opened condition. In the closed position, mating water/air tight grommets are engaged (that is, sandwiched between the two halves of the carrier). In use, then, a watertight barrier, such as a grommet, gasket, sealant, washer, or the like, may be disposed along a watertight element ridge (and along a corresponding watertight element channel), so that a complete seal is formed when the two halves of the carrier are mated together (that is, closed). Accordingly, an interior wall outlines or rings the entire perimeter of the carrier in its closed position, wherein two corresponding gaskets, for example, are disposed along the edges or ends of said interior wall, wherein the mating gaskets seal off the interior cavity of the carrier, from the exterior of the carrier. This methodology is somewhat akin to double or triple walled underground storage tanks, whereby a plurality of barriers are constructed to prevent leakage. Said construction fulfills a long felt need in the field of pneumatic tube carrier design.
Also in accordance with the alternate embodiment of the invention, the carrier includes means for securing the shells in the closed position. A raised area on the external face of each of the internal closure pieces, and an indented area is formed in the internal face of the external closure pieces, such that the raised and reciprocal indented areas are aligned for engaging one another and securing the shells of the carrier in the closed position. A detent or indented lock or clip is used to secure the two halves of the carrier together.
Also in accordance with the alternate embodiment of the invention, a sensor (e.g., an electronic computer controlled sensor) is included within the cavity formed between the two halves of the carrier. That sensor is capable of ascertaining the release of any materials from within the vessels contained within the carrier. For example, the sensor could detect liquids or gasses that should not normally be present within the carrier. IN accordance therewith, the sensor can activate a lock or warning light or signal, that alerts the carrier handler that something has been released within the water/air tight carrier, and that special care must be taken before opening the carrier.
Although the present invention relates primarily to carriers in pneumatic tube systems which are used in hospitals, laboratories, and the like, carriers according to the present invention may also be used to transfer papers, currency and other articles between stations within a building or building complex. Carriers are moved within the tube system by applying air pressure to a tube on one side of a carrier to propel the carrier away from the source of pressure. Such pneumatic tube carrier systems are frequently installed in banks and commercial retail sales establishments. In that case, an important feature would be to keep water out of the carrier, which may contain important, irreplaceable documents. For example, if a retail outlet is transporting bearer bonds or cash, and a roof leak or other flooding condition is present, the carrier should remain dry within.
A further object of the invention is the formation of a carrier for a pneumatic tube system from identically shaped generally semi-cylindrical hull sections. The modular production of hull sections in this manner allows the two sections of the carrier hull to be manufactured of plastic, such as polycarbonate, and produced from a single mold. Naturally the requirement for a single mold to produce both hull sections which can be fitted together in a reverse orientation relative to each other reduces the tooling cost for producing carriers according to the invention by 50%. Such tooling costs are considerable in producing a durable hull by injection molding which is the preferred manner of construction.
Yet a further object of the invention is the construction of a carrier hull from plastic. While a plastic carrier is functionally equivalent to conventional steel, aluminum or cardboard carriers in some respects, plastic has the unique characteristic in that it has a certain "memory" for its original shape. That is, if twisted, struck or otherwise subjected to abuse, the plastic of the carrier of the present invention will tend to return to its original shape. In contrast, metal or cardboard carriers, when subjected to heavy use, are frequently permanently bent or distorted, thus detracting from their geometric symmetry and reducing their useful lives. Conventional carriers which are deformed in this way do not maintain a good air seal in the pneumatic line nearly as well as does the present invention. Also, conventional carriers which have been bent or distorted frequently open in the carrier line during use, thus necessitating the closure of the pneumatic tube system as aforesaid.
There are numerous criteria used in designing a carrier for pneumatic systems. The carrier should preferably be light, inexpensive and foolproof. Also, the carrier should be arranged so that it cannot be entered into a tube system when in an open position or open while in the tube. Such an arrangement ensures that the carrier is closed before it is entered into the system thereby limiting the possibilities that the carrier contents will be lost in the system and that the carrier will become lodged in the system. The carrier should preferably also be capable of carrying a maximum length of materials around given bends in the system and be capable of being locked in a closed position.
According to a particular embodiment of the present invention, a carrier is provided having first and second shells disposed about a longitudinal axis and connected by hinges such that the shells are moved transversely relative to one another when opening and closing the carrier. A pair of ring seals (referred to also as accelerator, glide or travel rings, etc.) are provided intermediate the ends of the carrier for guiding the carrier through a pneumatic tube system and for limiting air seepage past the carrier. End portions of the carrier are tapered to terminate in bumpers and a pair of latches are coupled to the shells for retaining the carrier in a closed position. A lock is provided for combining with the closed shells to prevent unauthorized opening of the carrier.
BRIEF DESCRIPTION OF THE DRAWINGS
The invention will be better understood with reference to the drawings, in which:
FIG. 1 is an overall view of a carrier according to the invention;
FIG. 2A is a perspective view of the interior of a half of a carrier according to the present invention;
FIG. 2B is a side view of a half of a carrier according to the present invention, which shows a latch to lock the carrier in its closed position, and an indicator for signaling conditions interior to a carrier;
FIG. 2C is an end view of a half of a carrier according to the present invention;
FIG. 2D shows a top plan view of the interior of a half of a carrier according to the present invention;
FIG. 3A is a gasket according to the present invention;
FIG. 3B is a detailed view of a portion of a gasket according to the present invention;
FIG. 4A is a perspective view of the interior of a half of a carrier according to the prior art;
FIG. 4B is a top plan view of the interior of a half of a carrier according to the prior art;
FIG. 5A is a cross-sectional view of a carrier according to the present invention, shown in its open position;
FIG. 5B is a cross-sectional view of a carrier according to the present invention, shown in its closed position;
FIG. 5C is a cross-sectional view of a gasket according to the present invention, shown in its closed position; and
FIG. 6 is a detailed top plan view of a half of a carrier according to the present invention.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT
The preferred embodiment of the invention is set forth below.
FIG. 1 is an overall view of a carrier according to the present invention. FIG. 1 shows a carrier 10 consisting of first and second shells 12, 12' which extend longitudinally and which are interconnected by hinges 14 and rod locking members 28. Members 28 lock the rod in place, so that hinges 14 can provide for the opening and closing of the carrier 10 halves 12 and 12'. A detailed view of this configuration can be found at FIG. 6. The carrier 10 halves 12 and 12' are formed of plastic, for example, and raised areas are formed along the exterior surface, around the transverse perimeter of the carrier, as shown beneath travel or accelerator rings 16. Two such accelerator or glide or travel rings 16 are used for each carrier 10, and may consist of Velcro® secured plastic or rubber strips. A suitable felt material or Neoprene® material may also be used to make the seals 16, which may also be cut from a sheet of the material such that moisture will tend to cause dimension changes substantially in the direction longitudinal with respect to the carrier, rather than radially. The seals 16 may be adhesively attached to the shells 12, 12' at respective raised portions. The purpose of the rings 16 is so that carrier 10 forms a tight, consistent and secure fit within the interior of the carrier tubes, so that the carrier 10 may travel effectively through the carrier tubes. As the carriers 10 often reach speeds in excess of 25 feet per second, the rings 16 serve to form an air barrier around the carrier 10, so that the carrier 10 does not jam. Also, by minimizing air leakage around the carrier 10, rings 16 can minimize the air required to propel carrier 10. Felt insert 94 is provided, as well, so that the rings 16 appear as continuous concentric circles--and no air can escape the seal which the rings 16 form in relation to the interior of the carrier tubes, even where the hinge assemblies 14 are concerned. Ends of the carrier are defined by respective resilient bumpers 22. Each of the bumpers 22 is preferably larger than half the diameter of the pneumatic tube to avoid possible jamming of one carrier 10 with a second carrier within the pneumatic tube. The shells 12 and 12' are substantially identical in shape and are preferably molded in the same or a similar mold form from a suitable plastic material such as LEXAN (a trademark for a polycarbonate plastic sold by The Canadian General Electric Co.). Because the shells 12 and 12' are substantially identical and can often be made from even the same mold, molding costs can be significantly reduced.
In order to simplify this description, parts of shell 12 will be described, but it should be understood that corresponding parts of shell 12' also may exist, as desired. The shell 12 is generally semi-cylindrical over the major portion of its length, l with the exception, for example, of the raised portions under rings 16. Those raised portions may also correspond to internally concave zones, which may contribute to the overall structural integrity of the carrier 10.
The portions of carrier 10 that support the seals 16 are positioned intermediate the ends of the carrier 10 at positions which maximize the available length and diameter dimensions of the carrier. The shells 12 and 12' further includes tapered or frusto-conical end portions 42.
Hinge assemblies 14 are preferably molded as a part of the shells 12 and 12' and (as shown in FIG. 5A) the pivot points of the hinges 14 are offset from mating edges of the shells 12 and 12' to permit the ends of the rings 16 and shells 12 ans 12' to securely mate together when closed, without damage to the seal halves 16. The hinges 14 are preferably located so that they will not contact the interior of the carrier tube walls. Although the carrier tube walls are often made of steel, and the carriers 10 are often made of plastic, it is generally desirable to have only smooth, continuous surfaces contacting the interior of the carrier tube walls. For example, if a metallic hinge 14 were to scratch the interior of the carrier tube wall, ruts could result, which would facilitate air seepage, and a loss of system efficiency, as air passes through said ruts.
FIG. 2A shows the interiors of both halves (12 and 12') of a carrier 10 according to the present invention. FIG. 2B is a side view of a half of a carrier 10 according to the present invention, which shows a latch 26 to lock the carrier 10 into its closed position, and an indicator 90 for signaling conditions interior to a carrier 10. FIG. 2C is an end view of a carrier 10 according to the present invention, which shows the bumper 22.
Shells 12 and 12' form an internal cavity when closed together. That internal cavity is usually entire reason why the carrier 10 exists in the first place. However, certain exceptions may exist. For example, carrier 10 may not be a cavity bearing carrier at all, but rather a sophisticated monitoring vehicle, which contains video or other sensors, to inspect the interior workings of a pneumatic tube system. In that case, carrier 10 would be sent through a tube system, and could transmit or record information indicative of the interior walls of the pneumatic tube system. More usually, the carrier 10 with its internal cavity in place will be used to carry articles between remote points.
Carrier 10 is capable of carrying papers, such as drawings, business documents, cash, x-ray negatives and the like. Carrier 10 is often used to carry vessels, wherein the vessels often contain liquid, solid or gaseous materials that should ideally remain within the vessels. That is, the carrier 10, which moves at high speeds, is often used to carry vessels that contain various liquid substances, which are prone toward leaking out of the carrier 10, if the vessels should break within the carrier 10, or should the vessels become opened in transit (because, for example, a rubber stopper was not securely fastened in the first place, or otherwise failed). Specifically, when the present invention is used within the hospital environment, problems can result when vessels break or open within the carrier 10. The vessels in hospitals often include test tubes with rubber stoppers, intravenous ("IV") bags, blood samples, viral or bacteria cultures, chemicals or other drugs, medicines, acids, or other materials that must be controlled or contained at all times. Indeed, the vessels may even contain biohazardous materials, such as HIV infected blood, cultures of various viral infections, toxic chemicals such as cyanide, and the like.
Naturally, whenever fragile objects (such as glass test tubes) are to be placed in the carrier 10, these objects are typically mounted in a container or retaining unit, which has been formed to fit snugly with in the cavity defined by the interior surfaces of shells 12 and 12', thereby limiting the possibility of damage to the contents as the carrier 10 passes through the pneumatic tube system. To safeguard against the leakage of such materials, and others, l the carrier 10 according to the present invention has been designed with an internal perimeter wall 34. Perimeter wall 34 provides an additional layer of protection against exposure to the outside world.
Perimeter wall 34 outlines the entire perimeter of carrier 10--more specifically, the boundaries of shells 12 and 121, as set forth in FIG. 2A. Also as shown in FIG. 2A, projections and receptors 72 (on both shells 12 and 121) are adapted to engage each other, (as opposed on the opposing shells 12 and 121), to retain the shells 12 and 121 in a closed position as shown in FIG. 1, with the use of detent latches or locks (not shown). The projections 72 have respective inclined leading faces for deflecting the projections radially inwards as the shells 12 and 12' are brought together. As the shells 12 and 121 move into a closed position, the projections and receptors 72 move radially outward into respective openings, to retain the shells 12 and 121 in the closed position. Projections and receptors 72 are also shown in detail in FIG. 6. One major advantage of this arrangement is that the closing of the shells 12 and 121 is a natural action and requires no teaching. Anyone wishing to close the carrier 10 will naturally bring the shells 12 and 121 together resulting in a snap-action as the detent or interlocking latches move into their mating openings. Respective longitudinal edges of the shells 12 and 12' define interlocking recesses and projections indicated generally by the numerals 72. These edges locate the shells 12 and 121 relative to one another when the shells are in the closed position. Also, because of their shape, the projections/receptors 72 align corresponding edges of the shells on closing the carrier and also prevent closing the carrier unless the' contents are entirely inside the shells. Further advantages of these projections 72 include increased torsional stability because of the interlocking arrangement; and an incidental advantage that because a carrier which is not completely closed will not fit into a pneumatic tube, an operator is forced to ensure that none of the contents project out of the carrier.
In use, it will be evident that unless the shells 12 and 121 are closed, the carrier 10 cannot be entered into a pneumatic tube. This is a significant advantage of the carrier because in the past, if carriers are entered into a tube without first closing the carrier, the result may be to lose the contents of the carrier 10 within the pneumatic tube system or in fouling the system to the extent that it no longer functions satisfactorily. Once the shells 12 and 121 are brought together so that the projections 72 engage in respective openings, the carrier 10 can be locked by inserting a key in, for example, a tumbler, lock 26 (shown in FIG. 2B) and turning a key, or setting a combination. The carrier 10 can then be opened only by further use of the key. However, reference is again made to FIG. 2B to describe the lock switch 26. Alternatively, only authorized persons having a key for an actual lock 26 could be established, to open the carrier, for example, if a controlled substance such as morphine is contained within the carrier 10.
As shown in FIG. 2B, latch switch (or lock) 26 is used to depress the detent locking mechanism, so that the shells 12 and 121 can be separated, and the carrier 10 opened. Locking latches 26 are provided for retaining shells 12 and 121 in the closed position. In addition, electronically activated locks with pins (not shown) may be disposed between shells 12 and 121, so that latch switch 26 may be overridden, or defeated, so that the user of a carrier 10 will not open it if a vessel has become opened or broken in travel. To facilitate this function, indicator 90 is provided on the exterior of the carrier 10. Indicator 90 is connected to internal sensor unit 96 via line 97, as shown in FIG. 2A. Indicator 90, shown in FIG. 2B, will serve to inform the user that a spill or leak has occurred within the cavity of carrier 10. When sensor unit 96 detects the presence of a leak or spill (blood, gas, chemicals, liquids, etc.), indicator 90, which may be a digital display, LED, or even an RS 232 communications port, will inform the user or an external computer, that something has become uncontrolled within the carrier 10. Then, proper precautions may be taken when opening the carrier 10. For example, if toluene has become released within carrier 10, the sensor 96 will identify it as such (via, for example, gas chromatography), and will output its result to indicator 90. Then, indicator 90, which may be an LED, series of LEDs (which may indicate, for example, the severity of the interior condition), or an RS 232 port, can then output the result to a computer (not shown). In automated carrier tube systems, the carrier could even inform the receiving station (the opening to the vacuum tubes) of the condition, so that a user will be presented by, for example, a warning light, so that they will not open the carrier 10 until, in the case of toluene, the carrier 10 is brought to a ventilation hood, so that hazardous fumes may be vented safely away.
In FIGS. 3A and 3B, a gasket, grommet, washer, or other water and air sealing barrier 33 is shown. The gasket 33 is formed to directly track the perimeter wall 34 in size or shape. Importantly, the gasket 33 will be attached to one or both shells 12 and 121, and may sit within or mate within one or two gasket channels, as set forth in FIG. 6. In FIG. 6, the gasket channel 34 (which is merely a part, the top, of perimeter wall 34), is used to seal the carrier 10, so that materials may not escape, and so materials may not enter the internal cavity. Importantly, the shells 12 and 121 may be formed with any number of perimeter walls 34, and in any configuration, so that a plurality of subcompartments may exist. Also, concentric perimeter walls 34 may be formed, as with, for example, triple walled storage tanks in the petroleum industry, for added safety.
In FIG. 4, a shell according to the prior art is found, wherein no interior perimeter wall is used, and no watertight or airtight properties exist.
In FIG. 5A, the shells 12 and 121 are shown in their open position. Hinge/pivot rod assembly 14 is shown, wherein gasket 33 and shells 12 and 121 are affixed at an offset, with respect to one another. In FIG. 5B, the carrier 10 is shown in its closed position, wherein shells 12 and 121 are seated, and gasket 33 has formed a seal around @he entire cavity of the carrier 10. overlapping lip/groove assembly 19 has been provided, so that the barrier is more secure. That is, lip 19A fit snugly into groove 19B. In FIG. 5C, the gasket 33 is shown in its closed position.
It will be appreciated that although the above description is limited to a generally cylindrical carrier, the invention is applicable to carriers having any suitable cross-section. For instance, carriers having a generally oval cross-section have been used, and the invention is intended for use in carriers of this and other shapes.
While the foregoing embodiments of the invention have been set forth in considerable detail for the purposes of making a complete disclosure of the invention, it will be apparent to those of skill in the art that numerous changes may be made in such details without departing from the spirit and the principles of the invention.
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A carrier for transporting articles through pneumatic tube systems is disclosed. The carrier has first and second shells disposed about a longitudinal axis and connected by hinges such that the shells are moved transversely relative to one another when opening and closing the carrier. A seal such as a gasket or rubber seal is included within the interior of the carrier. Optionally, a sensor is used to indicate the presence of an abnormal condition within the carrier. Optionally, a lock is used to prevent opening.
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CROSS REFERENCE TO RELATED APPLICATION
[0001] This application claims the benefit of Provisional Application No. 60/650,206 filed Feb. 4, 2005, the disclosure of which is incorporated by reference.
FIELD OF THE INVENTION
[0002] This invention relates to lubricating fluids and oils. Specifically, it is directed to compositions that provide for decreased traction coefficients, a method of lowering traction coefficients in lubricating compositions, and the uses of such compositions.
BACKGROUND OF THE INVENTION
[0003] Elastohydrodynamic lubrication (EHL) is the mode of lubrication that exists in non-conforming concentrated contacts. Examples include the contact between meshing gear teeth used in hypoid axles, worm gears, etc. and between the components in a rolling element bearing. In these contacts the load is supported over a very small contact area which results in very high contact pressures. As lubricants are drawn into the contact zone by the movement of the component surfaces, the lubricant experiences an increase in pressure. Pressures on the order of 1 GPa and above are common in EHL contacts. Most lubricating oils exhibit a large increase in viscosity in response to higher pressures. It is this characteristic that results in the separation of the two surfaces in the contact zone.
[0004] If there is relative sliding between the two contacting surfaces in the central contact region, the lubricant is sheared under these high-pressure conditions. The shearing losses depend on how the oil behaves under these extreme conditions. The properties of the oil under high pressure, in turn, depend on the type of base stocks used in the manufacture of the finished lubricant. The generation of the EHL film is governed by what happens in the inlet region of the contact; however, the energy losses are governed by what happens when the lubricant is sheared in the high-pressure central contact region.
[0005] The resistance of the lubricant to the shearing effects within an EHL contact is referred to as traction. This is not to be confused with friction, which is associated with surface interactions. The traction response is dominated by the shear behavior of the lubricant in the central high contact pressure region of an EHL contact. The traction properties generally depend on the base stock type.
[0006] Traction coefficients can be defined as the traction force divided by the normal force. The traction force is the force transmitted across a sheared EHL film. The normal force or contact load is the force of one element (such as a roller) pushing down on a second element. Therefore, the traction coefficient is a non-dimensional measure of the shear resistance imparted by a lubricant under EHL conditions. Lower traction coefficients result in lower shearing forces and hence less energy loss if the two surfaces are in relative motion. Low traction is believed to be related to improved fuel economy, increased energy efficiency, reduced operating temperatures, and improved durability.
[0007] FIG. 1 compares traction curves for a typical mineral oil and a typical PAO. As two surfaces move past one another, if they are moving at the same speed, there is pure rolling and no sliding. The lubricant is not sheared in the contact zone and no traction force is generated (% slide-roll ratio=0; traction coefficient=0; see FIG. 1 ). The % slide-to-roll ratio is defined as the difference in speed of the two surfaces divided by their average speed and multiplied by 100%. As the ratio of sliding to rolling increases (i.e., moving along the curves in FIG. 1 to the right) the lubricant begins to be sheared between the two surfaces, and since the oil is also under very high pressure, there is a rapid rise in the traction force which is transmitted across the lubricant film. In some cases, the lubricant behaves like an elastic solid. As the sliding increases still further, the traction coefficient may reach a maximum beyond which there is no further significant increase in traction. Under the conditions that exist in many gear and bearing contacts, this maximum is thought to be associated with reaching a maximum yield stress that can be supported by the lubricant. This maximum is determined by the conditions in the contact as well as the type of lubricant used.
[0008] As shown in FIG. 1 , the PAO has a much lower traction coefficient, relative to mineral oil, over the range of slide-roll ratios, pressures and temperatures evaluated. This means that less energy will be required to shear the EHL film which separates moving surfaces. When gear oils are formulated based on PAO vs. mineral oil, one sees the same lowering of the traction coefficient. This concept is well documented in the industry.
[0009] It is also well documented that certain types of synthetic base stocks can provide reduced traction over a wide range of conditions. FIG. 2 is a qualitative comparison of traction coefficients of typical mineral oils, PAOs, and polyalkylene glycols (PAGs).
[0010] U.S. Pat. No. 4,956,122 discloses combinations of high and low viscosity synthetic hydrocarbons. A composition is claimed comprising a PAO having a viscosity of between 40 and 1000 cSt (100° C.), optionally further comprising a synthetic hydrocarbon having a viscosity of between 1 and 10 cSt (100° C.), a carboxylic acid ester having a viscosity of between 1 and 10 cSt (100° C.), an additive package, and mixtures thereof.
[0011] U.S. Pat. No. 5,360,562 teaches a transmission fluid comprising a PAO having a viscosity of from about 2 to about 10 cSt (100° C.) and a PAO having a viscosity in the range of about 40 to about 120 cSt (100° C.) and devoid of high molecular weight viscosity index improvers.
[0012] U.S. Pat. No. 5,863,873 teaches a composition comprising a base oil having a viscosity of about 2.5 to about 9 cSt (or mm 2 /s) at 100° C. as a major component and a fuel economy improving additive comprising a polar compound with a viscosity greater than the bulk lubricant present from 2 to about 15 wt % of the composition. The compositions are said to improve fuel economy in an internal combustion engine.
[0013] U.S. Pat. No. 6,713,438 is directed to engine oils comprising a basestock having a viscosity of from 1.5 to 12 cSt (100° C.) blended with two dissolved polymer components of differing molecular weights.
[0014] U.S. Pat. No. 6,713,439 is directed to a composition comprising a PAO with a viscosity of about 40 cSt (100° C.), a basestock havng a viscosity of from 2 to 10 cSt (100° C.), and a polyol ester.
[0015] Publication WO 03/091369 discloses lubricating compositions comprising a high viscosity fluid blended with a lower viscosity fluid, wherein the final blend has a viscosity index greater than or equal to 175. In an embodiment, the high viscosity fluid is preferably a polyalphaolefin and/or the lower viscosity fluid comprises a synthetic hydrocarbon. In another embodiment, the novel lubricating compositions of the present invention further comprise one or more of an ester, mineral oil and/or hydroprocessed mineral oil.
[0016] Publication US2003/0207775 is directed to compositions including a higher viscosity fluid (40 cSt to 3000 cSt at 100° C.) and a lower viscosity fluid (less than or equal to 40 cSt at 100° C.) wherein the final blend has a viscosity index of greater than or equal to 175. All of the examples include a PAO 2 (“SHF™ 23”) as well as a higher viscosity PAO.
[0017] Publications US 2004/0094453 and 2005/0241990 are directed to the use of Fischer-Tropsch derived distillate fractions, the latter patent application said to be related to low traction coefficients.
[0018] Publication US2004/029407 discloses lubricating compositions comprising high viscosity PAOs blended with a lower viscosity ester, wherein the final blend has a viscosity index greater than or equal to 200, including a composition comprising a PAO having a viscosity of greater than or equal to about 40 cSt at 100° C. and less than or equal to about 1,000 cSt at 100° C.; and an ester having a viscosity of less than or equal to about 2.0 cSt at 100° C., wherein said blend has a viscosity index greater than or equal to about 200.
[0019] “Effect of Lubricant Traction on Scuffing”, STLE Tribology Transactions, Vol. 37 No., Apr. 2, 1994, p. 387-395 reported the use of low traction PAO-based lubricants with mineral oils in basestock, antiwear and extreme pressure (EP) formulations and at both high (greater than 6) and moderate (approximately 1.2) specific film thickness lambda. At lambda greater than 6, the benefits of the synthetics over their mineral counterparts ranged from 25 percent to 220 percent and at lambda nearly 1.2, the benefits were a uniform 40 percent. It was particularly interesting to observe that the antiwear PAO-based oil gave a similar scuff load per unit contact width to an EP mineral gear oil. In addition, it was shown that scuffing load increased with decreasing traction coefficient.
[0020] “Influence of Molecular Structure on the Lubrication Properties of Four Different Esters”, Tribologia, Vol. 19 No. 4, 2000, p. 3-8, compared the lubricating properties of esters. The lubrication properties that were expected to be dependent on chemical structure such as film thickness and traction, viscosity and friction coefficients were compared by experiment. The results showed that molecular length has a significant influence on lubrication properties, with longer molecules giving the highest viscosity and greatest film thickness. The length of the molecule did not influence the coefficients of friction, but the traction coefficient, gamma, decreased with increasing molecular length.
[0021] Other references of interest include U.S. Pat. Nos. 4,956,122; 4,912,272; 4,990,711; 5,858,934; and EP 088453.
[0022] The present inventors have discovered that certain fluids act as traction reducers when combined with higher viscosity fluids and that blends of traction reducers and higher viscosity fluids will increase the efficiency of gear systems.
SUMMARY OF THE INVENTION
[0023] The invention is directed to fluids, referred to herein as traction reducers, which have the ability to impart low traction characteristics to compositions incorporating them, and to a method of modifying the traction coefficient of high viscosity fluids by the addition of these traction reducer fluids thereto. The invention is also directed to the use of traction reducers in compositions, and also the use of said compositions with machine elements in which sliding and rolling is observed, i.e., non-conforming concentrated contacts, such as with roller and spherical bearings, hypoid gears, worm gears, and the like.
[0024] In some embodiments, the traction reducers may be blended with at least one other Group I-V basestocks, optionally with additives and/or viscosity index (VI) improvers. In other embodiments, the invention may be a blend of traction reducers and basestocks and may be further characterized by the absence of high molecular weight VI improvers, particularly those VI improvers having a molecular weight of 100,000 or greater.
[0025] In other embodiments, the traction reducers may be blended with at least one basestock selected from esters (especially monobasic acid esters), PAGs, and alkylated naphthalenes.
[0026] In preferred embodiments, the traction reducer is selected from Group IV basestocks, Group V basestocks, and mixtures thereof. In other preferred embodiments, the traction reducer is selected from esters, PAOs, hydrocarbon fluids, and mixtures thereof.
[0027] In an embodiment, the traction reducers are characterized as fluids having a viscosity of less than or equal to 3 cSt or less than or equal to 1.5 cSt, or less than or equal to 1.3 cSt, or less than or equal to 1.2 cSt, or less than or equal to 1.0 cSt at 100° C., and in a preferred embodiment are further characterized by having a carbon number of C5 to C30.
[0028] In another embodiment, a lubricating composition comprises one or more traction reducers according to the present invention blended with at least one fluid having a viscosity greater than the traction reducer(s), wherein the resulting blend has a traction coefficient lower than the traction coefficient of said second fluid(s).
[0029] In yet another embodiment, the traction reducer is blended with a higher viscosity fluid, preferably selected from PAOs.
[0030] It is an object of the invention to characterize traction reducers and provide a method of decreasing the traction coefficient of lubricant compositions.
[0031] It is another object of the invention to provide useful compositions exhibiting low traction coefficients.
[0032] Another object of the invention is to provide a method of increasing eh efficiency of gear systems and/or improve the fuel efficiency of machines including said gear systems.
[0033] It is still another object of the invention to provide low traction coefficient lubricants suitable for use in machine elements in which sliding and rolling is observed, i.e., non-conforming concentrated contacts, such as with roller and spherical bearings, hypoid gears, worm gears, and the like. Fluids that exhibit low traction properties will reduce the losses in components that contain sliding EHL contacts.
[0034] These and other embodiments, objects, features, and advantages will become apparent as reference is made to the following detailed description, including figures, tables, preferred embodiments, examples, and the appended claims.
BRIEF DESCRIPTION OF THE DRAWINGS
[0035] FIG. 1 shows an idealized traction curve comparing typical mineral oils with typical PAO oils.
[0036] FIG. 2 compares relative values of traction coefficients for mineral oils, PAOs, and PAGs.
[0037] FIGS. 3-9 illustrate experimental results for various embodiments of the invention and comparative compositions.
DETAILED DESCRIPTION
[0038] The invention is directed to low traction coefficient lubricants and lubricant compositions in the preparation of finished gear, transmission, engine, and industrial lubricants and in a preferred embodiment are used as lubricants for non-conforming concentrated contacts with high sliding such as spur gears, helical gears, hypoid gears, bevel gears, worm gears and the like.
[0039] In an embodiment, the low traction coefficient lubricants comprise “traction reducers,” which may be used to modify base fluids having higher traction, to produce compositions having lower traction coefficients than the base fluids. In an embodiment, the traction reducers are extremely low viscosity (or low molecular weight) fluids. In an embodiment, these traction reducers are blended with high viscosity fluids, with the resulting blends exhibiting low traction properties. In yet another embodiment they are used to formulate viscosity grade lubricants, e.g. those that meet the requirements of SAE J306, the viscosity classification for automotive gear oils, or the requirements of ISO 3448, the industrial oil classification system. The traction reducer is a low viscosity fluid, which in an embodiment will be a viscosity of ≦3 cSt, or <3 cSt, or ≦2 cSt, or <2 cSt, or ≦1.5 cSt or <1.5 cSt, or ≦1.3 cSt, or ≦1.2 cSt or ≦1 cSt, or <1 cSt. and possessing a traction coefficient less than the base oil that it is to be combined with. Viscosities used herein are kinematic viscosities unless otherwise specified, determined at 100° C. according to any such suitable method for measuring kinematic viscosities, e.g. ASTM D445.
[0040] For purposes of the present invention, the term “traction reducers” excludes therefrom the Fischer-Tropsch derived fluids.
[0041] While it is believed that there is no lower limit to the viscosity of a traction reducer according to the invention they will typically have a viscosity of ≧0.5 cSt. Viscosities of at least some of the hydrocarbon fluids set forth herein, however, will have lower viscosities. It is critical, however, that the traction reducer be miscible with the basestock(s) with which it is combined. Otherwise the reduction in the traction coefficient of the resulting lubricating composition is severely reduced. The term miscible takes its ordinary meaning of “the ability to mix in all proportions”. The inventors further define the meaning of this term as used herein to specify that miscibility is determined at 25° C. and 1 atm.
[0042] In preferred embodiments, the traction reducers according to the present invention will be further characterized by having a viscosity of from ≧0.5 cSt, or >0.5 cSt, or ≧1.0 cSt, or >1.0 cSt, or ≧1.5 cSt to ≦3 cSt, or <3 cSt, or ≦2 cSt, or <2 cSt.
[0043] Other preferred embodiments for the viscosity of traction reducers according to the invention include ≧0.5 cSt to ≦1.5 cSt, or ≧0.5 cSt to <1.5 cSt. Specific preferred embodiments include about 1.0 cSt fluids, 1.1 cSt fluids, 1.2 cSt fluids, 1.3 cSt fluids, 1.4 cSt fluids, 1.5 cSt fluids, about 2 cSt fluids, about 2.5 cSt fluids , or about 3 cSt fluids, and mixtures thereof. Again, the traction reducer may be a blend, so that, by way of example, it may be a blend of a 1.0 cSt fluid and a 2.0 cSt fluid, and so on.
[0044] While not critical to characterization of traction reducers according to the invention, typical carbon numbers of these materials would be from C5 to C30, in a preferred embodiment from C10 to C25, and in another preferred embodiment from C12 to C20. Additional embodiments are given herein, and it is to be understood that the various characteristics describing such embodiments may be combined to describe still further embodiments, as would be understood by one of ordinary skill in the art in possession of the present disclosure. Note that all carbon number ranges used herein refer to average carbon numbers, unless otherwise specified.
[0045] It has been surprisingly found that an efficient traction-reducing composition consists essentially of (a) at least one basestock characterized by having a viscosity greater than 3 cSt at 100° C. and (b) at least one traction reducer characterized by being miscible with said at least one basestock (a) and having a viscosity of less than or equal to 3 cSt (or in embodiments further characterized by one or more of the viscosity limitations set forth above in paragraphs [0038], [0041], and [0042]) at 100° C. and having a traction coefficient less than the traction coefficient of said at least one basestock (a), wherein (a) is present in the amount of from 1 to 99 wt. %, and (b) is present in the amount of 99 wt. % to 1 wt. %, based on the weight of said lubricating composition; and wherein said lubricating composition is characterized by a traction coefficient less than the traction coefficient of (a) for every percent slide-to-roll ratio greater than 5%, measured over the operating range of 0.1 to 3.5 GPa peak contact pressure, −40° C. to 200° C. lubricant temperature, with a lubricant entraining velocity of from 0.25 to 10.0 m/s.
[0046] In other words, for the purpose of traction reduction, only a single traction reducing material is necessary; there is no necessity of having a second material with a low viscosity such as exemplified in U.S. Patent Application 2003/0207775, discussed above. Particularly in the case where the traction reducing material is a monobasic acid: ester, a low viscosity PAO is not required to obtain the traction coefficient reduction according to the present invention.
[0047] Fluids that can meet these criteria of traction reducers according to the present invention are varied. They may fall into any of the well-known American Petroleum Institute (API) categories of Group I through Group V. The API defines Group I stocks as solvent-refined mineral oils. Group I stocks contain the most saturates and sulfur and have the lowest viscosity indices. Group I defines the bottom tier of lubricant performance. Group II and III stocks are high viscosity index and very high viscosity index base stocks, respectively. The Group III oils contain fewer unsaturates and sulfur than the Group II oils. With regard to certain characteristics, both Group II and Group III oils perform better than Group I oils, particularly in the area of thermal and oxidative stability.
[0048] Group IV stocks consist of polyalphaolefins, which are produced via the catalytic oligomerization of linear alphaolefins (LAOs), particularly LAOs selected from C5-C14 alphaolefins, preferably from 1-hexene to 1-tetradecene, more preferably from 1-octene to 1-dodecene, and mixtures thereof, although oligomers of lower olefins such as ethylene and propylene, oligomers of ethylene/butene-1 and isobutylene/butene-1, and oligomers of ethylene with other higher olefins, as described in. U.S. Pat. No. 4,956,122 and the patents referred to therein, and the like may also be used. PAOs offer superior volatility, thermal stability, and pour point characteristics to those base oils in Group I, II, and III.
[0049] Group V includes all the other base stocks not included in Groups I through IV. Group V base stocks includes the important group of lubricants based on or derived from esters. It also includes alkylated aromatics, polyinternal olefins (PIOs), polyalkylene glycols (PAGs), etc.
[0050] One of the great benefits of the present invention is that it is applicable to base oils fitting into any of the above five categories, API Groups I to V, as well as other materials, such as described below. As used herein, whenever the terminology “Group . . . ” (followed by one or more of Roman Numerals I through V) is used, it refers to the API classification scheme set forth above.
[0051] Additional materials which may be used as traction reducers, either alone or combined with other types of traction reducers, may be classified simply as hydrocarbon fluids, such as ExxonMobil's Norpar™ fluids (comprising normal paraffins), and Isopar™ fluids (comprising isoparaffins), Exxsol™ fluids (comprising dearomatized hydrocarbon fluids), Varsol™ fluids (comprising aliphatic hydrocarbon fluids), which do not traditionally fall into any of the API categories and would not previously have been expected to be useful in such formulations. As used herein, the term “fluid” means materials that may function as one or more of a carrier, a diluent, a surface tension modifier, dispersant, and the like, as well as a material functioning as a solvent, in the traditional sense of a liquid which solvates a substance (e.g., a solute), and the term “hydrocarbon fluid” additionally means a material consisting of hydrogen and carbon atoms which is liquid at ambient temperature and pressure (25° C., 1 atm). Furthermore, the term “hydrocarbon fluid” as used herein is intended to exclude materials classified as API Group I-V materials, and also the Fischer-Tropsch derived fluids, and preferably will have an average carbon number from about C5 to C25. It will be recognized that commercially-available hydrocarbon fluids also typically contain small amounts of heteroatom-containing species (e.g., oxygen, sulfur, nitrogen, and the like), typically on the order of less than 1 wt. %, preferably less than 100 ppm. Heteroatom-containing materials may be substantially removed, if desired, by methods per se known in the art. In embodiments, the hydrocarbon fluids of the invention may be further characterized as selected from: (i) normal paraffins, preferably characterized by a viscosity at 25° C. (ASTM D445) of from about 1.6 to about 3.3 cSt and/or by a distillation range of from about 180 to about 280° C.; (ii) isoparaffins, preferably characterized by a viscosity at 25° C. (ASTM D445) of from about 0.7 to about 14.8 cSt, preferably from about 0.7 to about 4.0 cSt, and/or a distillation range of from about 200 to about 600° C., preferably from about 200 to about 500° C.; (iii) dearomatized aliphatics, preferably characterized by a viscosity at 25° C. (ASTM D445) of less than 7.0 cSt and/or a distillation range of about 135 to about 600 C; (iv) aliphatic hydrocarbons (in some cases referred to as naphtha), preferably characterized by a viscosity at 25° C. (ASTM D445) of less than 4.0 cSt, preferably less than 2.0 cSt and/or a distillation range of from about 60 to about 300° C.; and (v) mixtures thereof. As used herein, the term “distillation range” means that the material identified has an initial boiling point greater than or equal to the lower temperature (e.g., 60° C. for the aliphatic hydrocarbon example just given) specified and a dry point less than or equal to the higher temperature specified (e.g., 300° C. for the aliphatic hydrocarbon example just given). In another preferred embodiment, the hydrocarbon fluid blended in as traction reducer has a narrow boiling range of, for example, 50° C. or 40° C. or 30° C. or 20° C. The term “boiling range” is the temperature difference between when the material begins to boil and the dry point. Thus, by way of further example, in embodiments it is preferred to use a narrow boiling range cut of about 20° C. of naphtha within the preferred distillation range of about 60 to about 300° C.
[0052] Mixtures of one or more traction reducers combined with one or more higher viscosity base oil may be used. As an example, a hydrocarbon solvent such as Norpar® 12 fluid may be blended with PAO 2 and PAO 150 or it may be blended alone with the PAO 150, or it may be blended with PAO 100 and/or PAO 1000. All of these final compositions would meet the requirements. Note that the term “PAO x” (e.g., PAO 2) means that the material is a PAO having a kinematic viscosity of about x cSt at 100° C. PAO 2 and PAO 150 are commercially available, for instance, as SpectraSyn™ 2 and SuperSyn™ 2150, respectively, from ExxonMobil Chemical Company.
[0053] The treat rate of traction modifiers in finished lubricants may not be solely governed by the resulting traction performance. Other properties such as flash point, viscosity, seal compatibility, demulsibility, foam and air release, paint and sealant compatibility and volatility among others will also have to be considered. This is within the skill of the ordinary artisan, in possession of the present disclosure.
[0054] The traction reducers according to the invention are used (optionally with additives) to modify the traction of a high viscosity fluid, e.g. 100 cSt PAO, by creating a blend where the traction reducer (or mixture of traction reducers) is present in the amount of from 1 to 99 wt %, preferably from 5 to 95 wt %. In an embodiment, the traction reducer(s) is present in the blend in the amount of from 20 to 80 wt %, or from 30 to 70 wt %, or from 40 to 60 wt %, or from 45 to 55 wt %, based on the weight of the entire composition. Ranges from any lower limit to any upper limit are also contemplated, so that, by way of additional examples, traction reducer may be present in the blend in the amount of from 5 to 55 wt %, or from 45 to 95 wt %, and so on. Additional embodiments include traction reducers according to the present invention present in the amount of 5 to less than 50 wt %, greater than 50 to 95 wt %, greater than 70 to 95 wt %. All weight percentages used herein are based on the weight of the final composition, unless otherwise specified.
[0055] In more preferred embodiments, traction reducers may include very light neutral Group I and II mineral oils, which may be characterized by one of the aforementioned viscosities (paragraphs [0038], [0041], and [0042], above), and which may optionally be further characterized by the aforementioned carbon number ranges, e.g., C5-C30, and other embodiments set forth in paragraph [0043], above. Group III hydrocracked stocks may also be suitable if they fall into the proper viscosity range, as previously described, and which may also be further characterized by the aforementioned carbon number ranges.
[0056] Group IV and V fluids having the aforementioned viscosity ranges and optional carbon number ranges (paragraphs [0038], [0041]-[0043], above) are preferred embodiments of this invention.
[0057] Group IV basestocks are the polyalphaolefins. PAOs meeting the aforementioned viscosity criteria and preferably the aforementioned carbon numbers (paragraph [0043]), for a traction reducer are particularly useful as traction reducers of the invention.
[0058] In an embodiment, more preferred PAOs are those low molecular weight hydrogenated oligomers of alpha olefins having carbon numbers from C10 to C30, preferably C12 to C25. In other embodiments, the carbon number range will be C12-C25, or C12 to C20. PAO 2 is a commercially-available PAO (as mentioned previously) that can serve as the low viscosity fluid useful as a traction reducer according to the present invention. Its average carbon number is approximately C20. Following the usual convention in the art, viscosities listed herein will be for 100° C. unless otherwise specified.
[0059] More generally, PAO fluids suitable for the present invention, as either lower viscosity (the traction reducer of the present invention), or higher viscosity fluids (the greater than 3 cSt at 100° C. according to ASTM D-445 material) depending on their viscosity properties, may be conveniently made by the polymerization of an alphaolefin in the presence of a polymerization catalyst, such as, by way of non-limiting example, Friedel-Crafts catalysts, including, for example, aluminum trichloride, boron trifluoride, or complexes of boron trifluoride with water, alcohols such as ethanol, propanol, or butanol, carboxylic acids, or esters such as ethyl acetate or ethyl propionate. Numerous methods are disclosed; see for instance, the patents listed in paragraphs [0093]-[0094] of the aforementioned U.S. Patent Application No. 2003/0207775.
[0060] Group V basestocks meeting the aforementioned viscosity criteria and preferably the aforementioned carbon numbers for a traction reducer are likewise useful. Group V includes esters that are a preferred embodiment of a traction reducer. In a preferred embodiment, traction reducers according to the present invention may be selected from esters of mono and poly acids with monoalcohols or polyalcohols. Monobasic esters are preferred—they are the most readily available esters having viscosity sufficient to meet the criteria of a traction reducer according to the invention.
[0061] Esters that meet the criteria of the invention may be selected from the reaction product of at least one C1 to C20 alcohols and at least one C1 to C20 carboxylic acids to prepare a variety of esters that would meet the criteria of this invention, i.e. a kinematic viscosity of less than or equal to 3 cSt, or in embodiments characterized further by one or more of the viscosities set forth in paragraphs [0038], [0041], and [0042], herein. The alcohols can be linear, cyclic, or branched. Near linear or less branched alcohols, such as described by Godwin in U.S. Pat. Nos. 6,969,735; 6,969,736; and 6,982,295; are used as the esterifying alcohol(s) in preferred embodiments. The esters can contain additional oxygen in the form of ethers and other heteroatoms, like N, and S. They can be saturated or unsaturated. There can be more than one hydroxy group per molecule, so diols and triols are also considered, however monobasic acid esters are preferred and in still more preferred embodiments polyol esters are excluded from compositions according to the invention. The same would hold true for the carboxylic acids: linear, branched, cyclic, saturated, unstaturated, with or without other heteroatoms, mono or poly carboxylic acids, although monocarboxylic acids are preferred. Some specific examples include the C8-C10 ester of pentanoic acid, C8-C10 ester of hexanoic acid, the C8-C10 ester of heptanoic acid, the C8-C10 ester of the C8-C10 acid, 2-ethylhexyl ester of C8-C10 acid, the isoctyl ester of C8-C10 acid, the isononyl ester of C8-C10 acid, pentaeyrithritol ester of C8-C10 acid, trimethylol propane ester of C8-C10, 2-ethylhexyl palmitate, isooctyl pentanoate, isononyl pentanoate, isononyl heptanoate, isooctyl isopentanoate, isononyl isopentanoate, 2-ethylhexyl 2-ethylhexanoate, isooctyl 2-ethylhexanoate, isononyl 2-ethylhexanoate, isononyl heptanoate, isooctyl heptanoate, isononyl isopentanoate, decyl heptanoate, nonyl heptanoate, ethyl decanoate, di-isooctyl adipate, neopentylglycol ester of pentanoic acid, the neopentylglycol ester of isopentanoic acid, neopentylgylcol ester of heptanoic and nonanoic acid, etc. Some preferred embodiments include isononyl heptanoate, the C8-C10 ester of pentanoic acid, the C8-C10 ester of heptanoic acid, iso-octyl pentanoate, isononyl pentanoate, isooctyl heptanoate, isooctyl isopentoate, and isononyl pentanoate.
[0062] Group V basestocks also include poly internal olefins (PIOs). Important PIOs useful in the present invention are PIOs having a viscosity less than or equal to 4 cSt (100° C.), preferably less than 3 cSt (100° C.), or in embodiments any of the viscosities listed in paragraphs [0038], and [0041]-[0042] above, more preferably those further characterized by the carbon ranges set forth in paragraph [0043] herein. See, for instance, U.S. Pat. Nos. 6,686,511 and 6,515,193, with regard to PIOs per se.
[0063] Group V basestock components can also include hydrocarbon-substituted aromatic compounds, such as long chain alkyl substituted aromatics, including alkylated naphthalenes, alkylated benzenes, alkylated diphenyl compounds and alkylated diphenyl methanes. Here also, the viscosity of these fluids would be less than or equal to 3 cSt at 100° C., or in embodiments further characterized by any of the viscosities set forth in paragraphs [0038], [0041], and [0042], While not critical to the characterization thereof, the carbon numbers of these are most preferably between C12 and C20.
[0064] The basestocks characterized by having a viscosity greater than 3 cSt at 100° C. are quite varied. The may be selected from any one of the API Group I-V materials, or mixtures thereof, provided they meet the viscosity limitations. PAOs are particularly preferred, and in preferred embodiments may be selected from HVI-PAOs and/or metallocene PAOs, Numerous PAOs are commercially available, such as PAO 150, PAO 100. Bright Stock (blend of API Group I with monobasic acid ester), and also Fischer-Tropsch derived materials and GTL or “gas to liquid” materials are all preferred embodiments of the high viscosity component (a).
[0065] Hydroisomerate/isodewaxate base stocks and base oils include base stocks and base oils derived from one or more Gas-to-Liquids (GTL) materials, slack waxes, natural waxes and the waxy stocks such as gas oils, waxy fuels hydrocracker bottoms, waxy raffinate, hydrocrackate, thermal crackates, or other mineral or non-mineral oil derived waxy materials, and mixtures of such base stocks.
[0066] GTL materials are materials that are derived via one or more synthesis, combination, transformation, rearrangement, and/or degradation/deconstructive processes from gaseous carbon-containing compounds, hydrogen-containing compounds, and/or elements as feedstocks such as hydrogen, carbon dioxide, carbon monoxide, water, methane, ethane, ethylene, acetylene, propane, propylene, propyne, butane, butylenes, and butynes. GTL base stocks and base oils are GTL materials of lubricating viscosity that are generally derived from hydrocarbons, for example waxy synthesized hydrocarbons, that are themselves derived from simpler gaseous carbon-containing compounds, hydrogen-containing compounds and/or elements as feedstocks. GTL base stocks and base oils include oils boiling in the lube oil boiling range separated from GTL materials such as for example by distillation, thermal diffusion, etc., and subsequently subjected to well known solvent or catalystic dewaxing processes to produce lube oils of low pour point; wax isomerates, comprising, for example, hydroisomerized or isodewaxed synthesized waxy hydrocarbons; hydroisomerized or isodewaxed Fischer-Tropsch (F-T) material (i.e., hydrocarbons, waxy hydrocarbons, waxes and possible analogous oxygenates); preferably hydroisomerized or isodewaxed F-T waxy hydrocarbons or hydroisomerized or isodewaxed F-T waxes, hydroisomerized or isodewaxed synthesized waxes, or mixtures thereof. The GTL base stocks and base oil may be used as such or in combination with other hydroisomerized or isodewaxed materials comprising for example, hydroisomerized or isodewaxed mineral/petroleum-derived hydrocarbons, hydroisomerized or isodewaxed waxy hydrocarbons, or mixtures thereof, derived from different feed materials including, for example, waxy distillates such as gas oils, waxy hydrocracked hydrocarbons, lubricating oils, high pour point polyalphaolefins, foots oil, normal alpha olefin waxes, slack waxes, deoiled waxes, and microcrystalline waxes.
[0067] The GTL base stocks and base oils are typically highly paraffinic (>90 wt % saturates), and may contain mixtures of monocycloparaffins and multicycloparaffins in combination with non-cyclic isoparaffins. The ratio of the naphthenic (i.e., cycloparaffin) content in such combinations varies with the catalyst and temperature used. Further, GTL base stocks and base oils typically have very low sulfur and nitrogen content, generally containing less than about 10 ppm, and more typically less than about 5 ppm of each of these elements. The sulfur and nitrogen content of GTL base stock and base oil obtained by the hydroisomerization/isodewaxing of F-T material, especially F-T wax is essentially nil. Useful compositions of GTL base stocks and base oils, hydroisomerized or isodewaxed F-T material derived base stocks and base oils, and wax-derived hydroisomerized/isodewaxed base stocks and base oils, such as wax isomerates/isodewaxates, are recited in U.S. Pat. Nos. 6,080,301; 6,090,989, and 6,165,949 for example.
[0068] Wax isomerate/isodewaxate base stocks and base oils derived from waxy feeds which are also suitable for use in this invention, are paraffinic fluids of lubricating viscosity derived from hydroisomerized or isodewaxed waxy feedstocks of mineral or natural source origin, e.g., feedstocks such as one or more of gas oils, slack wax, waxy fuels hydrocracker bottoms, hydrocarbon raffinates, natural waxes, hyrocrackates, thermal crackates or other suitable mineral or non-mineral oil derived waxy materials, linear or branched hydrocarbyl compounds with carbon number of about 20 or greater, preferably about 30 or greater, and mixtures of such isomerate/isodewaxate base stocks and base oils.
[0069] While PAOs useful in the present invention for both the high and low viscosity components have already been mentioned, HVI-PAOs are a particularly preferred embodiment of the greater than 3 cSt (100° C., ASTM D-445) component. HVI-PAOs (“High Viscosity Index Polyalphaolefin”) are per se well-known, and may be prepared by, for instance, polymerization of alpha-olefins using reduced metal oxide catalysts (e.g., chromium) such as described in U.S. Pat. Nos. 4,827,064; 4,827,073; 4,990,771; 5,012,020; and 5,264,642. These HVI-PAOs are characterized by having a high viscosity index (VI) and one or more of the following characteristics: a branch ratio of less than 0.19, a weight average molecular weight of between 300 and 45,000, a number average molecular weight of between 300 and 18,000, a molecular weight distribution of between 1 and 5, and pour point below −15° C. Measured in carbon number, these molecules range from C30 to C1300. Viscosities of the HVI-PAO oligomers useful in the present invention, measured at 100° C., range from greater than 3 cSt to about 15,000 cSt. These HVI-PAOs are commercially available, such as for instance SpectraSyn Ultra™ fluid, from ExxonMobil Chemical Co.
[0070] Another advantageous property of these HVI-PAOs is that, while lower molecular weight unsaturated oligomers are typically and preferably hydrogenated to produce thermally and oxidatively stable materials, higher molecular weight unsaturated HVI-PAO oligomers useful as lubricant are sufficiently thermally and oxidatively stable to be utilized without hydrogenation and, optionally, may be so employed. In embodiments, the. HVI-PAOs useful in the present invention may be prepared by non-isomerization polymerization of alpha-olefins using reduced metal oxide catalysts (e.g., reduced chromium on silica gel), zeolite catalysts, activated metallocene catalysts, or Zeigler-Natta (“ZN”) catalyst.
[0071] For the purposes of the present invention, other preferred PAOs useful in blends with traction reducers may be characterized as including oligomers and/or polymers of C5-C14 linear alpha olefins (LAOs), particularly C8-C12 LAOs. Other suitable high viscosity fluids include other synthetic hydrocarbons, e.g. liquid ethylene propylene copolymers, polyisobutylenes, other polyolefins (e.g. PIOs), polymethacrylates. Other high viscosity fluids include mineral oils. Still other preferred high viscosity fluids would be those components of suitable viscosity in the API Group V category, e.g. high viscosity esters, alkylated napthalene, PAGs, etc.
[0072] In an embodiment, the invention includes the mixing of one or more low viscosity blend components selected from traction reducers set forth above, with one or more high viscosity fluids to provide lube weight fluids with low traction. These fluids may be combined with additive packages, thickeners, defoamants, VI improvers, pour point depressants, extreme pressure agents, anti-wear additives, demulsifiers, haze inhibitors, chromophores, anti-oxidants, dispersants, detergents, anti-rust additives, metal passivators, and the like, to provide lubricating oils for various automotive and industrial applications. The order of blending is not particularly critical and it will be recognized that adding a traction reducer to a basestock is substantially similar to adding the basestock to the traction reducer.
[0073] In embodiments, compositions according to the invention do not contains VI improvers. In more preferred embodiments, VI improvers having a molecular weight of about 100,000 and greater are excluded. Such ingredients are per se well-known in the art, such as disclosed in the above-mentioned U.S. Pat. Nos. 4,956,122 or 6,713,438. It is not particularly important whether the molecular weight of the VI improver is number average or weight average molecular weight. The molecular weight may be measured and determined by any known technique.
[0074] Compositions according to the present invention are particularly useful in applications wherein there are EHL contacts that have a component of sliding. Examples include spherical roller bearings, deep groove ball bearings, angular contact bearings among others. Additionally, most gear systems contain multiple sliding EHL contacts between meshing gear teeth. Examples include spur gears, helical gears, hypoid gears, bevel bears, worm gears, and the like.
[0075] An embodiment of the invention comprises a blend of at least one traction reducer with at least one higher viscosity material. In a preferred embodiment, at least one traction reducer is blended with a higher viscosity fluid to yield a gear lubricant that is SAE 70W or higher, based on the SAE J306 classification system. This classification system was designed to provide limits with respect to the kinematic viscosity at 100° C. and the Brookfield viscosity for automotive gear oils. Due to the nature of the traction reducers according to the present invention, when they are employed at concentrations where the traction coefficient of the final composition is significantly reduced relative to the traction coefficient of the higher viscosity fluid, cold temperature fluidity of the final composition is also affected because of the very low viscosity of the traction reducers. Consequently, the resulting gear lubricants that are formulated to contain the traction reducers described by this invention will, in embodiments, have significantly lower Brookfield viscosities than gear lubricants with similar kinematic viscosities that do not contain the traction reducers. Brookfield viscosities used herein are measure according to ASTM D-2983.
[0076] In a preferred embodiment, a lubricating oil composition is provided which comprises at least one traction reducer according to the invention, characterized by a low viscosity of ≦3 cSt at 100° C., and at least one fluid characterized by having a viscosity greater than the traction reducer, wherein the resulting composition has a traction coefficient that is lower than the traction coefficient of the higher viscosity fluid.
[0077] An important feature of the traction modifiers is their ability to reduce traction below that of a linear reduction based on their treat rate in the final blend. As an illustration FIG. 3 shows the traction coefficient results obtained for 3 different compositions (100/0, 41/59, and 0/100 wt. % of pentanoic acid ester/PAO 1000 respectively). The traction coefficient at 41% pentanoic acid falls significantly below the line predicted by a simple linear variation of traction with blend composition. This feature is a preferred embodiment of the invention.
[0078] Thus, when the traction reducers according to the invention are blended with higher viscosity base stocks, a tremendous benefit is seen in the area of traction. For example, as shown in FIG. 4 , the traction curves for several fluid combinations are shown. Table 1 provides a description of each combination. The data in the figure show the effect on the traction coefficient when various traction modifiers are added to PAO 150. The traction data used herein was, generated using a Mini Traction Machine (MTM) manufactured by PCS Instruments Ltd. in the UK. All remaining traction data were generated using this same apparatus. The lubricating composition of the invention may further be characterized by a having a traction coefficient less than the traction coefficient of the higher viscosity base stock for every percent slide-to-roll ratio greater than 5%, measured over the operating range of 0.1 to 3.5 GPa peak contact pressure, −40° C. to 200 C. lubricant temperature, with a lubricant entraining velocity of from 0.25 to 10.0 m/s. This data was obtained using the MTM set forth in this paragraph.
[0079] In FIG. 4 , Fluid 1 is neat PAO 150 (SuperSyn™ 2150). Fluid 2 is a blend of this same PAO 150 with the traction reducer, 2 cSt PAO (SpectraSyn™ 2). Fluids 3 and 4 are blends of this same PAO 150 with monobasic esters isononyl heptanoate and C8-C10 ester of pentanoic acid, respectively, as the traction reducers. Fluids 5 and 6 are blends of PAO 150 with hydrocarbon solvents (Exxsol™ D110 and Norpar™ 14, respectively) as the traction reducers. Each of the traction reducers are present at a level of 55 wt. % in the PAO 150, the remainder being PAO 150. From the data in FIG. 4 , it will be noted that the traction coefficients of Fluids 2 through 6 are lower at every slide-roll ratio tested. The C8-C10 ester of pentanoic acid is especially effective when combined with PAO 150.
TABLE 1 Fluid Identification Description 1 100 wt % PAO 150 2 55 wt % PAO 2 - 45 wt. % PAO 150 3 55 wt % Heptanoic acid ester of isononyl alcohol - 45 wt. % PAO 150 4 55 wt % Pentanoic acid ester of C8-C10 alcohol - 45 wt. % PAO 150 5 55% wt % Exxsol ™ D110 (hydrocarbon solvent) - 45 wt. % PAO 150 6 55% wt % Norpar ™ 14 (hydrocarbon solvent) - 45 wt. % PAO 150 7 Synalox 40 D300 (low traction PAG reference)
[0080] FIG. 5 shows another example of different traction reducers, each from the ester family and each with a different kinematic viscosity: ranging from 1.1 to 2.7 cSt. These traction reducers were combined with the high viscosity base oil PAO 1000, at several different concentrations. The coefficients of traction were measured at the slide-roll ratio of 30%. The reader will note that for each of these traction reducers, the traction of the blend containing the traction reducer, was significantly lessened over that of neat PAO 1000.
[0081] A formulator often has a choice of basestocks for thickening a formulation and the choice will depend on different factors such as targeted viscosity grade, degree of desired oxidative stability, economics, etc. Four such heavy base stocks are shown in Table 2 below: bright stock, PAO 100, PAO 150 (SuperSyn™ 2150), and PAO 1000 (SuperSyn™ 21000). When each of these are combined with a traction reducer, described by this invention, in this case, a pentanoic acid ester of a C8-C10 alcohol, the traction is reduced considerably for all four base stocks. Table 2 gives the traction coefficients for these four base stocks, both with and without the presence of a traction modifier, at a slide-roll ratio of 30%. FIG. 6 is a graphical representation of the resulting data, where the fluids containing the traction reducer are illustrated by the cross-hatched bars and stand alongside the corresponding fluids without a traction reducer (solid bars). For each base stock, the presence of the traction reducer, a C8-C10 ester of pentanoic acid, greatly reduced the coefficient of traction.
TABLE 2 Base Stock + 55 wt % Base Stock Base Stock Traction Modifier Bright Stock 0.04310 0.01157 PAO 1000 0.03760 0.006071 PAO 150 0.02615 0.005736 PAO 100 0.02303 0.006084 Note: Coefficients of friction obtained using the following conditions: 30% slide-roll, 1 GPa, 100° C.
[0082] When a lubricant, e.g. an automotive gear oil, is formulated according to the invention, i.e. combining one or more traction reducers with a higher viscosity fluid, the resulting fluid is expected to produce reduced traction relative to fluids that are not formulated in this manner. Two fluids, Gear Oil A and B, were formulated in accordance with a preferred embodiment of this invention. Both contain two traction reducers, PAO 2 (SpectraSyn™ 2) and a monobasic ester with a kinematic viscosity of 1.3 cSt blended with PAO 150 (SuperSyn™ 2150). The formulation specifics are given in Table 3. These fluids were then evaluated for traction coefficient, along with a commercial gear oil 75W-90. The traction coefficient data are plotted in FIG. 7 , which shows that traction coefficients at each slide-roll ratio are much lower than those of a commercial formulation for non-conforming concentrated contacts.
TABLE 3 PAO 2, PAO 150, i-Nonyl Heptanoate, wt % wt % wt % Gear Oil A 36.4 47.4 16.2 Gear Oil B 31.2 52.7 16.0
[0083] It is well known in the industry that lubricants with lower traction result in lower energy losses and less heat input to the oil. In gears for example, as teeth are meshing, the lubricant is subjected to high shear as the two surfaces move past one another. If low traction fluids are used, at any given instant in time there will be less traction between gear teeth, and hence, reduced energy losses. In general, low traction lubricants will reduce the load dependent losses in a system.
[0084] If there is less resulting heat input, then one would expect lower lubricant temperatures with reduced traction fluids. Evidence for this was collected using an Axle Efficiency-Durability Test, described below, using the compositions set forth in Table 4. In Table 4, compositions listed as Gear Oils C and D are formulations according to the present invention, in weight percent relative to the entire composition. The 75W-140 and 75W-90 are commercially available factory fill/service fill gear oils provided by Original Equipment Manufacturers (OEMs). These factory/service fill oils are used by major North American passenger car builders, and will be referred to as OEM A and B, respectively.
[0085] Conditioned axles were used in a T-bar type test configuration similar to ASTM D6121-01 (the L-37 gear durability test), with the exception that the power source is from a 250 hp electric motor and constant heat removal is provided by air fans directed at the axle carrier. The axle carrier is filled with test oil and then run through stages of torques and rpms. Each stage is held until the oil sump temperature has stabilized. The temperature of each stage is recorded along with torque out readings if the axle is properly instrumented. The test then moves to the next stage until all stages are completed.
TABLE 4 i-Nonyl PAO 2 PAO 150 Heptanoate KV 100° C., cSt Gear Oil C 44.6 38.6 16.8 8.6 Gear Oil D 0 40.0 60.0 8.0 75W-90 OEM B na Na Na 17.5 Factory Fill 75W-140 OEM na Na Na 25.1 A Factory Fill
[0086] Sump temperatures were collected at each stage only after equilibrium was reached. In this particular test, Stages 1-3 were chosen to simulate fuel economy conditions, i.e. light loads and medium to high speeds. Stages 4, 6, 7, and 8 were higher stress conditions, yet still within equipment design. Stages 5, 9, 10, and 11 are considered to be durability stages, where high stress conditions prevail that are close to or beyond the hardware design envelope.
[0087] The data in Table 5 is plotted in the corresponding FIG. 8 . The temperature differences (in ° F.) for three fluids at each stage relative to the factory fill 75W-140 are shown.
TABLE 5 Test Stage Oil C Oil D 75W-90 OEM B FF 1 −28 −31 −9 2 −28 −31 −8 3 −26 −30 −9 4 −16 −20 −5 5 6 12 −1 6 −24 −28 −11 7 −21 −25 −7 8 −16 −23 −6 9 −14 −19 −8 10 9 1 −2 11 −3 −6 −12
[0088] The Oil C and D, described by this invention, gave significantly lower temperatures than the 75W-140, except for stages 5 and 10, where they were slightly higher in temperature. The temperature reductions are also significantly greater than the factory fill 75W-90.
[0089] What is most interesting to note is that despite the low viscosities of these two low traction fluids, they are able to adequately maintain durability protection in the heavy load stages 5, 9, 10 and 11, which are meant to simulate uphill towing. The temperatures of Oils C and D are only about 5-10 degrees higher than the 75W-140 reference oil, which is a considerably more viscous oil. Therefore, one will get the fuel efficiency benefits attributed to a lower viscosity oil but will be able to maintain durability protection. This is typically not possible with a lighter viscosity oil.
[0090] In a similar test, a conditioned axle from yet another axle manufacturer was used. Again, fuel economy and durability stages were combined, this time into a ten-stage test. Oil E, formulated according to the invention, was tested relative to the 75W-140 reference oil, and in every stage of the test was found to exhibit lower sump temperatures than the commercial 75W-140 and the commercial 75W-90, both of which are factory fill oils. The composition of Gear Oil E is shown in Table 6 below, and the results illustrated in FIG. 9 . Compared to the 75W-140 synthetic factory fill gear oil and a commercial 75W-90 gear oil, Oil E provides substantial temperature reductions as demonstrated in the Axle Efficiency-Durability Test.
TABLE 6 Name Description 100° C. KV Gear Oil E 17% isononyl heptanoate 14 49% PAO 150 34% PAO 2 75W-90 Commercial Gear Oil 14 75W-140 OEM FF Commercial Factory Fill Gear Oil 25
[0091] Note also that this predicted improvement in efficiency is accomplished without compromise to high load application protection. The comparative data demonstrates that film thickness was not compromised in the durability region. Oil E is significantly better at temperature control for the high load stages 5, 9 and 10 when contrasted to the commercial 75W-90 fluid, which has the same viscosity at 100° C. as Oil E. Oil E often beat the 75W-140 reference. This temperature reduction should increase the lifetime of the lubricant, i.e. longer oil drains can be anticipated, which will mean a cost savings to the equipment owner. The equipment lifetime and reliability should also increase if there are lower operating temperatures.
[0092] Fluids containing traction reducers, described by this invention, were tested at an independent testing facility in a five-day efficiency test. An axle fluid and a transmission fluid prepared using traction reducers according to the invention and PAO 150 (SuperSyn™ 2150) were tested along with a commercial mineral transmission oil, a synthetic transmission oil, a mineral axle oil and a synthetic axle oil. All the oils tested are listed in Tables 7 and 8. The composition of the transmission oil TO 3 and axle oil AO 2 is approximately the same as that shown by “Gear Oil A” in Table 3. The difference between the transmission oil TO 3 and axle oil AO 2 are the additive packages; the transmission oil contains a commercial transmission additive package and the axle oil contains a commercial gear additive package. It is interesting to note how much lower the Brookfield viscosities are of the fluids governed by this invention relative to the commercial fluids.
TABLE 7 Base KV100 Brookfield (cP) Transmission Oils SAE Stock cSt −26° C. −40° C. TO1 - Commercial 80 Mineral 10.0 46,000 — TO2 - Commercial 75W-80 Synthetic 10.5 — 27,600 TO3 - Invention 75W-85 Synthetic 11.7 — 8,850
[0093]
TABLE 8
Base
KV100
Brookfield (cP)
Axle Oils
SAE
Stock
cSt
−26° C.
−40° C.
AO1 -
75W-90
Synthetic
16.9
—
193,200
Commercial
AO2 -
70W-85
Synthetic
11.5
—
8,000
Invention
AO3 -
90
Mineral
17.2
>400,000
—
Commercial
[0094] Over a five week period, five different pairings of these fluids were examined, one per week. The pairings are shown in Table 9 below, along with the percent fuel efficiency improvement relative to the reference pairing AO 1 and TO 1.
TABLE 9 Pair Axle Transmission % FEI 1 AO 1 TO 1 0 2 AO 2 TO 1 1.92 3 AO 2 TO 2 2.62 4 AO 2 TO 3 2.74 5 AO 3 TO 1 0.74
[0095] The results in Table 9 reveal that the highest percentage of fuel efficiency improvement could be found with the two fluids of this invention, pair # 4. In fact, there was substantial fuel economy improvement when the axle oil described by this invention was paired with any of the three transmission oils, including the commercial mineral and the commercial synthetic.
[0096] For industrial gears, one common type of gearing is worm gears. Worm gears form an extended elliptical contact against the wheel and operate under high sliding EHL conditions. Therefore, there is a significant benefit to low traction fluids in terms of energy savings.
[0097] Quantifying the amount of efficiency that can be expected is difficult because it is dependent on many factors. In worm gears for example, the amount of efficiency seen will depend on many factors including the shaft bearings, seals, churning losses, gear meshing, gear reduction ratios, etc. However, it is estimated that the gains may be substantial due to the high sliding and generally high energy losses. Steel gears are generally more efficient than bronze worm gears, and therefore, the absolute efficiency gains will be lessened.
[0098] Nevertheless, one of ordinary skill in the art can quantify fuel efficiency of a gear system by numerous methods and more particularly can determine an improvement in such system for embodiments of compositions according to the present invention compared with lubricant composition that do not show an improvement. Likewise, the energy efficiency of a machine operating said gear system can be readily determined and comparisons made.
[0099] Rolling element bearings have many configurations and depending on the type of configuration, there may or may not be a benefit to having a lower traction fluid. This may also be determined by one of ordinary skill in the art in possession of the present disclosure. Where there is sliding between the ball and the raceway, the oil is being sheared such that the reduced traction properties of the lubricants described in this invention will reduce the energy losses.
[0100] The present invention is particularly beneficial in any system that includes machine elements that contain gears of any kind and rolling element bearings. Examples of such systems include electricity generating systems, industrial manufacturing equipment such as paper, steel and cement mills, hydraulic systems, automotive drive trains, aircraft propulsion systems, etc. It will be recognized by one of ordinary skill in the art in possession of the present invention that the various embodiments set forth herein, including preferred and more preferred embodiments, may be combined in a manner consistent with achieving the objectives of the present invention. Thus by way of example, a preferred embodiment of the present invention includes a lubricating composition comprising:(a) at least one basestock, said basestock characterized by having a viscosity greater than 3 cSt at 100° C. (ASTM D-445); (b) at least one traction reducer, said traction reducer characterized by being miscible with said basestock and having a viscosity of less than or equal to 3 cSt at 100° C. (ASTM D-445) and having a traction coefficient less than the traction coefficient of the base stock described in (a); wherein (a) is present in the amount of from 1 to 99 wt. %, and (b) is present in the amount of 99 wt. % to 1 wt. %, based on the weight of said lubricating composition; and wherein said lubricating composition is characterized, after blending, by a traction coefficient less than the traction coefficient of (a) for every percent slide-to-roll ratio greater than or equal to 5% (or greater than 5% or from greater than 5% to 30% or from 5% to 20%, or greater than or equal to 20%, or greater than 20%), measured over the operating range of 0.1 to 3.5 GPa peak contact pressure, −40° C. to 200° C. lubricant temperature, with a lubricant entraining velocity of from 0.25 to 10.0 m/s; and especially wherein said composition is further characterized by one of the following: (i) wherein (a) is selected from esters, PAGs, and alkylated naphthalenes; (ii) wherein (b) is selected from monobasic acid esters and (a) is not a PAO; (iii) wherein (b) is a hydrocarbon fluid selected from normal paraffins, isoparaffins, dearomatized hydrocarbon fluids, and aliphatic hydrocarbon fluids; and/or or one or more of the following preferred embodiments: wherein said at least one basestock has a viscosity of at least 100 cSt, optionally greater than 140 cSt, optionally greater than or equal to 150 cSt, said viscosity measured according to ASTM D-445 at 100° C.; wherein (a) and (b) combined comprise greater than 50 wt. % of said lubricating composition; wherein said traction reducer is characterized by a viscosity of less than 3 cSt, optionally less than or equal to 2 cSt, optionally less than 2 cSt, optionally less than 1.3 or 1.2, or 1 cSt, said viscosity measured according to ASTM D-445 at 100° C.; wherein said traction reducer is further characterized by having an average carbon number of C5-C30, optionally C10-C25, optionally C12-C20; wherein said traction reducer is characterized by having a viscosity less than 2 cSt according to ASTM D-445 at 100° C. and an average carbon number of C5-C30; wherein said base stock is characterized by having a viscosity of greater than or equal to 20 cSt according to ASTM D-445 at 100° C.; wherein said base stock is characterized by having a viscosity of at least 100 cSt according to ASTM D-445 at 100° C.; wherein said base stock is characterized by having a viscosity of greater than 140 cSt according to ASTM D-445 at 100° C.; wherein (a) comprises at least one material selected from API Groups I-V and hydrocarbon fluids; wherein (a) comprises at least one basestock selected from API Group V; wherein (a) comprises at least one basestock selected from esters, PAGs, and alkylated naphthalenes; wherein (a) comprises at least one polyalphaolefin; wherein (a) comprises at least one basestock selected from API Group V, synthetic hydrocarbons, and mineral oils; wherein (b) is selected from PAO 2 and a monobasic acid ester; wherein (b) comprises at least one monobasic acid ester, particularly where the esterifying alcohol is selected from at least one C8-C13 alcohol or more preferably at least one C8-C10 alcohol and/or where the esterifying acid is a C5-C7 acid; wherein (a) comprises PAO 150 and (b) comprises PAO 2; wherein (a) comprises PAO 150 and (b) comprises isoheptanoate and PAO 2; wherein the −40° C. Brookfield viscosity is <150,000 cP and the −55° C. Brookfield viscosity is <1,000,000 cP (ASTM D-2983); wherein (a) is present in the amount of greater than 5 wt. %, optionally greater than 20 wt. %, optionally greater than 25 wt. %, optionally greater or equal to 45 wt. %, optionally greater than 55 wt. %, based on the weight of the lubricant composition; wherein (b) is present in the amount of greater than 5 wt. %, optionally greater than 20 wt. %, optionally greater than 25 wt. %, optionally greater or equal to 45 wt. %, optionally greater than 55 wt. %, based on the weight of the lubricant composition; wherein said lubricant composition is characterized by having a traction coefficient at least 5% lower, preferably 10% lower, more preferably 20% lower, still more preferably 30% lower, yet still more preferably 40% lower, yet again more preferably 50% lower than the traction coefficient of (a) for every percent slide-roll ratio from 5 to 30; wherein the composition(s) further comprising additives selected from thickeners, VI improvers, pour point depressants, extreme pressure agents, anti-wear additives, friction modifiers, demulsifiers, haze inhibitors, chromophores, anti-oxidants, dispersants, detergents, defoamants, anti-rust additives, metal passivators, limited slip additives, and mixtures thereof; or where the composition is characterized by the absence of one or more of said additives, especially where it is characterized by the absence of VI improvers having a number average or weight average molecular weight of about 100,000 or greater; wherein said lubricating composition is further characterized as formulated so as to be suitable for use as an automatic transmission fluid, a manual transmission fluid, an axle lubricant, a transaxle lubricant, an industrial gear lubricant, a circulating lubricant, an open gear lubricant, an enclosed gear lubricant, an hydraulic/tractor fluid, or a grease; wherein said lubricating composition is further characterized as formulated so as to be suitable for use as an automotive gear lubricating composition; wherein said lubricating composition is further characterized by a traction coefficient of less than 0.15, preferably from 0.15 and 0.0001, more preferably 0.015 to 0.001, measured over the operating range for determination of traction performance of 0.1 GPa to 3.5 GPa peak contact pressure, at −40° C. to 200° C. lubricant temperature and at % slide-to-roll ratios of greater than 20%, with a lubricant entraining velocity 0.25 m/s to 10 m/s; and also to compositions that do not contain PAO 2 or do not contain PAO 150, or do not contain PAO 2 and do not contain PAO 150; to compositions that contain GTL fluids and also to compositions that do not contain GTL fluids; and also to a method of reducing the traction coefficient of a lubricant composition comprising a basestock having a viscosity greater than 3 cSt at 100° C. (ASTM D-445), said method comprising adding a traction reducer to said lubricant composition (or otherwise blending the traction reducer and the ingredients of said lubricant composition) in an amount sufficient to reduce the traction coefficient of said lubricant composition for every percent slide-roll ratio greater than or equal to 5, meassured over the operating range of 0.1 to 3.5 GPa peak contact pressure, at −40° C. to 200° C. lubricant temperature, with a lubricant entraining velocity of from 0.25 to 10.0 m/s, said traction reducer further characterized by being miscible with said basestock and having a viscosity of less than or equal to 3 cSt at 100° C. (ASTM D-445); and to a preferred method wherein said lubricant composition is further characterized by any one of the compositions set forth in this paragraph or any embodiments of the invention set forth herein.
[0101] Trade names used herein are indicated by a ™ symbol or ® symbol, indicating that the names may be protected by certain trademark rights, e.g., they may be registered trademarks in various jurisdictions. All patents and patent applications, test procedures (such as ASTM methods, UL methods, API classifications, and the like), and other documents cited herein are fully incorporated by reference to the extent such disclosure is not inconsistent with this invention and for all jurisdictions in which such incorporation is permitted. When numerical lower limits and numerical upper limits are listed herein, ranges from any lower limit to any upper limit are contemplated.
[0102] While the illustrative embodiments of the invention have been described with particularity, it will be understood that various other modifications will be apparent to and can be readily made by those skilled in the art without departing from the spirit and scope of the invention. Accordingly, it is not intended that the scope of the claims appended hereto be limited to the examples and descriptions set forth herein but rather that the claims be construed as encompassing all the features of patentable novelty which reside in the present invention, including all features which would be treated as equivalents thereof by those skilled in the art to which the invention pertains.
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The invention relates to lubricating fluids and oil formulations which provide exceptionally low traction, a method of lowering traction coefficients in lubricating compositions, and to uses of such compositions.
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CROSS-REFERENCE TO RELATED APPLICATIONS
This application is a continuation of U.S. application Ser. No. 14/857,308, filed Sep. 17, 2015, now U.S. Pat. No. 9,487,498, which is a continuation of U.S. application Ser. No. 14/280,133, filed May 16, 2014, now U.S. Pat. No. 9,221,780, which is a continuation of U.S. application Ser. No. 13/213,480, filed Aug. 19, 2011, which is a continuation of U.S. application Ser. No. 11/724,792, filed Mar. 16, 2007, now U.S. Pat. No. 8,030,356, which claims the benefit under 35 U.S.C. 119(e) of U.S. Provisional Patent Application Ser. No. 60/783,556, filed Mar. 17, 2006, the contents of all of which are incorporated herein by reference.
STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT
This invention was made in part with government support under Grant No. CHE-0518406 from the National Science Foundation. The government may have certain rights in this invention.
BACKGROUND OF THE INVENTION
Summary of Heart Failure
Congestive heart failure (CHF) is a generally progressive, life threatening condition in which myocardial contractility is depressed such that the heart is unable to adequately pump the blood returning to it, also referred to as decompensation. Symptoms include breathlessness, fatigue, weakness, leg swelling, and exercise intolerance. On physical examination, patients with heart failure often have elevated heart and respiratory rates (an indication of fluid in the lungs), edema, jugular venous distension, and enlarged hearts. The most common cause of CHF is atherosclerosis, which causes blockages in the coronary arteries that provide blood flow to the heart muscle. Ultimately, such blockages may cause myocardial infarction with subsequent decline in heart function and resultant heart failure. Other causes of CHF include valvular heart disease, hypertension, viral infections of the heart, alcohol consumption, and diabetes. Some cases of CHF occur without clear etiology and are called idiopathic. The effects of CHF on a subject experiencing the condition can be fatal.
There are several types of CHF. Two types of CHF are identified according to which phase of the cardiac pumping cycle is more affected. Systolic heart failure occurs when the heart's ability to contract decreases. The heart cannot pump with enough force to push a sufficient amount of blood into the circulation leading to a reduced left ventricular ejection fraction. Lung congestion is a typical symptom of systolic heart failure. Diastolic heart failure refers to the heart's inability to relax between contractions and allow enough blood to enter the ventricles. Higher filling pressures are required to maintain cardiac output, but contractility as measured by left ventricular ejection fraction is typically normal. Swelling (edema) in the abdomen and legs is a typical symptom of diastolic heart failure. Often, an individual experiencing heart failure will have some degree of both systolic heart failure and diastolic heart failure.
CHF is also classified according to its severity. The New York Heart Association classifies CHF into four classes: Class I involves no obvious symptoms, with no limitations on physical activity; Class II involves some symptoms during or after normal activity, with mild physical activity limitations; Class III involves symptoms with less than ordinary activity, with moderate to significant physical activity limitations; and Class IV involves significant symptoms at rest, with severe to total physical activity limitations. Typically, an individual progresses through the classes as they live with the condition.
Although CHF is generally thought of as a chronic, progressive condition, it can also develop suddenly. This type of CHF is called acute CHF, and it is a medical emergency. Acute CHF can be caused by acute myocardial injury that affects either myocardial performance, such as myocardial infarction, or valvular/chamber integrity, such as mitral regurgitation or ventricular septal rupture, which leads to an acute rise in left ventricular and diastolic pressure resulting in pulmonary edema and dyspnea.
Common treatment agents for CHF include vasodilators (drugs that dilate blood vessels), positive inotropes (drugs that increase the heart's ability to contract), and diuretics (drugs to reduce fluid). Additionally, beta-antagonists (drugs that antagonize beta-adrenergic receptors) have become standard agents for treating mild to moderate heart failure. Lowes et al, Clin. Cardiol., 23:III 11-6 (2000).
Positive inotropic agents include beta-adrenergic agonists, such as dopamine, dobutamine, dopexamine, and isoproterenol. However, use of a beta-agonist has potential complications, such as arrhythmogenesis and increased oxygen demand by the heart. Additionally, the initial short-lived improvement of myocardial contractility afforded by these drugs is followed by an accelerated mortality rate resulting largely from a greater frequency of sudden death. Katz, HEART FAILURE: PATHOPHYSIOLOGY, MOLECULAR BIOLOGY AND CLINICAL MANAGEMENT, Lippincott, Williams & Wilkins (1999).
Beta-antagonists antagonize beta-adrenergic receptor function. While initially contra-indicated in heart failure, they have been found to provide a marked reduction in mortality and morbidity in clinical trials. Bouzamondo et al., Fundam. Clin. Pharmacol., 15: 95-109 (2001). Accordingly, they have become an established therapy for heart failure. However, even subjects that improve under beta-antagonist therapy may subsequently decompensate and require acute treatment with a positive inotropic agent. Unfortunately, as their name suggests, beta-antagonists block the mechanism of action of the positive inotropic beta-agonists that are used in emergency care centers. Bristow et al., J. Card. Fail., 7: 8-12 (2001).
Vasodilators, such as nitroglycerin, have been used for a long period of time to treat heart failure. However, the cause of nitroglycerin's therapeutic effect was not known until late in the last century when it was discovered that the nitric oxide molecule (NO) was responsible for nitroglycerin's beneficial effects. In some subjects experiencing heart failure, a nitric oxide donor is administered in combination with a positive inotropic agent to both cause vasodilation and to increase myocardial contractility. However, this combined administration can impair the effectiveness of positive inotropic treatment agents. For example, Hart et al, Am. J. Physiol. Heart Circ. Pyhsiol., 281:146-54 (2001) reported that administration of the nitric oxide donor sodium nitroprusside, in combination with the positive inotropic, beta-adrenergic agonist dobutamine, impaired the positive inotropic effect of dobutamine. Hare et al., Circulation, 92:2198-203 (1995) also disclosed the inhibitory effect of nitric oxide on the effectiveness of dobutamine.
As described in U.S. Pat. No. 6,936,639, compounds that donate nitroxyl (HNO) under physiological conditions have both positive inotropic and lusitropic effects and offer significant advantages over existing treatments for failing hearts. Due to their concomitant positive inotropic/lusotropic action and unloading effects, nitroxyl donors were reported as helpful in treating cardiovascular diseases characterized by high resistive load and poor contractile performance. In particular, nitroxyl-donating compounds were reported as useful in the treatment of heart failure, including heart failure in individuals receiving beta-antagonist therapy.
Summary of Ischemia
Ischemia is a condition characterized by an interruption or inadequate supply of blood to tissue, which causes oxygen deprivation in the affected tissue. Myocardial ischemia is a condition caused by a blockage or constriction of one or more of the coronary arteries, such as can occur with atherosclerotic plaque occlusion or rupture. The blockade or constriction causes oxygen deprivation of the non-perfused tissue, which can cause tissue damage. Further, upon reperfusion with subsequent reoxygenation of the tissue, when the blood is able to flow again or the oxygen demand of the tissue subsides, additional injury can be caused by oxidative stress.
Ischemia/reperfusion injury refers to tissue damage caused by oxygen deprivation followed by reoxygenation. The effects of ischemia/reperfusion injury in a subject experiencing the condition can be fatal, particularly when the injury occurs in a critical organ such as the heart or brain.
Accordingly, compounds and compositions effective in preventing or protecting against ischemia/reperfusion injury would be useful pharmaceuticals. Compounds such as nitroglycerin have been used for a long period of time to help control vascular tone and protect against myocardial ischemia/reperfusion injury. It was discovered that the nitric oxide molecule was responsible for nitroglycerin's beneficial effects. This discovery prompted interest in medical uses for nitric oxide and investigations into related species such as nitroxyl. As reported in U.S. patent application Ser. No. 10/463,084 (U.S. Publication No. 2004/0038947) administration of a compound that donates nitroxyl under physiological conditions, prior to ischemia, can attenuate ischemia/reperfusion injury to tissues, for example, myocardial tissues. This beneficial effect was reported as a surprising result given that nitroxyl was previously reported to increase ischemia/reperfusion injury (See, Ma et al., “Opposite Effects of Nitric Oxide and Nitroxyl on Postischemic Myocardial Injury,” Proc. Nat'l Acad. Sci., 96(25): 14617-14622 (1999), reporting that administration of Angeli's salt (a nitroxyl donor under physiological conditions) to anesthetized rabbits during ischemia and 5 minutes prior to reperfusion increased myocardial ischemia/reperfusion injury and Takahira et al., “Dexamethasone Attenuates Neutrophil Infiltration in the Rat Kidney in Ischemia/Reperfusion Injury: The Possible Role of Nitroxyl,” Free Radical Biology & Medicine, 31(6):809-815 (2001) reporting that administration of Angeli's salt during ischemia and 5 minutes before reperfusion of rat renal tissue contributed to neutrophil infiltration into the tissue, which is believed to mediate ischemia/reperfusion injury). In particular, pre-ischemic administration of Angeli's salt and isopropylamine/NO has been reported to prevent or reduce ischemia/reperfusion injury.
Summary of Nitroxyl Donors
To date, the vast majority of studies of the biological effect of HNO have used the donor sodium dioxotrinitrate (“Angeli's salt” or “AS”). However, the chemical stability of AS has made it unsuitable to develop as a therapeutic agent. N-hydroxybenzenesulfonamide (“Piloty's acid” or “PA”) has previously been shown to be a nitroxyl donor at high ph (>9) (Bonner, F. T.; Ko, Y. Inorg. Chem. 1992, 31, 2514-2519). However, under physiological conditions, PA is a nitric oxide donor via an oxidative pathway (Zamora, R.; Grzesiok, A.; Weber, H.; Feelisch, M. Biochem. J. 1995, 312, 333-339). Thus, the physiological effects of AS and PA are not the same because AS is a nitroxyl donor under physiological conditions whereas PA is a nitric oxide donor under physiological conditions.
Although U.S. Pat. No. 6,936,639 and U.S. Publication No. 2004/0038947 describe PA as a compound that donates nitroxyl and note that other sulfohydroxamic acids and their derivatives are therefore also useful as nitroxyl donors, PA does not in fact donate significant amounts of nitroxyl under physiological conditions (See Zamora, supra).
Several substituted N-hydroxylbenzenesulfonamides have been reported as inhibitors of carbonic anhydrase, with no mention of HNO production (see, (a) Mincione, F.; Menabuoni, L.; Briganti, F; Mincione, G.; Scozzafava, A.; Supuran, C. T. J. Enzyme Inhibition 1998, 13, 267-284 and (b) Scozzafava, A.; Supuran, C. T., J. Med. Chem. 2000, 43, 3677-3687).
Significant Medical Need
Despite efforts towards the development of new therapies for the treatment of diseases and conditions such as heart failure and ischemia/reperfusion injury, there remains a significant interest in and need for additional or alternative compounds that treat or prevent the onset or severity of these and related diseases or conditions. In particular, there remains a significant medical need for alternative or additional therapies for the treatment of diseases or conditions that are responsive to nitroxyl therapy. New compounds that donate nitroxyl under physiological conditions and methods of using compounds that donate nitroxyl under physiological conditions may thus find use as therapies for treating, preventing and/or delaying the onset and/or development of diseases or conditions responsive to nitroxyl therapy, including heart disease and ischemia/reperfusion injury. Preferably, the therapeutic agents can improve the quality of life and/or prolong the survival time for patients with the disease or condition.
BRIEF SUMMARY OF THE INVENTION
Methods, compounds and compositions for treating and/or preventing the onset or development of diseases or conditions that are responsive to nitroxyl therapy are described. Aromatic and non-aromatic N-hydroxylsulfonamide derivatives that donate nitroxyl under physiological conditions are described. By modifying PA with appropriate substituents, such as electron-withdrawing groups or groups that sterically hinder the sulfonyl moiety, the HNO producing capacity of these derivatives is substantially enhanced under physiological conditions. Significantly, when compared to AS, PA has the capacity for broad substituent modification, enabling optimization of physicochemical and pharmacological properties. Such optimization is reported herein.
In one embodiment, the present invention provides a method of administering to a subject in need thereof, a therapeutically effective amount of a derivative of PA wherein the derivative donates nitroxyl under physiological conditions. In one embodiment, the invention embraces a method of treating or preventing the onset and/or development of a disease or condition that is responsive to nitroxyl therapy, the method comprising administering to an individual in need thereof an N-hydroxylsulfonamide that donates an effective amount of nitroxyl under physiological conditions. Also embraced are methods of treating heart failure or ischemia/reperfusion injury by administering to an individual in need thereof an N-hydroxysulfonamide that donates an effective amount of nitroxyl under physiological conditions.
Kits comprising the compounds are also described, which may optionally contain a second therapeutic agent such as a positive inotropic compound, which may be, e.g., a beta-adrenergic receptor agonist.
Novel compounds that find use in the invention described herein include compounds of the formula (I), (II), (III) or (IV):
where R 1 is H; R 2 is H, aralkyl or heterocyclyl; m and n are independently an integer from 0 to 2; x and b are independently an integer from 0 to 4; y is an integer from 0 to 3; T is an alkyl or substituted alkyl; Z is an electron withdrawing group; R 3 , R 4 , R 5 , R 6 and R 7 are independently selected from the group consisting of H, halo, alkylsulfonyl, N-hydroxylsulfonamidyl, perhaloalkyl, nitro, aryl, cyano, alkoxy, perhaloalkoxy, alkyl, substituted aryloxy, alkylsulfanyl, alkylsulfinyl, heterocycloalkyl, substituted heterocycloalkyl, dialkylamino, cycloalkoxy, cycloalkylsulfanyl, arylsulfanyl and arylsulfinyl, provided that: (1) at least one of R 3 , R 4 , R 5 , R 6 and R 7 is other than H; (2) at least one of R 3 , R 4 , R 5 , R 6 and R 7 is other than halo; (3) when R 3 , R 4 , R 6 and R 7 are H, R 5 is other than halo, nitro, cyano, alkyl or alkoxy; (4) when one of R 3 or R 7 is halo and the R 3 or R 7 that is not halo is H and one, of R 4 or R 6 is halo and the R 4 or R 6 that is not halo is H, R 5 is other than halo; (5) when R 3 , R 7 and R 5 are H and one of R 4 and R 6 is H, the R 4 or R 6 that is not H is other than N-hydroxysulfonamidyl, perhaloalkyl or nitro; (6) when R 4 , R 5 and R 6 are H and one of R 3 and R 7 is H, the R 3 or R 7 that is not H is other than nitro or alkyl; (7) when R 3 and R 7 are H, R 5 is nitro and one of R 4 and R 6 is H, the R 4 or R 6 that is not H is other than halo; (8) when R 4 and R 6 are nitro and R 3 and R 7 are H, R 5 is other than dialkylamino; (9) when R 4 and R 6 are H and R 3 and R 7 are alkyl, R 5 is other than alkyl; and (10) when R 3 and R 7 are H and R 4 and R 6 are nitro, R 5 is other than dialkylamino; each R 8 and R 9 is independently selected from the group consisting of halo, alkylsulfonyl, N-hydroxylsulfonamidyl, perhaloalkyl, nitro, aryl, cyano, alkoxy, perhaloalkoxy, alkyl, substituted aryloxy, alkylsulfanyl, alkylsulfinyl, heterocycloalkyl, substituted heterocycloalkyl, dialkylamino, NH 2 , OH, C(O)OH, C(O)Oalkyl, NHC(O)alkylC(O)OH, C(O)NH 2 , NHC(O)alkylC(O)alkyl, NHC(O)alkenylC(O)OH, NHC(O)NH 2 , OalkylC(O)Oalkyl, NHC(O)alkyl, C(═N—OH)NH 2 , cycloalkoxy, cycloalkylsulfanyl, arylsulfanyl, and arylsulfinyl; A is a cycloalkyl, heterocycloalkyl, aromatic or heteroaromatic ring containing ring moieties Q 1 , Q 2 , Q 3 and Q 4 , which are taken together with V and W to form ring A; B is a cycloalkyl, heterocycloalkyl, aromatic or heteroaromatic ring containing ring moieties Q 5 , Q 6 , Q 7 and Q 8 , which are taken together with the V and W to form ring B; V and W are independently C, CH, N or Ne; Q 1 , Q 2 , Q 3 , Q 4 , Q 5 , Q 6 , Q 7 and Q 8 are independently selected from the group consisting of C, CH 2 , CH, N, NR 10 , O and S, provided that either (1) when rings A and B form naphthalene, x is an integer from 1 to 3 or y is an integer from 2 to 4 or R 8 is other than Cl or (2) at least one of Q 1 , Q 2 , Q 3 , Q 4 , Q 5 , Q 6 , Q 7 and Q 8 is N, NR 10 , O or S; C is a heteroaromatic ring containing ring moieties Q 9 , Q 10 , Q 11 , Q 12 , Q 13 and Q 14 that are independently selected from the group consisting of C, CH 2 , CH, N, NR 10 , O and S, provided that at least one of Q 9 , Q 10 , Q 11 , Q 12 , Q 13 and Q 14 is N, NR 10 , O or S; and R 10 is H, alkyl, acyl or sulfonyl. Pharmaceutically acceptable salts of any of the foregoing are also described. In one variation, the compound is of the formula (I), (II), (III) or (IV) where R 1 is H; R 2 is H; m and n are independently an integer from 0 to 2; x and b are independently an integer from 0 to 4; y is an integer from 0 to 3; T is an alkyl or substituted alkyl; Z is an electron withdrawing group; R 3 , R 4 , R 5 , R 6 and R 7 are independently selected from the group consisting of H, halo, alkylsulfonyl, substituted alkylsulfonyl, N-hydroxylsulfonamidyl, substituted N-hydroxylsulfonamidyl, perhaloalkyl, substituted perhaloalkyl (where one or more halo may be substituted with a substituent), nitro, aryl, substituted aryl, cyano, alkoxy, substituted alkoxy, perhaloalkoxy, substituted perhaloalkoxy, alkyl, substituted alkyl, aryloxy, substituted aryloxy, alkylsulfanyl, substituted alkylsulfanyl, alkylsulfinyl, substituted alkylsulfinyl, heterocycloalkyl, substituted heterocycloalkyl, dialkylamino, substituted dialkylamino, cycloalkoxy, substituted cycloalkoxy, cycloalkylsulfanyl, substituted cycloalkylsulfanyl, arylsulfanyl, substituted arylsulfanyl, arylsulfinyl and substituted arylsulfinyl, provided that: (1) at least one of R 3 , R 4 , R 5 , R 6 and R 7 is other than H; (2) at least one of R 3 , R 4 , R 5 , R 6 and R 7 is other than halo; (3) when R 3 , R 4 , R 6 and R 7 are H, R 5 is other than halo, nitro, cyano, alkyl or alkoxy; (4) when one of R 3 or R 7 is halo and the R 3 or R 7 that is not halo is H and one of R 4 or R 6 is halo and the R 4 or R 6 that is not halo is H, R 5 is other than halo; (5) when R 3 , R 7 and R 5 are H and one of R 4 and R 6 is H, the R 4 or R 6 that is not H is other than N-hydroxysulfonamidyl, perhaloalkyl or nitro; (6) when R 4 , R 5 and R 6 are H and one of R 3 and R 7 is H, the R 3 or R 7 that is not H is other than nitro or alkyl; (7) when R 3 and R 7 are H, R 5 is nitro and one of R 4 and R 6 is H, the R 4 or R 6 that is not H is other than halo; (8) when R 4 and R 6 are nitro and R 3 and R 7 are H, R 5 is other than dialkylamino; (9) when R 4 and R 6 are H and R 3 and R 7 are alkyl, R 5 is other than alkyl; and (10) when R 3 and R 7 are H and R 4 and R 6 are nitro, R 5 is other than dialkylamino; each R 8 and R 9 is independently selected from the group consisting of halo, alkylsulfonyl, substituted alkylsulfonyl, N-hydroxylsulfonamidyl, substituted N-hydroxylsulfonamidyl, perhaloalkyl, substituted perhaloalkyl, nitro, aryl, substituted aryl, cyano, alkoxy, substituted alkoxy, perhaloalkoxy, substituted perhaloalkoxy, alkyl, substituted alkyl, aryloxy, substituted aryloxy, alkylsulfanyl, substituted alkylsulfanyl, alkylsulfinyl, substituted alkylsulfinyl, heterocycloalkyl, substituted heterocycloalkyl, dialkylamino, substituted dialkylamino, NH 2 , OH, C(O)OH, C(O)Oalkyl, NHC(O)alkylC(O)OH, C(O)NH 2 , NHC(O)alkylC(O)alkyl, NHC(O)alkenylC(O)OH, NHC(O)NH 2 , OalkylC(O)Oalkyl, NHC(O)alkyl, C(═N—OH)NH 2 , cycloalkoxy, substituted cycloalkoxy, cycloalkylsulfanyl, substituted cycloalkylsulfanyl, arylsulfanyl, substituted arylsulfanyl, arylsulfinyl and substituted arylsulfinyl (where any listing of alkyl or alkenyl in the moieties above intends unsubstituted or substituted alkyl or alkenyl); A is a cycloalkyl, heterocycloalkyl, aromatic or heteroaromatic ring containing ring moieties Q 1 , Q 2 , Q 3 and Q 4 , which are taken together with V and W to form ring A; B is a cycloalkyl, heterocycloalkyl, aromatic or heteroaromatic ring containing ring moieties Q 5 , Q 6 , Q 7 and Q 8 , which are taken together with the V and W to form ring B; V and W are independently C, CH, N or NR 10 ; Q 1 , Q 2 , Q 3 , Q 4 , Q 5 , Q 6 , Q 7 and Q 8 are independently selected from the group consisting of C, CH 2 , CH, N, NR 10 , O and S, provided that either (1) when rings A and B form naphthalene, x is an integer from 1 to 3 or y is an integer from 2 to 4 or R 8 is other than Cl or (2) at least one of Q 1 , Q 2 , Q 3 , Q 4 , Q 5 , Q 6 , Q 7 and Q 8 is N, NR 10 , O or S; C is a heteroaromatic ring containing ring moieties Q 9 , Q 10 , Q 11 , Q 12 , Q 13 and Q 14 that are independently selected from the group consisting of C, CH 2 , CH, N, NR 10 , O and S, provided that at least one of Q 9 , Q 10 , Q 11 , Q 12 , Q 13 and Q 14 is N, NR 10 , O or S; and R 10 is H, alkyl, acyl or sulfonyl. Pharmaceutically acceptable salts of any of the foregoing are also described.
Methods are also described, including a method of treating, preventing or delaying the onset or development of a disease or condition that is responsive to nitroxyl therapy, comprising administering to an individual in need thereof an N-hydroxysulfonamide that donates nitroxyl under physiological conditions or a pharmaceutically acceptable salt thereof. In one variation, the method comprises administering to the individual a compound of the formula:
where R 1 is H; R 2 is H; m and n are independently an integer from 0 to 2; x and b are independently an integer from 0 to 4; y is an integer from 0 to 3; T is an alkyl or substituted alkyl; Z is an electron withdrawing group; R 3 , R 4 , R 5 , R 6 and R 7 are independently selected from the group consisting of H, halo, alkylsulfonyl, N-hydroxylsulfonamidyl, perhaloalkyl, nitro, aryl, cyano, alkoxy, perhaloalkoxy, alkyl, substituted aryloxy, alkylsulfanyl, alkylsulfinyl, heterocycloalkyl, substituted heterocycloalkyl, dialkylamino, cycloalkoxy, cycloalkylsulfanyl, arylsulfanyl and arylsulfinyl, provided that: (1) at least one of R 3 , R 4 , R 5 , R 6 and R 7 is other than H; each R 8 and R 9 is independently a substituent; A is a cycloalkyl, heterocycloalkyl, aromatic or heteroaromatic ring containing ring moieties Q 1 , Q 2 , Q 3 and Q 4 , which are taken together with V and W to form ring A; B is a cycloalkyl, heterocycloalkyl, aromatic or heteroaromatic ring containing ring moieties Q 5 , Q 6 , Q 7 and Q 8 , which are taken together with V and W to form ring B; V and W are independently C, CH, N or NR 10 ; Q 1 , Q 2 , Q 3 , Q 4 , Q 5 , Q 6 , Q 7 and Q 8 are independently selected from the group consisting of C, CH 2 , CH, N, NR 10 , O and S; C is a heteroaromatic ring containing ring moieties Q 9 , Q 10 , Q 11 , Q 12 , Q 13 and Q 14 that are independently selected from the group consisting of C, CH 2 , CH, N, NR 10 , O and S; and R 10 is H, alkyl, acyl or sulfonyl.
Pharmaceutical compositions comprising a compound of the invention are disclosed, such as pharmaceutical compositions that are amenable to intravenous injection. Kits comprising a compound of the invention and instructions for use are also described.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 depicts the nitrous oxide headspace analysis of compounds tested as nitroxyl donors as compared to the nitrous oxide headspace analysis of the nitroxyl donor Angeli's Salt (AS). Nitrous oxide (N 2 O) is the product of nitroxyl (HNO) dimerization and is thus indicative of whether a compound is a nitroxyl donor under the test conditions.
DETAILED DESCRIPTION OF THE INVENTION
Definitions
Unless clearly indicated otherwise, the following terms as used herein have the meanings indicated below.
Use of the terms “a”, “an” and the like refers to one or more.
“Aralkyl” refers to a residue in which an aryl moiety is attached to the parent structure via an alkyl residue. Examples include benzyl (—CH 2 -Ph), phenethyl (—CH 2 CH 2 Ph), phenylvinyl (—CH═CH-Ph), phenylallyl and the like.
“Acyl” refers to and includes the groups C(O)H, —C(O)alkyl, —C(O)substituted alkyl, —C(O)alkenyl, —C(O)substituted alkenyl, —C(O)alkynyl, —C(O)substituted alkynyl, —C(O)cycloalkyl, —C(O)substituted cycloalkyl, —C(O)aryl, —C(O)substituted aryl, —C(O)heteroaryl, —C(O)substituted heteroaryl, —C(O)heterocyclic, and —C(O)substituted heterocyclic wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic are as defined herein or otherwise known in the art.
“Heterocyclyl” or “Heterocycloalkyl” refers to a cycloalkyl residue in which one to four of the carbons is replaced by a heteroatom such as oxygen, nitrogen or sulfur. Examples of heterocycles whose radicals are heterocyclyl groups include tetrahydropyran, morpholine, pyrrolidine, piperidine, thiazolidine, oxazole, oxazoline, isoxazole, dioxane, tetrahydrofuran and the like. A specific example of a heterocyclyl residue is tetrahydropyran-2-yl.
“Substituted heterocylco” or “substituted heterocylcoalkyl” refers to an heterocyclyl group having from 1 to 5 substituents. For instance, a heterocyclyl group substituted with 1 to 5 groups such as halo, nitro, cyano, oxo, aryl, alkoxy, alkyl, acyl, acylamino, amino, hydroxyl, carboxyl, carboxylalkyl, thiol, thioalkyl, heterocyclyl, —OS(O) 2 -alkyl, and the like is a substituted alkyl. A particular example of a substituted heterocylcoalkyl is N-methylpiperazino.
“Alkyl” intends linear hydrocarbon structures having 1 to 20 carbon atoms, preferably 1 to 12 carbon atoms and more preferably 1 to 8 carbon atoms. Alkyl groups of fewer carbon atoms are embraced, such as so-called “lower alkyl” groups having 1 to 4 carbon atoms. “Alkyl” also intends branched or cyclic hydrocarbon structures having 3 to 20 carbon atoms, preferably 3 to 12 carbon atoms and more preferably 3 to 8 carbon atoms. For any use of the term “alkyl,” unless clearly indicated otherwise, it is intended to embrace all variations of alkyl groups disclosed herein, as measured by the number of carbon atoms, the same as if each and every alkyl group was explicitly and individually listed for each usage of the term. For instance, when a group such as R 3 may be an “alkyl,” intended is a C 1 -C 20 alkyl or a C 1 -C 12 alkyl or a C 1 -C 8 alkyl or a lower alkyl or a C 2 -C 20 alkyl or a C 3 -C 12 alkyl or a C 3 -C 8 alkyl. The same is true for other groups listed herein, which may include groups under other definitions, where a certain number of atoms is listed in the definition. When the alkyl group is cyclic, it may also be referred to as a cycloalkyl group and have e.g., 1 to 20 annular carbon atoms, preferably 1 to 12 annular carbon atoms and more preferably 1 to 8 annular carbon atoms. When an alkyl residue having a specific number of carbons is named, all geometric isomers having that number of carbons are intended to be encompassed; thus, for example, “butyl” is meant to include n-butyl, sec-butyl, iso-butyl and t-butyl; “propyl” includes n-propyl and iso-propyl. Examples of alkyl groups include methyl, ethyl, n-propyl, propyl, t-butyl, n-heptyl, octyl, cyclopentyl, cyclopropyl, cyclobutyl, norbornyl, and the like. One or more degrees of unsaturation may occur in an alkyl group. Thus, an alkyl group also embraces alkenyl and alkynyl residues. “Alkenyl” is understood to refer to a group of 2 or more carbon atoms, such as 2 to 10 carbon atoms and more preferably 2 to 6 carbon atoms and having at least 1 and preferably from 1-2 sites of alkenyl unsaturation. Examples of an alkenyl group include —C═CH 2 , —CH 2 CH═CHCH 3 and —CH 2 CH═CH—CH═CH 2 . “Alkynyl” refers to alkynyl group preferably having from 2 to 10 carbon atoms and more preferably 3 to 6 carbon atoms and having at least 1 and preferably from 1-2 sites of alkynyl unsaturation, such as the moiety —CCH. Alkyl is also used herein to denote an alkyl residue as part of a larger functional group and when so used, is taken together with other atoms to form another functional group. For instance, reference to —C(O)Oalkyl intends an ester functional group, where the alkyl portion of the moiety may be any alkyl group, and provide by way of example only, the functional group —C(O)OCH 3 , —C(O)(O)CH═CH 2 and the like. Another example of an alkyl group as part of a larger structure includes the residue —NHC(O)alkylC(O)OH, which e.g., may be NHC(O)CH 2 CH 2 C(O)OH when alkyl is —CH 2 CH 2 —.
“Substituted alkyl” refers to an alkyl group having from 1 to 5 substituents. For instance, an alkyl group substituted with a group such as halo, nitro, cyano, oxo, aryl, alkoxy, acyl, acylamino, amino, hydroxyl, carboxyl, carboxylalkyl, thiol, thioalkyl, heterocyclyl, —OS(O) 2 -alkyl, and the like is a substituted alkyl. Likewise, “substituted alkenyl” and “substituted alkynyl” refer to alkenyl or alkynyl groups having 1 to 5 substituents.
As used herein the term “substituent” or “substituted” means that a hydrogen radical on a compound or group (such as, for example, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, aralkyl, substituted aralkyl, heteroaryl, substituted heteroaryl, heteroaralkyl, substituted heteroaralkyl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, heterocyclyl and substituted heterocyclyl) is replaced with any desired group that does not substantially adversely affect the stability of the compound. In one embodiment, desired substituents are those which do not adversely affect the activity of a compound. The term “substituted” refers to one or more substituents (which may be the same or different), each replacing a hydrogen atom. Examples of substituents include, but are not limited to, halogen (F, Cl, Br, or 1), hydroxyl, amino, alkylamino, arylamino, dialkylamino, diarylamino, cyano, nitro, mercapto, oxo (i.e., carbonyl), thio, imino, formyl, carbamido, carbamyl, carboxyl, thioureido, thiocyanato, sulfoamido, sulfonylalkyl, sulfonylaryl, alkyl, alkenyl, alkoxy, mercaptoalkoxy, aryl, heteroaryl, cyclyl, heterocyclyl, wherein alkyl, alkenyl, alkyloxy, aryl, heteroaryl, cyclyl, and heterocyclyl are optionally substituted with alkyl, aryl, heteroaryl, halogen, hydroxyl, amino, mercapto, cyano, nitro, oxo (═O), thioxo (═S), or imino (=Nalkyl). In other embodiments, substituents on any group (such as, for example, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, aralkyl, substituted aralkyl, heteroaryl, substituted heteroaryl, heteroaralkyl, substituted heteroaralkyl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, heterocyclyl and substituted heterocyclyl) can be at any atom of that group (such as on a carbon atom of the primary carbon chain of a substituted alkyl group or on a substituent already present on a substituted alkyl group) or at any atom of, wherein any group that can be substituted (such as, for example, alkyl, alkenyl, alkynyl, aryl, aralkyl, heteroaryl, heteroaralkyl, cycloalkyl, cyclyl, heterocycloalkyl, and heterocyclyl) can be optionally substituted with one or more substituents (which may be the same or different), each replacing a hydrogen atom. Examples of suitable substituents include, but not limited to alkyl, alkenyl, alkynyl, cyclyl, cycloalkyl, heterocyclyl, heterocycloalkyl, aralkyl, heteroaralkyl, aryl, heteroaryl, halogen, haloalkyl, cyano, nitro, alkoxy, aryloxy, hydroxyl, hydroxylalkyl, oxo (i.e., carbonyl), carboxyl, formyl, alkylcarbonyl, alkylcarbonylalkyl, alkoxycarbonyl, alkylcarbonyloxy, aryloxycarbonyl, heteroaryloxy, heteroaryloxycarbonyl, thio, mercapto, mercaptoalkyl, arylsulfonyl, amino, aminoalkyl, dialkylamino, alkylcarbonylamino, alkylaminocarbonyl, or alkoxycarbonylamino; alkylamino, arylamino, diarylamino, alkylcarbonyl, or arylamino-substituted aryl; arylalkylamino, aralkylaminocarbonyl, amido, alkylaminosulfonyl, arylaminosulfonyl, dialkylaminosulfonyl, alkyl sulfonylamino, arylsulfonylamino, imino, carbamido, carbamyl, thioureido, thiocyanato, sulfoamido, sulfonylalkyl, sulfonylaryl, or mercaptoalkoxy. Additional suitable substituents on alkyl, alkenyl, alkynyl, aryl, aralkyl, heteroaryl, heteroaralkyl, cycloalkyl, cyclyl, heterocycloalkyl, and heterocyclyl include, without limitation halogen, CN, NO 2 , OR 11 , SR 11 , S(O) 2 OR 11 , NR 11 R 12 , C 1 -C 2 perfluoroalkyl, C 1 -C 2 perfluoroalkoxy, 1,2-methylenedioxy, (═O), (═S), (═NR 11 ), C(O)OR 11 , C(O)R 11 R 12 , OC(O)NR 11 R 12 , —NR 11 C(O)NR 11 R 12 , C(NR 12 )NR 11 R 12 , NR 11 C(NR 12 )NR 11 R 12 , S(O) 2 NR 11 R 12 R 13 , C(O)H, C(O)R 13 , NR 11 C(O)R 13 , Si(R 11 ) 3 , OSi(R 11 ) 3 , Si(OH) 2 R 11 , B(OH) 2 , P(O)(OR 11 ) 2 , S(O)R 13 , or S(O) 2 R 13 . Each R 11 is independently hydrogen, C 1 -C 6 alkyl optionally substituted with cycloalkyl, aryl, heterocyclyl, or heteroaryl. Each R 12 is independently hydrogen, C 3 -C 6 cycloalkyl, aryl, heterocyclyl, heteroaryl, C 1 -C 4 alkyl or C 1 -C 4 alkyl substituted with C 3 -C 6 cycloalkyl, aryl, heterocyclyl or heteroaryl. Each R 13 is independently C 3 -C 6 cycloalkyl, aryl, heterocyclyl, heteroaryl, C 1 -C 4 alkyl or C 1 -C 4 alkyl substituted with C 3 -C 6 cycloalkyl, aryl, heterocyclyl or heteroaryl. Each C 3 -C 6 cycloalkyl, aryl, heterocyclyl, heteroaryl and C 1 -C 4 alkyl in each R 11 , R 12 and R 13 can optionally be substituted with halogen, CN, C 1 -C 4 alkyl, OH, C 1 -C 4 alkoxy, COOH, C(O)OC 1 -C 4 alkyl, NH 2 , C 1 -C 4 alkylamino, or C 1 -C 4 dialkylamino. Substituents can also be “electron-withdrawing groups.”
“Electron withdrawing group” refers to groups that reduce electron density of the moiety to which they are attached (relative to the density of the moiety without the substituent). Such groups include, for example, F, Cl, Br, I, —CN, —CF 3 , —NO 2 , —SH, —C(O)H, —C(O)alkyl, —C(O)Oalkyl, —C(O)OH, —C(O)Cl, —S(O) 2 OH, —S(O) 2 NHOH, —NH 3 and the like.
“Halo” refers to fluorine, chlorine, bromine or iodine.
“Alkylsulfonyl” refers to groups —SO 2 alkyl and —SO 2 substituted alkyl, which includes the residues —SO 2 cycloalkyl, —SO 2 substituted cycloalkyl, —SO 2 alkenyl, —SO 2 substituted alkenyl, —SO 2 alkynyl, —SO 2 substituted alkynyl, where alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl and substituted cycloalkyl are as defined herein.
“N-hydroxylsulfonamidyl” refers to —S(O) 2 NROH, where R is H or alkyl.
“Perhaloalkyl” refers to an alkyl group where each H of the hydrocarbon is replaced with F. Examples of perhalo groups include —CF 3 and —CF 2 CF 3 .
“Aryl” intends a monocyclic, bicyclic or tricyclic aromatic ring. An aryl group is preferably a 5- or 6-membered aromatic or heteroaromatic ring containing 0-3 annular heteroatoms selected from O, N, or S; a bicyclic 9- or 10-membered aromatic or heteroaromatic ring system (meaning the ring system has 9 or 10 annular atoms) containing 0-3 annular heteroatoms selected from O, N, or S; or a tricyclic 13- or 14-membered aromatic or heteroaromatic ring system (meaning the ring system has 13 or 14 annular atoms) containing 0-3 annular heteroatoms selected from O, N, or S. Examples of groups whose radicals are aryl groups include e.g., benzene, naphthalene, indane, tetralin, imidazole, pyridine, indole, thiophene, benzopyranone, thiazole, furan, benzimidazole, benzoxazole, benzthiazole, quinoline, isoquinoline, quinoxaline, pyrimidine, pyrazine, tetrazole and pyrazole.
“Substituted aryl” refers to a group having from 1 to 3 substituents. For instance, an aryl group substituted with 1 to 3 groups such as halo, nitro, cyano, oxo, aryl, alkoxy, alkyl, acyl, acylamino, amino, hydroxyl, carboxyl, carboxylalkyl, thiol, thioalkyl, heterocyclyl, —OS(O) 2 -alkyl, and the like is a substituted aryl.
“Alkoxy” refers to an alkyl group that is connected to the parent structure through an oxygen atom (—O-alkyl). When a cycloalkyl group is connected to the parent structure through an oxygen atom, the group may also be referred to as a cycloalkoxy group. Examples include methoxy, ethoxy, propoxy, isopropoxy, cyclopropyloxy, cyclohexyloxy and the like. A “perhaloalkoxy” intends a perhaloalkyl group attached to the parent structure through an oxygen, such as the residue —O—CF 3 .
“Aryloxy” refers to an aryl group that is connected to the parent structure through an oxygen atom (—O-aryl), which by way of example includes the residues phenoxy, naphthoxy, and the like. “Substituted aryloxy” refers to a substituted aryl group connected to the parent structure through an oxygen atom (—O-substituted aryl).
“Alkylsulfanyl” refers to an alkyl group that is connected to the parent structure through a sulfur atom (—S-alkyl) and refers to groups S-alkyl and S-substituted alkyl, which includes the residues —S-cycloalkyl, —S-substituted cycloalkyl, —S-alkenyl, —S-substituted alkenyl, —S-alkynyl, —S-substituted alkynyl, where alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl and substituted cycloalkyl are as defined herein. When a cycloalkyl group is connected to the parent structure through an sulfur atom, the group may also be referred to as a cycloalkylsulfanyl group. By way of example, alkylsulfanyl includes —S—CH(CH 3 ), —S—CH 2 CH 3 and the like.
“Alkylsulfinyl” refers to an alkyl group that is connected to the parent structure through a S(O) moiety and refers to groups —S(O)alkyl and —S(O)substituted alkyl, which includes the residues —S(O)cycloalkyl, —S(O)substituted cycloalkyl, —S(O)alkenyl, —S(O)substituted alkenyl, —S(O)alkynyl, —S(O)substituted alkynyl, where alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl and substituted cycloalkyl are as defined herein. By way of example, alkylsulfinyl includes the residues S(O)CH(CH 3 ), —S(O)CH 3 , —S(O)cyclopentane and the like.
“Arylsulfinyl” refers to an aryl group that is connected to the parent structure through a S(O) moiety, which by way of example includes the residue S(O)Ph.
“Dialkylamino” refers to the group —NR 2 where each R is an alkyl group. Examples of dialkylamino groups include —N(CH 3 ) 2 , —N(CH 2 CH 2 CH 2 CH 3 ) 2 , and N(CH 3 )(CH 2 CH 2 CH 2 CH 3 ).
“Pharmaceutically acceptable salt” refers to pharmaceutically acceptable salts of a compound described herein, such as a compound of Formula (I), (II), (III) or (IV) or other nitroxyl donor of the invention, which salts may be derived from a variety of organic and inorganic counter ions well known in the art and include, by way of example only, sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium, and the like; when the molecule contains a basic functionality, salts of organic or inorganic acids, such as hydrochloride, hydrobromide, tartrate, mesylate, acetate, maleate, oxalate and the like. Illustrative salts include, but are not limited, to sulfate, citrate, acetate, chloride, bromide, iodide, nitrate, bisulfate, phosphate, acid phosphate, lactate, salicylate, acid citrate, tartrate, oleate, tannate, pantothenate, bitartrate, ascorbate, succinate, maleate, besylate, fumarate, gluconate, glucaronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, and p-toluenesulfonate salts. Accordingly, a salt may be prepared from a compound of any one of the formulae disclosed herein having an acidic functional group, such as a carboxylic acid functional group, and a pharmaceutically acceptable inorganic or organic base. Suitable bases include, but are not limited to, hydroxides of alkali metals such as sodium, potassium, and lithium; hydroxides of alkaline earth metal such as calcium and magnesium; hydroxides of other metals, such as aluminum and zinc; ammonia, and organic amines, such as unsubstituted or hydroxy-substituted mono-, di-, or trialkylamines; dicyclohexylamine; tributyl amine; pyridine; N-methyl,N-ethylamine; diethylamine; triethylamine; mono-, bis-, or tris-(2-hydroxy-lower alkyl amines), such as mono-, bis-, or tris-(2-hydroxyethyl)amine, 2-hydroxy-tert-butylamine, or tris-(hydroxymethyl)methylamine, N,N,-di-lower alkyl-N-(hydroxy lower alkyl)-amines, such as N,N-dimethyl-N-(2-hydroxyethyl) amine, or tri-(2-hydroxyethyl)amine; N-methyl-D-glucamine; and amino acids such as arginine, lysine, and the like. A salt may also be prepared from a compound of any one of the formulae disclosed herein having a basic functional group, such as an amino functional group, and a pharmaceutically acceptable inorganic or organic acid. Suitable acids include hydrogen sulfate, citric acid, acetic acid, hydrochloric acid (HCl), hydrogen bromide (HBr), hydrogen iodide (HI), nitric acid, phosphoric acid, lactic acid, salicylic acid, tartaric acid, ascorbic acid, succinic acid, maleic acid, besylic acid, fumaric acid, gluconic acid, glucaronic acid, formic acid, benzoic acid, glutamic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, and p-toluenesulfonic acid.
Unless clearly indicated otherwise, “an individual” as used herein intends a mammal, including but not limited to a human.
The term “effective amount” intends such amount of a compound or a pharmaceutically acceptable salt thereof, which in combination with its parameters of efficacy and toxicity, as well as based on the knowledge of the practicing specialist should be effective in a given therapeutic form. As is understood in the art, an effective amount may be in one or more doses.
As used herein, “treatment” or “treating” is an approach for obtaining a beneficial or desired result, including clinical results. For purposes of this invention, beneficial or desired results include but are not limited to inhibiting and/or suppressing the onset and/or development of a disease or condition that is responsive to nitroxyl therapy or reducing the severity of such disease or condition, such as reducing the number and/or severity of symptoms associated with the disease or condition, increasing the quality of life of those suffering from the disease or condition, decreasing the dose of other medications required to treat the disease or condition, enhancing the effect of another medication an individual is taking for the disease or condition and prolonging survival of individual's having the disease or condition. The disease or condition may be a cardiovascular disease or condition, which includes, but is not limited to, coronary obstructions, coronary artery disease (CAD), angina, heart attack, myocardial infarction, high blood pressure, ischemic cardiomyopathy and infarction, diastolic heart failure, pulmonary congestion, pulmonary edema, cardiac fibrosis, valvular heart disease, pericardial disease, circulatory congestive states, peripheral edema, ascites, Chagas' disease, ventricular hypertrophy, heart valve disease, heart failure, including but not limited to congestive heart failure such as acute congestive heart failure and acute decompensated heart failure. Related symptoms that may be alleviated by the methods herein include shortness of breath, fatigue, swollen ankles or legs, angina, loss of appetite, weight gain or loss, associated with aforementioned diseases or disorders. The disease or condition may involve ischemia/reperfusion injury.
As used herein, “preventing” refers to reducing the probability of developing a disorder or condition in an individual who does not have, but is at risk of developing a disorder or condition.”
An individual “at risk” may or may not have a detectable disease or condition, and may or may not have displayed a detectable disease or condition prior to the treatment methods described herein. “At risk” denotes that an individual has one or more so-called risk factors, which are measurable parameters that correlate with development of a disease or condition and are known in the art. An individual having one or more of these risk factors has a higher probability of developing the disease or condition than an individual without these risk factor(s).
“Nitroxyl” refers to the species HNO.
As used herein, a compound is a “nitroxyl donor” if it donates nitroxyl under physiological conditions. As used herein, nitroxyl donors of the invention may alternatively be referred to as “a compound” or “the compound.” Preferably, the nitroxyl donor is capable of donating an effective amount of nitroxyl in vivo and has a safety profile indicating the compound would be tolerated by an individual in the amount necessary to achieve a therapeutic effect. One of ordinary skill in the art would be able to determine the safety of administering particular compounds and dosages to live subjects. One of skill in the art may also determine whether a compound is a nitroxyl donor by evaluating whether it releases HNO under physiological conditions. Compounds are easily tested for nitroxyl donation with routine experiments. Although it is impractical to directly measure whether nitroxyl is donated, several tests are accepted for determining whether a compound donates nitroxyl. For example, the compound of interest can be placed in solution, for example in water, in a sealed container. After sufficient time for disassociation has elapsed, such as from several minutes to several hours, the headspace gas is withdrawn and analyzed to determine its composition, such as by gas chromatography and/or mass spectroscopy. If the gas N 2 O is formed (which occurs by HNO dimerization), the test is positive for nitroxyl donation and the compound is a nitroxyl donor. The level of nitroxyl donating ability may be expressed as a percentage of a compound's theoretical maximum. A compound that donates a “significant level of nitroxyl” intends a compound that donates 40% or more or 50% or more of its theoretical maximum amount of nitroxyl. In one variation, the compounds for use herein donate 60% or more of the theoretical maximum amount of nitroxyl. In another variation, the compounds for use herein donate 70% or more of the theoretical maximum amount of nitroxyl. In another variation, the compounds for use herein donate 80% or more of the theoretical maximum amount of nitroxyl. In another variation, the compounds for use herein donate 90% or more of the theoretical maximum amount of nitroxyl. In yet another variation, the compounds for use herein donate between about 70% and about 90% of the theoretical maximum amount of nitroxyl. In yet another variation, the compounds for use herein donate between about 85% and about 95% of the theoretical maximum amount of nitroxyl. In yet another variation, the compounds for use herein donate between about 90% and about 95% of the theoretical maximum amount of nitroxyl. Compounds that donate less than 40% or less than 50% of their theoretical amount of nitroxyl are still nitroxyl donors and may be used in the invention disclosed herein. A compound that donates less than 50% of the theoretical amount of nitroxyl may be used in the methods described, and may require higher dosing levels as compared to compounds that donate a significant level of nitroxyl. Nitroxyl donation also can be detected by exposing the test compound to metmyoglobin (Mb 3+ ). Nitroxyl reacts with Mb 3+ to form an Mb 2+ —NO complex, which can be detected by changes in the ultraviolet/visible spectrum or by Electron Paramagnetic Resonance (EPR). The Mb 2+ —NO complex has an EPR signal centered around g-value of about 2. Nitric oxide, on the other hand, reacts with Mb 3+ to form an Mb 3+ —NO complex that is EPR silent. Accordingly, if the candidate compound reacts with Mb 3+ to form a complex detectable by common methods such as ultraviolet/visible or EPR, then the test is positive for nitroxyl donation. Testing for nitroxyl donation may be performed at physiologically relevant pH.
A “positive inotrope” as used herein is an agent that causes an increase in myocardial contractile function. Such an agent includes a beta-adrenergic receptor agonist, an inhibitor of phosphodiesterase activity, and calcium-sensitizers. Beta-adrenergic receptor agonists include, among others, dopamine, dobutamine, terbutaline, and isoproterenol. Analogs and derivatives of such compounds are also intended. For example, U.S. Pat. No. 4,663,351 describes a dobutamine prodrug that can be administered orally. One of ordinary skill in the art would be able to determine if a compound is capable of causing positive inotropic effects and also additional beta-agonist compounds. In particular embodiments, the beta-receptor agonist is selective for the beta-1 receptor. However, in other embodiments the beta-agonist is selective for the beta-2 receptor, or is not selective for any particular receptor.
Diseases or conditions that are “responsive to nitroxyl therapy” intends any disease or condition in which administration of a compound that donates an effective amount of nitroxyl under physiological conditions treats and/or prevents the disease or condition, as those terms are defined herein. A disease or condition whose symptoms are suppressed or diminished upon administration of nitroxyl donor is a disease or condition responsive to nitoxyl therapy. Non-limiting examples of diseases or conditions that are responsive to nitroxyl therapy include coronary obstructions, coronary artery disease (CAD), angina, heart attack, myocardial infarction, high blood pressure, ischemic cardiomyopathy and infarction, diastolic heart failure, pulmonary congestion, pulmonary edema, cardiac fibrosis, valvular heart disease, pericardial disease, circulatory congestive states, peripheral edema, ascites, Chagas' disease, ventricular hypertrophy, heart valve disease, heart failure, including but not limited to congestive heart failure such as acute congestive heart failure and acute decompensated heart failure. Other cardiovascular diseases or conditions are also intended, as are diseases or conditions that implicate ischemia/reperfusion injury.
N-Hydroxysulfonamide Compounds
The compounds of this invention and for use in the methods described herein include N-hydroxylsulfonamides that donate nitroxyl under physiological conditions. Preferably, the compounds predominately donate nitroxyl under physiological conditions, meaning that a compound that donates both nitoxyl and nitric oxide under physiological conditions donates more nitroxyl than nitric oxide. Preferably, the compounds for use herein do not donate significant levels of nitric oxide under physiological conditions. Most preferably, the compounds for use herein donate significant levels of nitroxyl under physiological conditions.
In one embodiment, the invention embraces a compound of the formula (I):
where R 1 is H; R 2 is H, aralkyl or heterocyclyl; R 3 , R 4 , R 5 , R 6 and R 7 are independently H, halo, alkylsulfonyl, N-hydroxylsulfonamidyl, perhaloalkyl, nitro, aryl, cyano, alkoxy, perhaloalkoxy, alkyl, substituted aryloxy, alkylsulfanyl, alkylsulfinyl, heterocycloalkyl, substituted heterocycloalkyl, dialkylamino, cycloalkoxy, cycloalkylsulfanyl, arylsulfanyl or arylsulfinyl, provided that: (1) at least one of R 3 , R 4 , R 5 , R 6 and R 7 is other than H; (2) at least one of R 3 , R 4 , R 5 , R 6 and R 7 is other than halo; (3) when R 3 , R 4 , R 6 and R 7 are H, R 5 is other than halo, nitro, cyano, alkyl or alkoxy; (4) when one of R 3 or R 7 is halo and the R 3 or R 7 that is not halo is H and one of R 4 or R 6 is halo and the R 4 or R 6 that is not halo is H, R 5 is other than halo; (5) when R 3 , R 7 and R 5 are H and one of R 4 and R 6 is H, the R 4 or R 6 that is not H is other than N-hydroxysulfonamidyl, perhaloalkyl or nitro; (6) when R 4 , R 5 and R 6 are H and one of R 3 and R 7 is H, the R 3 or R 7 that is not H is other than nitro or alkyl; (7) when R 3 and R 7 are H, R 5 is nitro and one of R 4 and R 6 is H, the R 4 or R 6 that is not H is other than halo; (8) when R 4 and R 6 are nitro and R 3 and R 7 are H, R 5 is other than dialkylamino; (9) when R 4 and R 6 are H and R 3 and R 7 are alkyl, R 5 is other than alkyl; and (10) when R 3 and R 7 are H and R 4 and R 6 are nitro, R 5 is other than dialkylamino.
In one embodiment, the compound is of the formula (I), where R 1 , R 2 , R 3 , R 4 , R 5 , R 6 and R 7 are as defined above, provided that (1) at least one of R 3 , R 4 , R 5 , R 6 and R 7 is other than H; (2) at least one of R 3 , R 4 , R 5 , R 6 and R 7 is other than F; (3) when R 3 , and R 7 are H, R 5 is other than F, Cl, Br, I, NO 2 , CN, CH 3 or OCH 3 ; (4) when one of R 3 or R 7 is Cl and the R 3 or R 7 that is not Cl is H and one of R 4 or R 6 is Cl and the R 4 or R 6 that is not Cl is H, R 5 is other than Cl; (5) when R 3 , R 7 and R 5 are H and one of R 4 and R 6 is H, the R 4 or R 6 that is not H is other than SO 2 NHOH, CF 3 or NO 2 ; (6) when R 4 , R 5 and R 6 are H and one of R 3 and R 7 is H, the R 3 or R 7 that is not H is other than NO 2 or CH 3 ; (7) when R 3 and R 7 are H, R 5 is NO 2 and one of R 4 and R 6 is H, the R 4 or R 6 that is not H is other than Cl; (8) when R 4 and R 6 are nitro and R 3 and R 7 are H, R 5 is other than a C 1 -C 5 dialkylamino; (9) when R 4 and R 6 are H and R 3 and R 7 are alkyl, R 5 is other than CH 3 ; and (10) when R 3 and R 7 are H and R 4 and R 6 are nitro, R 5 is other than a C 1 -C 5 dialkylamino.
In another embodiment, the compound is of the formula (I) where R 1 is H; R 2 is H, aralkyl or heterocyclyl; R 4 , R 5 and R 6 are independently H, halo, alkylsulfonyl, N-hydroxylsulfonamidyl, perhaloalkyl, nitro, aryl, cyano, alkoxy, perhaloalkoxy, alkyl, substituted aryloxy, alkylsulfanyl, alkylsulfinyl, heterocycloalkyl, substituted heterocycloalkyl, dialkylamino, cycloalkoxy, cycloalkylsulfanyl, arylsulfanyl or arylsulfinyl; at least one of R 3 and R 7 is an electron withdrawing group or a group that sterically hinders the sulfonyl moiety, provided that: (1) when one of R 3 or R 7 is halo and the R 3 or R 7 that is not halo is H and one of R 4 or R 6 is halo and the R 4 or R 6 that is not halo is H, R 5 is; other than halo and (2) when R 4 , R 5 and R 6 are H and one of R 3 and R 7 is H, the R 3 or R 7 that is not H is other than nitro or alkyl. In one variation, at least one of R 3 or R 7 is an electron withdrawing group. In another variation, both R 3 and R 7 are electron withdrawing groups. In another variation, at least one of R 3 or R 7 is a group that sterically hinders the sulfonyl moiety of compound (I). In one variation, at least one of R 3 or R 7 is a branched alkyl group, such as i-propyl or t-butyl. In another variation, both R 3 and R 7 are alkyl groups provided that one of the alkyl groups is a branched alkyl group, such as when both groups are isopropyl or when one group is ethyl and the other is sec-butyl. In one variation, one of R 3 and R 7 is an electron withdrawing group and the R 3 or R 7 that is not an electron withdrawing group is an alkyl group, which may be a branched alkyl group such as isopropyl.
Also embraced is a compound of the formula (I) where R 1 is H; R 2 is H, benzyl or tetrahydropyran-2-yl; R 3 , R 4 , R 5 , R 6 and R 7 are independently selected from the group consisting of H, Cl, F, I, Br, SO 2 CH 3 , SO 2 NHOH, CF 3 , NO 2 , phenyl, CN, OCH 3 , OCF 3 , t-Bu, O-iPr, 4-nitrophenyloxy (OPh4-NO 2 ), propane-2-thiyl (SCH(CH 3 ) 2 ), propane-2-sulfinyl (S(O)CH(CH 3 ) 2 ), morpholino, N-methyl-piperazino, dimethylamino, piperidino, cyclohexyloxy, cyclopentylsulfanyl, phenylsulfanyl and phenylsulfinyl, provided that: (1) at least one of R 3 , R 4 , R 5 , R 6 and R 7 is other than H; (2) at least one of R 3 , R 4 , R 5 , R 6 and R 7 is other than F; (3) when R 3 , R 4 , R 6 and R 7 are H, R 5 is other than F, Cl, Br, I, NO 2 , CN or OCH 3 ; (4) when one of R 3 or R 7 is Cl and the R 3 or R 7 that is not Cl is H and one of R 4 or R 6 is Cl and the R 4 or R 6 that is not Cl is H, R 5 is other than Cl; (5) when R 3 , R 7 and R 5 are H and one of R 4 and R 6 is H, the R 4 or R 6 that is not H is other than SO 2 NHOH, CF 3 or NO 2 ; (6) when R 4 , R 5 and R 6 are H and one of R 3 and R 7 is H, the R 3 or R 7 that is not H is other than NO 2 ; and (7) when R 3 and R 7 are H, R 5 is NO 2 and one of R 4 and R 6 is H, the R 4 or R 6 that is not H is other than Cl.
For any of the variations described for formula (I), included are variations of formula (I) where R 1 is H and R 2 is H, benzyl or tetrahydropyran-2-yl. In one variation, the compound is of the formula (I) where at least two of R 3 , R 4 , R 5 , R 6 and R 7 are halo, such as the compound of formula (I) where R 5 is halo (such as F or Br) and one of R 3 and R 7 is halo (such as Br, or Cl) or where both R 3 and R 7 or both R 3 and R 4 are halo (such as when both are Cl or both are F or one is Cl and one is F), and the remaining substituents are as described in the variations above. In one variation, the compound is of the formula (I) where at least one of R 3 , R 4 , R 5 , R 6 and R 7 is —S(O)Oalkyl, such as when one of R 3 or R 7 is —S(O)OCH 3 . In one variation, the compound is of the formula (I) where at least one of R 3 , R 5 and R 7 is a perhaloalkyl, such as when R 3 is CF 3 or when R 3 and R 5 are CF 3 . In one variation, the compound is of the formula (I) where R 5 is CF 3 and at least one of R 3 and R 7 is other than H, such as when R 5 is CF 3 and R 3 is NO 2 or Cl. In one variation, the compound is of the formula (I) where at least one of R 3 , R 4 , R 5 , R 6 and R 7 is an aryl group, such as when at least one of R 3 and R 7 is an aryl group, such as phenyl. In one variation, the compound is of the formula (I) where at least one of R 3 , R 4 , R 5 , R 6 and R 7 is a heterocyclyl group, such as when at least one of R 3 , R 5 and R 7 is a heterocyclyl group or substituted heterocylco group, such as morpholino, N-methyl, piperizino and piperidino. In one variation, the compound is of the formula (I) where at least one of R 3 , R 4 , R 5 , R 6 and R 7 is a cycloaloxy or cycloalkylsulfanyl group such as when at least one of R 3 , R 5 and R 7 is a cyclohexyloxy, cyclopentyloxy, cyclohexylsulfanyl or cyclopentylsulfanyl group. In one variation, the compound is of the formula (I) where at least one of R 3 , R 4 , R 5 , R 6 and R 7 is an arylsulfanyl or arylsulfinyl group, such as when at least one of R 3 , R 5 and R 7 is a phenylsulfanyl or phenylsulfinyl group.
Representative compounds of the formula (I) include, but are not limited to, the compounds listed in Table 1.
TABLE 1
Representative Compounds of Formula (I):
In one embodiment, the nitroxyl donating compound is a compound of the formula (II):
where R 1 is H; R 2 is H, aralkyl or heterocyclyl; m and n are independently an integer from 0 to 1; x is an integer from 0 to 4; y is an integer from 0 to 3; A is a cycloalkyl, heterocycloalkyl, aromatic or heteroaromatic ring containing ring moieties Q 1 , Q 2 , Q 3 and Q 4 , which are taken together with the carbons at positions a and a′ to form ring A; B is a cycloalkyl, heterocycloalkyl, aromatic or heteroaromatic ring containing ring moieties Q 5 , Q 6 , Q 7 and Q 8 , which are taken together with the carbons at positions a and a′ to form ring B; Q 1 , Q 2 , Q 3 , Q 4 , Q 5 , Q 6 , Q 7 and Q 8 are independently selected from the group consisting of C, CH 2 , CH, N, NR 16 , O and S, provided that either (1) when rings A and B form naphthalene, x is an integer from 1 to 3 or y is an integer from 2 to 4 or R 8 is other than Cl or (2) at least one of Q 1 , Q 2 , Q 3 , Q 4 , Q 5 , Q 6 , Q 7 and Q 8 is N, NR 10 , O or S; each R 8 and R 9 is independently selected from the group consisting of halo, alkylsulfonyl, N-hydroxylsulfonamidyl, perhaloalkyl, nitro, aryl, cyano, alkoxy, perhaloalkoxy, alkyl, substituted aryloxy, alkylsulfanyl, alkylsulfinyl, heterocycloalkyl, substituted heterocycloalkyl, dialkylamino, NH 2 , OH, C(O)OH, C(O)Oalkyl, NHC(O)alkylC(O)OH, C(O)NH 2 , NHC(O)alkylC(O)alkyl, NHC(O)alkenylC(O)OH, NHC(O)NH 2 , OalkylC(O)Oalkyl, NHC(O)alkyl, C(═N—OH)NH 2 , cycloalkoxy, cycloalkylsulfanyl, arylsulfanyl, and arylsulfinyl; and R 10 is H, alkyl, acyl, or sulfonyl.
In one variation, the compound is of the formula (II) where each R 8 and R 9 is independently selected from the group consisting of Cl, F, I, Br, SO 2 CH 3 , SO 2 NHOH, CF 3 , CH 3 , NO 2 , phenyl, CN, OCH 3 , OCF 3 , t-Bu, O-iPr, 4-nitrophenyloxy (OPh4-NO 2 ), propane-2-thiyl (SCH(CH 3 ) 2 ), propane-2-sulfinyl (S(O)CH(CH 3 ) 2 ), morpholino, N-methyl-piperazino, dimethylamino, piperidino, cyclohexyloxy, cyclopentylsulfanyl, phenylsulfanyl and phenylsulfinyl; and R 10 is H, alkyl, acyl or sulfonyl, provided that when rings A and B form naphthalene, x is an integer from 1 to 3 or y is an integer from 2 to 4.
For any of the variations described for formula (II), included are variations of formula (II) where R 1 is H and R 2 is H, benzyl or tetrahydropyran-2-yl. In one variation, A and B form a benzofuran or benzothiophene or benzoimidazole or N-alkylbenzoimidazole (such as N-methylbenzoimidazole) or N-acylbenzoimidazole (such as N—C(O)CH 3 benzoimidazole) or benzothiazole or benzooxazole. In one variation, A and B form a benzofuran. In one variation, A and B form a benzofuran and x and y are 0. In one variation, A and B form a benzothiophene. In one variation, A and B form a benzothiophene, y is 0 and x is 1. In one variation, A and B form naphthyl and x is 0, y is 1 and R 8 is a halo group. In one variation, ring A is phenyl and ring B is a heteroaryl group, such as when rings A and B form quinoline and ring B is the nitrogen containing ring. The invention also embraces compounds according to any of the variations for formula (II) where y is 0, x is 1 and R 9 is a halo, alkyl or perhaloalkyl group. The invention also embraces compounds according to any of the variations for formula (II) where x is 2 and y is 0.
Representative compounds of the formula (II) include, but are not limited to, the compounds listed in Table 2.
TABLE 2
Representative Compounds of Formula (II):
In another embodiment, the nitroxyl donating compound is a compound of the formula (III):
where R 1 is H; R 2 is H, aralkyl or heterocyclyl; n is an integer from 0 to 1; b is an integer from 0 to 4; C is a heteroaromatic ring containing ring moieties Q 9 , Q 10 , Q 11 , Q 12 , Q 13 and Q 14 that are independently selected from the group consisting of C, CH 2 , CH, N, NR 10 , O and S, provided that at least one of Q 9 , Q 10 , Q 11 , Q 12 , Q 13 and Q 14 is N, NR 10 , O or S; each R 8 is independently selected from the group consisting of halo, alkylsulfonyl, N-hydroxylsulfonamidyl, perhaloalkyl, nitro, aryl, cyano, alkoxy, perhaloalkoxy, alkyl, substituted aryloxy, alkylsulfanyl, alkylsulfinyl, heterocycloalkyl, substituted heterocycloalkyl, dialkylamino, NH 2 , OH, C(O)OH, C(O)Oalkyl, NHC(O)alkylC(O)OH, C(O)NH 2 , NHC(O)alkylC(O)alkyl, NHC(O)alkenylC(O)OH, NHC(O)NH 2 , OalkylC(O)Oalkyl, NHC(O)alkyl, C(═N—OH)NH 2 , cycloalkoxy, cycloalkylsulfanyl, arylsulfanyl, and arylsulfinyl; and R 10 is H, alkyl, acyl or sulfonyl.
In one variation, the compound is of the formula (III) and each R 8 is independently selected from the group consisting of Cl, F, I, Br, SO 2 CH 3 , SO 2 NHOH, CF 3 , CH 3 , NO 2 , phenyl, CN, OCH 3 , OCF 3 , t-Bu, O-iPr, 4-nitrophenyloxy (OPh4-NO 2 ), propane-2-thiyl (SCH(CH 3 ) 2 ), propane-2-sulfinyl (S(O)CH(CH 3 ) 2 ), morpholino, N-methyl-piperazino, dimethylamino, piperidino, cyclohexyloxy, cyclopentylsulfanyl, phenylsulfanyl and phenylsulfinyl. In another variation, the compound is of the formula (III) and each R 8 is independently selected from the group consisting of F, Br, Cl, CF 3 , phenyl, methyl, SO 2 NHOH, morpholino, piperidino, 4-methyl-piperazino.
For any of the variations described for formula (III), included are variations of formula (III) where R 1 is H and R 2 is H, benzyl or tetrahydropyran-2-yl. In one variation, n is 0 and C is a thiophene or isoxazole or pyrazole or pyrrole or imidazole or furan or thiazole or triazole or N-methylimidazole or thiadiazole. In another variation, n is 0 and C is a thiophene or isoxazole or pyrazole or pyrrole or imidazole or furan or thiazole or triazole or N-methylimidazole or thiadiazole and either (1) b is 1 and R 8 is either a halo (such as Cl or Br), nitro, alkyl (such as methyl), cyano or (2) b is 2 and each R 8 is a halo group. In one variation, n is 1 and C is a pyrimidine or pyrazine or pyridine. In one variation, n is 1 and C is a pyrimidine or pyrazine or pyridine and b is either 0 or 1, and where R 8 is halo or heterocyclyl if b is 1. In one variation, n is 1 and C is a pyrimidine or pyrazine or pyridine, b is 1, and R 8 is chloro or morpholino or piperidino or N-methylpiperizino. In one variation, C is thiophene and b is 1. In one variation, C is thiophene, b is 1 and R 8 is halo. In one variation, C is thiophene and b is 0.
Representative compounds of the formula (III) include, but are not limited to, the compounds listed in Table 3.
TABLE 3
Representative compounds of the formula (III).
In one embodiment, the nitroxyl donating compound is of the formula (IV):
where R 1 is H; R 2 is H, aralkyl or heterocyclyl; T is alkyl or substituted alkyl (which includes a cycloalkyl or substituted cycloalkyl) and Z is an electron withdrawing group. In one variation, T is a C 1 to C 6 branched alkyl, such as isopropyl, t-butyl or sec-butyl. In another variation, T is a C 1 to C 6 branched alkyl, such as isopropyl, t-butyl or sec-butyl and Z is selected from the group consisting of F, Cl, Br, I, —CN, —CF 3 , —NO 2 , —SH, —C(O)H, —C(O)alkyl, —C(O)Oalkyl, —C(O)OH, —C(O)Cl, —S(O) 2 OH, —S(O) 2 NHOH, —NH 3 . For any of the variations described for formula (IV), included are variations of formula (IV) where R 1 is H and R 2 is H, benzyl or tetrahydropyran-2-yl.
Representative compounds of the formula (IV) include, but are not limited to, the compounds listed in Table 4.
TABLE 4 Representative compounds of the formula (IV).
Compounds for Use in the Methods
The methods described employ N-hydroxysulfonamides that donate an effective amount of nitroxyl under physiological conditions. Any of the methods may employ an N-hydroxylsulfonamide compound described above under “N-Hydroxysulfonamide Compounds.” The methods may also employ other N-hydroxysulfonamides that donate an effective amount of nitroxyl under physiological conditions, including those described by the formulae below:
where R 1 is H; R 2 is H; m and n are independently an integer from 0 to 2; x and b are independently an integer from 0 to 4; y is an integer from 0 to 3; T is an alkyl or substituted alkyl; Z is an electron withdrawing group; R 3 , R 4 , R 5 , R 6 and R 7 are independently selected from the group consisting of H, halo, alkylsulfonyl, N-hydroxylsulfonamidyl, perhaloalkyl, nitro, aryl, cyano, alkoxy, perhaloalkoxy, alkyl, substituted aryloxy, alkylsulfanyl, alkylsulfinyl, heterocycloalkyl, substituted heterocycloalkyl, dialkylamino, cycloalkoxy, cycloalkylsulfanyl, arylsulfanyl and arylsulfinyl, provided that provided that: (1) at least one of R 3 , R 4 , R 5 , R 6 and R 7 is other than H; each R 8 and R 9 is independently selected from the group consisting of halo, alkylsulfonyl, N-hydroxylsulfonamidyl, perhaloalkyl, nitro, aryl, cyano, alkoxy, perhaloalkoxy, alkyl, substituted aryloxy, alkylsulfanyl, alkylsulfinyl, heterocycloalkyl, substituted heterocycloalkyl, dialkylamino, NH 2 , OH, C(O)OH, C(O)Oalkyl, NHC(O)alkylC(O)OH, C(O)NH 2 , NHC(O)alkylC(O)alkyl, NHC(O)alkenylC(O)OH, NHC(O)NH 2 , OalkylC(O)Oalkyl, NHC(O)alkyl, C(═N—OH)NH 2 , cycloalkoxy, cycloalkylsulfanyl, arylsulfanyl, and arylsulfinyl; A is a cycloalkyl, heterocycloalkyl, aromatic or heteroaromatic ring containing ring moieties Q 1 , Q 2 , Q 3 and Q 4 , which are taken together with the carbons at positions a and a′ to form ring A; B is a cycloalkyl, heterocycloalkyl, aromatic or heteroaromatic ring containing ring moieties Q 5 , Q 6 , Q 7 and Q 8 , which are taken together with the carbons at positions a and a′ to form ring B; Q 1 , Q 2 , Q 3 , Q 4 , Q 5 , Q 6 , Q 7 and Q 8 are independently selected from the group consisting of C, CH 2 , CH, N, O and S; C is a heteroaromatic ring containing ring moieties Q 9 , Q 10 , Q 11 , Q 12 , Q 13 and Q 14 that are independently selected from the group consisting of C, CH 2 , CH, N, NR 10 , O and S; and R 10 is H, alkyl, acyl or sulfonyl.
Any of the methods may also utilize any of the specific N-hydroxylsulfonamide compounds listed in Tables 1-4. The methods may also employ any of the compounds listed Table 5. Certain compounds of Table 5 have been described in the literature (See, e.g., Mincione, F.; Menabuoni, L.; Briganti, F.; Mincione, G.; Scozzafava, A.; Supuran, C. T. J. Enzyme Inhibition 1998, 13, 267-284 and Scozzafava, A.; Supuran, C. T. J. Med. Chem. 2000, 43, 3677-3687) but have not been proposed for use in the treatment or prevention of diseases or conditions that are responsive to nitroxyl therapy, such as use in the treatment of heart failure, including acute congestive heart failure, or ischemia/reperfusion injury. Compounds that donate nitroxyl but do not donate significant levels of nitroxyl may be used in the methods, but will generally require a higher dosing to produce the same physiological effect as compared to compounds that donate significant levels of nitroxyl.
TABLE 5
Additional Compounds for use in the Methods.
For any of the compounds of the invention, such as the compounds of formula (I), (II), (III) or (IV) or other compounds for use in the methods described herein, the invention intends and includes all salts, solvates, hydrates, polymorphs, or prodrugs thereof, where applicable. As such, all salts, such as pharmaceutically acceptable salts, solvates, hydrates, polymorphs and prodrugs of a compound are expressly included herein the same as if each and every salt, solvate, hydrate, polymorph, or prodrug were specifically and individually listed.
For all compounds disclosed herein, where applicable due to the presence of a stereocenter, the compound is intended to embrace all possible stereoisomers of the compound depicted or described. Compositions comprising a compound with at least one stereocenter are also embraced by the invention, and includes racemic mixtures or mixtures containing an enantiomeric excess of one enantiomer or single diastereomers or diastereomeric mixtures. All such isomeric forms of these compounds are expressly included herein the same as if each and every isomeric form were specifically and individually listed. The compounds herein may also contain linkages (e.g., carbon-carbon bonds) wherein bond rotation is restricted about that particular linkage, e.g. restriction resulting from the presence of a ring or double bond. Accordingly, all cis/trans and E/Z isomers are also expressly included in the present invention. The compounds herein may also be represented in multiple tautomeric forms, in such instances, the invention expressly includes all tautomeric forms of the compounds described herein, even though only a single tautomeric form may be represented. Also embraced are compositions of substantially pure compound. A composition of substantially pure compound means that the composition contains no more than 25%, or no more than 15%, or no more than 10%, or no more than 5%, or no more than 3% impurity, or no more than 1% impurity, such as a different biologically active compound, which may include a different stereochemical form of the compound if the composition contains a substantially pure single isomer.
The compounds of the invention can be made according to the general methods described in Schemes A-C or by procedures known in the art. Starting materials for the reactions are either commercially available or may be prepare by known procedures or obvious modifications thereof. For example, many of the starting materials are available from commercial suppliers such as Sigma-Aldrich. Others may be prepared by procedures or obvious modifications thereof described in standard reference texts such as March's Advanced Organic Chemistry, (John Wiley and Sons) and Larock's Comprehensive Organic Transformations (VCH Publishers Inc.).
In Scheme A, a solution of hydroxylamine hydrochloride in water is chilled to 0° C. A solution of potassium carbonate in water is added dropwise, maintaining an internal reaction temperature between about 5° C. and about 15° C. The reaction mixture is stirred for about 15 minutes, whereupon tetrahydrofuran (THF) and methanol (MeOH) are added. Compound A1 (where R is an alkyl, aryl or heterocyclyl group) is added portionwise maintaining a temperature below about 15° C. and the reaction mixture is stirred at ambient temperature until complete consumption of the sulfonyl chloride is observed by thin layer chromatography (TLC). The resulting suspension is concentrated to remove any volatiles and the aqueous suspension is extracted with diethyl ether. The organic portion is dried over magnesium sulfate, filtered and concentrated in vacuo to yield the crude N-hydroxy sulphonamide A2. Purification may be achieved by conventional methods, such as chromatography, filtration, crystallization and the like.
N-Benzyloxysulfonamides are chemical intermediates that are used as protected N-hydroxysulfonamides for the further modification of the R moiety of compound B2. In Scheme B, a suspension of O-benzylhydroxylamine hydrochloride B1 in methanol and water is added to a chilled solution of potassium carbonate in water, maintaining an internal reaction temperature below about 10° C. The reaction mixture is stirred for about 5 minutes, whereupon THF and A1 (where R is an alkyl, aryl or heterocyclyl group) are added. The reaction mixture is stirred at ambient temperature until complete consumption of the sulfonyl chloride was observed by TLC. The resulting suspension is concentrated in vacuo to remove any volatiles, and the aqueous suspension was extracted with diethyl ether. The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo to yield the crude target compound B2. Purification may be achieved by conventional methods, such as chromatography, filtration, crystallization and the like. The reaction product B2 may be deprotected by removing the benzyl group. For instance, a suspension of 10% palladium on charcoal may be added to a suspension of B2 in methanol. The reaction mixture is stirred under a hydrogen atmosphere at ambient temperature and atmospheric pressure overnight. The reaction mixture is filtered through microfibre glass paper. The resulting filtrate is concentrated in vacuo, and the residue purified by conventional methods to yield the corresponding N-hydroxylsulfonamide.
N-(tetrahydro-pyran-2-yloxy)sulfonamides are chemical intermediates that are used as protected N-hydroxysulfonamides for the further modification of the R moiety of compound C2. In Scheme C, to a solution of Cl in water at 0° C. is added a solution of potassium carbonate in water dropwise, maintaining an internal reaction temperature below about 10° C. After about 15 minutes, methanol and THF are added dropwise, followed by A1 portionwise. The reaction mixture is stirred at ambient temperature until complete consumption of the sulfonyl chloride is observed by TLC. The resulting suspension was concentrated to remove any volatiles and the aqueous suspension was extracted with diethyl ether. The organic portion is dried over sodium sulfate, filtered and concentrated in vacuo to yield the crude target compound C2. Purification may be achieved by conventional methods, such as chromatography, filtration, crystallization and the like. Deprotection of C2 to yield the corresponding N-hydroxylsulfonamide may be carried out according to methods known in the art.
Particular examples of compounds made according to the general synthetic procedures of Schemes A-C are found in Examples 1-3.
Methods of Using the Compounds and Compositions
The compounds and compositions herein may be used to treat and/or prevent the onset and/or development of a disease or condition that is responsive to nitroxyl therapy.
The invention embraces methods of administering to an individual (including an individual identified as in need of such treatment) an effective amount of a compound to produce a desired effect. Identifying a subject in need of such treatment can be in the judgment of a physician, clinical staff, emergency response personnel or other health care professional and can be subjective (e.g. opinion) or objective (e.g. measurable by a test or diagnostic method).
One embodiment provides a method of modulating (including increasing) in vivo nitroxyl levels in an individual in need thereof, the method comprising administering to the individual a compound that donates nitroxyl under physiological conditions or a pharmaceutically acceptable salt thereof. An individual is in need of nitroxyl modulation if they have or are suspected of having or are at risk of having or developing a disease or condition that is responsive to nitroxyl therapy.
Particular diseases or conditions embraced by the methods of the invention include cardiovascular diseases such as heart failure or conditions and diseases or conditions that implicate or may implicate ischemia/reperfusion injury. These methods are described in more detail below.
Compositions comprising a nitroxyl-donating compound of the invention are embraced by the invention. However, the methods described may use more than one nitroxyl donating compound; for example, the methods may employ Angeli's salt and an N-hydroxysulfonamide of the present invention or two or more N-hydroxysulfonamides of the present invention, which may be administered together or sequentially.
Cardiovascular Diseases
Provided herein are methods of treating cardiovascular diseases such as heart failure by administering an effective amount of at least one nitroxyl donating compound to an individual in need thereof. Also provided are methods of administering a therapeutically effective dose of at least one nitroxyl donating compound in combination with at least one other positive inotropic agent to an individual in need thereof. Further provided are methods of administering a therapeutically effective amount of at least one nitroxyl donating compound to an individual who is receiving beta-antagonist therapy and who is experiencing heart failure. Methods are provided herein for administering compounds of the invention in combination with beta-adrenergic agonists to treat heart failure. Such agonists include dopamine, dobutamine, and isoproterenol, and analogs and derivatives of such compounds. Also provided are methods of administering nitroxyl donors to individuals receiving treatment with beta-antagonizing agents such as propranolol, metoprolol, bisoprolol, bucindolol, and carvedilol. Further, methods are provided herein for treating specific classifications of heart failure, such as Class III heart failure and acute heart failure.
Also embraced by the invention is a method of treating congestive heart failure (CHF), including acute congestive heart failure, by administering an effective amount at least one nitroxyl donating compound to an individual in need thereof, which individual may be experiencing heart failure. Also disclosed is a method of treating CHF by administering an effective amount of at least one nitroxyl donating compound in combination with an effective amount of at least one other positive inotropic agent to an individual in need thereof, which individual may be experiencing heart failure. In one variation, the other positive inotrope is a beta-adrenergic agonist, such as dobutamine. The combined administration of a nitroxyl donor and at least one other positive inotropic agent comprises administering the nitroxyl donor either sequentially with the other positive inotropic agent for example, the treatment with one agent first and then the second agent, or administering both agents at substantially the same time, wherein there is an overlap in performing the administration. With sequential administration, an individual is exposed to the agents at different times, so long as some amount of the first agent, which is sufficient to be therapeutically effective in combination with the second agent, remains in the subject when the other agent is administered. Treatment with both agents at the same time can involve administration of the agents in the same dose, such as a physically mixed dose, or in separate doses administered at the same time.
In particular an embodiment, a nitroxyl donor is administered to an individual experiencing heart failure that is receiving beta-antagonist therapy. A beta-antagonist (also known as a beta-blocker) includes any compound that effectively acts as an antagonist at a subject's beta-adrenergic receptors, and provides desired therapeutic or pharmaceutical results, such as diminished vascular tone and/or heart rate. A subject who is receiving beta-antagonist therapy is any subject to whom a beta-antagonist has been administered, and in whom the beta-antagonist continues to act as an antagonist at the subject's beta-adrenergic receptors. In particular embodiments a determination of whether a subject is receiving beta-blocking therapy is made by examination of the subject's medical history. In other embodiments the subject is screened for the presence of beta-blocking agents by chemical tests, such as high-speed liquid chromatography as described in Thevis et al., Biomed. Chromatogr., 15:393-402 (2001).
The administration of a nitroxyl donating compound either alone, in combination with a positive inotropic agent, or to a subject receiving beta-antagonist therapy, is used to treat heart failure of all classifications. In particular embodiments a nitroxyl donating compound is used to treat early-stage chronic heart failure, such as Class II heart failure. In other embodiments a nitroxyl donating compound is used in combination with a positive inotropic agent, such as isoproterenol to treat Class IV heart failure. In still other embodiments a nitroxyl donating compound is used in combination with another positive inotropic agent, such as isoproterenol to treat acute heart failure. In some embodiments, when a nitroxyl donor is used to treat early stage heart failure, the dose administered is lower than that used to treat acute heart failure. In other embodiments the dose is the same as is used to treat acute heart failure.
Ischemia/Reperfusion Injury
The invention embraces methods of treating or preventing or protecting against ischemia/reperfusion injury. In particular, compounds of the invention are beneficial for individuals at risk for an ischemic event. Thus, provided herein is a method of preventing or reducing the injury associated with ischemia/reperfusion by administering an effective amount of at least one nitroxyl donating compound to an individual, preferably prior to the onset of ischemia. A compound of the invention may be administered to an individual after ischemia but before reperfusion. A compound of the invention may also be administered after ischemia/reperfusion, but where the administration protects against further injury. Also provided is a method in which the individual is demonstrated to be at risk for an ischemic event. Also disclosed is a method of administering a nitroxyl donating compound to an organ that is to be transplanted in an amount effective to reduce ischemia/reperfusion injury to the tissues of the organ upon reperfusion in the recipient of the transplanted organ.
Nitroxyl donors of the invention may thus be used in methods of preventing or reducing injury associated with future ischemia/reperfusion. For example, administration of a nitroxyl donor prior to the onset of ischemia may reduce tissue necrosis (the size of infarct) in at-risk tissues. In live subjects this may be accomplished by administering an effective amount of a nitroxyl donating compound to an individual prior to the onset of ischemia. In organs to be transplanted this is accomplished by contacting the organ with a nitroxyl donor prior to reperfusion of the organ in the transplant recipient. Compositions comprising more than one nitroxyl-donating compound also could be used in the methods described, for example, Angeli's salt and an N-hydroxysulfonamide of the present invention or two or more N-hydroxysulfonamides of the present invention. The nitroxyl-donating compound also can be used in combination with other classes of therapeutic agents that are designed to minimize ischemic injury, such as beta blockers, calcium channel blockers, anti-platelet therapy or other interventions for protecting the myocardium in individuals with coronary artery disease.
One method of administering a nitroxyl donor to live subjects includes administration of the nitroxyl-donating compound prior to the onset of ischemia. This refers only to the onset of each instance of ischemia and would not preclude performance of the method with subjects who have had prior ischemic events, i.e., the method also contemplates administration of nitroxyl-donating compounds to a subject who has had an ischemic event in the past.
Individuals can be selected who are at risk of a first or subsequent ischemic event. Examples include individuals with known hypercholesterolemia, EKG changes associated with risk of ischemia, sedentary lifestyle, angiographic evidence of partial coronary artery obstruction, echocardiographic evidence of myocardial damage, or any other evidence of a risk for a future or additional ischemic event (for example a myocardial ischemic event, such as a myocardial infarction (MI), or a neurovascular ischemia such as a cerebrovascular accident CVA). In particular examples of the methods, individuals are selected for treatment who are at risk of future ischemia, but who have no present evidence of ischemia (such as electrocardiographic changes associated with ischemia (for example, peaked or inverted T-waves or ST segment elevations or depression in an appropriate clinical context), elevated CKMB, or clinical evidence of ischemia such as crushing sub-sternal chest pain or arm pain, shortness of breath and/or diaphoresis). The nitroxyl-donating compound also could be administered prior to procedures in which myocardial ischemia may occur, for example an angioplasty or surgery (such as a coronary artery bypass graft surgery). Also embraced is a method of administering a nitroxyl-donating compound to an individual at demonstrated risk for an ischemic event. The selection of an individual with such a status could be performed by a variety of methods, some of which are noted above. For example, an individual with one of more of an abnormal EKG not associated with active ischemia, prior history of myocardial infarction, elevated serum cholesterol, etc., would be at risk for an ischemic event. Thus, an at-risk individual could be selected by physical testing or eliciting the potential subject's medical history to determine whether the subject has any indications of risk for an ischemic event. If risk is demonstrated based on the indications discussed above, or any other indications that one skilled in the art would appreciate, then the individual would be considered at demonstrated risk for an ischemic event.
Ischemia/reperfusion may damage tissues other than those of the myocardium and the invention embraces methods of treating or preventing such damage. In one variation, the method finds use in reducing injury from ischemia/reperfusion in the tissue of the brain, liver, gut, kidney, bowel, or in any other tissue. The methods preferably involve administration of a nitroxyl donor to an individual at risk for such injury. Selecting a person at risk for non-myocardial ischemia could include a determination of the indicators used to assess risk for myocardial ischemia. However, other factors may indicate a risk for ischemia/reperfusion in other tissues. For example, surgery patients often experience surgery related ischemia. Thus, individuals scheduled for surgery could be considered at risk for an ischemic event. The following risk factors for stroke (or a subset of these risk factors) would demonstrate a subject's risk for ischemia of brain tissue: hypertension, cigarette smoking, carotid artery stenosis, physical inactivity, diabetes mellitus, hyperlipidemia, transient ischemic attack, atrial fibrillation, coronary artery disease, congestive heart failure, past myocardial infarction, left ventricular dysfunction with mural thrombus, and mitral stenosis. Ingall, “Preventing ischemic stroke: current approaches to primary and secondary prevention,” Postgrad. Med., 107(6):34-50 (2000). Further, complications of untreated infectious diarrhea in the elderly can include myocardial, renal, cerebrovascular and intestinal ischemia. Slotwiner-Nie & Brandt, “Infectious diarrhea in the elderly,” Gastroenterol, Clin. N. Am., 30(3):625-635 (2001). Alternatively, individuals could be selected based on risk factors for ischemic bowel, kidney or liver disease. For example, treatment would be initiated in elderly subjects at risk of hypotensive episodes (such as surgical blood loss). Thus, subjects presenting with such an indication would be considered at risk for an ischemic event. Also embraced is a method of administering a nitroxyl donating compound of the invention to an individual who has any one or more of the conditions listed herein, such as diabetes mellitus or hypertension. Other conditions that may result in ischemia such as cerebral arteriovenous malformation would be considered to demonstrate risk for an ischemic event.
The method of administering nitroxyl to organs to be transplanted includes administration of nitroxyl prior to removal of the organ from the donor, for example through the perfusion cannulas used in the organ removal process. If the organ donor is a live donor, for example a kidney donor, the nitroxyl donor can be administered to the organ donor as described above for a subject at risk for an ischemic event. In other cases the nitroxyl donor can be administered by storing the organ in a solution comprising the nitroxyl donor. For example, the nitroxyl donor can be included in the organ preservation solution, such as University of Wisconsin “UW” solution, which is a solution comprising hydroxyethyl starch substantially free of ethylene glycol, ethylene chlorohydrin and acetone (see U.S. Pat. No. 4,798,824).
Pharmaceutical Composition, Dosage Forms and Treatment Regimens
Also included are pharmaceutically acceptable compositions comprising a compound of the invention or pharmaceutically acceptable salt thereof and any of the methods may employ the compounds of the invention as a pharmaceutically acceptable composition. A pharmaceutically acceptable composition includes one or more of the compounds of the invention together with a pharmaceutically acceptable carrier. The pharmaceutical compositions of the invention include those suitable for oral, rectal, nasal, topical (including buccal and sublingual), vaginal or parenteral (including subcutaneous, intramuscular, intravenous and intradermal) administration.
The compounds or compositions may be prepared as any available dosage form. Unit dosage forms are also intended, which includes discrete units of the compound or composition such as capsules, sachets or tablets each containing a predetermined amount of the compound; as a powder or granules; as a solution or a suspension in an aqueous liquid or a non-aqueous liquid; or as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion, or packed in liposomes and as a bolus, etc.
A tablet containing the compound or composition may be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as a powder or granules, optionally mixed with a binder, lubricant, inert diluerit, preservative, surface-active or dispersing agent. Molded tablets may be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent. The tablets optionally may be coated or scored and may be formulated so as to provide slow or controlled release of the active ingredient therein. Methods of formulating such slow or controlled release compositions of pharmaceutically active ingredients, such as those herein and other compounds known in the art, are known in the art and described in several issued US patents, some of which include, but are not limited to, U.S. Pat. Nos. 4,369,174 and 4,842,866, and references cited therein. Coatings can be used for delivery of compounds to the intestine (see, e.g., U.S. Pat. Nos. 6,638,534, 5,217,720 and 6,569,457, and references cited therein). A skilled artisan will recognize that in addition to tablets, other dosage forms can be formulated to provide slow or controlled release of the active ingredient. Such dosage forms include, but are not limited to, capsules, granulations and gel-caps.
Compositions suitable for topical administration include lozenges comprising the ingredients in a flavored basis, usually sucrose and acacia or tragacanth; and pastilles comprising the active ingredient in an inert basis such as gelatin and glycerin, or sucrose and acacia.
Compositions suitable for parenteral administration include aqueous and non-aqueous sterile injection solutions which may contain anti-oxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents. The formulations may be presented in unit-dose or multi-dose containers, for example, sealed ampules and vials, and may be stored in a freeze dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example water for injections, immediately prior to use.
Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets.
Administration of the compounds or compositions to an individual may involve systemic exposure or may be local administration, such as when a compound or composition is to be administered at the site of interest. Various techniques can be used for providing the subject compositions at the site of interest, such as via injection, use of catheters, trocars, projectiles, pluronic gel, stems, sustained drug release polymers or other device which provides for internal access. Where an organ or tissue is accessible because of removal from the patient, such organ or tissue may be bathed in a medium containing the subject compositions, the subject compositions may be painted onto the organ, or may be applied in any convenient way. The methods of the invention embrace administration of the compounds to an organ to be donated (such as to prevent ischemia/reperfusion injury). Accordingly, organs that are removed from one individual for transplant into another individual may be bathed in a medium containing or otherwise exposed to a compound or composition as described herein.
The compounds of the invention, such as those of the formulae herein, may be administered in any suitable dosage amount, which may include dosage levels of about 0.0001 to 4.0 grams once per day (or multiple doses per day in divided doses) for adults. Thus, in certain embodiments of this invention, a compound herein is administered at a dosage of any dosage range in which the low end of the range is any amount between 0.1 mg/day and 400 mg/day and the upper end of the range is any amount between 1 mg/day and 4000 mg/day (e.g., 5 mg/day and 100 mg/day, 150 mg/day and 500 mg/day). In other embodiments, a compound herein, is administered at a dosage of any dosage range in which the low end of the range is any amount between 0.1 mg/kg/day and 90 mg/kg/day and the upper end of the range is any amount between 1 mg/kg/day and −32 1 00 mg/kg/day (e.g., 0.5 mg/kg/day and 2 mg/kg/day, 5 mg/kg/day and 20 mg/kg/day). The dosing interval can be adjusted according to the needs of the individual. For longer intervals of administration, extended release or depot formulations can be used. The dosing can be commensurate with intravenous administration. For instance, the compound can be administered, such as in a pharmaceutical composition that is amenable to intravenous administration, in an amount of between about 0.01 μg/kg/min to about 100 μg/kg/min or between about 0.05 μg/kg/min to about 95 μg/kg/min or between about 0.1 μg/kg/min to about 90 μg/kg/min or between about 1.0 μg/kg/min to about 80 μg/kg/min or between about 10.0 μg/kg/min to about 70 μg/kg/min or between about 20 μg/kg/min to about 60 μg/kg/min or between about 30 μg/kg/min to about 50 μg/kg/min or between about 0.01 μg/kg/min to about 1.0 μg/kg/min or between about 0.01 μg/kg/min to about 10 μg/kg/min or between about 0.1 μg/kg/min to about 1.0 μg/kg/min or between about 0.1 μg/kg/min to about 10 μg/kg/min or between about 1.0 μg/kg/min to about 5 μg/kg/min or between about 70 μg/kg/min to about 100 μg/kg/min or between about 80 μg/kg/min to about 90 μg/kg/min. In one variation, the compound is administered to an individual, such as in a pharmaceutical composition that is amenable to intravenous administration, in an amount of at least about 0.01 μg/kg/min or at least about 0.05 μg/kg/min or at least about 0.1 μg/kg/min or at least about 0.15 μs/kg/min or at least about 0.25 μg/kg/min or at least about 0.5 μg/kg/min or at least about 1.0 μg/kg/mm n or at least about 1.5 μg/kg/min or at least about 5.0 μg/kg/min or at least about 10.0 μg/kg/min or at least about 20.0 μg/kg/min or at least about 30.0 μg/kg/min or at least about 40.0 μg/kg/min or at least about 50.0 μg/kg/min or at least about 60.0 μg/kg/min or at least about 70.0 μg/kg/min or at least about 80.0 μg/kg/min or at least about 90.0 μg/kg/min or at least about 100.0 μg/kg/min or more. In another variation, the compound is administered to an individual, such as in a pharmaceutical composition that is amenable to intravenous administration, in an amount of less than about 100.0 μg/kg/min or less than about 90.0 μg/kg/min or less than about 80.0 μg/kg/min or less than about 80.0 μg/kg/min or less than about 70.0 μg/kg/mm n or less than about 60.0 μg/kg/min or less than about 50.0 μg/kg/min or less than about 40.0 μg/kg/min or less than about 30.0 μg/kg/min or less than about 20.0 μg/kg/min or less than about 10.0 μg/kg/min or less than about 5.0 μg/kg/mm n or less than about 2.5 μg/kg/min or less than about 1.0 μs/kg/min or less than about 0.5 μg/kg/min or less than about 0.05 μg/kg/min or less than about 0.15 μg/kg/min or less than about 0.1 μg/kg/min or less than about 0.05 μg/kg/min or less than about 0.01 μg/kg/min.
The invention further provides kits comprising one or more compounds as described herein. The kits may employ any of the compounds disclosed herein and instructions for use. The compound may be formulated in any acceptable form. The kits may be used for any one or more of the uses described herein, and, accordingly, may contain instructions for any one or more of the stated uses (e.g., treating and/or preventing and/or delaying the onset and/or the development of heart failure or ischemia/reperfusion injury).
Kits generally comprise suitable packaging. The kits may comprise one or more containers comprising any compound described herein. Each component (if there is more than one component) can be packaged in separate containers or some components can be combined in one container where cross-reactivity and shelf life permit.
The kits may optionally include a set of instructions, generally written instructions, although electronic storage media (e.g., magnetic diskette or optical disk) containing instructions are also acceptable, relating to the use of component(s) of the methods of the present invention (e.g., treating, preventing and/or delaying the onset and/or the development of heart disease or ischemia/reperfusion injury). The instructions included with the kit generally include information as to the components and their administration to an individual.
The following examples are provided to illustrate various embodiments of the invention, and are not intended to limit the invention in any manner.
EXAMPLES
In the following examples, All HPLC analysis was carried out using a CTC PAL HTS autosampler with a waters 2487 uv detector powered by an Agilent G1312A binary pump. The following method and column were used for determination of retention time (TR) 0-100% B [MeCN: H 2 O: 0.2% HCO 2 H], 2.5 min gradient, 0.5 min hold, 215 nm, Atlantis dC18 2.1×50 mm, 5 μm.
All NMR were recorded on a Bruker AVANCE 400 MHz spectrometer operating at ambient probe temperature using an internal deuterium lock. Chemical shifts are reported in parts per million (ppm) at lower frequency relative to tetramethylsilane (TMS). Standard abbreviations are used throughout (s singlet; br. s broad singlet; d doublet; dd doublet of doublets; t triplet; q quartet; quin quintet; m multiplet). Coupling constants are reported in Hertz (Hz).
All microwave reactions were carried out using a CEM explorer system following standard methods.
Example 1. Preparation of Compounds According to General Synthesis of Scheme A
The preparation of 2-bromo-N-hydroxy-benezene-sulfonamide is detailed below as a representative example of the synthetic method exemplified in Scheme A.
To a solution of hydroxylamine hydrochloride (0.82 g, 0.012 mol) in water (1.2 ml) at 0° C. was added a solution of potassium carbonate (1.6 g, 0.012 mol) in water (1.8 ml) dropwise maintaining an internal reaction temperature between 5° C. and 15° C. The reaction mixture was stirred for 15 minutes, whereupon THF (6 ml) and MeOH (1.5 ml) were added. 2-Bromobenzene sulfonyl Chloride (1.51 g, 0.006 mol) was added portionwise maintaining a temperature below 15° C. and the reaction mixture was stirred at ambient temperature until complete consumption of the sulfonyl chloride was observed by TLC. The resulting suspension was concentrated to remove any volatiles and the aqueous suspension was extracted with diethyl ether (2×100 ml). The organic portion was dried over magnesium sulfate, filtered and concentrated in vacuo to yield the crude N-hydroxy sulfonamide. Purification was achieved by chromatography on silica gel eluting with hexane:ether (1:1 v:v) to give the parent compound as a white solid (0.30 g, 20% yield) δH (400 MHz, DMSO) 9.81-9.84 (1H, m), 9.78-9.81 (1H, m), 7.99 (1H, dd, 7.7, 1.8 Hz), 7.86 (1H, dd, 7.6, 1.5 Hz), 7.55-7.64 (2H, m); TR=1.44 min.
Using the experimental conditions reported above and the appropriate starting materials, which were either commercially available or synthesised using standard methodology, the following compounds were prepared:
Systematic name
1-H NMR
T R
2,6-Dichloro-N-hydroxy
δ H (400 MHz, DMSO) 9.92 (1H, d, 3.0 Hz),
1.52
benzene sulfonamide
9.77 (1H, d, 2.9 Hz), 7.59-7.69 (3H, m)
4-Bromo-N-hydroxy
δ H (400 MHz, DMSO) 9.70-9.72 (1H, m),
1.56
benzene sulfonamide
9.67-9.69 (1H, m), 7.83-7.88 (2H, m),
7.73-7.78 (2H, m)
3-Bromo-N-hydroxy
δ H (400 MHz, DMSO) 9.75 (1H, d, 8.1 Hz),
1.57
benzene sulfonamide
9.77 (1H, s), 7.92 (1H, d, 8.1 Hz), 7.95
(1H, t, 1.7 Hz), 7.84 (1H, d, 7.8 Hz),
7.60 (1H, t, 7.9 Hz)
2-Bromo-4-fluoro-N-
δ H (400 MHz, DMSO) 9.86 (1H, d, 2.7 Hz),
1.52
hydroxy benzene
9.81 (1H, d, 2.9 Hz), 8.04 (1H, dd, 8.9,
sulfonamide
6.0 Hz), 7.88 (1H, dd, 8.6, 2.4 Hz), 7.52
(1H, td, 8.6, 2.4 Hz)
2,5-Di-trifluoromethyl-N-
δ H (400 MHz, DMSO) 10.49 (1H, br. s.),
1.88
hydroxy benzene
10.18 (1H, s), 8.42 (1H, s), 8.25-8.33 (2H, m)
sulfonamide
Thiophene-2-N-
δH (400 MHz, DMSO) 9.77 (1H, s), 9.67 (1H,
0.99
hydroxysulfonamide
s), 8.02 (1H, dd, 4.9, 1.2 Hz), 7.65 (1H, d,
3.7 Hz), 7.23 (1H, dd, 4.6, 3.9 Hz)
4-Bromo-thiophene-3-N-
δ H (400 MHz, DMSO) 9.84 (1H, d, 3.2 Hz),
1.32
hydroxysulfonamide
9.80-9.82 (1H, m), 8.06 (1H, d, 5.1 Hz), 7.30
(1H, d, 5.1 Hz)
2-Chloro-4-fluoro-N-
δ H (400 MHz, DMSO) 9.84 (1H, d, 2.9 Hz),
1.46
hydroxy benzene
9.80 (1H, d, 2.9 Hz), 8.04 (1H, dd, 8.9,
sulfonamide
6.0 Hz), 7.73 (1H, dd, 8.8, 2.7 Hz), 7.47 (1H,
td, 8.5, 2.6 Hz)
2,3-Dichloro-N-hydroxy
δ H (400 MHz, DMSO) 10.01 (1H, d, 2.7 Hz),
1.63
benzene sulfonamide
9.87 (1H, d, 2.7 Hz), 7.98 (1H, d, 7.8 Hz),
7.97 (1H, s), 7.60 (1H, t, 8.1 Hz)
2-Chloro-4-bromo-N-
δ H (400 MHz, DMSO) 9.90 (1H, s), 9.83 (1H,
1.70
hydroxy benzene
s), 8.01 (1H, d, 2.0 Hz), 7.86-7.91 (1H, m),
sulfonamide
7.79-7.84 (1H, m)
Thiophene-3-N-hydroxy
δ H (400 MHz, DMSO) 9.60 (1H, d, 3.2 Hz),
0.90
sulfonamide
9.53 (1H, d, 3.2 Hz), 8.24 (1H, dd, 2.8,
1.1 Hz), 7.75 (1H, dd, 5.0, 3.1 Hz), 7.36 (1H,
dd, 5.1, 1.2 Hz)
2-Nitro-4-trifluoromethyl-N-
δ H (400 MHz, DMSO) 10.46 (1H, d, 1.7 Hz),
1.80
hydroxy benzene
10.17 (1H, d, 2.3 Hz), 8.60 (1H, s), 8.36 (1H,
sulfonamide
s), 8.26 (1H, d, 8.2 Hz)
3,4,5-trifluoro-N-hydroxy
δ H (400 MHz, DMSO) 9.89 (1H, d, 3.0 Hz),
1.58
benzene sulfonamide
9.88 (1H, d, 3.0 Hz), 7.76 (2H, t, 6.7 Hz)
2-Iodo-N-hydroxy benzene
δ H (400 MHz, DMSO) 9.78 (1H, d, 2.8 Hz),
1.50
sulfonamide
9.72 (1H, d, 2.9 Hz), 8.15 (1H, dd, 7.8,
0.9 Hz), 7.96 (1H, dd, 8.0, 1.5 Hz), 7.61 (1H,
dd, 15.4, 0.9 Hz), 7.33 (1H, td, 7.6, 1.5 Hz)
4-Phenyl-5-trifluoromethyl-
δ H (400 MHz, DMSO) 9.70 (1H, s), 9.58 (1H,
2.00
thiophene-3-N-
br. s.), 8.60 (1H, s), 7.37-7.44 (3H, m),
hydroxysulfonamide
7.31-7.33 (2H, m)
1,3 Di-N-hydroxy benzene
δ H (400 MHz, DMSO) 9.88 (2H, br. s.), 9.81
1.03
sulfonamide
(2H, s), 8.28 (1H, t, 1.7 Hz), 8.14 (2H, dd,
7.8, 1.8 Hz), 7.90 (1H, t, 7.9 Hz)
2,5-Di-fluoro-N-hydroxy
δ H (400 MHz, DMSO) 9.91 (2H, s), 7.77 (1H,
1.18
benzene sulfonamide
tt, 8.5, 6.1 Hz), 7.31 (2H, t, 8.9 Hz)
N-Hydroxy-2-
δ H (400 MHz, DMSO) 10.12 (1H, d, 3.5 Hz),
1.31
methanesulfonyl-benzene
8.96 (1H, d, 3.5 Hz), 8.25-8.27 (1H, m),
sulfonamide
8.16-8.21 (1H, m), 7.99-8.04 (2H, m), 3.47 (3H, s)
2,4-Di-bromo-N-hydroxy
δ H (400 MHz, DMSO) 9.93 (1H, d, 2.9 Hz),
1.76
benzene sulfonamide
9.84 (1H, d, 2.9 Hz), 8.16 (1H, d, 1.5 Hz),
7.88 (1H, s), 7.87 (1H, d, 1.7 Hz)
2-Chloro-4-trifluoromethyl-
δ H (400 MHz, DMSO) 10.13 (1H, d, 2.9 Hz),
1.81
N-hydroxy benzene
9.94 (1H, d, 2.7 Hz), 8.15 (1H, d, 1.0 Hz),
sulfonamide
8.19 (1H, d, 8.3 Hz), 7.99 (1H, dd, 8.4,
1.1 Hz)
2,4,6-Tri-isopropyl-N-
δ H (400 MHz, DMSO) 9.34 (1H, d, 3.0 Hz),
2.30
hydroxy benzene
9.28 (1H, d, 2.9 Hz), 7.24 (2H, s), 4.05-4.19
sulfonamide
(2H, sept, 6.8 Hz), 2.87-2.97 (1H, sept,
6.9 Hz), 1.20 (18H, t, 6.9 Hz)
3,5-Dimethyl-isoxazole-4-
δ H (400 MHz, DMSO) 9.80 (1H, d, 3.2 Hz),
1.16
N-hydroxy sulfonamide
9.64 (1H, d, 3.2 Hz), 2.60 (3H, s), 2.34 (3H,
s)
2,4-Di-fluoro-N-hydroxy
δ H (400 MHz, DMSO) 9.81 (1H, d, 2.9 Hz),
1.28
benzene sulfonamide
9.77 (1H, d, 2.9 Hz), 7.88 (1H, td, 8.6,
6.4 Hz), 7.56 (1H, ddd, 10.3, 9.4, 2.6 Hz),
7.33 (1H, td, 7.7, 1.7 Hz)
4-Bromo-2,5-dichloro-
δ H (400 MHz, DMSO) 9.92 (1H, d, 2.4 Hz),
1.79
thiophene-3-N-hydroxy
9.86 (1H, d, 2.7 Hz)
sulfonamide
Quinoline-8-N-hydroxy
δ H (400 MHz, DMSO) 9.83 (1H, d, 3.7 Hz),
1.34
sulfonamide
9.21 (1H, d, 3.7 Hz), 9.09 (1H, dd, 4.4,
1.7 Hz), 8.60 (1H, dd, 8.3, 1.7 Hz), 8.39 (1H,
s), 8.39 (1H, dd, 16.4, 1.2 Hz), 7.83 (1H, d,
7.8 Hz), 7.76 (1H, dd, 8.4, 4.3 Hz)
5-Methyl-
δ H (400 MHz, DMSO) 9.90 (1H, d, 3.2 Hz),
1.81
benzo[b]thiophene-2-N-
9.86 (1H, d, 3.1 Hz), 7.97-8.01 (2H, m), 7.87
hydroxy sulfonamide
(1H, s), 7.39 (1H, dd, 8.6, 1.5 Hz), 2.44 (3H,
s)
Benzofuran-2-N-hydroxy
δ H (400 MHz, DMSO) 10.25 (1H, d, 2.8 Hz),
1.58
sulfonamide
9.87 (1H, d, 2.8 Hz), 7.84 (1H, d, 7.8 Hz),
7.72 (1H, d, 0.8 Hz), 7.75 (1H, d, 8.5 Hz),
7.56 (1H, ddd, 8.4, 7.2, 1.3 Hz), 7.42 (1H,
dd, 15.1, 0.6 Hz)
1-Methyl-1H-pyrazole-3-N-
δ H (400 MHz, DMSO) 9.61 (1H, d, 3.2 Hz),
0.47
hydroxy sulfonamide
9.49 (1H, d, 1.0 Hz), 7.89 (1H, d, 2.2 Hz),
6.68 (1H, d, 2.2 Hz), 3.94 (3H, s)
4-Fluoro-naphthalene-1-N-
δ H (400 MHz, DMSO) 9.87 (1H, d, 2.9 Hz),
1.72
hydroxy sulfonamide
9.64 (1H, d, 2.9 Hz), 8.75 (1H, d, 8.3 Hz),
8.19-8.25 (2H, m), 7.81 (2H, ddd, 12.0, 8.3,
1.2 Hz), 7.56 (1H, dd, 10.0, 8.3 Hz)
3-Bromo-thiophene-2-N-
δ H (400 MHz, DMSO) 9.83-9.86 (1H, m),
1.32
hydroxy sulfonamide
9.81-9.83 (1H, m), 8.05 (1H, d, 5.1 Hz), 7.30
(1H, d, 5.1 Hz)
Propane-2-N-hydroxy
δ H (400 MHz, DMSO) 9.44 (1H, d, 2.2 Hz),
sulfonamide
9.24 (1H, s), 3.39-3.50 (1H, sept, 6.9 Hz),
1.25 (6H, d, 6.9 Hz)
Methyl-N-hydroxy
δ H (400 MHz, DMSO) 9.56 (1H, d, 3.4 Hz),
sulfonamide
9.03 (1H, d, 3.4 Hz), 2.92 (3H, s)
Biphenyl-2-N-hydroxy
δ H (400 MHz, DMSO) 9.63 (1H, br. s.), 9.51
1.74
sulfonamide
(1H, s), 8.00 (1H, dd, 7.8, 1.2 Hz), 7.67 (1H,
dd, 7.5, 1.3 Hz), 7.62 (1H, dd, 7.7, 1.3 Hz),
7.34-7.41 (6H, m)
The following procedure, which may involve modifications to the representative reaction above, was used in the preparation of the following compounds (1-10):
2-Fluoro-N-hydroxybenzenesulfonamide (1). 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.78 (d, 1H), 9.73 (d, 1H), 7.81 (dt, 1H), 7.76 (m, 1H), 7.44 (m, 2H); mp 127-129° C.
2-Chloro-N-hydroxybenzenesulfonamide (2). 1 HNMR (400 MHz, DMSO-d 6 ) δ 9.80 (s, 1H), 9.78 (bs, 1H), 8.00 (d, 1H), 7.68 (d, 2H), 7.56 (m, 1H); mp 152-155° C. with decomposition
2-Bromo-N-hydroxybenzenesulfonamide (3). 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.82 (s, 1H), 9.78 (s, 1H), 8.00 (dd, 1H), 7.86 (dd, 1H), 7.60 (m, 2H); mp 156-159° C. with decomposition
2-(Trifluoromethyl)-N-hydroxybenzenesulfonamide (4). 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.12 (d, 1H), 9.91 (d, 1H), 8.12 (d, 1H), 8.01 (d, 1H), 7.93 (t, 1H), 7.87 (t, 1H); mp 124-127° C. with decomposition.
5-Chlorathiophene-2-sulfohydroxainic acid (5). 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.90 (bps, 1H), 9.72 (s, 1H), 7.54 (d, 1H), 7.30 (d, 1H); 13 C NMR (100 MHz, DMSO-d 6 ) δ 136.0, 135.5, 133.4, 127.9; mp 94-95° C. with decomposition.
2,5-Dichlorothiophene-3-sulfohydroxamic acid (6). 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.88 (s, 2H), 7.30 (s, 1H); 13 C NMR (100 MHz, DMSO-d 6 ) δ 133.3, 131.7, 127.1, 126.0; mp 118-122° C. with decomposition.
4-Fluoro-N-hydroxybenzenesulfonamide (7). NMR Previously reported.
4-(Trifluoromethyl)-N-hydroxybenzenesulfonamide (8). 1 H NMR (400 MHZ, DMSO-d 6 ) δ 9.85 (d, 1H), 9.80 (d, 1H), 8.05 (m, 4H); mp 117-121° C. with decomposition.
4-Cyano-N-hydroxybenzenesulfonamide (9). 1 H NMR (400 MHZ, DMSO-d 6 ) δ 9.88 (d, 1H), 9.81 (d, 1H), 8.12 (d, 2H), 8.00 (d, 2H); mp 151-155° C. with decomposition.
4-Nitro-N-hydroxybenzenesulfonamide (10). NMR Previously reported.
60 mmol (2 eq.) of hydroxylamine hydrochloride was dissolved in 12 mL of water and cooled to 0° C. in an ice bath. A solution of 60 mmol (2 eq.) of potassium carbonate in 18 mL of water was added dropwise with stirring. The solution was stirred for 15 min, at which time was sequentially added 25 mL of methanol and 75 mL of tetrahydrofuran. A solution of 30 mmol (1 eq.) of sulfonyl chloride in 10 mL of tetrahydrofuran was added dropwise, and the resultant solution was allowed to warm to room temperature with stirring for 2-3 hours. The volatiles were evaporated under reduced pressure and 100 mL water was added. The aqueous solution was acidified to approximately pH 3 with 1 N aqueous hydrochloric acid, and extracted with diethyl ether (2×100 mL). The organic layer was dried over magnesium sulfate and evaporated to yield in all cases crystalline solids with sufficient purity (25-50% yield).
Example 2. Preparation of Compounds According to General Synthesis of Scheme B
The preparation of N-benzyloxy-2-bromo-benzenesulfonamide
is detailed below as a representative example of the synthetic method exemplified in Scheme B.
To a suspension of O-benzylhydroxylamine hydrochloride (3.75 g, 23.48 mmol) in MeOH (3 ml) and water (3.6 ml) was added a solution of potassium carbonate (3.24 g, 23.48 mmol) in water (3.6 ml), maintaining an internal reaction temperature below 10° C. The reaction mixture was stirred for 5 minutes, whereupon THF (12 ml) and 2-bromobenzene sulfonyl chloride (3 g, 11.74 mmol) were added. The reaction mixture was stirred at ambient temperature until complete consumption of the sulfonyl chloride was observed by TLC. The resulting suspension was concentrated in vacuo to remove any volatiles, and the aqueous suspension was extracted with diethyl ether (3×100 ml). The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo to yield the crude target compound. Purification was achieved by trituration of the solid in heptane, followed by filtration and further washing of the solid with heptane, to give the expected compound as a white solid (3.62 g, 90% yield). 0.54400 MHz, DMSO) 10.83 (1H, s), 8.04 (1H, d, 1.7 Hz), 8.02 (1H, d, 1.9 Hz), 7.57-7.66 (2H, m), 7.30-7.36 (5H, m), 4.87 (1H, s); T R =2.15.
N-benzyloxy-2-bromo-benzenesulfonamide may be further derivatized as detailed in the synthesis of N-benzyloxy-2-phenyl-benzenesulfonamide
A microwave vial was charged successively with N-benzyloxy-2-bromo-benzenesulfonamide (0.2 g, 0.58 mmol), benzene boronic acid (0.11 g, 0.88 mmol), Pd(dppf)Cl 2 (0.05 g, 0.06 mmol), THF (3 ml), then a solution of potassium carbonate in water (2N, 1.5 ml). The mixture was heated in the microwave at 130° C. for 15 minutes (5 minutes ramp time, power=150 W). The reaction mixture was then diluted with ethyl acetate (20 ml), and the organic layer was washed with water (2×20 ml). The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo. The crude mixture was then purified by column chromatography on silica gel, eluting with heptane:ethyl acetate (9:1 v:v) to give the target compound as a colourless oil (0.12 g, 60% yield). δ H (400 MHz, DMSO) 10.61 (1H, s), 8.06 (1H, dd, 7.8, 1.2 Hz), 7.77 (1H, td, 7.3, 1.5 Hz), 7.69 (1H, td, 7.5, 1.4 Hz), 7.40-7.46 (9H, m), 7.33-7.35 (2H, m), 4.82 (2H, s). T R =1.74 min.
N-benzyloxy-2-phenyl-benzenesulfonamide may be deprotected to the corresponding N-hydroxysulfonamide as detailed below:
To a suspension of N-benzyloxy-2-phenyl-benzenesulfonamide (1.39 g, 4.1 mmol) in EtOH (20 ml) was added 10% palladium on charcoal (0.14 g). The reaction mixture was stirred under a hydrogen atmosphere at ambient temperature and atmospheric pressure overnight. The reaction mixture was filtered through microfibre glass paper. The resulting filtrate was concentrated in vacuo, and the residue purified by column chromatography on silica gel eluting with heptane:ethyl acetate (gradient from 9:1 to 8:2 v:v) to give the target compound as a white solid (0.24 g, 22% yield). δ H (400 MHz, DMSO) 9.68 (1H, s), 9.57 (1H, s), 8.06 (1H, dd, 7.8, 1.2 Hz), 7.74 (1H, td, 7.3, 1.5 Hz), 7.67 (1H, td, 7.6, 1.3 Hz), 7.40-7.46 (6H, m).
Example 3. Preparation of Compounds According to General Synthesis of Scheme C
The preparation of 4-Bromo-N-(tetrahydro-pyran-2-yloxy)-benzenesulfonamide
is detailed below as a representative example of the synthetic method exemplified in Scheme C.
To a solution of O-(tetrahydro-2H-pyran-2-yl)hydroxylamine (1.83 g, 15.65 mmol) in water (1.6 ml) at 0° C. was added a solution of potassium carbonate (1.1 g, 7.83 mmol) in water (2.4 ml) dropwise maintaining an internal reaction temperature below 10° C. After 15 minutes MeOH (2 ml) and THF (8 ml) were added was dropwise, followed by 4-bromobenzene sulfonyl chloride (2 g, 7.83 mmol) portionwise. The reaction mixture was stirred at ambient temperature until complete consumption of the sulfonyl chloride was observed by TLC. The resulting suspension was concentrated to remove any volatiles and the aqueous suspension was extracted with diethyl ether (3×100 ml). The organic portion was dried over sodium sulfate, filtered and concentrated in vacuo to yield the crude target compound. Purification was achieved by column chromatography on silica gel eluting with a heptane:ethyl acetate (gradient from 9:1 to 7:3 v:v) to give the target compound as a white solid (2.1 g, 80% yield). δ H (400 MHz, DMSO) 10.53 (1H, s), 7.86-7.90 (2H, m), 7.75-7.79 (2H, m), 4.94 (1H, t, 2.93 Hz), 3.70-3.76 (1H, m), 3.48-3.52 (1H, m). 1.59-1.68 (1H, m), 1.39-1.52 (5H, m); T R =2.03 min.
4-Bromo-N-(tetrahydro-pyran-2-yloxy)-benzenesulfonamide may be further modified to biphenyl-2-N-hydroxysulfonamide as detailed below:
To a solution of 4-bromo-N-(tetrahydro-pyran-2-yloxy)-benzenesulfonamide (0.1 g, 0.3 mmol) in MeOH (2 ml), was added MP-tosic acid resin (91 mg, loading 3.3 mmol/g). The mixture was stirred at ambient temperature until complete consumption of the starting material was observed by LC. The resin was then filtered off, and washed with MeOH (2×5 ml). The resulting filtrate was concentrated in vacuo to afford the target compound as colourless oil (0.08 g, 100% yield). δ H (400 MHz, DMSO) 9.70 (1H, d, 3.2 Hz), 9.67 (1H, d, 3.4 Hz), 7.84-7.88 (2H, m), 7.73-7.77 (2H, m); T R =1.60 min
Example 4. Kinetics of HNO Release
The decomposition rates of the compounds may be determined by UV-Vis spectroscopy.
The decomposition of compounds 1-4 and 6 from Example 1 was monitored by UV-Vis spectroscopy in 0.1 M PBS buffer at pH 7.4 and 37° C. The spectral behavior was isosbectic and the time course fit well to a single exponential. The decomposition rate is increased in aerated solutions compared to argon-saturated solutions because of the introduction of an oxygen-dependent decomposition pathway that, for the parent N-hydroxybenzenesulfonamide (PA) has been shown to release NO (Bonner, F. T.; Ko, Y. Inorg. Chem. 1992, 31, 2514-2519). Decomposition kinetics for compounds 5, 7-10 of Example 1 are not first-order and thus only approximate half-lives are reported. Compounds with more than one number in a single column in the table below indicates the results of two experiments for the same compound.
Compound
t 1/2 (Ar) (min)
t 1/2 (air) (min)
k O2 /k Ar
1
17.5; 18.0
2.67; 4.0
5.82
2
3.61; 4.0
1.75; 1.9
1.06
3
1.05; 2.1
0.68; 1.2
0.55
4
0.96; 1.2
0.55; 0.6
0.75
5
18.8
6.3
6
9.17
2.60
2.52
7
72.1; 72.2
10.0; 10.0
8
33.0; 33.0
7.0; 7.0
9
17.8
4.0
10
5.78; 19.2
3.3; 4.2
Example 5. HNO Production Via N 2 O Quantification
HNO production of the compounds may be determined by UV-Vis spectroscopy.
Nitrous oxide is produced via the dimerization and dehydration of HNO, and is the most common marker for HNO production (Fukuto, J. M.; Bartberger, M. D.; Dutton, A. S.; Paolocci, N.; Wink, D. A.; Houk, K. N. Chem. Res. Toxicol. 2005, 18, 790-801). HNO, however, can also be partially quenched by oxygen to yield a product that does not produce N 2 O (See, (a) Mincione, F.; Menabuoni, L.; Briganti, F.; Mincione, G.; Scozzafava, A.; Supuran, C. T. J. Enzyme Inhibition 1998, 13, 267-284 and (b) Scozzafava, A.; Supuran, C. T. J. Med. Chem. 2000, 43, 3677-3687.) Using Angeli's salt (AS) as a benchmark, the relative amounts of N 2 O released from compounds 2-4 from Example 1 was examined via GC headspace analysis. The results, shown in FIG. 1 , show that the amounts of N 2 O released from compounds 2-4 are comparable to the amount released from AS under both argon and air.
The ability of compounds to donate nitroxyl at pH 7.4 in PBS buffer at 37° C. was assessed. In particular, the compounds of Tables 1-3 and certain compounds from Table 4 are tested and their nitroxyl donating ability at pH 7.4 in PBS buffer at 37° C. is assessed. The compounds tested, with the exception of 2-phenyl-N-hydroxylbenzenesulfonamide, all produced detectable levels of N 2 O, indicating their ability to donate nitroxyl. 2-phenyl-N-hydroxylbenzenesulfonainide may be retested to confirm whether it is a nitroxyl donor.
Example 6. Use of an In Vitro Model to Determine the Ability of Compounds of the Invention to Treat, Prevent and/or Delay the Onset and/or the Development of a Disease or Condition Responsive to Nitroxyl Therapy
a. Cardiovascular Diseases or Conditions.
In vitro models of cardiovascular disease can also be used to determine the ability of any of the compounds described herein to treat, prevent and/or delay the onset and/or the development of a cardiovascular disease or condition in an individual. An exemplary in vitro model of heart disease is described below.
In-vitro models could be utilized to look at vasorelaxation properties of the compounds. Isometric tension in isolated rat thoracic aortic ring segment can be measured as described previously by Crawford, J. H., Huang, J, Isbell, T. S., Shiva, S., Chacko, B. K., Schechter, A., Darley-Usmar, V. M., Kerby, J. D., Lang, J. D., Krauss, D., Ho, C., Gladwin, M. T., Patel, R. P., Blood 2006, 107, 566-575. Upon sacrifice aortic ring segments are excised and cleansed of fat and adhering tissue. Vessels are then cut into individual ring segments (2-3 mm in width) and suspended from a force-displacement transducer in a tissue bath. Ring segments are bathed at 37° C. in a bicarbonate-buffered, Krebs-Henseleit (K-H) solution of the following composition (mM): NaCl 118; KCl 4.6; NaHCO 3 27.2; KH 2 PO 4 1.2; MgSO 4 1.2; CaCl 2 1.75; Na 2 EDTA 0.03; and glucose 11.1 and perfused continuously with 21% O 2 /5% CO 2 /74% N 2 . A passive load of 2 g is applied to all ring segments and maintained at this level throughout the experiments. At the beginning of each experiment, indomethacin-treated ring segments are depolarized with KCl (70 mM) to determine the maximal contractile capacity of the vessel. Rings are then washed extensively and allowed to equilibrate. For subsequent experiments, vessels are submaximally contracted (50% of KCl response) with phenylephrine (PE, 3×10 −8 -10 −7 M), and L-NMMA, 0.1 mM, is also added to inhibit eNOS and endogenous NO production. After tension development reaches a plateau, nitroxyl donating compounds are added cumulatively to the vessel bath and effects on tension monitored.
In vitro models can be utilized to determine the effects of nitroxyl donating compounds in changes in developed force and intracellular calcium in heart muscles. Developed force and intracellular calcium can be measured in rat trabeculae from normal or diseased (i.e. rats with congestive heart failure or hypertrophy) as described previously (Gao W D, Atar D, Backx P H, Marban E. Circ Res. 1995; 76:1036-1048). Rats (Sprague-Dawley, 250-300 g) are used in these experiments. The rats are anesthetized with pentobarbital (100 mg/kg) via intra-abdominal injection, the heart exposed by mid-sternotomy, rapidly excised and placed in a dissection dish. The aorta is cannulated and the heart perfused retrograde (˜15 mM/min) with dissecting Krebs-Henseleit (H-K) solution equilibrated with 95% O 2 and 5% CO 2 . The dissecting K-H solution is composed of (mM): NaCl 120, NaHCO 3 20, KCl 5, MgCl 1.2, glucose 10, CaCl 2 0.5, and 2,3-butanedione monoximine (BDM) 20, pH 7.35-7.45 at room temperature (21-22° C.). Trabeculae from the right ventricle of the heart are dissected and mounted between a force transducer and a motor arm and superfused with normal K-H solution (KCl, 5 mM) at a rate of ˜10 ml/min and stimulated at 0.5 Hz. Dimensions of the muscles are measured with a calibration reticule in the ocular of the dissection microscope (×40, resolution˜10 μm).
Force is measured using a force transducer system and is expressed in milli newtons per square millimeter of cross-sectional area. Sarcomere length is measured by laser diffraction. Resting sarcomere length is set at 2.20-2.30 μm throughout the experiments.
Intracellular calcium is measured using the free acid form of fura-2 as described in previous studies (Gao et al., 1994; Backx et al., 1995; Gao et al., 1998). Fura-2 potassium salt is microinjected iontophoretically into one cell and allowed to spread throughout the whole muscle (via gap junctions). The tip of the electrode (˜0.2 μm in diameter) is filled with fura-2 salt (1 mM) and the remainder of the electrode was filled with 150 mM KCl. After a successful impalement into a superficial cell in non-stimulated muscle, a hyperpolarizing current of 5-10 nA is passed continuously for 15 min. Fura-2 epifluorescence is measured by exciting at 380 and 340 nm. Fluorescent light is collected at 510 nm by a photomultiplier tube. The output of photomultiplier is collected and digitized. Ryanodine (1.0 μM) is used to enable steady-state activation. After 15 min of exposure to ryanodine, different levels of tetanizations are induced briefly (˜4-8 seconds) by stimulating the muscles at 10 Hz at varied extracellular calcium (0.5-20 mM). All experiments are performed at room temperature (20-22° C.).
b. Diseases or Conditions Implicating Ischemia/Reperfusion.
In vitro models can also be used to determine the ability of any of the compounds described herein to treat, prevent and/or delay the onset and/or the development of a disease or condition implicating ischemia/reperfusion injury in an individual.
Example 7. Use of In Vivo and/or Ex Vivo Models to Determine the Ability of Compounds of the Invention to Treat, Prevent and/or Delay the Onset and/or the Development of a Disease or Condition Responsive to Nitroxyl Therapy
a. Cardiovascular Diseases or Conditions.
In vivo models of cardiovascular disease can also be used to determine the ability of any of the compounds described herein to treat, prevent and/or delay the onset and/or the development of a cardiovascular disease or condition in an individual. An exemplary animal model of heart disease is described below.
In vivo cardiovascular effects obtained with a nitroxyl donor compound may be assessed in a control (normal) dog. The study is conducted in adult (25 kg) mongrel (male) dogs chronically instrumented for conscious hemodynamic analysis and blood sampling, as previously described (Katori, T.; Hoover, D. B.; Ardell, J. L.; Helm, R. H.; Belardi, D. F.; Tocchetti, C. G.; Forfia, P. R.; Kass, D. A.; Paolocci, N. Circ. Res. 96(2): 2004). Micromanometer transducers in the left ventricle provide pressure, while right atrial and descending aortic catheters provide fluid-pressures and sampling conduits. Endocardial sonomicrometers (anteriorposterior, septal-lateral) measure short-axis dimensions, a pneumatic occluder around the inferior vena cave facilitated pre-load manipulations for pressure-relation analysis. Epicardial pacing leads are placed on the right atrium, and another pair is placed on the right ventricle free wall linked to a permanent pacemaker to induce rapid pacing-cardiac failure. After 10 days of recovery, animals are evaluated at baseline sinus rhythm and with atrial pacing (120-160 bpm). Measurements include conscious hemodynamic recordings for cardiac mechanics.
Compounds of the invention are administrated to a healthy control dog at the dose of 1-5 μg/kg/min and the resulting cardiovascular data is obtained.
Demonstration that a compound of the invention improves cardiac hemodynamics in hearts with congestive failure: After completing protocols under baseline conditions, congestive heart failure is induced by tachypacing (210 bpm×3 weeks, 240 bpm×1 week), as previously described (Katori, T.; Hoover, D. B.; Ardell, J. L.; Helm, R. H.; Belardi, —37 D. F.; Tocchetti, C. G.; Forfia, P. R.; Kass, D. A.; Paolocci, N. Circ. Res. 96(2): 2004). Briefly, end-diastolic pressure and +dP/dt,max are measured weekly to monitor failure progression. When animals demonstrate a rise in EDP more than 2×, and dp/dt,max of >50% baseline, they are deemed ready for congestive heart failure studies.
The values for test compounds are obtained after 15 mm continuous i.v. infusion (2.5 or 1.25 μg/kg/min) in control and heart failure preparations, respectively, both in the absence and in the presence of volume restoration. For comparison, the same hemodynamic measurements are obtained with AS in heart failure preparations.
b. Diseases or Conditions Implicating Ischemia/Reperfusion.
Ex-vivo models of ischemia/reperfusion can also be used to determine the ability of any of the compounds described herein to treat, prevent and/or delay the onset and/or the development of a disease or condition implicating ischemia/reperfusion injury in an individual. An exemplary ex vivo model of ischemia/reperfusion injury is described below.
Male Wistar rats are housed in identical cages and allowed access to tap water and a standard rodent diet ad libitum. Each animal is anesthetized with 1 g/kg urethane i.p. 10 min after heparin (2,500 U, i.m.) treatment. The chest is opened, and the heart is rapidly excised, placed in ice-cold buffer solution and weighed. Isolated rat hearts are attached to a perfusion apparatus and retrogradely perfused with oxygenated buffer solution at 37° C. The hearts are instrumented as previously described in Rastaldo et al., “P-450 metabolite of arachidonic acid mediates bradykinin-induced negative inotropic effect,” Am. J. Physiol., 280:H2823-H2832 (2001), and Paolocci et al. “cGMP-independent inotropic effects of nitric oxide and peroxynitrite donors: potential role for nitrosylation,” Am. J Physiol., 279: H1982-H1988 (2000). The flow is maintained constant (approximately 9 mL/min/g wet weight) to reach a typical coronary perfusion pressure of 85-90 mm Hg. A constant proportion of 10% of the flow rate is applied by means of one of two perfusion pumps (Terumo, Tokyo, Japan) using a 50 mL syringe connected to the aortic cannula. Drug applications are performed by switching from the syringe containing buffer alone to the syringe of the other pump containing the drug (nitroxyl donating compound) dissolved in a vehicle at a concentration 10× to the desired final concentration in the heart. A small hole in the left ventricular wall allows drainage of the thebesian flow, and a polyvinyl-chloride balloon is placed into the left ventricle and connected to an electromanometer for recording of left ventricular pressure (LVP). The hearts are electrically paced at 280-300 bpm and kept in a temperature-controlled chamber (37° C.). Coronary perfusion pressure (CPP) and coronary flow are monitored with a second electromanometer and an electromagnetic flow-probe, respectively, both placed along the perfusion line. Left ventricular pressure, coronary flow and coronary perfusion pressure are recorded using a TEAC R-71 recorder, digitized at 1000 Hz and analyzed off-line with DataQ-Instruments/CODAS software, which allow quantification of the maximum rate of increase of LVP during systole (dP/dt max ).
Hearts are perfused with Krebs-Henseleit solution gassed with 95% O 2 and 5% CO 2 of the following composition: 17.7 mM sodium bicarbonate, 127 mM NaCl, 5.1 mM KCl, 1.5 mM CaCl 2 , 1.26 mM MgCl 2 , 11 mM D-glucose, supplemented with 5 μg/mL lidocaine.
Experimental Compounds. The nitroxyl donors are diluted in buffer immediately prior to use.
Experimental Protocols. Hearts are allowed to stabilize for 30 min, and baseline parameters are recorded. Typically, coronary flow is adjusted within the first 10 min and kept constant from thereon. After 30 min stabilization, hearts are randomly assigned to one of the treatment groups, and subjected to 30 min global, no-flow ischemia, followed by 30 min of reperfusion (I/R). Pacing of the hearts is stopped at the beginning of the ischemic period and restarted after the third minute of reperfusion.
Hearts in a control group are perfused with buffer for an additional 29 min after stabilization. Treated hearts are exposed to a nitroxyl donor (e.g., 1 μM final concentration for about 20 min followed by a 10 min buffer wash-out period).
In all hearts pacing is suspended at the onset of ischemia and restarted 3 minutes following reperfusion. As isolated heart preparations may deteriorate over time (typically after 2-2.5 hrs perfusion), the re-flow duration is limited to 30 min in order to minimize the effects produced by crystalloid perfusion on heart performance, and consistently with other reports.
Assessment of ventricular function. To obtain the maximal developed LVP, the volume of the intra-ventricular balloon is adjusted to an end-diastolic LVP of 10 mm Hg during the stabilization period, as reported in Paolocci, supra, and Hare et al., “Pertussis toxin-sensitive G proteins influence nitric oxide synthase III activity and protein levels in rat hearts,” J. Clin. Invest., 101:1424-31 (1998). Changes in developed LVP, dP/dt max and the end-diastolic value induced by the I/R protocol are continuously monitored. The difference between the end-diastolic LVP (EDLVP) before the end of the ischemic period and during pre-ischemic conditions is used as an index of the extent of contracture development. Maximal recovery of developed LVP and dP/dt max during reperfusion is compared with respective pre-ischemic values.
Assessment of myocardial injury. Enzyme release is a measure of severe myocardial injury that has yet to progress to irreversible cell injury. Samples of coronary effluent (2 mL) are withdrawn with a catheter inserted into the right ventricle via the pulmonary artery. Samples are taken immediately before ischemia and at 3, 6, 10, 20 and 30 min of reperfusion. LDH release is measured as previously described by Bergmeyer & Bernt, “Methods of Enzymatic Analysis,” Verlag Chemie (1974). Data are expressed as cumulative values for the entire reflow period.
To corroborate the data relative to myocardial injury, determined by LDH release, infarct areas are also assessed in a blinded fashion. At the end of the course (30 min reperfusion), each heart is rapidly removed from the perfusion apparatus, and the LV dissected into 2-3 mm circumferential slices. Following 15 min of incubation at 37° C. in 0.1% solution of nitro blue tetrazolium in phosphate buffer as described in Ma et al., “Opposite effects of nitric oxide and nitroxyl on postischemic myocardial injury,” Proc. Natl. Acad. Sci., 96:14617-14622 (1999), unstained necrotic tissue is separated from the stained viable tissue. The areas of viable and necrotic tissue are carefully separate by and independent observer who is not aware of the origin of the hearts. The weight of the necrotic and non-necrotic tissues is then determined and the necrotic mass expressed as a percentage of total left ventricular mass.
Data may be subjected to statistical methods such as ANOVA followed by the Bonferroni correction for post hoc t tests.
Example 8. Use of Human Clinical Trials to Determine the Ability to Combination Therapies of the Invention to Treat, Prevent and/or Delay the Onset and/or the Development of a Disease or Condition Responsive to Nitroxyl Therapy
If desired, any of the compounds described herein can also be tested in humans to determine the ability of the compound to treat, prevent and/or delay the onset and/or the development of a disease or condition responsive to nitroxyl therapy. Standard methods can be used for these clinical trials. In one exemplary method, subjects with such a disease or condition, such as congestive heart failure, are enrolled in a tolerability, pharmacokinetics and pharmacodynamics phase I study of a therapy using the compounds of the invention in standard protocols. Then a phase II, double-blind randomized controlled trial is performed to determine the efficacy of the compounds using standard protocols.
Although the foregoing invention has been described in some detail by way of illustration and example for purposes of clarity of understanding, it is apparent to those skilled in the art that certain minor changes and modifications will be practiced. Therefore, the description and examples should not be construed as limiting the scope of the invention.
All references, publications, patents, and patent applications disclosed herein are hereby incorporated by reference in their entirety.
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The invention relates to N-hydroxysulfonamide derivatives that donate nitroxyl (HNO) under physiological conditions and are useful in treating and/or preventing the onset and/or development of diseases or conditions that are responsive to nitroxyl therapy, including heart failure and ischemia/reperfusion injury. Novel N-hydroxysulfonamide derivatives release NHO at a controlled rate under physiological conditions, and the rate of HNO release is modulated by varying the nature and location of functional groups on the N-hydroxysulfonamide derivatives.
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FIELD OF INVENTION
The present invention relates to compositions containing chlorine dioxide. More specifically, the present invention concerns chlorine dioxide formation in compositions containing sodium chlorite and an initiator, the compositions having a viscosity suitable for suspendably retaining the gaseous chlorine dioxide formed subsequent to composition preparation.
BACKGROUND OF INVENTION
Chlorine dioxide is a well-known disinfecting and sterilizing agent. However, chlorine dioxide, because it is gaseous at room temperature and atmospheric pressure, has not achieved widespread use except where its gaseous nature can be used to effect, for example, in the treatment of water supplies.
U.S. Pat. No. 4,104,190 to Hartshorn discloses a solid composition capable of generating chlorine dioxide when dissolved in water, the solid composition containing sodium chlorite and a chlorine release agent. When dissolved in water, the chlorine species provided by the chlorine release agent reacts with the chlorite to form chlorine dioxide. Suitable chlorine release agents include sodium N-chloro-p-toluenesulfonamide, and sodium dichloroisocyanurate. In an alternate embodiment, a chlorite-free solid composition containing the chlorine release agent may be added to an aqueous solution of stabilized sodium chlorite, as disclosed in U.S. Pat. No. 3,123,521 to Wentworth, et al. In a preferred embodiment, the solid composition also contains an effervescent agent.
Recently, U.S. Pat. No. 4,084,747 to Alliger (U.S. Pat. Re. No. 31,779) proposed the incorporation of lactic acid in an aqueous sodium chlorite composition, the lactic acid lowering the pH of the aqueous media to less than about 7, thereby promoting the formation of chlorine dioxide. It is preferable to form the Alliger composition by admixture of a sodium chlorite-containing and a lactic acid-containing portion within 48 hours of use, for optimum germ-killing effect. To this end, U.S. Pat. No. 4,330,531, also to Alliger, discloses applicators whereby the chlorite portion and the lactic acid portion may be admixed at the time of use. The '531 patent discloses compositions for acne treatment, soaps, and toothpaste.
Another two-part composition is disclosed in Mason, et al., U.S. Pat. No. 4,731,193, which comprises a first part containing stated concentrations of dodecylbenzene sulfonic acid, a phosphate ester, hexamethylene glycol, hydrochloric acid, sodium xylene sulfonate, and water, and a second part containing an aqueous solution of sodium chlorite and sodium xylene sulfonate. The first and second parts are diluted with water.
Kenjo, et al., U.S. Pat. No. 4,731,192, discloses a two-composition cleaning system for contact lenses wherein free oxygen is released when a composition containing a chlorite salt, in aqueous solution, and a solid composition containing solid acid or organic acid salt, an oxygen-consuming agent, and polyvinyl pyrrolidone are combined. Reducing sugars may be included with the solid composition part. Suitable solid acids are tartaric, citric, lactic, malic and gluconic acids.
Quite clearly, the need to admix two parts to achieve a final composition is undesirable. A level of sophistication is needed by the ultimate user, lest incorrectly mixed dosage amounts of the two portions provide too little or too much chlorine dioxide. Alternately, special packaging for mixing aliquot amounts of the two premixes is needed, which special packaging raises the cost of the final product to the ultimate user.
The difficulty in providing a single composition containing sodium chlorite that forms chlorine dioxide when the composition is intended for direct use is that the chlorine dioxide formation heretofore continues unabated. Although the mechanism is not fully understood, it is believed that, at least in part, there is some form of autocatalysis that takes place, with a chloro or oxychloro species first formed continuing the formation of the chlorine dioxide from the sodium chlorite. Alternately, or cooperatively, it is suspected that certain chloro or oxychloro species that are formed acquire sufficient energy levels to activate some type of autocatalytic formation of the chlorine dioxide. Once said activated species is formed, the reaction proceeds accordingly. Whatever the mechanism, the fact remains that compositions containing chlorine dioxide formed in situ from sodium chlorite demonstrate a gradual yet continued reduction in composition pH until substantially all of the sodium chlorite is depleted.
It is an object of the present invention to provide a sodium chlorite-containing composition which releases into the composition levels of chlorine dioxide effective in killing germs and bacteria.
It is a further object of the present invention that in such composition the chlorine dioxide levels obtained achieve an equilibrium concentration, thereby assuring stability over time.
Another object of the present invention is that such composition be complete upon manufacture, there being no necessity to admix other ingredients prior to its use.
Another object of the present invention is to provide compositions wherein there is an excess of sodium chlorite to serve as a source for formation of additional chlorine dioxide, to replace chlorine dioxide diffusing from or otherwise leaving the composition.
These and other benefits and advantages of the present invention will be readily perceived upon a reading of the detailed invention disclosure, a summary of which follows.
SUMMARY OF THE INVENTION
The compositions in accordance with the present invention comprise sodium chlorite, an initiator, and water, the sodium chlorite and initiator each being present in the composition in at last an amount adapted to form interactively an antimicrobially effective concentration of chlorine dioxide in the composition, said composition having a viscosity suitable to suspendably retain the chlorine dioxide in the composition. Suitable as an initiator are hydroxy alkylcelluloses having 2 to about 5 carbons in the alkyl group; alkali metal alginates; xanthan; carrageenan; agar; compounds containing an aldehyde substituent group, including perfumes; perfumes not included in the previous class of aldehydic compounds, and dyes. Mixtures of such initiators may also be used.
Typically, the viscosity of the composition is above about 75 cps., preferably 75 to 1000 cps.
It is believed the initiator interacts with the chlorite ion in the aqueous composition to provide the chlorine dioxide, which interaction apparently ceases when an equilibrium concentration for the chlorine dioxide is reached. Such interactions normally take place within about several days.
The composition preferably has a sodium chlorite concentration of about 0.01 to 1% by weight, while the initiator is typically present at a level above about 0.05%, preferably above about 0.1%. At higher sodium chlorite levels, the time required for interaction becomes increasingly longer. Accordingly, while not excluded herein, such higher sodium chlorite concentrations are not preferred. Because the initiator may provide other properties to the composition, e.g., color, scent, thickening, it may be present at a level in excess of its initiating concentration.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT
Generally, the compositions of the present invention comprise sodium chlorite, an initiator, and water, the composition having a viscosity or a rheology suitable for suspendably maintaining chlorine dioxide within the composition. As hereinafter considered in some detail, it has been found that the materials suitable as an initiator are also suitable to provide other functional attributes to the composition. Accordingly, the initiator (or initiators) may be used in excess so as to provide these other attributes. Moreover, other materials which provide such attributes may also be included in the compositions of the present invention, even though not providing initiation of chlorine dioxide formation.
Compositions of the present invention have a viscosity of above about 75 cps., preferably from about 200 to about 1000 cps. At such viscosity levels, chlorine dioxide, which is formed by interaction between the initiator and the sodium chlorite, is suspendably retained in the composition, that is, diffusion from the composition is slow when the composition is exposed to the atmosphere. It has been found that the formation of chlorine dioxide in the composition reaches an equilibrium or steady-state level. Thus, in an enclosed container, the concentration of chlorine dioxide remains constant when the steady-state level has been reached, while in an open container for the composition (or when the closure for the container is left open), the steady-state level is maintained by formation of additional chlorine dioxide to replace that which diffuses to the atmosphere. Because the chlorine dioxide is highly soluble and because the compositions of the present invention are viscous, the diffusion rate of chlorine dioxide from such open container, however, is quite low. Accordingly, the compositions of the present invention are viewed as being quite stable, inasmuch as the sodium chlorite concentration is generally sufficiently high to operate as a source for the replenishment of chlorine dioxide escaping from the system.
The initially prepared compositions, prior to the formation of chlorine dioxide, comprise an effective level of sodium chlorite, that is, a concentration that is sufficient to form within the composition the aforementioned germicidally effective level of chlorine dioxide. Preferably, the sodium chlorite level is provided in excess, as to provide a source to replace chlorine dioxide leaving the composition. Typically, the sodium chlorite is present in an amount from about 0.01% to about 1.0% by weight of the composition, preferably from about 0.05 to about 0.5%. Other water-soluble chlorite salts may be employed, but are not preferred.
The initiator is present in an amount suitable to interact with the sodium chlorite to form the chlorine dioxide. An excess amount may be used, however, inasmuch as the formation of the chlorine dioxide appears to terminate at an equilibrium concentration. Of course, the equilibrium concentration that is achieved will depend on the precise concentration of each of the constituents in the composition, as well as the composition viscosity and other physical and chemical parameters. The initiator concentration is preferably in excess of that which is initially needed to provide the equilibrium level of the chlorine dioxide, so that additional chlorine dioxide may be formed with the sodium chlorite in the event of chlorine dioxide loss from the composition. An excess of the initiator may also be provided to achieve another desired functional purpose, as discussed below.
Several classes of initiators have been found to be suitable to form chlorine dioxide in the compositions of the present invention, as described below in greater detail. In each class the initiator is believed to interact with the chlorite anion so as to form chlorine dioxide, although the exact mechanism by way of which the chlorine dioxide is formed is not fully understood. The compositions as initially prepared are basic, and although an organic or inorganic acid constituent such as described in the prior art patents is not present, the compositions, after reaching equilibrium, have pH values that are slightly basic, neutral, or somewhat acidic, the pH typically not falling below a value of about 6. It is believed that the initiators herein described effect electron transfer from the chlorite anion to form the chlorine dioxide, but do so at a low rate, possibly through the formation of intermediate reaction products and/or intermediate activation species. The possibility that the initiator somehow autocatalyzes the transformation of the chlorite ion to chlorine dioxide should not be ruled out. That such compositions achieve an equilibrium is surprising and unexpected, as one would expect a shift in the reaction equilibrium towards chlorine dioxide formation at a pH value of less than 8.0.
Suitable initiators are:
(A) Certain materials suitable to thicken aqueous compositions. Such materials are selected from the group consisting of hydroxyalkyl cellulose having 2 to about 5 carbons in the alkyl group and including hydroxyalkyl methyl- and hydroxyalkyl ethylcellulose, alkali metal alginates, xanthan gum, carrageenan, and agar. Quite surprisingly, other materials suitable for functional use as a thickener such as methyl cellulose and sodium carboxymethyl cellulose have been found not to initiate chlorine dioxide formation, but might be incorporated as a thickener or cothickener.
(B) Dyes. The dyes usable in connection with the present invention include many different classes. Thus, it has been found that suitable colorants include Basic Blue No. 1 and Colour Index Dye Nos. 22,610 (Direct Blue 6); 42,045 (Acid Blue No. 1); 42,080 (Acid Blue No. 7); 42,090 (Hidacid Azure Blue); 52,035 (Hidacid Aqua Blue); and 74,180 (Direct Blue 86), which dyes include the phthalocyanine, diazo, thiazine, and triarylmethane classes of dyes. With regard to dyes not specifically referred to herein, potential for use as an initiator may easily be ascertained by routine experimentation, as described in greater detail in the examples below.
(C) Materials including an aldehyde or an acetal substituent group including perfumes containing such groups. Applicant has found that compounds containing an aldehyde group are suitable as initiators. It is believed that the pair of free electrons associated with the oxygen makes the aldehyde substituent group particularly suitable for use as an initiator. Suitable aldehydes include acetaldehyde, propionaldehyde, butyraldehyde and benzaldehyde, as well as aldehydes present in perfumes as a fragrance constituent. Of the latter, mention may be made of aldehydes having from about 5 to about 20 carbons, especially from about 8 to about 16 carbons, including cinnamic aldehyde, decaldehyde, citronellyl oxy-acetaldehyde, cuminic aldehyde, phenol acetaldehyde (monomer), p-methyl hydratropic aldehyde, and cyclamen aldehyde.
(D) Perfumes not including an aldehyde substituent group. Because perfumes are generally mixtures of various materials, the identification of the precise perfume ingredient that causes the formation of chlorine dioxide is more difficult to identify.
Typically, the perfume incorporated in the composition of the present invention is a mixture of organic compounds admixed so that the combined odors of the individual components produce a pleasant or desired fragrance. While perfumes are generally mixtures of variuus materials, individual compounds may also be used as the perfume ingredient, for example, methyl salicylate. The perfume compositions generally contain a main note or the "bouquet" of the perfume composition, modifiers which round off and accompany the main note, fixatives including odorous substances that lend a particular note to the perfume throughout each of the stages of evaporation, substances which retard evaporation, and top notes which are usually low-boiling, fresh-smelling materials.
Perfumery raw materials may be divided into three main groups: (1) the essential oils and products isolated from these oils; (2) products of animal origin; and (3) synthetic chemicals. In addition to aldehyde and acetal substituent groups considered above under (C), these materials include substituent groups, for example, the carbonyl group in ketones; the hydroxyl group in alcohols; the acyl group in esters; the C═O groups in lactones; nitrile groups, and the oxy moiety in ethers, that might be causing the initiation.
The essential oils consist of complex mixtures of volatile liquid and solid chemicals found in various parts of plants. Mention may be made of oils found in flowers, e.g., jasmine, rose, mimosa, and orange blossom; flowers and leaves, e.g., lavender and rosemary; leaves and stems, e.g., geranium, patchouli, and petitgrain; barks, e.g., cinnamon; woods, e.g., sandalwood and rosewood; roots, e.g., angelica; rhizomes, e.g., ginger; fruits, e.g., orange, lemon, and gergamot; seeds, e.g., aniseed and nutmeg; and resinous exudations, e.g., myrrh. These essential oils consist of a complex mixture of chemicals, the major portion thereof being terpenes, including hydrocarbons of the formula (C 5 H 8 ) n and their oxygenated derivatives. Hydrocarbons such as these give rise to a large number of oxygenated derivatives, e.g., alcohols and their esters, aldehydes and ketones. Some of the more important of these are geraniol, citronellol and terpineol, citral and citronellal, and camphor. Other constituents include aliphatic aldehydes and also aromatic compounds including phenols such as eugenol. In some instances, specific compounds may be isolated from the essential oils, usually by distillation in a commercially pure state, for example, geraniol and citronellal from citronella oil; citral from lemon-grass oil; eugenol from clove oil; linalool from rosewood oil; and safrole from sassafras oil. The natural isolates may also be chemically modified as in the case of citronellal to hydroxy citronellal, citral to ionone, eugenol to vanillin, linalool to linalyl acetate, and safrol to heliotropin.
Animal products used in perfumes include musk, ambergris, civet and castoreum, and are generally provided as alcoholic tinctures.
The synthetic chemicals include not only the synthetically made, also naturally occurring isolates mentioned above, but also include their derivatives and compounds unknown in nature, e.g., isoamylsalicylate, amylcinnamic aldehyde, cyclamen aldehyde, heliotropin, ionone, phenylethyl alcohol, terpineol, undecalactone, and gamma nonyl lactone.
Perfume compositions as received from the perfumery house may be provided as an aqueous or organically solvated composition, and may include as a hydrotrope or emulsifier a surface-active agent, typically an anionic or nonionic surfactant, in minor amount.
The perfume compositions quite usually are proprietary blends of many of the different fragrance compounds. However, one of ordinary skill in the art, by routine experimentation, may easily determine whether such a proprietary perfume blend is suitable to initiate chlorine dioxide formation in the compositions of the present invention, as illustrated in the examples below. Nonaldehydic perfumery constituents found to be suitable include methyl salicylate, amyl salicylate, bornyl acetate and eugenol.
(E) Reducing sugars. It has been found that mono- and disaccharides which are categorized as reducing sugars are suitable for use as initiators in the practice of the present invention. Thus, fructose, glucose, maltose, cellobiose, α-lactose and β-lactose were suitable. Sucrose, a nonreducing sugar, was not. Polysaccharides such as dextran and starch were found to be unsuitable.
The concentration of the initiators (A) through (E) qua initiator is generally low, and an effective amount is generally from about 0.01 to about 2% by weight of the composition, the actual concentration depending on the intrinsic activity of the particular initiator.
Because initiators (A) through (D) also fulfill a functional purpose, they may be incorporated in greater or lesser amount than required for the initiation function. Where less is employed, the difference may be made up by using one or more of the other initiators (A) through (E). Thus, the Group (A) initiator is typically included in an amount of less than about 2% by weight of the composition for initiation, but may be incorporated in an amount of up to 10% by weight of the composition to achieve a desired thickening. The Group (B) initiator may be included in the composition in an amount of less than about 5% by weight of the composition, preferably from about 0.01 to about 0.5%, to provide a desired tinctorial value. The Groups (C) and (D) initiators would be included in an amount of less than about 1% by weight of the composition, preferably from about 0.01 to about 0.25%, to provide a desired fragrance result. Often, when included at a concentration to provide their intended noninitiating function, the total level of the initiators (A), (B), (C) or (D) is in excess of that needed to form chlorine dioxide. However, the additional amount of the initiator does not promote formation of an unwanted level of chlorine dioxide, which achieves an equilibrium at a low concentration. Rather, the additional amount of the initiator is employed functionally to achieve the particular composition property, i.e., viscosity, tint, or scent. Two or more of these initiators may be included in the compositions of the present invention, especially to obtain in concert the effective level for initiation.
The formation of chlorine dioxide commences upon or shortly after admixing of the ingredients, the equilibrium levels generally being reached within a week, preferably within two or three days, of admixture. Suitable equilibrium concentrations of the chlorine dioxide are from about 0.1 to about 10 ppm, preferably 0.1 to 2 ppm, depending upon the ultimate use of the composition. Where the intended utility is disinfection, the equilibrium chlorine dioxide concentration is preferably above about 1 ppm, while when the intended utility is to enhance cleaning and provide some sanitizing effect, the equilibrium chlorine dioxide level is less than about 2 ppm. The amount of chlorine dioxide formed may be controlled by the concentrations of the ingredients, the viscosity of the composition, and by incorporation of an anionic surfactant, which has been found to suppress the conversion of chlorite to chlorine dioxide, possibly by forming a ligand with the chlorite anion. Inclusion of less than about 1% anionic surfactant would be suitable for this purpose.
Other constituents may be incorporated in the compositions of the present invention to provide a particular utility, provided such other constituents are compatible with the formation of the chlorine dioxide and do not themselves deactivate in the compositions. Mention may be made of nonionic surfactants, to provide a cleaning composition.
In preparing the compositions, it is preferred to first form a dilute sodium chlorite premix, which is then thickened with either a noninitiating or a initiating thickener, and then to add in, with stirring, the remaining constituents.
The present invention is illustrated by the examples below.
EXAMPLES
General
In the examples, chlorine dioxide gas is often easily detectable by its characteristic odor. While such sensory evaluations do not indicate the presence of chlorine dioxide, one of several analytical methods was used: (1) spectrophometric measurement of a sample, chlorine dioxide having a peak absorbence of 356 nm, unique among the oxychloro species; (2) titration of an alkaline sample with sodium thiosulfate in the presence of potassium iodide, and (3) purging chlorine dioxide gas from the sample with inert gas and passing the purged gas through a potassium iodide solution.
In the specific examples which follow, all concentrations are reported on an active-ingredient basis, unless otherwise indicated. The perfumes were premixed with the surfactants prior to the addition to the chlorite solution. Except for dye and perfume, all concentrations are reported on an active material basis, by weight percent of the composition.
EXAMPLE 1
Compositions 1-A to 1-E were prepared as indicated below. Commercial sodium chlorite was used, which is 80% active, and contains 5% sodium hydroxide and about 15% sodium chlorite. The sodium chlorite level reported in Table I and throughout these examples is on an active chlorite basis.
TABLE I__________________________________________________________________________ Concentration (wt. %)Constituent 1-A 1-B 1-C 1-D 1-E 1-F 1-G__________________________________________________________________________Sodium chlorite 0.24 0.24 0.24 0.24 0.24 0.32 0.32Methyl cellulose 1Sodium carboxymethylcellulose 1Hydroxyethylcellulose 1Hydroxypropylcellulose 1Hydroxybutylcellulose 1Xanthan gum 0.5Sodium alginate 0.5Water QS 100%Days observed 12* 228 -- >1 yr >1 yr >1 yr --ClO.sub.2 formation No No Yes Yes Yes Yes Yes*ClO.sub.2 present atend of period No No Yes Yes Yes Yes YespH Initial 9.34 9.3 9.3 9.9 9.9 9.4 9.6pH at end of period 9.2 9.0 5.4 7.3 7.1 7.0 7.1Viscosity (cps. at20° C.) Initial -- 884 824 786 404 510 --Viscosity (cps. at20° C.) Final -- 165 101 255 150 303 --__________________________________________________________________________ *At 125° F. for 12 days. **At 180° F. for two hours.
Each of the compositions 1-C through 1-G formed ClO 2 within about seven days of preparation. The decrease in viscosity ocurs within about one month before attaining an essentially constant value, as identified above.
EXAMPLE 2
the compositions 2-A through 2-H were prepared.
TABLE II______________________________________ Concentration (wt. %)Constituent 2-A to 2-G 2-H______________________________________Sodium chlorite 0.16 0.16Carboxymethyl cellulose 0.80 0.80Dye 0.05 --Deionized water QS 100% QS 100%______________________________________
Compositions 2-A to 2G contained the following dyes:
TABLE III______________________________________Composition Dye C.I. No. Activity (%)______________________________________2-A Acid Blue No. 1 42,045 1002-B Direct Blue 86 74,180 1002-C Acid Blue No. 7 42,080 1002-D Hidacid Aqua Blue 52,035 912-E Basic Blue No. 1 -- 1002-F Acid Blue No. 9 42,090 892-G Acid Blue No. 9 42,090/45,350 89/75 and Yellow Dye______________________________________
Each of these compositions was monitored for chlorine dioxide formation. Compositions 2-A and 2-C to 2-G produced chlorine dioxide, while Compositions 2-B and 2-H did not, within 11 days at 125° F. Composition pH, viscosity, and ClO 2 concentration were measured initially and at the end of the storage period. The results are provided in Table IV.
TABLE IV______________________________________ First Day Viscosity (cps.) pHComposition ClO.sub.2 Observed Initial Final Initial Final______________________________________2-A 7 316 130 9.3 6.92-B None 300 20 9.5 8.82-C 7 318 140 9.3 6.72-D 11 310 135 9.4 6.92-E 4 312 85 8.9 5.82-F 7 320 100 9.4 6.42-G 11 352 80 9.4 7.12-H None 430 185 9.3 9.2______________________________________
EXAMPLE 3
The following Compositions 3-A to 3-J were prepared.
TABLE V______________________________________ Concentration (wt. %)Constituent 3-A to 3-I 3-J______________________________________Sodium chlorite 0.16 0.16Sodium carboxymethyl cellulose 0.8 0.8Triton X-100.sup.(1) 2 2Perfume (per Table V) 0.2 --Deionized water QS 100 QS 100______________________________________ .sup.(1) Octylphenoxy polyethoxy ethanol (100% active) manufactured by Rohm and Haas Co. Solubilizer for the perfume.
TABLE VI______________________________________Composition Perfume______________________________________3-A Dragoco 0/7105313-B Florasynth S-19233-C BBA 8604163-D Florasynth T-46083-E BBA 8715233-F Dragoco 0/7122273-G Lautier LA 79019463-H Neutroleum Gamma3-I Methyl salicylate______________________________________
The Compositions 3-A to 3-J were placed in an oven at 125° F. for 11 days. pH and viscosity measurements were made initially and at the end of 11 days. During the test period, the compositions were monitored for the onset of chlorine dioxide formation. The results are reported in Table VII.
TABLE VII______________________________________ Viscosity at First Day 20° C. (cps.) pHComposition ClO.sub.2 Observed Initial Final Initial Final______________________________________3-A 4 258 160 9.2 6.53-B 4 268 60 9.2 5.53-C 4 260 200 9.3 6.33-D 4 250 30 8.8 5.73-E 4 266 110 9.2 6.03-F 4 262 -- 9.3 --3-G 4 282 170 9.2 6.23-H 4 482 315 9.2 6.23-I 4 752 125 8.6 6.23-J None 440 330 9.4 9.1______________________________________
EXAMPLE 4
Compositions were prepared containing 0.8% sodium chlorite, 4% Triton X-100, 0.25% of a perfume constituent as identified in Table VIII below, and water Q.S. 100%.
TABLE VIII______________________________________Comp. First Day pHNo. Perfume Component ClO.sub.2 Observed Initial Final______________________________________4-A C-10 aldehyde 1 10.7 7.04-B Methylhexylketone None after 10.8 9.7 29 days4-C Phenylethyl alcohol None after 10.7 9.7 29 days4-D Cinnamic aldehyde 2 10.8 7.44-E Amyl salicylate 7 10.5 3.94-F Bornyl acetate 21 10.7 6.04-G Eugenol 7 10.0 4.34-H Acetophenone None after 11.2 11.0 30 days4-J 80% Dragoco 0/712227 Yes after 1 10.9 6.4 and 20% C-10 Aldehyde day______________________________________
EXAMPLE 5
Compositions were prepared containing 1.28% sodium chlorite, 0.5% of a saccharide material as identified in Table IX, and water Q.S. 100%.
TABLE IX______________________________________Comp. First Day pHNo. Perfume Component ClO.sub.2 Observed Initial Final______________________________________5-A Fructose Yes 10.1 5.75-B Glucose Yes 10.2 6.65-C Maltose Yes 10.2 6.65-D Celliobiose Yes 10.2 6.85-E α-Lactose Yes 10.3 6.65-F β-Lactose Yes 10.2 6.95-G Sucrose No 10.5 10.25-H Dextran No 10.6 10.05-I Starch* No 10.8 7.3______________________________________ *Present at 2% level.
EXAMPLE 6
The following examples could be prepared to utilize the special properties of a thickened, one-part, chlorine dioxide cleaner.
______________________________________Consumer Hand Soap 0.25% Sodium chlorite 0.5% Xanthan gum 1.0% Alpha olefin sulfonate 0.2% Perfume 98.05% WaterToilet Bowl Cleaner 0.25% Sodium chlorite 0.8% Sodium carboxymethyl cellulose 0.05% Acid Blue #9 0.20% Perfume 3.0% Sodium sulfate 95.7% WaterHard Surface Cleaner 5.0% Isopropyl alcohol 0.25% Perfume 0.5% Triton X-100 0.8% Sodium carboxymethyl cellulose 0.25% Sodium chlorite 93.2% WaterDisinfecting Skin Cream 2.0% Lanolin 0.5% Hydroxypropyl methyl cellulose 0.25% Sodium chlorite 1.0% Isopropyl alcohol 5.0% Sodium lauryl sulfate 91.25% WaterInstitutional Rinse for 0.5% Sodium chloriteDishwashers (Disinfecting) 1.5% Hydroxyethyl cellulose 2.5% Isopropyl alcohol 1.0% Polyacrylic acid salt 94.5% Water______________________________________
Several days after preparation, the above compositions would form chlorine dioxide, which would be stably entrapped in the composition.
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A chlorine dioxide-containing composition comprising sodium chlorite; an initiator selected from the group consisting of (A) a thickening agent; (B) a colorant, (C) a perfume and mixtures thereof; chlorine dioxide at an antimicrobial concentration, and water, the sodium chlorite and the initiator being present in the composition in an amount adapted to form interactively said antimicrobial chlorine oxide concentration, said composition having a viscosity suitable to maintain the thus-formed chlorine dioxide at a steady-state concentration.
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TECHNICAL FIELD
The present invention relates generally to a dispenser for granular materials such as fertilizers, pesticides, fungicides and seed. More particularly, this invention concerns a granular applicator incorporating a plurality of discharge openings with individual metering and shut-off mechanisms including an interchangeable metering wheel assembly for more precise flow control.
BACKGROUND ART
Modern-day agricultural practice requires precise application of various dry granular materials for various purposes. Such materials include fertilizers, pesticides, fungicides, herbicides and seed. For example, dry granular chemicals can be applied to the soil before, during, or after planting. Some may also be applied directly to growing plants long after the planting operation. The type of material to be applied and its application rate depend upon the plants involved, and it will be understood that the materials and application rates can vary widely. After one type of material has been applied, it may be necessary to clean out the applicator and adjust it for application of another material at a different rate.
A variety of applicators for this purpose have been available heretofore. Such applicators usually include metering apertures at the bottom of a hopper through which material is discharged by means of gravity and a feed rotor located inside the hopper above the apertures. U.S. Pat. No. 3,776,430 to the assignee hereof shows one such prior device. U.S. Pat. Nos. 3,128,921 to Henderson and 2,784,881 to Hines are also representative of the in this regard.
Although various granular applicators have been available heretofore, they have not been without certain drawbacks. The applicators of the prior art generally require complete clean-out of the hopper before the metering or feed wheels can be replaced and/or repaired, and are thus not readily adapted for efficient changeover. Material changeover and/or metering wheel changeover can be time-consuming and thus expensive with such applicators. In addition, it may not be possible to accomplish thorough cleanout without at least some disassembly. Some prior applicators are relatively complicated in construction, and are thus expensive to manufacture and difficult to maintain. Further, many of the prior applicators incorporate a relatively long, internal feed rotor together with multiple discharge openings. This arrangement is subject to inaccuracies when the unit is operated on a hill at a tilt because the material tends to collect in one side of the hopper, exposing one end of the feed rotor and thus resulting in uneven or interrupted metering at some of the discharge openings.
A need has thus arisen for a more versatile granular applicator which incorporates a removable metering assembly including interchangeable feed wheels that can be removed and replaced as necessary without emptying the hopper so that the applicator can be readily adapted for applying various granular materials.
SUMMARY OF THE INVENTION
The present invention comprises an improved applicator which overcomes the foregoing and other difficulties associated with the prior art. In accordance with the invention, there is provided a granular applicator for mounting on a planter or other implement which is typically towed or driven across a field. The applicator comprises a hopper including an open top end and closed convergent bottom end with a inclined side wall. The side wall includes a lateral opening with a metering assembly mounted therein, preferably by means of releasable fasteners for removability. The metering assembly includes a plate having a plurality of spaced-apart material discharge openings therein, individual receivers with fixed lower lips mounted over the discharge openings, individual metering wheels mounted in the receivers adjacent to the discharge openings, and individual slideable gate plates mounted between the wheels and the discharge openings.
BRIEF DESCRIPTION OF DRAWINGS
A better understanding of the invention can be had by reference to the following Detailed Description in conjunction with the accompanying Drawings, wherein:
FIG. 1 is a perspective view of the granular applicator of the invention mounted on a portion of an agricultural implement;
FIG. 2 is an end view of the applicator herein;
FIG. 3 is a partial end view of the hopper showing the cover in closed and open positions;
FIG. 4 is a top view of the hopper, without the cover;
FIG. 5 is a vertical sectional view taken along lines 5--5 of FIG. 1 in the direction of the arrows;
FIG. 6 is a partially exploded perspective view of the removable metering assembly of the applicator;
FIG. 7 is a perspective view of one of the receivers in the metering assembly; and
FIG. 8 is a perspective view of an alternate feed wheel in the metering assembly.
DETAILED DESCRIPTION
Referring now to the Drawings, wherein like reference numerals designate like or corresponding elements throughout the views, and particularly referring to FIG. 1, there is shown the spreader or granular applicator 10 of the invention. The applicator 10 is shown mounted on a portion of an implement 12, such as a seeder or the like, drawn across a field by a tractor (not shown). Although the applicator 10 is shown mounted on a portion of an implement 12, it will be understood that the applicator can also be mounted on a truck or other vehicle which is either towed or driven across the field to dispense herbicides, pesticides, insecticides or seed. As will be explained more fully hereinafter, the applicator 10 incorporates a unique metering assembly of fewer parts and less complicated construction to effect precise distribution of desired amounts of granular materials without undue susceptibility to tilt, and which also permits changeover of the metering wheels without emptying the hopper.
The applicator 10 includes a hopper 14 with an open rectangular top end 16 and a convergent bottom end 18. A cover 20 is mounted on the top end 16 of the hopper. The cover 20 includes a handle 22 on one side thereof to facilitate opening and closing. The cover 20 can be hinged along one side thereof to the hopper 14. However, in the preferred embodiment, the cover 20 is supported by opposite pairs of pivot arms 24 and 26, only one of which is shown for movement between open and closed positions as shown in FIG. 3. This arrangement is preferable because it is easier for the operator to handle and it presents a lower profile that is less susceptible to wind gusts.
The bottom end 18 of the hopper 14 is secured between a pair of side plates 28, the lower ends of which are attached to a hollow beam 30 defining a pressurized air chamber as will be explained more fully hereinafter. The crossbeam 30 is secured, such as by U clamps or the like, to a pair of arms 32 which in turn are secured to the implement 12. It will thus be appreciated that the applicator 10 is securely mounted on the implement for movement therewith. Suitable releasable fasteners, such as U bolts and nuts are preferred so that the applicator can be adapted for mounting on a variety of implements.
The convergent bottom end 18 of hopper 14 is defined by opposing pairs of upright end walls and inclined side walls. A lateral opening 34 is provided in the side wall of relatively steeper inclination. As illustrated, the side wall in which the lateral opening 34 is located and is inclined at about 60 degrees to the horizontal.
The external metering assembly 40 is mounted over the opening 34 in the convergent bottom end 18 of the hopper 14. The metering assembly 40 includes a panel 42 adapted for closing the opening 34. The panel 42 includes a turned lower edge adapted for engagement with a ledge 44 secured between the side plates 28. Opposite side edges of the panel 42 are also turned to overlap edges of the hopper 14. The metering assembly 40 can be secured over opening 34 in any suitable fashion.
In accordance with the preferred construction, the metering assembly 40 is removably secured to the hopper 14. As illustrated, notches 46 are located at opposite sides of the upper end of panel 42 for receiving the threaded ends of bolts 48. The opposite ends of bolts 48 are turned for hooked engagement with lugs 50 secured to the side plates 28. Wing nuts 52 are provided on the bolts 48 for securing the metering assembly in place. Although a nut-and-bolt arrangement has been illustrated for purposes of releasably securing the metering assembly 40, it will be understood that other suitable connections could also be utilized. Removability, of course, facilitates maintenance of the metering assembly 40, and also facilitates cleaning of the hopper 14.
The metering assembly 40 includes individual material discharge openings, individual metering wheels, and individual shut-off valves for precise flow control and better tolerance to tilt during operation of the applicator 10. In particular, a plurality of laterally spaced-apart material disharge openings 54 are provided in the panel 42. As illustrated, nine such openings 54 are provided, although any suitable number can be utilized. A receiver 56 is normally secured over each opening 54 although, as illustrated, a spout 57 is provided over the middle opening to facilitate emptying the hopper 14. Each receiver 56 generally includes a pair of spaced-apart side walls defining a generally horizontal passageway, bounded underneath by a bottom wall which has an inclined lip 58 at its free end, as is best seen in FIG. 5, terminating adjacent to an open generally vertical passageway defined in one end of the receiver. The side walls of receivers 56 are flanged at their inner ends to facilitate mounting on panel 42 by screws or other suitable fasteners.
Individual slideable gate plates 60 are mounted between the receivers 56 and spout 57 and openings 54. The gate plate 60 for spout 57 is normally closed, while the plates for receivers 56 are normally open. Bolts 62 are provided for securing the gate plates 60 in the desired predetermined positions such as open, closed and partially opened. If desired, however, the slideable gate plates 60 could be mounted for continuous adjustment by means of bolt-and-slot connections, for example.
Individual metering wheels 64, one of which is provided for each opening 54 within the respective receiver 56, are mounted on a common shaft 66. The shaft 66 is supported for rotation between a pair of bearings 68 mounted on lugs 70 at opposite ends of panel 42. The central portion of shaft 66 is preferably noncircular or hexagonal in cross section so that the metering wheels 64 are drivingly secured thereon yet slideable along the shaft for alignment purposes. FIG. 6 illustrates in phantom lines one of the metering wheels 64 as positioned within receiver 56 when carried by shaft 66. When the metering wheels 64 are so positioned in receivers 56, the wheels do not extend into the bottom end 18 of hopper 14, but are exposed to the material in the hopper through vertical projection of the openings 54.
This arrangement comprises a significant feature of the present invention. The metering wheels 64 are located outside hopper 14, yet are exposed to the material therein and can be individually isolated by means of gate plates 60 without affecting overall performance of the applicator 10. When all of the gate plates 60 are closed, the bearings 68 can be disconnected, permitting shaft 66 to be lifted away from receivers 56 so that that the metering wheels 64 can be replaced as necessary depending upon the material to be applied. As illustrated, the metering wheels 64 include straight teeth or flutes extending completely across the wheels. FIG. 8 illustrates an alternate metering wheel 72 having two circumferential rows of offset teeth. The metering wheel 72 can be used for metering relatively coarser materials. Continuous or offset straight fluted metering wheels 64 are preferred because of their positive shut-off characteristics.
The metering wheels 64 are driven in unison by means of a sprocket 74 secured to one end of the shaft 66. The drive sprocket 74 in turn is connected to a chain 76 leading to another sprocket (not shown) secured to a conventional ground engaging wheel (not shown). Such a drive arrangement compensates for the speed of travel of the implement. If desired, however, a conventional hydraulic or electric motor drive could be used instead.
The metering wheels 64 are driven in a counter-clockwise direction as shown in FIG. 5, feeding material from the hopper 14 under the wheels and over lip 58, depositing the material into the generally vertical open channel portion in receiver 56 for flow by gravity into an underlying mixing chamber 78 for distribution and final application. It will thus be appreciated that the metering assembly 40 functions to carry the metered streams of material from hopper 14 into the individual mixing chambers 78.
The mixing chambers 78 are secured along the hollow frame member 30, and take the general form of a cup open at the top end which converges downwardly and opens at the bottom end into a nozzle 80. The nozzles 80 are open at their inner ends through openings in the beam 30, which is connected to a source of pressure (not shown) so that its interior is pressurized. A restriction, 82 is provided in each nozzle 80 between beam 30 and the lower ends of the mixing chambers 78 in order to create a venturi effect past the lower end of the mixing chambers, thereby entraining the granular material without blowback and carrying it down through pneumatic delivery tubes 84 to the points of application. The other end of each tube 84 can be connected to a pair of discs (not shown) for incorporation into the soil, or to a deflector (not shown) for broadcast application, in conventional fashion.
Referring again to FIG. 1, in the preferred embodiment, a gear 86 is secured to the metering wheel drive shaft 66 at one end thereof. The gear 86 is enmeshed with another gear 88 on another shaft 90 extending through the bottom end 18 of hopper 14. The shaft 90 is supported for rotation between a pair of bearings 92 on opposite sides of the hopper 14. The ratio between gears 86 and 88 can be 1:1, for example. The shaft 90, which is optional, is provided for purposes of driving a rotor or agitator (not shown) in counter direction to the metering wheel drive shaft 66 for purposes of agitating the material in the hopper to maintain flowability. It will be understood that some materials may have a greater tendency than others to bridge or clog at the bottom end 18 of the hopper, in which case it may be desirable to utilize shaft 90 for purposes of agitation.
From the foregoing, it will thus be apparent that the present invention comprises an improved granular spreader or applicator which incorporates numerous advantages over the prior art. One important advantage involves the use of a metering assembly, preferably removably secured to the hopper, which utilizes fewer parts arranged so that the metering wheels can be removed and replaced as necessary without emptying the hopper. Individual material discharge openings, individual metering wheels and individual shut-off valves are provided for more precise control and better tolerance to tilt. Other advantages will be evident to those skilled in the art.
Although particular embodiments of the invention have been illustrated in the accompanying Drawings and described in the foregoing Detailed Description, it will be understood that the invention is not limited only to the specific embodiments, but is intended to embrace any equivalents, modifications, alternatives and/or rearrangements of elements falling within the scope of the invention as defined by the following Claims.
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An improved, more versatile applicator (10) for precisely dispensing granular chemicals, fertilizers or seed, includes a hopper (14) with a metering assembly (40) mounted over a material discharge opening (34) in an inclined wall of the closed, convergent bottom end (18) of the hopper. The metering assembly (40), which is preferably removably secured to the hopper (14), includes a plurality of individual sets of metering wheels (64), receivers (56) and gate plates (60) for precise control and more tolerance to tilt. The metering assembly (40) is also adapted to facilitate thorough clean-out of the hopper (14) as well as removal and replacement of the metering wheels (64) without emptying the hopper.
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BACKGROUND AND SUMMARY OF THE INVENTION
Manure spreaders for handling slurry material generally include a tank for containing material, an auger rotatably mounted in the bottom of the tank for moving material toward an opening formed in the tank, and an expeller disposed at the opening in the tank to discharge material in a lateral direction from the spreader. One prior manure spreader of this type disclosed in
U.S. Pat. No. 4,362,272 includes a drive system consisting of a pair of gearboxes for rotating the auger and the expeller. It is an object of this invention to provide an improved manure spreader drive system that is more reliable and more economical than the drive system disclosed in U.S. Pat. No. 4,362,272.
The present invention provides a novel drive system for rotating the auger and the expeller in the type of manure spreader generally described above. In one embodiment, the drive system includes a shaft adapted for connection to a tractor PTO, first and second drive members mounted on the shaft for rotation in a first direction, a third drive member connected to the first drive member for rotation in the first direction, and a fourth drive member connected for rotation with the third drive member in the first direction. This embodiment of the drive system also includes a fifth drive member connected to the fourth drive member for rotation in a second direction which is opposite the first direction. The fifth drive member is connected to the auger to rotate the auger in the second direction, and means are also provided connecting the second drive member to the expeller to rotate the expeller in the first direction.
In another embodiment of the drive system of the present invention, the third drive member is connected to the first drive member for rotation in the second direction. The fourth drive member is connected for rotation with the third drive member in the second direction, and the fifth drive member is connected to the fourth drive member for rotation in the second direction. The fifth drive member is connected to the auger to rotate the auger in the second direction, and means are provided connecting the second drive member to the expeller to rotate the expeller in the first direction.
DESCRIPTION OF THE DRAWINGS
FIG. 1 is a side elevational view of a manure spreader incorporating one embodiment of the drive system of the present invention;
FIG. 2 is an enlarged sectional view of the embodiment of the drive system of FIG. 1 taken along lines 2--2 in FIG. 1; and
FIG. 3 is a view similar to FIG. 2 of another embodiment of the drive system of the present invention.
DESCRIPTION OF THE PREFERRED EMBODIMENTS
Referring generally to FIG. 1, a manure spreader 10 includes a base frame 12 supported by wheels 14. A tongue 16, partially shown, is provided at the forward end of the base frame 12 and is adapted for connection to a towing vehicle such as a tractor (not shown). A tank 18 for containing manure is mounted on the base frame 12, and includes sidewalls 20,22 converging or sloping toward each other and merging into a bottom wall 24 as seen in FIG. 2. The tank 18 also has endwalls 26,28 disposed substantially parallel to each other.
An auger 30 is rotatably mounted in the bottom of the tank 18. The auger 30 has stub shafts 32,34 at its ends extending through and rotatably disposed in bearings carried on the endwalls 26,28 of the tank 18. Stub shaft 32 is driven in the manner described hereafter from a shaft 36 which is adapted for connection to the PTO of a tractor. The auger 30 includes paddles 38 arranged to move manure toward an opening formed in the sidewall 22 of the tank 18 when the auger 30 is rotated by the tractor PTO, and an expeller assembly 40 is provided at this opening in the tank sidewall 22 to discharge manure laterally away from the spreader 10. The expeller assembly 40 includes a central shaft 42 which is driven from the shaft 36 in the manner described hereafter. The expeller assembly 40 also includes a plurality of flails 44 pivotally mounted on further shafts which are connected to be rotated with and around the central shaft 42.
One embodiment of the drive system of the present invention is seen in FIG. 2, and includes a first drive member or sprocket 46 and a second drive member or sheave 48 both fixed on the shaft 36. The sprocket 46 is connected via a chain 50 to a third drive member or sprocket 52 which is of larger diameter than sprocket 46. Sprocket 52 is secured by a pair of shear bolts 54 to a plate 56 which in turn is fixed to a shaft 58 rotatably mounted on a support beam 60 carried on the base frame 12. An idler mechanism 62 is mounted on the support beam 60 to maintain tension in the chain 50. A fourth drive member or sprocket 64, of smaller diameter than sprocket 52, is fixed on the shaft 58 behind the sprocket 52.
The sprocket 64 is connected via a chain 66 in a backwrap manner to a fifth drive member or sprocket 68 fixed to the stub shaft 32 of the auger 30. The chain 66 extends around idler sprockets 70 and 72. Idler sprocket 70 is stationarily mounted on a support beam 74 attached to the support beam 60. Idler sprocket 72 is carried on a lever 76 which is pivoted by a pin 78 on the support beam 74. A spring 80, connected between the lever 76 and a bracket 82 on the support beam 74, normally urges the lever 76 to rotate in a counterclockwise direction about pin 78 as viewed in FIG. 2 to maintain proper tension in the chain 66.
Sheave 48 is connected via a belt 84 to a sixth drive member or sheave 86 fixed to the central shaft 42 of the expeller assembly 40. The shaft 42 is rotatably mounted in a support beam 88 on the base frame 12, and an idler mechanism 90 is carried on the support beam 88 to maintain tension in the belt 84.
When the manure spreader 10 is connected to a tractor (not shown) for normal operation utilizing the embodiment of the drive system of FIG. 2, the sprocket 46 and the sheave 48 are driven in a counterclockwise direction by the shaft 36 as seen in FIG. 2. This causes concurrent counterclockwise rotation of the sprocket 52 and the sheave 86 via the chain 50 and the belt 84, respectively. The flails 44 of the expeller assembly 40 are thus rotated in a counterclockwise direction, as viewed from the front of the manure spreader 10, by the central shaft 42. The counterclockwise rotation of the sprocket 52 results in counterclockwise rotation of the sprocket 64 via the shaft 58 and clockwise rotation of the sprocket 68 via the chain 66. The sprocket 68 is rotated clockwise due to the chain 66 extending around the sprocket 64 in a backwrap manner. The auger 30 is thus rotated in a clockwise direction, as viewed from the front of the manure spreader 10, by the stub shaft 32 at a substantially slower speed than the flails 44 of the expeller assembly 40.
Another embodiment of the drive system of the present invention is seen in FIG. 3, and includes the same first, second, third, fourth, fifth and sixth drive members 46,48,52,64,68 and 86, respectively, that are also included in the embodiment of the drive system shown in FIG. 2. The main difference between the two embodiments of the drive system disclosed herein resides in that the chains 50 and 66 used in the embodiment of FIG. 2 are replaced by chains 92 and 94, respectively, in the embodiment of FIG. 3.
The chain 92 connects the third drive member or sprocket 52 in a backwrap manner to the first drive member or sprocket 46. The chain 92 also extends around idler sprockets 96 and 98, at least one of which may be adjustably mounted on plate 100 carried on the base frame 12 to maintain proper tension in the chain 92. The chain 94 connects the fourth drive member or sprocket 64 to the fifth drive member or sprocket 68, and an idler mechanism 102 is provided to maintain tension in the chain 94. Belt 84 connects the second drive member or sheave 48 to the sixth drive member or sheave 86 in the same manner as shown in FIG. 2.
During normal operation of the manure spreader 10 with the embodiment of the drive system of FIG. 3, the sprocket 52 is driven in a clockwise direction via the chain 92 as seen in FIG. 3 due to the chain 92 extending around the sprocket 52 in a backwrap manner. The sprocket 64 is rotated clockwise via the shaft 58, and the sprocket 68 is rotated clockwise via the chain 94. The sheave 86 is rotated counterclockwise via the belt 84. The auger 30 is rotated in a clockwise direction by the stub shaft 32 when viewed from the front of the manure spreader 10, and the expeller assembly flails 44 are rotated in a counterclockwise direction by the central shaft 42 when viewed from the front of the manure spreader 10 at a substantially faster speed than the auger 30.
The following claims are intended to cover all modifications and variations of the preferred embodiment of the drive system disclosed herein without departing from the spirit and scope of the invention.
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In a manure spreader for handling slurry material, an auger is mounted in the bottom of a tank and an expeller is disposed at an opening in the tank to discharge material therefrom. A drive system is provided to rotate the auger and the expeller in different directions when the drive system is connected to a tractor PTO. the drive system includes a series of drive members such as chains and sprockets arranged and connected to cause rotation of the expeller in the same direction as the tractor PTO and rotation of the auger in the opposite direction at a substantially slower speed than the expeller.
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This is a continuation of U.S. application Ser. No. 078,041, filed 27 July 1987, now U.S. Pat. No. 4,790,483, which is a continuation-in-part of U.S. application Ser. No. 555,958, filed 29 Nov. 1983, now U.S. Pat. No. 4,609,148.
TECHNICAL FIELD
This invention relates to spraying equipment and particularly, although not exclusively, to equipment for spraying herbicides.
BACKGROUND AND PRIOR ART
It is becoming increasingly common for herbicides to be applied in the form of oil-based emulsions. Such herbicides are highly efficient and very small quantities, if properly applied, can be used to treat large areas. However, to be effective, the herbicides must be applied in the form of droplets of uniform size and distribution. The nature of the herbicide, which is commonly a viscous liquid having a viscosity, for example, of 20-40 centistokes, has made it difficult for this requirement to be met.
In known proposals for promoting the creation of fine droplets of uniform size, the fluid is supplied to a rapidly rotating disc from which the fluid is ejected by centrifugal force. The face of the atomising disc over which the fluid flows is formed with radial grooves terminating in radially extending points. Examples of such proposals can be found in British Patent Specifications Nos. 1515511 and 2008439. The radial grooves constitute channels along which fluid flows under the action of centrifugal force when the disc is rotated. At the radially outer ends of the grooves, the individual streams of fluid are ejected from the points and break up into fine droplets. When using such discs, however, it is not possible to control the spraying width or the droplet size to suit prevailing conditions.
SUMMARY OF THE INVENTION
According to the present invention there is provided a spraying device comprising a body and an atomising disc which is mounted on the body for rotation about a rotary axis. Drive means is provided for driving the disc in rotation. The atomizing disc has a fluid-receiving surface which is defined by an outer periphery of the disc from which fluid is discharged in operation. The outer periphery is polygonal as viewed parallel to the rotary axis of the disc, each side of the polygonal periphery being defined by the junction of the fluid receiving surface and a side surface which extends substantially parallel to the rotary axis, this junction being curved as viewed perpendicular to the rotary axis.
The drive means may comprise an electric motor and the equipment may further comprise an electrical lead connected to the motor and a liquid supply tube for supplying liquid to the atomising disc. The electrical lead and the supply tube may be accommodated within a support tube on which the body is mounted and emerge at the end of the support tube away from the body for connection to, respectively, a source of electrical power and a container of liquid to be sprayed.
In an embodiment in accordance with the invention, the support tube is mounted on a bracket which is adapted to be connected to a battery constituting the source of electrical power. The bracket also includes a handle so that the equipment can be carried and operated by hand. The bracket may be provided with a manually operated valve for controlling the supply of liquid to the spraying head and an on/off switch for controlling the supply of electrical power to the spraying head. The bracket may also be provided with an adjustable voltage regulator so that the voltage at the electric motor, and consequently the speed of rotation of the atomising disc, can be varied. This variability enables the spraying width of the equipment and the size of the droplets issuing from the atomising disc to be varied.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 is a perspective view of spraying equipment;
FIG. 2 is a partly sectioned view taken along the line II--II in FIG. 1;
FIG. 3 is a partly sectioned view taken along the line III--III in FIG. 1;
FIG. 4 is a partial end view taken in the direction of the arrow IV in FIG. 3;
FIG. 5 is a perspective view of an outlet fitting for a liquid container;
FIGS. 6, 7 and 8 are perspective views of, respectively, three elements of the outlet fitting of FIG. 5;
FIG. 9 is a circuit diagram representing a voltage regulating circuit of the spraying equipment;
FIG. 10 is a side view of an atomising disc for use with the spraying head of FIG. 1;
FIG. 11 is a perspective view from the rear of the disc shown in FIG. 10;
FIG. 12 is a perspective view from the front of the disc shown in FIG. 10;
FIG. 13 is a view taken in the direction of the arrow XIII in FIG. 10;
FIG. 14 is a sectional view of the disc shown in FIGS. 10 and 11;
FIG. 15 is a view corresponding to FIG. 10 but showing an alternative form of disc;
FIG. 16 is an end view of another form of atomising disc;
FIG. 17 is a partially sectioned side view of the disc. of FIG. 16;
FIG. 18 is an end view of a third form of atomising disc;
FIG. 19 is a partially sectioned side view of the disc of FIG. 18;
FIG. 20 is an end view of a fourth form of atomising disc;
FIG. 21 is a partial side view of the disc of FIG. 20; and
FIG. 22 is a sectional view of the disc of FIGS. 20 and 21.
DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS
Referring to FIG. 1, the spraying equipment comprises a support tube 2 which is connected at one end to a supply assembly 4 and carries at the other end a spraying head 6. The supply assembly 4 comprises a battery carrier 8 to which a battery 10 is connected and which is provided with a hollow handle 12. The handle 12 is mounted between front and rear limbs 14 and 16 of the battery carrier 8 and is connected at its rear end to a fluid supply line 18. Near its front end, the handle 12 is provided with an on/off tap 20, and at its extreme end it is connected to the support tube 2 by a fitting 22. A supply tube 38 communicates with the interior of the handle 12 and consequently with the fluid supply line 18. As can be seen from FIG. 2, the supply tube 38 is provided at its end with a flanged connector 40. An O-ring 42 is compressed between the connector 40 and a face provided on the handle 12 under the action of the fitting 22.
The battery 10 is connected to the bracket 8 by terminal nuts 24 (only one of which is visible in FIG. 1). The two terminals are connected by a lead 26 to an adjustable voltage regulator 28 controlled by a knob 30. The output of the voltage regulator 28 is connected by a short lead 32 to an on/off switch 34. The on/off switch 34 is connected by a further lead 36 to the spraying head 6.
As will be appreciated from FIGS. 1 and 2, both the lead 36 and the supply tube 38 extend down the support tube 2. The lead 36 extends through an opening 44 in the front limb 14 of the bracket 8 and through an opening 46 in the support tube 2.
As shown in FIG. 3, the spraying head 6 comprises a body 48 which accommodates an electric motor 50 having an output spindle 52. The lead 36 is connected to the input terminals of the motor 50. The output spindle 52 of the motor carries a rotary atomiser disc 54, the spindle 52 being a friction fit within a bore 56 in the disc 54.
The body 48 has three angularly spaced passages 58. Each of these passages is inclined to the axis of the motor 50 such that it extends inwardly and towards the atomising disc 54. At the inner end of each passage 58 there is a jet 60 having a restrictor passage 62. The diameters of the restrictor passages 62 of the jets are different from one another. The restrictor passages 62 open into a cavity 64 in the end of the body 48. An annular chamber is defined between a circumferential wall of the cavity and a shank of the disc 54. the circumferential wall terminates at a lip 66 which defines, with the disc 54, an annular outlet slot 68. The slot 68 is shown greatly enlarged in FIG. 3, for the sake of clarity. The width of the slot 68 is very small compared to the corresponding dimension of the annular chamber. Thus, in the illustrated embodiment, the width of the slot 68 is very small compared with the axial dimension of the annular chamber. In practice, the disc 54 may be pushed onto the drive shaft 52 until it contacts the annular lip 66, the slot 68 then being provided as a result of axial play in the bearings of the motor 50. The width of the slot is sufficiently small to make it impossible for a stream of liquid to flow across the surface of the disc 54 without contacting the lip 66. The maximum width of the slot may, for example, be 0.1 millimeter.
The radially outer portion of each passage 58 constitutes a socket for receiving an end fitting 70 of the supply tube 38.
The end of the fluid supply line 18 away from the handle 12 is provided with a plug element 72 (FIGS. 5 and 7). The plug element 72 has a barbed connector 74 which fits into the supply line 18 and communicates with a passage 76 extending through the plug element 72. The plug element has a cylindrical portion 78 carrying an O-ring 80. There is a flange 82 at the end of the cylindrical portion nearer the connector 74.
The plug element 72 is adapted to mate with a socket element 74 (FIGS. 5 and 6). The socket element 84 would, in use, be part of a container of liquid to be dispensed by the spraying equipment. The socket element 84 comprises a cylindrical socket 86 for receiving the cylindrical portion 78 of the plug element 72. The socket 86 has an end wall 88 from which projects a hollow spigot 90 which is a close fit in the opening 76 in the plug element 72. Before first use, the through passage of the spigot 90 is closed by a breakable diaphragm 92. The interior of the spigot 90 opens into a space enclosed by an apertured skirt 94 which, in use, would be disposed within the container to which the socket element 84 is fitted. In a preferred embodiment, the container is a collapsible bag and may be supported in a rigid box, for example of cardboard, in a manner similar to that which is sometimes used for packaging wine.
Thus, to connect the supply tube 18 to the container, the diaphragm 92 is pierced and the plug element 72 is inserted into the socket 86 until the flanges 82 and 94 abut one another. To secure the plug element 72 within the socket 86, a clip element 96 (FIG. 8) is provided. This clip element has a circumferential wall 98 the ends of which subtend an angle of slightly greater than 180° . The axial edges of the circumferential wall 98 are provided with radially extending walls 100 which, when the clip element 96 is fitted to the mating plug element 72 and socket element 84, extend on opposite sides of the abutting flanges 82 and 94, as shown in FIG. 5.
FIG. 9 represents the circuitry for regulating the voltage at the motor 50. The circuitry comprises an adjustable regulator 100, a stabilizing feedback resistor 102 and a variable resistor 104, controlled by the knob 30 of FIG. 2. FIG. 9 also shows the battery 10 and the on/off switch 34. Adjustment of the variable resistor 104 alters the current input to the control terminal of the voltage regulator 100, so altering the gain between the input and the output of the voltage regulator. The stabilizing feedback resistor 102 stabilizes the output current, preventing fluctuations which might otherwise be caused, for example, by internal variations in the voltage regulator 100 or by back e.m.f.'s generated by the motor 50. The circuitry shown in FIG. 9 is capable of adjusting the output voltage between 1.25 volts and 5.4 volts, the current drain of the voltage regulator being not more than 0.003 milliamps.
In the use of the equipment, the fluid supply line 18 is connected to the container in the manner described above and the bracket 8 is connected to the battery 10 by the nuts 24. The control rocker of the tap 20 is depressed to allow liquid, such as herbicide, from the container to descend under the action of gravity through the handle 12 and the supply tube 38 to the spraying head 6, where it passes through the end fitting 70 and the restrictor passage 62 into the cavity 64. The switch 34 is turned to the "on" position which causes power to be supplied from the battery 10 to the motor 50 to spin the atomiser disc 54. The liquid flows as an annular stream through the aperture 68 and is ejected by centrifugal force from the atomising disc 54 over the entire periphery of the atomiser disc. The cooperation between the disc 54 and the body 48 provides a pumping action which promotes the flow of herbicide through the jet 60. the width of the annular gap 68 is carefully selected, in dependence of the viscosity of the liquid to be sprayed, so as to ensure than an even distribution of the liquid reaches the rotary atomiser disc to achieve all-round spraying. The lip 66 provides a wiping action over the surface of the disc 54 to spread the herbicide over the disc. Thus, even through the herbicide is admitted to the cavity 64 at a single point and the disc has a relatively small diameter, even distribution can be obtained.
By controlling the voltage applied to the motor 50 by means of the voltage regulator 28, the speed of rotation of the atomiser disc 54 can be adjusted. Such adjustment will vary not only the distance over which the liquid is ejected from the disc 54, but also the size of the droplets into which the liquid is broken up as it leaves the atomising disc 54. Thus, the higher the speed of rotation, the greater the spreading width and the smaller the droplet size. In the embodiment illustrated, the speed of rotation of the atomising disc 54 is variable between approximately 200 and 4000 rpm. The disc 54 shown fitted to the output shaft 52 has a diameter of approximately 20 mm and will, at low speed, spray the liquid over a circular area having a diameter of approximately 10 cms with a large droplet size. Increasing the speed reduces the size of the droplets but will increase the diameter of the sprayed area to approximately 60 cms.
In order to achieve both a desired droplet size and a desired spreading width, the atomizing disc 54 may be replaced by alternative discs 54' and 54", illustrated in FIG. 3. The disc 54' has a diameter of approximately 30 mm and, at low speed, will spray over a circular area of approximately 30 cms diameter with large droplets and, at high speed, an area of approximately 1.2 meters diameter with small droplets. The smaller disc 54' has a diameter of approximately 10 mm and, at low speeds, will spray over an area of approximately 5 cms diameter with large droplets and an area of approximately 45 cms diameter with finer droplets, although the variation of droplet sizes at all spraying widths is likely to occur with the smaller disc.
The discs are a simple push fit on the output shaft 52 of the motor 50. However, in order to withdraw a disc from the output shaft 52 without damaging the periphery of the disc, a suitable tool may be provided for insertion into the passage 56. For example, the tool may comprise a screw threaded shank and the passage 56, at least at the end away from the output shaft 52, may be tapped to receive the shank.
The discs 54, 54' and 54" are circular as viewed axially and have peripheral edges which lie in a single transverse plane.
FIGS. 10 and 22 illustrate various alternative configurations of atomising disc which have been found to give good results.
The disc shown in FIGS. 10 to 14 has a square periphery as viewed parallel to the rotary axis of the disc (FIG. 13). This shape is achieved by cutting segments from a circular disc, and consequently the periphery of the disc is defined by four flat surfaces 126 (FIG. 10). Each surface 126 has the shape of a crescent, tapering to points 110 at the corners of the disc. Alternatively, as shown in FIG. 15, the surfaces 126 could meet each other at common edges 138 which extend parallel to the rotary axis of the disc. In operation, the liquid flows as a film over the surface 127 of the disc which receives the fluid to be sprayed, and then flows from the surface 127 to the surfaces 126 at a position midway along each surface 126 (i.e. at the radially innermost part of the periphery). The fluid then migrates to the corners of the disc over the surfaces 126. The liquid is then thrown off as droplets from the points 110 or edges 138 at which the surfaces 126 meet each other. Because the inner surface 127 (i.e. that surface over which liquid flows during use of the disc) is concave, the peripheral edge 112 of the surface 127 does not lie in a single transverse plane. Instead the periphery 112 of the disc at the corners of the square is further from a notional plane 128 passing through the end face 129 of the atomising disc than are points on the periphery 112 of the disc midway between the corners. In other words, as shown in FIG. 10, the dimension d 1 is greater than the dimension d 2 . The length of each side of the square may be 12 mm. Good results are achieved if the diameter of the lip 66 is also approximately 12 mm.
The disc shown in FIGS. 16 and 17 is generally circular, as viewed parallel to the rotary axis (FIG. 16), but is provided with serrations or teeth 130. The tips of the teeth 130 are further from a plane passing through the end face of the disc than are the roots of the teeth, and so again, different portions of the periphery of the disc are at different positions along the axis of the disc.
The outer diameter of the disc is 34 mm, the height of each tooth being 2.5 mm. The angular pitch of the teeth is approximately 8° , giving 45 teeth in all. The teeth may be raked in either direction, but preferably, if they are raked, they slope towards the rear, with respect to the intended direction of rotation of the disc in operation. In operation, the teeth 130 cause air to be drawn between them as the disc rotates. The flow of air promotes the formation of fine droplets of consistent size.
The disc shown in FIGS. 18 and 19 is similar to that of FIGS. 16 and 17 in that it is provided with teeth 132, but is more suitable for discs of smaller diameter, such as 10 mm. In the disc of FIGS. 18 and 19, the teeth 32 have arcuate, rather than pointed, tips separated from each other by radial notches 133.
In the embodiment of FIGS. 20 to 22, the periphery, as viewed along the axis of the disc, is again generally square, although somewhat barrelled. This configuration is achieved by bending segments of a circular disc into a more axial position, and again has the effect of positioning different portions of the periphery at different positions along the axis of the disc. The bent-back portions 134 are provided, both inside and outside, with grooves 136 which lie in planes perpendicular to the axis of the disc.
The discs illustrated in FIGS. 10 and 22 result, in operation, in fine liquid droplets of consistent size. It is believed that this effect is achieved because the shapes of the discs create turbulence in their vicinity which causes liquid being discharged from them to collide with parts of the rapidly rotating disc and so to be broken into fine droplets.
Adjustment of the flow rate of liquid to the cavity 64 and thus from the disc 54 may be achieved by inserting the fitting 70 into the appropriate socket 58, since the flow rate will be controlled by the diameter of the restrictor passage 62 in the jet 60. These passages may, for example, range from 0.75 mm to 2 mm.
The spraying equipment described with reference to the drawings provides simple adjustment of spraying width and droplet size to meet the requirements of different circumstances. For example, in windy conditions, it is desirable to have a large droplet size in order to avoid wind drift.
The use of the connector described with reference to FIGS. 5 to 8 provides a convenient method of connecting the spraying equipment to containers of ready-to-use weed killing chemicals, i.e. chemicals which require no mixing by the operator. The connector enables the spraying equipment to be "plugged in" directly to the container in which the chemical is supplied, thus avoiding any handling of the chemical by the operator.
Although the present invention has been described with reference to the spraying of herbicides, it is also suitable for other spraying operations, such as the spraying of lubricants or coating compositions such as varnish.
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Equipment for spraying a fluid such as a herbicide comprises a support tube on which is mounted a head comprising a body and a rotatable disc. Electrical supply loads and a supply hose for fluid pass to the head through the support tube. The head and the body define between them a narrow annular gap. Fluid is supplied to the disc at a position radially inwards of the gap and flows through the gap to be discharged as fine droplets from the periphery of the disc. The width of the gap is such that the fluid passing through it is wiped circumferentially so that it is distributed around the disc. This promotes an even spray of fluid from all parts of the periphery of the disc. Special shapes for the disc are proposed in order to promote the formation of small droplets of uniform size.
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INCORPORATION BY REFERENCE TO ANY PRIORITY APPLICATIONS
[0001] Any and all applications for which a foreign or domestic priority claim is identified in the Application Data Sheet as filed with the present application are hereby incorporated by reference under 37 CFR 1.57.
FIELD OF THE INVENTION
[0002] The invention concerns a jettison device for a ship, platform or similar, particularly for a potentially hazardous object.
BACKGROUND OF THE INVENTION
[0003] Most ships and other ocean-going vessels, as well as mobile and stationary platforms for offshore use, have a number of potentially hazardous objects on board. Such objects may be pressurized gas cylinders (also referred to as gas bottles), canisters containing explosives, or other flammable or explosive substances or objects. A common denominator for these objects is that they pose a threat to the ship or platform, including its crew, in case of fire. Maritime regulations stipulate that in case of a fire in the vicinity of gas bottles, the bottles shall be moved to a safe area. The process of locating and removing such gas bottles is time-consuming, and potentially hazardous, and tends to delay the fire-fighting operations. It is therefore a need for a device by means of which such hazardous objects may be isolated.
[0004] CA 2 151 880 A1 describes a flexible, inflatable, recoverable “environmental hazard container assembly”, capable of containing a product while not allowing the introduction of any contaminants, and able to be rapidly deployed from either a vessel or a barge. The assembly is comprises a container, a cap, a storage and deployment device. In operation, latches holding a lid and platform portions of a box are tripped manually. Hydraulic cylinders located on the sides of the box are then activated, which rotates the main part of the box upward and outward around the hinge connecting the main part of the box to the platform.
[0005] DD 283 115 A5 describes a device configured for—in one operation—throwing a container from a ship, particularly a container with dangerous content. A container frame is provided with two rocker arms , which are hinged to the frame, parially supporting the container, and driven by actuators. When the pivot arms are lifted , the container is released from its attachment to the frame and is allowed to fall into the water.
SUMMARY OF THE INVENTION
[0006] The invention is set forth and characterized in the main claim, while the dependent claims describe other characteristics of the invention.
[0007] It is thus provided a jettison device for a ship, platform or similar, comprising a housing having an opening configured for facing towards an outside region of the ship or platform, a container for holding one or more objects, and removably arranged in the housing and locked in the housing via releasable locking means ( 28 ); a launch platform releasably connected to the housing and configured for supporting the container; characterized by complementary slanted surfaces on the launch platform and the container, respectively, or by a releasable hinged connection between the container and the launch platform. The container may comprise a cover panel configured for covering the opening.
[0008] In one embodiment, the container comprises signal emitting means, such as sonar transmitters or similar. The container may comprise retrieval means, whereby the container may retrieved from a submerged state. The container jettison means may comprise complementary slanted surfaces on the launch platform and the container, respectively.
[0009] It is also provided a ship, platform or other vessel, characterized in that it comprises at least one of the jettison devices and that at least one jettison device is arranged in or near a hull surface, with the opening facing a region outside the hull surface.
[0010] The invented system provides a jettison device for removing potentially hazardous objects (such as gas bottles) from a secure storage position on in or near the side of a ship, platform or other vessel, and deploying the object(s) safely to sea.
BRIEF DESCRIPTION OF THE DRAWINGS
[0011] These and other characteristics of the invention will become clear from the following description of a preferential form of embodiment, given as a non-restrictive example, with reference to the attached schematic drawings, wherein:
[0012] FIG. 1 is a perspective view of a ship having a plurality of the invented jettison device;
[0013] FIG. 2 is a part-sectional drawing of a ship's hull, illustrating the invented jettison device arranged in the vicinity of the hull surface;
[0014] FIG. 3 is a perspective view of an embodiment of the invented jettison device;
[0015] FIG. 4 is a perspective view of the embodiment shown in FIG. 3 , but where the removable container and launch platform are outside its housing;
[0016] FIG. 5 is a perspective view of the removable container, as shown in FIG. 3 , but from a different perspective;
[0017] FIG. 6 is a part-sectional drawing, illustrating the removable container being jettisoned from the housing;
[0018] FIGS. 7 and 8 are side views of embodiments of the removable device, located on a seabed;
[0019] FIGS. 9 and 10 as part-sectional views illustrating alternative jettisoning means; and
[0020] FIG. 11 is a perspective view of a ship having a plurality of the invented jettison device.
DETAILED DESCRIPTION OF THE INVENTION
[0021] The following description will use terms such as “horizontal”, “vertical”, “lateral”, “back and forth”, “up and down”, “upper”, “lower”, “inner”, “outer”, “forward”, “rear”, etc. These terms generally refer to the views and orientations as shown in the drawings and that are associated with a normal use of the invention. The terms are used for the reader's convenience only and shall not be limiting.
[0022] FIG. 1 illustrates the invented jettison device 4 installed on a ship 1 having a superstructure 2 and a cargo deck 3 . All jettison devices are installed in an opening in the hull surface 5 . Although three jettison devices 4 are shown in FIG. 1 , it should be understood that fewer or more devices may be installed. They may be installed at suitable locations on the vessel. Also, the invention shall not be limited to installation on a ship, but is equally applicable to installation on any floating vessel, as well as to floating and fixed platforms.
[0023] FIG. 2 shows the jettison device 4 installed in an inboard compartment 10 between an upper deck 9 a and a lower deck 9 b, facing the outside O of the ship through an opening in the hull surface 5 .
[0024] Referring now to FIGS. 3 and 4 , the jettison device 4 comprises a housing 6 , a launch platform 8 and a removable container 7 . In the illustrated embodiment, the housing 6 comprises a steel frame with lifting pad eyes 12 . The housing 6 also comprises forklift openings 11 in a lower base 19 . The lower base 19 provides a support for the launch platform 8 . The launch platform 8 comprises in the illustrated embodiment an upward-slanting base 17 and a rear wall 20 . The launch platform 8 may be removable (as shown in the figures) from the housing 6 and connected to the housing by means (not shown) that per se are known, but may alternatively be permanently integrated in the housing.
[0025] The removable container 7 comprises a protective cage structure 21 on a downward-slanting base 18 , the base being configured for support on the upward-slanting base 17 as shown in FIGS. 3 and 4 , and a cover panel 16 . The slanting bases are preferably equipped with a material with low friction. In the position shown in FIGS. 3 and 4 , the bases 17 , 18 are locked with respect to one another by suitable releasable locking means (not shown), such as rotatable latches, electro-magnetic couplers, etc. The downward-slanting base 18 on the removable container also provides a support for the desired cargo. In the illustrated embodiment, this cargo is four gas bottles 14 . The gas bottles are connected to onboard systems and/or appliances via hoses with quick-release couplings 15 , as is known in the art. The cover panel 16 is preferably designed to be generally flush with the hull surface 5 when the jettison device is installed in a ship (see e.g. FIG. 2 ).
[0026] Referring to FIG. 5 , showing the removable container 7 from another perspective than that shown in FIGS. 3 and 4 , the removable container also comprises a sonar transmitter 22 and cartridge 23 for retrieval devices (to be described below).
[0027] The complete jettison device 4 (as shown in FIG. 3 ) may be installed in a ship, platform or other vessel as one unit. The jettison device may installed in new-builds or retrofitted into existing vessels. Such installation or retrofitting will typically entail that the housing 6 is bolted or welded to a deck 9 b, near the hull surface 5 and having an opening 29 facing the outside O, shown in FIG. 2 .
[0028] FIG. 4 illustrates a situation where the removable container 7 and launch platform 8 are moved into (or out of) the housing 6 , via removable skidding beams 13 . Such removal or insertion is relevant if the removable container is to be replaced, removed for repair or refurbishment, or for use elsewhere on the ship. It should thus be understood that the removable container 7 may be a mobile unit.
[0029] FIGS. 2 and 3 illustrate the jettison device 4 in a stand-by position, i.e. with the removable container 7 (with its gas bottles 14 ) and the launch platform 8 installed and locked in the housing 6 . In this position, the gas bottles are supplying the relevant on-board systems via the couplings 15 . In an emergency, for example an on-board fire, where it becomes necessary to isolate or remove the hazardous cargo (e.g. gas bottles) 14 , the removable container 7 is released from the launch platform 8 by unlocking the aforementioned locking devices (not shown). Such unlocking may be done manually at the jettison device, remotely, or automatically (e.g. as a response to a temperature sensor input). When the unlocking procedure has been completed, the removable container 7 is no longer locked to the housing 6 (and its launch platform 8 ) and will slide out of the housing 6 opening 29 by virtue of the complementary slanting bases 17 , 18 and under the influence of gravitational forces. As the slanting bases are oriented with a sliding direction facing the hull surface 5 , the removable container 7 will slide out of the housing opening 29 and consequently out of the hull surface 5 , as illustrated in FIG. 6 . The removable container is thus falling away from the ship, and into the sea. The potentially hazardous gas bottles are thus removed from the fire.
[0030] Although not shown, it should be understood that the launch platform or/and housing may comprise ejection means, for example explosive charges, pressurized cartridges, loaded spring devices, or other actuators, configured to push the container 7 out of the housing 6 .
[0031] The removable container 7 may be furnished with floatation devices (not shown), whereby it will remain floating in the water surface. However, in a hazardous situation, for example involving a fire, it may be advantageous to have the removable container sink to the seabed or to a predetermined depth beneath the water surface. Therefore the removable container may be furnished with suitable weights and/or buoyancy devices (not shown) as the case may be.
[0032] FIGS. 7 and 8 illustrate two retrieval devices for submerged containers 7 , resting on a seabed B below a water surface S. The container 7 may comprise a sonar transmitter 22 ( FIG. 5 ) configured to emit acoustic waves W when the container 7 is submerged. Also, alternatively or as a supplement, the container 7 may comprise a retrieval tether 26 and buoyancy device 27 .
[0033] FIG. 9 illustrates an alternative container launching means. Instead of the container 7 sliding out of the housing 6 as described above, a releasable hinged connection 25 is provided between the container and the launch platform. When the locking means (not shown) are released, the container 7 pivots out of the housing, either by a ship rolling or pitching movement or aided by an ejection mechanism (not shown).
[0034] FIG. 10 illustrates yet another alternative container launching means. Here, the container 7 is suspended by an beam 24 , which is extendable from an inboard compartment 10 to beyond the hull surface 5 . When the extendable beam 24 (alternatively a telescopic beam) has been moved to the position shown in FIG. 10 , a locking mechanism 28 is released, whereupon the container is allowed to free-fall from the beam.
[0035] A key feature of the invented jettison device 7 is that it is installed in or near the hull surface 5 , such that at least one side of the jettison device is facing environment outside the ship 0 . In addition to the advantages mentioned above, this close proximity to the outside environment also provides for efficient cooling of the gas bottles, due to their exposure to the ambient air.
[0036] An alternative placement of the jettison device 4 , on a ship 1 ′ having an aft superstructure 2 ′, is illustrated in FIG. 11 .
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A jettison device isolates an object, particularly a potentially hazardous object on a ship, platform or similar object. The jettison device includes a housing with an opening configured to face towards an outside region, and a container configured to hold one or more of the objects. The jettison device further includes a container lock and a container jettison. A ship, platform or other vessel includes at least one of the jettison devices above and at least one jettison device arranged in or near a hull surface with the opening facing a region outside the hull surface.
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[0001] This application claims the priority benefit under 35, U.S.C. section 119 of U.S. Provisional Patent Application No. 61/663,333 entitled “Device For Extracorporeal Photo-Isomerization For Hyperbilirubinemia, And Method Thereof” filed on Jun. 22, 2012; which is in its entirety herein incorporated by reference.
FIELD OF THE INVENTION
[0002] The present invention relates to devices and methods for the phototherapeutic treatment of illness and diseases. This invention is also a phototherapy apparatus for treating jaundice, which is also known as hyperbilirubinemia. The invention emits a particular wavelength of blue light that is suitable for the conformational and structural photo-isomerization of bilirubin into water-soluble forms that are easier for the body to eliminate.
[0003] The invention is also directed to an apparatus for extracorporeal irradiation of a liquid containing bilirubin in which bilirubin is converted into its water-soluble photo-isomers. The invention additionally covers a process for the reduction of the bilirubin level in a human being. The instant invention also refers to an apparatus for phototherapy, particularly for the treatment of hyperbilirubinemia and is designed to deliver excellent performance and high operational flexibility and safety due to its unique construction.
[0004] The invention further relates to both method and apparatus for irradiating blood with blue radiation, and more particularly to such method and apparatus for extracorporeal radiation of blood from both humans and animals with stored blood or blood circulated outside the patient and returned to the patient after treatment.
[0005] This invention also relates generally to the treatment of neonatal hyperbilirubinemia (jaundice) and related conditions, such as Crigler-Najjar Syndrome, and more specifically it relates to phototherapy treatment methods and apparatus.
[0006] This invention also relates generally to a method and system for medical treatment of a living mammal, and more specifically relates to a method for treating the blood supply of a living subject by irradiating the blood for the purpose of photo-isomerizing bilirubin to reduce high levels in the blood stream.
[0007] The present invention further relates to an apparatus for treating blood or plasma by extracorporeal circulation and processes for manufacturing and using the apparatus.
[0008] This invention further relates generally to methods and systems for medical treatment of the human body, and more specifically relates to a method and system usable in treating the blood supply of a human subject for the purpose of reducing high levels of bilirubin in the blood supply of such subject.
BACKGROUND OF THE INVENTION
[0009] Jaundice is a condition experienced by many newborn babies as well as adults stricken with certain diseases where abnormally high levels of bilirubin have accumulated in their body. Its most pronounced symptom is yellow coloring of the skin and eyes. Jaundice is also known as hyperbilirubinemia.
[0010] Bilirubin is primarily a byproduct of the death and decomposition of red blood cells. Normally, bilirubin is conjugated with glucuronic acid in the liver so that it can be eliminated from the body through the bile. However, several of the proteins and enzymes that perform this function are not present at the necessary levels in newborns and in certain adult diseases. This leads to a rise in bilirubin levels in their blood. Since the bilirubin is not water-soluble it tends to accumulate in body tissues, thereby causing the yellow coloration. The danger of high levels of bilirubin is that it can be neurotoxic. If levels get too high there can be nerve damage, or even death.
[0011] In most cases, newborn jaundice is not very severe and disappears within a few weeks as the baby's body develops to a point where it is better able to rid itself of the bilirubin. However, if bilirubin levels are too high when the baby is still very young, then treatment may be necessary to prevent possible nerve damage. The most common treatment for jaundice is phototherapy.
[0012] Phototherapy is comprised of shining light onto skin. The light penetrates the skin to a certain degree and interacts with bilirubin. Bilirubin has the chemical structure shown in FIG. 1A . The carboxyl groups form hydrogen bonds with nearby nitrogen atoms, which hides the hydrophilic moieties and increases the molecule's overall hydrophobicity. Bilirubin's hydrophobicity makes it dangerous because it will readily absorb into tissue.
[0013] Phototherapy light can cause two distinct and important changes of bilirubin. The first is a configurational isomerization where intramolecular hydrogen bonds within bilirubin are broken. This change exposes a carboxyl group and helps makes bilirubin water-soluble for a limited time. Water-soluble bilirubin is safer because it cannot easily enter tissues or penetrate the blood-brain barrier; it is slowly eliminated through the bile. In this manner, phototherapy reduces the amount of total bilirubin that can potentially cause damage by about 20% during phototherapy. The second change is a structural isomerization of bilirubin to lumirubin. This change is irreversible and exposes one of the carboxyl groups, thereby making lumirubin more hydrophilic than bilirubin. The liver easily eliminates lumirubin through the bile. The amount of lumirubin produced by phototherapy is dependant on the intensity of the light. Higher light intensities generate more lumirubin. The quick elimination of lumirubin may account for the majority of total serum bilirubin reduction provided by phototherapy.
[0014] Phototherapy is considered to be extremely safe. The only potential risk is damage to a baby's eyes by the intense light. Therefore, it is highly recommended that the baby's eyes be covered appropriately during phototherapy. Otherwise, no significant side effects of phototherapy have been documented.
[0015] The appropriate wavelength of light varies within the available literature. The most appropriate wavelength for treating jaundice is 450 nm, which is the most efficient wavelength for the isomerization of bilirubin. It is likely that wavelengths that fall within the range of 400 nm-500 nm, and more specifically 445 nm-475 nm, will have a beneficial effect. In addition, a light intensity of at least 6 microWatts per square centimeter per nanometer of light wavelength is also needed. This intensity is equivalent to 2.7 milliwatts per square centimeter of 450 nm wavelength light.
[0016] Hyperbilirubinemia, an elevation in bilirubin circulating in the blood, can arise from both acute and congenital circumstances. Bilirubin is a natural byproduct of the metabolism of hemoglobin derived from aged or injured red blood cells. Infant hyperbilirubinemia (neonatal jaundice) is common but easily treated by placing the infant under blue lights. Unmanaged hyperbilirubinemia, however, leads to kernicterus (brain damage, ataxia) and early mortality. Solitary bilirubin is insoluble in the blood and cannot be efficiently excreted in this form. It is therefore conjugated and solubilized by the enzyme uridine diphosphate glycosyltransferase 1-A1 (UGT1A1), allowing excretion through the feces and urine. Unconjugated hyperbilirubinemia is a hallmark of Crigler-Najjar Syndrome (CNS) Type 1, a genetic deficiency of UGT1A1. The current standard treatment for CNS is phototherapy, which is conducted within a bed or chamber fitted with blue lights (wavelength of approximately 450 to 530 nm). Light of this wavelength initiates a photo-isomerization reaction which converts unconjugated bilirubin into an isomer known as lumirubin, which is water soluble and readily excreted. However, the onset of puberty is characterized by thickening and pigmentation of the skin, accompanied by a decrease in the body's surface area:volume ratio. These changes represent barriers to light penetration into circulating blood (which contains the majority of bilirubin). Therefore, the efficacy of phototherapy decreases substantially following puberty. Consequently, CNS life expectancy is 30 years of age even with regular phototherapy, in the absence of liver transplantation. Exchange transfusion and exchange plasmapheresis have been used as emergency measures prior to life-saving liver transplantation.
[0017] As already mentioned above, bilirubin is a byproduct of the natural turnover and destruction of red blood cells, which releases hemoglobin into the blood. Breakdown of hemoglobin releases a heme group which is further catabolized into bilirubin. At physiological blood pH (around pH 7.4), bilirubin's hydrophilic domain is masked by hydrogen bonding, reducing its solubility. However, bilirubin is conjugated to glucuronic acid in the endoplasmic reticulum of hepatocytes by the enzyme uridine diphosphate glycosyltransferase 1-A1 (UGT1A1), disrupting the hydrogen bonds. The resulting configurational and structural changes facilitate bilirubin solubilization and excretion through the liver, kidneys, and intestines. Crigler-Najjar Syndrome (CNS) Type 1 patients lack UGT1A1 activity due to a genetic abnormality and suffer from chronic unconjugated hyperbilirubinemia. While the normal level of unconjugated bilirubin in the blood is 0.2-0.9 mg/dL, CNS patients have ≧20 mg/dL of bilirubin in their blood. Young CNS patients sleep under beds fitted with long fluorescent blue lights, a treatment known as phototherapy. Phototherapy provides an alternative mechanism for disruption of bilirubin's hydrogen bonds (i.e. light absorption), allowing for conversion of unconjugated bilirubin into soluble, excretable lumirubin isoforms even in the absence of UGT1A1 activity ( FIG. 1 ).
[0018] However, phototherapy requires several hours of blue light exposure per day. Furthermore, the efficacy of phototherapy decreases in childhood as thickening and pigmentation of the skin interferes with penetration of blue light into the bloodstream. Effectiveness of phototherapy decreases further during puberty as the body's surface area:volume ratio decreases, such that CNS patients still die early despite regular phototherapy.
BRIEF DESCRIPTION OF THE FIGURES
[0019] FIG. 1 shows the conversion of bilirubin into lumirubin.
[0020] FIG. 2 illustrates the irradiation chamber used for the extracorporeal photo-isomerization of circulating bilirubin.
[0021] FIG. 3 describes the device used to control the fluid flow rate.
[0022] FIG. 4 illustrates the use of the apparatus of the invention for bilirubin photo-isomerization.
SUMMARY OF THE INVENTION
[0023] The invention is an apparatus for the extracorporeal (i.e. outside the body) photo-isomerization of circulating bilirubin and could serve as a replacement for the aforementioned transfusion and plasmapheresis emergency measures mentioned in the background section of this application. Using the apparatus, the direct irradiation of bilirubin in body fluid will improve photo-isomerization and decrease duration of treatment as compared to traditional phototherapy. Furthermore, extracorporeal photo-isomerization is applicable to any case of unconjugated hyperbilirubinemia, both acute and chronic, independently of cause.
[0024] The invention provides an extracorporeal photo-isomerization apparatus for treating mammals having diseases associated with abnormal levels of bilirubin, said apparatus comprising: (a) means for drawing body fluids from said mammal; (b) means for pumping said body fluids through flexible and clear sterile tubing; (c) optional means for oxygenating said body fluids; and (d) an extracorporeal irradiation chamber for exposing said fluids to blue light.
[0025] The invention described also concerns an apparatus for extracorporeal irradiation of a liquid containing bilirubin, with subsequent photo-isomerization of bilirubin. The invention further covers a process for improving bilirubin clearance in a human being.
[0026] The invention further provides a closed loop method for reducing high levels of bilirubin in the blood of a patient comprising: (a) removing blood from the patient; (b) pumping said blood through an irradiation chamber thereby photoisomerizing said bilirubin in said blood; and (c) returning the irradiated blood to the patient.
[0027] The invention also provides a closed loop method for reducing harmful levels of bilirubin in the blood supply of a mammal, comprising the steps of: (a) withdrawing whole blood from said mammal; (b) forming said whole blood into an extracorporeal stream; (c) flowing said stream through flexible and clear sterile tubing housed in an irradiation chamber; (d) irradiating said withdrawn whole blood in said irradiation chamber with blue light radiation to effect photoisomerization of bilirubin, thereby reducing the harmful levels of bilirubin; and (e) returning the irradiated whole blood to said mammal.
DETAILED DESCRIPTION OF THE INVENTION
[0028] As required, detailed embodiments of the present invention are disclosed herein; however, it is to be understood that the disclosed embodiments are merely exemplary of the invention that may be embodied in various and alternative forms. The figures are not necessarily to scale; some features may be exaggerated or minimized to show details of particular components. Therefore, specific structural and functional details disclosed herein are not to be interpreted as limiting, but merely as a representative basis for the claims and/or as a representative basis for teaching one skilled in the art to utilize the present invention.
[0029] FIG. 1 shows the conversion of bilirubin into lumirubin. Bilirubin (left) contains a hydrophilic domain that is masked by hydrogen bonds, shown by dotted lines (A). Photo-isomerization, indicated by the arrow, disrupts the hydrogen bonds (B) and converts bilirubin into the water-soluble lumirubin.
[0030] FIG. 2 illustrates the extracorporeal photo-isomerization of the circulating bilirubin. The patient's body fluid is passed through sterile tubing 1 in direct proximity to blue lights in the bottom of the irradiating chamber 2 which irradiate at a wavelength between 450 to 530 nm 4 . A solid clear layer 3 resides over the blue lights and provides support for the tubing. The photo-isomerization device has a reflective, hinged lid 5 a which can be lowered 5 b to cover the apparatus and to contain and focus the light waves in the direct proximity of the bodily fluid. The body fluid is routed continuously and unidirectionally through the tubing and exits out of the irradiation chamber device 6 to ultimately return to the patient.
[0031] FIG. 3 is a pump that controls the fluid flow rate. A peristaltic pump as shown in FIG. 3 , is one example of a mechanism to regulate the flow of a patient's body fluid. The fluid is drawn toward the pump 1 by the unidirectional rotation of the pump's spindle 2 . Body fluid is then subsequently propelled away from the pump 3 .
[0032] In the bilirubin photo-isomerization apparatus shown in FIG. 4 , body fluid is drawn from the patient's peripheral vein 1 into sterile tubing (shown as a thick black line), routed toward the photo-isomerization irradiation chamber device by a peristaltic pump 2 , passed through an optional oxygenation antechamber 3 , exposed to blue lights within the photo-isomerization irradiation chamber 4 , then returned to the body 5 .
[0033] The direct exposure of circulating bilirubin to blue light as described in the instant invention, therefore, would improve the efficacy of the photo-isomerization reaction ( FIG. 2 ).
[0034] The apparatus and method of the invention can be used in conjunction with other equipment requiring vascular access to which a patient may already be connected; for example, dialysis or transfusion equipment. The invention can be integrated in-line with existing equipment by using the same sterile tubing to pass bodily fluids directly from existing equipment into the instant invention (or vice versa).
[0035] The invention is further exemplified in more detail in connection with each component as follows:
Extracorporeal Photo-Isomerization Device
[0036] The aforementioned extracorporeal bilirubin photo-isomerization device draws body fluid (especially blood) from the patient into flexible sterile tubing, exposes bilirubin-containing body fluid to blue light within an extracorporeal irradiation chamber, then returns the fluid to the body (See FIG. 2 ). The body fluid within the tubing is propelled mechanically, for example by a peristaltic pump (See FIG. 3 ). The tubing passes across the irradiation chamber's clear horizontal surface, under which the blue lights reside. The flow rate is typically in the range of 100 to 500 ml/min. In liver support therapy this rate is preferably 300 ml/min. The body fluid feed unit can be, for example, a pump such as peristaltic pump.
[0037] The blue lights are chosen for light emission wavelengths of approximately 450 to 530 nm, which is the optimal range of absorption for bilirubin. Lights that emit within approximately 450 to 530 nm are commercially available as fluorescent tubes as well as newer LED (light-emitting diode) bulbs. LED bulbs hold the advantages of lower operational temperatures, reduced power consumption, and long operational lifespan. Current LED bulbs offer an emission intensity of >12 μW/cm 2 /nm. Indeed, LED exposure (410-490 nm wavelength range) has been shown to be sufficient for bilirubin photoconversion in experimental assays. A pediatric study has suggested that increasing the intensity of blue light exposure will expedite the bilirubin photoconversion reaction, which will shorten the necessary treatment duration. It is recommended that exposure of the skin to blue light surpasses 30 μW/cm 2 /nm for neonatal hyperbilirubinemia (jaundice). Unlike neonatal bilirubin phototherapy units, however, the present invention places body fluid in close proximity to blue light, allowing direct penetration of light into the circulating bilirubin. Therefore, even low intensity blue bulbs are likely to be sufficient for bilirubin photo-isomerization in the context of the invention.
[0038] The blue lights sit in the bottom of the irradiation chamber, beneath a clear horizontal surface, for example plexiglass, glass or other plastic that is clear and suitable for use. The material is chosen to ensure it does not restrict the passage of light rays from blue bulbs toward the body fluid in the tubing (See FIG. 2 ). For example, commercially available glass allows ˜90% transmission of visible light. The body fluid will pass through clear, light-transmissive medical grade tubing. The tubing passes back and forth multiple times across the horizontal surface, maximizing the dwell time of the body fluid within the irradiation chamber and thereby increasing exposure of circulating bilirubin to blue light. The irradiation chamber will also have a hinged lid at the top with a reflective coating on the lid's lower surface (See FIG. 2 ). When the lid is closed it will rest atop the tubing (without compressing the tubing), and the reflective surface will focus the light rays onto the bilirubin-containing fluid in the tubing. The body fluid travels within a closed loop, providing an unbroken sterile environment and minimizing the need for junctions and/or couplings in the tubing (See FIG. 4 ). Junctions may be susceptible to damage or leakage which would compromise sterility of the tubing's contents, so elimination of junctions is desirable.
[0039] Another common feature of the apparatus of the invention is that it comprises a blood compartment provided with two accesses, in which, during the treatment the patient's blood is circulated. To do this, a blood withdrawal line is connected between a blood vessel of the patient and an access, employed as entry, of the blood compartment; a blood return line is connected between the other access of the blood compartment, employed as exit, and a blood vessel of the patient; and the patient's blood is circulated in this extracorporeal circuit looped onto the patient, by means of a pump, usually placed in the withdrawal line.
[0040] In the practice of the present invention, blood is retained within sterile tubing the entire time and therefore there is no need for extra couplings and junctions and therefore reduces risk of blood contamination.
Vascular Access
[0041] For patients with recurring hyperbilirubinemia, regular treatment with the extracorporeal photo-isomerization apparatus of the invention may be necessary to maintain curative bilirubin conversion and subsequent excretion. Patients expected to require regular extracorporeal photo-isomerization treatment are fitted surgically with vascular access mechanisms which are designed to provide frequent access to the patient's blood. Some examples of these mechanisms are venous catheter, arteriovenous graft and arteriovenous fistula; a common example of their use is for kidney failure patients who require several hemodialysis sessions per week, at 3 to 4 hours per session. Of the current mechanisms, the arteriovenous fistula (AV) is considered the best candidate for long-term use and can be generated in up to 90% of candidate patients. These vascular access mechanisms will provide long-term, reusable access points at convenient locations for the patient, facilitating recurring circulation of body fluid through the photo-isomerization chamber.
[0042] An AV fistula has proven to be the best kind of vascular access for people whose veins are large enough, not only because it lasts longer but it is also less likely than other types of access to form clots or become infected.
[0043] Surgery to create an arteriovenous fistula is usually conducted using a local anesthetic, injected at the site of the proposed fistula. The procedure is performed in a hospital or one-day surgery center and can usually be performed on an outpatient basis if the patient is not already hospitalized. After cleaning and sterilizing the site, the surgeon will make a small incision in the forearm sufficient to allow the permanent joining together of a vein and an artery in the arm. The blood vessels will be appropriately blocked to stop blood flow for the procedure and incisions will be made to join them. Silk sutures, just as those used in other types of surgical incisions, will be used to close incised areas as needed after the vein and artery have been joined. Once joined, blood flow will increase, the vein will become thicker, and over a period of months the connection will become strong and develop into the fistula that will allow permanent vascular access.
Oxygenation of Body Fluid
[0044] The apparatus and method of the invention is enhanced by an (aerobic) oxygenated environment which makes the bilirubin photo-isomerization process more efficient. More specifically, decay of unconjugated bilirubin is faster and production of lumirubin is concomitantly enhanced. Therefore, oxygenation of bilirubin-containing bodily fluid expedites and/or enhances the bilirubin photo-isomerization capability of the present invention. One example of an oxygenation strategy is to use oxygen-permeable medical tubing and an external oxygen source (such as an oxygen tank). In this embodiment, the tubing containing body fluid would pass through a small antechamber containing pressurized oxygen before reaching the irradiation chamber (See FIG. 4 ). The oxygen in the antechamber will therefore diffuse through the tubing into the body fluid before the body fluid undergoes the photo-isomerization reaction in the irradiation chamber. The embodiment is compatible with the single, unbroken length of sterile tubing as described above in the Extracorporeal Photo-isomerization device section.
[0045] In another embodiment for increasing the oxygen concentration of the body fluid prior to photo-isomerization, the patient is fitted with an oxygen mask before and/or during the treatment time with the extracorporeal apparatus of the invention.
Disease Applications for the Extracorporeal Bilirubin Photo-Isomerization Device
[0046] Hyperbilirubinemia typically arises from a variety of causes involving hemolysis, liver dysfunction, or problems with the gallbladder or bile duct. The apparatus of the invention is useful for the treatment of unconjugated hyperbilirubinemia arising from any cause. Any disorder that causes hyperbilirubinemia can be treated with the apparatus and method of the invention.
[0047] Increases in bilirubin levels result from excessive erythrocyte decomposition, liver dysfunction or impaired hepatic excretion of bile. When bilirubin levels exceed glucuronidation and the subsequent excretion into bile, the result is hyperbilirubinemia, in which nonconjugated bilirubin (i.e. that bound to albumin) is elevated in plasma. Bilirubin concentrates in the phospholipid membranes of cells and, in sufficiently high concentrations, can pass through the blood-brain barrier (kernicterus). An increased risk of neurotoxic effects exists at a serum-bilirubin concentration of 20 mg/dl and up. The normal range of blood-bilirubin concentration in adults and children is less than 1 mg/dl. In patients with Crigler-Najjar syndrome type 1, the range is between 20 to 50 mg/dl.
[0048] Exemplary disorders that can treated using the apparatus and method of the invention include:
[0049] (1) Sickle cell anemia: exchange transfusion is typically indicated for intrahepatic cholestasis (SCIC), an uncommon but potentially fatal complication of sickle cell disease which can lead to hyperbilirubinemia. The severity of hyperbilirubinemia also depends on the patient's UGT1A1 genotype. The instant invention represents a potential alternative to exchange transfusion.
[0050] (2) Hereditary spherocytosis (HS): this is the most common inherited hemolytic disease in people of Northern European descent and can lead to neonatal hyperbilirubinemia severe enough to require exchange transfusion.
[0051] (3) α- and β-Thalassemia: variable status of the UGT1A1 gene affects bilirubin concentrations in both α- and β-thalassemia heterozygotes. The long-term increase in red-cell turnover causes hyperbilirubinemia and bilirubin-containing gallstones.
[0052] (4) Crigler-Najjar Syndrome (CNS) Type 1 is also treated with the method and apparatus of the instant invention.
[0053] The content of all references cited and/or introduced in the future for the record by an IDS by Applicant in connection with the instant specification of this invention and all cited references in each of those references are incorporated in their entirety by reference herein as if those references were denoted in the text.
[0054] While the many embodiments of the invention have been disclosed above and include presently preferred embodiments, many other embodiments and variations are possible within the scope of the present disclosure and in the appended claims that follow. Accordingly, the details of the preferred embodiments and examples provided are not to be construed as limiting. It is to be understood that the terms used herein are merely descriptive rather than limiting and that various changes, numerous equivalents may be made without departing from the spirit or scope of the claimed invention.
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The invention provides a device for extracorporeal photo-isomerization of bodily fluid containing bilirubin. The bodily fluid derives from a patient suffering from an elevation of unconjugated bilirubin. The device includes a sterile tubing which accesses the patient's bodily fluids (especially blood), routes the fluid into an extracorporeal chamber within which irradiation of bodily fluids takes place, and returns bodily fluids to the patient. Bodily fluids are continuously circulated through a single length of sterile tubing using an adjustable pump to regulate the flow, and as the fluid passes into the extracorporeal chamber it is irradiated by blue light within the chamber with an emission wavelength range of approximately 450 to 530 nm. This irradiation induces a photochemical reaction in bilirubin that changes its structure and facilitates improved excretion of bilirubin once it is returned to the patient. The extracorporeal photo-isomerization turns the bilirubin into a more readily excreted form.
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CROSS-REFERENCE TO RELATED APPLICATION
[0001] This application claims the benefit of U.S. Provisional Patent Application Ser. No. 60/227,637 filed Aug. 24, 2000.
REFERENCE TO MICROFICHE APPENDIX
[0002] not applicable.
STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT
[0003] not applicable.
BACKGROUND OF THE INVENTION
[0004] 1. Field of Invention
[0005] The present invention relates generally to chalk lines of the type suitable for temporarily marking a board or drywall or other relatively flat member or surface with a straight chalk line marking.
[0006] More particularly the invention relates to chalk lines provided with an adjustable dual-use clip adapted for quickly and securely connecting to the edge of the board for ease of snapping a line at any desired angle.
[0007] 2. Description of Prior Art
[0008] Conventional chalk lines comprise a string line coiled on a spool that is rotatably mounted in a housing partially filled with chalk powder. The free end of the line extends through a snug opening in the housing such that the line can be manually drawn from the housing for snapping a chalk line marking and can then be re-coiled into the housing for re-chalking of the line and for storage between uses.
[0009] Prior conventional chalk lines are typically provided with a hook at the free end of the string line for “hooking” over the edge of the board. (Reference herein to a “board” includes reference to any relatively flat member except where such inclusion would be contrary to such use and a plain reading thereof.) During use, the hook is positioned over an edge of the board, the chalked string is uncoiled from the housing and drawn taught over the board in the direction of the desired chalk line marking, after which the line is drawn away from the board and then let go such that the string snaps onto the surface of the board leaving a chalk marking along the line of contact therebetween.
[0010] If the desired chalk line marking is perpendicular to the edge over which the clip is hooked, the tension in the line will generally keep the hook in place while the line is snapped.
[0011] However, snapping a line at any other angle relative to the edge is more difficult and time consuming. If the string is drawn along an angle other than perpendicular to the edge, the hook tends to slip from the desired location. In addition, there are instances when a straight edge is not available such as attempting to hook over an outwardly curved edge. In either event, the hook tends to slip as the line is drawn taught prior to and/or during snapping thereof. To maintain the hook in the desired location, either one person must hold the clip in place while a second person draws and snaps the line, or a nail must be temporarily secured at the edge of the board for connecting the free end of the string. In the later instance, the nail must be removed after the line is snapped. Moreover, there are instances where it becomes extremely difficult to snap an angled line if a second person is not available. For example, it can be difficult to put a nail firmly at the edge of a piece of plywood that is very “springy”, or at the edge of a piece of drywall that tends to flake apart. In any event, use of the conventional prior chalk line for such “angled” lines results in inconvenience to the user, and additional labor and construction expense associated therewith.
[0012] Accordingly, it is apparent there is a need for a chalk line that eliminates the above-described disadvantages of prior conventional chalk lines when snapping angled lines. In particular, there is a need for a chalk line that connects quickly and firmly to the edges of a board regardless of the stiffness, material or configuration of the edge so as to eliminate the inconvenience and costs associated with use of prior conventional chalk lines for snapping angled lines.
SUMMARY OF THE INVENTION
[0013] The general aim of the present invention is to provide a new and improved chalk line that is adapted to quickly, easily and firmly clip to the edge of a board regardless of the stiffness, material and configuration of the edge so as to enable line chalking at any desired angle and without the disadvantages of prior chalk lines.
[0014] A detailed objective is to achieve the foregoing by providing a chalk line with a spring-loaded adjustable clip adapted to releasably grip the edge of a board.
[0015] Another detailed objective of the invention is to provide a chalk line with an adjustable clip that is further adapted for use as a conventional chalk line hook.
[0016] Accordingly, the clip hereof provides a dual-use function, to be able to clip onto a board, as well as hook onto the board similar to conventional prior chalk lines, permitting snapping of a chalk line quicker and easier that with conventional chalk lines.
[0017] These and other objectives and advantages of the invention will become more apparent from the following detailed description when taken in conjunction with the accompanying drawings.
[0018] In a preferred embodiment, the chalk line is provided with a clip comprising a pair of opposing gripping jaws that are pivotally connected together for opening and closing, that are spring biased to the closed position, and that are provided with opposite free end portions for manually opening the jaws when squeezed together. With this arrangement, the clip is firmly connected to a convenient edge by simply squeezing the free end portions of the clip to open the jaws, positioning the clip with the edge of the board between the jaws, and releasing the clip such that the spring closes the jaws to grip the edge of the board.
BRIEF DESCRIPTION OF THE DRAWINGS
[0019] [0019]FIG. 1 is a perspective view of a chalk line including a clip incorporating the unique aspects of the present invention connected to the edge of a board.
[0020] [0020]FIG. 2 is an enlarged perspective view of the clip of FIG. 1 shown in a closed position.
[0021] [0021]FIG. 3 is a side view of the clip in an open position.
[0022] [0022]FIG. 4 is a bottom plan view of the clip.
[0023] [0023]FIG. 5 is a top plan view of the clip.
[0024] [0024]FIGS. 6 and 7 are front and rear views of the clip.
[0025] [0025]FIGS. 8 and 9 are side diagrammatic views of the clip in the closed and in an alternate open position.
[0026] While the invention is susceptible of various modifications and alternative constructions, a certain illustrated embodiment has been shown in the drawings and will be described below in detail. It should be understood, however, that there is no intention to limit the invention to the specific form disclosed, but on the contrary, the intention is to cover all modifications, alternative constructions, and equivalents falling within the spirit and scope of the invention.
DETAILED DESCRIPTION OF THE INVENTION
[0027] For purposes of illustration, the present invention is shown in the drawings in connection with a chalk line 100 (FIG. 1) for creating a temporary chalk line mark on a board 110 .
[0028] Briefly, the chalk line 100 includes a string line 124 coiled on a spool (not shown) that is rotatably mounted in a housing 122 partially filled with chalk powder. The line 124 extends through a snug opening 128 in the housing, with the free end of the line passing through a hole 12 formed in the forward end of the clip 120 and being tied thereto.
[0029] To make the desired chalk line marking, the clip 120 is connected to the edge 126 , the string line 124 is manually drawn from the housing 122 and over the board 110 in the direction of the desired marking (such as shown in FIG. 1), after which the line is pulled away from the board and then let go to snap onto the board and create the chalk line marking along the line of contact therebetween. After use, or for re-chalking, the string line 124 is drawn back into the housing, and wrapped around the spool with the assistance of a rotatable handle (not shown) connected thereto.
[0030] In accordance with the present invention, the clip 120 of the chalk line 100 is uniquely adapted for quick and easy, yet firm connection to any convenient edge of the board 110 .
[0031] In carrying out one aspect of the invention, the clip 120 includes a pair of opposing clip members 1 and 2 that are adapted for releasably gripping the edge 126 of the board. The clip members 1 and 2 comprise gripping end portions 1 A and 2 A, preferably provided with teeth 7 and 8 , respectively, and free end portions 1 B and 2 B opposite the gripping end portions. The clip members 1 and 2 are pivotally connected together with pin 6 generally centrally thereof. In the embodiment shown, the clip members 1 and 2 are provided with pairs of laterally spaced overlapping flaps 9 and 10 , respectively, having aligned holes through which the pin 6 extends to define the hinge. A spring 5 is provided to bias the gripping ends of the clip members to the closed position. In the embodiment shown, a coil spring is held between the clip members by the pin 6 extending therethrough, the spring including free ends that engage the inside of the free end portions of the clip members to bias the clip closed.
[0032] With this arrangement, the normally closed clip 120 can be manually opened, by simply squeezing the free end portions 1 B, 2 B of the clip members, and then slipped onto the edge 126 of the board at the desired location. After the clip is released, with the teeth 7 , 8 gripping the board to maintain the clip firmly as positioned, the string line 124 can be drawn out at any angle therefrom to snap the line without concern that the clip will slip.
[0033] In carrying out a second aspect of the invention, the clip 120 is adapted for alternate use similar to a conventional hook associated with prior conventional chalk lines. To this end, the handle portion 2 B of the clip member 2 is formed with an L-shaped hook 3 at the free end thereof, with the hook extending away from the upper clip. As a result, if desired, the clip 120 can be simply hooked over the edge 126 in a conventional manner such as when edge is straight and extends generally perpendicular to the desired chalk line marking. Alternately, the clip can be hooked to a nail in the board with the teardrop shaped hole 11 in the clip member 2 .
[0034] As will be apparent to those skilled in the art that numerous alternate embodiment clips will fall within the scope of the present innovation. By way of example only, a clip in accordance herewith may be provided with alternately configured gripping rather than gripping teeth. In the embodiment shown, the clip members 1 and 2 are of sheet metal construction, but be made in any suitable manner such from a casting or forging. The clip may be made from any suitable material, but is preferably made from durable, lightweight metal or resilient plastic suitable for use at construction sites. The clips can be provided of any convenient size, such as for standard thickness drywall and plywood and dimensional lumber. And alternate shapes, constructions and pivot connections are known and may be provided within the present invention.
[0035] From the foregoing, it will be apparent that the present invention brings to the art a new and improved chalk line with an adjustable due-use clip. In particular, the clip will out perform prior hooks with its dual function that allows straight lines as well as angle lines in an effortless, effective, and time efficient manner. Instead of the necessity of driving a nail or having a second person hold one end of the string or even going through the trouble of getting a straight edge and a pencil, the user can simply clip the dual-use chalk line clip at one point of the angle and place the other end on the mark and snap the line.
[0036] Accordingly, the dual-use clip according to the invention permits faster more productive work by eliminating the need for an extra person to snap angled lines or the need of for a straight edge. Moreover, the dual-use clip does not substantially change the size, weight or appearance of the conventional chalk line, and it use will be intuitively obvious to the user upon sight without further instruction.
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A chalk line is provided with an adjustable clip that is adapted for positive gripping connection to an edge for drawing the chalk coated string line across the board. The adjustable clip includes a pair of opposing gripping jaws that are spring biased closed and manually operable for clipping onto the edge of the board. The clip also includes a hook and eyelet for alternate use as a conventional chalk line.
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BACKGROUND OF THE INVENTION
(1) Field of the Invention
The present invention relates to a catalyst for steam reforming of methanol which can be used to obtain hydrogen by decomposing methanol in the presence of steam, and to a method for producing hydrogen with the catalyst.
(2) Description of the Prior Art
Conventionally, there have been proposed, as catalysts for steam reforming of methanol, a number of catalysts having platinum or palladium supported on carriers such as alumina, or alternatively having a carried base metal like copper, nickel, chromium, zinc, or the like.
In general, it is commonly known that catalysts formed of element(s) of the copper group have excellent activity and selectivity (“Shokubai Koza (Catalysis Course), vol. 9,” edited by the Catalysis Society of Japan (published on May 10, 1985), Kodansha Ltd., pp. 132-134). On the other hand, it is believed that these catalysts formed of element(s) of the copper group, although they are excellent in activities, have problems in terms of heat stability.
Catalysts formed of copper compounds further containing palladium or platinum element are known, for example, there are disclosed catalysts having zinc, chromium, as a major component, and containing any one of copper, cobalt, platinum, palladium, rhodium, nickel, manganese, magnesium, and molybdenum (Japanese Patent Laid-Open No. 57-56302).
In addition, with respect to catalysts having a small deterioration of activity at elevated temperatures and showing a high catalytic activity, there are known methods in which the activity can be improved by supporting one or more metals from the group consisting of copper, zinc, chromium, and nickel and one or more metals from the group consisting of platinum and palladium on a carrier, alumina pre-coated with zirconia (Japanese Patent Laid-Open No. 57-7255).
As methods for preparing catalysts with superior activity and stability, there are known methods of preparing catalysts containing at least one metal of copper, zinc, aluminum and rare metals, and zirconium and further containing at least one metal selected from palladium, silver, rhenium and platinum (Japanese Patent Laid-Open No. 60-209255).
Furthermore, with respect to catalysts having high durability, there are known ones composed of metal oxide having, as essential components, copper oxide, zinc oxide, aluminum oxide, and silicon oxide, which may contain zirconium oxide, gallium oxide, palladium oxide as an optional component (Japanese Patent Laid-Open No. 10-309466).
As described above, although there are many known catalysts containing copper and platinum, and palladium, such catalysts are limited to ones having a range of relatively high atomic ratios of copper to platinum, palladium.
As general methods for preparing copper-based catalysts, kneading, coprecipitating, Cu plating, Cu spray coating methods, and the like are known, which methods have limitations on the minimum particle size of the catalysts. As catalysts displaying superior activity and durability, alloy-based catalysts of ultrafine particles are disclosed (Japanese Patent Laid-Open Nos. 07-116517, 07-265704, 08-215571, and 08-215576).
However, in all of the known methods mentioned above, it is at the actual circumstance that there exists no method having sufficient properties in terms of both activity and durability.
SUMMARY OF THE INVENTION
The present invention is intended to solve the disadvantages of catalysts hitherto known, thereby providing a new catalyst for steam reforming of methanol which can provide both sufficient catalyst activity and durability, and further providing an efficient method for producing hydrogen with the catalyst.
The inventors have conducted extensive research to solve the above-mentioned problems. In consequent, the inventor have found that the improvement in not only durability but also catalyst activity can be obtained surprisingly by adding palladium and/or platinum element(s), which have conventionally displayed an extremely low activity when used alone, to copper- and zinc-based catalysts in large amounts. On the basis of such findings, the present invention has been made.
The present invention is specified by the followings.
[1] A catalyst for steam reforming of methanol, characterized by comprising copper and zinc, and palladium and/or platinum, and in that an atomic ratio of copper to palladium and/or platinum is 0.5 to 10 and an atomic ratio of zinc to copper is 0.1 to 10.
[2] The catalyst for steam reforming of methanol according to [1], characterized in that the catalyst comprises palladium and/or platinum and the atomic ratio of copper to palladium and/or platinum is 0.5 to 5.
[3] The catalyst for steam reforming of methanol according to [1], characterized in that the catalyst comprises palladium and/or platinum and the atomic ratio of copper to palladium and/or platinum is 0.5 to 3.
[4] The catalyst for steam reforming of methanol according to any one of [1] to [3], characterized in that a catalyst comprising copper and zinc, and palladium and/or platinum is prepared by a coprecipitation method and subjected to calcining at 200° C. to 470° C.
[5] A method for producing hydrogen, characterized in that methanol is subjected to steam reforming in the presence of the catalyst according to any one of [1] to [4].
BRIEF DESCRIPTION OF THE DRAWING
FIG. 1 shows a relation of Cu/Pd atomic ratio to activity reduction rate and gas production rate.
DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS
Catalysts for steam reforming of methanol in the present invention are those comprising, as essential components, zinc, and palladium and/or platinum in addition to copper. In these catalysts, an atomic ratio of copper to palladium or platinum is in the range of 0.5 to 10. In the case of only palladium and/or platinum, the durability will be improved, whereas the activity is extremely low. In the case of only copper and zinc, the activity is high, but the durability is extremely low. In the present invention, when the atomic ratio of copper to palladium and/or platinum element(s) is 0.1 to 10, it has been surprisingly formed that the activity and durability are extremely high. The catalyst activity will be decreased, when the atomic ratio of copper to palladium and/or platinum element(s) is less than 0.1. The durability will be decreased at atomic ratios of more than 10. The atomic ratio is preferably in the range of 0.5 to 5, and preferably in particular in the range of 0.5 to 3. When catalysts are formed having compositions in which both palladium and platinum are contained, the atomic ratio of copper to the sum of these elements can be in the range of 0.1 to 10, and more preferably in the range of preferably 0.5 to 5. Further preferably, the atomic ratio is in the range of 0.5 to 3.
In addition, in the case of the catalysts for steam reforming of methanol in the present invention, it is necessary to have compositions in which zinc is also contained, because the catalytic activity is increased to a higher extent. The content of zinc is in such a range that the atomic ratio of zinc/copper is 0.1 to 10, and preferably 0.2 to 4. Furthermore, as far as the purpose of the present invention is not impaired, compositions containg other oxides can be possible.
It is possible to prepare the catalysts in the present invention by wet processes. For example, the catalysts can be prepared by general methods as described in “Shokubai Koza (Catalysis Course), vol. 5,” edited by the Catalysis Society of Japan (published on Nov. 1, 1986), Kodansha Ltd. If copper and zinc substances are prepared by known methods, followed by carrying palladium or platinum by impregnation and others, then sufficient activity and durability cannot be obtained, and such processing is not preferable.
When producing the catalysts by coprecipitation in the present invention, one can employ methods by which a metal salt solution is mixed with a basic carbonate or bicarbonate salt solution in a pH range of 6 to 9 and in a temperature range of room temperature to about 80° C., and the deposited coprecipitates (catalyst precursor) are washed in a temperature range of room temperature to about 50° C., filtered at room temperature, dried in a temperature range of about 100 to 160° C., and subjected to burning.
The burning temperature of the catalysts is preferably at low temperatures, and calcining is preferably carried out in the range of about 200° C. to 470° C. In the case of calcining at higher temperatures, the catalysts will be sintered, resulting in a decrease in activity. Therefore, calcining at temperatures of 470° C. or higher are not preferable. At temperatures lower than 100° C., on the other hand, the catalyst precursor prepared by coprecipitation is decomposed insufficiently, and desired levels of the activity cannot be achieved.
It is preferable that the catalysts obtained by the above-described processes are subjected to hydrogen treatment in a liquid or gas phase, and employed in reactions.
Furthermore, the steam reforming catalysts of the present invention, after prepared by the above-described processes, can be not only employed as formed catalysts by means of subsequent tablet molding or extrusion, but also formed into honeycomb in which they are carried on ceramics carriers such as mullite and cordierite, silica cloth, spongy metal-sintered porous plates, and the like.
Methods for producing hydrogen in the present invention are performed in the presence of the above described catalyst preferably in the manner allowing the catalyst in contact with methanol and water (steam). In this case, reaction conditions for methanol reforming are preferably a reaction temperature of 150 to 600° C. and preferably a reaction pressure of not more than 50 kg/cm 2 G, preferably in particular a reaction pressure of 30 kg/cm 2 G to normal pressure. The ratio of water to methanol is preferably in the range of 0.5 to 30 mole water per mole of methanol. The space velocity of a mixed vapor of methanol and water is preferably in the range of 50 to 50,000 hr −1 , and preferably in particular in the range of 100 to 15,000 hr −1 . The reaction can be also carried out with adding optional hydrogen gas, carbon monoxide gas, carbon dioxide gas, nitrogen, air, and others.
The reactions for producing hydrogen in the present invention can be performed by contacting the catalyst with methanol and water as described above, and are not of types having limitations, particularly on apparatus scales and others. For the mode of its contacting with the catalyst, any reaction manner hitherto known can be employed, such as fixed and fluidized bed manners.
The following will further explains the present invention by reference to Examples and Comparative Examples, and Testing Examples of the catalyst activity, which put no limitation at all on the scope of the present invention. In the following, all the percentages are on a mass basis.
1) Catalyst Preparation
EXAMPLE 1
An aqueous solution was prepared by dissolving 28.3 g of 10% aqueous solution of palladium nitrate [Pd(NO 3 ) 2 ], 1.49 g of copper nitrate trihydrate [Cu(NO 3 ) 2 ·3H 2 O], and 10.06 g of zinc nitrate hexahydrate [Zn(NO 3 ) 2 ·6H 2 O] into 200 ml of pure water. Next, to this solution was added 1N sodium carbonate [Na 2 CO 3 ] at room temperature with stirring and mixing until the solution reached a pH of 6.6 to 6.8. The formed slurry was stirred for 150 minutes, and then the formed precipitates were filtered under reduced pressure and washed thoroughly with distilled water. After that, the filtered precipitates were dried in an oven at 80° C. for 12 hours, and then subjected to calcining in an electric furnace at 350° C. for 3 hours in the air. The resulting oxide was subjected to tablet molding and crushed, and a 1 ml aliquot was removed. The aliquot was filled into a small reaction tube and subjected to reduction treatment using a mixed gas of H 2 /N 2 ={fraction (1/9)} at GHSV=6000 [hr −1 ] to obtain a catalyst.
EXAMPLE 2
A catalyst was prepared in a similar way to that of Example 1, except that 22.8 g of 10% aqueous solution of palladium nitrate and 2.39 g of copper nitrate trihydrate were added so as to achieve a copper/palladium atomic ratio=1 in Example 1.
EXAMPLE 3
A catalyst was prepared in a similar way to that of Example 1, except that 16.3 g of 10% aqueous solution of palladium nitrate and 3.43 g of copper nitrate trihydrate were added so as to achieve a copper/palladium atomic ratio=2 in Example 1.
EXAMPLE 4
A catalyst was prepared in a similar way to that of Example 1, except that 14.3 g of 10% aqueous solution of palladium nitrate and 3.76 g of copper nitrate trihydrate were added so as to achieve a copper/palladium atomic ratio=2.5 in Example 1.
EXAMPLE 5
A catalyst was prepared in a similar way to that of Example 1, except that 12.7 g of 10% aqueous solution of palladium nitrate and 4.01 g of copper nitrate trihydrate were added so as to achieve a copper/palladium atomic ratio=3 in Example 1.
EXAMPLE 6
A catalyst was prepared in a similar way to that of Example 1, except that 8.8 g of 10% aqueous solution of palladium nitrate and 4.64 g of copper nitrate trihydrate were added so as to achieve a copper/palladium atomic ratio=5 in Example 1.
EXAMPLE 7
A catalyst was prepared in a similar way to that of Example 1, except that 6.1 g of 10% aqueous solution of palladium nitrate and 5.09 g of copper nitrate trihydrate were added so as to achieve a copper/palladium atomic ratio=8 in Example 1.
EXAMPLE 8
A catalyst was prepared in a similar way to that of Example 1, except that 5.01 g of 10% aqueous solution of palladium nitrate and 5.26 g of copper nitrate trihydrate were added so as to achieve a copper/palladium atomic ratio=10 in Example 1.
EXAMPLE 9
The copper/platinum atomic ratio=2.5 was achieved by adding 2.53 g of chloroplatinic acid hexahydrate, instead of 10% aqueous solution of palladium nitrate, and adding 2.95 g of copper nitrate trihydrate in Example 1. These chemicals were dissolved in 200 ml of pure water to prepare an aqueous solution, to which aqueous ammonia was added at room temperature with stirring and mixing until the solution reached a pH of 6.6 to 6.8. The other procedures were the same as in Example 1 to prepare a catalyst.
EXAMPLE 10
The copper/platinum atomic ratio=3 was achieved by adding 2.30 g of chloroplatinic acid hexahydrate, instead of 10% aqueous solution of palladium nitrate, and adding 3.22 g of copper nitrate trilhydrate in Example 1. These chemicals were dissolved in 200 ml of pure water to prepare an aqueous solution, to which aqueous ammonia was added at room temperature with stirring and mixing until the solution reached a pH of 6.6 to 6.8. The other procedures were the same as in Example 1 to prepare a catalyst.
EXAMPLE 11
The copper/platinum atomic ratio=5 was achieved by adding 1.70 g of chloroplatinic acid hexahydrate, instead of 10% aqueous solution of palladium nitrate, and adding 3.97 g of copper nitrate trihydrate in Example 1. These chemicals were dissolved in 200 ml of pure water to prepare an aqueous solution, to which aqueous ammonia was added at room temperature with stirring and mixing until the solution reached a pH of 6.6 to 6.8. The other procedures were the same as in Example 1 to prepare a catalyst.
EXAMPLE 12
A catalyst prepared in a similar way to that of Example 5 was subjected to calcining in an electric oven at 400° C. for 3 hours in the air. The other procedures were the same as in Example 1 to prepare a catalyst.
EXAMPLE 13
A catalyst prepared in a similar way to that of Example 5 was subjected to calcining in an electric oven at 470° C. for 3 hours in the air. The other procedures were the same as in Example 1 to prepare a catalyst.
EXAMPLE 14
A catalyst prepared in a similar way to that of Example 5 was subjected to calcining in an electric oven at 500° C. for 3 hours in the air. The other procedures were the same as in Example 1 to prepare a catalyst.
EXAMPLE 15
A catalyst prepared in a similar way to that of Example 5 was subjected to calcining in an electric oven at 600° C. for 3 hours in the air. The other procedures were the same as in Example 1 to prepare a catalyst.
Comparative Example 1
A catalyst was prepared in a similar way to that of Example 1, except that 10% aqueous solution of palladium nitrate was not added and 6.07 g of copper nitrate trihydrate was added in Example 1.
Comparative Example 2
A catalyst was prepared in a similar way to that of Example 1, except that 2.69 g of 10% aqueous solution of palladium nitrate and 5.64 g of copper nitrate trihydrate were added so as to achieve a copper/palladium ratio=20 in Example 1.
Comparative Example 3
A catalyst was prepared in a similar way to that of Example 1, except that 1.1 g of 10% aqueous solution of palladium nitrate and 5.89 g of copper nitrate trihydrate were added so as to achieve a copper/palladium ratio=50 in Example 1.
Comparative Example 4
A catalyst was prepared in a similar way to that of Example 1, except that 33.3 g of 10% aqueous solution of palladium nitrate and 0.70 g of copper nitrate trihydrate were added so as to achieve a copper/palladium ratio=0.2 in Example 1.
2) Activity Testing
Copper/palladium catalysts and copper/platinum catalysts prepared in the above-described procedures were measured for the activity of the steam reforming reaction of methanol. As the starting material was employed 54.2% by weight of aqueous methanol solution (H 2 O/CH 3 OH=1.5(mol/mol)), and the reaction was carried out under the following conditions: a reaction temperature of 250° C., normal pressure, and a feeding velocity of the aqueous methanol solution as the starting material of 60(L-solv/L-cat·h) relative to the unit amount of the catalyst. The amount of a mixed gas of hydrogen and carbon dioxide formed by the reaction was measured, and the activity reduction rate was calculated from the activity reduction rate at the initial stage of the reaction and at 48 hours after starting the reaction. The obtained results of the activity testing are shown in Table 1 and FIG. 1 .
TABLE 1
Gas
production
Activity
Calcining
Cu/Pd
Cu/Pt
rate
reduction
tem-
atomic
atomic
(mol/ml-
rate
perature
ratio
ratio
cat · h
(%)
(° C.)
Example 1
0.5
2.56
1.2
Example 2
1
2.68
1.2
Example 3
2
2.41
1.6
Example 4
2.5
1.82
2.3
Example 5
3
1.98
2.5
Example 6
5
2.05
3.3
Example 7
8
1.97
5.4
Example 8
10
1.95
7.6
Example 9
2.5
1.81
3.2
Example 10
3
1.86
3.5
Example 11
5
1.96
4.7
Example 12
3
1.94
2.5
400° C.
Example 13
3
1.93
2.5
470° C.
Example 14
3
1.88
2.4
500° C.
Example 15
3
1.58
2.4
600° C.
Comparative
—
1.8
18.8
Example 1
Comparative
Example 2
20
1.83
11.8
Comparative
50
1.83
16.8
Example 3
Comparative
0.2
0.63
1.3
Example 4
As indicated obviously by the catalysts given in the above-described Examples and Comparative Examples, and from the results of the activity testing of the catalysts, it has been found that the catalysts of the present invention have sufficiently superior properties in terms of not only activity but also durability.
In addition, according to the method for producing hydrogen of the present invention, it is possible to produce hydrogen efficiently for a long period by employing the above-described catalyst of the present invention.
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The object of the present invention is to provide a new catalyst for steam reforming of methanol which can provide both sufficient catalyst activity and durability and additionally an efficient method for producing hydrogen with the catalyst, and for that purpose there is provided a catalyst for steam reforming of methanol, characterized by comprising copper and zinc, and palladium and/or platinum, and in that an atomic ratio of copper to palladium and/or platinum is 0.5 to 10 and an atomic ratio of zinc to copper is 0.1 to 10, and a method for producing hydrogen, characterized in that methanol is subjected to steam reforming in the presence of the catalyst.
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[0001] The invention relates to gel-coated materials suitable for use in applications in which flame retardancy is a highly desired characteristic, and methods for fabricating such materials.
BACKGROUND OF THE INVENTION
[0002] Materials desirably made fire resistant include polymeric materials, both natural and synthetic, woven and nonwoven fabrics, fibers, matting and batting. From a chemical structure perspective, low flammability can be achieved by introducing ring structures, and side groups which are not readily oxidized. For example, aromatic polyimides show excellent fire resistance, but are too costly for routine use.
[0003] A more common approach is to introduce one or more fire-retardant constituents to an inherently flammable material, such as in the case of a flammable polymer. The additive can be a fire-retardant monomer which is copolymerized to some degree with the inherently flammable monomer. Alternatively, the additive can be an unreactive material which is coated onto the material post-production, or molded or extruded with a polymeric material in a physical blend The inherently flammable material could also be reactively treated with a fire-retardant additive after polymer production, as in the chlorination of polymers such as polyethylene.
[0004] Compounds which have found use as fire-retardants include inorganic compounds such as antimony compounds, including antimony trioxide, antimony pentoxide, and sodium antimonate. Boron compounds such as zinc borate, boric acid and sodium borate. Alumina trihydrate and molybdenum oxides are also useful inorganic compounds.
[0005] Halogenated compounds have also been used, including decabromodiphenyl oxide, chlorendic acid, tetrabromophthalic anhydride, and similarly halogenated compounds. These halogenated compounds, especially chlorinated compounds, are often combined with the above-mentioned inorganic compounds, especially antimony-, iron-, cobalt-, nickel-, molybdenum-, and other metal-containing compounds, to produce synergistic fire-retarding effects.
SUMMARY OF THE INVENTION
[0006] The invention uses gel coatings on base materials to greatly increase the fire retardance of such materials. The gel coatings can be produced through sol-gel processing of foamed materials. The gel coating provides a degree of physical and flame protection for the materials thus produced. The oxidative resistance of such materials is unimproved as well. The coating is believed to minimize oxygen contact with the material. This can result in reduced incidence of oxidation from atmospheric oxygen for the materials, or any components contained within the materials, for example, reduced flammability for flammable contents, or reduced chemical oxidation for atmospheric oxidation-sensitive contents. The contents which can be included in the gel-coated materials include phase change materials in various forms.
[0007] The invention further provides a method for providing a gel coating on a material by a sol-gel process.
[0008] The invention provides flame-retardancy without altering the physical processing of the material, while undesirable alteration is commonly the case when inert halogen-containing additives are added. The gel-coated materials of the invention possess excellent light stability, in contrast to many halogen-based and phosphorus-based flame-retardant materials. The thermal stability of the gel-coated materials of the invention is at least as high as the untreated material; this is often not the case for halogen-based flame-retardant materials, which can produce corrosive hydrogen halides upon exposure to heat. The density of the gel-coated materials of the invention is lower than that of halogen-containing fire-retardant materials. The invention provides a gel-coated material having permanent fire-retardant properties.
[0009] The gel-coated materials of the invention are noncombustible, maintain their integrity upon exposure to flame, and seal the material completely from fire. The gel coatings are easily applied, and can easily be modified, with, for example, coloring agents. The gel coatings are repeatedly washable with commonly available solvents, and the fire-retardancy is retained upon such repeated washing.
[0010] The gel-coated materials of the invention possess excellent hydrolytic and chemical resistance, whereas phosphorus-containing flame-retardant materials generally do not.
[0011] Base materials generally described are adapted to be placed within articles of clothing including footwear and various articles of protective clothing designed for environments of extreme temperature and hazard from fire. According to the invention, a base material such as a foamed polymer, fiber, woven or nonwoven fabric, batting or matting is coated with a gel coating. The gel coating can also provide increased resistance to chemical reactants such as acids, bases and other chemicals that can damage or dissolve foamed materials. Such materials are ideal in protective clothing, for example, fire fighting suits. Gel-coated foamed materials are suitable foreflame-resistant cushions used in aircraft, automobiles, furniture and other cushioned articles. Fabrics, matting and batting are other applications for which the invention is suited.
[0012] The gel-coated materials of the invention can also contain heat control agents, such as those which store latent heat. Such heat control agents include phase change materials, which can be integral to the base materials or gel coatings of the invention.
[0013] For the purposes of this specification, metal oxides, and metal alkoxides also include those materials which are calcinable (or otherwise oxidizible) to metal oxides, and metal alkoxides, as described below. For the purposes of this specification, calcination includes oxidation processes in general.
[0014] A flammable base material can be inherently flammable, or can become flammable upon the introduction of flammable materials in the interior or exterior of the base material.
[0015] 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.
DETAILED DESCRIPTION
[0016] The gel-coated materials of the invention feature base materials coated with a gel, specifically a gel produced by sol-gel processing. The gel coating provides flame-, physical- and chemical-resistances to the coated material, resulting in enhanced performances in critical applications. The materials which are coated with a gel can be fabrics, fibers, matting, batting or polymeric materials. Useful polymeric materials can be foamed polymeric materials, for example, foam insulation layers of footwear or garments.
[0017] The burning of polymeric materials is highly influenced by the density of materials in general. Most unexpanded plastic polymers have densities commonly in the range of at least 0.7 g/cm 3 and at most 1.5 g/cm 3 . On the other hand, foamed polymeric materials have densities of about 0.03 g/cm 3 , so that only a few percent (typically less than 5%) of the total volume of these foams is solid polymer. The presence of so much gas in the structure of a foamed polymer influences the burning characteristics greatly.
[0018] The exposure of a large surface area to the oxygen present in air results in an increased rate of burning. On the other hand, since the amount of potentially flammable material per unit volume is relatively small, the heat available for flame propagation per unit area is relatively low. Also, for thermoplastic foams such as polystyrene foam, rapid melting results from the heat of flames. This causes the foam to recede rapidly from the flame, and the spread of flame is minimized, or the material is self-extinguishing.
[0019] Thermoset foams, in contrast, are highly crosslinked. Flame does not cause them to melt appreciably, so that the material does not recede from the advancing flame front. If the thermoset foam is intrinsically flammable, a rapid ignition of the entire foam can ensue.
[0020] There are five fundamental ways to increase the fire-retardance of polymeric base materials: increase the crosslinking density of the polymeric base material to increase its decomposition temperature; replace material which can serve as fuel with material that cannot serve as fuel in the polymeric base material, by adding inert fillers, halogen substituents, or inorganic constituents; induce the polymeric base material to flow when ignited by interrupting the polymer backbone, thereby allowing the polymer to drip and recede from the flame front; introduce pathways which allow alternate means of decomposition, for example pathways which lead to carbon charring; and mechanical means such as a non-flammable skin bonded to the surface of the polymeric base material, covering the polymer with an intumescent or nonintumescent coating, or simply installing a sprinkler system proximate the polymeric base material.
[0021] Fire-resistant coatings are generally of two types, intumescent and nonintumescent. Intumescence is the expansion of a coating into a foamlike carbonaceous char upon heating. Continuous heating of intumescent coatings pyrolyzes them into heat-resistant carbonaceous foam-like coatings.
[0022] The coating used to coat the foamed polymeric materials of the present invention is a gel coating. Specifically, the gel is prepared by a process known as the sol-gel coating process. A colloid is a suspension in which the dispersed phase is not affected by gravitational forces, due to the dimensions of the dispersed phase (1-1000 nm). A sol is a colloidal suspension of solid particles in a liquid. A gel can be considered to be the agglomeration of these particles into a structure of macroscopic dimensions, such that it extends throughout the solution. It is, therefore, a substance that contains a continuous solid skeleton enclosing a continuous liquid phase.
[0023] Sol-gel processing according to this invention involves chemical processing of gel precursors to prepare a colloid. These gel precursors consist of metal atoms surrounded by ligands. The metal atoms and the ligands fall into wide classes described below.
[0024] Generally, chemical processing of the gel precursors involves hydrolysis and condensation reactions in which the ligands of the precursors are replaced by bonds to the ligands of other metal or metalloid elements. This process results in a growing network of metal or metalloid elements linked together, eventually forming a gel.
[0025] The gels for use in the invention can be prepared via reactions which use monomeric, metal oxides as gel precursors. Metal oxides for use in sol-gel processing are generally represented by M(—OH 2 ) n (aquo ligand), M(—OH) n (hydroxo ligand), and M(═O) n (oxo ligand), where M is the metal atom, and n depends on the coordination state of M. Metal oxides for use in such reactions include TiO 2 , ZrO 2 , RuO 2 , RuO 4 , V 2 O 5 s, WO 3 , ThO 2 , Fe 2 O 3 , MgO, Y 2 O 3 , HfO 2 , Nb 2 O 5 , UO 2 , BeO, CoO, NiO, CuO, ZnO, In 2 O 3 , Sb 2 O 3 , Al 2 O 3 and SnO 2 . Mixtures of such oxides are also useful, such as ZnO—TiO 2 , TiO 2 —Fe 2 O 3 , SnO 2 —TiO 2 , Nd 2 O 3 —TiO 2 , Al 2 O 3 —Cr 2 O 3 , MgO—Al 2 O 3 , MgO—TiO 2 , MgO—ZrO 2 , ThO 2 —UO 2 , ThO 2 —CeO 2 , Bi 2 O 3 —TiO 2 , BeO—Al 2 O 3 , TiO 2 —Fe 2 O 3 —Al 2 O 3 , Al 2 O 3 —Cr 2 O 3 —Fe 2 O 3 , PbO—ZrO 2 -TiO 2 , ZnO-Al 2 O 3 —Cr 2 O 3 , Al 2 O 3 —Cr 2 O 3 —Fe 2 O 3 —TiO 2 , and ThO 2 -Al 2 O 3 —Cr 2 O 3 —Fe 2 O 3 —TiO 2 . It is also within the scope of this invention to use dispersions or sols of the ceramic metal oxides in combination or admixture with dispersions or sols of one or more metal oxides which are unstable in normal air environment (such as Li 2 O, Na 2 O, K 2 O, CaO, SrO, and BaO) and/or ceramic oxides having an atomic number of 14 or greater (such as SiO 2 , As 2 O 3 , and P 2 O 5 ), representative combinations including Al 2 O 3 —Li 2 O, TiO 2 —K 2 O, ZrO 2 —CaO, ZrO 2 —Al 2 O 3 —CAO, ZrO 2 —SrO, TiO 2 —BaO, B 2 O 3 —SiO 2 , TiO 2 —ZrO 2 —BaO, Al 2 O 3 —Na 2 O, TiO 2 —SiO 2 , MgO—SiO 2 , Fe 2 O 3 —BaO, ZrO 2 —SiO 2 , Al 2 O 3 —As 2 O 3 , ZrO 2 —P 2 O 5 , Al 2 O 3 —SiO 2 , Al 2 O 3 —B 2 O 3 , and Al 2 O 3 —Cr 2 O 3 —SiO 2 .
[0026] Instead of using the precursor material in the form of dispersions or sols of the oxides, it is within the scope of the invention to use the precursor materials in the form of water soluble or dispersible inorganic or organic compounds which are calcinable, or otherwise oxidizible, to the corresponding metal oxide or metalloid oxide. These compounds representatively include many carboxylates and alcoholates, e.g., acetates, formates, oxalates, lactates, propylates, citrates, and acetylacetonates, and salts of mineral acids, e.g., bromides, chlorides, chlorates, nitrates, sulfates, and phosphates, selection of the particular precursor compound being dictated by availability and ease of handling. Representative calcinable precursor compounds useful in this invention include ferric chloride or nitrate, chromium chloride, cobalt nitrate, nickel chloride, copper nitrate, zinc chloride or carbonate, lithium propylate, sodium carbonate or oxalate, potassium chloride, beryllium chloride, magnesium acetate, calcium lactate, strontium nitrate, barium acetate, yttrium bromide, zirconium acetate, hafnium oxychloride, vanadium chloride, ammonium tungstate, aluminum chloride, indium iodide, titanium acetylacetonate, stannic sulfate, lead formate, bismuth nitrate, neodymium chloride, phosphoric acid, cerium nitrate, uranium nitrate, and thorium nitrate.
[0027] The sol-gels for use in the invention can also be prepared via reactions which use monomeric, metal alkoxide precursors. This class of compounds is represented by M(OR) n , where M is a metal, OR is an alkoxide (an alkoxide with from one to six carbons which may be further substituted), and n is from 2 to 8, depending on the coordination state of the metal. The metals used in the metal alkoxide precursors are Ti, Cr, W, Th, Fe, Mg, Y, Zr, Hf, V, Nb, U, Be, Co, Ni, Cu, Zn, In, Sb, Al, Sn and Si. The alkoxy ligands are generally alkoxides with from one to six carbons such as methoxy, ethoxy, propoxy, butoxy, pentoxy, and hexoxy ligands, or substituted or unsubstituted aryloxy groups. oligomeric precursors can be used such as ethoxypolysiloxane (ethyl polysilicate), hexamethoxydisiloxane (Si 2 (OCH 3 ) 6 ) and octamethoxytrisilioxane (Si 3 (OCH 3 ) 8 ).
[0028] The monomeric, tetrafunctional alkoxysilane precursors are represented by the following formula.
[0029] where RO is a C 1 -C 6 substituted or unsubstituted alkoxy group, or a substituted or unsubstituted aryloxy group. Typical examples include methoxy, ethoxy, n-propoxy, n-butoxy, 2-methoxyethoxy, and phenylphenoxy groups. Ethoxypolysiloxane (ethyl polysilicate), hexamethoxydisiloxane (Si 2 (OCH 3 ) 6 ) and octamethoxytrisilioxane (Si 3 (OCH 3 ) 8 ) can also be used, as well as the cubic octamer (Si 8 O 12 ) (OCH 3 ) 8 . Organically modified silicates having various organic ligands can be used, such as those formed by combining tetraalkoxysilanes with alkyl-or aryl-substituted and organofunctional alkoxysilanes. Organic functionality can be introduced to the alkoxy ligands with substituents such as —(CH 2 ) n1 NH 2 , —(CH 2 ) n1 NHCO—O—NH 2 , —(CH 2 ) n1 S(CH 2 ) n2 CHO, and like substituents, where n1 and n2 are from 0 to 6. Polymerizible ligands can also be employed, such as epoxides, to form organic networks in addition to an inorganic network. Choice of precursor can be made according to solubility or thermal stability of the ligands.
[0030] To produce gels with somewhat less dense structure, to impart more organic character to the gel, or to allow for derivitization, organotrialkoxysilanes (R′Si(OR) 3 ) or diorganodialkoxysilanes (R′ 2 Si(OR) 2 ) can be used as gel precursors. The groups R′ need not be the same as each other on a given precursor molecule. Examples of such precursors are methyltriethoxysilane, methyltrimethoxysilane, methyltri-n-propoxysilane, phenyltriethoxysilane, and vinyltriethoxysilane.
[0031] Catalysts are optionally but generally present in sol-gel processing. Acids and bases are suitable catalysts for sol-gel processing as carried out in the invention. Such catalysts facilitate both hydrolysis and condensation reactions, and can play a role in product structures. Preferred catalysts include inorganic acids (e.g., hydrochloric, nitric, sulfuric and hydrofluoric acid), amines including ammonia and ammonium hydroxide, organic acids (e.g., acetic acid), bases (e.g., potassium hydroxide), potassium fluoride, metal alkoxides (e.g., titanium alkoxide, vanadium alkoxide). All other factors being equal, acid catalysis produces gels which are cross-linked to a lesser extent than gels produced by base catalysis. A suitable catalyst for the sol-gel processing reactions of the invention is nitric acid.
[0032] Sol-gel processing can take place in the presence of solvents. Suitable solvents include water, alcohols (e.g., methanol, ethanol), amides (e.g., formamide, dimethylformamide), ketones (e.g., acetone), nitrites (e.g., acetonitrile), and aliphatic or alicyclic ethers (e.g., diethyl ether, tetrahydrofuran, or dioxane). These solvents can facilitate hydrolysis reactions as described below, especially if the ligands present on the sol-gel precursor molecules are bulky, such as phenylphenoxy ligands.
[0033] Inasmuch as water is often a reactant involved in sol-gel processing reactions, as in the hydrolysis reaction described below, it is included in the list of solvents to the extent that water in excess of a stoichiometric minimum amount is provided. Solvents other than water are generally employed to prevent phase separation in those sol-gel processing reactions which involve water-immiscible components. Control over the concentration of the reactants is also provided through the use of a solvent.
[0034] The first reaction generally taking place is hydrolysis, in which the alkoxide ligands of the alkoxysilanes are replaced by hydroxide ligands, from water. This reaction is represented here.
[0035] where RO is a C 1 -C 6 substituted or unsubstituted alkoxy group, or substituted or unsubstituted aryloxy group. The product of this reaction is an alcohol, reducing the need for alcohol or other mutual solvents as the reaction proceeds. Since the reaction is reversible, the alcohol can also participate in reverse reactions, reesterification and transesterification. All substituents attached to silicon are labile, and populations of substituents will depend in an equilibrium sense on control exerted over the concentrations of alcohol and water, the type of catalyst used and the extent of reaction.
[0036] Under acid-catalysed hydrolysis conditions, the alkoxide ligand is likely to be protonated as a first step, making it a better leaving group as water attacks from the backside of the central silicon atom. Seemingly for this reason, steric effects of the ligands play a significant role in determining the rate of this reaction. Under base-catalysed hydrolysis, dissociation of water to produce hydroxide ion likely takes place. The hydroxide attacks the backside of the central silicon atom, displacing the alkoxide ion. Inductive effects of the ligands are likely to be important here since the silicon atom develops charge in the transition state.
[0037] The subsequent condensation reactions can either be between Si—OR and Si—OH or between two molecules of Si—OH to produce a silicate gel as shown in the following reactions.
[0038] The mechanism of silicate gel formation is distinct from that of organic polymers, in that the silicic acid (Si(OH) 4 ) polymerizes into discrete particles. These particles then aggregate into chains and networks. The resulting macroscopic structure of the gel can be characterized as either a dense network with well-defined solid-liquid interfaces, a uniformly porous network, or an open network.
[0039] This gel is then desirably applied to a base material, and dried to eventually produce a glassy material. Dried gels are referred to as xerogels or aerogels Xerogels are produced by evaporation of liquid, while aerogels are dried by supercritical extraction of solvent. During this phase of the process, consolidation of the gel occurs. This process is also referred to as curing. The rate of curing gives control over the porosity of the resulting gel coating.
[0040] The gel initially tends to shrink as liquid is removed, through removal of liquid at the surface of the gel. The amount of shrinkage that occurs initially is dependent both on how the gel is produced and how it is dried. Drying by evaporation of solvent produces xerogels which are denser than aerogels produced by supercritical extraction of liquid.
[0041] At pH values below about 2, hydrolysis reactions involve protonated alkoxide groups and the rate of hydrolysis is large compared to the rate of condensation. The supply of precursor monomers is essentially depleted at an early point in the condensation reaction. Resulting cluster-cluster aggregation leads to weakly branched structures. Above pH of about 7, hydroxide and SiO − ions are the reactive species in hydrolysis and condensation reactions, respectively. If at least stoichiometric ratios of water to gel precursor are used ([H 2 O]/[Si]≧4), more compact and highly branched structures result as described in Brinker et al. Sol-Gel Science, Chapter 3.
[0042] Thus, gels produced through acid-catalysis are cross-linked to a lesser extent. Such gels shrink more during initial drying because the structures can interpenetrate each other more. The pores in such a gel are smaller, so that capillary pressure which is exerted during final stages of drying further compacts the structure. The resulting gel is characterized by an extremely fine texture.
[0043] The pores in gels produced by acid-catalysis and drying by evaporation range in size from 10 to 50 Å.
[0044] According to the invention, gel coatings of metal oxides, metalloid oxides or the compounds calcinable (or otherwise oxidizible) to such oxides (such as those listed above) are produced on the surface of a base material. The gel coatings desirably provide a continuous coating on the surface of the base material.
[0045] As an example, the base material can be a foamed polymeric material. This material can be hydrophobic, hydrophilic or amphipathic. Exemplary of acceptable polymers are polyurethane, polypropylene, butyl, silicone, cellulose acetate, neoprene, epoxy, polystyrene, phenolic, and polyvinyl chloride. Foams such as styrofoam are not particularly well suited for the gel-coatings of the invention, and are not preferred. The foamed material should not react appreciably with the sol used to produce the gel in such a way as to structurally weaken the foamed material. Limited chemical reaction with the surface of the foamed material may take place, and in fact may be beneficial in certain applications, for example, on silicon foam. Preferred are materials such as a moldable foamed organic plastic. The foamed materials need not be inherently flammable. Foams such as silicon foams are not inherently flammables but if a flammable material is contained within the interior, or on the surface of, a non-flammable foam, a gel coating is useful.
[0046] The gel coatings of the invention are equally useful with open- or closed cell foams. For applications in which the foam is desired to be breathable, an open cell foam is preferred. An open cell foam structure also allows for the possibility that the entire foam can become impregnated with the gel coating. In such cases, uncured sol can be removed by squeezing the open cell foam after it has been soaking in the sol to clear air passages and allow the foam to remain breathable. Open cell foams with particularly fine cell structure could become impermeable in this way, however, as the air passages could conceivably become solidified. Foams with closed cell structures will only have gel coatings on their exposed surfaces, since the uncured sol will not penetrate to the interior of a closed cell foam. The choice of open or closed cell foam is made based on the particular application. If a high level of flame resistance is necessary, an open cell foam is preferred, as it will absorb a much greater amount of sol than a closed cell foam. If the foam is required to remain relatively lightweight, a closed cell foam may be better, since its interior will remain as an uncoated foam. This also makes the bulk properties of gel-coated closed cell foams similar to those of uncoated closed cell foams, since the vast majority of the foam is unaffected by the coating, and its physical properties are largely retained.
[0047] The base material can also be a fabric. Suitable fabrics include those typically used for clothing materials, such as natural fabrics, including cotton, linen, wool, hemp, jute, ramie, silk, mohair, vicuna, and the like. Other fabrics include man-made fabrics such as organic polymer fabrics including rayon, viscose, acetate, azlon, acrylic, aramid, nylon, olefin, polyester, spandex, vinyon and the like. Such fabrics can be knitted, woven or nonwoven. The base material may also be the fibers or filaments of the materials listed above which are composed of fibers or filaments. In either case, the gel coating is applied in essentially the same way as described for polymeric materials and foamed polymeric materials.
[0048] Such base materials, in addition to themselves having a potential for flammability, may contain other desirable constituents which are independently flammable, and may render an otherwise nonflammable base material flammable by virtue of their flammability. In such cases, the gel-coated materials of the invention also provide protection against flame.
[0049] Such desirable constituents which may be present in a base material include materials which can absorb heat and protect an underlying material from overheating. Thermal energy is absorbed by the phase change of such materials without causing an increase in the temperature of these materials. Suitable phase change materials include paraffinic hydrocarbons, that is, straight chain hydrocarbons represented by the formula C n H n+2 , where n can range from 13 to 28. Other compounds which are suitable for phase change materials are 2,2-dimethyl-1,3-propane diol (DMP), 2-hydroxymethyl-2-methyl-1,3-propane diol (HMP) and similar compounds. Also useful are the fatty esters such as methyl palmitate. Preferred phase change materials are paraffinic hydrocarbons.
[0050] Such constituents can be encapsulated, as is desired in the case of phase change materials. Such encapsulated constituents can further be encapsulated in microcapsules. The microcapsules can be made from a wide variety of materials, including polyethylene, polypropylenes, polyesters, polyvinyl chloride, tristarch acetates, polyethylene oxides, polypropylene oxides, polyvinylidene chloride or fluoride, polyvinyl alcohols, polyvinyl acetates, urethanes, polycarbonates, and polylactones. Further details on microencapusulation are to be found in U.S. Pat. Nos. 5,589,194 and 5,433,953. Microcapsules suitable for use in the base materials of the present invention have diameters from about 1.0 to 2,000 microns.
[0051] Such constituents can be introduced to the base materials pre- or post-manufacture, that is, before or after the material is formed in its final state. This depends on the nature of the constituent, and whether it can survive the manufacturing or processing of the base material and still retain its desired function, or whether the manufacturing or processing can impart new and desired functionality to the constituent.
[0052] For example, if a microencapusulated phase change material is to be introduced into a foamed polymeric material, it could be dispersed throughout the polymeric material prior to the foaming of the polymer. In some embodiments, the microencapusulated phase change material could be dispersed throughout the polymeric material so that it forms a product in which the microcapsules are individually surroundingly encapsulated and embedded within the base material. Alternatively, such phase change material could be pressed directly into the foam after it is made, for example, by pressing the microcapsules into the foam with an applicating instrument. Gel coatings can be formed on base materials containing various loadings of phase change containing additives. The fire-retardant capabilities of the sol-gel can suppress the flammability of any flammable phase change materials.
[0053] The invention also provides a method for producing gel-coated materials, by the method of sol-gel processing. In general, base materials as described above are mixed with a sol which is allowed to cure into a gel.
[0054] Sols are generally prepared by mixing metal-containing gel precursor and solvent together in a precursor/solvent ratio which can vary from about 3:1 to about 5:1 by volume. Preferably, the precursor/solvent ratio varies from about 3.5:1 to about 4.3:1. Separately, catalyst and water are mixed in a catalyst/water ratio which can vary from about 1:12 to about 1:22 by volume. The two solutions are mixed together with stirring.
[0055] As the mixture warms and subsequently cools, the onset and completion of reaction is indicated. At the completion of reaction, the mixture is contacted with a base material surface. The mixture can be sprayed onto the material, brushed onto the material, or the material can be dipped into the sol.
[0056] Spraying of the sol onto an article is however, less likely to result in a continuous coating on the base material surface. A sprayed sol is likely to cure more rapidly than a brushed sol, for example. In certain instances, this is a desirable situation. For example, if the material is particularly reactive with the sol, spraying may be the best way to avoid prolonged contact with the sol which would occur if the base material were soaked in, or brushed with a sol. If further materials are to be included, they can be included directly in the sol before curing creates a gel.
[0057] The invention will be further described in the following examples, which do not limit the scope of the invention described in the claims.
EXAMPLES
[0058] The following examples illustrate certain embodiments of the gel-coated materials of the invention, their properties, and methods of their manufacture.
Example 1
Preparation of a Gel-Coated Foamed Material
[0059] A gel-coated foamed silicon material was prepared. The procedure required handling materials that are hazardous to human health. Suitable protective equipment was worn and appropriate precautions were taken to prevent the inhalation of any hazardous solvents, and particular care was taken to avoid the inhalation or skin contact with nitric acid and tetraethyl orthosilicate. No open flames were allowed in the vicinity during the procedure. The reactions were carried out in a fume hood with a filter for volatile organic compounds. The operator wore protective clothing, latex gloves, protective goggles and a respirator for dust and volatile organic compounds. All transfers were one by pipette.
[0060] Ethanol (16.5 mL of 95% ethanol) and 63 mL of 98% tetraethyl orthosilicate (TEOS) were added to a 150 mL polypropylene or polymethyl propylene container, and mixed well. In a separate container, 20.4 mL of deionized water and 1.62 g of nitric acid were mixed. The acidic solution was added to the TEOS solution and stirred with a Teflon-coated stirring stick for 30 minutes. The mixture was observed to become warm and then cool as the reaction was completed. This material was placed in a shallow tray and a sample of open cell silicon foam was placed in the sol. The foam was soaked in the sol long enough to fully cover all surface, and then removed. Excess sol was removed by squeezing and wringing of the foamed material. Open cell foams may need to be squeezed while in the sol to ensure coverage of all exposed cell surfaces. The foam was left to cure overnight.
[0061] Gel-coated polyurethane was prepared similarly, and produced a somewhat more brittle coating, although the open cell structure of the foam was retained.
Example 2
Flammability Testing on Gel-coated Foamed Material
[0062] Tests have been conducted on open-cell silicone foams. Foam samples were coated with sol-gel by dipping the foam into the liquid sol, squeezing the foam to ensure complete coverage inside the foam cells, removing the foam from the sol, blotting off the excess sol, and setting the cured foam aside to allow the gel coating to cure overnight. Open-celled foam structures were found to require less curing time. It was also discovered that slow curing (not accelerated by heat) resulted in less cracking. Faster cures gave more flexible gel coatings.
[0063] Both coated and uncoated foam samples were exposed to an open flame for 12 seconds. This open flame test was carried out as described in FSTM 191A, which is also similar to FAR part 25, Appendix F, Part I.
[0064] Although neither silicone foam sample burned, the uncoated foam became friable at the area of flame contact and crumbled into sand (SiO 2 ) when touched after cooling. When a single coating (approximately 1-2 microns) of sol-gel was applied and cured, there was some indication of discoloration, but the foam did not become friable and remained flexible.
[0065] Similar tests on polyurethane foams showed that an uncoated foam burned readily. A single gel coating also burned but at a much more controlled rate, and a double gel coating (second coating applied after curing of the first coating) resulted in a polyurethane foam that completely inhibited continuous burning when the flame was removed, although the foam did burn with the flame applied directly.
[0066] It is to be understood that while the invention has been described in conjunction with the detailed description thereof, the foregoing description is intended to illustrate and not limit the scope of the invention, which is defined by the scope of the appended claims. Other aspects, advantages, and modifications are within the scope of the following claims.
[0067] For example, the gel coatings described herein can also be applied to fabrics, or individual natural and man-made fibers, thereby imparting fire-, physical-, and chemical-resistance to those materials. The application of the sol to fabrics or fibers would be undertaken according to methods which are analogous to those described for foamed polymeric materials.
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The invention provides gel-coated materials that provide enhanced flame-, physical- and chemical-resistance to the foamed materials. The gel coatings can be created with a sol-gel process. Such treated materials can be used, for example, in the manufacture of articles of clothing that are to be used in environments in which fire and exposure to acids, bases or other chemicals which tend to corrode foamed materials is a potential hazard.
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CROSS REFERENCE TO RELATED APPLICATIONS
This application is a division of U.S. application Ser. No. 11/315,774, filed Dec. 22, 2005, now allowed, which is a continuation of International application No. PCT/FR2004/001,580, filed Jun. 24, 2004, which is incorporated herein by reference in its entirety; which claims the benefit of priority of French Patent Application No. 03/07,698, filed Jun. 25, 2003.
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to 4-cyano-pyrazole-3-carboxamide derivatives, their preparation and their therapeutic application.
2. Description of the Art
A 4-cyanopyrazole-3-carboxamide derivative is known: N-phenyl-1-(2-chlorophenyl)-4-cyano-5-(4-methoxyphenyl)-1H-pyrazole-3-carboxamide which is described in Biochem. Pharmacol., 2000, 60(9), 1315-1323. It is presented as having antagonist properties for the CB 1 cannabinoid receptors and more precisely inverse agonist properties for said receptors.
SUMMARY OF THE INVENTION
The subject of the present invention is a compound corresponding to formula (I):
in which:
R 1 represents hydrogen or a (C 1 -C 4 )alkyl; R 2 represents:
a (C 3 -C 7 ) alkyl group; a nonaromatic C 3 -C 10 carboxyl radical which is unsubstituted or substituted once or several times with a (C 1 -C 4 )alkyl and/or hydroxyl group; a phenyl which is substituted once or several times with a halogen atom and/or with a (C 1 -C 4 )alkyl and/or trifluoromethyl and/or (C 1 -C 4 )alkoxy group; an NR 9 R 10 group; a CH[(C 1 -C 4 )alkyl]benzhydryl group in which one or both of the phenyl groups are unsubstituted or substituted once or several times with a halogen atom and/or with a (C 1 -C 4 )alkyl and/or (C 1 -C 4 )alkoxy group;
or R 1 and R 2 together with the nitrogen atom to which they are attached constitute a piperidin-1-yl radical which is disubstituted at the 4-position with a phenyl or benzyl group and with a (C 1 -C 4 )alkyl group or a (C 1 -C 3 )alkanoyl; R 3 , R 4 , R 5 , R 6 , R 7 , R 8 represent, each independently of the other, a hydrogen or halogen atom, a (C 1 -C 6 )-alkyl, (C 1 -C 6 )alkoxy or trifluoromethyl group; provided that at least one of the substituents R 3 , R 4 , R 5 , R 6 , R 7 , R 8 is different from hydrogen; R 9 represents a hydrogen atom; R 10 represents a (C 3 -C 6 )alkyl; or R 9 and R 10 together with the nitrogen atom to which they are attached constitute a saturated or unsaturated heterocyclic radical of 5 to 10 atoms, possibly containing a second heteroatom chosen from O or N, said radical being unsubstituted or substituted once or several times with a (C 1 -C 4 )alkyl and/or hydroxyl and/or (C 1 -C 4 )alkoxy and/or methoxy(C 1 -C 2 )alkylene and/or (C 1 -C 4 )alkanoyl group, or substituted with a spirocyclobutane, a spirocyclopentane or a spirocyclohexane;
and their salts, their solvates and their hydrates.
DETAILED DESCRIPTION OF THE INVENTION
The compounds of formula (I) may contain one or more asymmetric carbon atoms. They can therefore exist in the form of enantiomers or diastereoisomers. These enantiomers, diastereoisomers and mixtures thereof, including racemic mixtures, form part of the invention.
The compounds of formula (I) can exist in the salt form. Such addition salts form part of the invention.
These salts are advantageously prepared with pharmaceutically acceptable acids, but the salts of other acids which are useful, for example, for the purification or isolation of the compounds of formula (I) also form part of the invention.
The compounds of formula (I) can also exist in the form of hydrates or solvates, namely in the form of associations or combinations with one or more water molecules or with a solvent. Such hydrates and solvates also form part of the invention.
According to the present invention, it is possible to distinguish the compounds of formula (I) in which:
R 1 represents hydrogen or a (C 1 -C 4 )alkyl; R 2 represents:
a (C 3 -C 7 )alkyl group; a nonaromatic C 3 -C 10 carboxyl radical which is unsubstituted or substituted once or several times with a (C 1 -C 4 )alkyl; a phenyl which is substituted with a halogen atom and/or with a (C 1 -C 4 )alkyl, trifluoromethyl or (C 1 -C 4 )alkoxy group; an NR 9 R 10 group; a CH[(C 1 -C 4 )alkyl]benzhydryl group in which one or both of the phenyl groups are unsubstituted or substituted with a halogen atom or with a (C 1 -C 4 )alkyl or (C 1 -C 4 )alkoxy group;
or R 1 and R 2 together with the nitrogen atom to which they are attached constitute a piperidin-1-yl radical which is disubstituted at the 4-position with a phenyl or benzyl group and with a (C 1 -C 4 )alkyl group or a (C 1 -C 3 )alkanoyl; R 3 , R 4 , R 5 , R 6 , R 7 , R 8 represent, each independently of the other, a hydrogen or halogen atom, a (C 1 -C 6 )-alkyl, (C 1 -C 6 )alkoxy or trifluoromethyl group; provided that at least one of the substituents R 3 , R 4 , R 5 , R 6 , R 7 , R 8 is different from hydrogen; R 9 represents a hydrogen atom; R 10 represents a (C 3 -C 6 )alkyl; or R 9 and R 10 together with the nitrogen atom to which they are attached constitute a saturated or unsaturated heterocyclic radical of 5 to 10 atoms, possibly containing a second heteroatom chosen from O or N, said radical being unsubstituted or substituted once or several times with a (C 1 -C 4 )alkyl, hydroxyl or (C 1 -C 4 )alkoxy group, methoxy(C 1 -C 2 )alkylene, or substituted with a spirocyclobutane, a spirocyclopentane or a spirocyclohexane;
and their salts, their solvates and their hydrates.
In the context of the present invention, the expression:
alkyl group is understood to mean a linear or branched radical such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, n-hexyl, isohexyl, the methyl group being preferred for a (C 1 -C 4 )alkyl; the tert-butyl groups, 1,1-dimethylpropyl and 2-methylbutyl-2 being preferred for a (C 3 -C 7 )alkyl; (C 1 -C 4 )alkoxy group is understood to mean a linear or branched radical containing 1 to 4 carbon atoms, the methoxy group being preferred; halogen atom is understood to mean a fluorine, chlorine, bromine or iodine atom, the fluorine, chlorine or bromine atoms being preferred.
The C 3 -C 10 carbocyclic or aromatic radicals comprise fused or bridged mono- or polycyclic radicals. The monocyclic radicals include cycloalkyls, for example cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl; cyclohexyl and cyclopentyl being preferred. The fused, bridged or spiro di- or tricyclic radicals include for example the bicyclo[2.2.1]heptanyl, bicyclo[3.1.1]heptanyl, bicyclo[2.2.2.]octanyl, bicyclo[3.2.1]octanyl, bicyclo-[3.2.1]octanyl, and adamantyl, bicyclo[3.1.1]heptanyl and bicyclo[3.2.1]octanyl being preferred.
The expression saturated or unsaturated heterocyclic radical of 5 to 10 atoms, containing or otherwise a second heteroatom such as O or N is understood to mean radicals such as morpholin-4-yl, piperidin-1-yl, piperazin-1-yl, pyrrolidin-1-yl, 3,6-dihydropyridin-1-yl, and octahydrocyclopenta[c]-pyrrol-2-yl, the piperidin-1-yl and morpholin-4-yl radicals being preferred.
According to the present invention, the compounds of formula (I) are preferred in which:
R 1 represents a hydrogen atom or a (C 1 -C 4 )alkyl group, preferably a hydrogen atom; R 2 represents a (C 3 -C 7 )alkyl group or an NR 9 R 10 group in which R 9 and R 10 together with the nitrogen atom to which they are attached constitute a piperidin-1-yl radical which is unsubstituted or disubstituted with a 4,4-dimethyl group or substituted at the 4-position with a spirocyclopentane group; and/or one or two of the substituents R 3 , R 4 , R 5 represent(s) a halogen atom or a methyl or methoxy group; preferably R 3 is at the 4-position and represents a chlorine or bromine atom or a methoxy group, R 4 , R 5 representing a hydrogen atom; and/or one or two of the substituents R 6 , R 7 , R 8 represent(s) a halogen atom or a methyl group; preferably R 6 and R 7 are at the 2,4-position and represent two chlorine atoms, R 8 representing a hydrogen atom;
and their salts, their solvates and their hydrates.
According to the present invention,
5-(4-bromophenyl)-4-cyano-1-(2,4-dichlorophenyl)-N-tert-butyl-1H-pyrazole-3-carboxamide, 5-(4-bromophenyl)-4-cyano-1-(2,4-dichlorophenyl)-N-(1,1-dimethylpropyl)-1H-pyrazole-3-carboxamide, 5-(4-chlorophenyl)-4-cyano-1-(2,4-dichlorophenyl)-N-piperidin-1-yl-1H-pyrazole-3-carboxamide, 5-(4-methoxyphenyl)-4-cyano-1-1(2,4-dichlorophenyl)-N-tert-butyl-1H-pyrazole-3-carboxamide and 5-(4-chlorophenyl)-4-cyano-1-(2,4-dichlorophenyl)-N-hexahydrocyclopenta[c]pyrrol-2(1H)-yl-1H-pyrazole-3-carboxamide, are most particularly preferred.
The subject of the present invention is also a method for preparing the compounds according to the invention.
This method is characterized in that a functional derivative of 4-cyano-1,5-diphenylpyrazole-3-carboxylic acid of formula:
in which R 3 , R 4 , R 5 , R 6 , R 7 , R 8 are as defined for (I), is treated with an amine of formula HNR 1 R 2 (III) in which R 1 and R 2 are as defined for (I). Optionally, the compound thus obtained is converted to one of its salts or solvates.
As a functional derivative of the acid (II), it is possible to use the chloride of an acid, the anhydride, a mixed anhydride, a C 1 -C 4 alkyl ester in which the alkyl is straight or branched, an activated ester, for example p-nitrophenyl ester, or the free acid opportunely activated, for example, with N,N-di-cyclohexylcarbodiimide or with benzotriazol-N-yloxo-tris(dimethylamino)phosphonium hexafluorophosphate (BOP) or benzotriazol-1-yloxotris(pyrrolidino)-phosphonium hexafluorophosphate (PyBOP).
Thus, in the method according to the invention, it is possible to react the chloride of a pyrazole-3-carboxylic acid, obtained by reacting thionyl chloride with the acid of formula (II), with an amine HNR 1 R 2 , in an inert solvent, such as a chlorinated solvent (dichloromethane, dichloroethane, chloroform for example), an ether (tetrahydrofuran, dioxane for example), or an amide(N,N-dimethylformamide for example) under an inert atmosphere, at a temperature of between 0° C. and room temperature, in the presence of a tertiary amine such as triethylamine, N-methyl-morpholine or pyridine.
An alternative method consists of preparing the mixed anhydride of the acid of formula (II) by reacting ethyl chloroformate with the acid of formula (II), in the presence of a base such as triethylamine, and in reacting it with an amine HNR 1 R 2 , in a solvent such as dichloromethane, under an inert atmosphere, at room temperature, in the presence of a base such as triethylamine.
The compounds of formula (II) may be prepared by various methods known in the literature, for example as described in J. Heterocyclic Chem., 1977, 14 (3), 375-381.
In step a 1 ) an aniline of formula (IV) is converted to a diazonium salt (V) by the action of a nitrite in an acidic medium, as described in Razdan et al., Med. Chem. Res., 1995, 5, 54. The diazonium salt (V) is then reacted with ethyl 2-chloro-3-oxo-butanoate (VI) to give the hydrazone derivative (VII).
The hydrazone derivative (VII) is fused with the nitrite of formula (VIII) in the presence of a strong base such as sodium ethoxide in ethanol in order to obtain the pyrazole derivative (IX). The latter is finally converted to an acid (II) by saponification using gentle conditions, for example LiOH in a THF/water mixture.
The acids of formula (II) and their esters of formula (IX) are generally novel. Some of these compounds are described in J. Heterocyclic Chem., 1977, 14 (3), 375-381; the ethyl ester of 1-(4-bromophenyl)-4-cyano-5(4-methoxyphenyl)1H-pyrazole-3-carboxylic acid is cited in the Interchim. Intermediates catalog.
Thus, the subject of the present invention is also the compounds of formula:
in which R is a hydrogen atom or a (C 1 -C 4 )alkyl group and R 3 , R 4 , R 5 , R 6 , R 7 , R 8 are as defined for (I) provided that at least one of the substituents R 3 , R 4 , R 5 and at least one of the substituents R 6 , R 7 , R 8 is different from hydrogen and provided that when R 3 represents a methoxy group and R 6 represents a bromine atom, the substituents R 4 , R 5 , R 7 , R 8 are different from hydrogen.
According to the present invention, it is possible to distinguish the compounds of formula (IIa) in which:
R 3 is at the 4-position and represents a chlorine or bromine atom, or a methyl, ethyl, trifluoromethyl or methoxy group; R 6 is at the 2-position and represents a chlorine atom; R 7 is at the 4-position and represents a hydrogen atom or a chlorine atom; R 4 , R 5 and R 8 represent a hydrogen atom.
More particularly, the compounds of formula (IIbis) are preferred in which:
R 3 is at the 4-position and represents a chlorine or bromine atom; R 6 and R 7 are at the 2,4-position and represent two chlorine atoms; R 4 , R 5 and R 8 represent a hydrogen atom.
The amines HNR 1 R 2 are known or prepared by known methods such as those described in Chem. Ber., 1986, 119, 1413-1423.
The following examples describe the preparation of some compounds in accordance with the invention. These examples are not limiting and merely illustrate the present invention. The exemplified compound numbers refer to those given in the table below, which illustrates the chemical structures and the physical properties of a few compounds according to the invention.
In the present description, the following abbreviations are used:
AcOEt: ethyl acetate; BOP: benzotriazolyloxytris-dimethylaminophosphonium hexafluorophosphate; DCM: Dichloromethane; DMF: dimethylformamide; EtOH: ethanol; m.p. melting point; iPr 2 O: isopropyl ether; RT: room temperature; THF: tetrahydrofuran.
The compounds according to the invention are analyzed by LC/UV/MS (liquid chromatography/UV detection/mass spectrometry) coupling. The molecular peak (MH + ) and the retention time (t) in minutes are measured.
There is used an Xterra Waters® MS C18 column, marketed by Waters, of 2.1×30 mm, 3.5 μm, at room temperature, flow rate 1 ml/minute.
The eluent is made up as follows:
solvent A: 0.025% of trifluoroacetic acid (TFA) in water solvent B: 0.025% of TFA in acetonitrile.
Gradient: The percentage of solvent B varies from 0 to 100% over 2 minutes with a plateau at 100% of B for 1 minute.
The UV detection is carried out between 210 nm and 400 nm and the mass detection in chemical ionization mode at atmospheric pressure.
The NMR spectra were recorded at 200 MHz in DMSO-d 6 .
For the interpretation of the nuclear magnetic resonance (NMR) spectra, the following abbreviations are used: s: singlet; d: doublet; m: unresolved complex; bs: broad singlet; dd: doublet of doublet; mt: multiplet.
Preparation 1
5-(4-Chlorophenyl)-4-cyano-1-(2,4-dichloro-phenyl)-1H-pyrazole-3-carboxylic acid
A) Ethyl chloro[(2,4-dichlorophenyl)hydrazino]acetate
7.3 g of dichloroaniline in 75 ml of a 24% HCl solution and 200 ml of water are mixed, with stirring, and the stirring is maintained for 2 hours. The mixture is cooled in an ice bath and a solution containing 3.1 g of NaNO 2 in 21 ml of water is added dropwise over 30 minutes. The mixture obtained is added to a solution containing 3.51 g of sodium acetate and 6.21 ml of ethyl 2-chloro-3-oxobutanoate in 450 ml of EtOH, cooled in an ice bath. The temperature is allowed to rise slowly while the stirring is maintained. The precipitate formed is filtered, washed with water and then dried under vacuum. 11.43 g of the expected compound are obtained.
NMR: 1.40 ppm: t: 3H; 4.40 ppm: d: 2H; 7.40-7.80 ppm: m: 3H; 9.25 ppm: s: 1H.
B) Ethyl 5-(4-chlorophenyl)-4-cyano-1-(2,4-dichloro-phenyl)-1H-pyrazole-3-carboxylate
A mixture containing 3.27 g of the compound from the preceding step, 1.99 g of 3-(4-chlorophenyl)-3-oxopropanenitrile in 120 ml of EtOH and sodium ethoxide prepared by mixing 0.28 g of sodium in 25 ml of EtOH, are heated under reflux for 18 hours. After returning to RT, the mixture is evaporated to dryness and taken up in 150 ml of AcOEt, the precipitate formed is filtered and the organic phase is washed with water and then with a saturated NaCl solution. The oil obtained is chromatographed on silica, eluting with an AcOEt/toluene (2/98 to 3/97; v/v) mixture. The solid obtained is recrystallized twice from a CH 2 Cl 2 /iPr 2 O mixture to give 1.12 g of the expected compound in the form of white crystals, m.p.=112° C.
C) 5-(4-Chlorophenyl)-4-cyano-1-(2,4-dichlorophenyl)-1H-pyrazole-3-carboxylic acid
0.436 g of the ester obtained in the preceding step in 25 ml of THF and 50 mg of LiOH in 5 ml of water are mixed and the mixture is heated for 2 hours at 65° C. The medium is concentrated by half, the reaction medium is poured into 50 ml of ice-cold water and 5 ml of 5% HCl. The organic mixture is extracted with CH 2 Cl 2 and then washed with NaCl. 0.41 g of the expected compound is obtained in solid form. m.p.=132-137° C.
NMR: 7.42 ppm: d: 2H; 7.61 ppm: d: 2H; 7.69 ppm: dd: 1H; 7.89 ppm: s: 1H; 7.92 ppm: d: 1H; 13.8-14.6 ppm: bs: 1H.
Preparation 2
5-(4-Bromophenyl)-4-cyano-1-(2,4-dichloro-phenyl)-1H-pyrazole-3-carboxylic acid
A) 3-(4-Bromophenyl)-3-oxopropanenitrile
A solution containing 9.4 g of KCN in 20 ml of water is prepared and then it is poured dropwise over a mixture containing 20 g of 2-bromo-1-(4-bromo-phenyl)ethanone dissolved in 800 ml of 90% ethanol. After stirring for 5 hours at RT, the solid formed is filtered and then it is rinsed with ice-cold water. The solid obtained is dissolved in 400 ml of water and then activated charcoal is added, the mixture is kept stirring for 20 minutes, and then filtered on Celite®. The filtrate obtained is treated with HCl at 10% and the white precipitate formed is filtered, washed with water and then dried under vacuum. 7.63 g of the expected compound are obtained. m.p.=164° C.
NMR: 4.75 ppm: bs: 2H; 7.80 ppm: mt: 4H
B) Ethyl 5-(4-bromophenyl)-4-cyano-1-(2,4-dichloro-phenyl)-1H-pyrazole-3-carboxylate
A sodium ethoxide solution is prepared by mixing 0.86 g of sodium in 107 ml of EtOH, 7.63 g of the compound prepared in the preceding step in 610 ml of EtOH are rapidly added, followed by 9.2 g of the compound obtained in step A of Preparation 1 and the reaction medium is kept stirring overnight at RT. The insoluble material is filtered and then the filtrate is concentrated under vacuum. The product obtained is concentrated on silica, eluting with a toluene/AcOEt (96/4; v/v) mixture. 5 g of the expected compound are obtained.
NMR: 1.25 ppm: t: 3H; 4.30 ppm: q: 2H; 7.20 ppm: d: 2H; 7.50-7.70 ppm: m: 3H; 7.70-8.00 ppm: m: 2H.
C) 5-(4-Bromophenyl)-4-cyano-1-(2,4-dichlorophenyl)-1H-pyrazole-3-carboxylic acid
2.8 g of the ester obtained in the preceding step are placed in 90 ml of THF and 0.4 g of LiOH in 8 ml of water are added and then the mixture is heated at 65° C. for 3 hours. The reaction medium is poured over a mixture of 240 ml of ice-cold water and 16 ml of HCl at 10%. The organic phase is extracted with CH 2 Cl 2 and then washed with a saturated NaCl solution. 2.3 g of the expected compound are obtained.
NMR: 7.30 ppm: d: 2H; 7.60-7.80 ppm: m: 3H; 7.80-8.00 ppm: m: 2H; 14.15 ppm: bs: 1H.
By carrying out the procedure according to the procedures set forth in the above preparations, the compounds in the following table are obtained:
TABLE 1
(II)
Preparation
R 3
R 6 , R 7
Melting point
3
—OMe
—Cl, —Cl
m.p. = 230° C.
4
—Me
—Cl, —Cl
m.p. = 223° C.
5
—CF 3
—Cl, —Cl
m.p. = 238° C.
6
—Et
—Cl, H
m.p. = 254° C.
EXAMPLE 1
Compound 1
5-(4-Chlorophenyl)-4-cyano-1-(2,4-dichlorophenyl)-N-piperidin-1-yl-1H-pyrazole-3-carboxamide
0.39 g of the acid from Preparation 1 is added dropwise to a solution containing 0.20 ml of 1-aminopiperidine and 0.50 ml of triethylamine in 15 ml of CH 2 Cl 2 , and then 0.80 g of BOP is added dropwise and the mixture is kept stirring at RT for 20 hours. The reaction medium is hydrolyzed with water and then the organic phase is washed with a 2% HCl solution, with a 5% Na 2 CO 3 solution and then with a saturated NaCl solution. After drying, the product obtained is chromatographed on silica, eluting with an MeOH/CH 2 Cl 2 (0.5/99.5; v/v) mixture to give a foam. The expected compound crystallizes from a CH 2 Cl 2 /iPr 2 O mixture, 0.28 g is obtained, m.p.=227-229° C.
EXAMPLE 2
Compound 12
5-(4-Bromophenyl)-4-cyano-1-(2,4-dichlorophenyl)-N-tert-butyl-1H-pyrazole-3-carboxamide
0.437 g of the acid from Preparation 2, 0.19 ml of tert-butylamine, 0.5 ml of NEt 3 and then 0.79 g of BOP are mixed in 20 ml of CH 2 Cl 2 and the mixture is kept stirring at RT for 48 hours. The reaction medium is hydrolyzed with water and then the organic phase is washed with a 2% HCl solution, a 5% Na 2 CO 3 solution and then a saturated NaCl solution. After drying, the product obtained is chromatographed on silica, eluting with a toluene/AcOEt (95/5; v/v) mixture to give a product which crystallizes from isopropyl ether. 370 mg are obtained, m.p.=184° C.
NMR: 1.35 ppm; s: 9H; 7.30 ppm: d: 2H; 7.60-8.00 ppm; m: 6H.
The table which follows illustrates the chemical structure and the physical properties of a few examples of compounds according to the invention.
In this table, Me, Et and tBu represent the methyl, ethyl and tert-butyl groups, respectively.
TABLE 2
(I)
Compounds
R 3
R 6 , R 7
—NR 1 R 2
Characterization
1
—Cl
—Cl, —Cl
m.p. = 227° C.
2
—Br
—Cl, —Cl
m.p. = 228° C.
3
—Cl
—Cl, —Cl
—NH—tBu
m.p. = 197° C.
4
—Cl
—Cl, —Cl
m.p. = 159° C.
5
—Cl
—Cl, —Cl
m.p. = 243° C.
6
—Cl
—Cl, —Cl
m.p. = 233° C.
7
—Cl
—Cl, —Cl
m.p = 200° C.+ polar
8
—Cl
—Cl, —Cl
m.p = 241° C.− polar
9
—Br
—Cl, —Cl
m.p. = 231° C.
10
—Br
—Cl, —Cl
m.p. = 252° C.
11
—Br
—Cl, —Cl
m.p. = 160° C.
12
—Br
—Cl, —Cl
—NH—tBu
m.p. = 184° C.
13
—Br
—Cl, —Cl
m.p. = 212° C.+ polar
14
—Br
—Cl, —Cl
m.p. = 250° C.− polar
15
—Cl
—Cl, —Cl
MH + = 577t = 2.59
16
—Cl
—Cl, —Cl
MH + = 527t = 2.78
17
—Cl
—Cl, —Cl
MH + = 497t = 2.52
18
—Cl
—Cl, —Cl
MH + = 485t = 2.55
19
—Cl
—Cl, —Cl
MH + = 619t = 2.71
20
—Cl
—Cl, —Cl
MH + = 499t = 2.80
21
—Br
—Cl, —Cl
m.p. = 209° C.
22
—OMe
—Cl, H
m.p. = 260° C.
23
—OMe
—Cl, —Cl
—NH—tBu
mp. = 229° C.
24
—Et
—Cl, H
m.p. = 227° C.
25
—Et
—Cl, —Cl
—NH—tBu
m.p. = 225° C.
26
—Et
—Cl, H
m.p. = 192° C.
27
—Br
—Cl, —Cl
m.p. = 222° C.
28
—CF 3
—Cl, —Cl
—NH—tBu
m.p. = 192° C.
29
—CF 3
—Cl, —Cl
m.p. = 223° C.
30
—CF 3
—Cl, —Cl
m.p. = 177° C.
31
—OMe
—Cl, —Cl
—NH—tBu
m.p. = 157° C.
32
—OMe
—Cl, —Cl
m.p. = 180° C.
33
—OMe
—Cl, —Cl
m.p. = 143° C.
34
—Me
—Cl, —Cl
—NH—tBu
m.p. = 171° C.
35
—Cl
—Cl, —Cl
m.p. = 239° C.
36
—Me
—Cl, —Cl
m.p. = 157° C.
37
—Me
—Cl, —Cl
m.p. = 206° C.
38
—OMe
—Cl, —Cl
m.p. = 197° C.
39
—OMe
—Cl, —Cl
m.p. = 206° C.
40
—OMe
—Cl, —Cl
m.p. = 266° C.
41
—OMe
—Cl, —Cl
m.p. = 196° C.
42
—OMe
—Cl, —Cl
m.p. = 164° C.
The compounds according to the invention have been the subject of pharmacological trials which make it possible to determine their antagonist effect of CB 1 cannabinoid receptors.
The compounds of formula (I) possess a very good affinity in vitro (IC 50 ≦10 −7 M) for the CB 1 cannabinoid receptors, under the experimental conditions described by M. Rinaldi-Carmona et al. (FEBS Letters, 1994, 350, 240-244).
The antagonist nature of the compounds of formula (I) has been demonstrated by the results obtained in adenylate cyclase inhibition models as described in M. Rinaldi-Carmona et al., J. Pharmacol. Exp. Ther., 1996, 278, 871-878 and M. Bouaboula et al., J. Biol. Chem., 1997, 272, 22330-22339.
The compounds according to the invention were tested in vivo (binding ex vivo) in mice after intravenous and/or oral administration, according to the experimental conditions described by Rinaldi-Carmona et al. (J. Pharmacol. Exp., 1998, 284, 644-650). By the intravenous route, the effective dose (ED 50 ) of these compounds for the CB 1 receptors is less than or equal to 10 mg/kg. By the oral route, compounds 2, 3, 4, 11 and 12 have an ED 50 of between 1 and 20 mg/kg for the CB 1 receptors.
The toxicity of the compounds of formula (I) is compatible with their use as a medicament.
According to another of these aspects, the present invention relates to the use of a compound of formula (I), or of one of its pharmaceutically acceptable salts, solvates or hydrates, for the preparation of medicaments intended for treating or preventing diseases involving the CB 1 cannabinoid receptors.
For example and without limitation, the compounds of formula (I) are useful as psychotropic medicaments, in particular for the treatment of psychiatric disorders including anxiety, depression, mood disorders, insomnia, delirium disorders, obsessive disorders, psychoses in general, schizophrenia, attention deficit hyperactivity disorder (ADHD), in particular in hyperkinetic children (MBD), and for the treatment of disorders linked to the use of psychotropic substances, in particular in the case of a substance abuse and/or of dependence on a substance, including alcohol dependence and nicotine dependence.
The compounds of formula (I) according to the invention may be used as medicaments for the treatment of migraine, stress, diseases of psychosomatic origin, panic attacks, epileptic attacks, motion disorders, in particular dyskinesia or Parkinson's disease, tremors and dystonia.
The compounds of formula (I) according to the invention can also be used as medicaments in the treatment of memory disorders, cognitive disorders, in particular in the treatment of senile dementia, Alzheimer's disease, and in the treatment of attention or vigilance disorders. Furthermore, the compounds of formula (I) may also be useful as neuroprotectants, in the treatment of ischemia, cranial traumas and the treatment of neurodegenerative diseases: including chorea, Huntington's chorea, Tourette's syndrome.
The compounds of formula (I) according to the invention can be used as medicaments in the treatment of pain: neuropathic pain, acute peripheral pain, chronic pain of inflammatory origin.
The compounds of formula (I) according to the invention may be used as medicaments in the treatment of appetite disorders, craving disorders (for sugars, carbohydrates, drugs, alcohol or any appetizing substance) and/or alimentary canal disorders, in particular as anorexics or for the treatment of obesity or of bulimia and for the treatment of type II diabetes or non-insulin-dependent diabetes and for the treatment of dyslipidemia and of metabolic syndrome. Furthermore, the compounds of formula (I) according to the invention may be used as medicaments in the treatment of gastrointestinal disorders, diarrheal disorders, ulcers, emesis, bladder and urinary disorders, disorders of endocrine origin, cardiovascular disorders, hypotension, hemorrhagic shock, septic shock, chronic cirrhosis of the liver, asthma, chronic bronchitis and chronic obstructive pulmonary disease, Raynaud's syndrome, glaucoma, fertility disorders, inflammatory phenomena, immune system diseases, in particular autoimmune and neuroinflammatory diseases such as rheumatoid arthritis, reactive arthritis, diseases causing demyelinization, multiple sclerosis, infectious and viral diseases such as encephalitis, stroke and as medicaments for anticancer chemotherapy and for the treatment of Guillain-Barré syndrome.
According to the present invention, the compounds of formula (I) are particularly useful for the treatment of psychotic disorders, in particular schizophrenia, attention deficit hyperactivity disorders (ADHD), in particular in hyperkinetic children (MBD); for the treatment of appetite disorders and obesity, for the treatment of memory and cognitive disorders; for the treatment of alcohol dependence, nicotine dependence, that is to say for withdrawal from alcohol and for smoking cessation; and for the treatment of dyslipidemia and of metabolic syndrome.
According to one of its aspects, the present invention relates to the use of a compound of formula (I), of its pharmaceutically acceptable salts and of their solvates or hydrates, for the treatment of the disorders and diseases indicated above.
The compounds of formula (I) according to the invention may be used in combination with one or more other active ingredients useful for the prevention and/or treatment of the diseases indicated above: by way of example of active ingredients which may be combined with a compound of formula (I), there may be mentioned antipsychotics, anxiolytics, memory enhancers, anti-Parkinson agents, antiepileptics, anorexics or other antiobesity agents, nicotine agonists, monoamine oxidase inhibitors, analgesics, antiinflammatory agents, antihypertensives such as: angiotensin II AT 1 receptor antagonists, converting enzyme inhibitors, calcium antagonists, beta-blockers, antidiabetics, antihyperlipidemics, anticholesterolemics, PPAR (peroxisome proliferator activated receptor) agonists.
The compound according to the invention is generally administered in dosage unit form.
Said dosage units are preferably formulated in pharmaceutical compositions in which the active ingredient is mixed with a pharmaceutical excipient.
Thus according to another of its aspects, the present invention relates to pharmaceutical compositions containing, as active ingredient, a compound of formula (I), one of its pharmaceutically acceptable salts or one of their solvates.
The compound of formula (I) above and its pharmaceutically acceptable salts or solvates may be used in daily doses of 0.01 to 100 mg per kg of body weight of the mammal to be treated, preferably in daily doses of 0.02 to 50 mg/kg. In human beings, the dose can vary preferably from 0.05 to 4000 mg per day, more particularly from 0.1 to 1000 mg per day according to the age of the subject to be treated or the type of treatment, namely prophylactic or curative. Although these dosages are examples of average situations, there may be particular cases when higher or lower dosages are appropriate, such dosages also belong to the invention. According to customary practice, the dosage appropriate for each patient is determined by the doctor according to the mode of administration, the age, the weight and the response of said patient.
In the pharmaceutical compositions of the present invention for oral, sublingual, inhaled, subcutaneous, intramuscular, intravenous, transdermal, local or rectal administration, the active ingredient may be administered in unit form for administration, mixed with conventional pharmaceutical carriers, to animals and to humans. The appropriate unit forms for administration comprise the forms by the oral route such as tablets, gelatin capsules, powders, granules and oral solutions or suspensions, the forms for sublingual or buccal administration, aerosols, the forms for topical administration, implants, the forms for subcutaneous, intramuscular, intravenous, intranasal or intraocular administration and the forms for rectal administration.
In the pharmaceutical compositions of the present invention, the active ingredient is generally formulated in dosage units containing from 0.05 to 1000 mg, advantageously from 0.1 to 500 mg, preferably from 1 to 200 mg of said active ingredient per dosage unit for daily administrations.
By way of example, a unit form for administration of a compound according to the invention in tablet form may comprise the following compounds:
Compound according to the invention
50.0
mg
Mannitol
223.75
mg
Croscaramellose sodium
6.0
mg
Maize starch
15.0
mg
Hydroxypropylmethylcellulose
2.25
mg
Magnesium stearate
3.0
mg
By the oral route, the dose of active ingredient administered per day may be up to 0.01 to 100 mg/kg, in single or divided doses, preferably 0.02 to 50 mg/kg.
There may be specific cases where higher or lower doses are appropriate; such doses do not depart from the scope of the invention. According to the usual practice, the appropriate dose for each patient is determined by the doctor according to the mode of administration, the weight and the response of said patient.
The present invention, according to another of its aspects, also relates to a method for treating the pathologies indicated above, which comprises the administration, to a patient, of an effective dose of a compound according to the invention, or one of its pharmaceutically acceptable salts or hydrates or solvates.
|
The invention relates to 4-cyanopyrazole-3-carboxamide derivatives of formula (I):
in which R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 are as described herein. Also disclosed and claimed are the method of preparation and therapeutic application of compound of formula (I).
| 2 |
FIELD OF THE INVENTION
The present invention relates to novel compounds capable of modulating, regulating and/or inhibiting tyrosine kinase signal transduction. The present invention is also directed to methods of regulating, modulating or inhibiting tyrosine kinases, whether of the receptor or non-receptor class, for the prevention and/or treatment of disorders related to unregulated tyrosine kinase signal transduction, including cell growth, metabolic, and blood vessel proliferative disorders.
DESCRIPTION OF THE RELATED ART
Protein tyrosine kinases (PTKs) comprise a large and diverse class of proteins having enzymatic activity. The PTKs play an important role in the control of cell growth and differentiation.
For example, receptor tyrosine kinase mediated signal transduction is initiated by extracellular interaction with a specific growth factor (ligand), followed by receptor dimerization, transient stimulation of the intrinsic protein tyrosine kinase activity and phosphorylation. Binding sites are thereby created for intracellular signal transduction molecules and lead to the formation of complexes with a spectrum of cytoplasmic signaling molecules that facilitate the appropriate cellular response (e.g., cell division, metabolic homeostasis, and responses to the extracellular microenvironment).
With respect to receptor tyrosine kinases, it has been shown also that tyrosine phosphorylation sites function as high-affinity binding sites for SH2 (src homology) domains of signaling molecules. Several intracellular substrate proteins that associate with receptor tyrosine kinases (RTKs) have been identified. They may be divided into two principal groups: (1) substrates which have a catalytic domain; and (2) substrates which lack such domain but serve as adapters and associate with catalytically active molecules. The specificity of the interactions between receptors or proteins and SH2 domains of their substrates is determined by the amino acid residues immediately surrounding the phosphorylated tyrosine residue. Differences in the binding affinities between SH2 domains and the amino acid sequences surrounding the phosphotyrosine residues on particular receptors are consistent with the observed differences in their substrate phosphorylation profiles. These observations suggest that the function of each receptor tyrosine kinase is determined not only by its pattern of expression and ligand availability but also by the array of downstream signal transduction pathways that are activated by a particular receptor. Thus, phosphorylation provides an important regulatory step which determines the selectivity of signaling pathways recruited by specific growth factor receptors, as well as differentiation factor receptors.
Aberrant expression or mutations in the PTKs have been shown to lead to either uncontrolled cell proliferation (e.g. malignant tumor growth) or to defects in key developmental processes. Consequently, the biomedical community has expended significant resources to discover the specific biological role of members of the PTK family, their function in differentiation processes, their involvement in tumorigenesis and in other diseases, the biochemical mechanisms underlying their signal transduction pathways activated upon ligand stimulation and the development of novel drugs.
Tyrosine kinases can be of the receptor-type (having extracellular, transmembrane and intracellular domains) or the non-receptor type (being wholly intracellular).
The receptor-type tyrosine kinases (RTKs) comprise a large family of transmembrane receptors with diverse biological activities. The intrinsic function of RTKs is activated upon ligand binding, which results in phosphorylation of the receptor and multiple cellular substrates, and subsequently in a variety of cellular responses. The non-receptor tyrosine kinases represent a collection of cellular enzymes which lack extracellular and transmembrane sequences. A more detailed discussion of receptor and non-receptor tyrosine kinases is provided in Cowan-Jacob Cell Mol. Life Sci., 2996, 63, 2608-2625.
There are a number of examples where RTK kinases, have been found to be involved in cellular signaling pathways leading to pathological conditions, including exudative age-related macular degeneration (Ni et al. Opthalmologica 2009 223 401-410; Chappelow et al. Drugs 2008 68 1029-1036), diabetic retinopathy (Zhang et al., Int. J. Biochem. Cell Biol. 2009 41 2368-2371), cancer (Aora et al. J. Path. Exp. Ther. 2006, 315, 971), psoriasis (Heidenreich et al Drug News Perspective 2008 21 97-105), rosacea (Smith, J. R., V. B. Lanier, et al. Br J Ophthalmol 2007, 91(2): 226-229) and hyper immune response. In ophthalmic diseases such as exudative age-related macular degeneration and diabetic retinopathy aberrant activation of VEGF receptors can lead to abnormal blood vessel growth. The importance of VEGFR signaling in the exudative age-related macular degeneration disease process is evident by the clinical success of multiple anti-VEGF targeting agents including Lucentis®, Avastin®, and EYLEA™ (Barakat et al., Expert Opin. Investig. Drugs 2009, 18, 637). Recently it has been suggested that inhibition of multiple RTK signaling pathways may provide a greater therapeutic effect than targeting a single RTK signaling pathway. For example in neovascular ocular disorders such as exudative age-related macular degeneration and diabetic retinopathy the inhibition of both VEGFR and PDGFRβ may provide a greater therapeutic effect by causing regression of existing neovascular blood vessels present in the disease (Adamis et al., Am. J. Pathol. 2006 168 2036-2053). In cancer inhibition of multiple RTK signaling pathways has been suggested to have a greater effect than inhibiting a single RTK pathway (DePinho et al., Science 2007 318 287-290; Bergers et al. J. Clin Invest. 2003 111 1287-1295).
The identification of effective small compounds which specifically inhibit signal transduction by modulating the activity of receptor and non-receptor tyrosine kinases to regulate and modulate abnormal or inappropriate cell proliferation is therefore desirable and one object of this invention.
SUMMARY OF THE INVENTION
The present invention relates to organic molecules capable of modulating, regulating and/or inhibiting tyrosine kinase signal transduction by blocking the VEGF and/or PDGF receptors. Such compounds are useful for the treatment of diseases related to unregulated PTKs transduction, including cell proliferative diseases such as cancer; vascular (blood vessel) proliferative disorders such as mesangial cell proliferative disorders and metabolic diseases, lung carcinomas, breast carcinomas, Non Hodgkin's lymphomas, ovarian carcinoma, pancreatic cancer, malignant pleural mesothelioma, melanoma, arthritis, restenosis, hepatic cirrhosis, atherosclerosis, psoriasis, rosacea, diabetic mellitus, wound healing and inflammation and preferably ophthalmic diseases, i.e. diabetic retinopathy, retinopathy of prematurity, macular edema, retinal vein occlusion, exudative or neovascular age-related macular degeneration, high-risk eyes (i.e. fellow eyes have neovascular age-related macular degeneration) with dry age-related macular degeneration, neovascular disease associated with retinal vein occlusion, neovascular disease (including choroidal neovascularization) associated with the following: pathologic myopia, pseudoxanthoma elasticum, optic nerve drusen, traumatic choroidal rupture, central serous retinopathy, cystoid macular edema, diabetic retinopathy, proliferative diabetic retinopathy, diabetic macular edema, rubeosis iridis, retinopathy of prematurity, Central and branch retinal vein occlusions, inflammatory/infectious retinal, neovascularization/edema, corneal neovascularization, hyperemia related to an actively inflamed pterygia, recurrent pterygia following excisional surgery, post-excision, progressive pterygia approaching the visual axis, prophylactic therapy to prevent recurrent pterygia, of post-excision, progressive pterygia approaching the visual axis, chronic low grade hyperemia associated with pterygia, neovascular glaucoma, iris neovascularization, idiopathic etiologies, presumed ocular histoplasmosis syndrome, retinopathy of prematurity, chronic allergic conjunctivitis, ocular rosacea, blepharoconjunctivitis, recurrent episcleritis, keratoconjunctivitis sicca, ocular graft vs host disease, etc.
In one aspect, the invention provides a compound represented by Formula I or a pharmaceutically acceptable salt thereof or stereoisomeric forms thereof, or the enantiomers, diastereoisomers, tautomers, zwitterions and pharmaceutically acceptable salts thereof:
wherein:
R 1 is H or NR 13a R 14a ;
R 2 is substituted or unsubstituted heterocyle or is substituted or unsubstituted aryl;
R 3 is substituted or unsubstituted heterocyle or is substituted or unsubstituted aryl;
R 4 is H or NR 13a R 14a ;
R 5 is H or substituted or unsubstituted C 1-8 alkyl;
R 6 is H or substituted or unsubstituted C 1-8 alkyl;
R 7 is H or substituted or unsubstituted C 1-8 alkyl;
R 8 is H or substituted or unsubstituted C 1-8 alkyl;
R 9 is H or substituted or unsubstituted C 1-8 alkyl;
R 10 is H or substituted or unsubstituted C 1-8 alkyl;
X is
Y is CR 11 or N;
W is CR 12 or N;
R 11 is hydrogen, halogen, C(O)OR 17 , CF 3 , C 1 to C 8 alkyl, NR 13a R 14a , C(O)NR 13a R 14a , (CR 15 R 16 ) p NR 13a R 14a , (CR 15 R 16 ) p C(O)OR 17 , (CR 15 R 16 ) p OR 17 , NR 13 C(O)(CR 15 R 16 ) p NR 13a R 14a , NR 13 C(O)(CR 15 R 16 ) p C(O)OR 17 , NR 13 C(O)(CR 15 R 16 ) p OR 17 , C(O)(CR 15 R 16 ) p NR 13a R 14a , C(O)(CR 15 R 16 ) p C(O)OR 17 , C(O)(CR 15 R 16 ) p COR 17 , C(O)NR 13 (CR 15 R 16 ) p NR 13 R 14 , C(O)NR 13 (CR 15 R 16 ) p C(O)OR 17 , C(O)NR 13 (CR 15 R 16 ) p COR 17 , NR 13 C(O)NR 14 (CR 15 R 16 ) p NR 13 R 14 , NR 13 C(O)NR 14 (CR 15 R 16 ) p C(O)OR 17 , or NR 13 C(O)NR 14 (CR 15 R 18 ) p OR 17 ;
R 12 is hydrogen, halogen, C(O)OR 17 , CF 3 , C 1 to C 8 alkyl, NR 13a R 14a , C(O)NR 13a R 14a , (CR 15 R 16 ) p NR 13a R 14a , (CR 15 R 16 ) p C(O)OR 17 , (CR 15 R 16 ) p OR 17 , NR 13 C(O)(CR 15 R 16 ) p NR 13 R 14 , NR 13 C(O)(CR 15 R 16 ) p C(O)OR 17 , NR 13 C(O)(CR 15 R 16 ) p OR 17 , C(O)(CR 15 R 16 ) p NR 1a3 R 14a , C(O)(CR 15 R 16 ) p C(O)OR 17 , C(O)(CR 15 R 16 ) p COR 17 , C(O)NR 13 (CR 15 R 16 ) p NR 13 R 14 , C(O)NR 13 (CR 15 R 16 ) p C(O)OR 17 , C(O)NR 13 (CR 15 R 16 ) p COR 17 , NR 13 C(O)NR 14 (CR 15 R 16 ) p NR 13a R 14a , NR 13 C(O)NR 14 (CR 15 R 16 ) p C(O)OR 17 , or NR 13 C(O)NR 14 (CR 15 R 16 ) p OR 17 ;
R 13 is H or substituted or unsubstituted C 1-8 alkyl;
R 14 is H or substituted or unsubstituted C 1-8 alkyl;
R 13a is H, substituted or unsubstituted C 1-8 alkyl or together with R 14a and the N can form a substituted or unsubstituted heterocycle;
R 14a is H, substituted or unsubstituted C 1-8 alkyl or together with R 13a and the N can form a substituted or unsubstituted heterocycle;
R 15 is H, halogen, hydroxyl, CF 3 , or substituted or unsubstituted C 1-8 alkyl;
R 16 is H halogen, hydroxyl, CF 3 , or substituted or unsubstituted C 1-8 alkyl;
R 17 is H or substituted or unsubstituted C 1-8 alkyl;
a is 0 or 1; and
p is 1, 2, 3 or 4.
In another aspect, the invention provides a compound represented by Formula I wherein:
R 1 is H or NR 13a R 14a ;
R 2 is substituted or unsubstituted heterocyle or substituted or unsubstituted aryl;
R 3 is substituted or unsubstituted heterocyle or substituted or unsubstituted aryl;
R 4 is H or NR 13a R 14a ;
R 5 is H or substituted or unsubstituted C 1-8 alkyl;
R 6 is H or substituted or unsubstituted C 1-8 alkyl;
R 9 is H or substituted or unsubstituted C 1-8 alkyl;
R 10 is H or substituted or unsubstituted C 1-8 alkyl;
X is
Y is CR 11 or N;
W is CR 12 or N;
R 11 is hydrogen, halogen, C(O)OR 17 , CF 3 , C 1 to C 8 alkyl, NR 13a R 14a , C(O)NR 13a R 14a , (CR 15 R 16 ) p NR 13a R 14a , (CR 15 R 16 ) p C(O)OR 17 , (CR 15 R 16 ) p OR 17 , NR 13 C(O)(CR 15 R 16 ) p NR 13a R 14a , NR 13 C(O)(CR 15 R 16 ) p C(O)OR 17 , NR 13 C(O)(CR 15 R 16 ) p OR 17 , C(O)(CR 15 R 16 ) p NR 13a R 14a , C(O)(CR 15 R 16 ) p C(O)OR 17 , C(O)(CR 15 R 16 ) p COR 17 , C(O)NR 13 (CR 15 R 16 ) p NR 13 R 14 , C(O)NR 13 (CR 15 R 16 ) p C(O)OR 17 , C(O)NR 13 (CR 15 R 16 ) p COR 17 , NR 13 C(O)NR 14 (CR 15 R 16 ) p NR 13 R 14 , NR 13 C(O)NR 14 (CR 15 R 16 ) p C(O)OR 17 , NR 13 C(O)NR 14 (CR 15 R 16 ) p OR 17 ;
R 12 is hydrogen, halogen, C(O)OR 17 , CF 3 , C 1 to C 8 alkyl, NR 13a R 14a , C(O)NR 13a R 14a , (CR 15 R 16 ) p NR 13a R 14a , (CR 15 R 16 ) p C(O)OR 17 , (CR 15 R 16 ) p OR 17 , NR 13 C(O)(CR 15 R 16 ) p NR 13 R 14 , NR 13 C(O)(CR 15 R 16 ) p C(O)OR 17 , NR 13 C(O)(CR 15 R 16 ) p OR 17 , C(O)(CR 15 R 16 ) p NR 1a3 R 14a , C(O)(CR 15 R 16 ) p C(O)OR 17 , C(O)(CR 15 R 16 ) p COR 17 , C(O)NR 13 (CR 15 R 16 ) p NR 13 R 14 , C(O)NR 13 (CR 15 R 16 ) p C(O)OR 17 , C(O)NR 13 (CR 15 R 16 ) p COR 17 , NR 13 C(O)NR 14 (CR 15 R 16 ) p NR 13a R 14a , NR 13 C(O)NR 14 (CR 15 R 16 ) p C(O)OR 17 , NR 13 C(O)NR 14 (CR 15 R 16 ) p OR 17 ;
R 13 is H or substituted or unsubstituted C 1-8 alkyl;
R 14 is H or substituted or unsubstituted C 1-8 alkyl;
R 13a is H, substituted or unsubstituted C 1-8 alkyl or together with R 14a and the N can form a substituted or unsubstituted heterocycle;
R 14a is H, substituted or unsubstituted C 1-8 alkyl or together with R 13a and the N can form a substituted or unsubstituted heterocycle;
R 15 is H, halogen, hydroxyl, CF 3 or substituted or unsubstituted C 1-8 alkyl;
R 16 is H halogen, hydroxyl, CF 3 or substituted or unsubstituted C 1-8 alkyl;
R 17 is H or substituted or unsubstituted C 1-8 alkyl;
a is 0; and
p is 1, 2, 3 or 4.
In another aspect, the invention provides a compound represented by Formula I wherein:
R 1 is H or NR 13a R 14a ;
R 2 is substituted or unsubstituted heterocyle or substituted or unsubstituted aryl;
R 3 is substituted or unsubstituted heterocyle or substituted or unsubstituted aryl;
R 4 is H or NR 13a R 14a ;
R 5 is H or substituted or unsubstituted C 1-8 alkyl;
R 6 is H or substituted or unsubstituted C 1-8 alkyl;
R 7 is H or substituted or unsubstituted C 1-8 alkyl;
R 8 is H or substituted or unsubstituted C 1-8 alkyl;
R 9 is H or substituted or unsubstituted C 1-8 alkyl;
R 10 is H or substituted or unsubstituted C 1-8 alkyl;
X is
Y is CR 11 or N;
W is CR 12 or N;
R 11 is hydrogen, halogen, C(O)OR 17 , CF 3 , C 1 to C 8 alkyl, NR 13a R 14a , C(O)NR 13a R 14a , (CR 15 R 16 ) p NR 13a R 14a , (CR 15 R 16 ) p C(O)OR 17 , (CR 15 R 16 ) p OR 17 , NR 13 C(O)(CR 15 R 16 ) p NR 13a R 14a , NR 13 C(O)(CR 15 R 16 ) p C(O)OR 17 , NR 13 C(O)(CR 15 R 16 ) p OR 17 , C(O)(CR 15 R 16 ) p NR 13a R 14a , C(O)(CR 15 R 16 ) p C(O)OR 17 , C(O)(CR 15 R 16 ) p COR 17 , C(O)NR 13 (CR 15 R 16 ) p NR 13 R 14 , C(O)NR 13 (CR 15 R 16 ) p C(O)OR 17 , C(O)NR 13 (CR 15 R 16 ) p COR 17 , NR 13 C(O)NR 14 (CR 15 R 16 ) p NR 13 R 14 , NR 13 C(O)NR 14 (CR 15 R 16 ) p C(O)OR 17 , NR 13 C(O)NR 14 (CR 15 R 16 ) p OR 17 ;
R 12 is hydrogen, halogen, C(O)OR 17 , CF 3 , C 1 to C 8 alkyl, NR 13a R 14a , C(O)NR 13a R 14a , (CR 15 R 16 ) p NR 13a R 14a , (CR 15 R 16 ) p C(O)OR 17 , (CR 15 R 16 ) p OR 17 , NR 13 C(O)(CR 15 R 16 ) p NR 13 R 14 , NR 13 C(O)(CR 15 R 16 ) p C(O)OR 17 , NR 13 C(O)(CR 15 R 16 ) p OR 17 , C(O)(CR 15 R 16 ) p NR 1a3 R 14a , C(O)(CR 15 R 16 ) p C(O)OR 17 , C(O)(CR 15 R 16 ) p COR 17 , C(O)NR 13 (CR 15 R 16 ) p NR 13 R 14 , C(O)NR 13 (CR 15 R 16 ) p C(O)OR 17 , C(O)NR 13 (CR 15 R 16 ) p COR 17 , NR 13 C(O)NR 14 (CR 15 R 16 ) p NR 13a R 14a , NR 13 C(O)NR 14 (CR 15 R 16 ) p C(O)OR 17 , NR 13 C(O)NR 14 (CR 15 R 16 ) p OR 17 ;
R 13 is H or substituted or unsubstituted C 1-8 alkyl;
R 14 is H or substituted or unsubstituted C 1-8 alkyl;
R 13a is H, substituted or unsubstituted C 1-8 alkyl or together with R 14a and the N can form a substituted or unsubstituted heterocycle;
R 14a is H, substituted or unsubstituted C 1-8 alkyl or together with R 13a and the N can form a substituted or unsubstituted heterocycle;
R 15 is H, halogen, hydroxyl, CF 3 or substituted or unsubstituted C 1-8 alkyl;
R 16 is H halogen, hydroxyl, CF 3 or substituted or unsubstituted C 1-8 alkyl;
R 17 is H or substituted or unsubstituted C 1-8 alkyl;
a is 1; and
p is 1, 2, 3 or 4.
In another aspect, the invention provides a compound represented by Formula I wherein:
R 1 is H or NR 13a R 14a ;
R 2 is substituted or unsubstituted heterocyle or substituted or unsubstituted aryl;
R 3 is substituted or unsubstituted heterocyle or substituted or unsubstituted aryl;
R 4 is H or NR 13a R 14a ;
R 5 is H or substituted or unsubstituted C 1-8 alkyl;
R 6 is H or substituted or unsubstituted C 1-8 alkyl;
R 7 is H or substituted or unsubstituted C 1-8 alkyl;
R 8 is H or substituted or unsubstituted C 1-8 alkyl;
R 9 is H or substituted or unsubstituted C 1-8 alkyl;
R 10 is H or substituted or unsubstituted C 1-8 alkyl;
X is
Y is CR 11 or N;
W is CR 12 or N;
R 11 is hydrogen, halogen, C(O)OR 17 , CF 3 , C 1 to C 8 alkyl, NR 13a R 14a , C(O)NR 13a R 14a , (CR 15 R 16 ) p NR 13a R 14a , (CR 15 R 16 ) p C(O)OR 17 , (CR 15 R 16 ) p OR 17 , NR 13 C(O)(CR 15 R 16 ) p NR 13a R 14a , NR 13 C(O)(CR 15 R 16 ) p C(O)OR 17 , NR 13 C(O)(CR 15 R 16 ) p OR 17 , C(O)(CR 15 R 16 ) p NR 13a R 14a , C(O)(CR 15 R 16 ) p C(O)OR 17 , C(O)(CR 15 R 16 ) p COR 17 , C(O)NR 13 (CR 15 R 16 ) p NR 13 R 14 , C(O)NR 13 (CR 15 R 16 ) p C(O)OR 17 , C(O)NR 13 (CR 15 R 16 ) p COR 17 , NR 13 C(O)NR 14 (CR 15 R 16 ) p NR 13 R 14 , NR 13 C(O)NR 14 (CR 15 R 16 ) p C(O)OR 17 , NR 13 C(O)NR 14 (CR 15 R 16 ) p OR 17 ;
R 12 is hydrogen, halogen, C(O)OR 17 , CF 3 , C 1 to C 8 alkyl, NR 13a R 14a , C(O)NR 13a R 14a , (CR 15 R 16 ) p NR 13a R 14a , (CR 15 R 16 ) p C(O)OR 17 , (CR 15 R 16 ) p OR 17 , NR 13 C(O)(CR 15 R 16 ) p NR 13 R 14 , NR 13 C(O)(CR 15 R 16 ) p C(O)OR 17 , NR 13 C(O)(CR 15 R 16 ) p OR 17 , C(O)(CR 15 R 16 ) p NR 1a3 R 14a , C(O)(CR 15 R 16 ) p C(O)OR 17 , C(O)(CR 15 R 16 ) p COR 17 , C(O)NR 13 (CR 15 R 16 ) p NR 13 R 14 , C(O)NR 13 (CR 15 R 16 ) p C(O)OR 17 , C(O)NR 13 (CR 15 R 16 ) p COR 17 , NR 13 C(O)NR 14 (CR 15 R 16 ) p NR 13a R 14a , NR 13 C(O)NR 14 (CR 15 R 16 ) p C(O)OR 17 , NR 13 C(O)NR 14 (CR 15 R 16 ) p OR 17 ;
R 13 is H or substituted or unsubstituted C 1-8 alkyl;
R 14 is H or substituted or unsubstituted C 1-8 alkyl;
R 13a is H, substituted or unsubstituted C 1-8 alkyl or together with R 14a and the N can form a substituted or unsubstituted heterocycle;
R 14a is H, substituted or unsubstituted C 1-8 alkyl or together with R 13a and the N can form a substituted or unsubstituted heterocycle;
R 15 is H, halogen, hydroxyl, CF 3 or substituted or unsubstituted C 1-8 alkyl;
R 16 is H halogen, hydroxyl, CF 3 or substituted or unsubstituted C 1-8 alkyl;
R 17 is H or substituted or unsubstituted C 1-8 alkyl;
a is 1; and
p is 1, 2, 3 or 4.
In another aspect, the invention provides a compound represented by Formula I wherein:
R 1 is H or NR 13a R 14a ;
R 2 is substituted or unsubstituted heterocyle or substituted or unsubstituted aryl;
R 3 is substituted or unsubstituted heterocyle or substituted or unsubstituted aryl;
R 4 is H or NR 13a R 14a ;
R 5 is H or substituted or unsubstituted C 1-8 alkyl;
R 6 is H or substituted or unsubstituted C 1-8 alkyl;
R 7 is H or substituted or unsubstituted C 1-8 alkyl;
R 8 is H or substituted or unsubstituted C 1-8 alkyl;
R 9 is H or substituted or unsubstituted C 1-8 alkyl;
R 10 is H or substituted or unsubstituted C 1-8 alkyl;
X is
Y is CR 11 or N;
W is CR 12 or N;
R 11 is hydrogen, halogen, C(O)OR 17 , CF 3 , C 1 to C 8 alkyl, NR 13a R 14a , C(O)NR 13a R 14a , (CR 15 R 16 ) p NR 13a R 14a , (CR 15 R 16 ) p C(O)OR 17 , (CR 15 R 16 ) p OR 17 , NR 13 C(O)(CR 15 R 16 ) p NR 13a R 14a , NR 13 C(O)(CR 15 R 16 ) p C(O)OR 17 , NR 13 C(O)(CR 15 R 16 ) p OR 17 , C(O)(CR 15 R 16 ) p NR 13a R 14a , C(O)(CR 15 R 16 ) p C(O)OR 17 , C(O)(CR 15 R 16 ) p COR 17 , C(O)NR 13 (CR 15 R 16 ) p NR 13 R 14 , C(O)NR 13 (CR 15 R 16 ) p C(O)OR 17 , C(O)NR 13 (CR 15 R 16 ) p COR 17 , NR 13 C(O)NR 14 (CR 15 R 16 ) p NR 13 R 14 , NR 13 C(O)NR 14 (CR 15 R 16 ) p C(O)OR 17 , NR 13 C(O)NR 14 (CR 15 R 16 ) p OR 17 ;
R 12 is hydrogen, halogen, C(O)OR 17 , CF 3 , C 1 to C 8 alkyl, NR 13a R 14a , C(O)NR 13a R 14a , (CR 15 R 16 ) p NR 13a R 14a , (CR 15 R 16 ) p C(O)OR 17 , (CR 15 R 16 ) p OR 17 , NR 13 C(O)(CR 15 R 16 ) p NR 13 R 14 , NR 13 C(O)(CR 15 R 16 ) p C(O)OR 17 , NR 13 C(O)(CR 15 R 16 ) p OR 17 , C(O)(CR 15 R 16 ) p NR 1a3 R 14a , C(O)(CR 15 R 16 ) p C(O)OR 17 , C(O)(CR 15 R 16 ) p COR 17 , C(O)NR 13 (CR 15 R 16 ) p NR 13 R 14 , C(O)NR 13 (CR 15 R 16 ) p C(O)OR 17 , C(O)NR 13 (CR 15 R 16 ) p COR 17 , NR 13 C(O)NR 14 (CR 15 R 16 ) p NR 13a R 14a , NR 13 C(O)NR 14 (CR 15 R 16 ) p C(O)OR 17 , NR 13 C(O)NR 14 (CR 15 R 16 ) p OR 17 ;
R 13 is H or substituted or unsubstituted C 1-8 alkyl;
R 14 is H or substituted or unsubstituted C 1-8 alkyl;
R 13a is H, substituted or unsubstituted C 1-8 alkyl or together with R 14a and the N can form a substituted or unsubstituted heterocycle;
R 14a is H, substituted or unsubstituted C 1-8 alkyl or together with R 13a and the N can form a substituted or unsubstituted heterocycle;
R 15 is H, halogen, hydroxyl, CF 3 or substituted or unsubstituted C 1-8 alkyl;
R 16 is H halogen, hydroxyl, CF 3 or substituted or unsubstituted C 1-8 alkyl;
R 17 is H or substituted or unsubstituted C 1-8 alkyl;
a is 1; and
p is 1, 2, 3 or 4.
In another aspect, the invention provides a compound represented by Formula I wherein:
R 1 is H or NR 13a R 14a ;
R 2 is substituted or unsubstituted heterocyle or substituted or unsubstituted aryl;
R 3 is substituted or unsubstituted heterocyle or substituted or unsubstituted aryl;
R 4 is H or NR 13a R 14a ;
R 5 is H or substituted or unsubstituted C 1-8 alkyl;
R 6 is H or substituted or unsubstituted C 1-8 alkyl;
R 7 is H or substituted or unsubstituted C 1-8 alkyl;
R 8 is H or substituted or unsubstituted C 1-8 alkyl;
R 9 is H or substituted or unsubstituted C 1-8 alkyl;
R 10 is H or substituted or unsubstituted C 1-8 alkyl;
X is
Y is CR 11 or N;
W is CR 12 or N;
R 11 is hydrogen, halogen, C(O)OR 17 , CF 3 , C 1 to C 8 alkyl, NR 13a R 14a , C(O)NR 13a R 14a , (CR 15 R 16 ) p NR 13a R 14a , (CR 15 R 16 ) p C(O)OR 17 , (CR 15 R 16 ) p OR 17 , NR 13 C(O)(CR 15 R 16 ) p NR 13a R 14a , NR 13 C(O)(CR 15 R 16 ) p C(O)OR 17 , NR 13 C(O)(CR 15 R 16 ) p OR 17 , C(O)(CR 15 R 16 ) p NR 13a R 14a , C(O)(CR 15 R 16 ) p C(O)OR 17 , C(O)(CR 15 R 16 ) p COR 17 , C(O)NR 13 (CR 15 R 16 ) p NR 13 R 14 , C(O)NR 13 (CR 15 R 16 ) p C(O)OR 17 , C(O)NR 13 (CR 15 R 16 ) p COR 17 , NR 13 C(O)NR 14 (CR 15 R 16 ) p NR 13 R 14 , NR 13 C(O)NR 14 (CR 15 R 16 ) p C(O)OR 17 , NR 13 C(O)NR 14 (CR 15 R 16 ) p OR 17 ;
R 12 is hydrogen, halogen, C(O)OR 17 , CF 3 , C 1 to C 8 alkyl, NR 13a R 14a , C(O)NR 13a R 14a , (CR 15 R 16 ) p NR 13a R 14a , (CR 15 R 16 ) p C(O)OR 17 , (CR 15 R 16 ) p OR 17 , NR 13 C(O)(CR 15 R 16 ) p NR 13 R 14 , NR 13 C(O)(CR 15 R 16 ) p C(O)OR 17 , NR 13 C(O)(CR 15 R 16 ) p OR 17 , C(O)(CR 15 R 16 ) p NR 1a3 R 14a , C(O)(CR 15 R 16 ) p C(O)OR 17 , C(O)(CR 15 R 16 ) p COR 17 , C(O)NR 13 (CR 15 R 16 ) p NR 13 R 14 , C(O)NR 13 (CR 15 R 16 ) p C(O)OR 17 , C(O)NR 13 (CR 15 R 16 ) p COR 17 , NR 13 C(O)NR 14 (CR 15 R 16 ) p NR 13a R 14a , NR 13 C(O)NR 14 (CR 15 R 16 ) p C(O)OR 17 , NR 13 C(O)NR 14 (CR 15 R 16 ) p OR 17 ;
R 13 is H or substituted or unsubstituted C 1-8 alkyl;
R 14 is H or substituted or unsubstituted C 1-8 alkyl;
R 13a is H, substituted or unsubstituted C 1-8 alkyl or together with R 14a and the N can form a substituted or unsubstituted heterocycle;
R 14a is H, substituted or unsubstituted C 1-8 alkyl or together with R 13a and the N can form a substituted or unsubstituted heterocycle;
R 15 is H, halogen, hydroxyl, CF 3 or substituted or unsubstituted C 1-8 alkyl;
R 16 is H halogen, hydroxyl, CF 3 or substituted or unsubstituted C 1-8 alkyl;
R 17 is H or substituted or unsubstituted C 1-8 alkyl;
a is 1; and
p is 1, 2, 3 or 4.
In another aspect, the invention provides a compound represented by Formula I wherein:
R 1 is H or NR 13a R 14a ;
R 2 is substituted or unsubstituted heterocyle or substituted or unsubstituted aryl;
R 3 is substituted or unsubstituted heterocyle or substituted or unsubstituted aryl;
R 4 is H or NR 13a R 14a ;
R 5 is H or substituted or unsubstituted C 1-8 alkyl;
R 6 is H or substituted or unsubstituted C 1-8 alkyl;
R 7 is H or substituted or unsubstituted C 1-8 alkyl;
R 8 is H or substituted or unsubstituted C 1-8 alkyl;
R 9 is H or substituted or unsubstituted C 1-8 alkyl;
R 10 is H or substituted or unsubstituted C 1-8 alkyl;
X is
Y is CR 11 or N;
W is CR 12 or N;
R 11 is hydrogen, halogen, C(O)OR 17 , CF 3 , C 1 to C 8 alkyl, NR 13a R 14a , C(O)NR 13a R 14a , (CR 15 R 16 ) p NR 13a R 14a , (CR 15 R 16 ) p C(O)OR 17 , (CR 15 R 16 ) p OR 17 , NR 13 C(O)(CR 15 R 16 ) p NR 13a R 14a , NR 13 C(O)(CR 15 R 16 ) p C(O)OR 17 , NR 13 C(O)(CR 15 R 16 ) p OR 17 , C(O)(CR 15 R 16 ) p NR 13a R 14a , C(O)(CR 15 R 16 ) p C(O)OR 17 , C(O)(CR 15 R 16 ) p COR 17 , C(O)NR 13 (CR 15 R 16 ) p NR 13 R 14 , C(O)NR 13 (CR 15 R 16 ) p C(O)OR 17 , C(O)NR 13 (CR 15 R 16 ) p COR 17 , NR 13 C(O)NR 14 (CR 15 R 16 ) p NR 13 R 14 , NR 13 C(O)NR 14 (CR 15 R 16 ) p C(O)OR 17 , NR 13 C(O)NR 14 (CR 15 R 16 ) p OR 17 ;
R 12 is hydrogen, halogen, C(O)OR 17 , CF 3 , C 1 to C 8 alkyl, NR 13a R 14a , C(O)NR 13a R 14a , (CR 15 R 16 ) p NR 13a R 14a , (CR 15 R 16 ) p C(O)OR 17 , (CR 15 R 16 ) p OR 17 , NR 13 C(O)(CR 15 R 16 ) p NR 13 R 14 , NR 13 C(O)(CR 15 R 16 ) p C(O)OR 17 , NR 13 C(O)(CR 15 R 16 ) p OR 17 , C(O)(CR 15 R 16 ) p NR 1a3 R 14a , C(O)(CR 15 R 16 ) p C(O)OR 17 , C(O)(CR 15 R 16 ) p COR 17 , C(O)NR 13 (CR 15 R 16 ) p NR 13 R 14 , C(O)NR 13 (CR 15 R 16 ) p C(O)OR 17 , C(O)NR 13 (CR 15 R 16 ) p COR 17 , NR 13 C(O)NR 14 (CR 15 R 16 ) p NR 13a R 14a , NR 13 C(O)NR 14 (CR 15 R 16 ) p C(O)OR 17 , NR 13 C(O)NR 14 (CR 15 R 16 ) p OR 17 ;
R 13 is H or substituted or unsubstituted C 1-8 alkyl;
R 14 is H or substituted or unsubstituted C 1-8 alkyl;
R 13a is H, substituted or unsubstituted C 1-8 alkyl or together with R 14a and the N can form a substituted or unsubstituted heterocycle;
R 14a is H, substituted or unsubstituted C 1-8 alkyl or together with R 13a and the N can form a substituted or unsubstituted heterocycle;
R 15 is H, halogen, hydroxyl, CF 3 or substituted or unsubstituted C 1-8 alkyl;
R 16 is H halogen, hydroxyl, CF 3 or substituted or unsubstituted C 1-8 alkyl;
R 17 is H or substituted or unsubstituted C 1-8 alkyl;
a is 0; and
p is 1, 2, 3 or 4.
In another aspect, the invention provides a compound represented by Formula I wherein:
R 1 is H;
R 2 is substituted or unsubstituted heterocyle or substituted or unsubstituted aryl;
R 3 is substituted or unsubstituted heterocyle or substituted or unsubstituted aryl;
R 4 is H;
R 5 is H;
R 6 is H;
R 7 is H;
R 8 is H;
R 9 is H;
R 10 is H;
X is
Y is N;
W is CR 12 ;
R 12 is hydrogen, C(O)OR 17 ;
R 17 is H or substituted or unsubstituted C 1-8 alkyl; and
a is 0 or 1.
In another aspect, the invention provides a compound represented by Formula I wherein:
R 1 is H;
R 2 is substituted or unsubstituted heterocyle or substituted or unsubstituted aryl;
R 3 is substituted or unsubstituted heterocyle or substituted or unsubstituted aryl;
R 4 is H;
R 5 is H;
R 6 is H;
R 7 is H;
R 8 is H;
R 9 is H;
R 10 is H;
X is
Y is N;
W is CR 12 ;
R 12 is hydrogen or C(O)OR 17 ;
R 17 is H or substituted or unsubstituted C 1-8 alkyl; and
a is 0 or 1.
In another aspect, the invention provides a compound represented by Formula I wherein:
R 1 is H;
R 2 is substituted or unsubstituted aryl;
R 3 is substituted or unsubstituted aryl;
R 4 is H;
R 5 is H;
R 6 is H;
R 7 is H;
R 8 is H;
R 9 is H;
R 10 is H;
X is
Y is N;
W is CR 12 ;
R 12 is hydrogen or C(O)OR 17 ;
R 17 is H or substituted or unsubstituted C 1-8 alkyl; and
a is 1.
The term “alkyl”, as used herein, refers to saturated, monovalent or divalent hydrocarbon moieties having linear or branched moieties or combinations thereof and containing 1 to 12 carbon atoms. One methylene (—CH 2 —) group, of the alkyl group can be replaced by oxygen, sulfur, sulfoxide, nitrogen, carbonyl, carboxyl, sulfonyl, sulfate, sulfonate, amide, sulfonamide, by a divalent C 3-8 cycloalkyl, by a divalent heterocycle, or by a divalent aryl group. Alkyl groups can have one or more chiral centers. Alkyl groups can be independently substituted by halogen atoms, hydroxyl groups, cycloalkyl groups, amino groups, heterocyclic groups, aryl groups, carboxylic acid groups, phosphonic acid groups, sulphonic acid groups, phosphoric acid groups, nitro groups, amide groups, sulfonamide groups, ester groups, ketone groups.
The term “cycloalkyl”, as used herein, refers to a monovalent or divalent group of 3 to 8 carbon atoms derived from a saturated cyclic hydrocarbon. Cycloalkyl groups can be monocyclic or polycyclic. Cycloalkyl can be independently substituted by halogen atoms, sulfonyl C 1-8 alkyl groups, sulfoxide C 1-8 alkyl groups, sulfonamide groups, nitro groups, cyano groups, —OC 1-8 alkyl groups, —SC 1-8 alkyl groups, —C 1-8 alkyl groups, —C 2-6 alkenyl groups, —C 2-6 alkynyl groups, ketone groups, alkylamino groups, amide groups, amino groups, aryl groups, C 3-8 cycloalkyl groups or hydroxyl groups.
The term “cycloalkenyl”, as used herein, refers to a monovalent or divalent group of 3 to 8 carbon atoms derived from a saturated cycloalkyl having at least one double bond. Cycloalkenyl groups can be monocyclic or polycyclic. Cycloalkenyl groups can be independently substituted by halogen atoms, sulfonyl groups, sulfoxide groups, nitro groups, cyano groups, —OC 1-6 alkyl groups, —SC 1-6 alkyl groups, —C 1-6 alkyl groups, —C 2-6 alkenyl groups, —C 2-6 alkynyl groups, ketone groups, alkylamino groups, amide groups, amino groups, aryl groups, C 3-8 cycloalkyl groups or hydroxyl groups.
The term “halogen”, as used herein, refers to an atom of chlorine, bromine, fluorine, iodine.
The term “alkenyl”, as used herein, refers to a monovalent or divalent hydrocarbon moiety having 2 to 6 carbon atoms, derived from a saturated alkyl, having at least one double bond. One methylene (—CH 2 —) group, of the alkenyl can be replaced by oxygen, sulfur, sulfoxide, nitrogen, carbonyl, carboxyl, sulfonyl, sulfate, sulfonate, amide, sulfonamide, by a divalent C 3-8 cycloalkyl, by a divalent heterocycle, or by a divalent aryl group. C 2-6 alkenyl can be in the E or Z configuration. Alkenyl groups can be substituted by alkyl groups, as defined above or by halogen atoms.
The term “alkynyl”, as used herein, refers to a monovalent or divalent hydrocarbon moiety having 2 to 6 carbon atoms, derived from a saturated alkyl, having at least one triple bond. One methylene (—CH 2 —) group, of the alkynyl can be replaced by oxygen, sulfur, sulfoxide, nitrogen, carbonyl, carboxyl, sulfonyl, sulfate, sulfonate, amide, sulfonamide, by a divalent C 3-8 cycloalkyl, by a divalent heterocycle, or by a divalent aryl group. Alkynyl groups can be substituted by alkyl groups, as defined above, or by halogen atoms.
The term “heterocycle” as used herein, refers to a 3 to 10 membered ring, which can be aromatic or non-aromatic, saturated or unsaturated, containing at least one heteroatom selected form oxygen, nitrogen, sulfur, or combinations of at least two thereof, interrupting the carbocyclic ring structure. The heterocyclic ring can be interrupted by a C═O; the S and N heteroatoms can be oxidized. Heterocycles can be monocyclic or polycyclic. Heterocyclic ring moieties can be substituted by halogen atoms, sulfonyl groups, sulfoxide groups, nitro groups, cyano groups, —OC 1-6 alkyl groups, —SC 1-6 alkyl groups, —C 1-8 alkyl groups, —C 2-6 alkenyl groups, —C 2-6 alkynyl groups, amide groups, ketone groups, alkylamino groups, amino groups, aryl groups, ester groups, ketone groups, carboxylic acid groups, C 3-8 cycloalkyl groups or hydroxyl groups. Heterocyclic ring moieties in R 2 can be meta or para substituted by X. Heterocyclic ring moieties groups in R 2 are meta substituted by X.
The term “aryl” as used herein, refers to an organic moiety derived from an aromatic hydrocarbon consisting of a ring containing 6 to 10 carbon atoms, by removal of one hydrogen atom. Aryl can be substituted by halogen atoms, sulfonyl C 1-6 alkyl groups, sulfoxide C 1-6 alkyl groups, sulfonamide groups, carboxcyclic acid groups, C 1-6 alkyl carboxylates (ester) groups, amide groups, nitro groups, cyano groups, —OC 1-6 alkyl groups, —SC 1-6 alkyl groups, —C 1-6 alkyl groups, —C 2-6 alkenyl groups, —C 2-6 alkynyl groups, ketone groups, aldehydes, alkylamino groups, amino groups, aryl groups, C 3-8 cycloalkyl groups or hydroxyl groups. Aryls can be monocyclic or polycyclic. Aryl groups in R 2 can be meta or para substituted by X. Aryl groups in R 2 are meta substituted by X.
The term “hydroxyl” as used herein, represents a group of formula “—OH”.
The term “carbonyl” as used herein, represents a group of formula “—C(O)—”.
The term “ketone” as used herein, represents an organic compound having a carbonyl group linked to a carbon atom such as —C(O)R x wherein R x can be alkyl, aryl, cycloalkyl, cycloalkenyl, heterocycle as defined above.
The term “ester” as used herein, represents an organic compound having a carbonyl group linked to a carbon atom such as —C(O)OR x wherein R x can be alkyl, aryl, cycloalkyl, cycloalkenyl, heterocycle as defined above.
The term “amine” as used herein, represents a group of formula “—NR x R y ”, wherein R x and R y can be the same or independently H, alkyl, aryl, cycloalkyl, cycloalkenyl, heterocycle as defined above.
The term “carboxyl” as used herein, represents a group of formula “—C(O)O—”.
The term “sulfonyl” as used herein, represents a group of formula “—SO 2 − ”.
The term “sulfate” as used herein, represents a group of formula “—O—S(O) 2 —O—”.
The term “sulfonate” as used herein, represents a group of the formula “—S(O) 2 —O—”.
The term “carboxylic acid” as used herein, represents a group of formula “—C(O)OH”.
The term “nitro” as used herein, represents a group of formula “—NO 2 ”.
The term “cyano” as used herein, represents a group of formula “—CN”.
The term “amide” as used herein, represents a group of formula “—C(O)NR x R y ,” or “NR x R y C(O)—” wherein R x and R y can be the same or independently H, alkyl, aryl, cycloalkyl, cycloalkenyl, heterocycle as defined above.
The term “sulfonamide” as used herein, represents a group of formula “—S(O) 2 NR x R y ” wherein R x and R y can be the same or independently H, alkyl, aryl, cycloalkyl, cycloalkenyl, heterocycle as defined above.
The term “sulfoxide” as used herein, represents a group of formula “—S(O)—”.
The term “phosphonic acid” as used herein, represents a group of formula “—P(O)(OH) 2 ”.
The term “phosphoric acid” as used herein, represents a group of formula “—OP(O)(OH) 2 ”.
The term “sulphonic acid” as used herein, represents a group of formula “—S(O) 2 OH”.
The formula “H”, as used herein, represents a hydrogen atom.
The formula “O”, as used herein, represents an oxygen atom.
The formula “N”, as used herein, represents a nitrogen atom.
The formula “S”, as used herein, represents a sulfur atom.
Other defined terms are used throughout this specification:
“CV” refers to column volume
“DMAP” refers to dimethylaminopyridine
“HPLC” refers to high pressure liquid chromatography
“MTBE” refers to tert-butyl methyl ether
“PDGF” refers to platelet derived growth factor
“PDGFRβ” refers to platelet derived growth factor receptor beta
“PTKs” refers to protein tyrosine kinase
“RTKs” refers to receptor tyrosine kinase
“rt” refers to room temperature
“VEGF” refers to vascular endothelial growth factor
“VEGFR” refers to vascular endothelial growth factor receptor
Compounds of the invention are tabulated in Table 1.
Example
Number
Structure
Compound Name
1
Methyl 3-(8,9- dihydropyrazolo[1,5- a]pyrido[3,4-e]pyrimidin- 7(6H)-yl)benzoate
2
3-(8,9-dihydropyrazolo[1,5- a]pyrido[3,4-e]pyrimidin- 7(6H)-yl)benzoic acid
3
3-(8,9-dihydropyrazolo[1,5- a]pyrido[3,4-e]pyrimidin- 7(6H)-yl)-N-(3- isopropylphenyl)benzamide
4
3-(8,9-dihydropyrazolo[1,5- a]pyrido[3,4-e]pyrimidin- 7(6H)-yl)-N-[3- (trifluoromethyl)phenyl] benzamide
5
Methyl 3-(6,8-dihydro-7H- pyrazolo[1,5-a]pyrrolo[3,4- e]pyrimidin-7-yl)benzoate
6
3-(6,8-dihydro-7H- pyrazolo[1,5-a]pyrrolo[3,4- e]pyrimidin-7-yl)benzoic acid
7
3-(6,8-dihydro-7H- pyrazolo[1,5-a]pyrrolo[3,4- e]pyrimidin-7-yl)-N-(3- isopropylphenyl)benzamide
8
tert-Butyl (3-(8,9- dihydropyrazolo[1,5- a]pyrido[3,4-e]pyrimidin- 7(6H)-yl)phenyl)carbamate
9
3-(8,9-Dihydropyrazolo[1,5- a]pyrido[3,4-e]pyrimidin- 7(6H)-yl)benzenamine
10
N-[3-(8,9-dihydropyrazolo[1,5- a]pyrido[3,4-e]pyrimidin- 7(6H)-yl)phenyl]benzamide
11
N-[3-(8,9-dihydropyrazolo[1,5- a]pyrido[3,4-e]pyrimidin- 7(6H)-yl)phenyl]-3- (trifluoromethyl)benzamid
12
1-[3-(8,9-dihydropyrazolo[1,5- a]pyrido[3,4-e]pyrimidin- 7(6H)-yl)phenyl]-3-(3- methylphenyl)urea
13
Methyl 3-(2-((tert- butoxycarbonyl)amino)-8,9- dihydropyrazolo[1,5- a]pyrido[3,4-e]pyrimidin- 7(6H)-yl)benzoate
14
7-(3- Methoxycarbonyl)phenyl)- 6,7,8,9- tetrahydropyrazolo[1,5- a]pyrido[3,4-e]pyrimidine-2- carboxylic acid
In another embodiment, compounds of the invention are:
3-(8,9-dihydropyrazolo[1,5-a]pyrido[3,4-e]pyrimidin-7(6H)-yl)-N-(3-isopropylphenyl)benzamide; 3-(8,9-dihydropyrazolo[1,5-a]pyrido[3,4-e]pyrimidin-7(6H)-yl)-N-[3-(trifluoromethyl)phenyl]benzamide; 3-(6,8-dihydro-7H-pyrazolo[1,5-a]pyrrolo[3,4-e]pyrimidin-7-yl)-N-(3-isopropylphenyl)benzamide; tert-Butyl (3-(8,9-dihydropyrazolo[1,5-a]pyrido[3,4-e]pyrimidin-7(6H)-yl)phenyl)carbamate; N-[3-(8,9-dihydropyrazolo[;1,5-a]pyrido[3,4-e]pyrimidin-7(6H)-yl)phenyl]benzamide N-[3-(8,9-dihydropyrazolo[1,5-a]pyrido[3,4-e]pyrimidin-7(6H)-yl)phenyl]-3-(trifluoromethyl)benzamide; 1-[3-(8,9-dihydropyrazolo[1,5-a]pyrido[3,4-e]pyrimidin-7(6H)-yl)phenyl]-3-(3-methylphenyl)urea.
Compounds of formula I are useful as protein kinase inhibitors. As such, compounds of formula I will be useful for treating diseases related to protein kinase signal transduction, for example, cancer, blood vessel proliferative disorders, fibrotic disorders, and neurodegenerative diseases. In particular, the compounds of the present invention are useful for treatment of mesangial cell proliferative disorders and metabolic diseases, lung carcinomas, breast carcinomas, Non Hodgkin's lymphomas, ovarian carcinoma, pancreatic cancer, malignant pleural mesothelioma, melanoma, arthritis, restenosis, hepatic cirrhosis, atherosclerosis, psoriasis, rosacea, diabetic mellitus, wound healing, inflammation and neurodegenerative diseases and preferably ophthalmic diseases, i.e. diabetic retinopathy, retinopathy of prematurity, macular edema, retinal vein occlusion, exudative or neovascular age-related macular degeneration, high-risk eyes (i.e. fellow eyes have neovascular age-related macular degeneration) with dry age-related macular degeneration, neovascular disease associated with retinal vein occlusion, neovascular disease (including choroidal neovascularization) associated with the following: pathologic myopia, pseudoxanthoma elasticum, optic nerve drusen, traumatic choroidal rupture, serous retinopathy, cystoid macular edema, diabetic retinopathy, proliferative diabetic retinopathy, diabetic macular edema, rubeosis iridis, retinopathy of prematurity, Central and branch retinal vein occlusions, inflammatory/infectious retinal, neovascularization/edema, corneal neovascularization, hyperemia related to an actively inflamed pterygia, recurrent pterygia following excisional surgery, post-excision, progressive pterygia approaching the visual axis, prophylactic therapy to prevent recurrent pterygia, of post-excision, progressive pterygia approaching the visual axis, chronic low grade hyperemia associated with pterygia, neovascular glaucoma, iris neovascularization, idiopathic etiologies, presumed ocular histoplasmosis syndrome, retinopathy of prematurity, chronic allergic conjunctivitis, ocular rosacea, blepharoconjunctivitis, recurrent episcleritis, keratoconjunctivitis sicca, ocular graft vs host disease, etc.
The fibrotic disorder is selected from the group consisting of hepatic cirrhosis and atherosclerosis.
The mesangial cell proliferative disorder is selected from the group consisting of glomerulonephritis, diabetic nephropathy, malignant nephrosclerosis, thrombotic microangiopathy syndromes, transplant rejection and glomerulopathies.
The metabolic disease is selected from the group consisting of psoriasis, diabetes mellitus, wound healing, inflammation and neurodegenerative diseases. The blood vessel proliferative disorder is selected from the group consisting of diabetic retinopathy, exudative age-related macular degeneration, retinopathy of prematurity, pterigium, rosacea, arthritis and restenosis.
Some compounds of Formula I and some of their intermediates may have at least one asymmetric center in their structure. This asymmetric center may be present in an R or S configuration, said R and S notation is used in correspondence with the rules described in Pure Applied Chem. (1976), 45, 11-13.
The term “pharmaceutically acceptable salts” refers to salts or complexes that retain the desired biological activity of the above identified compounds and exhibit minimal or no undesired toxicological effects. The “pharmaceutically acceptable salts” according to the invention include therapeutically active, non-toxic base or acid salt forms, which the compounds of Formula I are able to form.
The acid addition salt form of a compound of Formula I that occurs in its free form as a base can be obtained by treating the free base with an appropriate acid such as an inorganic acid, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid and the like; or an organic acid such as for example, acetic acid, hydroxyacetic acid, propanoic acid, lactic acid, pyruvic acid, malonic acid, fumaric acid, maleic acid, oxalic acid, tartaric acid, succinic acid, malic acid, ascorbic acid, benzoic acid, tannic acid, pamoic acid, citric acid, methylsulfonic acid, ethanesulfonic acid, benzenesulfonic acid, formic and the like (Handbook of Pharmaceutical Salts, P. Heinrich Stahl & Camille G. Wermuth (Eds), Verlag Helvetica Chimica Acta-Zurich, 2002, 329-345).
The base addition salt form of a compound of Formula I that occurs in its acid form can be obtained by treating the acid with an appropriate base such as an inorganic base, for example, sodium hydroxide, magnesium hydroxide, potassium hydroxide, calcium hydroxide, ammonia and the like; or an organic base such as for example, L-Arginine, ethanolamine, betaine, benzathine, morpholine and the like. (Handbook of Pharmaceutical Salts, P. Heinrich Stahl & Camille G. Wermuth (Eds), Verlag Helvetica Chimica Acta-Zurich, 2002, 329-345).
Compounds of Formula I and their salts can be in the form of a solvate, which is included within the scope of the present invention. Such solvates include for example hydrates, alcoholates and the like.
With respect to the present invention reference to a compound or compounds, is intended to encompass that compound in each of its possible isomeric forms and mixtures thereof unless the particular isomeric form is referred to specifically.
Compounds according to the present invention may exist in different polymorphic forms. Although not explicitly indicated in the above formula, such forms are intended to be included within the scope of the present invention.
The actual amount of the compound to be administered in any given case will be determined by a physician taking into account the relevant circumstances, such as the severity of the condition, the age and weight of the patient, the patient's general physical condition, the cause of the condition, and the route of administration.
The patient will be administered the compound orally in any acceptable form, such as a tablet, liquid, capsule, powder and the like, or other routes may be desirable or necessary, particularly if the patient suffers from nausea. Such other routes may include, without exception, transdermal, parenteral, subcutaneous, intranasal, via an implant stent, intrathecal, intravitreal, topical to the eye, back to the eye, intramuscular, intravenous, and intrarectal modes of delivery. Additionally, the formulations may be designed to delay release of the active compound over a given period of time, or to carefully control the amount of drug released at a given time during the course of therapy.
In another embodiment of the invention, there are provided pharmaceutical compositions including at least one compound of the invention in a pharmaceutically acceptable carrier thereof. The phrase “pharmaceutically acceptable” means the carrier, diluent or excipient must be compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.
Pharmaceutical compositions of the present invention can be used in the form of a solid, a solution, an emulsion, a dispersion, a patch, a micelle, a liposome, and the like, wherein the resulting composition contains one or more compounds of the present invention, as an active ingredient, in admixture with an organic or inorganic carrier or excipient suitable for enteral or parenteral applications. Invention compounds may be combined, for example, with the usual non-toxic, pharmaceutically acceptable carriers for tablets, pellets, capsules, suppositories, solutions, emulsions, suspensions, and any other form suitable for use. The carriers which can be used include glucose, lactose, gum acacia, gelatin, mannitol, starch paste, magnesium trisilicate, talc, corn starch, keratin, colloidal silica, potato starch, urea, medium chain length triglycerides, dextrans, and other carriers suitable for use in manufacturing preparations, in solid, semisolid, or liquid form. In addition auxiliary, stabilizing, thickening and coloring agents and perfumes may be used. Invention compounds are included in the pharmaceutical composition in an amount sufficient to produce the desired effect upon the process or disease condition.
Pharmaceutical compositions containing invention compounds may be in a form suitable for oral use, for example, as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs. Compositions intended for oral use may be prepared according to any method known in the art for the manufacture of pharmaceutical compositions and such compositions may contain one or more agents selected from the group consisting of a sweetening agent such as sucrose, lactose, or saccharin, flavoring agents such as peppermint, oil of wintergreen or cherry, coloring agents and preserving agents in order to provide pharmaceutically elegant and palatable preparations. Tablets containing invention compounds in admixture with non-toxic pharmaceutically acceptable excipients may also be manufactured by known methods. The excipients used may be, for example, (1) inert diluents such as calcium carbonate, lactose, calcium phosphate or sodium phosphate; (2) granulating and disintegrating agents such as corn starch, potato starch or alginic acid; (3) binding agents such as gum tragacanth, corn starch, gelatin or acacia, and (4) lubricating agents such as magnesium stearate, stearic acid or talc. The tablets may be uncoated or they may be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay material such as glyceryl monostearate or glyceryl distearate may be employed.
In some cases, formulations for oral use may be in the form of hard gelatin capsules wherein the invention compounds are mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin. They may also be in the form of soft gelatin capsules wherein the invention compounds are mixed with water or an oil medium, for example, peanut oil, liquid paraffin or olive oil.
The pharmaceutical compositions may be in the form of a sterile injectable suspension. This suspension may be formulated according to known methods using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example, as a solution in 1,3-butanediol. Sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil may be employed including synthetic mono- or diglycerides, fatty acids (including oleic acid), naturally occurring vegetable oils like sesame oil, coconut oil, peanut oil, cottonseed oil, etc., or synthetic fatty vehicles like ethyl oleate or the like. Buffers, preservatives, antioxidants, and the like can be incorporated as required.
Pharmaceutical compositions containing invention compounds may be in a form suitable for topical use, for example, as oily suspensions, as solutions or suspensions in aqueous liquids or nonaqueous liquids, or as oil-in-water or water-in-oil liquid emulsions. Pharmaceutical compositions may be prepared by combining a therapeutically effective amount of at least one compound according to the present invention, or a pharmaceutically acceptable salt thereof, as an active ingredient with conventional ophthalmically acceptable pharmaceutical excipients and by preparation of unit dosage suitable for topical ocular use. The therapeutically efficient amount typically is between about 0.0001 and about 5% (w/v), preferably about 0.001 to about 2.0% (w/v) in liquid formulations.
For ophthalmic application, preferably solutions are prepared using a physiological saline solution as a major vehicle. The pH of such ophthalmic solutions should preferably be maintained between 4.5 and 8.0 with an appropriate buffer system, a neutral pH being preferred but not essential. The formulations may also contain conventional pharmaceutically acceptable preservatives, stabilizers and surfactants. Preferred preservatives that may be used in the pharmaceutical compositions of the present invention include, but are not limited to, benzalkonium chloride, chlorobutanol, thimerosal, phenylmercuric acetate and phenylmercuric nitrate. A preferred surfactant is, for example, Tween 80. Likewise, various preferred vehicles may be used in the ophthalmic preparations of the present invention. These vehicles include, but are not limited to, polyvinyl alcohol, povidone, hydroxypropyl methyl cellulose, poloxamers, carboxymethyl cellulose, hydroxyethyl cellulose cyclodextrin and purified water.
Tonicity adjustors may be added as needed or convenient. They include, but are not limited to, salts, particularly sodium chloride, potassium chloride, mannitol and glycerin, or any other suitable ophthalmically acceptable tonicity adjustor.
Various buffers and means for adjusting pH may be used so long as the resulting preparation is ophthalmically acceptable. Accordingly, buffers include acetate buffers, citrate buffers, phosphate buffers and borate buffers. Acids or bases may be used to adjust the pH of these formulations as needed.
In a similar manner an ophthalmically acceptable antioxidant for use in the present invention includes, but is not limited to, sodium metabisulfite, sodium thiosulfate, acetylcysteine, butylated hydroxyanisole and butylated hydroxytoluene.
Other excipient components which may be included in the ophthalmic preparations are chelating agents. The preferred chelating agent is edentate disodium, although other chelating agents may also be used in place of or in conjunction with it.
The ingredients are usually used in the following amounts:
Ingredient Amount (% w/v)
active ingredient about 0.001-5
preservative 0-0.10
vehicle 0-40
tonicity adjustor 0-10
buffer 0.01-10
pH adjustor q.s. pH 4.5-7.8
antioxidant as needed
surfactant as needed
purified water to make 100%
The actual dose of the active compounds of the present invention depends on the specific compound, and on the condition to be treated; the selection of the appropriate dose is well within the knowledge of the skilled artisan.
The ophthalmic formulations of the present invention are conveniently packaged in forms suitable for metered application, such as in containers equipped with a dropper, to facilitate application to the eye. Containers suitable for dropwise application are usually made of suitable inert, non-toxic plastic material, and generally contain between about 0.5 and about 15 ml solution. One package may contain one or more unit doses. Especially preservative-free solutions are often formulated in non-resealable containers containing up to about ten, preferably up to about five units doses, where a typical unit dose is from one to about 8 drops, preferably one to about 3 drops. The volume of one drop usually is about 20-35 μl.
The pharmaceutical compositions may be in the form of a sterile injectable suspension. This suspension may be formulated according to known methods using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example, as a solution in 1,3-butanediol. Sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil may be employed including synthetic mono- or diglycerides, fatty acids (including oleic acid), naturally occurring vegetable oils like sesame oil, coconut oil, peanut oil, cottonseed oil, etc., or synthetic fatty vehicles like ethyl oleate or the like. Buffers, preservatives, antioxidants, and the like can be incorporated as required.
The compounds of the invention may also be administered in the form of suppositories for rectal administration of the drug. These compositions may be prepared by mixing the invention compounds with a suitable non-irritating excipient, such as cocoa butter, synthetic glyceride esters of polyethylene glycols, which are solid at ordinary temperatures, but liquefy and/or dissolve in the rectal cavity to release the drug.
Since individual subjects may present a wide variation in severity of symptoms and each drug has its unique therapeutic characteristics, the precise mode of administration and dosage employed for each subject is left to the discretion of the practitioner.
The present invention is further directed to pharmaceutical compositions comprising a pharmaceutically effective amount of one or more of the above-described compounds and a pharmaceutically acceptable carrier or excipient, wherein said compositions are effective for treating the above diseases and conditions; especially ophthalmic diseases and conditions. Such a composition is believed to modulate signal transduction by a tyrosine kinase, either by inhibition of catalytic activity, affinity to ATP or ability to interact with a substrate.
More particularly, the compositions of the present invention may be included in methods for treating diseases comprising proliferation, fibrotic or metabolic disorders, for example cancer, fibrosis, psoriasis, rosacea, atherosclerosis, arthritis, and other disorders related to abnormal vasculogenesis and/or angiogenesis, such as exudative age related macular degeneration and diabetic retinopathy.
The present invention concerns also processes for preparing the compounds of Formula I. The compounds of formula I according to the invention can be prepared analogously to conventional methods as understood by the person skilled in the art of synthetic organic chemistry. Synthetic Schemes set forth below, illustrate how the compounds according to the invention can be made.
At this stage, those skilled in the art will appreciate that many additional compounds that fall under the scope of the invention may be prepared by performing various common chemical reactions. Details of certain specific chemical transformations are provided in the examples.
Those skilled in the art will be able to routinely modify and/or adapt the following scheme to synthesize any compounds of the invention covered by Formula I.
The present invention is not to be limited in scope by the exemplified embodiments which are intended as illustrations of single aspects of the invention only. Indeed, various modifications of the invention in addition to those described herein will become apparent to those skilled in the art from the foregoing description.
DETAILED DESCRIPTION OF THE INVENTION
The present invention relates to a method of regulating, modulating or inhibiting tyrosine kinases, whether of the receptor or non-receptor class, for the prevention and/or treatment of disorders related to unregulated tyrosine kinase signal transduction, including cell growth, metabolic, and blood vessel proliferative disorders, which comprises administering a pharmaceutical composition comprising a therapeutically effective amount of at least one kinase inhibitor as described herein.
In another aspect, the invention provides the use of at least one kinase inhibitor for the manufacture of a medicament for the treatment of a disease or a condition mediated by tyrosine kinases in a mammal.
It is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive of the invention claimed. As used herein, the use of the singular includes the plural unless specifically stated otherwise.
It will be readily apparent to those skilled in the art that some of the compounds of the invention may contain one or more asymmetric centers, such that the compounds may exist in enantiomeric as well as in diastereomeric forms. Unless it is specifically noted otherwise, the scope of the present invention includes all enantiomers, diastereomers and racemic mixtures. Some of the compounds of the invention may form salts with pharmaceutically acceptable acids or bases, and such pharmaceutically acceptable salts of the compounds described herein are also within the scope of the invention.
The present invention includes all pharmaceutically acceptable isotopically enriched compounds. Any compound of the invention may contain one or more isotopic atoms enriched or different than the natural ratio such as deuterium 2 H (or D) in place of hydrogen 1 H (or H) or use of 13 C enriched material in place of 12 C and the like. Similar substitutions can be employed for N, O and S. The use of isotopes may assist in analytical as well as therapeutic aspects of the invention. For example, use of deuterium may increase the in vivo half-life by altering the metabolism (rate) of the compounds of the invention. These compounds can be prepared in accord with the preparations described by use of isotopically enriched reagents.
The following examples are for illustrative purposes only and are not intended, nor should they be construed as limiting the invention in any manner. Those skilled in the art will appreciate that variations and modifications of the following examples can be made without exceeding the spirit or scope of the invention.
As will be evident to those skilled in the art, individual isomeric forms can be obtained by separation of mixtures thereof in conventional manner. For example, in the case of diasteroisomeric isomers, chromatographic separation may be employed.
Compound names were generated with ACDLabs version 12.5. Some of the intermediate and reagent names used in the examples were generated with software such as Chem Bio Draw Ultra version 12.0 or Auto Nom 2000 from MDL ISIS Draw 2.5 SP1.
In general, characterization of the compounds is performed according to the following methods; NMR spectra are recorded on 300 or 600 MHz Varian and acquired at room temperature. Chemical shifts are given in ppm referenced either to internal TMS or to the solvent signal.
All the reagents, solvents, catalysts for which the synthesis is not described are purchased from chemical vendors such as Sigma Aldrich, Fluka, Bio-Blocks, Combi-blocks, TCI, VWR, Lancaster, Oakwood, Trans World Chemical, Alfa, Fisher, Maybridge, Frontier, Matrix, Ukrorgsynth, Toronto, Ryan Scientific, SiliCycle, Anaspec, Syn Chem, Chem-Impex, MIC-scientific, Ltd; however some known intermediates, were prepared according to published procedures.
Usually the compounds of the invention were purified by medium pressure liquid chromatography, unless noted otherwise.
A 500 mL round-bottomed flask was equipped with a magnetic stirrer and stir bar, heating bath, air condenser, nitrogen inlet. The flask was charged with 1-t-butoxycarbonylpiperid-4-one (50 g, 250 mmol) and N,N-dimethylformamide dimethyl acetal (36.5 mL, 32.5 g, 273 mmol). The stirred solution was heated to 90° C. under nitrogen for 20 hours. Assay of an aliquot by HPLC showed that the reaction was nearly complete. After cooling, the batch was concentrated in vacuo (bath temperature 54° C.). The residue was partitioned between saturated aqueous sodium chloride (1 L) and ethyl acetate (1 L). The separated organic layer was dried over anhydrous sodium sulfate (200 g), filtered, and concentrated under reduced pressure to give the title compound as an amber oil (68.3 g, 107% yield).
A 1 L, three-necked round-bottomed flask was equipped with a magnetic stirrer and stir bar, air condenser, thermocouple, heating bath and nitrogen inlet. To a solution of (E)-tert-butyl 3-((dimethylamino)methylene)-4-oxopiperidine-1-carboxylate (66.8 g, 250 mmol) in N,N-dimethylformamide (600 mL) was added 3-aminopyrazole (22.8 g, 274 mmol). The batch was stirred at 120° C. for 20 hours. An aliquot analyzed by HPLC at 18 hours showed starting material remaining. The cooled mixture was concentrated under reduced pressure (58° C. bath), and the residue was taken-up in diethyl ether (1 L); after washing with saturated aqueous sodium chloride (1 L), the organic layer was dried over anhydrous sodium sulfate (210 g). Filtration and concentration in vacuo afforded crude product (64.5 g). The crude product was dissolved in ethyl acetate (100 mL) and loaded onto a 1500 g KP-Sil SNAP cartridge pre-equilibrated with 20% by volume ethyl acetate in hexanes (3 CV). Gradient elution was run with 20% to 40% by volume ethyl acetate in hexanes (9 CV), followed by isocratic elution with 40% by volume ethyl acetate in hexanes (9 CV), and collecting four fractions. Fraction 1 (10-14 L of eluent), fraction 2 (14-15.1 L of eluent), and fraction 3 (15.1-17 L of eluent) contained pure product and were combined. Fraction 4 (17-20 L of eluent) provided the title compound (6.15 g) of 92% pure product after concentration in vacuo. This impure material was re-purified as above, using a 100 g KP-Sil cartridge; pure fractions were pooled with those previously obtained. Removal of solvent under reduced pressure afforded the title compound (48.4 g, 71% yield).
A 1 L, three-necked, round-bottomed flask was equipped with a magnetic stirrer and stir bar, 250 mL addition funnel, heating bath, thermocouple, condenser, nitrogen inlet and ice water bath. To a stirred solution of tert-butyl 8,9-dihydropyrazolo[1,5-a]pyrido[3,4-e]pyrimidine-7(6H)-carboxylate (41.9 g) in methanol (300 mL) at 40° C. was added aqueous 12 N hydrochloric acid (112 mL) via the addition funnel (exotherm to 60° C. and gas evolution). Analysis of an aliquot by HPLC after 23 hours showed the reaction to be complete. The batch was cooled with an external ice bath while aqueous 50% by weight sodium hydroxide (83 mL) was added via the addition funnel to bring the pH>9. The mixture was concentrated in vacuo by removing ˜350 mL of distillate. The residue was diluted with of water (100 mL) and saturated aqueous sodium chloride (200 mL). The batch was extracted with dichloromethane (10×100 mL), and the combined organic extracts were dried over anhydrous sodium sulfate (250 g), filtered, and concentrated in vacuo to give the title compound (26.2 g, 98% yield).
Example 1
A 500 mL heavy-walled vessel with threaded stopper was equipped with a magnetic stirrer and stir bar and heating bath. The vessel was charged under a nitrogen blanket with palladium(II) acetate (700 mg, 3.12 mmol), 2-(dicyclohexylphosphino)-2′,4′,6′-tri-i-propyl-1,1′-biphenyl (1.5 g, 3.15 mmol), cesium carbonate (10.2 g, 31 mmol), and degassed toluene-t-BuOH 5:1 (50 mL). This mixture was stirred under nitrogen for 5 minutes. A degassed solution of 6,7,8,9-tetrahydropyrazolo[1,5-a]pyrido[3,4-e]pyrimidine (5 g, 28.7 mmol) and methyl 3-bromobenzoate (12.9 g, 60 mmol) in toluene-t-BuOH 5:1 (250 mL) was quickly added. The vessel was sealed under nitrogen and heated at 120° C. for 18 hours. The cooled batch was filtered through a pad of Celite® (14 g) layered upon 230-400 mesh silica gel (32 g), completing the transfer through the pad with ethyl acetate (300 mL). The filtrate and rinse were concentrated in vacuo to provide 14 g of dark oil. This material was purified on a Biotage® unit (340 g SNAP KP-Sil cartridge equilibrated with 3 CV of 20% by volume ethyl acetate in hexane). Gradient elution was performed with 20% by volume ethyl acetate in hexane (1 CV), 20-50% by volume ethyl acetate in hexanes (3 CV), 50% by volume ethyl acetate in hexanes (10 CV), 50-60% by volume ethyl acetate in hexanes (2 CV), and 60-70% by volume ethyl acetate in hexane (2 CV). Pooling the clean fractions (12-16 CV) and concentration under reduced pressure afforded the title compound (2.25 g, 25% yield) of 99% purity.
Example 2
A 250 mL, single-necked, round-bottomed flask was equipped with a magnetic stirrer and stir bar, heating bath, condenser and nitrogen inlet. The flask was charged with methyl 3-(8,9-dihydropyrazolo[1,5-a]pyrido[3,4-e]pyrimidin-7(6H)-yl)benzoate (2.9 g, 9.4 mmol), tetrahydrofuran (70 mL), methanol (50 mL), and aqueous 3 N sodium hydroxide (15 mL). The reaction mixture was then heated with stirring to 45° C. and kept at that temperature for 4 hours. An aliquot showed that hydrolysis was complete. After cooling, the batch was acidified to pH 6 with aqueous 3 N hydrochloric acid (21 mL). Solvent removal in vacuo provided a yellowish solid (6.2 g), which was triturated in boiling methanol (200 mL) and filtered through a fritted glass funnel. The filtrate was concentrated under reduced pressure to afford the title compound (3.9 g).
Example 3
To a mixture of 3-(8,9-dihydropyrazolo[1,5-a]pyrido[3,4-e]pyrimidin-7(6H)-yl)benzoic acid (0.20 mmol, 59 mg), triethylamine (0.40 mmol, 0.056 mL), and catalytic DMAP in 2.0 mL 1,2-dichloroethane at rt was added propylphosphonic anhydride solution (50 wt % in EtOAc, 0.24 mmol, 0.143 mL). After 10 min at rt, 3-isopropylaniline (0.30 mmol, 0.042 mL) was added and the reaction stirred at rt for 1 hour. The reaction was quenched into dilute aqueous Na 2 CO 3 solution, extracted into EtOAc, the EtOAc layer washed with H 2 O, dilute aqueous Na 2 CO 3 solution, brine, dried with anhydrous Na 2 SO 4 and rotary evaporated. This material was chromatographed eluting with CHCl 3 /EtOAc and then recrystallized from EtOAc/hexane to give the title compound as a light yellow solid (16 mg, 20%).
1 H NMR (Acetone-d6) δ: 9.41 (br. s., 1H), 8.51 (s, 1H), 8.12 (d, J=2.1 Hz, 1H), 7.71-7.75 (m, 2H), 7.66-7.71 (m, 1H), 7.33-7.48 (m, 3H), 7.27 (t, J=7.8 Hz, 1H), 7.01 (d, J=7.6 Hz, 1H), 6.66 (d, J=2.3 Hz, 1H), 4.63 (s, 2H), 3.93 (t, J=5.9 Hz, 2H), 3.35-3.42 (m, 2H), 2.91 (spt, J=7.0 Hz, 1H), 1.25 (d, J=7.0 Hz, 6H).
Example 4
To a mixture of 3-(8,9-dihydropyrazolo[1,5-a]pyrido[3,4-e]pyrimidin-7(6H)-yl)benzoic acid (0.20 mmol, 59 mg), triethylamine (0.40 mmol, 0.056 mL), and catalytic DMAP in 2.0 mL 1,2-dichloroethane at rt was added propylphosphonic anhydride solution (50 wt % in EtOAc, 0.24 mmol, 0.143 mL). After 10 min at rt, 3-(trifluoromethyl)aniline (0.30 mmol, 0.042 mL) was added and the reaction stirred at rt for 20 hours. The reaction was quenched into dilute aqueous Na 2 CO 3 solution, extracted into EtOAc, the EtOAc layer washed with H 2 O, dilute aqueous Na 2 CO 3 solution, brine, dried with anhydrous Na 2 SO 4 and rotary evaporated. This material was chromatographed eluting with CHCl 3 /EtOAc and then recrystallized from EtOAc/hexane to give the title compound as a light yellow solid (20 mg, 23%).
1 H NMR (Acetone-d6) δ: 9.76 (br. s., 1H), 8.50 (s, 1H), 8.32 (s, 1H), 8.11-8.13 (m, 1H), 8.08 (d, J=8.5 Hz, 1H), 7.77 (s, 1H), 7.60 (t, J=8.1 Hz, 1H), 7.37-7.50 (m, 4H), 6.65-6.67 (m, 1H), 4.64 (s, 2H), 3.94 (t, J=5.9 Hz, 2H), 3.35-3.42 (m, 2H)
A 3 L, four-necked, round-bottomed flask, was equipped with a mechanical stirrer, 1 L addition funnel, K-type thermocouple, cooling bath and nitrogen inlet. A stirred solution of DL-pyrrolidinol (140.0 g, 1.61 mol), triethylamine (228 g, 314 mL, 2.25 mol), and MeOH (1500 mL) was aged under nitrogen at 15-20° C. in a cold water bath for 20 minutes. Neat di-t-butyl dicarbonate (528.0 g, 2.42 mol) was added drop-wise, adding ice to the cooling bath to maintain an internal temperature below 30° C. After the addition was complete, the batch was stirred at 15-25° C. overnight. The mixture was concentrated under reduced pressure to a residue, which was purified by passage through silica gel (230-400 mesh, 1000 g) packed with 50% by volume ethyl acetate-hexane (2000 mL). The product was eluted with ethyl acetate (8000 mL), taking 250 mL fractions. Pure fractions were pooled and concentrated in vacuo to give the title compound as an off white solid (294 g, 98% yield).
A 3 L, four-necked round-bottomed flask was equipped with a mechanical stirrer, 500 mL addition funnel, cooling bath, K-type thermocouple and a nitrogen inlet. The flask was charged with oxalyl chloride (149.8 g, 1.18 mol) and dichloromethane (700 mL) and cooled to −69° C. The stirred solution was treated drop-wise with a solution of dimethyl sulfoxide (99.2 g, 1.27 mol) in dichloromethane (150 mL), maintaining an internal temperature below −60° C. (copious gas generation). This mixture was briefly warmed to −40° C. before cooling to −69° C. A solution of tert-butyl 3-hydroxypyrrolidine-1-carboxylate (100.0 g, 0.534 mol) in dichloromethane (350 mL) was charged drop-wise to the batch, maintaining an internal temperature below −60° C. The stirred reaction mixture was allowed to age at −50° C. for 30 minutes and cooled to −69° C. Neat triethylamine (270 g, 2.67 mol) was added drop-wise, while maintaining an internal temperature below −60° C. Upon completion of the addition, the batch was allowed to age for 30 minutes at −60° C., before warming to ambient temperature over about 1 hour. The reaction mixture was washed with 5% mass to volume aqueous citric acid solution (2×180 mL). The separated aqueous layer was extracted with dichloromethane (2×200 mL), and the combined the organic phases were dried over anhydrous sodium sulfate (30 g), filtered and concentrated under reduced pressure. The title compound was obtained as a dark brown oily product (95.0 g, 96% yield) and was used in the next step without further purification.
A 125 mL round-bottomed flask was equipped with a magnetic stirrer and stir bar, distillation head, heating bath, thermocouple and nitrogen inlet. The flask was charged with tert-butyl 3-oxopyrrolidine-1-carboxylate (17 g, 91.9 mmol) and N,N-dimethylformamide dimethyl acetal (14.4 g, 120.8 mmol). The stirred mixture was heated to 95° C. over 2.33 hours, while the methanol formed was distilled-off. During this operation, the internal temperature was at 78° C. and later rose to 95° C. after 1 hour (matching external heating bath temperature). The batch was placed under 1 torr vacuum to remove N,N-dimethylformamide dimethyl acetal, which left the crude enamine (22 g, 91.9 mmol) behind. Neat 3-aminopyrazole (17.7 g, 212 mmol) was added to the batch and the mixture was heated at 95° C. for another 19 hours. After cooling, the crude product was diluted with ethyl acetate (10 mL) and adsorbed onto 50 g of silica gel (230-400 mesh), evaporating the solvent in vacuo. This material was loaded onto a column of silica gel (230-400 mesh, 120 g) equilibrated with hexane. Product was isolated by eluting the column with 50% by volume ethyl acetate-hexanes (2 L), collecting a single fraction. Concentration under reduced pressure provided 13 g of product as a mixture of linear and bent isomers. Re-crystallization of this material from boiling ethyl acetate (7 mL) gave the title compound (5.92 g, 25% yield) in 97+% purity.
A 500 mL single-necked round-bottomed flask was equipped with a magnetic stirrer and stir bar, condenser, heating/cooling bath, nitrogen inlet. The vessel was charged with tert-butyl 6,8-dihydro-7H-pyrazolo[1,5-a]pyrrolo[3,4-e]pyrimidine-7-carboxylate (21.3 g, 81.6 mmol) and MeOH (200 mL). The contents were heated to 65° C. with stirring to give a solution. After cooling the batch to 50° C., aqueous 12 N hydrochloric acid (27.5 mL) was added slowly with care, resulting in an exotherm to 61° C. and gas evolution. After stirring the batch at 60° C. for 1 hour, a aliquot indicated that the reaction was complete. The mixture was chilled in an ice-water bath for 30 minutes, and the precipitated crystalline salt was collected on a filter. The filter cake was rinsed with cold methanol (100 mL) and air dried to provide the title compound (18 g, 112% yield). The title compound free base is prone to oxidize to 7H-pyrazolo[1,5-a]pyrrolo[3,4-e]pyrimidine.
Example 5
A 250 mL, single-necked, round-bottomed flask was equipped with a magnetic stirrer and stir bar, heating bath, thermocouple, rubber septum and nitrogen line with needle, gas bubbler. The flask was charged with 7,8-dihydro-6H-pyrazolo[1,5-a]pyrrolo[3,4-e]pyrimidine hydrochloride salt (1.7 g, 8.6 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (522 mg, 0.90 mmol), cesium carbonate (5.8 g, 17.8 mmol), methyl 3-bromobenzoate (2.15 g, 10.0 mmol), and a 5:1 mixture by volume of toluene and t-butanol (100 mL). The stirred mixture was degassed by passing nitrogen through it for 5 minutes. Powdered palladium(II) acetate (207 mg, 0.92 mmol) was added rapidly, and the mixture was degassed again for 3 minutes. The stirred batch was heated to 93° C. under nitrogen for 23 hours. The mixture was cooled to 22° C. and filtered through a short pad of silica gel (20 g), rinsing the reactor and the silica gel pad with ethyl acetate (100 mL). The filtrate and rinse were concentrated in vacuo to yield 3.1 g of a solid. This material was swished in a 50% by volume mixture of ethyl acetate and hexanes (40 mL), filtered, and dried under reduced pressure to give the title compound (1.53 g, 61% yield) in 97% purity.
Example 6
A 1 L, three-necked, round-bottomed flask was equipped with a magnetic stirrer and stir bar, heating bath, condenser, thermocouple and nitrogen inlet. The flask was charged with methyl 3-(6,8-dihydro-7H-pyrazolo[1,5-a]pyrrolo[3,4-e]pyrimidin-7-yl)benzoate (2.5 g, 8.5 mmol), aqueous 3 N sodium hydroxide (13 mL, 39 mmol), tetrahydrofuran (50 mL), and methanol (50 mL). The stirred mixture was heated to 65° C. for 1 hour, at which time analysis by HPLC indicated complete reaction. The batch was cooled to ambient temperature and the pH adjusted to 6.5 with aqueous 3 N hydrochloric acid (22 mL, 66 mmol). After standing for 30 minutes, the batch was filtered through a fritted glass funnel and concentrated under reduced pressure. The resulting solids were slurried with 5:2 by volume methanol-water (35 mL) at ambient temperature for 3 hours. Solids were collected on a fritted glass filter, washed with methanol (5 mL), and dried to constant weight in vacuo to give the title compound as a light beige solid (1.2 g, 54% yield).
Example 7
To a mixture of 3-(6,8-dihydro-7H-pyrazolo[1,5-a]pyrrolo[3,4-e]pyrimidin-7-yl)benzoic acid (0.40 mmol, 112 mg), N, N-diisopropylethylamine (1.8 mmol, 0.314 mL), and catalytic DMAP in 3.0 mL DMF at rt was added propylphosphonic anhydride solution (50 wt % in EtOAc, 0.52 mmol, 0.309 mL). After 7 min at rt, 3-isopropylaniline (0.60 mmol, 0.085 mL) was added and the reaction stirred at rt for 24 hours. The reaction was quenched with saturated aqueous NaHCO 3 solution, extracted into EtOAc, the EtOAc layer washed with brine, dried with anhydrous Na 2 SO 4 and rotary evaporated. The residue was chromatographed eluting with CHCl 3 /EtOAc to give the title compound as a light beige solid (30 mg, 19%).
1 H NMR (Acetone-d6) δ: 9.44 (br. s., 1H), 8.67 (s, 1H), 8.23 (d, J=1.8 Hz, 1H), 7.69-7.75 (m, 2H), 7.36-7.46 (m, 3H), 7.27 (t, J=8.1 Hz, 1H), 7.01 (d, J=7.6 Hz, 2H), 6.77 (d, J=1.8 Hz, 1H), 5.12 (t, J=3.1 Hz, 2H), 4.92 (t, J=3.2 Hz, 2H), 2.84-2.99 (m, 1H), 1.26 (d, J=7.0 Hz, 6H).
Example 8
A mixture of 6,7,8,9-tetrahydropyrazolo[1,5-a]pyrido[3,4-e]pyrimidine (3.65 g, 20.95 mmol), N-(tert-butoxycarbonyl)-3-bromoanline (8.85 g, 32.52 mmol), SPhos (1.71 g, 4.16 mmol), Pd(OAc) 2 (0.939 g, 4.18 mmol) and Cs 2 CO 3 (18.0 g, 55.2 mmol) in toluene (140 mL) stirred at 85° C. for 48 hours. The mixture was cooled to room temperature and filtered over a fritted funnel, washing with EtOAc and acetone. The filter cake was taken up in H 2 O and extracted with EtOAc (3×150 mL). The organic extracts were dried (MgSO 4 ), filtered and concentrated. The initial filtrate was concentrated. The residue was taken up in MeOH and stirred for 2 hours. The solid was filtered off, washed with MeOH and combined with the previous solid to afford the title compound as a light yellow solid (3.4 g, 44.4%).
Example 9
A mixture of tert-Butyl (3-(8,9-dihydropyrazolo[1,5-a]pyrido[3,4-e]pyrimidin-7(6H)-yl)phenyl)carbamate, (3.27 g, 8.94 mmol) and TFA (7.12 mL, 93.6 mmol) in CH 2 Cl 2 (116 mL) was stirred at room temperature for 24 hours. The mixture was concentrated, then partitioned between CH 2 Cl 2 and 1N NaOH. Extracted with CH 2 Cl 2 (3×75 mL). The organic extracts were washed with water, dried (MgSO 4 ), filtered and concentrated. The residue was taken up in a small amount of MTBE and triturated with hexanes. The resultant solid was filtered off, washed with hexanes and dried under high vacuum to afford the title compound as an orange solid (1.82 g, 77%).
Example 10
To a solution of 3-(8,9-dihydropyrazolo[1,5-a]pyrido[3,4-e]pyrimidin-7(6H)-yl)aniline (0.30 mmol, 79.6 mg) and N, N-diisopropylethylamine (0.60 mmol, 0.105 mL) in 3.0 mL dichloromethane at rt was added benzoyl chloride (0.33 mmol, 0.038 mL). After stirring at rt for 1.5 hours the reaction was quenched with 1.5 mL MeOH, stirred 10 min, and then evaporated. The residue was treated to an EtOAc/saturated aqueous NaHCO 3 workup. The resulting oil was chromatographed eluting with EtOAc/CHCl 3 and the product triturated with EtOAc to give the title compound as a yellow solid (82 mg, 74%).
1 H NMR (DSMO-d6) δ: 10.13 (s, 1H), 8.51 (s, 1H), 8.20 (d, J=1.8 Hz, 1H), 7.95 (d, J=7.3 Hz, 2H), 7.49-7.63 (m, 4H), 7.28-7.33 (m, 1H), 7.19-7.27 (m, 1H), 6.90 (d, J=7.6 Hz, 1H), 6.74 (d, J=1.8 Hz, 1H), 4.49 (s, 2H), 3.77 (t, J=5.7 Hz, 2H), 3.25-3.30 (m, 2H).
Example 11
In a manner similar to that described in Example 10, 3-(8,9-dihydropyrazolo[1,5-a]pyrido[3,4-e]pyrimidin-7(6H)-yl)aniline (0.30 mmol, 79.6 mg) and (3-trifluoro methyl) benzoyl chloride (0.315 mmol, 0.047 mL) were reacted to give the title compound as light beige solid (86 mg, 66%).
1 H NMR (DSMO-d6) δ: 10.37 (s, 1H), 8.51 (s, 1H), 8.24-8.30 (m, 2H), 8.20 (d, J=2.3 Hz, 1H), 7.97 (d, J=7.6 Hz, 1H), 7.76-7.83 (m, 1H), 7.54-7.57 (m, 1H), 7.22-7.32 (m, 2H), 6.93 (dt, J=7.8, 2.0 Hz, 1H), 6.74 (d, J=2.3 Hz, 1H), 4.50 (s, 2H), 3.78 (t, J=5.7 Hz, 2H), 3.26-3.31 (m, 2H).
Example 12
To a mixture of 3-(8,9-dihydropyrazolo[1,5-a]pyrido[3,4-e]pyrimidin-7(6H)-yl)aniline (0.30 mmol, 79.6 mg) and N, N-diisopropylethylamine (0.60 mmol, 0.105 mL) in 3.5 mL dichloromethane at rt was added meta-tolyl isocyanate (0.45 mmol, 0.057 mL). The reaction was stirred at rt for 1.7 hours, and the resulting precipitate filtered and rinsed with dichloromethane, EtOAc, and 50% EtOAc/hexane to give the title compound as a yellow solid (95 mg, 79%).
1 H NMR (DSMO-d6) δ: 8.56 (d, J=1.2 Hz, 2H), 8.51 (s, 1H), 8.19 (d, J=2.3 Hz, 1H), 7.29-7.34 (m, 2H), 7.19-7.24 (m, 1H), 7.15 (td, J=7.9, 2.1 Hz, 2H), 6.84 (dd, J=7.9, 1.2 Hz, 1H), 6.73-6.81 (m, 3H), 4.46 (s, 2H), 3.74 (t, J=5.9 Hz, 2H), 3.27 (t, J=5.6 Hz, 2H), 2.28 (s, 3H).
A mixture of 1,4-dioxa-8-azaspiro[4.5]decane (7.0 g, 48.9 mmol), methyl 3-bromobenzoate (12.6 g, 58.6 mmol), BiNAP (3.64 g, 5.84 mmol), Pd(OAc) 2 (0.455 g, 2.02 mmol) and Cs 2 CO 3 (45.0 g, 138 mmol) in toluene (210 mL) was stirred at 85° C. for 24 h. The mixture was cooled to room temp and filtered over celite, washing with EtOAc. The filtrate was dried (MgSO 4 ) and concentrated. The residue was purified via column chromatography, eluting with 40% EtOAc/hexanes to afford the title compound as a yellow oil (12.9 g, 95%).
A mixture of methyl 2-(1,4-dioxa-8-azaspiro[4.5]decan-8-yl)benzoate (2.0 g, 7.21 mmol), pTsOH.H 2 O (0.137 g, 0.72 mmol), acetone (23.0 mL) and water (40.0 mL) was stirred at 80° C. for 3 days. The mixture was cooled to room temp. and diluted with CH 2 Cl 2 . The solution was washed with sat. NaHCO 3 and extracted with CH 2 Cl 2 (3×100 mL). The organic extracts were washed with water, dried (MgSO 4 ) and concentrated to afford the title compound (1.57 g, 93%).
A mixture of methyl 3-(4-oxopiperidin-1-yl)benzoate (1.0 g, 4.28 mmol), DMF-DMA (1.0 mL, 7.46 mmol) and toluene (8.0 mL) was stirred at 100° C. for 20 h. The mixture was concentrated and dried under high vacuum to afford the title compound (1.23 g, quantitative).
A mixture of 3-nitro-1H-pyrazole-5-carboxylic acid (1.0 g, 6.36 mmol), diphenylphosphorazidate (2.7 mL, 12.5 mmol) and Et 3 N (1.7 mL, 12.2 mmol) in tBuOH (4.0 mL) was stirred at reflux for 18 hours. The mixture was cooled to room temp and diluted with water. Extracted with EtOAc (4×50 mL). The organic extracts were washed with water, dried (MgSO 4 ) and concentrated. Purified via column chromatography, eluting with 40-50% EtOAc/hexanes to afford the title compound as a light yellow solid (0.452 g).
To a stirring solution of tert-Butyl 5-nitro-1H-pyrazol-3-ylcarbamate (0.450 g, 1.97 mmol) in EtOAc (16.0 mL) under N 2 was added Pd/C (10%, 0.10 g). The mixture was stirred under an atmosphere of H 2 at room temp for 18 hours. The mixture was filtered over celite, washing with EtOAc and MeOH. The filtrate was concentrated to an orange oil. Dried under high vacuum to afford the title compound as a brown solid (0.301 g, 77%).
Example 13
A mixture of methyl 3-(3-((dimethylamino)methylene)-4-oxopiperidin-1-yl)benzoate (0.145 g, 0.503 mmol) and tert-Butyl (5-amino-1H-pyrazol-3-yl)carbamate (0.150 g, 0.756 mmol) in EtOH (4.0 mL) was stirred at 80° C. for 20 h. The mixture was cooled and concentrated. The residue was washed with MTBE and hexanes. Dried under high vacuum. A mixture of the title compound and methyl 3-(2-((tert-butoxycarbonyl)amino)-5,6-dihydropyrazolo[1,5-a]pyrido[4,3-d]pyrimidin-7(8H)-yl)benzoate was afforded, which was separated by prep HPLC to afford the title compound (0.011 g) and methyl 3-(2-((tert-butoxycarbonyl)amino)-5,6-dihydropyrazolo[1,5-a]pyrido[4,3-d]pyrimidin-7(8H)-yl)benzoate (0.050 g). Prep HPLC Method: Phenomex Luna 100×21.2 mm, 10 μM, C(18) column; Gradient of 55% H 2 O and 45% CH 3 CN; Flow Rate 1 mL/min.; uv @215 nm.
To a mixture of 3-nitro-1H-pyrazole-5-carboxylic acid (0.50 g, 3.18 mmol) in EtOAc/MeOH (3:1, 10.0 mL) was added a solution of Pearlman's Catalyst (Wet PdOH/C, 20%; 0.050 g) and Degussa Catalyst (Wet PdOH/C, 20%, En101 NE/W; 0.050 g) in EtOAc (2.0 mL). The mixture was stirred under an atmosphere of H 2 at room temp. for 20 h. The mixture was purged with N 2 . A 1N NaOH (3.2 mL) solution was added and the mixture stirred at room temp. for 30 minutes. The mixture was filtered over celite, washing with EtOAc and MeOH. The filtrate was concentrated then acidified to pH=2 with 1N HCl to afford the title compound (0.404 g, quantitative) as a lavender solid. The solid was filtered off, washed with water and dried under high vacuum. No further purification.
Example 14
A mixture of methyl 3-(3-((dimethylamino)methylene)-4-oxopiperidin-1-yl)benzoate (0.606 g, 2.10 mmol) and 5-amino-1H-pyrazole-3-carboxylic acid (0.404 g, 3.18 mmol) in EtOH (8.0 mL) was stirred at 80° C. for 20 h. The mixture was cooled and concentrated. The residue was taken up in H 2 O and acidified to pH=2 with 1N HCl. The precipitate was filtered off and washed with water, MTBE and hexanes. Dried under high vacuum to afford the title compound (0.362 g, 49%) as a brown solid.
VEGFR2 and PDGFRβ kinase potencies of select analogs was determined by the following assay:
VEGFR2 Kinase Assay:
Biochemical KDR kinase assays were performed in 96 well microtiter plates that were coated overnight with 75 μg/well of poly-Glu-Tyr (4:1) in 10 mM Phosphate Buffered Saline (PBS), pH 7.4. The coated plates were washed with 2 mls per well PBS+0.05% Tween-20 (PBS-T), blocked by incubation with PBS containing 1% BSA, then washed with 2 mls per well PBS-T prior to starting the reaction. Reactions were carried out in 100 μL reaction volumes containing 2.7 μM ATP in kinase buffer (50 mM Hepes buffer pH 7.4, 20 mM MgCl 2 , 0.1 mM MnCl 2 and 0.2 mM Na 3 VO 4 ). Test compounds were reconstituted in 100% DMSO and added to the reaction to give a final DMSO concentration of 5%. Reactions were initiated by the addition 20 ul per well of kinase buffer containing 200-300 ng purified cytoplasmic domain KDR protein (BPS Bioscience, San Diego, Calif.). Following a 15 minute incubation at 30° C., the reactions were washed 2 mls per well PBS-T. 100 μl of a monoclonal anti-phosphotyrosine antibody-peroxidase conjugate diluted 1:10,000 in PBS-T was added to the wells for 30 minutes. Following a 2 mis per well wash with PBS-Tween-20, 100 μl of O-Phenylenediamine Dihydrochloride in phosphate-citrate buffer, containing urea hydrogen peroxide, was added to the wells for 7-10 minutes as a colorimetric substrate for the peroxidase. The reaction was terminated by the addition of 100 μl of 2.5N H 2 SO 4 to each well and read using a microplate ELISA reader set at 492 nm. IC 50 values for compound inhibition were calculated directly from graphs of optical density (arbitrary units) versus compound concentration following subtraction of blank values.
VEGFR2 Cellular Assay
Automated FLIPR (Fluorometric Imaging Plate Reader) technology was used to screen for inhibitors of VEGF induced increases in intracellular calcium levels in fluorescent dye loaded endothelial cells. HUVEC (human umbilical vein endothelial cells) (Clonetics) were seeded in 384-well fibronectin coated black-walled plates overnight @ 37° C./5% CO2. Cells were loaded with calcium indicator Fluo-4 for 45 minutes at 37° C. Cells were washed 2 times (Elx405, Biotek Instruments) to remove extracellular dye. For screening, cells were pre-incubated with test agents for 30 minutes, at a single concentration (10 uM) or at concentrations ranging from 0.0001 to 10.0 uM followed by VEGF 165 stimulation (10 ng/mL). Changes in fluorescence at 516 nm were measured simultaneously in all 384 wells using a cooled CCD camera. Data were generated by determining max-min fluorescence levels for unstimulated, stimulated, and drug treated samples. IC 50 values for test compounds were calculated from inhibition of VEGF stimulated responses in the absence of inhibitor.
PDGFRβ Kinase Assay
Biochemical PDGFRβ kinase assays were performed in 96 well microtiter plates that were coated overnight with 75 μg of poly-Glu-Tyr (4:1) in 10 mM Phosphate Buffered Saline (PBS), pH 7.4. The coated plates were washed with 2 mls per well PBS+0.05% Tween-20 (PBS-T), blocked by incubation with PBS containing 1% BSA, then washed with 2 mls per well PBS-T prior to starting the reaction. Reactions were carried out in 100 μL reaction volumes containing 36 μM ATP in kinase buffer (50 mM Hepes buffer pH 7.4, 20 mM MgCl 2 , 0.1 mM MnCl 2 and 0.2 mM Na 3 VO 4 ). Test compounds were reconstituted in 100% DMSO and added to the reaction to give a final DMSO concentration of 5%. Reactions were initiated by the addition 20 ul per well of kinase buffer containing 200-300 ng purified cytoplasmic domain PDGFR-b protein (Millipore). Following a 60 minute incubation at 30° C., the reactions were washed 2 mls per well PBS-T. 100 μl of a monoclonal anti-phosphotyrosine antibody-peroxidase conjugate diluted 1:10,000 in PBS-T was added to the wells for 30 minutes. Following a 2 mis per well wash with PBS-Tween-20, 100 μl of 0-Phenylenediamine Dihydrochloride in phosphate-citrate buffer, containing urea hydrogen peroxide, was added to the wells for 7-10 minutes as a colorimetric substrate for the peroxidase. The reaction was terminated by the addition of 100 μl of 2.5N H 2 SO 4 to each well and read using a microplate ELISA reader set at 492 nm. IC 50 values for compound inhibition were calculated directly from graphs of optical density (arbitrary units) versus compound concentration following subtraction of blank values.
PDGFRβ Cellular Assay
Automated FLIPR (Fluorometric Imaging Plate Reader) technology was used to screen for inhibitors of PDGF-induced increases in intracellular calcium levels in fluorescent dye loaded endothelial cells. NHDF-Ad (Normal Human Dermal Fibroblasts, Adult; Lonza) were seeded in 384-well fibronectin coated black-walled plates overnight @ 37° C./5% CO2. Cells were loaded with calcium indicator Fluo-4 for 45 minutes at 37° C. Cells were washed 2 times (Elx405, Biotek Instruments) to remove extracellular dye. For screening, cells were pre-incubated with test agents for 30 minutes, at a single concentration (10 uM) or at concentrations ranging from 0.0001 to 10.0 uM followed by PDGF-BB stimulation (30 ng/mL). Changes in fluorescence at 516 nm were measured simultaneously in all 384 wells using a cooled CCD camera. Data were generated by determining max-min fluorescence levels for unstimulated, stimulated, and drug treated samples. IC 50 values for test compounds were calculated from % inhibition of PDGF-BB stimulated responses in the absence of inhibitor.
TABLE 2
In vitro VEGFR2 and PDGFRβ data
VEGFR2
VEGFR2
PDGFR
PDGFR
Kinase
Cellular
βKinase
βCellular
Ex.
Assay
Assay
Assay
Assay
No.
Structure
(IC 50 nM)
(IC 50 nM)
(IC 50 nM)
(IC 50 nM)
3
8
26
20
NA
4
6
70
27
192
7
>10000
NA
NA
NA
8
>10000
NA
NA
NA
10
101
NA
202
NA
11
6
NA
21
NA
12
27
NA
32
NA
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The present invention relates to organic molecules capable of modulating tyrosine kinase signal transduction in order to regulate, modulate and/or inhibit abnormal cell proliferation.
| 2 |
BACKGROUND OF THE INVENTION
The term "polyphenylene ether resin" is descriptive of a well known group of polymers that may be made by a variety of catalytic and non-catalytic processes. By way of illustration, certain of the polyphenylene ethers are disclosed in Hay, U.S. Pat. Nos. 3,306,874 and 3,306,875, and in Stamatoff, 3,257,357 and 3,257,358. In the Hay patents, the polyphenylene ethers are prepared by an oxidative coupling reaction comprising passing an oxygen-containing gas through a reaction solution of a phenol and a metal-amine complex catalyst. Other disclosures relating to processes for preparing polyphenylene ethers are found in Fox, U.S. Pat. No. 3,356,761; Sumitomo, U.K. Pat. No. 1,291,609; Bussink et al, U.S. Pat. Nos. 3,337,499; Blanchard et al, 3,219,626; Laakso et al, 3,342,892; Borman, 3,344,166; Hori et al, 3,384,619; Faurote et al, 3,440,217; and disclosures relating to metal based catalysts which do not include amines are known from patents such as Wieden et al, U.S. Pat. No. 3,442,885 (copper-amidines); Nakashio et al, U.S. Pat. No. 3,573,257 (Metal alcoholate or phenolate); Kobayashi et al, U.S. Pat. No. 3,455,880 (cobalt chelates); and the like. In the Stamatoff patents, the polyphenylene ethers are produced by reacting the corresponding phenolate ion with an initiator, such as peroxy acid salt, an acid peroxide, a hypophalite, and the like, in the presence of a complexing agent. Disclosures relating to non-catalytic processes, such as oxidation with lead dioxide, silver oxide, etc., are described in Price et al, U.S. Pat. No. 3,382,212. All of the above-mentioned disclosures are incorporated herein by reference.
Cizek, U.S. Pat. No. 3,383,435 describes compositions of polyphenylene ether resins and styrene resins, including rubber modified high impact styrene resins.
The rubber modified-high impact polystyrenes, that were described by the Cizek specification, have rubber particles that have a composite structure, with an outer shell of rubber enclosing polyhedral occlusions of polystyrene that are separated by a thin rubber membrane. These are called "salami" or "cellular" particles.
A different type of rubber modified polystyrene has been described by Kruse, U.S. Pat. No. 4,097,549 and in Die Angewandte Makromolekulare Chemie 58/59 1977 pp. 175-198 which are incorporated by reference. These rubber modified polystyrenes have the rubber moiety structured on different morphological forms comprising ordinary cellular forms, bundles of rubber fibers, rubber sheets and mixtures thereof. It has been found that when this type of improved rubber modified polystyrene is combined with a polyphenylene ether resin, the resulting compositions have equal or slightly higher impact strength than analogous compositions that are made with ordinary rubber modified high impact polystyrene having a higher content of rubber. This is quite surprising in view of the fact that the impact strength of the improved rubber modified polystyrene is inferior to the impact strength of the ordinary rubber modified high impact polystyrene. The polyphenylene ether composition that contain the improved rubber modified polystyrene also have higher distortion temperatures and better gloss. It has also been found that equivalent gloss can be obtained in a polyphenylene ether composition containing the improved rubber modified polystyrene as compared to a polyphenylene ether composition containing ordinary rubber modified polystyrene, at molding temperatures that are lower by approximately 25° F.
Accordingly, it is an object of this invention to provide a polyphenylene ether resin-alkenyl aromatic resin composition that has improved properties as compared to the prior art compositions.
It is also an object of this invention to provide a composition of a polyphenylene ether and an alkenyl aromatic resin that may be molded at lower temperatures.
DETAILED DESCRIPTION OF THE INVENTION
The novel compositions of the invention comprise:
(a) a polyphenylene ether resin; and
(b) a polymeric composition of
a polymer of at least one monoalkenyl aromatic monomer having dispersed therein, an amount sufficient to toughen said polymer, of a diene rubber, said rubber being dispersed as crosslinked rubber particles and being grafted with said monomer as polymer and having occluded therein said polymer, said particles having a weight average diameter of from 0.5 to 10 microns, said rubber being structured in a morphological form comprising aggregations of rubber fibers or aggregations of rubber sheets and mixtures thereof.
These polymeric compositions may be prepared by continuously polymerizing a solution of a monoalkenyl aromatic monomer and a diene rubber under catalytic conditions with back mixed agitation to about 10 to 50% conversion, thereafter discontinuing said back mixed agitation and continuing the polymerization of said solution until the monomer is substantially polymerized; then heating and separating said polymeric compositions from unpolymerized monomer.
The polyphenylene ether resins have structural units of the formula: ##STR1## wherein Q is selected from the group consisting of hydrogen, hydrocarbon radicals, halohydrocarbon radicals having at least two carbon atoms between the halogen atom and the phenyl nucleus, hydrocarbonoxy radicals and halohydrocarbonoxy radicals having at least two carbon atoms between the halogen atom and the phenyl nucleus, Q' and Q" are the same as Q and in addition halogen with the proviso that Q and Q' are both free of a tertiary carbon atom and n is an integer of at least 50.
The preferred polyphenylene ether resin is one where Q and Q' are both hydrocarbon and Q" are both hydrogen. An especially preferred polyphenylene ether resin is a poly(2,6-dimethyl-1,4-phenylene) ether resin having an intrinsic viscosity of about 0.40 dl/g-0.65 dl/g as measured in chloroform at 30° C.
The composition of the invention may comprise from 20 to 80 parts by weight, or more preferably 35 to 65 parts by weight of component (a) and from 80-20 parts by weight or more preferably from 65-35 parts by weight of component (b). Materials of the type comprehended by component (b) are commercially available from Dow Chemical as Dow 70510 and from Monsanto as Q301 polystyrene. In addition, materials such as that described in example 1 of U.S. Pat. No. 4,097,549 may be utilized.
If desired, reinforcing fillers may be added to the composition in reinforcing amounts such as from 1-40 parts by weight of fibrous glass or other fillers such as quartz, metal fibers, wollastonite or the fillers mentioned in U.S. Pat. No. 4,080,351, columns 3 and 4 which is incorporated by reference. Flame retardants such as those described in U.S. Pat. No. 3,833,535 which is incorporated by reference may be utilized in the compositions of the invention.
The compositions may be prepared by tumble blending powders, beads or extruded pellets of components (a) and (b) with or without suitable reinforcing agents, stabilizers, pigments, fillers, flame retardants, plasticizers or extrusion aids. The blends are extruded into a continuous strand, the strands are chopped into pellets and the pellets are molded to the desired shape.
All reference to "parts" in the Examples are parts by weight.
DESCRIPTION OF THE PREFERRED EMBODIMENT
EXAMPLE 1
Molding compositions are prepared from poly(2,6-dimethyl-1,4-phenylene) ether, rubber modified high impact polystyrene resin and triaryl phosphate*. Each composition also contained 3 phr of titanium dioxide; 1.5 phr polyethylene; 1 phr diphenyl decylphosphite; 0.15 phr zinc sulfide and 0.15 zinc oxide. The compositions were extruded in a twin screw extruder and molded into standard test preces using a screw injection molding machine. The compositions had the following ingredients:
______________________________________poly(2-6-dimethyl- Ordinary Improved1,4-phenylene) ether* HIPS** HIPS*** Triaryl Phosphate______________________________________1..sup.a 50 50 32. 50 50 33..sup.a 35 65 74. 35 65 7______________________________________ *PPO General Electric Co. 1V of 0.5 dl/g in CHCl.sub.3 at 30° C. **Foster Grant 834 ***Dow 70510 .sup.A Controls
The molding compositions were tested and were found to have the following properties:
TABLE I______________________________________Elong. T.Y. T.S. Izod Gardner HDT(%) (psi) (psi) (ft.lb/in.) (in-lbs) (°F.)______________________________________1..sup.a61 9000 8300 3.7 175 2462. 52 9600 8400 3.9 175 2513..sup.a59 7100 7100 4.2 150 1994. 53 8000 7200 4.3 125 206______________________________________ .sup.a Control
The properties of the HIPS are as follows:
______________________________________ Improved Ordinary HIPS HIPS______________________________________Rubber (%) 8.4 9.2Number average particlediameter (microns) 1.4 1.6Weight average particlediameter (microns) 2.1 2.1Notched Izod Impact Strength(ft.ib/in.n.) 1.9 2.5______________________________________
EXAMPLE 2
The composition in Example 1 was molded into 21/2"×21/2"×1/8" plaques at mold temperature of 130°, 155° and 180° F. Stock temperature was 520° F. for the 50:50 materials and 480° F. for the 35:65 compositions. Gloss (45°) was measured with the results listed in Table II. Compositions made with the improved polystyrene containing bundles of fibers and sheets of rubber had higher gloss that the control at all three mold temperatures, but the difference was greatest at low temperatures, as much as ten gloss units for 50:50 compositions in a mold at 130° F.
TABLE II______________________________________ GlossComposition 130° mold 155° mold 180° mold______________________________________1. 50:50 45.7 53.8 59.02. 50:50 55.0 58.9 61.63. 35:65 55.6 57.3 62.04. 35:65 59.4 62.2 64.0______________________________________
EXAMPLE 3
The following compositions were prepared according to the procedure of Example 1. Compositions 5 and 6 contained 50 parts of poly(2,6-dimethyl-1,4-phenylene) ether; 50 parts of the rubber modified polystyrene; 3 parts titanium dioxide; 3 parts triaryl phosphate*; 1 part diphenyl decylphosphite; 1.5 parts polyethylene; 0.15 parts zinc sulfide and 0.15 parts of zinc oxide. Compositions 7 and 8 contained 35 parts of poly(2,6-dimethyl-1,4-phenylene) ether; 65 parts of the rubber modified polystyrene; 0.5 parts diphenyl decylphosphite; 3 parts titanium dioxide; 8 parts triaryl phosphate*; 1.5 parts polyethylene zinc sulfide and 0.15 parts zinc oxide. Properties are shown in Tables III and IV.
TABLE III______________________________________HIPS Elong. T.Y. T.S. Izod Gardner HDT______________________________________5. ordinary** 86 9,800 8900 3.8 200 2456. improved*** 63 10,000 8400 3.8 200 2497. ordinary** 67 7,400 7000 4.4 90 2008. improved*** 53 7,600 7000 4.4 125 201______________________________________ **Foster Grant 834 ***Monsanto 0301
TABLE IV______________________________________ Gloss180° mold 155° mold 130° mold______________________________________5. 60.4 52.1 50.46. 63.6 60.3 56.37. 59.4 54.1 52.18. 63.4 60.1 58.4______________________________________
Obviously many variations will suggest themselves to those skilled in the art from the above detailed description without departing from the scope or spirit of the invention. It is, therefore, to be understood that changes may be made in the particular embodiments of the invention as defined by the appended claims.
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Novel thermoplastic molding compositions are described which are based on the combination of a polyphenylene ether resin and an alkenyl aromatic resin that is modified by rubber particles in the form of bundles of rubber fibers or rubber sheets.
| 2 |
BACKGROUND OF THE INVENTION
1. Technical Field
The present invention relates to tools. In particular, it relates to specialized pliers for repairing and/or joining segments of fluid carrying hoses located above and below ground level and methods for using the tools.
2. Background Art
Flexible hosing is used for a variety of applications and for many types of fluids. A principle advantage of this type of conduit is its low cost and ease of use. Typically, sections of hosing can be mated together to provide desired lengths and configurations.
Methods used to join flexible hoses together often rely on nipple structures to which sections of flexible hose are attached. A variety of methods are used to secure the nipples to the hosing. Where suitable, bonding techniques can be used. More often however, mechanical clamping or pressure devices are used.
One form of clamping device commonly used are wire ring hose clamps. A nipple is inserted into a section of hose and the wire ring hose clamp is spread apart by a pair of pliers, slid over the expanded section of hose which covers the nipple and then released.
A second known type of clamping devices is the compression ring. A compression ring is mounted on the flexible hosing prior to insertion of the nipple. After the nipple is inserted, the compression ring is forced over the section of hose which surrounds the nipple. While the compression ring may slide freely over unexpanded sections of hosing, the section of hose which surrounds the nipple is typically expanded by the nipple to a diameter which prevents movement of the compression ring. When the compression ring is forced over the expanded section of hose, it provides enough pressure to prevent the nipple from disengaging the hose and also to prevent leakage of fluid at the hose/nipple joint.
Typical methods of moving the compression ring into place involve the use of common tools such as a pliers to force the ring over the expanded hose section. There are several problems associated with this approach. For example, the pliers are prone to slip off the compression ring. In addition, inability to provide equal pressure on both sides of the hose tends to skew the compression ring, thereby causing the installer to use a step approach involving small moves of the compression ring on alternating sides of the hose. While it would be preferable to slide the compression ring over the expanded section of hose, it is impossible to do this with a common pliers.
While the aforedescribed problems are a nuisance for most applications which use compression rings, there are some applications in which the inability to conveniently attach compression rings is particularly undesirable. Installation of underground hoses for applications such as sprinkler systems is one such application.
A particular problem associated with underground systems is the difficulty in reaching sections of hose which may need to be repaired. For example, in applications such as golf course irrigation systems, water hoses may be run at sufficient depths below the ground surface that the repair of hose sections and installation of new nipple joints may be significantly impaired by the use of conventional tools such as pliers. Due to the depth of the hose, slippage of the pliers may cause excessive time to be used to repair a hose. Likewise, the use of common pliers may increase the difficulty involved with insertion of the nipples into the hose.
While addressing the various aspects of hose joining, the prior art has not provided a quick, convenient method of attaching compression rings to two sections of hose. In particular, prior art attempts have failed to address problems associated with hose joining in hard to reach places such as underground hose systems used in environments such as golf course sprinkler systems.
SUMMARY OF THE INVENTION
The present invention solves the foregoing problems by providing a device which engages compression rings on both sides of the ring. This allows the ring to be inserted onto the expanded section of hose in a single procedure. In addition, the device uses a jaw structure which has cutouts on the opposing jaws which allow the hose to fit between finger-like projections on either side of the cutouts. The jaws are shaped to provide a pocket structure which surrounds the compression rings such that the device cannot slip off the ring. An optional cutter is integrated into the device along with optional nipple pushers which allow the entire repair operation to be performed with a single tool.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 is a diagram of a prior art hose connection nipple. FIG. 1A is a side view, FIG. 1B is an end view, and FIG. 1C is a perspective view.
FIG. 2 is a diagram of a prior art hose connection nipple inserted into two sections of hose.
FIG. 3 a diagram of a prior art hose connection nipple inserted into two sections of hose with compression rings located beyond the expanded hose section.
FIG. 4 is a diagram of a prior art method of moving the compression rings onto the expanded section of hose.
FIG. 5 shows a front view of the invention with optional nipple pushers in the jaws and the handle. A handle spring is shown connecting the handles.
FIG. 6A shows a left side view of the invention. FIG. 6B shows a right side view of the invention with optional nipple pusher in the jaws.
FIG. 7 shows a top view of the invention with the jaws in the open position.
FIG. 8 shows a top view of the invention with the jaws in the open position and a hose resting in the pocket of the jaws.
FIG. 9 shows a top view of the invention with the jaws in the closed position and a hose resting in the pocket of the jaws.
FIG. 10 shows alternative embodiments of the jaws. FIG. 10A shows a circular pocket. FIG. 10B shows a square pocket. FIG. 10C shows a flat open-sided pocket. FIG. 10D shows a flat open-sided pocket with distal retainers.
FIG. 11 shows a perspective view of the handle with optional nipple pusher pushing a nipple into a section of hose.
FIG. 12 shows a rear view of the invention with optional cutter on the rear edge of the jaws. The handle spring is not shown.
FIG. 13 shows an alternative embodiment of the invention. FIG. 13A shows a left side view of the invention. FIG. 13B shows a right side view of the invention with optional nipple pusher in the jaws. FIG. 13C shows a top view of the invention.
FIG. 14 shows another alternative embodiment of the invention. FIG. 14A shows a left side view of the invention. FIG. 14B shows a right side view of the invention with optional nipple pusher in the jaws.
FIG. 15 another alternative embodiment of the invention with the pivot point located at the proximal end of the device.
FIG. 16 shows another alternative embodiment of the invention with multiple cutout sizes for multiple hose sizes. FIG. 16A shows a left side view of the invention. FIG. 16B shows a right side view of the invention.
DESCRIPTION OF THE PREFERRED EMBODIMENT
FIG. 1 shows a prior art hose connection nipple 102. Flange 108 and stem 106 are inserted into a hose (not shown) and pressed into the hose until ridge 104 comes to rest against the edge of the hose. A second hose is inserted onto flange 108 and stem 106 at the other end of nipple 102. Conduit 110 extends through nipple 102 allowing free flow of fluid through nipple 102 after the hoses are connected.
FIG. 2 shows prior art hose segments 202, 204 installed onto nipple 102. Ridge 104 is shown with hoses 202, 204 resting against either side.
FIG. 3 illustrates the location of prior art compression rings 302, 304 prior to placement of hoses 202, 204 on the expanded section 306 of hoses 302, 304 above nipple 102.
FIG. 4 illustrates the prior art method of installation of compression rings 302, 304 using common pliers 402. As can be seen, this method causes skewing of the compression rings, which in turn requires additional time and maneuvering of pliers 402. As can be seen, this results in a tedious series of repetitive maneuvers to get the compression rings 302, 304 into place. While this amounts to no more than a time wasting nuisance in many applications, the installation of compression rings 302, 304 on hoses 202, 204 in underground systems may be difficult and require extensive digging to provide room to maneuver. Further, the need to manipulate several components at the same time creates an awkward situation for the installer which may result in errors, faulty installations and the inadvertent dropping of parts.
FIG. 5 shows a front view of the compression ring tool 502. Opposing members 516, 518 are pivotally attached at pivot 508. Handles 504 are pushed apart by spring 506 such that the device is normally in the open position. For ease of illustration, handles 504 are not shown with any covering. However, those skilled in the art will recognize that a variety of materials can and would be used to cover the handles 504 for the purpose of increasing user comfort, providing a better grip, etc.
At the opposite end of compression ring tool 502 from handles 504 are jaws 510. On the side edges of jaws 510 are cutouts 514. Cutouts 514 are sized to fit commonly available hose 202, 204 sizes such that the hose 202, 204 can slide freely in the cutout. As can be seen, cutouts 514 oppose one another to facilitate ease of movement of hoses 202, 204. Nipple pushers 512, 520 are shown on jaws 510 and handle 504 respectively. By placing nipple pushers 512, 520 on compression ring tool 502, the nipple 102 may be installed in hose 202, 204 with the same tool that installs compression rings 302, 304, thereby enhancing ease of use and reducing the time required to effect repairs.
Those skilled in the art will recognize that a variety of alternative pivot arrangements may be used, such as rivets, nuts and bolts, etc. Likewise, the location of nipple pushers 512, 520 can vary, and they may in fact be located in any convenient location. The size of the aperture used by nipple pusher 512, 520 is not critical and will vary depending on the size of the nipple 102 intended for use with a particular hose size. Of course, a variety of nipple pusher 512, 520 sizes may be used on a single compression ring tool 502 to allow the same tool to be used for multiple sizes of nipples and hoses. Cutout 514 sizes will also vary to suit particular hose 202, 204 sizes, etc.
FIG. 6 shows a left and right side view of compression ring tool 502. Cutouts 514 result in the formation of fingers 602 which extend upward on either side of cutout 514. As a result, hoses 202, 204 are held securely by compression ring tool 502 without risk of slippage. A significant advantage of this structure is the elimination of the slippage problem caused by the use of common pliers for the installation of compression rings 302, 304.
FIG. 7 is a more detailed top view of compression ring tool 502 in the open position. As can be more readily seen in this view, fingers 602 form a pocket which encloses compression rings 302, 304 to prevent slippage. In addition, the pocket structure simultaneously applies pressure to both sides of compression rings 302, 304, thereby avoiding any problems caused by skewing.
FIG. 8 shows the top view of compression ring tool 502 in the open position as was discussed above in regard to FIG. 7. However, in this figure hoses 202, 204 and nipple 102 are shown mounted in cutouts 514. As can readily be seen, the hose 202, 204 and nipple 102 are held in place in the pocket formed by fingers 602.
FIG. 9 shows compression ring tool 502 in the closed position. The diameters of compression rings 302, 304 are larger than the distance between fingers 602. Therefore, fingers 602 force compression rings 302, 304 toward ridge 104 which in turn moves compression rings 302, 304 over the section of hose 202, 204 which is expanded by nipple 102. The effect of the fingers 602 which form a pocket around compression rings 302, 304 is to provide successful installation of compression rings 302, 304 without risk of slippage in difficult to reach locations.
FIG. 10 shows several alternative embodiments of jaws 510, each having different shapes for fingers 602. FIG. 10A shows the embodiment discussed above in regard to FIG. 9. FIG. 10B shows an embodiment in which fingers 602 have a rectangular configuration. FIG. 10C uses a flat, open sided configuration. In FIG. 10D, fingers 602 have extension 1002 which extend over the edge of compression ring 302, 304. As these figure indicate, the particular shape of the pocket is of no concern so long as the pocket captures compression ring 302, 304, thereby allowing it to install compression rings 302, 304 without slippage and in a single procedure.
FIG. 11 shows a nipple 102 being installed in hose 202. The end of nipple 102 opposite hose 202 is inserted in nipple pusher 520. Handle 504 is then used to hold nipple 102 and to apply pressure to force it into hose 202. The selection of which nipple pusher 512, 520 to use would be one of convenience. As noted above, a variety of sizes of nipple pushers 512, 520 can be used on a single compression ring tool 502.
FIG. 12 shows a rear view of compression ring tool 502. In this embodiment, spring 506 is not shown to illustrate spring retainers 1204. On the inside edge of jaws 510 are cutting edges 1202. The addition of these optional cutting edges allows the single tool to effect all require repair operations. Damages sections of hose 202, 204 can be cut out by cutting edge 1202, a new nipple 102 can be inserted by nipple pusher 520, and compression rings 302, 304 can be installed by closing jaws 510 while the compression rings 302, 304 are inside the pocket formed by jaws 510.
FIG. 13 shows an alternative embodiment in which the cutouts are on the side of the jaws rather than on the distal end. FIGS. 13A and 13B provide left and right side views respectively. FIG. 13C is a top view which shows the formation of the pocket from the side. The advantage of this configuration is that it provides an alternative method of forming the pocket.
FIG. 14 is another embodiment which provides cutouts on the distal end and on the sides of jaws 510. The advantage of this embodiment is that it provides more flexibility to the user when the hose 202, 204 is in a difficult to reach location.
FIG. 15 is another alternative embodiment in which the pivot 508 is located at the proximal end of compression ring tool 502. Handles 504 are in the middle of the device and jaws 510 are at the opposite end from the pivot 508.
FIG. 16 is another alternative embodiment in which multiple size cutouts 514, 1602 are used. This allows the same compression ring tool 502 to be used for a variety of hose 202, 204 sizes.
While the invention has been described with respect to a preferred embodiment thereof, it will be understood by those skilled in the art that various changes in detail may be made therein without departing from the spirit, scope, and teaching of the invention. For example, the number and size of nipple pushers can vary, the number and size of cutouts can vary, the location of the cutouts can vary, etc. Accordingly, the invention herein disclosed is to be limited only as specified in the following claims.
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A plier-like tool for joining flexible hosing with hose connection nipples and hose compression rings. The tool has cutouts in the jaws which allow the flexible hose to pass through. The portion of the jaws adjacent to the cutouts form a pocket structure which surrounds the compression rings on the flexible hose. When the jaws are closed, the compression rings are held in place by the pocket structure while they are pressed onto the sections of flexible hose which are joined by a hose connection nipple. The tool has an optional hose cutter for trimming the hose and optional nipple pushers for insertion of the nipples into the flexible hose.
| 1 |
BACKGROUND OF THE INVENTION
The present invention relates generally to fabrication of metal parts including sheet form and three-dimensional form by diffusion bonding in patterns followed by super plastic inflation. More particularly, it relates to the diffusion bonding of sheets as well as three dimensional structures in patterns which permit expansion by pneumatic means of the unbonded portions of the sheets and three dimension structures, such as turbine blades used for power generation or for aircraft engines.
The formation of articles from sheets by selective bonding of metal areas of the sheets and the selective prevention of bonding in other areas of the sheets is a well-developed art. Numerous articles, such as refrigerator evaporators, have been made in this fashion from lower-melting metals such as aluminum. In such conventional practice, a resist material or stop-off coating is printed on a sheet surface in a pattern and the sheet is bonded to another sheet in those areas which do not have a stop-off on the surface. By this conventional practice, the bonding occurs where no stop-off is present and does not occur where the stop-off is present.
When this conventional practice is applied to higher melting metals, such as titanium base metals superalloys and the like, additional problems arise because of the higher temperature and higher pressures which are needed to form the surface-to-surface metal bonds and also because of the difficulty of defining the patterns where the bond is to be generated and separating these from the areas where bonding is to be avoided.
In addition, where the high melting alloy starting materials are themselves non-planar and where the starting structures themselves have complex shapes such as double curvatures, such as turbine fan blades used in power generation or jet engines, in the bonding areas. The resist or stop-off which is useful in processing lower melting metal, such as aluminum alloys, is not satisfactory for processing the higher melting alloys, such as titanium base alloys.
Moreover, the conventional practice of silk screening the resist out of the starting sheet stock does not work where the starting stock is itself nonplanar or a complex shape in the bonding portions. This conventional practice is not suitable for achieving the high degree of precision required in masking complex curved surfaces, such as the component halves of a multicurved configuration turbine blade.
There continues to be a need for an improved effective way to economically bond together high melting alloy into articles having complex shapes. Such methods desirably would provide the same strength of interface at the bonding surface as achieved by previous methods; would be less expensive to utilize; would be simpler; and would maintain bonded interfaces equivalent to interfaces which are diffusion bonded after acid cleaning.
SUMMARY OF THE INVENTION
The present invention represents a new method for patterning stop-off which can be automated for precise location of the stop-off and is particularly applicable to patterning surfaces with complex surfaces, such as turbine fan blades used in power generation turbines and jet engines.
In carrying out the present invention in preferred forms thereof, we provide a process for diffusion bonding Ti-6A1-4V component for sheet as well as components having double curvatures in the bonding areas, such as turbine fan blades, used in power generation turbines and aircraft engines.
One illustrated specific method of the invention disclosed herein, comprises the steps of: providing first and second metal parts formed of a base metal, such as titanium; applying a coating of a strippable masking material to one surface of the first part; cutting a pattern in the masking material for defining portions thereof to be removed; removing a portion of the masking material pattern from the metal surface to expose a defined area of uncoated metal on the first part adapted to be diffusion bonded to a complimentary surface on the second part; applying a stop-off coating to the defined area to prevent bonding with the second part; removing the masking material from the uncoated portion of the surface of the first part; permitting bonding to occur in the areas of the first part from which the coating of masking material has been removed and, after cleaning, superposing the patterned surface of the first part over a surface of the second part.
A further aspect of the present invention includes cleaning the residue from the surface of the first part not covered by stop-off, such as by washing with a detergent.
Another aspect of the invention includes applying heat and pressure to induce diffusion bonding between the exposed surface of the first part and the opposed surface of the second part.
According, an object of the present invention is to provide an improved method for diffused bonding of two components to produce high melting alloy to produce complex shapes, such as turbine blades.
Another object of the present invention is to provide a diffused bonded part having interfaces equivalent to interfaces which are diffused bonded after as in cleaning.
A further object of the present invention is to provide a method whereby application of stop-off can both prevent diffusion bonding in the stop-off coated areas and lead to good diffusion bond strength equivalent to clean surfaces in the area not coated by the stop-off.
Other objects and advantages of the invention will be apparent from the following description, the accompanying drawings and the appended claims.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 is a perspective view of a titanium base metal substrate on which a deposit (such as by spraying, dipping or painting) of strippable material is being formed;
FIG. 2 is the substrate of FIG. 1 on which the completed sprayed layer has been formed and a portion cut and removed;
FIG. 3 is a perspective view of the substrate of FIG. 2 on which a spray formed stop-off layer is being formed; and
FIG. 4 is the substrate layer of FIG. 3 having the remaining strippable coating which leaves the stop-off displayed in a patterned configuration.
DETAILED DESCRIPTION OF THE INVENTION
In carrying out the subject method, a number of steps are performed in sequence. The sequence is described with reference to the accompanying Figures. As shown in FIG. 1, the sequence starts with the application of a strippable masking material 10 to the surface of a first article, such as sheet 11. It will be appreciated that although the article sprayed as illustrated in FIG. 1, is a planar sheet like object, illustration in this form is for convenience and clarity of illustration. The present invention is, in fact, particularly useful in facilitating solid state bonding of non-planar parts such as parts to be formed along curved surfaces including multicurved surfaces, for example, turbine fan blades used in power generation turbines and aircraft engines.
Application of the masking material 10 may be by any convenient means such as dipping, brushing or spraying, and it is believed preferable to use a spray mechanism 12, where the surfaces of the article to be formed are curved.
Next, a pattern is cut into the layer of the masking material 10 with a laser or with a sharp knife and a guide template. In an actual test, a YAG pulse laser of moderate power was found suitable for this purpose.
After the pattern has been cut, a portion 14 of the applied masking material 10 is removed from the surface of the article to expose a patterned area, as illustrated in FIG. 2.
A stop-off coating 16, as illustrated in FIG. 3, for prevention of bonding at that portion of the surface, such as a by air brushing or other conventional techniques, to which the stop-off 16 is applied is then applied to the patterned area. Finally, the remainder of the strippable masking material 10 is then removed.
The first article having the patterned area of stop-off 16, as illustrated in FIG. 4, is then disposed on a conforming uncoated part and heat and pressure are applied to cause diffusion bonding of the surface of the article bearing no stop-off material to the confronting portion of the complimentary article to form a bonded composite part. After the bonding of those portions having no stop-off coating thereon of the two confronting articles, high pressure gas is introduced into the unbonded area between the parts to inflate the composite in the unbonded area.
Above, we have described the process in generic terms, now we will provide a specific explanation of the individual steps of this method. Specific individual steps are carried out in sequence as follows. The first step involves providing a metal part, such as one portion of a turbine blade, to be diffusion bonded. The metal part is preferably a titanium base alloy metal and may be, for example, Ti64 (an alloy containing 6 parts by weight of vanadium, 4 parts by weight of aluminum, with the remainder being titanium) or alloy Ti6242 (an alloy containing by weight 6 parts of vanadium, 2 parts of titanium, 4 parts of aluminum, 2 parts of tin, and the balance titanium). Other titanium alloys as well as other metal alloys may be used as well.
This specific process is generally for forming a metal article having a high melting temperature of about 1,000° C. or more. However, it is principally directed toward the formation of titanium base metal articles.
A second metal part having surfaces which conform to the first part must also be provided in order to complete the bonding process. It is possible to produce valuable products from combinations of parts having different thicknesses. The inflation of a pair of diffusion bonded parts having different thicknesses will, of course, produce articles which have some asymmetry in the shape of the inflated composite.
A patterning process is then performed on a selected surface of the first part. This selected surface is first coated with the flexible strippable masking material 10. A suitable material for this masking coating is available commercially under the designation "Sterling Compound A-446". This product is available from the Diversified Products Group of Sterling Engineered Products, at 5201 Grant Avenue, in Cleveland, Ohio 44125. The strippable mask may be any other material that may be commercially available or formulated. Requirements for such material include that the mask coating be easily removed from the metal; that it be tough and strong enough to permit it to be stripped in mostly one-piece from the metal before application of the stop-off coating; that the flexible mask material be tough and strong enough to be strippable from the metal, removing the stop-off coating from areas that are to be diffusion bonded without leaving remnants of the stop-off or the strippable mask material.
The mask 10 is a temporary coating and is essentially completely removed before the diffusion bonding is carried out. However, removal of the mask 10 is a two step process.
The first step in the removal process comprises cutting a predesigned pattern into the strippable masking material 10. Such cutting can be accomplished conveniently with a laser, for example, to give a very sharp edge definition to the masking material and to clearly define the pattern of the masking material to be removed from the surface of the first metal part. It is important to set laser parameters so that the strippable mask is volatilized or cut, but that the titanium base metal is not damaged.
Alternatively, a sharp blade or knife edge focused ultrasound or equivalent methods may be employed to cut through the deposited flexible mask material 10 to define the portion to be removed at this stage of the processing. Where non-planar parts are to be joined the use of laser cutting or other cutting which can be automated for curved and other irregular surfaces is preferred.
The pattern of the mask material defining the non-bonding, as described above, is peeled from the surface of the first sheet of metal to expose the surface of the metal therebeneath. It is not necessary to clean the surface of the exposed metal as it is to be coated with a stop-off material 16 to prevent diffusion bonding.
The next step in the processing is the application of the stop-off 16 to the exposed surface of metal as well as to the surface of the adjoining strippable masking material. Such a stop-off material may be, for example, a metal oxide contained within an organic binder The organic binder facilitates the application of the stop-off 16 to the exposed surface of the first sheet of metal. Such a stop-off should preferably include yttrium oxide and/or other rare earth oxide as the yttrium oxide has been found to be effective in preventing the diffusion bonding.
There is some art involved in the application of the stop-off coating by air brushing. If the coating was applied so that the surface became wet with undried stop-off then the stop-off coating fractured irregularly upon removal of strippable mask. A coating which was applied relatively dry produced the best edge definition. The edge definition of the stop-off pattern was of the order of 0.015 inch for "wet" applied stop-off and less than 0.0075 inch for "dry" applied stop-off. The technique was refined until an edge resolution of 0.0025 inch was repeatable. In the actual experiments, a well-defined "H" pattern with 0.5 inches wide and 2 inches long was produced for diffusion bonding and superplastic forming trials. The center "H" was coated with yttria stop-off coating with ethyl-methacrylate binder. It was observed that after removable of the strippable mask, a light oily residue was present on the surfaces to be diffusion bonded.
In order to produce good diffusion bond ductility and Charpy impact energy, it was necessary for the surfaces to be diffusion bonded to be free of any compounds which could react with the titanium alloy and embrittle the bonded surface or prevent diffusion bonding. The processing of the stop-off coating utilized a 500° F. vacuum bakeout to remove volatile hydrocarbon binder before diffusion bonding. We baked samples containing only oily residue from the strippable mask at the same time and found that most of the oil was removed. Some non-volatized residue was evident, however.
The stop-off material 16 is dried so that its position on the surface of the first sheet is well defined and delineated.
Following the application of the stop-off material 16, the remainder of the original flexible plastic mask material 10 is removed, such as by peeling or other acceptable methods. After the remaining flexible mask 10 is removed, we have determined that it is important to remove the oily residue of the strippable mask material 10 that is left on the part in order to provide clean surfaces which are necessary for good diffusion bonding. We have found that the residue which remains after removal of the Sterling A-446 flexible mask 10 can be removed by an aqueous detergent solution and preferably by an aqueous solution of a detergent such as "Alconox", "Microclean " or "Taski-Profi" or the like may also work but no successful trials have been run with other the "Alconox".
Following the cleaning step with the aqueous detergent solution, the surfaces are rinsed with distilled water and air dried. The patterned stop-off 16 is then vacuum baked at a temperature of between about 350° F. and about 550° F. to remove the majority of the organic binder from the patterned stop-off material. Removal of excess organic binder material from the stop-off prevents contaminants forming on the titanium alloy surfaces.
The organic binder must dry or cure completely so that when the patterned stop-off coating is washed in an aqueous detergent solution, no binder dissolution or removal of the oxide particles occur. It is important that no stop-off material be deposited on the uncoated areas that are to be diffusion bonded.
EXAMPLE
Seven blocks of solution treated and aged (STA) Ti-64A1-4V were cut along the mid-plane of a thick block. The cut surfaces were lapped to provide a good fitting surface when re-assembled. The surfaces were then acid etched clean and given different treatments prior to electron beam welding the periphery of the joint and diffusion bonded at 900° C. for 3 hours at a maximum argon gas pressure of 30 ksi. The treatment of the seven blocks are tabulated in Table 1.
TABLE 1______________________________________Interface Treatment of Diffusion BondedTi--6Al--4V STA Blocks DiffusionBlock BondingNumber Interface Treatment After Lapping Conditions______________________________________137 Acid clean 900° C./ 3 hr/30 ksi138 Acid clean Apply Mask (Sterling Compound A-446*) 900° C./ Strip Mask 3 hr/30 ksi Vacuum Bakeout 500° F.163 Acid clean Apply Mask (Sterling Compound A-446) 900° C./ Strip Mask 3 hr/30 ksi Detergent wash-Alconox167 Acid clean Apply Mask (Sterling Compound A-446) 900° C./ Strip Mask 3 hr/30 ksi Detergent wash-Alconox 2× longer than block 163208 Acid clean Apply Mask (Sterling Compound A-446) 925° C./ Strip Mask 3 hr/30 ksi Detergent wash-Microclean-10 minutes209 Acid clean Apply Mask (Sterling Compound A-446) 925° C./ Strip Mask 3 hr/30 ksi Detergent wash-Taski-Profi-10 minutes210 Acid clean Apply Mask (Sterling Compound A-446) 925° C./ Strip Mask 3 hr/30 ksi Detergent wash-Alconox-10 minutes______________________________________ *Sterling Engineered Products, Diversified Products Group, 5201 Grant Avenue, Cleveland, OH 44125
Full size Charpy samples were EDM cut and ground from the bonded blocks with the notch plane aligned with the bonded interface of the block. Samples were tested at room temperature at a scale of 0-60 ft.lbs. After fracture, the fracture surfaces were examined optically to determine the percentage of the fracture surface which followed the plane of the bond line (the bonded interface). The criterion was that flat fracture surfaces in the plane of the notch were judged to be along the interface. Fracture along bulk microstructural features generally did not follow the interface plane.
The Charpy Impact Energies and interface fracture percentages of the diffusion bonded blocks are shown in Table 2.
TABLE 2______________________________________Charpy Impact Energy of Diffusion BondedTi--6Al--4V STA BlocksBlock Charpy Impact Percentage ofNumber and Energy Fracture alongTreatment (ft. lbs.) Bonded Interface______________________________________137 20.0 0% 23.5 0%138 9.8 100% 17.5 80% 9.3 100%163 19.8 15% 14.8 15%167 21.5 0% 21.5 0% 23 0%208 17.0 100% 13.0 12.5209 18.0 55% 22.5 13.0210 12.0 95% 11.0______________________________________
The first sample, 137, although notched near the diffusion bonded interface, appeared to exhibit Charpy impact values that are associated with properties of the bulk Ti-6A1-4V microstructure. All fracture was through the bulk of the sample and not along the interface. The Charpy impact energies ranged from 20 to 23.5 ft. lb.
Block 138 was diffusion bonded without removing the residue of the Streling Compound A-446 mask, but was baked in vacuum to simulate the processing of SPF/DB samples containing stop-off coatings. The very low Charpy energy and 80-100% interface fracture showed that contamination by strippable mask residue severely reduced the strength and fracture resistance of the interface.
In contrast, blocks that were washed with an aqueous detergent solution after mask application and removal had good Charpy energy and fracture path characteristics. Blocks 163 and 167 were cleaned with detergent after mask removal. Block 163 was washed for approximately half the time of block 167. It had good Charpy energy but exhibited approximately 15% interface fracture. Block 167, washed longer, exhibited no interface fracture and had good Charpy energy. This suggests that washing for the appropriate time appears to remove the damaging residue of the strippable mask. Inadequate washing may have led to partial interface fracture.
Comparison of the Charpy energies of sample 137 (clean interface) with 163 and 167 (masked and washed interfaces), one can see that the Charpy energies are equivalent. The percentage of interface fracture of 167 was the same as for the clean samples, indicating that the bulk properties of the block, not interface properties, determined the Charpy energy.
In summary, diffusion bonded Ti-6A1-4V interfaces formed after strippable mask patterning and detergent washing with Alconox for 5 minutes are equivalent to interfaces which are diffusion bonded after acid cleaning. The process of stop-off patterning by strippable masking with Sterling Compound A-446 and airbrush application of stop-off can both prevent diffusion bonding in the stop-off coated areas and lead to good diffusion bond strengths equivalent to clean surfaces in the areas not coated by stop-off.
In a second series of tests, 208-210, we found that all three detergents cleaned samples were degraded relative to cleanly acid-etched surfaces. The reason for this large difference in the behavior of Alconox in the five-minute test and the ten-minute test is not understood. One possibility is that the diffusion bonding HIP cycle was inadequate. Because of this difference, experiments will have to be repeated to develop better statistics in order to qualify detergent cleaning as a means of removing oily residue, such as that from strippable mask coatings.
Treatment Details
The procedure for all bond blocks was to chemically clean them prior to any treatment. This was done by using a nitric-hydrofloric cleaning etch. Immediately after rinsing with distilled water and drying, the various surface treatments were applied. The detergent cleaning procedure was to place the Ti-6A1-4V in a solution of the detergent and gently swirl for ten minutes, in the case of the ten-minute test. Because we did not want to disturb the remaining stopoff coating, rubbing was not used. Rubbing would improve the speed and effectiveness of cleaning. The cleaning solutions that were used were the concentrations recommended by the manufacturers. They are:
______________________________________Detergent Recommended Dilution______________________________________Microclean 2-/2 oz. Microclean added to one gallon waterTaski-Profi 50 ml Taski-Profi to 1 L water (1:20)Alconox 1 pkg (1/2 oz.) Alconox powder in 1/2 gal. water______________________________________
In summary, it appears that, all other factors being equal, the amount of wash time of the area after removal of the strippable coating may be important. Specifically, it appears that washing the area to be diffusion bonded for approximately 5 minutes produces the best diffusion bonded articles. If the area is washed for about three minutes, the Charpy impact energy is reduced as well as an increase in the percentage of fracture along the bonded interface. However, if the same area is washed for ten minutes utilizing the same detergent used in the three and the five minute tests, the Charpy impact is severely reduced and the diffusion bonded percentages of fractures is one-hundred percent. Therefore, it seems that there is a need to wash for a sufficient time to remove all of the residue but not too long in order to produce other residue or other conditions which have led to the fracture along the bonded interface when washed for ten minutes.
While the methods and articles herein described constitute preferred embodiments of the invention, it is to be understood that the invention is not limited to these precise methods and articles, and that changes can be made therein without departing from the scope of the invention which is defined in the appended claims.
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An improved method for forming fluid inflatable metal structures is taught. The improvement concerns the patterning of the portion of the structure to be inflated. Patterning is accomplished by first applying a strippable flexible mask coating and then scoring this coating so that a patterned portion may be removed therefrom. The parent portion is the portion of the sheet article to be inflated by subsequent processing. After the patterned portion has been removed, a stop-off is applied to the exposed surface of the first sheet. After the stop-off material has been applied, the remainder of the strippable mask is removed and washed with a detergent to remove the residue from the mask. The sheet having stop-off applied in the pattern to the first sheet is then superposed over a second sheet, and heat and pressure are applied to cause diffusion bonding between the exposed surfaces of the two sheets. Following this bonding, the portion of the sheet carrying the stop-off is inflated to give the article its final configuration.
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BACKGROUND OF THE INVENTION
The present invention relates generally to computer portraits and more particularly to a doll having a computer portrait for a face.
The prior art has produced a rather crude doll with a person's face transferred onto it. In order to accomplish this feat, the face was first heat pressed on to a flat sleeve with a stretch-type back which was then slipped over the head of an already stuffed doll. It was not possible to press the face directly on to the stuffed doll because the surface had to be completely flat to press the picture onto it without wrinkling the surface during the process and thus distorting the image. Therefore, the resulting doll did not look very lifelike.
The technology for computer generated photographs was developed by NASA in the late 1960's to enable the world to get its first close-up glimpse of the moon through use of the technology. This space age technology lead to the development of a process in which a video camera could take a picture, capture it on a television monitor, feed it through a computer which would then send the information to a high speed printer. Such a system has been commercially developed and marketed by Computer Amusement Systems, Inc., 160 S.W. 12th Ave. Suite 106, Deerfield Beach, Fla. 33442. The print-out could then be heat pressed onto various objects such as t-shirts, cups, buttons, aprons, and caps through the use of readily available equipment. Heretofore, however, there has not been available a method or pattern designed that would allow the transfer of the print-out onto a surface other than one that was flat and which was supported so that the pressure of the heat press would not distort the surface and therefore distort the image being transferred. This deficiency in the prior an has limited the ability to use the space-age technology in the creation of three-dimensional products, such as dolls, which bear the likeness of the image on the print-out.
There is no prior art product or method which will create a life-like doll with a face that has an undistorted image of a person. What is needed, then, is a system which allows a portrait to be placed on a doll's face without wrinkling. This needed system must allow the portrait to be placed on the face without undue distortion. This system is presently lacking in the prior art.
SUMMARY OF THE INVENTION
The present invention discloses a specially designed doll (and pattern for making the doll face) that can accept the transfer of a computer generated portrait directly on its face without wrinkling. The face of the doll is shaped similar to a real face and cut out on the straight of the material to ensure that it does not stretch or wrinkle. The two sides of the head are cut on the bias of the material in order to stretch with the pressure of the heat press but not affect the face area. This allows the face to remain flat so that the picture does not wrinkle and the result is a clear picture.
Accordingly, one object of the present invention is to provide a system which allows a computer portrait to be placed on a doll.
Another object of the present invention is to provide a doll which looks lifelike.
A still further object of the present invention is to provide a doll capable of having a computer portrait placed on its face without wrinkling and distortion.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 is a plan view of the pattern for the side of the head.
FIG. 2 is a plan view of the pattern for the face.
FIG. 3 is a plan view of the pattern for the front body.
FIG. 4 is a plan view of the pattern for the back body.
FIG. 5 is a plan view of the pattern for the arm.
FIG. 6 is a plan view of the pattern for the bootie or foot.
FIG. 7 is a plan view of the pattern for the leg.
FIG. 8 is a side view of the entire doll.
DESCRIPTION OF THE PREFERRED EMBODIMENT
Referring now to FIG. 1 there is shown generally at 12 the pattern for the side of the head of the doll of the present invention. Head pattern 12 is cut such that head top 26 is wider than chin 28 so that rear edge 30 and front edge 32 approach each other as they go from head top 26 to chin 28. Further, the side of head pattern 12 has cut-out 34. Around the perimeter of the side of head pattern 12 there is placed side of head pattern seam 36 which is approximately one-quarter (1/4") of an inch. The side of the head panel is made in the shape of the side of the head pattern 12 and is constructed of a square grid grain fabric. The square grid grain of the fabric for the side of the head panel in the shape of the side of the head pattern 12 is shown at 38' in FIG. 1. A square grid grain fabric is one in which the threads of the fabric run perpendicular to each other and form a grid of many squares as is shown at 38'. The grain line of a square grid grain fabric is a line that runs parallel to one set of the threads of the fabric and perpendicular to the other set of threads the fabric. When the side of the head panel is cut from the square grid grain fabric, it is cut so that the side of head grain line 38 lies at an approximate forty-five degree (45°) angle from rear edge 30 substantially shown in FIG. 1.
Referring now to FIG. 2 there is shown generally at 14 the face pattern of the present invention. Face has top 40 and bottom 42 such that bottom 42 resides proximate to chin 28. Front face seam 44 encircles perimeter of face pattern 14 leaving approximately a one-quarter inch (1/4") seam. The face of the doll panel which is cut in the shape of the face pattern 14, is cut from a square grid grain fabric. The square grid grain of the fabric of the face panel of the doll is shown in exploded illustration at 46' in FIG. 2. When the face panel is cut in the shape of face pattern 14 from fabric having a square grid grain 46', the face panel is cut from the fabric so that the grain line 46 runs substantially from between bottom 42 and top 40 in a vertical direction as shown in FIG. 2.
Referring now to FIG. 3 there is shown generally at 16 the front body pattern of the present invention. Front body pattern 16 has upper edge 48 and lower edge 50. In the preferred embodiment, lower edge 50 is substantially flat whereas upper edge 48 has collar 52 and shoulders 54. Front body pattern 16 has left edge 56 and right edge 58 which are substantially parallel. Front body seam 60 passes around perimeter of front body pattern 16 leaving a substantially one-quarter inch (1/4") seam. In the preferred embodiment, front body pattern grain line 62 lies substantially parallel to edges 56, 58 as shown in FIG. 3.
Referring now to FIG. 4 there is shown generally at 18 the back of body pattern of the present invention. Back of body pattern 18 has upper silhouette 64 and lower silhouette 66 joined by neck 68. In the preferred embodiment, grain line 70 of back of body pattern 18 runs vertically from upper silhouette 64 to lower silhouette 66 in the manner shown in FIG. 4. Back of body seam 65 runs around silhouette 64,66 leaving a substantially one-quarter inch (1/4") seam. Around upper portion of upper silhouette 64 there are placed, in the preferred embodiment, four darts 74.
Referring now to FIG. 5 there is shown generally at 20 the arm pattern of the present invention. Arm pattern 20 has thumb 76, hand 78, and wrist 80. In the preferred embodiment, arm grain line 82 runs substantially from wrist 80 to hand 78. Arm pattern seam 84 is placed around perimeter leaving approximately a one-quarter inch (1/4") seam. In the preferred embodiment, four arm patterns 20 are used.
Referring now to FIG. 6 there is shown generally at 22 the foot pattern of the present invention. Foot pattern 22 has ankle 86 and sole 88 along with toe 90 and heel 92. Around perimeter of foot pattern 22 there is placed foot pattern seam 94 which leaves substantially a one-quarter inch (1/4") seam. In the preferred embodiment, two foot patterns 22 are used. In the preferred embodiment, foot grain line runs substantially from ankle 86 to sole 88.
Referring now to FIG. 7 there is shown generally at 24 the leg pattern of the present invention. Leg pattern 24 has upper leg 98 and lower leg 100. In the preferred embodiment, grain line 102 of leg pattern 24 runs parallel to upper leg 98 and lower leg 100. Around perimeter of leg pattern 24 there is placed leg pattern seam 104 thereby leaving approximately a one-quarter inch (1/4") seam. In the preferred embodiment, two leg patterns 24 are used.
Referring now to FIG. 8 there is shown generally at 10 the doll of the present invention having a photograph for a face. Doll 10 is constructed by sewing two sides of head patterns 12 together at chin 28 and top 26. Face pattern 14 is then sewed to the connected side of head patterns 12. Face pattern 14 and the two side of head patterns 12 are sewn to front body pattern 16. Darts 74 are taken from upper silhouette 64 and then upper silhouette 64 is sewn to side patterns 12 whereas lower silhouette 66 is sewn to front body pattern 16 thereby creating head 106, neck 108, and shoulders 110. Each pair of arm patterns 20 is sewn thereby creating two arms 112 which are then sewn to the body. Foot patterns 22 are sewn together to create feet 114. Foot patterns 22 are sewn together to a point between heel 92 and sole 88. One each of leg patterns 24 is sewn to feet 114 while leg patterns 24 are also sewed from body pattern 16. Head 106 and body 116 are then stuffed tightly.
The pattern for the head of the doll and the assembly of the pattern is the particularly unique aspect of this invention. Because of the neck 34, the front edge 32 of the side of the head pattern is longer than the rear edge 30. When the side of the head pattern is connected at the top 26 and chin 28, it creates a front (front edge 32) which will be formed into an oval shape having an edge with a perimeter concentric with the seam line of the face 14 of the doll and a rear edge 30 with a seam line concentric with the seam line of the back of the head 64. Darts 74, when sewn together, cause the back of the head to be smaller than the face and, when stuffed with filler material, to have a spherical shape so that the head of the doll will simulate the shape of a person's head.
As shown in FIGS. 1 and 8, the side of the head pattern is cut diagonally of the grain 38. If the cut of the side of the head pattern is square to the grain of the fabric, any pull on the side of the head pattern caused by pressure applied to the face of the doll will tend to cause the face to pucker and wrinkle. However, by cutting the side of the head pattern at an angle to the grain, pressure on the face of the doll causes the face to collapse in a flat plane and not to wrinkle. Looking at FIG. 1, if one were to attempt to pull the fabric in the direction of the grain line 38, or in a line perpendicular to the grain line 38 which would be the alternate grain line of the fabric, the fabric would not pull, stretch or give substantially because the stretching ability of the threads themselves would be the limiting factor on the ability of the fabric to stretch. On the other hand, if one were to pull on the fabric from rear edge 30 to front edge 32, the pull would be at an angle to the direction to the running of the threads of the fabric so that the fabric could expand or stretch because the grids could expand or stretch. The fabric could stretch in either one of two directions, by pulling on the fabric in the direction of front 32 or from top 26 in the direction of bottom 28. In other words, the grain line 38 is the line of strength and a line of stretch would have to be at an angle to the grain line of the fabric. Because face 14 is larger than back of head 64, once the head 106 of doll 10 is stuffed after darts 74 are placed in back of head 64, any pressure that is applied to face 14 will be directed to back of head 64 and cause the back of the head to flatten and allow the face to remain wrinkle free.
In the preferred embodiment, the computer portrait is made by using well-known technology such as the CASI Futura II Computer Portrait System sold by the supplier identified above. The portrait is then heat pressed onto the face of the doll using standard technology which is well known in the art.
Thus, although there have been described particular embodiments of the present invention of a new and useful doll having a photograph for a face, it is not intended that such references be construed as limitations upon the scope of this invention except as set forth in the following claims. Further, although there have been described certain dimensions used in the preferred embodiment, it is not intended that such dimensions be construed as limitations upon the scope of this invention except as set forth in the following claims.
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The present invention discloses a specially designed doll that could accept the transfer of a computer portrait directly on its face without wrinkling. The face of the doll is shaped similar to a real face and cut out on the straight of the material to ensure that it does not stretch or wrinkle. The panels forming the sides of the head are cut on the bias of the material in order to stretch with the pressure of the heat press but not affect the face area. This allows the face to remain flat so that the picture does not wrinkle and the result is a clear picture.
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BACKGROUND OF THE INVENTION
This invention relates to cement slurry reclamation techniques for ready-mix concrete plants in which the aggregate and coarse sand constituents are separated from returned concrete mix and the remaining ingredients are stored in slurry form for total consumption during the following production day.
U.S. Pat. No. 4,226,542 issued Oct. 7, 1980, for "Cement Slurry Reclamation System and Method", the disclosure of which is hereby incorporated by reference, illustrates a slurry reclamation system for use with a concrete ready-mix plant which enables one hundred percent reclamation of the constituents of concrete mix returned to the plant site by vehicles. Returned concrete mix is dumped into an inlet hopper having a screw classifier for removing aggregate and coarse sand, and a weired channel enabling gravity flow of the water, cement fines and sand fines constituents into a slurry vessel. The slurry vessel is sized in such a manner as to guarantee complete consumption of the slurry returned during a day's production by the end of the following production day, the volumetric capacity of the vessel being related to the total average volume of water used to produce fresh concrete during a representative production day.
The slurry is consumed by admixture to fresh water, cement, sand and aggregate at a rate selected in accordance with the slurry specific gravity and the scheduled or estimated production requirements for that particular day. As disclosed more fully in the above-referenced patent, the percentage of slurry to be admixed to the fresh ingredients is selected by the operator and determined by the slurry vessel working level volume, the measured specific gravity of the slurry (typically obtained at the beginning of the production day) and the scheduled day's production. Typically, the operator manually selects a programmed amount of cement, sand, aggregate and water by weight into a set point controller physically incorporated in the batching console in the ready-mix plant, the amounts being determined by the operator in accordance with the concrete design mix figures normally used by the operator. Next, the set point amounts of these ingredients are then modified or compensated for in accordance with the percentage of slurry activity (a predetermined figure), the specific gravity obtained from a density cell and the percentage of slurry substitution obtained from the day's production schedule. It should be noted that the set amount of the aggregate by weight is normally unaffected by the slurry values, since the slurry ordinarily contains no aggregates. The batch controls for cement, water, sand and aggregate are then used to meter the relative amounts of the constituent ingredients from the water supply and the storage bins for the dry ingredients to the ready-mix mechanism.
SUMMARY OF THE INVENTION
This invention comprises an improvement over the one hundred percent slurry reclamation technique disclosed in the above-referenced U.S. patent, which results in improvement in the quality of concrete produced while maintaining one hundred percent recycling of all returned concrete.
In the most general aspect, the invention comprises a method for adjusting the design mix of concrete to substitute slurry formed by mixing returned concrete and water for design values of water, cement and sand while maintaining substantially constant the yield and water/cement ratio of the concrete. The method proceeds by determining the specific gravity of the slurry; establishing the percentage of slurry to be substituted for fresh cement mix constituent ingredients; computing the amount of water, sand and active cement in the slurry from the relative amounts of active and passive solids in the slurry and also from the slurry specific gravity; and reducing the design values of water, cement and sand by the amounts computed. The design value reduction is preferably performed automatically without operator intervention.
The computation of the water, sand and active cement amounts in the slurry includes the step of compensating for moisture in the sand design value, the compensation being performed after the sand design value has been reduced by the computed amount of sand in the slurry.
The water in the slurry is computed by multiplying the total slurry amount by the fractional portion representing liquids (normally water alone) in the slurry. The sand in the slurry is computed by multiplying the total slurry by the fractional portion representing non-active slurry solids and also by the fractional portion representing all solids in the slurry. Preferably, the slurry sand computation is adjusted by further multiplying the total slurry by a correction factor representing the ratio of the specific gravity of the sand to the specific gravity of the cement. The amount of cement in the slurry is computed by multiplying the total slurry by the fractional portion representing active slurry solids and also by the fractional portion representing all solids in the slurry.
The total slurry is computed by subtracting the amount of moisture in the sand design value from the total water design value, and dividing this result by a value obtained by multiplying the fractional portion of the slurry representing liquids by the slurry substitution percentage, multiplying the percentage moisture in the sand by the fractional portion representing non-active slurry solids and also by the fractional portion representing all solids in the slurry and subtracting the result, and adding to the two multiplicative results the fractional portion representing all liquids in the slurry.
The fractional portion representing all solids in the slurry is obtained by subtracting a value representing the product of the specific gravity of water and the specific gravity of the slurry solids from the determined value of the slurry specific gravity, and dividing the resulting difference by a value representing the product of the determined value of the slurry specific gravity and the specific gravity of the slurry solids minus 1.0.
By automatically reducing the design values of water, cement and sand by the computed amounts and substituting slurry for portions of the water, cement and sand in accordance with the method of the invention, maximum usage of the recycled constituent ingredients from the slurry is obtained without sacrificing quality of the concrete produced, particularly with reference to the slump, water/cement ratio, yield and compressive strength.
For a fuller understanding of the nature and advantages of the invention, reference should be had to the ensuing detailed description taken in conjunction with the accompanying drawings.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 is a block diagram of a one hundred percent slurry reclamation system in which the invention is implemented; and
FIG. 2 is a flow chart illustrating the slurry reclamation process in accordance with the invention.
DESCRIPTION OF THE PREFERRED EMBODIMENTS
Turning now to the drawings, FIGS. 1 illustrates a one hundred percent slurry reclamation system in which the invention is implemented. As seen in this figure, a ready-mix truck station 11 is provided for loading of batched concrete from a ready-mix plant 12 to which mix materials are supplied from a cement storage unit 13, a plant aggregate storage unit 14 and a normal plant water supply unit 15, all under control of a plant operator normally located at a station 16, who controls a batching console 17 and a density controlling device 18. Plant 12 and cement storage units 13 and 14 may comprise any conventional arrangement known to those skilled in the art and found in ready-mix concrete yards. Similarly, the plant water supply unit 15 and batching console 17 are conventional units known to those skilled in the art. The density controlling device 18 is preferably an Enviromatic unit of the type sold by Challenge-Cook Bros., Inc. of Industry, Calif. and comprises a multi-function unit for controlling the amount of washout water supplied to a truck at station 11, for sequencing pump motors and other motors associated to the several system components at the concrete yard to minimize electrical power consumption, and for controlling back flushing of predetermined fluid conduits at the end of a production day.
The ready-mix truck station 11 is provided with truck washout water supplied from a normal plant water supply 15 or a cement slurry vessel 27 via an auto changeover unit 20 described in detail in the above-referenced patent. Returned concrete mix from the ready-mix truck station 11 is also coupled to an aggregate classifier unit 21, which preferably comprises a dewatering screw classifier of known design.
Aggregates and coarse sand separated from the aggregate classifier unit 21 are supplied via an optional vibrating screen unit 22, also conventional, to coarse, medium and fine aggregate temporary storage hoppers 23-25, from which the separated and classified aggregate components are transported periodically to the plant aggregate storage unit 14 via any suitable means, e.g. separate conveyor belts. Alternatively, the separated aggregates may simply be stockpiled, as indicated by the broken line.
The returned concrete mix minus the separated aggregate and coarse sand is coupled from aggregate classifier unit 21 to a cement slurry vessel 27. Water is supplied to vessel 27 from the normal plant water unit 15 via auto changeover unit 20 and also by drainage of fugitive water (e.g. ground water from the truck washout operation, storm water and the like) into the vessel 27 by appropriate drain channels.
The slurry in vessel 27 is coupled to a density cell 31 on demand from the plant operator at station 16. Density cell 31 may comprise any one of a number of known density measuring units capable of providing a static or dynamic density reading upon demand. The slurry in vessel 27 is also connected to the ready-mix plant 12 for use in concrete fabrication in the manner described below.
In operation, at the beginning of each production day at the ready-mix yard, the plant operator at station 16 initiates operation of the ready-mix plant 12 by manipulating the various controls on the batching console 17. If fresh batched concrete is to be produced without the addition of any slurry from vessel 27, or if no slurry remains in the vessel 27, the batched concrete supplied to the ready-mix truck station 11 is fresh concrete produced from the proper design mix of dry cement in storage unit 13, aggregate from storage unit 14 and water supplied from normal plant water unit 15. The fresh batched concrete is then supplied to the ready-mix truck station 11. As an empty truck becomes available, each truck is filled and driven to the job site where the truck is emptied. As each truck returns to the truck station 11, it is typically reloaded with additional freshly batched concrete. At the end of the production period, typically late in the afternoon, each truck returns to station 11 wherein the concrete mix residue is washed out and supplied to the aggregate classifier unit 21. During wash out, either fresh water from the normal plant water unit 15 or clarified water from the vessel 27 is supplied to the truck station 11 via the auto change over unit 20, depending on whether sufficient clarified water is present in vessel 27. This same water is also supplied to the aggregate classifier unit 21 to separate the cement and sand fines from the aggregates in the returned concrete mix.
The mixture of cement, water and sand fines from aggregate classifier unit 21 flows into the vessel 27; the returned aggregate and coarse sand from classifier unit 21 are deposited on a vibrating screen 22, in which the returned aggregate-sand combination is separated into two or more sizes depicted in FIG. 1 as coarse, medium and fine. After separation, the reclaimed aggregate is transported to the plant aggregate storage unit 14 for reuse.
The mixture of returned cement and sand fines, as well as the water, deposited in the vessel 27 is periodically cycled through a centrifugal separator 29 in order to remove the sand fines therefrom. The remaining cement and water mixture is then returned to the vessel 27, while the sand fines are coupled to the classifier unit 21 for separation and reuse, or deposited as waste silt in a separate location.
When a slurry is present in the vessel 27 and when the plant operator opts to use reclaimed slurry in combination with fresh mix, the plant operator at station 16 initially measures the specific gravity of the slurry using density cell 31. In addition, the scheduled quantity of cement to be batched during that day's production period (or the operator's estimate thereof) is also used to determine the percentage of reclaimed slurry to be added to the fresh mix, the object being to completely empty the slurry from vessel 27 before the end of the day's production period. Further, the percent slurry activity, which is a predetermined figure of merit available to the operator obtained by known laboratory procedures for slurries of different specific gravities, is the remaining value selected by the operator for use in determining the amount of slurry to be admixed to the fresh ingredients.
With reference to FIG. 2, the method of the invention proceeds initially with operator selection of percent slurry activity, percent slurry substitution and the measured or determined value of the slurry specific gravity. The operator next specifies the design value for the cement, pure water, sand and aggregate constituents of a particular concrete design mix.
The first three parameters are then used in calculating compensation values for the design values of the cement (set cement weight), pure water (set water weight), and sand (set sand weight). After the compensation calculations have been performed automatically, the cement, pure water and sand design values are reduced by the compensating amounts of the corresponding ingredients present in the slurry in the course of the batching process and a compensating amount of slurry is pumped from the vessel 27 to the ready-mix plant 12 for admixture to the compensated amounts of the fresh ingredients.
The compensating values are computed in accordance with the invention in the following manner. The total amount of water in the slurry is obtained by multiplying a quantity termed the total slurry by the fractional portion of the slurry representing liquids alone using the following mathematical relationship: ##EQU1##
The total amount of sand in the slurry is obtained by multiplying the total slurry by the fractional portion representing non-active slurry solids and by the fractional portion representing all solids in the slurry, in accordance with the following mathematical relationship: ##EQU2##
The total amount of cement in the slurry is obtained by multiplying the total slurry by the fractional portion representing active slurry solids and by the fractional portion representing all solids in the slurry in accordance with the following mathematical relationship: ##EQU3##
The three compensating values (i.e. water, sand and cement in slurry) are then subtracted from the total water, total sand and total cement design values (i.e. the set weights) and the total slurry is added to these lowered fresh ingredient values. The total slurry value is obtained by subtracting the amount of moisture in the sand design value from the total water design value, and dividing this result by a value obtained by multiplying the fractional portion of the slurry representing liquids by the slurry substitution percentage, multiplying the percentage moisture in the sand by the fractional portion representing non-active slurry solids and by the fractional portion representing all solids in the slurry and subtracting the result, and adding the fractional portion representing all liquids in the slurry to the result, all in accordance with the following mathematical relationship: ##EQU4##
The value of the percentage moisture in the sand is a measured value obtained from the sand stook pile stored in the plant aggregate storage unit 14. The fractional portion representing all solids in the slurry is a calculated value obtained by subtracting the product of the specific gravity of water and the specific gravity of slurry solids (usually assumed to be 3.15) from the measured value of the slurry specific gravity, dividing this value by another value obtained by multiplying the measured slurry specific gravity by the specific gravity of solids minus 1.0, and multiplying the quotient by a normalization factor of one hundred, all in accordance with the following mathematical relationship: ##EQU5##
For completeness, the following mathematical relationships express the individual contributions from the various ingredients which together make up the total design value of the water, sand and cement for the concrete mixture: ##EQU6##
As a comparison of the above equations demonstrates, the slurry compensation amounts applied to the set weights for the cement, water and sand for a particular design mix not only result in a savings of cement, pure water and stock piled sand, but also leaves unaffected the water/cement ratio, which is a significant figure of merit when measuring the quality of concrete. Further, from tests conducted on cement produced in accordance with the method of the invention, it has been determined that the slump is substantially unaffected when preparing concrete in accordance with the invention. In addition, the design mix yield also remains essentially constant when preparing concrete in accordance with the invention, the yield being measured by comparing the total design weight per cubic yard with the actual weight per cubic yard of concrete fabricated in accordance with the invention.
The following is an example showing the difference in values of the amount of cement, pure water, and sand which would be consumed by preparing a concrete mixture with a particular mixture design, and by preparing the same yield (pounds per cubic yard) of concrete using the invention. It should be emphasized that the quality of the concrete, as measured by slump and cement/water ratio, of the slurry substituted mixture is substantially the same as the design mix.
______________________________________GIVEN MIX DESIGN 1 CUBIC YARD______________________________________Total H.sub.2 O SSD 320#Total Sand SSD 1356#Total Cement 564#Rock 1779#Flyash NoneAdmixs NoneTotal Weight 4019.00#/CUWater Cement Ratio .57______________________________________
______________________________________GIVEN OPERATION CONDITIONS______________________________________Sand Moisture 6%Percent Substitution 50%Percent Activity of Slurry 50%Specific Gravity of Slurry 1.20______________________________________
THE BATCH MAN ENTERS THE FOLLOWING INFORMATION TO HIS AUTOMATIC BATCHING CONSOLE:
1--Mix design
2--Cu. yds. required
3--Sand moisture
4--Percent Substitution of Cold or Hot H 2 O for cement slurry
5--Percent Activity of cement slurry
6--Specific gravity of cement slurry
IF THE BATCH MAN ELECTS TO BYPASS SLURRY FOR CERTAIN LOADS HE SIMPLY ENTERS ZERO FOR SUBSTITUTION LIKEWISE IF HE ELECTS TO COMPENSATE ONLY THE SAND HE ENTERS ZERO FOR ACTIVITY AND SHOULD HE WISH TO USE SLURRY AND NOT COMPENSATE FOR THE SOLIDS HE ENTERS ZERO FOR SPECIFIC GRAVITY.
THE ACTUAL BATCH WEIGHTS FOR THE ABOVE OPERATING CONDITION ARE (1 CU. YD. WTS.)
______________________________________Batch Slurry 211.86Batch H.sub.2 O 80.06Batched Sand 1409.94Batched Cement 538.13Batched Rock 1779.00Total Weight 4019.00Water Cement Ratio .57______________________________________
In some applications of the invention, it has been found that the assumed value of the specific gravity of the slurry solids used in calculating the percentage of solids in the slurry results in a slightly different yield from the design mix. In such cases, a correction factor may be applied to formula two above by multiplying the computed value of the sand in the slurry by a correction factor comprising the quotient of the specific gravity of sand and the specific gravity of cement, i.e. modifying the sand in slurry formula by adding the following multiplicative factor: ##EQU7##
The invention may be readily implemented by those having ordinary skill in the art of computer programming in those ready-mix plant installations in which the control console 18 is based on a computer or a microcomputer by preparing the appropriate routines to carry out the computations noted above. If desired, equivalent analog circuitry may also be used to perform the equivalent computations, although a digital implementation is believed to be more practical and is thus preferred.
While the above provides a full and complete disclosure of the preferred embodiment of the invention, various modifications, alternate constructions and equivalents may be employed without departing from the true spirit and scope of the invention. For example, in some ready-mix plant installations, a water trim override control is provided, which enables the operator to vary the set water amount in order to vary the slump of the concrete. In such installations, the water trim override control should be inserted in the system in such a manner that the water trim is performed after compensation of the set water amount. In addition, in other installations a provision is made to compensate for moisture in the set aggregate amount. In such installations, the amount of aggregate moisture compensation should be added into the equation for the total water (equations (6)). Therefore, the above description should not be construed as limiting the scope of the invention, which is defined by the appended claims.
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In a one hundred percent slurry reclamation installation, the design mix of the concrete is adjusted by measuring the specific gravity of a slurry to be substituted, selecting the percentage of slurry to be substituted for the fresh concrete mix design ingredients, computing the amount of water, sand and active cement in the slurry from the relative amounts of active and passive solids in the slurry and the slurry specific gravity, and reducing the design values of water, cement and sand by the computed amounts when admixing the slurry to the reduced quantities of fresh ingredients. The amount of slurry water, slurry sand and slurry cement to be substituted, respectively, for the fresh water, fresh sand and fresh cement are each computed and these computed amounts are used to reduce the design mix amounts in accordance with specific mathematical relationships, which ensure that the quality of the concrete produced, as measured by slump, water/cement ratio and yield, is substantially the same as concrete produced according to the same design mix from entirely fresh ingredients.
The process is implemented in existing control console equipment normally coupled to the batching console of a ready-mix plant.
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This is a division of application Ser. No. 08/673,136, filed Jul. 1, 1996, now U.S. Pat. No. 5,851,502.
BACKGROUND OF THE INVENTION
1. Field of the Invention
The invention relates to a precipitated silica, the process for its preparation, and to its use for the production of battery separators.
2. Description of Related Art
It is known to use precipitated silicas for the production of microporous polyethylene battery separators (U.S. Pat. Nos. 3,351,495, 4,024,323, and 4,681,750). The known silicas are precipitated silicas with a normal structure processed to battery separator films according to a conventional standard recipe by the compounding-extrusion process.
SUMMARY OF THE INVENTION
The object and aim of the invention is the development of a highly structured silica with good structural stability and a low BET surface, a process for its preparation, and its use in the production of highly porous polyethylene-silica separators with a total porosity of ≧64%, with an ash content of ≧68 wt. %, both with a residual oil content of 12-14%.
The invention provides a precipitated silica with the following physical-chemical data:
______________________________________BET surface: DIN 66131 100-130 m.sup.2 /gDBP absorption DIN 53601 ≧275 g/100 g(anhydrous) ASTM D 2414Loss on drying DIN ISO 787/II(2 h/105° C.): ASTM D 280 3.5-5.5 wt. % JIS K 5101/21______________________________________Oversize withALPINE air-jet sieve:______________________________________ >63 μm ≦10.0 wt. %>150 μm ≦0.1 wt. %>250 μm ≦0.01 wt. %______________________________________
The invention provides a precipitated silica with the following physical-chemical data:
______________________________________BET surface: DIN 66131 100-130 m.sup.2 /gDBP absorption DIN 53601 ≧275 g/100 g(anhydrous) ASTM D 2414Loss on drying DIN ISO 787/II(2 h/105° C.): ASTM D 280 3.5-5.5 wt. % JIS K 5101/21______________________________________Oversize withALPINE air-jet sieve:______________________________________ >63 μm ≦10.0 wt. % 150 μm ≦0.1 wt. %>250 μm ≦0.01 wt. %______________________________________
wherein hot water at a temperature of 90-91° C. is introduced into a precipitation vessel, with stirring, commercial water glass with an SiO 2 : Na 2 O modulus of 3.34:1 (SiO 2 =26.8 wt. %; Na 2 O=8.0 wt. %) is added until a certain alkali value is reached (the alkali value is the consumption of 1N HCl in milliliters which is required for the neutralization of 100 ml of the starting solution with the use of phenolphthalein as indicator), whilst keeping the temperature constant throughout the precipitation period of 90 minutes further water glass with the same specification and sulfuric acid are then added simultaneously at two separate places in such a way that the prescribed alkali value is maintained; the precipitated silica suspension is then acidified with concentrated sulfuric acid to a pH-value of 8.5 within approx. 20 minutes, precipitation is interrupted for thirty minutes, with stirring and at 90-91° C., the suspension is then further acidified to a pH-value of 4 with concentrated sulfuric acid, the precipitated silica having a solids content in the suspension of approx. 88 g/l is then separated by means of a chamber filter press, washed, the filter cake obtained is liquefied by means of water and mechanical shear forces and ground with a roller mill, which is characterized in that a constant alkali value in the region of 5-15, preferably 7, is maintained during precipitation.
In one particular embodiment, spray drying of the silica is carried out with a solids content of the silica feed to be sprayed of 16-20%, preferably 18%, a centrifugal atomizer speed of 10,000-12,000 rpm, and inlet temperatures of the hot gases of 700-750° C. and outlet temperatures of 90-120° C.
In another embodiment of the invention, a crossflow mill may be used for grinding instead of the roller mill.
In another embodiment of the invention, washing of the filter cake separated by means of a filter press may be carried out with low-chloride water (with≦20 ppm chloride), preferably with deionized water or condensate, until the chloride content in the ground end product is≧100 ppm chloride.
In another embodiment of the invention, a spin flash drier may be used instead of the spray drier. Optionally, it is possible to dispense with grinding the silica in this case.
The invention also provides the use of the precipitated silica according to the invention with the following physical-chemical data:
______________________________________BET surface: DIN 66131 100-130 m.sup.2 /gDBP absorption DIN 53601 ≧275 g/100 g(anhydrous) ASTM D 2414Loss on drying DIN ISO 787/II(2 h/105° C.): ASTM D 280 3.5-5.5 wt. % JIS K 5101/21______________________________________Oversize withALPINE air-jet sieve:______________________________________ >63 μm ≦10.0 wt. %>150 μm ≦0.1 wt. %>250 μm ≦0.01 wt. %______________________________________
in polyethylene-silica battery separators for industrial batteries on a lead-acid basis, which are characterized in that they have a total porosity of ≧64%, a resistivity after 24 hours of immersion in 37% battery acid of<0.60 m Ohm . inch 2 /mil and an ash content of≧68 wt. % with a residual oil content of 12-14%.
The precipitated silica according to the invention may also be used in silica battery separators for starter batteries on a lead-acid basis with a silica-polyethylene ratio of 2.5:1-3.5:1, wherein the 8 to 10 mil separators may have a resistivity of≦0.60 m Ohm·inch 2 /mil with a residual oil content of 12-14%.
The microporous separating elements for batteries are produced by intensive mixing of a high molecular weight polyethylene with the precipitated silica (prepared according to the invention), process liquid and stabilizers to form a powder mixture which is extruded to obtain a film having a thickness of 0.2 to 0.7 mm which is subjected to an extraction treatment to remove the process liquid.
The highly porous battery separator films are produced from the silicas of the invention using known methods, e.g., those set forth in U.S. Pat. Nos. 3,351,495, and 4,237,083 or DE-AS 1,496,123.
The following procedure is preferred:
A composition comprising:
5.4-7.7 wt. % of high molecular weight polyethylene
0.1-0.2 wt. % of carbon black masterbatch
0.1-0.3 wt. % of stabilizer
26.1-27.8 wt. % of precipitated silica
66.2-67.9 wt. % of mineral oil
is converted to a mixture in powder form by intensive mixing of the individual components in a high speed mixer. The mixture is then processed in a twin-screw extruder at temperatures between 190 and 200° C. Forming of the separator film takes place using a flat-sheet die and a downstream calendar. The resulting film thickness is 0.2 to 0.7 mm.
The process of extrusion and calendaring is followed by extraction. To this end, the mineral oil is removed to a large extent by extraction with n-hexane. The n-hexane absorbed is then removed by drying at room temperature. An important aspect when assessing a silica is its behavior during processing (torque values and melt pressures).
Moreover, the absorbency of the silica and flow properties of the mixture are assessed during its preparation. The torque on the extruder shaft and the melt pressure in front of the die are assessed during metering and extrusion of the mixture.
The torque measurement is based on the power consumption of the drive motor and is given as a percentage of the maximum permissible power consumption. The melt pressure in bar is measured with a pressure cell. The pressure cell has a sensor which is immersed in the melt in front of the barrel wall. This measuring point is situated between the end of the screw and the beginning of the die.
The separator films were tested in the following manner:
Examples of Test Methods
The following test methods are used:
Extraction of Oil from the Extruded Film (Blacksheet)
Residual oil content 12-14%.
A)
The oil is transferred to a solvent by extraction of battery separator films (blacksheet). This oil-reduced film is then known as greysheet and corresponds to the end product of the separator production process
B) Aim of the Test
1. To obtain as constant as possible a residual oil content of 12-14% in the film (greysheet).
2. Production of a film for further applications-related tests.
3. To determine the shrinkage due to extraction.
C) Preparation of Samples
1.1 A certain number of samples (min. 10) are cut off from the battery separator film roll (blacksheet) (scissors or knife).
1.2 The film sections are cut to a particular size with paper crocodile shears.
1.3 Dimensions:
MD=180 mm
MD=Moving direction of machine
CMD=150 mm
CMD=Crosswise to the moving direction of machine
D) Procedure
The oil is extracted from the film with n-hexane in 3 stages.
1.1 Weigh all the samples (blacksheet).
Accuracy:±0.01 gr
1.2 Lay the samples individually in the solvent bath.
1.3 Residence time in the solvent bath:
a) 5-10 mil* films: 2 minutes each per solvent bath
b) 22 mil* films: 5 minutes each per solvent bath * 1 mil=0.0254 mm
1.4 Drying time
Leave films to dry for 15 minutes in the fume cupboard with continuous aeration.
1.5 Weigh all the samples (greysheet).
Accuracy:±0.01 gr
Determination of the Resistivity of Extruded Films (Greysheet)
A)
A film sample is tested for resistivity in an acid bath.
B) Aim of the Test
A defined measure of the resistivity of the separator film shall be determined as the sheet resistance based on the film thickness.
Unit: mOhm×inch 2 /mil.
C) Apparatus
1.1 Battery Tester Model 9100-2 Low Resistance Test System
Manufacturer: Palico Instrument Laboratories USA
1.2 Water bath/temperature-controlled.
D) Preparation of Samples
A certain number of samples (min. 3) undergo the test in sequence.
E) Procedure
1.1 The film thicknesses of the prepared samples are determined.
Accuracy:±0.01 mm.
1.2 The samples are stored in battery acid.
1.3 After 20 minutes of storage in battery acid, the samples are introduced individually into the appropriate device of the battery tester.
1.4 The measuring procedure is started in accordance with the operating instructions of the battery tester and the relevant measurement data are recorded.
1.5 An arithmetic mean is formed from the values determined.
1.6 The measured samples are stored again in battery acid.
1.7 After 24 hours' storage in battery acid, the samples are introduced individually into the appropriate device of the battery tester.
1.8 The measuring procedure is started in accordance with the operating instructions of the battery tester and the relevant measurement data are recorded.
1.9 An arithmetic mean is formed from the values determined.
F) Evaluation of the Measurements
1.1 "Resistivity"
Determination of the Mechanical Properties of Extruded Films (Greysheet) in Terms of Tensile Strength and Elongation at Break
A)
A film sample is extended until it ruptures, the rate of extension being kept constant. The elongation and the force applied are measured.
B) Aim of Test
A defined measure of the tensile strength and elongation at break of the separator film shall be determined.
C) Apparatus
1.1 Universal test machine, TZM 771 type, 20 kN
Manufacturer: Otto Wolpert Werke GmbH
1.2 Accessories: Pneumatic clamping grip for thin films.
Manufacturer: Otto Wolpert Werke GmbH
1.3 Accessories: Load cell 500 N.
Manufacturer: Otto Wolpert Werke GmbH
1.4 Film roll cutting machine
D) Preparation of Samples
A certain number of samples (min. 2) undergo the test in sequence.
E) Procedure
1.1 4 strips are cut out of each sample (crosswise to the direction of extrusion CMD) to a size of 100 (CMD)×25 (MD) mm.
1.2 The film thickness of the strips is determined. Accuracy:±0.01 mm.
1.3 The universal test machine is set up in accordance with the operating instructions.
1.4 The individual test strip is clamped into the pneumatic clamping grips of the universal test machine so that there is a gap of 50 mm between the clamping grips. The clamping depth of the strips is 25 mm per grip.
1.5 The load cell is adjusted to zero in accordance with the operating instructions.
Range of measurement: 0-50 N.
1.6 The speed applied is 500 mm/min.
1.7 The measuring procedure is started.
1.8 An arithmetic mean is formed from the values determined.
F) Evaluation of the Measurements
1.1 "Tensile strength"
Load in N/surface area in mm 2 (Test strip width×test strip thickness)=tensile strength in N/mm 2
1.2 "Elongation at break"
Total length of the sample after rupture based on the initial length between the clamping devices multiplied by 100% gives the elongation at break.
Extraction of Oil from the Extruded Film (Blacksheet) Residual Oil Content<0.5% /"Zero Extraction"
A)
The oil is transferred to a solvent by extraction of battery separator films (blacksheet). This approximately oil-free film then undergoes further tests.
B) Aim of Method
1. To obtain as constant as possible a residual oil content of 12-14% in the film (greysheet).
2. Production of films for further applications-related tests.
3. To determine the shrinkage due to extraction.
C) Preparation of Samples
1.1 A certain number of samples (min. 10) are cut off from the battery separator film roll (blacksheet) (scissors or knife).
1.2 The film sections are cut to a particular size with paper crocodile shears.
1.3 Dimensions:
MD=180 mm
MD=Moving direction of machine
CMD=150 mm
CMD=Crosswise to the moving direction of machine
D) Procedure
The oil is extracted from the film in 3 stages (3×10 1 refined steel containers), n-hexane being used as the extraction agent.
1.1 Weigh all the samples (blacksheet).
Accuracy:±0.01 gr
1.2 Lay the samples individually in the solvent bath.
1.3 Residence time in the solvent bath:
a) 5-10 mil* films: 2 minutes each per solvent bath
b) 22 mil* films: 5 minutes each per solvent bath * 1 mil=0.0254 mm
1.4 Extract the samples once again as described under 1.3 in the 4th stage, but with pure, oil-free n-hexane, i.e. the solvent should be free from oil residues.
1.5 Drying time
Leave films to dry for 15 minutes in the fume cupboard with continuous aeration.
1.6 Weigh all the samples (greysheet).
Accuracy:±0.01 gr
Pore Volume
A. Aim of Test
The open pore volume is determined in relation to the total volume.
B.
The pore volume is significant for the electrical behavior in the battery and the volume of the electrolyte displaced.
C. Apparatus
1.1 Scales with wire and hook
1.2 1 liter beaker
1.3 Vacuum desiccator
1.4 Vacuum pump
1.5 Paper knife
1.6 Aerosol CT (Cyanamid) Aqueous solution with a concentration of 0.1%.
D. Samples
1.1 Cut 3 separator samples to a size of 3.0"×4.0" (76 mm×102 mm).
1.2 Weigh each sample to an accuracy of 0.01 g (dry weight).
E. Procedure
1.1 Lay the samples in the 1 liter beaker and cover them completely with 0.1% Aerosol OT.
1.2 Lay the samples in the vacuum desiccator and evacuate with the vacuum pump.
1.3 After 4 hours, hang the samples on the scales and determine the weight of the samples immersed in water (weight when immersed).
1.4 Dry the samples by wiping them with a cloth.
1.5 Weigh the samples in the air (weight when wet).
F. Calculation ##EQU1## Determination of the Ash Content of Silica-Containing Polyethylene Battery Separators
A. Apparatus Required
1.1 Analytical balance, weighing accuracy 0.1 mg
1.2 Desiccator
1.3 Muffle furnace: 950±10° C.
1.4 Crucible: either porcelain crucible, Al type with cover, which should have a hole with a diameter of 2 mm; or a quartz crucible with cover, QGT type, Bad Harzburg, Dr. Rademacher type, dimensions: diameter 27 mm, height 47 mm
B. Procedure
1.1 Determination of the volatile constituents
Approx. 1 g of a plastic preparation dried beforehand for 1 h at 105° C. is weighed to an accuracy of±0.0001 g into the quartz crucible provided with a cover (E); the covered crucible is placed in a muffle furnace for 7.0 min at a controlled temperature of 950±10° C. in order to distil off the volatile constituents. After cooling in the desiccator, the crucible with lid is weighed again (A).
1.2 Determination of the ash content
The open crucible and the cover are then calcined again under air until the weight is constant (1-1.5 h at 950° C.). After cooling in the desiccator, the crucible with cover is weighed again (A 1 ).
1.3 Calculation
1.3.1 Volatile constituents: (1-A)×100 [%]
1.3.2 Ash content: ##EQU2## [%]1.3.3 Silica content: ##EQU3## ×100[%] ##EQU4## E=Initial weight of concentrate after pre-drying [g]A=Weight after determination of the volatile constituents (2.1) [g]
A 1 =Weight after determination of the ash (2.2) [g]
DESCRIPTION OF THE PREFERRED EMBODIMENTS
EXAMPLE 1
Comparison Example
The commercial product HiSil® SBG from the US company Pittsburgh Plate Glass Company, Pittsburgh, USA, is produced according to the disclosure of U.S. Pat. No. 4,681,750. The physical-chemical data are given in Table 1.
EXAMPLE 2
According to the Invention
A starting mixture is prepared in a 75 m 3 wooden tank, for which purpose 1,698 kg of sodium silicate solution (8.90 wt. % of Na 2 O; 27.73 wt. % of SiO 2 with an SiO 2 : Na 2 O modulus=3.22) and 56.6 m 3 of hot water are mixed and the temperature adjusted to 90° C. The alkali value of the starting mixture (consumption of 1N HCl per 100 ml of starting solution against phenolphthalein) is 7.0.
During the next 90 minutes, whilst keeping a constant alkali value of 7 and a temperature of 90-91° C., 21,140 kg of sodium silicate solution (57° C., 8.90 wt. % of Na 2 O and 27.73 wt. % of SiO 2 with an SiO 2 : Na 2 O modulus of 3.22) and 2,851 kg of 94% sulfuric acid are allowed to flow into the starting mixture, with stirring.
The addition of sodium silicate solution is then stopped and the addition of 94% sulfuric acid is continued in such a way that the pH-value of the precipitation suspension after approx. 25 minutes is 8.5.
There then follows a 30 minute interruption phase at pH 8.5, during which neither acid nor water glass solution flow into the precipitation suspension.
Finally, the addition of 94% sulfuric acid is continued in such a way that the pH-value of the precipitation suspension after approx. 10 minutes is approx. 4.0. The solids content of the suspension is 88 g SiO 2 /liter.
Said precipitated silica suspension is diluted with 45,920 liters of water, then introduced into a chamber filter press in order to separate the silica and then washed with low-chloride water.
After the wash process, the filter cake with a solids content of approx. 20 wt. % is liquefied by means of mechanical shear forces with the addition of concentrated sulfuric acid. Sulfuric acid is added until the pH-value of the silica suspension is approx. 3.7 to 4.0.
Said silica suspension is then passed to a spray drier which is fitted with a rapidly rotating atomizer disc for the purpose of atomization. Approx. 9.0 m 3 of the suspension are atomized and spray dried per hour. The speed of the disc is 10,000 rpm. Approx. 1.8 t (9 m 3 ·20 wt. %=1.8 t SiO 2 ) of silica per hour are obtained. The spray drier is heated with natural gas. The inlet temperature of the hot gases is 700 to 750° C., the temperature of the effluent gases is 113 to 118° C.
The average residence time of a silica particle in the hot gas stream is approx. 9 to 10 seconds. The spray-dried precipitated silica is separated from the hot gas stream by a filter. It is ground with a roller mill. The physical-chemical data of the silica obtained are given in Table 1.
EXAMPLE 3
According to the Invention
The silica is prepared according to Example 2. Only grinding is carried out in a cross-flow mill UP 1000 from ALPINE, Augsburg. The physical-chemical data of the silica obtained are given in Table 1.
EXAMPLE 4
According to the Invention
The silica is prepared according to example 2 as far as the stage of washing the chamber filter cake. This is followed by spin flash drying. The physical-chemical data are given in Table 1.
The parameters are determined with the following methods of measurement:
1) BET surface: DIN 66 131
2) DBP absorption: DIN 53 601/ASTM D 2414
3) Loss on drying: DIN ISO 787/II, ASTM D 280, JIS K 5101/21
4) Oversize with ALPINE air-jet sieve: DEGUSSA in-house method, as described below
5) Chloride content: By chemical analysis
Determination of the Oversize with the ALPINE Air-Jet Sieve
In order to determine the oversize, the precipitated silica is screened through a 500 μm sieve to remove any deaeration lumps. 10 g of the screened material are then placed on a particular air-jet sieve and screened at a reduced pressure of 200 mm water column.
TABLE 1__________________________________________________________________________Physical-chemical data of precipitated silicas (Examples nos. 1-4) Example no. 1 2 3 4 Commercial Silica Silica SilicaPrecipitated silica: product according to according to according toName/choice of parameter HiSil SBG the invention the invention the invention__________________________________________________________________________BET surface (m.sup.2 /g) 155 121 116 128DBP absorption (g/100 g) 226 285 278 275(anhydrous)Loss on drying (wt. %) 5.6 4.6 5.5 4.2(2 h/105° C.)Oversize with ALPINEair-jet sieve (wt. %)>63 μm 0.23 1.0 <0.4 8.4>150 μm <0.01 0.01 not det. not det.>250 μm <0.01 <0.01 not det. 0.02Chloride content (ppm) 176 68 158 270__________________________________________________________________________
Precipitated silica particles that settle on the acrylic glass cover of the sieve device are knocked off by a few taps on the knob of the sieve lid. Screening ends when the oversize remains constant, a situation which can usually be recognized from the free-flowing appearance. For safety's sake, screening is then continued for another minute. The screening process generally takes five minutes. In the case of materials that contain only particle size fractions of<500 μm, the sample is not screened beforehand, but placed directly on the air-jet sieve.
In the event of any agglomerates forming, the screening process is briefly interrupted and the agglomerates broken up with a brush under gentle pressure. After screening, the oversize is carefully tapped off the air-jet sieve and reweighed.
Calculation: The oversize is given in weight percent in conjunction with the mesh size of the sieve.
Apparatus: ALPINE air-jet sieve, laboratory type S 200, with screen fabric according to DIN 4188.
Determination of the Chloride Content in Precipitated Silicas
Procedure
On the basis of silica samples containing approx. 100 ppm chloride, 1-3 g are weighed out accurately and stirred with 25 ml of distilled water and 25 ml of a 5 N sodium hydroxide solution in a 150 ml glass beaker. The suspension is heated over a hotplate until a clear solution is obtained. The solution is cooled in a water bath and 25 ml of 50% nitric acid are added. The nitric acid is added in one operation, with stirring. After renewed cooling of the solution, a little acetone is added. Titration is then carried out with 0.05 N silver nitrate solution.
For each series of determinations, a blank titration is carried out, the blank value being deducted from the value of the sample determination. To this end, it is necessary to use the same reagents as those used for the chloride determination of the individual samples.
The first derivation of the titration curve is plotted. The end point of the titration is reached when the curve passes through a pronounced maximum. According to the differential curve, a 1 cm section corresponds to the consumption of 0.1 ml of the 0.05 N silver nitrate solution.
Calculation
1 cm corresponds to 0.1 ml of AgNO 3 solution
V=consumption in ml (zone A-blank value)
E=initial weight of sample in grams
N=normality of the silver nitrate solution
F=factor for silver nitrate solution ##EQU5##
Solutions, Reagents and Apparatus
Silver nitrate solution: 0.05 N
Nitric acid: 50%
30 NaOH solution: 5 N Acetone
Hydrochloric acid solution: 0.01 N (for standardization of the silver nitrate solution)
Titrator TTT 60: (Manufacturer: Radiometer)
Digital pH meter PHM 63: (Manufacturer: Radiometer)
Automatic burette ABU 12: (Manufacturer: Radiometer) with 2.5 ml burette
Recorder REC 61: (Manufacturer: Radiometer)
Selective chloride electrode: (Manufacturer: Radiometer)
Reference electrode: (Manufacturer: Radiometer) Magnetic stirrer
In Examples 5-19, the precipitated silicas obtained according to examples 1-4 are tested in separator films.
EXAMPLE 5
750 g of silica according to Example 1 are mixed in a fluid mixer (FM 10 C type from Thyssen Henschel, Kassel, FRG) with 222 g of Hostalen GUR 4150 (ultra-high molecular weight type of high density polyethylene from HOECHST AG, Frankfurt a.M.) with 2.4 g of Topanol® O antioxidant (ICI, England, butylated hydroxytoluene) and with 4.8 g of COLCOLOR® E50/G carbon black masterbatch (Degussa AG., Frankfurt/Main containing 50% PRINTEX® G carbon black pigment in low density polyethylene) at a speed of 700 rpm and then sprayed with a quantity of 1655 g of Gravex mineral oil 942 (Shell) with the aid of a gear pump and a single-component nozzle. The product thereby obtained is a free-flowing, and continuously meterable powder which is processed with the aid of a twin-screw extruder (ZSK 30 M 9/2 type from Werner & Pfleiderer, Stuttgart) with a heated flat-sheet die 220 mm wide (Gottfert Prufmaschinen GmbH, Buchen) and a triple roll calender (Polyfol 150 3 S type from Ruth Schwabenthan, Berlin) to obtain a film about 0.550-0.600 mm thick. At a screw speed of 105 rpm, a temperature profile of 150 to 200° C. is chosen between the feed zone of the extruder and the die. The melt temperature measured between the extruder and the die is 196° C. The melt pressure in bar and the torque of the screws as a t of the maximum permissible torque are read off the twin-screw extruder as a measure of the processing behavior of the mixture during extrusion. The mineral oil is then extracted to a large extent from the film thus produced with hexane so that a microporous separator film is obtained.
The resistivity, the mechanical properties such as tensile strength, elongation at break, total porosity and ash content of the films extracted to a residual oil content of 12-14% are measured in accordance with the methods described above. The measured values determined from the films produced according to Example 5 are summarized in Table 2. These values form the reference values for Examples 6-8, in which silica according to the invention according to Example 2 is used.
EXAMPLE 6
Procedure according to Example 5, wherein the precipitated silica is replaced by the silica according to the invention according to Example 2. The film data may be found in Table 2
EXAMPLE 7
In this Example, the procedure according to Example 6 is adopted, a quantity of 1700 g of process oil being used instead of 1655 g. The film data may be found in Table 2.
EXAMPLE 8
In this Example, the procedure according to Example 6 is adopted. The only exception is the use of a quantity of 1900 g of process oil instead of 1655 g. The film data may be found in Table 2.
EXAMPLE 9
Separator mixtures with a silica polymer ratio of 4:1 are produced, extruded and characterized. The procedure adopted is that of Example 5, but only 188 g of the polymer used in Example 5 are used (instead of 222 g). Moreover, unlike Example 5, a quantity of 1700 g of oil is used instead of 1655 g. The film data determined may be found in Table 3. These values form the reference values for Examples 10-12, in which silica according to the invention according to Example 2 is used.
TABLE 2__________________________________________________________________________Production conditions and properties of highly porous separator filmscontainingcommercial precipitated silica and spray-dried precipitated silicasaccording to theinvention. Silica:polymer ratio = 3.4:1 Example no. 6 7 5 Silica acc. Silica acc. 8 Commercial to the to the Silica acc. to product invention invention the inventionPrecipitated silica HiSil SBG (Ex. 2) (Ex. 2) (Ex. 2)__________________________________________________________________________Oil quantity grams 1655 1655 1700 1900Melt temperature ° C. 196 198 195 193Melt pressure bar 133 148 136 96Torque % 53 51 50 44Resistivity mA ·after 20 min. soak in.sup.2 /mil 1.46 1.27 1.43 1.23after 24 hours' soak 1.06 0.87 0.94 0.81Total porosity vol % 55.1 58.7 58.8 58.4Ash content wt. % 68.1 68.2 68.0 67.9Mechanical properties:Elongation % 749 592 782 815Tensile strength N/mm.sup.2 4.15 4.79 4.47 4.47__________________________________________________________________________
TABLE 3__________________________________________________________________________Production conditions and properties of highly porous separator filmscontainingcommercial precipitated silica and spray-dried precipitated silicasaccording to theinvention. Silica:polymer ratio = 4:1 Example no. 10 11 9 Silica acc. Silica acc. 12 Commercial to the to the Silica acc. to product invention invention the inventionPrecipitated silica HiSil SBG (Ex. 2) (Ex. 2) (Ex. 2)__________________________________________________________________________Oil quantity grams 1700 1700 1900 2100Melt temperature ° C. 194 197 192 193Melt pressure bar 102 116 82 61Torque 47 44 40 35Resistivity mA ·after 20 min. soak in.sup.2 /mil 1.27 0.92 0.90 0.83after 24 hours' soak 0.85 0.64 0.60 0.57Total porosity vol % 60.3 63.9 64.3 64.8Ash content wt. % 70.4 70.1 70.2 70.1Mechanical properties:Elongation % 722 759 750 702Tensile strength N/mm.sup.2 3.43 3.65 2.90 2.50__________________________________________________________________________
TABLE 4__________________________________________________________________________Production conditions and properties of highly porous separator filmscontainingcommercial precipitated silica and spray-dried precipitated silicasaccording to theinvention. Silica:polymer ratio = 5:1 Example no. 14 15 13 Silica acc. Silica acc. 16 Commercial to the to the Silica acc. to product invention invention the inventionPrecipitated silica HiSil SBG (Ex. 2) (Ex. 2) (Ex. 2)__________________________________________________________________________Oil quantity grams 1700 1700 1900 2000Melt temperature ° C. 192 195 191 190Melt pressure bar 76 100 70 60Torque % 48 44 37 34Resistivity mA ·after 20 min. soak in.sup.2 /mil 0.86 0.68 0.73 0.60after 24 hours' soak 0.68 0.49 0.42 0.51Total porosity vol % 63.1 68.7 70.1 70.4Ash content wt. % 73.4 73.1 73.5 73.0Mechanical properties:Elongation % 558 591 608 596Tensile strength N/mm.sup.2 2.20 2.44 2.18 2.24__________________________________________________________________________
EXAMPLE 10
The separator film is produced in accordance with Example 9. The silica HiSil® SBG used in Example 9 is replaced by the silica according to the invention according to Example 2. The film data are contained in Table 3.
EXAMPLE 11
The procedure according to Example 10 is adopted. The only exception is the use of a quantity of 1900 g of process oil instead of 1700 g. The film data are given in Table 3.
EXAMPLE 12
The procedure according to Example 10 is adopted. The only exception is the use of a further increased quantity of 2100 g of process oil instead of 1700 g oil. The film data are given in Table 3.
EXAMPLE 13
Separator mixtures with a silica:polymer ratio of 5:1 are produced, then extruded, extracted and characterized.
The procedure according to Example 5 is adopted, but only 150 g of the polymer used therein is used (instead of 222 g). Moreover, an oil quantity of 1700 g instead of 1655 g is used. The film data determined may be found in Table 4. These values form the reference data and comparison data for Examples 14-16 in which silica according to the invention according to Example 2 is used.
EXAMPLE 14
The separator film is produced in accordance with Example 13. The commercial silica HiSil® SBG used in Example 13 is replaced by the silica according to the invention according to Example 2. The film data determined are summarized in Table 4.
EXAMPLE 15
The procedure according to Example 14 is adopted. The only exception is the use of a quantity of 1900 g of process oil instead of 1700 g. The film data are listed in Table 4.
EXAMPLE 16
The procedure according to Example 14 is adopted. The only exception is the use of a quantity of 2000 g of process oil instead of 1700 g. The film data are given in Table 4.
The results according to Tables 2-4 show:
in the case of the extrusion data, the melt temperature falls by 4-5° C. as the oil quantity increases in the case of all the SiO 2 :PE ratios examined and comparable separator mixtures (same silica); this also applies to the melt pressure and the particularly important torque value. The fall of 40-55 bar for the melt pressure is particularly pronounced; the fall in torque is in the region of 15-25%. These results show that an increase in performance during extrusion may be achieved.
Surprisingly, the melt pressure falls as the silica:polymer ratio rises in the case of comparable separator mixtures; the same applies to the torque.
The commercial product HiSil® SBG exhibits this phenomenon only for the melt pressure development, not for the torque.
In the direct comparison of the same separator mixtures containing on the one hand HiSil® SBG and on the other hand silica according to the invention according to Example 2, the melt pressures for HiSil® SBG-containing mixtures are 10-24% below the level of separator mixtures containing silica according to the invention; the situation is reversed for the torque: in this case, the values for the separator mixtures containing silica according to the invention are 4-9% lower than those of the commercial product.
As regards the film data, the separator films with the silica according to the invention according to Example 2 under the same conditions of production exhibit a markedly reduced resistivity of 18-20% depending on the mixing ratio of SiO 2 :PE. The resistivity falls as the SiO 2 :PE ratio increases, referred to mixtures containing HiSil® SBG.
With all the SiO 2 :PE ratios and comparable separator mixtures examined (silicas according to the invention), the total porosity increases with increasing oil quantity by a maximum of 1.7 absolute percentage points (with an SiO 2 :PE ratio of 5:1). If the SiO 2 :PE ratio is equal to 4:1, this increase is only approx. 1% in absolute terms, whilst there is no change if the SiO 2 :PE ratio is equal to 3.4:1. When the SiO 2 :PE ratio changes from 3.4:1 to SiO 2 :PE=5:1, an increase in porosity of 12 absolute percentage points (+20%) is achieved for the silica according to the invention according to Example 2; in the case of SiO 2 : PE ratios of 4:1 and 5:1, total porosity values of 65 and 70% respectively are achieved, which exceeds the level of values for the silica-containing separator with the highest porosity on the market hitherto, namely the PVC-silica separating element made by Amersil (Example 17). The values of the separator are just achieved if HiSil® SBG-containing PE films are produced with an
SiO.sub.2 :PE ratio of 5:1.
EXAMPLE 17
A commercial PVC-silica separator from AMERSIL in Kehlen, Luxembourg was characterized in terms of its film data. The result of these investigations may be found in Table 5, last column. The data do not, therefore, fall within the range of the invention of this invention.
TABLE 5__________________________________________________________________________Highly porous PE-SiO.sub.2 industrial battery separators containing theprecipitated silicas accordingto the invention in an SiO.sub.2 :PE ratio of 3.4:1-5:1. Comparison withcommercial silica andcomparison with commercial PVC-SiO.sub.2 separator. Example Example Example Example 12 Example Example 15 Example 17 Separa- 5 8 9 according 13 according AMERSIL torSepara- Compari- Compari- Compari- to the Compari- to the separator acc. totor son son son invention son invention comparison claim 9__________________________________________________________________________Type of HiSil Silica HiSil Silica HiSil Silica Unknown Precip.silica: SBG acc. to SBG acc. SBG acc. 1.1:1 silicaSiO.sub.2 :PE 3.4:1 inv. 4:1 to inv. 5:1 to inv. ≧4:1ratio acc. acc. acc. to Ex. 2 to Ex. 2 to Ex. 2 3.4:1 4:1 5:1Total 55.1 58.4 60.3 64.8 63.1 70.1 63.2 ≧64porosity(%)Ash 68.1 67.9 70.4 70.1 73.1 73.5 51.5 ≧68content(%)Resistivity 1.06 0.81 0.85 0.57 0.68 0.42 0.73 ≦0.60after 24h soak (mAin..sup.2 /mil)__________________________________________________________________________
TABLE 6__________________________________________________________________________Production conditions and properties of highly porous separator filmscontaining commercialprecipitated silica and spray-dried precipitated silicas according to theinvention.Silica:polymer ratio = 4:1 Example no. 18 19 9 Silica acc. Silica acc. Commercial to the to the 17 product invention invention Unknown AMERSILPrecipitated silica HiSil SBG (Ex. 3) (Ex. 4) (comparison)__________________________________________________________________________Oil quantity grams 1700 1900 1900 --Melt temperature ° C. 194 196 190 --Melt Pressure bar 102 98 71 --Torque % 47 47 38 --Resistivity mA ·after 20. min. soak in.sup.2 /mil 1.27 0.78 1.05 0.93after 24 hours' soak 0.85 0.45 0.58 0.73Total porosity vol % 60.3 64.9 65.0 63.2Ash content wt. % 70.4 70.8 70.3 51.5Mechanical properties:Elongation % 722 785 713 --Tensile strength N/mm.sup.2 3.43 3.36 2.82 --__________________________________________________________________________
EXAMPLE 18
In this Example, the commercial silica HiSil® SBG of Example 5 is replaced by the silica according to the invention according to Example 3. Moreover, the oil proportion in the recipe of Example 5 is increased from 1655 g to 1900 g oil . The film data may be found in Table 6.
EXAMPLE 19
In this Example, the commercial silica HiSil® SBG of Example 5 is replaced by the silica according to the invention according to Example 4. Moreover, the oil proportion in the recipe of Example 5 is increased from 1655 g to 1900 g oil . The film data may be found in Table 6.
The highly structured precipitated silicas according to the invention (DBP value, anhydrous:≧275 g/100 g and BET surface of 100-130 m 2 /g) are also highly suitable for the production of silica-polyethylene separators for car starter batteries with an SiO 2 :PE ratio of 2.5:1 to 3.5:1 and a separator thickness of 0.20-0.25 mm. Surprisingly, there is a marked decrease in the resistivity to values below 0.60 m Ohm·inch 2 /mil.
This finding is confirmed by Examples 20 and 21:
EXAMPLE 20
750 g of silica according to Example 3 are mixed in a mixer (vertical universal mixer EM 25 type from Mischtechnik Industrieanlagen GmbH, Detmold/FRG) with 288 g of Hostalen GUR×106 (ultra-high molecular weight type of high density polyethylene from HOECHST AG, Frankfurt a.M.) with 45 g of a highly effective wetting agent and with 8.4 g of a phenolic resin at a speed of 120 rpm, and a quantity of 1,900 g of Mobil oil FBK 150 extra heavy is then added. After all the oil has been added, mixing is continued for another 1/2 minute. The product thereby obtained is a free-flowing and continuously meterable powder which is processed with the aid of a twin-screw extruder (ZSK 30 M 9/2 type from Werner & Pfleiderer, Stuttgart) with a heated flat-sheet die 220 mm wide (Gottfert Prufmaschinen GmbH, Buchen) and a triple roll calender (Polyfol 150 3 S type from Ruth Schwabenthan, Berlin) to obtain a film about 0.25 mm thick. At a screw speed of 93 rpm, a temperature profile of 150 to 200° C. is chosen between the feed zone of the extruder and the die. The melt temperature measured between the extruder and the die is 191° C. The melt pressure in bar and the torque of the screws as a % of the maximum permissible torque are read off the twin-screw extruder as a measure of the processing behavior of the mixture during extrusion. The mineral oil is then extracted to a large extent from the film thus produced with hexane so that a microporous separator film is obtained.
The resistivity and the mechanical properties such as tensile strength and elongation at break of the films extracted to a residual oil content of 12-14% are measured according to the methods described above. The measured values determined from the films produced according to Example 20 are summarized in Table 7.
EXAMPLE 21
A separator mixture with a silica polymer ratio of 3:1 is prepared, then extruded and characterized. The procedure adopted is substantially the same as that described in Example 20, but only 250 g of the polymer used in Example 20 are used (instead of 288 g).
Table 7 shows that the reduction in the resistivity during the change from a silica:polyethylene ratio of 2.6:1 to 3:1 is 7% with an extremely low value of 0.58 m Ohm·inch 2 /mil, and the processing data develop in a more favourable manner as the SiO 2 :PE ratio increases. The mechanical data fall somewhat, but remain within the absolutely safe range of the requirements to be met by battery manufacturers.
TABLE 7______________________________________Production conditions and properties of highly porous silica-polyethylenebattery separators for car starter batteries on a lead-acid basis with afilmthickness of 0.25 mm. Variable: Silica-polymer ratio (SiO.sub.2 :PE) Example no. 20 21 Silica according to Silica according the invention to the inventionPrecipitated silica (Example 3) (Example 3)______________________________________SiO.sub.2 :PE ratio 2.6:1 3.0:1Melt temperature ° C. 191 189Melt pressure bar 116 102Torque % 55 53Resistivityafter 20 minutes' soak mA · 0.76 0.66 in.sup.2 /milafter 24 hours' soak mA · 0.58 0.54 in.sup.2 /milMechanical properties:Elongation % 999 940Tensile strength N/mm.sup.2 5.30 4.20______________________________________
|
A process for preparing microporous separating elements for batteries by intensive mixing of a high molecular weight polyethylene with a precipitated silica having specific chemical and physical characteristics, a process liquid and a stabilizer to form a powder mixture, which is extruded to form a film, from which the process liquid is removed, thereby leaving the desired microporous separating elements which are recovered.
| 2 |
This application is a continuation, of application Ser. No. 255,120, filed 10/7/88, now abandoned.
FIELD OF THE INVENTION
This invention relates to the art of medicine and, more specifically, to oncology.
The best advantage may be derived from use of the present invention for diagnostics, including at an early stage, of malignant growths for assessment of the extent of malignant affection, for determining the required volume of surgical operations, for finalizing diagnoses under clinical and dispensary conditions, for control during treatment of malignant tumours, and for detection of post-operative relapses.
BACKGROUND OF THE INVENTION
At present, the problem of diagnostics of malignant neoplasms, especially at early stages, is of vital importance in oncology. In spite of an extensive use of histological analytical methods, great successes of ultrasonic and X-ray diagnostics, in spite of great progress achieved in endoscopic examination methods, as well as in X-ray and nuclear magnetic resonance (NMR) tomography, the sensitivity, accuracy and availability of these methods still remain inadequate. One of the promising trends for perfecting the diagnosis of malignant tumours resides in the use of contrasting agents capable of being selectively accumulated in such tumours. It is a well established fact, for instance, that malignant tumours accumulate some dyes at elevated concentrations as compared to healthy body tissues, and this fact is used for fluorescent diagnosis of tumours using the fluorescence characteristic of a dye accumulated therein.
Various compositions, such as, antibiotics of the tetracycline group, have been used as fluorescent contrasting agents. One of the diagnostic methods made it possible to detect stomach cancer at late IIIrd and IVth stages of the disease, however, with a degree of precision found insufficient for diagnostic purposes (Cf. I. Klinger, K. Katz. Gastroenterology, enterology, 1961, 41, 29-32). Use of endoscopic technique, in combination with fluorescent contrasting tetracycline agents (Cf. I. Ya. Barsky, G. V. Papayan, V. V. Shchedrunov and Yu. A. Glukhir Luminescent Analytical Methods in Medical and Biological Examinations, (a collection of publications), Riga, 1983, pp. 182-189) has also demonstrated poor reliability in diagnostics of tumours because of blurred contrast in which tetracycline accumulated in malignant tissues stands out as compared to healthy tissues.
Fluorescent contrasting using fluorescein as a dyeing agent has been used for detecting metastases into regional lymph nodes in larynx cancer (Cf. S. I. Mostovoy, J. of Disorders of the Ear, Nose and Throat, 1961, No. 4, pp. 34-36). It has been stated that not only cancer-affected lymph nodes, but also other body organs exhibited bright fluorescence, and this fact renders the method unsuitable for diagnostics. Some other authors also have arrived to the same conclusions (Cf. G. E. Moore, Science, 1977, 106, 130-131; F. H. I. Figge, G. S. Weiland, L. O. I. Manganiello, Proc. Soc. Exper. Biol. Med., 68, 640-641, 1948).
For contrasting malignant growths, attempts have been also made to use a contrasting agent containing, as a contrasting substance, fluorescin and used either in the form of a 20%-solution for intravenous administration in 2 to 5 ml doses, or in the form of 1 gr of powder washed down with soda water (Cf. Yu. N. Yefuni, Vestnik Otorhinolaryngology [in Russian], 1961, No. 2, pp. 11-15). The disadvantage of the latter contrasting agent lies in poor contrast offered by fluorescein accumulated in a malignant tissue as against a healthy tissue, whereby the accuracy of diagnostics is affected. The degree of contrast offered by fluorescein accumulated in a malignant tissue versus that accumulated in a normal body tissue has been assessed in terms of a ratio of the concentrations of fluorescein contained in these two types of tissues per gram of the tissue weight. According to the prior art, the reliability of fluorescent diagnostics of, e.g. malignant growths in the organs of the upper respiratory tract, was 30%. Accordingly, an inference may be arrived at that epithelial malignant tumours do not fluoresce, i.e. they do not accumulate fluorescein.
SUMMARY OF THE INVENTION
It is the object of the present invention to develop a composition for contrasting malignant neoplasms with a high degree of reliability of diagnostics. The above-formulated object has been unexpectedly attained due to using in a composition for contrasting, along with fluorescein, or with salts thereof, or with an anion thereof, additives in the form of sugars and/or disaccharides, vitamins and agents for blocking the permeability of cellular membranes. The mechanism of action of these additives in contact with fluorescein is by no means obvious a priori and resides in the following:
Fluorescein, being a fluorescent dyeing agent, has been since long used in biology and medicine. It is common knowledge that fluorescein does not penetrate into living cells, since its anion has a negative charge which prevents its passage through the cellular membrane. It has been established quite unexpectedly that addition of organic acids which are a product of cellular metabolism, to a fluorescein solution leads to the formation of a complex neutralizing the charge of the fluorescein anion and, as a result, fluorescein starts penetrating and accumulating in cells. This effect has been used in the present invention for carrying out fluorescent diagnostics. The main point is that the malignant cells exhibit respiration of glycolytic type which is characterized by a higher rate of carbohydrate consumption and an acidification of inter-tissue fluid due to ejection of organic acids as final respiration products. As has been shown experimentally, a lower acidity of the medium leads to proteinization of fluorescein and to its greater solubility in cellular membranes and, as a result, to a sharp increase in the fluorescein concentration within malignant cells. Preferably, glucose or fructose as monosaccharides, and saccharose as a disaccharide are used as carbohydrates, which is determined by the specific physiological particular features of a human organism, for instance, by the fact that a patient suffers from diabetes mellitus.
Additions of vitamins A (retinol), B 1 (thiamine), B 2 (riboflavin), B 6 (chloride pyridoxine), P (rutin), E (acetate tocopherol), C (ascorbic acid), PP (nicotinic acid) lead to an all-out stimulation of the metabolic processes required for active transfer of fluorescein to malignant cells, in particular, they intensify the glycolysis process.
Use of agent for blocking the permeability of cellular membranes, preferably antihistaminic preparations, such as 3-methyl-9-benzyl-1,2,3,4-tetrahydrocarboline-naphthalin-1,5-disulphonate, or 10-(2-dimethylaminopropyl)-phenothiazine hydrochloride, or N-dimethylaminoethyl-N-(parachlorobenzyl)-aminopyridine hydrochloride, or 1-methyl-2-[2-(alpha-methylparachlorobenzohydryloxy)-ethyl]-pyrromedine, or 4,9-dihydro-4-(1-methyl-4-piperidinyliden)-1-OH-benzo[4,5]cyclohepta[1,2]-thiophen-10-OH (hydrofumarate), or beta-dimethylaminoethylic ether benzohydrol hydrochloride, or chinuclidyl-3-diphenylcarbinol hydrochloride as aimed at reducing the speed of removal of fluorescein from malignant cells. The other effect of the membrane-permeability blocking agents is to increase the fluorescein concentration in malignant cells and, as a result, a deeper contrast offered by fluroescein built-up in a greater amount in malignant cells. Consequently, the above-mentioned additives have a dual purpose, namely, they increase the selective build-up of fluorescein in cells, and, at the same time, they reduce the speed at which fluorescein leaves the cells. It will be appreciated that the selectivity of this process conditioned by the specific features of metabolism in malignant cells, is expressed, on the whole, by a deeper contrast offered by fluorescein accumulated in malignant tissues as against healthy tissues.
DETAILED DESCRIPTION OF THE INVENTION
Taking in due consideration the individual specific features of human organisms, the composition in accordance with the present invention may be recommended for administration in the following alternative formulations, %% by weight:
______________________________________1. Fluorescein or salts thereof 0.1 to 80 Sugar and/or disaccharide 20 to 99.9______________________________________
The preferable composition comprises, %% by weight:
______________________________________fluorescein or salts thereof 10sugar and/or disaccharide 90______________________________________
TABLE 1______________________________________Contrasting composition comprises,%% by weight ContrastFluorescein offered by theor composition insalts thereof Glucose Fructose Saccharose relative units1 2 3 4 5______________________________________Known com-position forcomparison100 -- -- -- 1.520 -- 80 -- 5.01 -- -- 99 8.5 0.1 99.9 -- -- 12.03 50 -- 47 8.0______________________________________
______________________________________2. Fluorescein or salts thereof 1 to 90 wt. % Vitamins 10 to 99 wt. %______________________________________
The preferable composition comprises %% by weight:
______________________________________fluorescein or salts thereof 50vitamins 50______________________________________
TABLE 2______________________________________Contrasting composition comprises, %% by weight Con-Fluorescein trastor salts Vitamins in rel.thereof B.sub.1 B.sub.2 B.sub.6 A P E C PP units______________________________________Known com-position forcomposition100 -- -- -- -- -- -- -- -- 1.590 2 1 2 0.2 2 1 1 0.8 3.050 3 1.5 3 0.5 3 1.5 30 7.5 6.510 5.4 2.7 5.4 0.9 5.4 2.7 54 13.5 5.010 5.4 2.7 -- -- 5.4 2.7 60.3 13.5 4.5______________________________________
______________________________________3. Fluorescein or salts thereof 20 to 90 wt. %Agents for blocking the permeability 10 to 80 wt. %of cellular membranes______________________________________
The preferable composition comprises, %% by weight:
______________________________________fluorescein or salts thereof 80agents for blocking the 20permeability of cellularmembranes______________________________________
TABLE 3______________________________________Fluorescein 3-methyl-9-benzyl-1,2,3,4-tetra- Contrastor salts hydrocarbolin of naphthalin-1,5-di- in rel.thereof sulphonate units______________________________________Known com-position forcomparison100 -- 1.590 10 4.550 50 3.010 90 2.5______________________________________
The contrasting composition in accordance with the present invention may also comprise other combinations of the above-disclosed components, the most preferred being the following complete make-up of the composition, %% by weight:
______________________________________Fluorescein or salts thereof 0.1 to 79.6Sugar and/or disaccharide 19.4 to 98.9Vitamins 0.5 to 80Permeability-blocking agents 0.5 to 80The preferable composition comprises, %% by weight:fluorescein or salts thereof 15sugar and/or disaccharide 70vitamins 10permeability-blocking agents 5______________________________________
TABLE 4__________________________________________________________________________Fluorescein Contrast inor salts Contrasting composition comprises, %% by weight relativethereof * ** *** B.sub.1 B.sub.2 B.sub.6 C A **** units__________________________________________________________________________Known compositionfor comparison100 -- -- -- -- -- -- -- -- -- 1.510 -- -- -- -- -- -- 60 -- 30 510 -- -- -- 5 5 10 20 -- 50 6 5 -- -- 50 5 5 5 25 5 -- 10 0.1 98 -- -- -- -- -- 1 0.4 0.5 12 1 -- 35 -- 10 10 10 10 -- 24 1825 -- 35 -- 5 5 5 15 5 5 20__________________________________________________________________________ Note: *glucose; **fructose; ***saccharose; ****3methyl-3-benzyl-1,2,3,4-tetrahydrocarbolin naphthalin1,5-disulphonat
If one of the above-identified ingredients of the contrasting composition in accordance with the present invention is excluded from the formulation specified in Table 4, the contrast offered by the present composition built-up in malignant tumours becomes somewhat weaker, remaining, nevertheless, at a higher level than that attainable with its prior-art analogues (See Tables 1-4).
Of basic importance is the fact that it is the fluorescein anion that constitutes the active principle in the present contrasting composition. The fluorescein anion penetrates into the patient's blood and is transported through the body tissues to be built-up in malignant neoplasms. For this reason, the present contrasting composition according to the present invention contains either fluorescein, or the salts thereof with, preferably, alkali metals or ammonium. When fluorescein or its salts are found in an alkaline medium, they dissociate to liberate the fluorescein anion.
The composition for contrasting malignant growths according to the present invention may be administered into the patient's body in a number of ways, such as by intravenous injections, enterally or through the rectum. Other variants are also possible, e.g. vitamins and carbohydrates are administered enterally, while fluorescein or its salts are administered intravenously.
The individual ingredients of the present contrasting composition may be used either in the form of a single solution, or as a powder, or as a plurality of individual solutions, or in solid state.
Used as a solvent for the present contrasting composition, either on the whole or for its individual ingredients, may be water or a 5- to 30%-aqueous solution of ethyl alcohol. Once the solution of the present contrasting composition is prepared, it is possible to adjust its optimum acidity by additions of salts and acids and also flavour additives.
A solvent may be used either jointly with the present contrasting composition (the latter being in dissolved form), or separately (the composition in pulverized form plus a solvent).
The assessment of the ability of fluorescein or its salts to be accumulated in malignant cells and tumours has been carried out on cellular cultures He-La, 3T3, IG-fibroregion, cultivated by the standard techniques. Fluorescein or its salts, along with the other ingredients of the present contrasting composition, have been added to the cellular culture, incubated for a few hours, followed by isolating a cellular fraction and washing it. The dye concentration was determined in the cells using chromatographic and fluorescent analytical methods.
In experiments on laboratory animals, use has been made of mice (a linear breed, CBA, C-57 Black and BALB-C) affected with cross-linked tumours of uterine neck cancer, Lewis and colon cancer, respectively. Upon expiration of a certain lapse of time after administration of fluorescein or its salts, along with the other above-identified ingredients, the animals have been anesthesized and killed to determine the dye concentration in the malignant and healthy tissues. The degree of contrast offered by the present composition was expressed in terms of a ratio of the dye concentration in a malignant tissue to that in a healthy tissue.
Laparoscopic examinations have demonstrated that fluorescein or its salts are accumulated in an ascitic fluid. It means that this fluid may be detected in very small amounts. Consequently, it becomes possible to detect the presence of malignant, visually undetectable, deeply embedded metastases in internal organs, such as liver, transperitoneal region, spleen, etc. This fact considerably expands the diagnostic potentialities of the laparoscopic technique.
Tables 1 to 4 report the results of experimental work on mice belonging to the CBA breed, affected with uterine neck cancer inoculated to the hip. These Tables also report data on the degree of contrast offered by fluorescein accumulated in malignant tissues as against normal surrounding tissues, depending on the present contrasting composition.
Malignant elements present in blood accumulate fluorescein or its salts, and they may be detected by their fluorescent contrast under a microscope.
The study of the localization of fluorescein in the body tissues has been started upon expiration of a certain lapse of time after administration of the present composition, since during this lapse of time, as shown by our experience, the dye has sufficient time, in the first place, to be uniformly distributed throughout all the tissues of the body and, in the second place, to get accumulated in malignant growths. Removal of the composition through the liver and kidneys starts practically immediately after administration of the present composition and, upon expiration of a specific lapse of time characteristic of exact localization, type and size of a malignant tumour, an elevated concentration of fluorescein or of its salts is detected in the tumour. Detection of the localization of fluorescein was conducted by the fluorescent analysis. The tissues having an elevated or a lower fluorescein concentrations have been subjected to a histological analysis for a final diagnosis as to their malignant nature.
It has been established that the reliability of diagnostics of malignant processes based on the detection of fluorescence of fluorescein accumulated in the body tissues as compared to the conventional histological analysis of tissue samples taken by biopsy accounts for 75 to 90%, depending on the localization of a tumour.
Identical results for the percentage of reliability of the fluorescent diagnostics have been obtained in clinical tests during which, all in all, 350 patients suffering from cancer of the gastrointestinal tract, skin cancer and mammary gland cancer have been examined.
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The present invention is used for diagnosis, including early diagnosis, of malignant growths, for assessment as of the extent of malignant infection, for determining of the required volume for surgical intervention, for finalizing diagnoses under clinical and dispensary conditions, for control during the process of treatment of malignant tumors, and for detection of post-operative relapses.
The contrasting composition according to the present invention is characterized in that, in addition to the contrasting composition, namely, fluorescein, or salts thereof, it comprises sugar.
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