PROCESS FOR LESSENING POLYMORPHIC CONVERSION OF A DRUG

Abstract: The present invention is directed to maintaining a therapeutic agent comprising a drug in its preferred polymorphic form for providing an indicated therapy. The therapeutic agent is maintained in the polymorphic form by blending a polymer with the therapeutic agent which lessens the conversion of the therapeutic agent from the desired form to a different, undesired form.

Description: PROCESS FOR LESSENING POLYMORPHIC CONVERSION OF A DRUG FIELD OF THE INVENTION This invention pertains to a novel composition and process for maintaining a drug in a preferred therapeutic form. More particularly, the present invention pertains to a composition, method of administration and process for substantially lessening the conversion of a drug from one polymorphic form to a different polymorphic form. BACKGROUND OF THE INVENTION In the practice of pharmacy and medicine, it is most important to both know and to maintain a drug in its active form for good therapy. Many drugs, for example, can exhibit more than one morphological form, generally known as polymorphs. Polymorphs, or polymorphic forms, as used for the purpose of this invention, denote the possible existence of a drug in one or more crystalline and/or amorphous forms. As generally applied to drugs, it refers to the different structures of the same drug. More importantly, drugs that can exhibit different solubilities and/or release rates as associated with this scientific phenomenon can exhibit different polymorphic forms. With many drugs, for which release rate from a dosage form in which dissolution is a rate-limiting factor, different solubilities of drug in the gastrointestinal environment is a rate-limiting step in drug absorption. Thus, different , solubilities associated with various polymorphic forms can exhibit an increase or a decrease in the drug's therapeutic effect. This can lead to uncertainty in therapy, in the absence of knowing the drug is administered to the patient in the desired polymorphic form. The above presentation dictates of the critical need for a composition and process for maintaining a drug in its desired polymorphic form. It is thus, a purpose of this invention to provide a composition and process for maintaining a drug in the desired polymorphic form and methods of administering a dose of drug to a patient for good therapy. SUMMARY OF INVENTION In one aspect, the invention comprises a therapeutic composition comprising a polymorphic drug in a preselected morphological form and a stabilizing pharmaceutically-acceptable excipient maintaining greater than 90% of the drug in the desired morphological form prior to and during delivery of the drug to the environment of use. The excipient may a polymer, and the pre-selected morphological form may be amorphorous or crystalline. The composition may be formed as a granule and may optionally comprise a binder and/or a solubility regulating agent. The solubility regulating agent may control the pH of the composition. The composition may be formed as a granule by a wet or dry granulation process. The composition may be formed as an aggregate of granules, such as in a tablet by compression or in a capsule containing the granules. In another aspect, the invention comprises a method for maintaining a pre-selected morphological form of a polymorphic drug in a therapeutic composition which comprises granulating the drug in its pre-selected morphological form with a pharmaceutically-acceptable excipient. The excipient may be a polymer, and the polymer may be selected from the group consisting of poly(olefin), poly(vinyl), poly(carbohyate) and poly(peptide) polymers. The method may optionally include granulation with a binder and/or a solubility regulating agent that may also control the pH of the granule. Granulation may occur as a wet granulation process or a dry granulation process. The composition may be formed as an aggregate of granules, such as in a tablet by compression or in a capsule containing the granules. In yet another aspect, the invention comprises a method of administering a drug to an environment of use comprising a patient, wherein the method comprises administering the drug from a dosage form comprising the drug and a pharmaceutically acceptable excipient that substantially keeps the drug in a pre-selected morphological form and delivers the drug at a controlled rate that correlates with the dissolution rate of the drug when in the environment of use. The method may comprise administering the dose of drug from a dosage form comprising granules of the drug and a pharmaceutically acceptable polymer that substantially maintains the drug in a pre-selected morphological form, the dosage for optionally comprising one or more binders or solubility regulating agents The dose of drug may be formed an aggregate of granules in tablet or capsule form DESCRIPTION OF THE DRAWINGS Figure 1 is a graphical representation of the cumulative amount of drug dissolved and released as a function of time from a representative composition of the invention, Figure 2 is a graphical representation of the cumulative amount of drug released as a function of time from a representative composition of the invention prepared in accordance with Example 5, Figure 3 is a graphical representation of the cumulative amount of drug dissolved as a function of time from a representative composition of the invention prepared in accordance with Example 5, Figure 4 is a graphical representation of the cumulative amount of drug released as a function of time from a representative composition of the invention prepared in accordance with Example 6, Figure 5 is a graphical representation of the cumulative amount of drug dissolved as a function of time from a representative composition of the invention prepared in accordance with Example 6, and Figure 6 is a graphical representation of the cumulative amount of drug released as a function of time from a representative composition of the invention prepared in accordance with Example 7 DESCRIPTION OF THE INVENTION The present invention has unexpectedly discovered the sciences of pharmacy and medicine and their accompanying therapy can be advanced by providing a composition and process for substantially lessening the polymorphic conversion of a drug The therapeutic compositions of the invention comprise a polymorphic drug in a preselected morphological form and a pharmaceutically-acceptable stabilizing excipient maintaining greater than 90% of the drug in the desired morphological form prior to and during delivery of the drug to the environment of use. The excipient may a polymer, and the pre-selected morphological form may be amorphorous or crystalline. The composition may be formed as a granule and may optionally comprise a binder and/or a solubility regulating agent. The solubility regulating agent may control the pH of the composition. The composition may be formed as a granule by a wet or dry granulation process. The composition may be formed as an aggregate of granules, such as in the form of a tablet by compression using conventional techniques or as a capsule in which the granules are contained. The process generally comprises granulating the drug with a polymer and with optional excipients to provide a formulation that substantially lessens conversion of one morphological form of a polymorphic drug to another morphological form. The term lessening as used herein includes inhibiting and it denotes substantially keeping greater than 90% of the drug in the polymorphic form in the dosage form. Often greater than 95% of the drug will be maintained in a pre-selected polymorphic form. As used herein, a "polymorphic drug" means a drug that may exist in one or more crystalline and/or one or more amorphous forms. For example, and without limitation, a polymorphic drug may have multiple crystalline forms; or it may have a simple crystalline form and an amorphous form; or it may have multiple crystalline forms and an amorphous form; and so on. A "polymorphic form," "polymorph" or "morphological form," as used with respect to a drug means a single form of the drug selected from the multitude of polymorphic forms in which the drug may exist. The process comprises a granulation technique. Granulation is a process of size enlargement. In a granulation process, small particles are gathered into larger aggregates in which the original particles can still be identified. Granulation can be divided into a dry method, wherein no liquid is used for the aggregation, or into a wet method wherein a liquid is used for granule agglomeration of powder particles followed by a drying process. In the wet granulation technique, for example, the drug and other ingredients comprising composition are blended using a solvent, such as an organic solvent, or a cosolvent such an organic-aqueous solvent like ethyl alcohol-water, 98:2 V:V (volume:volume) as the granulation fluid. Other granulating fluid, such as denatured alcohol 100% can be used for this purpose. The ingredients forming the drug composition are individually passed through a mesh screen, such as a U.S. Sieve Series screen, and then thoroughly blended in a mixer. Other ingredients comprising the drug composition are dissolved in a portion of the granulating fluid, such as the solvent or cosolvent described above. Then, the latter prepared wet blend is produced, which wet mass is next forced through a mesh screen onto oven trays. The blend is dried for 18 to 24 hours at 30° - 50°C. The dry granules are then sized with a mesh screen. Next, a lubricant is screened and added to the dry screened granule blend. The granulation is placed into a blender and blended for up to 15 minutes. Additional compositions are made by the same granulation techniques, consisting in suspending and tumbling the granule-composition in a current of air with a coating that forms a membrane that surrounds the drug granulation. Drug granulations used for the present invention comprise roller compactions and slugging, and granulation by extrusion and globulation can be used additionally for producing granules or pellets for controlled release dosage forms. In using dry granulation, in one manufacture, powder particles are aggregated under high pressure and aggregate because of bonding forces established by the direct contact between solid surfaces. The high pressure serves to improve the contact area between the surface and thus the overall bonding strength. A binding agent can be added to the powder mix. Polymeric binders form bridges between the particles and contribute thereby to the strength of the composition. Dry granulation does not utilize heat or moisture, and therefore has application where heat-or moisture-sensitive powders are processed alternatively, a wet granulation process may be used. The advantages of using wet or dry granulation to maintain a drug in a chosen polymorphic form additionally include improving the flow properties and hence the mass uniformity of a dose of drug, to lessen the incidence of segregation of the drug and other ingredients in a granulation, to improve the manufacturing characteristics of a granulation, to enhance the solubility of a polymorphic form of a poorly water soluble drug by granulating the drug with a polymer, and to keep certain drugs in an amorphous form to enhance the solubility and the bioavailability compared to the crystalline form of the drug. The amount of a polymer used for homogenously blending with a drug to provide the granule dose of drug is 10 ng to 100 mg. The granulation processes used by the invention produce granules with a size distribution in the range of 0.1 mm to 3.0 mm. Techniques for granulation are reported in Encyclopedia of Pharmaceutical Technology, Vol. 7, pp 121 -160, (1960), published by Marcel Dekker, Inc; Pharmaceutical Sciences, Remington, 17 th Ed, pp 1610-1615, (1985), published by Mack Publishing Co., air suspension procedures are described in U.S. Pat. No. 2,799,241 ; J Amer Pharm Assoc , Vol 48, pp 451-454, (1979); and ibid., Vol. 49, pp 82-84 (1960). Other standard manufacturing procedures are described in Modern Plastic Encyclopedia, Vol. 46, pp 62-70 (1969); and Pharmaceutical Sciences, Remington, 14 th Ed., pp 1626-1678 (1970), published by Mack Publishing Co., granulation techniques are described in ibid., pp1655-1660 (1970). The granular compositions of the invention may be formed into aggregates of granules, such as tablets formed by compression of the granules or capsules containing the granules. Such forms are convenient for administering the drug in its perselected polymorphic form, which will be throughout the tablet or capsule, as the case may be. Representative of drugs that possess polymorphic forms comprise a member selected from the group consisting of acetamide, acetaminophen, amitriptyline, amobarbitol, amiperone, amcinonide, apronalide, acemetacin, amisometradine, betamethasone acetate, bupicomide, buspirone, bentiromide, biotiizolam, benoxaprofen, bupranolol hydrochloride, butoxycaine hydrochloride, butyrophenone, bolandiol dipropionate, benzocaine picrate, cephalexin, chlordiazepoxide hydrochloride, carazolal, chlorpropamide, codeine, clomipramine hydrochloride, clominorex, dimethoxanate hydrochloride, diphenidol, dobutamine hydrochloride, erythromycin, enitabas, ethinyl estradiol, etafedrine hydrochloride, flurbiprofen, fenbufen, famotidine, flupirtine maleate, griseofulvin, heptolamide, ibuprofen, indomethacin, indalpine, imipramine, levobunolol hydrochloride, mefenamic acid, meprobomate, methisazone, methylprednisolone, methyltestosterone, metahexamide, moclobemide, moperone, medrogestone, nifedipine, nystatin, naftifine hydrochloride, noxiptiline hydrochloride, oxamiquine, piracetam, piretanide, paxamate, propentofylline, piroxicam, propranolol hydrochloride, penothiazine, phensuximide, protionamide, piribedil, pentobarbital, phenylpropylmethylamiπe, phenytoin, resorantel, suloctidil, spironolactone, sulfameter, sulfabenzamide, sulfapyridine, triclabendozole, terconazole, tolbutamide hydrochloride, testosterone cypronate, theophylliπe, tolbulamide, and leukotriene-antagonist exemplified by acitaganolast, iralukast, montelukast, pranlukast, verlukast, zafirlukast, and zileton. The dose of polymorphic drug blended with a polymer and/or other granule forming ingredients is 10 ng (nanogram) to 40 mg (milligram) per granule. Polymorphic drugs are known in Pharmaceutical Manufacturing, pp 35-42, Feb. (1986); Drug Dev. Ind. Pharm., Vol. 13 (15) pp 2749-2769, (1987); Pharmacy International, pp 233-237, Sept. (1986); Pharmaceutical Manufacturing, pp 27-30, Jan. (1985); J Pharm Sci, Vol. 88(1 ), pp 103-108, (1999); Sci Pharm. Vol. 62, pp 307-316, (1994); Sci Pharm, Vol. 58, pp 37-53, (1990); Sci Pharm, Vol. 48, pp 55-67, (1990); Sci Pharm. Vol. 2, pp 81-96, (1989); J Anal Chem. Vol. 338, pp 752-758, (1989); Sci Pharm. Vol. 55, pp 13-25, (1987); Sci Pharm., Vol. 55, No. 1 , pp 27-39, (1987); Sci Pharm Vol. 54, No. 2, pp 61-69, (1986); J Anal Chem.. Vol. 322, No. 2, pp 164-169, (1985); Mikrochim Acta. Vol. 2, pp 205-217, (1984); Mikrochim Acta. Vol. 2, No. 1 -2, pp 103-119, (1984); Arch Pharm. Vol. 311 , No. 9, pp 757-761 , (1978); Sci Pharm, Vol. 46 (No. 1 ), pp 62-67, (1978), and Arch Pharm. Vol. 307, No. 5, pp 377-384, (1974). Representative of pharmaceutically-acceptable polymers for granulating a drug to maintain the drug substantially in a dispensable form comprise a pharmaceutically acceptable polymer selected from the group consisting of a poly(olefin), poly(vinyl), poly(carbohydrate), poly(peptide), poly(addition), poly(condensation), and poly(erodible) polymer. The term poly(addition) refers to polymers prepared by addition polymerization processes, and the term poly(condensation) refers to polymers prepared by condensation polymerization. The term poly(erodible) refers to polymers that erode in the environment of use, namely the gastrointestinal tract. The pharmaceutically acceptable polymers are selected from the group consisting of poly(alkylene oxide) possessing a 10,000 to 5,250,000 weight average molecular weight, exemplified by poly(ethylene oxide) of 100,000 molecular weight, poly(ethylene oxide) of 200,000 molecular weight, poly(ethylene oxide) of 300,000 molecular weight, poly(ethylene oxide) of 400,000 molecular weight, poly(propylene oxide) of 600,000 molecular weight, copoly(ethylene-propylene oxide) of 1 ,250,000 molecular weight; carboxyalkylcellulose, comprising alkali carboxyalkylcellulose including sodium carboxymethylcellulose, potassium carboxymethylcellulose, and calcium carboxyethylcellulose, wherein the carboxyalkylcellulose possess a molecular weight of 10,000 to 2,750,000; poly(hydroxyalkyl methacrylate) of 5,000 to 5,000,000 molecular weight; poly(vinylpyrrolidone) of 10,000 to 360,000 molecular weight; polysaccharides such as agar, acacia, karaya, tragacanth, algin, and guar of 5,000 to 750,000 molecular weight; poly(glucan); poly(amine); and poly(amino acid). The amount of polymer in the polymorphic granulation is 10 ng to 100 mg. The polymers are known in U.S. Pat. Nos. 3,865,108; 4,002,173; 4,207,893; 4,327,725; and 4,844,984; and in Handbook of Common Polymers, by Scott and Roff, published by Cleveland Ruther Company, Cleveland, Ohio. The drug-polymer granule provided by the invention to substantially maintain, wherein substantially maintain denotes ninety percent or higher to 100% of the drug, in a preselected polymorphic form optimally comprises 10 ng to 20 mg of a binder. The pharmaceutically acceptable binders used for the purpose of this invention comprise a member selected from the group consisting of a 2,500 to 3,000,000 viscosity-average molecular weight poly(vinylpyrrolidone) polymer and copolymer thereof, such as a copolymer of poly(vinylpyrrolidone) with vinyl acetate, copolymer of polyvinylpyrrolidone with vinyl alcohol, copolymer of polyvinylpyrrolidone with vinyl chloride, copolymer of polyvinylpyrrolidone with vinyl fluoride, copolymer of polyvinylpyrrolidone with vinyl butyrate, copolymer of polyvinylpyrrolidone with vinyl laurate, and a copolymer of polyvinylpyrrolidone with vinyl stearate. The binder can be selected from a hydroxypropylalkylcellulose of 9,200 to 225,000 number-average molecular weight wherein alkyl is one to seven carbon atoms, as selected from the group consisting of hydroxypropylmethylcellulose, hydroxypropylethylcellulose, hydroxypropylbutylcellulose, and hydroxypropylpentylcellulose. Additional binders that can be used for the purpose of this invention comprise a member selected from the group consisting of acacia, aiginic acid, acrylic acid cross-linked with allylsucrose, acrylic acid cross-linked with allyl ether of pentaerythritol, dextrin, gelatin, guar gum, liquid glucose, maltodextrin, pregelatinized starch, sodium alginate, starch, and zein. The binder may be present in the granule on the order of 10 ng to 200 mg per granule. The binders impart cohesive qualities to the manufacture. Binders are known in Handbook of Pharmaceutical Excipients, Second Edition, by Wade and Weller, (1994), published by the American Pharmaceutical Association, Washington, D.C. The polymorphic-drug granule may comprise a solubility regulating agent for increasing the concentration of drug and for and concomitantly regulating the pH of drug in a dispensed granule dose. The regulating agent regulates the pH environment of the manufactured product. For poorly soluble drug in aqueous fluids that need an increase in solubility, an increased dose often can be delivered without the drug conversion to a different form. The solubility regulating agents useful for this invention comprise a member selected from the group consisting of acidic and basic groups represented by tromethamine also known as tris(hydroxymethyl)-aminomethane; diethanolamine; glycineamide; triethanolamine; N-[tris-(hydroxymethyl)methyl] glycine; sodium acetate; sodium lactate; sodium glycocholate; sodium propionate; sodum butyrate; sodium glycocholate; glycocholate sodium phosphate; potassium phosphate monobasic; potassium biphthalate; boric acid; sodium borate; and sodium phosphate; acidic groups such as glycine, leucine, methionine, serine, and other acids to regulate a basic compound wherein the acid group is represented by adipic acid, succine acid, citric acid, tartaric acid, maleic acid, and malic acid. The amount of regulator when present in a granule composition is 10 ng to 200 mg per granule. The regulating agents are disclosed in Handbook of Pharmaceutical Excipients, Second Edition, edited by Wade and Waller, (1994), published by American Pharmaceutical Association, Washington, D.C. The drug-polymer polymorphic composition can be manufactured by a wet granulation technique, for example, the drug and the preselected polymer and/or additional ingredients comprising the drug-poiymer polymorphic composition are blended using a solvent, such as ethyl alcohol-water 98:2 V:V (volume:volume) as the granulation fluid. Other fluids, such as denatured alcohol 100%) can be used for this purpose. The drug and other ingredients optionally are passed through a mesh screen, such as the U.S. Sieve Series Screen, and then blended thoroughly. Other ingredients are dissolved in a portion of the fluid, such as the cosolvent described above. Then, the latter- prepared wet blend is added slowly to the drug-polymer blend with mixing continually. The fluid is added until a wet blend is produced, which wet mass is forced through a mesh screen onto oven trays. The polymorphic drug- polymer blend is dried for 15 to 24 hours at 20° to 50°C. The dry polymorphic- drug blend are sized then with a mesh screen and formulated into a dosage form. The polymorphic-drug polymer formulation can be provided by a dry- granulation method. This method can be used when the ingredients possess inherent binding or cohesive properties, slugging may be used to form granules of polymorphic-drug polymer formulation. This method is known in the formulation art as precompression, or the double-compression method. This method comprises the conventional steps including weighing, mixing, slugging, dry screening, and dosage form formulation. Prior art procedures for effecting these methods are disclosed in Pharmaceutical Sciences, by Remington, 17 th ed., pp 1610-1615, (1985), published by Mack Publishing Co., Easton, PA. Exemplary solvents suitable for manufacturing the polymorphic-drug polymer complex and dosage form provided by this invention comprise inorganic and organic solvents. The solvents include a member selected from the group consisting of aqueous, alcohol, ketone, ester, ether, aliphatic hydrocarbon, halogenated, cycoaliphatic, aromatic, heterocyclic solvents, and mixtures thereof. Representative solvents comprise acetone, methanol, ethanol, isopropyl alcohol, butyl alcohol, methyl acetate, ethyl acetate, isopropyl acetate, n-butyl ketone, methyl isobutyl ketone, n-hexane, m- heptane, ethylene glycol monoethyl ether, ethylene glycol monoethyl acetate, methylene dichloride, ethylene dichloride, propylene dichloride, carbon tetrachloride, chloroform, nitroethane, nitropropane, tetrachloroethane, ethyl ether, isopropyl ether, cyclohexane, cyclooctane, benzene, toluene, naptha, tetrahydrofuran, diglyme, aqueous and nonaqueous cosolvents, such as, acetone and water, acetone and methanol, acetone and ethyl alcohol, methylene dichloride and methanol, ethylene dichloride and methanol, trisolvents such as acetone-methanol and water, and, acetone-water and isopropyl alcohol. The compositions of the invention may be formed into aggregates of granules, such as in the form of tablets or filled capsules prepared by conventional manufacturing process. Such dosage forms are convenient for administration of the drug which is distributed throughout the tablet or capsule in its pre-selected polymorphic form. EXAMPLES PROVIDED BY THE INVENTION The following examples are illustrative of the present invention. The examples should not be considered as limiting the scope of the invention in any way, as these examples and equivalents thereof, will become apparent to those versed in the art in light of the present disclosure, the drawings and the accompanying claims. EXAMPLE 1 A dosage form is prepared for maintaining a drug in an amorphous polymorphic form as follows: first, a compositional binder solution is prepared by adding 7650 g of purified water into a solution vessel. Next, 1350 g of polyvinylpyrrolidone possessing a viscosity-average molecular weight of 40,000 is added slowly to the vessel, and the solution mixed gently for about 40 minutes to produce a homogenous solution. Next, a drug composition is prepared as follows: first, 2010 g of tromethamine, (2-amino-2-hydroxymethyl-1 , 3-propanediol) is passed through a 20 mesh screen, U.S. Sieve Series. Then, 60 g of colloidal silicon dioxide is passed through a 40 mesh screen. Then, 2400 g of sodium carboxymethylcellulose possessing a viscosity, measured by a Brookfield viscometer, at 25°C, of a 2% concentration between 25-45 cps, a degree of substitution of 0.70 - 0.80 mol, about 35,000 molecular weight, is placed into a plastic bag. Next, 2280 g of polyvinylpyrrolidone of 40,000 viscosity-average molecular weight is passed through a 40 mesh screen and added to the same plastic bag. Then, the screened colloidal silicon dioxide is added to the same plastic bag and the bag tumbled for 1 minute to obtain a blend of sodium carboxymethylcellulose, polyvinylpyrrolidone and colloidal silicon dioxide. Next, a fluid bed granulator bowl is heated to 28°C. Then, 4320 g of the leukotriene-receptor antagonist, amorphous zafirlukast is added to the bowl. Next, the 2010 g of tromethamine is added to the granulator bowl, followed by the triblend comprising the sodium carboxymethylcellulose, the polyvinylpyrrolidone and the colloidal silicon dioxide. Then, 6000 g of the binder solution is sprayed into the bowl at a rate of 80-125 ml/min. Then, 3000 g of purified water is added to the granulation bowl. During spraying the air flow is maintained at 50 slpm (standard liters per minute). Also, during the granulation process, the binder solution is sprayed for 40 seconds, followed by shaking for 15 seconds. Next, the granulation is dried to obtain a moisture content of 5.0-7.5%. The granulation is passed through an 8 mesh screen into a laboratory mill. Then, 30 g of magnesium stearate is passed through a 40 mesh screen, added to the blend and blended for 2 minutes. The drug composition is pressed into dosage form tablets, comprising 10 mg, 20 mg, 40 mg, or 80 mg of the leukotriene-receptor antagonist zafirlukast indicated for the prophylaxis and chronic treatment of asthma in adult and children patients EXAMPLE 2 A composition for use in a sustained-release dosage form is provided by first providing a composition possessing expandable kinetics The composition is prepared as follows first, a binder solution is prepared by adding 9660 g of hydroxypropylmethylcellulose possessing a number-average molecular weight of 13,000 (5 cps) into a mixing vessel containing 133,400 g of purified water Next, 6900 g of hydroxypropylceliulose possessing a molecular weight of 80,000 is added to the mixing vessel This mixture is stirred until the ingredients dissolve in the water and to obtain a homogenous solution Next, granules for forming an expandable osmotic composition are prepared as follows first, 36,000 g of osmagent sodium chloride are milled in a grinder and passed through a 21 mesh screen Also, 600 g of red ferric oxide colorant is milled and passed through a 21 mesh screen Then, a granulator is heated to 40°C and 68,400 g of sodium carboxymethylcellulose possessing a viscosity at 25°C in a 1 % concentration of 3,000 to 4,000 cps, a degree of substitution of 0 8 to 0 9 mol, and a molecular weight of 300,000 is placed into the bowl of a granulator Then, the 36,000 g of milled sodium chloride is added to the granulator followed by 600 g of the colorant red ferric oxide, accompanied by granulation Next, 30,400 g of the binder solution is sprayed onto the powder bed at a rate of 1100 g/minute, during a processing temperature of 40 C C, with constant shaking to dislodge powders from adhering from the granulator At the end of the process, the moisture content is adjusted to 6 5 to 8 5% Next, the granulation is screened and placed into a blender, followed by the addition of 586 g of colloidal silicon dioxide screened through a 30 mesh screen The mixture is blended at 7 rpm for four minutes, to yield an expandable composition for use in a controlled release dosage form that delivers a drug at a controlled rate of release up to thirty hours EXAMPLE 3 A pair of compositions, expressed as a bilayer core for use in a controlled-sustained release dosage form for oral administration is manufactured by compressing into layered arrangement the leukotriene- receptor antagonist zafirlukast and the expandable osmotic composition The drug layer comprising the leukotriene-receptor antagonist zafirlukast composition and the expandable-push layer disclosed above comprising the expandable composition are compressed in a bilayer tablet press fitted with a 9 53 mm round cavity and concave punches and dies The drug composition is filled into the first hopper attached to the bilayer tablet press, and the expandable composition is filled into the second hopper attached to the bilayer tablet press The press automatically dispenses 242 mg of the drug composition into a die cavity which is tamped under a force of 80 lbs, (pounds) Next, 155 mg of the expandable composition is added to the die cavity and both the drug layer and the expandable layer are compressed under a force of 1800 lbs This process produces a thickness of the bilayer core of 5 33 mm and an average hardness of 10 kp (kilopons) The bilayer core produced by this manufacture comprises a drug layer comprising 80 mg of amorphous zafirlukast, 47 4 mg of sodium carboxymethylcellulose, 62 mg of polyvinylpyrrolidone, 39 6 mg of tromethamine, 11 mg of water, 1 3 mg of colloidal silicon dioxide and 06 mg of magnesium stearate, the expandable layer comprises 88 4 mg of sodium carboxymethylcellulose, 46 5 mg of sodium chloride, 7 8 mg of hydroxypropylceliulose, 10 8 mg of hydroxypropylmethylcellulose, 0 8 mg of ferric oxide, and 0 8 mg of colloidal silicon dioxide The bilayer can be administered as a bilayer dosage form to a patient in need of leukotπene-antagonist therapy, and/or it can be enveloped with a semipermeable wall and administered as a drug delivery device The bilayer comprises the drug-polymeric composition drug with the maintained in its original pre-selected polymorphic form EXAMPLE 4 A dosage form provided by the invention is prepared as follows: first, the bilayer core, described immediately above, is coated with a wall comprising a semipermeable composition as follows: a closed, mixing vessel is used to manufacture a mixing solution. The mixing vessel is purged with nitrogen. Then, 47,600 g of acetone is charged to the mixing vessel, and the vessel heated to 25°C to 30°C. Next, 1 g of Poloxamer ® 188, a polyoxyethylene-polyoxypropylene glycol copolymer of the formula H0(C 2 H 4 0) a (C 3 H 6 0) b (C 2 H 4 0 2 ) a H wherein a equals 80 and b equals 27 having a average molecular weight between 7680 and 9510 is slowly added with stirring to the mixing vessel. Next, the Poloxamer and the acetone are mixed for 10 to 15 minutes. Then, 1979.1 g of cellulose acetate comprising an acetyl content of 39.8% is added to the mixing vessel. Then, the ingredients are mixed for 2 hours to produce a clear solution. Next, the bilayer cores are coated in a 24-inch perforated pan coater. The coating pan is heated to an exhaust temperature of 40°C to 45°C. Then, 11 ,000 g of the bilayer compressed cores are placed into the pan coater. Then, the pan is rotated at 13 rotations per minute. Next, the wall-forming coating solution is sprayed onto the rotating cores at a rate of 110 ml/min from 2 spray guns. During the coating process, the air volume in the coater is maintained between 350 and 370 cfm, cubic feet per minute. The coating process is stopped when the desired amount of semipermeable wall-forming composition is sprayed onto the cores. Next, a 30 mil (0.76 mm) orifice is drilled through the semipermeable wall on the drug side of the just manufactured dosage forms. Then, the residual acetone is removed by drying at 45°C and at 45% relative humidity in an oven for 68 hours. At the end of the drying cycle, the humidity is turned off and the dosage forms are dried at 45°C, for an additional 4 hours, to yield an osmotic dosage form. EXAMPLE 5 The dosage form provided by the above examples is analyzed in this example. The dissolution of the drug zafirlukast indicates the drug entered into solution upon its delivery from a dosage form provided by this invention as measured by the following procedure. First, an aqueous sodium dodecyl sulfate, 1 %o (w/v) (weight/volume) solution is used as the dissolution media. A dosage form prepared by this invention is placed into the dissolution media and the drug released by the dosage form into the dissolution media is sampled at a constant time interval over the time period of dissolution. The filtered samples are assayed by a reversed high pressure liquid chromatography with detection by UV at 224 nm. The concentration of the samples are measured against a standard curve containing at least five standard points. The dissolution test indicates the zafirlukast remains in its amorphous state in the dissolution media. Procedures for dissolution testing are reported in The United States Pharmacopoeia, The National Formulary, pg. 1791 to 1796, (1995); Pharmaceutical Sciences, by Remington, 17th. Ed., pg. 653 to 666 (1985); and USP XXII, Dissolution Paddle Analysis, pg. 1578- 1579 (1990). The release rate of drug, zafirlukast, from a dosage form manufactured by this invention is ascertained by the following procedure. The procedure comprises placing the dosage form in a solution, usually water, and taking aliquots of the release rate solution, followed by their injection into a chromatographic system to quantify the amount of drug released during specified test intervals. The drug, for example, zafirlukast, is resolved on a column and detected by UV absorption at 224 nm. Quantitation is performed by linear regression analysis of peak areas from a standard curve containing at least five standard points. The release rate procedure comprises attaching a dosage form to a plastic rod with the orifice exposed to the drug receiving solution. Then, attaching the rod to a release rate arm, with the arm affixed to an up/down reciprocating shaker, which operates at an amplitude of about 3 cm and 2 seconds per cycle. Then, continuously immersing the dosage form in 50 ml test tubes containing 30 ml of H 2 0, equilibrated in a constant temperature water bath at 37°C ± 0.5°C. Next, at the end of each interval, transfer the dosage form to the next row of new test tubes containing water. After the release pattern is complete, remove the tubes and allow the tubes to cool to room temperature, followed by filling the calibrated tubes to the 50 ml mark with acetone. The samples are mixed immediately, transferred to sample vials, followed by chromatography analysis. The dosage form prepared by the example comprises a drug layer comprising 80 mg of micronized, amorphous zafirlukast, 47.4 mg of sodium carboxymethylcellulose, 62 mg of polyvinylpyrrolidone, 39.6 mg of tromethamine, 11 mg of water, 1.3 mg of colloidal silicon dioxide, and 0.6 mg of magnesium stearate; a push layer comprising 88.4 mg of sodium carboxymethylcellulose, 46.5 mg of sodium chloride, 7.8 mg of hydroxypropylceliulose, 10.8 mg of hydroxypropylmethylcellulose, 0.8 mg of red ferric oxide, and 0.8 mg of colloidal silicon dioxide; a wall comprising 26 mg of cellulose acetate comprising 39.8 acetyl content and 5 mg of surfactant Poloxamer 188; and, a 0.76 mm orifice. Accompanying drawing Figure 1 illustrates the average cumulative drug dissolved depicted by clear boxes and the average cumulative drug released, depicted by dark diamonds, over an extended period of 16 hours. The graph illustrates zafirlukast is delivered by the dosage form without conversion to a crystalline monohydrate form, and the release rate and the dissolution rate are substantially the same, with dual scientific analysis confirming the disclosed and claimed invention unexpectedly lessens the incidence of the starting polymorph converting to a different polymorph. That is, the release rate and dissolution rate are substantially the same, indicting that the conversion of the amorphous polymorph to the crystalline polymorph is inhibited as seen by the solubility of the drug form. Figure 2 depicts the cumulative percent of zafirlukast released versus time for the dosage form; and Figure 3 depicts the cumulative percent dissolved for zafirlukast versus time. EXAMPLE 6 The above procedures are followed with all manufacturing conditions as set-forth, except for the present manufacture the semipermeable wall comprises 85% cellulose acetate with an acetyl content of 39 8% and 15% Poloxamer ® 188, a ethylene oxide-propylene oxide-ethylene oxide triblock copolymer available as Pluronic F68 from BASF Corporation, Mt. Olive, NJ. to provide a dosage form comprising the bilayer drug and push layers with a mean release rate of 10 51 mg/hr Accompanying Figure 4 depicts the cumulative release rate percent over a time period of 20 hours from the dosage form Accompanying Figure 5 depicts the cumulative percent of the drug dissolved versus time on release from a dosage form EXAMPLE 7 A dosage form designed and shaped like an osmotic dosage form to deliver the crystalline form of zafirlukast is manufactured as follows: first, a drug layer comprising zafirlukast is made by passing 16.75 g of tromethamine through a 20 mesh screen. Next, 33 g of crystalline zafirlukast is added to a 500 ml beaker, then 20 g of polyvinylpyrrolidone with an average molecular weight of 40,000 is added to the beaker Next, 30 g of carboxymethylcellulose sodium, having an average molecular weight of 35,000 is added to the beaker. Next, all the ingredients are mixed with a spatula and 60 ml of denatured anhydrous ethanol is added to the beaker with mixing to change the consistency of the dry powder ingredients to granules The granulation then are placed in a hood overnight to dry The dried granules are passed through a 20 mesh screen to obtain a consistency in granule size Next, the granulation is transferred to a glass jar, 0 25 g of magnesium stearate is added thereto, and the granulation mixed on rollers to produce a zarfirlukast drug composition for processing into a drug- composition layer An expandable-push layer is prepared by following the expandable- push procedure described above Next, a tablet press was used to compress the two layers comprising the drug and expandable layers into a bilayered arrangement to form a tablet. First, 260 mg of the drug layer provided immediately above is added to a 10.32 mm die cavity and lightly tamped to yield the drug layer. Next, 140 mg of the expandable-push layer is placed in the same cavity and the two layers compressed under 1 ton of pressure to form a bilayer tablet. Next, the bilayered tablet is surrounded with a wall comprising a semipermeable polymeric composition by following the procedures set-forth above. The wall- forming composition comprises 100% cellulose acetate possessing an acetyl content of 32.0%. The wall-forming composition is dissolved in a mixture of acetone and water to provide a cosolvent ratio of 88:12 (v:v), with a solid composition of 5%. The dosage form provided by this example exhibited an average release rate of 12 mg/hr for 16 hours. The percent cumulative zafirlukast (crystalline) released for this osmotic dosage form is depicted in drawing Figure 6. The dosage form comprised a 0.76 mm drug-releasing orifice. EXAMPLE 8 A dosage form tablet designed and shaped for oral administration to a patient wherein the drug maintains its polymorphic form is manufactured as follows: first 16.75 g of tromethamine is passed through a 20 mesh screen. Then, 33 g of a drug selected from the group consisting of an analgesic, anti- inflammatory, antihypertensive, antibiotic, anesthetic, antidiabetic, antimicrobial, antifungal, antiepileptic, antihistaminic, anticonvulsant, antiparkinson, antimalarial, antiparasitic, antiarthritic, cold-cough, cardioprotective, corticoid, central nervous system acting drugs, contraceptive, cardiovascular, diuretic, depressant, decongestant, dietary supplement, electrolyte, hypnotic, hormonal, hypoglycemic, gastrointestinal drugs, gonadotropins, leukotriene-receptor antagonist, minerals, muscle relaxant, muscle contractant, neoplastic modifiers, proteins, peptide, psychic energizers, sedative, sympathomimetic, steroid, tranquilizer, vasodilator, and vitamin, 20 g of polyvinylpyrrolidone to the beaker, possessing a average molecular weight of 40,000. Then, 5.2 g of osmagent sodium chloride is added to the beaker with mixing to produce a homogenous mass. Next, 30 g of osmagel poly(ethylene oxide) possessing a 100,000 molecular weight is added to the beaker and all the ingredients are mixed in the presence of anhydrous ethanol, to form granules. The granules are dried at 25°C for 12 hours and then passed through a 20 mesh screen. Next, the granules are transferred to a glass jar, and, 0.25 g of magnesium stearate is added thereto, and the granules mixed to produce a therapeutic composition comprising the selected polymorphic drug. Next, 260 mg of the therapeutic composition is added to a tablet press and compressed under a pressure of 1-1/2 tons to a tablet core. Then, the tablet core is enveloped with a wall composition comprising 90% cellulose acetate having an acetyl content of 32% and 10% polyethylene glycol having a molecular weight of 3,350 dissolved in a solvent. The solvent comprises acetone and water, 88:12, w wt, to effect a solid composition of the solution of 5%. The coating temperature is 35°C to apply the semipermeable wall around the drug compositional core. Next, a 50 mil (1.27 mm) passageway is drilled through the semipermeable wall and the residual solvent is removed by drying at 45°C and 45% relative humidity in an oven for 48 hours. At the end of the drying, the humidity is turned off, and the dosage form dried at 45°C for an additional 4 hours to provide an elementary osmotic dosage form for orally administering the drug in its unchanged polymorphic form to a patient in need of therapy. EXAMPLE 9 A therapeutic composition comprising a pharmaceutically acceptable polymer for maintaining the polymorphic state of a drug is selected from the generic group consisting of a poly(olefin), poly(vinyl), poly(carbohydrate), poly(addition), poly(condensation), poly(erodible), poly(hydrophilic), hydrogel, osmagel, and osmopolymer, as represented by a species selected from the group consisting of a poly(aklylene oxide), poly(ethylene oxide), poly(propylene oxide), carboxyalkylcellulose, sodium carboxymethylcellulose, potassium carboxymethylcellulose, calcium carboxyethylcellulose, agar, carrageenan, amylpectin, and starch graft copolymer; and a drug selected from from the group consisting of acitazanolast, iralukast, montelukast, pranlukast, verlukast, zafirlukast, and zileuton is prepared as follows: first, 2,580 g of polyethylene oxide having a weight-average molecular weight of 200,000 is passed through a 40 mesh screen. Then, 1 ,290 g of the screened poly( ethylene oxide) is placed into the bowl of a mixer. Then, 2,400 g of a drug listed above is placed in the mixer over the poly(ethylene oxide). Next, 300 g of polyvinylpyrrolidone of 40,000 viscosity-average molecular weight is passed through a 40-mesh screen and added to the mixer. The remaining 1 ,290 g of polyethylene oxide then is added to the bowl. Next, 300 g of sorbitol and 360 g of tromethamine (2-amino-2-hydroxymethyl-1 , 3- propanediol) is passed through a 40 mesh screen and added to the mixer. The addition of the dry ingredients is performed with the drug located between the two layers of poly(ethylene oxide). The granulation process is initiated by the gradual addition of 3,200 g of ethyl alcohol with continuous mixing to the mixer. Mixing is continued over a period of 5 to 10 minutes to effect a consistency to change the dry powder to granules. The wet granulation is dried at 40°C for 16 hours and then passed through a fluid air mill with a 7- mesh screen for size reduction. Next, the size-reduced granules are placed into a blender. Then, 60 g of magnesium stearate that is passed through a 60-mesh screen is added to the granulation, and all the ingredients mixed for 4 minutes. This composition provides a drug, poly(ethylene oxide), polyvinylpyrrolidone, tromethamine, sorbitol, and magnesium stearate, useful for the therapy. Next, a composition possessing expandable kinetics is prepared as follows: first, a binder solution is prepared by adding 300 g of polyvinylpyrrolidone of 40,000 average-molecular weight to a mixer containing 2,700 g of water. Then, the mixture is stirred until the polyvinylpyrrolidone dissolves in the water and forms a clear binder solution. Next, the granules for forming an expandable, osmotic composition are prepared as follows: first, 7,370 g of poly(ethylene oxide) having an average- molecular weight of 7,000,000 is placed into the bowl of a fluid bed granulator. Then, 200 g of polyvinylpyrrolidone possessing an average-molecular weight of 40,000 is added to the granulator. Next, 2,000 g of sodium chloride and 100 g of red ferric oxide, which is milled using a 20-mesh screen are added to the granulator. The powder ingredients are fluidized for 3 minutes to produce a uniform mixing of the powders. Next, the binder solution is sprayed onto the powders at a solution spray rate of 50 g/min. During the spraying process the process air flow is maintained at 500 cfm and the temperature maintained at 24°C. During the spraying operation the solution is sprayed for 30 seconds, followed by a shaking time of 10 seconds. At the end of the spraying operation, the granules are dried in the granulator for an additional 10 to 15 minutes to obtain a dry granulation. The granules are passed through a fluid air mill with a 7-mesh screen for size reduction. The size reduced granules then are placed into a blender. Then, 25 g of magnesium stearate, previously screened through a 40-mesh screen, and 5 g of powdered butylated hydroxytoluene, previously screened through a 60-mesh screen, are added to the granules and mixed together to provide an osmotically expandable composition. Next, a bilayered core is manufactured by compressing in layered arrangement the drug composition and the osmotic, expandable composition described above as follows: first, 750 mg of the drug composition is added into the cavity of a 5/16-in. (8-mm) diameter, and then 300 mg of the osmotic expandable composition is placed into the die and the two compositions compressed into layered arrangement with 1 ton (2,000 lb.) of pressure. Next, a wall forming composition comprising 90% cellulose acetate having an acetyl content of 32% and 10% polyethylene glycol having a molecular weight of 3,350 is dissolved in a solvent. The solvent comprises acetone and water, 88:12, w wt, to effect a solid composition of the solution of 5%. Then, the bilayer cores are placed into a 12-inch (30-cm) coating pan and the coating solution is sprayed onto the bilayer cores at a spray rate of 25 g/min. The coating temperature is 35°C to apply 140 mg of the semipermeable wall around and in contact with the bilayer core. Next, a 50-mil (1.27 mm) passageway is drilled through the semipermeable wall into the drug side of the dosage form. The residual solvent is removed by drying at 45°C and 45% relative humidity in an oven for 48 hours. At the end of the drying, the humidity is turned off and the dosage 5 forms are dried at 45°C for an additional 4 hours, to provide an osmotic dosage form for orally administering a controlled, sustained delivery of the polymorphic drug over thirty-hours of therapy. PROCESSES AND METHODS OF USING THE INVENTION o The mode and the manner of the invention comprises applying the invention in a plurality of embodiments. The applications comprise; (1 ) a composition and process for maintaining a therapeutic drug in a known, preselected polymorphic state selected from the group consisting of amorphous and crystalline by blending the therapeutic drug with a s pharmaceutically-acceptable excipient that keeps the therapeutic drug in the desired state; (2) a composition and process for maintaining a drug in a polymorphic form by blending the drug with a polymer, wherein the polymer member selected from the group consisting of poly(vinyl), poly(olefin), poly(addition), poly(condensation), poly(cellulose), and poly(erodible) that o provides the chemokinetics for maintaining the drug in the polymorphic form; (3) a process for lessening the conversion of a polymorphic drug to a different polymorphic form, wherein the process comprises blending the drug with a gastrointestinal administrable polymer that lessens the incidence of conversion of the polymorphic drug to a different polymorphic form when 5 administered from a dosage form and in a gastrointestinal tract; (4) a composition and process for keeping a drug in a first-therapeutic polymorphic form by blending the drug with a pharmaceutically-acceptable polymer that retards the conversion of the drug to a second polymorphic form and simultaneously provides granules comprising the drug in the pre-selected o polymorphic form and the polymer; (5) a method of administering a drug to an environment of use comprising a patient, wherein the method comprises administering the drug from a dosage form comprising the drug and a pharmaceutically acceptable-polymer that substantially keeps the drug in its original pre-selected polymorphic form and delivers the drug at a controlled rate that correlates with the dissolution rate of the drug when in the environment of use; and (6) a method of administering a dose of drug to a patient, wherein the method comprises administering the dose of drug from a dosage form comprising granules of the drug and a pharmaceutically- acceptable polymer that substantially keeps the drug in its preferred pre-selected therapeutic polymorphic form for essentially providing a complete dose of the drug to the patient. And, while the above examples, figures and disclosure are set forth for illustrating the mode and manner of the invention, various modifications and embodiments can be made by those skilled in the pharmacy, medicine, and the drug delivery and, in the light of the invention, without departing from the spirit of the invention.

Claims: What Is Claimed Is: 1. A therapeutic composition comprising a polymorphic drug in a preselected morphological form and a pharmaceutically-acceptable stabilizing excipient maintaining greater than 90% of the drug in the desired morphological form prior to and during delivery of the drug to the environment of use. 2. The composition of claim 1 wherein the excipient is a polymer. 3. The composition of claim 2 wherein the pre-selected morphological form is amorphorous. 4. The composition of claim 2 formed as a granule. 5. The composition of claim 4 comprising a binder. 6. The composition of claim 4 comprising a solubility regulating agent. 7. A therapeutic composition comprising a polymorphic drug in a preselected morphological form and a stabilizing excipient comprising a pharmaceutically-acceptable polymer selected from the group consisting of poly(olefin), poly(vinyl), poly(carbohydrate), and poly(peptide) polymers. 8. The composition of claim 7 wherein the polymer is bioerodible. 9. The composition of claim 7 formed as a granule. 10. The composition of claim 9 comprising a binder. 11. The composition of claim 9 comprising a solubility regulating agent. 12. The composition of claim 9 wherein the pre-selected morphological form is amorphous. 13. The composition of claim 9 wherein the polymer is selected from the group consisting of poly(alkylene) oxide having a molecular weight in the range 10,000 to 5,250,000; alkali metal carboxyalkyl cellulose having a molecular weight in the range of 10,000 to 2,750,000; poly(hydroxyalkyl methaccrylate) having a molecular weight in the range of 5,000 to 5,000,000; poly(vinylpyrrolidone) having a molecular weight in the range 10,000 to 360,000; polysaccha de having a molecular weight in the range 5,000 to 750,000; poly(glucose), poly(amine) and poly(amino acid). 14. The composition of claim 13 comprising a binder selected from the group consisting of poly(vinylpyrrolidone), copolymers of poly(vinylpyrrolidone), hydroxypropylalkylcellulose, acacia, alginic acid, acrylic acid derivatives, dextrin, gelatin, guar gum, liquid glucose, maltodextrin, pregelatinized starch, sodium alginate, starch and zein. 15. The composition of claim 14 comprising a solubility regulating agent regulating the pH of the granule. 16. The composition of claim 15 wherein the solubility regulating agent is selected from the group consisting of tromethamine; diethanolamine; glycineamide; triethanolamine; N-[tris-(hydroxymethyl)methyl] glycine; sodium acetate; sodium lactate; sodium glycocholate; sodium propionate; sodium butyrate; sodium glycocholate; glycocholate sodium phosphate; potassium phosphate monobasic; potassium biphthalate; boric acid; sodium borate; sodium phosphate; glycine, leucine, methionine, serine, adipic acid, succinic acid, citric acid, tartaric acid, maleic acid, and malic acid. 17. The composition of claim 9 formed in a wet granulation process. 18. A method for maintaining a pre-selected morphological form of a polymorphic drug in a therapeutic composition which comprises granulating the drug in its pre-selected morphological form with a polymer selected from the group consisting of poly(olefin), poly(vinyl), poly(carbohyate) and poly(peptide) polymers. 19. The method of claim 18 wherein the polymer is selected from the group consisting of poly(alkylene) oxide having a molecular weight in the range 10,000 to 5,250,000; alkali metal carboxyalkyl cellulose having a molecular weight in the range of10,000 to 2,750,000; poly(hydroxyalkyl methaccrylate) having a molecular weight in the range of 5,000 to 5,000,000; poly(vinylpyrrolidone) having a molecular weight in the range 10,000 to 360,000; polysaccharides having a molecular weight in the range 5,000 to 750,000; poly(glucose); poly(amine) and poly(amino acid). 20. The method of claim 18 wherein the granulating includes granulation with an excipient selected from the group consisting of a vinder and a solubility regulating agent. 21. The method of claim 20 comprising a wet granulation process. 22. A method of administering a drug to an environment of use comprising a patient which comprises administering the drug from a dosage form comprising the drug and a pharmaceutically-acceptable polymer that substantially keeps the drug in a pre-selected morphological form and delivers the drug at a controlled rate that correlates with the dissolution rate of the drug when in the environment of use. 23 A method of administering a dose of drug to a patient, which comprises administering the dose of drug from a dosage form comprising granules of the drug and a pharmaceutically-acceptable polymer that substantially keeps the drug in its preferred therapeutic polymorphic form. 24. The composition of claim 1 formed as an aggregate of granules. 25. The composition of claim 24 formed as a tablet. 26. The composition of claim 24 formed as a capsule.

Inventors: AYER ATUL D, MARKS SUSAN M, SHIVANAND PADMAJA, AYER, ATUL, D., MARKS, SUSAN, M., SHIVANAND, PADMAJA
Applicants: ALZA CORP, ALZA CORPORATION
Application year: 2000
Main classification: A61K47
IPC codes: A61K9, A61K47