OA12003A

OA12003A - Hydrodynamically balancing oral drug delivery system.

Info

Publication number: OA12003A
Application number: OA1200200041A
Authority: OA
Inventors: John N Staniforth; Naresh Talwar; Michael J Tobyn
Original assignee: Ranbaxy Lab Ltd
Priority date: 1999-08-04
Filing date: 2000-08-01
Publication date: 2006-04-18
Also published as: AP2002002410A0; WO2001010405A1; CA2378468A1; AU774957B2; SK1832002A3; AU5060499A; WO2001010419A1; EP1206249A4; EA200200126A1; JP2003506400A; NZ516959A; TR200200467T2; EP1206249A1; CZ2002415A3; HUP0202497A3; CN1376059A; HK1047226A1; AU6309900A; IL147966A0; MXPA02001272A

Abstract

The present invention relates to a gastro-retentive oral drug delivery system comprising a highly porous matrix comprising at least one drug substance, sugar(s), gas generating components and optionally, pharmaceutically acceptable auxiliary components. The pharmaceutical composition, either in the form of pellets (multiparticulate or single unit dosage form), beads, granules or capsules, is retained in the stomach while selectively delivering the drug(s) at gastric levels and upper parts of the small intestine over an extended period of time.

Description

s t 12003”

HYDRODYNAMICALLY BALANCING

ORAL DRUG DELIVERY SYSTEM

FIELD OF THE INVENTION 5 The présent invention relates to a gastro-retentive oral drug delivery

System comprising a highly porous matrix comprising at least one drugsubstance, sugar(s), gas generating components and optionally, pharmaceuti-cally acceptable auxiliary components. The pharmaceutical composition,either in the form of pellets (multiparticulate or single unit dosage form), 10 beads, granules or capsules, is retained in the stomach while selectiveiydelivering the drug(s) at gastric levels and upper parts of the small intestineover an extended period of time.

BACKGROUND OF THE INVENTION

An orally administered drug delivery System is exposed to a wide range 15 of highly variable conditions, such as pH, agitation intensity, gastric emptyingtimes and composition of the gastrointestinal fluids during its transit throughthe digestive tract. In addition, presence of food in the tract may affect thedosage form performance. Therefore, to design an optimum oral controlledrelease System it is necessary to tàke into account the physico-chemical and 20 physiological environment of the gastrointestinal tract. The conventionalapproaches to controlled release formulation known in the art are notapplicable to a variety of drugs having an “absorption window" in the stomachor upper parts of small intestine. Furthermore, it is advantageous to retain thedosage form in the stomach thereby increasing the contact time for local -1 - 120 0 3 activity and to achieve better therapeutic efficacy for the diseases which areconfined to the upper parts of the gastrointestinal tract such as peptic andduodenal uicers.

It is readily apparent that a sustained release formulation which slowly 5 releases médicament over an extended period and is retained in the upperparts of gastrointestinal tract for a prolonged period would be désirable for such diseases.

The prior art discloses varions approaches for therapeutic dosageforms which are designed to be retained in the upper parts of the 10 gastrointestinal tract and possess sustained release characteristics. U.S. Patent No. 5,780,057 discloses a pharmaceutical tablet having amultilayer structure wherein at least one layer swells in the presence ofbiological aqueous fluids resulting in an increase by at least 50% of the totalvolume of the tablet and thereby allegedly exhibiting a high résidence time in 15 the stomach and/or in the upper portion of the gastrointestinal tract. Theswellable layer, being a granular mixture of biocompatible hydrophilicpolymers and highly swellable (super disintegrating) polymers, allegedly actsas a barrier and allegedly modulâtes the slow release of the active ingrédientfrom the pharmaceutical form. It is believed that the expanded dosage forms 20 could block the pyloric sphincter or could cause unfavorable conditionsfollowing multiple dosing resulting from rétention of swollen dosage units in the stomach. -2- 12003- U.S. Patent No. 5,651,985 discloses a composition comprising 30-90%, by weight of the composition, a homogenous mixture of poiymerscontaining lactam groups and poiymers containing carboxyl groups as gelforming agents, which swells to form a gel of allegedly high mechanical anddimensional stabîlity in the aqueous environment of the stomach. It isbelieved that as the concentration of the poiymers is very high, the deeageforms containing a high dose médicament would be large and inconvénient fororal administration. U.S. Patent No. 5,007,790 discloses a sustained-release oral drugdosage form comprising a plurality of solid particles of a solid - State drugdispersed within a hydrophiiic, water swellable polymer that swells onimbibition of gastric fluid to increase the particle size to a ievel that promûtesrétention in the stomach over said time period, permitting dissolution of thedispersed drug and release of the resulting solution through a leaching action.The swellable polymer also allegedly maintains its physical integrity for atleast a substantial portion of the time period during which the drug is releasedinto the stomach and thereafter, rapidly dissolves. It is well recognized bythose skilled in the art that it may be difficult to obtain the desired rate ofrelease for a drug that has a high water solubility from such multiparticulateSystems as described in this patent, in which the drug first undergoesdissolution followed by release of the resulting solution by leaching action. U.S. Patent No. 5,169,638 discloses a buoyancy controlled releasepowder formulation for releasing a pharmaceutical of a basic character -3- 120 0 3 regardless of tbe pH of the environment and which formulation includes uptoabout 45% by weight of a pH dépendent polymer which is a water soluble saitof a polyuronic acid and upto about 35% by weight of a pH independenthydrocolloid gelling agent having a viscosity from about 50 to about 100,000centipoises in a 2% solution at 20sC. The said formulation allegedly floats inthe gastric fluid and release the drug at a controlled rate irrespective of the pHof the environment. However, the invention is particularly adapted for releaseof médicaments of only basic nature. Acidic drugs are not amenable for thisSystem. U.S. Patent No. 4,814,179 discloses a floating, sustained releasetherapeutic composition in form of a non-compressed tablet having a networkof muftitudinous air holes and passages therein and a density of less than onecomprising a matrix containing 0.5 - 4% gelling agent, 10-20% oil, 50-75%therapeutic agent and water. As exemplified therein, the préparation of non-compressed tablet requires unconventional Processing techniques and usesmolds with cylindrical holes for the same. This involves manufacturingdifficulties and are cost enhancing too. U.S. Patent No. 4,702,918 discloses a floating, sustained releaseformulation formed by heating a mixture of a gelling agent (cellulose or starchdérivative) and a fat/oil which is solid at room température. A sustained -release capsule dosage form as disclosed therein contains a mixture of (a)from about 10 to about 90% by weight of a cellulose dérivative or a starchdérivative which forms a gel in water and (b) from about 90 to 10% by weight -4- 1 20 0 3 of a higher fatty acid glyceride or higher alcohol or a mixture thereof which issoiid at room température and (c) from 0.01 to about 85% by weight of apharmaceutical. The capsules are prepared by filling with the said mixture of (a), (b) and (c), heating to a température above the meiting point of fatty acid 5 glyceride or higher alcohol and cooling and solidifying the said mixture. Morethan mere mixing is required to impart buoyancy to the formulation,„i.e.,meiting followed by cooling are additional unit operations. The spécifie gravityof digestive fluids especially that of gastric juices is between 1.004 to 1.101. Itis weli known to those skilled in the art that it may be difficult to maintain the 10 low spécifie gravity for the sustained release composition as described in thispatent, for a prolonged period. Further, as aiso exemplified therein, theconcentration of gelling agente and fat/oil required is high and hence theSystem is suited for low dose drugs, whiie dosage form containing high dosemédicaments would be large and difficult for oral administration. 15 U.S. Patent No.4,126,672 discloses formulations comprising one or more médicaments in combination with a hydrocolloid or mixtures ofhydrocolloids so as to hâve a bulk density less than one and behydrodynamically balanced when in contact with gastric fluid. A sustainedrelease capsule dosage form as described therein comprises finely 20 particulate, homogenous mixture of chloriazepoxide and diazepam, about 5%to 60% by weight of therapeutically inert, pharmaceutically acceptable adjunctmaterials, about 0% to 60% by weight of a fatty material having a spécifiegravity of less than one and about 20% to 75% by weight of one or a mixture -5- 120 0 3 of hydrocolloids selected from the group consisting of methyl cellulose,hydroxypropyl cellulose hydroxypropyl methylcellulose, hydroxymethylcellulose and sodium carboxymethyl cellulose. Upon contact with gastricfluid, the hydrophilic colloid hydrates and this hydrated layer allegedlythereafter slowly dissolves to release the médicament. The release ofmédicament is also said to take place by leaching action at or near thesurface. The hydrated colloid allegedly forms an outside barrier which retainsthe shape of the capsule and therefore acts to prevent the mass fromdisintegrating. However, it is well recognized that the application of such aSystem to obtain the desired rate of release of the drug wherein it is regulatedby the érosion of the polymer, is difficult to maintain.

For the above stated reasons and because the prior art discloses eithercomplicated devices and Systems which are difficult to manufacture on theindustrial scale or the components used therein are not so user friendiy, noneof the oral controlled drug delivery Systems heretofore described is completelysatisfactory.

Our co-pending U.S. patent application No. 09/152,932 descri bes apharmaceutical composition in the form of tablets or capsules which providesa combination of spatial and temporal control of drug delivery when ingestedby a patient. The pharmaceutical composition constitutes an oral controlleddrug delivery System, comprising a drug, a gas generating component, aswelling agent, a viscolyzing agent and optionaliy a gel forming polymer. Theviscolyzing agent and the gel forming polymer form a hydrated gel matrix -6- 1 20 0 3 which entraps the gas, causing the tablet or capsule to retain in the stomachor upper part of the small intestine (spatial control) and also créâtes a tortuousdiffusion path for the drug, resulting in sustained release of the drug (temporalcontrol). 5 The principle of sustained release which characterizes the formulations of the subject invention is unique in the art and no teaching has been foundwhich recognizes the application of such a porous matrix to buoyancy andsustained release as is taught by the présent invention.

SUMMARY OF THE INVENTION 10 It is an object of the présent invention to provide a pharmaceutical composition in the form of pellets, beads, granules or capsules whichconstitutes a gastro-retentive oral drug delivery System that : (a) generates a gas to form a highly porous (preferably honeycombed)matrix with good floating characteristics and also evolves gas upon 15 contact with gastric fiuid which helps in retaining the buoyancy of the dosage form in the stomach, (b) provides increased gastric résidence and thereby extends residency ofthe drug delivery System in the gastrointestinal tract, (c) delivers the drug at a controlled rate and exhibits reproducibility of 20 release rate into aqueous media while floating in the stomach and -7- 1 20 0 3 (d) provides, as compared to other oral controlled drug delivery Systems,increased absorption of a drug that is absorbed largely from the upperparts of the gastrointestinal tract.

It is also an object of the présent invention to provide a pharmaceuticalcomposition constituting an oral controlled drug delivery System that maintainsits physical integrity and dimensional stability when in contact with gastricfluids. The System remains floating in-vitro in the simulated gastric fiuid tillsubstantially ail the drug is released.

The présent invention describes a therapeutic System either in the formof beads, pellets, or granules filled in a capsule (multiparticulate System) orsingle unit pellets and matrix capsules (monolithic System) which constitutesan orally administered buoyant delivery System capable of extended rétentionin gastric fluids. The delivery System is structurally composed of a highlyporous matrix (preferably honeycombed) with large volume of entrapped airwhich makes it light and imparts good floatation characteristics.

The therapeutic System comprises drug, sugar, gas generating compo-nents and optionally, pharmaceutically acceptable auxiliary components.

The gas generating components used herein are a combination ofatleast one thermostable and atleast one thermolabile agent. During thepréparation of formulation, on exposure to high température, the thermolabileagent generates gas and aids in attaining the porous internai structure, whilethe thermostable agent reacts with acidic gastric contents of the stomach to -8- 1 2 0 0 3 evolve gas which helps in maintaining buoyancy of the dosage form. Thus,the combination of gas generating components permits the therapeuticSystem to act as a floating matrix that extends the rétention of the dosageform in the stomach and also prolongs its reiease in the stomach and upperparts of the small intestine. That is, the System is not transported past the"absorption window" prior to releasing ail or substantially ail of the drug andmaximum bioavailability is attained.

Preferably, the oral controlled drug delivery System of the présentapplication which is in the form of multiparticulate or a monolithic System,comprises an amount ranging from a pharmaceutically acceptable amount upto 35% of drug, about 5% to about 90% by weight of a sugar, about 1 % toabout 30% by weight of the gas generating components and, pharmaceuti-cally acceptable auxiliary components.

DETAILED DESCRIPTION OFTHE INVENTION

According to the présent invention, the oral pharmaceutical composi-tion indudes at least one drug substance, sugar(s), a combination of gasgenerating agents and optionally other pharmaceutical auxiliary componentswhich may be used by one skilled in the art to formulate the therapeuticSystem. The choice of auxiliary components and the amounts to be used areconsidered to be within the purview of one skilled in the art. It is to be bornein mind, however, that these conventional pharmaceutical auxiliary compo-nents which might adversely affect the hydrodynamic balance of theformulation of the présent invention are not suitable for use therein. -9- 120 0 3

The gas evolved during the préparation of the formulation by the gasgenerating components causes the System to attain a highly porous structure.The drug is incorporated within this highly porous, preferably honeycombedmatrix. 5 The composition may be in the form of pellets, beads or granules filled within a capsule or a sachet (a multiparticulate drug delivery System) orTnatrixcapsules and single unit pellets (monolithic System). The art of producingspherical pellets by extrusion and spheronisation techniques or spheronisa-tion using techniques based on high shear granulation or fluidized bed tech- 10 niques is well known and may be used for the préparation of pellets, beads orgranules in the subject invention. Single unit pellets can be produced onindustrial scale using lozenge and troches cutting machines.

Drugs which are thermostable may be added into the matrix whilethermolabile drugs can be loaded onto the carrier spheres (drug free pellets) 15 using techniques of drug loading based on fluidized bed principle (equipmentslike Glatt) which are well known in the art. The pharmaceutical composition ofthe présent invention may be in the form of a multiparticulate drug deliverySystem (up to 4mm in size pellets, granules or beads) or a single unit form asmatrix capsule or large size pellets (more than 5mm in size). The matrix cap- 20 suie of the présent invention may be produced by filling the powder accordingto the invention in a capsule made up of either gelatin, starch or hydroxy-propyl methylcellulose followed with heat treatment. -10- 1 20 0 3

Additional polymers recognized in the art of pharmaceutical compound-ing for their release retarding properties may also be incorporated into thegastro-retentive formulation of the présent invention. These release retardingpolymers may be hydrophilic or hydrophobie in nature or may be pH depen- 5 dent or independent polymers. Examples of the polymers suitable for thisinvention include hydroxypropyl methylcellulose, hydroxypropyl cellulose,Eudragit, ethyl cellulose, xanthan gum, and the like.

The pharmaceutical composition of the présent invention may becoated with a film forming polymer to contrai the release of the drug or to 10 impart better/improved floating characteristics (which is a resuit of betterentrapment of the gas) or to improve its organoleptic properties. Furthermore,the pharmaceutical composition may also contain bioadhesive polymersincorporated within the coating or présent as a film coat on the pellets,granules, beads or capsules in order to improve its gastro-retentive proper- 15 ties. In another application, some highly swelling polymers may also beadded to increase the size of the dosage form so as to improve its gastricrétention.

The pharmaceutical composition of the subject invention, when addedto simulated gastric fluids, floats on the fluid till substantially ail the drug is 20 reieased. The thermostable gas generating agent included therein reacts withthe acid présent in the media and generates gases which become entrappedwithin the matrix thereby enhancing the buoyancy of the formulation. -11 - 12 0 0 3

The various eomponents of the présent invention are described in more details below.

DRUG Açcording to the présent invention, the pharmaceutical composition isin the form of pellets, beads or granules filled in a capsule, a matrix capsule ora matrix pellet, as a single unit that provides controlled release of at least onetherapeutic agent or drug. The drug may be pharmacologically active itself ormay be converted Info the active form by biotransformation in the body. Thedrug can be any drug for which therapy would be improved as a resuit ofcontrolled drug delivery and increased gastric rétention.

The médicament or combination of médicaments which are amenableto controlled release therapy utitising the novel formulations of the présentinvention include any of those suitable for oral administration. The présentinvention is not to be construed as beihg limited to any particular médicamentor class of médicaments.

The gastro-retentive formulations of the subject invention are partic-ularly amenable to the administration of médicaments which are predomi-nantly absorbed through the upper portion of the gastro intestinal tract, drugshaving pH dépendent solubility, i.e., more soluble in the gastric pH ascompared to the intestinal pH, drugs having stomach as a site of action whichincludes H-2 receptor antagoniste, antacids, antimuscarinic agents, proton -12- 120 0 3 pump inhibitors, drugs active against H. pylori, cytoprotective agents, and the like.

Illustrative examples of drugs that are absorbed predominantly from theupper parts of gastrointestinal tract include ciprofloxacin, cyclosporin, furose-mide, metoprolol, oxprenolol, baclofen, aliopurinol, sumatriptan, benazepril,enalapril, quinapril, mœxipril, indolapril, olindapril, retinapril, spirapril, clilaze-prilat, lisinopril, imidapril, benazeprilat, cilazapril, captopril, delapril, tosinopril,libenzapril, pentopril, perindopril, altiopril, quinaprilat, ramîpril, spiraprilat,zofenopril, and the like; ail of which are suitable for use in the présent inven-tion.

Drugs having the stomach as site of action include H-2 receptorantagonists such as ranitidine, famotidine, nizatidine, bifentidine, erbrotidine,nifentidine, roxatidine and cimetidÎne, and the like; proton pump inhibitors likeomeprazole, lansoprazole, pentoprazole, and the like; antacids like magné-sium carbonate, aluminium hydoxide, magnésium oxide and simethicone, andthe like; cytoprotectives such as sucralphate, carbenoxolone sodium andmisoprostol, and the like; antimuscarinic agents like pirenzepine, telenzepineand propanthelene bromide, and the like; drugs active against H. Pylori likebismuth salts such as bismuth subsalicylate, tripotassium dicitratobismuthate,ranitidine bismuth citrate, and the like; antibiotics for example clarithromycin,amoxycillin, and the like; ail of which are suitable for use in the présentinvention. -13- 1 2 0 0 3 ’

Other médicaments that are suitable for this invention are drugs havingsolubility in acidic pH or ones having spécifie absorption sites in the upper partof the gastro-intestinal tract and those that are subjected to gastro-intestinalfirst pass metabolism (as in some reports stomach absorption is known to 5 bypass gastrointestinal first pass metabolism) include antihypertensive agentslike verapamil, nifedipine, propranolol, nimodipine, nicardipine, amlodipine,prazosin, ketanserin, guanabenz acetate, hydralazide, carvedilol, methyldopa,levodopa, carbidopa; antivirals like acyclovir, inosine, pranobex, zidovudine(AZT), tribavirin, vidarabine; lipid lowering agents like simvastatin, pravastatin, 10 atorvastatin and lovastatin; antipsychotic agents like selegiline; sédatives likemidazolam; ail of which are suitable for use in the présent invention.

The drug itself or its pharmacologicaily active sait or ester can be usedin the présent invention. Moreover, combination of drugs that are typicallyadministered together may be included as the drug component. The amount 15 of drug is that which is typically administered for a given period of time.Accordingly, the drug may be présent in amount ranging from a pharma-ceutically acceptable amount up to 35% by weight of the total weight of thecomposition.

SUGARS 20 According to the présent invention the pharmaceutical composition contains sugars which provide low density airy structure of the desired textureto the matrix. Sugars preferably comprises a pharmaceutically acceptablesaccharide, including a monosaccharide, a disaccharide, or a polyhydric -14- 1 20 0 3 alcohol, and/or mixtures of any of the foregoing. Examples of sugarspreferred for the présent invention include sucrose, glucose syrup, corn syrup,crystalline fructose, fructose, lactose, dextrose, galactose, maltodextrin,maltose, and the like, sugar alcohols like sorbitol, mannitol, maltol, maltitol, 5 xylitol, lactitol. In more preferred embodiments of the subject invention thesugar is glucose syrup either in the dried form or as a liquid. Sugars may beused alone or in combination with other similar sugars to achieve suitablematrix properties. In one preferred embodiment, sugar which is availableunder the brand name Glucidex (Roquette, UK) may be used. 10 The sugar may be présent in an amount from about 5% to about 90% preferably from about 10% to about 85% and more preferably from about 15%to about 85% by weight of the total weight of the composition.

GAS GENERATING COMPONENTS

According to the présent invention, the pharmaceutical composition 15 contains a combination of thermolabile and thermostable gas generatîngagents which aid in the formation of highly porous, preferably honeycombedstructure and enhances the buoyancy of the formulation. As the namesuggests, frie thermolabile gas generating agent produces gas upon exposureto high température (of about or less than 200°C) during heating operation 20 while the thermostable agent does not dissociate upon exposure to tempéra-tures stated above and produce gas upon contact with gastric fluid. Examplesof thermolabile gas generating agents that may be used in the présentinvention include sodium bicarbonate, sodium glycine carbonate, potassium -15 - 12003* bicarbonate, ammonium bicarbonate, sodium bisulfite, sodium metabisulfite,and the like. The thermostable gas generating agent interacts with an acidsource triggered by contact with water or simply with gastric acid to generatecarbon dioxide or sulphur dioxide that gets entrapped within the highly porous, 5 preferably honeycombed matrix of the composition and improves its floatingcharacteristics. An example of a thermostable gas generating agent iscalcium carbonate and sulfites such as sodium sulfite.

In those embodiments of the présent invention, where the pharma-ceutical composition is in the form of a capsule, thermostable gas generating 10 agents may be used atone or in combination with an acid source as a couple.The acid source may be one or more of edible organic acids, a sait of anedibie organic acid, or mixtures thereof. Examples of organic acids that maybe used as the acid source in the présent invention include citric acid or itssalts such as sodium citrate or calcium citrate, malic acid, tartaric acid, 15 succinic acid, fumaric acid, maleic acid or their salts, and the like. Theorganic acid salts which may be used as the acid source in the présentinvention include, for example, a mono-alkali sait of an organic acid havingmore than one carboxylic acid functional group, a bialkaii métal sait of anorganic acid having more than two carboxylic acid functional groups, and the 20 like.

The gas generating components may be présent in amounts fromabout 1 % to about 40 % preferably from about 1 % to about 35 % and more -16- 120 0 3 preferably from about 1 % to about 30% by weight of the total weight of the composition.

AUXILIARY COMFONENTS

Optionally, other conventional pharmaceutical excipients known in the5 art of formulation development such as diluents, release retarding agents,inert oils, binding agents and spheronising agents may also be incorporated into the buoyant formulation of the présent invention.

According to the présent invention, the pharmaceutical compositionmay comprise a diluent which is stable to heating operation and form a part of 10 the highly porous, preferably honeycombed structure. The diluent that maybe used in the présent invention, belongs to the class of excipients recognisedin the art of pharmaceutical compounding. In preferred embodiments of theprésent invention, diluent is starch. Examples of starches that may be used inthe présent invention include maize starch, rice starch, potato starch or wheat 15 starch. Examples of other diluents include dibasic calcium phosphate,calcium sulfate, powdered cellulose, microcrystalline cellulose, and the like.

The diluent may be présent in an amount from about 3% to about 50%by weight of the total weight of the composition, preferably from about 5% toabout 40% and more preferably from about 7% to about 35% by weight of the 20 total weight of the composition.

The pharmaceutical composition according to the présent inventionmay also contain polymers to retard the release of the drug. These polymers -17- 1 20 0 3 may be présent within the matrix structure of the pellets or capsules or maybe coated onto the composition or may be added in capsule présentations ofthe présent invention in the powder form. The polymers obtained as aqueousdispersions may replace water as granulating agent in the pellet préparations. 5 Solid polymers may be added directly into the powder blend.

The polymers used may be of the hydrophi,ic or the hydrophobie typeor pH dépendent or pH independent in nature. Examples of the polymerssuitable for this invention include the polymers well known in the pharma-ceutical art for their release retarding properties, for example, cellulose ethers 10 as hydroxypropy, celluloses of different grades, hydroxyethylcellulose, methyl-cellulose, hydroxypropy! ethylcellulose carboxymethyl cellulose, sodiumcarboxymethyl cellulose, hydroxyethyl methyl cellulose; acrylic polymerswhich are obtained as aqueous dispersions like Eudragit NE30D, EudragitRS30D, Eudragit RL30D, Eudragit L30D or available as powders such as 15 Eudragit RSPO, Eudragit RLPO, Eudragit L10055 (ail supplied by RohmPharma, Germany), ethyl cellulose as aqueous dispersion or in powder form.Examples of highly swellable polymers that may be used in the présentinvention include hydroxypropyl methylcellulose of different grades, xanthangums, sodium alginate, and the like. 20 The release retarding polymers may also be selected from the class of natural gums as karaya gum, locust bean gum, guar gum, gellan.gum, and the like. -18- 120 0 3 z The one or more release retarding agents from the same or two different classes may be présent from about 0.3% to about 25%, preferablyfrom about 1.0% to about 20% or more preferably from about 1.5% to about15% by weight of the total weight of the composition. 5 According to the présent invention, the pharmaceutical composition may further contain a therapeutically inert oil which is solid at room tempéra-ture but softens at higher températures, that is, around 50-80sC. The oil, ifprésent, acts as a release retarding agent. The oil is preferably, a fullyhydrogenated or partially hydrogenated vegetable fat or oil. Examples of oils 10 that may be used in the présent invention include partially or fully hydro-genated cottonseed oil, coconut oil, soyabean oil, palm oil, kernel oil, peanutoil, sunflower oil, and the like. The oils preferred for the présent invention arementioned in the United States Pharmacopoeia as type 1 hydrogenatedvegetable oils. These oils may be used alone or in combination with other oils 15 having the same characteristics.

The oil may be présent in an amount from about 0.2% to about 50%preferably about 0.2% to about 45% and more preferably about 0.4% to about35% by weight of the total weight of the composition.

The pharmaceutical composition in the form of beads may also include20 a binder to provide cohesiveness to the powder mass. The binders commonlyknown to the pharmaceutical art may be used in the présent invention.Examples of the binders are pregelatinised starch, polyvinylpyroll idone, -19- 120 0 3 hydroxypropyl methylcellulose, sodium carboxymethyl cellulose, starch paste, gelatin, xanthan gum, acacia, guar gum, and the like.

The binder may be présent in amounts from about 0.1% to about 15%,preferably about 0.2% to about 12% and more preferably about 0.5% to about 5 10% by weight of the final weight of the composition.

According to the présent invention, the pharmaceutical composition isprepared either in the form of pellets, granules, beads or as matrix capsules.The pellet/beads can be prepared using the commonly known techniques forextrusion and spheronisation and also other granulation techniques. Spher- 10 onising agents are added to the composition to get uniform spherical granulesor pellets. Commonly used spheronisation aids are microcrystalline cellulose(Avicel PH 101 of FMC Corpn. and Emcocel 50M or Emcocel 9OM ofMendell), mixture of microcrystalline cellulose and sodium carboxymethylcellulose (Avicel RC 591 of FMC Corph.) 15 The spheronising agent may be présent in amounts from about 1% to about 30% preferably from about 2% to about 20% and more preferably fromabout 4% to about 15% by weight of the final weight of the composition.

In addition to the above ingrédients, pharmaceutical grade magnésiumstéarate or stearic acid, and frie like as a glidant, talc, and the like as an anti- 20 adhèrent and Silicon dioxide or hydrogenated vegetable oil or sodium stearylfumarate, and the like as a lubricant may be incorporated in the pharma-ceutical composition according to this invention. -20- 1 20 0 3

The pharmaceutical composition in accordance to the présent inventionmay be optionally coated with a rapidly dissolving water soluble film coat.Examples of water soluble polymers include hydroxypropyl methylcellulose,hydroxypropyl cellulose, and the like. The pharmaceutical composition may 5 be coated to a weight build up of about 1% by weight to about 10% by weight,preferabiy from about 1% to about 4% by weight of the total weight of thecomposition.

According to the présent invention the capsule shell may be of a hardgelatin or a soft gelatin type. Furthermore, the capsules made of starch or 10 hydroxypropyl methylcellulose may aiso be used.

The présent invention is iilustrated by, but is by no means limited to,the following exampies: EXAMPLE 1

This example illustrâtes the présent invention in the form of pellets in 15 which Eudragit NE 30 D has been used as a release retarding polymer inconjunction with hydrogenated vegetable oil within the matrix. The activeingrédient is Diltiazem Hydrochloride. The pharmaceutical composition isgiven in Table 1. -21 - 1 20 0 3 TABLE 1 INGREDIENTS %W/W Diltiazem Hydrochloride 20.40 Hydrogenated cottonseed oïl (Lubritab) 16.48 Starch (Maize) 22.09 Dried Glucose Syrup (Glucidex 40*) 16.48 Pregelatinised starch (Starch 1500) 1.32 Microcrystalline cellulose (Avicel PH 101) 988 Ammonium Bicarbonate 2.75 Calcium Carbonate 4.95 Eudragit NE 30D 5.65 (as solids) 'Dextrose équivalent - 40%

Diltiazem Hydrochloride, Hydrogenated cottonseed oïl, Starch, Glucose 5 syrup, Pregelatinised starch, Microcrystalline cellulose, Ammonium bicarbon-ate and Calcium carbonate were sieved through a sieve (British StandardSieve (BSS) 44; 355 gm) and mixed. The blend was granulated with EudragitNE 30 D dispersion and extruded through an extruder (GA 65, Alexender-werk) fitted with 3.5 mm roller. The extradâtes were spheronised in a 1.0 spheronizer (Caleva 120mm) for 20 minutes. The pellets thus obtained weredried in an oven maintained at 120aC for 25 minutes. The pellets wereallowed to cool down to room température.

The pellets were tested for their floating properties and drug release in900ml of 0.1 N HCl using USP Apparatus 2 ( paddle type) at 50 rpm. The 15 pellets équivalent to 30 mg of Diltiazem Hydrochloride were added to the dissolution vessel. -22- 120 0 3

At periodic time intervals the Visual observations were made to checkbuoyancy of the peliets, if any. It was noted that ail the pellets remainedfloating until 21 hours. The samples of the dissolution media were periodicallywithdrawn and analysed for Diltiazem content spectrophotometrically. The 5 results are shown in Table 2. TABLE2 TIME (HRS) CUMULATIVE % RELEASE 1 53.95 2 67.95 3 76.91 4 85.00 5 88.42 EXAMPLE 2 10 This example illustrâtes the présent invention in the form of matrix capsules using Propranolol Hydrochloride as an active agent. The pharma-ceutical composition is illustrated in Table 3. -23- 120 0 3 TABLE 3 INGREDIENTS %W/W Propranolol Hydrochloride 20.00 Hydrogenated cottonseed oil(Lubritab) 22.86 Starch (Maize) 14.28 Dried Glucose Syrup (Glucidex 40*) 28.58 Ammonium Bicarbonate 7.14 Calcium Carbonate 7.14 ‘Dextrose équivalent - 40%

Propranolol hydrochloride, Starch, Hydrogenated vegetable oil, 5 Glucose syrup, Ammonium bicarbonate and Calcium carbonate were togethersieved through a sieve (British Standard Sieve (BSS) 44, 355pm) and mixed.The blend was manually filled in size-2 gelatin capsules. The averagecapsule fill weight of the composition was 320 mg. The filled capsules werekept in an oven maintained at 11OSC for 2.5 minutes, following which they 10 were cooled to room température.

The capsules were tested for their buoyancy and drug release in a900ml of 0.1 N HCl using USP Apparatus 2 (paddle) at 50 rpm. At periodictime intervals the Visual observations were carried out to see the buoyancy ofthe capsules. It was noted that the capsules remained buoyant till 20 hours. 15 The samples of the media were periodically withdrawn and tested forpropranolol content spectrophotometrically. The dissolution results arerecorded in Table 4. -24- 120 0 3 TABLE 4 TIME (HRS) CUMULATIVE % RELEASE 1 12.41 2 21.02 4 34.06 20 81.71 EXAMPLE 3 5 This example illustrâtes single unit pellets (6 to 8 mm in diameter) which may be used as single unit dosage forms, containing Diltiazem Hydro-chloride as an active ingrédient. The pharmaceutical composition is illustratedin Table 5. TABLE 5 INGREDIENTS %W/W Diltiazem Hydrochloride 22.37 Hydrogenated cottonseed oil (Lubritab) 10.28 Starch (Maize) 30.30 Dried Glucose Syrup (Glucidex 40*) 12.12 Pregelatinised starch (Starch 1500) 6.04 Microcrystalline cellulose (EMCOCEL 50M) 9.62 Ammonium Bicarbonate 3.87 Calcium Carbonate 5.40 10 ‘Dextrose équivalent -40%

Diltiazem Hydrochloride, Hydrogenated cottonseed oil, Starch, Glucosesyrup, Pregelatinised starch, Microcrystalline cellulose, Ammonium bicarbon- -25- 120 0 3 ate and Calcium carbonate were sieved through 355 pm mesh (BritishStandard Sieve (BSS) 44) and mixed. The blend was granulated with waterto get a dough like consistency. The dough was rolled into cylindrical shapeand small pièces weighing for 30 mg of Diltiazem Hydrochloride were eut out 5 and manually rolled into spherical shape.

The pellets were dried in an oven maintained at 120BC for 10 minutesfollowing which they were allowed to cool down to room température. Thepellets were characterised for floating and drug release as described inExample 1. The pellets were found to float on the media for 20 hours. The 10 dissolution résulte are recorded in Table 6. TABLE 6 TIME (HRS) CUMULATIVE % RELEASE 1 36.29 2 52.39 3 67.06 4 75.14 5 82.97 6 86.72 7 87.74 EXAMPLE 4 15 This example illustrâtes the capsule type of dosage form in which an organic acid is used in combination with the gas generating agents as acouple. The pharmaceutical composition is given in Table 7. -26· 120 0 3 TABLE 7 INGREDIENTS %W/W Propranolol Hydrochloride 21.46 Hydrogenated cottonseed oil (Lubritab) 28.06 Starch (Maize) 10.52 Dried Glucose Syrup (Glucidex 40*) 22.45 Citric acid, anhydrous 3.51 Ammonium Bicarbonate 7-00 Calcium Carbonate 7.00 * Dextrose équivalent - 40%

Ail the Ingrédients were sieved through 355 gm mesh (British Standard5 Sieve (BSS), 44) and mixed. The blend was filled manually in size-2 gelatincapsules. The average fill weight was 320 mg. The capsules were given heattreatment at 110flC for 2.5 minutes, following which they were cooled to room température.

The capsules were tested for in-vitro dissolution and floating charac-10 teristics as described in Example 2. The capsules remained floating on thedissolution media throughout the dissolution test of 24 hours. Dissolution results are recorded in Table 8. -27- 12 0 0 3 TABLE 8 TIME (HRS) CUMULATIVE % RELEASE 1 22.77 2 33.46 4 49.06 6 60.18 10 73.24 24 86.39 EXAMPLE 5

The présent example illustrâtes the capsule type of dosage form made5 according to the présent invention containing a polymer within the matrix(xanthan gum) together with the gas generating couple consisting of anorganic acid and the gas generating agents. The blend was filled in size-2gelatin and size-0 HPMC capsules. Table 9 illustrâtes the pharmaceutical composition. 10 TABLE 9 INGREDIENTS %W/W Propranolol Hydrochloride 19.41 Hydrogenated cottonseed oil (Lubritab) 25.38 Starch (Maize) 9.52 Dried Glucose Syrup (Glucidex 40*) 20.30 Citric acid, anhydrous 3.17 Xanthan Gum . , 9.52 Ammonium Bicarbonate 6.35 Calcium Carbonate 6.35 *Dextrose équivalent - 40% -28- 12003’

Ail the ingrédients were weighed and passed through 355 pm mesh(British Standard Sieve (BSS), 44) and mixed. The blend was filled manuallyin size-2 gelatin capsules (average fill weight 325 mg) and size-0 Hydroxy- 5 propyl methylcellulose capsules (average fill weight 520 mg). The capsuleswere kept in an oven maintained at 110e C for 2.5 minutes, following whichthey were cooled to room température.

The capsules were tested for floating characteristics and dissolutionprofile as described in Example 2. The capsules remained floating on the top 10 of the media for 24 hours. Dissolution results are recorded in Table 10. TABLE 10 TIME (HOURS) CUMULATIVE % RELEASE SIZE 2 SIZE 0 1 19.02 6.60 2 32.15 19.52 4 57.54 50.24 6 73.42 70.59 10 87.80 88.09 24 92.41 95.08 EXAMPLE 6 15 This example illustrâtes the présent invention in the form of capsule formulation using carvedilol as an active agent. The pharmaceutical composi-tion is illustrated in Table 11. -29- 120 03 TABLE 11 INGREDIENTS %\NW Carvedilol 10.00 Dried Glucose Syrup 79.50 Calcium carbonate 6.00 Ammonium bicarbonate 2.00 Sodium Alginate 2.00 Hydrogenated cottonseed oil (lubritab) 0.50 5

Ail the ingrédients were sieved through 180 μ mesh (British StandardSieve (BSS), 85) and were blended in a mixer (Turbula mixer) for 30 minutes.The blend was filled manually in size-0 gelatin capsules. The average fillweight was 500 mg. The capsules were given heat treatment at 1008C for 9.0 10 minutes, following which they were cooled to room température.

The capsules were tested for in-vitro drug release in 1000 ml dissolu-tion media of 0.1 N HCl containing 1% sodium lauryl sulphate. The USPapparatus 2 with paddle speed at 50 rpm was used for the study. Paddleswere fixed at 4.5 cm away from the base of the vessel and baskets, capped at 15 the open end, were used as sinkers. The samples of the media were with-drawn at prescheduled timings and assayed for carvedilol content spectro-photometrically. The dissolution results are recorded in Table 12. -30- 120 0 3 TABLE 12 TIME (HRS) CUMULATIVE % RELEASE 0.5 15.39 1.0 27.83 2.0 47.36 3.0 58.00 4.0 63.34 6.0 71.00 EXAMPLE7 5 This example illustrâtes the présent invention in the form of capsule dosage form. The active ingrédient is carvedilol. The pharmaceutical compo-sition is given in Table 13. TABLE 13 INGREDIENTS %W/W Carvedilol 9.99 Dried Glucose Syrup 79.65 Calcium carbonate 5.99 Ammonium bicarbonate 1.99 Xanthan Gum 1.59 Sodium Stearyl fumarate 0.79

The capsule dosage form was prepared as described in Example 6.The capsules were given heat treatment at 100°C for 13 minutes, followingwhich they were cooled to room température. -31 - 120 0 3

The capsules were evaluated for dissolution profile as described inExample 6. The dissolution résulte are tabulated in Table 14. TABLE 14 TIME (HRS) CUMULATIVE % RELEASE 0.5 11.95 1.0 29.63 2.0 63.70 3.0 80.24 4.0 90.34 5 EXAMPLE 8

This example illustrâtes the présent invention in the capsule dosageform using pravastatin sodium as the active ingrédient. The pharmaceuticalcomposition is given in Table 15. 10 TABLE 15 INGREDIENTS %W/W Pravastatin sodium 8.10 Dried Glucose Syrup 74.77 Calcium carbonate 5.72 Ammonium bicarbonate 1.91 Xanthan Gum 7.62 Hydrogenated cottonseed oil (lubritab) 1.91

The pharmaceutical composition was prepared as described inExample 6. The average fill weight of capsules was 525 mg. The capsules -32- 1·*·1 < 1 2 0 0 3 were given heat treatment at 1OO°C for 7.5 minutes, following which they wereallowed to cool to room température.

The dosage form was characterised for drug release in 1000 ml waterusing USP apparatus 2 (paddle type) at 50 rpm. The samples of the media 5 were withdrawn at regular time intervals and analysed for pravastatin contentspectrophotometrically. The résulte are shown in Table 16. TABLE 16 TIME (HRS) CUMULATIVE % RELEASE 0.5 9.15 1.0 19.54 2.0 36.89 3.0 55.19 4.0 74.76 5.0 93.91 10 · EXAMPLE 9

This example illustrâtes the présent invention in the form of matrixcapsules using pravastatin sodium as an active ingrédient. The pharma-ceutical composition is illustrated in Table 17. -33- 1 20 0 3 TABLE 17 INGREDIENTS %W/W Pravastatin sodium 7.73 Dried Glucose Syrup 71.37 Calcium carbonate 5.46 Ammonium bicarbonate 1.82 Xanthan Gum 7.28 Microcrystalline cellulose (Emcocel 90M) 4.55 Hydrogenated cottonseed oil (lubritab) 1.82

The pharmaceutical composition was préparée! as described in5 Example 6. The average fil! weight of capsules was 550 mg. The capsuleswere given heat treatment at 1008C for 7.0 minutes, following which they were allowed to cool to room température.

The dosage form was evaluated for dissolution profile as described inExample 8. The dissolution results are recorded in Table 18. 10 TABLE 18 TIME (HRS) CUMULATIVE % RELEASE 0.5 10.79 1.0 20.68 2.0 39.01 3.0 59.44 4.0 81.75 6.0 99.22 -34- 120 0 3

While the invention has been described by reference to spécifieexamples, this was for the purpose of illustration on,y. Numerous alternativeembodiments will be apparent to those skilled in the art and are considered tobe within the scope of this invention. -35-

Claims

120 0 3 WHATIS CLAIMEDIS:

1. A pharmaceutical composition which constitutes an oral drug deliverySystem for prolonged gastric rétention having a highly porous matrix,comprising at least one drug substance, sugar(s), a gas generatingcomponent which is a combination of at least one thermostable and atleast one thermolabile component, and optionally pharmaceuticallyacceptable auxiliary components wherein the pharmaceutical composi-tion substantially maintains its hydrodynamic balance and physicalintegrity for the time period during which the drug(s) is/are released intothe stomach.

2. A pharmaceutical composition according to daim 1 wherein the drugcomprises at least one active compound selected from the therapeuticcategory of antiulcer, analgésie, antihypertensive, antibiotic, anti-psychotic, anticancer, antimuscarinic, diuretic, antimigraine, antiviral,anti-inflammatory, sédatives, antidiabetic, antidepressant, antihista-minic, antiparasitic, antiepileptic, lipid lowering drugs, and mixtures thereof.

3. A pharmaceutical composition according to claim 1 wherein the drug isselected from the group consisting of enalapril, captopril, benazepril,lisinopril, ranitidine, famotidine, ranitidine bismuth citrate, diltiazem,propranolol, verapamil, carvedilol, nifedipine, acyclovir, ciprofloxacin,simvastatïn, atorvastatin, pravastatin, lovastatin, selegiline, midazolam, -36- 120 0 3 4. 5 5. 6. W 7. 8. 9. fluoxetine, acarbose, buspirone, nimesulide, captopril, nabumetone,glimepiride, glipizide, etodolac, nefazodone, and mixtures thereof. A pharmaceutical composition according to claim 1 wherein the drug isprésent in an amount ranging from a pharmaceutically acceptableamount up to 35% by weight of said composition. A pharmaceutical composition according to claim 1 wherein the sugaris selected from a group comprising of saccharide and polyhydricalcohol and mixtures thereof. A pharmaceutical composition according to claim 5 wherein sugar isselected from the group consisting of sucrose, glucose syrup, cornsyrup, fructose, lactose, dextrose, galactose, maltose, maltodextrin,sorbitol, mannitol, maltol, maltitol, xylitol and lactitol. A pharmaceutical composition according to claim 1 wherein the sugarcomprises about 5% to about 90% by weight of said composition. A pharmaceutical composition according to claim 1 wherein the sugarcomprises about 10% to about 85% by weight of said composition. A pharmaceutical composition according to claim 1 wherein the sugarcomprises about 15% to about 85% by weight of said composition. -37- 120 0 3

10. A pharmaceutical composition according to claim 1 wherein the gasgenerating component comprises a sulfite, a carbonate or a bicarbon-ate sait.

11. A pharmaceutical composition according to claim 10 wherein the gas 5 generating component is selected from the group consisting of ammonium bicarbonate, calcium carbonate, sodium bicarbonate,potassium bicarbonate, sodium glycine carbonate, sodium sulfite,sodium bisulfite and sodium metabisulfite.

12. A pharmaceutical composition according to claim 1 wherein the gas 1° generating component comprises a gas couple comprising a thermo- stable gas generating sait and an edible organic acid or a sait of an edible organic acid.

13. A pharmaceutical composition according to claim 12 wherein the edibleorganic acid is selected from the group consisting of citric acid, 15 ascorbic acid, tartane acid, succinic acid, fumaric acid, malic acid, maleic acid, glycine, sarcosine, alanine, taurine and glutamic acid.

14. A pharmaceutical composition according to claim 1 wherein the gasgenerating component comprises about 1% to about 40% by weight ofsaid composition. -38- 120 0 3

15. A pharmaceutical composition according to claim 1 wherein the gasgenerating component comprises about 1% to about 35 % by weight ofsaid composition.

16. A pharmaceutical composition according to claim 1 wherein the gasgenerating component comprises about 1% to about 30% by weight ofsaid composition.

17. A pharmaceutical composition according to claim 1 wherein the phar-maceutical auxiliary component is selected from the group comprisingof diluents, release retarding agents, inert oils, binding agents andspheronising agents.

18. A pharmaceutical composition according to claim 17 wherein diluent isselected from the group consisting of starch, starch dérivatives, cellu-lose dérivatives, dibasic calcium phosphate and calcium sulfate.

19. A pharmaceutical composition according to claim 17 wherein thediluent is starch.

20. A pharmaceutical composition according to claim 19 wherein starch isselected from tire group consisting of maize starch, rice starch, potatostarch and wheat starch. -39- 120 0 3

21. A pharmaceutical composition according to claim 17 wherein thediluent comprises about 3% to about 50% by weight of said composi-tion.

22. A pharmaceutical composition according to claim 17 wherein thediluent comprises about 7% to about 35 % by weight of said composi-tion.

23. A pharmaceutical composition according to claim 17 wherein therelease retarding agent is either incorporated into the matrix or coatedonto said composition.

24. A pharmaceutical composition according to claim 17 wherein therelease retarding agent is selected from the group consisting of cellu-lose ethers, acrylic polymers, natural gums, and mixtures thereof.

25. A pharmaceutical composition according to claim 24 wherein the cellu-lose ethers is selected from the group consisting of hydroxypropylmethylcellulose, hydroxypropyl cellulose, hydroxyethyl cellulose,hydroxypropyl ethylcellulose, methylcellulose, ethyl cellulose carboxy-methyl cellulose, sodium carboxymethy, cellulose, hydroxyethyl methyl-cellulose, and mixtures thereof. -40- 1 20 0 3

26. A pharmaceutical composition according to claim 24 wherein theacrylic polymer is selected from the group consisting of méthacrylates,polyacrylates copolymers, and mixtures thereof.

27. A pharmaceutical composition according to claim 24 wherein the 5 natural gum is selected from the group consisting of xanthan gum, karaya gum, locust bean gum, sodium alginate, guar gum, gellan gum,and mixtures thereof.

28. A pharmaceutical composition according to claim 17 wherein therelease retarding agent comprises about 0.3% to about 25% by weight !° of said composition.

29. A pharmaceutical composition according to claim 17 wherein therelease retarding agent comprises about 1.5% to about 15% by weightof said composition.

30. A pharmaceutical composition according to claim 17 wherein inert oilcomprises a partially or fully hydrogenated vegetable oil.

31. A pharmaceutical composition according to claim 17 wherein the inertoi, is selected from the group consisting of partially or fullyhydrogenated cottonseed oil, castor oil, coconut oil, kernel oil, palm oil,soyabean oil, peanut oil, and mixtures thereof. -41 - 1 ? Ο ο 3

32. A pharmaceutical composition according to claim 17 wherein the inert oi, comprises about 0.2% to about 50% by weight of said composition. 33. A pharmaceutical composition according to claim 17 wherein the inert oil comprises about 0.4% to about 35% by weight of said composition. 5 * 34. A pharmaceutical composition according to claim 17 wherein the binding agent is selected from the group consisting of pregelatinised starch, polyvinylpyroliidone, gelatin, hydroxypropy, methylcelluiose, sodium carboxymethyi cellulose, natural gums, and mixtures thereof. 35. 10 A pharmaceutical composition according to claim 17 wherein the binding agent comprises about 0.1 % to about 15 % by weight of said composition. 36. A pharmaceutical composition according to claim 17 wherein the binding agent comprises about 0.5% to about 10% by weight of said composition. 15 w 37. A pharmaceutical composition according to claim 17 wherein the spheronising agent is microcrystalline cellulose or a mixture of micro-crystalline cellulose and sodium carboxymethyi cellulose. ·* -42- 1 20 0 3

38. A pharmaceutical composition according to claim 17 wherein thespheronising agent comprises about 1% to about 30% by weight ofsaid composition.

39. A pharmaceutical composition according to claim 17 wherein the S spheronising agent comprises about 4% to about 15% by weight of said composition.

40. A pharmaceutical composition according to ciaim 1 further comprisinga bioadhesive polymer.

41. A pharmaceutical composition according to claim 1 further comprising W a highly swellable polymer.

42. A pharmaceutical composition according to claim 1 being formed into aphysical form selected from thè group consisting of multiple or singleunit peilets, beads, granules, soft gelatin Shell capsules and hard gela-tin sheli capsules. 15 43. A pharmaceutical composition according to claim 42 wherein the form of peilets, beads or granules is coated with a pharmaceutically accept-able film forming polymer or a pharmaceutical excipient. -43- 120 0 3

44. A pharmaceutical composition according to claim 42 wherein thecapsule shell is made of gelatin, hydroxypropyl methyicellulose orstarch. -44-