GB2189702A - Osmotic dosage form - Google Patents

Description

GB 2 189 702 A SPECIFICATION versed in the delivery arts, that if a dosage

form is provided comprising means for substantially Dosageform with improved delivery capability preventing the migration and the entrapment of the beneficial agent, such a dosage form would have a The present invention pertains to a dosage form with 70 positive practical value and it would also represent improved delivery capability. More particularly, the both an unobvious improvement and advancement dosageform comprises a first layer comprising a in the dispensing arts.

drug formulation, a third layer comprising a An object of the invention is to provide a dosage hydrophilic composition, and a second layer form having a compartment comprising a beneficial comprising hydrophobic composition interposed 75 agentthat is from soluble to very soluble in an between thefirst and third layers. The second layer aqueousfluid, an expandable hydrophilic hydrogel exhibits a low solubility to the drug formulation. The and means for substantially preventing the second layer substantially preventsthe migration of migration of the beneficial agent into the hydrophilic drug formulation from the first layer into the third hydrogel.

layerwith its entrapment in the third layer,thereby 80 Another object of the invention is to provide a assuring the maximum amount of the drug dosage form having a compartment containing an formulation is available for delivery from the dosage agent formulation that is soluble to very soluble in an form. aqueous fluid, an expandable driving member Dosage forms for delivering a beneficial agent, comprising a hydrophilic hydrogel, and a mainly a beneficial drug, to environments of use are 85 hydrophobicv composition interposed between the known to the prior art in US Patent No: 3,845,770 agent formulation and the hydrophilic hydrogel and issued to Felix Theeuwes and Takeru Higuchi and in which hydrogel operates by expanding to diminish US Patent No: 3,916,899 issued to the same the volume occupied by the beneficial agent, thereby patentees. The dosage forms disclosed in the delivering the agent from the dosage form at a patents comprises a wall that surrounds an internal 90 controlled rate overtime.

compartment containing the beneficial agent. The Another object of the invention isto provide an wall is permeable to the passage of an external fluid osmotic device having a compartment housing a and substantially impermeable t6the passage of layer of a beneficial agent formulation, an adjacent beneficial agent. There is at least one passageway layer of a hydrophobic composition in which layer through the wall for delivering the beneficial agent 95 the agent formulation is poorly orsubstantially from the dosage form. These dosage forms release insoluble, and an adjacent layer of an expandable the agent by fluid being imbibed through the wall driving member comprising a hydrogel,which into the compartment at a rate determined bythe hydrogel can continuously increase itsvolurnewhHe permeability& thewall andtheosmotic pressure correspondingly decrease the volume initially gradient across the wall to producean aqueous 100 occupied bythe agent formulation with thevolume solution containing agentthat is dispensed through occupied bythe hydrophobic layerremaining the passagewayfrom the dosageform. These substantially unchanged througoutthe operation of dosageforms are extraordinarily effective for the osmotic device.

del ivering an agent that is soluble in fl uid imbibed Another object of the invention is to provide a into the dosage form and exhibits an osmotic 105 dosage form adapted and shaped as an oral, osmotic pressu re g radient across the wall against the dosage form that can continuously maintain externalfluid. su bstantially the major amount of the beneficial A pioneer advancement in dosage forms was agent present for delivery and free from being presented to the delivery arts by Richard Cortese and retained in the dosage form throughout the agents Felix Theeuwes in U.S. Pat. No. 4,327,725. The 110 release from the dosage form when in operation in invention in this patent enhances the delivery the gastrointestinal tract.

kinetics of the dosageform, for delivering agents According to the present invention, therefore, with various degrees of solubility in aqueous fluids there is provided a dosageform for delivering a that are difficult to deliver, by manufacturing the beneficial agentto a fluid environment of use, dosage form with a hydrogel. The hydrogel in 115 comprising:

presence of fluid that enters the dosage form, swells a) awall comprising in atleasta parta and moves from a rested state to an expanded state. semipermeable composition permeable to the The increase in volume of the hydrogel acts as a passage of an exteriorfluid and substantially driving force that is applied againstthe beneficial impermeable to the passage of a beneficial agent, agent thereby urging the beneficial agentthrough 120 the wall surrounding and forming:

the passageway from the dosage form. b) a compartment; The dosageform operates successfullyfor its c) a first layer comprising a beneficial agent intended use, and it can delivery numerous difficult formulation in the compartment; to deliver agents. Its use, however, can be limited for d) a third layer comprising means for expanding agents that exhibit a high degree of solubility in an 125 and occupying space in the presence of fluid in the aqueous medium that enters the dosage form. That compartment; is, these agents can migrate into the fluid-expanding e) a second layer interposed between the first hydrogel become entrapped therein and, and third layer in the compartment, said second consequently, they are not available for delivery layer means for substantially preventing the from the dosage form. It wil i be appreciated bythose 130 migration of beneficial agentfrom thefirst layer into 2 GB 2 189 702 A 2 thethird layer; and, substantially change during the dispensing life of f) means for connecting the exterior of the dosage form 20. Wall 22 in a presently preferred dosage form with the internal compartment. embodiment isformed totally or in at least apart of a Other objects features, aspects and advantages of member selected from cellulose acylate, cellulose the invention will be more apparent to those skilled 70 diacylate, cellulose triacylate, cellulose acetate and in the pharmaceutical arts from the following cellulose triacetate. The composition comprising detailed specification taken in conjunction with the wall 22 may additionally contain (a) hydroxypropyl

Figures of the accompanying drawings which are cellulose or (b) hydroxypropyl cellulose and included byway of illustration only. polyethylene glycol. In one presently preferred In the drawings, which are not drawn to scale, but 75 manufacture wall 22 comprises 100 wt % cellulose are setforth to illustrate various embodiments of the acylate, diacylate ortriacylate. In another invention, the drawing Figures are as follows: embodimentwall 22 comprises 70 to 80 wt% Figure 1 is a view of a dosage form adapted, cellulose acylate, diacylate ortriacylate and 20 to 30 shaped and sized as an oral, osmotic devicefor wt % hydroxypropyl cellulose with thetotal amount administering a beneficial drug to the 80 of the wall forming members equal to 100 wt %. In gastrointestinal tract of a warm-blooded animal over another manufacture wall 22 comprises 85 to 95 wt % a prolonged period of time; cellulose acylate, diacylate, ortriacylate and 5 to 15 Figure2 is a partially opened view of the dosage wt % polyethylene glycol, with the total amount of form of Figure 1 with a part of the exteriorwall of the wall forming ingredients equal to 100 wt %. In yet dosage form section ed-away for illustrating the 85 another preferred manufacture, wall 22 comprises 55 structure of the dosage form; and, to 70 wt % cellulose acylate, diacylate or triacylate, 20 Figure 3 is a View of the opened dosage form of to 30 wt % hydroxypropyl cellulose, and 5 to 15 wt % Figu re 2, with the dosage form in Figu re 3 depicting polyethylene glycol, with the total amou nt of the wal 1 the internal structure of the dosageform nearing the forming members equal to 100 wt%.

end of the drug delivery period. 90 Internal compartment 25 of dosageform 20 house In the drawings and in the specification, like parts a first layer comprising a dispensable agent in related Figures are identified by like numbers. The formulation 26, identified by dots, a middle layer 27 terms appearing earlier in the sp6cification and in the in contact arrangementwith thefirst layer, which description of the drawings, as well as embodiments middle layer comprises non-expandable thereof, are further detailed elsewhere in the 95 hydrophobic composition, and a third layer 28, disclosure. distantfrom the first layer and in contact arrangementwith the middle layer, which third layer Detailed description of the drawings 28 comprises hydrophilic composition.

Turning nowto the drawing Figures in detail, The expression beneficial agent 26, as used herein, which drawing Figures are an example of the dosage 100 includes any beneficial agent or compound that can form provided bythe invention, and which example be delivered from dosageform 20to produce a is notto be construed as limitingthe invention one beneficial and useful result. In the specification and example isthe dosageform, manufactured as an the accompanying claims,the term agent includes osmotic device, as illustrated in Figure 1 bythe drug, and the term drug includes any physiologically numeral 20. In Figure 1,the osmotic dosage form 20 105 or pharmacologically active substance that produces comprises a body member 21 comprising a wall 22 a local or a systemic effect in animals, including that surrounds and forms an internal compartment, warm-blooded mammals, humans, primates, not seen in Figure 1. Dosageform 20 comprises at avains, sport, farm, and zoo animals. Exemplary least one exit passageway 23 for connecting the drugsthat are soluble orvery soluble in water and interior of dosageform 20 with the exterior 110 can be delivered by the dosage form include environment, and more preferably a biological prochlorperazine, ferrous sulfate, potassium environment of use. chloride, procainamide hydrochloride, In Figure 2, osmotic dosageform 20 is seen in amphetamine sulfate, oxprenolol hydrochloride, opened viewwith wall 22 sectioned at24. In Figure 2, and metoprolol tartrate.

dosageform 20 comprises body 21,wall 22that 115 The solubility of a drug in an aqueous liquid, such surround and defines an internal compartment25, asfluid 29 imbibed through wall 22 into and at least one passageway 23 for dispensing the compartment 26 during operation of dosageform 20 contents of compartment 25from dosageform 20. can be determined byvarious art known techniques.

Wall 22 of dosageform 20 comprises totally, orin Onetechnique consists of preparing a solution of a at least a part, a composition thatis permeableto the 120 given drug and ascertaining by analysisthe amount passage of an exteriorfluid present inthe of drug present in a definite quantity of fluid, such as environmentof use. Wall 22 is substantially an aqueous-typefluid including a biological fluid. A impermeabieto the passage of a beneficial agent simple apparatus for this purpose consists of atest and other optional ingredients that may be present in tube of medium size fastened upright in a bath compartment 25. Semipermeable wall 22 is 125 maintained at constarittemperature. The fluid and substantially inert, that is, it maintains its physical the drug are placed in the tube and stirred. After a and chemical integrity during the dispensing of a given period of stirring, a definite weight of solution beneficial agentfrom dosage form 20. The phrase is analyzed and the stirring continued for an "keeps its physical and chemical integrity" means additional period of time. If the analysis shows no wall 22 does not lose its structure and it does not 130 increase of dissolved drug after the second period of 3 GB 2 189 702 A 3 stirring, the results are taken as the degree of to 82 and 794 to 807, 1968, and the references acted solubility of the drug in the aqueous media. therein.

Generally, on a weight basis at 250C the amount of The hydrophilic composition suitable forforming drug dissolved in aqueous media that is termed layer 28 are swellable, hydrophilic polymers. The soluble is about apart of drug to 5 to 25 parts of 70 presently preferred materials useful forforming aqueous media. Details of various methods for layer 28 comprise hydrogels that exhibitthe ability to determining solubilities are described in United swell and expand in the presence of water and retain States Public Health Service Bulletin No. 67 of the a significantfraction of waterwithin the hydrogel Hygenic Laboratory; Encyclopedia of Scienceand structure. The hydrogels can be no'ncross-linked, or Technology, Vol. 12, pages 542 to 556,1971 75 they can be lightly crossed linked. The polymer published by McGraw-Hill, Inc., and Encyclopedic hydrogels swell or expand to a very high degree in Dictionary of Physics, Vol. 6, pages 545to 557,1962, the presence of aqueous type fluids, usually published by Pergamon Press, Inc. exhibiting a 2to 5Ovolume increase. This expansion Layer27 of dosageform 20, in laminated position against layers 27 and layer26 results in the drug with drug layer 26 and hydrophobic hydrogel layer 80 being delivered through exit passageway 23.

28, isformed of a hydrophobic composition that Hydrophilic polymeric compositions useful forthe exhibits poor solubilityto drug 26. Drug 26 is poorly present purpose include poly(hydroxyalkyl soluble in layer 27 and accordingly it does not methacrylate); poly(N- vinyi-2-pyrrolidone); anionic migrate into layer27 and it is not entrapped in layer hydrogels; cationic hydrogels; polyelectrolyte 27. Typical material that can be used forforming 85 hydrogel complexes; poiy(vinyl alcohol) layer 27 include the polyolef ins, polyethylene, cross-linked with glyoxal, formaldehyde or polypropylene, polytetrafluoroethylene, glutaraidehyde; copolymers produced byforming a polystyrene; polyvinyl formal, polyvinyl butyral, dispersion of finely divided copolymer of maleic polyvinylidene chloride, polyamide, polyethylene anhydride with styrene, ethylene, propylene, terephthalate, polyaminotriazole and glass. 90 butylene or isobutylene; polymeric N-vinyl lactams; The materials can be used in a sheetform and acidic carboxypolymers available as Carbopo19 pressed laminate to layer 28, orthe materials can be polymer; Cyanamerg polyacrylamides cross-lined use in a crystalline form. in this Idtterform, the with indene-maleic anhydride; Good-RiteO crystalline polymer is prepared by grinding the polyacrylic acid; Aqua- Keeps@ acrylate polymer; polymerto an average particle size of 1 to 15 95 diester cross-linked polyglucan; polyethylene oxide; microns, followed by applying and pressing a 1 to 7 copolymers of N-vinyl lactam with N-vinyl mm layer against layer 28. pyrrolidone, N-vinyl caprolactam and N-vinyl The rate of migration of a drug into these materials piperidone and Water Lock@ starch-graft-poly(iodine can easily be determined bythose skilled in the artby acylate-co- acrylamide). The degree of expansion is standard procedures. In this manner, particular 100 calculated by subtracting the weight of the dryfilm materials can be selected forforming layer 27. from the weight of the aqueous swollen film divided Various techniques, such as thetransmission bythe weight of the dryfilm times 100.

method,the sorption-desorption methods, and the The expression "exit means" 23 as used herein like can be used to ascertain the rate of migration, or comprises means and methods suitable for the rejection rate of the polymerto any preselected 105 dispensing the beneficial drug 26through drug. One technique that can be used is to cast a film passageway 23 from dosage form 20. The means of the material to a thickness in the range of 2 to 20 include at least one passageway or orifice that mils, (0.05 mm to 0.512 mm), that is used as a barrier passes through wall 22 for communicating drug 26 between a rapidly stirred saturated solution of a with the exterior of dosage form 20. The expression drug, for example 150 r.p.m., and a solvent-sink at a 110 "at least one passageway" includes aperture, orifice, constant tem peratu re, for exam pie 37'C. Then, bore, pore, porous elementthrough which drug 26 samples are periodically withdrawn from the can migrate, hollowfiber orcapillary.

solvent-sink bath and analyzed for its concentration The expression includes also a material that of drug. If the drug exhibits a low migration into the erodes or is leached from wall 22 in thefluid polymer, that is the polymer rejectsthe passage of 115 environment of use to produce at least one the drug, the polymer is useful forthe present passageway of controlled releasing dimensions in purpose. For example, if the preselected drug is the dosage form. The expression includes also a progesterone and the film is formed polyethylene, microporous member comprising preformed the film would exhibit a permeability constant of 1.4 passageways or passageways formed in a fluid X 10-CM2 /hr, and if the film is polydimethyl siloxane, 120 environment of use. Representative materials the film would exhibit a permeability constant of 8.0 suitable forforming at least one passageway, ortwo X 10-2 cm2/hr. Thus, forthis preselected drug, passageways, include an erodible poly(glycolic) or polyethylene is used for manufacturing layer 27. poly(lactic) acid member in the wall, a gelatinous Material demonstration a passage of zero to 1 X filament, poly(vinyl alcohol), leachable materials 10 are operable for the intended purpose. The rate 125 such as removable pore forming polysaccha rides, of rejection of a film can be determined by salts or oxides. A passageway or a plurality of procedures described in J Pharm. Vol. 52, pages passageways can beformed by leaching a material 1145 to 1149,1963; ibid. Vol. 53, pages 798 to 802; such as sorbitol from the wall. Th ' e dosage form can ibid. Vol. 55 pages 840 to 843, and 1224to 1239,1966; be constructed with one ore more passageways in a Encyl. Polymer. Sci.Technol, Vol. 5 and 9, pages 63 130 spaced apart relation on more than a single distant 4 GB 2 189 702 A 4 surface of a dosage form. Passageways and passageway on the preselected surface.

equipment for forming passageways are disclosed In another manufacture, the dosage form is in U.S. Pat. Nos. 3,916,889; 4,063,064 and 4k088,864. manufactured by the wet granulation technique. In Representative passageways formed by governed the wet granulation technique, the drug and the leaching to produce a pore of pre-controlled sizes are 70 ingredients comprising the first layer are blended disclosed in U.S. Pat No. 4,200,098. using an organic solvent, such as isopropyl Wall 22 of osmotic dosageform 20 can beformed alcohol-methylene dichloride 80/20 v/v in one technique using the airsuspension (volumelvolume) as the granulation fluid. Other procedure. This procedure consists in suspending granulating fluid such as denatured alcohol 100% and tumbling the three compressed laminate in a 75 can be used forthis purpose. The ingredients currentof air and wall forming composition until a forming thefirst layer are individually passed wall is applied tothe drug forming compartment. through a 40 mesh screen and then thoroughly The air suspension procedure is weli-suited for blended in a mixer. Next, other ingredients independently forming the wall. The air suspension comprising the first layer are dissolved in a portion procedure is described in U.S. Pat. No. 2,799,241; J. 80 of the granulation fluid, such as the cosolvent Am. Pharm. Assoc.,Vol. 48, pages 451 to 459,1959; described above. Then, the latter prepared wet blend and ibid, Vol. 49, pages 82 to 84,1960. Osmotic is slowly added to the drug blend with continual dosage forms can also be coated with a wall-forming mixing in the blender. The granulating fluid is added composition in a Wursters air suspension coater, until a wet blend is produced, which wet massthen is using methylene dichloride-methanol cosolvent, 85 forced through a 20 mesh screen onto oven trays.

80120, vlv, using 2.5to 4% solids. The Aeromati& air The blend is dried for 18 to 24 hours at 50'C. The dry suspension coaterusing a methylene granules are sized then with a 20 mesh screen. Next, dichloride-methanol cosolvent, 87/13, vlv, also can magnesium stearate is passed through an 80 mesh be used for applying the wall. Otherwall forming screen and added to the dry screen granule blend.

techniques such as pan coating can be used for 90 The granulation is put into milling jars and mixed on providing the dosage form. In the pan coating a jar mill for 10 to 15 minutes. The composition is system, wall forming compositions are deposited by pressed into layers, for example in a ManestyO press successive spraying of the composition on the three layer press. The middle and third layers are pressed layered compartment, accompanying bytumbling in in a similar manner.

a rotating pan. A pan coater is used to produce 95 Another manufacturing process that can be used thickerwalls. A largervolume of methanol can be for providing the compartment-forming used in a cosolventto produce a thinner wall. Finally, composition comprises blending the powdered the wall coated compartments are dried in a forced ingredients in a fluid bed granulator. Afterthe air oven at 50'Cfor a weekto free the dosage form of powdered ingredients are dry blended in the solvent. Generally, the walls formed bythese 100 granulator, a granulating fluid, for example techniques haveathickness of 2to 20 milswith a poiy(vinyi-pyrrolidone) inwater, issprayed ontothe presently preferred thickness of 4to 10 mils. powders.The coated powders arethen dried in a Dosageform 20 of the invention is manufactured granulator. This process granulates all the by standard manufacturing techniques. For ingredients presenttherein while adding the example, in one manufacturerthe beneficial drug 105 granulating fluid. Afterthe granules are dried, a and other ingredients comprising thefirst layer lubricantsuch as stearic acid or magnesium stearate facing the exit means are blended and pressed into a is added to the granulator. The granules are pressed solid layer. The layer possesses dimensions that then in the manner described above.

correspond to the internal dimensions of the area the A novel dosage form provided bythe invention is layer isto occupy in the dosageform and it also 110 manufactured as described hereinafter. First, 75.5% possesses dimensions corresponding to the second (based on a 300 g batch) of mannitol, granular is put layerforforming a contacting arrangement through a 40 mesh screen and sieved through a 60 therewith. The drug and other ingredients can be mesh screen (all the mannitol thatweritthrough the blended also with a solventand mixed into a solid or 60 mesh screen is used for preparing the dosage semisolid formed by conventional methods such as 115 form). Next, chlorpheniramine maleate 14%, ballmilling, calendering, stirring or rollmilling and microcrystalline cellulose 5%, and polyvinyl then pressed into a preselected shape. Next,the pyrrolidone independently are screened through a middle is pressed againstthe first layer. The layer 40 mesh screen, and the screened ingredients mixed can be pressed as a film, or a layer of crystalline in a blenderwith the mannitol for about 20 minutes hydrophobic composition can be pressed against 120 to produce a homogeneous blend. Next, 0.5% silicon thefirst layer. Next, a layer of hydrogel is placed in dioxide is screened through the 80 mesh screen, and contactwith the hydrophobic middle layer. The then 1% magnesium stearate is screen through the layering of the drug layer,the middle layer and the 80 mesh screen. The screened silicon dioxide and the hydrogel layer can be fabricated by conventional screened magnesium stearate are added to the blend press-layering techniques. Finally,the three-layer 125 comprising the mannitol, chlorpheniramine, compartmentforming members are surrounded and microcrystalline cellulose and polyvinyl pyrrolidone, coated with an outer wall. A passageway is laser and blended for 5 minutes.

drilled through the wall to contactthe drug layer, Next, 93% phenylene oxide having a molecular with the dosage form optically oriented weight of about 5,000,000; 5% hydroxypropyl methyl automatically by the laser equipment for forming the 130 cellulose; and 1 Merric oxide are wet granulated GB 2 189 702 A 5 using ethyl alcohol as the granulatingfluid. The wet embrace those equivalents within the scope of the granulation is screened through a 16 mesh screen claims which follow.

and dried on trays at 500C in an oven overnight. The

Claims (1)

1. dried granulation is screened through a 16 mesh CLAIMS screen. Then, 1 %

   magnesium stearate is screened 70 through a 80 mesh screen and added to the dried 1. A dosage form for delivering a beneficial agent granulation. Finally, ail of the ingredients are to a fluid environment of use, comprising:

   blended for 5 minutes to yield a homogeneous a) a wall comprising in at leasta part a blend. semipermeable composition permeable to the A dosage form comprising a first drug layer, a 75 passage of an exteriorfluid and substantially middle hydrophobic layer and a third hydrophilic impermeable to the passage of a beneficial agent, layer is prepared in a Carvere press using a 1/4 inch, the wall surrounding and forming:

   standard concave die. First, 86 mg of the b) a compartment; composition comprising the drug chlorpheniramine c) a first layer comprising a beneficial agent is placed in the die and pinched to compress the 80 formulation in the compartment; granulation. Next, a middle-forming layer d) a third layer comprising means for expanding comprising 20 mg of flakes of caranuba wax is and occupying space in the presence of fluid in the placed on tap of the drug layer and compressed to compartment; form a continuous middle layer. Then, the e) a second layer interposed between the first third-forming layer comprising phenylene oxide 85 and third layer in the compartment, said second hydrophilic polymer is placed on top of the middle layer means for substantially preventing the layer and compressed with 2.5 tons of force. migration of beneficial agentfrom the first layer into The three-layered laminate is surrounded with a the third layer, and, wall in an AeromaticO Coater. The wall-forming f) means for connecting the exterior of the composition comprised 51 g of cellulose acetate 90 dosageform with the internal compartment.

   having an acetyl content of 43.5%,9 g of 2. The dosage form for delivering the beneficial hydroxypropyl cellulose, and a cosolvent ageritto a fluid environment of use according to comprising 1,170 m] of methylen chloride and 490 claim 1, wherein the means connecting the exterior mi of methanol. During the wall-forming process, of the dosage form with the internal compartment 960 mi of wall-forming solution are used to apply a 95 comprises at least one passageway.

   12.3 mg wall on each three-layered dosage form. The 3. The dosage form for delivering the beneficial dosage forms are dried in an oven overnight at 500C agentto a fluid environment of use according to to yield a final drywall of 10.4 mg per dosageform.A either of claims 1 or 2 wherein the beneficial agent is single 15 mil, (0.325 mm) passageway is drilied a member selected from a local and systemic acting through the wall connecting the exterior of the 100 drug.

   dosage form with the first layer. The first layer is 4. The dosage form for delivering the beneficial selected by visual examination.] n an automatic laser agentto a fluid environment of use according to any drilling technique, the drug layer is selected by the preceding claim wherein the beneficial agent is photo examination apparatus of the laser. The poorly soluble in the means comprising a second dosage form delivers 98.6% of chlorpheniramine 105 layer.

   maleate in 24 hrs as determined by cumulative 5. The dosage form for delivering the beneficial amount released assay. The dosage format the end agent to a fluid environment of use according to any of the delivery period is illustrated in Figure 3, preceding claim wherein the second layer means wherein the first layer is substantially delivered from comprises a hydrophobic polymeric composition.

   the dosage form. 110 6. The dosage form for delivering the beneficial The above procedure is repeated with all the agent to a fluid environment of use according to any conditions asset forth, except that the middle layer of claims 1 to 3 wherein beneficial agent is poorly in this example comprises a microcrystal line soluble in the second layer means comprising a polyolefin, polyethylene. The microcrystal line hydrophobic polymeric composition.

   polyethylene had an average particle size of 3 115 7. The dosage form for delivering the beneficial microns. agent to a fluid environment of use according to any The dosage form provided by the invention preceding claim wherein the second layer contacts release the beneficial drug throughoutthe the first and third layerwith the second layer gastrointestinal tract, including in the acidic substantially precluding thefirst layer contacting the environment of the stomach and in the alkaline 120 third layer.

   environmentof the intestine. Itwill be appreciated 8. The dosage form for delivering the beneficial the present invention contributes to the delivery art agentto a fluid environment of use according to any an unobvious dosage form thatpossesses practical preceding claim wherein the third layer comprises a utility. Whilethe invention has been described and hydrophilic hydrogel that expands in the presence of pointed out in details with reference to operative 125 an aqueous fluid.

   embodiments thereof, itwill be understood that 9. The dosage form for delivering the beneficial those skilled in the art will appreciate the various agentto a fluid environment of use according to changes, modifications, substitution and omissions preceding claim wherein the environment of use is can be made without departing from the spirit of the the gastrointestinal tract and the dosage form is invention. It is intended therefore, that the invention 130 adapted and sized for oral admittance into the 6 GB 2 189 702 A 6 gastrointestinal tract.

   10. The dosage form for delivering the beneficial agent to a fluid environment of use according to any preceding claim wherein the beneficial agent is 5 chlorpheniramine.

   11. The dosage form for delivering the beneficial agent to a fluid environment of use according to any preceding claim wherein the means for connecting the exterior of the dosage form with the interior 10 compartment is a microporous mem ber.

   12. A dosage form for delivering the beneficial agentto a fluid environment of use substantially as hereinbefore setforth.

   Printed for Her Majesty's Stationery Office by Croydon Printing Company (U K) Ltd,9187, D8991685. Published byThe PatentOffice,25 Southampton Buildings, London,WC2A lAY, from which copies maybe obtained.

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