FORM-2 THE PATENTS ACT, 1970 (39 of 1970) COMPLETE Specification (Section 10, rule 13) A CONTROLLED BENEFICIAL AGENT DELIVERY SYSTEM ALKEM LABORATORIES LIMITED of 510 Shah Nahar Industrial Estates, Dr. E.Moses Road, Worli, Mumbai 400 018, Maharashtra, India, an Indian Company THE FOLLOWING SPECIFICATION PARTICULARLY DESCRIBES THE NATURE OF THIS INVENTION AND THE MANNER IN WHICH IT IS TO BE PERFORMED:- original 317/mum/2003 31/03/2003 The invention relates to a novel beneficial agent delivery system. In particular, this invention relates to a beneficial agent delivery system using polymers to obtain sustained release beneficial agent delivery systems. Traditionally, there is no unique oral controlled release delivery system that delivers both acidic and basic and also water soluble and insoluble beneficial agents. Present invention to some extent solves the problem for both acid and base type of beneficial agents and also water soluble and insoluble beneficial agents to deliver it at predictable and reproducible kinetics for a predetermined period throughout the course of the gastrointestinal transit. Polymers are used to embed beneficial agents for sustained release delivery. The process using polymers are based on two principles of incorporating beneficial agents, 1. Dissolving the polymer and the beneficial agent in a solvent with the disadvantage of the residual solvent retention and 2. Mixing the polymer, the beneficial agent and excipients and directly compressing the mixture with the possibility of segregation of individual components due to differences in density and size during 2 processing. This causes non uniform distribution of beneficial agents in unit doses and non uniform delivery of the beneficial agent to the body. This invention envisages a novel process of using osmotic pressure generated inside a capsule to deliver active therapeutic agents through a miniature hole in the capsule. In addition this invention uses a novel process of incorporating or dispersing active therapeutic agents in a mixture of inert excipients in a molten state (between 40° to 60° C). This invention can use a wide range of active therapeutic agents with different physico-chemical properties like solubility based on hydrophilic or lipophilic nature of the said active therapeutic agent. This invention utilizes osmotic agents already known to those skilled in the art to generate osmotic pressure in combination with other processes to deliver the active therapeutic agents. These other processes include unidirectional flow of aqueous medium (or water) inside the semi permeable membrane of the capsule by virtue of the properties of the capsule. 3 This invention relies on the division of the formulation in more than one compartment. This invention relies on the simultaneity of various processes, which must occur in synchrony for the desired release profile for various active therapeutic agents. These processes include but are not limited to 1. Dissolution of water soluble ingredients in a membrane, 2. Penetration of water from all sides of a plurality of compartments in a capsule, 3. The dissolution of an osmotic agent to create osmotic pressure 4. Swelling of a swellable polymer by imbibing the aqueous fluid, 5. The invention also relates to creation of a piston between two compartments by virtue of an inert, non disintegrating excipient which may be formed into different shapes such as pellets or tablets or slab, which assist in release of the said therapeutic agents. This invention relates to the imbibing of aqueous medium (or water) on the formulation compartment and dissolution or suspension or emulsification and forming a microsuspension or microemulsion of the active therapeutic agent depending on its hydrophilic or lipophilic nature. 4 This invention also relates to the creation of hole or orifice of passageway which uni directionally releases the active therapeutic agent in the formulation, in a controlled manner in a zero order or near zero order fashion for 12-24 hrs. The process in accordance with this invention is schematically represented in Figures 1A, IB, and 1C of the accompanying drawings. Referring to figures 1A,B and C A controlled beneficial agent delivery system based on Osmotic Pressure for controlled delivery of a beneficial agent is shown. Figure 1A shows the initial view of the capsule in which the capsule has two compartments, a first compartment having two parts a first part having impermeable walls and an orifice 18 or passageway for delivering a beneficial agent 16 contained within the said first compartment and a second part having walls 20 which are semi-permeable; and a second compartment containing an osmotic agent 12 and a swellable polymer 14. The walls of the second compartment being also semi permeable, the semi permeable material, being sufficiently rigid to withstand deformation due to expansion of the osmotic agent and swell able polymer contained within the second compartment of the delivery device but impermeable to fluids in the environment as well as to ingredients contained within the compartments. 5 The capsule also contains a movable separating member or piston 22 provided between the first and the second compartments, said member or piston separating the osmotic agent and swell able polymer in the second compartment of the capsule from the beneficial agent in the first compartment, the member or piston being formed of a material, which is impermeable to the compositions within the capsule. Figure IB shows an intermediate stage when the swelling polymer 14, the beneficial agent and its base 16 and the osmagent agent 12 have been contacted with water 24 from within the body and starts to change state. The agent 12 absorbs water under osmotic pressure forms a solution. This solution provides fluid to the polymer 14 which starts to swell and thereby pushes the piston 22. Meanwhile fluid also enters the first compartment which contains the beneficial agent 16 in its base and the fluid causes a microsuspension or a microsolution. This solution or suspension is pushed up by the piston and is slowly released in the body fluids through the orifice 18 in a slow and sustained manner. The novel process in accordance with this invention satisfies an object of using low melting carrier material with varying composition using different excipients 6 and beneficial agent concentrations which overcomes the disadvantages of segregation due to rapid congealing of dispersed or soluble material. It also overcomes the disadvantage of residual solvent obviously because no solvent is employed. Thus, both the safety and efficacy are achieved which are a matter of concern even for regulatory authorities. In addition the release from the polymers normally is modified by several properties of the incorporated beneficial agents including solubility, where as the novel oral osmotic controlled release delivery system based process employed here is independent of the solubility of the incorporated beneficial agents for the purposes of dissolution. The novel process described in the invention utilizes direct melting and incorporating the active therapeutic agent that have a range of solubility based on hydrophilic or lipophilic nature of the said active therapeutic agent. In addition to modifying the beneficial agent release profile kinetically, the process does not effect the stability of the incorporated beneficial agents. This invention gives slow release in-vitro extending between 12-24 hrs. 7 In addition, in the present formulation the components are clearly separated by a piston composed of inert excipients with dimensions such that it fits inside a capsule without any gap. The provision of a piston overcomes the mixing of the components from different compartments that could affect the release. Beneficial agent agents, which may be delivered in a constant delivery rate for a prolonged period of time usually 12-24 hours by the present invention include beneficial agents which act on the peripheral nerves, adrenergic receptors, cholinergic receptors, the skeletal muscles, the cardiovascular system, the reproductive system, the skeletal system, autacoid systems, the alimentary and excretory systems, the histamine system and the central nervous system. Suitable agents may be selected from, for example, proteins, enzymes, hormones, polynucleotides, nucleoproteins, polysaccharides, glycoproteins, lipoproteins, polypeptides, steroids, analgesics, local anesthetics, antibiotic agents, anti-inflammatory corticosteroids, ocular beneficial agents and synthetic analogs of these species. Another advantage of the system in accordance with this invention is the ease of making the present controlled release system without any special processes or equipment but modification of available equipment. 8 The present invention can be used to modify the release of some water soluble and water insoluble therapeutic agents in a constant release manner for prolonged period of time usually 12-24 hours. According to this invention there is provided a a controlled beneficial agent delivery system based on Osmotic Pressure for controlled delivery of a beneficial agent, said system comprising [1] a capsule having two compartments, a first compartment having two parts a first part having impermeable walls and an orifice or passageway for delivering a beneficial agent contained within the said first compartment and a second part having walls which are semi-permeable; and a second compartment containing an osmotic agent and a swellable polymer, the walls of the second compartment being also semi permeable, the semi permeable material, being sufficiently rigid to withstand deformation due to expansion of the osmotic agent and swell able polymer contained within the second compartment of the delivery device but impermeable to fluids in the environment as well as to ingredients contained within the compartments; [2] a movable separating member or piston provided between the first and the second compartments, said member or piston separating the osmotic agent and 9 swell able polymer in the second compartment of the capsule from the beneficial agent in the first compartment, the member or piston being formed of a material, which is impermeable to the compositions within the capsule. Materials that may be used for the osmotic capsule must be sufficiently strong to ensure that the capsule will not leak, crack, break, or distort under stresses to which it is subjected during implantation or under stresses due to the pressures generated during operation. The osmotic capsule may be formed of chemically inert and bio compatible, natural or synthetic materials, which are known in the art. Semi permeable compositions suitable for the semi permeable membrane of the capsule are well known in the art. Such possible semi permeable materials from which the membrane can be made include, but are not limited to, for example, cellulose esters, cellulose ethers and cellulose ester-ethers, water flux enhanced ethylene-vinyl acetate co polymers, semi permeable membranes made by blending a rigid polymer with water-soluble low molecular weight compounds, and other semi permeable materials well. The above cellulosic polymers should have a degree of substitution, D.S., on the anhydroglucose unit, from greater than 0 up to 3 inclusive. By "degree of substitution" or "D.S." is meant the average number of hydroxyl groups originally present on the anhydroglucose unit comprising the cellulose polymer that are replaced by a 10 substituting group. Representative materials include, but are not limited to, one selected from the group consisting, of cellulose acylate, cellulose diacylate, cellulose triacylate, cellulose acetate, cellulose diacetate, cellulose triacetate, mono-, di- and tricellulose alkanylates, mono, di-, and tricellulose aroylates, and the like. Exemplary cellulosic polymers include cellulose acetate having a D.S. up to 1 and an acetyl content up to 21%: cellulose acetate having a D.S. of 1 to 2 and an acetyl content of 21% to 35%; cellulose acetate having a D.S. of 2 to 3 and an acetyl content of 35% to 44.8%, and the like. More specific cellulosic polymers include cellulose propionate having a D.S. of 1.8 an a propionyl content of 39.2% to 45% and a hydroxyl content of 2.8% to 5.4%; cellulose acetate butyrate having a D.S. of 1.8, an acetyl content of 13% to 15% and a butyryl content of 34% to 39%; cellulose acetae butyrate having a n acetyl content of 2% to 29%, a butyryl content of 17% to 53%, and a hydroxyl content of 0.5% to 4.7%; cellulose acetae butyrate having a D.S. of 1.8, an acetyl content of 4% average weight percent, and a butyryl content of 51%; cellulose triacylates hving D.S. of 2.9 to 3 such as cellulose trivalerate, cellulose trilaurate, cellulose tripalmitate, cellulose trisuccinate, and cellulose trioctanoate; cellulose dipentate; co esters of cellulose such as cellulose acetate butyrate and cellulose, cellulose acetate propionate; and the like. 11 In accordance with one embodiment of the invention the movable separating member or piston is a substantially circular pellet which is configured to fit within the capsule in a sealed manner which allows the piston to slide along a longitudinal direction within the capsule. The walls of the capsule are such that the migration of such materials into or out of the device through the impermeable material of the capsule is so low as to have substantially no adverse impact on the function . In general, typical materials of construction suitable for the impermeable walls of the capsule according to the present invention include non-reactive polymers. The polymers include acrylonitrile polymers such as acrylonitrile-butadienene-styrene terpolymer, and the like; halogenated polymers such as polytetrafluoropropylene; polymide; polysulfone; polycarbonate; polyethylene; polypropylene; polyvinylchloride acrylic copolymer; polycarbonate-acrylonitrile-butadiene-styrene; polystyrene and the like. The osmotic capsule may be formed from any of the wall-forming materials disclosed above by the use of a mold, with the materials applied either over the mold or inside the mold, depending on the mold configuration. Any of the wide 12 variety of techniques known in the pharmaceutical industry may be used to form the osmotic capsules like dip coating. In general, materials suitable for use in the movable separating member or piston are non-reactive pharmaceutical excipients like dicalcium phophate, microcrystalline cellulose and also elastomeric materials including the non-reactive polymers listed above, as well as elastomers in general, such as polyurethanes and polyamides, chlorinated rubbers, styrene-butadiene rubbers, and chloroprene rubbers. The osmotic agent is a liquid-attracting agent used to drive the flow of the beneficial agent. The osmotic agent may be an osmagnet, i.e the non-volatile species that are soluble in water and create the osmotic gradient driving the osmotic inflow of water vary widely. Examples are well known in the art and include magnesium sulfate, magnesium chloride, potassium sulfate, sodium chloride, sodium sulfate, lithium sulfate, sodium phosphate, potassium phosphate, d-mannitol, sorbitol, inositol, urea, magnesium succinate, tartaric acid, raffinose and various monosaccharides, oligosaccharides and polysaccharides such as sucrose, glucose, lactose, fructose, and dextran as well as mixtures of any of these various species. 13 The osmotically effective compounds are known also as osmotically effective solutes, or osmagents. The osmotically effective compounds are used by mixing them with a beneficial agent and osmopolymer for forming a solution, or suspension containing the beneficial agent that is osmotically delivered from the device. The expression limited solubility as used here in means the agent has a solubility of about less than 5% by weight in the aqueous fluid present in the environment. Homogeneously or heterogeneously mixing the solute with the agent or osmopolymer and then charging them into the reservoir uses the osmotic solutes. The solutes and osmopolymers attract fluid into the reservoir producing a solution of solute in a gel that is delivered from the system concomitantly transporting undissolved and dissolved beneficial agent to the exterior of the system. Osmotically effective solutes used for the former purpose include magnesium sulfate, magnesium chloride, potassium sulfate, sodium sulfate, lithium sulfate, potassium acid phosphate, d-mannitol, urea, inositol, magnesium succinate, tartaric acid, carbohydrates such as raffinose, sucrose, glucose, alpha-d-lactose monohydrate, and mixtures thereof. The amount of osmagent in the compartment will generally be from 0.01% to 40% of the total composition . The osmotic pressure generated by these agents 14 is well known in the art and selection and/or combination of these agents can produce any desired osmotic gradient. Species that fall within the category of swellable polymers are hydrophilic polymers that swell upon contact with water, and these vary widely as well. Osmopolymers may be of plant or animal origin, or synthetic , and examples of osmopolymers are well known in the art. Examples include: poly(hydroxy-alkyl methacrylates) with molecular weight of 30,000 to 5,000,000, poly(hydroxy-alkyl methacrylates) with molecular weight of 10,000 to 360,000 anionic and cationic hydrogels, polyelectrolyte complexes , poly(vinyl alcohol) having low acetate residual, optionally cross linked with glyoxal, formaldehyde, or glutaraldehyde and having a degree of polymerization of 200 to 30,000, a mixture of methyl cellulose, cross linked agar and carboxymethylcellulose, polymers of N-vinllactams, polyoxyethylene-polyoxypropylene gels, polyoxybutylene-polyethylene block co polymer gels, carbo gum, polyacrylic gels, polyester gels, polyuria gels, polyether gels, polyamide gels, polypeptide gels, polyamino acid gels, polycellulosic gels, carbopol acidic carboxy polymers having molecular weights of 250,000 to 4,000,000, Cyanamer polyacrylamides, cross linked indene-maleic anhydride polymers, Good-Rite polyacrylic acids having molecular weights of 80,000 to 200.000, Polyox, Polyethylene oxide 15 polymers having molecular weights of 100,000 to 5,000,000, starch graft copolymers, and Aqua-Keeps acrylate polymer polysaccharides. Other osmopolymers include polymers that form hydrogels such as Carbopol, acidic carboxy polymers having a molecular weight of 450,000 to 4,000,000; Cyanamer RTM. polyacrylamides; cross-linked water swellable indene-maleic anhydride polymers, Good-rite RTM. polyacrylic acid having a molecular weight of 80,000 to 200,000; Polyox.RTM. polyethylene oxide polymers having a molecular weight of 100,000 to 5,000,000 and higher; starch graft co polymers; Aqua-Keeps.RTM. acrylate polymer polysaccharides composed of condensed glucose units such as diester cross-linked polyglucan, and the like. Representative polymers that form hydrogels are known to the prior art in U.S. Pat. Nos. 3,865,108 [no Indian equivalent] issued to Hartop; 4,002,173 [no Indian equivalent] issued to Manning; 4,207,893 [no Indian equivalent] issued to Michaels; and in Handbook of Common Polymers, by Scott and Roff, published by the Chemical Rubber Company, Cleveland, Ohio. The amount of osmopolymer in the second osmotic compartment is 15 to 95% with the total weight of all ingredients in a composition equal to 100%. During operation of the osmotic beneficial agent delivery system fluid is imbibed into the device 16 resulting in the swelling of the polymer and pushing of piston for successful delivery of the beneficial agent which is in the form of microsuspension or microemulsion from the osmotic beneficial agent delivery system. The osmotic agent may be solid osmotic tablet or a fluid osmotic agent. The osmotic tablet may be formed in many different conceivable shapes, textures, densities, and consistencies and still be within the confines of the present invention. The osmotic agent may be manufactured by a variety of techniques, many of which are known in the art. In one such technique, the osmotically active agent is prepared as solid or semisolid formulation and pressed into pellets or tablets whose dimensions correspond to slightly less than the internal dimensions of the respective compartments which they will occupy in the capsule interior. Depending on the nature of the materials used, the agent and other solid ingredients which may be included may be processed prior to the formulation of the pellets by such procedures as ball milling, calendaring, stirring, or roll milling to achieve a fine particle size and hence fairly uniform mixtures of each. In assembling the osmotic delivery device according to the present invention, the osmotic capsule is prepared with the orifice being formed by mechanical drilling, laser drilling, molding, or any other known method. Once the osmotic capsule has been prepared with an orifice, having a size to 17 achieve a desired delivery rate of the beneficial agent, the osmotic agent is placed inside the preformed capsule on which the swellable polymer pellet(s) or tablets are placed in the second compartment. The piston is inserted into the osmotic capsule on top of the swellable polymer pellet(s) or tablet(s). Then the base containing beneficial agent, according to one embodiment of the present invention, is placed into the osmotic capsule and closed off. The osmotic capsule contains at least one such delivery orifice in the form of a port, and in most configurations, one delivery port will suffice. However, two or more delivery ports may be present without departing from the present invention. The dimensions of the port in terms of diameter will vary with the type of beneficial agent, the rate at which the beneficial agent is to be delivered, and the environment into which it is to be delivered . The considerations involved in determining the optimum dimensions of the delivery port for any particular capsule or beneficial agent and the selection of the appropriate dimensions will be readily apparent to those skilled in the art. According to the present invention, the beneficial agent contained in the first compartment of the osmotic capsule is a flow able composition such as a liquid, suspension, or slurry, and is typically poured into the first compartment of the 18 capsule after the osmotic agent, swellable polymer pellet(s) or tablet(s) and the piston have been inserted. In the present invention a unique formulation is developed taking into consideration the sequence and balance of various process, which must be optimized to ensure a tailored delivery of the beneficial agents. These processes are: 1. The penetration of fluid in the osmotic compartment and 2. The penetration of fluid into the beneficial agent/ formulation compartment. The first allows the creation of osmotic gradient as well as swelling of the swellable polymer pellet. The second process allows the formation of microsuspension or microemulsion or solution of the beneficial agent. It is well known to those skilled in the art that these processes must be balanced to achieve the desired delivery rate from the osmotic beneficial agent delivery system over a prolonged period of time usually 18 to 24 hours. If the osmotic pressure is generated too rapidly before the formation of microsuspension or microemulsion or solution of the beneficial agent, then the delivery will be too slow or nonexistent. On the other hand, if the formation of 19 microsuspension or microemulsion or solution of the beneficial agent is too fast before the generation of the osmotic pressure, then the hydrodynamic pressure would oppose the osmotic beneficial agent delivery system. In the case of insoluble or poorly soluble beneficial agents, a microemulsion or microsuspension would from in the case of soluble beneficial agents a solution would form. It is the process which makes the present invention formulation, which is a solid at room temperature that allows the delivery of a wide range of beneficial agents in a controlled continuous manner over a prolonged period of time usually 18 to 24 hours. The present invention applies to the administration of beneficial agents in general, which include any physiologically or pharmacologically active substance. Beneficial agents which may be delivered by the present invention include beneficial agents which act on the peripheral nerves, adrenergic receptors, cholinergic receptors, the skeletal muscles, the cardiovascular system, smooth muscles, the blood circulatory system, synoptic sites, neuroeffector junctional sites, endocrine and hormones systems, the immunological system, the reproductive system, the skeletal system and the central nervous system. Suitable agents may be selected from, for example, proteins, enzymes, hormones, polynulceotides, nucleoproteins, polysaccharides, glycoproteins, 20 lipoproteins, enzymes, hormones, polynulceotides, nucleoproteins, polysaccharides, glycoprotein, lipoproteins, polypeptides steroids, analgesics, local anesthetics, antibiotic agents, anti-inflammatory corticosteroids, ocular beneficial agents and synthetic analogs of these species. Examples of beneficial agents which may be delivered by devices according to this invention include, but are not limited to prochlorperazine edisylate, ferrous sulfate, aminocaproic acid, mecamylamine hydrochloride, procainamide hydrochloride, amphetamine sulphate, methamphetamine sulphate, benzamphetamine hydrochloride, isoproterenol sulfate, phenmetrazine hydrochloride, bethanechol chloride, methacholine chloride, pilocarpine hydrochloride, atropine sulfate, scopolamine bromide, isopropamide iodide, tridihexethyl chloride, phenformin hydrochloride, methylphenidate hydrochloride, theophylline cholinate, cephalexin hydrochloride, diphenidol, meclizine hydrochloride, prochlorperazine maleate, phenoxybenzamine, thiethylperizine maleate, anisindone, diphenadione erythrityl tertranitrate, digoxin, isoflurophate, acetazolamide, methazolamide, bendroflumethiazide, chloropromide, tolazamide, chlormadinone acetate, phenaglycodol, allopurinol, aluminium aspirin, methotrexate, acetyl sulfisoxazole, erythromycin, hydrocortisone, hydrocortisone acetate, cortisone acetate, dexamethasone and its 21 derivatives such as betamethasone, triamcinolone, methyltestosterone, 17-S- estradiol, ethinyl estradiol, etthinyl estardiol 3-methyl ether, prednisolone, 17- varies-hydroxyprogestrone acetate, 19-nor-progestrone, norgestrel, norethinderone, norethisterone, norethisterone, norethiederone, progesterone, norgesterone, norethynodrel, aspirin, indomethacin, naproxen, fenoprofen, sulindac, indoprofen, nitroglycerin, isosorbide dinitarte, propranolol, timolol, atenolol, alprenolol, cimetidine, clonidine, imipramine, levadopa, chlorpromazine, methyldopa, dihydroxyphenylalanine, theophylline, calcium gluconate, ketoprofen, ibuprofen, cephalexin, erythromycin, haloperidol, zomepirac, ferrous lactate, vincamine, diazepam, phenoxybenzamine, diltiazem, milrinone, capropril, mandol, quanbenz, hydrochlochlorothiazide, ranitidine, flurbiprofen, fenufen, fluprofen, tolmetin, aclofenac, mefenamic, flufenamic, difuinal, nimodipine, nitrendipine, nisoldipine, nicardipine, felodipine, lidoflazine, tiapamil,gallopamil, amlodipine, mioflazine, lisinopril, enalapril, enalaprilat, captopril, ramipril, famotidine,nizatidine, sucralfate, etintidine, tetratolol, minoxidil, chlordiazepoxide, diazepam, amitriptyline, and imipramine. Further examples are proteins and peptides which include, but are not limited to, insulin, colchicine, glucagon, thyroid stimulating hormone, parathyroid and pituitary hormones, calcitonin, rennin, prolactin, corticotrophin, thyrotropic hormone, follicle stimulating hormone, chorionic gonadotropin, 22 gonadotropin releasing hormone, bovine somatotropin, procine somatotropin, oxytocin, vasopressin, GRF, prolactin, somatostatin, lypressin, pancreozymin, luteinizing hormone, LHRH, LHRH agonists and antagonists, leuprolide, interferons, interleukins, growth hormones such as human growth hormone, bovine growth hormone and porcine growth hormone, fertility inhibitors such as the prostaglandins, fertility promoters, growth factors, coagulation factors, human pancreas hormone releasing factor, analogs and derivatives of these compounds, and pharmaceutically acceptable salts of these compounds, or their analogs or derivatives. On the molecular level, the various forms of the beneficial agent may include uncharged molecules, molecular complexes and pharmaceutically acceptable acid addition and base addition salts such as hydrochlorides, hydrobromides, acetate, sulfate, laurylate, oleate and salicylate. For acidic compounds, salts of metals, amines or organic cations may be used. Derivatives such as esters, ethers and amides pan also be used. A beneficial agent can be used alone or mixed with other agents. The beneficial agent may optionally include pharmaceutically acceptable carriers and/or additional ingredients such as antioxidants, stabilizing agents, permeation enhancers etc. 23 The examples as in Table No. 1 and Table No. 2 in figures 2 and 3 of the accompanying drawings are illustrative of the present invention, and they should not be considered as limiting the scope of the invention in any way, as these examples and other equivalents thereof will become apparent to those versed in the art in the light of the present disclosure, the drawings and the accompanying claims. The preparation or process of making formulations is as follows: Osmotic capsules are made with a passageway as follows: 1. Osmotic agent, an agent that creates osmotic gradient in presence of liquid medium, is blended with sodium starch glycollate and filled in semipermeable capsules. 2. The osmotic polymer pellets are made comprising osmotic polymer and agents that assist the osmotic polymer to swell by utilizing the microenvironment surrounding the osmotic polymer with talc and magnesium stearate. The swelling pellets are inserted in the capsules. The swelling pellet swells and forms gel in presence of water, which in turn pushes the beneficial agent through passageway. 24 3. The pistons are made comprising non disintegrating inert excipient, magnesium stearate and talc. The piston separates the beneficial agents and swelling pellets and help in a) Pushing the microsuspension containing beneficial agent, b) Preventing the migration of beneficial agent in swelling polymer. The pistons are placed in the semipermeable capsules above the swelling pellets. 4. A low melting beneficial agent carrier is melted and beneficial agent is mixed with constant stirring. The beneficial agent and beneficial agent carrier mixture is heated further till it forms the clear solution or homogeneous dispersion. 5. The beneficial agent mixture is filled in the semipermeable capsules containing osmagents, swelling pellets and pistons, which solidify at room temperature. Optionally the beneficial agent mixture containing a low melting carrier is allowed to solidify at room temperature and then pulverized and then the powder is filled in osmotic capsules using conventional capsule filling machine. 6. Finally, the semipermeable capsule bodies are locked with impermeable capsule caps and semipermeable capsules are coated or sealed at the junction of cap and body. 25 In-Vitro Release Evaluation: For evaluating the beneficial agent release behaviour of the experimental formulations, a test- method was devised based upon the USP XXIV dissolution test for tablets and capsules. The dissolution apparatus (Make: Electrolab Tablet Dissolution Tester USP 24 Model: TDT-06P) as specified by the USP XXIV (apparatus 1) was used with Sorensens Phosphate buffer, pH 7.8 equilibrated to 37°C. The total volume of buffer added to each dissolution vessel was 1000 ml, with a basket rotation speed of 100 rpm, unless effect of agitation was studied. The test sample of nimesulide was dropped into the basket, which was further immersed into the dissolution medium. After every hour, a 10 ml aliquot of the dissolution medium was removed and replaced with 10 ml of fresh buffer solution. Each 10 ml sample was initially filtered through 1.2JLX coarse filter > The absorbance for the filtered solution was then determined at 395 nm using UV/VIS Spectrophotometer (Make Jasco, Model: V-530) dissolution medium was calculated using a calibration curve for Nimesulide. For Venlafaxine Hydrochloride the dissolution medium used was water. The total volume of water added in each vessel was 1000 ml. Remaining procedure 26 was same as that for Nimesulide. The absorbance for the filtered solution was then determined at 226 and 273.5 nm using a UV/VIS Spectrophotometer (Make: Jasco, Model: V-530). The beneficial agent released was calculated using a calibration curve for Venlafaxine. The kinetics of the release data were analyzed in terms of equation: Mt / Mo = ktn Where Mt; Moo, are the amount of beneficial agent released at time t, K is the total amount of beneficial agent, a constant, and n is the exponent for the release kinetics used to characterize the release mechanism. According to the known criteria of release kinetics from systems zero-order, anomalous kinetics and Fickian release are represented by 0.89